Pharmacokinetics of halofuginone in cattle

Copyright 2008 Elsevier B.V., All rights reserved.The pharmacokinetics of the antitheilerial drug halofuginone were evaluated in healthy calves following oral administration, at a dose of 1·2 mg/kg body weight, repeated after 48 h. The maximum plasma concentration after the first dose ranged from 3·8 to 7·7 ng/ml (6·5 ng/ml, mean) and occurred at between 12 and 32 h (22 h, mean). After the second dose, the maximum plasma concentration was 4·8-8·6 ng/ml (7·2 ng/ml, mean) occurring between 12 and 32 h (17 h, mean). The apparent terminal elimination half-life ranged from 24·2 to 28·9 h with a harmonic mean of 27·3 h. No significant difference was found in the apparent volume of distribution and the body clearance between the values calculated after the first dose and the two doses. The results show that the concentrations which persist in plasma from 8 to 120 h are above the in-vitro concentration of halofuginone required to reduce by 50% the proportion of lymphoblastoid cells containing Theileria parva schizonts (EC=3 ng/ml), but the maximum plasma concentrations are only about 46% of the in-vitro optimal effective concentration, EC (15 ng/ml).Peer reviewe

Isometamidium in goats : disposition kinetics, mammary excretion and tissue residues

The pharmacokinetics of the antitrypanosomal drug isometamidium were studied in lactating goats after intravenous and intramuscular administration at a dose of 0.5 mg/kg body weight, in a crossover design at an interval of 6 weeks. Following intravenous administration, the half-life of the disappearance of the drug from plasma during the terminal phase was 3.2 h, and the mean residence time was 2.4 h. The apparent volume of distribution averaged 1.52 l/kg, and the mean total body clearance was 0.308 l/kg/h. After intramuscular administration, the absolute bioavailability was low, averaging 27%. This was consistent with a low mean maximum concentration of 24 ng/ml which occurred after 6 h. No drug was detectable (less than 10 ng/ml) in milk samples collected over a period of 14 days following drug administration by either the intravenous or intramuscular route. In tissues analysed when the goats were killed 6 weeks after administration of the second dose, no drug was detectable (less than 0.4 micrograms/g wet tissue) in the liver, kidney and muscle. However, at the injection site, drug concentrations varied from less than 0.4 to 18.8 micrograms/g wet tissue.Peer reviewe

Generation of monoclonal antibodies to the anti-trypanosomal drug Samorin

Isometamidium chloride (Samorin, Trypanidium is a phenanthridine-aromatic amidine that is commonly used in cattle as a prophylactic agent against trypanosomiasis. Although the compound has been used for over 30 years, very little is known about its mode of action. Various workers have demonstrated that the molecule interferes with DNA polymerases purine nucleotide synthesis polyamine metabolism and mitochondrial type II topoisomerase .However, the contribution of such activities to the compound's anti-trypanosomal activity in vivo is not known. In the work presented here we describe the production and characterisation of a set of monoclonal antibodies (MAbs) that were raised against isometamidium. Such reagents constitute a potential tool for determining the site of action of isometamidium within trypanosomes. Two drug conjugates were synthesised for this work; an isometamidium-human serum albumin (HSA) conjugate was prepared as described by Kinabo and Bogan (1988). An isometamidium-porcine thyroglobulin (PTG) conjugate was prepared as described by Whitelaw et al. (1991). Thereafter, anti-isometamidium monoclonal antibodies were produced using two methods

Generation of monoclonal antibodies to the anti-trypanosomal drug isometamidium

Mice were immunized with either an isometamidium-human serum albumin (HSA) conjugate or an isometamidium-porcine thyroglobulin conjugate (PTG). Thereafter, monoclonal antibodies (MAbs) IL-A 1001, IL-A 1002, IL-A 1003, 5F7.B7, and 5F7.C9 were generated and selected on the basis that they recognized conjugated and unconjugated isometamidium, but lacked cross-reactivity with the carrier molecules. All five MAbs were of the IgG1 isotype. Each of the five MAbs was assessed in a competitive ELISA for isometamidium; in each case, the minimum level of detection was approximately 10ng/ml. Each MAb exhibited approximately 0.1% cross-reactivity with the anti-trypanosomal compound diminazene. However, based on their cross-reactivity with the anti-trypanosomal compound homidium, the MAbs could be divided into two groups; IL-A 1001, IL-A 1002, and IL-A 1003, produced using an isometamidium-HSA conjugate as an immunogen, exhibited low levels of cross-reactivity (approximately 0.1%). In contrast, 5F7.B7 and 5F7.C9, produced using an isometamidium-PTG conjugate as an immunogen, exhibited high levels of cross-reactivity

Plasma disposition of amikacin and interactions with gastrointestinal microflora in Equidae following intravenous and oral administration

Amikacin was detectable (> 0.02 micrograms/ml) in plasma for 12 h in horses and donkeys and for 8 h in ponies following intravenous (i.v.) administration at a dose rate of 6 mg/kg bodyweight. The elimination half-life (harmonic mean) of amikacin was 2.8, 1.6 and 1.9 h in horses, ponies and donkeys, respectively, and the mean body clearance was relatively slow (45.2, 82.4 and 58.0 ml/h.kg, respectively). A suitable dosage interval for the i.v. administration of amikacin sulphate to horses, ponies and donkeys, at a dose rate of 6 mg/kg, would be every 8 h in horses, and every 6 h in ponies and donkeys. Following i.v. administration there were no marked alterations in caecal liquor pH, the number of viable bacteria isolated, or the short chain fatty acid (SCFA) concentrations in caecal liquor and faeces. Amikacin was not detected (<0.02 micrograms/ml) in plasma following administration by nasogastric tube to ponies with cannulated caecal fistulae; however, there were high concentrations of amikacin measured in caecal liquor (maximum 16.2-99.4 micrograms/ml). Despite the high drug concentrations in caecal liquor, there were only slight alterations in the number of viable bacteria isolated. However, there was a reduction in caecal liquor pH to <6.6, but few changes in caecal liquor SCFA concentrations. Faecal SCFA concentrations, dry matter content and consistency did not alter markedly.Peer reviewe