Pharmacokinetics and pharmacokinetic interactions of orally administered oxfendazole and oxyclozanide tablet formulation to sheep.

The combination of oxfendazole and oxyclozanide is used to provide activity against fluke and gastrointestinal nematodes. This study aimed to determine both the pharmacokinetics of oxfendazole (7.5 mg/kg) and oxyclozanide (15 mg/kg) tablet formulation administered orally to sheep and whether there is a pharmacokinetic interaction between these two drugs. The study was conducted in a three-period, crossover pharmacokinetic design and on six healthy Awassi sheep 1-3 years of age. The plasma concentrations of oxfendazole and its metabolites (fenbendazole and fenbendazole sulphone) and oxyclozanide were determined by high-performance liquid chromatography using an ultraviolet detector. Compounds recovered in plasma when oxfendazole was administered alone or combined with oxyclozanide were oxfendazole, fenbendazole sulphone, and fenbendazole, respectively. When oxfendazole was administered alone and co-administered with oxyclozanide, the AUCFBZ /AUCOFZ was 0.26 and 0.23, respectively, and the AUCFBZSO2 /AUCOFZ was 0.35 and 0.32, respectively. The volume of distribution (Vz/F) of oxfendazole was large in both groups. Oxyclozanide did not change the plasma disposition of oxfendazole. When the oxyclozanide tablet formulation was administered alone, the elimination half-life (21.35 h) and the Vz/F (940.17 ml/kg) were long and large, respectively. The area under the curve (AUC) and the maximum plasma concentration of oxyclozanide were significantly larger and higher, respectively, in the oxyclozanide plus oxfendazole group (1146.61 h × µg/ml and 29.80 µg/ml) compared with the oxyclozanide group (491.44 h × µg/ml and 14.24 µg/ml) while a significant decrease in apparent Vz/F (940.17 vs 379.14 ml/kg) and total clearance (30.52 vs 13.08 ml/h/kg) was detected. In conclusion, co-administration with oxfendazole causing an increase in the plasma profile of oxyclozanide may increase the antiparasitic activity of oxyclozanide.

Can diarrhea affect the pharmacokinetics of racecadotril in neonatal calves?

This study was aimed to determine the pharmacokinetics of antisecretory-acting racecadotril, used in the treatment of diarrhea in humans and dogs, following oral administration in both neonatal calves with healthy and neonatal calves with infectious diarrhea. The study was carried out on a total of 24 Holstein calves (2-20 days), of which 6 were healthy and 18 were infectious diarrhea. Calves with infectious diarrhea were divided into 3 groups according to the infectious agent (Escherichia coli, Cryptosporidium parvum, and rotavirus/coronavirus). Racecadotril was administered orally at 2.5 mg/kg dose to calves. The plasma concentrations of racecadotril and its main active metabolite (thiorphan) were determined using HPLC-UV. The pharmacokinetic parameters were analyzed using the non-compartmental method. In healthy calves, the t1/2ʎz , Cmax , Tmax, and AUC0-12 of racecadotril were determined 4.70 h, 377 ng/ml, 0.75 h, and 1674 h × ng/ml, respectively. In the plasma of calves with infectious diarrhea, racecadotril and thiorphan were only detected at the sampling time from 0.25 to 1.5 h. As in calves with infectious diarrhea, thiorphan in plasma was only detected in healthy calves from 0.25 to 1.5 h. Racecadotril showed a large distribution volume, rapid elimination, and low metabolism to thiorphan in healthy calves.

Treatment and protective effects of metalloproteinase inhibitors alone and in combination with N-Acetyl cysteine plus vitamin E in rats exposed to aflatoxin B1.

This study was conducted to investigate the effects of matrix metalloproteinase (MMP) inhibitors dexamethasone and minocycline administrations -both single and in combination with N-acetylcysteine (NAC) and vitamin E-on the tissue distribution and lethal dose (LD)50 of aflatoxin (AF)B1 in rats. We performed this study on male Wistar rats (8-10 weeks) in two phases. In the first phase, rats were administered dexamethasone (5 and 20 mg/kg) and minocycline (45 and 90 mg/kg), both as single treatments and in combination with NAC (200 mg/kg) and vitamin E (600 mg/kg); these treatments followed AFB1 administration (2 mg/kg). In the second phase, the therapeutic effect value (TEV) was calculated to determine the treatment effect on the LD50 level of AFB1. The tissue affinity of AFB1 from high to low was liver, kidney, intestine, brain, heart, spleen, lung, testis, and vitreous humor, respectively. Dexamethasone at the 20 mg/kg dose significantly reduced AFB1 concentrations in the plasma and the other tissues, except for the vitreous humor. The effects of minocycline on the plasma and tissue concentrations of AFB1 varied by dose and tissue. The combinations of dexamethasone or minocycline with NAC and vitamin E increased the AFB1 concentrations in the plasma and all tissues, except for vitreous humor and liver. In male rats, the LD50 value of AFB1 was 11.86 mg/kg. The TEV of dexamethasone (20 mg/kg) was calculated to be 1.5. Dexamethasone can be administered in repeated doses at ≥20 mg/kg to increase survival in AFB1 poisoning.