Intravascular plasma disposition and salivary secretion of closantel and rafoxanide in sheep

The plasma and salivary disposition of closantel and rafoxanide were examined following intravenous administration in adult sheep. Two studies were conducted with rafoxanide at 7.5 mg/kg and 1 with closantel using 2 doses (5 and 15 mg/kg). The pharmacokinetic profile of both drugs in plasma were best described by a 2-compartmental model with 1st-order rate constants. Plasma disposition of closantel and rafoxanide were characterised by a rapid distribution (t1/2(alpha)) of <30 min), long elimination half-life (t1/2(beta)) of 17.0 +/- 4.0 days for closantel and 7.2 +/- 0.6 days for rafoxanide), small apparent volume of distribution (V(SS) of <0.15 l/kg) and a slow rate of total body clearance (Cl of <0.01 ml/min/kg). The area under the drug plasma concentration curve (AUC) of closantel at 5 mg/kg was nearly twice as large as that of rafoxanide at 7.5 mg/kg resulting from the slower t1/2(beta) observed with closantel compared to rafoxanide. Large individual differences were observed in the rate measurements of distribution (k12, k21 and t1/2(alpha)), whereas the parameters of elimination (k10, t1/2(beta) and Cl), were more consistent between animals. A dose proportional increase in AUC was observed for closantel administered at 5 and 15 mg/kg. A low, constant salivary concentration of closantel (mean of 0.04 +/- 0.05 microg/mL) and rafoxanide (mean of 0.07 +/- 0.04 microg/mL) was observed during the 24-h examination period after dosing.     

The pharmacodynamics of the flukicidal salicylanilides, rafoxanide, closantel and oxyclosanide

The pharmacokinetics of oxyclosanide, rafoxanide and closantel were investigated in sheep (n = 5). All three drugs were extensively (greater than 99%) bound to plasma proteins and the plasma concentration/time curve was best described by a tri-exponential equation. Closantel and rafoxanide had long terminal half-lives (mean 14.5 and 16.6 days, respectively) compared with oxyclosanide (mean 6.4 days). In a study of the efficacy of rafoxanide against Fasciola hepatica, a dose rate of 7.5 mg kg-1 against 6-week-old flukes appeared to be similarly effective to a dose rate of 2.5 mg kg-1 against 10-week-old flukes (86% and 88% efficacy, respectively), as assessed at autopsies carried out on all sheep when the flukes were 14 weeks old. Part of this putative efficacy against immature flukes may be due to rafoxanide persisting in the plasma and affecting the mature flukes when they reach the bile ducts.     

Comparative pharmacokinetic disposition of closantel in sheep and goats

The pharmacokinetic disposition of closantel was examined following intraruminal (i.r.) or intramuscular (i.m.) administration to adult Merino sheep and to adult and 3-month-old, suckling Angora goats. In adult goats the maximum concentration (C_max) and area under the plasma concentration with time curve ( AUC ) following 3.75, 7.5 and 15.0 mg closantel/kg given i.r. increased with dose however the time of C_max (r_max= 2.6d) in plasma was unaffected by dose rate. The elimination phase (K₁₀) of closantel was monoexponential with a half-life ( t _½) of 4.7d again unaffected by dose rate. Apart from a more rapid absorption phase and earlier T_max following 3.75 mg closantel/kg i.m., pharmacokinetic behaviour was similar to that following i.r. administration at 3.75 or 7.5 mg/kg. Although absorption rate was more rapid in kids after i.r. administration at 7.5 mg/kg, pharmacokinetic disposition of closantel was otherwise similar to that in adult goats. No closantel was detected in milk of treated does or in the plasma of their kids. I.R. closantel at 7.5 mg/kg was more slowly absorbed in goats than in sheep but C_max was similar in both species. However, K₁₀ t _½ was significantly shorter in goats (4d) than in sheep (14d). Faster elimination resulted in an almost three-fold lowering of AUC in goats and could dramatically reduce the sustained action of closantel in this species compared with sheep.     

Amaurosis in sheep resulting from treatment with rafoxanide

Amarurosis occurred in sheep on various farms in the Republic of South Africa after treatment with rafoxamide. Histopathological examination revealed a status spongiosus of varying severity in the central nervous system in all the cases, having a predilection for certain areas such as the periventricular area of the lateral ventricles, optic tracts, lateral geniculates and optic fasiculi. The retina was the only ocular tissue affected and lesions observed in the retina included necrosis of nerve cells in the ganglionic layer. In chronic cases of amaurosis this layer showed a complete absence of nerve cells. The possible pathogenesis of the lesions and their differentiation from those found in certain plant toxicoses are discussed.     

Relative bioavailability of rafoxanide following intraruminal and intra-abomasal administration in sheep

The bioavailability of rafoxanide was compared after intraruminal and intra-abomasal administration in healthy adult sheep (n = 6) in a single dose, 2 parallel group study at 7.5 mg/kg. Rafoxanide concentrations in plasma were measured by means of HPLC analysis. Primary pharmacokinetic parameters for bioavailability and disposition of rafoxanide in plasma for both routes of administration were determined by non-compartmental and non-linear, 1-compartmental pharmacokinetic analysis, respectively. Significantly (P < or = 0.05) higher peak plasma concentrations (c(max)) of rafoxanide and a more rapid rate of absorption (c. 3.5 times) was observed in sheep after intra-abomasal (i-a) administration compared to intraruminal (i.r.) administration. A significantly (P < or = 0.05) longer lag period (t(lag)) before absorption (6.8 +/- 2.9 h) occurred after i.r. than after i-a treatment (1.9 +/- 0.6 h). There was no significant difference (P > 0.05) in AUC, MRT and in the rates of elimination (k10-HL and t(1/2beta)) between the i.r. and i-a routes of administration. The results of the study demonstrated the important influence of the rumino-reticulum on absorption of rafoxanide in sheep.     

Activity of closantel against experimentally induced Fascioloides magna infection in sheep

The efficacy of closantel against experimentally induced Fascioloides magna infection in sheep was studied. In each of 3 experiments, closantel was administered 8 weeks after the sheep were given (oral inoculation) 100 metacercariae of F magna. In the 1st experiment, closantel was given orally to 5 groups of 6 sheep each at dosages of 0 (nontreated control), 5, 7.5, 10, and 15 mg/kg of body weight. In the 2nd and 3rd experiments, groups of 10 or 12 sheep were treated to confirm the efficacy of the previously determined optimal dosage of 15 mg/kg. An additional group of sheep (n = 10) was used in the 3rd experiment to evaluate the efficacy of closantel given IM at a dosage of 7.5 mg/kg. Closantel given orally at a dosage level of 15 mg/kg was highly effective (94.6% to 97.7%) in reducing F magna burdens. Also, pathologic scores associated with the F magna infection were reduced by 81.3% to 92.6% in sheep given this dosage of closantel. Efficacy of the IM administered dosage of 7.5 mg of drug/kg was equivalent to that of the 15 mg/kg oral dosage. Other than mild, transient lameness of the limbs which were injected with the drug (group 10), side effects were not observed.     

Field trials with closantel and Haemonchus contortus in sheep in Papua New Guinea

Sheep treated once with closantel at 7.5 or 15.0 mg/kg and grazing with untreated sheep remained free of Haemonchus contortus for at least 4 to 5 weeks and 6 to 7 weeks respectively after treatment. When the whole flock was treated with 15.0 mg/kg, H. contortus began to become re-established 7 to 8 weeks later. Maximum benefit of the residual anthelmintic effect of closantel against H.contortus was obtained only when all sheep in the flock were treated; it took 10 weeks longer for H.contortus to form 50% of larval cultures when the whole flock was treated than when only a part of the flock was treated.     

绵羊瘤胃酸中毒的诊疗

绵羊主要由于过食玉米、小麦等谷物饲料,于瘤胃内高度发酵,产生大量乳酸而致代谢性酸中毒.报告如下.     

Comparative efficacy of closantel and triclabendazole against Fasciola hepatica in experimentally infected sheep

The effect of closantel (10 mg/kg orally) and triclabendazole (10 mg/kg orally) on the reappearance of a patent infection of Fasciola hepatica was studied in experimentally infected sheep. The treatments resulted in the interruption of faecal egg output for 11 weeks with triclabendazole and 13 weeks with closantel. Necropsy of untreated control animals revealed a mean burden of 360 flukes with a mean (+/- se) surface area of 171 +/- 64.3 mm2, whereas the fluke burdens in the closantel and triclabendazole-treated animals 14 weeks after treatment were 61 (83 per cent reduction) and 21 (94 per cent reduction), respectively. The surface areas of the flukes in the triclabendazole-group were comparable with the untreated controls (141 +/- 51.8 mm2), but the flukes in the closantel group were markedly smaller (43.1 +/- 26.9 mm2). It is concluded that closantel has, in epidemiological terms, a potency comparable with that of triclabendazole, despite its slightly lower efficacy against the very immature stages.