Split (1)

train · 7.32k rows

page_title stringlengths 1 91	page_text stringlengths 0 34.2k
Intermezzo	In music, an intermezzo (, Italian pronunciation: [interˈmɛddzo], plural form: intermezzi), in the most general sense, is a composition which fits between other musical or dramatic entities, such as acts of a play or movements of a larger musical work. In music history, the term has had several different usages, which fit into two general categories: the opera intermezzo and the instrumental intermezzo. Renaissance intermezzo The Renaissance intermezzo was also called the intermedio. It was a masque-like dramatic piece with music, which was performed between the acts of a play at Italian court festivities on special occasions, especially weddings. By the late 16th century, the intermezzo had become the most spectacular form of dramatic performance, and an important precursor to opera. The most famous examples were created for Medici weddings in 1539, 1565, and 1589. In Baroque Spain the equivalent entremés or paso was a one-act comic scene, often ending in music and dance, between jornadas (acts) of a play. Opera intermezzo The intermezzo, in the 18th century, was a comic operatic interlude inserted between acts or scenes of an opera seria. These intermezzi could be substantial and complete works themselves, though they were shorter than the opera seria which enclosed them; typically they provided comic relief and dramatic contrast to the tone of the bigger opera around them, and often they used one or more of the stock characters from the opera or from the commedia dellarte. In this they were the reverse of the Renaissance intermezzo, which usually had a mythological or pastoral subject as a contrast to a main comic play. Often they were of a burlesque nature, and characterized by slapstick comedy, disguises, dialect, and ribaldry. The most famous of all intermezzi from the period is Pergolesis La serva padrona, which was an opera buffa that after the death of Pergolesi kicked off the Querelle des Bouffons. In some cases the intermezzo repertory spread more quickly than did the opera seria itself; the singers were often renowned, the comic effects were popular, and intermezzi were relatively easy to produce and stage. In the 1730s the style spread around Europe, and some cities—for example Moscow—recorded visits and performances by troupes performing intermezzi years before any actual opera seria were done. The intermède (the French equivalent of the intermezzo) was the single most important outside operatic influence in Paris in the mid-18th century, and helped create an entire new repertory of opera in France (see opéra comique). The word was used (with a hint of irony) as the title of Richard Strausss two-act opera, Intermezzo (1924), the scale of which far exceeds the intermezzo of tradition. Many of the most celebrated intermezzi are from operas of the verismo period: Mascagnis Cavalleria rusticana and Lamico Fritz, Leoncavallos Pagliacci, Puccinis Manon Lescaut and Suor Angelica, Giordanos Fedora, Cileas Adriana Lecouvreur, and especially that from Massenets Thais, which became known as the Méditation. Instrumental intermezzo In the 19th century, the intermezzo acquired another meaning: an instrumental piece which was either a movement between two others in a larger work or a character piece that could stand on its own. These intermezzi show a wide variation in the style and function: in Mendelssohns incidental music to A Midsummer Nights Dream the intermezzo serves as musical connecting material for action in Shakespeares play; in chamber music by Mendelssohn and Brahms, the intermezzi are names for interior movements which would otherwise be called scherzi; and the piano intermezzi by Brahms, some of his last compositions, are sets of independent character pieces not intended to connect anything else together. Stylistically, intermezzi of the 19th century are usually lyrical and melodic, especially compared to the movements on either side, when they occur in larger works. The Brahms piano intermezzi in particular have an extremely wide emotional range, and are often considered some of the finest character pieces written in the 19th century. Opera composers sometimes wrote instrumental intermezzi as connecting pieces between acts of operas. In this sense, an intermezzo is similar to the entracte. The most famous of this type of intermezzo is probably the intermezzo from Mascagnis Cavalleria rusticana. Puccini also wrote intermezzi for Manon Lescaut and Madama Butterfly, and examples exist by Wolf-Ferrari, Delius and others. Also, incidental music for plays usually contained several intermezzi. Schuberts Rosamunde music as well as Griegs Peer Gynt contained several intermezzi for the respective plays. In the 20th century, the term was used occasionally. Shostakovich named one movement of his dark String Quartet No. 15 "intermezzo"; Bartók used the term for the fourth movement (of five) of his Concerto for Orchestra. See also Entracte Divertimento Interlude (disambiguation) Entremet Entremés Sources The New Harvard Dictionary of Music, ed. Don Randel. Cambridge, Massachusetts, Harvard University Press, 1986. ISBN 0-674-61525-5 Articles "Intermezzo," "Intermedio" in The New Grove Dictionary of Music and Musicians, ed. Stanley Sadie. 20 vol. London, Macmillan Publishers Ltd., 1980. ISBN 1-56159-174-2
Balsalazide	Balsalazide is an anti-inflammatory drug used in the treatment of inflammatory bowel disease. It is sold under the brand names Giazo, Colazal in the US and Colazide in the UK. It is also sold in generic form in the US by several generic manufacturers. It is usually administered as the disodium salt. Balsalazide releases mesalazine, also known as 5-aminosalicylic acid, or 5-ASA, in the large intestine. Its advantage over that drug in the treatment of ulcerative colitis is believed to be the delivery of the active agent past the small intestine to the large intestine, the active site of ulcerative colitis. It is in the category of disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. Synthesis Ex 3 is actually for Ipsalazide. See Ex 4 for Balsalazide proper. Same protocol but uses β-Alanine. Starting material is 4-aminohippuric acid, obtained by coupling para-aminobenzoic acid and glycine. That product is then treated with nitrous acid to give the diazonium salt. Reaction of this species with salicylic acid proceeds at the position para to the phenol to give balsalazide. References External links "Balsalazide". Drug Information Portal. U.S. National Library of Medicine.
Penicillin	Penicillins (P, PCN or PEN) are a group of antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G (intramuscular or intravenous use) and penicillin V (given by mouth). Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are members of the β-lactam antibiotics. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use. About 10% of people report that they are allergic to penicillin; however, up to 90% of this group may not actually be allergic. Serious allergies only occur in about 0.03%. Research highlights the importance of both doctors and patients discussing recorded penicillin allergies. Those who are allergic to penicillin are most often given cephalosporin C (another β-lactam antibiotic) because there is only 10% crossover in allergy between the penicillins and cephalosporins.Penicillin was discovered in 1928 by Scottish scientist Alexander Fleming as a crude extract of P. rubens. Flemings student Cecil George Paine was the first to successfully use penicillin to treat eye infection (ophthalmia neonatorum) in 1930. The purified compound (penicillin F) was isolated in 1940 by a research team led by Howard Florey and Ernst Boris Chain at the University of Oxford. Fleming first used the purified penicillin to treat streptococcal meningitis in 1942. For the discovery, Fleming shared the 1945 Nobel Prize in Physiology or Medicine with Florey and Chain. Several semisynthetic penicillins are effective against a broader spectrum of bacteria: these include the antistaphylococcal penicillins, aminopenicillins and the antipseudomonal penicillins. Nomenclature The term "penicillin" is defined as the natural product of Penicillium mould with antimicrobial activity. It was coined by Alexander Fleming on 7 March 1929 when he discovered the antibacterial property of Penicillium rubens. Fleming explained in his 1929 paper in the British Journal of Experimental Pathology that "to avoid the repetition of the rather cumbersome phrase Mould broth filtrate, the name penicillin will be used." The name thus refers to the scientific name of the mould, as described by Fleming in his Nobel lecture in 1945:I have been frequently asked why I invented the name "Penicillin". I simply followed perfectly orthodox lines and coined a word which explained that the substance penicillin was derived from a plant of the genus Penicillium just as many years ago the word "Digitalin" was invented for a substance derived from the plant Digitalis.In modern usage, the term penicillin is used more broadly to refer to any β-lactam antimicrobial that contains a thiazolidine ring fused to the β-lactam core, and may or may not be a natural product. Like most natural products, penicillin is present in Penicillium moulds as a mixture of active constituents (gentamicin is another example of a natural product that is an ill-defined mixture of active components). The principal active components of Penicillium are listed in the following table: Other minor active components of Penicillium include penicillin O, penicillin U1 and penicillin U6. Other named constituents of natural Penicillium, such as penicillin A, were subsequently found not to have antibiotic activity and are not chemically related to antibiotic penicillins.The precise constitution of the penicillin extracted depends on the species of Penicillium mould used and on the nutrient media used to culture the mould. Flemings original strain of Penicillium rubens produces principally penicillin F, named after Fleming. But penicillin F is unstable, difficult to isolate, and produced by the mould in small quantities.The principal commercial strain of Penicillium chrysogenum (the Peoria strain) produces penicillin G as the principal component when corn steep liquor is used as the culture medium. When phenoxyethanol or phenoxyacetic acid are added to the culture medium, the mould produces penicillin V as the main penicillin instead.6-Aminopenicillanic acid (6-APA) is a compound derived from penicillin G. 6-APA contains the beta-lactam core of penicillin G, but with the side chains stripped off; 6-APA is a useful precursor for manufacturing other penicillins. There are many semi-synthetic penicillins derived from 6-APA and these are in three groups: antistaphylococcal penicillins, broad-spectrum penicillins, and antipseudomonal penicillins. The semi-synthetic penicillins are all referred to as penicillins because they are all derived ultimately from penicillin G. Penicillin units One unit of penicillin G sodium is defined as 0.600 micrograms. Therefore, 2 million units (2 megaunits) of penicillin G is 1.2 g. One unit of penicillin V potassium is defined as 0.625 micrograms. Therefore 400,000 units of penicillin V is 250 mg.The use of units to prescribe penicillin is a historical accident and is largely obsolete outside of the US. Since the original penicillin was an ill-defined mixture of active compounds (an amorphous yellow powder), the potency of each batch of penicillin varied from batch to batch. It was therefore impossible to prescribe 1 g of penicillin because the activity of 1 g of penicillin from one batch would be different from the activity from another batch. After manufacture, each batch of penicillin had to be standardised against a known unit of penicillin: each glass vial was then filled with the number of units required. In the 1940s, a vial of 5,000 Oxford units was standard, but the depending on the batch, could contain anything from 15 mg to 20 mg of penicillin. Later, a vial of 1,000,000 international units became standard, and this could contain 2.5 g to 3 g of natural penicillin (a mixture of penicillin I, II, III, and IV and natural impurities). With the advent of pure penicillin G preparations (a white crystalline powder), there is little reason to prescribe penicillin in units. The "unit" of penicillin has had three previous definitions, and each definition was chosen as being roughly equivalent to the previous one. Oxford or Florey unit (1941). This was originally defined as the minimum amount of penicillin dissolved in 50 ml of meat extract that would inhibit the growth of a standard strain of Staphylococcus aureus (the Oxford Staphylococcus). The reference standard was a large batch of impure penicillin kept in Oxford. The assay was later modified by Floreys group to a more reproducible "cup assay": in this assay, a penicillin solution was defined to contain one unit/ml of penicillin when 339 microlitres of the solution placed in a "cup" on a plate of solid agar produced a 24 millimetre zone of inhibition of growth of Oxford Staphylococcus.: 107 First International Standard (1944). A single 8 gram batch of pure crystalline penicillin G sodium was stored at The National Institute for Medical Research at Mill Hill in London (the International Standard). One penicillin unit was defined at 0.6 micrograms of the International Standard. An impure "working standard" was also defined and was available in much larger quantities distributed around the world: one unit of the working standard was 2.7 micrograms (the amount per unit was much larger because of the impurities). At the same time, the cup assay was refined, where instead of specifying a zone diameter of 24 mm, the zone size were instead plotted against a reference curve to provide a readout on potency. Second International Standard (1953). A single 30 gram batch of pure crystalline penicillin G sodium was obtained: this was also stored at Mill Hill. One penicillin unit was defined as 0.5988 micrograms of the Second International Standard.There is an older unit for penicillin V that is not equivalent to the current penicillin V unit. The reason is that the US FDA incorrectly assumed that the potency of penicillin V is the same mole-for-mole as penicillin G. In fact, penicillin V is less potent than penicillin G, and the current penicillin V unit reflects that fact. First international unit of penicillin V (1959). One unit of penicillin V was defined as 0.590 micrograms of a reference standard held at Mill Hill in London. This unit is now obsolete.A similar standard was also established for penicillin K. Types Natural penicillins Penicillin G (benzylpenicillin) was first produced from a penicillium fungus that occurs in nature. The strain of fungus used today for the manufacture of penicillin G was created by genetic engineering to improve the yield in the manufacturing process. None of the other natural penicillins (F, K, N, X, O, U1 or U6) are currently in clinical use. Semi-synthetic penicillin Penicillin V (phenoxymethylpenicillin) is produced by adding the precursor phenoxyacetic acid to the medium in which a genetically modified strain of the penicillium fungus is being cultured. Antibiotics created from 6-APA There are three major groups of other semi-synthetic antibiotics related to the penicillins. They are synthesised by adding various side-chains to the precursor 6-APA, which is isolated from penicillin G. These are the antistaphylococcal antibiotics, broad-spectrum antibiotics, and antipseudomonal antibiotics. Antistaphylococcal antibiotics Cloxacillin (by mouth or by injection) Dicloxacillin (by mouth or by injection) Flucloxacillin (by mouth or by injection) Methicillin (injection only) Nafcillin (injection only) Oxacillin (by mouth or by injection)Antistaphylococcal antibiotics are so-called because they are resistant to being broken down by staphylococcal penicillinase. They are also, therefore, referred to as being penicillinase-resistant. Broad-spectrum antibiotics This group of antibiotics is called "broad-spectrum" because they are active against a wide range of Gram-negative bacteria such as Escherichia coli and Salmonella typhi, for which penicillin is not suitable. However, resistance in these organisms is now common. Ampicillin AmoxicillinThere are many ampicillin precursors in existence. These are inactive compounds that are broken down in the gut to release ampicillin. None of these pro-drugs of ampicillin are in current use: Pivampicillin (pivaloyloxymethyl ester of ampicillin) Bacampicillin Metampicillin (formaldehyde ester of ampicillin) Talampicillin Hetacillin (ampicillin conjugated to acetone)Epicillin is an aminopenicillin that has never seen widespread clinical use. Antipseudomonal antibiotics The Gram-negative species, Pseudomonas aeruginosa, is naturally resistant to many antibiotic classes. There were many efforts in the 1960s and 1970s to develop antibiotics that are active against Pseudomonas species. There are two chemical classes within the group: carboxypenicillins and ureidopenicillins. All are given by injection: none can be given by mouth. Carboxypenicillins Carbenicillin Ticarcillin Temocillin Ureidopenicillins Mezlocillin Piperacillin Azlocillin β-lactamase inhibitors Clavulanic acid Sulbactam Tazobactam Medical usage The term "penicillin", when used by itself, may refer to either of two chemical compounds, penicillin G or penicillin V. Penicillin G Penicillin G is destroyed by stomach acid, so it cannot be taken by mouth, but doses as high as 2.4 g can be given (much higher than penicillin V). It is given by intravenous or intramuscular injection. It can be formulated as an insoluble salt, and there are two such formulations in current use: procaine penicillin and benzathine benzylpenicillin, which are used only in the treatment of syphilis. When a high concentration in the blood must be maintained, penicillin G must be administered at relatively frequent intervals, because it is eliminated quite rapidly from the bloodstream by the kidney. Penicillin G is licensed for use to treat septicaemia, empyema, pneumonia, pericarditis, endocarditis and meningitis caused by susceptible strains of staphylococci and streptococci. It is also licensed for the treatment of anthrax, actinomycosis, cervicofacial disease, thoracic and abdominal disease, clostridial infections, botulism, gas gangrene (with accompanying debridement and/or surgery as indicated), tetanus (as an adjunctive therapy to human tetanus immune globulin), diphtheria (as an adjunctive therapy to antitoxin and for the prevention of the carrier state), erysipelothrix endocarditis, fusospirochetosis (severe infections of the oropharynx, lower respiratory tract and genital area), Listeria infections, meningitis, endocarditis, Pasteurella infections including bacteraemia and meningitis, Haverhill fever; rat-bite fever and disseminated gonococcal infections, meningococcal meningitis and/or septicaemia caused by penicillin-susceptible organisms and syphilis. Penicillin V Penicillin V can be taken by mouth because it is relatively resistant to stomach acid. Doses higher than 500 mg are not fully effective because of poor absorption. It is used for the same bacterial infections as those of penicillin G and is the most widely used form of penicillin. However, it is not used for diseases, such as endocarditis, where high blood levels of penicillin are required. Bacterial susceptibility Because penicillin resistance is now so common, other antibiotics are now the preferred choice for treatments. For example, penicillin used to be the first-line treatment for infections with Neisseria gonorrhoeae and Neisseria meningitidis, but it is no longer recommended for treatment of these infections. Side effects Common (≥ 1% of people) adverse drug reactions associated with use of the penicillins include diarrhoea, hypersensitivity, nausea, rash, neurotoxicity, urticaria, and superinfection (including candidiasis). Infrequent adverse effects (0.1–1% of people) include fever, vomiting, erythema, dermatitis, angioedema, seizures (especially in people with epilepsy), and pseudomembranous colitis. Penicillin can also induce serum sickness or a serum sickness-like reaction in some individuals. Serum sickness is a type III hypersensitivity reaction that occurs one to three weeks after exposure to drugs including penicillin. It is not a true drug allergy, because allergies are type I hypersensitivity reactions, but repeated exposure to the offending agent can result in an anaphylactic reaction. Allergy will occur in 1-10% of people, presenting as a skin rash after exposure. IgE-mediated anaphylaxis will occur in approximately 0.01% of patients.Pain and inflammation at the injection site are also common for parenterally administered benzathine benzylpenicillin, benzylpenicillin, and, to a lesser extent, procaine benzylpenicillin. The condition is known as livedoid dermatitis or Nicolau syndrome. Structure The term "penam" is used to describe the common core skeleton of a member of the penicillins. This core has the molecular formula R-C9H11N2O4S, where R is the variable side chain that differentiates the penicillins from one another. The penam core has a molar mass of 243 g/mol, with larger penicillins having molar mass near 450—for example, cloxacillin has a molar mass of 436 g/mol. 6-APA (C8H12N2O3S) forms the basic structure of penicillins. It is made up of an enclosed dipeptide formed by the condensation of L-cystein and D-valine. This results in the formations of β-lactam and thiazolidinic rings.The key structural feature of the penicillins is the four-membered β-lactam ring; this structural moiety is essential for penicillins antibacterial activity. The β-lactam ring is itself fused to a five-membered thiazolidine ring. The fusion of these two rings causes the β-lactam ring to be more reactive than monocyclic β-lactams because the two fused rings distort the β-lactam amide bond and therefore remove the resonance stabilisation normally found in these chemical bonds. An acyl side side chain attached to the β-lactam ring.A variety of β-lactam antibiotics have been produced following chemical modification from the 6-APA structure during synthesis, specifically by making chemical substitutions in the acyl side chain. For example, the first chemically altered penicillin, methicillin, had substitutions by methoxy groups at positions 2’ and 6’ of the 6-APA benzene ring from penicillin G. This difference makes methicillin resistant to the activity of β-lactamase, an enzyme by which many bacteria are naturally unsusceptible to penicillins. Pharmacology Entry into bacteria Penicillin can easily enter bacterial cell in case of Gram-positive species. This is because Gram-positive bacteria do not have an outer cell membrane and are simply enclosed in a thick cell wall. Penicillin molecules are small enough to pass through the spaces of glycoproteins in the cell wall. For this reason Gram-positive bacteria are very susceptible to penicillin (as first evidenced by the discovery of penicillin in 1928).Penicillin, or any other molecule, enters Gram-negative bacteria in a different manner. The bacteria have thinner cell walls but the external surface is coated with an additional cell membrane, called the outer membrane. The outer membrane is a lipid layer (lipopolysaccharide chain) that blocks passage of water-soluble (hydrophilic) molecules like penicillin. It thus acts as the first line of defence against any toxic substance, which is the reason for relative resistance to antibiotics compared to Gram-positive species But penicillin can still enter Gram-negative species by diffusing through aqueous channels called porins (outer membrane proteins), which are dispersed among the fatty molecules and can transport nutrients and antibiotics into the bacteria. Porins are large enough to allow diffusion of most penicillins, but the rate of diffusion through them is determined by the specific size of the drug molecules. For instance, penicillin G is large and enters through porins slowly; while smaller ampicillin and amoxicillin diffuse much faster. In contrast, large vancomycin can not pass through porins and is thus ineffective for Gram-negative bacteria. The size and number of porins are different in different bacteria. As a result of the two factors—size of penicillin and porin—Gram-negative bacteria can be unsusceptible or have varying degree of susceptibility to specific penicillin. Mechanism of action The chemical structure of penicillin is triggered with a very precise, pH-dependent directed mechanism, affected by a unique spatial assembly of molecular components, which can activate by protonation. It can travel through bodily fluids, targeting and inactivating enzymes responsible for cell-wall synthesis in gram-positive bacteria, meanwhile avoiding the surrounding non-targets. Penicillin can protect itself from spontaneous hydrolysis in the body in its anionic form while storing its potential as a strong acylating agent, activated only upon approach to the target transpeptidase enzyme and protonated in the active centre. This targeted protonation neutralizes the carboxylic acid moiety, which is weakening of the β-lactam ring N–C(=O) bond, resulting in a self-activation. Specific structural requirements are equated to constructing the perfect mousetrap for catching targeted prey.Penicillin kills bacteria by inhibiting the completion of the synthesis of peptidoglycans, the structural component of bacterial cell wall. It specifically inhibits the activity of enzymes that are needed for the cross-linking of peptidoglycans during the final step in cell wall biosynthesis. It does this by binding to penicillin binding proteins with the β-lactam ring, a structure found on penicillin molecules. This causes the cell wall to weaken due to fewer cross-links and means water uncontrollably flows into the cell because it cannot maintain the correct osmotic gradient. This results in cell lysis and death. Bacteria constantly remodel their peptidoglycan cell walls, simultaneously building and breaking down portions of the cell wall as they grow and divide. During the last stages of peptidoglycan biosynthesis, uridine diphosphate-N-acetylmuramic acid pentapeptide (UDP-MurNAc) is formed in which the fourth and fifth amino acids are both D-alanyl-D-alanine. The transfer of D-alanine is done (catalysed) by the enzyme DD-transpeptidase (penicillin-binding proteins are such type). The structural integrity of bacterial cell wall depends on the cross linking of UDP-MurNAc and N-acetyl glucosamine. Penicillin and other β-lactam antibiotics act as an analogue of D-alanine-D-alanine (the dipeptide) in UDP-MurNAc owing to conformational similarities. The DD-transpeptidase then binds the four-membered β-lactam ring of penicillin instead of UDP-MurNAc. As a consequence, DD-transpeptidase is inactivated, the formation of cross-links between UDP-MurNAc and N-acetyl glucosamine is blocked so that an imbalance between cell wall production and degradation develops, causing the cell to rapidly die.The enzymes that hydrolyze the peptidoglycan cross-links continue to function, even while those that form such cross-links do not. This weakens the cell wall of the bacterium, and osmotic pressure becomes increasingly uncompensated—eventually causing cell death (cytolysis). In addition, the build-up of peptidoglycan precursors triggers the activation of bacterial cell wall hydrolases and autolysins, which further digest the cell walls peptidoglycans. The small size of the penicillins increases their potency, by allowing them to penetrate the entire depth of the cell wall. This is in contrast to the glycopeptide antibiotics vancomycin and teicoplanin, which are both much larger than the penicillins.Gram-positive bacteria are called protoplasts when they lose their cell walls. Gram-negative bacteria do not lose their cell walls completely and are called spheroplasts after treatment with penicillin.Penicillin shows a synergistic effect with aminoglycosides, since the inhibition of peptidoglycan synthesis allows aminoglycosides to penetrate the bacterial cell wall more easily, allowing their disruption of bacterial protein synthesis within the cell. This results in a lowered MBC for susceptible organisms.Penicillins, like other β-lactam antibiotics, block not only the division of bacteria, including cyanobacteria, but also the division of cyanelles, the photosynthetic organelles of the glaucophytes, and the division of chloroplasts of bryophytes. In contrast, they have no effect on the plastids of the highly developed vascular plants. This supports the endosymbiotic theory of the evolution of plastid division in land plants.Some bacteria produce enzymes that break down the β-lactam ring, called β-lactamases, which make the bacteria resistant to penicillin. Therefore, some penicillins are modified or given with other drugs for use against antibiotic-resistant bacteria or in immunocompromised patients. The use of clavulanic acid or tazobactam, β-lactamase inhibitors, alongside penicillin gives penicillin activity against β-lactamase-producing bacteria. β-Lactamase inhibitors irreversibly bind to β-lactamase preventing it from breaking down the beta-lactam rings on the antibiotic molecule. Alternatively, flucloxacillin is a modified penicillin that has activity against β-lactamase-producing bacteria due to an acyl side chain that protects the beta-lactam ring from β-lactamase. Pharmacokinetics Penicillin has low protein binding in plasma. The bioavailability of penicillin depends on the type: penicillin G has low bioavailability, below 30%, whereas penicillin V has higher bioavailability, between 60 and 70%.Penicillin has a short half-life and is excreted via the kidneys. This means it must be dosed at least four times a day to maintain adequate levels of penicillin in the blood. Early manuals on the use of penicillin, therefore, recommended injections of penicillin as frequently as every three hours, and dosing penicillin has been described as being similar to trying to fill a bath with the plug out. This is no longer required since much larger doses of penicillin are cheaply and easily available; however, some authorities recommend the use of continuous penicillin infusions for this reason. Resistance When Alexander Fleming discovered the crude penicillin in 1928, one important observation he made was that many bacteria were not affected by penicillin. This phenomenon was realised by Ernst Chain and Edward Abraham while trying to identify the exact of penicillin. In 1940, they discovered that unsusceptible bacteria like Escherichia coli produced specific enzymes that can break down penicillin molecules, thus making them resistant to the antibiotic. They named the enzyme penicillinase. Penicillinase is now classified as member of enzymes called β-lactamases. These β-lactamases are naturally present in many other bacteria, and many bacteria produce them upon constant exposure to antibiotics. In most bacteria, resistance can be through three different mechanisms: reduced permeability in bacteria, reduced binding affinity of the penicillin-binding proteins (PBPs) or destruction of the antibiotic through the expression of β-lactamase. Using any of these, bacteria commonly develop resistance to different antibiotics, a phenomenon called multi-drug resistance. The actual process of resistance mechanism can be very complex. In case of reduced permeability in bacteria, the mechanisms are different between Gram-positive and Gram-negative bacteria. In Gram-positive bacteria, blockage of penicillin is due to changes in the cell wall. For example, resistance to vancomycin in S. aureus is due to additional peptidoglycan synthesis that makes the cell wall much thicker preventing effective penicillin entry. Resistance in Gram-negative bacteria is due to mutational variations in the structure and number of porins. In bacteria like Pseudomonas aeruginosa, there is reduced number of porins; whereas in bacteria like Enterobacter species, Escherichia coli and Kle
Penicillin	bsiella pneumoniae, there are modified porins such as non-specific porins (such as OmpC and OmpF groups) that cannot transport penicillin.Resistance due to PBP alterations is highly varied. A common case is found in Streptococcus pneumoniae where there is mutation in the gene for PBP, and the mutant PBPs have decreased binding affinity for penicillins. There are six mutant PBPs in S. pneumoniae, of which PBP1a, PBP2b, PBP2x and sometimes PBP2a are responsible for reduced binding affinity. S. aureus can activate a hidden gene that produces a different PBP, PBD2, which has low binding affinity for penicillins. There is a different strain of S. aureus named methicillin-resistant S. aureus (MRSA) which is resistant not only to penicllin and other β-lactams, but also to most antibiotics. The bacterial strain developed after introduction of methicillin in 1959. In MRSA, mutations in the genes (mec system) for PBP produce a variant protein called PBP2a (also termed PBP2), while making four normal PBPs. PBP2a has poor binding affinity for penicillin and also lacks glycosyltransferase activity required for complete peptidoglycan synthesis (which is carried out by the four normal PBPs). In Helicobacter cinaedi, there are multiple mutations in different genes that make PBP variants.Enzymatic destruction by β-lactamases is the most important mechanism of penicillin resistance, and is described as "the greatest threat to the usage [of penicillins]". It was the first discovered mechanism of penicillin resistance. During the experiments when purification and biological activity tests of penicillin were performed in 1940, it was found that E. coli was unsusceptible. The reason was discovered as production of an enzyme penicillinase (hence, the first β-lactamase known) in E. coli that easily degraded penicillin. There are over 2,000 types of β-lactamases each of which has unique amino acid sequence, and thus, enzymatic activity. All of them are able to hydrolyse β-lactam rings but their exact target sites are different. They are secreted on the bacterial surface in large quantities in Gram-positive bacteria but less so in Gram-negative species. Therefore, in a mixed bacterial infection, the Gram-positive bacteria can protect the otherwise penicillin-susceptible Gram-negative cells.There are unusual mechanisms in P. aeruginosa, in which there can be biofilm-mediated resistance and formation of multidrug-tolerant persister cells. History Discovery Starting in the late 19th century there had been reports of the antibacterial properties of Penicillium mould, but scientists were unable to discern what process was causing the effect. Scottish physician Alexander Fleming at St Marys Hospital in London (now part of Imperial College) was the first to show that Penicillium rubens had antibacterial properties. On 3 September 1928 he observed that fungal contamination of a bacterial culture (Staphylococcus aureus) appeared to kill the bacteria. He confirmed this observation with a new experiment on 28 September 1928. He published his experiment in 1929, and called the antibacterial substance (the fungal extract) penicillin.C. J. La Touche identified the fungus as Penicillium rubrum (later reclassified by Charles Thom as P. notatum and P. chrysogenum, but later corrected as P. rubens). Fleming expressed initial optimism that penicillin would be a useful antiseptic, because of its high potency and minimal toxicity in comparison to other antiseptics of the day, and noted its laboratory value in the isolation of Bacillus influenzae (now called Haemophilus influenzae).Fleming did not convince anyone that his discovery was important. This was largely because penicillin was so difficult to isolate that its development as a drug seemed impossible. It is speculated that had Fleming been more successful at making other scientists interested in his work, penicillin would possibly have been developed years earlier.The importance of his work has been recognized by the placement of an International Historic Chemical Landmark at the Alexander Fleming Laboratory Museum in London on 19 November 1999. Medical application In 1930, Cecil George Paine, a pathologist at the Royal Infirmary in Sheffield, successfully treated ophthalmia neonatorum, a gonococcal infection in infants, with penicillin (fungal extract) on November 25, 1930.In 1940, Australian scientist Howard Florey (later Baron Florey) and a team of researchers (Ernst Chain, Edward Abraham, Arthur Duncan Gardner, Norman Heatley, Margaret Jennings, Jean Orr-Ewing and Arthur Gordon Sanders) at the Sir William Dunn School of Pathology, University of Oxford made progress in making concentrated penicillin from fungal culture broth that showed both in vitro and in vivo bactericidal action. In 1941, they treated a policeman, Albert Alexander, with a severe face infection; his condition improved, but then supplies of penicillin ran out and he died. Subsequently, several other patients were treated successfully. In December 1942, survivors of the Cocoanut Grove fire in Boston were the first burn patients to be successfully treated with penicillin.The first successful use of pure penicillin was when Fleming treated Harry Lambert of fatal infection of the nervous system (streptococcal meningitis) in 1942. By that time the Oxford team could produce only a small amount. Florey willingly gave the only available sample to Fleming. Lambert showed improvement from the very next day of the treatment, and was completely cured within a week. Fleming published his clinical trial in The Lancet in 1943. Following the medical breakthrough the British War Cabinet set up the Penicillin Committee on 5 April 1943 that led to projects for mass production. Mass production As the medical application was established, the Oxford team found that it was impossible to produce usable amounts in their laboratory. Failing to persuade the British government, Florey and Heatley travelled to the US in June 1941 with their mould samples in order to interest the US government for large-scale production. They approached the USDA Northern Regional Research Laboratory (NRRL, now the National Center for Agricultural Utilization Research) at Peoria, Illinois, where facilities for large-scale fermentations were established. Mass culture of the mould and search for better moulds immediately followed.On March 14, 1942, the first patient was treated for streptococcal sepsis with US-made penicillin produced by Merck & Co. Half of the total supply produced at the time was used on that one patient, Anne Miller. By June 1942, just enough US penicillin was available to treat ten patients. In July 1943, the War Production Board drew up a plan for the mass distribution of penicillin stocks to Allied troops fighting in Europe. The results of fermentation research on corn steep liquor at the NRRL allowed the United States to produce 2.3 million doses in time for the invasion of Normandy in the spring of 1944. After a worldwide search in 1943, a mouldy cantaloupe in a Peoria, Illinois market was found to contain the best strain of mould for production using the corn steep liquor process. Pfizer scientist Jasper H. Kane suggested using a deep-tank fermentation method for producing large quantities of pharmaceutical-grade penicillin.: 109 Large-scale production resulted from the development of a deep-tank fermentation plant by chemical engineer Margaret Hutchinson Rousseau. As a direct result of the war and the War Production Board, by June 1945, over 646 billion units per year were being produced.G. Raymond Rettew made a significant contribution to the American war effort by his techniques to produce commercial quantities of penicillin, wherein he combined his knowledge of mushroom spawn with the function of the Sharples Cream Separator. By 1943, Rettews lab was producing most of the worlds penicillin. During World War II, penicillin made a major difference in the number of deaths and amputations caused by infected wounds among Allied forces, saving an estimated 12%–15% of lives. Availability was severely limited, however, by the difficulty of manufacturing large quantities of penicillin and by the rapid renal clearance of the drug, necessitating frequent dosing. Methods for mass production of penicillin were patented by Andrew Jackson Moyer in 1945. Florey had not patented penicillin, having been advised by Sir Henry Dale that doing so would be unethical.Penicillin is actively excreted, and about 80% of a penicillin dose is cleared from the body within three to four hours of administration. Indeed, during the early penicillin era, the drug was so scarce and so highly valued that it became common to collect the urine from patients being treated, so that the penicillin in the urine could be isolated and reused. This was not a satisfactory solution, so researchers looked for a way to slow penicillin excretion. They hoped to find a molecule that could compete with penicillin for the organic acid transporter responsible for excretion, such that the transporter would preferentially excrete the competing molecule and the penicillin would be retained. The uricosuric agent probenecid proved to be suitable. When probenecid and penicillin are administered together, probenecid competitively inhibits the excretion of penicillin, increasing penicillins concentration and prolonging its activity. Eventually, the advent of mass-production techniques and semi-synthetic penicillins resolved the supply issues, so this use of probenecid declined. Probenecid is still useful, however, for certain infections requiring particularly high concentrations of penicillins.After World War II, Australia was the first country to make the drug available for civilian use. In the U.S., penicillin was made available to the general public on March 15, 1945.Fleming, Florey, and Chain shared the 1945 Nobel Prize in Physiology or Medicine for the development of penicillin. Structure determination and total synthesis The chemical structure of penicillin was first proposed by Edward Abraham in 1942 and was later confirmed in 1945 using X-ray crystallography by Dorothy Crowfoot Hodgkin, who was also working at Oxford. She later in 1964 received the Nobel Prize for Chemistry for this and other structure determinations. Chemist John C. Sheehan at the Massachusetts Institute of Technology (MIT) completed the first chemical synthesis of penicillin in 1957. Sheehan had started his studies into penicillin synthesis in 1948, and during these investigations developed new methods for the synthesis of peptides, as well as new protecting groups—groups that mask the reactivity of certain functional groups. Although the initial synthesis developed by Sheehan was not appropriate for mass production of penicillins, one of the intermediate compounds in Sheehans synthesis was 6-aminopenicillanic acid (6-APA), the nucleus of penicillin.6-APA was discovered by researchers at the Beecham Research Laboratories (later the Beecham Group) in Surrey in 1957 (published in 1959). Attaching different groups to the 6-APA nucleus of penicillin allowed the creation of new forms of penicillins which are more versatile and better in activity. Developments from penicillin The narrow range of treatable diseases or "spectrum of activity" of the penicillins, along with the poor activity of the orally active phenoxymethylpenicillin, led to the search for derivatives of penicillin that could treat a wider range of infections. The isolation of 6-APA, the nucleus of penicillin, allowed for the preparation of semisynthetic penicillins, with various improvements over benzylpenicillin (bioavailability, spectrum, stability, tolerance). The first major development was ampicillin in 1961. It offered a broader spectrum of activity than either of the original penicillins. Further development yielded β-lactamase-resistant penicillins, including flucloxacillin, dicloxacillin, and methicillin. These were significant for their activity against β-lactamase-producing bacterial species, but were ineffective against the methicillin-resistant Staphylococcus aureus (MRSA) strains that subsequently emerged.Another development of the line of true penicillins was the antipseudomonal penicillins, such as carbenicillin, ticarcillin, and piperacillin, useful for their activity against Gram-negative bacteria. However, the usefulness of the β-lactam ring was such that related antibiotics, including the mecillinams, the carbapenems, and, most important, the cephalosporins, still retain it at the center of their structures. Production Penicillin is produced by the fermentation of various types of sugar by the fungus penicillium rubens. The fermentation process produces penicillin as a secondary metabolite when the growth of the fungus is inhibited by stress. It is not produced during active growth. Production is also limited by feedback in the synthesis pathway of penicillin. α-ketoglutarate + AcCoA → homocitrate → L-α-aminoadipic acid → L-lysine + β-lactamThe by-product, l-lysine, inhibits the production of homocitrate, so the presence of exogenous lysine should be avoided in penicillin production. The Penicillium cells are grown using a technique called fed-batch culture, in which the cells are constantly subject to stress, which is required for induction of penicillin production. The available carbon sources are also important: glucose inhibits penicillin production, whereas lactose does not. The pH and the levels of nitrogen, lysine, phosphate, and oxygen of the batches must also be carefully controlled.The biotechnological method of directed evolution has been applied to produce by mutation a large number of Penicillium strains. These techniques include error-prone PCR, DNA shuffling, ITCHY, and strand-overlap PCR. Semisynthetic penicillins are prepared to start from the penicillin nucleus 6-APA. Biosynthesis Overall, there are three main and important steps to the biosynthesis of penicillin G (benzylpenicillin). The first step is the condensation of three amino acids—L-α-aminoadipic acid, L-cysteine, L-valine into a tripeptide. Before condensing into the tripeptide, the amino acid L-valine must undergo epimerization to become D-valine. The condensed tripeptide is named δ-(L-α-aminoadipyl)-L-cysteine-D-valine (ACV). The condensation reaction and epimerization are both catalyzed by the enzyme δ-(L-α-aminoadipyl)-L-cysteine-D-valine synthetase (ACVS), a nonribosomal peptide synthetase or NRPS. The second step in the biosynthesis of penicillin G is the oxidative conversion of linear ACV into the bicyclic intermediate isopenicillin N by isopenicillin N synthase (IPNS), which is encoded by the gene pcbC. Isopenicillin N is a very weak intermediate, because it does not show strong antibiotic activity. The final step is a transamidation by isopenicillin N N-acyltransferase, in which the α-aminoadipyl side-chain of isopenicillin N is removed and exchanged for a phenylacetyl side-chain. This reaction is encoded by the gene penDE, which is unique in the process of obtaining penicillins. See also Medicinal fungi Penicillinase References Further reading External links Model of Structure of Penicillin, by Dorothy Hodgkin et al., Museum of the History of Science, Oxford The Discovery of Penicillin, A government-produced film about the discovery of Penicillin by Sir Alexander Fleming, and the continuing development of its use as an antibiotic by Howard Florey and Ernst Boris Chain on YouTube. Penicillin at The Periodic Table of Videos (University of Nottingham) "Penicillin Released to Civilians Will Cost $35 Per Patient", Popular Science, August 1944, article at bottom of page Episode 2 (of 4): "Medical Drugs" of the BBC Four and PBS show: Extra Life: A Short History of Living Longer (2021)
Rolapitant	Rolapitant (INN, trade name Varubi və-ROO-bee in the US and Varuby in the European Union) is a drug originally developed by Schering-Plough and licensed for clinical development by Tesaro, which acts as a selective NK1 receptor antagonist (antagonist for the NK1 receptor). It has been approved as a medication for the treatment of chemotherapy-induced nausea and vomiting (CINV) after clinical trials showed it to have similar or improved efficacy and some improvement in safety over existing drugs for this application. Medical uses Rolapitant is used in combination with other antiemetic (anti-vomiting) agents in adults for the prevention of delayed nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including, but not limited to, highly emetogenic chemotherapy. The approved antiemetic combination consists of rolapitant plus dexamethasone and a 5-HT3 antagonist. Contraindications Under the US approval, rolapitant is contraindicated in combination with thioridazine, whose inactivation could be inhibited by rolapitant. Under the European approval, it is contraindicated in combination with St. Johns Wort, which is expected to accelerate inactivation of rolapitant. Side effects In studies comparing chemotherapy plus rolapitant, dexamethasone and a 5-HT3 antagonist to chemotherapy plus placebo, dexamethasone and a 5-HT3 antagonist, most side effects had comparable frequencies in both groups, and differed more between chemotherapy regimens than between rolapitant and placebo groups. Common side effects included decreased appetite (9% under rolapitant vs. 7% under placebo), neutropenia (9% vs. 8% or 7% vs. 6%, depending on the kind of chemotherapy), dizziness (6% vs. 4%), indigestion and stomatitis (both 4% vs. 2%). Overdose Up to eightfold therapeutic doses have been given in studies without problems. Interactions Rolapitant moderately inhibits the liver enzyme CYP2D6. Blood plasma concentrations of the CYP2D6 substrate dextromethorphan have increased threefold when combined with rolapitant; and increased concentrations of other substrates are expected. The drug also inhibits the transporter proteins ABCG2 (breast cancer resistance protein, BCRP) and P-glycoprotein (P-gp), which has been shown to increase plasma concentrations of the ABCG2 substrate sulfasalazine twofold and the P-gp substrate digoxin by 70%.Strong inducers of the liver enzyme CYP3A4 decrease the area under the curve of rolapitant and its active metabolite (called M19); for rifampicin, this effect was almost 90% in a study. Inhibitors of CYP3A4 have no relevant effect on rolapitant concentrations. Pharmacology Pharmacodynamics Both rolapitant and its active metabolite M19 block the NK1 receptor with high affinity and selectivity: to block the closely related receptor NK2 or any other of 115 tested receptors and enzymes, more than 1000-fold therapeutic concentrations are necessary. Pharmacokinetics Rolapitant is practically completely absorbed from the gut, independently of food intake. It undergoes no measurable first-pass effect in the liver. Highest blood plasma concentrations are reached after about four hours. When in the bloodstream, 99.8% of the substance are bound to plasma proteins.It is metabolized by the liver enzyme CYP3A4, resulting in the major active metabolite M19 (C4-pyrrolidine-hydroxylated rolapitant) and a number of inactive metabolites. Rolapitant is mainly excreted via the feces (52–89%) in unchanged form, and to a lesser extent via the urine (9–20%) in form of its inactive metabolites. Elimination half-life is about seven days (169 to 183 hours) over a wide dosing range. Chemistry The drug is used in form of rolapitant hydrochloride monohydrate, a white to off-white, slightly hygroscopic crystalline powder. Its maximum solubility in aqueous solutions is at pH 2–4. See also Palonosetron References External links "Rolapitant". Drug Information Portal. U.S. National Library of Medicine. "Rolapitant Injection: MedlinePlus Drug Information". MedlinePlus. 20 August 2020.
Methazolamide	Methazolamide (trade name Neptazane) is a potent carbonic anhydrase inhibitor. It is indicated in the treatment of increased intraocular pressure (IOP) in chronic open-angle glaucoma and secondary glaucoma. Also it is used preoperatively in acute angle-closure (narrow-angle) glaucoma where lowering the IOP is desired before surgery. This drug has displayed teratogenic effects in rats. Compared to another drug in the same class, Acetazolamide, Methazolamide requires a lower dose when administered to patients. References Iyer G, Bellantone R, Taft D (1999). "In vitro characterization of the erythrocyte distribution of methazolamide: a model of erythrocyte transport and binding kinetics". J Pharmacokinet Biopharm. 27 (1): 45–66. doi:10.1023/A:1020630712388. PMID 10533697. S2CID 24294348. RxList. "Neptazane". Archived from the original on August 12, 2006. Retrieved August 20, 2006. Shirato S, Kagaya F, Suzuki Y, Joukou S (1997). "Stevens–Johnson syndrome induced by methazolamide treatment". Arch Ophthalmol. 115 (4): 550–3. doi:10.1001/archopht.1997.01100150552021. PMID 9109770. Skorobohach B, Ward D, Hendrix D (2003). "Effects of oral administration of methazolamide on intraocular pressure and aqueous humor flow rate in clinically normal dogs". Am J Vet Res. 64 (2): 183–7. doi:10.2460/ajvr.2003.64.183. PMID 12602587.
Omeprazole	Omeprazole, sold under the brand names Prilosec and Losec, among others, is a medication used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger–Ellison syndrome. It is also used to prevent upper gastrointestinal bleeding in people who are at high risk. Omeprazole is a proton-pump inhibitor (PPI) and its effectiveness is similar to other PPIs. It can be taken by mouth or by injection into a vein.Common side effects include nausea, vomiting, headaches, abdominal pain, and increased intestinal gas. Serious side effects may include Clostridium difficile colitis, an increased risk of pneumonia, an increased risk of bone fractures, and the potential of masking stomach cancer. It is unclear if it is safe for use in pregnancy. It works by blocking the release of stomach acid.Omeprazole was patented in 1978, and approved for medical use in 1988. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the eighth most commonly prescribed medication in the United States, with more than 56 million prescriptions. It is also available without a prescription in the United States. Medical uses Omeprazole can be used in the treatment of gastroesophageal reflux disease (GERD), peptic ulcers, erosive esophagitis, Zollinger–Ellison syndrome, and eosinophilic esophagitis. Peptic ulcers Peptic ulcers may be treated with omeprazole. Treatment of a Helicobacter pylori infection can be completed by taking a triple therapy combination of omeprazole, amoxicillin, and clarithromycin for 7–14 days. Amoxicillin may be replaced with metronidazole in patients who are allergic to penicillin. Adverse effects Adverse effects occurring in at least 1% of people include: Central nervous system: headache (7%), dizziness (2%) Respiratory: upper respiratory tract infection (2%), cough (1%) Gastrointestinal: abdominal pain (5%), diarrhea (4%), nausea (4%), vomiting (3%), flatulence (3%), acid regurgitation (2%), constipation (2%) Neuromuscular and skeletal: back pain (1%), weakness (1%) Dermatologic: rash (2%)Other concerns related to adverse effects are: Recurrence of Clostridium difficile associated diarrhea Osteoporosis-related fractures HypomagnesemiaConcern has been expressed regarding vitamin B12 and iron malabsorption, but effects seem to be insignificant, especially when supplement therapy is provided.Since their introduction, proton-pump inhibitors (PPIs, especially omeprazole) have also been associated with several cases of acute interstitial nephritis, an inflammation of the kidneys that often occurs as an adverse drug reaction. Long-term use Long-term use of PPIs is strongly associated with the development of benign polyps from fundic glands (which is distinct from fundic gland polyposis); these polyps do not cause cancer and resolve when PPIs are discontinued. No association is seen between PPI use and cancer, but use of PPIs may mask gastric cancers or other serious gastric problems and physicians should be aware of this effect.There is a possible association between long term use and dementia which requires further study to confirm.A review article in U.S. Pharmacist in 2013 states that long-term use of PPIs is associated with decreased calcium absorption (causing increased risk of osteoporosis and fractures), decreased magnesium absorption (causing electrolyte disturbances), and increased risk of certain infections such as C. difficile and community-acquired pneumonia. They hypothesize that this is due to decreased stomach acid production. Pregnancy and breastfeeding The safety of using omeprazole has not been established in pregnant or breastfeeding women. Epidemiological data do not show an increased risk of major birth defects after maternal use of omeprazole during pregnancy.No clinical trials have deeply evaluated the potential consequences of the use of omeprazole in breastfeeding. However, the pharmacokinetics of the omeprazole molecule strongly suggest the safety of omeprazole use during breastfeeding: Omeprazole has a high plasma protein binding rate (95%), indicating that a little amount of drug is transferred to the milk duct during breast milk formation. Omeprazole needs to be administered in an enteric-coated formulation due to its rapid degradation in the acidic conditions of the stomach. This suggests that most of the free molecules ingested by the infant are likely degraded before being absorbed.Omeprazole at normal doses is likely safe during breastfeeding. Interactions Important drug interactions are rare. However, the most significant major drug interaction concern is the decreased activation of clopidogrel when taken together with omeprazole. Although still controversial, this may increase the risk of stroke or heart attack in people taking clopidogrel to prevent these events. This interaction is possible because omeprazole is an inhibitor of the enzymes CYP2C19 and CYP3A4. Clopidogrel is an inactive prodrug that partially depends on CYP2C19 for conversion to its active form. Inhibition of CYP2C19 may block the activation of clopidogrel, which could reduce its effects.Almost all benzodiazepines are metabolised by the CYP3A4 and CYP2D6 pathways, and inhibition of these enzymes results in a higher area under the curve (i.e., the total effect over time of a given dose). Other examples of drugs dependent on CYP3A4 for their metabolism are escitalopram, warfarin, oxycodone, tramadol, and oxymorphone. The concentrations of these drugs may increase if they are used concomitantly with omeprazole.Omeprazole is also a competitive inhibitor of p-glycoprotein, as are other PPIs.Drugs that depend on an acidic stomach environment (such as ketoconazole or atazanavir) may be poorly absorbed, whereas acid-labile antibiotics (such as erythromycin which is a very strong CYP3A4 inhibitor) may be absorbed to a greater extent than normal due to the more alkaline environment of the stomach.St. Johns wort (Hypericum perforatum) and Gingko biloba significantly reduce plasma concentrations of omeprazole through induction of CYP3A4 and CYP2C19.Proton-pump inhibitors like omeprazole have been found to increase the plasma concentrations of methotrexate. Pharmacology Omeprazole irreversibly blocks the enzyme system on parietal cells that is needed for the secretion of gastric acid. It is a specific H+/K+ATPase inhibitor. This is the enzyme needed for the final step in the secretion of gastric acid. Mechanism of action Omeprazole is a selective and irreversible proton pump inhibitor. It suppresses stomach acid secretion by specific inhibition of the H+/K+-ATPase system found at the secretory surface of gastric parietal cells. Because this enzyme system is regarded as the acid (proton, or H+) pump within the gastric mucosa, omeprazole inhibits the final step of acid production.Omeprazole also inhibits both basal and stimulated acid secretion irrespective of the stimulus as it blocks the last step in acid secretion. The drug binds non-competitively so it has a dose-dependent effect.The inhibitory effect of omeprazole occurs within 1 hour after oral administration. The maximum effect occurs within 2 hours. The duration of inhibition is up to 72 hours. When omeprazole is stopped, baseline stomach acid secretory activity returns after 3 to 5 days. The inhibitory effect of omeprazole on acid secretion will plateau after 4 days of repeated daily dosing. Pharmacokinetics The absorption of omeprazole takes place in the small intestine and is usually completed within 3 to 6 hours. The systemic bioavailability of omeprazole after repeated doses is about 60%. Omeprazole has a volume of distribution of 0.4 L/kg. It has high plasma protein binding of 95%.Omeprazole, as well as other PPIs, are only effective on active H+/K+-ATPase pumps. These pumps are stimulated in the presence of food to aid in digestion. For this reason, patients should be advised to take omeprazole with a glass of water on an empty stomach. Additionally, most sources recommend that after taking omeprazole, at least 30 minutes should be allowed to elapse before eating (at least 60 minutes for immediate-release omeprazole plus sodium bicarbonate products, such as Zegerid), though some sources say that with delayed-release forms of omeprazole, waiting before eating after taking the medication is not necessary.Omeprazole is completely metabolized by the cytochrome P450 system, mainly in the liver, by CYP2C19 and CYP3A4 isoenzymes. Identified metabolites are the sulfone, the sulfide, and hydroxy-omeprazole, which exert no significant effect on acid secretion. About 77% of an orally given dose is excreted as metabolites in the urine, and the remainder is found in the feces, primarily originating from bile secretion. Omeprazole has a half life of 0.5 to 1 hour. The pharmacological effects of omeprazole last longer as it is covalently bonded to proton pump on parietal cells to induce effects. Chemistry Omeprazole contains a tricoordinated sulfinyl sulfur in a pyramidal structure and therefore can exist as either the (S)- or (R)-enantiomers. Omeprazole is a racemate, an equal mixture of the two. In the acidic conditions of the canaliculi of parietal cells, both enantiomers are converted to achiral products (sulfenic acid and sulfenamide configurations) which react with a cysteine group in H+/K+ ATPase, thereby inhibiting the ability of the parietal cells to produce gastric acid. AstraZeneca also developed esomeprazole (Nexium) which is a eutomer, purely the (S)-enantiomer, rather than a racemate like omeprazole. Omeprazole undergoes a chiral shift in vivo which converts the inactive (R)-enantiomer to the active (S)-enantiomer, doubling the concentration of the active form. This chiral shift is accomplished by the CYP2C19 isozyme of cytochrome P450, which is not found equally in all human populations. Those who do not metabolize the drug effectively are called "poor metabolizers". The proportion of the poor metabolizer phenotype varies widely between populations, from 2.0 to 2.5% in African Americans and white Americans to >20% in Asians. Several pharmacogenomics studies have suggested that PPI treatment should be tailored according to CYP2C19 metabolism status. Measurement in body fluids Omeprazole may be quantified in plasma or serum to monitor therapy or to confirm a diagnosis of poisoning in hospitalized patients. Plasma omeprazole concentrations are usually in a range of 0.2–1.2 mg/L in persons receiving the drug therapeutically by the oral route and 1–6 mg/L in people with acute overdose. Enantiomeric chromatographic methods are available to distinguish esomeprazole from racemic omeprazole. History Omeprazole was first made in 1979 by Swedish AB Hässle, part of Astra AB. It was the first of the proton pump inhibitors (PPI). Astra AB, now AstraZeneca, launched it as an ulcer medicine under the name Losec in Sweden. It was first sold in the United States in 1989 under the brand name Losec. In 1990, at the request of the U.S. Food and Drug Administration, the brand name Losec was changed to Prilosec to avoid confusion with the diuretic Lasix (furosemide). The new name led to confusion between omeprazole (Prilosec) and fluoxetine (Prozac), an antidepressant.When Prilosecs U.S. patent expired in April 2001, AstraZeneca introduced esomeprazole (Nexium) as a patented replacement drug. Many companies introduced generics as AstraZenecas patents expired worldwide, which are available under many brand names. Society and culture Dosage forms It can be taken by mouth, as a capsule, tablet, or suspension, or by injection into a vein.Omeprazole is available in strengths of 10, 20, 40, and in some markets 80 mg; and as a powder (omeprazole sodium) for intravenous injection. Most oral omeprazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach. This is most commonly achieved by formulating enteric-coated granules within capsules, enteric-coated tablets, and the multiple-unit pellet system (MUPS). An immediate release formulation was approved by the FDA in the United States, which does not require enteric coating. It is also available for use in injectable form (IV) in Europe, but not in the U.S. The injection pack is a combination pack consisting of a vial and a separate ampule of reconstituting solution. Each 10 mL clear glass vial contains a white to off-white lyophilised powder consisting of omeprazole sodium 42.6 mg, equivalent to 40 mg of omeprazole. Omeprazole is also available as an oral suspension of enteric-coated beads in the UK as an unlicensed product. Oral suspensions are predominantly used for children, but can also be used by those with difficulty swallowing or those using a feeding tube. Brand names Brand names include Losec, Prilosec, Zegerid, Miracid, and Omez. References Further reading Dean L (2012). "Omeprazole Therapy and CYP2C19 Genotype". In Pratt VM, McLeod HL, Rubinstein WS, et al. (eds.). Medical Genetics Summaries. National Center for Biotechnology Information (NCBI). PMID 28520353. Bookshelf ID: NBK100895. External links "Omeprazole". Drug Information Portal. U.S. National Library of Medicine.
Loteprednol	Loteprednol (as the ester loteprednol etabonate) is a corticosteroid used to treat inflammations of the eye. It is marketed by Bausch and Lomb as Lotemax and Loterex. It was patented in 1980 and approved for medical use in 1998. Medical uses Applications for this drug include the reduction of inflammation after eye surgery, seasonal allergic conjunctivitis, uveitis, as well as chronic forms of keratitis (e.g. adenoviral and Thygesons keratitis), vernal keratoconjunctivitis, pingueculitis, and episcleritis. Contraindications As corticosteroids are immunosuppressive, loteprednol is contraindicated in patients with viral, fungal or mycobacterial infections of the eye. Adverse effects The most common adverse effects in patients being treated with the gel formulation are anterior chamber inflammation (in 5% of people), eye pain (2%), and foreign body sensation (2%). Interactions Because long term use (more than 10 days) can cause increased intraocular pressure, loteprednol may interfere with the treatment of glaucoma. Following ocular administration, the drug is very slowly absorbed into the blood, therefore the blood level is limited to an extremely small concentration, and interactions with drugs taken by mouth or through any route other than topical ophthalmic are very unlikely. Pharmacology Mechanism of action Pharmacokinetics Neither loteprednol etabonate nor its inactive metabolites Δ1-cortienic acid and Δ1-cortienic acid etabonate are detectable in the bloodstream, even after oral administration. A study with patients receiving loteprednol eye drops over 42 days showed no adrenal suppression, which would be a sign of the drug reaching the bloodstream to a clinically relevant extent.Steroid receptor affinity was 4.3 times that of dexamethasone in animal studies. Retrometabolic drug design Loteprednol etabonate was developed using retrometabolic drug design. It is a so-called soft drug, meaning its structure was designed so that it is predictably metabolised to inactive substances. These metabolites, Δ1-cortienic acid and its etabonate, are derivatives of cortienic acid, itself an inactive metabolite of hydrocortisone. Chemistry Loteprednol etabonate is an ester of loteprednol with etabonate (ethyl carbonate). The pure chemical compound has a melting point between 220.5 °C (428.9 °F) and 223.5 °C (434.3 °F). Its solubility in water is 1:2,000,000, therefore it is formulated for ophthalmic use as either an ointment, a gel, or a suspension.Loteprednol is a corticosteroid. The ketone side chain of classical corticosteroids such as hydrocortisone is replaced by a cleavable ester, which accounts for the rapid inactivation. (This is not the same as the etabonate ester.) Chemical synthesis References == Further reading ==
Galantamine	Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimers disease and various other memory impairments. It is an alkaloid that has been isolated from the bulbs and flowers of Galanthus nivalis (Common snowdrop), Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronovs snowdrop), and some other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically. Studies of usage in modern medicine began in the Soviet Union in the 1950s. Galantamine was isolated for the first time from bulbs of Galanthus nivalis (common snowdrop) by the Bulgarian chemist D. Paskov and his team in 1956. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The first industrial process was developed in 1959. However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.Since the alkaloid was isolated from a botanical source, it only had contents around 0.1%, which caused the yield to also be extremely low—in the single digits. Uses in mythology In Homers Odyssey the god Hermes gives Odysseus a herb with "a black root, but milklike flower" called "moly", which Hermes claims will make Odysseus immune to the sorceress Circes drugs. It is believed that moly is the snowdrop Galanthus nivalis, which is a source of galantamine. The descriptions of moly given by Greek physician and herbalist Dioscorides support molys identity as Galanthus nivalis. It has been proposed that the drugs Circe used were an extract from Datura stramonium (also known as jimsonweed), which causes memory loss and delirium. This would give a basis for the snowdrops use as an antidote, as Datura stramonium is anticholinergic, while galantamine is an acetylcholinesterase inhibitor. Medical uses Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimers. In the United States, it is approved by the Food and Drug Administration as safe and effective for the treatment of mild to moderate dementia. As with other cholinesterase inhibitors, galantamine may not be effective for treating mild cognitive impairment.The FDA considers galantamine to have dual status as a prescription drug and as a OTC dietary supplement. Alzheimers disease Alzheimers disease is characterized by the impairment of cholinergic function. One hypothesis is that this impairment contributes to the cognitive deficits caused by the disease. This hypothesis forms the basis for use of galantamine as a cholinergic enhancer in the treatment of Alzheimers. Galantamine inhibits acetylcholinesterase, an enzyme which hydrolyzes acetylcholine. As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission. Additionally, galantamine binds to the allosteric sites of nicotinic receptors, which causes a conformational change. This allosteric modulation increases the nicotinic receptors response to acetylcholine. The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine. Galantamines competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action.To reduce the prevalence of negative side effects associated with galantamine, such as nausea and vomiting, a dose-escalation scheme may be used. The use of a dose-escalation scheme has been well accepted in countries where galantamine is used. A dose-escalation scheme for Alzheimers treatment involves a recommended starting dosage of 4 mg galantamine tablets given twice a day (8 mg/day). After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day). After a minimum of 4 weeks at 16 mg/day, the treatment may be increased to 12 mg given twice a day (24 mg/day). Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage. If treatment is interrupted for more than three days, the process is usually restarted, beginning at the starting dosage, and re-escalating to the current dose. It has been found that a dosage between 16–24 mg/day is the optimal dosage. Available forms The product is supplied in prescription form only in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution. Side effects Galantamines side effect profile was similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. One study reports higher proportions of patients treated with galantamine experiencing nausea and vomiting as opposed to the placebo group. Another study using a dose-escalation treatment has found that incidences of nausea would decrease to baseline levels soon after each increase in administered dosage. In practice, some other cholinesterase inhibitors might be better tolerated; however, a careful and gradual titration over more than three months may lead to equivalent long-term tolerability.The U.S. Food and Drug Administration (FDA) and international health authorities have published an alert of galantamine based on data from two studies during the treatment for mild cognitive impairment (MCI); higher mortality rates were seen in drug-treated patients. However, it reduced mortality in Alzheimers patients. On April 27, 2006, FDA approved labeling changes concerning all form of galantamine preparations (liquid, regular tablets, and extended release tablets) warning of the risk of bradycardia (slow resting heart rate), and sometimes atrioventricular block, especially in predisposed persons. At the same time, the risk of syncope (fainting) seems to be increased relative to placebo. "In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation" These side effects have not been reported in Alzheimers Disease related studies. Pharmacology Galantamines chemical structure contains a tertiary amine. At a neutral pH, this tertiary amine will often bond to a hydrogen, and appear mostly as an ammonium ion.Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α3β4, and α6β4, and chicken/mouse nAChRs α7/5-HT3 in certain areas of the brain. By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine. This modulation of the nicotinic cholinergic receptors on cholinergic neurons in turn causes an increase in the amount of acetylcholine released. However, recent studies suggest that Galantamine does not functionally act at human nAChRs α4β2 or α7 as a positive allosteric modulator.Galantamine also works as a weak competitive and reversible cholinesterase inhibitor in all areas of the body. By inhibiting acetylcholinesterase, it increases the concentration and thereby action of acetylcholine in certain parts of the brain. Galantamines effects on nAChRs and complementary acetylcholinesterase inhibition make up a dual mechanism of action. It is hypothesized that this action might relieve some of the symptoms of Alzheimers. Galantamine in its pure form is a white powder. The atomic resolution 3D structure of the complex of galantamine and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (PDB code: 1DX6; see complex). There is no evidence that galantamine alters the course of the underlying dementing process. Pharmacokinetics Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a terminal elimination half-life of seven hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers. The coadministration of food delays the rate of galantamine absorption, but does not affect the extent of absorption.Plasma protein binding of galantamine is about 18%, which is relatively low. Metabolism Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that hepatic CYP2D6 and CYP3A4 are involved in galantamine metabolism. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.In humans, several metabolic pathways for galantamine exist. These pathways lead to the formation of a number of different metabolites. One of the metabolites that may result can be formed through the glucuronidation of galantamine. Additionally, galantamine may undergo oxidation or demethylation at its nitrogen atom, forming two other possible metabolites. Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation. Lastly, galantamine may be oxidized and then reduced before finally undergoing demethylation or oxidation at its nitrogen atom, or demethylation and subsequent glucuronidation at its oxygen atom. For Razadyne ER, the once-a-day formulation, CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation; however, because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population. Drug interactions Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of these isoenzymes will increase the cholinergic effects of galantamine. Inhibiting these enzymes may lead to adverse effects. It was found that paroxetine, an inhibitor of CYP2D6, increased the bioavailability of galantamine by 40%. The CYP3A4 inhibitors ketoconazole and erythromycin increased the bioavailability of galantamine by 30% and 12%, respectively. Synthesis Galantamine is produced from natural resources, but also has many industrial syntheses. Companies such as Janssen, Ortho-McNeil Pharmaceutical, Sanochemia Pharmazeutika, Shire, and Takeda Pharmaceutical Company have industrial processes for synthesizing Galantamine. Research Organophosphate poisoning The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase. Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown. In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors. This leads to severe skeletal muscle fasciculations (involuntary contractions). The effects on the central nervous system include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma. As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition. Additionally, galantamine has anticonvulsant properties which may make it even more desirable as an antidote.Research supported in part by the US Army has led to a US patent application for the use of galantamine and/or its derivatives for treatment of organophosphate poisoning. The indications for use of galantamine in the patent application include poisoning by nerve agents "including but not limited to soman, sarin, and VX, tabun, and Novichok agents". Galantamine was studied in the research cited in the patent application for use along with the well-recognized nerve agent antidote atropine. According to the investigators, an unexpected synergistic interaction occurred between galantamine and atropine in an amount of 6 mg/kg or higher. Increasing the dose of galantamine from 5 to 8 mg/kg decreased the dose of atropine needed to protect experimental animals from the toxicity of soman in dosages 1.5 times the dose generally required to kill half the experimental animals. Autism Galantamine given in addition to risperidone to autistic children has been shown to improve some of the symptoms of autism such as irritability, lethargy, and social withdrawal. Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes. Some studies have noted that cholinergic and nicotinic treatments have improved attention in autistic children. As such, it is hypothesized that galantamines dual action mechanism might have a similar effect in treating autistic children and adolescents. Anesthesia Galantamine may have some limited use in reducing the side-effects of anesthetics ketamine and diazepam. In one study, a control group of patients were given ketamine and diazepam and underwent anesthesia and surgery. The experimental group was given ketamine, diazepam, and nivalin (of which the active ingredient is galantamine). The degree of drowsiness and disorientation of the two groups was then assessed 5, 10, 15, 30 and 60 minutes after surgery. The group that had taken nivalin were found to be more alert 5, 10, and 15 minutes after the surgery. Lucid dreaming Though not approved by the FDA, there is interest in the recreational use of galantamine for its purported ability to induce lucid dreaming. One study has provided some limited evidence for this practice, although it is notable that its authors have financial ties to the Lucidity Institute. See also Heyneanine References External links "Galantamine". Drug Information Portal. U.S. National Library of Medicine.
Fesoterodine	Fesoterodine (INN, used as the fumarate under the brand name Toviaz) is an antimuscarinic drug developed by Schwarz Pharma AG to treat overactive bladder syndrome (OAB). It was approved by the European Medicines Agency in April 2007, the US Food and Drug Administration on October 31, 2008 and Health Canada on February 9, 2012.Fesoterodine is a prodrug. It is broken down into its active metabolite, desfesoterodine, by plasma esterases. Efficacy Fesoterodine has the advantage of allowing more flexible dosage than other muscarinic antagonists. Its tolerability and side effects are similar to other muscarinic antagonists and as a new drug seems unlikely to make great changes in practices of treatment for overactive bladder.A Japanese study from 2017, showed that urgency and urge incontinence are improved after 3 days administration of the drug, with full efficacy able to be judged after 7 days administration. Overactive bladder was found to be resolved in 88% of patients after seven days usage. References External links "Fesoterodine". Drug Information Portal. U.S. National Library of Medicine.
Albendazole	Albendazole, also known as albendazolum, is a medication used for the treatment of a variety of parasitic worm infestations. It is useful for giardiasis, trichuriasis, filariasis, neurocysticercosis, hydatid disease, pinworm disease, and ascariasis, among other diseases. It is taken orally.Common side effects include nausea, abdominal pains, and headaches. Potentially serious side effects include bone marrow suppression which usually improves on stopping the medication. Liver inflammation has been reported and those with prior liver problems are at greater risk. It is pregnancy category C in the United States and category D in Australia, meaning it may cause harm if taken by pregnant women. Albendazole is a broad-spectrum antihelminthic agent of the benzimidazole type.Albendazole was developed in 1975. It is on the World Health Organizations List of Essential Medicines. Medical uses Albendazole is an effective treatment for: Flatworms Fasciolosis Cestodes (tapeworms), as an alternative to praziquantel or niclosamide for adult beef tapeworms (Taenia saginata) and as an alternative to praziquantel for pork tapeworms (T. solium). It is also given for infections by T. crassiceps. Though praziquantel is often better at treating tapeworm infections, albendazole is used more often in endemic countries due to being cheaper and having a broader spectrum.Cysticercosis (especially neurocysticercosis), which is caused by the larval form of the pork tapeworm (i.e. albendazole is the drug of choice for larval pork tapeworms, but not adult pork tapeworms). Old cysts are not affected. Hydatid disease (aka echinococcosis) of the liver, lung, and peritoneum (caused by the larval form of the dog tapeworm, Echinococcus granulosus) or of the alveoli (caused by E. multilocularis) when surgical excision is not possible. Some suggest that alveolar and cystic echinococcosis require lifelong treatment with albendazole, which only prevents the parasites from growing and reproducing rather than killing them outright. Nematodes Ascariasis, which can be cured with a single dose of albendazole. Baylisascariasis, caused by the raccoon roundworm. If treatment with Albendazole is initiated within 72 hours of ingestion of the egg-containing raccoon feces, good results (95%-100% efficacy, with Albendazole being orally administered for a 10-day period) can be expected. Corticosteroids are sometimes added in cases of eye and CNS infections. Enterobiasis (pinworm infection) Filariasis; since albendazoles disintegration of the microfilarie ("pre-larva") can cause an allergic reaction, antihistamines or corticosteroids are sometimes added to treatment. In cases of lymphatic filariasis (elephantiasis) caused by Wuchereria bancrofti or Brugia malayi, albendazole is sometimes given as an adjunct to ivermectin or diethylcarbamazine in order to suppress microfilaremia. It can also be given for loa loa filariasis as an adjunct or replacement to diethylcarbamazine. Albendazole has an embryotoxic effect on Loa loa adults and thus slowly reduces microfilaremia. Gnathostomiasis when caused by Gnathostoma spinigerum. Albendazole has a similar effectiveness to ivermectin in these cases, though it needs to be given for 21 days rather than the 2 days needed for ivermectin. Gongylonemiasis Hookworm infections, including cutaneous larva migrans caused by hookworms in the genus Ancylostoma. A single dose of albendazole is sufficient to treat intestinal infestations by A. duodenale or Necator americanus Intestinal capillariasis, as an alternative to mebendazole Mansonelliasis when caused by Mansonella perstans. Albendazole works against the adult worms but not against the younger microfilariae. Oesophagostomumiasis, when caused by Oesophagostomum bifurcum Strongyloidiasis, as an alternative to ivermectin or thiabendazole Albendazole can be given with diethylcarbamazine to lower microfilaremia levels. Toxocariasis, also called "visceral larva migrans", when caused by the dog roundworm Toxocara canis or cat roundworm T. catis. Corticosteroids can be added in severe cases, and surgery might be required to repair secondary damage. Trichinosis, when caused by Trichinella spiralis or T. pseudospiralis. Albendazole has a similar efficacy to thiabendazole, but fewer side effects. It works best when given early, acting on the adult worms in the intestine before they generate larva that can penetrate the muscle and cause a more widespread infection. Corticosteroids are sometimes added on to prevent inflammation caused by dying larva. Trichostrongyliasis, as an alternative to pyrantel pamoate. A single dose is sufficient for treatment. Trichuriasis (whipworm infection), sometimes considered as an alternative to mebendazole and sometimes considered to be the drug of choice. Only a single dose of albendazole is needed. It can also be given with ivermectin. Giardiasis, as an alternative or adjunct to metronidazole, especially in children Microsporidiosis, including ocular microsporidiosis caused by Encephalitozoon hellem or E. cuniculi, when combined with topical fumagillin Granulomatous amoebic encephalitis, when caused by the ameba Balamuthia mandrillaris, in combination with miltefosine and fluconazole Arthropods Crusted scabies, when combined with topical crotamiton and salicylic acid Head lice infestation, though ivermectin is much better Intestinal myiasisThough albendazole is effective in treating many diseases, it is only FDA-approved for treating hydatid disease caused by dog tapeworm larvae and neurocysticercosis caused by pork tapeworm larvae. Pregnancy Albendazole is a pregnancy class D drug in Australia and pregnancy class C in the United States. It is contraindicated in the first trimester of pregnancy, and should be avoided up to one month before conception. While studies in pregnant rats and rabbits have shown albendazole to be teratogenic, albendazole has been found to be safe in humans during the second and third trimesters. It can, however, possibly cause infantile eczema when given during pregnancy.In pregnant dogs, albendazole use has led to puppies with reduced weight and with cleft palates. Birds have lower rates of laying eggs and hatching when given albendazole.Albendazole sulfoxide is secreted into breast milk at around 1.5% of the maternal dose, though oral absorption is poor enough that it is unlikely to affect nursing infants. Contraindications Hypersensitivity to the benzimidazole class of compounds contraindicates its use. Side effects The most common side effects by albendazole are experienced by over 10% of people and include headache and abnormal liver function. Elevation of liver enzymes occur in 16% of patients receiving treatment specifically for hydatid disease and goes away when treatment ends. Liver enzymes usually increase to two to four times the normal levels (a mild to moderate increase). An estimated 1–10% of people experience abdominal pain, nausea or vomiting, dizziness or vertigo, increased intracranial pressure, meningeal signs, temporary hair loss, and fever. The headache, nausea, and vomiting are thought to be caused by the sudden destruction of cysticerci (tapeworm larvae), which causes acute inflammation. Fewer than 1% of people get hypersensitivity reactions such as rashes and hives, leukopenias (drop in white blood cell levels) such as agranulocytosis and granulocytopenia, thrombocytopenia (reduced platelet count), pancytopenia (drop in white blood cells, red blood cells, and platelets), hepatitis, acute liver failure, acute kidney injury, irreversible bone marrow suppression, and aplastic anemia.Side effects can be different when treating for hydatid disease versus neurocysticercosis: for example, those being treated for the former are more likely to experience elevated liver enzymes and abdominal pain, while those being treated for the latter are more likely to experience headache. Treating hydatid disease can also unmask undiagnosed neurocysticercosis. People receiving albendazole for the treatment of neurocysticercosis can have neurological side effects such as seizures, increased intracranial pressure, and focal signs caused by the inflammatory reaction that occurs when parasites in the brain are killed. Steroids and anticonvulsants are often given with albendazole when treating neurocysticercosis to avoid these effects. Those being treated for retinal neurocysticercosis can face retinal damage if they are not first checked for ocular cysticeri, since changes to existing lesions in the eye by albendazole can cause permanent blindness. Overdose Because of its low solubility, albendazole often cannot be absorbed in high enough quantities to be toxic. The oral LD50 of albendazole in rats was found to be 2,500 mg/kg. It takes 20 times the normal dose to kill a sheep, and 30 times the normal dose to kill cattle. Overdose affects the liver, testicles, and GI tract the most. It can manifest with lethargy, loss of appetite, vomiting, diarrhea, intestinal cramps, dizziness, convulsions, and sleepiness. There is no specified antidote. Interactions The antiepileptics carbamazepine, phenytoin, and phenobarbital lower the plasma concentration and the half life of albendazole sulfoxides R(+) enantiomer. The antacid cimetidine heightens serum albendazole concentrations, increases the half life of albendazole, and doubles albendazole sulfoxide levels in bile. It was originally thought to work by increasing albendazole bioavailability directly; however, it is now known that cimetidine inhibits the breakdown of albendazole sulfoxide by interfering with CYP3A4. The half-life of albendazole sulfoxide thus increases from 7.4 hours to 19 hours. This might be a helpful interaction on more severe cases, because it boosts the potency of albendazole. Paradoxically, cimetidine also inhibits the absorption of albendazole by reducing gastric acidity.Several other interactions exist. Corticosteroids increase the steady-state plasma concentration of albendazole sulfoxide; dexamethasone, for example, can increase the concentration by 56% by inhibiting the elimination of albendazole sulfoxide. The anti-parasitic praziquantel increases the maximum plasma concentration of albendazole sulfoxide by 50%, and the anti-parasitic levamisole increases the AUC (total drug exposure) by 75%. Grapefruit inhibits the metabolism of albendazole within the intestinal mucosa. Finally, long-term administration of the antiretroviral ritonavir, which works as a CYP3A4 inhibitor, decreases the maximum concentration of albendazole in the plasma as well as the AUC. Pharmacology Mechanism of action As a vermicide, albendazole causes degenerative alterations in the intestinal cells of the worm by binding to the colchicine-sensitive site of β-tubulin, thus inhibiting its polymerization or assembly into microtubules (it binds much better to the β-tubulin of parasites than that of mammals). Albendazole leads to impaired uptake of glucose by the larval and adult stages of the susceptible parasites, and depletes their glycogen stores. Albendazole also prevents the formation of spindle fibers needed for cell division, which in turn blocks egg production and development; existing eggs are prevented from hatching. Cell motility, maintenance of cell shape, and intracellular transport are also disrupted. At higher concentrations, it disrupts the helminths metabolic pathways by inhibiting metabolic enzymes such as malate dehydrogenase and fumarate reductase, with inhibition of the latter leading to less energy produced by the Krebs cycle. Due to diminished ATP production, the parasite is immobilized and eventually dies. Some parasites have evolved some resistance to albendazole by having a different set of acids constituting β-tubulin, decreasing the binding affinity of albendazole. Some are not vulnerable to albendazole itself but instead live in symbiosis with Wolbachia. Wolbachia are necessary to the parasitic worms moulting and population reduction by albendazole prevents this and kills the adults. Pharmacokinetics Oral absorption of albendazole varies among species, with 1–5% of the drug being successfully absorbed in humans, 20–30% in rats, and 50% in cattle.The absorption also largely depends on gastric pH. People have varying gastric pHs on empty stomachs, and thus absorption from one person to another can vary wildly when taken without food. Generally, the absorption in the GI tract is poor due to albendazoles low solubility in water. It is, however, better absorbed than other benzimidazole carbamates. Food stimulates gastric acid secretion, lowering the pH and making albendazole more soluble and thus more easily absorbed. Oral absorption is especially increased with a fatty meal, as albendazole dissolves better in lipids, allowing it to cross the lipid barrier created by the mucus surface of the GI tract. To target intestinal parasites, albendazole is taken on an empty stomach to stay within the gut.Absorption is also affected by how much of the albendazole is degraded within the small intestine by metabolic enzymes in the villi. The pharmacokinetics of albendazole differ slightly between men and women: women have a lower oral clearance and volume of distribution, while men have a lower serum peak concentration.Albendazole undergoes very fast 1st-pass metabolism in all species, such that the unchanged drug is undetectable in plasma. Most of it is oxidized into albendazole sulfoxide (also known as ricobendazole and albendazole oxide) in the liver by cytochrome P450 oxidases (CYPs) and a flavin-containing monooxygenase (FMO), which was discovered later. In humans, the cytochrome P450 oxidases are thought to include CYP3A4 and CYP1A1, while those in the rats are thought to be CYP2C6 and CYP2A1.Oxidation to albendazole sulfoxide by FMO produces R(+) enantiomers, while oxidation the cytochromes and by some enzymes in the gut epithelium produce S(-). Different species produce the R(+) and S(-) enantiomers in different quantities; humans, dogs, and most other species produce the R(+) enantiomer more (with the human AUC ratio being 80:20). Compared to the S(-) enantiomer, the R(+) has greater pharmacological activity, lasts longer in the bloodstream, is found in higher concentrations in the infected host tissues, and is found in higher concentrations within the parasites themselves. Some albendazole is also converted to hydroxyalbendazole, mainly by CYP2J2.For systemic parasites, albendazole acts as a prodrug, while albendazole sulfoxide reaches systemic circulation and acts as the real antihelminthic. Albendazole sulfoxide is able to cross the blood-brain barrier and enter the cerebrospinal fluid at 43% of plasma concentrations; its ability to enter the central nervous system allows it to treat neurocystocercosis.Albendazole sulfoxide is converted to the inactive albendazole sulfone by cytochrome P450 oxidases, thought to include CYP3A4 or CYP2C. Other inactive metabolites include: 2-aminosulfone, ω-hydroxysulfone, and β-hydroxysulfone. The major final metabolites that are excreted by humans are: methyl [5-(propylsulfonyl-1H-benzimidazol-2-yl)] carbamate, methyl [6-hydroxy 5-(n-propylsulfonyl)-1H-benzimidazole-2-yl)] carbamate, methyl [5-(n-propylsulfinyl)-1H-benzimidazole-2-yl)] carbamate, 5-(n-propylsulfonyl)-1H-benzimidazole-2-yl amine, and 5-(n-propysulfinyl)-1H-benzimidazole-2-yl amine.There are also some minor hydroxylated sulfated or glucuronidated derivatives. No unchanged albendazole is excreted, as it is metabolized too quickly.In humans, the metabolites are excreted mostly in bile, with only a small amount being excreted in the urine (less than 1%) and feces. In ruminants, 60–70% of the metabolites are excreted in the urine.Like all benzimidazoles, albendazole has no residual effect, and thus protects poorly against reinfestations. History Albendazole, patented in 1975, was invented by Robert J. Gyurik and Vassilios J. Theodorides and assigned to SmithKline Corporation. It was introduced in 1977 as an antihelminthic for sheep in Australia, and was registered for human use in 1982. Society and culture Brand names Brand names include: Albenza, Alworm, Andazol, Eskazole, Noworm, Zentel, Alben-G, ABZ, Cidazole, Wormnil etc. Cost In Raleigh, North Carolina, the brand-name prescription cost was around US$800, and US$540 for the generic. The pharmaceutical company Amedra increased the price after purchasing the rights to the drug, instead of lowering it as generics are predicted to do, drawing criticism from patients rights advocates.In 2013, GlaxoSmithKline donated 763 million albendazole tablets for the treatment and prevention of parasitic infections in developing countries, bringing the total to over 4 billion tablets donated since 1998. Veterinary use Albendazole is mainly used in cattle and sheep, but has found some use in cats and dogs as well; it is also used in ratite birds for flagellate parasites and tapeworms. It is also used off-label to treat endoparasites in goats and pigs. Albendazole has been used as an anthelminthic and for control of flukes in a variety of animal species, including cattle, sheep, goats, swine, camels, dogs, cats, elephants, poultry, and others. Side effects include anorexia in dogs and lethargy, depression, and anorexia in cats, with more than 10% of dogs and cats having anorexia. Of dogs and cats, 1–10% experience elevated liver enzymes, nausea, vomiting, and diarrhea. Less than 1% experience neutropenia or aplastic anemia, though these require a use of at least 5 days. While it is also associated with bone marrow suppression and toxicity in cats and dogs at high doses, albendazole has a higher margin of safety in other species. Thus, it is usually only prescribed in cats and dogs when an infection is present that is resistant to the commonly prescribed metronidazole and fenbendazole.It is extensively used for ruminant livestock in Latin America. It is marketed for this purpose by Zoetis (formerly Pfizer Animal Health) in numerous countries (including the United States and Canada) as Valbazen in oral suspension and paste formulations; by Interchemie in the Netherlands and elsewhere as Albenol-100; by Channelle Animal Health Ltd. in the United Kingdom as Albex; and by Ravensdown in New Zealand (as Albendazole). Although most formulations are administered orally, Ricomax (ricobendazole, or albendazole sulfoxide) is administered by subcutaneous injection.Albendazole has greater bioavailability in ruminants: some albendazole sulfoxide, when released back into the rumen, is reduced to albendazole by the resident microbiota, with a preference of the (+) enantiomer being the substrate. Cats and dogs, having no rumen reservoir, sometimes need higher or more frequent doses as compared to ruminants. In dogs, albendazole sulfoxide is detectable in the plasma for less than 12 hours, but in sheep and goats, it remains at measurable levels for around three days. Meat The limitations in early pregnancy are due to a limited period during which teratogenic effects may occur. Summarized research data relating to the durations of these preslaughter and early pregnancy periods when albendazole should not be administered are found in US FDA NADA 110-048 (cattle) and 140-934 (sheep). Some data and inferences regarding goats are found in US FDA Supplemental NADA 110-048 (approved January 24, 2008). Maximum residue limits (MRLs) for albendazole in food, adopted by the FAO/WHO Codex Alimentarius in 1993, are 5000, 5000, 100, and 100 micrograms per kilogram of body weight (μg/kg) for kidney, liver, fat, and muscle, respectively, and 100 μg/L for milk. For analysis purposes, MRLs of various nations may pertain to concentration of a marker substance which has been correlated with concentrations of the administered substance and its metabolized products. For example, in Canada, the marker substance specified by Health Canada is albendazole-2-aminosulfone, for which the MRL in liver of cattle is 200 μg/kg. There is a 27 days cattle withdrawal time for meat. Research Albendazole and related compounds or metabolites like albendazole sulfone (ALB-SO2) exhibit antibacterial effects via an unknown, possibly FtsZ-related, mechanism. It inhibits division of Wolbachia and Mycobacterium tuberculosis, turning them into a long "filament" shape as they grow and fail to divide. Since Brugia malayi relies on symbiotic Wolbachia, this would mean that albendazole is targeting both the worm and its essential symbioant. See also Mebendazole Eradication of infectious disease Neglected tropical diseases References External links The Carter Center Lymphatic Filariasis Elimination Program MedicineNet article Albenza description at RxList "Albendazole". Drug Information Portal. U.S. National Library of Medicine.
Protriptyline	Protriptyline, sold under the brand name Vivactil among others, is a tricyclic antidepressant (TCA), specifically a secondary amine, indicated for the treatment of depression and attention-deficit hyperactivity disorder (ADHD). Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes used for narcolepsy to achieve a wakefulness-promoting effect. TCAs including protriptyline are also used to reduce the incidence of recurring headaches such as migraine, and for other types of chronic pain. Medical uses Protriptyline is used primarily to treat depression and to treat the combination of symptoms of anxiety and depression. Like most antidepressants of this chemical and pharmacological class, protriptyline has also been used in limited numbers of patients to treat panic disorder, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, enuresis, eating disorders such as bulimia nervosa, cocaine dependency, and the depressive phase of bipolar disorder (manic-depressive) disorder. It has also been used to support smoking cessation programs.Protriptyline is available as 5 mg and 10 mg tablets. Doses range from 15 to 40 mg per day and can be taken in one daily dose or divided into up to four doses daily. Some people with severe depression may require up to 60 mg per day.In adolescents and people over age 60, therapy should be initiated at a dose of 5 mg three times a day and increased under supervision of a physician as needed. Patients over age 60 who are taking daily doses of 20 mg or more should be closely monitored for side effects such as rapid heart rate and urinary retention.Like all TCAs, protriptyline should be used cautiously and with close physician supervision. This is especially so for persons with glaucoma, especially angle-closure glaucoma (the most severe form) or urinary retention, for men with benign prostatic hypertrophy (enlarged prostate gland), and for the elderly. Before starting treatment, people should discuss the relative risks and benefits of treatment with their doctors to help determine if protriptyline is the right antidepressant for them. Contraindications Protriptyline may increase heart rate and stress on the heart. It may be dangerous for people with cardiovascular disease, especially those who have recently had a heart attack, to take this drug or other antidepressants in the same pharmacological class. In rare cases in which patients with cardiovascular disease must take protriptyline, they should be monitored closely for cardiac rhythm disturbances and signs of cardiac stress or damage.When protriptyline is used to treat the depressive component of schizophrenia, psychotic symptoms may be aggravated. Likewise, in manic-depressive psychosis, depressed patients may experience a shift toward the manic phase if they are treated with an antidepressant drug. Paranoid delusions, with or without associated hostility, may be exaggerated. In any of these circumstances, it may be advisable to reduce the dose of protriptyline or to use an antipsychotic drug concurrently. Side effects Protriptyline shares side effects common to all TCAs. The most frequent of these are dry mouth, constipation, urinary retention, increased heart rate, sedation, irritability, decreased coordination, anxiety, blood disorders, confusion, decreased libido, dizziness, flushing, headache, impotence, insomnia, low blood pressure, nightmares, rapid or irregular heartbeat, rash, seizures, sensitivity to sunlight, stomach and intestinal problems. Other more complicated side effects include; chest pain or heavy feeling, pain spreading to the arm or shoulder, nausea, sweating, general ill feeling; sudden numbness or weakness, especially on one side of the body; sudden headache, confusion, problems with vision, speech, or balance; hallucinations, or seizure (convulsions); easy bruising or bleeding, unusual weakness; restless muscle movements in your eyes, tongue, jaw, or neck; urinating less than usual or not at all; extreme thirst with headache, nausea, vomiting, and weakness; or feeling light-headed or fainting.Dry mouth, if severe to the point of causing difficulty speaking or swallowing, may be managed by dosage reduction or temporary discontinuation of the drug. Patients may also chew sugarless gum or suck on sugarless candy in order to increase the flow of saliva. Some artificial saliva products may give temporary relief. Men with prostate enlargement who take protriptyline may be especially likely to have problems with urinary retention. Symptoms include having difficulty starting a urine flow and more difficulty than usual passing urine. In most cases, urinary retention is managed with dose reduction or by switching to another type of antidepressant. In extreme cases, patients may require treatment with bethanechol, a drug that reverses this particular side effect.A common problem with TCAs is sedation (drowsiness, lack of physical and mental alertness), but protriptyline is considered the least sedating agent among this class of agents. Its side effects are especially noticeable early in therapy. In most people, early TCA side effects decrease or disappear entirely with time, but, until then, patients taking protriptyline should take care to assess which side effects occur in them and should not perform hazardous activities requiring mental acuity or coordination. Protriptyline may increase the possibility of having seizures. Withdrawal Though not indicative of addiction, abrupt cessation of treatment after prolonged therapy may produce nausea, headache, and malaise. List of side effects Cardiovascular: Myocardial infarction; stroke; heart block; arrhythmias; hypotension, particularly orthostatic hypotension; hypertension; tachycardia; palpitation.Psychiatric: Confusional states (especially in the elderly) with hallucinations, disorientation, delusions, anxiety, restlessness, agitation; hypomania; exacerbation of psychosis; insomnia, panic, and nightmares.Neurological: Seizures; incoordination; ataxia; tremors; peripheral neuropathy; numbness, tingling, and paresthesias of extremities; extrapyramidal symptoms; drowsiness; dizziness; weakness and fatigue; headache; syndrome of inappropriate ADH (antidiuretic hormone) secretion; tinnitus; alteration in EEG patterns.Anticholinergic: Paralytic ileus; hyperpyrexia; urinary retention, delayed micturition, dilatation of the urinary tract; constipation; blurred vision, disturbance of accommodation, increased intraocular pressure, mydriasis; dry mouth and rarely associated sublingual adentitis.Allergic: Drug fever; petechiae, skin rash, urticaria, itching, photosensitization (avoid excessive exposure to sunlight); edema (general, or of face and tongue).Hematologic: Agranulocytosis; bone marrow depression; leukopenia;thrombocytopenia; purpura; eosinophilia.Gastrointestinal: Nausea and vomiting; anorexia; epigastric distress; diarrhea; peculiar taste; stomatitis; abdominal cramps; black tongue.Endocrine: Impotence, increased or decreased libido: gynecomastia in the male; breast enlargement and galactorrhea in the female; testicular swelling; elevation or depression of blood sugar levels.Other: Jaundice (simulating obstructive); altered liver function; parotid swelling; alopecia; flushing; weight gain or loss; urinary frequency, nocturia; perspiration. Overdose Deaths may occur from overdose with this class of drugs. Multiple drug ingestion (including alcohol) is common in deliberate TCA overdose. As management of overdose is complex and changing, it is recommended that the physician contact a poison control center for current information on treatment. Signs and symptoms of toxicity develop rapidly after TCA overdose, therefore, hospital monitoring is required as soon as possible.Critical manifestations of overdose include: cardiac dysrhythmias, severe hypotension, convulsions, and CNS depression, including coma. Changes in the electrocardiogram, particularly in QRS axis or width, are clinically significant indicators of TCA toxicity. Other signs of overdose may include: confusion, disturbed concentration, transient visual hallucinations, dilated pupils, agitation, hyperactive reflexes, stupor, drowsiness, muscle rigidity, vomiting, hypothermia, hyperpyrexia. Interactions The side effects of protriptyline are increased when it is taken with central nervous system depressants, such as alcoholic beverages, sleeping medications, other sedatives, or antihistamines, as well as with other antidepressants including SSRIs, SNRIs or monoamine oxidase inhibitors. It may be dangerous to take protriptyline in combination with these substances. Pharmacology Pharmacodynamics Protriptyline acts by decreasing the reuptake of norepinephrine and to a lesser extent serotonin (5-HT) in the brain. Its affinity for the human norepinephrine transporter (NET) is 1.41 nM, 19.6 nM for the serotonin transporter and 2,100 nM for the dopamine transporter. TCAs act to change the balance of naturally occurring chemicals in the brain that regulate the transmission of nerve impulses between cells. Protriptyline increases the concentration of norepinephrine and serotonin (both chemicals that stimulate nerve cells) and, to a lesser extent, blocks the action of another brain chemical, acetylcholine. The therapeutic effects of protriptyline, like other antidepressants, appear slowly. Maximum benefit is often not evident for at least two weeks after starting the drug.Protriptyline is a TCA. It was thought that TCAs work by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin by neurons. However, this response occurs immediately, yet mood does not lift for around two weeks. It is now thought that changes occur in receptor sensitivity in the cerebral cortex and hippocampus. The hippocampus is part of the limbic system, a part of the brain involved in emotions. TCAs are also known as effective analgesics for different types of pain, especially neuropathic or neuralgic pain. A precise mechanism for their analgesic action is unknown, but it is thought that they modulate anti-pain opioid systems in the central nervous system via an indirect serotonergic route. TCAs are also effective in migraine prophylaxis, but not in abortion of acute migraine attack. The mechanism of their anti-migraine action is also thought to be serotonergic, similar to psilocybin. Pharmacokinetics Metabolic studies indicate that protriptyline is well absorbed from the gastrointestinal tract and is rapidly sequestered in tissues. Relatively low plasma levels are found after administration, and only a small amount of unchanged drug is excreted in the urine of dogs and rabbits. Preliminary studies indicate that demethylation of the secondary amine moiety occurs to a significant extent, and that metabolic transformation takes place in the liver. It penetrates the brain rapidly in mice and rats, and moreover that which is present in the brain is almost all unchanged drug. Studies on the disposition of radioactive protriptyline in human test subjects showed significant plasma levels within 2 hours, peaking at 8 to 12 hours, then declining gradually.Urinary excretion studies in the same subjects showed significant amounts of radioactivity in 2 hours. The rate of excretion was slow. Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.Protriptyline has uniquely low dosing among TCAs, likely due to its exceptionally long terminal half-life. It is used in dosages of 15 to 40 mg/day, whereas most other TCAs are used at dosages of 75 to 300 mg/day. The maximum dose is 60 mg/day. Therapeutic levels of protriptyline are typically in the range of 70 to 250 ng/mL (266-950 nmol/L), which is similar to that of other TCAs Chemistry Protriptyline is a tricyclic compound, specifically a dibenzocycloheptadiene, and possesses three rings fused together with a side chain attached in its chemical structure. Other dibenzocycloheptadiene TCAs include amitriptyline, nortriptyline, and butriptyline. Protriptyline is a secondary amine TCA, with its N-methylated relative amitriptyline being a tertiary amine. Other secondary amine TCAs include desipramine and nortriptyline. The chemical name of protriptyline is 3-(5H-dibenzo[a,d][7]annulen-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C19H21N1 with a molecular weight of 263.377 g/mol. The drug is used commercially mostly as the hydrochloride salt; the free base form is not used. The CAS Registry Number of the free base is 438-60-8 and of the hydrochloride is 1225-55-4. History Protriptyline was developed by Merck. It was patented in 1962 and first appeared in the literature in 1964. The drug was first introduced for the treatment of depression in 1966. Society and culture Generic names Protriptyline is the English and French generic name of the drug and its INN, BAN, and DCF, while protriptyline hydrochloride is its USAN, USP, and BANM. Its generic name in Spanish and Italian and its DCIT are protriptylina, in German is protriptylin, and in Latin is protriptylinum. Brand names Protriptyline is or has been marketed throughout the world under a variety of brand names including Anelun, Concordin, Maximed, Triptil, and Vivactil. Availability The sale of protriptyline was discontinued in the United Kingdom, Australia, and Ireland in 2000. == References ==
Roflumilast	Roflumilast, sold under the trade name Daxas among others, is a drug that acts as a selective, long-acting inhibitor of the enzyme phosphodiesterase-4 (PDE-4). It has anti-inflammatory effects and is used as an orally administered drug for the treatment of inflammatory conditions of the lungs such as chronic obstructive pulmonary disease (COPD).In June 2010, it was approved in the European Union for severe COPD associated with chronic bronchitis. In February 2011, it gained FDA approval in the United States for reducing COPD exacerbations. Medical uses Roflumilast is indicated for the treatment of severe chronic obstructive pulmonary disease (COPD) and for the treatment of plaque psoriasis.It is used in the prevention of exacerbations (lung attacks) in severe chronic obstructive pulmonary disease (COPD).A topical formulation of Rolflumilast was recently approved by the U.S. Food and Drug Administration for plaque psoriasis. Adverse effects Common (1–10% incidence) adverse effects include: Diarrhea Weight loss Nausea Headache Insomnia Decreased appetite Abdominal pain Rhinitis Sinusitis Urinary tract infection Depression References External links "Roflumilast". Drug Information Portal. U.S. National Library of Medicine.
Macrogol	Macrogol, also known as polyethylene glycol (PEG), is used as a medication to treat constipation in children and adults. It is also used to empty the bowels before a colonoscopy. It is taken by mouth. Benefits usually occur within three days. Generally it is only recommended for up to two weeks. It is also used as an excipient.Side effects may include increased bowel gas, abdominal pain, and nausea. Rare but serious side effects may include an abnormal heartbeat, seizures, and kidney problems. Use appears to be safe during pregnancy. It is classified as an osmotic laxative. It works by increasing the amount of water in the stool.Macrogol came into use as a bowel prep in 1980 and was approved for medical use in the United States in 1999. It is available as a generic medication and over the counter. In 2018, it was the 163rd most commonly prescribed medication in the United States, with more than 3 million prescriptions. Typically it is formulated together with electrolytes. Medical uses Constipation Macrogol 3350, often in combination with electrolytes, is used for short-term relief of constipation as well as for long-term use in constipation of various causes, including in multiple sclerosis and Parkinsons disease patients (an often-overlooked non-motor symptom) as well as constipation caused by pharmaceutical drugs such as opioids and anticholinergics. Whole bowel irrigation with macrogol is part of the bowel preparation before surgery or colonoscopy. Limited data also support its use for the treatment of fecal impaction.In those with chronic constipation it works better than lactulose.A 2007 comparison showed that people with constipation had a better response to macrogol than to tegaserod. Popular types include: macrogol 3350, macrogol 4000, and macrogol 6000. The number represents the average molecular mass. Combining different molecular masses provides some control over the consistency. Excipient Macrogol is used as an excipient in pharmaceutical products. Lower-molecular-weight variants are used as solvents in oral liquids and soft capsules, whereas solid variants are used as ointment bases, tablet binders, film coatings, and lubricants.For example, PEG-2000 is one of the excipients in the Moderna COVID-19 vaccine. PEGylation Macrogols are also attached to biopharmaceutical drugs to slow down their degradation in the human body and increase their duration of action, as well as to reduce immunogenicity. This process is called PEGylation. Contraindications Contraindications for macrogol taken orally as a laxative are intestinal perforation, bowel obstruction, ileus, inflammatory bowel diseases, and toxic megacolon.The doses of macrogol as an excipient are too low to have relevant contraindications.Allergy to macrogol is rare, and usually appears as an allergy to an increasing number of seemingly unrelated products, including cosmetics, drugs that use it as an excipient, and peri-procedural substances such as ultrasound gel. Adverse effects Oral macrogol is generally well tolerated. Possible side effects include headache, bloating, nausea, allergies, and electrolyte imbalance, mainly hypokalaemia (low blood potassium levels) and hyperkalaemia (high blood potassium levels). Hyperkalaemia is not an effect of macrogol itself but of potassium salts which are usually part of macrogol formulations. With excessive use, it can cause diarrhea. Interactions The interaction potential is low. Resorption of other pharmaceutical drugs can be reduced because oral macrogol accelerates intestinal passage, but this is seldom clinically relevant. For antiepileptic drugs, such a mechanism has been described in rare cases. Pharmacology Mechanism of action as a laxative Macrogol is an osmotically acting laxative; that is, an inert substance that passes through the gut without being absorbed into the body. It relieves constipation because it causes water to be retained in the bowel instead of being absorbed into the body. This increases the water content and volume of the stools in the bowel, making them softer and easier to pass, as well as improving gut motility. Chemistry Available forms Macrogol is sold as a non-prescription preparation in the form of powder. When sold for gut cleansing (and as a laxative), it is usually in combination with salts such as sodium bicarbonate, sodium chloride and potassium chloride to help mitigate the possibility of electrolyte imbalance and dehydration. Brand names include SoftLax, Purelax, MiraLax, Laxido, Glycoprep, CosmoCol, Movicol, Cololyt, Osmolax, and others.It is dissolved in water to create a clear and odorless solution which is then drunk. While most consumers find the taste of macrogol itself to be very mild and unobjectionable, the electrolytes contained in formulations for purging and cleansing give the solution an extremely salty and bitter taste.Polyethylene glycol-electrolyte solution is a prescription product sold under various brand names including Colyte, Gavilyte, Golytely, Nulytely, Moviprep, and Trilyte. Research PEGylation When attached to various biopharmaceutical medications (which are proteins), macrogol results in a slowed clearance of the carried protein from the blood. This makes for a longer-acting medicinal effect and reduces toxicity, and it allows for longer dosing intervals. It also reduces the proteins immunogenicity. Examples for PEGylated proteins include peginterferon alfa-2a and -2b, which are used to treat hepatitis C, pegfilgrastim, which is used to treat neutropenia, and pegloticase for the treatment of gout. Nerves and spinal cords There is evidence demonstrating PEG-induced repair of specific nerve cells in animal models: It has been shown that macrogol can improve healing of spinal injuries in dogs. One of the earlier findings is that macrogol can aid in nerve repair in earthworms. The subcutaneous injection of macrogol 2000 in guinea pigs after spinal cord injury leads to rapid recovery through molecular repair of nerve membranes. The effectiveness of this treatment to prevent paraplegia in humans after an accident is not known yet. Macrogol is being used in the repair of motor neurons damaged in crush or laceration incidents in vivo and in vitro. When coupled with melatonin, 75% of damaged sciatic nerves were rendered viable. Cancer prevention High-molecular-weight macrogol (e.g., 8000 g/mol) has been shown to be a dietary preventive agent against colorectal cancer in animal models. The Chemoprevention Database shows macrogol is the most effective known agent for the suppression of chemical carcinogenesis in rats. Cancer prevention applications in humans, however, have not yet been tested in clinical trials. Other Macrogol is also used to fuse B-cells with myeloma cells in monoclonal antibody production. References External links "Macrogol". Drug Information Portal. U.S. National Library of Medicine.
Gelesis100	Gelesis100, sold under the brand name Plenity, is an oral hydrogel used to treat overweight and obesity. It absorbs water and expands in the stomach and small bowel thereby increasing feelings of fullness. Possible side effects include primarily gastrointestinal symptoms, such as diarrhea, abdominal distention, infrequent bowel movements, constipation, abdominal pain, and flatulence. It is contraindicated in pregnancy, chronic malabsorption syndromes, and cholestasis. The US Food and Drug Administration approved it in 2019 as a medical device. Gelesis100 was developed by the company Gelesis. History The US Food and Drug Administration approved the use of Gelesis100 in April 2019 as a medical device. Gelesis100 is the first treatment of its kind for overweight and obesity. Uses Gelesis100 is used to treat obesity and overweight. Gelesis100 is taken as a pill before meals and with water. Mechanism and physiology Gelesis100 is an oral superabsorbent hydrogel, which is produced from carboxymethylcellulose and citric acid. The cross-linked product forms a hydrophilic matrix, which absorbs water. Taken in capsule form by mouth, as Gelesis100 absorbs water, it expands in the stomach and small intestine. After absorbing water, a semisolid gel structure forms, which may promote satiety and result in weight loss. Contraindications Gelesis100 is contraindicated in pregnancy, chronic malabsorption syndromes, and cholestasis. Side effects Side effects consist of minor gastrointestinal symptoms, including diarrhea, abdominal distention, infrequent bowel movements, constipation, abdominal pain, and flatulence. Gelesis100 is not associated with any severe adverse events. However, long-term safety data beyond 24 weeks is not available. References External links Official website
Edaravone	Edaravone, sold under the brand name Radicava among others, is a medication used to treat stroke and amyotrophic lateral sclerosis (ALS). It is given by intravenous infusion and by mouth.The most common side effects include bruising (contusions), problems walking (gait disturbances), and headaches.The mechanism by which edaravone might be effective is unknown. The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Edaravone is used to help people recover from stroke in Japan, and is used to treat ALS in the US and Japan. Adverse effects The label carries a warning about the potential for hypersensitivity reactions to edaravone, and adverse effects include bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.The following adverse effects in at least 2% more people given the medication than were given placebo: bruising, gait disturbances, headache, skin inflammation, eczema, problems breathing, excess sugar in urine, and fungal skin infections.There is no data on whether it is safe for pregnant women to take, and it is unknown if edaravone is secreted in breast milk. Pharmacology The mechanism by which edaravone might be effective in ALS is unknown. The medication is known to be an antioxidant, and oxidative stress has been hypothesized to be part of the process that kills neurons in people with ALS.The half-life of edaravone is 4.5 to 6 hours and the half-lives of its metabolites are 2 to 3 hours. It is metabolized to a sulfate conjugate and a glucuronide conjugate, neither of which are active. It is primarily excreted in urine as the glucuronide conjugate form. History Researchers first developed the free radical scavenger edaravone in late 1980s as a treatment for stroke. The approach, introduced by Koji Abe, now at Okayama University Hospital in Japan, aimed to prevent the swelling of the brain which may occur after a stroke.It has been marketed in Japan by Mitsubishi Pharma for stroke since 2001 and is now generic.Mitsubishi Tanabe started a phase III clinical trial in ALS in 2011, in Japan, and by June 2015, it had been approved for that use in Japan. The company had received Orphan Drug Designation for edaravone from the FDA and EU by 2016.It was approved for ALS in the US in 2017, based on a small randomized controlled clinical trial with people who had early-stage ALS in Japan, who were administered the medication for 6 months; it had failed two earlier trials in people with all stages of ALS.In May 2017, I.V. edaravone was approved by the FDA to treat people with amyotrophic lateral sclerosis (ALS) in the United States. The FDA approval was conditioned on Mitsubishi Tanabe completing several additional studies to clarify the risks of cancer and liver disease, among other effects of the medication.Formulation of edaravone by mouth called TW001 (mixture of the edaravone and SBE-HP-βCD ) has been under development by Treeway for ALS; as of 2015, it had successfully completed Phase I trial and had received orphan status in the US and in the European Union.An oral formulation of edaravone was approved for medical use in the United States in May 2022. The effectiveness of oral edaravone is based on a study that showed comparable levels of oral edaravone in the bloodstream to the levels from the IV formulation of edaravone. The efficacy of edaravone for the treatment of ALS was previously demonstrated in a six-month clinical trial that served as the basis for approval in 2017. In that trial, 137 participants were randomized to receive edaravone or placebo. At week 24, individuals receiving edaravone declined less on a clinical assessment of daily functioning compared to those receiving placebo. Society and culture Economics The price for the medication when it launched in Japan for stroke in 2001, was set by the Japanese government at 9,931 yen/ampule.When the medication launched in Japan for ALS in 2001, the price was $35,000; the price in Japan in 2017 was $5,000, the US price at launch was around $145,000. In the US the medication was approved for all people with ALS but it was unclear at approval whether insurers would agree to pay for the medication for all people with ALS, or only people in the early stages of the disease. There are three filed trials for edaravone, demonstrating it may work in less than 5% of all ALS population. Brand names Brand names include Radicut, ラジカット, Radicava, Xavron. References Further reading Yoshino H (March 2019). "Edaravone for the treatment of amyotrophic lateral sclerosis". Expert Rev Neurother. 19 (3): 185–193. doi:10.1080/14737175.2019.1581610. PMID 30810406. S2CID 73490631. Canadian Agency for Drugs and Technologies in Health (April 2019). Pharmacoeconomic Review Report: Edaravone (Radicava): (Mitsubishi Tanabe Pharma Corporation). CADTH Common Drug Reviews. PMID 31211530. NBK542526. External links "Edaravone". Drug Information Portal. U.S. National Library of Medicine.
Crotalidae polyvalent immune fab	Crotalidae polyvalent immune fab, sold under the brandname CroFab, is a snake antivenin, indicated for minimal or moderate North American Crotalid (Rattlesnake, Copperhead and Cottonmouth/Water moccasin) snake envenomation. CroFab is composed of several monovalent Fragment antigen-binding proteins (Fab) derived from the blood of sheep immunized with one of four snake venom: Crotalus atrox (western diamondback rattlesnake), Crotalus adamanteus (Eastern diamondback rattlesnake), Crotalus scutulatus (Mojave rattlesnake), or Agkistrodon piscivorus (Cottonmouth or Water Moccasin). Each monospecific antivenin is purified from sheep serum, digested with the enzyme papain, and purified further resulting in specific Fab fragments. The resulting four different Fab preparations are mixed to formulate the final product. Background It was developed by the Venom Immunochemistry, Pharmacology and Emergency Response (VIPER) Institute, University of Arizona, and commercialized by BTG plc (formerly Protherics PLC). As reported in the Washington Post in July 2015, this was the only commercially available antivenin in the United States for the treatment of venomous snakebites until the release of a competing product, ANAVIP. Treatment Crotalid snakebites can range from mild to life-threatening, depending on the size and type of snake, the amount of venom injected and the location of the bite. This in turn determines the number of vials of CroFab that are required by the patient. Untreated, the snake venom can cause severe pain and tissue damage that can result in the loss of a limb or even death. Prompt (within six hours of snake bite) treatment with CroFab is recommended. Fab refers to Fragment Antigen-Binding, the active mechanism for this antivenom. Adverse events The most common adverse events reported in clinical studies were mild or moderate reactions involving the skin and appendages (primarily urticaria, rash, or pruritus), which occurred in 14 out of 42 patients. Three patients experienced a serious adverse event. Two patients had a severe allergic reaction (severe hives and a severe rash and pruritus) following treatment. One patient had a recurrent coagulopathy due to envenomation, which required re-hospitalisation and additional antivenin administration. In clinical trials, recurrent coagulopathy (the return of a coagulation abnormality after it has been successfully treated with antivenin), characterised by decreased fibrinogen, decreased platelets and elevated prothrombin time, occurred in approximately half of the patients studied. Recurrent coagulopathy may persist for one to two weeks or more. One patient discontinued CroFab therapy due to an allergic reaction. Patients with allergies to papain, chymopapain, other papaya extracts or the pineapple enzyme bromelain may also be at risk for an allergic reaction to CroFab. Cost Leslie Boyer, Director of the VIPER Institute, who was on the team that developed CroFab, said they were "crestfallen" to discover that the wholesale price of Anascorp, their latest antivenom, was too high to be cost effective, even in the treatment of critically ill children. The industry website Fierce Pharma called the product a “drug launch disaster” and “one of the most bizarre marketing tales in the industry.” Boyer said that CroFab, a US drug whose sister product retailed in Mexico at $100, was resulting in bills to Arizona patients of between $7,900 and $39,652 per vial. One person rejected treatment and died because he couldnt afford to pay for it. Boyer collected data on the cost of production and marketing, and found that the largest true cost to payers, $4100/vial, was that of the legal, regulatory and hospital activities involved in selling the drug. Clinical trials contributed $300/vial, and 25% of that had been paid for by government grants. Other costs were the same as in Mexico. References External links RxList: Crotalidae Polyvalent Immune Fab (Ovine)
Vasopressin	Human vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized from the AVP gene as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon terminating in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.A third function is possible. Some AVP may be released directly into the brain from the hypothalamus, and may play an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress.Vasopressin induces differentiation of stem cells into cardiomyocytes and promotes heart muscle homeostasis.It has a very short half-life, between 16 and 24 minutes. Physiology Function Vasopressin regulates the tonicity of body fluids. It is released from the posterior pituitary in response to hypertonicity and causes the kidneys to reabsorb solute-free water and return it to the circulation from the tubules of the nephron, thus returning the tonicity of the body fluids toward normal. An incidental consequence of this renal reabsorption of water is concentrated urine and reduced urine volume. AVP released in high concentrations may also raise blood pressure by inducing moderate vasoconstriction. AVP also may have a variety of neurological effects on the brain. It may influence pair-bonding in voles. The high-density distributions of vasopressin receptor AVPr1a in prairie vole ventral forebrain regions have been shown to facilitate and coordinate reward circuits during partner preference formation, critical for pair bond formation.A very similar substance, lysine vasopressin (LVP) or lypressin, has the same function in pigs and its synthetic version was used in human AVP deficiency, although it has been largely replaced by desmopressin. Kidney Vasopressin has three main effects which are: Increasing the water permeability of distal and cortical collecting tubules (DCT & CCT), as well as outer and inner medullary collecting duct (OMCD & IMCD) in the kidney, thus allowing water reabsorption and excretion of more concentrated urine, i.e., antidiuresis. This occurs through increased transcription and insertion of water channels (Aquaporin-2) into the apical membrane of collecting tubule and collecting duct epithelial cells. Aquaporins allow water to move down their osmotic gradient and out of the nephron, increasing the amount of water re-absorbed from the filtrate (forming urine) back into the bloodstream. This effect is mediated by V2 receptors. Vasopressin also increases the concentration of calcium in the collecting duct cells, by episodic release from intracellular stores. Vasopressin, acting through cAMP, also increases transcription of the aquaporin-2 gene, thus increasing the total number of aquaporin-2 molecules in collecting duct cells. Increasing permeability of the inner medullary portion of the collecting duct to urea by regulating the cell surface expression of urea transporters, which facilitates its reabsorption into the medullary interstitium as it travels down the concentration gradient created by removing water from the connecting tubule, cortical collecting duct, and outer medullary collecting duct. Acute increase of sodium absorption across the ascending loop of Henle. This adds to the countercurrent multiplication which aids in proper water reabsorption later in the distal tubule and collecting duct. Central nervous system Vasopressin released within the brain may have several actions: Vasopressin is released into the brain in a circadian rhythm by neurons of the suprachiasmatic nucleus. Vasopressin released from posterior pituitary is associated with nausea. Recent evidence suggests that vasopressin may have analgesic effects. The analgesia effects of vasopressin were found to be dependent on both stress and sex. Regulation Gene regulation Vasopressin is regulated by AVP gene expression which is managed by major clock controlled genes. In this circadian circuit known as the transcription-translation feedback loop (TTFL), Per2 protein accumulates and is phosphorylated by CK1E. Per2 subsequently inhibits the transcription factors Clock and BMAL1 in order to reduce Per2 protein levels in the cell. At the same time, Per2 also inhibits the transcription factors for the AVP gene in order to regulate its expression, the expression of vasopressin, and other AVP gene products.Many factors influence the secretion of vasopressin: Ethanol (alcohol) reduces the calcium-dependent secretion of AVP by blocking voltage-gated calcium channels in neurohypophyseal nerve terminals in rats. Angiotensin II stimulates AVP secretion, in keeping with its general pressor and pro-volumic effects on the body. Atrial natriuretic peptide inhibits AVP secretion, in part by inhibiting Angiotensin II-induced stimulation of AVP secretion. Cortisol inhibits secretion of antidiuretic hormone. Production and secretion The physiologic stimulus for secretion of vasopressin is increased osmolality of the plasma, monitored by the hypothalamus. A decreased arterial blood volume, (such as can occur in cirrhosis, nephrosis and heart failure), stimulates secretion, even in the face of decreased osmolality of the plasma: it supersedes osmolality, but with a milder effect. In other words, vasopressin is secreted in spite of the presence of hypoosmolality (hyponatremia) when the arterial blood volume is low. The AVP that is measured in peripheral blood is almost all derived from secretion from the posterior pituitary gland (except in cases of AVP-secreting tumours). Vasopressin is produced by magnocellular neurosecretory neurons in the paraventricular nucleus of hypothalamus (PVN) and supraoptic nucleus (SON). It then travels down the axon through the infundibulum within neurosecretory granules that are found within Herring bodies, localized swellings of the axons and nerve terminals. These carry the peptide directly to the posterior pituitary gland, where it is stored until released into the blood. There are other sources of AVP, beyond the hypothalamic magnocellular neurons. For example, AVP is also synthesized by parvocellular neurosecretory neurons of the PVN, transported and released at the median eminence, from which it travels through the hypophyseal portal system to the anterior pituitary, where it stimulates corticotropic cells synergistically with CRH to produce ACTH (by itself it is a weak secretagogue). Vasopressin during surgery and anaesthesia Vasopressin concentration is used to measure surgical stress for evaluation of surgical techniques. Plasma vasopressin concentration is elevated by noxious stimuli, predominantly during abdominal surgery, especially at gut manipulation and traction of viscera. Receptors Types of AVP receptors and their actions: Structure and relation to oxytocin The vasopressins are peptides consisting of nine amino acids (nonapeptides). The amino acid sequence of arginine vasopressin (argipressin) is Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly-NH2, with the cysteine residues forming a disulfide bond and the C-terminus of the sequence converted to a primary amide. Lysine vasopressin (lypressin) has a lysine in place of the arginine as the eighth amino acid, and is found in pigs and some related animals, whereas arginine vasopressin is found in humans.The structure of oxytocin is very similar to that of the vasopressins: It is also a nonapeptide with a disulfide bridge and its amino acid sequence differs at only two positions. The two genes are located on the same chromosome separated by a relatively small distance of less than 15,000 bases in most species. The magnocellular neurons that secrete vasopressin are adjacent to magnocellular neurons that secrete oxytocin, and are similar in many respects. The similarity of the two peptides can cause some cross-reactions: oxytocin has a slight antidiuretic function, and high levels of AVP can cause uterine contractions.Comparison of vasopressin and oxytocin neuropeptide families: Medical use Vasopressin is used to manage anti-diuretic hormone deficiency. Vasopressin is used to treat diabetes insipidus related to low levels of antidiuretic hormone. It is available as Pressyn.Vasopressin has off-label uses and is used in the treatment of vasodilatory shock, gastrointestinal bleeding, ventricular tachycardia and ventricular fibrillation. Vasopressin agonists are used therapeutically in various conditions, and its long-acting synthetic analogue desmopressin is used in conditions featuring low vasopressin secretion, as well as for control of bleeding (in some forms of von Willebrand disease and in mild haemophilia A) and in extreme cases of bedwetting by children. Terlipressin and related analogues are used as vasoconstrictors in certain conditions. Use of vasopressin analogues for esophageal varices commenced in 1970.Vasopressin infusions are also used as second line therapy for septic shock patients not responding to fluid resuscitation or infusions of catecholamines (e.g., dopamine or norepinephrine) to increase the blood pressure while sparing the use of catecholamines. These argipressins have much shorter elimination half-life (around 20 minutes) comparing to synthetic non-arginine vasopresines with much longer elimination half-life of many hours. Further, argipressins act on V1a, V1b, and V2 receptors which consequently lead to higher eGFR and lower vascular resistance in the lungs. A number of injectable arginine vasopressins are currently in clinical use in the United States and in Europe. Pharmacokinetics Vasopressin is administered through an intravenous device, intramuscular injection or a subcutaneous injection. The duration of action depends on the mode of administration and ranges from thirty minutes to two hours. It has a half life of ten to twenty minutes. It is widely distributed throughout the body and remains in the extracellular fluid. It is degraded by the liver and excreted through the kidneys. Arginin vasopressins for use in septic shock are intended for intravenous use only. Side effects The most common side effects during treatment with vasopressin are dizziness, angina, chest pain, abdominal cramps, heartburn, nausea, vomiting, trembling, fever, water intoxication, pounding sensation in the head, diarrhoea, sweating, paleness, and flatulence. The most severe adverse reactions are myocardial infarction and hypersensitivity. Contraindications The use of lysine vasopressin is contraindicated in the presence of hypersensitivity to beef or pork proteins, increased BUN and chronic kidney failure. It is recommended that it be cautiously used in instances of perioperative polyuria, sensitivity to the drug, asthma, seizures, heart failure, a comatose state, migraine headaches, and cardiovascular disease. Interactions alcohol - may lower the antidiuretic effect carbamazepine, chloropropamide, clofibrate, tricyclic antidepressants and fludrocortisone may raise the diuretic effect lithium, demeclocycline, heparin or norepinephrine may lower the antidiuretic effect vasopressor effect may be higher with the concurrent use of ganglionic blocking medications Deficiency Decreased AVP release (neurogenic — i.e. due to alcohol intoxication or tumour) or decreased renal sensitivity to AVP (nephrogenic, i.e. by mutation of V2 receptor or AQP) leads to diabetes insipidus, a condition featuring hypernatremia (increased blood sodium concentration), polyuria (excess urine production), and polydipsia (thirst). Excess Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) in turn can be caused by a number of problems. Some forms of cancer can cause SIADH, particularly small cell lung carcinoma but also a number of other tumors. A variety of diseases affecting the brain or the lung (infections, bleeding) can be the driver behind SIADH. A number of drugs have been associated with SIADH, such as certain antidepressants (serotonin reuptake inhibitors and tricyclic antidepressants), the anticonvulsant carbamazepine, oxytocin (used to induce and stimulate labor), and the chemotherapy drug vincristine. It has also been associated with fluoroquinolones (including ciprofloxacin and moxifloxacin). Finally, it can occur without a clear explanation. Hyponatremia can be treated pharmaceutically through the use of vasopressin receptor antagonists. History Vasopressin was elucidated and synthesized for the first time by Vincent du Vigneaud. Animal studies Evidence for an effect of AVP on monogamy vs polygamy comes from experimental studies in several species, which indicate that the precise distribution of vasopressin and vasopressin receptors in the brain is associated with species-typical patterns of social behavior. In particular, there are consistent differences between monogamous species and polygamous species in the distribution of AVP receptors, and sometimes in the distribution of vasopressin-containing axons, even when closely related species are compared. Human studies Vasopressin has shown nootropic effects on pain perception and cognitive function. Vasopressin also plays a role in autism, major depressive disorder, bipolar disorder, and schizophrenia. See also Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH) Oxytocin Vasopressin receptor Vasopressin receptor antagonists Copeptin Anterior Pituitary Hypothalamus References == Further reading ==
Tralokinumab	Tralokinumab sold under the brand names Adtralza (EU/UK) and Adbry (US) among others, is a human monoclonal antibody used for the treatment of atopic dermatitis. Tralokinumab targets the cytokine interleukin 13.The most common side effects include upper respiratory tract infections (colds and other infections of the nose and throat), reactions at the injection site, and redness and discomfort in the eye.Tralokinumab was approved for medical use in the European Union and in the United Kingdom in June 2021. It was approved for medical use in the United States in December 2021. Medical uses Tralokinumab is indicated for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy.In the United States, tralokinumab is indicated for the treatment of moderate-to-severe atopic dermatitis in adults whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable. Discovery and development Tralokinumab was discovered by Cambridge Antibody Technology scientists using protein optimization based on Ribosome Display. They used the extensive data sets from ribosome display to patent protect CAT-354 in a world-first of sequence-activity-relationship claims. In 2004, clinical development of CAT-354 was initiated with this first study completing in 2005. On 21 July 2011, MedImmune LLC initiated a Phase IIb, randomized, double-blind study to evaluate the efficacy of tralokinumab in adults with asthma.In 2016, MedImmune and AstraZeneca started developing tralokinumab for asthma (Phase III) and atopic dermatitis (Phase IIb) while clinical development for moderate-to-severe ulcerative colitis and idiopathic pulmonary fibrosis (IPF) have been discontinued. In July of that year AstraZeneca licensed tralokinumab to Leo Pharma for skin diseases.A phase IIb study of tralokinumab found that treatment was associated with early and sustained improvements in atopic dermatitis symptoms and tralokinumab had an acceptable safety and tolerability profile, thereby providing evidence for targeting IL-13 in patients with atopic dermatitis.On 15 June 2017, Leo Pharma announced that they were starting phase III clinical trials with tralokinumab in atopic dermatitis. Society and culture Legal status On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Adtralza, intended for the treatment of moderate‑to‑severe atopic dermatitis. The applicant for this medicinal product is LEO Pharma A/S. Tralokinumab was approved for medical use in the European Union in June 2021. Names Tralokinumab is the international nonproprietary name (INN) and the United States Adopted Name (USAN). References External links "Tralokinumab". Drug Information Portal. U.S. National Library of Medicine.
Pralidoxime	Pralidoxime (2-pyridine aldoxime methyl chloride) or 2-PAM, usually as the chloride or iodide salts, belongs to a family of compounds called oximes that bind to organophosphate-inactivated acetylcholinesterase. It is used to treat organophosphate poisoning in conjunction with atropine and either diazepam or midazolam. It is a white solid. Chemical synthesis Pralidoxime, 2-pyridinaldoxime methylchloride, is prepared by treating pyridine-2-carboxaldehyde with hydroxylamine. The resulting pyridine-2-aldoxime is alkylated with methyl iodide giving pralidoxime as the iodide salt. Mechanism of action Pralidoxime is typically used in cases of organophosphate poisoning. Organophosphates such as sarin bind to the hydroxy component (the esteric site) of the active site of the acetylcholinesterase enzyme, thereby blocking its activity. Pralidoxime binds to the other half (the unblocked, anionic site) of the active site and then displaces the phosphate from the serine residue. The conjoined poison / antidote then unbinds from the site, and thus regenerates the fully functional enzyme. Some phosphate-acetylcholinesterase conjugates continue to react after the phosphate docks to the esteric site, evolving into a more recalcitrant state. This process is known as aging. Aged phosphate-acetylcholinesterase conjugate are resistant to antidotes such as pralidoxime. Pralidoxime is often used with atropine (a muscarinic antagonist) to help reduce the parasympathetic effects of organophosphate poisoning. Pralidoxime is only effective in organophosphate toxicity. It has no beneficial effects if the acetylcholinesterase enzyme is carbamylated, as occurs with neostigmine, pyridostigmine, or insecticides such as carbaryl. Pralidoxime has an important role in reversing paralysis of the respiratory muscles but due to its poor blood–brain barrier penetration, it has little effect on centrally-mediated respiratory depression. Atropine, which is choice of drug to antagonise the muscarinic effects of organophosphates, is administered even before pralidoxime during the treatment of organophosphate poisoning. While the efficacy of atropine has been well-established, clinical experience with pralidoxime has led to widespread doubt about its efficacy in treatment of organophosphorus poisoning. Dosage Adults: 30 mg/kg (typically 1–2 g), administered by intravenous therapy over 15–30 minutes, repeated 60 minutes later. It can also be given as a 500 mg/h continuous IV infusion. Children: 20–50 mg/kg followed by a maintenance infusion at 5–10 mg/kg/h.Intravenous infusions can lead to respiratory or cardiac arrest if given too quickly. Interactions When atropine and pralidoxime are used together, the signs of atropinization (flushing, mydriasis, tachycardia, dryness of the mouth and nose) may occur earlier than might be expected when atropine is used alone. This is especially true if the total dose of atropine has been large and the administration of pralidoxime has been delayed. The following precautions should be kept in mind in the treatment of anticholinesterase poisoning, although they do not bear directly on the use of pralidoxime: since barbiturates are potentiated by the anticholinesterases, they should be used cautiously in the treatment of convulsions; morphine, theophylline, aminophylline, succinylcholine, reserpine, and phenothiazine-type tranquilizers should be avoided in patients with organophosphate poisoning. Contraindications There are no known absolute contraindications for the use of pralidoxime. Relative contraindications include known hypersensitivity to the drug and other situations in which the risk of its use clearly outweighs possible benefit. See also Pyridostigmine Mark I NAAK Galantamine References External links Drugs.com
Progesterone vaginal ring	Progesterone vaginal ring, also known as progesterone-only vaginal ring, is a form of vaginal ring used for birth control when breastfeeding. Use can begin at four weeks and continue for at least up to a year following childbirth. Failure rates with usual use is about 1.5 per 100 women. It is used within the vagina with one ring lasting three months. The woman is able to place and remove the ring herself. It is sold under the brand names Progering among others.Side effects include vaginal discharge and pain with urination. It does not appear to be associated with serious side effects. With use menstrual periods often do not resume. It was specifically made for use with breastfeeding as it does not affect milk production. It works by gradually releasing the hormone progesterone.Progesterone vaginal rings have been approved for medical use since 1998. It is on the World Health Organizations List of Essential Medicines. As of 2014, they are available in a number of South and Central American countries. As of 2016, it is not available in the United States. It was developed by the Population Council. See also Pharmacokinetics of progesterone § Vaginal administration == References ==
Spironolactone	Spironolactone, sold under the brand name Aldactone among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of transgender hormone therapy in transfeminine people. Spironolactone is taken by mouth.Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects. Spironolactone belongs to a class of medications known as potassium-sparing diuretics.Spironolactone was discovered in 1957, and was introduced in 1959. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2020, it was the 51st most commonly prescribed medication in the United States, with more than 13 million prescriptions. Medical uses Spironolactone is used primarily to treat heart failure, edematous conditions such as nephrotic syndrome or ascites in people with liver disease, essential hypertension, low blood levels of potassium, secondary hyperaldosteronism (such as occurs with liver cirrhosis), and Conns syndrome (primary hyperaldosteronism). The most common use of spironolactone is in the treatment of heart failure. On its own, spironolactone is only a weak diuretic because it primarily targets the distal nephron (collecting tubule), where only small amounts of sodium are reabsorbed, but it can be combined with other diuretics to increase efficacy. The classification of spironolactone as a "potassium-sparing diuretic" has been described as obsolete. Spironolactone is also used to treat Bartters syndrome due to its ability to raise potassium levels.Spironolactone has antiandrogenic activity. For this reason, it is frequently used to treat a variety of dermatological conditions in which androgens play a role. Some of these uses include acne, seborrhea, hirsutism, and pattern hair loss in women. Spironolactone is the most commonly used medication in the treatment of hirsutism in the United States. High doses of spironolactone, which are needed for considerable antiandrogenic effects, are not recommended for men due to the high risk of feminization and other side effects. Spironolactone is also commonly used to treat symptoms of hyperandrogenism, such as due to polycystic ovary syndrome, in women. Heart failure While loop diuretics remain first-line for most people with heart failure, spironolactone has shown to reduce both morbidity and mortality in numerous studies and remains an important agent for treating fluid retention, edema, and symptoms of heart failure. Current recommendations from the American Heart Association are to use spironolactone in patients with NYHA Class II-IV heart failure who have a left ventricular ejection fraction of less than 35%.In a randomized evaluation which studied people with severe congestive heart failure, people treated with spironolactone were found to have a relative risk of death of 0.70 or an overall 30% relative risk reduction compared to the placebo group, indicating a significant death and morbidity benefit of the medication. People in the studys intervention arm also had fewer symptoms of heart failure and were hospitalized less frequently. Likewise, it has shown benefit for and is recommended in patients who recently had a heart attack and have an ejection fraction less than 40%, who develop symptoms consistent with heart failure, or have a history of diabetes mellitus. Spironolactone should be considered a good add-on agent, particularly in those patients "not" yet optimized on ACE inhibitors and beta-blockers. Of note, a recent randomized, double-blinded study of spironolactone in patients with symptomatic heart failure with "preserved" ejection fraction (i.e. >45%) found no reduction in death from cardiovascular events, aborted cardiac arrest, or hospitalizations when spironolactone was compared to placebo.It is recommended that alternatives to spironolactone be considered if serum creatinine is greater than 2.5 mg/dL (221 μmol/L) in males or greater than 2 mg/dL (176.8 μmol/L) in females, if glomerular filtration rate is below 30 mL/min or with a serum potassium of greater than 5.0 mEq/L given the potential for adverse events detailed elsewhere in this article. Doses should be adjusted according to the degree of kidney function as well.According to a systematic review, in heart failure with preserved ejection fraction, treatment with spironolactone did not improve patient outcomes. This is based on the TOPCAT Trial examining this issue, which found that of those treated with placebo had a 20.4% incidence of negative outcome vs 18.6% incidence of negative outcome with spironolactone. However, because the p-value of the study was 0.14, and the unadjusted hazard ratio was 0.89 with a 95% confidence interval of 0.77 to 1.04, it is determined the finding had no statistical significance. Hence the finding that patient outcomes are not improved with use of spironolactone. When blood samples from 366 participants in the TOPCAT study were analyzed for presence of canrenone (an active metabolite of spironolactone), 30% of blood samples from Russia lacked detectable residues of canrenone. This led to the conclusion that the TOPCAT trial results in Russia do not reflect actual clinical experience with spironolactone in patients with preserved ejection fraction. The TOPCAT study results are now considered to have been invalidated. The studys prime investigator and other prominent research cardiologists are now advising physicians treating heart failure with preserved ejection fraction to consider prescribing spironolactone pending outcome of two multicenter trials of newer medications.Due to its antiandrogenic properties, spironolactone can cause effects associated with low androgen levels and hypogonadism in males. For this reason, men are typically not prescribed spironolactone for any longer than a short period of time, e.g., for an acute exacerbation of heart failure. A newer medication, eplerenone, has been approved by the U.S. Food and Drug Administration for the treatment of heart failure, and lacks the antiandrogenic effects of spironolactone. As such, it is far more suitable for men for whom long-term medication is being chosen. However, eplerenone may not be as effective as spironolactone or the related medication canrenone in reducing mortality from heart failure.The clinical benefits of spironolactone as a diuretic are typically not seen until 2–3 days after dosing begins. Likewise, the maximal antihypertensive effect may not be seen for 2–3 weeks.Unlike with some other diuretics, potassium supplementation should not be administered while taking spironolactone, as this may cause dangerous elevations in serum potassium levels resulting in hyperkalemia and potentially deadly abnormal heart rhythms. High blood pressure About 1 in 100 people with hypertension have elevated levels of aldosterone; in these people, the antihypertensive effect of spironolactone may exceed that of complex combined regimens of other antihypertensives since it targets the primary cause of the elevated blood pressure. However, a Cochrane review found adverse effects at high doses and little effect on blood pressure at low doses in the majority of people with high blood pressure. There is no evidence of person-oriented outcome at any dose in this group. High aldosterone levels Spironolactone is used in the treatment of hyperaldosteronism (high aldosterone levels or mineralocorticoid excess), for instance primary aldosteronism (Conns syndrome). Antimineralocorticoids like spironolactone and eplerenone are first-line treatments for hyperaldosteronism. They improve blood pressure and potassium levels, as well as left ventricular hypertrophy, albuminuria, and carotid intima-media thickness, in people with primary aldosteronism. In people with hyperaldosteronism due to unilateral aldosterone-producing adrenocortical adenoma, adrenalectomy should be preferred instead of antimineralocorticoids. Spironolactone should not be used to treat primary aldosteronism in pregnancy due to its antiandrogen-related risk of teratogenicity in male fetuses. Skin and hair conditions Androgens like testosterone and DHT play a critical role in the pathogenesis of a number of dermatological conditions including oily skin, acne, seborrhea, hirsutism (excessive facial/body hair growth in women), and male pattern hair loss (androgenic alopecia). In demonstration of this, women with complete androgen insensitivity syndrome (CAIS) do not produce sebum or develop acne and have little to no body, pubic, or axillary hair. Moreover, men with congenital 5α-reductase type II deficiency, 5α-reductase being an enzyme that greatly potentiates the androgenic effects of testosterone in the skin, have little to no acne, scanty facial hair, reduced body hair, and reportedly no incidence of male-pattern hair loss. Conversely, hyperandrogenism in women, for instance due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH), is commonly associated with acne and hirsutism as well as virilization (masculinization) in general. In accordance with the preceding, antiandrogens are highly effective in the treatment of the aforementioned androgen-dependent skin and hair conditions.Because of the antiandrogenic activity of spironolactone, it can be quite effective in treating acne in women. In addition, spironolactone reduces oil that is naturally produced in the skin and can be used to treat oily skin. Though not the primary intended purpose of the medication, the ability of spironolactone to be helpful with problematic skin and acne conditions was discovered to be one of the beneficial side effects and has been quite successful. Oftentimes, for women treating acne, spironolactone is prescribed and paired with a birth control pill. Positive results in the pairing of these two medications have been observed, although these results may not be seen for up to three months. Spironolactone has been reported to produce a 50 to 100% improvement in acne at sufficiently high doses. Response to treatment generally requires 1 to 3 months in the case of acne and up to 6 months in the case of hirsutism. Ongoing therapy is generally required to avoid relapse of symptoms. Spironolactone is commonly used in the treatment of hirsutism in women, and is considered to be a first-line antiandrogen for this indication. Spironolactone can be used in the treatment of female-pattern hair loss (pattern scalp hair loss in women). There is tentative low quality evidence supporting its use for this indication. Although apparently effective, not all cases of female-pattern hair loss are dependent on androgens.Antiandrogens like spironolactone are male-specific teratogens which can feminize male fetuses due to their antiandrogenic effects. For this reason, it is recommended that antiandrogens only be used to treat women who are of reproductive age in conjunction with adequate contraception. Oral contraceptives, which contain an estrogen and a progestin, are typically used for this purpose. Moreover, oral contraceptives themselves are functional antiandrogens and are independently effective in the treatment of androgen-dependent skin and hair conditions, and hence can significantly augment the effectiveness of antiandrogens in the treatment of such conditions.Spironolactone is not generally used in men for the treatment of androgen-dependent dermatological conditions because of its feminizing side effects, but it is effective for such indications in men similarly. As an example, spironolactone has been reported to reduce symptoms of acne in males. An additional example is the usefulness of spironolactone as an antiandrogen in transgender women.Topical spironolactone has been found to be effective in the treatment of acne as well. As a result, topical pharmaceutical formulations containing 2% or 5% spironolactone cream became available in Italy for the treatment of acne and hirsutism in the early 1990s. The products were discontinued in 2006 when the creams were added to the list of doping substances with a decree of the Ministry of Health that year. Comparison Spironolactone, the 5α-reductase inhibitor finasteride, and the nonsteroidal antiandrogen flutamide all appear to have similar effectiveness in the treatment of hirsutism. However, some clinical research has found that the effectiveness of spironolactone for hirsutism is greater than that of finasteride but is less than that of flutamide. The combination of spironolactone with finasteride is more effective than either alone for hirsutism and the combination of spironolactone with a birth control pill is more effective than a birth control pill alone. One study showed that spironolactone or the steroidal antiandrogen cyproterone acetate both in combination with a birth control pill had equivalent effectiveness for hirsutism. Spironolactone is considered to be a first-line treatment for hirsutism, finasteride and the steroidal antiandrogen cyproterone acetate are considered to be second-line treatments, and flutamide is no longer recommended for hirsutism due to liver toxicity concerns. The nonsteroidal antiandrogen bicalutamide is an alternative option to flutamide with improved safety.The combination of spironolactone with a birth control pill in the treatment of acne appears to have similar effectiveness to a birth control pill alone and the combination of a birth control pill with cyproterone acetate, flutamide, or finasteride. However, this was based on low- to very-low-quality evidence. Spironolactone may be more effective than birth control pills in the treatment of acne, and the combination of spironolactone with a birth control pill may have greater effectiveness for acne than either alone. In addition, some clinical research has found that flutamide is more effective than spironolactone in the treatment of acne. In one study, flutamide decreased acne scores by 80% within 3 months, whereas spironolactone decreased symptoms by only 40% in the same time period. However, the use of flutamide for acne is limited by its liver toxicity. Bicalutamide is a potential alternative to flutamide for acne as well. Spironolactone can be considered as a first-line treatment for acne in those who have failed other standard treatments such as topical therapies and under certain other circumstances, although this is controversial due to the side effects of spironolactone and its teratogenicity.There is insufficient clinical evidence to compare the effectiveness of spironolactone with other antiandrogens for female-pattern hair loss. The effectiveness of spironolactone in the treatment of both acne and hirsutism appears to be dose-dependent, with higher doses being more effective than lower doses. However, higher doses also have greater side effects, such as menstrual irregularities. Transgender hormone therapy Spironolactone is frequently used as a component of feminizing hormone therapy in transgender women, especially in the United States (where cyproterone acetate is not available), usually in addition to an estrogen. Other clinical effects include decreased male pattern body hair, the induction of breast development, feminization in general, and lack of spontaneous erections. The medication is not approved for use as an antiandrogen by the Food and Drug Administration; instead, it is used off-label for such purposes. Doses and forms Spironolactone is typically used at a low dosage of 25 to 50 mg/day in the treatment of heart failure, while it is used at low to high dosages of 25 to 200 mg/day in the treatment of essential hypertension, and at high dosages of 100 to 400 mg/day for hyperaldosteronism and ascites due to cirrhosis. The medication is typically used at high dosages of 100 to 200 mg/day in the treatment of skin and hair conditions in women, and at high dosages of 100 to 400 mg/day in feminizing hormone therapy for transgender women.Spironolactone is available in the form of tablets (25 mg, 50 mg, 100 mg; brand name Aldactone, others) and suspensions (25 mg/5 mL; brand name CaroSpir) for use by mouth. It has also been marketed in the form of 2% and 5% topical cream in Italy for the treatment of acne and hirsutism under the brand name Spiroderm, but this product is no longer available. The medication is also available in combination with other medications, such as hydrochlorothiazide (brand name Aldactazide, others). Spironolactone has poor water solubility, and for this reason, only oral and topical formulations have been developed; other routes of administration such as intravenous injection are not used. The only antimineralocorticoid that is available as a solution for parenteral use is the related medication potassium canrenoate. Contraindications Contraindications of spironolactone include hyperkalemia (high potassium levels), severe and end-stage kidney disease (due to high hyperkalemia risk, except possibly in those on dialysis), Addisons disease (adrenal insufficiency and low aldosterone levels), and concomitant use of eplerenone. It should also be used with caution in people with some neurological disorders, no urine production, acute kidney injury, or significant impairment of kidney excretory function with risk of hyperkalemia. Side effects One of the most common side effects of spironolactone is frequent urination. Other general side effects include dehydration, hyponatremia (low sodium levels), mild hypotension (low blood pressure), ataxia (muscle incoordination), drowsiness, dizziness, dry skin, and rashes. Because of its antiandrogenic activity, spironolactone can, in men, cause breast tenderness, gynecomastia (breast development), feminization in general, and demasculinization, as well as sexual dysfunction including loss of libido and erectile dysfunction, although these side effects are usually confined to high doses of spironolactone. At very high doses (400 mg/day), spironolactone has also been associated with testicular atrophy and reversibly reduced fertility, including semen abnormalities such as decreased sperm count and motility in men. However, such doses of spironolactone are rarely used clinically. In women, spironolactone can cause menstrual irregularities, breast tenderness, and breast enlargement. Aside from these adverse effects, the side effects of spironolactone in women taking high doses are minimal, and it is well tolerated.The most important potential side effect of spironolactone is hyperkalemia (high potassium levels), which, in severe cases, can be life-threatening. Hyperkalemia in these people can present as a normal anion-gap metabolic acidosis. It has been reported that the addition of spironolactone to loop diuretics in patients with heart failure was associated with a higher risk of hyperkalemia and acute kidney injury (AKI). Spironolactone may put people at a heightened risk for gastrointestinal issues like nausea, vomiting, diarrhea, cramping, and gastritis. In addition, there has been some evidence suggesting an association between use of the medication and bleeding from the stomach and duodenum, though a causal relationship between the two has not been established. Also, spironolactone is immunosuppressive in the treatment of sarcoidosis.Most of the side effects of spironolactone are dose-dependent. Low-dose spironolactone is generally very well tolerated. Even higher doses of spironolactone, such as 100 mg/day, are well tolerated in most individuals. Dose-dependent side effects of spironolactone include menstrual irregularities, breast tenderness and enlargement, orthostatic hypotension, and hyperkalemia. The side effects of spironolactone are usually mild and rarely result in discontinuation. High potassium levels Spironolactone can cause hyperkalemia, or high blood potassium levels. Rarely, this can be fatal. Of people with heart disease prescribed typical dosages of spironolactone, 10 to 15% develop some degree of hyperkalemia, and 6% develop severe hyperkalemia. At a higher dosage, a rate of hyperkalemia of 24% has been observed. An abrupt and major increase in the rate of hospitalization due to hyperkalemia from 0.2% to 11% and in the rate of death due to hyperkalemia from 0.3 per 1,000 to 2.0 per 1,000 between early 1994 and late 2001 has been attributed to a parallel rise in the number of prescriptions written for spironolactone upon the publication of the Randomized Aldactone Evaluation Study (RALES) in July 1999. However, another population-based study in Scotland failed to replicate these findings. The risk of hyperkalemia with spironolactone is greatest in the elderly, in people with renal impairment (e.g., due to chronic kidney disease or diabetic nephropathy), in people taking certain other medications (including ACE inhibitors, angiotensin II receptor blockers, nonsteroidal anti-inflammatory drugs, the antibiotic trimethoprim, and potassium supplements), and at higher dosages of spironolactone.Although spironolactone poses an important risk of hyperkalemia in the elderly, in those with kidney or cardiovascular disease, and/or in those taking medications or supplements which increase circulating potassium levels, a large retrospective study found that the rate of hyperkalemia in young women without such characteristics who had been treated with high doses of spironolactone for dermatological conditions did not differ from that of controls. This was the conclusion of a 2017 hybrid systematic review of studies of spironolactone for acne in women as well, which found that hyperkalemia was rare and was invariably mild and clinically insignificant. These findings suggest that hyperkalemia may not be a significant risk in such individuals, and that routine monitoring of circulating potassium levels may be unnecessary in this population. However, other sources have claimed that hyperkalemia can nonetheless also occur in people with more normal renal function and presumably without such risk factors. Occasional testing on a case-by-case basis in those with known risk factors may be justified. Side effects of spironolactone which may be indicative of hyperkalemia and if persistent could justify serum potassium testing include nausea, fatigue, and particularly muscle weakness. Notably, non-use of routine potassium monitoring with spironolactone in young women would reduce costs associated with its use. Breast changes Spironolactone frequently causes breast pain and breast enlargement in women. This is "probably because of estrogenic effects on target tissue." At low doses, breast tenderness has been reported in only 5% of women, but at high doses, it has been reported in up to 40% of women. Breast enlargement and tenderness may occur in 26% of women at high doses. Some women regard spironolactone-induced breast enlargement as a positive effect.Spironolactone also commonly and dose-dependently produces gynecomastia (breast development) as a side effect in men. At low doses, the rate is only 5 to 10%, but at high doses, up to or exceeding 50% of men may develop gynecomastia. In the RALES, 9.1% of men taking 25 mg/day spironolactone developed gynecomastia, compared to 1.3% of controls. Conversely, in studies of healthy men given high-dose spironolactone, gynecomastia occurred in 3 of 10 (30%) at 100 mg/day, in 5 of 8 (62.5%) at 200 mg/day, and in 6 of 9 (66.7%) at 400 mg/day, relative to none of 12 controls. The severity of gynecomastia with spironolactone varies considerably, but is usually mild. As with breast enlargement caused by spironolactone in women, gynecomastia due to spironolactone in men is often although inconsistently accompanied by breast tenderness. In the RALES, only 1.7% of men developed breast pain, relative to 0.1% of controls.The time to onset of spironolactone-induced gynecomastia has been found to be 27 ± 20 months at low doses and 9 ± 12 months at high doses. Gynecomastia induced by spironolactone usually regresses after a few weeks following discontinuation of the medication. However, after a sufficient duration of gynecomastia being present (e.g., one year), hyalinization and fibrosis of the tissue occurs and drug-induced gynecomastia may become irreversible. Menstrual disturbances Spironolactone at higher doses can cause menstrual irregularities as a side effect in women. These irregularities include metrorrhagia (intermenstrual bleeding), amenorrhea (absence of menstruation), and breakthrough bleeding. They are common during spironolactone therapy, with 10 to 50% of women experiencing them at moderate doses and almost all experiencing them at a high doses. For example, about 20% of women experienced menstrual irregularities with 50 to 100 mg/day spironolactone, whereas about 70% experienced menstrual irregularities at 200 mg/day. Most women taking moderate doses of spironolactone develop amenorrhea, and normal menstruation usually returns within two months of discontinuation. Spironolactone produces an irregular and anovulatory pattern of menstrual cycles. It is also associated with metrorrhagia and menorrhagia (heavy menstrual bleeding) in large percentages of women, as well as with polymenorrhea (short menstrual cycles). The medication reportedly has no birth control effect.It has been suggested that the weak progestogenic activity of spironolactone is responsible for these effects, although this has not been established and spironolactone has been shown to possess insignificant progestogenic and antiprogestogenic activity even at high dosages in women. An alternative proposed cause is inhibition of 17α-hydroxylase and hence sex steroid metabolism by spironolactone and consequent changes in sex hormone levels. Indeed, CYP17A1 genotype is associated with polymenorrhea. Regardless of their mechanism, the menstrual disturbances associated with spironolactone can usually be controlled well by concomitant treatment with a birth control pill, due to the progestin component. Mood changes Research is mixed on whether antimineralocorticoids like spironolactone have positive or negative effects on mood. In any case, it is possible that spironolactone might have the capacity to increase the risk of depressive symptoms. However, a 2017 hybrid systematic review found that the incidence of depression in women treated with spironolactone for acne was less than 1%. Likewise, a 10-year observational study found that the incidence of depression in 196 transgender women taking high-dose spironolactone in combination with an
Spironolactone	estrogen was less than 1%. Rare reactions Aside from hyperkalemia, spironolactone may rarely cause adverse reactions such as anaphylaxis, kidney failure, hepatitis (two reported cases, neither serious), agranulocytosis, DRESS syndrome, Stevens–Johnson syndrome or toxic epidermal necrolysis. Five cases of breast cancer in patients who took spironolactone for prolonged periods of time have been reported. Spironolactone bodies Long-term administration of spironolactone gives the histologic characteristic of "spironolactone bodies" in the adrenal cortex. Spironolactone bodies are eosinophilic, round, concentrically laminated cytoplasmic inclusions surrounded by clear halos in preparations stained with hematoxylin and eosin. Pregnancy and breastfeeding In the United States, spironolactone is considered pregnancy category C meaning that it is unclear if it is safe for use during pregnancy. It is able to cross the placenta. Likewise, it has been found to be present in the breast milk of lactating mothers and, while the effects of spironolactone or its metabolites have not been extensively studied in breastfeeding infants, it is generally recommended that women also not take the medication while nursing. However, only very small amounts of spironolactone and its metabolite canrenone enter breast milk, and the amount received by an infant during breastfeeding (<0.5% of the mothers dose) is considered to be insignificant.A study found that spironolactone was not associated with teratogenicity in the offspring of rats. Because it is an antiandrogen, however, spironolactone could theoretically have the potential to cause feminization of male fetuses at sufficient doses. In accordance, a subsequent study found that partial feminization of the genitalia occurred in the male offspring of rats that received doses of spironolactone that were five times higher than those normally used in humans (200 mg/kg per day). Another study found permanent, dose-related reproductive tract abnormalities rat offspring of both sexes at lower doses (50 to 100 mg/kg per day).In practice however, although experience is limited, spironolactone has never been reported to cause observable feminization or any other congenital defects in humans. Among 31 human newborns exposed to spironolactone in the first trimester, there were no signs of any specific birth defects. A case report described a woman who was prescribed spironolactone during pregnancy with triplets and delivered all three (one boy and two girls) healthy; there was no feminization in the boy. In addition, spironolactone has been used at high doses to treat pregnant women with Bartters syndrome, and none of the infants (three boys, two girls) showed toxicity, including feminization in the male infants. There are similar findings, albeit also limited, for another antiandrogen, cyproterone acetate (prominent genital defects in male rats, but no human abnormalities (including feminization of male fetuses) at both a low dose of 2 mg/day or high doses of 50 to 100 mg/day). In any case, spironolactone is nonetheless not recommended during pregnancy due to theoretical concerns relating to feminization of males and also to potential alteration of fetal potassium levels.A 2019 systematic review found insufficient evidence that spironolactone causes birth defects in humans. However, there was also insufficient evidence to be certain that it does not. Overdose Spironolactone is relatively safe in acute overdose. Symptoms following an acute overdose of spironolactone may include drowsiness, confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, and diarrhea. In rare cases, hyponatremia, hyperkalemia, or hepatic coma may occur in individuals with severe liver disease. However, these adverse reactions are unlikely in the event of an acute overdose. Hyperkalemia can occur following an overdose of spironolactone, and this is especially so in people with decreased kidney function. Spironolactone has been studied at extremely high oral doses of up to 2,400 mg per day in clinical trials. Its oral median lethal dose (LD50) is more than 1,000 mg/kg in mice, rats, and rabbits.There is no specific antidote for overdose of spironolactone. Treatment may consist of induction of vomiting or stomach evacuation by gastric lavage. The treatment of spironolactone overdose is supportive, with the purpose of maintaining hydration, electrolyte balance, and vital functions. Spironolactone should be discontinued in people with impaired kidney function or hyperkalemia. Interactions Spironolactone often increases serum potassium levels and can cause hyperkalemia, a very serious condition. Therefore, it is recommended that people using this medication avoid potassium supplements and salt substitutes containing potassium. Physicians must be careful to monitor potassium levels in both males and females who are taking spironolactone as a diuretic, especially during the first twelve months of use and whenever the dosage is increased. Doctors may also recommend that some patients may be advised to limit dietary consumption of potassium-rich foods. However, recent data suggests that both potassium monitoring and dietary restriction of potassium intake is unnecessary in healthy young women taking spironolactone for acne. Spironolactone together with trimethoprim/sulfamethoxazole increases the likelihood of hyperkalemia, especially in the elderly. The trimethoprim portion acts to prevent potassium excretion in the distal tubule of the nephron.Spironolactone has been reported to induce the enzymes CYP3A4 and certain UDP-glucuronosyltransferases (UGTs), which can result in interactions with various medications. However, it has also been reported that metabolites of spironolactone irreversibly inhibit CYP3A4. In any case, spironolactone has been found to reduce the bioavailability of oral estradiol, which could be due to induction of estradiol metabolism via CYP3A4. Spironolactone has also been found to inhibit UGT2B7. Spironolactone can also have numerous other interactions, most commonly with other cardiac and blood pressure medications, for instance digoxin.Licorice, which has indirect mineralocorticoid activity by inhibiting mineralocorticoid metabolism, has been found to inhibit the antimineralocorticoid effects of spironolactone. Moreover, the addition of licorice to spironolactone has been found to reduce the antimineralocorticoid side effects of spironolactone in women treated with it for hyperandrogenism, and licorice hence may be used to reduce these side effects in women treated with spironolactone as an antiandrogen who are bothered by them. On the opposite end of the spectrum, spironolactone is useful in reversing licorice-induced hypokalemia. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have been found to attenuate the diuresis and natriuresis induced by spironolactone, but, not to affect its antihypertensive effect.Some research has suggested that spironolactone might be able to interfere with the effectiveness of antidepressant treatment. As the medication acts as an antimineralocorticoid, it is thought that it might be able to reduce the effectiveness of certain antidepressants by interfering with normalization of the hypothalamic–pituitary–adrenal axis and by increasing levels of glucocorticoids such as cortisol. However, other research contradicts this hypothesis and has suggested that spironolactone might actually produce antidepressant effects, for instance studies showing antidepressant-like effects of spironolactone in animals. Pharmacology Pharmacodynamics The pharmacodynamics of spironolactone are characterized by high antimineralocorticoid activity, moderate antiandrogenic activity, and weak steroidogenesis inhibition, among other more minor activities. Spironolactone is a prodrug, so most of its actions are actually mediated by its various active metabolites. The major active forms of spironolactone are 7α-thiomethylspironolactone (7α-TMS) and canrenone (7α-desthioacetyl-δ6-spironolactone).Spironolactone is a potent antimineralocorticoid. That is, it is an antagonist of the mineralocorticoid receptor (MR), the biological target of mineralocorticoids like aldosterone and 11-deoxycorticosterone. By blocking the MR, spironolactone inhibits the effects of mineralocorticoids in the body. The antimineralocorticoid activity of spironolactone is responsible for its therapeutic efficacy in the treatment of edema, high blood pressure, heart failure, hyperaldosteronism, and ascites due to cirrhosis. It is also responsible for many of the side effects of spironolactone, such as urinary frequency, dehydration, hyponatremia, low blood pressure, fatigue, dizziness, metabolic acidosis, decreased kidney function, and its risk of hyperkalemia. Due to the antimineralocorticoid activity of spironolactone, levels of aldosterone are significantly increased by the medication, probably reflecting an attempt of the body to maintain homeostasis.Spironolactone is a moderate antiandrogen. That is, it is an antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). By blocking the AR, spironolactone inhibits the effects of androgens in the body. The antiandrogenic activity of spironolactone is mainly responsible for its therapeutic efficacy in the treatment of androgen-dependent skin and hair conditions like acne, seborrhea, hirsutism, and pattern hair loss and hyperandrogenism in women, precocious puberty in boys with testotoxicosis, and as a component of feminizing hormone therapy for transgender women. It is also primarily responsible for some of its side effects, like breast tenderness, gynecomastia, feminization, and demasculinization in men. Blockade of androgen signaling in the breast disinhibits the actions of estrogens in this tissue. Although useful as an antiandrogen in women, who have low testosterone levels compared to men, spironolactone is described as having relatively weak antiandrogenic activity.Spironolactone is a weak steroidogenesis inhibitor. That is, it inhibits steroidogenic enzymes, or enzymes involved in the production of steroid hormones. Spironolactone and/or its metabolites have been found in vitro to weakly inhibit a broad array of steroidogenic enzymes including cholesterol side-chain cleavage enzyme, 17α-hydroxylase, 17,20-lyase, 5α-reductase, 3β-hydroxysteroid dehydrogenase, 11β-hydroxylase, 21-hydroxylase, and aldosterone synthase (18-hydroxylase). However, although very high doses of spironolactone can considerably decrease steroid hormone levels in animals, spironolactone has shown mixed and inconsistent effects on steroid hormone levels in clinical studies, even at high clinical doses. In any case, the levels of most steroid hormones, including testosterone and cortisol, are usually unchanged by spironolactone in humans, which may in part be related to compensatory upregulation of their synthesis. The weak steroidogenesis inhibition of spironolactone might contribute to its antiandrogenic efficacy to some degree and may explain its side effect of menstrual irregularities in women. However, its androgen synthesis inhibition is probably clinically insignificant.Spironolactone has been found in some studies to increase levels of estradiol, an estrogen, although many other studies have found no changes in estradiol levels. The mechanism of how spironolactone increases estradiol levels is unclear, but it may involve inhibition of the inactivation of estradiol into estrone and enhancement of the peripheral conversion of testosterone into estradiol. It is notable that spironolactone has been found in vitro to act as a weak inhibitor of 17β-hydroxysteroid dehydrogenase 2, an enzyme that is involved in the conversion of estradiol into estrone. Increased levels of estradiol with spironolactone may be involved in its preservation of bone density and in its side effects such as breast tenderness, breast enlargement, and gynecomastia in women and men.In response to the antimineralocorticoid activity spironolactone, and in an attempt to maintain homeostasis, the body increases aldosterone production in the adrenal cortex. Some studies have found that levels of cortisol, a glucocorticoid hormone that is also produced in the adrenal cortex, are increased as well. However, other clinical studies have found no change in cortisol levels with spironolactone, and those that have found increases often have observed only small changes. In accordance, spironolactone has not been associated with conventional glucocorticoid medication effects or side effects.Other activities of spironolactone may include very weak interactions with the estrogen and progesterone receptors and agonism of the pregnane X receptor. These activities could contribute to the menstrual irregularities and breast side effects of spironolactone and to its drug interactions, respectively. Pharmacokinetics The pharmacokinetics of spironolactone have not been studied well, which is in part because it is an old medication that was developed in the 1950s. Nonetheless, much has been elucidated about the pharmacokinetics of spironolactone over the decades. Absorption The bioavailability of spironolactone when taken by mouth is 60 to 90%. The bioavailability of spironolactone and its metabolites increases significantly (+22–95% increases in levels) when spironolactone is taken with food, although it is uncertain whether this further increases the therapeutic effects of the medication. The increase in bioavailability is thought to be due to promotion of the gastric dissolution and absorption of spironolactone, as well as due to a decrease of the first-pass metabolism. The relationship between a single dose of spironolactone and plasma levels of canrenone, a major active metabolite of spironolactone, has been found to be linear across a dose range of 25 to 200 mg spironolactone. Steady-state concentrations of spironolactone are achieved within 8 to 10 days of treatment initiation.Little or no systemic absorption has been observed with topical spironolactone. Distribution Spironolactone and its metabolite canrenone are highly plasma protein bound, with percentages of 88.0% and 99.2%, respectively. Spironolactone is bound equivalently to albumin and α1-acid glycoprotein, while canrenone is bound only to albumin. Spironolactone and its metabolite 7α-thiospironolactone show very low or negligible affinity for sex hormone-binding globulin (SHBG). In accordance, a study of high-dosage spironolactone treatment found no change in steroid binding capacity related to SHBG or to corticosteroid-binding globulin (CBG), suggesting that spironolactone does not displace steroid hormones from their carrier proteins. This is in contradiction with widespread statements that spironolactone increases free estradiol levels by displacing estradiol from SHBG.Spironolactone appears to cross the blood–brain barrier. Metabolism Spironolactone is rapidly and extensively metabolized in the liver upon oral administration and has a very short terminal half-life of 1.4 hours. The major metabolites of spironolactone are 7α-thiomethylspironolactone (7α-TMS), 6β-hydroxy-7α-thiomethylspironolactone (6β-OH-7α-TMS), and canrenone (7α-desthioacetyl-δ6-spironolactone). These metabolites have much longer elimination half-lives than spironolactone of 13.8 hours, 15.0 hours, and 16.5 hours, respectively, and are responsible for the therapeutic effects of the medication. As such, spironolactone is a prodrug. The 7α-thiomethylated metabolites of spironolactone were not known for many years and it was originally thought that canrenone was the major active metabolite of the medication, but subsequent research identified 7α-TMS as the major metabolite. Other known but more minor metabolites of spironolactone include 7α-thiospironolactone (7α-TS), which is an important intermediate to the major metabolites of spironolactone, as well as the 7α-methyl ethyl ester of spironolactone and the 6β-hydroxy-7α-methyl ethyl ester of spironolactone.Spironolactone is hydrolyzed or deacetylated at the thioester of the C7α position into 7α-TS by carboxylesterases. Following formation of 7α-TS, it is S-oxygenated by flavin-containing monooxygenases to form an electrophilic sulfenic acid metabolite. This metabolite is involved in the CYP450 inhibition of spironolactone, and also binds covalently to other proteins. 7α-TS is also S-methylated into 7α-TMS, a transformation catalyzed by thiol S-methyltransferase. Unlike the related medication eplerenone, spironolactone is said to not be metabolized by CYP3A4. However, hepatic CYP3A4 is likely responsible for the 6β-hydroxylation of 7α-TMS into 6β-OH-7α-TMS. 7α-TMS may also be hydroxylated at the C3α and C3β positions. Spironolactone is dethioacetylated into canrenone. Finally, the C17 γ-lactone ring of spironolactone is hydrolyzed by the paraoxonase PON3. It was originally thought to be hydrolyzed by PON1, but this was due to contamination with PON3. Elimination The majority of spironolactone is eliminated by the kidneys, while minimal amounts are handled by biliary excretion. Chemistry Spironolactone, also known as 7α-acetylthiospirolactone, is a steroidal 17α-spirolactone, or more simply a spirolactone. It can most appropriately be conceptualized as a derivative of progesterone, itself also a potent antimineralocorticoid, in which a hydroxyl group has been substituted at the C17α position (as in 17α-hydroxyprogesterone), the acetyl group at the C17β position has been cyclized with the C17α hydroxyl group to form a spiro 21-carboxylic acid γ-lactone ring, and an acetylthio group has been substituted in at the C7α position. These structural modifications of progesterone confer increased oral bioavailability and potency, potent antiandrogenic activity, and strongly reduced progestogenic activity. The C7α substitution is likely responsible for or involved in the antiandrogenic activity of spironolactone, as 7α-thioprogesterone (SC-8365), unlike progesterone, is an antiandrogen with similar affinity to the AR as that of spironolactone. In addition, the C7α substitution appears to be responsible for the loss of progestogenic activity and good oral bioavailability of spironolactone, as SC-5233, the analogue of spironolactone without a C7α substitution, has potent progestogenic activity but very poor oral bioavailability similarly to progesterone. Names Spironolactone is also known by the following equivalent chemical names: 7α-Acetylthio-17α-hydroxy-3-oxopregn-4-ene-21-carboxylic acid γ-lactone 7α-Acetylthio-3-oxo-17α-pregn-4-ene-21,17β-carbolactone 3-(3-Oxo-7α-acetylthio-17β-hydroxyandrost-4-en-17α-yl)propionic acid lactone 7α-Acetylthio-17α-(2-carboxyethyl)androst-4-en-17β-ol-3-one γ-lactone 7α-Acetylthio-17α-(2-carboxyethyl)testosterone γ-lactone Analogues Spironolactone is closely related structurally to other clinically used spirolactones such as canrenone, potassium canrenoate, drospirenone, and eplerenone, as well as to the never-marketed spirolactones SC-5233 (6,7-dihydrocanrenone; 7α-desthioacetylspironolactone), SC-8109 (19-nor-6,7-dihydrocanrenone), spiroxasone, prorenone (SC-23133), mexrenone (SC-25152, ZK-32055), dicirenone (SC-26304), spirorenone (ZK-35973), and mespirenone (ZK-94679). Synthesis Chemical syntheses of spironolactone and its analogues and derivatives have been described and reviewed. History The natriuretic effects of progesterone were demonstrated in 1955, and the development of spironolactone as a synthetic antimineralocorticoid analogue of progesterone shortly followed this. Spironolactone was first synthesized in 1957, was patented between 1958 and 1961, and was first marketed, as an antimineralocorticoid, in 1959. Gynecomastia was first reported with spironolactone in 1962, and the antiandrogenic activity of the medication was first described in 1969. This shortly followed the discovery in 1967 that gynecomastia is an important and major side effect of AR antagonists. Spironolactone was first studied in the treatment of hirsutism in women in 1978. It has since become the most widely used antiandrogen for dermatological indications in women in the United States. Spironolactone was first studied as an antiandrogen in transgender women in 1986, and has since become widely adopted for this purpose as well, particularly in the United States where cyproterone acetate is not available.Early oral spironolactone tablets showed poor absorption. The formulation was eventually changed to a micronized formulation with particle sizes of less than 50 μg, which resulted in approximately 4-fold increased potency. Society and culture Generic names The English, French, and generic name of the medication is spironolactone and this is its INN, USAN, USP, BAN, DCF, and JAN. Its name is spironolactonum in Latin, spironolacton in German, espironolactona in Spanish and Portuguese, and spironolattone in Italian (which is also its DCIT).Spironolactone is also known by its developmental code names SC-9420 and NSC-150339. Brand names Spironolactone is marketed under a large number of brand names throughout the world. The major brand name of spironolactone is Aldactone. Other important brand names include Aldactone-A, Berlactone, CaroSpir, Espironolactona, Espironolactona Genfar, Novo-Spiroton, Prilactone (veterinary), Spiractin, Spiridon, Spirix, Spiroctan, Spiroderm (discontinued), Spirogamma, Spirohexal, Spirolon, Spirolone, Spiron, Spironolactone Actavis, Spironolactone Orion, Spironolactone Teva, Spirotone, Tempora (veterinary), Uractone, Uractonum, Verospiron, and Vivitar.Spironolactone is also formulated in combination with a variety of other medications, including with hydrochlorothiazide as Aldactazide, with hydroflumethiazide as Aldactide, Lasilacton, Lasilactone, and Spiromide, with altizide as Aldactacine and Aldactazine, with furosemide as Fruselac, with benazepril as Cardalis (veterinary), with metolazone as Metolactone, with bendroflumethiazide as Sali-Aldopur, and with torasemide as Dytor Plus, Torlactone, and Zator Plus. Availability Spironolactone is marketed widely throughout the world and is available in almost every country, including in the United States, Canada, the United Kingdom, other European countries, Australia, New Zealand, South Africa, Central and South America, and East and Southeast Asia. Usage There was a total of 17.2 million prescriptions for spironolactone in the United States between the beginning of 2003 and the end of 2005. There was a total of 12.0 million prescriptions for spironolactone in the United States in 2016 alone. It was the 66th top prescribed medication in the United States in 2016. Research Prostate conditions Spironolactone has been studied at a high dosage in the treatment of benign prostatic hyperplasia (BPH; enlarged prostate). It was found to be better than placebo in terms of symptom relief following three months of treatment. However, this was not maintained after six months of treatment, by which point the improvements had largely disappeared. Moreover, no difference was observed between spironolactone and placebo with regard to volume of residual urine or prostate size. Gynecomastia was observed in about 5% of people. On the basis of these results, it has been said that spironolactone has no place in the treatment of BPH.Spironolactone has been studied and used limitedly in the treatment of prostate cancer. Epstein–Barr virus Spironolactone has been found to block Epstein–Barr virus (EBV) production and that of other human herpesviruses by inhibiting the function of an EBV protein SM, which is essential for infectious virus production. This effect of spironolactone was determined to be independent of its antimineralocorticoid actions. Thus, spironolactone or compounds based on it have the potential to yield novel antiviral medications with a distinct mechanism of action and limited toxicity. Other conditions Spironolactone has been studied in the treatment of rosacea in both males and females.Spironolactone has been studied in fibromyalgia in women. It has also been studied in bulimia nervosa in women, but was not found to be effective. References External links "Spironolactone". Drug Information Portal. U.S. National Library of Medicine.
Caspofungin	Caspofungin (INN) (brand name Cancidas) is a lipopeptide antifungal drug from Merck & Co., Inc. discovered by James Balkovec, Regina Black and Frances A. Bouffard. It is a member of a new class of antifungals termed the echinocandins. It works by inhibiting the enzyme (1→3)-β-D-glucan synthase and thereby disturbing the integrity of the fungal cell wall. Caspofungin was the first inhibitor of fungal (1→3)-β-D-glucan synthesis to be approved by the United States Food and Drug Administration. Caspofungin is administered intravenously. It is on the World Health Organizations List of Essential Medicines. Spectrum of Activity Caspofungin has been effective in treating fungal infections caused by Aspergillus and Candida species. It is a member of the echinocandin family, a new class of antifungal agents with broad spectrum of activity against all Candida species. In comparison to treatment with either fluconazole or Amphotericin B, all three drugs in this class have been demonstrated to be highly effective or superior in well-defined clinical settings including invasive Candida infections, Candida oesophagitis and candidaemia. Higher minimum inhibitory concentration (MIC) of these agents has been observed against C. parapsilosis and C. guilliermondii.The following summarizes MIC susceptibility for a few medically significant organisms. Candida albicans 0.015 — 16 μg/mL Candida krusei 0.03 — 8 μg/mL Cryptococcus neoformans — 16 μg/mL Indications Caspofungin acetate for injection was originally approved by both the Food and Drug Administration (FDA), in the U.S., and the EMEA, in Europe, in 2001. Its currently approved therapeutic indications by both organisations include the empirical therapy of presumed fungal infections in febrile, neutropenic adult patients and for salvage therapy in patients treatment of invasive aspergillosis in adult patients whose disease is refractory to, or who are intolerant of, other antifungal agents (i.e., conventional or lipid formulations of amphotericin B and/or itraconazole). Additionally, the FDA approval includes indication for the treatment of candidemia and some specific Candida infections (intra-abdominal abscesses, peritonitis, pleural cavity infections, and esophagitis) and the EMEA approval includes indication for the treatment of general invasive candidiasis in adult patients. Metabolism Slowly metabolized by peptide hydrolysis and N-acetylation in liver. Therefore, in case of liver impairment the dose needs to be reduced. Caspofungin also undergoes spontaneous chemical degradation to an open-ring peptide compound, L-747969. Additional metabolism involves hydrolysis into constitutive amino acids and their derivatives, including dihydroxyhomotyrosine and N-acetyl-dihydroxyhomotyrosine. Clinical efficacy About 36% of patients refractory to other therapies responded well to caspofungin therapy, while even 70% of patients intolerant to other therapies were classified as responders. Direct comparative studies to other drugs in the treatment of invasive aspergillosis have so far not been undertaken. Contraindications Known hypersensitivity to caspofungin acetate or any other ingredient contained in the formulation contraindicate its use. Warnings Hepatic effectsThe concomitant use of caspofungin and cyclosporine in healthy volunteers led to a more frequent increase of liver enzymes (ALT=SGPT and AST=SGOT) than noted with cyclosporine alone. Combination treatment is only indicated if the potential benefit for the patient outweighs the potential risk. Dosage reduction in patients with moderately impaired liver function is recommended. No clinical data exist regarding the use of caspofungin in patients with severely impaired liver function. Sensitivity reactionsReactions due to histamine release (rash, facial swelling, pruritus, sensation of warmth and one case of anaphylaxis) have been seen. Health-care providers should carefully watch for these reactions. Drug resistanceIn a few patients with infections caused by Candida albicans, mutants with reduced sensitivity to caspofungin have been noticed. Currently there are no data regarding development of resistance in other fungi than C. albicans. Pregnancy and lactation Caspofungin has been shown in animal studies to have embroyotoxic properties, and therefore has been assigned to class C. It should only be given to pregnant women if the benefit to the mother clearly outweighs the potential risk to her fetus. The drug is found in the milk of lactating rats, but it is not known whether this is seen in humans. Thus, lactating women should be treated cautiously. Geriatric patients Ordinarily, no dose adjustments are necessary, however, greater sensitivity of some older individuals cannot be ruled out. Pediatric patients Caspofungin is FDA approved for pediatric patients 3 months and older. Dosing is based on body surface area (BSA) as calculated by the Mosteller formula. Side effects Compared to amphotericin B, caspofungin seems to have a relatively low incidence of side effects. In clinical studies and postmarketing reports, the side effects seen in 1% or more of the patients were as follows: Gastrointestinal system: nausea, vomiting, abdominal pain, and diarrhea Central nervous system: headache Whole body: fever, phlebitis or thrombophlebitis, complications at the intravenous cannulation site (e.g. induration), unspecified pain, flu-like syndrome, myalgia, chills, and paresthesia Respiratory: dyspnea Renal: increased plasma creatinine Hematological: anemia Electrolytes: hypokalemia Liver: increased liver enzymes (asymptomatic) Hypersensitivity: rash, facial edema, pruritus Other: tachycardiaAdditionally, infrequent cases of symptomatic liver damage, peripheral edema and swelling, and hypercalcemia have been seen. One case of anaphylaxis (severe allergic reaction) has also been noted. Resistance Resistance in C. albicans has been described, but is currently still rare. The mechanism is probably a point mutation in the (1→3)-β-D-glucan synthase gene. Drug interactions Cyclosporin: see under hepatic effects Tacrolimus: potential pharmacokinetic interactions Other systemic antimycotic agents: with amphotericin B, itraconazole and mycophenolate, no interactions have been seen Inducers of drug clearance (e.g. carbamazepine, phenytoin, rifampin, dexamethasone): consider 70 mg intravenous as maintenance dose instead of 50 mg Duration of treatment The mean duration of therapy in previous studies was 34 days. Some patients were even healed by a one-day treatment. However, a few patients were treated for as long as 162 days and tolerated the drug well, indicating that longtime use may be indicated and tolerated favourably in complicated cases of aspergillosis. Generally, the duration of treatment is dictated by the severity of the disease, the clinical response, and the improvement of immunocompetence in immunocompromised patients. Dosage An initial dose of 70 mg by intravenous infusion is given followed by 50 mg intravenous daily. If no response is seen or if inducers of caspofungin clearance (see above) are coadministered the daily dose may be increased to 70 mg. An infusion should take approximately 1 hour. Dosage forms Cancidas 50 mg for intravenous infusion (manufacturer Merck) Cancidas 70 mg for intravenous infusion (manufacturer Merck) Brand names in countries other than the U.S. may vary. Semisynthesis Caspofungin is semisynthesized from pneumocandin B0, a fermentation product of Glarea lozoyensis. References External links "Caspofungin". Drug Information Portal. U.S. National Library of Medicine. U.S. Full Prescribing Information EMA on Cancidas (Summary of Product Characteristics)
Amifampridine	Amifampridine is used as a drug, predominantly in the treatment of a number of rare muscle diseases. The free base form of the drug has been used to treat congenital myasthenic syndromes and Lambert–Eaton myasthenic syndrome (LEMS) through compassionate use programs since the 1990s and was recommended as a first line treatment for LEMS in 2006, using ad hoc forms of the drug, since there was no marketed form. Around 2000 doctors at Assistance Publique – Hôpitaux de Paris created a phosphate salt form, which was developed through a series of companies ending with BioMarin Pharmaceutical which obtained European approval in 2009 under the trade name Firdapse, and which licensed the US rights to Catalyst Pharmaceuticals in 2012. As of January 2017, Catalyst and another US company, Jacobus Pharmaceutical, which had been manufacturing and giving it away for free since the 1990s, were both seeking FDA approval for their iterations and marketing rights. Amifampridine phosphate has orphan drug status in the EU for Lambert–Eaton myasthenic syndrome and Catalyst holds both an orphan designation and a breakthrough therapy designation in the US. In May 2019 the U.S. Food and Drug Administration (FDA) approved amifampridine tablets under the trade name Ruzurgi for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical. The only other treatment approved for LEMS (Firdapse) is only approved for use in adults. Medical uses Amifampridine is used to treat many of the congenital myasthenic syndromes, particularly those with defects in choline acetyltransferase, downstream kinase 7, and those where any kind of defect causes "fast channel" behaviour of the acetylcholine receptor. It is also used to treat symptoms of Lambert–Eaton myasthenic syndrome. Contraindications Because it affects voltage-gated ion channels in the heart, it is contraindicated in people with long QT syndrome and in people taking a drug that might prolong QT time like sultopride, disopyramide, cisapride, domperidone, rifampicin or ketoconazol. It is also contraindicated in people with epilepsy or badly controlled asthma. Adverse effects The dose-limiting side effects include tingling or numbness, difficulty sleeping, fatigue, and loss of muscle strength.Amifampridine can cause seizures, especially but not exclusively when given at high doses and/or in particularly vulnerable individuals who have a history of seizures. Interactions The combination of amifampridine with pharmaceuticals that prolong QT time increases the risk of ventricular tachycardia, especially torsade de pointes; and combination with drugs that lower the seizure threshold increases the risk of seizures. Interactions via the livers cytochrome P450 enzyme system are considered unlikely. Pharmacology Mechanism of action In Lambert–Eaton myasthenic syndrome, acetylcholine release is inhibited as antibodies involved in the host response against certain cancers cross-react with Ca2+ channels on the prejunctional membrane. Amifampridine works by blocking potassium channel efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for a longer time and allow greater acetylcholine release to stimulate muscle at the end plate. Pharmacokinetics Amifampridine is quickly and almost completely (93–100%) absorbed from the gut. In a study with 91 healthy subjects, maximum amifampridine concentrations in blood plasma were reached after 0.6 (±0.25) hours when taken without food, or after 1.3 (±0.9) hours after a fatty meal, meaning that the speed of absorption varies widely. Biological half-life (2.5±0.7 hrs) and the area under the curve (AUC = 117±77 ng∙h/ml) also vary widely between subjects, but are nearly independent of food intake.The substance is deactivated by acetylation via N-acetyltransferases to the single metabolite 3-N-acetylamifampridine. Activity of these enzymes (primarily N-acetyltransferase 2) in different individuals seems to be primarily responsible for the mentioned differences in half-life and AUC: the latter is increased up to 9-fold in slow metabolizers as compared to fast metabolizers.Amifampridine is eliminated via the kidneys and urine to 74–81% as N-acetylamifampridine and to 19% in unchanged form. Chemistry 3,4-Diaminopyridine is a pale yellow to pale brown crystalline powder that melts at about 218–220 °C (424–428 °F) under decomposition. It is readily soluble in methanol, ethanol and hot water, but only slightly in diethyl ether. Solubility in water at 20 °C (68 °F) is 25 g/L. The drug formulation amifampridine phosphate contains the phosphate salt, more specifically 4-aminopyridine-3-ylammonium dihydrogen phosphate. This salt forms prismatic, monoclinic crystals (space group C2/c) and is readily soluble in water. The phosphate salt is stable, and does not require refrigeration. History The development of amifampridine and its phosphate has brought attention to orphan drug policies that grant market exclusivity as an incentive for companies to develop therapies for conditions that affect small numbers of people.Amifampridine, also called 3,4-DAP, was discovered in Scotland in the 1970s, and doctors in Sweden first showed its use in LEMS in the 1980s.In the 1990s, doctors in the US, on behalf of Muscular Dystrophy Association, approached a small family-owned manufacturer of active pharmaceutical ingredients in New Jersey, Jacobus Pharmaceuticals, about manufacturing amifampridine so they could test it in clinical trials. Jacobus did so, and when the treatment turned out to be effective, Jacobus and the doctors were faced with a choice — invest in clinical trials to get FDA approval or give the drug away for free under a compassionate use program to about 200 patients out of the estimated 1500-3000 LEMS patients in the U.S.. Jacobus elected to give the drug away to this subset of LEMS patients, and did so for about twenty years.Doctors at the Assistance Publique – Hôpitaux de Paris had created a phosphate salt of 3,4-DAP (3,4-DAPP), and obtained an orphan designation for it in Europe in 2002. The hospital licensed the intellectual property on the phosphate form to the French biopharma company OPI, which was acquired by EUSA Pharma in 2007, and the orphan application was transferred to EUSA in 2008. In 2008 EUSA submitted an application for approval to market the phosphate form to the European Medicines Agency under the brand name Zenas. EUSA, through a vehicle called Huxley Pharmaceuticals, sold the rights to 3,4-DAPP to BioMarin in 2009, the same year that 3,4-DAPP was approved in Europe under the new name Firdapse.The licensing of Firdapse in 2010 in Europe led to a sharp increase in price for the drug. In some cases, this has led to hospitals using an unlicensed form rather than the licensed agent, as the price difference proved prohibitive. BioMarin has been criticized for licensing the drug on the basis of previously conducted research, and yet charging exorbitantly for it. A group of UK neurologists and pediatricians petitioned to prime minister David Cameron in an open letter to review the situation. The company responded that it submitted the licensing request at the suggestion of the French government, and points out that the increased cost of a licensed drug also means that it is monitored by regulatory authorities (e.g. for uncommon side effects), a process that was previously not present in Europe. A 2011 Cochrane review compared the cost of the 3,4-DAP and 3,4-DAPP in the UK and found an average price for 3,4-DAP base of £1/tablet and an average price for 3,4-DAP phosphate of £20/tablet; and the authors estimated a yearly cost per person of £730 for the base versus £29,448 for the phosphate formulation.Meanwhile, in Europe, a task force of neurologists had recommended 3,4-DAP as the firstline treatment for LEMS symptoms in 2006, even though there was no approved form for marketing; it was being supplied ad hoc.: 5 In 2007 the drugs international nonproprietary name was published by the WHO.In the face of the seven-year exclusivity that an orphan approval would give to Biomarin, and of the increase in price that would accompany it, Jacobus began racing to conduct formal clinical trials in order to get approval for the free base form before BioMarin; its first Phase II trial was opened in January 2012.In October 2012, while BioMarin had a Phase III trial ongoing in the US, it licensed the US rights to 3,4-DAPP, including the orphan designation and the ongoing trial, to Catalyst Pharmaceuticals. Catalyst anticipated that it could earn $300 to $900 million per year in sales at peak sales for treatment of people with LEMS and other indications, and analysts anticipated the drug would be priced at around. $100,000 in the US. Catalyst went on to obtain a breakthrough therapy designation for 3,4-DAPP in LEMS in 2013, an orphan designation for congenital myasthenic syndromes in 2015 and an orphan designation for myasthenia gravis in 2016.In August 2013, analysts anticipated that FDA approval would be granted to Catalyst in LEMS by 2015.In October 2014, Catalyst began making available under an expanded access program.In March 2015, Catalyst obtained an orphan designation for the use of 3,4-DAPP to treat of congenital myasthenic syndrome. In April 2015, Jacobus presented clinical trial results with 3,4-DAP at a scientific meeting.In December 2015 a group of 106 neuromuscular doctors who had worked with both Jacobus and BioMarin/Catalyst published an editorial in the journal, Muscle & Nerve, expressing concern about the potential for the price of the drug to be dramatically increased should Catalyst obtain FDA approval, and stating that 3,4-DAPP represented no real innovation and didnt deserve exclusivity under the Orphan Drug Act, which was meant to spur innovation to meet unmet needs. Catalyst responded to this editorial with a response in 2016 that explained that Catalyst was conducting a full range of clinical and non-clinical studies necessary to obtain approval in order to specifically address the unmet need among the estimated 1500-3000 LEMs patients since about 200 were receiving the product through compassionate use – and that this is exactly what the Orphan Drug Act was intended to do: deliver approved products to orphan drug populations so that all patients have full access.In December 2015, Catalyst submitted its new drug application to the FDA, and in February 2016 the FDA refused to accept it, on the basis that it wasnt complete. In April 2016 the FDA told Catalyst it would have to gather further data. Catalyst cut 30% of its workforce, mainly from the commercial team it was building to support an approved product, to save money to conduct the trials. In March 2018 the company re-submitted its NDA. The FDA approved amifampridine for the treatment of adults with Lambert-Eaton myasthenic syndrome on November 29, 2018.In February 2019, U.S. Senator Bernie Sanders questioned the high price ($375,000) charged by Catalyst Pharmaceuticals for Firdapse.In May 2019, the privately held US company Jacobus Pharmaceutical, Princeton, New Jersey gained approval by the FDA for amifampridine tablets (Ruzurgi) for the treatment of LEMS in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. Firdapse is only approved for use in adults. Although Ruzurgi has been approved for pediatric patients, this approval makes it possible for adults with LEMS to get the drug off-label. Jacobus Pharmaceutical had been manufacturing and giving it away for free since the 1990s. The FDA decision dropped the stock of Catalyst Pharmaceuticals. The companys stock price has dropped about 50%. Research Amifampridine has also been proposed for the treatment of multiple sclerosis (MS). A 2002 Cochrane systematic review found that there was no unbiased data to support its use for treating MS. There was no change as of 2012. References External links "Amifampridine". Drug Information Portal. U.S. National Library of Medicine. "Amifampridine phosphate". Drug Information Portal. U.S. National Library of Medicine.
Mesalazine	Mesalazine, also known as mesalamine or 5-aminosalicylic acid (5-ASA), is a medication used to treat inflammatory bowel disease, including ulcerative colitis and Crohns disease. It is generally used for mildly to moderately severe disease. It is taken by mouth or rectally. The formulations which are taken by mouth appear to be similarly effective.Common side effects include headache, nausea, abdominal pain, and fever. Serious side effects may include pericarditis, liver problems, and kidney problems. Use in pregnancy and breastfeeding appears safe. In people with a sulfa allergy certain formulations may result in problems. Mesalazine is an aminosalicylate and anti-inflammatory. It works by direct contact with the intestines.Mesalazine was approved for medical use in the United States in 1987. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication and sold under many brand names worldwide. In 2019, it was the 229th most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses It is used to treat inflammatory bowel disease, including ulcerative colitis and Crohns disease (effective only in colonic diseases). It is generally used for mildly to moderately active disease. It is taken by mouth or rectally. The formulations which are taken by mouth appear to be similarly effective. Side effects There are no data on use in pregnant women, but the drug does cross the placenta and is excreted in breast milk. The drug should not be used in children under two years of age, people with kidney disease, or people who are allergic to aspirin.Side effects are primarily gastrointestinal but may also include headache; GI effects include nausea, diarrhea and abdominal pain. There have been scattered reports of various problems when the oral form is used, including: problems caused by myelosuppression (leukopenia, neutropenia, agranulocytosis, aplastic anaemia, and thrombocytopenia), as well as hair loss, peripheral neuropathy, pancreatitis, liver problems, myocarditis and pericarditis, allergic and fibrotic lung reactions, lupus erythematosus-like reactions and rash (including urticaria), drug fever, interstitial nephritis and nephrotic syndrome, usually reversible on withdrawal. Very rarely, use of mesalazine has been associated with an exacerbation of the symptoms of colitis, Stevens Johnson syndrome and erythema multiforme. Chemistry Mesalazine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine. It is also the active component of the prodrug balsalazide along with the inert carrier molecule 4-aminobenzoyl-beta-alanine. It is in the category of disease-modifying antirheumatic drugs (DMARDs) family of medications. It is unclear exactly how it works. Mechanism of action Exact mechanism of mesalazine is unknown, but is speculated that mesalazine decreases synthesis of prostaglandin and leukotriene, modulating the inflammatory response derived from the cyclooxygenase and lipooxygenase pathways. It appears to act locally on colonic mucosa. Society and culture Brand names Mesalazine is sold under various names including Apriso, Asacol, Asacol HD, Canasa, Delzicol, Fivasa, Lialda, Pentasa, Rowasa, and Sfrowasa. References External links "Mesalamine". Drug Information Portal. U.S. National Library of Medicine.
Prostaglandin E1	Prostaglandin E1 (PGE1), also known as alprostadil, is a naturally occurring prostaglandin which is used as a medication. In infants with congenital heart defects, it is delivered by slow injection into a vein to open the ductus arteriosus until surgery can be carried out. By injection into the penis or placement in the urethra, it is used to treat erectile dysfunction.Common side effects when given to babies include decreased breathing, fever, and low blood pressure. When used for erectile dysfunction side effects may include penile pain, bleeding at the site of injection, and prolonged erection (priapism). Prostaglandin E1 is in the vasodilator family of medications. It works by opening blood vessels and relaxing smooth muscle.Prostaglandin E1 was isolated in 1957 and approved for medical use in the United States in 1981. It is on the World Health Organizations List of Essential Medicines. Medical uses Patent ductus arteriosus Alprostadil is also used in maintaining a patent ductus arteriosus in newborns. This is primarily useful when the threat of premature closure of the ductus arteriosus exists in an infant with ductal-dependent congenital heart disease, including cyanotic lesions (e.g., hypoplastic left heart syndrome, pulmonary atresia/stenosis, tricuspid atresia/stenosis, transposition of the great arteries) and acyanotic lesions (e.g., coarctation of the aorta, critical aortic stenosis, and interrupted aortic arch). Sexual dysfunction Alprostadil is sold in the United States as urethral suppositories and in injectable form. The suppositories are sold under the brand name Muse. The injectable forms are Edex and Caverject. Muse delivers alprostadil as a penile suppository, inserted into the urethra, at least ten minutes before the erection is needed. Caverject and Edex are similarly fast-acting, but instead are injected by syringe directly into the corpus cavernosum of the penis. Alprostadil is also available as a generic. The major cost is that it must be mixed by a compounding pharmacy and supplies may be difficult to obtain. The different formulations, including Bimix and Trimix, may include papaverine and/or phentolamine. A typical mix might be 30 mg of papaverine, 2 mg of phentolamine, and 20 μg alprostadil. As a generic, it is much less expensive than the packaged injectables. It is premixed and must be kept refrigerated and the user must load a syringe with the quantity needed.Most recently, the compound has been made easily accessible in an applicable topical cream form known as Vitaros. Made by Takeda UK Ltd, it is now available in Europe and contains either 200 or 300 micrograms of alprostadil in 100 mg of cream which is directly administered as a topical cream applied to the urethra in a preloaded delivery device. The tip of the device is placed in the urethral meatus and the cream delivered into the urethra. Clinical trials for the treatment showed positive results in over 3000 men that it was tested on, and unlike other sexual dysfunction medication, it is said to be usable by men with diabetes or heart problems and those who have undergone a prostatectomy. It has no known interactions with food, alcohol or other medications making it safer than other treatments containing alprostadil. Similarly to the Bimix and Trimix injections though, it must be kept under cool temperatures. Critical limb ischemia Prostanoids, including alprostadil, do not reduce the risk of limb amputation but may offer a slight improvement in rest-pain and leg ulcer healing in persons with critical limb ischemia. Contrast-induced nephropathy Preventative administration of alprostadil may reduce the risk of kidney injury (specifically contrast-induced nephropathy) in persons having cardiac angiography or percutaneous coronary intervention. Adverse effects Biosynthesis Prostaglandin E1 is biosynthesized on an as-needed basis from dihomo-γ-linolenic acid (an omega-6 fatty acid) in healthy humans without coronary artery disease and/or a genetic disorder. Other versions Misoprostol is another synthetic prostaglandin E1 analog used to prevent gastric ulcers when taken on a continuous basis, to treat missed miscarriage, to induce labor, and to induce abortion. References External links "Alprostadil". Drug Information Portal. U.S. National Library of Medicine.
Nitrofurantoin	Nitrofurantoin is an antibacterial medication used to treat urinary tract infections, but it is not as effective for kidney infections. It is taken by mouth.Common side effects include nausea, loss of appetite, diarrhea, and headaches. Rarely numbness, lung problems, or liver problems may occur. It should not be used in people with kidney problems. While it appears to be generally safe during pregnancy it should not be used near delivery. While it usually works by slowing bacterial growth, it may result in bacterial death at the high concentrations found in urine.Nitrofurantoin was first sold in 1953. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 192nd most commonly prescribed medication in the United States, with more than 2 million prescriptions. Medical uses Current uses include the treatment of uncomplicated urinary tract infections (UTIs) and prophylaxis against UTIs in people prone to recurrent UTIs.Increasing bacterial antibiotic resistance to other commonly used agents, such as trimethoprim/sulfamethoxazole and fluoroquinolones, has led to increased interest in using nitrofurantoin. The efficacy of nitrofurantoin in treating UTIs combined with a low rate of bacterial resistance to this agent makes it one of the first-line agents for treating uncomplicated UTIs as recommended by the Infectious Diseases Society of America and the European Society for Microbiology and Infectious Diseases.Nitrofurantoin is not recommended for the treatment of pyelonephritis, prostatitis, and intra-abdominal abscess, because of extremely poor tissue penetration and low blood levels. Antibacterial activity Nitrofurantoin has been shown to have good activity against: E. coli Staphylococcus saprophyticus Coagulase negative staphylococci Enterococcus faecalis Staphylococcus aureus Streptococcus agalactiae Citrobacter species Klebsiella species Bacillus subtilis speciesIt is used in the treatment of infections caused by these organisms.Many or all strains of the following genera are resistant to nitrofurantoin: Enterobacter Proteus PseudomonasAntibiotic susceptibility testing should always be performed to further elucidate the resistance profile of the particular strain of bacteria causing infection. Special populations Pregnancy Nitrofurantoin is pregnancy category B in the United States and pregnancy category A in Australia. It is one of the few drugs commonly used in pregnancy to treat UTIs. It however should not be used in late pregnancy due to the potential risk of hemolytic anemia in the newborn. Newborns of women given this drug late in pregnancy had a higher risk of developing neonatal jaundice.Evidence of safety in early pregnancy is mixed as of 2017. The American College of Obstetricians and Gynecologists states that while they can be used in the first trimester other options may be preferred. They remain a first line treatment in the second trimester. A 2015 meta analysis found no increased risk from first trimester use in cohort studies that was a slight increase of malformations in case control studies. Available forms There are two formulations of nitrofurantoin: Macrocrystals - (Macrodantin, Furadantin) – 25, 50, or 100 mg capsules – taken once every 6 hours Monohydrate/macrocrystals - (Macrobid) – 100 mg capsules – taken once every 12 hours or 2 times a day (written on prescriptions as BID, which is the last part of the trade name MacroBID). It is 75% monohydrate and 25% macrocrystals. Contraindications Nitrofurantoin is contraindicated in patients with decreased renal function (CrCl < 60 ml/min) due to systemic accumulation and subtherapeutic levels reached in the urinary tract. However, a retrospective chart review suggests the data for this cutoff are slim and a cutoff of CrCl < 40 ml/min would be more appropriate. Many of the severe side effects of this drug are more common in the elderly and those with renal impairment, as this causes the drug to be retained in the body and reach higher systemic levels. Thus, the drug is not recommended for the elderly population according to 2012 AGS Beers criteria.Nitrofurantoin is also contraindicated in babies up to the age of one month, as they have immature enzyme systems in their red blood cells (glutathione instability), so nitrofurantoin must not be used because it can cause haemolytic anaemia. For the same reason, nitrofurantoin should not be given to pregnant women after 38 weeks of pregnancy. Nitrofurantoin is contraindicated in patients with glucose-6-phosphate dehydrogenase deficiency (G6PD) because of risk of intravascular hemolysis resulting in anemia. Adverse effects The most common side effects with nitrofurantoin are nausea, headache, and flatulence. Less common adverse events (occurring in less than 1% of those taking the drug) include: Gastrointestinal: diarrhea, dyspepsia, abdominal pain, constipation, emesis Neurologic: dizziness, drowsiness, amblyopia Respiratory: acute pulmonary hypersensitivity reaction Allergic: pruritus, urticaria Dermatologic: hair loss Miscellaneous: fever, chills, malaisePatients should be informed that nitrofurantoin colors urine brown; this is completely harmless.Some of the more serious but rare side effects of nitrofurantoin have been a cause of concern. These include pulmonary reactions, hepatotoxicity, and neuropathy. Lung toxicity The pulmonary toxicity caused by nitrofurantoin can be categorized into acute, subacute, and chronic pulmonary reactions. The acute and subacute reactions are thought to be due to a hypersensitivity reaction and often resolve when the drug is discontinued. Acute reactions have been estimated to occur in about one in 5000 women who take the drug. These reactions usually develop 3–8 days after the first dose of nitrofurantoin, but may occur from a few hours to a few weeks after starting the drug. Symptoms include fever, dyspnea, chills, cough, pleuritic chest pain, headache, back pain, and epigastric pain. Chest radiograph will often show unilateral or bilateral infiltrates similar to pulmonary edema. Treatment includes discontinuation of the nitrofurantoin, which should result in symptom improvement within 24 hours.Chronic pulmonary reactions caused by nitrofurantoin include diffuse interstitial pneumonitis, pulmonary fibrosis, or both. This uncommon reaction may occur 1 month to 6 years after starting the drug and is usually related to its total lifetime dose. This reaction manifests with progressive shortness of breath. It is important to recognize nitrofurantoin as possible cause of symptoms and discontinue the drug when the suspicion of pulmonary side effects arises as it can be reversible if the drug is stopped early. Liver toxicity Hepatic reactions, including hepatitis, cholestatic jaundice, chronic active hepatitis, and hepatic necrosis, occur rarely. The onset of chronic active hepatitis may be insidious, and patients should be monitored periodically for changes in biochemical tests that would indicate liver injury. These reactions usually occur after exposure to the drug for more than 6 weeks. If signs of liver failure are observed in a patient taking nitrofurantoin, the drug should be discontinued. Re-challenge with the drug at a later date is not recommended, as the reaction may have a hypersensitivity component and recur when the drug is resumed. Neuropathy Neuropathy is a rare side effect of taking nitrofurantoin. Patients may experience numbness and tingling in a stocking-glove pattern, which may or may not improve upon discontinuation of the drug. Pharmacology Organisms are said to be susceptible to nitrofurantoin if their minimum inhibitory concentration is 32 μg/mL or less. The peak blood concentration of nitrofurantoin following an oral dose of nitrofurantoin 100 mg is less than 1 μg/mL and may be undetectable. Its bioavailability is about 90% and the urinary excretion is 40% tissue penetration is negligible; the drug is well concentrated in the urine: 75% of the dose is rapidly metabolised by the liver, but 25% of the dose is excreted in the urine unchanged, reliably achieving levels of 200 μg/mL or more. In studies of dogs, the majority of urinary excretion is through glomerular filtration with some tubular secretion. There is also tubular absorption which is increased with urine acidification. However the activity of nitrofurantoin is also pH dependent and mean inhibitory concentration rises sharply with increased pH above 6. Nitrofurantoin cannot be used to treat infections other than simple cystitis. At the concentrations achieved in urine (>100 μg/mL), nitrofurantoin is a bactericide. It is bacteriostatic against most susceptible organisms at concentrations less than 32 μg/mL.Nitrofurantoin and the quinolone antibiotics are mutually antagonistic in vitro. It is not known whether this is of clinical significance, but the combination should be avoided.Resistance to nitrofurantoin may be chromosomal or plasmid-mediated and involves inhibition of nitrofuran reductase. Acquired resistance in E. coli continues to be rare. Nitrofurantoin and its metabolites are excreted mainly by the kidneys. In renal impairment, the concentration achieved in urine may be subtherapeutic. Nitrofurantoin should not be used in patients with a creatinine clearance of 60 mL/min or less. However, a retrospective chart review may suggest nitrofurantoin is not contraindicated in this population. Mechanism of action Nitrofurantoin is concentrated in the urine, leading to higher and more effective levels in the urinary tract than in other tissues or compartments. With a 100 mg oral dose, plasma levels are typically less than 1 µg/mL while in the urine it reaches 200 µg/mL.The drug works by damaging bacterial DNA, since its reduced form is highly reactive. This is made possible by the rapid reduction of nitrofurantoin inside the bacterial cell by flavoproteins (nitrofuran reductase) to multiple reactive intermediates that attack ribosomal proteins, DNA, respiration, pyruvate metabolism and other macromolecules within the cell. Nitrofurantoin exerts greater effects on bacterial cells than mammalian cells because bacterial cells activate the drug more rapidly. It is not known which of the actions of nitrofurantoin is primarily responsible for its bactericidal activity. The broad mechanism of action for this drug likely is responsible for the low development of resistance to its effects, as the drug affects many different processes important to the bacterial cell. History Nitrofurantoin has been available for the treatment of lower urinary tract infections (UTIs) since 1953. Society and culture Brand names Nitrofurantoin is marketed under many names in countries worldwide. Animal feed Residues from the breakdown of nitrofuran veterinary antibiotics, including nitrofurantoin, have been found in chicken in Vietnam, China, Brazil, and Thailand. The European Union banned the use of nitrofurans in food producing animals by classifying it in ANNEX IV (list of pharmacologically active substances for which no maximum residue limits can be fixed) of the Council Regulation 2377/90. The Food and Drug Administration (FDA) of the United States has prohibited furaltadone since February 1985 and withdrew the approval for the other nitrofuran drugs (except some topical uses) in January 1992. The topical use of furazolidone and nitrofurazone was prohibited in 2002. Australia prohibited the use of nitrofurans in food production in 1992. Japan did not allocate MRLs for nitrofurans leading to the implementation of a "zero tolerance or no residue standard". In Thailand, the Ministry of Health issued in 2001 Proclamation No. 231 MRL of veterinary drug in food which did not allocate MRL for nitrofurans. The Ministry of Agriculture and Cooperatives had already prohibited importation and use of furazolidone and nitrofurazone in animal feed in 1999 which was extended to all nitrofurans in 2002. Several metabolites of nitrofurans, such as furazolidone, furaltadone and nitrofurazone cause cancer or genetic damage in rats. References External links "Nitrofurantoin". Drug Information Portal. U.S. National Library of Medicine.
Semaglutide	Semaglutide, sold under the brand names Wegovy and Ozempic among others, is an antidiabetic medication used for the treatment of type 2 diabetes and long-term weight management.Semaglutide is a GLP-1 receptor agonist, meaning that it mimics the action of the human incretin glucagon-like peptide-1 (GLP-1), thereby increasing insulin secretion and increasing blood sugar disposal and improving glycemic control. An injectable version (Ozempic) was approved for medical use in the United States in December 2017, and in the European Union, Canada, and Japan in 2018. A version which is taken by mouth (Rybelsus) was approved for medical use in the United States in September 2019, and in the European Union in April 2020. It is the first glucagon-like peptide receptor protein treatment approved for use in the United States that does not need to be injected. It was developed by Novo Nordisk. Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation.In June 2021, the US Food and Drug Administration (FDA) approved semaglutide injection sold under the brand name Wegovy for long-term weight management in adults. It was approved for medical use in the European Union in January 2022. Medical uses Semaglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes.Semaglutide is also indicated as an adjunct to diet and exercise for long-term weight management in adults with obesity (initial body mass index (BMI) ≥ 30 kg/m2) or overweight (initial BMI ≥ 27 kg/m2) with at least one weight-related comorbidity. A 2022 review of anti-obesity treatments found that semaglutide as well as tirzepatide (which has an overlapping mechanism of action) were more promising than previous anti-obesity drugs, although less effective than bariatric surgery. Adverse effects Side effects include nausea, vomiting, diarrhea, abdominal pain, and constipation. In people with heart problems, it can cause damage to the retina of the eye (retinopathy). Other, less common side effects include kidney problems, allergic reactions, low blood sugar, and pancreatitis. Contraindications Due to data from rodents studies of GLP1 mediated thyroid C-cell hyperplasia, their use is contraindicated in patients with a personal or family history of medullary thyroid carcinoma and in patients with multiple endocrine neoplasia syndrome type 2. Mechanism of action Semaglutide is a glucagon-like peptide-1 receptor agonist. By mimicking the action of the incretin GLP-1, it increases the production of insulin, a hormone that lowers the blood sugar level. It appears to enhance growth of pancreatic beta cells, which are responsible for insulin production and release. It also inhibits the production of glucagon, which is a hormone that increases glycogenolysis (release of stored carbohydrate from the liver) and gluconeogenesis (synthesis of new glucose). It reduces food intake by lowering appetite and slowing down digestion in the stomach, helping to reduce body fat. Its half-life in the blood is about seven days (165–184 hours). Structure Semaglutide is chemically similar to human GLP-1, with 94% similarity. The only differences are two amino-acid substitutions at positions 8 and 34, where alanine and lysine are replaced by 2-aminoisobutyric acid and arginine, respectively. Amino-acid substitution at position 8 prevents chemical breakdown by dipeptidyl peptidase-4. In addition, the lysine at position 26 is in its derivative form (acylated with stearic diacid). Acylation with a spacer and C-18 fatty diacid chain increases the drugs binding to blood protein (albumin), which enables longer presence in the blood circulation. History Semaglutide was developed in 2012, by a team of researchers at Novo Nordisk as a longer-acting alternative to liraglutide as a once-weekly diabetes therapy. It was given the brand name Ozempic. Clinical trials were started on 6 January 2016, and completed on 19 May 2017.Researchers at the University of Leeds and Novo Nordisk reported in 2017, that it can also be used for the treatment of obesity. It reduces hunger, food craving and body fat. A phase 3 randomized controlled trial found that once-weekly injection of 2.4 mg of the drug resulted in an average change of −14.9% body weight at 68 weeks compared to −2.4% for the placebo.The US FDA New Drug Application (NDA) was filed in December 2016, and in October 2017, the FDA Advisory Committee approved it unanimously. It can be administered by injection or orally. Authorization was granted in February 2018 for the European Union, in March 2018 in Japan, on 4 January 2018 in Canada, and in August 2019 in Australia.In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion on Wegovy, the formulation intended for the treatment of people with obesity or who are overweight in the presence of other related conditions, recommending the granting of a marketing authorization. The applicant for this medicinal product is Novo Nordisk A/S. Wegovy was approved for medical use in the European Union in January 2022. 2022 shortages As a result of an increase in prescriptions for weight loss in non-diabetic patients, a shortage of Semaglutide/Ozempic was reported in Australia in 2022. This shortage resulted in many people with type 2 diabetes being unable to access the drug. In May 2022, the Australian Therapeutic Goods Administration, along with Novo Nordisk, sent out guidelines to all health professionals, reminding them that people with type 2 diabetes need to be prioritised in terms of supply. An update to the guidelines was released in August 2022.Shortages were also reported contemporaneously in the United States In the same month, rival Eli Lilly stated in its quarterly investors call that it was working "around the clock" to ensure adequate supply of its rival GLP-1 agonist tirzepatide (Mounjaro). Research Semaglutide was found to be inferior to tirzepatide in a 2021 study of tirzepatide (LY3298176) vs semaglutide once weekly as add-on therapy to metformin in participants with type 2 diabetes (SURPASS-2), in both endpoints of reduction in A1C and body weight, with a roughly similar safety profile.A meta-analysis including a small number of patients found that semaglutide may be effective in lowering liver enzymes (transaminitis) and improving certain radiologically observed features of metabolic-dysfunction–associated fatty-liver disease (MAFLD). References External links "Semaglutide". Drug Information Portal. U.S. National Library of Medicine. "Semaglutide". MedlinePlus.
Afrin	Afrin may refer to: Places Afrin Canton, one of the cantons of the de facto autonomous Democratic Federation of Northern Syria Afrin District, a district of Aleppo Governorate in northern Syria. The administrative centre is the city of Afrin Afrin Subdistrict, a subdistrict of the Afrin District Afrin Region, the westernmost of the three regions of the de facto autonomous Democratic Federation of Northern Syria Afrin River, a river in Turkey and Syria Afrin Dam, dam on the Afrin River in northwest Syria Afrin, Syria, a city in northwestern Syria, administratively part of Aleppo Governorate Institutions Afrin SC, a football club based in Afrin, Syria University of Afrin, an unrecognized university established in the city of Afrin by the Afrin Canton Board of Education Products Afrin (nasal spray), a nasal decongestant People Given name Afrin Ali (born 1986), Indian politician Surname Jill Afrin (born 1962), psychiatrist Nahid Afrin (born 2001), Indian playback singer Narin Afrin, resistance leader
Bremelanotide	Bremelanotide, sold under the brand name Vyleesi, is a medication used to treat low sexual desire in women. Specifically it is used for low sexual desire which occurs before menopause and is not due to medical problems, psychiatric problems, or problems within the relationship. It is given by an injection just under the skin of the thigh or abdomen.Common side effects include nausea, pain at the site of injection, and headache. It may also cause a temporary increase in blood pressure and decrease in heart rate after each dose, and darkening of the gums, face, and breasts. The medication is a peptide and acts by activating the melanocortin receptors.Bremelanotide was approved for medical use in the United States in 2019. It was developed by Palatin Technologies. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Bremelanotide is used for the treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Specifically it is only recommended in those who have the condition without an underlying cause, such as medical, psychiatric, or relationship problems.It should be used at least 45 minutes before anticipated sexual activity. Only one dose per 24 hours or no more than eight doses per month is recommended. It should be stopped after eight weeks if there is no improvement in sexual desire and associated distress. Contraindications Due to its effects on blood pressure (generally a transient increase in systolic blood pressure by 6 mmHg, and diastolic blood pressure by 3 mmHg), bremelanotide is considered contraindicated in people with uncontrolled high blood pressure or cardiovascular disease. As long as bremelanotide is not used more than once in one day, it is not expected to cause more severe increases in blood pressure. Side effects The most frequently encountered side effect of bremelanotide is nausea (40.0%), which may be intolerable to some people. The use of anti-nausea medications (e.g. ondansetron) prior to administration of bremelanotide may help to reduce the nausea. Other side effects may include flushing (20.3%), injection site reactions (13.2%), headache (11.3%), vomiting (4.8%), cough (3.3%), fatigue (3.2%), hot flushes (2.7%), paresthesia (2.6%), dizziness (2.2%), and nasal congestion (2.1%). Discoloration of the skin, specifically hyperpigmentation, may occur—especially if bremelanotide is used more than eight times in one month. The discoloration may not resolve upon stopping use of bremelanotide, and may occur on the face, gums, or breasts. Experiments in animals, even at high doses, failed to find any negative consequence of bremelanotide on fertility. Interactions Bremelanotide does not meaningfully interact with alcohol, unlike flibanserin (for which the interaction with alcohol is a major barrier to its use). However, bremelanotide does interact with certain medications that people take by mouth. By slowing gastric motility, bremelanotide is thought to reduce the oral absorption (bioavailability) of certain medications, such as naltrexone and indomethacin. Pharmacology Pharmacodynamics Bremelanotide is a non-selective agonist of the melanocortin receptors, MC1 through MC5 (with the exception of MC2, the receptor of ACTH), but acting primarily as an MC3 and MC4 receptor agonist. Pharmacokinetics The bioavailability of bremelanotide with subcutaneous injection is about 100%. Following a subcutaneous injection of bremelanotide, maximal levels occur after about one hour, with a range of 0.5 to 1.0 hours. The plasma protein binding of bremelanotide is 21%. Bremelanotide is metabolized via hydrolysis of its peptide bonds. The elimination half-life of bremelanotide is 2.7 hours, with a range of 1.9 to 4.0 hours. Bremelanotide is excreted 64.8% in urine and 22.8% in feces. Chemistry Bremelanotide is a cyclic heptapeptide lactam analogue of α-melanocyte-stimulating hormone (α-MSH). It has the amino acid sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, and is also known as cyclo-[Nle4,Asp5,D-Phe7,Lys10]α-MSH-(4-10). Bremelanotide is an active metabolite of melanotan II that lacks the C-terminal amide group.Aside from melanotan II and endogenous melanocyte-stimulating hormones like α-MSH, other peptide analogues of the same family as bremelanotide include afamelanotide (NDP-α-MSH), modimelanotide, and setmelanotide. History Studies in the early 1960s showed that administration of α-MSH caused sexual arousal in rats, sparking interest in α-MSH. In the 1980s, scientists at University of Arizona began developing α-MSH and analogs as potential sunless tanning agents. They synthesized and tested several analogs, including peptides they subsequently named, melanotan-I and melanotan II.Very early in the process one of the scientists, Mac Hadley, who was conducting experiments on himself with the peptide melanotan II, injected himself with twice the dose he intended and experienced an eight-hour erection, along with nausea and vomiting.To pursue the tanning agent, melanotan-I was licensed by Competitive Technologies, a technology transfer company operating on behalf of University of Arizona, to an Australian startup called Epitan, which changed its name to Clinuvel in 2006.To pursue the sexual dysfunction agent, melanotan II was licensed by Competitive Technologies to Palatin Technologies. Palatin ceased development of melanotan-II in 2000, and synthesized, patented, and began to develop bremelanotide, a likely metabolite of melanotan-II that differs from melanotan-II in that it has a hydroxyl group where melanotan-II has an amide. Competitive Technologies sued Palatin for breach of contract and to try to claim ownership of bremelanotide; the parties settled in 2008, with Palatin retaining rights to bremelanotide, returning rights to melanotan-II to Competitive Technologies, and paying $800,000.In August 2004, Palatin signed an agreement with King Pharmaceuticals to co-develop bremelanotide in the US and jointly license it outside the US; King paid Palatin $20M upfront.Palatin conducted Phase II trials of intranasal bremelanotide in both female sexual dysfunction (FSD) and male erectile dysfunction (ED) but these trials were halted by the FDA in 2007, due to increased blood pressure in clinical trial subjects; Palatin stopped development of the intranasal formulation in 2008. Four trials were conducted in ED, the last being a Phase IIb published in 2008. King terminated the co-development agreement shortly after the FDA halted the trials.The drug was then reformulated to be delivered by injection and trials continued in FSD. A phase II dose-finding trial in FSD in which the drug was administered 45 minutes before sex showed promise at the highest dose and only transient signs of high blood pressure; two Phase III trials were launched at the end of 2014. Palatin launched the Phase III trials with bremelanotide administered via an autoinjector.In 2014, Palatin licensed European rights to bremelanotide to Gedeon Richter Plc. for around $10 million, and Palatin received a milestone payment of around $3 million when it started the Phase III trials in the US. In September 2016, Palatin and Gedeon RIchter terminated that agreement.In November 2016, Palatin announced results of the Phase III trials, and shortly thereafter began seeking a partner to complete development in the US. In January 2017, Palatin and AMAG Pharmaceuticals agreed that AMAG exclusively would complete development and market bremelanotide in North America and the two would work together to license it in other territories; AMAG agreed to pay $60 million upfront, up to $80 million in regulatory milestones, up to $300 million in sales milestones, and tiered royalties ranging from high single digit to low double digit percentages.A New Drug Application of bremelanotide for female sexual dysfunction was accepted by the U.S. Food and Drug Administration (FDA) in June 2018, with a Prescription Drug User Fee Act (PDUFA) goal date set for 23 March 2019. It was approved for use in the United States in June 2019. References External links "Bremelanotide Acetate". Drug Information Portal. U.S. National Library of Medicine. "Drug Approval Package: Vyleesi". U.S. Food and Drug Administration (FDA).
Moxifloxacin	Moxifloxacin is an antibiotic, used to treat bacterial infections, including pneumonia, conjunctivitis, endocarditis, tuberculosis, and sinusitis. It can be given by mouth, by injection into a vein, and as an eye drop.Common side effects include diarrhea, dizziness, and headache. Severe side effects may include spontaneous tendon ruptures, nerve damage, and worsening of myasthenia gravis. Safety of use in pregnancy and breastfeeding is unclear. Moxifloxacin is in the fluoroquinolone family of medications. It usually kills bacteria by blocking their ability to duplicate DNA.Moxifloxacin was patented in 1988 and approved for use in the United States in 1999. It is on the World Health Organizations List of Essential Medicines. Medical uses Moxifloxacin treats a number of infections, including respiratory-tract infections, cellulitis, anthrax, intra-abdominal infections, endocarditis, meningitis, and tuberculosis.In the United States, moxifloxacin is licensed for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, community-acquired pneumonia, complicated and uncomplicated infections of the skin and of the skin structure, and complicated intra-abdominal infections. In the European Union, it is licensed for acute bacterial exacerbations of chronic bronchitis, non-severe community-acquired pneumonia, and acute bacterial sinusitis. On the basis of its investigation into reports of rare but severe cases of liver toxicity and skin reactions, the European Medicines Agency recommended in 2008 that the use of the oral (but not the intravenous) form of moxifloxacin be restricted to infections in which other antibacterial agents cannot be used or have failed. In the United States, the marketing approval does not contain these restrictions, though the label contains prominent warnings of skin reactions. The initial approval by the Food and Drug Administration of the United States (December 1999) encompassed these indications: Acute exacerbations of chronic bronchitis Acute bacterial sinusitis Community acquired pneumoniaAdditional indications approved by the Food and Drug Administration: April 2001: Uncomplicated skin and skin-structure infections May 2004: Community-acquired pneumonia caused by multidrug-resistant Streptococcus pneumoniae June 2005: Complicated skin and skin-structure infections November 2005: Complicated intra-abdominal infectionsThe European Medicines Agency has advised that, for pneumonia, acute bacterial sinusitis, and acute exacerbations of COPD, it should only be used when other antibiotics are inappropriate.Oral and intravenous moxifloxacin have not been approved for children. Several drugs in this class, including moxifloxacin, are not licensed by the Food and Drug Administration for use in children, because of the risk of permanent injury to the musculoskeletal system. Moxifloxacin eye drops are approved for conjunctival infections caused by susceptible bacteria.Recently, alarming reports of moxifloxacin resistance rates among anaerobes have been published. In Austria 36% of Bacteroides have been reported to be reistant to moxifloxacin, while in Italy resistance rates as high as 41% have been reported. Susceptible bacteria A broad spectrum of bacteria is susceptible, including the following: Staphylococcus aureus Staphylococcus epidermidis Streptococcus pneumoniae Haemophilus influenzae Klebsiella spp. Moraxella catarrhalis Enterobacter spp. Mycobacterium spp. Bacillus anthracis Mycoplasma genitalium Adverse effects Rare but serious adverse effects that may occur as a result of moxifloxacin therapy include irreversible peripheral neuropathy, spontaneous tendon rupture and tendonitis, hepatitis, psychiatric effects (hallucinations, depression), torsades de pointes, Stevens–Johnson syndrome and Clostridium difficile-associated disease, and photosensitivity/phototoxicity reactions.Several reports suggest the use of moxifloxacin may lead to uveitis. Pregnancy and breastfeeding Exposure of the developing fetus to quinolones, including levofloxacin, during the first-trimester is not associated with an increased risk of stillbirths, premature births, birth defects, or low birth weight. There is limited data about the appearance of moxifloxacin in human breastmilk. Animal studies have found that moxifloxacin appears in significant concentration in breastmilk. Decisions as to whether to continue therapy during pregnancy or while breast feeding should take the potential risk of harm to the fetus or child into account, as well as the importance of the drug to the well-being of the mother. Contraindications Only two listed contraindications are found within the 2008 package insert: "Nonsteroidal anti-inflammatory drugs (NSAIDs): Although not observed with moxifloxacin in preclinical and clinical trials, the concomitant administration of a nonsteroidal anti-inflammatory drug with a fluoroquinolone may increase the risks of CNS stimulation and convulsions." "Moxifloxacin is contraindicated in persons with a history of hypersensitivity to moxifloxacin, any member of the quinolone class of antimicrobial agents, or any of the product components."Though not stated as such within the package insert, ziprasidone is also considered to be contraindicated, as it may have the potential to prolong QT interval. Moxifloxacin should also be avoided in patients with uncorrected hypokalemia, or concurrent administration of other medications known to prolong the QT interval (antipsychotics and tricyclic antidepressants).Moxifloxacin should be used with caution in patients with diabetes, as glucose regulation may be significantly altered.Moxifloxacin is also considered to be contraindicated within the pediatric population, pregnancy, nursing mothers, patients with a history of tendon disorder, patients with documented QT prolongation, and patients with epilepsy or other seizure disorders. Coadministration of moxifloxacin with other drugs that also prolong the QT interval or induce bradycardia (e.g., beta-blockers, amiodarone) should be avoided. Careful consideration should be given in the use of moxifloxacin in patients with cardiovascular disease, including those with conduction abnormalities. Children and adolescents The safety of moxifloxacin in human patients under age 18 has not been established. Animal studies suggest a risk of musculoskeletal harm in juveniles. Interactions Moxifloxacin is not believed to be associated with clinically significant drug interactions due to inhibition or stimulation of hepatic metabolism. Thus, it should not, for the most part, require special clinical or laboratory monitoring to ensure its safety. Moxifloxacin has a potential for a serious drug interaction with NSAIDs.The combination of corticosteroids and moxifloxacin has increased potential to result in tendonitis and disability.Antacids containing aluminium or magnesium ions inhibit the absorption of moxifloxacin. Drugs that prolong the QT interval (e.g., pimozide) may have an additive effect on QT prolongation and lead to increased risk of ventricular arrhythmias. The international normalised ratio may be increased or decreased in patients treated with warfarin. Overdose "In the event of acute overdose, the stomach should be emptied and adequate hydration maintained. ECG monitoring is recommended due to the possibility of QT interval prolongation. The patient should be carefully observed and given supportive treatment. The administration of activated charcoal as soon as possible after oral overdose may prevent excessive increase of systemic moxifloxacin exposure. About 3% and 9% of the dose of moxifloxacin, as well as about 2% and 4.5% of its glucuronide metabolite are removed by continuous ambulatory peritoneal dialysis and hemodialysis, respectively." (Quoting from 29 December 2008 package insert for Avelox) Pharmacology Mechanism of action Moxifloxacin is a broad-spectrum antibiotic that is active against both Gram-positive and Gram-negative bacteria. It functions by inhibiting DNA gyrase, a type II topoisomerase, and topoisomerase IV, enzymes necessary to separate bacterial DNA, thereby inhibiting cell replication. Pharmacokinetics About 52% of an oral or intravenous dose of moxifloxacin is metabolized via glucuronide and sulfate conjugation. The cytochrome P450 system is not involved in moxifloxacin metabolism, and is not affected by moxifloxacin. The sulfate conjugate (M1) accounts for around 38% of the dose, and is eliminated primarily in the feces. Approximately 14% of an oral or intravenous dose is converted to a glucuronide conjugate (M2), which is excreted exclusively in the urine. Peak plasma concentrations of M2 are about 40% those of the parent drug, while plasma concentrations of M1 are, in general, less than 10% those of moxifloxacin.In vitro studies with cytochrome (CYP) P450 enzymes indicate that moxifloxacin does not inhibit 80 CYP3A4, CYP2D6, CYP2C9, CYP2C19, or CYP1A2, suggesting that moxifloxacin is unlikely to alter the pharmacokinetics of drugs metabolized by these enzymes.The pharmacokinetics of moxifloxacin in pediatric subjects have not been studied.The elimination half-life of moxifloxacin is 11.5 to 15.6 hours (single-dose, oral). About 45% of an oral or intravenous dose of moxifloxacin is excreted as unchanged drug (about 20% in urine and 25% in feces). A total of 96 ± 4% of an oral dose is excreted as either unchanged drug or known metabolites. The mean (± SD) apparent total body clearance and renal clearance are 12 ± 2 L/h and 2.6 ± 0.5 L/h, respectively. The CSF penetration of moxifloxacin is 70% to 80% in patients with meningitis. Chemistry Moxifloxacin monohydrochloride is a slightly yellow to yellow crystalline substance. It is synthesized in several steps, the first involving the preparation of racemic 2,8-diazabicyclo[4.3.0]nonane which is then resolved using tartaric acid. A suitably derivatised quinolinecarboxylic acid is then introduced, in the presence of DABCO, followed by acidification to form moxifloxacin hydrochloride. History Moxifloxacin was first patented (United States patent) in 1991 by Bayer A.G., and again in 1997. Avelox was subsequently approved by the U.S. Food and Drug Administration (FDA) for use in the United States in 1999 to treat specific bacterial infections. Ranking 140th within the top 200 prescribed drugs in the United States for 2007, Avelox generated sales of $697.3 million worldwide.Moxifloxacin is also manufactured by Alcon as Vigamox. Patent A United States patent application was made on 30 June 1989, for Avelox, Bayer A.G. being the assignee, which was subsequently approved on 5 February 1991. This patent was scheduled to expire on 30 June 2009. However, this patent was extended for an additional two and one half years on 16 September 2004, and as such was not expected to expire until 2012. Moxifloxacin was subsequently (ten years later) approved by the FDA for use in the United States in 1999. At least four additional United States patents have been filed regarding moxifloxacin hydrochloride since the 1989 United States application, as well as patents outside of the US. Society and culture Regulatory actions Regulatory agencies have taken actions to address certain rare but serious adverse events associated with moxifloxacin therapy. Based on its investigation into reports of rare but severe cases of liver toxicity and skin reactions, the European Medicines Agency recommended in 2008 that the use of the oral (but not the IV) form of moxifloxacin be restricted to infections in which other antibacterial agents cannot be used or have failed. Similarly, the Canadian label includes a warning of the risk of liver injury.The U.S. label does not contain restrictions similar to the European label, but a carries a "black box" warning of the risk of tendon damage and/or rupture and warnings regarding the risk of irreversible peripheral neuropathy. Generic equivalents In 2007, the U.S. District Court for the District of Delaware held that two Bayer patents on Avelox are valid and enforceable, and infringed by Dr. Reddys ANDA for a generic version of Avelox. The district court sided with Bayer, citing the Federal Circuits prior decision in Takeda v. Alphapharm as "affirming the district courts finding that defendant failed to prove a prima facie case of obviousness where the prior art disclosed a broad selection of compounds, any one of which could have been selected as a lead compound for further investigation, and defendant did not prove that the prior art would have led to the selection of the particular compound singled out by defendant." According to Bayers press release announcing the courts decision, it was noted that Teva had also challenged the validity of the same Bayer patents at issue in the Dr. Reddys case. Within Bayers first-quarter 2008 stockholders newsletter Bayer stated that they had reached an agreement with Teva Pharmaceuticals USA, Inc., the adverse party, to settle their patent litigation with regard to the two Bayer patents. Under the settlement terms agreed upon, Teva would obtain a license to sell its generic moxifloxacin tablet product in the U.S. shortly before the second of the two Bayer patents expires in March 2014. In Bangladesh, it is available with brand name of Optimox. References External links "Moxifloxacin". Drug Information Portal. U.S. National Library of Medicine. "Moxifloxacin hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Pancreatic enzymes (medication)	Pancreatic enzymes, also known as pancreases or pancrelipase and pancreatin, are commercial mixtures of amylase, lipase, and protease. They are used to treat malabsorption syndrome due to certain pancreatic problems. These pancreatic problems may be due to cystic fibrosis, surgical removal of the pancreas, long term pancreatitis, or pancreatic cancer, among others. The preparation is taken by mouth.Common side effects include vomiting, abdominal pain, constipation, and diarrhea. Other side effects include perianal irritation and high blood uric acid. The enzymes are from pigs. Use is believed to be safe during pregnancy. The components are digestive enzymes similar to those normally produced by the human pancreas. They help the person digest fats, starches, and proteins.Pancreatic enzymes have been used as medications since at least the 1800s. They are on the World Health Organizations List of Essential Medicines. In 2017, it was the 275th most commonly prescribed medication in the United States, with more than one million prescriptions. Medical use Pancrelipases are generally a first line approach in treatment of exocrine pancreatic insufficiency and other digestive disorders, accompanying cystic fibrosis, complicating surgical pancreatectomy, or resulting from chronic pancreatitis. The formulations are generally hard capsules filled with gastro-resistant granules. Pancrelipases and pancreatins are similar, except pancrelipases has an increased lipase component.Pancreatin is a mixture of several digestive enzymes produced by the exocrine cells of the pancreas. It is composed of amylase, lipase and protease. This mixture is used to treat conditions in which pancreatic secretions are deficient, such as surgical pancreatectomy, pancreatitis and cystic fibrosis. It has been claimed to help with food allergies, celiac disease, autoimmune disease, cancer and weight loss. Pancreatin is sometimes called "pancreatic acid", although it is neither a single chemical substance nor an acid.Pancreatin contains the pancreatic enzymes trypsin, amylase and lipase. A similar mixture of enzymes is sold as pancrelipase, which contains more active lipase enzyme than does pancreatin. The trypsin found in pancreatin works to hydrolyze proteins into oligopeptides; amylase hydrolyzes starches into oligosaccharides and the disaccharide maltose; and lipase hydrolyzes triglycerides into fatty acids and glycerols. Pancreatin is an effective enzyme supplement for replacing missing pancreatic enzymes, and aids in the digestion of foods in cases of pancreatic insufficiency.Pancreatin reduces the absorption of iron from food in the duodenum during digestion.Some contact lens-cleaning solutions contain porcine pancreatin extractives to assist in the intended protein-removal process. Side effects High doses over a long period of time are associated with fibrosing colonopathy. Due to this association a maximum dose of 10,000 IU of lipase per kilogram per day is recommended.Though never reported there is a theoretical risk of a viral infection as they are from pigs. Brand names Brand names include Creon, Pancreaze, Pertzye, Sollpura (Liprotamase), Ultresa, and Zenpep. Regulation in the United States Longstanding pancreatic enzyme replacement products (PERPs)—some in use for a century or more—fell under a 2006 FDA requirement that pharmaceutical companies with porcine-derived PERP products submit a New Drug Application (NDA) for each; Creon (AbbVie Inc.), the first of the commercial PERP products approved after the FDA directive, reached market in 2009.The specific requirement and reasoning for the FDA directive was that manufacturers submit a Risk Evaluation and Mitigation Strategy (REMS) and Medication Guide to ensure patients are adequately informed regarding potential risks associated with administration of high doses of porcine-derived PERP products, especially with regard to "the theoretical risk of transmission of viral disease from pigs to patients", the risk of which (alongside other off-target effects) is reduced by patient adherence to label dosing instructions. Shortages and alternatives Due to its non-constant supply, being sourced from pigs, there have been several pancreatin shortages in different markets.This has led for alternative sources of enzymes to be studied and commercialised, mainly being of bacterial or fungal origin. Notes == References ==
Mirabegron	Mirabegron, sold under the brand name Myrbetriq among others, is a medication used to treat overactive bladder. Its benefits are similar to antimuscarinic medication such as solifenacin or tolterodine. It is taken by mouth.Common side effects include high blood pressure, headaches, and urinary tract infections. Other significant side effects include urinary retention, irregular heart rate, and angioedema. It works by activating the β3 adrenergic receptor in the bladder, resulting in its relaxation.Mirabegron is the first clinically available beta-3 agonist with approval for use in adults with overactive bladder. Mirabegron was approved for medical use in the United States and in the European Union in 2012. In 2019, it was the 189th most commonly prescribed medication in the United States, with more than 3 million prescriptions. In the United Kingdom it is less preferred to antimuscarinic medication such as oxybutynin. Medical uses Mirabegron is used is in the treatment of overactive bladder. It works equally well to antimuscarinic medication such as solifenacin or tolterodine. In the United Kingdom it is less preferred to these agents.Mirabegron is also indicated to treat neurogenic detrusor overactivity (NDO), a bladder dysfunction related to neurological impairment, in children ages three years and older. Adverse effects Adverse effects by incidence:Very common (>10% incidence) adverse effects include: Elevated blood pressureCommon (1–10% incidence) adverse effects include: Dry mouth Nasopharyngitis Urinary tract infection (UTI) Headache Influenza Constipation Dizziness Joint pain Cystitis Back pain Upper respiratory tract infection (URTI) Sinusitis Diarrhea High heart rate Fatigue Abdominal pain Neoplasms (cancers)Rare (<1% incidence) adverse effects include: Palpitations Blurred vision Glaucoma Indigestion Gastritis Abdominal distension Rhinitis Elevations in liver enzymes (GGTP, AST, ALT and LDH) Renal and urinary disorders (e.g., nephrolithiasis, bladder pain) Reproductive system disorders (e.g., vulvovaginal pruritus, vaginal infection) Skin and subcutaneous tissue disorders (e.g., urticaria, leukocytoclastic vasculitis, rash, pruritus, purpura, lip edema) Stevens–Johnson syndrome associated with increased serum ALT, AST and bilirubin Urinary retention References Further reading Sacco E, Bientinesi R (December 2012). "Mirabegron: a review of recent data and its prospects in the management of overactive bladder". Therapeutic Advances in Urology. 4 (6): 315–24. doi:10.1177/1756287212457114. PMC 3491758. PMID 23205058. Tyagi P, Tyagi V, Chancellor M (March 2011). "Mirabegron: a safety review". Expert Opin Drug Saf. 10 (2): 287–94. doi:10.1517/14740338.2011.542146. PMID 21142693. S2CID 207487296. External links "Mirabegron". Drug Information Portal. U.S. National Library of Medicine.
Ulobetasol propionate	Ulobetasol propionate, also known as halobetasol propionate and sold under the brand name Ultravate among others, is a synthetic glucocorticoid corticosteroid and a corticosteroid ester. It was patented in 1975 and approved for medical use in 1990. References External links "Halobetasol propionate". Drug Information Portal. U.S. National Library of Medicine.
Enfortumab vedotin	Enfortumab vedotin, sold under the brand name Padcev, is an antibody-drug conjugate used for the treatment of urothelial cancer. It is a nectin-4-directed antibody and microtubule inhibitor conjugate. Enfortumab refers to the monoclonal antibody part, and vedotin refers to the payload drug (MMAE) and the linker.The most common side effects include fatigue, peripheral neuropathy (nerve damage resulting in tingling or numbness), decreased appetite, rash, alopecia (hair loss), nausea, altered taste, diarrhea, dry eye, pruritus (itching) and dry skin.The fully humanized antibody was created by scientists at Agensys (part of Astellas) using Xenomice from Amgen; the linker technology holding the antibody and the toxin together was provided by and licensed from Seattle Genetics.The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication. Medical uses Enfortumab vedotin is indicated for the treatment of adults with locally advanced (when cancer has grown too large to be surgically removed) or metastatic (when cancer cells spread to other parts of the body) urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy. History Results of a Phase I clinical trial were reported in 2016.In December 2019, enfortumab vedotin was approved in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who had previously received a programmed cell death receptor-1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor and a platinum-containing chemotherapy.Enfortumab vedotin was approved based on the results of a clinical trial that enrolled 125 patients with locally advanced or metastatic urothelial cancer who received prior treatment with a PD-1 or PD-L1 inhibitor and platinum-based chemotherapy. The overall response rate, reflecting the percentage of patients who had a certain amount of tumor shrinkage, was 44%, with 12% having a complete response and 32% having a partial response. The median duration of response was 7.6 months.The U.S. Food and Drug Administration (FDA) granted the application for enfortumab vedotin accelerated approval, priority review designation, and breakthrough therapy designation. The FDA granted the approval of Padcev to Astellas Pharma US Inc.In July 2021, the FDA approved enfortumab vedotin for adults with locally advanced or metastatic urothelial cancer who have previously received a programmed death receptor-1 (PD-1) or programmed death-ligand (PD-L1) inhibitor and platinum-containing chemotherapy, or; are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. Society and culture Legal status On 16 December 2021, and on 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Padcev, intended for the treatment of adults with urothelial cancer. The applicant for this medicinal product is Astellas Pharma Europe B.V. Enfortumab vedotin was approved for medical use in the European Union in April 2022. Names Enfortumab vedotin is the international nonproprietary name (INN), and the United States Adopted Name (USAN). References External links "Enfortumab vedotin". Drug Information Portal. U.S. National Library of Medicine.
Monomethyl fumarate	Monomethyl fumarate, sold under the brand name Bafiertam is a medication for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. It is taken by mouth. The most common adverse reactions are flushing, abdominal pain, diarrhea, and nausea.It was approved for medical use in the United States in April 2020. Pharmacology Monomethyl fumarate alters the NFE2L2 (Nuclear factor erythroid 2-related factor 2) transcription factor. NFE2L2 (or NRF2) is a basic leucine zipper (bZIP) protein that regulates the expression of antioxidant proteins that protect against oxidative damage triggered by injury and inflammation. Several drugs that stimulate the NFE2L2 pathway are being studied for treatment of diseases that are caused by oxidative stress. Two precursors are also approved: Dimethyl fumarate (brand name Tecfidera), Diroximel fumarate (brand name Vumerity), approved by the FDA in October 2019. Society and culture Names Monomethyl fumarate is the international nonproprietary name (INN). References External links "Monomethyl fumarate". Drug Information Portal. U.S. National Library of Medicine.
Oxycodone/paracetamol	Oxycodone/paracetamol, sold under the brand name Percocet among others, is a combination of the opioid oxycodone with paracetamol (acetaminophen), used to treat moderate to severe pain. In 2019, it was the 59th most commonly prescribed medication in the United States, with more than 11 million prescriptions. History The United States Food and Drug Administration (FDA) first approved Percocet in 1976, under application ANDA 085106. Implicated in deaths On June 30, 2009, an FDA advisory panel recommended that Percocet, Vicodin, and every other combination of acetaminophen with narcotic analgesics be limited in their sales because of their contributions to an alleged 400 acetaminophen-related deaths in the U.S. each year, that were attributed to acetaminophen overdose and associated liver damage.In December 2009, the Canadian Medical Association Journal reported a study finding a fivefold increase in oxycodone-related deaths in Ontario (mostly accidental) between 1991 and 2007 that led to a doubling of all opioid-related deaths in Ontario over the same period.In March 2017, U.S. President Donald Trump initiated the Opioid and Drug Abuse Commission. In July 2017, an interim report was published. Some excerpts: References External links "Acetaminophen mixture with Oxycodone". Drug Information Portal. U.S. National Library of Medicine. "Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure". U.S. Food and Drug Administration. 13 January 2011. "FDA warns about several safety issues with opioid pain medicines; requires label changes". U.S. Food and Drug Administration. 22 March 2016. "FDA warns about serious risks and death when combining opioid pain or cough medicines with benzodiazepines; requires its strongest warning". U.S. Food and Drug Administration. 31 August 2016.
Betamethasone dipropionate	Betamethasone dipropionate is a glucocorticoid steroid with anti-inflammatory and immunosuppressive abilities. It is applied as a topical cream, ointment, lotion or gel (Diprolene) to treat itching and other minor skin conditions such as eczema. Minor side effects include dry skin and mild, temporary stinging when applied. Betamethasone dipropionate is a "super high potency" corticosteroid used to treat inflammatory skin conditions such as dermatitis, eczema and psoriasis. It is a synthetic analog of the adrenal corticosteroids. Although its exact mechanism of action is not known, it is effective when applied topically to cortico-responsive inflammatory dermatoses. It is available as a generic medication. Adverse effects Although the absorption of betamethasone dipropionate is small, when used for prolonged periods of time (periods exceeding two weeks), or across a large surface area (total use greater than 50 grams per week), it can have adverse effects. One such effect is the ability of the corticosteroid to suppress the hypothalamic–pituitary–adrenal axis. This can lead to a depression in the release of adrenal hormones such as cortisol and adrenocorticotropic hormone, or ACTH. Symptoms of HPA axis suppression are often subtle and variable, but can often be detected using simple blood or urine tests such at ACTH stimulation test or urinary free cortisol. Those at increased risk for HPA axis suppression are those who are more likely to absorb more of the steroid through the skin. These groups include: Those who have used topical corticosteroids over a prolonged period of time Those who have used corticosteroids to cover a large surface area Those with broken skin barrier or extensive abrasions Those who have recently undergone stress (such as illness, trauma, surgery) Children under the age of 12HPA axis suppression is preventable by supplementation with glucocorticosteroids. If HPA axis suppression occurs, it is often reversed shortly after discontinuation of treatment. Pharmacology Mechanism of action Pharmacokinetics Absorption of topical corticosteroids depends on several factors such as the vehicle, or delivery system used by the drug, the integrity of the epidermal barrier, and whether or not an occlusive bandage is used in combination with the drug.The absorption of topical betamethasone dipropionate is theoretically minuscule; however, if absorbed it follows the same pharmacokinetic profile that is typical of systemic corticosteroids. It is metabolized primarily by the liver by hydrolysis to its metabolites B17P (primary) and betamethasone and the 6β-hydroxy derivatives of those metabolites, and it is excreted primarily by the kidneys. Chemistry Betamethasone dipropionate is a white to almost white crystalline powder. Regulation Betamethasone dipropionate was patented by Merck in 1987, as an augmented cream/lotion, Diprolene in the U.S., and Disprosone in Europe. These patents expired in 2003 and 2007 respectively leading to generic production of betamethasone dipropionate. During this time other topical corticosteroids such as triamcinolone acetonide and clobetasol propionate also became available as generic creams. Merck filed for "pediatric exclusivity" in 2001 launching a clinical trial to prove betamethasone dipropionates safety and efficacy for use in pediatrics.Betamethasone has also been used in the formulation of combination products such as Luxiq, Lotrisone and Taclonex. Prestium Pharma: Luxiq (betamethasone valerate) Foam, 0.12% is a mid-strength corticosteroid foam used primarily to treat psoriasis or other inflammatory conditions of the scalp. Merck: Lotrisone (containing betamethasone dipropionate, clotrimazole) contains both a corticosteroid (betamethasone) and anti-fungal agent (clotrimazole) and is used to treat fungal infections that are also inflamed Leo Pharma: Taclonex (containing betamethasone dipropionate, calcipotriol) is a combination of corticosteroid (betamethasone) and a vitamin D analogue (calcipotriene) and is used to treat frequent and persistent dermatatoses by reducing inflammation and promoting healing of the skin barrier. Names Brand names include Alphatrex, Beta-Val, Diprolene, Diprolene AF, Diprosone, Dovobet (LEO Pharma A/S), Eleuphrat and Luxiq. References External links "Betamethasone dipropionate". Drug Information Portal. U.S. National Library of Medicine.
Cefuroxime	Cefuroxime, sold under the brand name Zinacef among others, is a second-generation cephalosporin antibiotic used to treat and prevent a number of bacterial infections. These include pneumonia, meningitis, otitis media, sepsis, urinary tract infections, and Lyme disease. It is used by mouth or by injection into a vein or muscle.Common side effects include nausea, diarrhea, allergic reactions, and pain at the site of injection. Serious side effects may include Clostridium difficile infection, anaphylaxis, and Stevens–Johnson syndrome. Use in pregnancy and breastfeeding is believed to be safe. It is a second-generation cephalosporin and works by interfering with a bacterias ability to make a cell wall resulting in its death.Cefuroxime was patented in 1971, and approved for medical use in 1977. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 342nd most commonly prescribed medication in the United States, with more than 800 thousand prescriptions. Medical uses Cefuroxime is active against many bacteria including susceptible strains of Staphylococci and Streptococci, as well as a range of gram negative organisms. As with the other cephalosporins, it is susceptible to beta-lactamase, although as a second-generation variety, it is less so. Hence, it may have greater activity against Haemophilus influenzae, Neisseria gonorrhoeae, and Lyme disease. Unlike other second-generation cephalosporins, cefuroxime can cross the blood-brain barrier.A systematic review found high quality evidence that injecting the eye with cefuroxime after cataract surgery will lower the chance of developing endophthalmitis after surgery. Side effects Cefuroxime is generally well tolerated, and its side effects are usually transient. If ingested after food, this antibiotic is both better absorbed and less likely to cause its most common side effects of diarrhea, nausea, vomiting, headaches/migraines, dizziness, and abdominal pain compared to most antibiotics in its class.Although a widely stated cross-allergic risk of about 10% exists between cephalosporins and penicillin, recent assessments have shown no increased risk for a cross-allergic reaction for cefuroxime and several other second-generation or later cephalosporins. Chemistry Cefuroxime axetil is an acetoxyethyl ester prodrug of cefuroxime which is effective when taken by mouth. It is a second-generation cephalosporin. Trade names In the U.S. it is marketed as Zinacef by Covis Pharmaceuticals since the company acquired the U.S. rights to the product from GSK. GSK had continued marketing a pediatric oral suspension as Ceftin; however, this presentation was discontinued as of 24 June 2017.In Bangladesh, it is available as Kilbac by Incepta, Axim by Aristopharma, Rofurox by Radiant and Xorimax by Sandoz. In India, it is available as Ceftum in tablet form and Supacef in injection form by GSK. In Poland, it is available as Zamur by Mepha, subsidiary of Teva Pharmaceutical Industries. In Australia, the "first generic" form of Cefuroxime axetil, Pharmacor Cefuroxime (tablets) from Pharmacor Pty Ltd, was registered on 27 March 2017, by the Therapeutic Goods Administration. Cefuroxime axetil is also available (in two strengths) as granules for oral suspension from Aspen Pharmacare Australia Pty Ltd under the brand name Zinnat cefuroxime. References External links "Cefuroxime". Drug Information Portal. U.S. National Library of Medicine.
Piperacillin/tazobactam	Piperacillin/tazobactam, sold under the brand name Zosyn among others, is a combination medication containing the antibiotic piperacillin and the β-lactamase inhibitor tazobactam. The combination has activity against many Gram-positive and Gram-negative bacteria including Pseudomonas aeruginosa. It is used to treat pelvic inflammatory disease, intra-abdominal infection, pneumonia, cellulitis, and sepsis. It is given by injection into a vein.Common adverse effects include headache, trouble sleeping, rash, nausea, constipation, and diarrhea. Serious adverse effects include Clostridium difficile infection and allergic reactions including anaphylaxis. Those who are allergic to other β-lactam are more likely to be allergic to piperacillin/tazobactam. Use in pregnancy or breastfeeding appears to generally be safe. It usually results in bacterial death through blocking their ability to make a cell wall.Piperacillin/tazobactam was approved for medical use in the United States in 1993. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Its main uses are in intensive care medicine (pneumonia, peritonitis), some diabetes-related foot infections, and empirical therapy in febrile neutropenia (e.g., after chemotherapy). The drug is administered intravenously every 6 or 8 hr, typically over 3–30 min. It may also be administered by continuous infusion over four hours. Prolonged infusions are thought to maximize the time that serum concentrations are above the minimum inhibitory concentration (MIC) of the bacteria implicated in infection. Piperacillin-tazobactam is recommended by the National Institute for Health and Care Excellence as first-line therapy for the treatment of bloodstream infections in neutropenic cancer patients.For β-lactam antipseudomonal antibiotics, including piperacillin/tazobactam, prolonged intravenous infusion is associated with lower mortality than bolus intravenous infusion in persons with sepsis due to Pseudomonas aeruginosa. Adverse effects The most common adverse effect is diarrhea (7–11%). Another adverse effect is inhibition of platelets which is also known as thrombocytopenia. Contraindications Zosyn is contraindicated when a patient has hypersensitivity to penicillins, cephalosporins, beta-lactamase inhibitors or any component of the formulation. Society and culture Trade names Apart from Tazocin and Zosyn, the drug is marketed in various countries under other trade names such as Tazovex,Tazact, Biopiper TZ, Brodactam, Piptaz, Maxitaz, Kilbac, Trezora, Du-Tazop, Tazopen, Sytaz, Tazin, and Inzalin TZ. 2017 shortage Various sources have referred to a shortage of the drug since May 2017, citing various reasons, including an earthquake in China and other issues at the major production facility in 海正 (Hisun); increased demand; withdrawal of funding by a major pharmaceutical company. == References ==
Varenicline	Varenicline (trade name Chantix and Champix) is a medication used for smoking cessation. Varenicline is also used for the treatment of dry eye disease.The most common side-effects include nausea (feeling sick), insomnia (difficulty sleeping), abnormal dreams, headache and nasopharyngitis (inflammation of the nose and throat).It is a high-affinity partial agonist for the α4β2 nicotinic acetylcholine receptor subtype (nACh) that leads to the release of the neurotransmitter dopamine in the nucleus accumbens reward center of the brain when activated, and therefore, has the capacity to reduce the feelings of craving and withdrawal caused by smoking cessation. In this respect it is similar to cytisine and different from the nicotinic antagonist bupropion and nicotine replacement therapies (NRTs) like nicotine patches and nicotine gum. It is estimated that varenicline successfully helps one of every eleven people who smoke remain abstinent from tobacco at six months. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. Medical uses Varenicline is used to help people stop smoking tobacco (smoking cessation). A meta-analysis found that less than 20% of people treated with varenicline remain abstinent from smoking at one year. In a 2009 meta-analysis varenicline was found to be more effective than bupropion (odds ratio 1.40) and nicotine replacement therapies (NRT) (odds ratio 1.56).A 2013 Cochrane overview and network meta-analysis concluded that varenicline is the most effective medication for tobacco cessation and that smokers were nearly three times more likely to quit tobacco use while on varenicline than with placebo treatment. Varenicline was more efficacious than bupropion or NRT and as effective as combination NRT for tobacco smoking cessation.Varenicline has not been tested in those under 18 years old or pregnant women and therefore is not recommended for use by these groups. Varenicline is considered a class C pregnancy drug, as animal studies have shown no increased risk of congenital anomalies; however, no data from human studies is available. An observational study is currently being conducted assessing for malformations related to varenicline exposure, but has no results yet. An alternate drug is preferred for smoking cessation during breastfeeding due to lack of information and based on the animal studies on nicotine. Side effects Mild nausea is the most common side effect and is seen in approximately 30% of people taking varenicline though this rarely (<3%) results in discontinuation of the medication. Other less common side effects include headache, difficulty sleeping, and vivid dreams. Rare side effects reported by people taking varenicline compared to placebo include change in taste, vomiting, abdominal pain, flatulence, and constipation. It has been estimated that for every five subjects taking varenicline at maintenance doses, there will be an event of nausea, and for every 24 of 35 treated subjects, there will be an event of constipation and flatulence, respectively. Gastrointestinal side-effects lead to discontinuation of the drug in 2% to 8% of people using varenicline. Incidence of nausea is dose-dependent: incidence of nausea was higher in people taking a larger dose (30%) versus placebo (10%) as compared to people taking a smaller dose (16%) versus placebo (11%). Depression and suicide In 2007, the US FDA had announced it had received post-marketing reports of thoughts of suicide and occasional suicidal behavior, erratic behavior, and drowsiness among people using varenicline for smoking cessation. In 2009, the US FDA required varenicline to carry a boxed warning that the drug should be stopped if any of these symptoms are experienced.A 2014 systematic review did not find evidence of an increased suicide risk. Other analyses have reached the same conclusion and found no increased risk of neuropsychiatric side effects with varenicline. No evidence for increased risks of cardiovascular events, depression, or self-harm with varenicline versus nicotine replacement therapy was found in one post-marketing surveillance study.In 2016 the FDA removed the black box warning. People are still advised to stop the medication if they "notice any side effects on mood, behavior, or thinking." Cardiovascular disease In June 2011, the US FDA issued a safety announcement that varenicline may be associated with "a small, increased risk of certain cardiovascular adverse events in people who have cardiovascular disease."A prior 2011 review had found increased risk of cardiovascular events compared with placebo. Expert commentary in the same journal raised doubts about the methodology of the review, concerns which were echoed by the European Medicines Agency and subsequent reviews. Of specific concern were "the low number of events seen, the types of events counted, the higher drop-out rate in people receiving placebo, the lack of information on the timing of events, and the exclusion of studies in which no-one had an event." In contrast, multiple recent systematic reviews and meta-analyses have found no increase in overall or serious adverse cardiovascular events (including for individuals at risk of developing cardiovascular disease) associated with varenicline use. Mechanism of action Varenicline displays full agonism on α7 nicotinic acetylcholine receptors and is a partial agonist on the α4β2, α3β4, and α6β2 subtypes. In addition, it is a weak agonist on the α3β2 containing receptors. Vareniclines partial agonism on the α4β2 receptors rather than nicotines full agonism produces less effect of dopamine release than nicotines. This α4β2 competitive binding reduces the ability of nicotine to bind and stimulate the mesolimbic dopamine system—similar to the method of action of buprenorphine in the treatment of opioid addiction. Pharmacokinetics Most of the active compound is excreted by the kidneys (92–93%). A small proportion is glucuronidated, oxidised, N-formylated or conjugated to a hexose. The elimination half-life is about 24 hours. History Use of Cytisus plants as a smoking substitutes during World War II led to use as a cessation aid in eastern Europe and extraction of cytisine. Cytisine analogs led to varenicline at Pfizer.Varenicline received a "priority review" by the US FDA in February 2006, shortening the usual ten-month review period to six months because of its demonstrated effectiveness in clinical trials and perceived lack of safety issues. The agencys approval of the drug came on May 11, 2006. On September 29, 2006, it was approved for sale in the European Union.On September 16, 2021, Pfizer announced a recall of "all lots of its anti-smoking treatment, Chantix [Varenicline], due to high levels of cancer-causing agents called nitrosamines in the pills". This followed a July 2, 2021 announcement by the FDA that it was "alerting patients and health care professionals to Pfizers voluntary recall of nine lots of the smoking cessation drug" and further recalls by Pfizer on July 19 and Aug. 8. On June 24, Pfizer had paused distribution of Chantix worldwide; "[t]he distribution halt [wa]s out of an abundance of caution, pending further testing, the company said in an email. According to the Pfizer Inc. 2020 Form 10-K Annual Report, high-revenue products by the company include[d] Chantix/Champix (varenicline) to treat nicotine addiction, [which] had $919 million in 2020 revenues.In October 2021, US FDA approved Oyster Point Pharma to market Tyrvaya as a new route of varenicline administration through nasal spray for the treatment of dry eye disease. References External links "Varenicline". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03636061 for "Clinical Trial to Evaluate the Efficacy of OC-01 Nasal Spray on Signs and Symptoms of Dry Eye Disease (The ONSET-1 Study)" at ClinicalTrials.gov Clinical trial number NCT04036292 for "Evaluating the Efficacy and Safety of OC-01 (Varenicline) Nasal Spray on Dry Eye Disease" at ClinicalTrials.gov
Cortisol	Cortisol is a steroid hormone, in the glucocorticoid class of hormones. When used as a medication, it is known as hydrocortisone. It is produced in many animals, mainly by the zona fasciculata of the adrenal cortex in the adrenal gland. It is produced in other tissues in lower quantities. It is released with a diurnal cycle and its release is increased in response to stress and low blood-glucose concentration. It functions to increase blood sugar through gluconeogenesis, to suppress the immune system, and to aid in the metabolism of fat, protein, and carbohydrates. It also decreases bone formation. Health effects Metabolic response Metabolism of glucose In general, cortisol stimulates gluconeogenesis (the synthesis of new glucose from non-carbohydrate sources, which occurs mainly in the liver, but also in the kidneys and small intestine under certain circumstances). The net effect is an increase in the concentration of glucose in the blood, further complemented by a decrease in the sensitivity of peripheral tissue to insulin, thus preventing this tissue from taking the glucose from the blood. Cortisol has a permissive effect on the actions of hormones that increase glucose production, such as glucagon and adrenaline.Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis (the breaking down of glycogen to glucose-1-phosphate and glucose) which occurs as a result of the action of glucagon and adrenaline. Additionally, cortisol facilitates the activation of glycogen phosphorylase, which is necessary for adrenaline to have an effect on glycogenolysis.Paradoxically, cortisol promotes not only gluconeogenesis in the liver, but also glycogenesis. Cortisol is thus better thought of as stimulating glucose/glycogen turnover in the liver. This is in contrast to cortisols effect in the skeletal muscle where glycogenolysis is promoted indirectly through catecholamines. Metabolism of proteins and lipids Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting. The reason for proteolysis is to provide the relevant tissue with a feedstock for gluconeogenesis; see glucogenic amino acids. The effects of cortisol on lipid metabolism are more complicated since lipogenesis is observed in patients with chronic, raised circulating glucocorticoid (i.e. cortisol) levels, although an acute increase in circulating cortisol promotes lipolysis. The usual explanation to account for this apparent discrepancy is that the raised blood glucose concentration (through the action of cortisol) will stimulate insulin release. Insulin stimulates lipogenesis, so this is an indirect consequence of the raised cortisol concentration in the blood but it will only occur over a longer time scale. Immune response Cortisol prevents the release of substances in the body that cause inflammation. It is used to treat conditions resulting from overactivity of the B-cell-mediated antibody response. Examples include inflammatory and rheumatoid diseases, as well as allergies. Low-dose topical hydrocortisone, available as a nonprescription medicine in some countries, is used to treat skin problems such as rashes and eczema. Cortisol inhibits production of interleukin 12 (IL-12), interferon gamma (IFN-gamma), IFN-alpha, and tumor necrosis factor alpha (TNF-alpha) by antigen-presenting cells (APCs) and T helper cells (Th1 cells), but upregulates interleukin 4, interleukin 10, and interleukin 13 by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over-activation of the inflammatory response.Cortisol can weaken the activity of the immune system. It prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1, and unable to produce the T-cell growth factor IL-2. Cortisol downregulates the expression of the IL2 receptor IL-2R on the surface of the helper T-cell which is necessary to induce a Th1 cellular immune response, thus favoring a shift towards Th2 dominance and the release of the cytokines listed above which results in Th2 dominance and favors the humoral B-cell mediated antibody immune response).Cortisol also has a negative-feedback effect on IL-1. The way this negative feedback works is that an immune stressor causes peripheral immune cells to release IL-1 and other other cytokines such as IL-6 and TNF-alpha. These cytokines stimulate the hypothalamus, causing it to release corticotropin-releasing hormone (CRH). CRH in turn stimulates the production of adrenocorticotropic hormone (ACTH) among other things in the adrenal gland, which (among other things) increases production of cortisol. Cortisol then closes the loop as it inhibits TNF-alpha production in immune cells and makes them less responsive to IL-1.Through this system, as long as an immune stressor is small, the response will be regulated to the correct level. Like a thermostat controlling a heater, the hypothalamus uses cortisol to turn off the heat once the production of cortisol matches the stress induced on the immune system. But in a severe infection or in a situation where the immune system is overly sensitized to an antigen (such as in allergic reactions) or there is a massive flood of antigens (as can happen with endotoxic bacteria) the correct set point might never be reached. Also because of downregulation of Th1 immunity by cortisol and other signaling molecules, certain types of infection, (notably Mycobacterium tuberculosis) can trick the body into getting locked in the wrong mode of attack, using an antibody-mediated humoral response when a cellular response is needed. Lymphocytes are the antibody-producing cells of the body, and are thus the main agents of humoral immunity. A larger number of lymphocytes in the lymph nodes, bone marrow, and skin means the body is increasing its humoral immune response. Lymphocytes release antibodies into the bloodstream. These antibodies lower infection through three main pathways: neutralization, opsonization, and complement activation. Antibodies neutralize pathogens by binding to surface adhering proteins, keeping pathogens from binding to host cells. In opsonization, antibodies bind to the pathogen and create a target for phagocytic immune cells to find and latch onto, allowing them to destroy the pathogen more easily. Finally antibodies can also activate complement molecules which can combine in various ways to promote opsonization or even act directly to lyse a bacteria. There are many different kinds of antibody and their production is highly complex, involving several types of lymphocyte, but in general lymphocytes and other antibody regulating and producing cells will migrate to the lymph nodes to aid in the release of these antibodies into the bloodstream.Rapid administration of corticosterone (the endogenous type I and type II receptor agonist) or RU28362 (a specific type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. On the other side of things, there are natural killer cells; these cells are equipped with the heavy artillery needed to take down larger in size threats like bacteria, parasites, and tumor cells. A separate study found that cortisol effectively disarmed natural killer cells, downregulating the expression of their natural cytotoxicity receptors. Interestingly, prolactin has the opposite effect. It increases the expression of cytotoxicity receptors on natural killer cells, increasing their firepower. Cortisol stimulates many copper enzymes (often to 50% of their total potential), including lysyl oxidase, an enzyme that cross-links collagen and elastin. Especially valuable for immune response is cortisols stimulation of the superoxide dismutase, since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria. Other effects Metabolism Glucose Cortisol counteracts insulin, contributes to hyperglycemia by stimulating gluconeogenesis and inhibits the peripheral use of glucose (insulin resistance) by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane. Cortisol also increases glycogen synthesis (glycogenesis) in the liver, storing glucose in easily accessible form. The permissive effect of cortisol on insulin action in liver glycogenesis is observed in hepatocyte culture in the laboratory, although the mechanism for this is unknown. Bone and collagen Cortisol reduces bone formation, favoring long-term development of osteoporosis (progressive bone disease). The mechanism behind this is two-fold: cortisol stimulates the production of RANKL by osteoblasts which stimulates, through binding to RANK receptors, the activity of osteoclasts – cells responsible for calcium resorption from bone – and also inhibits the production of osteoprotegerin (OPG) which acts as a decoy receptor and captures some RANKL before it can activate the osteoclasts through RANK. In other words, when RANKL binds to OPG, no response occurs as opposed to the binding to RANK which leads to the activation of osteoclasts. It transports potassium out of cells in exchange for an equal number of sodium ions (see above). This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine. Cortisol down-regulates the synthesis of collagen. Amino acid Cortisol raises the free amino acids in the serum by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis. Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves. Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE. Electrolyte balance Cortisol decreases glomerular filtration rate, and renal plasma flow from the kidneys thus increasing phosphate excretion, as well as increasing sodium and water retention and potassium excretion by acting on mineralocorticoid receptors. It also increases sodium and water absorption and potassium excretion in the intestines. Sodium Cortisol promotes sodium absorption through the small intestine of mammals. Sodium depletion, however, does not affect cortisol levels so cortisol cannot be used to regulate serum sodium. Cortisols original purpose may have been sodium transport. This hypothesis is supported by the fact that freshwater fish use cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium. Potassium A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case. For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell. This should make pH regulation much easier (unlike the normal potassium-deficiency situation, in which two sodium ions move in for each three potassium ions that move out—closer to the deoxycorticosterone effect). Stomach and kidneys Cortisol stimulates gastric-acid secretion. Cortisols only direct effect on the hydrogen-ion excretion of the kidneys is to stimulate the excretion of ammonium ions by deactivating the renal glutaminase enzyme. Memory Cortisol works with adrenaline (epinephrine) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol damages cells in the hippocampus; this damage results in impaired learning. Diurnal cycles Diurnal cycles of cortisol levels are found in humans. Stress and mood Sustained stress can lead to high levels of circulating cortisol (regarded as one of the more important of the several "stress hormones"). Such levels may result in an allostatic load, which can lead to various physical modifications in the bodys regulatory networks. Effects during pregnancy During human pregnancy, increased fetal production of cortisol between weeks 30 and 32 initiates production of fetal lung pulmonary surfactant to promote maturation of the lungs. In fetal lambs, glucocorticoids (principally cortisol) increase after about day 130, with lung surfactant increasing greatly, in response, by about day 135, and although lamb fetal cortisol is mostly of maternal origin during the first 122 days, 88% or more is of fetal origin by day 136 of gestation. Although the timing of fetal cortisol concentration elevation in sheep may vary somewhat, it averages about 11.8 days before the onset of labor. In several livestock species (e.g. cattle, sheep, goats, and pigs), the surge of fetal cortisol late in gestation triggers the onset of parturition by removing the progesterone block of cervical dilation and myometrial contraction. The mechanisms yielding this effect on progesterone differ among species. In the sheep, where progesterone sufficient for maintaining pregnancy is produced by the placenta after about day 70 of gestation, the prepartum fetal cortisol surge induces placental enzymatic conversion of progesterone to estrogen. (The elevated level of estrogen stimulates prostaglandin secretion and oxytocin receptor development.) Exposure of fetuses to cortisol during gestation can have a variety of developmental outcomes, including alterations in prenatal and postnatal growth patterns. In marmosets, a species of New World primates, pregnant females have varying levels of cortisol during gestation, both within and between females. Infants born to mothers with high gestational cortisol during the first trimester of pregnancy had lower rates of growth in body mass indices than infants born to mothers with low gestational cortisol (about 20% lower). However, postnatal growth rates in these high-cortisol infants were more rapid than low-cortisol infants later in postnatal periods, and complete catch-up in growth had occurred by 540 days of age. These results suggest that gestational exposure to cortisol in fetuses has important potential fetal programming effects on both pre and postnatal growth in primates. Synthesis and release Cortisol is produced in the human body by the adrenal gland in the zona fasciculata, the second of three layers comprising the adrenal cortex. The cortex forms the outer "bark" of each adrenal gland, situated atop the kidneys. The release of cortisol is controlled by the hypothalamus, a part of the brain. The secretion of corticotropin-releasing hormone by the hypothalamus triggers cells in the neighboring anterior pituitary to secrete another hormone, the adrenocorticotropic hormone (ACTH), into the vascular system, through which blood carries it to the adrenal cortex. ACTH stimulates the synthesis of cortisol and other glucocorticoids, mineralocorticoid aldosterone, and dehydroepiandrosterone. Testing of individuals Normal values indicated in the following tables pertain to humans (normal levels vary among species). Measured cortisol levels, and therefore reference ranges, depend on the sample type (blood or urine), analytical method used, and factors such as age and sex. Test results should, therefore, always be interpreted using the reference range from the laboratory that produced the result. Using the molecular weight of 362.460 g/mole, the conversion factor from µg/dL to nmol/L is approximately 27.6; thus, 10 µg/dL is about 276 nmol/L. Cortisol follows a circadian rhythm, and to accurately measure cortisol levels is best to test four times per day through saliva. An individual may have normal total cortisol but have a lower than normal level during a certain period of the day and a higher than normal level during a different period. Therefore, some scholars question the clinical utility of cortisol measurement.Cortisol is lipophilic, and is transported bound to transcortin (also known as corticosteroid-binding globulin) and albumin, while only a small part of the total serum cortisol is unbound and has biological activity. Serum cortisol assays measures total cortisol, and its results may be misleading for patients with altered serum protein concentrations. The salivary cortisol test avoids this problem because only free cortisol can pass through the salivary barrier. Transcortin particles are too large to pass through this barrier.Automated immunoassays lack specificity and show significant cross-reactivity due to interactions with structural analogs of cortisol, and show differences between assays. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) can improve specificity and sensitivity. Disorders of cortisol production Some medical disorders are related to abnormal cortisol production, such as: Primary hypercortisolism (Cushings syndrome): excessive levels of cortisolSecondary hypercortisolism (pituitary tumor resulting in Cushings disease, pseudo-Cushings syndrome) Primary hypocortisolism (Addisons disease, Nelsons syndrome): insufficient levels of cortisol Secondary hypocortisolism (pituitary tumor, Sheehans syndrome) Regulation The primary control of cortisol is the pituitary gland peptide, ACTH, which probably controls cortisol by controlling the movement of calcium into the cortisol-secreting target cells. ACTH is in turn controlled by the hypothalamic peptide corticotropin-releasing hormone (CRH), which is under nervous control. CRH acts synergistically with arginine vasopressin, angiotensin II, and epinephrine. (In swine, which do not produce arginine vasopressin, lysine vasopressin acts synergistically with CRH.) When activated macrophages start to secrete IL-1, which synergistically with CRH increases ACTH, T-cells also secrete glucosteroid response modifying factor (GRMF), as well as IL-1; both increase the amount of cortisol required to inhibit almost all the immune cells. Immune cells then assume their own regulation, but at a higher cortisol setpoint. The increase in cortisol in diarrheic calves is minimal over healthy calves, however, and falls over time. The cells do not lose all their fight-or-flight override because of interleukin-1s synergism with CRH. Cortisol even has a negative feedback effect on interleukin-1—especially useful to treat diseases that force the hypothalamus to secrete too much CRH, such as those caused by endotoxic bacteria. The suppressor immune cells are not affected by GRMF, so the immune cells effective setpoint may be even higher than the setpoint for physiological processes. GRMF affects primarily the liver (rather than the kidneys) for some physiological processes.High-potassium media (which stimulates aldosterone secretion in vitro) also stimulate cortisol secretion from the fasciculata zone of canine adrenals — unlike corticosterone, upon which potassium has no effect.Potassium loading also increases ACTH and cortisol in humans. This is probably the reason why potassium deficiency causes cortisol to decline (as mentioned) and causes a decrease in conversion of 11-deoxycortisol to cortisol. This may also have a role in rheumatoid-arthritis pain; cell potassium is always low in RA.Ascorbic acid presence, particularly in high doses has also been shown to mediate response to psychological stress and speed the decrease of the levels of circulating cortisol in the body post-stress. This can be evidenced through a decrease in systolic and diastolic blood pressures and decreased salivary cortisol levels after treatment with ascorbic acid. Factors increasing cortisol levels Viral infections increase cortisol levels through activation of the HPA axis by cytokines. Intense (high VO2 max) or prolonged aerobic exercise transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose; however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance) Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods. Low-carbohydrate diets cause a short-term increase in resting cortisol (~3 weeks), and increase the cortisol response to aerobic exercise in the short- and long-term. Biochemistry Biosynthesis Cortisol is synthesized from cholesterol. Synthesis takes place in the zona fasciculata of the adrenal cortex. (The name cortisol is derived from cortex.) While the adrenal cortex also produces aldosterone (in the zona glomerulosa) and some sex hormones (in the zona reticularis), cortisol is its main secretion in humans and several other species. (However, in cattle, corticosterone levels may approach or exceed cortisol levels.). The medulla of the adrenal gland lies under the cortex, mainly secreting the catecholamines adrenaline (epinephrine) and noradrenaline (norepinephrine) under sympathetic stimulation. The synthesis of cortisol in the adrenal gland is stimulated by the anterior lobe of the pituitary gland with ACTH; ACTH production is, in turn, stimulated by CRH, which is released by the hypothalamus. ACTH increases the concentration of cholesterol in the inner mitochondrial membrane, via regulation of the steroidogenic acute regulatory protein. It also stimulates the main rate-limiting step in cortisol synthesis, in which cholesterol is converted to pregnenolone and catalyzed by Cytochrome P450SCC (side-chain cleavage enzyme). Metabolism 11beta-hydroxysteroid dehydrogenases Cortisol is metabolized reversibly to cortisone by the 11-beta hydroxysteroid dehydrogenase system (11-beta HSD), which consists of two enzymes: 11-beta HSD1 and 11-beta HSD2. 11-beta HSD1 uses the cofactor NADPH to convert biologically inert cortisone to biologically active cortisol 11-beta HSD2 uses the cofactor NAD+ to convert cortisol to cortisoneOverall, the net effect is that 11-beta HSD1 serves to increase the local concentrations of biologically active cortisol in a given tissue; 11-beta HSD2 serves to decrease local concentrations of biologically active cortisol. An alteration in 11-beta HSD1 has been suggested to play a role in the pathogenesis of obesity, hypertension, and insulin resistance known as metabolic syndrome.An alteration in 11-beta HSD2 has been implicated in essential hypertension and is known to lead to the syndrome of apparent mineralocorticoid excess (SAME). A-ring reductases (5alpha- and 5beta-reductases) Cortisol is also metabolized irreversibly into 5-alpha tetrahydrocortisol (5-alpha THF) and 5-beta tetrahydrocortisol (5-beta THF), reactions for which 5-alpha reductase and 5-beta-reductase are the rate-limiting factors, respectively. 5-Beta reductase is also the rate-limiting factor in the conversion of cortisone to tetrahydrocortisone. Cytochrome P450, family 3, subfamily A monooxygenases Cortisol is also metabolized irreversibly into 6β-hydroxycortisol by cytochrome p450-3A monooxygenases, mainly, CYP3A4. Drugs that induce CYP3A4 may accelerate cortisol clearance. Chemistry Cortisol is a naturally occurring pregnane corticosteroid and is also known as 11β,17α,21-trihydroxypregn-4-ene-3,20-dione. Animals In animals, cortisol is often used as an indicator of stress and can be measured in blood, saliva, urine, hair, and faeces. See also Cortisone, a hormone Cortisol awakening response List of corticosteroids Membrane glucocorticoid receptor References External links Cortisol MS Spectrum Cortisol: analyte monograph – The Association for Clinical Biochemistry and Laboratory Medicine
Calcium gluconate	Calcium gluconate is a mineral supplement and medication. As a medication it is used by injection into a vein to treat low blood calcium, high blood potassium, and magnesium toxicity. Supplementation is generally only required when there is not enough calcium in the diet. Supplementation may be done to treat or prevent osteoporosis or rickets. It can also be taken by mouth but is not recommended for injection into a muscle.Side effects when injected include slow heart rate, pain at the site of injection, and low blood pressure. When taken by mouth side effects may include constipation and nausea. Blood calcium levels should be measured when used and extra care should be taken in those with a history of kidney stones. At normal doses, use is regarded as safe in pregnancy and breastfeeding. Calcium gluconate is made by mixing gluconic acid with calcium carbonate or calcium hydroxide.Calcium gluconate came into medical use in the 1920s. It is on the World Health Organizations List of Essential Medicines. Calcium gluconate is available as a generic medication. Production Medical uses Low blood calcium 10% calcium gluconate solution (given intravenously) is the form of calcium most widely used in the treatment of low blood calcium. This form of calcium is not as well absorbed as calcium lactate, and it only contains 0.93% (930 mg/dL) calcium ion (defined by 1 g weight solute in 100 mL of solution to make 1% solution w/v). Therefore, if the hypocalcemia is acute and severe, calcium chloride is given instead. High blood potassium Calcium gluconate is used as a cardioprotective agent in people with high blood potassium levels, with one alternative being the use of calcium chloride. It is recommended when the potassium levels are high (>6.5 mmol/L) or when the electrocardiogram (ECG) shows changes due to high blood potassium.Though it does not have an effect on potassium levels in the blood, it reduces the excitability of cardiomyocytes, thereby lowering the likelihood of cardiac arrhythmias. Magnesium sulfate overdose It is also used to counteract an overdose of Epsom salts magnesium sulfate, which is often administered to pregnant women in order to prophylactically prevent seizures (as in a patient experiencing preeclampsia). Magnesium sulfate is no longer given to pregnant women who are experiencing premature labor in order to slow or stop their contractions (other tocolytics are now used instead due to better efficacy and side effect profiles). Excess magnesium sulfate results in magnesium sulfate toxicity, which results in both respiratory depression and a loss of deep tendon reflexes (hyporeflexia). Hydrofluoric acid burns Gel preparations of calcium gluconate are used to treat hydrofluoric acid burns. The calcium gluconate reacts with hydrofluoric acid to form insoluble, non-toxic calcium fluoride. In addition to a 2.5% calcium gluconate gel being applied directly to the chemical burn, the person may also receive calcium gluconate supplements because the fluoride ion precipitates serum calcium, causing hypocalcemia. Cardiac arrest While intravenous calcium has been used in cardiac arrest, its general use is not recommended. Cases of cardiac arrest in which it is still recommended include high blood potassium, low blood calcium such as may occur following blood transfusions, and calcium channel blocker overdose. There is the potential that general use could worsen outcomes. If calcium is used, calcium chloride is generally the recommended form. Side effects Calcium gluconate side effects include nausea, constipation, and upset stomach. Rapid intravenous injections of calcium gluconate may cause hypercalcaemia, which can result in vasodilation, cardiac arrhythmias, decreased blood pressure, and bradycardia. Extravasation of calcium gluconate can lead to cellulitis. Intramuscular injections may lead to local necrosis and abscess formation.It is also reported that this form of calcium increases renal plasma flow, urine production, sodium excretion, glomerular filtration rate, and prostaglandin E2 and F1-alpha levels. Society and culture Shortages of medical calcium gluconate were reported in November 2012 and November 2015 in the United States. Historically, intravenous calcium gluconate was used as an antidote for black widow spider envenomation, often in conjunction with muscle relaxants. This therapy, however, has since been shown to be ineffective. See also Calcium lactate gluconate References External links "Calcium gluconate". Drug Information Portal. U.S. National Library of Medicine.
Terazosin	Terazosin, sold under the brand name Hytrin among others, is a medication used to treat symptoms of an enlarged prostate and high blood pressure. For high blood pressure, it is a less preferred option. It is taken by mouth.Common side effects include dizziness, headache, tiredness, swelling, nausea, and low blood pressure with standing. Severe side effects may include priapism and low blood pressure. Prostate cancer should be ruled out before starting treatment. It is an alpha-1 blocker and works by relaxing blood vessels and the opening of the bladder.Terazosin was patented in 1975 and came into medical use in 1985. It is available as a generic medication. In 2019, it was the 203rd most commonly prescribed medication in the United States, with more than 2 million prescriptions. Synthesis Reaction of piperazine with 2-furoyl chloride followed by catalytic hydrogenation of the furan ring leads to 2. This, when heated in the presence of 2-chloro-6,7-dimethoxyquinazolin-4-amine (1) undergoes direct alkylation to terazosin (3). == References ==
Tafamidis	Tafamidis, sold under the brand names Vyndaqel and Vyndamax, is a medication used to delay disease progression in adults with certain forms of transthyretin amyloidosis. It can be used to treat both hereditary forms, familial amyloid cardiomyopathy and familial amyloid polyneuropathy, as well as wild-type transthyretin amyloidosis, which formerly was called senile systemic amyloidosis. It works by stabilizing the quaternary structure of the protein transthyretin. In people with transthyretin amyloidosis, transthyretin falls apart and forms clumps called (amyloid) that harm tissues including nerves and the heart.The U.S. Food and Drug Administration considers tafamidis to be a first-in-class medication. Medical use Tafamidis is used to delay nerve damage in adults who have transthyretin amyloidosis with polyneuropathy, or heart disease in adults who have transthyretin amyloidosis with cardiomyopathy. It is taken by mouth.Women should not get pregnant while taking it and should not breastfeed while taking it. People with familial amyloid polyneuropathy who have received a liver transplant should not take it. Adverse effects More than 10% of people in clinical trials had one or more of urinary tract infections, vaginal infections, upper abdominal pain, or diarrhea. Interactions Tafamidis does not appear to interact with cytochrome P450 but it inhibits ATP-binding cassette super-family G member 2, so is likely to affect the levels of certain drugs including methotrexate, rosuvastatin, and imatinib. It also inhibits organic anion transporter 1 and organic anion transporter 3/solute carrier family 22 member 8 so is likely to interact with non-steroidal anti-inflammatory agents and other drugs that rely on those transporters. Pharmacology Tafamidis is a pharmacological chaperone that stabilizes the correctly folded tetrameric form of the transthyretin protein by binding in one of the two thyroxine-binding sites of the tetramer. In people with familial amyloid polyneuropathy, the individual monomers fall away from the tetramer, misfold, and aggregate; the aggregates harm nerves.The maximum plasma concentration is achieved around two hours after dosing; in plasma it is almost completely bound to proteins. Based on preclinical data, it appears to be metabolized by glucuronidation and excreted via bile; in humans, around 59% of a dose is recovered in feces, and approximately 22% in urine. Chemistry The chemical name of tafamidis is 2-(3,5-dichlorophenyl)-1,3-benzoxazole-6-carboxylic acid. The molecule has two crystalline forms and one amorphous form; it is manufactured in one of the possible crystalline forms. It is marketed as a meglumine salt. It is slightly soluble in water. History The laboratory of Jeffery W. Kelly at The Scripps Research Institute began looking for ways to inhibit transthyretin fibril formation in the 1990s.: 210 Tafamidis was eventually discovered by Kellys team using a structure-based drug design strategy; the chemical structure was first published in 2003. In 2003, Kelly co-founded a company called FoldRx with Susan Lindquist of the Massachusetts Institute of Technology and the Whitehead Institute, and FoldRx developed tafamidis up through submitting an application for marketing approval in Europe in early 2010. FoldRx was acquired by Pfizer later that year.Tafamidis was approved by the European Medicines Agency in November 2011, to delay peripheral nerve impairment in adults with transthyretin-related hereditary amyloidosis. The U.S. Food and Drug Administration rejected the application for marketing approval in 2012, on the basis that the clinical trial did not show efficacy based on a functional endpoint, and requested further clinical trials. In May 2019, the FDA approved two tafamidis preparations, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis), for the treatment of transthyretin-mediated cardiomyopathy. The drug was approved in Japan in 2013; regulators there made the approval dependent on further clinical trials showing better evidence of efficacy.The FDA approved tafamidis meglumine based primarily on evidence from a clinical trial of 441 adult patients conducted at 60 sites in Belgium, Brazil, Canada, Czech Republic, Spain, France, Greece, Italy, Japan, Netherlands, Sweden, Great Britain, and the United States.There was one trial that evaluated the benefits and side effects of tafamidis for the treatment of transthyretin amyloidosis with cardiomyopathy, in which patients were randomly assigned to receive either tafamidis (either 20 or 80 mg) or placebo for 30 months. About 90% of patients in the trial were taking other drugs for heart failure (consistent with the standard of care).The European Medicines Agency designated tafamidis an orphan medicine and the Food and Drug Administration designated tafamidis meglumine an orphan drug. Society and culture Legal status Tafamidis was approved in the European Union in 2011 for the treatment of transthyretin amyloidosis with polyneuropathy, and in Japan in 2013. In the United States, it was rejected for the treatment of transthyretin amyloidosis with polyneuropathy because the Food and Drug Administration saw insufficient evidence for its efficacy.Tafamidis can also be used to treat transthyretin amyloidosis with cardiomyopathy. It was approved for the treatment of this form of the disease in the United States in 2019 and in the European Union in 2020. In the United States, there are two approved preparations: tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax). The two preparations have the same active moiety, tafamidis, but they are not substitutable on a milligram to milligram basis.Tafamidis (Vyndamax) and tafamidis meglumine (Vyndaqel) were approved for medical use in Australia in March 2020. References Further reading Adams D (March 2013). "Recent advances in the treatment of familial amyloid polyneuropathy". Ther Adv Neurol Disord. 6 (2): 129–39. doi:10.1177/1756285612470192. PMC 3582309. PMID 23483184. Coelho T, Maia LF, Martins da Silva A, et al. (August 2012). "Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial". Neurology. 79 (8): 785–92. doi:10.1212/WNL.0b013e3182661eb1. PMC 4098875. PMID 22843282. External links "Tafamidis". Drug Information Portal. U.S. National Library of Medicine. "Tafamidis meglumine". Drug Information Portal. U.S. National Library of Medicine.
Naproxen	Naproxen, sold under the brand name Aleve among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain, menstrual cramps, inflammatory diseases such as rheumatoid arthritis, gout and fever. It is taken orally. It is available in immediate and delayed release formulations. Onset of effects is within an hour and lasts for up to twelve hours.Common side effects include dizziness, headache, bruising, allergic reactions, heartburn, and stomach pain. Severe side effects include an increased risk of heart disease, stroke, gastrointestinal bleeding, and stomach ulcers. The heart disease risk may be lower than with other NSAIDs. It is not recommended in people with kidney problems. Use is not recommended in the third trimester of pregnancy.Naproxen is a nonselective COX inhibitor. As an NSAID, naproxen appears to exert its anti-inflammatory action by reducing the production of inflammatory mediators called prostaglandins. It is metabolized by the liver to inactive metabolites.Naproxen was patented in 1967, and approved for medical use in the United States in 1976. In the United States it is available over the counter and as a generic medication. In 2019, it was the 61st most commonly prescribed medication in the United States, with more than 11 million prescriptions. Medical uses Naproxens medical uses are related to its mechanism of action as an anti-inflammatory compound. Naproxen is used to treat a variety of inflammatory conditions and symptoms that are due to excessive inflammation, such as pain and fever (naproxen has fever-reducing, or antipyretic, properties in addition to its anti-inflammatory activity). Inflammatory sources of pain that may respond to naproxens anti-inflammatory activity are conditions such as migraine, osteoarthritis, kidney stones, rheumatoid arthritis, psoriatic arthritis, gout, ankylosing spondylitis, menstrual cramps, tendinitis, and bursitis.Naproxen sodium is used as a "bridge therapy" in medication-overuse headache to slowly take patients off other medications. Available formulations Naproxen sodium is available as both an immediate release and as an extended release tablet. The extended release formulations (sometimes called "sustained release", or "enteric coated") take longer to take effect than the immediate release formulations, and therefore are less useful when immediate pain relief is desired. Extended release formulations are more useful for the treatment of chronic, or long-lasting, conditions, in which long-term pain relief is desirable. Pregnancy and lactation Small amounts of naproxen are excreted in breast milk. However, adverse effects are uncommon in infants breastfed from a mother taking naproxen. Adverse effects Common adverse effects include dizziness, drowsiness, headache, rash, bruising, and gastrointestinal upset. Heavy use is associated with increased risk of end-stage renal disease and kidney failure. Naproxen may cause muscle cramps in the legs in 3% of people.In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid. They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy. Gastrointestinal As with other non-COX-2 selective NSAIDs, naproxen can cause gastrointestinal problems, such as heartburn, constipation, diarrhea, ulcers and stomach bleeding. Naproxen should be taken orally with food to decrease the risk of gastrointestinal side effects. Persons with a history of ulcers or inflammatory bowel disease should consult a doctor before taking naproxen. In U.S. markets, naproxen is sold with boxed warnings about the risk of gastrointestinal ulceration or bleeding. Naproxen poses an intermediate risk of stomach ulcers compared with ibuprofen, which is low-risk, and indometacin, which is high-risk. To reduce stomach ulceration risk, it is often combined with a proton-pump inhibitor (a medication that reduces stomach acid production) during long-term treatment of those with pre-existing stomach ulcers or a history of developing stomach ulcers while on NSAIDs. Cardiovascular COX-2 selective and nonselective NSAIDs have been linked to increases in the number of serious and potentially fatal cardiovascular events, such as myocardial infarctions and strokes. Naproxen is, however, associated with the smallest overall cardiovascular risks. Cardiovascular risk must be considered when prescribing any nonsteroidal anti-inflammatory drug. The drug had roughly 50% of the associated risk of stroke compared with ibuprofen, and was also associated with a reduced number of myocardial infarctions compared with control groups.A study found that high-dose naproxen induced near-complete suppression of platelet thromboxane throughout the dosing interval and appeared not to increase cardiovascular disease (CVD) risk, whereas other non-aspirin high-dose NSAID regimens had only transient effects on platelet COX-1 and were associated with a small but definite vascular hazard. Conversely, naproxen was associated with higher rates of upper gastrointestinal bleeding complications compared with other NSAIDs. Interactions Drug–drug interactions Naproxen may interact with antidepressants, lithium, methotrexate, probenecid, warfarin and other blood thinners, heart or blood pressure medications, including diuretics, or steroid medicines such as prednisone.NSAIDs such as naproxen may interfere with and reduce the efficacy of SSRI antidepressants, as well as increase the risk of bleeding greater than the individual bleeding risk of either class of agent, when taken together. Naproxen is not contraindicated in the presence of SSRIs, though concomitant use of the medications should be done with caution. Alcohol consumption increases the risk of gastrointestinal bleeding when combined with NSAIDs like naproxen in a dose-dependent manner (that is, the higher the dose of naproxen, the higher the risk of bleeding). The risk is highest for people who are heavy drinkers. Pharmacology Mechanism of action Naproxen works by reversibly inhibiting both the COX-1 and COX-2 enzymes as a non-selective coxib. Pharmacokinetics Naproxen is a minor substrate of CYP1A2 and CYP2C9. It is extensively metabolized in the liver to 6-O-desmethylnaproxen, and both the parent drug and the desmethyl metabolite undergo further metabolism to their respective acylglucuronide conjugated metabolites. An analysis of two clinical trials shows that naproxens time to peak plasma concentration occurs between 2–4 hours after oral administration, though naproxen sodium reaches peak plasma concentrations within 1–2 hours. Pharmacogenetics The pharmacogenetics of naproxen has been studied in an effort to better understand its adverse effects. In 1998, a small pharmacokinetic (PK) study failed to show that differences in a patients ability to clear naproxen from the body could account for differences in a patients risk of experiencing the adverse effect of a serious gastrointestinal bleed while taking naproxen. However, the study failed to account for differences in the activity of CYP2C9, a drug-metabolizing enzyme that is necessary for clearing naproxen. Studies on the relationship between CYP2C9 genotype and NSAID-induced gastrointestinal bleeds have shown that genetic variants in CYP2C9 that reduce the clearance of major CYP2C9 substrates (like naproxen) increase the risk of NSAID-induced gastrointestinal bleeds, especially for homozygous defective variants. Chemistry Naproxen is a member of the 2-arylpropionic acid (profen) family of NSAIDs. The free acid is an odorless, white to off-white crystalline substance. It is lipid-soluble and practically insoluble in water. It has a melting point of 152–155 °C. Synthesis Naproxen has been industrially produced by Syntex starting from 2-naphthol as follows: Society and culture Brand names Naproxen and naproxen sodium are marketed under various brand names, including Accord, Aleve, Anaprox, Antalgin, Apranax, Feminax Ultra, Flanax, Inza, Maxidol, Nalgesin, Naposin, Naprelan, Naprogesic, Naprosyn, Narocin, Pronaxen, Proxen, and Soproxen. It is also available as the combination naproxen/esomeprazole magnesium in delayed release tablets under the brand name Vimovo. Access restrictions Syntex first marketed naproxen in 1976, as the prescription drug Naprosyn. They first marketed naproxen sodium under the brand name Anaprox in 1980. It remains a prescription-only drug in much of the world. In the United States, the Food and Drug Administration (FDA) approved it as an over-the-counter (OTC) drug in 1994. OTC preparations of naproxen in the U.S. are mainly marketed by Bayer HealthCare under the brand name Aleve and generic store brand formulations in 220 mg tablets. In Australia, packets of 275 mg tablets of naproxen sodium are Schedule 2 pharmacy medicines, with a maximum daily dose of five tablets or 1375 mg. In the United Kingdom, 250 mg tablets of naproxen were approved for OTC sale under the brand name Feminax Ultra in 2008, for the treatment of primary dysmenorrhoea in women aged 15 to 50. In the Netherlands, 220 mg and 275 mg tablets are available OTC in drugstores, 550 mg is OTC only at pharmacies. Aleve became available over the counter in some provinces in Canada on 14 July 2009, but not British Columbia, Quebec or Newfoundland and Labrador; it subsequently became available OTC in British Columbia in January 2010. Research Naproxen may have antiviral activity against influenza. In laboratory research, it blocks the RNA-binding groove of the nucleoprotein of the virus, preventing formation of the ribonucleoprotein complex—thus taking the viral nucleoproteins out of circulation. Veterinary use Horses Naproxen is given by mouth to horses at a dose of 10 mg/kg, and has shown to have a wide safety margin (no toxicity when given at three times the recommended dose for 42 days). It is more effective for myositis than the commonly used NSAID phenylbutazone, and has shown especially good results for treatment of equine exertional rhabdomyolysis, a disease of muscle breakdown; it is less commonly used for musculoskeletal disease. References External links "Naproxen". Drug Information Portal. U.S. National Library of Medicine. "Naproxen sodium". Drug Information Portal. U.S. National Library of Medicine.
Milrinone	Milrinone, sold under the brand name Primacor, is a pulmonary vasodilator used in patients who have heart failure. It is a phosphodiesterase 3 inhibitor that works to increase the hearts contractility and decrease pulmonary vascular resistance. Milrinone also works to vasodilate which helps alleviate increased pressures (afterload) on the heart, thus improving its pumping action. While it has been used in people with heart failure for many years, studies suggest that milrinone may exhibit some negative side effects that have caused some debate about its use clinically.Overall, milrinone supports ventricular functioning of the heart by decreasing the degradation of cyclic adenosine monophosphate (cAMP) and thus increasing phosphorylation levels of many components in the heart that contribute to contractility and heart rate. Milrinone is used as a drug that causes positive inotropy and it will lead to an increased force of contraction. Milrinone use following cardiac surgery has been under some debate because of the potential increase risk of postoperative atrial arrhythmias. However, in the short term milrinone has been deemed beneficial to those experiencing heart failure and an effective therapy to maintain heart function following cardiac surgeries. There is no evidence of any long term beneficial effects on survival. In critically ill patients with evidence of cardiac dysfunction there is limited good quality evidence to recommend its use.Milrinone is administered IV only and eliminated unchanged in the urine. Dose adjustment is required for patients with renal impairment. Contractility in the heart People experiencing some forms of heart failure have a significant decrease in the contractile ability of muscle cells in the heart (cardiomyocytes). This impaired contractility occurs through a number of mechanisms. Some of the main problems associated with decreased contractility in those with heart failure are issues arising from imbalances in the concentration of calcium. Calcium permits myosin and actin to interact which allows initiation of contraction within the cardiomyocytes. In those with heart failure there may be a decreased amount of calcium within the cardiomyocytes reducing the available calcium to initiate contraction. When contractility is decreased the amount of blood being pumped out of the heart into circulation is decreased as well. This reduction in cardiac output can cause many systemic implications such as fatigue, syncope and other issues associated with decreased blood flow to peripheral tissues. Mechanism of action cAMP causes increased activation of protein kinase A (PKA). PKA is an enzyme that phosphorylates many elements of the contractile machinery within the heart cell. In the short term this leads to an increased force of contraction. Phosphodiesterases are enzymes responsible for the breakdown of cAMP. Therefore, when phosphodiesterases lower the level of cAMP in the cell they also lower the active fraction of PKA within the cell and reduce the force of contraction. Milrinone is a phosphodiesterase-3 inhibitor. This drug inhibits the action of phosphodiesterase-3 and thus prevents degradation of cAMP. With increased cAMP levels there is an increase in the activation of PKA. This PKA will phosphorylate many components of the cardiomyocyte such as calcium channels and components of the myofilaments. Phosphorylation of calcium channels permits an increase in calcium influx into the cell. This increase in calcium influx results in increased contractility. PKA also phosphorylates potassium channels promoting their action. Potassium channels are responsible for repolarization of the cardiomyocytes therefore increasing the rate at which cells can depolarize and generate contraction. PKA also phosphorylates components on myofilaments allowing actin and myosin to interact more easily and thus increasing contractility and the inotropic state of the heart. Milrinone allows stimulation of cardiac function independently of β-adrenergic receptors which appear to be down-regulated in those with heart failure. Clinical use Milrinone is a commonly used therapy for severe pulmonary arterial hypertension (PAH), often in combination with other medications such as sildenafil. Targeting PDE3 with optimal doses and timing, milrinone prevents allergic inflammation in HDM-driven models of allergic airway inflammation.It can be used in cardiopulmonary bypass cases, as it increases the flow in saphenous grafts and has a beneficiary effect in Left Ventricle fanction. Adverse effects Common adverse effects include ventricular arrhythmias (including ventricular ectopy and nonsustained ventricular tachycardia), supraventricular arrhythmias, hypotension, and headache. References External links Mechanism of action
Irbesartan	Irbesartan, sold under the brand name Avapro among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth. Versions are available as the combination irbesartan/hydrochlorothiazide.Common side effects include dizziness, diarrhea, feeling tired, muscle pain, and heartburn. Serious side effects may include kidney problems, low blood pressure, and angioedema. Use in pregnancy may harm the baby and use when breastfeeding is not recommended. It is an angiotensin II receptor antagonist and works by blocking the effects of angiotensin II.Irbesartan was patented in 1990, and approved for medical use in 1997. It is available as a generic medication. In 2019, it was the 181st most commonly prescribed medication in the United States, with more than 3 million prescriptions. Structure activity relationship Irbesartan has the common structural features seen within the Angiotensin-II Receptor blockers or ARB medications. The medicine has an extended diphenyl group with a tetrazole at the 2-prime position. At the 4prime position, the molecule has a diazaspiro04-none, which is on a methyl. Medical uses Irbesartan is used for the treatment of hypertension. It may also delay progression of diabetic nephropathy and is also indicated for the reduction of renal disease progression in patients with type 2 diabetes, hypertension and microalbuminuria (>30 mg/24 h) or proteinuria (>900 mg/24 h). Combination with diuretic Irbesartan is also available in a fixed-dose combination formulation with hydrochlorothiazide, a thiazide diuretic, to achieve an additive antihypertensive effect. Irbesartan/hydrochlorothiazide combination preparations are marketed under various brand names. Society and culture It was developed by Sanofi Research (part of Sanofi-Aventis). It is jointly marketed by Sanofi-Aventis and Bristol-Myers Squibb under the brand names Aprovel, Karvea, and Avapro. References External links "Irbesartan". Drug Information Portal. U.S. National Library of Medicine. "Hydrochlorothiazide mixture with irbesartan". Drug Information Portal. U.S. National Library of Medicine.
Sodium phenylacetate/sodium benzoate	Sodium phenylacetate/sodium benzoate, sold under the brand name Ammonul among others, is a combination medication used to treat high blood ammonia. It is a combination of sodium phenylacetate and sodium benzoate. References External links "Ammonul". Drug Information Portal. U.S. National Library of Medicine.
Trandolapril	Trandolapril is an ACE inhibitor used to treat high blood pressure. It may also be used to treat other conditions. It is similar in structure to another ACE Inhibitor, Ramipril but has a cyclohexane group. It also is a pro-drug and must get metabolized. It has an extended half-life and therefore has a higher potency. It was patented in 1981, and approved for medical use in 1993. It is marketed by Abbott Laboratories under the brand name Mavik. Side effects Side effects reported for trandolapril include nausea, vomiting, diarrhea, headache, dry cough, dizziness or lightheadedness when sitting up or standing, hypotension, or fatigue. Possible drug interactions Patients also on diuretics may experience an excessive reduction of blood pressure after initiation of therapy with trandolapril. It can reduce potassium loss caused by thiazide diuretics, and increase serum potassium when used alone. Therefore, hyperkalemia is a possible risk. Increased serum lithium levels can occur in patients who are also on lithium. Contraindications and precautions Pregnancy and lactation Trandolapril is teratogenic (US: pregnancy category D) and can cause birth defects and even death of the developing fetus. The highest risk to the fetus is during the second and third trimesters. When pregnancy is detected, trandolapril should be discontinued as soon as possible. Trandolapril should not be administered to nursing mothers. Additional effects Combination therapy with paricalcitol and trandolapril has been found to reduce fibrosis in obstructive uropathy. Pharmacology Trandolapril is a prodrug that is de-esterified to trandolaprilat. It is believed to exert its antihypertensive effect through the renin–angiotensin–aldosterone system. Trandolapril has a half-life of about 6 hours, and trandolaprilat has a half life of about 10 h. Trandolaprilat has about eight times the activity of its parent drug. About one-third of trandolapril and its metabolites are excreted in the urine, and about two-thirds of trandolapril and its metabolites are excreted in the feces. Serum protein binding of trandolapril is about 80%. Mode of action Trandolapril acts by competitive inhibition of angiotensin converting enzyme (ACE), a key enzyme in the renin–angiotensin system which plays an important role in regulating blood pressure. References External links Trandolapril Information - rxlist.com (Rxlist.com, The Internet Drug Index)
Finasteride	Finasteride, sold under the brand names Proscar and Propecia among others, is a medication used to treat hair loss and benign prostatic hyperplasia in men. It can also be used to treat excessive hair growth in women and as a part of hormone therapy for transgender women. It is taken by mouth.Finasteride is a 5α-reductase inhibitor and therefore an antiandrogen. It works by decreasing the production of dihydrotestosterone (DHT) by about 70%, including in the prostate gland and the scalp.In addition to DHT, finasteride also inhibits the production of several anticonvulsant neurosteroids including allopregnanolone, androstanediol and THDOC.Adverse effects from finasteride are rare, however some men experience sexual dysfunction, depression, and breast enlargement. In some men, sexual dysfunction may persist after stopping the medication. It may also hide the early symptoms of certain forms of prostate cancer.Finasteride was patented in 1984 and approved for medical use in 1992. It is available as a generic medication. In 2019, it was the 86th most commonly prescribed medication in the United States, with more than 8 million prescriptions. Medical uses Finasteride is indicated for the treatment of symptomatic benign prostatic hyperplasia (BPH) in men with an enlarged prostate and for the treatment of male pattern hair loss (androgenetic alopecia) in men. Enlarged prostate Physicians sometimes prescribe finasteride for the treatment of benign prostatic hyperplasia (BPH), informally known as an enlarged prostate. Finasteride may improve the symptoms associated with BPH such as difficulty urinating, getting up during the night to urinate, hesitation at the start and end of urination, and decreased urinary flow. It provides less symptomatic relief than alpha-1 blockers such as tamsulosin and symptomatic relief is slower in onset (six months or more of treatment with finasteride may be required to determine the therapeutic results of treatment). Symptomatic benefits are mainly seen in those with prostate volume > 40 cm3. In long-term studies finasteride but not alpha-1 inhibitors reduce the risk of acute urinary retention (−57% at 4 years) and the need for surgery (−54% at 4 years). If the drug is discontinued, any therapeutic benefits are reversed within about 6–8 months. Scalp hair loss Finasteride is also used to treat male pattern baldness (androgenic alopecia) in men, a condition that develops in up to 80% of Caucasian men. In the United States, finasteride and minoxidil are the only two FDA approved drugs for the treatment of male pattern hair loss as of 2017. Treatment with finasteride slows further hair loss and provides about 30% improvement in hair loss after six months of treatment, with effectiveness persisting as long as the drug is taken. Taking finasteride leads to a reduction in scalp and serum DHT levels; by lowering scalp levels of DHT, finasteride can maintain or increase the amount of terminal hairs in the anagen phase by inhibiting and sometimes reversing miniaturization of the hair follicle. Finasteride is most effective on the crown but can reduce hair loss in all areas of the scalp. Finasteride has also been tested for pattern hair loss in women; however, the results were no better than placebo. Finasteride is less effective in the treatment of scalp hair loss than dutasteride. Prostate cancer In males over 55 years old finasteride decreases the risk of low-grade prostate cancer but may increase the risk of high-grade prostate cancer and has no effect on overall survival.A 2010 review found a 25% reduction in the risk of prostate cancer with 5α-reductase inhibitor. A follow-up study of the Medicare claims of participants in a 10-year Prostate Cancer Prevention Trial suggests the reduction in prostate cancer is maintained even after discontinuation of treatment. However, 5α-reductase inhibitors have been found to increase the risk of developing certain rare but aggressive forms of prostate cancer (27% risk increase), although not all studies have observed this. No impact of 5-α-reductase inhibitor on survival has been found in people with prostate cancer. Excessive hair growth Finasteride has been found to be effective in the treatment of hirsutism (excessive facial and/or body hair growth) in women. In a study of 89 women with hyperandrogenism due to persistent adrenarche syndrome, finasteride produced a 93% reduction in facial hirsutism and a 73% reduction bodily hirsutism after 2 years of treatment. Other studies using finasteride for hirsutism have also found it to be clearly effective. Transgender hormone therapy Finasteride is sometimes used in hormone replacement therapy for transgender women due to its antiandrogenic effects, in combination with a form of estrogen. However, little clinical research of finasteride use for this purpose has been conducted and evidence of safety or efficacy is limited. Moreover, caution has been recommended when prescribing finasteride to transgender women, as finasteride may be associated with side effects such as depression, anxiety, and suicidal ideation, symptoms that are particularly prevalent in the transgender population and in others at high risk already. Adverse effects A 2010 Cochrane review of finasteride for BPH found that, in men with a weighted mean age of 62.4, adverse effects are "rare; nevertheless, men taking finasteride are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder, versus placebo." As of 2016 fresh evidence suggested such effects, along with disturbed neurosteroid production, may persist after finasteride use is stopped.Finasteride is contraindicated in pregnancy. The Food and Drug Administration advises that donation of blood or plasma be deferred for at least one month after taking the last dose of finasteride.The FDA has added a warning to 5α-reductase inhibitors concerning an increased risk of high-grade prostate cancer, as the treatment of BPH lowers PSA (prostate-specific antigen), which could mask the development of prostate cancer. Although overall incidence of male breast cancer in clinical trials for finasteride 5 mg was not increased, there are post-marketing reports of breast cancer in association with its use, though available evidence does not provide clarity as to whether there is a causative relationship between finasteride and these cancers. A 2018 meta-analysis found no higher risk of breast cancer with 5α-reductase inhibitors. Some men develop gynecomastia (breast development or enlargement) following finasteride usage. The risk of gynecomastia with 5α-reductase inhibitors is low at about 1.5%. Depressive symptoms and suicidality have been reported. Sexual adverse effects Use of finasteride is associated with an increased risk of sexual dysfunction including erectile dysfunction, decreased libido and ejaculatory dysfunction. Sexual adverse effects of finasteride and dutasteride have been linked to lower quality of life and ability to maintain an intimate relationship, and can cause stress in relationships.The adverse effect profiles of finasteride are somewhat different for its indications of hair loss and BPH. Finasteride for androgenetic alopecia (hair loss in men) The most common adverse effects of finasteride taken for hair loss are: decrease in sex drive, erectile dysfunction and decrease in amount of semen.: 17 In addition, finasteride has been reported in case reports to cause sexual problems which persist after stopping the medication. A 2012 update to the FDA label noted reports of decreased sex drive, problems with ejaculation and difficulty achieving an erection which continued after stopping the medication. The update also referenced reports of testicular pain and "male infertility and/or poor quality of semen.": 17 Finasteride for BPH The most common adverse sexual effects of finasteride for BPH are: trouble getting or keeping an erection, decrease in sex drive, decreased volume of ejaculate and ejaculation disorders.: 16 A 2010 Cochrane review found that men taking finasteride for BPH (with a mean age of 62.4) are at increased risk for impotence, erectile dysfunction, decreased libido, and ejaculation disorder for the first year of treatment. The rates became indistinguishable from placebo after 2–4 years and these side effects usually got better over time. Long-term Finasteride may cause persistent adverse sexual, neurological and physical effects in a subset of men. A 2019 metastudy surveyed the literature on the reversibility of finasterides side effects. It identified three studies which demonstrated full reversibility of side effects and eleven that describe patients with irreversible adverse events. The findings were most convincing in a retrospective review of about 12,000 patients that 1.4% of the cohort developed persistent ED (ED lasting longer than 90 days post-withdrawal). Post-finasteride syndrome Men in the U.S. and Canada concerned about persistent sexual side effects "coined the phrase post-finasteride syndrome, which they say is characterized by sexual, neurological, hormonal and psychological side effects that can persist in men who have taken finasteride for hair loss or an enlarged prostate". As of 2016, Merck was a defendant in approximately 1,370 product liability lawsuits which had been filed by customers alleging they have experienced persistent sexual side effects following cessation of treatment with finasteride.A 2019 editorial in The BMJ called post finasteride syndrome "ill defined and controversial". It has common features with other self-diagnosed "mystery syndromes" such as morgellons syndrome or multiple chemical sensitivity. There is no known underlying biological mechanism for the proposed syndrome, and its incidence is also unclear. A lack of clear diagnostic criteria and the variable reporting fraction in different health-care settings make the problem challenging to evaluate.Self-reported symptoms of post-finasteride syndrome include penile atrophy and tissue changes, decreased ejaculate volume and quality, libido loss, erectile dysfunction, loss of penile sensitivity, decreased orgasm sensation, dry skin, metabolic changes, muscle and strength loss, gynecomastia, depression, anxiety, panic attacks, insomnia, anhedonia, concentration problems, memory impairment and suicidal ideation. A meta-analysis found significant association between finasteride use and post-discontinuation depression, suicide ideation, and sexual dysfunction, but the quality of evidence was limited.Plaintiffs have filed over one thousand court cases against Merck over the effects of finasteride. Most were settled by 2018 when Merck paid a lump sum of US$4.3 million to be distributed. As of September 2019, 25 cases remained outstanding in the United States.In 2019 Reuters reported that faulty redactions in court documents revealed allegations from plaintiffs that Merck had known of persistent side effects in their original clinical trials but chose not to disclose them in warning labels. Overdose Finasteride has been studied in humans at single doses of up to 400 mg and at continuous dosages of up to 80 mg/day for three months, without adverse effects observed. There is no specific recommended antidote for finasteride overdose. Interactions No significant drug interactions have been observed between finasteride and a limited selection of medications. Pharmacology Pharmacodynamics Finasteride is a 5α-reductase inhibitor. It is specifically a selective inhibitor of the type II and III isoforms of the enzyme. By inhibiting these two isozymes of 5α-reductase, finasteride reduces the formation of the potent androgen dihydrotestosterone (DHT) from its precursor testosterone in certain tissues in the body such as the prostate gland, skin, and hair follicles. As such, finasteride is a type of antiandrogen, or more specifically, an androgen synthesis inhibitor. However, some authors do not define finasteride as an "antiandrogen," a term which can refer more specifically to antagonists of the androgen receptor.Finasteride results in a decrease of circulating DHT levels by about 65 to 70% with an oral dosage of 5 mg/day and of DHT levels in the prostate gland by up to 80 to 90% with an oral dosage of 1 or 5 mg/day. In parallel, circulating levels of testosterone increase by approximately 10%, while local concentrations of testosterone in the prostate gland increase by about 7-fold and local testosterone levels in hair follicles increase by around 27 to 53%. An oral dosage of finasteride of only 0.2 mg/day has been found to achieve near-maximal suppression of DHT levels (68.6% for 0.2 mg/day relative to 72.2% for 5 mg/day). Finasteride does not completely suppress DHT production because it lacks significant inhibitory effects on the 5α-reductase type I isoenzyme, with more than 100-fold less inhibitory potency for type I as compared to type II (IC50 = 313 nM and 11 nM, respectively). This is in contrast to inhibitors of all three isoenzymes of 5α-reductase like dutasteride, which can reduce DHT levels in the entire body by more than 99%. In addition to inhibiting 5α-reductase, finasteride has also been found to competitively inhibit 5β-reductase (AKR1D1). However, its affinity for the enzyme is substantially less than for 5α-reductase (an order of magnitude less than for 5α-reductase type I) and hence is unlikely to be of clinical significance.As of 2012, the tissues in which the different isozymes of 5α-reductase are expressed are not fully clear. This is because different investigators have obtained varying results with different reagents, methods, and tissues examined. However, the different isozymes of 5α-reductase appear to be widely expressed, with notable tissues including the prostate gland, seminal vesicles, testes, epididymides, skin, hair follicles, liver, kidneys, and brain, among others.By inhibiting 5α-reductase and thus preventing DHT production, finasteride reduces androgen signaling in tissues like the prostate gland and the scalp. In the prostate, this reduces prostate volume, which improves BPH and reduces risk of prostate cancer. Finasteride reduces prostate volume by 20 to 30% in men with benign prostatic hyperplasia. Inhibition of 5α-reductase also reduces epididymal weight, and decreases motility and normal morphology of spermatozoa in the epididymis.Neurosteroids like 3α-androstanediol (derived from DHT) and allopregnanolone (derived from progesterone) activate the GABAA receptor in the brain; because finasteride prevents the formation of neurosteroids, it functions as a neurosteroidogenesis inhibitor and may contribute to a reduction of GABAA activity. Reduction of GABAA receptor activation by these neurosteroids has been implicated in depression, anxiety, and sexual dysfunction.In accordance with finasteride being a potent 5α-reductase inhibitor but a weak inhibitor of 5β-reductase, the medication decreases circulating levels of 5α-reduced steroids like allopregnanolone but does not reduce concentrations of 5β-reduced steroids like pregnanolone. Pregnanolone acts as a potent GABAA receptor positive allosteric modulator similarly to allopregnanolone. Pharmacokinetics The mean oral bioavailability of finasteride is approximately 65%. The absorption of finasteride is not affected by food. At steady-state with 1 mg/day finasteride, mean peak concentrations of finasteride were 9.2 ng/mL (25 nmol/L). Conversely, following a single 5 mg dose of finasteride, mean peak levels of finasteride were 37 ng/mL (99 nmol/L), and plasma concentrations increased by 47 to 54% following 2.5 weeks of continued daily administration. The volume of distribution of finasteride is 76 L. Its plasma protein binding is 90%. The drug has been found to cross the blood–brain barrier, whereas levels in semen were found to be undetectable.Finasteride is extensively metabolized in the liver, first by hydroxylation via CYP3A4 and then by aldehyde dehydrogenase. It has two major metabolites, which are the tert-butyl side chain monohydroxylated and monocarboxylic acid metabolites. These metabolites show approximately 20% of the inhibitory activity of finasteride on 5α-reductase. Hence, the metabolites of finasteride are not particularly active. The drug has a terminal half-life of 5 to 6 hours in adult men (18–60 years of age) and a terminal half-life of 8 hours or more in elderly men (more than 70 years of age). It is eliminated as its metabolites 57% in the feces and 40% in the urine. Chemistry Finasteride, also known as 17β-(N-tert-butylcarbamoyl)-4-aza-5α-androst-1-en-3-one, is a synthetic androstane steroid and 4-azasteroid. It is an analogue of androgen steroid hormones like testosterone and DHT. As an unconjugated steroid, finasteride is a highly lipophilic compound. History In 1942, James Hamilton observed that prepubertal castration prevents the later development of male pattern baldness in mature men. In 1974, Julianne Imperato-McGinley of Cornell Medical College in New York attended a conference on birth defects. She reported on a group of intersex children in the Caribbean who appeared sexually ambiguous at birth, and were initially raised as girls, but then grew external male genitalia and other masculine characteristic after onset of puberty. These children, despite being raised as girls until puberty, were generally heterosexual, and were termed "Guevedoces" by their local community, which means "penis at twelve" in Spanish. Her research group found these children shared a genetic mutation, causing deficiency of the 5α-reductase enzyme and male hormone dihydrotestosterone (DHT), which was found to have been the etiology behind abnormalities in male sexual development. Upon maturation, these individuals were observed to have smaller prostates which were underdeveloped, and were also observed to lack incidence of male pattern baldness.In 1975, copies of Imperato-McGinleys presentation were seen by P. Roy Vagelos, who was then serving as Mercks basic-research chief. He was intrigued by the notion that decreased levels of DHT led to the development of smaller prostates. Dr. Vagelos then sought to create a drug which could mimic the condition found in these children to treat older men who had benign prostatic hyperplasia.Finasteride was developed by Merck under the code name MK-906. A team led by chemist Gary Rasmusson and biologist Jerry Brooks developed potential 5α-reductase inhibitors based on transition state inhibitors, using an iterative process of molecular design, testing, and redesign. In 1992, finasteride (5 mg) was approved by the U.S. Food and Drug Administration (FDA) for treatment of BPH, which Merck marketed under the brand name Proscar. Rasmusson and Brooks were awarded IPOs "Inventor of the Year" award in 1993 for their work on finasteride. In 1997, Merck was successful in obtaining FDA approval for a second indication of finasteride (1 mg) for treatment of male pattern hair loss, which was marketed under the brand name Propecia. It was the first 5α-reductase inhibitor to be introduced and was followed by dutasteride in 2001. The first study of finasteride in the treatment of hirsutism in women was published in 1994. Society and culture Generic names Finasteride is the generic name of the drug and its INN, USAN, BAN, and JAN, while finastéride is its DCF. It is also known by its former developmental code names MK-906, YM-152, and L-652,931. Brand names Finasteride is marketed primarily under the brand names Propecia, for pattern hair loss, and Proscar, for BPH, both of which are products of Merck & Co. There is 1 mg of finasteride in Propecia and 5 mg in Proscar. Mercks patent on finasteride for the treatment of BPH expired in June 2006. Merck was awarded a separate patent for the use of finasteride to treat pattern hair loss and it expired in November 2013. Finasteride is also marketed under a variety of other brand names throughout the world. Athletics From 2005 to 2009, the World Anti-Doping Agency banned finasteride because it was discovered that the drug could be used to mask steroid abuse. It was removed from the list effective 1 January 2009, after improvements in testing methods made the ban unnecessary. Athletes who used finasteride and were banned from international competition include skeleton racer Zach Lund, bobsledder Sebastien Gattuso, footballer Romário, and ice hockey goaltender José Théodore. Miscellaneous The U.S. Food and Drug Administration advises that donation of blood or plasma be deferred for at least one month after taking the last dose of finasteride. The UK also has a one-month deferral period.Harold Bornstein, the former personal physician of United States President Donald Trump, stated in 2017 that Trump was taking finasteride to promote hair growth. Research Preliminary research suggests that topical finasteride may be effective in the treatment of pattern hair loss. Topical finasteride, like the oral preparation, reduces serum DHT.DHT may be involved in the cause of acne, and 5α-reductase inhibitors might be effective in the treatment of the condition. A small retrospective study reported that finasteride was effective in the treatment of acne in women with normal testosterone levels. A randomized controlled trial found that finasteride was less effective than flutamide or an ethinylestradiol/cyproterone acetate birth control pill in the treatment of acne in women with high androgen levels.Androgens and estrogens may be involved in the cause of hidradenitis suppurativa (acne inversa). Two case series have reported that finasteride is effective in the treatment of hidradenitis suppurativa in girls and women.Finasteride and other antiandrogens might be useful in the treatment of obsessive–compulsive disorder, but more research is needed. References External links "Finasteride". Drug Information Portal. U.S. National Library of Medicine.
Naratriptan	Naratriptan (trade names include Amerge) is a triptan drug marketed by GlaxoSmithKline and is used for the treatment of migraine headaches. It is a selective 5-HT1 receptor subtype agonist. It was patented in 1987 and approved for medical use in 1997. Medical uses Naratriptan is used for the treatment of the acute migraine attacks and the symptoms of migraine, including severe, throbbing headaches that sometimes are accompanied by nausea and sensitivity to sound or light. Efficacy A meta-analysis of 53 clinical trials has shown that all triptans are effective for treating migraine at marketed doses and that naratriptan, although less effective than sumatriptan and rizatriptan was more effective than placebo in reducing migraine symptoms at two hours and efficacy was demonstrated in almost two thirds of subjects after four hours of treatment. Side effects Side effects include: dizziness, drowsiness, tingling of the hands or feet, nausea, dry mouth and unsteadiness. If these effects persist or worsen, notify your doctor promptly. Side-effects which are unlikely and which should be promptly reported include: chest pain/pressure, throat pain/pressure, unusually fast/slow/irregular pulse, one-sided muscle weakness, vision problems, cold/bluish hands or feet, stomach pain, bloody diarrhea, mental/mood changes, and fainting. In the unlikely event you have a serious allergic reaction to this drug, seek immediate medical attention. Symptoms of a serious allergic reaction include: rash, itching, swelling, severe dizziness, trouble breathing (swelling of the throat). Mechanism of action The causes of migraine are not clearly understood; however, the efficacy of naratriptans and other triptans is believed to be due to their activity as 5-HT (serotonin) agonists. Society and culture In the United States, the Food and Drug Administration (FDA) approved naratriptan on February 11, 1998. It was covered by U.S. Patent no. 4997841; the FDA lists the patent as expiring on July 7, 2010.In July 2010, in the wake of the patent expiration, several drug manufacturers, including Roxane Labs, Sandoz and Teva Pharmaceuticals, announced that they were launching generic Naratriptan medications. The drug continued to be covered by European patent 0303507 in Germany, Spain, France and the United Kingdom through March 10, 2012, and by Australian patent 611469 in Australia through June 17, 2013. It had previously been covered by Canadian patent 1210968; but both Sandoz and Teva (formerly Novopharm) have offered generic equivalents in Canada since that patents expiration December 1, 2009.On December 23, 2014, in response to a request from Health Canada, importers in Canada agreed to quarantine the importation of health products, including generic Naratriptan manufactured for both Sandoz and Teva, from Dr. Reddys Laboratories in Srikakulam, India. Because Teva and Sandoz are the only approved suppliers of generic Naratriptan in Canada, the quarantine resulted in Naratriptan being placed on the Canadian drug shortage list.Following the Canadian quarantine, the United Arab Emirates Ministry of Health also imposed a similar quarantine. == References ==
Arsenic trioxide	Arsenic trioxide, sold under the brand name Trisenox among others, is an inorganic compound and medication. As an industrial chemical, whose major uses include in the manufacture of wood preservatives, pesticides, and glass. As a medication, it is used to treat a type of cancer known as acute promyelocytic leukemia. For this use it is given by injection into a vein.Common side effects include vomiting, diarrhea, swelling, shortness of breath, and headaches. Severe side effects may include APL differentiation syndrome and heart problems. Use during pregnancy or breastfeeding may harm the baby. Arsenic trioxide has the formula As2O3. Its mechanism in treating cancer is not entirely clear.Arsenic trioxide was approved for medical use in the United States in 2000. It is on the World Health Organizations List of Essential Medicines. Approximately 50,000 tonnes are produced a year. Due to its toxicity, a number of countries have regulations around its manufacture and sale. Uses Medical Arsenic trioxide is used to treat a type of cancer known as acute promyelocytic leukemia (APL). It may be used both in cases that are unresponsive to other agents, such as all-trans retinoic acid (ATRA) or as part of the initial treatment of newly diagnosed cases. This initial treatment may include combination therapy of arsenic trioxide with all-trans retinoic acid (ATRA).Effectiveness appears similar to Realgar/Indigo naturalis, which can be taken by mouth and is less expensive but is less available.In the 1970s, Chinese researcher Zhang Tingdong and colleagues discovered this use. It was approved for leukemia treatment in the United States in 2000. University of Hong Kong developed a liquid form of arsenic trioxide that can be given by mouth. Organoarsenic compounds, such as feed additives (roxarsone) and medication (neosalvarsan), are derived from arsenic trioxide. Manufacturing Industrial uses include usage as a precursor to forestry products, in colorless glass production, and in electronics. Being the main compound of arsenic, the trioxide is the precursor to elemental arsenic, arsenic alloys, and arsenide semiconductors. Bulk arsenic-based compounds sodium arsenite and sodium cacodylate are derived from the trioxide.A variety of applications exploit arsenics toxicity, including the use of the oxide as a wood preservative. Copper arsenates, which are derived from arsenic trioxide, are used on a large scale as a wood preservative in the U.S. and Malaysia, but such materials are banned in many parts of the world. This practice remains controversial. In combination with copper(II) acetate, arsenic trioxide gives the vibrant pigment known as Paris green used in paints and as a rodenticide. This application has been discontinued. Alternative medicine Despite the well known toxicity of arsenic, arsenic trioxide was used in traditional Chinese medicine, where it is known as pi-shuang (Chinese: 砒霜; pinyin: pīshuāng; lit. arsenic frost). In homeopathy, it is called arsenicum album. Some discredited patent medicines, e.g., Fowlers solution, contained derivatives of arsenic oxide. Toxicology Arsenic trioxide is readily absorbed by the digestive system: toxic effects are also well-known upon inhalation or upon skin contact. Elimination is rapid at first (half-life of 1–2 days), by methylation to monomethylarsonic acid and dimethylarsinic acid, and excretion in the urine, but a certain amount (30–40% in the case of repeated exposure) is incorporated into the bones, the muscles, the skin, the hair and the nails (all tissues rich in keratin) and eliminated over a period of weeks or months. The first symptoms of acute arsenic poisoning by ingestion are digestive problems: vomiting, abdominal pains, diarrhea often accompanied by bleeding. Sub-lethal doses can lead to convulsions, cardiovascular problems, inflammation of the liver and kidneys and abnormalities in the coagulation of the blood. These are followed by the appearance of characteristic white lines (Mees lines) on the nails and by hair loss. Lower doses lead to liver and kidney problems and to changes in the pigmentation of the skin. Even dilute solutions of arsenic trioxide are dangerous on contact with the eyes. The poisonous properties are well known and the subject of an extensive literature.Chronic arsenic poisoning is known as arsenicosis. This disorder affects workers in smelters, in populations whose drinking water contains high levels of arsenic (0.3–0.4 ppm), and in patients treated for long periods with arsenic-based pharmaceuticals. Similarly, studies on workers exposed in copper foundries in the U.S., Japan and Sweden indicate a risk of lung cancer 6–10 times higher for the most exposed workers compared with the general population. Long-term ingestion of arsenic trioxide either in drinking water or as a medical treatment can lead to skin cancer. Reproductive problems (high incidences of miscarriage, low birth weight, congenital deformations) have also been indicated in one study of women exposed to arsenic trioxide dust as employees or neighbours of a copper foundry. In Austria, there lived the so-called "arsenic eaters of Styria", who ingested doses far beyond the lethal dose of arsenic trioxide without any apparent harm. Arsenic is thought to enable strenuous work at high altitudes, e.g. in the Alps.In the U.S., the OSHA 1910.1018 occupational permissible exposure limit for inorganic arsenic compounds in breathing zone air is 0.010 mg/m3. Production and occurrence Arsenic trioxide can be generated via routine processing of arsenic compounds including the oxidation (combustion) of arsenic and arsenic-containing minerals in air. Illustrative is the roasting of orpiment, a typical arsenic sulfide ore. 2 As2S3 + 9 O2 → 2 As2O3 + 6 SO2Most arsenic oxide is, however, obtained as a volatile by-product of the processing of other ores. For example, arsenopyrite, a common impurity in gold- and copper-containing ores, liberates arsenic trioxide upon heating in air. The processing of such minerals has led to numerous cases of poisonings. Only in China are arsenic ores intentionally mined.In the laboratory, it is prepared by hydrolysis of arsenic trichloride: 2 AsCl3 + 3 H2O → As2O3 + 6 HClAs2O3 occurs naturally as two minerals, arsenolite (cubic) and claudetite (monoclinic). Both are relatively rare secondary minerals found in oxidation zones of As-rich ore deposits. Sheets of As2O3 stand for part of structures of the recently discovered minerals lucabindiite, (K,NH4)As4O6(Cl,Br), and its sodium-analogue torrecillasite. Properties and reactions Arsenic trioxide is an amphoteric oxide, and its aqueous solutions are weakly acidic. Thus, it dissolves readily in alkaline solutions to give arsenites. It is less soluble in acids, although it will dissolve in hydrochloric acid.With anhydrous HF and HCl, it gives AsF3 and the trichloride: As2O3 + 6 HX → 2 AsX3 + 3 H2O (X = F, Cl)Only with strong oxidizing agents such as ozone, hydrogen peroxide, and nitric acid does it yield arsenic pentoxide, As2O5 or its corresponding acid: 2 HNO3 + As2O3 + 2 H2O → 2 H3AsO4 + N2O3In terms of its resistance to oxidation, arsenic trioxide differs from phosphorus trioxide, which readily combusts to phosphorus pentoxide. Reduction gives elemental arsenic or arsine (AsH3) depending on conditions: As2O3 + 6 Zn + 12 HNO3 → 2 AsH3 + 6 Zn(NO3)2 + 3 H2OThis reaction is used in the Marsh test. Structure In the liquid and gas phase below 800 °C, arsenic trioxide has the formula As4O6 and is isostructural with P4O6. Above 800 °C As4O6 significantly dissociates into molecular As2O3, which adopts the same structure as N2O3. Three forms (polymorphs) are known in the solid state: a high temperature ( > 110 °C) cubic As4O6, containing molecular As4O6, and two related polymeric forms. The polymers, which both crystallize as monoclinic crystals, feature sheets of pyramidal AsO3 units that share O atoms. Society and culture Environmental effects Smelting and related ore processing often generate arsenic trioxide, which poses a risk to the environment. For example, the Giant Mine in Canada processed substantial amounts of arsenopyrite-contaminated gold ores. References External links "Arsenic trioxide". Drug Information Portal. U.S. National Library of Medicine. Case Studies in Environmental Medicine: Arsenic Toxicity "Arsenic and Arsenic Compounds". Summaries & Evaluations. International Agency for Research on Cancer (IARC). February 1998. International Chemical Safety Card 0378 Safety Data Sheet from American Elements NIOSH Pocket Guide to Chemical Hazards NTP Report on Carcinogens – Inorganic Arsenic Compounds Institut national de recherche et de sécurité (1989). "Trioxyde darsenic." Fiche toxicologique n° 89. Paris:INRS. (in French)
Asparaginase	Asparaginase is an enzyme that is used as a medication and in food manufacturing. As a medication, L-asparaginase is used to treat acute lymphoblastic leukemia (ALL). It is given by injection into a vein, muscle, or under the skin. A pegylated version is also available. In food manufacturing it is used to decrease acrylamide.Common side effects when used by injection include allergic reactions, pancreatitis, blood clotting problems, high blood sugar, kidney problems, and liver dysfunction. Use in pregnancy may harm the baby. As a food it is generally recognized as safe. Asparaginase works by breaking down the amino acid known as asparagine without which the cancer cells cannot make protein.The most common adverse reactions of asparaginase erwinia chrysanthemi (recombinant)-rywn include abnormal liver tests, nausea, musculoskeletal pain, fatigue, infection, headache, pyrexia, drug hypersensitivity, febrile neutropenia, decreased appetite, stomatitis, bleeding, and hyperglycemia.Asparaginase was approved for medical use in the United States in 1978. It is on the World Health Organizations List of Essential Medicines. It is often made from Escherichia coli (E. coli) or Erwinia chrysanthemi. Uses Asparaginases can be used for different industrial and pharmaceutical purposes. Medical E. coli strains are the main source of medical asparaginase. Branded formulations (with different chemical and pharmacological properties) available in 1998 include Asparaginase Medac, Ciderolase, and Oncaspar.: 5 (Crasnitin has been discontinued.) Spectrila is a recombinant E. coli asparaginase.Asparaginase produced by Dickeya dadantii (formerly called Erwinia chrysanthemi) instead is known as crisantaspase (BAN), and is available in the United Kingdom under the brand name Erwinase.One of the E. coli asparaginases marketed under the brand name Elspar for the treatment of acute lymphoblastic leukemia (ALL) is also used in some mast cell tumor protocols.On 30 June 2021, the U.S. Food and Drug Administration (FDA) approved asparaginase erwinia chrysanthemi (recombinant)-rywn) as a component of a multi-agent chemotherapeutic regimen for the treatment of acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) in people aged one month or older who have developed hypersensitivity to E. coli-derived asparaginase. The FDA granted the application for asparaginase erwinia chrysanthemi (recombinant)-rywn fast track and orphan drug designations. Food manufacturing The most common use of asparaginases is as a processing aid in the manufacture of food. Asparaginases are used as a food processing aid to reduce the formation of acrylamide, a suspected carcinogen, in starchy food products such as snacks, biscuits and fried potato. Side effects The main side effect is an allergic or hypersensitivity reaction; anaphylaxis is a possibility. Additionally, it can also be associated with a coagulopathy as it decreases protein synthesis, including synthesis of coagulation factors (e.g. progressive isolated decrease of fibrinogen) and anticoagulant factor (generally antithrombin III; sometimes protein C & S as well), leading to bleeding or thrombotic events such as stroke. Bone marrow suppression is common but only mild to moderate, rarely reaches clinical significance and therapeutic consequences are rarely required.Other common side effects include pancreatitis. These side effects mainly attributes to the dual activity of L.Asparaginase as it can also hydrolysis L.Glutamine to Glutamic acid and ammonia. Mechanism of action As a food processing aid Acrylamide is often formed in the cooking of starchy foods. During heating the amino acid asparagine, naturally present in starchy foods, undergoes a process called the Maillard reaction, which is responsible for giving baked or fried foods their brown color, crust, and toasted flavor. Suspected carcinogens such as acrylamide and some heterocyclic amines are also generated in the Maillard reaction. By adding asparaginase before baking or frying the food, asparagine is converted into another common amino acid, aspartic acid, and ammonium. As a result, asparagine cannot take part in the Maillard reaction, and therefore the formation of acrylamide is significantly reduced. Complete acrylamide removal is probably not possible due to other, minor asparagine-independent formation pathways.As a food processing aid, asparaginases can effectively reduce the level of acrylamide in a range of starchy foods without changing the taste and appearance of the end product. As a drug The rationale behind asparaginase is that it takes advantage of the fact that acute lymphoblastic leukemia cells and some other suspected tumor cells are unable to synthesize the non-essential amino acid asparagine, whereas normal cells are able to make their own asparagine; thus leukemic cells require high amount of asparagine. These leukemic cells depend on circulating asparagine. Asparaginase, however, catalyzes the conversion of L-asparagine to aspartic acid and ammonia. This deprives the leukemic cell of circulating asparagine, which leads to cell death. Enzyme regulation Type I L-asparaginase protein may use the morpheein model of allosteric regulation. Cost Normal asparaginase costs less than its pegylated version, pegaspargase. However, because it doesnt stay as long in the body, the injections need to be more frequent, with the result that total cost of treatment may be lower for the pegylated version. History The discovery and development of asparaginase as an anti-cancer drug began in 1953, when scientists first observed that lymphomas in rat and mice regressed after treatment with guinea pig serum. Later it was found out that it is not the serum itself which provoke the tumour regression, but rather the enzyme asparaginase.After researchers comparing different kinds of asparaginases, the one derived from Escherichia coli and Erwinia chrysanthemi turned out to have the best anti-cancer ability. E. coli has thereby become the main source of asparaginase due to the factor that it is also easy to produce in large amount. Society and culture Names Crisantaspase is the British Approved Name (BAN) for asparaginase obtained from Erwinia chrysanthemi. Colaspase is the BAN of asparaginase obtained from Escherichia coli. The United States Adopted Name of crisantaspase is asparaginase Erwinia chrysanthemi. Elspar, Kidrolase, Leunase and Spectrila are brand names for colaspase, while Erwinase and Erwinaze are brand names for crisantaspase. The pegylated version of colaspase is called pegaspargase. Oncaspar is the brand name of pegaspargase. References External links Eukaryotic Linear Motif resource motif class CLV_TASPASE1 Asparaginase at the US National Library of Medicine Medical Subject Headings (MeSH) "Asparaginase". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT04145531 for "An Open-Label Study of JZP-458 (RC-P) in Patients With Acute Lymphoblastic Leukemia (ALL)/Lymphoblastic Lymphoma (LBL)" at ClinicalTrials.gov
Daridorexant	Daridorexant, sold under the brand name Quviviq, is an orexin antagonist medication which is used for the treatment of insomnia. Daridorexant is taken by mouth.Side effects of daridorexant include headache, somnolence, and fatigue. The medication is a dual orexin receptor antagonist (DORA). It acts as a selective dual antagonist of the orexin receptors OX1 and OX2. Daridorexant has a relatively short elimination half-life of 8 hours and a time to peak of about 1 to 2 hours. It is not a benzodiazepine or Z-drug and does not interact with GABA receptors, instead having a distinct mechanism of action.Daridorexant was approved for medical use in the United States in January 2022 and became available in May 2022. It was approved in the European Union in April 2022, and is the first orexin receptor antagonist to become available in European Union. The medication is a schedule IV controlled substance in the United States and may have a modest potential for misuse. Medical uses Daridorexant is indicated for the treatment of adults with insomnia characterized by difficulties with sleep onset and/or sleep maintenance. The medication has been found to significantly improve latency to persistent sleep (LPS), wake after sleep onset (WASO), and subjective total sleep time (TST) in regulatory clinical trials. At doses of 25 to 50 mg and in terms of treatment–placebo difference, it reduces LPS by 6 to 12 minutes, reduces WASO by 10 to 23 minutes, and increases subjective TST by 10 to 22 minutes. Daridorexant has also been found to improve daytime functioning at a dose of 50 mg but not at 25 mg. It is the first insomnia medication to have been evaluated and shown effectiveness in improving not only nighttime symptoms but also daytime functioning.Network meta-analyses have assessed the sleep-promoting effects of orexin receptor antagonists and have compared them between one another as well as to other sleep aids including benzodiazepines, Z-drugs, antihistamines, sedative antidepressants (e.g., trazodone, doxepin, amitriptyline, mirtazapine), and melatonin receptor agonists. A major systematic review and network meta-analysis of insomnia medications published in 2022 found that daridorexant had an effect size (standardized mean difference (SMD)) against placebo for treatment of insomnia at 4 weeks of 0.23 (95% CI –0.01 to 0.48). This was similar to but numerically lower than the effect sizes at 4 weeks for suvorexant (SMD 0.31, 95% CI 0.01 to 0.62) and lemborexant (SMD 0.36, 95% CI 0.08 to 0.63). Benzodiazepines and Z-drugs generally showed larger effect sizes than orexin receptor antagonists (e.g., SMDs of 0.45 to 0.83). The review concluded on the basis of daridorexants small effect size that it did not show an overall material benefit in the treatment of insomnia. Conversely, it concluded that lemborexant—as well as the Z-drug eszopiclone—had the best profiles overall in terms of efficacy, tolerability, and acceptability among all of the assessed insomnia medications.Orexin receptor antagonists are not used as first-line treatments for insomnia due to their costs and concerns about possible misuse liability. Available forms Daridorexant is available in the form of 25 and 50 mg oral tablets. It is provided as the salt daridorexant hydrochloride, with each tablet containing 27 or 54 mg of this substance (equivalent to 25 or 50 mg daridorexant). Contraindications Daridorexant is contraindicated in people with narcolepsy. It is not recommended in people with severe hepatic impairment, whereas a lower maximum dose is recommended in people with moderate hepatic impairment. Concomitant use of daridorexant with strong CYP3A4 inhibitors and moderate to strong CYP3A4 inducers is not recommended and should be avoided due to unfavorable modification of daridorexant exposure. Side effects Side effects of daridorexant include headache (6% at 25 mg vs. 7% at 50 mg vs. 5% for placebo), somnolence or fatigue (includes somnolence, sedation, fatigue, hypersomnia, and lethargy) (6% at 25 mg vs. 5% at 50 mg vs. 4% for placebo), dizziness (2% at 25 mg vs. 3% at 50 mg vs. 2% for placebo), and nausea (0% at 25 mg vs. 3% at 50 mg vs. 2% for placebo). No residual effects have been found after administration of 25 mg daridorexant in the evening to either young or elderly individuals. However, daridorexant may cause next-morning driving impairment at the start of treatment or in some individuals. Orexin receptor antagonists like daridorexant may have less or no propensity for causing tolerance compared to other sedatives and hypnotics based on animal studies. Daridorexant did not produce signs of withdrawal or dependence upon discontinuation in animal studies and clinical trials, and orexin receptor antagonists are not associated with rebound insomnia. Loss of sleep-promoting effectiveness occurs rapidly upon discontinuation of daridorexant. Preclinical research has suggested that orexin antagonists may reduce appetite, but daridorexant and other orexin antagonists have not been associated with weight loss in rigorous clinical trials.Orexin receptor antagonists can affect the reward system and produce drug-liking responses in humans. Daridorexant at a dose of 50 mg (the maximum recommended dose) showed significantly greater drug liking than placebo but significantly less drug liking than zolpidem (30 mg) and suvorexant (150 mg) in recreational sedative drug users. At higher doses of 100 and 150 mg (greater than the recommended maximum dose), drug liking with daridorexant was similar to that with zolpidem (30 mg) and suvorexant (150 mg). In other studies, suvorexant showed similar drug liking compared to zolpidem but lower misuse potential on other measures (e.g., overall rate of misuse potential adverse events of 58% for zolpidem and 31% for suvorexant in recreational drug users). No reports indicative of misuse liability were observed in large clinical trials with daridorexant, although these studies excluded participants with history of drug or alcohol misuse. Overdose There is limited clinical experience with overdose of daridorexant. Overdose of the medication at a dose of up to four times the maximum recommended dose may result in adverse effects including somnolence, muscle weakness, catalepsy-like symptoms, sleep paralysis, attention disturbances, fatigue, headache, and constipation. There is no specific antidote to overdose of daridorexant. Interactions CYP3A4 inhibitors like ranitidine and diltiazem and CYP3A4 inducers like efavirenz can increase and decrease exposure to daridorexant, respectively. Concomitant use of daridorexant with strong CYP3A4 inhibitors or moderate or strong CYP3A4 inducers should be avoided, while it is recommended that the maximum dose of daridorexant be limited with moderate CYP3A4 inhibitors. Gastric pH modifiers like famotidine can decrease peak levels of daridorexant without affecting total exposure. Alcohol and selective serotonin reuptake inhibitors (SSRIs) like citalopram have not shown significant pharmacokinetic interactions with daridorexant. Coadministration of daridorexant with other sedatives like benzodiazepines, opioids, tricyclic antidepressants, and alcohol may increase the risk of central nervous system depression and daytime impairment. Daridorexant has not been found to significantly influence the pharmacokinetics of other drugs including midazolam (CYP3A4 substrate), rosuvastatin (BCRP substrate), and the SSRI citalopram. Pharmacology Pharmacodynamics Daridorexant acts as a selective dual antagonist of the orexin (hypocretin) receptors OX1 and OX2. The affinities (Ki) of daridorexant for the orexin receptors are 0.47 nM for the OX1 receptor and 0.93 nM for the OX2 receptor. Its Kb values for the human orexin receptors have been reported to be 0.5 nM for the OX1 receptor and 0.8 nM for the OX2 receptor. Hence, daridorexant is approximately equipotent in its antagonism of the orexin receptors. Daridorexant is selective for the orexin receptors over many other targets. In contrast to certain other sedatives and hypnotics, daridorexant is not a benzodiazepine or Z-drug and does not interact with GABA receptors. Mechanism of action The endogenous orexin neuropeptides, orexin A and orexin B, are involved in the regulation of sleep–wake cycles and act to promote wakefulness. Deficiency of orexin signaling is thought to be the primary cause of the sleep disorder narcolepsy. Disturbances in orexin signaling may also be involved in insomnia. Research suggests that orexin signaling may change with age, and this has been implicated in age-related sleep disturbances. By blocking the actions of orexins and modulating sleep–wake cycles, orexin receptor antagonists like daridorexant reduce wakefulness and improve sleep. The sleep-promoting effects of dual orexin receptor antagonists are thought to be mediated specifically by blockade of the OX2 receptor in the lateral hypothalamus. Although narcoleptic symptoms were a theoretical concern during the development of orexin receptor antagonists, this has not been observed in clinical trials of these agents. Pharmacokinetics Absorption The absolute bioavailability of daridorexant is 62%. It reaches peak concentrations within 1 to 2 hours following a dose. Food prolonged the time to peak by 1.3 hours and decreased the peak concentrations by 16%, but did not affect area-under-the-curve concentrations. Distribution The volume of distribution of daridorexant is 31 L. Its plasma protein binding is 99.7%. The plasma-to-blood ratio of daridorexant is 0.64. Daridorexant effectively crosses the blood–brain barrier in animals. Metabolism Daridorexant is extensively metabolized primarily by CYP3A4 (89%). Other cytochrome P450 enzymes contribute individually to less than 3% of the clearance of daridorexant. Elimination Daridorexant is eliminated primarily by feces (57%) then by urine (28%). It is excreted mainly in the form of metabolites, with only trace amounts of the parent compound identified.The medication has an elimination half-life of about 8 hours or of 6 to 10 hours. Its half-life is shorter than that of other orexin receptor antagonists such as suvorexant (12 hours) and lemborexant (~18–55 hours). The relatively short half-life of daridorexant may allow for reduced daytime sedation. The duration of action of daridorexant in terms of sedative effects is approximately 8 hours with a 50 mg dose. Chemistry Daridorexant is a small-molecule compound. The chemical name of daridorexant is (S)-(2-(5-chloro-4-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpyrrolidin-1-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone. Its molecular formula is C23H23N6O2Cl and its molecular weight is 450.93 g/mol (or 487.38 g/mol for the hydrochloride). Daridorexant hydrochloride is a white to light yellowish powder and is very slightly soluble in water. History Daridorexant was patented in 2013 and was first described in the scientific literature in 2017. It was approved for medical use in the United States in January 2022 and became available in this country in May 2022. On 24 February 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Quviviq, intended for the treatment of insomnia. On 29 April 2022, daridorexant was authorized for use in the European Union. It was the first orexin receptor antagonist to become available for use in the European Union. (The earlier orexin receptor antagonists suvorexant and lemborexant are not available in the European Union.) Regulatory review is also ongoing in Canada and Switzerland and is planned for the United Kingdom. Daridorexant was originated by Actelion Pharmaceuticals and was further developed by Idorsia. Society and culture Legal status Daridorexant is a schedule IV controlled substance under the Controlled Substances Act in the United States.Daridorexant (Quviviq) was approved for medical use in the European Union in April 2022. References Further reading "Application Number: 214985Orig1s000. Integrated Review. Daridorexant (Quviviq) for Insomnia" (PDF). Center for Drug Evaluation and Research (Food and Drug Administration). 2022. Archived from the original (PDF) on 22 April 2022. "Quviviq (Daridorexant) Assessment Report. Procedure No. EMEA/H/C/005634/0000" (PDF). Committee for Medicinal Products for Human Use (European Medicines Agency). 24 February 2022. External links "Daridorexant". Drug Information Portal. U.S. National Library of Medicine.
Japanese encephalitis vaccine	Japanese encephalitis vaccine is a vaccine that protects against Japanese encephalitis. The vaccines are more than 90% effective. The duration of protection with the vaccine is not clear but its effectiveness appears to decrease over time. Doses are given either by injection into a muscle or just under the skin.It is recommended as part of routine immunizations in countries where the disease is a problem. One or two doses are given depending on the version of the vaccine. Extra doses are not typically needed in areas where the disease is common. In those with HIV/AIDS or those who are pregnant an inactivated vaccine should be used. Immunization of travellers who plan to spend time outdoors in areas where the disease is common is recommended.The vaccines are relatively safe. Pain and redness may occur at the site of injection. As of 2015, 15 different vaccines are available: some are based on recombinant DNA techniques, others weakened virus, and others inactivated virus.The Japanese encephalitis vaccines first became available in the 1930s. It is on the World Health Organizations List of Essential Medicines. Efficacy Randomized control trials on JE-VAX have shown that a two-dose schedule provides protection for one year. History Japanese encephalitis vaccines first became available in the 1930s. One of them was an inactivated mouse brain-derived vaccine (the Nakayama and/or Beijing-1 strain), made by BIKEN and marketed by Sanofi Pasteur as JE-VAX, until production ceased in 2005. The other was an inactivated vaccine cultivated on primary hamster kidney cells (the Beijing-3 strain). The Beijing-3 strain was the main variant of the vaccine used in the Peoples Republic of China from 1968 until 2005.Three second-generation vaccines have entered markets since then: SA14-14-2, IC51 and ChimeriVax-JE. The live-attenuated SA14-14-2 strain was introduced in China in 1988. It is much cheaper than alternative vaccines, and is administered to 20 million Chinese children each year.A purified, formalin-inactivated, wholevirus vaccine known as IC51 (marketed in Australia and New Zealand as JESPECT and elsewhere as IXIARO) was licensed for use in the United States, Australia, and Europe during the spring of 2009. It is based on a SA14-14-2 strain and cultivated in Vero cells. In September 2012, the Indian firm Biological E. Limited launched an inactivated cell culture derived vaccine based on SA 14-14-2 strain which was developed in a technology transfer agreement with Intercell and is a thiomersal-free vaccine.Another vaccine, a live-attenuated recombinant chimeric virus vaccine developed using the Yellow fever virus known as ChimeriVax-JE (marketed as IMOJEV) was licensed for use in Australia in August 2010 and in Thailand in December 2012. References External links "Japanese Encephalitis Vaccine". Drug Information Portal. U.S. National Library of Medicine.
Testosterone (medication)	Testosterone (T) is a medication and naturally occurring steroid hormone. It is used to treat male hypogonadism, gender dysphoria, and certain types of breast cancer. It may also be used to increase athletic ability in the form of doping. It is unclear if the use of testosterone for low levels due to aging is beneficial or harmful. Testosterone can be used as a gel or patch that is applied to the skin, injection into a muscle, tablet that is placed in the cheek, or tablet that is taken by mouth.Common side effects of testosterone include acne, swelling, and breast enlargement in men. Serious side effects may include liver toxicity, heart disease, and behavioral changes. Women and children who are exposed may develop masculinization. It is recommended that individuals with prostate cancer not use the medication. It can cause harm to the baby if used during pregnancy or breastfeeding. Testosterone is in the androgen family of medications.Testosterone was first isolated in 1935, and approved for medical use in 1939. Rates of use have increased three times in the United States between 2001 and 2011. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication. In 2019, it was the 126th most commonly prescribed medication in the United States, with more than 5 million prescriptions. Medical uses The primary use of testosterone is the treatment of males with too little or no natural testosterone production, also termed hypogonadism or hypoandrogenism (androgen deficiency). This treatment is referred to as hormone replacement therapy (HRT), or alternatively, and more specifically, as testosterone replacement therapy (TRT) or androgen replacement therapy (ART). It is used to maintain serum testosterone levels in the normal male range. Decline of testosterone production with age has led to interest in testosterone supplementation.A 2020 guidelines from the American College of Physicians support the discussion of testosterone in adult men with age-related low levels of testosterone who have sexual dysfunction. They recommend yearly evaluation regarding possible improvement and, if none, to discontinue testosterone; physicians should consider intramuscular treatments, rather than transdermal treatments, due to costs and since the effectiveness and harm of either method is similar. Testosterone treatment for reasons other than possible improvement of sexual dysfunction may not be recommended. Deficiency Testosterone deficiency (also termed hypotestosteronism or hypotestosteronemia) is an abnormally low testosterone production. It may occur because of testicular dysfunction (primary hypogonadism) or hypothalamic–pituitary dysfunction (secondary hypogonadism) and may be congenital or acquired. Low levels due to aging Testosterone levels may decline gradually with age. The United States Food and Drug Administration (FDA) stated in 2015 that neither the benefits nor the safety of testosterone supplement have been established for low testosterone levels due to aging. The FDA has required that labels on testosterone include warnings about increased risk of heart attacks and stroke. Transgender men To take advantage of its virilizing effects, testosterone is administered to transgender men and other transmasculine individuals as part of masculinizing hormone therapy, titrated to clinical effect with a "target level" of the average males testosterone level. Women Testosterone therapy is effective in the short-term for the treatment of hypoactive sexual desire disorder (HSDD) in women. However, its long-term safety is unclear. Because of a lack data to support its efficacy and safety, the Endocrine Society recommends against the routine use of testosterone in women to treat low androgen levels due to hypopituitarism, adrenal insufficiency, surgical removal of the ovaries, high-dose corticosteroid therapy, or other causes. Similarly, because of a lack of data to support its efficacy and safety, the Endocrine Society recommends against the use of testosterone in women to improve general well-being, to treat infertility, sexual dysfunction due to causes other than HSDD, or to improve cognitive, cardiovascular, metabolic, and/or bone health.A 2014 systematic review and meta-analysis of 35 studies consisting of over 5,000 postmenopausal women with normal adrenal gland function found that testosterone therapy was associated with significant improvement in a variety of domains of sexual function. These domains included frequency of sexual activity, orgasm, arousal, and sexual satisfaction, among others. Women who were menopausal due to ovariectomy showed significantly greater improvement in sexual function with testosterone relative to those who had normal menopause. In addition to beneficial effects on sexual function, testosterone was associated with unfavorable changes in blood lipids. These included decreased levels of total cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and increased levels of low-density lipoprotein (LDL) cholesterol. However, the changes were small in magnitude, and the long-term significance in relation to cardiovascular outcomes is uncertain. The changes were more pronounced with oral testosterone undecanoate than with parenteral routes, such as transdermal testosterone. Testosterone showed no significant effect on depressed mood anxiety, bone mineral density (BMD), or anthropomorphic measures like body weight or body mass index. Conversely, it was associated with a significant incidence of androgenic side effects, including acne and hirsutism (excessive facial/body hair growth). Other androgenic side effects, such as weight gain, pattern hair loss, and voice deepening, were also reported in some trials, but were excluded from analyses due to insufficient data. The overall quality of the evidence was rated as low and was considered to be inconclusive in certain areas, for instance on long-term safety.A subsequent 2017 systematic review and meta-analysis of studies including over 3,000 postmenopausal women with HSDD similarly found that short-term transdermal testosterone therapy was effective in improving multiple domains of sexual function. Androgenic adverse effects such as acne and hirsutism were significantly greater in incidence with testosterone therapy, whereas no significant differences in "increase in facial hair, alopecia, voice deepening, urinary symptoms, breast pain, headache, site reaction to the patch, total adverse events, serious adverse events, reasons for withdrawal from the study, and the number of women who completed the study" were seen relative to controls.Although testosterone has been found to be effective at improving sexual function in postmenopausal women, the doses employed have been supraphysiological. In contrast to these high doses, there is little support for the notion that testosterone is a critical hormone for sexual desire and function in women under normal physiological circumstances. Low doses of testosterone resulting in physiological levels of testosterone (<50 ng/dL) have not been found to significantly increase sexual desire or function in women in most studies. Similarly, there appears to be little or no relationship between total or free testosterone levels in the normal physiological range and sexual desire in premenopausal women. Only high doses of testosterone resulting in supraphysiological levels of testosterone (>50 ng/dL) significantly increase sexual desire in women, with levels of testosterone of 80 to 150 ng/dL "slightly" increasing sex drive. In accordance, men experience sexual dysfunction at testosterone levels of below 300 ng/dL, and men that have levels of testosterone of approximately 200 ng/dL frequently experience such problems. The high doses of testosterone required to increase sexual desire in women may have a significant risk of masculinization with long-term therapy. For this reason, and due to the unknown health effects and safety of testosterone therapy, its use may be inappropriate. In 2003, the FDA rejected Intrinsa, a 300 µg/day testosterone patch for the treatment of sexual dysfunction in postmenopausal women. The reasons cited were limited efficacy (about one additional sexually satisfying event per month), concerns about safety and potential adverse effects with long-term therapy, and concerns about inappropriate off-label use. It appears that in women, rather than testosterone, estradiol may be the most important hormone involved in sexual desire, although data on the clinical use of estradiol to increase sexual desire in women is limited.There are no testosterone products approved for use in women in the United States and many other countries. There are approved testosterone products for women in Australia (where it is considered a drug of dependence, medicines that are subject to misuse and trafficking.) and some European countries. Testosterone pellet implants are approved for use in postmenopausal women in the United Kingdom. Testosterone products for men can be used off-label in women in the United States. Alternatively, testosterone products for women are available from compounding pharmacies in the United States, although such products are unregulated and manufacturing quality is not ensured. Available forms Testosterone has been marketed for use by oral, sublingual, buccal, intranasal, transdermal (patches), topical (gels), intramuscular (injection), and subcutaneous (implant administration. It is provided unmodified and as a testosterone ester such as testosterone cypionate, testosterone enanthate, testosterone propionate, or testosterone undecanoate, which act as prodrugs of testosterone. The most common route of administration for testosterone is by intramuscular injection. However, it has been reported that AndroGel, a transdermal gel formulation of testosterone, has become the most popular form of testosterone in androgen replacement therapy for hypogonadism in the United States. Non-medical use Athletics Testosterone is used as a form of doping among athletes in order to improve performance. Testosterone is classified as an anabolic agent and is on the World Anti-Doping Agency (WADA) List of Prohibited Substances and Methods. Hormone supplements cause the endocrine system to adjust its production and lower the natural production of the hormone, so when supplements are discontinued, natural hormone production is lower than it was originally.Anabolic–androgenic steroids (AAS), including testosterone and its esters, have also been taken to enhance muscle development, strength, or endurance. They do so directly by increasing the muscles protein synthesis. As a result, muscle fibers become larger and repair faster than the average persons.After a series of scandals and publicity in the 1980s (such as Ben Johnsons improved performance at the 1988 Summer Olympics), prohibitions of AAS use were renewed or strengthened by many sports organizations. Testosterone and other AAS were designated a "controlled substance" by the United States Congress in 1990, with the Anabolic Steroid Control Act. Their use is seen as an issue in modern sport, particularly given the lengths to which athletes and professional laboratories go to in trying to conceal such use from sports regulators. Steroid use once again came into the spotlight as a result of Canadian professional wrestler Chris Benoits double murder-suicide in 2007; however, there is no evidence implicating steroid use as a factor in the incident.Some female athletes may have naturally higher levels of testosterone than others, and may be asked to consent to sex verification and either surgery or drugs to decrease testosterone levels. This has proven contentious, with the Court of Arbitration for Sport suspending the IAAF policy due to insufficient evidence of a link between high androgen levels and improved athletic performance. Detection of abuse A number of methods for detecting testosterone use by athletes have been employed, most based on a urine test. These include the testosterone/epitestosterone ratio (normally less than 6), the testosterone/luteinizing hormone ratio and the carbon-13/carbon-12 ratio (pharmaceutical testosterone contains less carbon-13 than endogenous testosterone). In some testing programs, an individuals own historical results may serve as a reference interval for interpretation of a suspicious finding. Another approach being investigated is the detection of the administered form of testosterone, usually an ester, in hair. Contraindications Absolute contraindications of testosterone include prostate cancer, elevated hematocrit (>54%), uncontrolled congestive heart failure, various other cardiovascular diseases, and uncontrolled obstructive sleep apnea. Breast cancer is said by some sources to be an absolute contraindication of testosterone therapy, but androgens including testosterone have also actually been used to treat breast cancer. Relative contraindications of testosterone include elevated prostate-specific antigen (PSA) in men with a high risk of prostate cancer due to ethnicity or family history, severe lower urinary tract symptoms, and elevated hematocrit (>50%). Side effects Adverse effects may also include minor side effects such as oily skin, acne, and seborrhea, as well as loss of scalp hair, which may be prevented or reduced with 5α-reductase inhibitors. In women, testosterone can produce hirsutism (excessive facial/body hair growth), deepening of the voice, and other signs of virilization. Exogenous testosterone may cause suppression of spermatogenesis in men, leading to, in some cases, reversible infertility. Gynecomastia and breast tenderness may occur with high dosages of testosterone due to peripheral conversion of testosterone by aromatase into excessive amounts of the estrogen estradiol. Testosterone treatment, particularly in high dosages, can also be associated with mood changes, increased aggression, increased sex drive, spontaneous erections, and nocturnal emissions.Other side effects include increased hematocrit, which can require venipuncture in order to treat, and exacerbation of sleep apnea.The FDA stated in 2015 that neither the benefits nor the safety of testosterone have been established for low testosterone levels due to aging. The FDA has required that testosterone pharmaceutical labels include warning information about the possibility of an increased risk of heart attacks and stroke. They have also required the label include concerns about abuse and dependence.Injectable forms of testosterone can cause a lung problem called pulmonary oil microembolism (POME). Symptoms of POME include cough, shortness of breath, tightening of the throat, chest pain, sweating, dizziness, and fainting. A postmarketing analysis by the manufacturer of Aveed (testosterone undeconate injection) found that POME occurred at a rate of less than 1% per injection per year for Aveed. Long-term adverse effects Cardiovascular disease Adverse effects of testosterone supplementation may include increased cardiovascular events (including strokes and heart attacks) and deaths based on three peer-reviewed studies involving men taking testosterone replacement. In addition, an increase of 30% in deaths and heart attacks in older men has been reported. Due to an increased incidence of adverse cardiovascular events compared to a placebo group, a Testosterone in Older Men with Mobility Limitations (TOM) trial (a National Institute of Aging randomized trial) was halted early by the Data Safety and Monitoring Committee. On January 31, 2014, reports of strokes, heart attacks, and deaths in men taking FDA-approved testosterone-replacement led the FDA to announce that it would be investigating the issue. Later, in September 2014, the FDA announced, as a result of the "potential for adverse cardiovascular outcomes", a review of the appropriateness and safety of Testosterone Replacement Therapy (TRT). The FDA now requires warnings in the drug labeling of all approved testosterone products regarding deep vein thrombosis and pulmonary embolism.Up to the year 2010, studies had not shown any effect on the risk of death, prostate cancer or cardiovascular disease; more recent studies, however, do raise concerns. A 2013 study, published in the Journal of the American Medical Association, reported "the use of testosterone therapy was significantly associated with increased risk of adverse outcomes." The study began after a previous, randomized, clinical trial of testosterone therapy in men was stopped prematurely "due to adverse cardiovascular events raising concerns about testosterone therapy safety." Prostate cancer Testosterone in the presence of a slow-growing prostate cancer is assumed to increase its growth rate. However, the association between testosterone supplementation and the development of prostate cancer is unproven. Nevertheless, physicians are cautioned about the cancer risk associated with testosterone supplementation.Testosterone may accelerate pre-existing prostate cancer growth in individuals who have undergone androgen deprivation. It is recommended that physicians screen for prostate cancer with a digital rectal exam and prostate-specific antigen (PSA) level before starting therapy, and monitor PSA and hematocrit levels closely during therapy.Ethnic groups have different rates of prostate cancer. Differences in sex hormones, including testosterone, have been suggested as an explanation for these differences. This apparent paradox can be resolved by noting that prostate cancer is very common. In autopsies, 80% of 80-year-old men have prostate cancer. Pregnancy and breastfeeding Testosterone is contraindicated in pregnancy and not recommended during breastfeeding. Androgens like testosterone are teratogens and are known to cause fetal harm, such as producing virilization and ambiguous genitalia. Interactions 5α-Reductase inhibitors 5α-Reductase inhibitors like finasteride and dutasteride can slightly increase circulating levels of testosterone by inhibiting its metabolism. However, these drugs do this via prevention of the conversion of testosterone into its more potent metabolite dihydrotestosterone (DHT), and this results in dramatically reduced circulating levels of DHT (which circulates at much lower relative concentrations). In addition, local levels of DHT in so-called androgenic (5α-reductase-expressing) tissues are also markedly reduced, and this can have a strong impact on certain effects of testosterone. For instance, growth of body and facial hair and penile growth induced by testosterone may be inhibited by 5α-reductase inhibitors, and this could be considered undesirable in the context of, for instance, puberty induction. On the other hand, 5α-reductase inhibitors may prevent or reduce adverse androgenic side effects of testosterone like scalp hair loss, oily skin, acne, and seborrhea. In addition to the prevention of testosterone conversion into DHT, 5α-reductase inhibitors also prevent the formation of neurosteroids like 3α-androstanediol from testosterone, and this may have neuropsychiatric consequences in some men. Aromatase inhibitors Aromatase inhibitors like anastrozole prevent the conversion of testosterone into estradiol by aromatase. As only a very small fraction of testosterone is converted into estradiol, this does not affect testosterone levels, but it can prevent estrogenic side effects like gynecomastia that can occur when testosterone is administered at relatively high dosages. However, estradiol exerts negative feedback on the hypothalamic–pituitary–gonadal axis and, for this reason, prevention of its formation can reduce this feedback and disinhibit gonadal production of testosterone, which in turn can increase levels of endogenous testosterone. Testosterone therapy is sometimes combined with an aromatase inhibitor for men with secondary hypogonadism who wish to conceive children with their partners. Cytochrome P450 inhibitors Inhibitors and inducers of cytochrome P450 enzymes like CYP3A4 have been associated with little or no effect on circulating testosterone levels. Antiandrogens and estrogens Antiandrogens like cyproterone acetate, spironolactone, and bicalutamide can block the androgenic and anabolic effects of testosterone. Estrogens can reduce the effects of testosterone by increasing the hepatic production and in turn circulating levels of sex hormone-binding globulin (SHBG), a carrier protein that binds to and occupies androgens like testosterone and DHT, and thereby reducing free concentrations of these androgens. Pharmacology Pharmacodynamics Testosterone is a high affinity ligand for and agonist of the nuclear androgen receptor (AR). In addition, testosterone binds to and activates membrane androgen receptors (mARs) such as GPRC6A and ZIP9. Testosterone is also potentiated via transformation by 5α-reductase into the more potent androgen DHT in so-called androgenic tissues such as the prostate gland, seminal vesicles, skin, and hair follicles. In contrast to the case of testosterone, such potentiation occurs to a reduced extent or not at all with most synthetic AAS (as well as with DHT), and this is primarily responsible for the dissociation of anabolic and androgenic effects with these agents. In addition to DHT, testosterone is converted at a rate of approximately 0.3% into the estrogen estradiol via aromatase. This occurs in many tissues, especially adipose tissue, the liver, and the brain, but primarily in adipose tissue. Testosterone, after conversion into DHT, is also metabolized into 3α-androstanediol, a neurosteroid and potent positive allosteric modulator of the GABAA receptor, and 3β-androstanediol, a potent and preferential agonist of the ERβ. These metabolites, along with estradiol, may be involved in a number of the effects of testosterone in the brain, including its antidepressant, anxiolytic, stress-relieving, rewarding, and pro-sexual effects. Effects in the body and brain The ARs are expressed widely throughout the body, including in the penis, testicles, epididymides, prostate gland, seminal vesicles, fat, skin, bone, bone marrow, muscle, larynx, heart, liver, kidneys, pituitary gland, hypothalamus, and elsewhere throughout the brain. Through activation of the ARs (as well as the mARs), testosterone has many effects, including the following: Promotes growth, function, and maintenance of the prostate gland, seminal vesicles, and penis during puberty and thereafter Promotes growth and maintenance of muscles, particularly of the upper body Causes subcutaneous fat to be deposited in a masculine pattern and decreases overall body fat Suppresses breast development induced by estrogens, but can also still produce gynecomastia via excessive conversion into estradiol if levels are too high Maintains skin health, integrity, appearance, and hydration and slows the rate of aging of the skin, but can also cause oily skin, acne, and seborrhea Promotes the growth of facial and body hair, but can also cause scalp hair loss and hirsutism Contributes to bone growth and causes broadening of the shoulders at puberty Modulates liver protein synthesis, such as the production of sex hormone-binding globulin and many other proteins Increases production of erythropoietin in the kidneys and thereby stimulates red blood cell production in bone marrow and elevates hematocrit Exerts negative feedback on the hypothalamic–pituitary–gonadal axis by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland, thereby inhibiting gonadal sex hormone production as well as spermatogenesis and fertility Regulates the vasomotor system and body temperature via the hypothalamus, thereby preventing hot flashes Modulates brain function, with effects on mood, emotionality, aggression, and sexuality, as well as cognition and memory Increases sex drive and erectile capacity and causes spontaneous erections and nocturnal emissions Increases the risk of benign prostatic hyperplasia and prostate cancer and accelerates the progression of prostate cancer Decreases breast proliferation and the risk of breast cancer Pharmacokinetics Testosterone can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), rectal suppositories), by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant. The pharmacokinetics of testosterone, including its bioavailability, circulating testosterone levels, metabolism, biological half-life, and other parameters, differ by route of administration. Chemistry Testosterone is a naturally occurring androstane steroid and is also known by the chemical name androst-4-en-17β-ol-3-one. It has a double bond between the C4 and C5 positions (making it an androstene), a ketone group at the C3 position, and a hydroxyl (alcohol) group at the C17β position. Derivatives Testosterone esters are substituted at the C17β position with a lipophilic fatty acid ester moiety of varying chain length. Major testosterone esters include testosterone cypionate, testosterone enanthate, testosterone propionate, and testosterone undecanoate. A C17β ether prodrug of testosterone, cloxotestosterone acetate, has also been marketed, although it is little known and is used very rarely or no longer. Another C17β ether prodrug of testosterone, silandrone, also exists but was never marketed, and is notable in that it is orally active. In addition to ester and ether prodrugs, androgen prohormones or precursors of testosterone, such as dehydroepiandrosterone (DHEA), androstenediol, and androstenedione, exist as well, and convert into testosterone to variable extents upon oral ingestion. Unlike testosterone ester and ether prodrugs however, these prohormones are only weakly androgenic/anabolic.All synthetic AAS are derivatives of testosterone. Prominent examples include nandrolone (19-nortestosterone), metandienone (17α-methyl-δ1-testosterone), and stanozolol (a 17α-alkylated derivative of DHT). Unlike testosterone, AAS that are 17α-alkylated, like metandienone and stanozolol, are orally active. This is due to steric hindrance of C17β-position metabolism during the first-pass through the liver. In contrast, most AAS that are not 17α-alkylated, like nandrolone, are not active orally, and must instead be administered via intramuscular injection. This is almost always in ester form; for instance, in the case of nandrolone, as nandrolone decanoate or nandrolone phenylpropionate. History Testosterone was first isolated and synthesized in 1935. Shortly thereafter, in 1937, testosterone first became commercially available as a pharmaceutical drug in the form of pellets and then in ester form for intramuscular injection as the relatively short-acting testosterone propionate. Methyltestosterone, one of the first synthetic AAS and orally active androgens, was introduced in 1935, but was associated with hepatotoxicity and eventually became largely medically obsolete. In the mid-1950s, the longer-acting testosterone esters testosterone enanthate and testosterone cypionate were introduced. They largely superseded testosterone propionate and became the major testosterone esters used medically for over half a century. In the 1970s, testosterone undecanoate was introduced for oral use in Europe, although intramuscular testosterone undecanoate had already been in use in China for several years. Intramuscular testosterone undecanoate was not introduced in Europe and the United States until much later (in the early to mid 2000s and 2014, respectively).The history of testosterone as a medication has been reviewed. Society and culture Usage In the US in the 2000s, companies and figures in the popular media have heavily marketed notions of "andropause" as something parallel to menopause; these notions have been rejected by the medical community. Additionally, advertising from drug companies selling testosterone and human growth hormone, as well as dietary supplement companies selling all kinds of "boosters" for aging men, have emphasized the "need" of middle-aged or ageing men for testosterone. There is a medical condition called late-onset hypogonadism; according to Thomas Perls and David J. Handelsman, writing in a 2015 editorial in the Journal of the American Geriatrics Society, it appears that this condition is overdiagnosed and overtreated. Perls and Handelsman note that in the US, "sales of testosterone increased from $324 million in 2002 to $2 billion in 2012, and the number of testosterone doses prescribed climbed from 100 million in 2007 to half a billion in 2012, not including the additional contributions from compounding pharmacies, Internet, and direct-to-patient clinic sales." Generic names Testosterone is the generic name of testosterone in English and Italian and the INN, USAN, USP, BAN, and DCIT of the drug, while testostérone is its French name and the DCF. It is also referred to in Latin as testosteronum, in Spanish and Portuguese as testosterona, and in German, Dutch, and Russian and other Slavic languages as testosteron. The Cyrillic script of testosterone is тестостерон. Brand names Testosterone is marketed under a large number of brand names throughout the world
Testosterone (medication)	. Major brand names of testosterone and/or its esters include Andriol, Androderm, AndroGel, Axiron, Delatestryl, Depo-Testosterone, Intrinsa, Nebido, Omnadren, Primoteston, Sustanon, Testim, TestoGel, TestoPatch, Testoviron, and Tostran. Availability United States As of November 2016, unmodified (non-esterified) testosterone is available in the United States in the following formulations: Topical gels: AndroGel, Fortesta, Testim, Testosterone (generic) Topical solutions: Axiron, Testosterone (generic) Transdermal patches: Androderm, Testoderm (discontinued), Testoderm TTS (discontinued), Testosterone (generic) Intranasal gels: Natesto Buccal tablets: Striant Pellet implants: TestopelAnd the following ester prodrugs of testosterone are available in the United States in oil solutions for intramuscular injection: Testosterone cypionate: Depo-Testosterone, Testosterone Cypionate (generic) Testosterone enanthate: Delatestryl, Xyosted (auto-injector), Testosterone Enanthate (generic) Testosterone propionate: Testosterone Propionate (generic) Testosterone undecanoate: AveedUnmodified testosterone was also formerly available for intramuscular injection but was discontinued.Testosterone cypionate and testosterone enanthate were formerly available in combination with estradiol cypionate and estradiol valerate, respectively, under the brand names Depo-Testadiol and Ditate-DS, respectively, as oil solutions for intramuscular injection, but these formulations have been discontinued.Unlike in Europe, Canada, and much of the rest of the world, oral testosterone undecanoate is not available in the United States. Canada As of November 2016, testosterone is available in Canada in the form of topical gels (AndroGel, Testim), topical solutions (Axiron), transdermal patches (Androderm), and intranasal gels (Natesto). Testosterone cypionate (Depo-Testosterone, Testosterone Cypionate (generic)), testosterone enanthate (Delatestryl, PMS-Testosterone Enanthate), and testosterone propionate (Testosterone Propionate (generic)) are available as oil solutions for intramuscular injection and testosterone undecanoate (Andriol, PMS-Testosterone, Taro-Testosterone) is available in the form of oral capsules. Testosterone buccal tablets and pellet implants do not appear to be available in Canada. Other countries Testosterone and/or its esters are widely available in countries throughout the world in a variety of formulations. Legal status Testosterone and its esters, along with other AAS, are prescription-only controlled substances in many countries throughout the world. In the United States, they are Schedule III drugs under the Controlled Substances Act, in Canada, they are Schedule IV drugs under the Controlled Drugs and Substances Act, and in the United Kingdom, they are Class C drugs under the Misuse of Drugs Act. Litigation As of 2014, a number of lawsuits are underway against manufacturers of testosterone, alleging a significantly increased rate of stroke and heart attack in elderly men who use testosterone supplementation. Doping in sports There are many known cases of doping in sports with testosterone and its esters by professional athletes. Research Depression Testosterone has been used to treat depression in men who are of middle age with low testosterone. However, a 2014 review showed no benefit on the mood of the men with normal levels of testosterone or on the mood of the older men with low testosterone. Conversely, a 2009 review found that testosterone had an antidepressant effect in men with depression, especially those with hypogonadism, HIV/AIDS, and in the elderly. Heart failure Testosterone replacement can significantly improve exercise capacity, muscle strength and reduce QT intervals in men with chronic heart failure (CHF). Over the 3 to 6-month course of the studies reviewed, testosterone therapy appeared safe and generally effective, and (ruling out prostate cancer) the authors found no justification to absolutely restrict its use in men with CHF. A similar 2012 review also found increased exercise capacity and reasoned the benefits generlizable to women. However, both reviews advocate larger, longer term, randomized controlled trials. Male contraception Testosterone, as esters such as testosterone undecanoate or testosterone buciclate, has been studied and promoted as a male contraceptive analogous to estrogen-based contraceptives in women. Otherwise considered an adverse effect of testosterone, reduced spermatogenesis can be further suppressed with the addition of a progestin such as norethisterone enanthate or levonorgestrel butanoate, improving the contraceptive effect. Anorgasmia Testosterone is under development in a low-dose intranasal formulation for the treatment of anorgasmia in women. Miscellaneous Testosterone therapy may improve the management of type 2 diabetes. Low testosterone has been associated with the development of Alzheimers disease.Topical androgens like testosterone have been used and studied in the treatment of cellulite in women. References Further reading External links "Testosterone". Drug Information Portal. U.S. National Library of Medicine. "Testosterone Transdermal Patch". MedlinePlus. "Testosterone Buccal". MedlinePlus. "Testosterone Topical". MedlinePlus. "Testosterone Injection". MedlinePlus. "Testosterone Nasal Gel". MedlinePlus.
Disopyramide	Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent. Disopyramide has a negative inotropic effect on the ventricular myocardium, significantly decreasing the contractility. Disopyramide also has an anticholinergic effect on the heart which accounts for many adverse side effects. Disopyramide is available in both oral and intravenous forms, and has a low degree of toxicity. Mechanism of action Disopyramides Class 1a activity is similar to that of quinidine in that it targets sodium channels to inhibit conduction. Disopyramide depresses the increase in sodium permeability of the cardiac myocyte during Phase 0 of the cardiac action potential, in turn decreasing the inward sodium current. This results in an increased threshold for excitation and a decreased upstroke velocity. Disopyramide prolongs the PR interval by lengthening both the QRS and P wave duration. This effect is particularly well suited in the treatment of ventricular tachycardia as it slows the action potential propagation through the atria to the ventricles. Disopyramide does not act as a blocking agent for beta or alpha adrenergic receptors, but does have a significant negative inotropic effect on the ventricular myocardium. As a result, the use of disopyramide may reduce contractile force up to 42% at low doses and up to 100% in higher doses compared to quinidine.Levites proposed a possible secondary mode of action for disopyramide, against reentrant arrhythmias after an ischemic insult. Disopyramide decreases the inhomogeneity between infarcted and normal myocardium refractory periods; in addition to lengthening the refractory period. This decreases the chance of re-entry depolarization, because signals are more likely to encounter tissue in a refractory state which cannot be excited. This provides a possible treatment for atrial and ventricular fibrillation, as it restores pacemaker control of the tissue to the SA and AV nodes. Obstructive hypertrophic cardiomyopathy Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease, occurring in 1:500 individuals in the general population. It is estimated that there are 600,000 individuals in the United States with hypertrophic cardiomyopathy. The most common variant of HCM presents with left ventricular (LV) intracavitary obstruction due to systolic anterior motion of the mitral valve, and mitral-septal contact, diagnosed readily with echocardiography. Pharmacologic treatment with negative inotropic drugs is first-line therapy. Beta-blockers are used first, and while they improve symptoms of shortness of breath, chest pain and exercise intolerance, they do not reduce resting LV intraventricular pressure gradients and often are inadequate to control symptoms. Many investigators and clinicians believe that disopyramide controlled release is the most potent agent available for reducing resting pressure gradients and improving symptoms. Disopyramide has been actively used for more than 30 years. Disopyramide administration for obstructive HCM has a IB recommendation in the 2020 American Heart Association/American College of Cardiology Foundation guidelines for treatment of obstructive HCM. A IB treatment recommendation indicates that a treatment is recommended, and may be useful, and beneficial. Negative inotropes improve LV obstruction by decreasing LV ejection acceleration and hydrodynamic forces on the mitral valve. Disopyramides particular efficacy is due to its potent negative inotropic effects; in head-to-head comparison, it is more effective for gradient reduction than either beta-blocker or verapamil. Disopyramide is most often administered with beta-blockade. When used in patients resistant to beta-blockade, disopyramide is effective in 60% of cases, reducing symptoms and gradient to the extent that invasive procedures such as surgical septal myectomy are not required.Disopyramide, despite its efficacy, has one main side effect that has limited its use in the US, though it has seen wider application in Canada, UK and Japan. Vagal blockade predictably causes dry mouth, and in men with prostatism, may cause urinary retention. Teichman et al. showed that pyridostigmine used in combination with disopyramide substantially alleviates vagolytic side effects without compromising antiarrhythmic efficacy. This combination has also been shown to be effective and safe in obstructive HCM in a large cohort of patients. Some clinicians prescribe pyridostigmine sustained release (marketed in the US as Mestinon Timespan) to every patient begun on disopyramide. This combination increases acceptance of higher disopyramide dosing, important since there is a dose-response correlation in obstructive HCM, higher doses yielding lower gradients. Another concern about disopyramide has been the hypothetical potential for inducing sudden death from its type 1 anti-arrhythmic effects. However, a multicenter registry and two recent cohort registries have largely reduced this concern, by showing sudden death rates lower than that observed from the disease itself.These concerns about the drug must be viewed from the clinical perspective that disopyramide is generally the last agent that is tried for patients before they are referred for invasive septal reduction with surgical septal myectomy (an open-heart operation) or alcohol septal ablation (a controlled heart attack). Both of these invasive procedures have risk of morbidity and mortality. For selected patients, a trial of oral disopyramide is a reasonable approach before proceeding to invasive septal reduction. Patients who respond to disopyramide are continued on the drug. Those who continue to have disabling symptoms or who experience side effects are promptly referred for septal reduction. Using such a stepped strategy, investigators have reported that survival does not differ from that observed in the age-matched normal United States population. Cardiac adverse effects Acute heart failure – Disopyramide should not be given to patients with impaired LV systolic function and low ejection fraction. Heart failure is not seen when disopyramide is used in patients with normal or supernormal LV systolic function. Severe hypotension – Disopyramide should not be given to patients with impaired LV systolic function and low ejection fraction. Hypotension is not seen in patients with normal or supernormal LV systolic function. Extracardiac effects Atropine like effects (anticholinergic) Dry mouth Constipation Urinary retention – Disopyramide should not be given to patients with symptomatic prostatism. Blurred vision Glaucoma Rash AgranulocytosisAdditionally, disopyramide may enhance the hypoglycaemic effect of gliclazide, insulin, and metformin. See also Actisomide References External links Disopyramide on RxList
Erythromycin	Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.Common side effects include abdominal cramps, vomiting, and diarrhea. More serious side effects may include Clostridium difficile colitis, liver problems, prolonged QT, and allergic reactions. It is generally safe in those who are allergic to penicillin. Erythromycin also appears to be safe to use during pregnancy. While generally regarded as safe during breastfeeding, its use by the mother during the first two weeks of life may increase the risk of pyloric stenosis in the baby. This risk also applies if taken directly by the baby during this age. It is in the macrolide family of antibiotics and works by decreasing bacterial protein production.Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea. It is on the World Health Organizations List of Essential Medicines. In 2017, it was the 215th most commonly prescribed medication in the United States, with more than two million prescriptions. Medical uses Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including Streptococcus, Staphylococcus, Haemophilus and Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria: Haemophilus influenzae: 0.015 to 256 μg/ml Staphylococcus aureus: 0.023 to 1024 μg/ml Streptococcus pyogenes: 0.004 to 256 μg/ml Corynebacterium minutissimum: 0.015 to 64 μg/mlIt may be useful in treating gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill. Intravenous erythromycin may also be used in endoscopy to help clear stomach contents. Available forms Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections. The following erythromycin combinations are available for oral dosage: erythromycin base (capsules, tablets) erythromycin estolate (capsules, oral suspension, tablets), contraindicated during pregnancy erythromycin ethylsuccinate (oral suspension, tablets) erythromycin stearate (oral suspension, tablets)For injection, the available combinations are: erythromycin gluceptate erythromycin lactobionateFor ophthalmic use: erythromycin base (ointment) Adverse effects Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are very common because erythromycin is a motilin agonist. Because of this, erythromycin tends not to be prescribed as a first-line drug. More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxis. Cholestasis, Stevens–Johnson syndrome, and toxic epidermal necrolysis are some other rare side effects that may occur. Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally. Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants. Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats. Interactions Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily. The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor)—are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated. Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4. Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the QT interval. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline, which is used mostly in asthma, is also contraindicated. Erythromycin and doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.It may alter the effectiveness of combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and AUC of estradiol and dienogest.Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g., warfarin. Pharmacology Mechanism of action Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations. By binding to the 50s subunit of the bacterial rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action. Erythromycin increases gut motility by binding to Motillin receptor, thus it is a Motillin receptor agonist in addition to its antimicrobial properties. Pharmacokinetics Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released. Metabolism Most of erythromycin is metabolised by demethylation in the liver by the hepatic enzyme CYP3A4. Its main elimination route is in the bile with little renal excretion, 2%-15% unchanged drug. Erythromycins elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease. Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5-2.5 hours after dosing, but can be delayed if digested with food.Erythromycin crosses the placenta and enters breast milk. The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding. Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients. Chemistry Composition Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A. Some of these related compounds have been purified and can be studied and researched individually. Synthesis Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task. Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials. Woodward successfully completed the synthesis of erythromycin A. Erythromycin related compounds History In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer at Eli Lilly. Aguilar managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples. Aguilar received no further credit or compensation for his discovery. The scientist was allegedly promised a trip to the company’s manufacturing plant in Indianapolis, but it was never fulfilled. In a letter to the company’s president, Aguilar wrote: “A leave of absence is all I ask as I do not wish to sever my connection with a great company which has given me wonderful breaks in life.” The request was not granted.Aguilar reached out to Eli Lilly again in 1993, requesting royalties from sales of the drug over the years, intending to use them to put up a foundation for poor and sickly Filipinos. This request was also denied. He died in September of the same year.Lilly filed for patent protection on the compound which was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin. The antibiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin. Scientists at Chugai Pharmaceuticals discovered an erythromycin-derived motilin agonist called mitemcinal that is believed to have strong prokinetic properties (similar to erythromycin) but lacking antibiotic properties. Erythromycin is commonly used off-label for gastric motility indications such as gastroparesis. If mitemcinal can be shown to be an effective prokinetic agent, it would represent a significant advance in the gastrointestinal field, as treatment with this drug would not carry the risk of unintentional selection for antibiotic-resistant bacteria. Society and culture Cost It is available as a generic medication.In the United States in 2014 the price increased to seven dollars per tablet.The price of Erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015. In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates). By 2018, generic drug prices had climbed another 5% on average. Brand names Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Ranbaxy, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine, Acnasol, and Tiloryth. Fishcare brand name API E.M. ERYTHROMYCIN Use in fishcare This drug is also used in fishcare for the broad spectrum treatment and control of bacterial disease. Body slime, mouth fungus, Furunculosis, bacterial gill illness, and hemorrhagic septicaemia are all examples of bacterial diseases in fish that may be treated and controlled with this therapy. It mainly attacks gram-positive bacteria in fish. See also Erythromycin/tretinoin, a combination of tretinoin and the antibiotic erythromycin References External links "Erythromycin". Drug Information Portal. U.S. National Library of Medicine. U.S. Patent 2,653,899
Pimecrolimus	Pimecrolimus is an immunomodulating agent of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema). It is available as a topical cream, once marketed by Novartis (however, Galderma has been promoting the compound in Canada since early 2007) under the trade name Elidel. Medical uses It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis, cutaneous lupus erythematosus, oral lichen planus, vitiligo, and psoriasis. Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants. Side effects In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin cancer, as for the similar drug tacrolimus, whereas current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism. Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy. However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials. Dermatologists and allergists professional societies, the American Academy of Dermatology, and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship." Pharmacology Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to FKBP1A and also inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals. Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells. It has lower permeation through the skin than topical steroids or topical tacrolimus although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy. References External links FDA News NPS RADAR Article about American Academy of Dermatology speaking out against black box warning Archived 2008-04-07 at the Wayback Machine Report of the Calcineurin Task Force of the ACAAI and AAAAI
DTaP-IPV/Hib vaccine	DTaP-IPV/Hib vaccine is a 5-in-1 combination vaccine that protects against diphtheria, tetanus, whooping cough, polio, and Haemophilus influenzae type B.Its generic name is diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated poliovirus and haemophilus B conjugate vaccine, and it is also known as DTaP-IPV-Hib. Uses DTaP-IPV/Hib vaccine is administered to young children to immunise against diphtheria, tetanus, pertussis, poliomyelitis, and diseases caused by Haemophilus influenzae type B. Formulations A branded formulation marketed in the United States is Pentacel, manufactured by Sanofi Pasteur.Pentacel is known in the UK and Canada as Pediacel.An equivalent vaccine marketed in the UK and Canada by GlaxoSmithKline is Infanrix IPV + Hib. This is a two-part vaccine. The DTaP-IPV component is supplied as a sterile liquid, which is used to reconstitute lyophilized (freeze-dried) Hib vaccine. Pentaxim is a liquid formulation marketed by Sanofi Pasteur. Availability It is only licensed for young children. In the US the FDA have approved the vaccine for children from age 6 weeks up to age 5 years. It was used in the UK until 2017, following which a 6-in-1 vaccine became available containing the additional protection against Hepatitis B. == References ==
Fosphenytoin	Fosphenytoin, also known as fosphenytoin sodium, and sold under the brand name Cerebyx among others, is a water-soluble phenytoin prodrug that is administered intravenously to deliver phenytoin, potentially more safely than intravenous phenytoin. It is used in the acute treatment of convulsive status epilepticus. Fosphenytoin was developed in 1996. On 18 November 2004, Sicor (a subsidiary of Teva) received a tentative approval letter from the United States Food and Drug Administration for a generic version of fosphenytoin. Medical uses Fosphenytoin is approved in the United States for the short-term (five days or fewer) treatment of epilepsy when more widely used means of phenytoin administration are not possible or are ill-advised, such as endotracheal intubation, status epilepticus or some other type of repeated seizures; cluster seizure, vomiting, and/or the patient is unalert or not awake or both. Other In 2003, it was reported that even though anticonvulsants are often very effective in mania, and acute mania requires rapid treatment, fosphenytoin had no antimanic effect. Metabolism One millimole of phenytoin is produced for every millimole of fosphenytoin administered; the hydrolysis of fosphenytoin also yields phosphate and formaldehyde, the latter of which is subsequently metabolized to formate, which is in turn metabolized by a folate dependent mechanism. Side effects Side effects are similar to intravenous phenytoin and include hypotension, cardiac arrhythmias, CNS adverse events (nystagmus, dizziness, sedation/somnolence, ataxia and stupor), and local dermatological reactions. Purple glove syndrome probably occurs with fosphenytoin but possibly at lower frequency than with intravenous phenytoin. Fosphenytoin can cause hyperphosphatemia in end-stage renal failure patients. History Phenytoin, in both its acidic and sodium salt forms, is erratically bioavailable whether it is injected or taken orally due to its high melting point, weak acidity, and its being only sparingly soluble in water. Simply putting patients on other drugs is not always an option; this was especially true before 1993, when the number of anticonvulsants available was much more limited. One solution was to develop a prodrug that did not have these drawbacks. Fosphenytoin was approved by the Food and Drug Administration (FDA) on August 5, 1996, for use in epilepsy. See also Ethotoin Hydantoin Mephenytoin Phenytoin References External links "Fosphenytoin". Drug Information Portal. U.S. National Library of Medicine. "Fosphenytoin sodium". Drug Information Portal. U.S. National Library of Medicine.
Amlodipine/celecoxib	Amlodipine/celecoxib, sold under the brand name Consensi, is a fixed-dose combination medication used to treat both hypertension and osteoarthritis at the same time in adults. It contains amlodipine besylate and celecoxib. It is taken by mouth.The most common side effects include edema, abdominal pain, diarrhea, dyspepsia, flatulence, peripheral edema, accidental injury, dizziness, pharyngitis, rhinitis, sinusitis, upper respiratory tract infection, and rash.It was approved for medical use in the United States in May 2018. Medical uses Amlodipine/celecoxib is indicated for use in adults for whom treatment with amlodipine for hypertension and celecoxib for osteoarthritis are appropriate. History Amlodipine/celecoxib was approved for use in the United States in May 2018. References External links "Amlodipine mixture with celecoxib". Drug Information Portal. U.S. National Library of Medicine.
Fludarabine	Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatment of leukemia and lymphoma. These include chronic lymphocytic leukemia, non-Hodgkins lymphoma, acute myeloid leukemia, and acute lymphocytic leukemia. It is given by injection into a vein or by mouth.Common side effects include nausea, diarrhea, fever, rash, shortness of breath, numbness, vision changes, and feeling tired. Severe side effects include brain dysfunction, low blood cell counts, and lung inflammation. Use in pregnancy will likely result in harm to the fetus. Fludarabine is in the purine analog family of medications and works by interfering with the duplication of DNA.Fludarabine was approved for medical use in the United States in 1991. It is on the World Health Organizations List of Essential Medicines. Medical uses Fludarabine is highly effective in the treatment of chronic lymphocytic leukemia, producing higher response rates than alkylating agents such as chlorambucil alone. Fludarabine is used in various combinations with cyclophosphamide, mitoxantrone, dexamethasone and rituximab in the treatment of indolent non-Hodgkins lymphomas. As part of the FLAG or FLAMSA regimen, fludarabine is used together with cytarabine and granulocyte colony-stimulating factor in the treatment of acute myeloid leukaemia. Because of its immunosuppressive effects, fludarabine is also used in some conditioning regimens prior to allogeneic stem cell transplant. Side effects Fludarabine is associated with profound lymphopenia, and as a consequence, increases the risk of opportunistic infections. People who have been treated with fludarabine will usually be asked to take co-trimoxazole or to use monthly nebulised pentamidine to prevent Pneumocystis jiroveci pneumonia. The profound lymphopenia caused by fludarabine renders patients susceptible to transfusion-associated graft versus host disease, an oftentimes fatal complication of blood transfusion. For this reason, all patients who have ever received fludarabine should only be given irradiated blood components. Fludarabine causes anemia, thrombocytopenia and neutropenia, requiring regular blood count monitoring. Some patients require blood and platelet transfusion, or G-CSF injections to boost neutrophil counts. Fludarabine is associated with the development of severe autoimmune hemolytic anemia in a proportion of patients.Difficulties are often encountered when harvesting peripheral blood stem cells from patients previously treated with fludarabine. Pharmacology Fludarabine is a purine analog, and can be given both orally and intravenously. Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase. It is active against both dividing and resting cells. Being phosphorylated, fludarabine is ionized at physiologic pH and is effectually trapped in blood. This provides some level of specificity for blood cells, both cancerous and healthy. History Fludarabine was produced by John Montgomery and Kathleen Hewson of the Southern Research Institute in 1968. Names Fludarabine is generally administered as its 5-O-phosphorylated form known as fludarabine phosphate, which is rapidly dephosphorylated to fludarabine in the plasma. References External links "Fludarabine". Drug Information Portal. U.S. National Library of Medicine.
Sarecycline	Sarecycline is a narrow-spectrum tetracycline-derived antibiotic. It is specifically designed for the treatment of acne, and was approved by the FDA in October 2018 for the treatment of inflammatory lesions of non-nodular moderate to severe acne vulgaris in patients 9 years of age and older. Two randomized and well-controlled clinical trials reported efficacy data on both facial and truncal acne (back and chest). Efficacy was assessed in a total of 2002 subjects 9 years of age and older. Unlike other tetracycline-class antibiotics, sarecycline has a long C7 moiety that extends into and directly interact with the bacterial messenger RNA (mRNA). The spectrum of activity is limited to clinically relevant Gram-positive bacteria, mainly Cutibacterium acnes, with little or no activity against Gram-negative bacterial microflora commonly found in the human gastrointestinal tract. Sarecycline has not been tested in spirochetes. References External links "Sarecycline". Drug Information Portal. U.S. National Library of Medicine.
Busulfan	Busulfan (Myleran, GlaxoSmithKline, Busulfex IV, Otsuka America Pharmaceutical, Inc.) is a chemotherapy drug in use since 1959. It is a cell cycle non-specific alkylating antineoplastic agent, in the class of alkyl sulfonates. Its chemical designation is 1,4-butanediol dimethanesulfonate. History Busulfan was approved by the US Food and Drug Administration (FDA) for treatment of chronic myeloid leukemia (CML) in 1999. Busulfan was the mainstay of the chemotherapeutic treatment of chronic myeloid leukemia (CML) until it was displaced by the new gold standard, imatinib, though it is still in use to a degree as a result of the drugs relative low cost. Indications Busulfan is used in pediatrics and adults in combination with cyclophosphamide or fludarabine/clofarabine as a conditioning agent prior to bone marrow transplantation, especially in chronic myelogenous leukemia (CML) and other leukemias, lymphomas, and myeloproliferative disorders. Busulfan can control tumor burden but cannot prevent transformation or correct cytogenic abnormalities. The drug was recently used in a study to examine the role of platelet-transported serotonin in liver regeneration. Availability Myleran is supplied in white film coated tablets with 2 mg of busulfan per tablet. After 2002, a great interest has appeared for intravenous presentations of busulfan. Busulfex is supplied as an intravenous solution with 6 mg/ml busulfan. Busulfex has proved equally effective as oral busulfan, with presumedly less toxic side effects. Pharmacokinetic and dynamic studies support this use, that has prompted its usage in transplantation regimes, particularly in frail patients. Fludarabine + busulfan is a typical example of this use. Side effects Toxicity may include interstitial pulmonary fibrosis ("busulfan lung"), hyperpigmentation, seizures, hepatic (veno-occlusive disease) (VOD) or sinusoidal obstruction syndrome (SOS), emesis, and wasting syndrome. Busulfan also induces thrombocytopenia, a condition of lowered blood platelet count and activity, and sometimes medullary aplasia. Seizures and VOD are serious concerns with busulfan therapy and prophylaxis is often utilized to avoid these effects. Hepatic VOD is a dose-limiting toxicity. Symptoms of VOD include weight gain, elevated bilirubin, painful hepatomegaly, and edema. The reason busulfan causes VOD is mostly unknown and can be deadly. Ursodiol may be considered for prophylaxis of veno-occlusive disease. Antiemetics are often administered prior to busulfan to prevent vomiting (emesis). Phenytoin may be used concurrently to prevent the seizures. Levetiracetam, has shown efficacy for the prophylaxis against busulfan-induced seizures. Benzodiazepines can also be used for busulfan-induced seizures.Busulfan is listed by the IARC as a Group 1 carcinogen. Dosing, administration, and pharmacokinetics As an adjunct therapy with cyclophosphamide for conditioning prior to bone marrow transplantation in adults and children >12 kg, intravenous (IV) busulfan (Bulsulfex) is dosed at 0.8 mg/kg every six hours for 16 doses (four days). IV busulfan is usually administered over two hours. Both IV and oral formulations require prophylactic antiemetic agents administered prior to the busulfan dose and scheduled antiemetics administered thereafter. Oral bioavailability of busulfan shows a large interindividual variation. Taking busulfan on an empty stomach is recommended to reduce the risk of nausea and emesis. Peak plasma concentrations are achieved within one hour of oral administration. About 30% of the drug is bound to plasma proteins, such as albumin. Busulfan therapeutic drug monitoring is completed based on trough (pre-dose) levels with a target six-hour area under the curve (AUC) of between 900 and 1500 micromolxmin. AUCs (six-hour) >1500 micromolxmin are associated with hepatic VOD and subsequent dose reduction should be considered. AUCs (six-hour) <900 micromolxmin are associated with incomplete bone marrow ablation and subsequent dose escalation should be considered. Dose adjustments are performed using first order kinetics, such that the adjusted dose = current dose × (target AUC/actual AUC). Drug interactions Busulfan is metabolized via glutathione conjugation in the liver to inactive metabolites. Itraconazole can decrease busulfan clearance by up to 25%, resulting in AUC levels >1500 micromolxmin and increased risk of hepatic VOD. Concomitant use of acetaminophen within 72 hours of busulfan use can reduce busulfan clearance (resulting in increased busulfan AUC), as acetaminophen is also metabolized via glutathione and may deplete stores. Phenytoin increases hepatic clearance of busulfan (resulting in decreased busulfan AUC). However, clinical studies of busulfan were completed with patients taking phenytoin, so no empiric dose adjustment is necessary if patients are taking phenytoin with busulfan. Pharmacology Busulfan is an alkylsulfonate. It is an alkylating agent that forms DNA-DNA interstrand crosslinks between the DNA bases guanine and adenine and between guanine and guanine. This occurs through an SN2 reaction in which the relatively nucleophilic guanine N7 attacks the carbon adjacent to the mesylate leaving group. DNA crosslinking prevents DNA replication. Because the intrastrand DNA crosslinks cannot be repaired by cellular machinery, the cell undergoes apoptosis. Complexation The molecular recognition of ureido-cyclodextrin with busulfan was investigated. The formation of complexes was observed with electrostatic interactions between urea and the sulfonate part of busulfan. Another structure was used for this complexation type, two disaccharidyl units connected by urea linkers to a diazacrown ether organizing platform. References External links "Busulfan". Drug Information Portal. U.S. National Library of Medicine.
Cetrorelix	Cetrorelix (INN, BAN), or cetrorelix acetate (USAN, JAN), sold under the brand name Cetrotide, is an injectable gonadotropin-releasing hormone (GnRH) antagonist. A synthetic decapeptide, it is used in assisted reproduction to inhibit premature luteinizing hormone surges The drug works by blocking the action of GnRH upon the pituitary, thus rapidly suppressing the production and action of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). In addition, cetrorelix can be used to treat hormone-sensitive cancers of the prostate and breast (in pre-/perimenopausal women) and some benign gynaecological disorders (endometriosis, uterine fibroids and endometrial thinning). It is administered as either multiple 0.25 mg daily subcutaneous injections or as a single-dose 3 mg subcutaneous injection. The duration of the 3 mg single dose is four days; if human chorionic gonadotropin (hCG) is not administered within four days, a daily 0.25 mg dose is started and continued until hCG is administered. Medical uses Cetrorelix is marketed by Merck Serono for use in in-vitro fertilization in all countries except Japan, where it is marketed by Shionogi and Nippon Kayaku. Aeterna Zentaris receives royalties on these sales and retains rights to develop cetrorelix for other indications. In IVF use it is injected daily after follicle stimulation has been initiated and evidence of follicle maturation is approaching; given daily it prevents an endogenous LH surge that would trigger an untimely ovulation prior to the hCG administration by the treating physician. As an alternative to the GnRH antagonist, also a GnRH agonist could be given, but agonist have to be started earlier to overcome the agonistic effect. Cetrorelix can be mixed with follitropin alpha without compromising their reported safety and efficacy. Contraindications The use of cetrorelix is contraindicated in severe renal impairment. It is not intended for women aged 65 years or older. Use in women with severe allergic conditions is not recommended. Use with caution in women with active allergies or history of allergies. Research Cetrorelix was under development for the treatment of benign prostatic hyperplasia, premenopausal breast cancer, endometriosis, ovarian cancer, prostate cancer, and uterine fibroids, but development for these indications was discontinued.A study published in Nature Medicine found a link between hormonal imbalance in the womb and Polycystic ovary syndrome (PCOS), specifically prenatal exposure to anti-Müllerian hormone. For the study, the researchers injected pregnant mice with AMH so that they had a higher than normal concentration of the hormone. Indeed, they gave birth to daughters who later developed PCOS-like tendencies. These included problems with fertility, delayed puberty, and erratic ovulation. To reverse it, the researchers dosed the polycystic mice with cetrorelix, which made the symptoms to go away. These experiments should be confirmed in humans, but it could be the first step in understanding the relationship between the polycystic ovary and the anti-Müllerian hormone. In another study, over a period of 3 weeks, daily injections of cetrorelix were administered to 12 men in order to suppress testosterone levels. Testosterone levels were significantly suppressed as compared to a control group. During this time of suppression, increases in high density lipoproteins(HDLs) were seen. HDLs are responsible for removing cholesterol from the blood and higher amounts are correlated with increased cardiovascular health. See also Gonadotropin-releasing hormone receptor § Antagonists References External links "Cetrorelix". Drug Information Portal. U.S. National Library of Medicine. "Cetrorelix acetate". Drug Information Portal. U.S. National Library of Medicine.
Cysteamine	Cysteamine is a chemical compound that can be biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermediate pantetheine is broken down into cysteamine and pantothenic acid. It is the biosynthetic precursor to the neurotransmitter hypotaurine.It is a stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups. Cysteamine is a white, water-soluble solid. It is often used as salts of the ammonium derivative [HSCH2CH2NH3]+ including the hydrochloride, phosphocysteamine, and bitartrate.As a medication, cysteamine, sold under the brand name Cystagon among others, is indicated to treat cystinosis. Medical uses Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.When applied topically it can scavenge free radicals and lighten skin thats been darkened as a result of post-inflammatory hyperpigmentation, sun exposure and Melasma. Tentative evidence suggests that it may be a more effective depigmentation agent than hydroquinone, retinoids and topical corticosteroids in individuals with chronic skin discoloration. Topical application of cysteamine cream has also demonstrated similar efficacy to intradermal tranexamic acid injections for the treatment of Melasma but with much fewer adverse effects. Adverse effects Topical use The most important adverse effect related to topical use might be skin irritation. However its significantly better tolerated than alternative skin lightening treatments with similar efficacy. Oral use The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.For eye drops, the most common adverse effects are sensitivity to light, redness, and eye pain, headache, and visual field defects. Interactions There are no drug interactions for normal capsules or eye drops, but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly. It doesnt inhibit any cytochrome P450 enzymes. Pharmacology People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells. Cysteamine enters lysosomes and converts cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome. Biological function Cysteamine also promotes the transport of L-cysteine into cells, that can be further used to synthesize glutathione, which is one of the most potent intracellular antioxidants.Cysteamine is used as a drug for the treatment of cystinosis; it removes cystine that builds up in cells of people with the disease. History First evidence regarding the therapeutic effect of cysteamine on cystinosis dates back to 1950s. Cysteamine was first approved as a drug for cystinosis in the US in 1994. An extended release form was approved in 2013. Society and culture It is approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA).In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year. Research It was studied in in vitro and animal models for radiation protection in the 1950s, and in similar models from the 1970s onwards for sickle cell anemia, effects on growth, its ability to modulate the immune system, and as a possible inhibitor of HIV.In the 1970s it was tested in clinical trials for Paracetamol toxicity which it failed, and in clinical trials for systemic lupus erythematosus in the 1990s and early 2000s, which it also failed.Clinical trials in Huntingtons disease were begun in the 1990s and were ongoing as of 2015.As of 2013, it was in clinical trials for Parkinsons disease, malaria, radiation sickness, neurodegenerative disorders, neuropsychiatric disorders, and cancer treatment.It has been studied in clinical trials for pediatric nonalcoholic fatty liver disease References External links "Cysteamine". Drug Information Portal. U.S. National Library of Medicine. "Cysteamine hydrochloride". Drug Information Portal. U.S. National Library of Medicine.
Dacomitinib	Dacomitinib, sold under the brand name Vizimpro, is a medication for the treatment of non-small-cell lung carcinoma (NSCLC). It is a selective and irreversible inhibitor of EGFR.Dacomitinib has advanced to several Phase III clinical trials. The January 2014 results of the first trials were disappointing, with a failure to meet the study goals. Additional Phase III trials are ongoing.In 2017, results of a trial comparing dacomitinib to gefitinib for NSCLC (driven by mutated EGFR) were announced.Dacomitinib was approved for medical use in the United States in September 2018, in Japan in 2019, and in the European Union in 2019, for the treatment of non-small cell lung cancer with epidermal growth factor receptor (EGFR) gene mutation. References External links "Dacomitinib". Drug Information Portal. U.S. National Library of Medicine.
Netarsudil	Netarsudil, sold under the brand name Rhopressa among others, is a medication for the treatment of glaucoma. In the United States, in December 2017, the Food and Drug Administration (FDA) approved a 0.02% ophthalmic solution for the lowering of elevated intraocular pressure in people with open-angle glaucoma or ocular hypertension. The European Medicines Agency approved it in 2019 for the same uses under the brand name Rhokiinsa.The FDA considers it to be a first-in-class medication. Contraindications Netarsudil has no contraindications apart from known hypersensitivity to the drug. Adverse effects The most common side effects are hyperaemia (increased blood flow associated with redness, in 51% of patients) in the conjunctiva, cornea verticillata (drug deposits in the cornea, in 17%), and eye pain (in 17%). All other side effects occur in fewer than 10% of people. Hypersensitivity reactions occur in fewer than 1%. Overdose Overdosing netarsudil is unlikely because concentrations in the body are so low that they are generally not detectable. Interactions No interaction studies have been done. The European label recommends to apply other eye drops at least five minutes before, and eye ointments at least five minutes after netarsudil drops. Pharmacology Mechanism of action This drugs mechanism of action is not entirely clear. It inhibits the enzyme rho kinase. This appears to increase outflow of aqueous humor through the trabecular meshwork, and also to reduce pressure in the veins of the episcleral layer. The drug also inhibits the norepinephrine transporter. Pharmacokinetics After instillation into the eye, netarsudil is cleaved by esterases in the cornea to AR-13503, which is the active metabolite. Concentrations reached in the blood plasma are so low that they are generally not detectable. To judge from animal models, the drug acts for at least 24 hours. Its elimination half-life is 16 to 17 hours (in rabbits). Chemistry The drug is used in form of a salt, netarsudil dimesilate, which is a white to light yellow crystalline powder. It is a weak acid and moderately hygroscopic, freely soluble in water and soluble in methanol. See also Netarsudil/latanoprost, a combination drug References External links "Netarsudil". Drug Information Portal. U.S. National Library of Medicine. "Netarsudil mesylate". Drug Information Portal. U.S. National Library of Medicine.
Evinacumab	Evinacumab, sold under the brand name Evkeeza, is a monoclonal antibody medication for the treatment of homozygous familial hypercholesterolemia (HoFH).Common side effects include nasopharyngitis (cold), influenza-like illness, dizziness, rhinorrhea (runny nose), and nausea. Serious hypersensitivity (allergic) reactions have occurred in the Evkeeza clinical trials.Evinacumab binds to the angiopoietin-like protein 3 (ANGPTL3). ANGPTL3 slows the function of certain enzymes that break down fats in the body. Evinacumab blocks ANGPTL3, allowing faster break down of fats that lead to high cholesterol. Evinacumab was approved for medical use in the United States in February 2021.Regeneron invented evinacumab using the companys VelocImmune® technology, a proprietary genetically-engineered mouse platform endowed with a genetically-humanized immune system to produce optimized fully-human monoclonal antibodies. History The effectiveness and safety of evinacumab were evaluated in a double-blind, randomized, placebo-controlled, 24-week trial enrolling 65 participants with homozygous familial hypercholesterolemia (HoFH). In the trial, 43 participants received 15 mg/kg of evinacumab every four weeks and 22 participants received the placebo. Participants were taking other lipid-lowering therapies as well.The primary measure of effectiveness was the percent change in low-density lipoprotein (LDL-C) from the beginning of treatment to week 24. At week 24, participants receiving evinacumab had an average 47% decrease in LDL-C while participants on the placebo had an average 2% increase.The U.S. Food and Drug Administration (FDA) granted the application for evinacumab orphan drug, breakthrough therapy, and priority review designations. The FDA granted approval of Evkeeza to Regeneron Pharmaceuticals, Inc. Society and culture Legal status On 22 April 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization under exceptional circumstances for the medicinal product Evkeeza, intended for the treatment of adult and adolescent patients aged 12 years and older with homozygous familial hypercholesterolaemia (HoFH). The applicant for this medicinal product is Regeneron Ireland Designated Activity Company (DAC). Evinacumab was approved for medical use in the European Union in June 2021. References Further reading Dewey FE, Gusarova V, Dunbar RL, ODushlaine C, Schurmann C, Gottesman O, et al. (July 2017). "Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease". N Engl J Med. 377 (3): 211–221. doi:10.1056/NEJMoa1612790. PMC 5800308. PMID 28538136. External links "Evinacumab". Drug Information Portal. U.S. National Library of Medicine.
Latanoprost	Latanoprost, sold under the brand name Xalatan among others, is a medication used to treat increased pressure inside the eye. This includes ocular hypertension and open angle glaucoma. It is applied as eye drops to the eyes. Onset of effects is usually within four hours, and they last for up to a day.Common side effects include blurry vision, redness of the eye, itchiness, and darkening of the iris. Latanoprost is in the prostaglandin analogue family of medications. It works by increasing the outflow of aqueous fluid from the eyes through the uveoscleral tract.Latanoprost was approved for medical use in the United States in 1996. It is on the World Health Organizations List of Essential Medicines. Latanoprost is available as a generic medication. In 2019, it was the 77th most commonly prescribed medication in the United States with more than 9 million prescriptions. It is available as a combination with netarsudil and with timolol. Medical uses Open-angle glaucoma In people with ocular hypertension (intraocular pressure (IOP) ≥21 mm Hg) including open-angle glaucoma, treatment with latanoprost reduced IOP levels by 22 to 39% over 1 to 12 months’ treatment. Latanoprost was more effective than timolol 0.5% twice daily in 3 of 4 large (n = 163 to 267) randomised, double-blind trials. Latanoprost demonstrated a stable long-term IOP-lowering effect in 1- or 2-year continuations of these trials, with no sign of diminishing effect during prolonged treatment. The UKGTS trial found that latanoprost treatment results in more than halved risk of sight loss.Meta-analysis suggests that latanoprost is more effective than timolol in lowering intraocular pressure (IOP). However, it often causes iris pigmentation. While current evidence suggests that this pigmentation is benign, careful lifetime evaluation of patients is still justified. Closed-angle glaucoma Patients who had elevated IOP despite iridotomy and/or iridectomy (including patients of Asian descent), latanoprost was significantly more effective than timolol in two double-blind, monotherapy trials (8.2 and 8.8 mm Hg vs 5.2 and 5.7 mm Hg for latanoprost vs timolol at 12 and 2 weeks, respectively). Adverse effects Listed from most to least common: > 5–15%: blurred vision, burning and stinging, conjunctival hyperemia, foreign body sensation, itching, increased (brown) pigmentation of the iris (causing heterochromia), punctate epithelial keratopathy 4%: cold or upper respiratory tract infections, flu-like syndrome 1–4%: dry eyes, excessive tearing, eye pain, lid crusting, lid edema, lid erythema (hyperemia), lid pain, photophobia 1–2%: chest pain, allergic skin reactions, arthralgia, back pain, myalgia < 1 % (only severe or life-threatening effects): asthma, herpes keratitis, iritis, keratitis, retinal artery embolus, retinal detachment, toxic epidermal necrolysis, uveitis, vitreous hemorrhage from diabetic retinopathy A single case report links latanoprost use to the progression of keratoconus.Research suggests that wiping the eye with an absorbent pad after the administration of eye drops can result in shorter eyelashes and a lesser chance of hyperpigmentation in the eyelid, compared to not wiping off excess fluid. Pregnancy Use in pregnant women is limited due to high incidence of abortion shown in animal experiments. Because of this, latanoprost is classified as risk factor C (adverse events were observed in animal reproduction studies at maternally toxic doses) according to United States Food and Drug Administrations use-in-pregnancy ratings. Drug excretion in breast milk is unknown. Interactions Interactions are similar to other prostaglandin analogs. Paradoxically, the concomitant use of latanoprost and bimatoprost or other prostaglandins may result in increased intraocular pressure. Non-steroidal anti-inflammatory drugs (NSAIDs) can reduce or increase the effect of latanoprost. Pharmacology Mechanism of action Like tafluprost and travoprost, latanoprost is an ester prodrug that is activated to the free acid in the cornea. Also like the related drugs, latanoprost acid is an analog of prostaglandin F2α that acts as a selective agonist at the prostaglandin F receptor. Prostaglandins increase the scleras permeability to aqueous fluid. So, an increase in prostaglandin activity increases outflow of aqueous fluid thus lowering intraocular pressure. Pharmacokinetics Latanoprost is absorbed well through the cornea and completely hydrolysed to the active latanoprost acid. Highest concentrations of the acid in the aqueous humour are reached two hours after application, lowering of intraocular pressure starts after 3 to 4 hours, the highest effect is found after 8 to 12 hours, and its action lasts at least 24 hours. When latanoprost acid reaches the circulation, it is quickly metabolised in the liver by beta oxidation to 1,2-dinor- and 1,2,3,4-tetranor-latanoprost acid; blood plasma half life is only 17 minutes. The metabolites are mainly excreted via the kidney.The activation and deactivation pathway is analogous to the one of tafluprost (at least up to the tetranor-metabolite); compare Tafluprost#Pharmacokinetics. Chemistry Stability Latanoprost exhibits thermal and solar instability. The concentration of latanoprost stored at 50 °C will decrease by 10% every 8.25 days. When stored at 70 °C the concentration will decrease by 10% every 1.32 days. Ultraviolet light, for example in sunlight, causes rapid degradation of latanoprost. Society and culture The brand Xalatan is manufactured by Pfizer. Cosmetic use Lengthening and thickening of the eyelashes (used, like bimatoprost, in the cosmetic industry as eyelash growth enhancers). There is one small study that found benefit in androgenic alopecia. References External links "Latanoprost". Drug Information Portal. U.S. National Library of Medicine.
Cyclobenzaprine	Cyclobenzaprine (sold under the brand name Flexeril, among others) is a medication used for muscle spasms from musculoskeletal conditions of sudden onset. It is not useful in cerebral palsy. It is taken by mouth. Use is not recommended for more than a few weeks.Common side effects include headache, feeling tired, dizziness, and dry mouth. Serious side effects may include an irregular heartbeat. There is no evidence of harm in pregnancy, but it has not been well studied in this population. It should not be used with an MAO inhibitor. How it works is unclear.Cyclobenzaprine was approved for medical use in the United States in 1977. It is available as a generic medication. In 2020, it was the 39th most commonly prescribed medication in the United States, with more than 16 million prescriptions. It was not available in the United Kingdom as of 2012. Medical use Cyclobenzaprine is used, in conjunction with physical therapy, to treat muscle spasms that occur because of acute musculoskeletal conditions. After sustaining an injury, muscle spasms to stabilize the affected body part occur, which may increase pain to prevent further damage. Cyclobenzaprine is used to treat such muscle spasms associated with acute, painful musculoskeletal conditions. It decreases pain in the first two weeks, peaking in the first few days, but has no proven benefit after two weeks. Since no benefit is proven beyond that, therapy should not be continued long-term. It is the best-studied muscle relaxer. It is not useful for spasticity due to neurologic conditions such as cerebral palsy.A 2004 review found benefit for fibromyalgia symptoms, with a reported number needed to treat of 4.8 (meaning that 1 person out of every 4.8 benefits from treatment) for pain reduction, but no change in fatigue or tender points. A 2009 Cochrane review found insufficient evidence to justify its use in myofascial pain syndrome. It may also be used along with other treatments for tetanus. Side effects Cyclobenzaprine results in increased rates of drowsiness (38%), dry mouth (24%), and dizziness (10%). Drowsiness and dry mouth appear to intensify with increasing dose. The sedative effects of cyclobenzaprine are likely due to its antagonistic effect on histamine, serotonin, and muscarinic receptors.Agitation is a common side effect observed, especially in the elderly. Some experts believe that cyclobenzaprine should be avoided in elderly patients because it can cause confusion, delirium, and cognitive impairment. In general, the National Committee for Quality Assurance recommends avoiding the use of cyclobenzaprine in the elderly because of the potential for more severe side effects.Dysphagia, a life-threatening side-effect, may rarely occur. Treatment protocols and support should follow the same as for any structurally related tricyclic, such as tricyclic antidepressants. Overdose The most common effects of overdose are drowsiness and tachycardia. Rare but potentially critical complications are cardiac arrest, abnormal heart rhythms, severe low blood pressure, seizures, and neuroleptic malignant syndrome. Life-threatening overdose is rare, however, as the median lethal dose is about 338 milligrams/kilogram in mice and 425 mg/kg in rats. The potential harm is increased when central nervous system depressants and antidepressants are also used; deliberate overdose often includes alcohol among other drugs. Interactions Cyclobenzaprine has major contraindications with monoamine oxidase inhibitors (MAOIs). At least one study also found increased risk of serotonin syndrome when cyclobenzaprine was taken with the serotonergic drugs duloxetine or phenelzine.These substances may interact with cyclobenzaprine: Central nervous system depressants (e.g. alcohol, opioids, benzodiazepines, nonbenzodiazepines, phenothiazines, carbamates, barbiturates, major tranquilizers) Monoamine oxidase inhibitors taken within two weeks of cyclobenzaprine may result in serious, life-threatening side effects.Cyclobenzaprine may affect the medications used in surgical sedation and some surgeons request that patients temporarily discontinue its use prior to surgery. Pharmacology Cyclobenzaprine is a centrally acting muscle relaxant. Cyclobenzaprine is a 5-HT2 receptor antagonist; it relieves muscle spasm through action on the central nervous system at the brain stem, rather than targeting the peripheral nervous system or muscles themselves. Pharmacodynamics Pharmacokinetics Cyclobenzaprine has an oral bioavailability of about 55% and approximately 93% is bound to proteins in plasma. The half-life of the drug is 18 hours and it has a plasma clearance of 0.7 litres per minute. Comparison to other medications Cyclobenzaprine has been found to be not inferior to tizanidine, orphenadrine, and carisoprodol in the treatment of acute lower back pain, although none have been proven to be effective for long-term use (beyond two weeks of treatment). No differences in pain or spasm scores were noted among these agents, nor when compared to benzodiazepines. However, nonbenzodiazepine (including cyclobenzaprine) treatment was found to have a lower risk of medication abuse and continuation of use against medical advice. Side effects such as sedation and ataxia are also less pronounced with nonbenzodiazepine antispasmodics.In a study on the treatment of musculoskeletal pain treatment with cyclobenzaprine alone or in combination with ibuprofen, no significant differences in pain scores were noted among the three treatment groups. Peak benefit was found to occur on day seven of the treatment for all groups. Formulations By mouth, cyclobenzaprine is marketed as Apo-Cyclobenzaprin, Fexmid, Flexeril and Novo-Cycloprine. It is available in generic form. A once-a-day, extended-release formulation, Amrix, is available. Cyclobenzaprine is also used by compounding pharmacies in topical creams. References External links "Cyclobenzaprine". Drug Information Portal. U.S. National Library of Medicine.
Ranibizumab	Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment (Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related macular degeneration (AMD, also ARMD), diabetic retinopathy, and macular edema due to branch retinal vein occlusion or central retinal vein occlusion. Ranibizumab was developed by Genentech and marketed by them in the United States, and elsewhere by Novartis, under the brand name Lucentis.Ranibizumab (Lucentis) was approved for medical use in the United States in June 2006. Ranibizumab (Susvimo) was approved for medical use in the United States in October 2021. Medical uses In the United States, ranibizumab is indicated for the treatment of neovascular (wet) age-related macular degeneration, macular edema following retinal vein occlusion, diabetic macular edema, diabetic retinopathy, and myopic choroidal neovascularization.In the European Union, ranibizumab is indicated for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to diabetic macular edema, proliferative diabetic retinopathy, visual impairment due to macular edema secondary to retinal vein occlusion, and visual impairment due to choroidal neovascularisation.It is often used for age-related wet macular degeneration. Its effectiveness is similar to that of bevacizumab and aflibercept. A 2017 systematic review update found that while ranibizumab and bevacizumab provide similar functional outcomes in diabetic macular edema, there is low-certainty evidence suggesting that ranibizumab is more effective in reducing central retinal thickness than bevacizumab. Side effects A 2014 Cochrane review did not find a difference between bevacizumab and ranibizumab in deaths or total severe side effects when used for macular degeneration. There, however, was not a lot of evidence, and thus this conclusion is not that certain.Ranibizumab does appear to result in a lower risk of stomach and intestinal problems. It is also associated with a low rate of eye related side effects.The most common side effects in clinical trials were conjunctival haemorrhage, eye pain, vitreous floaters, increased intraocular pressure, and intraocular inflammation. Although there is a theoretical risk for arterial thromboembolic events in people receiving VEGF-inhibitors by intravitreal injection, the observed incidence rate was low (< 4%) and similar to that seen with placebo. Serious adverse events related to the injection procedure occurred with an incidence rate of less than 1% and included endophthalmitis, retinal detachment, and traumatic cataracts. Other serious ocular adverse events observed among ranibizumab-treated patients (incidence rate < 1%) included intraocular inflammation and blindness. Interactions No significant interactions are known. Pharmacology Ranibizumab is a monoclonal antibody that inhibits angiogenesis by inhibiting vascular endothelial growth factor A, a mechanism similar to that of Bevacizumab. Society & culture Economics Its effectiveness is similar to that of bevacizumab. Its rates of side effects also appear similar. However, ranibizumab typically costs $2,000 a dose, while the equivalent dose of bevacizumab typically costs $50.In November 2010, The New York Times reported that Genentech began offering secret rebates to about 300 ophthalmologists in an apparent inducement to get them to use more ranibizumab rather than their less expensive bevacizumab. This may have been in anticipation of the results of the CATT clinical trial, which was sponsored by the National Eye Institute, and compared the relative safety and efficacy of ranibizumab and bevacizumab in treating AMD. In 2008, bevacizumab cost Medicare only $20 million for about 480,000 injections, while ranibizumab cost Medicare $537 million for only 337,000 injections. A small study showed no superior effect of ranibizumab versus bevacizumab in direct comparison. The initial results of the larger Comparison of Age-related Macular Degeneration Treatments Trials (CATT) trial were published in the New England Journal of Medicine in May 2011. The trial showed that the two drugs "had equivalent effects on visual acuity when administered according to the same schedule;" however, serious adverse events were more common in the bevacizumab arm of the trial. The results of several subsequent head-to-head trials of the two anti-VEGF treatments were later published, and the overall results reinforced CATTs findings. The two therapies performed equally at restoring visual acuity according to a 2012 meta-analysis, and also in the IVAN trial, alone and in the investigators meta-analysis pooling its own results with CATTs. A 2012 meta-analysis focused specifically on safety issues concluded that the rates of several adverse events were higher with bevacizumab, although the absolute rates of ocular serious adverse events were low with both therapies: ocular adverse events were about 2.8 times as frequent with bevacizumab than with ranibizumab, and "The proportion of patients with serious infections and gastrointestinal disorders was also higher." The authors concluded that " clinicians and patients should continue to carefully weigh-up the benefits and harms when choosing between the two treatment options. We also emphasize the need for studies that are powered not just for efficacy, but for defined safety outcomes based on the signals detected in this systematic review". Biosimilars Byooviz was approved for medical use in the European Union in August 2021.Ranibizumab-nuna (Byooviz) was approved for medical use in the United States in September 2021.In India, Lupin Limited received marketing approval for its biosimilar of Ranibizumab.On 23 June 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ranivisio, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to macular edema or choroidal neovascularization, and proliferative diabetic retinopathy. The applicant for this medicinal product is Midas Pharma GmbH. Ranivisio was approved for medical use in the European Union in August 2022.Ranibizumab-eqrn (Cimerli) was approved for medical use in the United States in August 2022.On 15 September 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Ximluci, intended for the treatment of neovascular (wet) age-related macular degeneration, visual impairment due to diabetic macular edema, proliferative diabetic retinopathy, visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), and visual impairment due to choroidal neovascularization. The applicant for this medicinal product is STADA Arzneimittel AG. References External links "Ranibizumab". Drug Information Portal. U.S. National Library of Medicine.
Tolazamide	Tolazamide is an oral blood glucose lowering drug used for people with Type 2 diabetes. It is part of the sulfonylurea family (ATC A10BB). Synthesis para-Toluenesulfonamide is converted to its carbamate with ethyl chloroformate in the presence of a base. Heating that intermediate with 1-amino-azepane leads to the displacement of the ethoxy group and the formation of tolazemide:Azepane proper would lead to [13078-23-4]. References External links "Tolazamide". Medline Plus. U.S. National Library of Medicine.
Thyroid-stimulating hormone	Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid. Physiology Hormone levels TSH (with a half-life of about an hour) stimulates the thyroid gland to secrete the hormone thyroxine (T4), which has only a slight effect on metabolism. T4 is converted to triiodothyronine (T3), which is the active hormone that stimulates metabolism. About 80% of this conversion is in the liver and other organs, and 20% in the thyroid itself.TSH is secreted throughout life but particularly reaches high levels during the periods of rapid growth and development, as well as in response to stress. The hypothalamus, in the base of the brain, produces thyrotropin-releasing hormone (TRH). TRH stimulates the anterior pituitary gland to produce TSH. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release. The concentration of thyroid hormones (T3 and T4) in the blood regulates the pituitary release of TSH; when T3 and T4 concentrations are low, the production of TSH is increased, and, conversely, when T3 and T4 concentrations are high, TSH production is decreased. This is an example of a negative feedback loop. Any inappropriateness of measured values, for instance a low-normal TSH together with a low-normal T4 may signal tertiary (central) disease and a TSH to TRH pathology. Elevated reverse T3 (RT3) together with low-normal TSH and low-normal T3, T4 values, which is regarded as indicative for euthyroid sick syndrome, may also have to be investigated for chronic subacute thyroiditis (SAT) with output of subpotent hormones. Absence of antibodies in patients with diagnoses of an autoimmune thyroid in their past would always be suspicious for development to SAT even in the presence of a normal TSH because there is no known recovery from autoimmunity. For clinical interpretation of laboratory results it is important to acknowledge that TSH is released in a pulsatile manner resulting in both circadian and ultradian rhythms of its serum concentrations. Subunits TSH is a glycoprotein and consists of two subunits, the alpha and the beta subunit. The α (alpha) subunit (i.e., chorionic gonadotropin alpha) is nearly identical to that of human chorionic gonadotropin (hCG), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). The α subunit is thought to be the effector region responsible for stimulation of adenylate cyclase (involved the generation of cAMP). The α chain has a 92-amino acid sequence. The β (beta) subunit (TSHB) is unique to TSH, and therefore determines its receptor specificity. The β chain has a 118-amino acid sequence. The TSH receptor The TSH receptor is found mainly on thyroid follicular cells. Stimulation of the receptor increases T3 and T4 production and secretion. This occurs through stimulation of six steps in thyroid hormone synthesis: (1) Up-regulating the activity of the sodium-iodide symporter (NIS) on the basolateral membrane of thyroid follicular cells, thereby increasing intracellular concentrations of iodine (iodine trapping). (2) Stimulating iodination of thyroglobulin in the follicular lumen, a precursor protein of thyroid hormone. (3) Stimulating the conjugation of iodinated tyrosine residues. This leads to the formation of thyroxine (T4) and triiodothyronine (T3) that remain attached to the thyroglobulin protein. (4) Increased endocytocis of the iodinated thyroglobulin protein across the apical membrane back into the follicular cell. (5) Stimulation of proteolysis of iodinated thyroglobulin to form free thyroxine (T4) and triiodothyronine (T3). (6) Secretion of thyroxine (T4) and triiodothyronine (T3) across the basolateral membrane of follicular cells to enter the circulation. This occurs by an unknown mechanism.Stimulating antibodies to the TSH receptor mimic TSH and cause Graves disease. In addition, hCG shows some cross-reactivity to the TSH receptor and therefore can stimulate production of thyroid hormones. In pregnancy, prolonged high concentrations of hCG can produce a transient condition termed gestational hyperthyroidism. This is also the mechanism of trophoblastic tumors increasing the production of thyroid hormones. Applications Diagnostics Reference ranges for TSH may vary slightly, depending on the method of analysis, and do not necessarily equate to cut-offs for diagnosing thyroid dysfunction. In the UK, guidelines issued by the Association for Clinical Biochemistry suggest a reference range of 0.4–4.0 µIU/mL (or mIU/L). The National Academy of Clinical Biochemistry (NACB) stated that it expected the reference range for adults to be reduced to 0.4–2.5 µIU/mL, because research had shown that adults with an initially measured TSH level of over 2.0 µIU/mL had "an increased odds ratio of developing hypothyroidism over the [following] 20 years, especially if thyroid antibodies were elevated".TSH concentrations in children are normally higher than in adults. In 2002, the NACB recommended age-related reference limits starting from about 1.3 to 19 µIU/mL for normal-term infants at birth, dropping to 0.6–10 µIU/mL at 10 weeks old, 0.4–7.0 µIU/mL at 14 months and gradually dropping during childhood and puberty to adult levels, 0.3–3.0 µIU/mL.: Section 2 Diagnosis of disease TSH concentrations are measured as part of a thyroid function test in patients suspected of having an excess (hyperthyroidism) or deficiency (hypothyroidism) of thyroid hormones. Interpretation of the results depends on both the TSH and T4 concentrations. In some situations measurement of T3 may also be useful. A TSH assay is now also the recommended screening tool for thyroid disease. Recent advances in increasing the sensitivity of the TSH assay make it a better screening tool than free T4. Monitoring The therapeutic target range TSH level for patients on treatment ranges between 0.3 and 3.0 μIU/mL.For hypothyroid patients on thyroxine, measurement of TSH alone is generally considered sufficient. An increase in TSH above the normal range indicates under-replacement or poor compliance with therapy. A significant reduction in TSH suggests over-treatment. In both cases, a change in dose may be required. A low or low-normal TSH value may also signal pituitary disease in the absence of replacement.For hyperthyroid patients, both TSH and T4 are usually monitored. In pregnancy, TSH measurements do not seem to be a good marker for the well-known association of maternal thyroid hormone availability with offspring neurocognitive development.TSH distribution progressively shifts toward higher concentrations with age. Difficulties with interpretation of TSH measurement Heterophile antibodies (which include human anti-mouse antibodies (HAMA) and Rheumatoid Factor (RF)), which bind weakly to the test assays animal antibodies, causing a higher (or less commonly lower) TSH result than the actual true TSH level. Although the standard lab assay panels are designed to remove moderate levels of heterophilic antibodies, these fail to remove higher antibody levels. "Dr. Baumann [from Mayo Clinic] and her colleagues found that 4.4 percent of the hundreds of samples she tested were affected by heterophile antibodies.........The hallmark of this condition is a discrepancy between TSH value and free T4 value, and most important between laboratory values and patients conditions. Endocrinologists, in particular, should be on alert for this." Macro-TSH - endogenous antibodies bind to TSH reducing its activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity. TSH Isomers - natural variations of the TSH molecule, which have lower activity, so the pituitary gland would need to produce more TSH to obtain the same overall level of TSH activity. The same TSH concentration may have a different meaning whether it is used for diagnosis of thyroid dysfunction or for monitoring of substitution therapy with levothyroxine. Reasons for this lack of generalisation are Simpsons paradox and the fact that the TSH-T3 shunt is disrupted in treated hypothyroidism, so that the shape of the relation between free T4 and TSH concentration is distorted. Therapeutic A synthetic drug called recombinant human TSH alpha (rhTSHα or simply rhTSH) or thyrotropin alfa (INN) is manufactured by Genzyme Corp under the trade name Thyrogen. It is used to manipulate endocrine function of thyroid-derived cells, as part of the diagnosis and treatment of thyroid cancer. History In 1916, Bennett M. Allen and Philip E. Smith found that the pituitary contained a thyrotropic substance. References External links "Thyrotropin alfa". Drug Information Portal. U.S. National Library of Medicine. TSH at Lab Tests Online MedlinePlus Encyclopedia: 003684 Thyrotropin at the US National Library of Medicine Medical Subject Headings (MeSH)
Brinzolamide	Brinzolamide (trade names Azopt, Alcon Laboratories, Befardin, Fardi Medicals, ) is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension. Brinzolamide was approved as a generic medication in the United States in November 2020. Chemistry Brinzolamide is a carbonic anhydrase inhibitor (specifically, carbonic anhydrase II). Carbonic anhydrase is found primarily in erythrocytes (but also in other tissues including the eye). It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II). Indications Use for the treatment of open-angle glaucoma and raised intraocular pressure due to either excess aqueous humor production or inadequate drainage of the humor via the trabecular meshwork. Pharmacodynamics Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humor secretion and thus lowers the intraocular pressure in the anterior chamber, presumably by reducing the rate of formation of bicarbonate ions with subsequent reduction in sodium and fluid transport; this may alleviate the effects of open-angle glaucoma. Pharmacokinetics Absorption The recommended frequency for topical application is two times per day. Following ocular instillation, the suspension is systemically absorbed to some degree; however the plasma concentrations are low and generally below the limits of detection (less than 10 ng/mL) due to extensive binding by tissues and erythrocytes. Oral administration is less-favored due to variable absorption from the stomach mucosa and an increased side-effect profile versus ophthalmic administration. Distribution The compound is fairly well protein-bound (60%), but adheres extensively to the carbonic anhydrase-containing erythrocytes. Due to the abundance of readily-bound erythrocytes and minimal known metabolism, Brinzolamides whole blood half-life is very long (111 days). Metabolism While definitive sites of metabolism have not been firmly established, there are several metabolites worthy of note. N-Desethylbrinzolamide is an active metabolite of the parent compound, and thus exhibits carbonic anhydrase inhibitory activity (largely carbonic anhydrase-I, when in the presence of Brinzolamide) and also accumulates in the erythrocytes. However, Brinzolamides other known metabolites (N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide) either have no activity or their activity is currently unknown. Excretion Brinzolamide is excreted primarily unchanged (60%) in the urine, although the renal clearance rate has not been definitively determined. N-Desethylbrinzolamide is also found in the urine along with lower concentrations of the inactive metabolites, N-Desmethoxypropylbrinzolamide and O-Desmethylbrinzolamide; exact levels have not been definitively determined. Cautions Side effects Common, but mild: blurred vision; bitter, sour, or unusual taste; itching, pain, watering, or dryness of the eyes; feeling that something is in the eye; headache; runny nose Rare, but serious: fast or irregular heartbeat; fainting; skin rash, hives, or itching; severe eye irritation, redness, or swelling; swelling in the face, lips, or throat; wheezing or trouble breathing Precautions Hypersensitivity to other sulfonamides Acute angle-closure glaucoma Concomitant administration of oral carbonic anhydrase inhibitors Moderate-to-severe chronic kidney disease or liver disease Combinations With timolol The combination of brinzolamide with timolol is marketed under the trade name Azarga. This combination may be more effective than either medication alone. With brimonidine The combination of brinzolamide with brimonidine is marketed under the trade name Simbrinza. This combination may be more effective than either medication alone. References Further reading External links "Brinzolamide". Drug Information Portal. U.S. National Library of Medicine.
Carboprost	Carboprost (INN, trade names for the tromethamine salts Hemabate, Tham) is a synthetic prostaglandin analogue of PGF2α (specifically, it is 15-methyl-PGF2α) with oxytocic properties. Carboprost main use is in the obstetrical emergency of postpartum hemorrhage which reduces postpartum bleeding during these circumstances. Indication Used in postpartum hemorrhage caused by uterine atony not controlled by other methods. One study has shown that carboprost tromethamine is more effective than oxytocin in preventing postpartum hemorrhage in high-risk patients undergoing cesarean delivery. Carboprost is also used for the termination of pregnancy in the 2nd trimester.Unlabeled use: Hemorrhagic Cystitis PID Contraindication Contraindicated in severe cardiovascular, renal, and hepatic disease. It is also contraindicated in acute Pelvic Inflammatory Disease. Hypersensitivity to carboprost or any of its components is also a contraindication Exert caution in asthmatic patients as carboprost may cause bronchospasm. Precautions asthma anemia jaundice diabetes mellitus seizure disorders past uterine surgery Adverse Effects diarrhea (most common, may be sudden in onset) flushing or hot flashes fever chills nausea/vomiting Storage and Availability Carboprost is supplied with its salt derivative tromethamine in 1 milliliter ampules containing a 250 microgram/milliliter solution of the active drug. The drug must be refrigerated at a temperature between 2 – 8 degrees Celsius. Synthesis A significant deactivating metabolic transformation of natural prostaglandins is enzymatic oxidation of the C-15 hydroxyl to the corresponding ketone. This is prevented, with retention of activity, by methylation to give the C-15 tertiary carbinol series. This molecular feature is readily introduced at the stage of the Corey lactone (1) by reaction with methyl Grignard reagent or trimethylaluminium. The resulting mixture of tertiary carbinols (2) is transformed to oxytocic carboprost (3) by standard transformations, including separation of diastereomers, so that the final product is the C-15 analogue. This diastereomer is reputably freeer of porstaglandin side effects than the C-15 (S) isomer. See also Arbaprostil References Further reading External links Carboprost at the US National Library of Medicine Medical Subject Headings (MeSH)
Rocuronium bromide	Rocuronium bromide (brand names Zemuron, Esmeron) is an aminosteroid non-depolarizing neuromuscular blocker or muscle relaxant used in modern anaesthesia to facilitate tracheal intubation by providing skeletal muscle relaxation, most commonly required for surgery or mechanical ventilation. It is used for standard endotracheal intubation, as well as for rapid sequence induction (RSI). Pharmacology Mechanism of action Rocuronium bromide is a competitive antagonist for the Nicotinic acetyl-choline receptors at the neuromuscular junction. Of the Neuromuscular-blocking drugs it is considered to be a non-depolarizing neuromuscular junction blocker, because it acts by dampening the receptor action causing muscle relaxation, instead of continual depolarisation which is the mechanism of action of the depolarizing neuromuscular junction blockers, like succinylcholine. It was designed to be a weaker antagonist at the neuromuscular junction than pancuronium; hence its monoquaternary structure and its having an allyl group and a pyrrolidine group attached to the D ring quaternary nitrogen atom. Rocuronium has a rapid onset and intermediate duration of action.There is considered to be a risk of allergic reaction to the drug in some patients (particularly those with asthma), but a similar incidence of allergic reactions has been observed by using other members of the same drug class (non-depolarizing neuromuscular blocking drugs).The γ-cyclodextrin derivative sugammadex (trade name Bridion) has been recently introduced as a novel agent to reverse the action of rocuronium. Sugammadex has been in use since 2009 in many European countries; however, it was turned down for approval twice by the US FDA due to concerns over allergic reactions and bleeding, but finally approved the medication for use during surgical procedures in the United States on December 15, 2015. Neostigmine can also be used as a reversal agent of rocuronium but is not as effective as sugammadex. Neostigmine is often still used due to its low cost compared with sugammadex. History It was introduced in 1994, and is marketed under the trade name of Zemuron in the United States and Esmeron in most other countries. Executions On July 27, 2012, the U.S. state of Virginia replaced pancuronium bromide, one of the three drugs used in execution by lethal injection, with rocuronium bromide.On 3 October 2016, the U.S. state of Ohio announced that it would resume executions on January 12, 2017, using a combination of midazolam, rocuronium bromide, and potassium chloride. Prior to this, the last execution in Ohio was in January 2014.On August 24, 2017, the U.S. state of Florida executed Mark James Asay using a combination of etomidate, rocuronium bromide, and potassium acetate. == References ==
Trimethoprim/polymyxin	The drug combination trimethoprim/polymyxin (INNs, trade name Polytrim) is an antimicrobial solution for topical ophthalmic use in the treatment of acute bacterial conjunctivitis and blepharoconjunctivitis. == References ==
Fluocinolone acetonide	Fluocinolone acetonide is a corticosteroid primarily used in dermatology to reduce skin inflammation and relieve itching. It is a synthetic hydrocortisone derivative. The fluorine substitution at position 9 in the steroid nucleus greatly enhances its activity. It was first synthesized in 1959 in the Research Department of Syntex Laboratories S.A. Mexico City. Preparations containing it were first marketed under the name Synalar. A typical dosage strength used in dermatology is 0.01–0.025%. One such cream is sold under the brand name Flucort-N and includes the antibiotic neomycin. Fluocinolone acetonide was also found to strongly potentiate TGF-β-associated chondrogenesis of bone marrow mesenchymal stem/progenitor cells, by increasing the levels of collagen type II by more than 100 fold compared to the widely used dexamethasone.Fluocinolone acetonide intravitreal implants have been used to treat non-infectious uveitis. A systematic review could not determine whether fluocinolone acetonide implants are superior to standard of care treatment for uveitis. A fluocinolone acetonide intravitreal implant with the brand name Iluvien is sold by biopharmaceutical company Alimera Sciences to treat diabetic macular edema (DME).It was approved for medical use in 1961. Classification Fluocinolone is a group V (0.025%) or group VI (0.01%) corticosteroid under US classification. See also Topical steroid Fluocinonide Ciprocinonide Glucocorticoid References External links "Fluocinolone acetonide". Drug Information Portal. U.S. National Library of Medicine.
Peramivir	Peramivir (trade name Rapivab) is an antiviral drug developed by BioCryst Pharmaceuticals for the treatment of influenza. Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells. It is approved for intravenous administration.In October 2009, the U.S. Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for the use of peramivir based on safety data from phase I, phase II, and limited phase III trial data. The emergency use authorization for peramivir expired in June 2010. On 19 December 2014, the FDA approved peramivir to treat influenza infection in adults. History An intramuscular (IM) peramivir phase II study for seasonal influenza in 2008–2009 found no effect for the primary endpoint of improvement in the median time to alleviation of symptoms in subjects with confirmed, acute, uncomplicated influenza infection versus placebo. In October 2009, it was reported that the experimental antiviral drug peramivir had been "life-saving" effective in intravenous treating 8 serious cases of swine flu. On October 23, the U.S. Food and Drug Administration (FDA) issued an Emergency Use Authorization for peramivir, allowing the use of the drug in intravenous form for hospitalized patients only in cases where the other available methods of treatment are ineffective or unavailable; for instance, if oseltamivir resistance develops and a person is unable to take zanamivir via the inhaled route. The U.S. government (department of Health and Human Services) gave BioCryst Pharmaceuticals more than $77 million to finish the Phase III clinical development of peramivir. In 2009 the department of Health and Human Services had already given about $180 million to the program. Biocryst also donated 1200 courses of treatment to the US department of Health and Human Services. The Emergency Use Authorization expired on June 23, 2010. In 2011 a phase III trial found the median durations of influenza symptoms were the same with 1 intravenous injection of peramivir against 5 days of oral oseltamivir for people with seasonal influenza virus infection.In 2012 BioCryst reported that it should halt enrollment on its study for intravenous peramivir in potentially life-threatened people after an interim analysis led trial monitors to conclude that it would be futile to continue and the trial should be terminated. The difference between peramivir and control group (oral oseltamivir) for the primary endpoint, clinical or virologic, was small. In 2013 the Biomedical Advanced Research and Development Authority (BARDA/HHS) released new funding under the current $234.8 million contract to enable completion of a New Drug Application filing for intravenous (IV) peramivir.According to a research report published in June 2011, a new variant of swine flu had emerged in Asia with a genetic adaptation (a S247N neuraminidase mutation) giving some resistance to oseltamivir and zanamivir, but no significant reduction in sensitivity to peramivir. But a H274Y virus mutation showed resistance to oseltamivir and peramivir, but not to zanamivir, and only in N1 neuraminidases. Ultimately 3.2% (19/599) of A(H1N1)pdm09 viruses collected between 2009 and 2012 had highly reduced peramivir inhibition due to the H275Y NA mutation.BioCryst Pharmaceuticals submitted a new drug application (NDA) to the U.S. Food and Drug Administration (FDA) for intravenous peramivir in December 2013. Peramivir (Rapivab) was approved for intravenous administration in December 2014. References External links "Peramivir". Drug Information Portal. U.S. National Library of Medicine. "Peramivir: Requirements for Administration under EUA". Lifehugger. Archived from the original on 2011-07-13. "CDC H1N1 Flu - Termination of the Emergency Use Authorization (EUA) of Medical Products and Devices". U.S. Centers for Disease Control and Prevention (CDC). Clinical trial number NCT00957996 for "Safety Study of IV Peramivir in Hospitalized Subjects With Confirmed or Suspected Influenza" at ClinicalTrials.gov "A Novel Anti-viral Drug for Influenza, RAPIACTA Launch" (PDF). Shionogi & Co., Ltd. January 26, 2010. Archived from the original (PDF) on 2013-05-22.
Ezetimibe/atorvastatin	Ezetimibe/atorvastatin (trade names Liptruzet, Atozet) is a cholesterol lowering combination drug. In the United States, it was approved in May 2013, by the Food and Drug Administration for the treatment of elevated low-density lipoprotein (LDL) in patients with primary or mixed hyperlipidemia as adjunctive therapy to diet. It has also been approved to reduce elevated total cholesterol and elevated LDL in patients diagnosed with homozygous familial hypercholesterolemia as an adjunctive treatment to other hyperlipidemia treatments.Some cardiologists opposed the approval, because the combination reduced LDL cholesterol in a clinical trial, but it did not reduce heart disease. A clinical trial studying the endpoints of heart attacks, strokes and heart-related deaths is scheduled to conclude in 2014.Liptruzet was withdrawn from sale by its manufacturer in June 2015, but not for reasons of safety or effectiveness. Mechanism of action This combination drug works to reduce cholesterol levels through two different pathways. The ezetimibe component of the medication works by inhibiting cholesterol absorption from food while the atorvastatin component inhibits intrinsic cholesterol production in the liver. Safety The drug is not safe to use in patients with active liver disease or unexplained persistent elevations in hepatic transaminase. Women that are pregnant or may become pregnant should not use the drug. It is a teratogenic agent that may disrupt the growth and development of a fetus. Immediate discontinuation is recommended in patients that become pregnant while taking this drug. Adverse effects Commonly reported adverse effects include: Musculoskeletal pain Elevated liver enzymes (AST and ALT) Gastrointestinal problems such as abdominal pain and nausea See also Ezetimibe Ezetimibe/simvastatin == References ==
Ibrexafungerp	Ibrexafungerp, sold under the brand name Brexafemme, is an antifungal medication used to treat vulvovaginal candidiasis (VVC) (vaginal yeast infection). It is taken by mouth. An estimated 75% of women will have at least one episode and 40 to 45% will have two or more episodes in their lifetime.Ibrexafungerp is a triterpenoid antifungal. It acts via inhibition of glucan synthase, which prevents formation of the fungal cell wall.Ibrexafungerp was approved for medical use in the United States in June 2021. It is the first approved drug in a novel antifungal class. Medical uses Ibrexafungerp is indicated for the treatment of adult and postmenarchal pediatric females with vulvovaginal candidiasis (VVC). Pharmacology Pharmacodynamics Ibrexafungerp is a triterpenoid antifungal agent. It acts via inhibition of the enzyme glucan synthase, which is involved in the formation of 1,3-β-D-glucan—an essential component of the fungal cell wall. The compound has concentration-dependent fungicidal activity against Candida species. Pharmacokinetics Ibrexafungerp has a time to maximal concentrations of 4 to 6 hours. It is metabolized by hydroxylation via CYP3A4 and subsequently by glucuronidation and sulfation. The medication has an elimination half-life of approximately 20 hours. References Further reading Azie N, Angulo D, Dehn B, Sobel JD (September 2020). "Oral Ibrexafungerp: an investigational agent for the treatment of vulvovaginal candidiasis". Expert Opin Investig Drugs. 29 (9): 893–900. doi:10.1080/13543784.2020.1791820. PMID 32746636. Davis MR, Donnelley MA, Thompson GR (July 2020). "Ibrexafungerp: A novel oral glucan synthase inhibitor". Med Mycol. 58 (5): 579–592. doi:10.1093/mmy/myz083. PMID 31342066. Petraitis V, Petraitiene R, Katragkou A, Maung BB, Naing E, Kavaliauskas P, et al. (May 2020). "Combination Therapy with Ibrexafungerp (Formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1→3)-β-d-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis". Antimicrob Agents Chemother. 64 (6). doi:10.1128/AAC.02429-19. PMC 7269506. PMID 32179521. External links "Ibrexafungerp". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03734991 for "Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (VANISH 303)" at ClinicalTrials.gov Clinical trial number NCT03987620 for "Efficacy and Safety of Oral Ibrexafungerp (SCY-078) vs. Placebo in Subjects With Acute Vulvovaginal Candidiasis (Vanish 306)" at ClinicalTrials.gov
Wera	Wera may refer to: PeopleJulian Wera (1902–1975), Major League Baseball third baseman Wera Engels, German actress Wera Hobhouse, British politician Wera Sæther (born 1945), Norwegian psychologist, poet, novelist, essayist, writer of books for youth and of documentary booksOtherWERA (Western Eastern Roadracing Association), motorcycle racing sanctioning body WERA-LP, a low-power radio station (96.7 FM) licensed to serve Arlington, Virginia, United States Wera River, river of Flores, Indonesia Wera Tools, the popular name for German tool manufacturer, Wera Werk Hermann Werner GmbH & Co. KG, of Wuppertal, Germany A defunct radio station in Plainfield, New Jersey on 1590 kilocycles per second
Indapamide	Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics (indapamide and chlorthalidone) reduce risk of major cardiovascular events and heart failure in hypertensive patients compared with hydrochlorothiazide with a comparable incidence of adverse events. Both thiazide diuretics and thiazide-like diuretics are effective in reducing risk of stroke. Both drug classes appear to have comparable rates of adverse effects as other antihypertensives such as angiotensin II receptor blockers and dihydropyridine calcium channel blockers and lesser prevalence of side-effects when compared to ACE-inhibitors and non-dihydropyridine calcium channel blockers.It was patented in 1968 and approved for medical use in 1977. It is on the World Health Organizations List of Essential Medicines. Medical uses Its indications include hypertension and edema due to congestive heart failure. Indapamide has been shown to reduce stroke rates in people with high blood pressure. Studies have shown that the blood pressure lowering effects of indapamide in combination with perindopril reduce the rate of stroke in high risk patients (those with a history of high blood pressure, stroke or type two diabetes). The HYVET study was one of the first landmark trials to demonstrate a significant reduction in all cause mortality in octogenarians, with or without the addition of perindopril. Two systematic reviews also identified reductions in all cause mortality with thiazide-like diuretics, including indapamide, in octogenarians, as well as in young-elderly patients. Contraindications Indapamide is contraindicated in known hypersensitivity to sulfonamides, severe kidney failure, hepatic encephalopathy or severe liver failure, and a low blood potassium level. There is insufficient safety data to recommend indapamide use in pregnancy or breastfeeding. Adverse effects Commonly reported adverse events are low potassium levels, fatigue, orthostatic hypotension (an exaggerated decrease in blood pressure upon standing, often associated with syncope), and allergic manifestations. Monitoring the serum levels of potassium and uric acid is recommended, especially in subjects with a predisposition to low levels of potassium in the blood and gout. Interactions Caution is advised in the combination of indapamide with lithium and drugs causing prolonged QT interval (on EKG) or wave-burst arrhythmia (i.e.: astemizole, bepridil, IV erythromycin, halofantrine, pentamidine, sultopride, terfenadine, and vincamine). Overdose Symptoms of over dosage would be those associated with a diuretic effect (i.e. electrolyte disturbances), low blood pressure, and muscular weakness. Treatment should be symptomatic, directed at correcting electrolyte abnormalities. See also Perindopril/indapamide — a fixed-dose combination used for essential hypertension References External links "Indapamide". Drug Information Portal. U.S. National Library of Medicine.
Alcon	Alcon is an American Swiss medical company specializing in eye care products with headquarters in Geneva, Switzerland, and incorporated in Fribourg, Switzerland. Alcon began as a US company and its US subsidiary’s headquarters remain in Fort Worth, Texas, where the Alcon division of the company was founded. Alcon was a subsidiary of Novartis until April 9, 2019, when the company completed a shareholder approved 100% spinoff of Alcon eye care devices business from Novartis. History The US division of Alcon was founded as an independent company in 1945 in Fort Worth, Texas, USA. Since the current Swiss company that grew from multiple mergers retained the Alcon name, it is important to differentiate the former US company (now a subsidiary) from the much larger company that bears the same Alcon name. Alcon has not existed as a US-based company since 1977. The original US company Alcon started as a small pharmacy in Fort Worth and was named for its founders, pharmacists Robert Alexander and William Conner. Conner and Alexander focused on sterile ophthalmic products. Nestlé of Switzerland purchased Alcon in 1977. Alcon expanded its manufacturing capability with new plants in South America and Europe and drastically increased its investment in research. In 1979, Alcon acquired Texas Pharmacal Company which became Dermatological Products of Texas (and is now DPT Laboratories).In 1984, Alcon founded the Technical Excellence Award to promote achievements in R&D excellence and has awarded it to more than 100 recipients. The Alcon product line has expanded from pharmaceuticals to the surgical arena. Today, Alcon has operations in 75 countries and its products are sold in over 180 countries. Nestlé conducted an initial public offering of 25% of its stake in Alcon in 2002. The stock is traded under the ticker symbol ALC. In July 2008, Novartis purchased approximately 25% of Nestlés stake in Alcon, with an option to buy Nestlés remaining shares beginning in 2010. Novartis bought 52% stake from Nestlé for $28.1 Billion. This deal brought the total ownership of Alcon by Novartis to 77%. Beginning January 2010 Novartis formally announced it will be completing the exercise options for finishing purchasing the rest of Alcon and then promptly continue to exercise merger and takeover of Alcon.On March 29, 2010, Alcon acquired Durezol and Zyclorin from Sirion Therapeutics. Alcon received regulatory approval to acquire the rights of Durezol emulsion in the US and the global rights, excluding Latin America, for Zyclorin from Sirion Therapeutics.On June 28, 2010, Alcons Independent Director Committee announced that a recommendation by the committee was an indispensable first step before the board of the company can decide on the merger proposal of Novartis AG, refuted Novartis’ public implications that it would be able to unilaterally impose the merger irrespective of the Independent Director Committees position once Novartis became Alcons majority shareholder. On July 8, 2010, Alcons independent director committee (IDC) had set up a $50 million litigation trust to ensure companys minority shareholders get the best deal from bidder Novartis AG.On April 9, 2019, Alcon completed a 100% spin-off from Novartis. The new standalone company is worth up to 28 billion Swiss francs.In November 2021, Alcon announced it would acquire Ivantis and their glaucoma surgery stent technology for at least $475 million. In August 2022, Alcon agreed to buy Aerie Pharmaceuticals for US$770 million to enhance its ophthalmic pharmaceutical portfolio. References External links Business data for Alcon: Alcon Official Website Alcon : Novartis exercises option and proposes merger Novartis needs Alcon directors OK for buyout Swiss Corporate Governance Expert Supports Alcon Independent Director Committee’s Position against Novartis
Extended cycle combined hormonal contraceptive	Extended or continuous cycle combined oral contraceptive pills are a packaging of combined oral contraceptive pills (COCPs) that reduce or eliminate the withdrawal bleeding that would occur once every 28 days in traditionally packaged COCPs. It works by reducing the frequency of the pill-free or placebo days. Extended cycle use of COCPs may also be called menstrual suppression, although other hormonal medications or medication delivery systems (hormonal intrauterine devices—IUDs) may also be used to suppress menses. Any brand of combined oral contraceptive pills can be used in an extended or continuous manner by simply discarding the placebo pills; this is most commonly done with monophasic pills in which all of the pills in a package contain the same fixed dosing of a synthetic estrogen and a progestin in each active pill.Other combined hormonal contraceptives (those containing both an estrogen and a progestin) may also be used in an extended or continuous cycle. For example, the NuvaRing vaginal ring and the contraceptive patch have been studied for extended cycle use, and the monthly combined injectable contraceptive may similarly eliminate bleeding. History Before the advent of modern contraceptives, reproductive age women spent most of their time either pregnant or nursing. In modern Western society, women typically have about 450 periods during their lives, as compared to about 160 formerly.Although it was evident that the pill could be used to suppress menstruation for arbitrary lengths of time, the original regimen was designed to produce withdrawal bleeding every four weeks to mimic the menstrual cycle. Usage When a woman takes COCP, the hormones in the pills prevent both ovulation and shedding of the endometrium (menstruation). Traditionally, COCPs are packaged with 21 active (hormone-containing) pills and 7 placebo pills. During the week of placebo pills, withdrawal bleeding occurs and simulates an average 28-day menstrual cycle. The placebo pills are not required for pregnancy protection, and with any monophasic COCP the placebo pills may be discarded, and the next pack of active pills may be started to prevent the withdrawal bleeding. With bi- and tri-phasic pills, skipping the placebo week results in a sudden change in hormone levels, which may cause irregular spotting or flow. (Monophasic pills offer the same dose of estrogen and progestogen whereas multiphasic pills have varying doses from day to day; see formulations for details.) Recently, several pharmaceutical companies have gained FDA approval to package COCPs for the intended use of reducing the frequency of or eliminating withdrawal bleeding. Clinical indications Extended or continuous use of COCPs has been used for many years to treat endometriosis, dysmenorrhea, and menstruation-associated symptoms. Some studies have suggested that women who experience premenstrual-type symptoms during the placebo (hormone-free) week of traditionally packaged COCPs may experience significantly fewer symptoms when placed on extended cycle COCP regimens.More recently, personal preference to avoid menstruation has also become a common reason for use. Personal preference is the most common reason extended cycle or continuous use COCPs are prescribed to adolescents. The Society for Menstrual Cycle Research holds that this use of COCPs does not have sufficient safety studies to justify promotion as a lifestyle choice (as opposed to medical indications), and criticizes what it perceives as negative portrayals of normal menstrual cycles in promotional literature for extended and continuous COCP use.Womens satisfaction with their contraception, compliance in taking the pills on time, and discontinuation rates are not significantly different between traditional and extended cycle regimens. Side effects With all extended-cycle COCPs, breakthrough bleeding is the most common side effect, although it tends to decrease over time. In a 12-month study of a continuous COCP regimen, 59% of women experienced no bleeding in months six through twelve and 79% of women experienced no bleeding in month twelve. Extended or continuous use of COCPs or other combined hormonal contraceptives carries the same risk of side effects and medical risks as traditional COCP use. Ad campaign One of the early extended-cycle COCPs, Seasonale, was marketed with the campaign, "Fewer periods. More possibilities." In December 2004, Barr Pharmaceuticals was warned by the FDA concerning these television advertisements. As the warning stated, "By omitting and minimizing the risks associated with Seasonale, the TV ad misleadingly suggests that Seasonale is safer than has been demonstrated by substantial evidence or substantial clinical experience." Although clinical studies had proven Seasonale to be effective in preventing pregnancy, the FDA felt the commercial advertisements omitted the common side effects of irregular vaginal bleeding or spotting. Brands Seasonale is produced by Duramed Pharmaceuticals, a subsidiary of Barr Pharmaceuticals; Barr Pharmaceuticals also produces the same medicine as a generic called Jolessa. Quasense is the generic version produced by Watson Pharmaceuticals. Seasonale contains 30 micrograms of ethinylestradiol and 150 micrograms of levonorgestrel in each active pill. Seasonale reduces the frequency of menstrual periods from thirteen per year to four per year by changing the regimen of active pills from 21 to 84. Each package has 84 active pills and seven placebo pills to be taken at the end of the active cycle. It was first developed by Barr Pharmaceuticals, in collaboration with Eastern Virginia Medical School, under an agreement. The U.S. Food and Drug Administration (FDA) approved Seasonale in the United States on September 5, 2003. Barr Pharmaceuticals, its manufacturer, claimed at the time of Seasonales approval that it would cost one dollar per pill. Health Canada approved Seasonale in July 2007, and Paladin Labs began distributing it in Canada on January 4, 2008.Seasonique, also produced by Duramed Pharmaceuticals, has active pills and packaging identical to Seasonale, but replaces the placebo week with a low-dosage week of estrogen. Lybrel is produced by Wyeth Pharmaceuticals. It contains 90 µg levonorgestrel and 20 µg ethinylestradiol in each pill, and is designed to be taken continuously with no placebos. The FDA approved Lybrel for human consumption on May 22, 2007. References Further reading Elsimar M. Coutinho; Sheldon J. Segal (1999). Is menstruation obsolete?. Oxford: Oxford University Press. ISBN 0-19-513021-9. Susan Rako (2006). The Blessings of the Curse: No More Periods?. Lincoln, NE: Backinprint.com. ISBN 978-0-595-38655-0. Susan Rako (2003). No More Periods?: The Risks of Menstrual Suppression. Harmony Books. ISBN 1-4000-4503-7. External links Lybrel official site Seasonale and Seasonique official site Pro-extended cycle COCP site by Leslie Miller, M.D.
Estradiol (medication)	Estradiol (E2) is a medication and naturally occurring steroid hormone. It is an estrogen and is used mainly in menopausal hormone therapy and to treat low sex hormone levels in women. It is also used in hormonal birth control for women, in hormone therapy for transgender women, and in the treatment of hormone-sensitive cancers like prostate cancer in men and breast cancer in women, among other uses. Estradiol can be taken by mouth, held and dissolved under the tongue, as a gel or patch that is applied to the skin, in through the vagina, by injection into muscle or fat, or through the use of an implant that is placed into fat, among other routes.Side effects of estradiol in women include breast tenderness, breast enlargement, headache, fluid retention, and nausea among others. Men and children who are exposed to estradiol may develop symptoms of feminization, such as breast development and a feminine pattern of fat distribution, and men may also experience low testosterone levels and infertility. Estradiol may increase the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses if it is not taken together with a progestogen such as progesterone. The combination of estradiol with a progestin, though not with oral progesterone, may increase the risk of breast cancer. Estradiol should not be used in women who are pregnant or breastfeeding or who have breast cancer, among other contraindications.Estradiol is a naturally occurring and bioidentical estrogen, or an agonist of the estrogen receptor, the biological target of estrogens like endogenous estradiol. Due to its estrogenic activity, estradiol has antigonadotropic effects and can inhibit fertility and suppress sex hormone production in both women and men. Estradiol differs from non-bioidentical estrogens like conjugated estrogens and ethinylestradiol in various ways, with implications for tolerability and safety.Estradiol was discovered in 1933. It became available as a medication that same year, in an injectable form known as estradiol benzoate. Forms that were more useful by mouth, estradiol valerate and micronized estradiol, were introduced in the 1960s and 1970s and increased its popularity by this route. Estradiol is also used as other prodrugs, like estradiol cypionate. Related estrogens such as ethinylestradiol, which is the most common estrogen in birth control pills, and conjugated estrogens (brand name Premarin), which is used in menopausal hormone therapy, are used as medications as well. In 2020, it was the 59th most commonly prescribed medication in the United States, with more than 11 million prescriptions. Medical uses Hormone therapy Menopause Estradiol is used in menopausal hormone therapy to prevent and treat moderate to severe menopausal symptoms such as hot flashes, vaginal dryness and atrophy, and osteoporosis (bone loss). As unopposed estrogen therapy (using estrogen alone without progesterone) increases the risk of endometrial hyperplasia and endometrial cancer in women with intact uteruses, estradiol is usually combined with a progestogen like progesterone or medroxyprogesterone acetate to prevent the effects of estradiol on the endometrium. This is not necessary if the woman has undergone a hysterectomy (surgical removal of the uterus). A 2017 meta-analysis found that estradiol had no effect on depressive symptoms in peri- and postmenopausal women. Hypogonadism Estrogen is responsible for the mediation of puberty in females, and in girls with delayed puberty due to hypogonadism (low-functioning gonads, which can result in low sex hormone levels) such as in Turner syndrome, estradiol is used to induce the development of and maintain female secondary sexual characteristics such as breasts, wide hips, and a female fat distribution. It is also used to restore estradiol levels in adult premenopausal women with hypogonadism, for instance those with premature ovarian failure or who have undergone oophorectomy. It is used to treat women with hypogonadism due to hypopituitarism as well. Transgender women Estradiol is used as part of feminizing hormone therapy for transgender women. The drug is used in higher dosages prior to sex reassignment surgery or orchiectomy to help suppress testosterone levels; after this procedure, estradiol continues to be used at lower dosages to maintain estradiol levels in the normal premenopausal female range. Birth control Although almost all combined oral contraceptives contain the synthetic estrogen ethinylestradiol, natural estradiol itself is also used in some hormonal contraceptives, including in estradiol-containing oral contraceptives and combined injectable contraceptives. It is formulated in combination with a progestin such as dienogest, nomegestrol acetate, or medroxyprogesterone acetate, and is often used in the form of an ester prodrug like estradiol valerate or estradiol cypionate. Hormonal contraceptives contain a progestin and/or estrogen and prevent ovulation and thus the possibility of pregnancy by suppressing the secretion of the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), the peak of which around the middle of the menstrual cycle causes ovulation to occur. Hormonal cancer Prostate cancer Estradiol is used as a form of high-dose estrogen therapy to treat prostate cancer and is similarly effective to other therapies such as androgen deprivation therapy with castration and antiandrogens. It is used in the form of long-lasting injected estradiol prodrugs like polyestradiol phosphate, estradiol valerate, and estradiol undecylate, and has also more recently been assessed in the form of transdermal estradiol patches. Estrogens are effective in the treatment of prostate cancer by suppressing testosterone levels into the castrate range, increasing levels of sex hormone-binding globulin (SHBG) and thereby decreasing the fraction of free testosterone, and possibly also via direct cytotoxic effects on prostate cancer cells. Parenteral estradiol is largely free of the cardiovascular side effects of the high oral dosages of synthetic estrogens like diethylstilbestrol ad ethinylestradiol that were used previously. In addition, estrogens may have advantages relative to castration in terms of hot flashes, sexual interest and function, osteoporosis, cognitive function, and quality of life. However, side effects such as gynecomastia and feminization in general may be difficult to tolerate and unacceptable for many men. Breast cancer High-dose estrogen therapy is effective in the treatment of about 35% of cases of breast cancer in women who are at least 5 years menopausal and has comparable effectiveness to antiestrogen therapy with medications like the selective estrogen receptor modulator (SERM) tamoxifen. Although estrogens are rarely used in the treatment of breast cancer today and synthetic estrogens like diethylstilbestrol and ethinylestradiol have most commonly been used, estradiol itself has been used in the treatment of breast cancer as well. It has been used orally at very high doses (30 mg/day) in the treatment of therapy-naive breast cancer and orally at low doses (2 to 6 mg/day) in the treatment of breast cancer in women who were previously treated with and benefited from but acquired resistance to aromatase inhibitors. Polyestradiol phosphate is also used to treat breast cancer. Other uses Infertility Estrogens may be used in treatment of infertility in women when there is a need to develop sperm-friendly cervical mucous or an appropriate uterine lining.It is also commonly used during in vitro fertilization (IVF). Estrogen helps maintain the endometrial lining of the uterus and help prepare for pregnancy. Research shows higher pregnancy rate if the mother takes estrogen in addition to progesterone. Estradiol is the predominant form of estrogen during reproductive years and is most commonly prescribed. Lactation suppression Estrogens can be used to suppress and cease lactation and breast engorgement in postpartum women who do not wish to breastfeed. They do this by directly decreasing the sensitivity of the alveoli of the mammary glands to the lactogenic hormone prolactin. Tall stature Estrogens have been used to limit final height in adolescent girls with tall stature. They do this by inducing epiphyseal closure and suppressing growth hormone-induced hepatic production and by extension circulating levels of insulin-like growth factor-1 (IGF-1), a hormone that causes the body to grow and increase in size. Although ethinylestradiol and conjugated estrogens have mainly been used for this purpose, estradiol can also be employed. Breast enhancement Estrogens are involved in breast development and estradiol may be used as a form of hormonal breast enhancement to increase the size of the breasts. Both polyestradiol phosphate monotherapy and pseudopregnancy with a combination of high-dosage intramuscular estradiol valerate and hydroxyprogesterone caproate have been assessed for this purpose in clinical studies. However, acute or temporary breast enlargement is a well-known side effect of estrogens, and increases in breast size tend to regress following discontinuation of treatment. Aside from those without prior established breast development, evidence is lacking for a sustained increases in breast size with estrogens. Schizophrenia Estradiol has been found to be effective in the adjunctive treatment of schizophrenia in women. It has been found to significantly reduce positive, negative, and cognitive symptoms, with particular benefits on positive symptoms. Other estrogens, as well as selective estrogen receptor modulators (SERMs) like raloxifene, have been found to be effective in the adjunctive treatment of schizophrenia in women similarly. Estrogens may be useful in the treatment of schizophrenia in men as well, but their use in this population is limited by feminizing side effects. SERMs, which have few or no feminizing side effects, have been found to be effective in the adjunctive treatment of schizophrenia in men similarly to in women and may be more useful than estrogens in this sex. Sexual deviance Estradiol has been used at high doses to suppress sex drive in men with sexual deviance such as paraphilias and in sex offenders. It has specifically been used for this indication in the forms of intramuscular injections of estradiol valerate and estradiol undecylate and of subcutaneous pellet implants of estradiol. Available forms Estradiol is available in a variety of different formulations, including oral, intranasal, transdermal/topical, vaginal, injectable, and implantable preparations. An ester may be attached to one or both of the hydroxyl groups of estradiol to improve its oral bioavailability and/or duration of action with injection. Such modifications give rise to forms such as estradiol acetate (oral and vaginal), estradiol valerate (oral and injectable), estradiol cypionate (injectable), estradiol benzoate (injectable), estradiol undecylate (injectable), and polyestradiol phosphate (injectable; a polymerized ester of estradiol), which are all prodrugs of estradiol. Contraindications Estrogens like estradiol have a number of contraindications. Estradiol should be avoided when there is undiagnosed abnormal vaginal bleeding, known, suspected or a history of breast cancer, current treatment for metastatic disease, known or suspected estrogen-dependent neoplasia, deep vein thrombosis, pulmonary embolism or history of these conditions, active or recent arterial thromboembolic disease such as stroke, myocardial infarction, liver dysfunction or disease. Estradiol should not be taken by people with a hypersensitivity/allergy or those who are pregnant or are suspected pregnant. Side effects Common side effects of estradiol in women include headache, breast pain or tenderness, breast enlargement, irregular vaginal bleeding or spotting, abdominal cramps, bloating, fluid retention, and nausea. Other possible side effects of estrogens may include high blood pressure, high blood sugar, enlargement of uterine fibroids, melasma, vaginal yeast infections, and liver problems. In men, estrogens can cause breast pain or tenderness, gynecomastia (male breast development), feminization, demasculinization, sexual dysfunction (decreased libido and erectile dysfunction), hypogonadism, testicular atrophy, and infertility. Blood clots Oral estradiol and estradiol valerate, for instance in menopausal hormone therapy or birth control pills, are associated with a significantly higher risk of venous thromboembolism (VTE) than non-use. Higher doses of oral estrogens are associated with higher risks of VTE. In contrast to oral estradiol, transdermal and vaginal estradiol at menopausal replacement dosages are not associated with a higher incidence of VTE. Low doses (e.g., 50 μg/day) and high doses (e.g., 100 μg/day) of transdermal estradiol for menopausal replacement do not differ in terms of VTE risk. The higher risk of VTE with oral estradiol can be attributed to the first pass and a disproportionate effect on liver synthesis of coagulation factors. Even high doses of parenteral estradiol, such as high-dose polyestradiol phosphate, have minimal influence on coagulation factors, in contrast to oral estrogen therapy. However, sufficient doses of parenteral estradiol, for instance very high doses of estradiol valerate by intramuscular injection, can nonetheless activate coagulation, presumably increasing VTE risk.In addition to the route of administration, the type of estrogen influences VTE risk. Oral conjugated estrogens are associated with a higher risk of VTE than oral estradiol. Estradiol- and estradiol valerate-containing birth control pills are associated with a lower risk of VTE than birth control pills containing ethinylestradiol. The relative risk of VTE is thought to be highest with oral ethinylestradiol, intermediate with oral conjugated estrogens, low with oral estradiol and parenteral estradiol valerate, and very low with transdermal estradiol. Conjugated estrogens and ethinylestradiol are thought to have a higher risk of VTE than estradiol because they are resistant to hepatic metabolism and have a disproportionate influence on liver production of coagulation factors.The combination of oral or transdermal estradiol and a progestin is associated with a higher risk of VTE than estradiol alone. Dydrogesterone is associated with a lower risk than other progestins such as medroxyprogesterone acetate and norethisterone, while oral progesterone is associated with no increase in risk of VTE. Older age, higher body weight, lower physical activity, and smoking are all associated with a higher risk of VTE with oral estrogen therapy. Risk of VTE with estrogen therapy is highest at the start of treatment, particularly during the first year, and decreases over time.The absolute risk of VTE with estrogen and/or progestin therapy is small. Women who are not on a birth control pill or hormone therapy have a risk of VTE of about 1 to 5 out of 10,000 women per year. In women taking a birth control pill containing ethinylestradiol and a progestin, the risk of VTE is in the range of 3 to 10 out of 10,000 women per year. Birth control pills containing estradiol valerate and a progestin are associated with about half the risk of VTE of ethinylestradiol/progestin-containing birth control pills. Hormone therapy for transgender women likewise is associated with a lower risk of VTE than birth control pills containing ethinylestradiol and a progestin. The risk of VTE during pregnancy, when estrogens and progesterone increase to very high levels, is 5 to 20 in 10,000 women per year, while the risk is 40 to 65 per 10,000 women per year during the postpartum period. Long-term effects Uncommon but serious possible side effects of estrogens associated with long-term therapy may include breast cancer, uterine cancer, stroke, heart attack, blood clots, dementia, gallbladder disease, and ovarian cancer. Warning signs of these serious side effects include breast lumps, unusual vaginal bleeding, dizziness, faintness, changes in speech, severe headaches, chest pain, shortness of breath, pain in the legs, changes in vision, and vomiting.Due to health risks observed with the combination of conjugated estrogens and medroxyprogesterone acetate in the Womens Health Initiative (WHI) studies (see below), the United States Food and Drug Administration (FDA) label for Estrace (estradiol) advises that estrogens should be used in menopausal hormone therapy only for the shortest time possible and at the lowest effective dose. While the FDA states that is unknown if these risks generalize to estradiol (alone or in combination with progesterone or a progestin), it advises that in the absence of comparable data, the risks should be assumed to be similar. When used to treat menopausal symptoms, the FDA recommends that discontinuation of estradiol should be attempted every three to six months via a gradual dose taper.The combination of bioidentical transdermal or vaginal estradiol and oral or vaginal progesterone appears to be a safer form of hormone therapy than the combination of oral conjugated estrogens and medroxyprogesterone acetate and may not share the same health risks. Advantages may include reduced or no risk of venous thromboembolism, cardiovascular disease, and breast cancer, among others. Overdose Estrogens are relatively safe in overdose. During pregnancy, levels of estradiol increase to very high concentrations that are as much as 100-fold normal levels. In late pregnancy, the body produces and secretes approximately 100 mg of estrogens, including estradiol, estrone, and estriol, per day. Doses of estradiol of as high as 200 mg per day by intramuscular injection for several weeks have been administered to humans in studies. Serious adverse effects have not been described following acute overdose of large doses of estrogen- and progestogen-containing birth control pills by small children. Symptoms of estrogen overdosage may include nausea, vomiting, bloating, increased weight, water retention, breast tenderness, vaginal discharge, vaginal bleeding, heavy legs, and leg cramps. These side effects can be diminished by reducing the estrogen dosage. Interactions Inducers of cytochrome P450 enzymes like CYP3A4 such as St. Johns wort, phenobarbital, carbamazepine and rifampicin decrease the circulating levels of estradiol by accelerating its metabolism, whereas inhibitors of cytochrome P450 enzymes like CYP3A4 such as erythromycin, cimetidine, clarithromycin, ketoconazole, itraconazole, ritonavir and grapefruit juice may slow its metabolism resulting in increased levels of estradiol in the circulation. There is an interaction between estradiol and alcohol such that alcohol considerably increases circulating levels of estradiol during oral estradiol therapy and also increases estradiol levels in normal premenopausal women and with parenteral estradiol therapy. This appears to be due to a decrease in hepatic 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) activity and hence estradiol inactivation into estrone due to an alcohol-mediated increase in the ratio of NADH to NAD in the liver. Spironolactone may reduce the bioavailability of high doses of oral estradiol. Pharmacology Pharmacodynamics Estradiol is an estrogen, or an agonist of the estrogen receptors (ERs), the ERα and ERβ. It is also an agonist of membrane estrogen receptors (mERs), including the GPER, Gq-mER, ER-X, and ERx. Estradiol is highly selective for these ERs and mERs, and does not interact importantly with other steroid hormone receptors. It is far more potent as an estrogen than are other bioidentical estrogens like estrone and estriol. Given by subcutaneous injection in mice, estradiol is about 10-fold more potent than estrone and about 100-fold more potent than estriol.The ERs are expressed widely throughout the body, including in the breasts, uterus, vagina, fat, skin, bone, liver, pituitary gland, hypothalamus, and other parts of the brain. In accordance, estradiol has numerous effects throughout the body. Among other effects, estradiol produces breast development, feminization, changes in the female reproductive system, changes in liver protein synthesis, and changes in brain function. The effects of estradiol can influence health in both positive and negative ways. In addition to the aforementioned effects, estradiol has antigonadotropic effects due to its estrogenic activity, and can inhibit ovulation and suppress gonadal sex hormone production. At sufficiently high dosages, estradiol is a powerful antigonadotropin, capable of suppressing testosterone levels into the castrate/female range in men.There are differences between estradiol and other estrogens, such as non-bioidentical estrogens like natural conjugated estrogens and synthetic estrogens like ethinylestradiol and diethylstilbestrol, with implications for pharmacodynamics and pharmacokinetics as well as efficacy, tolerability, and safety. Pharmacokinetics Estradiol can be taken by a variety of different routes of administration. These include oral, buccal, sublingual, intranasal, transdermal (gels, creams, patches), vaginal (tablets, creams, rings, suppositories), rectal, by intramuscular or subcutaneous injection (in oil or aqueous), and as a subcutaneous implant. The pharmacokinetics of estradiol, including its bioavailability, metabolism, biological half-life, and other parameters, differ by route of administration. Likewise, the potency of estradiol, and its local effects in certain tissues, most importantly the liver, differ by route of administration as well. In particular, the oral route is subject to a high first-pass effect, which results in high levels of estradiol and consequent estrogenic effects in the liver and low potency due to first-pass hepatic and intestinal metabolism into metabolites like estrone and estrogen conjugates. Conversely, this is not the case for parenteral (non-oral) routes, which bypass the intestines and liver.Different estradiol routes and dosages can achieve widely varying circulating estradiol levels. For purposes of comparison with normal physiological circumstances, menstrual cycle circulating levels of estradiol in premenopausal women are 40 pg/mL in the early follicular phase, 250 pg/mL at the middle of the cycle, and 100 pg/mL during the mid-luteal phase. Mean integrated levels of circulating estradiol in premenopausal women across the whole menstrual cycle have been reported to be in the range of 80 and 150 pg/mL, according to some sources. Chemistry Estradiol is a naturally occurring estrane steroid. It is also known as 17β-estradiol (to distinguish it from 17α-estradiol) or as estra-1,3,5(10)-triene-3,17β-diol. It has two hydroxyl groups, one at the C3 position and the other at the C17β position, as well as three double bonds in the A ring (the estra-1,3,5(10)-triene core). Due to its two hydroxyl groups, estradiol is often abbreviated as E2. The structurally related estrogens, estrone (E1), estriol (E3), and estetrol (E4) have one, three, and four hydroxyl groups, respectively. Hemihydrate A hemihydrate form of estradiol, estradiol hemihydrate, is widely used medically under a large number of brand names similarly to estradiol. In terms of activity and bioequivalence, estradiol and its hemihydrate are identical, with the only disparities being an approximate 3% difference in potency by weight (due to the presence of water molecules in the hemihydrate form of the substance) and a slower rate of release with certain formulations of the hemihydrate. This is because estradiol hemihydrate is more hydrated than anhydrous estradiol, and for this reason, is more insoluble in water in comparison, which results in slower absorption rates with specific formulations of the drug such as vaginal tablets. Estradiol hemihydrate has also been shown to result in less systemic absorption as a vaginal tablet formulation relative to other topical estradiol formulations such as vaginal creams. Estradiol hemihydrate is used in place of estradiol in some estradiol products. Derivatives A variety of C17β and/or C3 ester prodrugs of estradiol, such as estradiol acetate, estradiol benzoate, estradiol cypionate, estradiol dipropionate, estradiol enantate, estradiol undecylate, estradiol valerate, and polyestradiol phosphate (an estradiol ester in polymeric form), among many others, have been developed and introduced for medical use as estrogens. Estramustine phosphate is also an estradiol ester, but with a nitrogen mustard moiety attached, and is used as a cytostatic antineoplastic agent in the treatment of prostate cancer. Cloxestradiol acetate and promestriene are ether prodrugs of estradiol that have been introduced for medical use as estrogens as well, although they are little known and rarely used.Synthetic derivatives of estradiol used as estrogens include ethinylestradiol, ethinylestradiol sulfonate, mestranol, methylestradiol, moxestrol, and quinestrol, all of which are 17α-substituted estradiol derivatives. Synthetic derivatives of estradiol used in scientific research include 8β-VE2 and 16α-LE2. History Estradiol was first discovered and synthesized in 1933 via reduction of estrone. Subsequently, estradiol was isolated for the first time in 1935. It was also originally known as dihydroxyestrin, dihydrofolliculin, or alpha-estradiol.Estradiol was first introduced for medical use, in the form of estradiol benzoate, a short-acting ester prodrug of estradiol administered by intramuscular injection in oil solution, under the brand name Progynon B in 1933. Estradiol itself was also marketed in the 1930s and 1940s in the form of oral tablets and solutions, vaginal suppositories, and topical ointments under a variety of brand names including Dimenformon, Gynoestryl, Ovocyclin, Progynon, and Progynon DH. Marketed vaginal estradiol suppositories were also used rectally. Estradiol dipropionate, another short-acting ester of estradiol in oil solution for use by intramuscular injection, was marketed under the brand name Di-Ovocylin by 1939. In contrast to estrone, estradiol was never marketed in oil solution for intramuscular injection. This is attributable to its short duration of action and
Estradiol (medication)	the availability of longer-acting estradiol esters like estradiol benzoate and estradiol dipropionate.Delivery of estrogens by nasal spray was studied in 1929, and an estradiol nasal spray for local use was marketed by Schering under the brand name Progynon DH Nasal Spray by 1941. Sublingual administration of estradiol was first described in the early 1940s. Buccal estradiol tablets were marketed by Schering under the brand name Progynon Buccal Tablets by 1949. Estradiol tablets for use by the sublingual route were marketed under the brand name Estradiol Membrettes in 1950, as well as under the brand name Diogynets by 1952. Longer-acting esters of estradiol in oil solution like estradiol valerate (Delestrogen, Progynon Depot), estradiol cypionate (Depo-Estradiol), and estradiol undecylate (Delestrec, Progynon Depot 100), as well as the polymeric estradiol ester polyestradiol phosphate in aqueous solution (Estradurin), were developed and introduced for use by intramuscular injection in the 1950s.Due to poor absorption and low potency relative to other estrogens, oral estradiol was not widely used as late as the early 1970s. Instead, synthetic and animal-derived estrogens like conjugated estrogens, ethinylestradiol, and diethylstilbestrol were typically used by the oral route. In 1966, oral estradiol valerate was introduced by Schering for medical use under the brand name Progynova. Esterification of estradiol, as in estradiol valerate, was believed to improve its metabolic stability with oral administration. Studies in the 1960s showed that micronization of steroids such as spironolactone and norethisterone acetate improved their absorption and oral potency by several-fold. In 1972, micronization of estradiol was studied in women and was likewise found to improve the absorption and potency of estradiol by the oral route. Subsequently, oral micronized estradiol was introduced for medical use in the United States under the brand name Estrace in 1975. However, oral micronized estradiol valerate had been introduced by Schering in 1968. Oral micronized estradiol and oral estradiol valerate have similar bioavailability and are both now widely used throughout the world.After the introduction of oral micronized estradiol, vaginal and intranasal micronized estradiol were evaluated in 1977 and both subsequently introduced.The first transdermal estradiol gel, a hydroalcoholic gel known as EstroGel, was initially described in 1980 and was introduced in Europe around 1981. Transdermal estradiol gel did not become available in the United States until 2004, when EstroGel was introduced in this country as well. A transdermal estradiol emulsion, Estrasorb, was marketed in the United States in 2003 as well. One of the earliest reports of transdermal estradiol patches was published in 1983. Estraderm, a reservoir patch and the first transdermal estradiol patch to be marketed, was introduced in Europe in 1985 and in the United States in 1986. The first transdermal matrix estradiol patches to be introduced were Climara and Vivelle between 1994 and 1996, and were followed by many others.Ethinylestradiol, a synthetic derivative of estradiol, was synthesized from estradiol by Inhoffen and Hohlweg in 1938 and was introduced for oral use by Schering in the United States under the brand name Estinyl in 1943. Starting in the 1950s, ethinylestradiol became widely used in birth control pills. Estradiol-containing birth control pills were initially studied in the 1970s, with the first report published in 1977. Development of birth control pills containing estradiol was motivated by the thrombotic risks of ethinylestradiol that were uncovered in the 1960s and 1970s. More than 15 attempts were made at development of an estradiol-containing birth control pill starting in the 1970s, but were unsuccessful due to unacceptable menstrual bleeding patterns. Estradiol valerate/cyproterone acetate (Femilar) was introduced for use as a birth control pill in Finland in 1993, but was never marketed elsewhere. Subsequently, estradiol valerate/dienogest (Natazia, Qlaira) was marketed as a birth control pill in 2008 and estradiol/nomegestrol acetate (Naemis, Zoely) was introduced in 2012. Society and culture Generic names Estradiol is the generic name of estradiol in American English and its INN, USAN, USP, BAN, DCF, and JAN. Estradiolo is the name of estradiol in Italian and the DCIT and estradiolum is its name in Latin, whereas its name remains unchanged as estradiol in Spanish, Portuguese, French, and German. Oestradiol was the former BAN of estradiol and its name in British English, but the spelling was eventually changed to estradiol. When estradiol is provided in its hemihydrate form, its INN is estradiol hemihydrate. Brand names Estradiol is marketed under a large number of brand names throughout the world. Examples of major brand names in which estradiol has been marketed in include Climara, Climen, Dermestril, Divigel, Estrace, Natifa, Estraderm, Estraderm TTS, Estradot, Estreva, Estrimax, Estring, Estrofem, EstroGel, Evorel, Fem7 (or FemSeven), Imvexxy, Menorest, Oesclim, OestroGel, Sandrena, Systen, and Vagifem. Estradiol valerate is marketed mainly as Progynova and Progynon-Depot, while it is marketed as Delestrogen in the U.S. Estradiol cypionate is used mainly in the U.S. and is marketed under the brand name Depo-Estradiol. Estradiol acetate is available as Femtrace, Femring, and Menoring.Estradiol is also widely available in combination with progestogens. It is available in combination with norethisterone acetate under the major brand names Activelle, Cliane, Estalis, Eviana, Evorel Conti, Evorel Sequi, Kliogest, Novofem, Sequidot, and Trisequens; with drospirenone as Angeliq; with dydrogesterone as Femoston, Femoston Conti; and with nomegestrol acetate as Zoely. Estradiol valerate is available with cyproterone acetate as Climen; with dienogest as Climodien and Qlaira; with norgestrel as Cyclo-Progynova and Progyluton; with levonorgestrel as Klimonorm; with medroxyprogesterone acetate as Divina and Indivina; and with norethisterone enantate as Mesigyna and Mesygest. Estradiol cypionate is available with medroxyprogesterone acetate as Cyclo-Provera, Cyclofem, Feminena, Lunelle, and Novafem; estradiol enantate with algestone acetophenide as Deladroxate and Topasel; and estradiol benzoate is marketed with progesterone as Mestrolar and Nomestrol.Estradiol valerate is also widely available in combination with prasterone enantate (DHEA enantate) under the brand name Gynodian Depot. Availability Estradiol and/or its esters are widely available in countries throughout the world in a variety of formulations. United States As of November 2016, estradiol is available in the United States in the following forms: Oral tablets (Femtrace (as estradiol acetate), Gynodiol, Innofem, generics) Transdermal patches (Alora, Climara, Esclim, Estraderm, FemPatch, Menostar, Minivelle, Vivelle, Vivelle-Dot, generics) Topical gels (Divigel, Elestrin, EstroGel, Sandrena), emulsions (Estrasorb), and sprays (Evamist) Vaginal tablets (Vagifem, generics), creams (Estrace), inserts (Imvexxy), and rings (Estring, Femring (as estradiol acetate)) Oil solution for intramuscular injection (Delestrogen (as estradiol valerate), Depo-Estradiol (as estradiol cypionate))Oral estradiol valerate (Progynova) and other esters of estradiol that are used by injection like estradiol benzoate, estradiol enantate, and estradiol undecylate all are not marketed in the U.S. Polyestradiol phosphate (Estradurin) was marketed in the U.S. previously but is no longer available.Estradiol is also available in the U.S. in combination with progestogens for the treatment of menopausal symptoms and as a combined hormonal contraceptive: Oral oil-filled capsules with progesterone (Bijuva) Oral tablets with drospirenone (Angeliq) and norethisterone acetate (Activella, Amabelz) and as estradiol valerate with dienogest (Natazia) Transdermal patches with levonorgestrel (Climara Pro) and norethisterone acetate (Combipatch)Estradiol and estradiol esters are also available in custom preparations from compounding pharmacies in the U.S. This includes subcutaneous pellet implants, which are not available in the United States as FDA-approved pharmaceutical drugs. In addition, topical creams that contain estradiol are generally regulated as cosmetics rather than as drugs in the U.S. and hence are also sold over-the-counter and may be purchased without a prescription on the Internet. Other countries Pharmaceutical estradiol subcutaneous pellet implants were formerly available in the United Kingdom and Australia under the brand name Estradiol Implants or Oestradiol Implants (Organon; 25, 50, or 100 mg), but have been discontinued. However, an estradiol subcutaneous implant with the brand name Meno-Implant (Organon; 20 mg) continues to be available in the Netherlands. Previously, for instance in the 1970s and 1980s, other subcutaneous estradiol implant products such as Progynon Pellets (Schering; 25 mg) and Estropel Pellets (25 mg; Bartor Pharmacol) were marketed. It has been said that pharmaceutical estradiol implants have been almost exclusively used in the United Kingdom. Subcutaneous estradiol implants are also available as custom compounded products in some countries. Cost Generic oral estradiol tablets are much less expensive than other forms of estradiol such as transdermal gel and patches and vaginal rings. Research A variety of estradiol-containing combined birth control pills were studied but never marketed. In addition, a variety of estradiol-containing combined injectable contraceptives were studied but never marketed.Estradiol has been studied in the treatment of postpartum depression and postpartum psychosis.Estrogens such as estradiol appear to improve sexual desire and function in women. However, the available evidence overall does not support the use of estradiol and other estrogens for improving sexual desire and function in women as of 2016. An exception is the use of estrogens to treat vaginal atrophy.Estrogen therapy has been proposed as a potential treatment for autism but clinical studies are needed. References Further reading External links "Estradiol". Drug Information Portal. U.S. National Library of Medicine.
Trifluoperazine	Trifluoperazine, marketed under the brand name Stelazine among others, is a typical antipsychotic primarily used to treat schizophrenia. It may also be used short term in those with generalized anxiety disorder but is less preferred to benzodiazepines. It is of the phenothiazine chemical class. Medical uses Schizophrenia Trifluoperazine is an effective antipsychotic for people with schizophrenia. There is low-quality evidence that trifluoperazine increases the chance of being improved when compared to placebo when people are followed up for 19 weeks. There is low-quality evidence that trifluoperazine reduces the risk of relapse when compared with placebo when people are followed for 5 months. As of 2014 there was no good evidence for a difference between trifluoperazine and placebo with respect to the risk of experiencing intensified symptoms over a 16-week period nor in reducing significant agitation or distress.There is no good evidence that trifluoperazine is more effective for schizophrenia than lower-potency antipsychotics like chlorpromazine, chlorprothixene, thioridazine and levomepromazine, but trifluoperazine appears to cause more adverse effects than these drugs. Other It appears to be effective for people with generalized anxiety disorder but the benefit–risk ratio was unclear as of 2005.It has been experimentally used as a drug to kill eukaryotic pathogens in humans. Side effects Its use in many parts of the world has declined because of highly frequent and severe early and late tardive dyskinesia, a type of extrapyramidal symptom. The annual development rate of tardive dyskinesia may be as high as 4%.A 2004 meta-analysis of the studies on trifluoperazine found that it is more likely than placebo to cause extrapyramidal side effects such as akathisia, dystonia, and Parkinsonism. It is also more likely to cause somnolence and anticholinergic side effects such as red eye and xerostomia (dry mouth). All antipsychotics can cause the rare and sometimes fatal neuroleptic malignant syndrome. Trifluoperazine can lower the seizure threshold. The antimuscarinic action of trifluoperazine can cause excessive dilation of the pupils (mydriasis), which increases the chances of patients with hyperopia developing glaucoma. Contraindications Trifluoperazine is contraindicated in CNS depression, coma, and blood dyscrasias. Trifluoperazine should be used with caution in patients suffering from renal or hepatic impairment. Mechanism of action Trifluoperazine has central antiadrenergic, antidopaminergic, and minimal anticholinergic effects. It is believed to work by blockading dopamine D1 and D2 receptors in the mesocortical and mesolimbic pathways, relieving or minimizing such symptoms of schizophrenia as hallucinations, delusions, and disorganized thought and speech. Names Brand names include Eskazinyl, Eskazine, Jatroneural, Modalina, Sizonil, Stelazine, Stilizan, Terfluzine, Trifluoperaz and Triftazin. In the United Kingdom and some other countries, trifluoperazine is sold and marketed under the brand Stelazine. The drug is sold as tablet, liquid and Trifluoperazine-injectable USP for deep intramuscular short-term use. GP studying pharmacological data has indicated cases of neck vertebrae irreversible fusing leading to NHS preparations being predominantly of the liquid form trifluoperazine as opposed to the tablet form as in Stela zine etc. In the past, trifluoperazine was used in fixed combinations with the MAO inhibitor (antidepressant) tranylcypromine (tranylcypromine/trifluoperazine) to attenuate the strong stimulating effects of this antidepressant. This combination was sold under the brand name Jatrosom N. Likewise a combination with amobarbital (potent sedative/hypnotic agent) for the amelioration of psychoneurosis and insomnia existed under the brand name Jalonac. In Italy the first combination is still available, sold under the brand name Parmodalin (10 mg of tranylcypromine and 1 mg of trifluoperazine). == References ==
Hydroxychloroquine	Hydroxychloroquine, sold under the brand name Plaquenil among others, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine. Other uses include treatment of rheumatoid arthritis, lupus, and porphyria cutanea tarda. It is taken by mouth, often in the form of hydroxychloroquine sulfate.Common side effects may include vomiting, headache, changes in vision, and muscle weakness. Severe side effects may include allergic reactions, vision problems, and heart problems. Although all risk cannot be excluded, it remains a treatment for rheumatic disease during pregnancy. Hydroxychloroquine is in the antimalarial and 4-aminoquinoline families of medication.Hydroxychloroquine was approved for medical use in the United States in 1955. It is on the World Health Organizations List of Essential Medicines. In 2019, it was the 122nd most commonly prescribed medication in the United States, with more than 5 million prescriptions.Hydroxychloroquine has been studied for an ability to prevent and treat coronavirus disease 2019 (COVID-19), but clinical trials found it ineffective for this purpose and a possible risk of dangerous side effects. Among studies that deemed hydroxychloroquine intake to cause harmful side effects, a publication by The Lancet was retracted due to data flaws. The speculative use of hydroxychloroquine for COVID-19 threatens its availability for people with established indications. Medical uses Hydroxychloroquine treats rheumatic disorders such as systemic lupus erythematosus, rheumatoid arthritis, and porphyria cutanea tarda, and certain infections such as Q fever and certain types of malaria. It is considered the first-line treatment for systemic lupus erythematosus. Certain types of malaria, resistant strains, and complicated cases require different or additional medication.It is widely used to treat primary Sjögren syndrome but does not appear to be effective. Hydroxychloroquine is widely used in the treatment of post-Lyme arthritis. It may have both an anti-spirochete activity and an anti-inflammatory activity, similar to the treatment of rheumatoid arthritis. Contraindications The drug label advises that hydroxychloroquine should not be prescribed to individuals with known hypersensitivity to 4-aminoquinoline compounds. There are several other contraindications, and caution is required if the person considered for treatment has certain heart conditions, diabetes, or psoriasis. Adverse effects Hydroxychloroquine has a narrow therapeutic index, meaning there is little difference between toxic and therapeutic doses. The most common adverse effects are nausea, stomach cramps, and diarrhea. Other common adverse effects include itching and headache. The most serious adverse effects affect the eye, with dose-related retinopathy as a concern even after hydroxychloroquine use is discontinued. Serious reported neuropsychiatric adverse effects of hydroxychloroquine use include agitation, mania, difficulty sleeping, hallucinations, psychosis, catatonia, paranoia, depression, and suicidal thoughts. In rare situations, hydroxychloroquine has been implicated in cases of serious skin reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, and Drug reaction with eosinophilia and systemic symptoms. Reported blood abnormalities with its use include lymphopenia, eosinophilia, and atypical lymphocytosis.For short-term treatment of acute malaria, adverse effects can include abdominal cramps, diarrhea, heart problems, reduced appetite, headache, nausea and vomiting. Other adverse effects noted with short-term use of Hydroxychloroquine include low blood sugar and QT interval prolongation. Idiosyncratic hypersensitivity reactions have occurred.For prolonged treatment of lupus or rheumatoid arthritis, adverse effects include the acute symptoms, plus altered eye pigmentation, acne, anemia, bleaching of hair, blisters in mouth and eyes, blood disorders, cardiomyopathy, convulsions, vision difficulties, diminished reflexes, emotional changes, excessive coloring of the skin, hearing loss, hives, itching, liver problems or liver failure, loss of hair, muscle paralysis, weakness or atrophy, nightmares, psoriasis, reading difficulties, tinnitus, skin inflammation and scaling, skin rash, vertigo, weight loss, and occasionally urinary incontinence. Hydroxychloroquine can worsen existing cases of both psoriasis and porphyria.Children may be especially vulnerable to developing adverse effects from hydroxychloroquine overdoses. Eyes One of the most serious side effects is retinopathy (generally with chronic use). People taking 400 mg of hydroxychloroquine or less per day generally have a negligible risk of macular toxicity, whereas the risk begins to increase when a person takes the medication over five years or has a cumulative dose of more than 1000 grams. The daily safe maximum dose for eye toxicity can be estimated from a persons height and weight. Macular toxicity is related to the total cumulative dose rather than the daily dose. Regular eye screening, even in the absence of visual symptoms, is recommended to begin when either of these risk factors occurs.Toxicity from hydroxychloroquine may be seen in two distinct areas of the eye: the cornea and the macula. The cornea may become affected (relatively commonly) by an innocuous cornea verticillata or vortex keratopathy and is characterized by whorl-like corneal epithelial deposits. These changes bear no relationship to dosage and are usually reversible on cessation of hydroxychloroquine. The macular changes are potentially serious. Advanced retinopathy is characterized by reduction of visual acuity and a "bulls eye" macular lesion which is absent in early involvement. Overdose Overdoses of hydroxychloroquine are extremely rare, but extremely toxic. Eight people are known to have overdosed since the drugs introduction in the mid-1950s, of which three have died. Chloroquine has a risk of death in overdose in adults of about 20%, while hydroxychloroquine is estimated to be two or threefold less toxic.Serious signs and symptoms of overdose generally occur within an hour of ingestion. These may include sleepiness, vision changes, seizures, coma, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure. Loss of vision may be permanent. Low blood potassium, to levels of 1 to 2 mmol/L, may also occur. Cardiovascular abnormalities such as QRS complex widening and QT interval prolongation may also occur.Treatment recommendations include early mechanical ventilation, heart monitoring, and activated charcoal. Supportive treatment with intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of choice. Stomach pumping may also be used. Sodium bicarbonate and hypertonic saline may be used in cases of severe QRS complex widening. Seizures may be treated with benzodiazepines. Intravenous potassium chloride may be required, however this may result in high blood potassium later in the course of the disease. Dialysis does not appear to be useful. Detection Hydroxychloroquine may be quantified in plasma or serum to confirm a diagnosis of poisoning in hospitalized victims or in whole blood to assist in a forensic investigation of a case of sudden or unexpected death. Plasma or serum concentrations are usually in a range of 0.1-1.6 mg/L during therapy and 6–20 mg/L in cases of clinical intoxication, while blood levels of 20–100 mg/L have been observed in deaths due to acute overdosage. Interactions The drug transfers into breast milk. There is no evidence that its use during pregnancy is harmful to the developing fetus and its use is not contraindicated in pregnancy.The concurrent use of hydroxychloroquine and the antibiotic azithromycin appears to increase the risk for certain serious side effects with short-term use, such as an increased risk of chest pain, congestive heart failure, and mortality from cardiovascular causes. Care should be taken if combined with medication altering liver function as well as aurothioglucose (Solganal), cimetidine (Tagamet) or digoxin (Lanoxin). Hydroxychloroquinecan increase plasma concentrations of penicillamine which may contribute to the development of severe side effects. It enhances hypoglycemic effects of insulin and oral hypoglycemic agents. Dose altering is recommended to prevent profound hypoglycemia. Antacids may decrease the absorption of hydroxychloroquine. Both neostigmine and pyridostigmine antagonize the action of hydroxychloroquine.While there may be a link between hydroxychloroquine and hemolytic anemia in those with glucose-6-phosphate dehydrogenase deficiency, this risk may be low in those of African descent.Specifically, the US Food and Drug Administrations (FDA) drug label for hydroxychloroquine lists the following drug interactions: Digoxin (wherein it may result in increased serum digoxin levels) Insulin or anti-diabetic medication (wherein it may enhance the effects of a hypoglycemic treatment) Drugs that prolong QT interval and other arrhythmogenic drugs (as Hydroxychloroquine prolongs the QT interval and may increase the risk of inducing serious abnormal heart rhythms (ventricular arrhythmias) if used concurrently) Mefloquine and other drugs known to lower the seizure threshold (co-administration with other antimalarials known to lower the convulsion threshold may increase risk of convulsions) Antiepileptics (concurrent use may impair the antiepileptic activity) Methotrexate (combined use is unstudied and may increase the frequency of side effects) Cyclosporin (wherein an increased plasma cyclosporin level was reported when used together). Pharmacology Pharmacokinetics Hydroxychloroquine has similar pharmacokinetics to chloroquine, with rapid gastrointestinal absorption, large distribution volume, and elimination by the kidneys. Cytochrome P450 enzymes (CYP2D6, 2C8, 3A4 and 3A5) metabolize hydroxychloroquine to N-desethylhydroxychloroquine. Both agents also inhibit CYP2D6 activity and may interact with other medications that depend on this enzyme. Pharmacodynamics Antimalarials are lipophilic weak bases and easily pass plasma membranes. The free base form accumulates in lysosomes (acidic cytoplasmic vesicles) and is then protonated, resulting in concentrations within lysosomes up to 1000 times higher than in culture media. This increases the pH of the lysosome from four to six. Alteration in pH causes inhibition of lysosomal acidic proteases causing a diminished proteolysis effect. Higher pH within lysosomes causes decreased intracellular processing, glycosylation and secretion of proteins with many immunologic and nonimmunologic consequences. These effects are believed to be the cause of a decreased immune cell functioning such as chemotaxis, phagocytosis and superoxide production by neutrophils. Hydroxychloroquine is a weak diprotic base that can pass through the lipid cell membrane and preferentially concentrate in acidic cytoplasmic vesicles. The higher pH of these vesicles in macrophages or other antigen-presenting cells limits the association of autoantigenic (any) peptides with class II MHC molecules in the compartment for peptide loading and/or the subsequent processing and transport of the peptide-MHC complex to the cell membrane. Mechanism of action Hydroxychloroquine increases lysosomal pH in antigen-presenting cells by two mechanisms: As a weak base, it is a proton acceptor and via this chemical interaction, its accumulation in lysozymes raises the intralysosomal pH, but this mechanism does not fully account for the effect of hydroxychloroquine on pH. Additionally, in parasites that are susceptible to hydroxychloroquine, it interferes with the endocytosis and proteolysis of hemoglobin and inhibits the activity of lysosomal enzymes, thereby raising the lysosomal pH by more than 2 orders of magnitude over the weak base effect alone. In 2003, a novel mechanism was described wherein hydroxychloroquine inhibits stimulation of the toll-like receptor (TLR) 9 family receptors. TLRs are cellular receptors for microbial products that induce inflammatory responses through activation of the innate immune system.As with other quinoline antimalarial drugs, the antimalarial mechanism of action of quinine has not been fully resolved. The most accepted model is based on hydrochloroquinine and involves the inhibition of hemozoin biocrystallization, which facilitates the aggregation of cytotoxic heme. Free cytotoxic heme accumulates in the parasites, causing death.Hydroxychloroquine increases the risk of low blood sugar through several mechanisms. These include decreased clearance of the hormone insulin from the blood, increased insulin sensitivity, and increased release of insulin from the pancreas. History After World War I, the German government sought alternatives to quinine as an anti-malarial. Chloroquine, a synthetic analogue with the same mechanism of action was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories.: 130–131 This was introduced into clinical practice in 1947 for the prophylactic treatment of malaria. Researchers subsequently attempted to discover structural analogs with superior properties and one of these was hydroxychloroquine. Chemical synthesis The first synthesis of hydroxychloroquine was disclosed in a patent filed by Sterling Drug in 1949. In the final step, 4,7-dichloroquinoline was reacted with a primary amine which in turn had been made from the chloro-ketone shown: Society and culture It is frequently sold as a sulfate salt known as hydroxychloroquine sulfate. In the sulfate salt form, 200 mg is equal to 155 mg of the pure form.Brand names of hydroxychloroquine include Plaquenil, Hydroquin, Axemal (in India), Dolquine, Quensyl, and Quinoric. COVID-19 References External links "Hydroxychloroquine". Drug Information Portal. U.S. National Library of Medicine.
Tisotumab vedotin	Tisotumab vedotin, sold under the brand name Tivdak, is an antibody-drug conjugate used to treat cervical cancer. It is a combination of tisotumab, a monoclonal antibody against tissue factor, and monomethyl auristatin E (MMAE), a potent inhibitor of cell division. Tisotumab vedotin was approved for medical use in the United States in September 2021. It is administered by infusion into a vein every 3 weeks.Tisotumab vedotin is the international nonproprietary name (INN). Adverse effects In the United States, Tivdak carries a black box warning for ocular toxicity, which occurs in up to 60% of treated patients. In clinical trials, the most common forms of ocular toxicity were dry eye, conjunctivitis, corneal damage, and blepharitis.To prevent eye damage, premedication with three different types of eye drops—a topical corticosteroid, a vasoconstrictor, and artificial tears—is recommended before each infusion, as well as the use of cold packs over the eyes.Other very common adverse effects include bleeding (occurring in approximately 60% of patients, most often nosebleed) and peripheral neuropathy (42% of patients). Like all drugs containing MMAE, tisotumab vedotin can cause inflammation of the lungs. Mechanism of action The antibody portion of tisotumab vedotin (tisotumab) binds to and forms a complex with tissue factor, a molecule expressed on the surface of cancer cells. This complex is then taken up into the cell, where tisotumab vedotin is broken down by proteolytic cleavage, releasing MMAE, which stops the cell cycle and kills the cell by apoptosis. History Tisotumab was developed by Genmab in Utrecht, the Netherlands, and Copenhagen, Denmark, with the code name TF-011-MMAE. It is marketed in a 50/50 partnership between Genmab and Seagen, which developed and owns the intellectual property for vedotin technology (monoclonal antibody–MMAE conjugates). References External links "Tisotumab vedotin". Drug Information Portal. U.S. National Library of Medicine. Clinical trial number NCT03438396 for "A Trial of Tisotumab Vedotin in Cervical Cancer" at ClinicalTrials.gov Clinical trial number NCT03245736 for "Tisotumab Vedotin Continued Treatment in Patients With Solid Tumors" at ClinicalTrials.gov Clinical trial number NCT02001623 for "Tisotumab Vedotin (HuMax-TF-ADC) Safety Study in Patients With Solid Tumors" at ClinicalTrials.gov Clinical trial number NCT02552121 for "Tisotumab Vedotin (HuMax-TF-ADC) Safety Study in Patients With Solid Tumors" at ClinicalTrials.gov
Interferon beta-1b	Interferon beta-1b is a cytokine in the interferon family used to treat the relapsing-remitting and secondary-progressive forms of multiple sclerosis (MS). It is approved for use after the first MS event. Closely related is interferon beta 1a, also indicated for MS, with a very similar drug profile. Mechanism of action Interferon beta balances the expression of pro- and anti-inflammatory agents in the brain, and reduces the number of inflammatory cells that cross the blood brain barrier. Overall, therapy with interferon beta leads to a reduction of neuron inflammation. Moreover, it is also thought to increase the production of nerve growth factor and consequently improve neuronal survival. Side effects Interferon beta-1b is available only in injectable forms, and can cause skin reactions at the injection site that may include cutaneous necrosis. Skin reactions vary greatly in their clinical presentation. They usually appear within the first month of treatment albeit their frequence and importance diminish after six months of treatment. Skin reactions are more prevalent in women. Mild skin reactions usually do not impede treatment whereas necroses appear in around 5% of patients and lead to the discontinuation of the therapy. Also over time, a visible dent at the injection site due to the local destruction of fat tissue, known as lipoatrophy, may develop. Interferons, a subclass of cytokines, are produced in the body during illnesses such as influenza in order to help fight the infection. They are responsible for many of the symptoms of influenza infections, including fever, muscle aches, fatigue, and headaches. Many patients report influenza-like symptoms hours after taking interferon beta that usually improve within 24 hours, being such symptoms related to the temporary increase of cytokines. This reaction tends to disappear after 3 months of treatment and its symptoms can be treated with over-the-counter nonsteroidal anti-inflammatory drugs, such as ibuprofen, that reduce fever and pain. Another common transient secondary effect with interferon-beta is a functional deterioration of already existing symptoms of the disease. Such deterioration is similar to the one produced in MS patients due to heat, fever or stress (Uhthoffs phenomenon), usually appears within 24 hours of treatment, is more common in the initial months of treatment, and may last several days. A symptom specially sensitive to worsening is spasticity. Interferon-beta can also reduce numbers of white blood cells (leukopenia), lymphocytes (lymphopenia) and neutrophils (neutropenia), as well as affect liver function. In most cases these effects are non-dangerous and reversible after cessation or reduction of treatment. Nevertheless, recommendation is that all patients should be monitored through laboratory blood analyses, including liver function tests, to ensure safe use of interferons.The injection-site reactions can be mitigated by rotating injection sites or by using one of the medications that requires less frequent injections. Side effects are often onerous enough that many patients ultimately discontinue taking Interferons (or glatiramer acetate, a comparable disease-modifying therapies requiring regular injections). Efficacy Clinically isolated syndrome The earliest clinical presentation of relapsing-remitting multiple sclerosis is the clinically isolated syndrome (CIS), that is, a single attack of a single symptom. During a CIS, there is a subacute attack suggestive of demyelination but the patient does not fulfill the criteria for diagnosis of multiple sclerosis. Treatment with interferons after an initial attack decreases the risk of developing clinical definite MS. Relapsing-remitting MS Medications are modestly effective at decreasing the number of attacks in relapsing-remitting multiple sclerosis and in reducing the accumulation of brain lesions, which is measured using gadolinium-enhanced magnetic resonance imaging (MRI). Interferons reduce relapses by approximately 30% and their safe profile make them the first-line treatments. Nevertheless, not all the patients are responsive to these therapies. It is known that 30% of MS patients are non-responsive to Beta interferon. They can be classified in genetic, pharmacological and pathogenetic non-responders. One of the factors related to non-respondance is the presence of high levels of interferon beta neutralizing antibodies. Interferon therapy, and specially interferon beta-1b, induces the production of neutralizing antibodies, usually in the second 6 months of treatment, in 5 to 30% of treated patients. Moreover, a subset of RRMS patients with specially active MS, sometimes called "rapidly worsening MS" are normally non-responders to interferon beta-1b.While more studies of the long-term effects of the drugs are needed, some data on the effects of interferons indicate that early-initiated long-term therapy is safe and it is related to better outcomes. More recent data suggest that interferon betas does not hasten disability.Interferon-β exacerbates Th17-mediated inflammatory disease. Commercial formulations Betaferon/Betaseron is marketed today by Bayer Pharma. The originator was Schering AG (Berlex in North America), now part of Bayer Pharma. Novartis has also introduced Extavia, a new brand of interferon beta-1b, in 2009. References External links "Interferon beta-1b". Drug Information Portal. U.S. National Library of Medicine.
Halls	Halls is a plural of the word hall. Halls may also refer to: People Walter Halls (1871–1953), British trade unionist and politician Ethel May Halls (1882–1967), American actress Julian Halls (born 1967), British field hockey player Evelyn Halls (born 1972), Australian fencer Roxana Halls (born 1974), English artist Monty Halls (born 1976), British marine biologist and TV presenter John Halls (born 1982), English footballer, mostly played for Stoke, Brentford and Aldershot, and model Andy Halls (born 1992), English footballer, has played for Stockport, Macclesfield and Chester Halls (footballer) (born 1999), Brazilian footballer Henrique Halls (born 2002), Brazilian footballer Places Halls, Georgia, an unincorporated community Halls, Missouri, an unincorporated community Halls, Tennessee, a town in West Tennessee Not to be confused with Halls Crossroads, Tennessee, a suburb of Knoxville sometimes colloquially referred to as "Halls" Business Halls (cough drop), a brand of cough drop Geo. Hall & Sons, a defunct Australian soft drink company Halls (department store), Kansas City, Missouri, United States
Extended-release morphine	Extended-release (or slow-release) formulations of morphine are those whose effect last substantially longer than bare morphine, availing for e.g. one administration per day. Conversion between extended-release and immediate-release (or "regular") morphine is easier than conversion to or from an equianalgesic dose of another opioid with different half-life, with less risk of altered pharmacodynamics. Brand names Brand names for this formulation of morphine include Avinza, Kadian, MS Contin, MST Continus, Morphagesic, Zomorph, Filnarine, MXL and Dolcontin. MS Contin is a trademark of Purdue Pharma, and is available in the United States, and Australia. In the UK, MS Contin is marketed by NAPP Pharmaceuticals as MST Continus. MS Contin is a DEA Schedule II substance in the United States, a Schedule 8 (controlled) drug in Australia and a Schedule 2 CD (Controlled Drug) in the UK. Avinza is made by King Pharmaceuticals and Kadian is made by Actavis Pharmaceuticals. Unlike the MS Contin brand and its generic versions, Kadian and Avinza are designed to be 12- to 24-hour release, not 8- to 12-hour. So instead of 2-3 times a day dosing, it can be 1-2 times. MST Continus and MXL are registered copyright and trademark of Napp Pharmaceuticals and are available in the UK. MXL is a 24-hour release formula designed to be taken once daily. It is available in doses between 30 mg and 200 mg in 30 mg intervals (equating to between 1.25 mg/hour and 8.33 mg/hour). MST Continus is a 12-hour release formula, therefore it is given 2 times per day. It is available in the following doses: 5 mg, 10 mg, 15 mg, 30 mg, 60 mg, 100 mg and 200 mg tablets (equating to between 0.83 mg/hour and 16.67 mg/hour). Dosage comparison For constant pain, the relieving effect of extended-release morphine given once (for Kadian) or twice (for MS Contin) every 24 hours is roughly the same as multiple administrations of immediate release (or "regular") morphine. Morphine sulfate pentahydrade (trade names including Dolcontin) has a higher molecular mass than morphine base, and therefore 10 mg morphine sulfate pentahydrate contains approximatively 7.5 mg of morphine free base. Extended-release morphine can be administered together with "rescue doses" of immediate-release morphine pro re nata in case of breakthrough pain, each generally consisting of 5% to 15% of the 24-hour extended-release dosage. Structure Some brands may have a pellet (spheroid) formulations (made by extrusion and spheronization) can be used for controlled release of the drug in the body whereas powder filled pellets generally cannot. The plastic spheres containing powder have micropores that open at varying PH levels, to maintain a mostly constant release during transit through the digestive tract. The spheres themselves, the outer shells, pass undigested in most patients. Other brands are thought to use ethylcellulose coatings to control drug release from pellets. Another use these style medications have is that they can be given via NG tube, the pellets being very small. This makes them one of the only extended release oral medications that can be given by feeding tube. Opioid replacement therapy According to a Cochrane review in 2013, extended-release morphine as an opioid replacement therapy for people with heroin addiction or dependence confers a possible reduction of opioid use and with fewer depressive symptoms but overall more adverse effects when compared to other forms of long-acting opioids. The length of time in treatment was not found to be significantly different. References External links Advanced consumer information: morphine sulfate Consumer Medicine Information (Australia)
Eptinezumab	Eptinezumab, sold under the brand name Vyepti, is a medication used for the preventive treatment of migraine in adults. It is a monoclonal antibody that targets calcitonin gene-related peptides (CGRP) alpha and beta. It is administered by intravenous infusion.Eptinezumab was approved for medical use in the United States in February 2020. History The U.S. Food and Drug Administration (FDA) approved eptinezumab based primarily on evidence from two clinical trials (Trial 1/ NCT02559895 and Trial 2/ NCT02974153) of 1741 subjects with chronic or episodic migraine headaches. Trials were conducted at 212 sites in United States, Georgia, Russia, Ukraine and European Union.The benefit and side effects of eptinezumab were evaluated in two clinical trials of adult subjects 18 – 71 years of age with a history of migraine headaches. The trials had similar designs.Trial 1 enrolled subjects with a history of episodic migraine headaches and Trial 2 enrolled subjects with chronic migraine headaches. Subjects were assigned to receive one of two doses of eptinezumab or placebo injections every three months for a total of twelve months in Trial 1, and for a total of 6 months in Trial 2. Neither the subjects nor the health care providers knew which treatment was being given until the trial was completed.The benefit of eptinezumab in comparison to placebo was assessed based on the change in the number of migraine days per month during the first three-month treatment period. Society and culture Legal status In November 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) recommended the granting of a marketing authorization for the medicinal product Vyepti, intended for the prophylaxis of migraine. The applicant for this medicinal product is H. Lundbeck A/S. Eptinezumab was approved for medical use in the European Union in January 2022. References External links "Eptinezumab". Drug Information Portal. U.S. National Library of Medicine.
Factor XIII	Factor XIII or fibrin stabilizing factor is a zymogen found in blood of humans and some other animals. It is activated by thrombin to factor XIIIa. Factor XIIIa is an enzyme of the blood coagulation system that crosslinks fibrin. Deficiency of XIII worsens clot stability and increases bleeding tendency.Human XIII is a heterotetramer. It consists of 2 enzymatic A peptides and 2 non-enzymatic B peptides. XIIIa is a dimer of activated A peptides. Function Within blood, thrombins cleave fibrinogens to fibrins during coagulation and a fibrin-based blood clot forms. Factor XIII is a transglutaminase that circulates in human blood as a heterotetramer of two A and two B subunits. Factor XIII binds to the clot via their B units. In the presence of fibrins, thrombin efficiently cleaves the R37–G38 peptide bond of each A unit within a XIII tetramer. A units release their N-terminal activation peptides.Both of the non-covalently bound B units are now able to dissociate from the tetramer with the help of calcium ions (Ca2+) in the blood; these ions also activate the remaining dimer of two A units via a conformational change.Factor XIIIa (dimer of two active A units) crosslinks fibrins within the clot by forming isopeptide bonds between various glutamines and lysines of the fibrins. These bonds make the clot physically more durable and protect it from premature enzymatic degradation (fibrinolysis).In humans, plasmin, antithrombin and TFPI are the most relevant proteolytic inhibitors of the active factor XIIIa. α2-macroglobulin is a significant non-proteolytic inhibitor. Genetics Human factor XIII consist of A and B subunits. A subunit gene is F13A1. It is on the chromosome 6 at the position 6p24–25. It spans over 160 kbp, has 14 introns and 15 exons. Its mRNA is 3.9 kbp. It has a 5 UTR of 84 bp and a 3 UTR of 1.6 kbp. F13A1 exon(s) 1 code 5 UTR 2 code activation peptide 2–4 code β-sandwich 4–12 code catalytic domain 12–13 code β-barrel 1 13–15 code β-barrel 2B subunit gene is F13B. It is on the chromosome 1 at the position 1q31–32.1. It spans 28 kpb, has 11 introns and 12 exons. Its mRNA is 2.2 kbp. Exon 1 codes 5 UTR. Exons 2–12 code the 10 different sushi domains. Structure Factor XIII of human blood is a heterotetramer of two A and two B linear polypeptides or "units". A units are potentially catalytic; B units are not. A units form a dimeric center. Non-covalently bound B units form a ring-like structure around the center. B units are removed when XIII is activated to XIIIa. Dimers containing only A units also occur within cells such as platelets. Large quantities of singular B units (monomers) also occur within blood. These dimers and monomers are not known to participate in coagulation, whereas the tetramers do.A units have a mass of about 83 kDa, 731 amino acid residues, 5 protein domains (listed from the N-terminal to C-terminal, residue numbers are in brackets): activation peptide (1–37) β-sandwich (38–184) catalytic domain (185–515), in which the residues C314, H373, D396 and W279 partake in catalysis β-barrel 1 (516–628) β-barrel 2 (629–731)B units are glycoproteins. Each has a mass of about 80 kDa (8.5% of the mass is from carbohydrates), 641 residues and 10 sushi domains. Each domain has about 60 residues and 2 internal disulfide bonds. Physiology A subunits of human factor XIII are made primarily by platelets and other cells of bone marrow origin. B subunits are secreted into blood by hepatocytes. A and B units combine within blood to form heterotetramers of two A units and two B units. Blood plasma concentration of the heterotetramers is 14–48 mg/L and half-life is 9–14 days.A clot that has not been stabilized by FXIIIa is soluble in 5 mol/L urea, while a stabilized clot is resistant to this phenomenon. Factor XIII deficiency Deficiency of Factor XIII (FXIIID), while generally rare, does occur, with Iran having the highest global incidence of the disorder with 473 cases. The city of Khash, located in Sistan and Balochistan provinces, has the highest incidence in Iran, with a high rate of consanguineous marriage. Diagnostic use Factor XIII levels are not measured routinely, but may be considered in patients with an unexplained bleeding tendency. As the enzyme is quite specific for monocytes and macrophages, determination of the presence of factor XIII may be used to identify and classify malignant diseases involving these cells. Discovery Factor XIII Deficiency is also known as Laki–Lorand factor, after Kalman Laki and Laszlo Lorand, the scientists who first proposed its existence in 1948. A 2005 conference recommended standardization of nomenclature. See also Catridecacog Coagulation D-dimer Factor XIII deficiency References External links Factor XIII deficiency at hemophilia.org med/3491 at eMedicine

Subsets and Splits

No saved queries yet

Save your SQL queries to embed, download, and access them later. Queries will appear here once saved.