Poor efficacy of the most commonly used anthelmintics in sport horse nematodes in Morocco in relation to resistance.

Sport and leisure horses in Morocco are treated with several anthelmintics, organophosphates (dichlorvos), benzimidazoles (mostly thiabendazole) or tetrahydropyrimidines (mostly pyrantel pamoate) against nematodes. We studied three horse stables in Rabat, one in Meknes and one in Bouznika. Two of the Rabat and Bouznika stables had introduced a large number of horses from countries (Argentina or Europe) where resistance to benzimidazoles is frequent, whereas the Meknes stud farm remained without foreign introduction. The number of treatments was not very frequent (twice a year in adult horses) but the same anthelmintics were used repeatedly. No resistance to dichlorvos was detected whereas benzimidazole and pyrantel pamoate resistances were detected for the first time in African horses, outside South Africa.

A comparative kinetic study of ivermectin and moxidectin in lactating camels (Camelus dromedarius).

The plasma and milk kinetics of ivermectin (IVM) and moxidectin (MXD) was evaluated in lactating camels treated subcutaneously (0.2 mg kg(-1)) with commercially available formulations for cattle. Blood and milk samples were taken concurrently at predetermined times from 12 h up to 60 days post-administration. No differences were observed between plasma and milk kinetics of IVM, while substantial differences were noted between plasma and milk profiles of MXD in that both the maximal concentration (Cmax) and the area under concentrations curves (AUC) were three to four-fold higher for milk than for plasma. The time (Tmax) to reach Cmax was significantly faster for MXD (1.0 day) than that for IVM (12.33 days). The Cmax and the AUC were significantly higher for MXD (Cmax = 8.33 ng ml(-1); AUC = 70.63 ng day ml(-1)) than for IVM (Cmax = 1.79 ng ml(-1); AUC = 30.12 ng day ml(-1)) respectively. Drug appearance in milk was also more rapid for MXD (Tmax = 3.66 days) compared to IVM (Tmax = 17.33 days). The extent of drug exchange from blood to milk, expressed by the AUCmilk/AUCplasma ratio, was more than three-fold greater for MXD (4.10) compared to that of IVM (1.26), which is consistent with the more lipophilic characteristic of MXD. However, the mean residence time (MRT) was similar in both plasma and milk for each drug.

The effect of feed quality on the kinetic disposition of orally administered triclabendazole in sheep.

The effect of two qualities of feed on the kinetic disposition of triclabendazole (TCBZ) metabolites was investigated in sheep (n = 4) following oral administration of TCBZ at 10 mg/kg body weight. The same sheep were given sequentially two qualitatively different diets: a low-quality (LQ) diet based on wheat straw ad libitum, and a high-quality (HQ) diet based on barley + alfalfa. The triclabendazole sulphoxide (TCBZSO) and triclabendazole sulphone (TCBZSO2) concentrations were determined in blood samples taken serially from the jugular vein between 5 min and 9 days after TCBZ administration. The parent drug TCBZ was not detected in any of the samples. The quality of feed affected the kinetics of both TCBZ metabolites. The rate of appearance (Tlag and Tmax) in the jugular blood was slower and the formed amount (AUC) of TCBZSO was slightly higher when the sheep were on the LQ diet (Tlag = 7.74 h; Tmax = 27.91 h; AUC = 1042 micrograms.h/ml) than when they were offered the HQ diet (Tlag = 1.90 h; Tmax = 16.01 h; AUC = 832.4 micrograms.h/ml). The MRT of TCBZSO was about 40% longer with the LQ diet than with the HQ diet. Similarly, the rate of appearance of TCBZSO2 in plasma of sheep was slower when they were on the LQ diet than when they were on the HQ diet, suggesting an impairment of the hepatic enzymatic activity involved in the oxidation of TCBZSO to TCBZSO2.

Pharmacokinetics of sulfonamides and trimethoprim in the donkey (Equus asinus).

The body disposition of sulfadimidine (SDM), sulfadiazine (SDZ), sulfamethoxypyridazine (SMPZ) and a trimethoprim-sulfadimethoxine combination (TMP-SDMX) was investigated in the donkey. The four sulfonamides and TMP were injected intravenously at doses of 20 mg/kg (SDM, SDZ, SMPZ), 12.5 mg/kg (SDMX) and 2.5 mg/kg (TMP). The body clearance (ClB) of SDZ (1.70 +/- 0.14 ml/min/kg) was significantly higher than those of SDM (1.13 +/- 0.18 ml/min/kg), SMPZ (1.10 +/- 0.09 ml/min/kg) and SDMX (0.75 +/- 0.04 ml/min/kg). In contrast, the volume of distribution at steady state (Vss) was similar for the four sulfonamides (0.68 +/- 0.08 L/kg, 0.63 +/- 0.07 L/kg, 0.47 +/- 0.06 L/kg, and 0.46 +/- 0.05 L/kg for SDM, SDZ, SMPZ and SDMX, respectively). Both ClB and Vss were significantly higher for TMP (4.36 +/- 0.60 ml/min/kg and 2.71 +/- 0.86 L/kg) than for sulfonamides. Antipyrine ClB (3.49 +/- 0.35 ml/min/kg) and Vss (0.66 +/- 0.16 L/kg), determined in order to assess hepatic oxidative function and total body water volume, respectively, were either different from (ClB), or similar to (Vss), values calculated for sulfonamides. The results obtained were compared to those reported in horses.

Effect of diet variations on the kinetic disposition of oxfendazole in sheep.

Pharmacokinetic parameters of oxfendazole (OFZ) were determined in five sheep submitted to two different feeding regimens: a poor/dry diet based on wheat straw ad libitum, and a rich/green diet based on fresh grass grazed on pasture. Animals were acclimatised to each diet before they were administered OFZ orally at a dose of 5 mg kg-1 body weight. Blood samples were taken serially between 10 min and 168 h post-administration. Plasma concentrations of OFZ and its metabolites (fenbendazole (FBZ) and fenbendazole sulphone) were quantified using an HPLC technique. Rates of absorption of OFZ and of formation of FBZ and fenbendazole sulphone were slower with the poor/dry diet; however, the area under FBZ plasma concentration vs time curve was higher when sheep were offered the low quality diet, suggesting a shift of OFZ metabolism towards FBZ formation.

Pharmacokinetic considerations in the camel (Camelus dromedarius): a review.

In this article the pharmacokinetic profile of several antibacterial, antiparasitic and antiinflammatory agents in camels has been reviewed. The effect of dehydration on the kinetics of these drugs has also been discussed.

Pharmacokinetics of ketoprofen in the donkey (Equus asinus).

The pharmacokinetic parameters of ketoprofen were determined in four donkeys after a single intravenous injection of a dose of 2.2 mg/kg body weight. The total body clearance (ClB) was 414.0 +/- 98.70 ml/h/kg (mean +/- SD), the volume of distribution at steady state (Vss) 263.10 +/- 55.43 ml/kg and the elimination half-life 1.30 +/- 0.75 h. These values were compared to those obtained in horses.

Influence of injection site on the absorption of benzylpenicillin sodium in the dromedary.

Benzylpenicillin absorption was compared in four dromedaries following injection subcutaneously and at three different intramuscular sites (neck, semitendinous and gluteal muscles). The rate of absorption (t1/2ab and Tmax) was slower after subcutaneous compared to intramuscular injection, but the extent of absorption (AUC) was similar for both routes of administration. Following intramuscular injection, the data suggest that the extent of absorption was highest from the semitendinous site and lowest in the neck site. These results were discussed and compared to those reported in other species.

[Pharmacokinetics and plasma protein binding of sulfamethoxypyridazine in camels (Camelus dromedarius)]. / Etude de la pharmacocinétique et de la liaison aux protéines plasmatiques de la sulfaméthoxypyridazine chez le dromadaire (Camelus dromedarius).

The pharmacokinetics of sulfamethoxypyridazine (SMPD) were investigated in the camel after intravenous and oral administration. After intravenous injection, the plasma concentration of the drug followed the kinetics of a two-compartment model. The steady-state volume of distribution (Vss) of 0.47 l/kg suggested that sulfamethoxypyridazine was mostly distributed within the vascular compartment and the strongly vascularized tissues. The elimination from the body was rather slow, with a biological half-life [t1/2(beta)] and a total plasma clearance of about 9.5 h and 0.037 l/kg.h, respectively. Oral treatment showed that the maximum plasma concentration was reached 17 hours post drug administration and that the bioavailability ranged around 57%. Study of the plasma protein binding showed that the percentage of SMPD binding to plasma proteins varied from 47 to 72% and seemed to be concentration-dependent. The total binding capacity and the dissociation constant at equilibrium were 196 micrograms/ml and 335 micrograms/ml, respectively.

Kinetic disposition of flunixin meglumine in the camel (Camelus dromedarius).

The kinetic disposition of flunixin meglumine was investigated in 5 camels after a single intravenous administration (1.1 mg/kg bwt). The plasma clearance was 1.012 ml.min-1.kg-1, the steady-state volume of distribution 0.168 l/kg and the elimination half-life 2.51 h. The results are discussed and compared with those reported in cattle and horses.

Effect of dietary nitrogen intake on gentamicin disposition in sheep.

The effect on gentamicin pharmacokinetics of a diet high (HP) (120 g/day) or low (LP) (25 g/day) in digestible proteins was studied in sheep. Gentamicin sulphate (4 mg/kg) and inulin (40 mg/kg) were administered by the intravenous route to six ewes of local Moroccan breed. The serum gentamicin concentrations were consistently higher in ewes that received a LP diet. Clearance was 0.93 +/- 0.13 ml/mm/kg in the LP group and 1.64 +/- 0.40 ml/mm/kg in the HP group. The volume of distribution at steady state (Vss) was lower in the LP group (11% of body weight) than in the HP group (21.8% of body weight). These diet-linked variations in pharmacokinetic parameters were also obtained in the disposition of inulin following the intravenous administration of a single dose. This suggests that the protein content of the diet modifies the distribution of body water and kidney function. The therapeutic, toxicological and hygienic implications of these modifications are discussed.

Effect of water deprivation on absorption (oral, intramuscular) and disposition of ampicillin in sheep.

The effects of a 72 h water deprivation on the absorption--intramuscular (i.m.) and oral and disposition of ampicillin, inulin and para-aminohippuric acid (PAH) were investigated in six sheep. After intravenous (i.v.) administration of ampicillin sodium (10 mg/kg), the water deprivation decreased slightly the initial volume of distribution (0.082 +/- 0.033 vs. 0.055 +/- 0.030 l/kg) but not the steady state volume of distribution. The plasma clearance was significantly decreased (6.21 +/- 1.94 vs. 3.90 +/- 1.92 ml/min/kg) and the mean residence time (MRT) was increased from 22.25 +/- 4.91 to 33.36 +/- 8.16 min. After i.m. administration of ampicillin sodium (20 mg/kg), ampicillin concentrations were systematically higher after a 3-day period of water deprivation than during the control period but the muscular absorption rate was not modified. After oral administration of ampicillin trihydrate (1 g in toto) plasma concentrations were much lower and more persistent than after an i.m. administration and the systemic availability remained low whatever the hydration status. Influences of water deprivation on ampicillin disposition were linked to adaptation of renal function as assessed by inulin and PAH clearances. The therapeutic relevance of the results are discussed for a better definition of dosage regimens for sheep reared in arid environments.

Pharmacokinetics and local tolerance of a long-acting oxytetracycline formulation in camels.

Disposition and local tolerance of a new oxytetracycline (OTC) long-acting formulation were evaluated in camels by measuring the dynamics of creatine kinase. Six camels (Camelus dromedarius) were administered OTC by IV and IM routes according to a 2-period cross-over, study design. Serum OTC concentration was measured, using a microbiological assay procedure. After IV administration (5 mg/kg of body weight), mean residence time was 7.7 +/- 2.8 hours, steady-state volume distribution was 706.1 +/- 168.6 ml.kg-1 and serum clearance was 75.3 +/- 23.2 ml.kg-1.h-1. After IM administration of the long-acting OTC formulation (10 mg/kg), maximal OTC concentration (3.49 +/- 0.44 micrograms.ml-1) was observed after 7.3 +/- 3.5 hours; the mean systemic availability was near 100%, and serum concentration greater than 0.5 micrograms.ml-1 was maintained for about 72 hours. After IM administration, mean control serum activity of creatine kinase was multiplied by a factor of 3.36 +/- 1.55; at 72 hours after OTC administration, the serum creatine kinase activity returned to control values. It was concluded that OTC is an antibiotic of potential interest in camels and that a dosage regimen of 10 mg.kg-1 deserves attention when using a long-acting formulation that has good local tolerance and near total systemic availability.

Food deprivation and refeeding in the camel (Camelus dromedarius).

Camels thrive in arid and semiarid areas, although food and water frequently are scarce. However, the mechanisms enabling camels to withstand food deprivation are poorly understood. In this study four female camels were totally deprived of food for 4 days. Their body weight decreased by 6%. Food deprivation caused no change in total plasma protein concentration in the camel, indicating that no alterations in plasma volume occurred. When the first meal was withheld water intake was unchanged. Next day the camels showed signs of hydration with a decreased plasma Na+ concentration and an increased excretion of diluted urine. In the afternoon water intake decreased. Urine K+ excretion fell the first day and urine volume and Na+ excretion from the third day. No activation of the renin-angiotensin-aldosterone system (RAAS) was observed. Plasma and urine urea concentration increased during food deprivation. Plasma glucose concentration and plasma cortisol and thyroxine levels did not change. Body temperature decreased during food deprivation. After refeeding, total plasma proteins increased temporarily by 12%, and a threefold increase in RAAS was seen, implying that both plasma volume and RAAs changed rapidly. Our results show that fluid balance was only slightly affected in the food-deprived camel. We suggest that strategies for the camel to endure food deprivation include maintenance of plasma volume and glucose concentration and a lowering of the body temperature.

Influence of the stage of pregnancy on gentamicin disposition in the ewe.

The influence of the state of pregnancy (mid- and end of pregnancy) on the kinetic disposition of gentamicin was determined in the ewe. Kinetic parameters were determined after a single intravenous bolus administration (4 mg/kg). It was shown that the steady state volume of distribution was significantly increased from mid to end of pregnancy (from 0.09 I.kg-1 to 0.194 I.kg-1). Similarly, plasma clearance was increased by about 150% at the end of pregnancy. These modifications must be taken into account in order to adapt the dosage regimen and determine a withdrawal time for gentamicin.

[Comparative pharmacokinetics of triclabendazole in camels and sheep]. / Etude pharmacocinétique comparée du triclabendazole chez le mouton et le dromadaire.

The authors describe the compared pharmacokinetics of triclabendazole in three camels and four sheep which were given orally a single dose of 10 mg/kg liveweight. Plasma concentrations of triclabendazole and its main metabolites were determined by high performance liquid chromatography. No parental drug was detected in the blood plasma due to a hepatic first passage effect. It appeared that there was a major difference between the two species, triclabendazole sulfoxide concentrations being two times lower in camels than in sheep.

Benzylpenicillin kinetics in the ewe: influence of pregnancy and lactation.

Benzylpenicillin kinetics were investigated in a breed of sheep adapted to life in barren areas. Important pharmacokinetic differences, dependent on reproductive status (control, pregnancy, lactation), were demonstrated. In control ewes, the steady state volume of distribution was 0.23 +/- 0.15 litre kg-1 and the plasma clearance was 12.4 +/- 3.19 ml kg-1 min-1. During pregnancy, these two parameters were not significantly modified. During lactation, the plasma clearance and volume of distribution were significantly higher than during the control period and pregnancy (27.4 +/- 3.22 ml kg-1 min-1 and 0.696 +/- 0.20 litre kg-1, respectively (P less than 0.01). In contrast the mean residence time (25.0 +/- 4.6 minutes) was similar to those of the control period (17.54 +/- 6.25 minutes) and pregnancy (23.18 +/- 5.94 minutes). These modifications in benzylpenicillin kinetics were explained in terms of fluid balance adjustments and renal function adaptation observed during pregnancy and lactation, and it is suggested that an appropriate dosage regimen for benzylpenicillin should take into account the physiological status of the animal.

Comparative benzylpenicillin pharmacokinetics in the dromedary Camelus dromedarius and in sheep.

Benzylpenicillin pharmacokinetics were compared in the dromedary Camelus dromedarius (n = 5) and in sheep (n = 5) after administration of a single intravenous injection of benzylpenicillin. The data were described by an open three-compartment model with elimination from the central compartment. Body clearance (Clb) was 4.87 +/- 0.63 ml/min/kg in the dromedary and 9.17 +/- 1.39 ml/min/kg in sheep, the steady-state volumes of distribution (Vss) were 0.151 +/- 0.023 l/kg and 0.165 +/- 0.038 l/kg and the mean residence times (MRT) 27.34 +/- 1.38 min and 14.95 +/- 4.16 min in the dromedary and in sheep, respectively. It was concluded that benzylpenicillin elimination occurs more slowly in the dromedary than in sheep and that use of the same dosage regimen for the two ruminant species may lead to significant differences in plasma concentrations and therapeutic efficacy.