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1.
J Vet Pharmacol Ther ; 42(4): 452-460, 2019 Jul.
Article in English | MEDLINE | ID: mdl-31206719

ABSTRACT

Values for pharmacokinetic variables are usually obtained in healthy animals, whereas drugs are frequently administered to diseased animals. This study investigated cefquinome pharmacokinetics in healthy goats and goats with experimentally induced mastitis. Five adult lactating goats received 75 mg of cefquinome intramammary infusion using a commercially available product into one udder half in healthy goats and goats with clinical mastitis that was induced by intracisternal infusion of 100 cfu of Staphylococcus aureus ATCC 29213 suspended in 5 ml of sterile culture broth. Cefquinome concentrations were determined in plasma and skimmed milk samples using high-performance liquid chromatography (HPLC). Pharmacodynamics was investigated using the California Mastitis Test and pH of milk. Experimentally induced mastitis significantly increased the California Mastitis Test score and pH, and decreased the maximal cefquinome concentration and shortened the half-life in milk when compared to healthy goats. In conclusion, mastitis facilitated the absorption of cefquinome from the mammary gland of lactating goats and induced marked changes in milk pH, emphasizing the importance of performing pharmacokinetic studies of antimicrobial agents in infected animals.


Subject(s)
Cephalosporins/pharmacokinetics , Goat Diseases/drug therapy , Mastitis/veterinary , Milk/chemistry , Staphylococcal Infections/veterinary , Animals , Anti-Bacterial Agents/therapeutic use , Cephalosporins/therapeutic use , Female , Goat Diseases/microbiology , Goats , Lactation , Mastitis/drug therapy , Mastitis/microbiology , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus
2.
Bioorg Chem ; 82: 86-99, 2019 02.
Article in English | MEDLINE | ID: mdl-30278282

ABSTRACT

Nowadays, diabetes and its associated inflammatory complications are important public health problems worldwide. Market limitations of drugs with dual actions as anti-inflammatory (AI) and anti-diabetic have been led to a temptation for focusing on the discovery and development of new compounds with potential AI and anti-diabetic activities. Herein, we synthesized two new series containing pyrazole ring with vicinal diaryl rings as selective COX-2 moiety and thiazolidindione (series 12a-f) or thiazolidinone (series 13a-f) as anti-diabetic moiety and the two moieties were linked together with methylene or methylenehydrazone functionality. The two series were evaluated for their COX inhibition, AI activity and ulcerogenic liability and for the anti-diabetic activity; 12a-f and 13a-f were assessed in vitro against α-glucosidase, ß- glucosidase, in vivo hypoglycemic activity (one day and 15 days studies) in addition to PPARγ activation study. Four compounds (12c, 12f, 13b and 13f) had higher COX-2 S.I. (8.69-9.26) than the COX-2 selective drug celecoxib (COX-2 S.I. = 8.60) and showed the highest AI activities and the lowest ulcerogenicity than other derivatives. Also, two thiazolidindione derivatives 12e and 12f and two thiazolidinone derivatives 13b and 13c showed higher inhibitory activities against α- and ß-glucosidase (% inhibitory activity = 62.15, 55.30, 65.37, 59.08 for α-glucosidase and 57.42, 60.07, 58.19, 66.90 for ß-glucosidase respectively) than reference compounds (acarbose with % inhibitory activity = 49.50 for α-glucosidase and d-saccharic acid 1,4-lactone monohydrate with % inhibitory activity = 53.42 for ß-glucosidase) and also showed good PPAR-γ activation and good hypoglycemic effect in comparison to pioglitazone and rosiglitazone. Moreover, Shape comparison and docking studies were carried out to understand their interaction and similarity with standard drugs.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Glycoside Hydrolase Inhibitors/pharmacology , PPAR gamma/agonists , Pyrroles/pharmacology , Thiazolidines/pharmacology , Animals , Anti-Inflammatory Agents/adverse effects , Anti-Inflammatory Agents/chemical synthesis , Anti-Inflammatory Agents/chemistry , Catalytic Domain , Celecoxib/chemistry , Celecoxib/pharmacology , Cellulases/metabolism , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/chemistry , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Drug Design , Glycoside Hydrolase Inhibitors/adverse effects , Glycoside Hydrolase Inhibitors/chemical synthesis , Glycoside Hydrolase Inhibitors/chemistry , Humans , Molecular Docking Simulation , Molecular Structure , PPAR gamma/chemistry , Pyrroles/adverse effects , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Sheep , Stomach Ulcer/chemically induced , Structure-Activity Relationship , Thiazolidines/adverse effects , Thiazolidines/chemical synthesis , Thiazolidines/chemistry , alpha-Glucosidases/metabolism
3.
Int Immunopharmacol ; 62: 165-169, 2018 Sep.
Article in English | MEDLINE | ID: mdl-30015236

ABSTRACT

The present study was planned to examine the effect of butylated hydroxy toluene (BHT) on the immune response of Rift Valley fever vaccine (RVFV) in Swiss mice. Animals were divided into four equal groups. The first group was kept as negative control. The 2nd group was orally administrated with the acceptable daily intake (ADI) of BHT 0.3 mg/kg b.wt. daily for 21 days and the 3rd group were vaccinated only by inactivated RVFV at a dose of 0.2 ml I/P two times. The 4th group was orally administrated BHT as in the 2nd group and vaccinated by inactivated RVFV as in the 4th group. Blood samples were collected from all groups two weeks from booster vaccination. The cellular immunity was determined by leucocytic indices and the neutrophil-lymphocyte ratio (NLR) whereas, humoral immunity was evaluated with IgG antibodies titer using enzyme-linked immune-sorbent assay (ELISA) test, serum neutralization test (SNT) and challenge test. BHT induced leucopenia, neutrophilia and marked lymphocytopenia in both non-vaccinated and vaccinated mice. Moreover, BHT significantly decreased the efficiency of vaccination by inducing 70% cytopathic effect (CPE) in the infected cell cultures and increasing the ED50 value of RVFV vaccine. The present study indicates that BHT possesses a potential for decreasing both cellular and humoral mediated mechanisms.


Subject(s)
Butylated Hydroxytoluene/pharmacology , Food Preservatives/pharmacology , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Rift Valley fever virus/immunology , Viral Vaccines/immunology , Animals , Antibodies, Viral/blood , Butylated Hydroxytoluene/administration & dosage , Cell Line , Cricetinae , Cytopathogenic Effect, Viral/drug effects , Dose-Response Relationship, Drug , Food Preservatives/administration & dosage , Mice , Rift Valley Fever/immunology
4.
Bioorg Chem ; 77: 568-578, 2018 04.
Article in English | MEDLINE | ID: mdl-29475165

ABSTRACT

Twelve new compounds of 1,3,4-trisubstituted-pyrazole derivatives possessing two cyclooxygenase-2 (COX-2) pharmacophoric moieties (SO2Me or/and SO2NH2) 11a-c, 12a-c, 13a-c and 14a-c were designed and synthesized to be evaluated for their COX inhibition, anti-inflammatory activity, ulcerogenic liability. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. The bisaminosulphonyl derivatives (14a-c) were the most COX-2 selective compounds (S.I. = 9.87, 9.50 and 9.22 respectively) and showed good anti-inflammatory potency (ED50 = 15.06, 42.51 and 50.43 µmol/kg respectively) in comparison with celecoxib (COX-2 S.I. = 8.61, ED50 = 82.2 µmol/kg). Also, compounds 14a-c were less ulcerogenic (ulcer indexes = 2.72-3.72) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.93). In addition, to explain the preferential (COX-2) inhibitory and selectivity, the designed compounds were subjected to molecular docking studies. It was found that compound 14c with the highest COX-2 activity and selectivity exhibited a binding pattern and interactions similar to that of celecoxib with formation of more hydrogen-bond features.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Pyrazoles/pharmacology , Stomach Ulcer/drug therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Edema/drug therapy , Humans , Models, Molecular , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Rats , Structure-Activity Relationship
5.
Future Med Chem ; 9(16): 1899-1912, 2017 10.
Article in English | MEDLINE | ID: mdl-29076755

ABSTRACT

AIM: A novel series of 2-arylimino-5-arylidenethiazolidin-4-ones 12a-n were synthesized and all the target compounds were fully characterized by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analysis. Materials & methods: All the target compounds were evaluated for their COX inhibition by enzyme immunoassay kit and in vivo anti-inflammatory activity. RESULTS: Tested compounds were found more potent inhibitors of COX-2 (IC50 = 0.54-3.14 µM) than COX-1 (IC50 = 4.97-11.52 µM). The ulcerogenic liability of compounds 12(d, e, f, h, k, m) was performed and showed gastric safety more than or comparable to celecoxib. CONCLUSION: In addition, docking study of the most potent and selective compound 12h into COX-2 active site revealed that this target compound assumed interactions and binding pattern similar to that of as a cocrystallized ligand bromocelecoxib (S-58).


Subject(s)
Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/pharmacology , Stomach Ulcer/prevention & control , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Animals , Celecoxib/chemistry , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Drug Discovery , Humans , Male , Molecular Docking Simulation , Molecular Structure , Rats , Structure-Activity Relationship
6.
J Enzyme Inhib Med Chem ; 31(sup3): 54-60, 2016.
Article in English | MEDLINE | ID: mdl-27541738

ABSTRACT

A new series of 1,5-diarylpyrazoles 10a-l was designed and synthesized for evaluation as COX inhibitors and as anti-inflammatory agents. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10e was the most COX-2 selective compound (S.I. = 10.67) and the most potent anti-inflammatory derivative (ED50 = 46 µmol/kg) which is approximately 11-folds more potent than ibuprofen (ED50 = 499 µmol/kg) and had 2/3 potency of celecoxib (ED50 = 31 µmol/kg). All compounds were less ulcerogenic (ulcer indexes = 1.20-4.61) than ibuprofen (ulcer index = 20.25) and comparable to celecoxib (ulcer index = 2.90).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cyclooxygenase 2 Inhibitors/pharmacology , Cyclooxygenase 2/metabolism , Pyrazoles/pharmacology , Stomach Ulcer/chemically induced , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Dose-Response Relationship, Drug , Inflammation/drug therapy , Inflammation/metabolism , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Structure-Activity Relationship
7.
Eur J Med Chem ; 118: 250-8, 2016 Aug 08.
Article in English | MEDLINE | ID: mdl-27131067

ABSTRACT

Two new series of 1,5-diaryl pyrazoles (5a, 5b, 7a, 7b and 10) and 1,5-diaryl pyrazoline (12a and 12b) were prepared as both Cyclooxygenase-2 and 15-lipoxygenase inhibitors. Carrageenan-induced rat paw edema, ulcer index and anti-COX-1/COX-2 and 15-LOX inhibition assays were also included. Cyclization of different pyrazoles was discussed using 2D NMR such as HSQC, HMBC and NOSEY determinations. Compound 5a is more effective with ED50 = 0.98 and 3.98 µM against COX-2 and 15-lipoxygenase respectively, than the references celecoxib (1.54 µM) and meclofenamate sodium (5.64 µM).


Subject(s)
Arachidonate 15-Lipoxygenase/metabolism , Celecoxib/chemical synthesis , Celecoxib/pharmacology , Cyclooxygenase 2/metabolism , Pyrazoles/chemistry , Thiazoles/chemistry , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/chemistry , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Cattle , Celecoxib/adverse effects , Celecoxib/chemistry , Chemistry Techniques, Synthetic , Cyclization , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2 Inhibitors/chemical synthesis , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Lipoxygenase Inhibitors/adverse effects , Lipoxygenase Inhibitors/chemical synthesis , Lipoxygenase Inhibitors/chemistry , Lipoxygenase Inhibitors/pharmacology , Magnetic Resonance Spectroscopy , Male , Rats , Stereoisomerism , Ulcer/chemically induced
8.
Bioorg Med Chem Lett ; 26(2): 406-412, 2016 Jan 15.
Article in English | MEDLINE | ID: mdl-26691756

ABSTRACT

Two new series of 1,3,5-triarylpyrazolines 10a-m and 1,5-diarylpyrazoles 14a-d were synthesized. All prepared compounds were evaluated for their in vitro COX-1/COX-2 inhibitory activity and the in vivo anti-inflammatory activity. All compounds were more selective for COX-2 isozyme and showed good in vivo anti-inflammatory activity. Compound 10k was the most COX-2 selective compound (S.I.=5.91) and the most potent anti-inflammatory derivative (ED50=99µmol/kg) which is approximately five folds more potent than ibuprofen (ED50=499µmol/kg) and had half potency of celecoxib (ED50=47µmol/kg). All compounds were less ulcerogenic (Ulcer Indexes=1.20-5.00) than ibuprofen (Ulcer Index=20.25) and comparable to celecoxib (Ulcer Index=2.90).


Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Cyclooxygenase 2 Inhibitors/chemistry , Cyclooxygenase 2 Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Anti-Inflammatory Agents/chemical synthesis , Cyclooxygenase 1/metabolism , Cyclooxygenase 2/metabolism , Cyclooxygenase 2 Inhibitors/chemical synthesis , Humans , Pyrazoles/chemical synthesis , Ulcer/chemically induced
9.
Acta Pol Pharm ; 70(3): 469-80, 2013.
Article in English | MEDLINE | ID: mdl-23757938

ABSTRACT

The reaction of acid hydrazides (1a-c) with 2-chloro-1-(4-chlorophenyl)ethanone (2a) or 2-bromo-1-(4-bromophenyl)ethanone (2b) afforded bis-hydrazones 6a-d, while the reaction of la-c with 2-oxo-N-arylpropanehydrazonoyl chlorides (3a,b) furnished N-(aryl)propanehydrazonoyl chlorides 8a-c. The reaction of the latter chlorides with sodium benzenesulfinate furnished sulfones 11a-c. On the other hand, treatment of benzothiazole-2-carbohydrazide (1c) with the appropriate ketones yielded the corresponding hydrazones 13a,b, while the reaction of 1c with 2-(ethoxymethylene)malononitrile (14) or with 2-[bis(methylthio)methylene]malononitrile (16) afforded pyrazole derivatives 15 and 17, respectively. In acute toxicity study, no mortalities were observed for the tested compounds. All the tested compounds showed significant anti-inflammatory activity, while some of them exhibited potent analgesic activity. In addition, all compounds exhibited lower ulcerogenic effects than the standard ketoprofen.


Subject(s)
Analgesics/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Hydrazones/chemical synthesis , Pyrazoles/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Female , Hydrazones/chemistry , Hydrazones/pharmacology , Hydrazones/toxicity , Male , Mice , Pyrazoles/chemistry , Pyrazoles/pharmacology , Pyrazoles/toxicity , Rats , Rats, Wistar , Stomach Ulcer/chemically induced
10.
Pharmacogn Mag ; 7(26): 109-15, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21716619

ABSTRACT

BACKGROUND: Moringa peregrina is a wild plant that grown in the eastern desert mountains in Egypt. Although, this plant is native to Egypt, no details studies were traced on its chemical composition and biological activity. MATERIALS AND METHODS: The different fractions of the ethanolic extract of the dried aerial parts of the plants were subjected to fractionation and purification on various silica and sephadex columns for the isolation of the major compounds which were tested for there anticancer activity. The aqueous and ethanolic extract as well as its different fractions were tested for antihyperglycemic effect on Streptozitocin-induced diabetes in rats. RESULTS: Investigation of the different fractions of the ethanolic extract of the aerial parts of M. peregrina yielded lupeol acetate (1), ß-amyrin (2), α-amyrin (3), ß-sitosterol (4), ß-sitosterol-3-O-glucoside (5), apigenin (6), rhamnetin (7), neochlorogenic acid (10), rhamnetin-3-O-rutinoside (12), and 6-methoxy-acacetin-8-C-ß-glucoside (13) which were isolated for the first time from the plant. Compound (13) was isolated for the first time from genus Moringa. In addition, quercetin (8), chryseriol-7-O-rhamnoside (9) and quercetin-3-O-rutinoside (11) were also isolated. Identification has been established by spectral data (UV, MS, IR, 1H, 1H -1H COSY, and 13C-NMR). The major isolated compounds were found to have valuable cytotoxic activities against breast (MCF 7) and colon (HCT 116) cancer cell lines and their activities were comparable to the reference drug doxorubicin. On the other hand, the aqueous and ethanolic extracts as well as the n-hexane fraction were found to have potent antihyperglycemic effect on Streptozitocin-induced diabetes in rats. CONCLUSION: The Egyptian plant M. peregrina is rich in biologically active ingredients which showed potent cytotoxic activity and also its ethanolic extraxt exert a significant antihyperglycemic effect.

11.
Food Chem Toxicol ; 48(11): 3209-14, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20736042

ABSTRACT

Following IV injection of doxycycline in a dose of 20 mg kg(-1) b.wt., its serum concentration was best fitted in two-compartment open model in chickens fed either on control or on anticoccidials-containing rations. Diclazuril and halofuginone resulted in a significant short distribution half-life (t(½α)) (7.17±0.39 and 11.88±1.05 min, respectively) and increased total body clearance (Cl(tot)) 0.37±0.024 and 0.295±0.034 L/kg/h, respectively. Following oral dosing the tested drug absorbed with t(½ab) of 41.38±1.6, 17.48±0.86 and 41.83±1.8 min, respectively and their C(max) values (3.18±0.18, 5.425±0.48 and 0.986±0.037 µg/ml) were attained at 2.07±0.097, 1.403±0.074 and 2.55±0.106 h. For doxycycline alone and in presence of diclazuril and halofuginone, respectively. Systemic bioavailability was 22.64±3.46, 86.74±9.23 and 22.38±3.09%, respectively. Following IM injection t(½ab) were 9.096±1.34 for doxycycline alone, 16.24±2.21 and 15.6±1.7 min in the presence of diclazuril and halofuginone, respectively. C(max) was 3.10±0.28, 4.63±0.57 and 0.55±0.07 µg/ml reached at 0.8±0.083, 1.13±0.126 and 1.21±0.105 h. For the antibiotic alone, and in presence of either diclazuril and halofuginone, respectively. Systemic bioavailability was 22.41±3.86, 88.97±12.9 and 12.31±0.99% in chickens fed on anticoccidial-free, diclazuril- and halofuginone-containing rations, respectively. Both the tested anticoccidials induced higher doxycycline tissue residues in all tested tissue samples.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Chickens/metabolism , Coccidiostats/therapeutic use , Doxycycline/pharmacokinetics , Nitriles/therapeutic use , Piperidines/therapeutic use , Quinazolinones/therapeutic use , Triazines/therapeutic use , Animal Feed , Animals , Coccidiosis/prevention & control , Drug Interactions , Drug Therapy, Combination , Female , Half-Life , Injections, Intramuscular , Injections, Intravenous , Male
12.
Pharmacol Res ; 50(2): 137-42, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15177301

ABSTRACT

The effect of alpha-tocopherol, simvastatin and both on male fertility in hypercholesterolemic rats was studied. Induction of hypercholesterolemia was done by feeding rats on a diet containing 1% cholesterol for 30 days. Hypercholesterolemic rats were orally given alpha-tocopherol (3 mg kg(-1) BW) or simvastatin (1 mg kg(-1) BW) or both for 65 days. Fertility index, serum testosterone level, sex organs weight, semen analysis and histopathological examination of testes, seminal vesicles and prostate glands were the parameters used to evaluate the reproductive efficiency of rats. In hypercholesterolemic rats (control +ve), there was a marked decrease in fertility index, testicular weight, sperm cell count, and percentages of sperm motility and viability associated with a significant increase in sperm cell abnormalities. Oral administration of either alpha-tocopherol or simvastatin to hypercholesterolemic rats for 65 days significantly improved the fertility index, testicular weight and semen quality. Concomitant administration of alpha-tocopherol and simvastatin to hypercholesterolemic rats markedly increased fertility index and sperm motility and viability associated with a significant reduction of sperm cell abnormalities. Histopathological examination revealed that testes of hypercholesterolemic rats (control +ve) had degenerated, non-functioning and atrophied seminiferous tubules associated with arrest of spermatogenesis. Oral administration of alpha-tocopherol and simvastatin concomitantly to hypercholesterolemic rats resulted in active mature and full functioning seminiferous tubules. In conclusion, concomitant administration of alpha-tocopherol and simvastatin to hypercholesterolemic male rats improved their reproductive efficiency and produced additional protection against reduced fertility induced by hypercholesterolemia.


Subject(s)
Hypercholesterolemia/drug therapy , Infertility, Male/drug therapy , Simvastatin/pharmacology , alpha-Tocopherol/pharmacology , Administration, Oral , Animals , Capsules , Cholesterol, Dietary/administration & dosage , Cholesterol, Dietary/adverse effects , Cholesterol, Dietary/pharmacology , Diet , Drug Administration Schedule , Drug Therapy, Combination , Female , Gelatin , Hypercholesterolemia/chemically induced , Hypercholesterolemia/complications , Infertility, Male/complications , Male , Organ Size/drug effects , Prostate/drug effects , Rats , Reproduction/drug effects , Reproduction/physiology , Semen/chemistry , Semen/drug effects , Seminiferous Tubules/drug effects , Seminiferous Tubules/pathology , Simvastatin/administration & dosage , Simvastatin/therapeutic use , Sperm Count/methods , Sperm Motility/drug effects , Spermatozoa/abnormalities , Spermatozoa/drug effects , Testis/chemistry , Testis/drug effects , Testis/ultrastructure , Testosterone/blood , Time Factors , alpha-Tocopherol/administration & dosage , alpha-Tocopherol/therapeutic use
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