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.

Influences of tolfenamic acid and flunixin meglumine on the disposition kinetics of levofloxacin in sheep.

The pharmacokinetics of levofloxacin (4 mg/kg), administered both alone and in combination with tolfenamic acid (2 mg/kg) and flunixin meglumine (2.2 mg/kg), was established after intravenous administration in sheep. Plasma levofloxacin concentrations were assayed by high-performance liquid chromatography and analysed according to the two-compartment open model. Following the administration of levofloxacin alone, the mean distribution half-life, elimination half-life, total clearance, volume of distribution at steady state and area under the plasma concentration-time curve were 0.20 h, 1.82 h, 0.39 L/h/kg, 0.96 L/kg and 10.40 h × µg/mL, respectively. Tolfenamic acid and flunixin meglumine caused a slow elimination and increased plasma concentrations of levofloxacin in combination administration. Levofloxacin, with an alteration in the dosage regimen, can be used effectively with tolfenamic acid and flunixin meglumine for the therapy of infections and inflammatory conditions in sheep.

Alpha lipoic acid and vitamin E improve atorvastatin-induced mitochondrial dysfunctions in rats.

To determine the effects of alpha lipoic acid (ALA) and vitamin E (Vit E) on mitochondrial dysfunction caused by statins. A total of 38 Wistar Albino rats were used in this study. The control group received dimethyl sulfoxide. The atorvastatin (A) group received atorvastatin (10 mg/kg). The A + ALA group received atorvastatin (10 mg/kg) and ALA (100 mg/kg). The A + Vit E group was administered atorvastatin (10 mg/kg) and Vit E (100 mg/kg). The A + ALA + Vit E group was administered atorvastatin (10 mg/kg), ALA (100 mg/kg) and Vit E (100 mg/kg). All applications were administered simultaneously by gavage for 20 days. ATP level and complex I activity were measured from liver, muscle, heart, kidney and brain. Atorvastatin significantly decreased the ATP levels in heart and kidney, while a slight decrease was seen in liver, muscle and brain. Atorvastatin caused an insignificant decrease in the complex I activity in all tissues examined. ALA administration significantly improved the ATP levels in the liver, heart and kidney, while Vit E improved the ATP levels in all tissues except the muscle compared to Atorvastatin group. Single administration of both ALA and vit E ameliorated complex I activity in the muscle, heart, kidney and brain. The combination of ALA and Vit E significantly improved the ATP levels in the liver, heart, kidney and brain and also provided significant improvements the complex I activity in all tissues. The undesirable effects of Atorvastatin on mitochondrial functions in this study ameliorated by using ALA and/or Vit E alone and in combination.

Intravenous pharmacokinetics of moxifloxacin following simultaneous administration with flunixin meglumine or diclofenac in sheep.

In this study, the pharmacokinetics of moxifloxacin (5 mg/kg) was determined following a single intravenous administration of moxifloxacin alone and co-administration with diclofenac (2.5 mg/kg) or flunixin meglumine (2.2 mg/kg) in sheep. Six healthy Akkaraman sheep (2 ± 0.3 years and 53.5 ± 5 kg of body weight) were used. A longitudinal design with a 15-day washout period was used in three periods. In the first period, moxifloxacin was administered by an intravenous (IV) injection. In the second and third periods, moxifloxacin was co-administered with IV administration of diclofenac and flunixin meglumine, respectively. The plasma concentration of moxifloxacin was assayed by high-performance liquid chromatography. The pharmacokinetic parameters were calculated using a two-compartment open pharmacokinetic model. Following IV administration of moxifloxacin alone, the mean elimination half-life (t1/2ß ), total body clearance (ClT ), volume of distribution at steady state (Vdss ) and area under the curve (AUC) of moxifloxacin were 2.27 hr, 0.56 L h-1  kg-1 , 1.66 L/kg and 8.91 hr*µg/ml, respectively. While diclofenac and flunixin meglumine significantly increased the t1/2ß and AUC of moxifloxacin, they significantly reduced the ClT and Vdss . These results suggest that anti-inflammatory drugs could increase the therapeutic efficacy of moxifloxacin by altering its pharmacokinetics.

Pharmacokinetics and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous, intramuscular, subcutaneous, and oral administrations.

The aim of the present study was to determine the pharmacokinetics (PKs) and bioavailability of danofloxacin in chukar partridge (Alectoris chukar) following intravenous (IV), intramuscular (IM), subcutaneous (SC), and oral (PO) administrations at a dose of 10 mg/kg. A total of eight clinically healthy chukar partridges weighing 480 ± 45 g were used for the investigation. The study was performed in a crossover design (2 × 2 × 2 × 2) with a 15-day washout period between two administrations in four periods. The plasma concentrations of danofloxacin were determined using reversed-phase high-performance liquid chromatography. Noncompartmental PK parameters were also estimated. No local or systemic adverse drug effects were observed in any of the chukar partridges. The mean elimination half-life ranged between 8.18 and 12.08 hr and differed statistically among administration routes. The mean peak plasma concentrations of danofloxacin following IM, SC, and PO administrations were 8.05, 9.58, and 3.39 µg/ml at 0.5, 1, and 4 hr, respectively. Following IM, SC, and PO administrations, the mean bioavailability was 86.33%, 134.40%, and 47.62%, respectively. The mean total clearance and volume of distribution at steady-state following IV administration were 0.13 L hr-1  kg-1 and 0.96 L/kg, respectively. These data, including favorable PKs and the absence of adverse drug effects, suggest that danofloxacin is a useful antibiotic in chukar partridges.

Determination of milk/plasma ratio and milk and plasma pharmacokinetics of amoxicillin after intramuscular administration in lactating cows.

This study was conducted to determine the passage ratio of amoxicillin into milk and its pharmacokinetics in milk and plasma after intramuscular administration. Five healthy dairy cows (Holstein, weighing 450-500 kg, aged 2-4 years) were used in this study. They received single intramuscular amoxicillin at a dose of 14 mg/kg body weight. Blood and milk samples were collected prior to drug administration (0); after 15, 30, 45, 60, and 90 min; and 2, 3, 4, 6, 8, 10, and 12 hr after administration. The plasma and milk concentrations of amoxicillin were determined using high-performance liquid chromatography with ultraviolet detection. The passage ratio of amoxicillin into milk and plasma was determined using both AUC-based calculation and milk and plasma concentrations at sampling times; it was calculated 0.46 and 0.52, respectively. The terminal half-life and mean residence time of amoxicillin were 6.05 and 8.60 hr in plasma and 2.62 and 5.35 hr in milk, respectively. The Cmax2 levels of amoxicillin in plasma and milk were measured as 1,096 and 457 ng/ml, respectively. It was observed that amoxicillin exhibited a secondary peak in plasma and milk. This study was the first to report on the passage ratio of amoxicillin into milk in lactating cows.

Combined treatment with interleukin-1 and tumor necrosis factor-alpha antagonists improve type 2 diabetes in rats.

In the present study, combined treatment with etanercept and anakinra were tested in the streptozotocin-induced diabetic rats. Forty male Wistar albino rats were divided into 5 groups: healthy control (HC), diabetic control (DC), diabetic + anakinra (DAT), diabetic + etanercept (DET), and diabetic + etanercept + anakinra (DEAT). HC and DC groups received subcutaneous (s.c.) injection with a saline solution, while DAT and DET groups received anakinra (10 mg/kg per day, s.c.) or etanercept (10 mg/kg, twice a week, s.c.), and DEAT rats received both anakinra and etanercept treatments for 21 days after diabetes has developed. Anakinra and etanercept treatments significantly increased insulin and homeostatic model assessment ß-cell function levels and decreased glucose levels compared to the DC group as single (DAT and DET) and combined treatments (DEAT). The thiobarbituric acid reactive substances level was significantly decreased in DAT group. The combine use of etanercept and anakinra can improve insulin and blood glucose in type 2 diabetic rats. The combined treatment of anakinra and etanercept together was more effective than single treatment and might have a potential new treatment strategy and to reduce the mortality and morbidity resulting from diabetes.