The disclosed invention generally relates to pharmaceutical and nutraceutical compounds and methods for reducing inflammation, muscle spasms, and pain associated with cancer, trauma, medical procedure, neurological diseases and disorders, as well as other conditions in subjects in need thereof. The disclosed invention further relates to Mitragyna speciose and Cannabis sativa based compounds and synthetic analogs of the alkaloids found in said plants, where said compounds can also contain a pharmacologically inactive substance for modifying certain qualities of said compounds.

The compounds and methods proposed by this invention are related to essentially a mixture of naturally accruing and other substances to produce a novel compound that exhibits strong anti-inflammatory, muscle relaxant, and analgesic qualities. A plurality of medicinal concoctions can be manufactured from said compound that have various pharmacological effects and different routes and methods of administration. The active ingredients of said compounds can be derived from Mitragyna speciosa (Kratom) and Cannabis sativa plants or can be chemically synthesized.
Mitragyna speciosa is an evergreen tree of the coffee (Rubiaceae) family native to Indonesia, Malaysia, Myanmar, Papua New Guinea, Indonesia, and Thailand. It is best known for generating leaves that contain more than 40 distinct psychoactive compounds. Mitragyna speciosa plant is a 4 to 16-meter-high tropical tree indigenous to South East Asia but now cultivated elsewhere. In Thailand, the tree and leaf preparations are called Kratom. Traditionally, fresh or dried Kratom leaves are chewed or made into a tea; they are seldom smoked. At a low dose, Kratom has stimulant effects and it is used to combat fatigue during long working hours. At high dosages, however, it has sedative-narcotic effect. It is also used in traditional medicine and as an opium substitute.
As already mentioned, the phytochemicals isolated from various parts of the tree include over 40 structurally related alkaloids as well as several flavonoids, terpenoid saponins, polyphenols, and various glycosides. The main psychoactive components in the leaves are mitragynine and 7-hydroxymitragynine, both found only in Mitragyna speciosa. Kartom contains other central nervous system stimulants and depressants that can act upon a variety of neurotransmitter systems within the human brain. As already mentioned, it has traditionally been consumed as a leaves decoction for its stimulant effects to counter fatigue, treat fever, diarrhea, as well as anesthetic, antinociceptive, analgesic and stimulating effects that help to combat fatigue and suppress appetite.
Cannabis sativa (marijuana) is an annual herbaceous flowering plant indigenous to eastern Asia but now of cosmopolitan distribution due to cultivation. It is placed in the Cannabis genus classification, which belongs to a small but diverse family, the Cannabaceae. Cannabinoid (CB) components of marijuana are known to exert behavioral and psychotropic effects but also to possess therapeutic properties including analgesia, ocular hypotension, and antiemesis. CBs-based medications are now being used for treatment of a wide range of medical conditions, including neuropathic pain, pain related to cancer and trauma, spasticity associated with Multiple Sclerosis (MS), fibromyalgia, and others.
This invention generally relates to pharmaceutical compounds and methods for reducing muscle fatigue and spasticity, reducing inflammation, and treating pain associated with cancer, trauma, medical procedure, and neurological diseases and disorders in subjects in need thereof, as well as a method of administering therapeutically-effective amount of said pharmaceutical compound containing certain natural and/or synthetic Mitragyna speciosa and Cannabis sativa alkaloids and/or their derivatives/analogs and other substances.
Other medical conditions are also contemplated by this invention that include, but are not limited to: Huntington's Disease (HD); Wilson's Disease; Parkinson's Disease (PD); metabolic and endocrine diseases and disorders; athetosis-related to damage or degeneration of basal ganglia; minor tranquilizers, alcohol, cocaine, (meta)amphetamine, and opioid withdrawal syndromes; symptoms or side effects associated with anti-retroviral therapy, chemotherapy and radiation therapy; AIDS; rheumatoid arthritis; osteoarthritis; fibromyalgia; pain and spasticity associated with MS, Neuromuscular Junction Disorder and other neurodegenerative disease, autoimmune diseases and disorders, motor neuron diseases and disorders, neurodegenerative diseases and disorders; pain associated with cancer; trauma; athletic performance; migraine; surgical intervention or medical treatment; dental and gum pain; stroke; heart attack; abdominal pain; bone pain, muscle pain; neurological pain; stomach ulcers-related pain; gallbladder disease-related pain; Central Pain Syndrome; chronic pain disorder (nociceptive pain, neuropathic pain, chronic back or leg pain, painful neuropathies, Complex Regional Pain Syndrome), and acute pain.
The principal mechanism of Kratom's psychoactive action involves mu-opioid receptor partial agonism, and to a lesser extent, kappa-opioid receptor antagonism—relatively analogous to the drug buprenorphine. Other, less prominent, mechanisms of Kratom's action include: delta-opioid receptor antagonism, alpha-2 receptor agonism, 5-HT2A receptor antagonism, and adenosine A2A receptor antagonism. Due to the aforesaid pharmacodynamics, when ingested, most individuals report opioidergic and/or stimulatory effects.
CBs are a group of chemicals known to activate CB receptors in cells. These chemicals, which are found in cannabis plants, are also produced endogenously in humans and other animals, these are termed endocannabinoids. There are also synthetic CBs that are chemicals with similar structures to plant CBs or endocannabinoids. Plant cannabinoids can also be isolated such that they are "essentially pure" compounds. These isolated CBs are largely free of other naturally occurring compounds, such as other minor CBs and molecules.
The primary CB receptor subtypes are CB receptors type 1 (CB1) and type 2 (CB2). CB1 receptors are highly expressed in the Central Nervous System (CNS), especially the basal ganglia, and also identified in almost all peripheral tissues and cell types. CB2 receptors are expressed primarily in the immune system, where they modulate inflammation, but are also expressed in the CNS, particularly in neurons within the dorsal vagal motor nucleus, the nucleus ambiguous, the spinal trigeminal nucleus, and microglia. CB2 receptors were also found in the basal ganglia and studies suggest that impairment of these receptors may be associated with dyskinesia. While most actions of CBs are related to CB1 and CB2 receptors, other receptor types have been described, including the Transient Receptor Potential Vanilloid type 1 (TRPV1) cation channel, the GTP-binding Protein-coupled Receptor GPR55, the abnormal-CBD receptor, and the Peroxisome-Proliferator-Activated Receptor (PPAR).
Endogenously produced CBs (eCBs) are lipophilic compounds that demonstrate varying degrees of affinity for G-protein coupled CB receptors and include anandamide and 2-arachidonoglycerol. eCBs primarily function through retrograde signaling, wherein post-synaptic activity leads to eCB production and release with backward transmission across the synapse to depress presynaptic neurotransmitter release. The Endo-Cannabinoid System (ECS) may also support synapse formation and neurogenesis. Within the basal ganglia, eCBs and CB1 receptors tend to increase GABAergic and inhibit glutamatergic transmission. eCBs also tend to inhibit dopamine release through GABAergic mechanisms. eCBs are not stored and are quickly degraded after exerting a transient and localized effect. Removal of eCBs from the extracellular space occurs through cellular uptake and metabolism with anandamide degraded primarily by Fatty Acid Amide Hydrolysis (FAAH) and 2-AG degraded by monoacylglycerol lipase.
The disclosed invention finds that, in one embodiment, a number of alkaloids contained in Mitragyna speciosa and Cannabis sativa plants, when combined, could be used as a substitute for morphine, having a potent analgesic action, and can provide a sedative and muscle relaxant effects akin to the effects of benzodiazepines. Mitragynine and 7-hydroxymitragynine, found in Mitragyna speciosa, as well as tetrahydrocannabinol (THC) and cannabidiol (CBD), found in Cannabis sativa, are the two groups of alkaloids mainly responsible for the analgesic and muscle relaxant effects. Mitragynine and 7-hydroxymitragynine are partial agonists of the μ-subtype opioid receptor (MOR) (Kruegel, et al., 2016). In mice, 7-hydroxymitragynine was thirteen times more potent analgesic than morphine even upon oral administration (Matsumoto, et al., 2004). The effect of Kratom alkaloids as opioid receptor agonist is confirmed by the fact that it is readily antagonized by the opioid receptor antagonist naloxone (Yamamoto, et al., 1999). In addition, 5-HT2a and postsynaptic α2-adrenergic receptors, as well as neuronal Ca2+channels are also involved in the unique pharmacological and behavioral activity of mitragynine.
In addition, mitragynine exhibits antinociceptive and cough-suppressant effects that are comparable to those of codeine in animal studies (Macko, Weisbach, & Douglas, 1972). It has been reported that a methanol extract of Kratom leaf and a major alkaloid, mitragynine, produced skeletal muscle relaxation. Thus, mitragynine also has a direct effect on skeletal muscle by decreasing the muscle twitch. More so, Chittrakarn et al. (2010), report that Kratom extract had a greater effect at the neuromuscular junction than on the skeletal muscle or somatic nerve.
With CBs, likewise, a number of clinical trials in humans demonstrated that CBs might be useful in the treatment of movement disorders and pain. It has been suggested that an endogenous CBs participate in the control of movements and, therefore, the central ECS might play a role in the pathophysiology of these diseases. There is also evidence that CBs are of therapeutic value in the treatment of tics in Tourette Syndrome (TS), the reduction of Levodopa-Induced Dyskinesia (LID) in PD and some forms of tremor and dystonia. There is also evidence that CBs are useful in the treatment of chorea in HD and hypokinetic parkinsonian syndromes. Currently, treatments of these and similar diseases are focused on relieving symptoms and preventing complications because there is no curative therapy. Preclinical research in animal models of several movement disorders have shown variable evidence for symptomatic benefits but more consistently suggest potential neuroprotective effects in several animal models of PD and HD. Clinical observations and clinical trials of CB-based therapies suggest a possible benefit of CBs for tics.
Kratom extract contains multiple alkaloids, where some of them have therapeutic potential. The following activity effects and concentrations are compiled from several studies of alkaloids and their concentrations in Mitragyna speciosa. Results of one of the studies is presented in FIG. 2. The following list, though, is not inclusive and the alkaloids shall be further studied to determine their activity: ajmalicine (raubasine)—cerebrocirculant, antiaggregant, anti-adrenergic (at alpha-1), sedative, anticonvulsant, smooth muscle relaxer (found in Rauwolfia serpentine); ciliaphylline—antitussive, analgesic <1% of total alkaloid content found in Kratom leaf; corynantheidine—μ-opioid antagonist (also found in Yohimbe)<1% of total alkaloid content found in Kratom leaf; corynoxeine—calcium channel blocker <1% of total alkaloid content found in Kratom leaf; corynoxine—dopamine mediating anti-locomotives <1% of total alkaloid content found in Kratom leaf; epicatechin—antioxidant, antiaggregant, antibacterial, antidiabetic, antihepatitic, anti-inflammatory, anti-leukemic, antimutagenic, antiperoxidant, antiviral, potential cancer preventative, alpha-amylase inhibitor (also found in dark chocolate); 9-hydroxycorynantheidine—partial opioid agonist; 7-hydroxymitragynine—analgesic, antitussive, antidiarrheal; primary psychoactive in Kratom, approximately 2% of total alkaloid content found in Kratom leaf; isomitraphylline—immune-stimulant, anti-leukemic <1% of total alkaloid content found in Kratom leaf; isomitrafoline <1% of total alkaloid content found in Kratom leaf; isopteropodine—immuno-stimulant; isorhynchophylline—immuno-stimulant <1% of total alkaloid content found in Kratom leaf; isospeciofoline: <1% of total alkaloid content found in Kratom leaf; mitraciliatine <1% of total alkaloid content found in Kratom leaf; mitragynine—indole alkaloid, analgesic, antitussive, antidiarrheal, adrenergic, antimalarial, possible psychedelic (5-HT2A) antagonist, approximately 66% of total alkaloid content found in Kratom leaf; mitragynine oxindole B<1% of total alkaloid content found in Kratom leaf; mitrafoline <1% of total alkaloid content found in Kratom leaf; mitraphylline—oxindole alkaloid, vasodilator, antihypertensive, muscle relaxer, diuretic, antiamnesic, anti-leukemic, possible immunostimulant <1% of total alkaloid contents in Kratom leaf; paynantheine—indole alkaloid, smooth muscle relaxer, 8.6% to 9% of total alkaloid contents in Kratom leaf; rhynchophylline—vasodilator, antihypertensive, calcium channel blocker, antiaggregant, anti-inflammatory, antipyretic, anti-arrhythmic, antithelmintic <1% of total alkaloid content found in Kratom leaf; speciociliatine—weak opioid agonist, 0.8% to 1% of total alkaloid content of Kratom leaf, unique to Kratom; speciogynine—smooth muscle relaxer, 6.6% to 7% of total alkaloid contents of Kratom leaf; speciophylline—indole alkaloid, anti-leukemic <1% of total alkaloid contents of Kratom leaf; tetrahydroalstonine—hypoglycemic, anti-adrenergic (at alpha-2).
As in all botanicals, Mitragyna speciosa and Cannabis sativa alkaloid content varies quantitatively from geographical location, and from month to month, at different leaf harvest times. This led some teams to conclude that there may be different geographical variants within the same species. The Chelsea College Pharmacognosy Research Laboratories collected thirty samples of Kratom from Thailand, Malaysia, and Papua New Guinea between 1961 and 1970. All contained mitragynine, but also proved to have considerable variation in the alkaloid makeup. For red and green/white leaved plants of Thailand, the most common alkaloidal profile was mitragynine, speciogynine, speciociliatine, paynantheine, traces of ajmalicine, traces of (C9) methoxy-oxindoles, and traces of other indoles.
Yet other Thai plants contained distinct alkaloidal profiles, some with many more alkaloids. In the Malay specimens, one contained mitragynine, speciofoline, and other indoles and oxindoles, while others contained mitragynine, ajmalicine, speciogynine, speciociliatine, paynantheine, traces of indoles, and (C9) methoxy-oxindoles. Specimens from Papua New Guinea contained mitragynine, speciogynine, speciociliatine, paynantheine, specionoxeine, and isospecionoxeine. Other researchers reported that Thai and Malay Kratom had the alkaloids mitragynine, speciogynine, speciociliatine, paynantheine and 7-hydroxymitragynine in common.
In both Thai and Malay samples, mitragynine was the most abundant alkaloid, yet it made up 66% of the total alkaloid in the Thai Kratom sample, while it made up only 12% of the alkaloids from the Malaysian sample. The Malay Kratom sample had mitragynaline and pinoresinol as major components, as well as mitralactonal, mitrasulgynine and 3,4,5,6-tetradehydromitragynine. In the Malay Kratom, 4 new types of indole alkaloids (corynantheidaline, corynantheidalinic acid, mitragynaline and mitragynalinic acid) were discovered in very young leaves.
Likewise, Cannabis sativa alkaloid content and yield also depends on the plant type (drug, fiber), pollination, sex, age, part of the plant, cultivation (indoor, outdoor etc.), harvest time and conditions, drying, as well as storage. From 1980 to 1997, a total of 35,213 samples of confiscated Cannabis products (Cannabis, hashish, hashish oil) representing more than 7717 tons seized in the United States were analyzed by gas chromatography (GC). The mean THC concentration increased from less than 1.5% in 1980 to 4.2% in 1997. The maximum levels found were 29.9 and 33.1% in marijuana and sinsemilla Cannabis, respectively, where the highest THC concentrations measured were 52.9 and 47.0%, respectively. Concentration of THC in marijuana has lately increased significantly due to the progress in breeding, the tendency to cultivate under indoor conditions, and the worldwide access to and exchange of seeds originating from high-THC cultivars via the Internet. However, this is not the case when it comes to CBD, it is rare to find such high numbers. Any CBD content level that is 4% or higher is considered a high CBD strain. Strains with up 18% CBD have emerged in the last several years, but commercially available high CBD strains contain on average between 8-12% CBD.
The Cannabis sativa plant and its products consist of many chemicals. Some of the 483+ compounds identified are unique to Cannabis, for example, more than 60 cannabinoids, whereas the terpenes, with about 140 members forming the most abundant class. So far, 66 cannabinoids have been identified, and they are divided into 10 subclasses: 1) Cannabigerol class: cannabigerolic acid (CBGA)—antibiotic; cannabigerolic acid monomethylether (CBGAM); cannabigerol (CBG)—antibiotic, antifungal, anti-inflammatory, relaxant (possibly inhibits the uptake of GABA); cannabigerol monomethylether (CBGM); cannabigerovarinic acid (CBGVA); cannabigerovarin (CBGV); 2) Cannabichromene class: cannabichromenic acid (CBCA); cannabichromene (CBC)—anti-inflammatory, antibiotic, antifungal, analgesic; cannabichromevarinic acid (CBCVA); cannabichromevarin (CBCV); 3) Cannabidiol class: cannabidiolic acid (CBDA)—antibiotic; cannabidiol (CBD)—anxiolytic, antipsychotic, analgesic, anti-inflammatory, antioxidant, antispasmodic; cannabidiol monomethylether (CBDM); cannabidiol-C4 (CBD-C4); cannabidivarinic acid (CBDVA); cannabidivarin (CBDV); cannabidiorcol (CBD-C1); 4) Delta-9-tetrahydrocannabinol class: delta-9-tetrahydrocannabinolic acid A (THCA-A), delta-9-tetrahydrocannabinolic acid B (THCA-B), delta-9-tetrahydrocannabinol (THC)—euphoric analgesic, anti-inflammatory, antioxidant, antiemetic; delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4), delta-9-tetrahydrocannabinol-C4 (THC-C4); delta-9-tetrahydrocannabivarinic acid (THCVA); delta-9-tetrahydrocannabivarin (THCV)—analgesic, euphoriant; delta-9-tetrahydrocannabiorcolic acid (THCA-C1); delta-9-tetrahydrocannabiorcol (THC-C1); delta-7-cis-iso-tetrahydrocannabivarin; 5) Delta-8-tetrahydrocannabinol class: delta-8-tetrahydrocannabinolic acid (Δ8-THCA); delta-8-tetrahydrocannabinol (Δ8-THC)—similar to THC (less potent); 6) Cannabicyclol class: cannabicyclic acid (CBLA); cannabicyclol (CBL); cannabicyclovarin (CBLV); 7) Cannabielsoin class: cannabielsoic acid A (CBEA-A); cannabielsoic acid B (CBEA-B); cannabielsoin (CBE); cannabinol (CBN)—sedative, antibiotic, anticonvulsant, anti-inflammatory; cannabinol methylether (CBNM); cannabinol-C4 (CBN-C4); cannabivarin (CBV); cannabinol-C2 (CBN-C2); cannabiorcol (CBN-C1); cannabinadiol (CBND); cannabinodivarin (CBVD); 8) Cannabitriol class: cannabitriol (CBT); 10-ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol; 8,9-dihydroxy-delta-6a-tetrahydrocannabinol; cannabitriolvarin (CBTV); ethoxy-cannabitriolvarin (CBTVE); 8) Miscellaneous cannabinoids class: dehydrocannabifuran (DCBF); cannabifuran (CBF); cannabichromanon (CBCN); cannabicitran (CBT); 10-oxy-delta-6a-tetrahydrocannabinol (OTHC); delta-9-cis-tetrahydrocannabinol (cis-THC); 3,4,5,6-tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol (OH-iso-HHCV); cannabiripsol (CBR); trihydroxy-delta-9-tetrahydrocannabinol (triOH-THC).
The typical scent of Cannabis results from about 140 different terpenoids—isoprene units (C5H8) form monoterpenoids (C10 skeleton), sesquiterpenoids (C15), diterpenoids (C20), and triterpenoids (C30). Terpenoids may be acyclic, monocyclic, or polycyclic hydrocarbons with substitution patterns including alcohols, ethers, aldehydes, ketones, and esters.
The essential oil (volatile oil) from Cannabis sativa can easily be obtained by steam distillation, vaporization, or other extraction methods. As already mentioned, the yield depends on the plant type, pollination, sex, age, part of the plant, cultivation (indoor, outdoor etc.), harvest time, drying, storage, etc. For example, fresh buds from an Afghani variety yielded 0.29% essential oil; where drying and storage reduced the content from 0.29% after 1 week and 3 months to 0.20% and 0.13%, respectively. Monoterpenes showed a significantly greater loss than sesquiterpenes, but none of the major components completely disappeared in the drying process. About 1.3 L of essential oil per ton, resulted from freshly harvested outdoor-grown Cannabis sativa, corresponding to about 10 L/ha.
The yield of nonpollinated (sinsemilla) plant at 18 L/ha was more than twofold compared with pollinated (8 L/ha). Sixty-eight components were detected by GC and GC/mass spectrometry in fresh bud oil distilled from high-potency, indoor-grown Cannabis sativa. Further, 57 constituents have been identified, where 92% were monoterpenes, 7% sesquiterpenes, and approximately 1% were other compounds. The dominating monoterpenes were myrcene (67%) and limonene (16%). In the essential oil from outdoor-grown Cannabis sativa, the monoterpene concentration varied between 47.9 and 92.1% of the total terpenoid content, and the sesquiterpenes ranged from 5.2 to 48.6%. The most abundant monoterpene was E-myrcene, followed by trans-caryophyllene, D-pinene, trans-ocimene, and D-terpinolene. "Drug-type" Cannabis plant generally contained less caryophyllene oxide than "fiber-type," but even in "drug-type," the THC content of the essential oil was not more than 0.08%.
The 50 known hydrocarbons detected in Cannabis sativa consist of n-alkanes ranging from C9 to C39, 2-methyl-, 3-methyl-, and some dimethyl alkanes. Cannabis sativa L. is one of the rare psychotropic plants in which the central nervous system activity is not linked to particular alkaloids. However, two spermidine-type alkaloids (cannabisativine and anhydrocannabisativine) have been identified among more than 70 nitrogen-containing constituents, and five lignanamide derivatives have been isolated, including cannabisin A, B, C, and D. Besides, twelve simple amines, including piperidine, hordenine, methylamine, ethylamine, and pyrrolidine, are present in Cannabies; three proteins: edestin, zeatin, and zeatinnucleoside; six enzymes: edestinase, glucosidase, polyphenoloxydase, peptidase, peroxidase, and adenosine-5-phosphatase; and 18 amino acids that are of a common structure for plants.
Thirteen monosacharides (fructose, galactose, arabinose, glucose, mannose, rhamnose, etc.), two disaccharides (sucrose, maltose), and five polysaccharides (raffinose, cellulose, hemicellulose, pectin, xylan) have been identified so far. In addition, 12 sugar alcohols and cyclitols (mannitol, sorbitol, glycerol, inositol, quebrachitol, etc.) and two amino sugars (galactosamine, glucosamine) were found; as well as twenty-three commonly occurring flavonoids have been identified in Cannabis plant, existing mainly as C-/O- and O-glycosides of the flavon- and flavonol-type aglycones apigenin, luteolin, quercetin, and kaempferol. Thirty-four noncannabinoid phenols are known to be present in Cannabis plant: nine with spiro-indan-type structure (e.g., cannabispiran, isocannabispiran), nine dihydrostilbenes (e.g., cannabistilbene I, -II), three dihydrophenanthrenes (e.g., cannithrene-1, -2), and six phenols, phenol methylethers, and phenolic glycosides. Seven alcohols (e.g., methanol, ethanol, 1-octene-3-ol), 12 aldehydes (e.g., acetaldehyde, isobutyraldehyde, pentanal), 13 ketones (e.g., acetone, heptanone-2, 2-methyl-2-heptene-6-one), and 21 acids (e.g., arabinic acid, azealic acid, gluconic acid) have also been identified. Cannabis also contains phytosterols: campesterol, ergosterol, E-sitosterol, and stigmasterol, as well as vitamin K, which is the only vitamin found in Cannabis, whereas carotene and xanthophylls are reported pigments; and 18 elements were detected as well (e.g., Na, K, Ca, Mg, Fe, Cu, Mn, Zn, Hg).
Prior to the late 1990's, nearly all chemical studies of Kratom activity focused on mitragynine with the assumption that mitragynine was the main active alkaloid in Mitragyna speciosa. With 7-hydroxymitragynine now clearly identified as the principal psychoactive alkaloid in Kratom, many elements of these studies must be revised. The variety of alkaloids discovered in diverse Kratom samples to date, still calls for further studies and experimentation, investigating their specific activity, effects and potential applications. Through its makeup and tradition of use, it is clear Mitragyna speciosa is much more than a simple opioid-like narcotic and mild stimulant. Many of the secondary chemicals found in Mitragyna speciosa are present in small yet appreciable quantities, and their synergetic role and activity in the general pharmacology of Mitragyna speciosa is not yet fully understood. Nonetheless, Kratom provides an opportunity for researchers and pharmaceutical industry to develop new medicines that are potentially safer and more effective. And even more so, when certain Kratom alkaloids are combined with cannabis the pharmacological effect is amplified.
One embodiment of this invention proposes several potentially more safe and effective compounds of Mitragyna speciosa and Cannabis sativa alkaloids that are extracted, purified and combined to provide a pharmaceutical-grade compound for treatment of pain and other symptoms associated with diseases, disorders, medical conditions, and having other applications that are contemplated by this invention. Another embodiment of this invention provides an effective drug delivery system that allows timed release of the active ingredients necessary to achieve high efficacy with minimum side effects. Another embodiment of this invention describes methodologies for effective treatment of patients having the medical and other conditions contemplated by this invention.
As already mentioned, Mitragyna speciosa contains certain alkaloids, such as the 7-hydroxymitragynine and mitragynine that reportedly exhibit more potent analgesic actions than that of morphine and having reduced side effects, most importantly—significantly reduced respiratory depression and lesser addiction liability due to the presence of kappa-opioid receptor antagonists (Kruegel, et al., 2016), relatively analogous in mechanism of action to the drug buprenorphine. The multiple receptor targets are beneficial in the treatment of pain, and especially complex pain syndromes, such as the neuropathic pain. But unlike the buprenorphine, in some embodiments, when certain Kratom alkaloids are combined with cannabinoids, such as THC, the proposed compound provides vasodilating, antihypertensive, muscle relaxing, immune-stimulating, anti-inflammatory, antipyretic, anti-arrhythmic, antitussive, and mild adrenergic effects, where the mild stimulating effect of mitragynine (in low doses) and THC helps to reduce drowsiness associated with higher doses of opioids or opioid-like substances.
Despite the addiction and other concerns, morphine and its derivatives remain to be the primary medicines to treat severe pain. Cannabis-based medicines are also now being offered for treatment of muscle spasticity in patients with MS. For example, Sativex—a CB extract oral spray containing THC and CBD—is known to relieve many MS symptoms. Sativex and other CB-based medicines can be used to treat neuropathic pain, nausea associated with cancer chemotherapy, as well as stimulate appetite in HIV patients. Nevertheless, morphine remains to be the indispensable analgesic for improving patients' quality of life (QOL) in the cases of cancer and other illnesses causing severe pain. However, morphine has problems of, for example, having low bioavailability and causing various side effects, such as formation of analgesic resistance and physical or psychological dependence due to continued use, nausea and vomiting, constipation, sleepiness, and most importantly respiratory depression.
With that said, the advent of a potent and more safe analgesic, serving as a substitute for morphine, has long been needed. In search of such analgesics, investigations of synthetic analogs were performed with chemical modification of a morphine molecule, starting the 1920s and until the present day. Many compounds were synthesized since then and evaluated. However, there are not many examples of an opioid analgesic substance that is as effective as morphine or its synthetic analogs but safer than them. Current research has focused on an analgesic action of morphine and efforts are currently made to elucidate a molecular mechanism of analgesia on the basis of, for example, classification of opioid receptors (δ-, μ- and κ-receptors) and determination of amino acid sequences thereof. However, there are complicated interactions among those three kinds of receptors, and a logical methodology for separating an analgesic property from side effects, such as a narcotic property, has not been established to date.
Several other opioid pharmaceutical products exist which provide analgesic relief but at the same time may have fewer side effects and lesser addiction liability. For example, buprenorphine, sold under the brand name Subutex, among others, is an opioid used to treat opioid addiction, acute pain, and chronic pain. It comes in injectable, transdermal, sublingual, and other dosage forms. Maximum pain relief is generally achieved within an hour with effects lasting up to 24 hours. Buprenorphine affects different types of opioid receptors in different ways. In simplified terms, buprenorphine can essentially be thought of as a non-selective, mixed agonist—antagonist opioid receptor modulator, acting as a weak partial agonist of the MOR, an antagonist of the KOR, an antagonist of the DOR, and a relatively low-affinity, very weak partial agonist of the ORL-1. Full analgesic efficacy of buprenorphine requires both exon 11 and exon 1-associated μ-opioid receptor splice variants. Side effects may include respiratory depression, sleepiness, adrenal insufficiency, QT prolongation, low blood pressure, allergic reactions, and opioid addiction. Among those with a history of seizures, there is a risk of further seizures. Opioid withdrawal following stopping is generally mild.
Tramadol is another opioid pharmaceutical product that provides analgesic relief but has fewer side effects and reduced addiction liability. Tramadol is sold under the brand name Ultram, among others, and it is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually occurs within an hour. It is often combined with paracetamol (acetaminophen) as this is known to improve the efficacy of tramadol in relieving pain. It works by binding to the μ-opioid receptor and as a serotonin-norepinephrine reuptake inhibitor (SNRT). Tramadol is in the benzenoid class, and in the body, it is converted to desmetramadol, which is a more potent opioid. Common side effects include: constipation, itchiness and nausea. Serious side effects may include seizures, increased risk of serotonin syndrome, decreased alertness, and drug addiction. Long-term use of high doses of tramadol will cause physical dependence and withdrawal syndrome. Tramadol withdrawal typically lasts longer than that of codeine and other weak opioids (seven days or more of acute withdrawal symptoms). However, according to a 2014 report by the World Health Organizations Expert Committee on Drug Dependence, evidence of tramadol physical dependence was considered minimal. Consequently, tramadol is generally considered to be a drug with low potential for dependence.
There are a number of opioid receptor-modulating investigational analgesics that are currently under development for clinical use. For example: Axelopran/oxycodone—combination of a centrally active μ-opioid receptor agonist and a peripherally selective μ-, κ-, and δ-opioid receptor antagonist; Cebranopadol (GRT-6005)—non-selective μ-opioid receptor, nociceptin receptor, and δ-opioid receptor full agonist and κ-opioid receptor partial agonist; Desmetramadol (O-desmethyltramadol; Omnitram)—μ-opioid receptor agonist, norepinephrine reuptake inhibitor (NRI), and 5-HT2C receptor antagonist; Difelikefalin (CR845, FE-202845)—peripherally selective κ-opioid receptor agonist. Lexanopadol (GRT-6006, GRT13106G)—non-selective opioid receptor agonist; Nalbuphine sebacate (dinaphine, sebacoyl dinalbuphine ester; LT-1001)—long-lasting prodrug of nalbuphine, μ- and κ-opioid receptor partial agonist; NKTR-181-selective μ-opioid receptor full agonist that slowly enters the brain; Oliceridine (TRV130)—μ-opioid receptor biased agonist; Oxycodone/naltrexone—combination of a μ-opioid receptor agonist and a μ- and κ-opioid receptor antagonist, and others.
A study was undertaken to determine the analgesic and anti-inflammatory activity of various CBs and CB pre-cursors. Oral administration of CBD was found to be the most effective at inhibition of phenyl-p-benzoquinone-induced writhing in mice. It was noted that with the exception of CBN and delta 1-THC, the cannabinoids and olivetol (their biosynthetic precursor) demonstrated activity in the PBQ test exhibiting their maximal effect at doses of about 100 micrograms/kg. Delta 1-THC only became maximally effective in doses of 10 mg/kg (this higher dose corresponded to that which induced catalepsy and is indicative of a central action). CNB demonstrated little activity and even at doses higher than 10 mg/kg could only produce a 40% inhibition of PBQ-induced writhing. And as mentioned earlier, CBD was the most effective of the cannabinoids at doses of 100 micrograms/kg. Doses of cannabinoids that were effective in the analgesic test orally were used topically to antagonize TPA-induced erythema of skin. Formukong et al. (1988) conclude that delta 1-THC and CBN were the least effective in this test, suggesting a structural relationship between analgesic activity and anti-inflammatory activity among the cannabinoids related to their peripheral actions and separate from the central effects of delta 1-THC.
Thus, considering the many therapeutic effects, and specifically the analgesic effect of compounds containing CBs, particularly CBD and (−)-Δ9-trans-THC, there is a continuing need for improving existing CB-containing products as well as a need for new products and delivery systems containing CBs, especially in the pharmaceutical field.
Recent methods have also sought to find new ways to deliver CBs to a patient including those which bypass the stomach and the associated first pass effect of the liver which can remove up to 90% of the active ingested dose and avoid the patient having to inhale unhealthy tars and associated carcinogens into their lungs. Such dosage forms include administering the CBs to the sublingual or buccal mucosae, inhalation of a CB vapor by vaporization or nebulization, enemas or solid dosage forms such as gels, capsules, tablets, pastilles and lozenges.
To attain the required purity of isolated CBs and Kratom alkaloids, up to at least 97% by total weight, consistent ratio of CBs and Kratom alkaloids in the formulation, attain pharmaceutical-grade stability of active CBs and Kratom alkaloids, effective and consistent delivery system for treating multiple conditions, as well as therapeutically-effective treatment methods—requires a know-how that is proposed in this document.
As already mentioned, one objective of this invention is to provide a compound that has a potent analgesic action, which may serve as a substitute for morphine—a pharmaceutical composition and a treatment method. The novel compositions and treatment methods, with several variations, some of which are exemplified herein, exhibit a potent analgesic, anti-inflammatory, and muscle relaxing actions, and other actions contemplated by this invention. The proposed invention has relied on new scientific findings, experiments and anecdotal evidence obtained through this research. Inventors believe that this invention is unique and different from the existing art related to Mitragyna speciosa-based and Cannabis sativa-based compounds, processes, and methods. Some of the existing art is briefly outlined below.
The U.S. Pat. No. 7,968,594 referenced herein, discloses the invention that relates to treatment of cancer related pain and constipation. The subject in need is administered a combination of CBD and delta-9-THC in a predefined ratio by weight of approximately 1:1 of CBD to THC (U.S. Pat. No. 7,968,594, 2005).
The U.S. patent application Ser. No. 15/032,070 referenced herein, discloses a formula of compound containing 7-hydroxymitragynine that has an analgesic effect and high metabolic stability. The invention further provides the following: an analgesic obtained from the compound, a salt thereof, or solvates of the compound and salt; a pharmaceutical composition containing the compound, a salt thereof, or solvates of the compound and salt; an analgesic treatment method using the compound, a salt thereof, or solvates of the compound and salt; and a use of the compound, a salt thereof, or solvates of the compound and salt, in the production of an analgesic composition (U.S. Pat. No. 15,032,070, 2014).
The U.S. Pat. Application No. 20110245287 referenced herein, discloses hybrid opioid compounds, mixed opioid salts, compositions comprising the hybrid opioid compounds and mixed opioid salts, and methods of use thereof that among other substances may contain Kratom alkaloids. More particularly, in one aspect the hybrid opioid compound includes at least two opioid compounds that are covalently bonded to a linker moiety. In another aspect, the hybrid opioid compound relates to mixed opioid salts comprising at least two different opioid compounds or an opioid compound and a different active agent. Also disclosed are pharmaceutical compositions, as well as methods of treating pain in humans using the hybrid compounds and mixed opioid salts (U.S. Pat. No. 20,110,245,287, 2011).
The U.S. Pat. Ser. No. 13/024,298 referenced herein, discloses a compound that may contain Kratom alkaloids, being a pharmaceutically acceptable salt or ester thereof, and a method of treating a subject afflicted with pain, a depressive disorder, a mood disorder or an anxiety disorder by administering the compound to the subject (U.S. Pat. No. 13,024,298, 2011).
The U.S. Pat. Application No. 20060135599 referenced herein, discloses the invention that relates to the use of one or more CBs in the treatment of neuropathic or chronic pain. A method of treating brachial plexus avulsion in a human patient comprising administering to a patient in need thereof effective amount one or more CBs (U.S. Pat. No. 20,060,135,599, 2003).

This patent is subject to a terminal disclaimer.

Compound and method for treating spasms, inflammation and pain


Mainly provided is a technique for directly identifying the genotype at locus Rf17 based on the specific base sequence data thereof. Also provided is a technique for artificially constructing a fertility-restored line. A method of restoring the fertility of CW-type cytoplasmic male sterile rice by inhibiting or reducing the expression of a gene comprising the base sequence represented by SEQ ID NO:2 in the above-described rice, and a method for determining the presence or absence of gene Rf17, which is a fertility restorer gene for CW-type cytoplasmic male sterility, comprising identifying a single nucleotide polymorphism (SNP) in the base at the 1812 position of the base sequence represented by SEQ ID NO:1 in the rice to be examined.

A method for breeding a first filial generation is also called a method for breeding of a hybrid-variety. This method is utilized in variety-breeding since a variety having excellent traits inherited from its parents and showing heterosis hybrid vigour can be bred by means of this method. In order to economically harvest F1 hybrid seeds in large quantity, a three-line method utilizing cytoplasmic male sterility is adopted in the case of seed-harvesting of a hybrid variety of rice. The three-line method refers to a method that utilizes a sterile line having male sterility, a fertility restorer line, and a maintainer line having the same nuclear genes as the sterile line but not having sterile cytoplasm. According to this three-line method, (1) a hybrid seed can be harvested by crossing the sterile line with pollen of the restorer line, while (2) the sterile line can be maintained by crossing the sterile line with the pollen of the maintainer line.
BT-type male sterile cytoplasm and WA-type male sterile cytoplasm have been used worldwide in order to breed the hybrid variety with the three-line method. On the other hand, CW-type male sterile cytoplasm has been hardly utilized since the structure and function of a fertility restorer gene Rf17 (Non Patent Document 1) have not been clarified. However, since there may be a risk of variety collapse due to limit in the genetic resources provided by the male sterile cytoplasm that have been used until now, utilization and development of novel male sterile cytoplasm are now desired.
In the prior arts, it has been necessary to breed plant body (F1) from a hybrid seed obtained by test cross, and then to make the F1 self-cross and to investigate frequency of appearance of a individual plant having seed-development rate over a certain level (for example, 90% or more) for the estimation of a genotype of Rf17 locus in the plant. It has not been possible to determine said genotype by means of DNA markers.    Non Patent Document 1: Sota Fujii and Kinya Toriyama (2005) Molecular mapping of the fertility restorer gene for ms-CW-type cytoplasmic male sterility of rice. Theor. Appl. Genet. 111:696-701

Fertility restorer gene and fertility restoration method for CW-type male sterile cytoplasm of rice


An and apparatus for the extermination of parasites including fleas and ticks characterized by hermetically enclosing the body of a host animal within a chamber and circulating an atoxic vapor through the chamber as a treatment repeated until the parasite count is reduced, and an apparatus comprised of a hermetic chamber with air recirculation of a vaporized liquid lethal to the parasites.

Heretofore,the known processes for the extermination of animal parasites such as fleas (CTENOCEPHALIDES CANNIS O FELIS) or ticks (DERMACENTOR VARIBILIS, IXODES) are based upon the use of toxic chemical agents applied directly to the skin or epidermis of the host animal. This is customarily done by soap bath, spraying or powdering with toxic antiparasitic substances of varied compositions and strengths. That is, toxic chemicals are used in bathing (dilluted in water) or sprayed or dusted in powder form, all of which does not permit frequent application and with the likelihood of animal intoxication by assmimilation through licking and swallowing and by absorbtion through the skin. And, the problem is critical with young or old and weakened animals. In the practice of prior art extermination methods, the parasite will leave the host animal only to return when the antiparasitic effect has decreased so as to be ineffective. Accordingly, it is an object of this invention to provide a method and apparatus that ensures extermination and riddance of the parasites from the host animal, and all without adverse effects.
The prior art parasite eradication methods that involve bathing in antiparasitic solutions require drying after bathing, it being an object of this invention to eliminate bathing and to avoid the necessity of drying. With the present invention a parasiticide is applied in vapor form, a substantially dry vapor.
The method of parasite extermination as it is disclosed herein involves the environment of the host animal involved, and all of which is implemented by the particular apparatus disclosed. The involved environment includes the habitat of the host animal, for example the dwelling and surrounding grounds where a pet animal is kept. It is the life cycle of the parasite that is of concern, it being an object of this invention to break its reproduction cycle which is characteristically PARASITE-LARVA-PUPA-PARASITE. It is known that parasites such as fleas and ticks inhabit the grounds, the vegetation and the furnishings of the pet animal habitat, it being an object of this invention to systematically interrupt the parasite life cycle when hosted by the animal upon which it feeds and dwells during copulation. To this end, this method involves progressive extermination that interrupts the life cycle of the parasite while it is dwelling on the host animal. With this invention, there is a direct attack on the parasite where it spends long periods of time feeding on the host animal. This feeding period is also the copulation period. Therefore, it is an object of this invention to provide a method that progressively exterminates parasites on the host animal during the feeding period of the parasite life cycle. It is also an object to provide a dry process by subjecting the host animal to dry atoxic vapors that effectively kill the parasite in situs.
The vapor method of parasite extermination herein disclosed is performed without fumigating the habitat of the host animal, and the atoxic vapor employed is, preferably a saturated vapor of trichloroethylene (C.sub.2 HCl.sub.3) in a closed circuit. Therefore, it is an object to provide an apparatus that performs this process, subjecting the host animal's body to said vapor while permitting the animal from breathing the atoxic vapor. In practicing this invention, there is a vaporizing means and a vapor pump means in a closed circuit through a bag that is closed around the body of the animal to form a hermetic chamber. The subjection time period is a factor to be regulated in treatment of the animal. Accordingly, it is an object to provide a timer means by which subjection to the atoxic vapor is controlled. In practice, the saturation capability of the atoxic vapor is regulated by the aforesaid vaporizing means. It is also an object to provide relief means to exhaust the used vapors when the time period of application is over.
A feature of this invention is the use of a vapor that is atoxic for the host pet and for the human keeper but deadly for the parasite, and which can be applied more frequently than conventional highly toxic chemicals. In practice, the atoxic vapor of the present invention is applied daily for the progressive parasitic extermination in numbers of parasites that exceeds their reproductive capacity, by interrupting their normal life cycle. In other words, the practice of this method and use of this apparatus enforces a systematic and continued reduction in the parasite colony whereby a definitive exterminaton thereof is reached. Effectiveness of this method and apparatus is detected by simple observation and number count of the fleas or ticks that drop off of the host animal at the conclusion of each treatment. In practice, a treatment is applied to the host animal each day. For example, a fifteen minute treatment is given to a severely infected large animal, and a lesser treatment for lesser infestations and to smaller animals, all as circumstances require. It is normal to continue treatments over a three month period of time, as is documented by the graph record of FIG. 3 of the drawings.

Apparatus for exterminating animal parasites in situs


A fluid injection system is disclosed The system is adapted to employ first and second injectors which may sequentially, or simultaneously, inject first and second fluids into a patient via a catheter. The first and second injectors may be power actuated. The actuation of the injectors may be controlled via a controller of the system. The user may be provided with an operator interface module to enable the control of the system to be affected during operation. A separate waste line may be provided to drain the system effectively and efficiently. A pressure sensor may be provided proximate the catheter to reduce pressure signal wave dampening and fluid waste.

During medical procedures, fluids of different types need to be injected into human tissue and vascular structures. One such procedure is known as angiography. Angiography is a procedure used in the detection and treatment of abnormalities or restrictions in blood vessels, heart chambers and heart valves. During angiography, a radiographic image of a vascular structure is obtained by injecting radiographic contrast material through a catheter into such a vessel, heart chamber, or heart valve. X-rays are then passed through the region of the body in which the contrast material was injected. The X-rays are absorbed by the contrast material causing a radiographic outline or image of the blood vessel containing the contrast material. The x-ray images of the blood vessels filled with the contrast material are usually recorded on the film or videotape and displayed on a fluoroscope monitor.
The injection of the contrast or other fluids can be performed either manually or automatically. In both procedures, a catheter is inserted into a vessel, which in turn is connected to a fluid line leading to a manifold and in turn to an injector or syringe. The plunger of the syringe is then either manually or automatically depressed to inject fluid through the fluid line, the catheter, and into the patient.
In certain situations, it is necessary to dilute the concentration of contrast being injected into a patient. For example, in those patients with renal insufficiency incapable of processing concentrated contrast through their system, or in cases where a large amount of contrast is used, such as complicated coronary interventions (PTCA) or peripheral (PTA) cases with runoffs, direct injections of contrasts, are not possible. Accordingly, it is necessary to mix the contrasts and saline prior to injection to arrive at the appropriate dilution percentage. Such processes are necessarily slow and are currently difficult to achieve.
In addition, during injections, it is desirable for the physician or technician to be provided with feedback as to the pressure within the vessel. This is commonly provided by way of a pressure transducer mounted relatively close to the injection apparatus. However, since a relatively long expanse of conduit exists between the catheter and the injector, typically on the order of four feet or more, pressure waveforms must be transmitted through the fluid contained within that conduit all the way from the body of the patient, through the catheter, and back to the pressure transducer. Due to such distances, the waveforms may be substantially dampened by the time they reach the transducer thereby providing an inaccurate or poor signal for display to the physician.
Furthermore, after an injection is made, and it is desired to remove the contrast from the injection system or change the fluid being injected, it is currently necessary to evacuate or aspirate the entire injection line. It would be advantageous if the waste could be quickly removed, while at the same time limiting the total volume of waste fluid encountered by the system.

Fluid management system for coronary intervention


According to one embodiment, a color erasing apparatus includes a color erasing section which erases a color of an image formed with an erasable color material on a sheet conveyed at first speed, a reading section which reads an image on the surface of the sheet conveyed at second speed higher than the first speed, a first conveying section, and a second conveying section. The first conveying section includes a first conveying roller arranged downstream in a sheet conveying direction of the color erasing section and conveys the sheet at the first speed. The second conveying section includes a second conveying roller arranged upstream in the sheet conveying direction of the reading section and in a position where the second conveying roller nips the conveyed sheet simultaneously with the first conveying roller. The second conveying section conveys the sheet to the reading section at the second speed.

There is a color erasing apparatus that erases a color of an image on a sheet subjected to image formation. The color erasing apparatus includes a color erasing section configured to apply heating processing to a sheet on which an image is formed with an erasable color material and erase a color of the image (the color material) on the sheet. The color erasing apparatus includes a reading section configured to read the image on the surface of the sheet. The color erasing apparatus determines, on the basis of the image read by the reading section, whether the sheet to be subjected to color erasing processing is color-erasable or whether the color erasing processing is successful.
The color erasing section of the color erasing apparatus erases a color of an image on the sheet by heating a conveyed sheet. In order for the color erasing section to surely perform the color erasing, the sheet conveyed through the color erasing section needs to be conveyed at appropriate conveying speed. On the other hand, in order for the reading section to surely read the image on the sheet, the sheet needs to be conveyed through the reading section at appropriate conveying speed. The conveying speed of the sheet passing through the color erasing section during the color erasing processing (hereinafter referred to as color erasing speed) and the conveying speed of the sheet passing through the reading section during reading processing or sorting processing (hereinafter referred to as reading speed) respectively depend on the performance of the color erasing section and the performance of the reading section. For example, the reading section could read the image on the sheet at the reading speed higher than the color erasing speed of the color erasing section. However, when a reduction in size of a conveying path is examined, the color erasing apparatus needs to convey the sheet to the reading section at the color erasing speed lower than the reading speed. In other words, the conveying speed of the sheet in the color erasing apparatus is controlled according to the lower conveying speed. Therefore, the performance of processing of the entire color erasing apparatus falls.
Therefore, there is a demand for a color erasing apparatus that can realize a reduction in size and improve processing performance.


An example image sensor system includes an image sensor having a first terminal and a host controller coupled to the first terminal. Logic is included in the image sensor system, that when executed transfers analog image data from the image sensor to the host controller through the first terminal of the image sensor and also transfers one or more digital control signals between the image sensor and the host controller through the same first terminal.

Image sensors are widely used in digital cameras, cellular phones, security cameras, as well as, medical, automobile, and other applications. One type of image sensor is known as a complementary metal-oxide-semiconductor (CMOS) image sensor. Multiple CMOS image sensors are typically formed on a semiconductor wafer that is then separated into several dies, each die including at least one image sensor. The semiconductor die is then assembled into a semiconductor package. The semiconductor package provides protection and includes pins, leads, or other chip-scale interfaces, which are then used to connect with circuits that are external to the package. The semiconductor die may be formed having a plurality of bonding pads on the surface of the die for internally connecting (e.g., wire bonding) the image sensor to the pins of the semiconductor package.
The technology used to manufacture image sensors, and in particular, CMOS image sensors, has continued to advance at great pace. For example, the demands of higher resolution and lower power consumption have encouraged the further miniaturization and integration of these image sensors. One field of application in which size and image quality is particularly important is medical applications (e.g., endoscopes). For medical applications the semiconductor package must typically be very small. For example, the need for the endoscopes to be smaller so as to access various small spaces inside the body may be limited by the size of the image sensors mounted on the endoscopes. This is due to the size and pitch requirements of the bonding pads which limit the overall size of the image sensors. The relative percentage of the die area taken up by bonding pads increases as the size of the typical image sensor decreases. Therefore, as the image sensors decrease in size, it becomes ever more difficult to accommodate the number of bonding pads typically included on the semiconductor die.

Shared terminal of an image sensor system for transferring image data and control signals


A bistable solenoid valve device for a fluid system is provided. The bistable solenoid valve device comprises a bistable solenoid valve. The bistable solenoid valve comprises a permanent magnet. The bistable solenoid valve further comprises an armature displaceable between a first armature position and a second armature position. The bistable solenoid valve further comprises a first switching coil for energization for a displacement of the armature into the first armature position. The bistable solenoid valve further comprises a second switching coil for energization for a displacement of the armature into the second armature position. The bistable solenoid valve further comprises an evaluation device adapted to measure an induced coil voltage, an induced coil current, or both the induced coil voltage and the induced coil current, at one or more of the non-energized switching coils. The evaluation device is further adapted to assess a switching behavior of the armature.

Bistable solenoid valves are used in a fluid system, for example a parking brake of a compressed-air system of a commercial vehicle, and make possible displacement between two valve positions, which can both be held in the currentless state of the solenoid valve. An end stage is provided for actuation, a control device is provided for actuating the bistable solenoid valve and, where necessary, further components are provided. The solenoid valve and further components therefore form the solenoid valve device.
The bistable solenoid valve generally has a permanent magnet and an armature that can be displaced relative to the permanent magnet, which in each case forms a magnetic circuit or permanent magnetic circuit on both sides, which holds the armature in the respective armature position. To this end, in particular, a yoke can be provided, which forms the magnetic circuit together with a first and second core, the armature, and the permanent magnet. The armature bears in its armature positions in each case against one of the two iron cores directly or without an air gap, with the result that a high magnetic flux density (a strong magnetic field) is formed. With respect to the other core, an air gap is formed, which weakens the other iron core.
The switchover processes between the armature positions are performed by a first and second switching coil, which may be formed, for example, so as to be stationary and in the yoke, but also, for example, as armature coils on the movable armature. For the switchover processes, a voltage pulse is given by employing a voltage ramp or as a square-wave signal to the respective switching coil so that a first or second electromagnetic field of the permanent magnet formation is superposed and displaces the armature into the respective other armature position, wherein the respective other switching coil remains with no current.
Beyond the switching processes, that is to say without applying a switching current, the armature therefore generally remains in the respective armature position thereof. On account, for example, of a mechanical shock, however, the armature can be displaced, in principle, when the magnetic holding force is overpowered and the armature is displaced into the other armature position, which is in turn held automatically.
In principle, reliable displacement processes are possible owing to the current pulses. However, on account of soiling, such as abrasion and wear, for example, accumulation or friction on the armature can arise, which threatens the reliable armature displacement. Sudden mechanical tremors occurring during the switching process can also threaten the mechanical displacement of the armature.
The disclosure is based on the object of providing a solenoid valve device and a method for monitoring same that ensure reliable operation.

Bistable solenoid valve device, and method for monitoring it


Each of two or more base stations notifies a communication controller of information on a first frequency band that the base station uses for radio communication. Based on the information on the first frequency bands acquired from the two or more base stations, the communication controller selects a second frequency band to be used by the two or more base stations to transmit the data with common content, and notifies the two or more base stations of information on the selected second frequency band. The two or more base stations transmit the data with common content based on the information on the second frequency band acquired from the communication controller.

Currently, radio communication systems such as mobile phone systems and wireless LAN (Local Area Networks) are widely in use. In addition, active discussions on next generation radio communication technology have been continued in order to further increase the speed and capacity of radio communication. For example, the 3GPP (3rd Generation Partnership Project), which is an international standards organization, has proposed a communication standard called LTE (Long Term Evolution) which allows data communication using a frequency band up to 20 MHz. Further, a communication standard called LTE-A (Long Term Evolution-Advanced) which allows data communication using up to five 20-MHz carriers (that is, 100 MHz) has been proposed as a next generation communication standard after the LTE standard.
In LTE and LTE-A, a data transmission scheme called MBSFN (Multimedia Broadcast multicast service Single Frequency Network) has been examined. In a radio communication system providing MBSFN transmission, one or more MBSFN areas each including multiple base stations are formed. The multiple base stations belonging to the same MBSFN area concurrently transmit data with the same content using the same frequency and the same modulation scheme. Data transmitted using MBSFN is sometimes referred to as the MBMS (Multimedia Broadcast Multicast Service) data. A mobile station combines MBMS data signals transmitted from multiple base stations, and demodulates and decodes the combined signal, which leads to an improvement in reception quality of the MBMS data.
As for LTE, a proposed technique is directed to a base station operating multiple cells, which acquires capability information from a mobile station in the case where frequency bands for data transmission and reception are different for different mobile stations, and determines a target cell of the mobile station based on the capability information (see, for example, International Publication Pamphlet No. WO 2008/023613). As for MBSFN, a technique has been proposed in which a serving cell selected from among cells in an MBSFN area and allocating radio resources to a mobile station notifies the mobile station of a frequency at which MBMS services are provided (see, for example, Japanese Laid-open Patent Publication No. 2009-182944). Another proposed MBSFN technique is directed to a control apparatus called MCE (Multi-cell/multicast Coordination Entity) which collects, via base stations, reports on quality of MBMS services evaluated by mobile stations and allocates radio resources based on the collected reports (see, for example, Japanese Laid-open Patent Publication No. 2009-246526).
In a radio communication system where multiple base stations may transmit data with the same content at the same frequency, a communication controller such as an MCE may select a frequency band used for transmitting the data with the same content and instruct the base stations to use the frequency band. On the other hand, the base stations may employ different frequency bandwidths, such as 10 MHz, 15 MHz, and 20 MHz, for their radio communication. Further, the base stations may operate at different center frequencies with the various frequency bands.
As a result, what remains an issue is how the communication controller selects the above-described frequency band used for transmitting the data with the same content. Assume, for example, that the communication controller selects a frequency band of 15 MHz for the transmission while there is a base station using a frequency band of only 10 MHz in the radio communication system. In this case, due to lack of radio resources, the base station is not able to transmit data for up to 5 MHz of the data with the same content. This may result in a decrease in reception quality at a radio receiver with respect to the data with the same content transmitted from two or more base stations.

Radio communication system, communication controller, and base station to transmit data with commom content with one or more other base stations


The invention relates to an electrochemical cell employing a resettable safety disconnect device operable by a nonresettable shape memory alloy element. The shape memory alloy element is preferably in the form of a twisted wire that is restrained in the normal operation of the cell and expands when the internal temperature exceeds a preselected value whereupon the shape memory alloy wire will exert force on a moveable element in the electrical circuit of the cell to break contact in the electrical circuit thereby rendering the cell inoperative. This device could also include an opposing spring member to restore the shape memory alloy element to its original shape upon cooling and thus restore electrical contact.

Under abuse conditions, high energy density electrochemical cells can leak or rupture which can cause damage to the device employing the cell or to people using the device. Examples of abuse conditions for a cell are abuse charging of the cell, forced discharging and external shorting. Such conditions cause the internal temperature of the cell to rise with a corresponding increase in pressure. Although such cells typically employ a venting mechanism wherein the electrolyte is expelled, the electrolyte can itself cause damage. Additionally, in cells which employ lithium as an anode material, if internal cell temperatures reach above 180.degree. C., the lithium can melt and result in a fire. Therefore, safety devices other than venting means which will disconnect the electrical circuit under abuse conditions are desirable. If the circuit can be disconnected, the rise in the cell's internal temperature as a result of the abuse conditions can be terminated.
One method of interrupting the flow of electrical current in the cell when the internal temperature of the cell rises is to employ a PolySwitch disc, tradename of Raychem Corp., in the cell. Such a disc is a resettable device which, when a threshold temperature is reached, will inhibit the flow of electrical current in the cell. When the temperature is lowered, the disc will allow the normal available current in the electrical circuit to be restored. Unfortunately, these devices are not suitable for all applications. For example, when the PolySwitch disc is designed to function at low temperatures, the disc may have a low breakdown voltage. Once the breakdown voltage is reached, the disc no longer inhibits the current flow. Therefore, if cells containing these discs are used in a multicell device, and abuse conditions are experienced, the breakdown voltage would be reached and the PolySwitch disc would not inhibit the current flow.
In Japanese Patent Publication No. 59-191273, a memory alloy terminal lead is employed in a lithium/thionyl chloride cell. When the internal temperature of the cell rises, the alloy lead wire folds down to break the electrical circuit. When the temperature falls, the lead wire returns to its original shape, restoring the contact. Forming a resettable disconnect member of this single lead wire is undesirable, because the member must be trained to fold down and back again, which requires great expense and time.
In Japanese Patent Publication No. 59-203376 a memory alloy terminal wire is employed in a lithium/thionyl chloride cell to connect the negative or positive electrode to a terminal on the cell housing. The memory alloy terminal wire operates such that as the cell is overheated, the wire will deflect from contact with the terminal and then return to contact the terminal when the temperature within the cell is decreased. The drawbacks of using this type of memory alloy terminal wire are the same as discussed above for Japanese Patent Publication No. 59-191273.
In Japanese Patent 63-72062 a shape memory alloy is placed between a terminal plate and a sealing body of a cell so that the sealing body is broken, thereby venting the cell, when the temperature of the cell exceeds the transformation temperature of the shape memory alloy.
U.S. Pat. No. 4,855,195 discloses electrochemical cells that employ a current collector-safety switch member comprised of a shape memory alloy in the electric circuit in the cell. The collector-safety switch member has a base portion and a plurality of legs extended therefrom and when the internal temperature of the cell rises, the legs of the collector-safety switch member are retracted to thereby disconnect the electrical circuit in the cell. These cells can also be comprised of a resettable thermal switch for inhibiting the flow of current in the cell at a temperature below the disconnect temperature of the current collector-safety switch member.
It is an object of the present invention to provide a safety circuit disconnect device for use in electrochemical cells.
It is another object of the present invention to provide a safety circuit disconnect device that can operate reliably when a cell employing the device is subjected to abuse conditions.
It is another object of the present invention to provide a resettable circuit disconnect device that employs a shape memory alloy twisted wire that is easy to produce and cost effective to assemble in the cell.
The foregoing and additional objects will become fully apparent from the following description and the accompanying drawings.

Electrochemical cell with circuit disconnect device


The invention comprises a polymeric demulsifier, methods of producing the demulsifier and methods of using the demulsifier. The demulsifier is the reaction product of at least one amine-containing group, and optionally a second amine-containing group which includes a tertiary amine group, with a diepoxy- or diglycidyl compound and an additional amine compound subsequently reacted with unreacted epoxy groups. This polymeric composition is subsequently reacted with N-alkylating agent containing compounds to produce novel demulsifiers useful to demulsify oil bearing formations.

Acid or other chemical based extraction of oil-bearing deposits can lead to emulsion formation within the extracted phase from the deposit. These emulsions can make it extremely difficult to remove the oil content from the deposit. "Demulsifiers" are used as one chemical means of destroying or "breaking" such unwanted emulsions. This process is defined in Hawley's 11th Chemical Dictionary, Van Nostrand Reinold Company Inc., N. Irving Sax, ed., (p. 352), 1987, as "Demulsification". Chemical means of breaking an emulsion include the addition of polyvalent ion sources or a material such as nonylphenol, to the emulsion. However, while such materials provide some measure of utility in demulsification, there is still an ongoing need for more effective and useful demulsifiers.

Demulsifiers, their preparation and use in oil bearing formations


Consolidating problem tickets for a multi-tiered application may comprise identifying a plurality of correlated virtual machines that are running one or more application components of the multi-tiered application. Problem reports may be identified that are generated by one or more of the plurality of correlated virtual machines and caused by a failure of a same single component of the multi-tiered application. The identified problem reports may be consolidated into a single ticket and placed into a ticket handling system.

In a data center with virtual environment, or in an environment with traditional physical servers, a system support or the like functionality monitors computing operations and generates tickets for events causing problems to be resolved by system administrators. Usually, every open problem ticket has to be handled by system administrators independently even if that problem was resolved in the meantime. Such individual handling costs time and effort.
In information technology (IT) management, enterprises are moving from physical servers toward virtualization, virtual machines (VMs) and cloud computing. Cloud computing generally refers to a model of service delivery for enabling convenient, on-demand network access to a shared pool of configurable computing resources (e.g. networks, network bandwidth, servers, processing, memory, storage, applications, virtual machines, and services). Cloud computing infrastructure may comprise of a network of interconnected nodes. Virtual environment provided, for example, via the cloud computing reduces cost through better resource utilization, standardization and simplified maintenance. In strategic outsourcing (SO) and cloud environment also, problem tickets are opened for events causing problems, to be resolved by system administrators.

Ticket consolidation for multi-tiered applications

INTERNATIONAL BUSINESS MACHINES CORPORATION


A decorative cake protector (1) for use on a cake (2) is disclosed in which the protection includes a shield (5) for protecting the cake from the residue or debris of at least one burning device (16,17), a support (16a,17a) for holding the burning device above the cake; and a decorative theme piece (10) mounted above the shield. The decorative cake protector preferably includes a stand (12) to space the shield from the cake surface.

This invention relates to a decorative cake protector. More particularly, this invention relates to a decorative cake protector for shielding a cake from the residue and byproducts of burning devices.
Persons skilled in the art of cake making will be familiar with the problems associated with burning the traditional and entertainment devices such and wick candles and sparklers on cakes such as birthday cakes. Wax tends to drip down from wax candles onto the icing or other surface of the cake and debris from the sparklers commonly falls onto the cake surface having undesirable health implications or, at the very least, leaving a distasteful residue.
It is an object of the present invention to alleviate the above mentioned problems of the prior art or to at least provide a useful alternative thereto.
Accordingly, the invention provides in one aspect a decorative cake protector for use on a cake, the protector comprising:
a shield for protecting the cake from the residue or debris of at least one burning device
a support for holding the burning device above the cake; and
a decorative theme piece mounted above the shield.
Preferably the decorative cake protector includes a stand to space the shield from the cake surface. The stand itself may rest directly on the surface of the cake. The stand may be in the form of spacing means to ensure that the under surface of the shield does not rest directly on the top surface of the cake, especially in situations where the surface is for example soft (eg made of cream or soft icing).
The shield may be adapted to move relative to the stand. For example, the shield may be rotationally mounted on the stand. Preferably, however, the shield is mounted in fixed relationship to the stand.
The spacing means may serve to leave undamaged any decoration on the top surface of the cake. The spacing means may be adapted to engage a side surface or wall of the cake. The spacing means may be adapted to support the protector over the cake without touching same. For example, the protector may include xe2x80x9cspider legsxe2x80x9d extending over or around the cake to rest on a support surface such as a table.
The shield and the stand may be separate components or may be integrally formed.
The shield and the stand may also contribute to the overall effect of the decorative theme piece, the whole protector thus being decorative.
In certain situations, there may be provided a secondary larger shield to protect particularly large cakes.
Whilst it will be understood that the burning devices are located above the shield, it may be useful in certain situations to allow the candle mounts and/or prongs of the sparklers to extend through the shield and rest on the cake thereby improving the overall stability of the cake protector.
The protector may be made from a variety of materials suitable for the purpose. For example, the protector may be made from moulded plastic cardboard, cardboard with a metal skin or full or woven material. Preferably, the protector is fire resistant and accordingly its surface may include a fire retardant. However, because the protector is likely to come into direct contact with food, any materials used in the protector should be xe2x80x9cfood safexe2x80x9d in accordance with the regulations in any particular jurisdiction.
The shield may include a range of designs. For example, the shield may be fluted. The shield may be shaped like the wings of the Opera House. Preferably, however the shield is planar. The shield when viewed from a top elevation may, be any of a number of shapes. For example, the shield may be rectangular, square, oval or triangular. Preferably, the shield is circular when viewed from a top elevation.
The decorative cake protector may include cutting means to pre-cut the cake. For example the cutting means may be in the form of downwardy depending blade panels attached to the underside of the protector means.
The support may extend upwardly from the shield. The support may form part of the shield. The support may include apertures for receiving mounting or other portions of the burning device, such as the wire handle of a sparklers or the tapered base of a candle.
The decorative theme piece may be mounted on the shield. The decorative theme piece may include a large variety of shapes and designs suitable for the occasion. For example, a birthday cake for a children""s party might include a theme piece in the form of a ballerina, rocket ship, sportsman, horse and rider, or feature any one of a number characters associated with the entertainment industry. The decorative theme piece may be stationary relative to the cake.
The decorative theme piece may be dynamic. For example, the decorative theme piece may be rotatable relative to the cake. The burning device may provide propulsion in order to rotate the decorative theme piece. The decorative theme piece may be adapted to pivot or oscillate by means, for example, of a spring mounting. The decorative then piece may be in the form of a xe2x80x9cjack in the boxxe2x80x9d in which a character or other object consistent with the theme emerges from a box or other hideaway.
The decorative cake protector may be formed in a number of ways. The decorate cake protector may include a number of components which may be pre-assembled prior to purchase or sold as blanks which may be assembled after purchase. The shield may include mounting means for receiving the support and the decorative theme piece. The shield may include slots through which the support and or the decorative theme piece may be inserted for mounting. The support and/or the theme piece may include stamped out blanks adapted to slot together or otherwise co-operate to form a unitary three dimensional display.
The decorative cake protector may be integrally moulded in one piece or formed from number of moulded pieces. The protector may be painted or otherwise coloured according to the theme.
Preferably, the decorative cake protector as a whole is formed from a number of cardboard stamped blanks adapted to be slotted together to form the decorative cake protector in suitable three dimensional arrangement.
It will be understood that whilst the cake protector will normally be used in conjunction with a cake, there may be situations in which the cake protector may be used in stand alone mode for example as a simple celebration decoration which functionally holds candles, sparklers and possibly treats (lollypops).


Pentanes are separated from a naphtha boiling range feedstock to provide a gasoline stock having a high RON and low RVP. The isopentane is isomerized to make normal pentane and normal pentane is withdrawn as a feed, preferably for a steam cracker.

Naphtha boiling range fractions have been used in the manufacture of stocks suitable for use or for blending with other petroleum and petrochemical stocks, to make gasoline motor fuels. A desirable component of a naphtha boiling range fraction for purposes of octane rating has been isopentane. Unfortunately, isopentane has a high vapor pressure (RVP of about 140 kPa) which can result in a gasoline product not meeting governmental standards. See, for instance, U.S. Pat. No. 6,429,349.
While isopentane can be removed from the naphtha boiling range feedstock, the demand for isopentane as a product or an intermediate in petrochemical processes is relatively limited. Moreover, isopentane is a less desirable as a feed to a cracking unit than is normal pentane. Cracking normal paraffins results in a higher product yield than does cracking isoparaffins. A paper entitled "Separation of Normal Paraffins from Isoparaffins" presented by I. A. Reddock, et al, at the Eleventh Australian Conference on Chemical Engineering, Brisbane, Sep. 4-7, 1983 discloses that the ethylene yield of a cracking unit can be increased if it is charged a C5-C9 stream of normal paraffins rather than a typical C5-C9 natural gasoline.
Consequently isopentane is often only of fuel value, e.g., to provide steam for other unit operations. However, often refineries and petrochemical facilities have sufficient waste gas that additional fuel values provided from isopentane removed from naphtha boiling range feedstocks are not needed.
Accordingly, processes are sought that can provide stocks desirable in gasoline applications in a manner that is efficient from capital cost and energy consumption standpoints while converting isopentane into a useful product.

Processes for making higher octane motor fuels having a low reid vapor pressure from naphtha boiling range feedstocks


A deposition chamber for delivering gases to a substrate or wafer for processing of said substrate or wafer is provided. The injector is provided comprising an elongated member with end surfaces and at least one gas delivery surface extending along the length of the member and which includes a number of first elongated passages formed therein for received a gas. Also formed within the member are a number of thin distribution channels which extend between the first elongated passages and the gas delivery surface. In another embodiment, the injector further includes at least one second elongated passage formed therein for receiving an etchant species. Metering tubes may be inserted into each elongated passage and are spaced from the walls of said passages and extend between the ends. The deposition chamber includes at least one injector as described above; a plurality of vent blocks having end surfaces and at least one elongated external surface extending along the length of each of the vent blocks; and a support positioned beneath the injector and vent blocks, creating a deposition region there between. The vent blocks are positioned adjacent one on each side of the injector, and spaced from the injector to define exhaust channels there between for removing the gas.

Chemical vapor deposition (CVD) is a critical component in semiconductor manufacturing. CVD occurs when a stable compound is formed by a thermal reaction or decomposition of certain gaseous chemicals and such compounds are deposited on a surface of a substrate. CVD systems come in many forms. One apparatus for such a process comprises a conveyorized atmospheric pressure CVD (APCVD) system which is described in U.S. Pat. No. 04,834,020 and is owned by assignee. This patent is incorporated herein by reference. Other CVD apparatus may be used such as plasma-enhanced CVD (PECVD) systems, and low pressure CVD (LPCVD) systems.
Important components of a CVD system include the deposition chamber where deposition occurs, and the injector utilized for delivering gaseous chemicals to the surface of the substrate. The gases must be distributed over the substrate, so that the gases react and deposit an acceptable film at the surface of the substrate. The deposition chamber must be carefully designed to provide a controlled environment in which deposition can take place. For example, the chamber must provide gas confinement, but reduce recirculation of the gases which can cause pre reaction of the gases and the deposition of a non-uniform film. The chamber must provide exhausting for the elimination of excess reactants and reaction by-products, yet not disrupt the flow of gases to the substrate for reaction. Moreover, the temperature of the chamber and its components must be carefully controlled to avoid condensation of reactant gases, minimize accumulation of byproduct dust and enable cleaning of the system. Additionally, the deposition chamber should preferably maintain mechanical integrity (such as tolerances) throughout its operation. All of these factors must be carefully balanced to provide a proper environment for deposition.
A function of the injector in such a deposition chamber is to distribute the gases to a desired location in a controlled manner. Controlled distribution of the gases maximizes the chance of complete, efficient and homogeneous reaction of the gases, in part by minimizing pre-mixing and prior reaction of the gases. A complete reaction provides a greater opportunity for a good quality film. If the gas flow is uncontrolled, the chemical reaction will not be optimal and the result will likely be a film which is not of uniform composition. When the film is not of uniform composition, the proper functioning of the semiconductor is impaired. Thus it is important that an injector design facilitates the desired flow of the gases in a controlled manner.
In a prior art injector, owned by the assignee and described in U.S. Pat. No. 5,136,975, a number of stacked plates each including a number of linear hole arrays is utilized. The plates produce a number of cascaded hole arrays and a chute surrounded by a cooling plate is positioned beneath the last hole array. The chute includes a central passage and ducts are formed between the chute and the cooling plate. Chemical lines deliver gases to a top plate which discretely conveys the gases to the top of individual cascaded hole arrays. The gases are fed through cascaded hole arrays which cause the gas to flow in an increasingly uniform manner. The chute passage receives the gases individually and then conveys the gases to a region above a wafer. In this region, the gases mix, react and then form a film or layer on the wafer.
The cascading action described above provides an uniformly distributed gas flow. However, flow control and simplicity of injector design can be improved. Further, the integration of the injector into the deposition chamber can be considered. Often, in prior art systems the injector is inserted into the deposition chamber, and sealed with a separate frame. The exhaust and purge arrangement, and temperature control systems add further mechanical components to the chamber. All of these components introduce mechanical complexity into the design. Additionally, the requirement for seals to mate all of these components makes temperature control of the component surfaces more difficult, and increase maintenance costs and downtime of the system due to their deterioration from exposure to eroding environments. Thus it is desirable to provide a deposition chamber that minimizes the aforementioned problems.

Single body injector and deposition chamber

Silicon Valley Group Thermal Systems LLC


Disclosed herein are methods of detecting tumors, monitoring cancer therapy, and selectively inhibiting the proliferation and/or killing of cancer cells utilizing a papilloma pseudovirus or a papilloma virus-like particle (VLP).

Cancer is diagnosed in more than 1 million people every year in the United States alone. In spite of numerous advances in medical research, cancer remains the second leading cause of death in the United States, accounting for roughly 1 in every four deaths. Although numerous treatments are available for various cancers, many forms of cancer remain uncurable, untreatable, and/or become resistant to standard therapies. For example, tumors may be inoperable because of their location or they may metastasize, making it difficult or impossible to treat the disease. Current therapies have considerable shortcomings. For instance, radiation therapy can cause damage to epithelial surfaces, swelling, infertility, fatigue, fibrosis, hair loss, dryness, and cancer. Chemotherapy can induce nausea, vomiting, diarrhea, constipation, anemia, malnutrition, hair loss, memory loss, depression of the immune system and hence infections and sepsis, hemorrhage, secondary neoplasms, cardiotoxicity, hepatotoxicity, nephrotoxicity, and otoxicity. Clearly the need for robust techniques to diagnose and treat cancer is manifest
Viruses have been shown to have tremendous utility in a variety of biomedical applications. Many of these techniques take advantage of the unique ability of viruses to enter cells at high efficiency. Some of these applications exploit viral gene expression and replication to induce expression of an inserted heterologous gene. It is well known that a variety of viruses deliver and express genes in cells (either viral or other genes), which may be useful, for example, in gene therapy, the development of vaccines, or cancer biology.
There is extensive literature on the use of viral vectors, particularly those based on adenovirus, adeno-associated virus (AAV), herpes virus and retrovirus, to increase the potency of anti-tumor therapy, however, these methodologies are in their infancy.

Papillomavirus pseudoviruses for detection and therapy of tumors

The United States of America as represented by the Secretary, Dept. of Health and Human Services National Institutes of Health