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Compositions and methods of natural products in nanoformulations for the prevention and treatment of osteoporosis
Compositions and methods of natural products in nanoformulations for the prevention and treatment of osteoporosis
Patent Drawings:
Mousa, et al.
Date Issued:
October 22, 2013
October 27, 2010
Mousa; Shaker A.
(Wynantskill, NY)
Qari; Mohammed H.
(Jeddah, SA)
Ardawi; Mohammed S.
(Jeddah, SA)
Primary Examiner:
Pak; John
Assistant Examiner:
Schlientz; Nathan W
Attorney Or Agent:
Schmeiser, Olsen & Watts, LLP
U.S. Class:
Field Of Search:
International Class:
U.S Patent Documents:
Foreign Patent Documents:
Other References:
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Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis; Report of a WHO Study Group. World Health Organization Technical Report Series, Geneva 1994; 843; pp. 1-129. cited by applicant.
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A composition and method for treating a bone condition of an animal. The composition includes a nanoformulation of active ingredients. The active ingredients include Lepidium Sativum or other Lepidium extracts, calcium, vitamin D, and antioxidants. The method for treating a bone condition includes introducing the composition into the animal.
What is claimed is:
1. A composition, comprising: a nanoformulation of active ingredients encapsulated within nanoparticles, wherein the active ingredients comprise Lepidium Sativum, calcium,vitamin D, and at least one antioxidant.
2. The composition of claim 1, wherein the active ingredients further comprise magnesium, and wherein the ratio of calcium to magnesium is 2/1.
3. The composition of claim 1, wherein the active ingredients further comprise manganese.
4. The composition of claim 1, wherein the at least one antioxidant comprises flavonoids, isoflavones, lycopene, green tea extract, pomegranate extract, or combinations thereof.
5. The composition of claim 4, wherein the at least one antioxidant comprises flavonoids.
6. The composition of claim 4, wherein the at least one antioxidant comprises the isoflavones.
7. The composition of claim 4, wherein the at least one antioxidant comprises lycopene.
8. The composition of claim 4, wherein the at least one antioxidant comprises green tea extract.
9. The composition of claim 4, wherein the at least one antioxidant comprises pomegranate extract.
10. The composition of claim 1, wherein the nanoparticles comprise chitosan nanoparticles, poly(lactic-co-glycolic acid) (PLGA) nanoparticles, chitosan cross linked to fatty acids nanoparticles, chitosan cross linked to bile acidsnanoparticles, alginate-chitosan nanoparticles, hybrid crosslinked polyvinylpyrrolidone (PVP) hydrogel nanoparticles, chitosan grafted PLGA nanoparticles, or combinations thereof.
11. The composition of claim 10, wherein the nanoparticles comprise the chitosan cross linked to fatty acids nanoparticles.
12. The composition of claim 10, wherein the nanoparticles comprise the chitosan cross linked to bile acids nanoparticles.
13. The composition of claim 10, wherein the nanoparticles comprise the alginate-chitosan nanoparticles.
14. The composition of claim 10, wherein the nanoparticles comprise the hybrid crosslinked PVP hydrogel nanoparticles.
15. The composition of claim 10, wherein the nanoparticles comprise the chitosan grafted PLGA nanoparticles.
16. A method of forming the composition of claim 1, comprising encapsulating the active ingredients within the nanoparticles.
17. A method for treating a bone condition of an animal, said method comprising: treating the bone condition of the animal, said treating comprising introducing a therapeutically effective amount of the composition of claim 1 into the animal.
18. The method of claim 17, wherein the animal is a human being.
19. The method of claim 17, wherein the animal is a non-human species of animal.
20. The method of claim 17, wherein the bone condition being treated is osteoporosis.
21. The method of claim 17, wherein the bone condition being treated is a bone fracture.
22. The method of claim 17, wherein said introducing the composition comprises introducing the composition into the animal via a delivery selected from the group consisting of an oral delivery, a topical delivery, an injectable delivery, atoothpaste delivery, and combinations thereof.
This invention pertains to methods and compositions for prevention and/or treatment of a bone condition such as osteoporosis and bone fracture.
Fracture healing and its pathophysiological process have been the axis of enormous studies and observations. Factors accelerating or hindering healing were diverse and unpredictable (Ketchen E E, Porter W E, Bolton N E, The biological effectsof magnetic fields on man, Am Ind Hyg Assoc J. 1978; 39:1). Examples were the utilization of recombinant osteogenic protein-1, which accelerates fracture healing (Cook S D, Barrack R L, Santman M, Patron L P, Salkeld S L, Whitecloud T S., The OttoAufranc Award, Strut allograft healing to the femur with recombinant human osteogenic protein-1, Clin Orthop Relat Res. 2000; 381:47-57, Abstract; Ripamonti U. Bone induction by recombinant human osteogenic protein-1 (hOP-1, BMP-7) in the primate Papioursinus with expression of mRNA of gene products of the TGF-beta superfamily, J Cell Mol Med. 2005; 9:911-928. Abstract), mechanical vibration along the axis of the fracture (Han Z B, Chen L P, Yang X Z. Experimental study of fracture healing promotionwith mechanical vibration in rabbits [in Chinese], Chung Hua Wai Ko Tsa Chih. 1994; 32:215-216, Abstract), ion resonance electromagnetic field stimulation (Diebert M C, McLeod B R, Smith S D, Liboff A R, Ion resonance electromagnetic field stimulationof fracture healing in rabbits with a fibular osteotomy. J Orthop Res. 1994; 12:878-885. Abstract), and static magnetic force with samarian cobalt magnets (Bruce G K, Howlett C R, Huckstep R L., Effect of a static magnetic field on fracture healing ina rabbit radius preliminary result, Clin Orthop Related Res. 1987; 222:300-305).
Osteoporosis is one of the critical diseases with which the aging population is faced, along with heart disease, stroke, diabetes, and cancer. Osteoporosis affects many women as they get older with the risk of bone fractures becoming a commonreality. In a Canadian review, researchers discovered 45 natural products claiming to be of benefit, of which 15 had some evidence of effectiveness. Only 3 products, phytoestrogens, dehydroepiandrosterone (DHEA) and vitamin K2, were found to havereliable evidence (although still limited) they were useful in treating osteoporosis. Since hormone replacement therapy (HRT) for osteoporosis has diverse and sometimes untoward effects, alternative methods have been sought from among natural products. Using an ovariectomized (OVX) rat model along with a bone tissue culture model, several kinds of natural products (e.g. traditional herbal formulae, herbal medicines, food components, isoflavone, and polyphenols) have been found to be effective asestradiol in preventing the development of bone loss by various mechanisms.
However, other products and therapies are needed for preventing osteoporosis generally, and postmenopausal osteoporosis specifically.
The present invention provides a composition, comprising a nanoformulation of active ingredients, wherein said active ingredients comprise Lepidium Sativum or other Lepidium extracts, calcium, vitamin D (e.g., vitamin D2/vitamin D3), andantioxidants.
The present invention provides a method for treating a bone condition of an animal, said method comprising: treating the bone condition of the animal, said treating comprising introducing the composition of the present invention into the animal.
The present invention provides nano-natural and natural products in a composition used for the prevention and treatment of a bone condition in an animal (e.g., osteoporosis and/orbone fracture). The composition of the present invention mayinclude natural supplements in osteoporosis and bone repair disorders.
In one embodiment, nanoformulations of the present invention include nanoparticles such as, inter alia, PLGA nanoparticles, chitosan nanoparticles, or chitosan cross linked to fatty/bile acids nanoparticles.
In one embodiment, the active ingredients of a composition of the present invention are in a nanoformulation that includes: Lepidium Sativum or other Lepidium extracts or isolated/synthesized active ingredients, calcium, vitamin D (e.g., vitaminD2/_vitamin D3), and at least one antioxidants such as lycopene, green tea extract, pomegranate extract and flavonoids or their combinations. In one embodiment, the active ingredients may be encapsulated within the nanoparticles. In one embodiment, theactive ingredients may additionally include: bromelain plus calcium/magnesium (2/1 ratio), manganese, and vitamin D to be encapsulated in natural nanoformulations for optimal oral delivery. In one embodiment, the at least one antioxidant is selectedfrom the group consisting of naturally driven or synthesized flavonoids/isoflavones, lycopene, green tea extract and/or its ingredients, pomegranate extract and/or its ingredients, and combinations thereof.
In one embodiment, routes of administration for introducing the composition into an animal (e.g., a human being or a non-human species of animal) include: oral, topical, injectable, toothpaste delivery.
The composition may be administered in any desired and effective manner: as compositions for oral ingestion, or for parenteral or other administration in any appropriate manner such as intraperitoneal, subcutaneous, intratumoral, topical,intradermal, inhalation, intranasal, rectal, vaginal, sublingual, intramuscular, intravenous, intra-arterial, intrathecal, or intralymphatic. Regardless of the route of administration selected, the composition may be formulated intopharmaceutically-acceptable dosage forms by conventional methods known to those of ordinary skill in the art (e.g., see: Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.). Pharmaceutical carriers are well known in the art (e.g.,see: Remington's Pharmaceutical Sciences cited above and The National Formulary, American Pharmaceutical Association, Washington, D.C.) and include sugars (e.g., lactose, sucrose, mannitol, and sorbitol), starches, cellulose preparations, calciumphosphates (e.g., dicalcium phosphate, tricalcium phosphate and calcium hydrogenphosphate), sodium citrate, water, aqueous solutions (e.g., saline, sodium chloride injection, Ringer's injection, dextrose injection, dextrose and sodium chloride injection,lactated Ringer's injection), alcohols (e.g., ethyl alcohol, propyl alcohol, and benzyl alcohol), polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), organic esters (e.g., ethyl oleate and triglycerides), biodegradable polymers (e.g.,polylactide-polyglycolide, poly[orthoesters], and poly[anhydrides]), elastomeric matrices, liposomes, microspheres, oils (e.g., corn, germ, olive, castor, sesame, cottonseed, and groundnut), cocoa butter, waxes, paraffins, silicones, talc, silicylate,and the like.
Suitable carriers used included in the composition of the present invention should be compatible with the other ingredients of the composition. Carriers suitable for a selected dosage form and intended route of administration are well known inthe art, and acceptable carriers for a chosen composition, dosage form and method of administration can be determined using ordinary skill in the art.
The composition of the present invention may, optionally, contain one or more additional agents commonly used in pharmaceutical compositions. These agents are well known in the art and include but are not limited to (1) fillers or extenders,such as starches, lactose, sucrose, glucose, mannitol, silicic acid or the like; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, hydroxypropylmethyl cellulose, sucrose, acacia or the like; (3) humectants, such asglycerol or the like; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium starch glycolate, cross-linked sodium carboxymethyl cellulose, sodium carbonate or the like; (5)solution retarding agents, such as paraffin or the like; (6) absorption accelerators, such as quaternary ammonium compounds or the like; (7) wetting agents, such as acetyl alcohol, glycerol monostearate or the like; (8) absorbents, such as kaolin,bentonite clay or the like; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate or the like; (10) suspending agents, such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol andsorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth or the like; (11) buffering agents; (12), excipients, such as lactose, milk sugars, polyethylene glycols, animal and vegetable fats, oils, waxes,paraffins, cocoa butter, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicones, bentonites, silicic acid, talc, salicylate, zinc oxide, aluminum hydroxide, calcium silicates, polyamide powder or the like; (13) inert diluents, suchas water, other solvents or the like; (14) preservatives; (15) surface-active agents; (16) dispersing agents; (17) control-release or absorption-delaying agents, such as hydroxypropylmethyl cellulose, other polymer matrices, biodegradable polymers,liposomes, microspheres, aluminum monostearate, gelatin, waxes or the like; (18) opacifying agents; (19) adjuvants; (20) emulsifying and suspending agents; (21), solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols, fatty acidesters of sorbitan or the like; (22) propellants, such as chlorofluorohydrocarbons or the like and volatile unsubstituted hydrocarbons, such as butane, propane or the like; (23) antioxidants; (24) agents which render the formulation isotonic with theblood of the intended recipient, such as sugars, sodium chloride or the like; (25) thickening agents; (26) coating materials, such as lecithin or the like; and (27) sweetening, flavoring, coloring, perfuming and preservative agents. Each such ingredientor material should be compatible with the other ingredients of the formulation. Agents suitable for a selected dosage form and intended route of administration are well known in the art, and acceptable ingredients and materials, dosage form and methodof administration may be readily determined by those of ordinary skill in the art.
A composition in accordance with the present invention that are suitable for oral administration may be in the form of capsules, cachets, pills, tablets, powders, granules, a solution or a suspension in an aqueous or non-aqueous liquid, anoil-in-water or water-in-oil liquid emulsion, an elixir or syrup, a pastille, a bolus, an electuary or a paste. These formulations can be prepared by methods well known in the art.
Example 1
Synthesis of Alginate-Chitosan Nanoparticles
Alginate-chitosan nanoparticles encapsulating natural product driven active ingredients will be synthesized using the ionic gelation method. Low viscosity sodium alginate and low molecular weight chitosan will be used for the synthesis of thenanoparticles. The alginate solution will be prepared in deionized water, The chitosan solution will be prepared in 1% v/v acetic acid. The pH of both solutions will be adjusted to approximately 6.0, and the solutions will be filtered (0.22 .mu.m poresize) prior to use. Nanoparticles will be prepared under sterile conditions by mixing appropriate volumes of 0.005% (w/w) sodium alginate and primary active ingredient, followed by the addition of 1% (w/w) chitosan under stiffing for 2 hours (hrs) atroom temperature. The amount of natural product driven active ingredients will be adjusted until maximum loading efficiency is achieved. Nanoparticles will be characterized by DLS, zeta size and TEM. For co-encapsulation of two or more natural productdriven active ingredients, an appropriate amount of the main ingredient will added to the solution along with other secondary active ingredients.
Example 2
Synthesis of Hybrid Cross Linked Polyvinylpyrrolidone (PVP) Hydrogel Nanoparticles
Hybrid crosslinked PVP hydrogel nanoparticles will be synthesized using a modification of the method described by Bharali et al (2003). Nanoparticles encapsulating natural product driven active ingredients will be synthesized by in situpolymerization of various monomers, as described below. Polymerization reactions will be carried in a reverse micellar environment. Sodium bisethylhexylsulphosuccinate or aerosol OT (AOT; Sigma Alidrich, St. Louis, Mo., USA) will be used as asurfactant for micelle formation. Surfactant (either sodium bisethylhexylsulphosuccinate or AOT) will be dissolved in n-hexane (typically 0.03M to 0.1M AOT in hexane). Aqueous solutions of monomer will be added together with the cross-linking reagent NN' methylenebisacrylamide (MBA), the initiator ammonium persulphate (APS), the activator ferrous ammonium sulphate (FAS), and where indicated, an aqueous solution of natural active ingredient (s). The polymerization reaction will be carried out in thepresence of N.sub.2 gas. The monomers to be tested are vinylpyrrolidone (VP), N-isopropylacrylamide (NIPAAM) and N-3 aminopropylmethylacrylamide (APAAM). For co-encapsulation of two or more natural product driven active ingredients, an appropriateamount of the main ingredient will added to the solution along with other secondary active ingredients to the reverse micelles. To initiate the polymerization reaction, 15 .mu.l of a saturated solution of APS (2% w/w of monomers) and 20 .mu.l of a 0.05%w/v solution FAS (0.07% w/w of monomers) will be used. The reaction will be allowed to proceed at room temperature for 2-3 hrs.
A typical experiment is as follows. In 40 ml of 0.03 M AOT in hexane, there will be added 63 .mu.l of freshly distilled VP, 30 .mu.l APAAM and 200 .mu.l of NIPAAM in water (200 mg/ml each), 50 .mu.l of MBA (0.5 mg/ml), 10 .mu.l of 1% FAS and100 .mu.l of aqueous of two or more natural product driven active ingredients. An appropriate amount of the main ingredient will added to the solution along with other secondary active ingredients. The reaction solution will be purged with N.sub.2 gasfor 30 minutes, and 15 .mu.l of a saturated solution of APS will be added. Polymerization will be carried out in the presence of N.sub.2 gas at room temperature for 2-3 hrs with continuous stirring. Nanoparticles of random copolymers of VP-NIPAAM-APAAMwill form in the aqueous core of the reverse micellar system. The nanoparticles will remain dispersed in the organic solvent, and be separated out by the addition of 10 mL of ethanol, followed by centrifugation at 10,000.times.g. The nanoparticles willbe repeatedly washed with ethanol at least 3-4 times and redispersed in sterile deionized water.
Example 3
Synthesis of Chitosan Grafted PLGA Nanoparticles
Chitosan grafted PLGA nanoparticles will be prepared by a modification of a method originally described by Kumar et al (2004). In brief, this double emulsion-diffusion-evaporation technique of synthesis of nanoparticles is as follows: 50 mg ofPLGA will be dissolved in 2 mL of ethyl acetate, and then 200 .mu.l of a solution of primary active ingredient will be added. The mixture will be sonicated for 5 seconds using a probe sonicator, and then the emulsion will immediately be added to anaqueous stabilizer mixture, containing 100 mg of polyvinyl alcohol (PVA) and 10 mg of chitosan in 10 ml of water, dropwise with stiffing. The entire solution will be sonicated again for approximately 10 seconds using a probe sonicator. The emulsionwill be stirred at room temperature for 1 hr, and then the organic phase will be removed using a rotatory evaporator. For co-encapsulation of primary ingredient, an appropriate amount will added along with the secondary ingredient during the synthesisstep.
Example 4
Entrapment Efficiency
Entrapment efficiency for of two or more natural product driven active ingredients will be determined by filtering a known amount of the nanoparticles through a 0.1 .mu.m filter membrane to separate free natural ingredients listed in theapplication. The amount of active ingredient will is determined using high performance liquid chromatography (HPLC). Entrapment efficiency (E %) will be determined based on the total concentration of drug (primary or secondary ingredient) in the system(free+encapsulated; [Drug].sub.0) and the concentration of drug in the filtrate ([Drug].sub.f) using the following formula: E%=(([Drug].sub.0-[Drug].sub.f)/[Drug].sub.0).times.100
Example 5
Release Kinetics of Natural Active Ingredients from the Nanoparticles
The in vitro release kinetics of the nanoparticles will be evaluated in phosphate buffered saline (PBS) and fetal bovine serum (FBS). A defined amount of primary/secondary ingredients encapsulated in nanoparticles will be suspended in 10 ml ofPBS, and the solution will be kept at room temperature. At various time intervals, the solution will be vortexed, and an aliquot (1 mL) of the solution removed and subjected to centrifugation at 13,000 rpm to separate released active ingredients fromnanoparticle-encapsulated material. The concentration of released drug will be determined by and HPLC or LC/MS/MS. The percent release of encapsulated ingredients will be determined according to the following formula: %Release=([Drug].sub.f,t)/([Drug].sub.0).times.100 where [Drug].sub.f,t is the concentration of primary and secondary active ingredients in the supernatant at time t. Similarly, to determine the release kinetics in FBS, a defined amount of primary andsecondary active ingredients encapsulated in nanoparticles will be suspended in 10 ml of 20% FBS. Release kinetics will be analyzed as described for PBS.
Example 6
Analysis of Particle Size by DLS and TEM
Size distribution of primary and secondary active ingredients-encapsulated nanoparticles in an aqueous dispersion will be determined using a Malvern zeta sizer (Malvern Instrumentation Co, Westborough, Mass., USA). The size and morphology ofthe nanoparticles will also be examined using a JEOL JEM-100CX transmission electron microscope.
Example 7
Lycopene and Bone Health
Work of the inventors of the present invention, both experimental work and work with humans, provides evidence for a positive effect of the potent antioxidant "Lycopene" on bone health. Postmenopausal women with low dietary intake of lycopene(based on dietary history food frequency questionnaire) exhibited lower serum lycopene values compared to corresponding postmenopausal women with high dietary intake of lycopene. Women with higher serum lycopene exhibited reduced oxidative stress (asindicated by decreases in lipid and protein oxidation, increases in the enzymatic activities of catalase an superoxide dismutase) that was associated with improve bone resorption markers (u-NTX, s-CTX) and bone formation markers (s-Osteocalcin andbone-specific ALP).
Example 8
Lycopene Plus Other Antioxidants and Bone Health
Supplementation of healthy postmenopausal women with 30 mg/day of lycopene for 6 months significantly improved oxidative stress and bone turnover markers: significant decreases in u-NTX and s-CTX and increases in s-OC and s-BALP. The benefit ofLycopene on bone turnover rate and bone health was further enhanced when combined with green tea extract and/or pomegranate extract.
In one embodiment, the composition of the present invention comprises active ingredients, wherein the active ingredients comprise Lepidium Sativum or other Lepidium extracts, calcium, vitamin D2/D3 and antioxidants.
In one embodiment, the active ingredients further comprise additional ingredients. The selected from the group consisting of flavonoids or isoflavones, bromelain and magnesium, manganese, and combinations thereof. In one embodiment, thecalcium/magnesium ratio is 2/1.
In one embodiment, the composition further comprises nanoparticles, wherein the active ingredients are encapsulated within each nanoparticle.
In one embodiment, the nanoparticles are selected from the group consisting of chitosan nanoparticles, poly(lactic-co-glycolic acid) (PLGA) nanoparticles, chitosan cross linked to fatty/bile acids nanoparticles, alginate-chitosan nanoparticles,hybrid crosslinked polyvinylpyrrolidone (PVP) hydrogel nanoparticles, chitosan grafted PLGA nanoparticles, and combinations thereof.
The present invention provides a method for treating a bone condition of an animal, wherein the method comprises: treating the bone condition of the animal, said treating comprising introducing the composition of the present invention into theanimal.
In one embodiment, the animal is a human being.
In one embodiment, the animal is a non-human species of animal.
In one embodiment, the bone condition being treated is osteoporosis.
In one embodiment, the bone condition being treated is a bone fracture.
In one embodiment, said introducing the composition comprises introducing the composition into the animal via a delivery selected from the group consisting of an oral delivery, a topical delivery, an injectable delivery, a toothpaste delivery,and combinations thereof.
While particular embodiments of the present invention have been described herein for purposes of illustration, many modifications and changes will become apparent to those skilled in the art. Accordingly, the appended claims are intended toencompass all such modifications and changes as fall within the true spirit and scope of this invention.
* * * * *
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Cervical cancer: Because the vaccine is not the worst case scenario. Jennifer L. Young, MD, MPH National Organization for Women Panel September 23, 2008. Objectives. Answer 2 questions Is cervical cancer worth preventing? How do we prevent it – the easy way or the hard way?.
Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.
Jennifer L. Young, MD, MPH
National Organization for Women Panel
September 23, 2008
HPV disease incidence by patient age
1. Ley et al. J Natl Cancer Inst. 1991.83.997
Winer RL, et al. Am J Epidemiol. 2003:157:318-226
Smith EM et al. Sex Transm Dis. 2004.31;57-62.
Vaginal scarring
Poor sexual function
Chronic diarrhea
Bowel obstruction
Blockage of ureters with kidney failure
Hemorrhagic cystitis
Chronic back pain
Skin changes
Lymphedema in legsComplications of treatment
Jennifer L. Young, MD, MPH
University of Virginia
September 23, 2008
National Coverage with 4:3:1:3:3:1 Series by Race/EthnicityChildhood vaccination racial disparities: closing the gap
1. CDC. MMWR September 5, 2008; 57(35): 961-966.
- John Schiller
National Cancer Institute
3 shot regimen costing $120/injection or $360 total
Coverage ≤ 18 years old
Public: Federal Vaccines for Children program for Medicaid qualifiers
Private: Most insurance companies cover but age range and reimbursements differ
Coverage > 18 years old
Public: Medicaid coverage of women 18-21 at high risk
Private: Most insurance companies cover but age range and reimbursements differ
1. Chesson HW. Emerg Infect Dis 2008 14(2): 244.
Olsson SE et al . Vaccine 2007; 25: 4931.


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Depo-Medrol Injection Sites
It may be necessary to distribute doses ranging from 20 to 40 mg by repeated local injections in the case of large.Cortisone is a powerful anti-inflammatory medication. (Depo-Medrol).She even offered to give me another 40mg dose to try and help with my allergies to which I.
Methyl prednisolone is a short-acting anti-inflammatory drug used to reduce severe inflammation and suppresses the immune system in dogs and cats. Depo-Medrol.
Musculoskeletal Injections: A Review of the Evidence. methylprednisolone acetate (Depo-Medrol) is the most commonly used intra-articular steroid,.
Depo-Medrol 40 mg/ml 10 ml depo-medrol, glucocorticoid, injectionDepo-Medrol has a very long half life and remains in. but a single IM injection of 80 mg may remain.
Depo-Medrol 40 Mg
DEPO-MEDROL İM/İA Flakon 40 mg/ml 1×1 ml'lik flakon
Depo-Medrol is an anti-inflammatory glucocorticoid for intramuscular, intra-articular, soft tissue, or intralesional injection.
Injection Depo-Medrol 40Mg
Reader Question: Depo-Medrol Billing - Published on Mon, Oct 01, 2001.
Injection Methylprednisolone Acetate 40 MgSome believe it is not advisable to mix the medications together pre-injection as the Depo-Medrol is a.The drug is hard on their system but the severe dermatitis was a kill or cure problem.It is prescribed for dogs to reduce allergy symptoms and control certain.
I was given solu medrol through a Iv at the er today 125 mg. is it gonna.Aldomet, see Methyldopate HCl. Alefacept. 0.5 mg. IM, IV. Cenacort A-40, see Triamcinolone acetonide.Question: Due to the unavailability of Celestone for injections, we are considering a switch to.


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Release Date:02/10/2015;Notes:Denver-based metallic hardcore perpetrators Call of the Void unleash another ferocious blast of sonic destruction with ...Click To Read More About This Product
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Release Date:02/10/2015;Notes:Denver-based metallic hardcore perpetrators Call of the Void unleash another ferocious blast of sonic destruction with their sophomore effort Ageless. A pummeling fusion of crusty grind, sludgy hardcore and groove injected metal, Ageless was recorded and mixed by Andy Patterson (Subrosa, Eagle Twin, Gaza) and mastered by Brad Boat right (Tragedy, from Ashes Rise, Integrity). Having cut their teeth playing live over the past two years with Today is the Day, Eyehategod, Code Orange, Ringworm, Brutal Truth and many others, Ageless sees Call of the Void further sharpen their aggressively vitriolic sound into a fine-tuned display of hardcore savagery.;Track List:1. Old Hate;2. Truth in Bone;3. the Sun Chaser;4. R.I.S.;5. Black Ice;6. I;7. the Hive;8. Cold Hands;9. Long Knives;10. Honor Among Thieves;11. II;12. Ageless
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text: Following Parsival (1977) and The Grail War (1979, paperback only), this third volume in Monaco's multi-crannied exploration of the Arthurian Grail legends begins at the close of the Grail War, a no-win holocaust. Ignorant armies, madmen, monsters, and soul-crippled knights (including Sir Parsival, that ""mighty hero of a non-existent Grail"") blunder through an acrid and blasted landscape of blood and muck. The ""victorious"" Norsemen strain for a seacoast they will never reach. Fat Baron Howtlande prates of renewed military might--if the bloodthirsty shreds of men will only ""join forces."" Sorcerer Clinschor raves on to his cannibalistic ""Truemen"" as he still pursues the Grail, and tattered priest John exalts in his vision of the Great Pig. But Parsival has had enough of dreams: ""I've seen all the visions I need to see. . . I'm an ordinary man. That's the remarkable thing."" So he will simply hunt for his once-abandoned family--and though wife Layla caustically takes to drink (and the Norseman who captured her), amnesiac son Lohengrin will eventually learn to slough off the blood memory and live in the present. The other knights also settle down: Sir Galahad discovers the simple reverent act of tilling the soil; Sir Gawain, mutilated, becomes healed and whole before death by doffing his helmet of war. There will, however, be one final trek, bringing the shattered survivors to the Grail fortress--a terrible blood-night of killings, cannibalistic orgies, and sour winds that climaxes in a vision of bloodthirsty children, buzzing horrors, industrial cities, and more. Yet even in the face of all this, Parsival reveals the gold thread of life that will cleanse and renew the earth. Monaco's dialogue and meditations are often salty and fresh, though at times maddeningly oblique; and he takes a diabolic delight in sustained ick: "". . . timbered tunnels for flies and long shuddering worms."" A restless, strenuous, often pretentious rumination on civilization's death and resurrection--probably worth the trouble for Arthurians and lovers of philosophical fantasy.


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Weapon top 20 songs
Weapon biography
There are at least six bands called "Weapon" (see below). The first band listed, from Alberta, Canada, owns the trademark for the name. As a result, the only other active Weapon as of 2012 (number 5, whose bio is listed below as Weapon 1980) have changed their name to Weapon UK in a settlement arrangement with the Canadian blackened death metal band WEAPON. 1) canadian black metal/death metal band 2) Folk/metal/ambient project from Portugal 3) Melodic Death Metal band from Newfoundland, Canada 5) british heavy metal band 6) Heavy Metal from United States 1) Weapon, the black/death act was formed in 2003 by Vetis Monarch in Calgary, Canada. After the formation of the band, Vetis Monarch the frontman temporarily moved to his birthplace of Dhaka, Bangladesh, where the 'Within the Flesh of the Satanist' Demo tape and 'Violated Hejab' EP were recorded. On that time In 2005, Vetis moved back to Canada, but relocated Weapon to Edmonton. WEAPON signed internationally with Relapse Records in 2011 in anticipation of a full-length debut in 2012, supported by a North American tour with Marduk starting in May 2012. On 28th June, 2013, it was confirmed that the majestic journey of the weapon has been ended up 2) Weapon 1980 Danny Hynes – Lead vocals Jeff Summers – Lead Guitar/Vocals Baz Downes – Bass/Vocals Bruce Bisland – Drums In March 1980 Danny placed an advert in Melody Maker looking for a band, at the same time Jeff had placed one looking for a singer. Danny auditioned and was offered the job in Jeff's band, Fast Relief. After several weeks' rehearsal and one gig under their belt, Danny & Jeff decided to replace the rhythm section. Danny recommended his best friend, bassist Baz Downes (ex- Inner City Unit), who played along side him in Snatch. Jeff suggested drummer Bruce Bisland (ex- Lip Service) one rehearsal later and Weapon was formed. After doing a showcase gig for Laurie Dunn, then head of Virgin Publishing, the band were signed to Virgin. Whilst playing at The Venue, in London's Victoria, Eddie Clarke from MOTORHEAD happened to be in the audience, he liked what he heard and put it to the rest of the band and management team that Weapon should support them on their forthcoming tour. A showcase gig was hastily arranged for the band at The Camden Palace, where MOTORHEAD and their manager came to see them. There had been a lot of personal problems between band members during the day, to the point where they were on the verge of splitting up so by the time they went on stage they were full of aggression and really pissed off with each other. This of course made for a great show; basically they didn't give a toss what happened. In the words of Lemmy "any band that can have that amount of contempt for their audience have to tour with us" Weapon was offered, and accepted, the tour. The 32 date U.K. 'Ace Up Your Sleeve' Tour started on 22nd October 1980 at Ipswich Gaumont and ended in November with a four-night stint at London's Hammersmith Odeon. The band released one single 'It's A Mad Mad World' b/w 'Set The Stage alight', which got to number 2 in the Heavy Metal charts. They also recorded several tracks for an album 'Set The Stage Alight', which never saw the light of day until October 2003 when it was released by Zoom Club Records. The band toured for the following 18 months before calling it a day due to managerial/contractual problems but all the guys remained the best of friends so much so that in the summer of 2005 they got together to celebrate what would have been their 25th anniversary. After a couple of warm-up shows in London they played Germany's 'Headbangers-Open-Air Ball' On Saturday, 8th July. A good time was had by all!! After which the members returned to their 'proper' jobs. Danny to his band, the legendary Paddy Goes To Holyhead. Bruce to Andy Scott's Sweet, Jeff to Statetrooper and Baz, unfortunately due to illness, has had to retire from live work. With a renewed interest in all things 'New Wave of British Heavy Metal', and a new manager on the horizon, Danny & Jeff have decided it's time for Weapon to 'Set The Stage Alight' again! Tracks taken from 'The Headbangers-Open-Air Ball' 2005 are currentley being mixed in London and there are plans to release the album, 'Set The Ball Alight', later this year or early 2010, the bands 30th anniversary. With Bruce unavailable, due to his commitments to The Sweet, and Baz retired due to ilness. Weapon have recruited the services of Bassist, Gavin Cooper (Lionsheart, Paul DI'Anno's Battlezone & Killers, and Statetrooper) and Drummer, Ian Sweeting (The Risen, The Sweethogs, "2Mentall" & Stone Katz) To a packed and hugely receptive audience, Weapons new line-up debuted at Premier London music venue "The Peel" on Saturday 14th November 2009. Hot on the heels of this, the band were offered the headline slot at the "Vikings Ball" during Britain's "Hard Rock Hell 3" festival on the 3rd December 2009. The band are currently rehearsing the material for the new Weapon album which along with "Set the ball alight (Live)" is scheduled for release during the first quarter of 2010, ironically the bands 30th Anniversary. More live work to support the new releases are being worked on for 2010 and so far the band have been offered shows in Ibiza, Greece and Italy! Look out world, rock and roll is back on the menu!!
- Oss - Virus Hokus Pokus
- Piccolo Coro Dell'antoniano - 06 - Piccolo Coro Dell'antoniano - Din Don Dan - Le 14 Più Belle Canzoni Dedicate Al Natale
- Alisha Chinai - Made In India
- Aha - Take On Me
- Eminem - 8 Mile
- Enrique Iglesias - Duele El Corazon (Feat. Tinashe & Javada) [English Version]
- Coldplay - Hymn For The Weekend
- Jojo - Too Little Too Late
- Bruce Springsteen - Glory Days
- Alan Walker - Sing Me To Sleep
- Francis Cabrel - Yo Vengo A Ofrecer Mi Corazñƒn - Mercedes Sosa Con Francis Cabrel
- Raghav - So Confused
- Raghav - Cant Get Enough.mp3
- Bruce Springsteen - The River
- Akon - Beautiful
- Taylor Swift - Blank Space
- Raghav - Let's Work It Out Tophit
- The Strokes - Last Night
- Frank Zappa - Cletus Awreetus-Awrightus
- Francis Cabrel - Octobre
- Delusions - Alanis Morissette
- Himesh Reshammiya - Tera Surroor
- Michael White - Sunset - Original Mix
- Take That - Patience
- Isabella Valentine - Wet Dreams
- Christmas - 05 - R2-D2 We Wish You A Merry Christmas
- Salim - Bia Dilbar Khumari Baloch Multimedia.com
- Frickin' A - Merry Frickin Christmas
- The Police - Message In A Bottle
- Survivors - Episode 039 - Merry Christmas
- Oss - Virus Hokus Pokus
- The Police - Message In A Bottle
- Michael White - Sunset - Original Mix
- Delusions - Alanis Morissette
- Halliday - Chanson D'emilie Jolie
- Dj Feel - Soft Touch
- Adele - Heart Of Steel - Part 01
- Michael Bublé - Blue Christmas
- Ravens - Catching Up On Losing It With
- Summers - John 12:20-26 - Finding Life By Losing It


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The event is considered satisfactory in regard to clause four.six as outlined under.(one) The objectives of this clause are as follows:(a) to deliver an acceptable diploma of versatility in making use of certain advancement requirements to particulardevelopment,(b) to realize much better outcomes for and from growth by permitting adaptability specifically conditions.(2) Progress consent may, topic to this clause, be granted for growth Despite the fact that the development wouldcontravene a advancement common imposed by this or some other environmental arranging instrument. However, thisclause isn't going to implement to your growth conventional that is certainly expressly excluded with the operation of this clause.(3) Development consent must not be granted for advancement that contravenes a improvement regular Except if the consentauthority has deemed a published ask for from your applicant that seeks to justify the contravention of the developmentstandard by demonstrating:(a) that compliance with the development typical is unreasonable or unwanted inside the instances of the situation,andGiven the prevailing accepted developing height, minimal character from the modification and location ofthe awning, compliance with the height Handle is considered unreasonable and unnecessary inthis circumstance. There will be no amenity impacts arising on adjoining progress and theappearance of the development won't change noticeably.(b) that there are adequate environmental planning grounds to justify contravening the development regular.The awning increases the amenity of the topic device throughout the provision of protection fromthe sun.(4) Progress consent must not be granted for enhancement that contravenes a improvement common Except:(a) the consent authority is content that:(i) equest has sufficiently tackled the matters required to be shown bysubclause (three), andThe applicant hasn't furnished a published ask for to fluctuate the conventional having said that supplied theminor mother nature of your variation and deficiency of any impacts Council has done this assessment.
The proposed bare minimum great deal sizes are per the good deal layouts for encompassing regions, is not going to adversely impact adjoining residences and therefore are effective at accomodating a compliant dwelling. The application was referred to IHAP on 12 November 2013. All panel associates concurred this contact form While using the Council Officer's suggestion.
20m separation distance concerning habitable areas of dwellings in which minimal 7m separation length proposed.
Demolition of present building and construction of two storey business premises and carparkModification A - variations to disorders of consent
The variation into the least internet site width may have only a minor influence on both the surrounding enhancement along with the street frontage obtain preparations for that proposed advancement. The minimized minimum amount website width hasn't prevented a suitable progress from being made for the internet site presented the unusual condition of your allotment using a slim frontage and much broader allotment dimensions guiding the present dwelling.
Residence ServicesServices and restrictions for people which includes your Animals, tree administration and waste
There aren't any overshadowing impacts to neighbouring residential properties. •The developing continues to be positioned regarding The present easements which traverse the website.•The height on the making is under the Original 'Block three' which was permitted for the website by using a zero setback on the northern boundary. It will probably be considerably considerably less visually obtrusive particularly Along with the retention of the existing Melaleuca on the website.Went to IHAP on 28 February 2018 plus the acceptance was granted for the application.
Development of a multi dwelling housing improvement comprising of eighteen (eighteen) x two (2) storey townhouses with linked strata subdivision. Conversion of existing heritage item to communal open House
Proposal is in keeping with the built method of The Sandon Position Estate with respect to the height, bulk and scale relative to encompassing developments.
The proposed growth is in line with the goals of your two(a) zone as the twin occupancy retains a scale that may be proportional to single detached housing.
The asked for exception to clause four.3 Top of Properties of the Wollongong Nearby Environmental Program 2009 is considered acceptable given the situations of the case. The applicant has provided sufficient justification for your variation sought and demonstrates that rigid compliance with the event conventional is unreasonable and unnecessary. It is taken into account that proposal will not likely detract from other accredited progress both equally around the adjoining property and in the locality that exceed 9m and is taken into account to fulfill the aims of your IN2 zone.
The applicant built genuine makes an attempt to acquire the adjoining residence and was unsuccessful. Council was from the feeling that strictly implementing this control could be unreasonable In this particular occasion. The proposal didn't lead to any unreasonable impacts on amenity of close by Qualities with regard to overshadowing, privateness and views, lack of daylight or normal air flow.
Applicant has shown that rigid compliance with the event specifications is unreasonable and unwanted in the conditions of the situation and it has furnished enough scheduling find out grounds to justify contravening the development site expectations.
You should Observe that it is the importer's obligation to check While using the company first to make certain they can provide the essential procedure According to import situations:
Financial DevelopmentWollongong is among Australia's significant metropolitan areas without the linked major town expenses, coupled with excellent connectivity
- 315 Visitors


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About this tutorial:
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When typing text into a PowerPoint text box, you may have noticed upon overflow words spilling out over the text box, or the font becoming smaller, or the text box stretching. This behavior might change from project to project, and it's a behavior that you can easily control.
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Our venerable and God-bearing Father John Cassian was born in the Danube Delta in what is now Dobrogea, Romania in about 360. In 382 he entered a monastery in Bethlehem and after several years at the monastery was granted permission, along with his friend St. Germanus, to visit the Desert Fathers in Egypt. They remained in Egypt until 399 except for a brief period when they returned to Bethlehem and were released from the monastery there.
Upon leaving Egypt they went to Constantinople where they met St. John Chrysostom who ordained St. John Cassian as a deacon. He had to leave Constantinople in 403 when St. John Chrysostom was exiled, and eventually settled close to Marseilles where he was ordained priest and found two monasteries, one for women and one for men.
St. John's most famous works are the Institutes, which detail how to live the monastic life, and the Conferences, which provide details of conversations between John and Germanus and the Desert Fathers. He also warned against some of the excesses in Blessed Augustine of Hippo's theology whilst refraining from criticising him by name. For this reason he has sometimes been accused of Semi-Palagianism by the Roman Catholic church.
St. John died peacefully in 435 and his feast day are February 29 and July 23.


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Does it void my CPU's warranty if I change settings without tweaking the voltage or frequency?
I turned off turbo and cool n' quiet so it has a stable voltage and frequency
pic unrelated
Maybe. I'm only tweeting because you appear to be a fellow gulagite.
No, overclocking is only not covered by your warranty, it doesn't void it.
You're also not overclocking it. The turbo core in my FX-8320 was causing it to idle at fucking ~45-50c
I don't know why I said tweeting, I don't even use it lol.
need some advice on these prebuilts yes i know i am cancer but i just wanted to know if either of these PC can handle games on high or ultra at 1080p 60fps
really want to play dragons dogma,total warhammer if it isnt infested with DLC, Xcom 2 and some of the demanding games i have missed out on that are PC only or best played on a PC just want to know if it can handle the majority of games
The first one will let you play anything at 1080p 60/fps but it's around 400 dollars more than building it yourself.
Source of image??
google image search + first result says galaxy express 999
Shit I used tineye like a fuckhead. Thanks
Can someone photoshop this picture or really any picture to give double d sunglasses, gold chains, and drugs lying around to have a more gangster feel. I just want a picture of double d where he looks like a straight g
bump again
I would love it if anyone of you could photoshop this with an angry expression similiar to the Todd Howard one (the preorder)
You mean this one
Over 9000^9000 [spoiler]milliseconds[/spoiler] in photoshop.
So I play this little shitty flash game with my sister from time to time on long journeys and whatever, but some of the races require to be on the site
Could some anon help me by taking it off?
Source on these three?
try google image search - You can SEARCH BY IMAGE and it will return best matches
Right one is GATE. S2 will air soon.
so left is Kono Subarashii Sekai ni Shukufuku wo! and in the middle is Hai to Gensou no Grimgar
Pic related,anime title please?
What manga is this?
Damn, serious? This shit looks crazy. Thanks.
Any experienced linux users here, need help with installing graphic card driver for nvidia fx 5200 on lubuntu 15.10? Pic not related
>drivers for linux
Surely you just install libuntu, and that's that?
Your card was manufactured in the late-neolithic, and the Nvidia blob hasn't supported it for nearly eight years.
so, i just throw away whole pc?
I want a manga that shares this theme.
Do you guys have any in mind?
I'm assuming you're not a faggot, so I took out the yaoi and shonen-ai:
Already seen Berserk and loved it. Is there anything similar to it but chock full of weird monsters getting gutted in graphic detail?
You can try Claymore, but be warned, the anime has a terrible ending (because it doesnt follow the manga)
Home from work sick, what are some top tier Anime on Netflix or other streaming sites? My favorite anime as of yet is either Basilisk or Samurai Champuloo.
I think Last Exile is on Netflix or Hulu.
The Devil Is a Part Timer on netflix.
Knights of Sidonia is great
just started seven deadly sins.. burdy funny
/r/ing this gif from tsuritama without the retarded text
Isn't that one of the 4chan banners aswell?
Just reverse search the image and you get the original in one of the first results. Properly put up an effort to find it before /r/ing something.
What is the origin of this image?
It's so weird. The mad, powerful looking woman. The weird servant with a white mask. All that milk. All these nazi references. I want to know where this is from. An Instagram profile? A movie? Anything.
it's at least 5 years old and just gets passed around on 4chan as presumably unexplainable.
i've always assumed it's just some whacky art project making fun of Nazis and their obsession with everything white. white race, white bellaclava, white milk, possibly trying to bleach skin with milk baths... that sort of thing.
agree, most of these unexplenaible pics are independant art projects or universitary works