Trials with rafoxanide. 6. The effect of repeated and single treatments with rafoxanide against Haemonchus contortus and Oestrus ovis in sheep.
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Administration, Oral↗
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Trials with rafoxanide. 3. Efficacy of rafoxanide against the larvae of the sheep nasal bot fly Oestrus ovis, Linné, 1761.
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Animals↗
Effect of early treatment with rafoxanide on antipyrine clearance in sheep infected with Fasciola hepatica.
1. The effect of the salicylanilide compound rafoxanide against immature stages of Fasciola hepatica was investigated in sheep using a series of antipyrine clearance tests and measuring glutamate dehydrogenase and gamma-glutamyl transferase activities in plasma. 2. Three animal groups were used. In two groups, sheep were infected with 200 metacercariae each. Four weeks after infection one of the two groups was treated with rafoxanide and the other was left untreated. The third group was unparasitized and also received rafoxanide. 3. Infection was confirmed by post-mortem examination of the livers of infected sheep. Infection did not alter the plasma disposition of rafoxanide. 4. The efficacy of rafoxanide, as assessed by the reduction in the number of adult flukes in treated animals compared with controls, was 85%. 5. Glutamate dehydrogenase activity fell dramatically 2 weeks after treatment but increased again at 12 weeks post-infection in the infected rafoxanide-treated group. 6. Antipyrine clearance decreased between 8 and 14 weeks post-infection in untreated sheep. In the infected rafoxanide-treated group plasma clearance of antipyrine remained unchanged until 10 weeks after rafoxanide administration when it decreased from the preinfection value of 5.09 to 3.90 ml.kg/min. Rafoxanide did not affect antipyrine disposition in uninfected sheep. 7. It was concluded that rafoxanide had an incomplete anthelmintic effect against immature stages of Fasciola hepatica, and that surviving parasites caused delayed liver damage which was reflected in an elevation in glutamate dehydrogenase activity and decreased plasma clearance of antipyrine.
Animals↗
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.
Animals↗
Oral toxicity in weanling and adult rats and in vitro genotoxicity of the veterinary anthelmintic rafoxanide.
The oral toxicity of the veterinary anthelmintic Rafoxanide was evaluated in newborn rats exposed in utero and during lactation. In another group, 3 months of oral treatment started after weaning. Rafoxanide administration to dams (10 mg kg-1) decreased the number of pups per litter, induced high mortality (42%) and delayed the growth of offsprings before weaning. Histopathological examination of the central nervous system revealed vacuolation of the white matter. Vacuolation was particularly severe in the cerebellum of the 14-21-day-old rats. Rafoxanide induced, in some pups (35%), the formation of cataracts. These toxic effects seemed to be reversible and were no longer detectable after a further 3-month administration of Rafoxanide (10 mg kg-1) to rats born of treated dams. In adult rats treated orally for 3 months with 1, 5 or 25 mg kg-1 Rafoxanide, biochemical and haematological tests did not reveal dose-related effects. Rafoxanide had no mutagenic activity in the Ames and CHO/HGPRT tests.
Aging↗
The metabolic profile of adult Fasciola hepatica obtained from rafoxanide-treated sheep.
Sheep infected with adult Fasciola hepatica were drenched with rafoxanide. At 4, 8, 16 and 24 h after drenching the sheep were killed and the flukes removed, washed and rapidly frozen in liquid nitrogen. The content of key metabolites in the fermentation pathway were determined and compared with those in control F. hepatica, whose hosts were not treated with rafoxanide. Rafoxanide decreased glycogen, malate, NADH and ATP levels. The level of other metabolites in the pathway increased for the first 8-16 h after rafoxanide treatment. The marked decrease in ATP and glycogen, and the increase in total [NAD+]/[NADH] and [oxaloacetate]/[malate], together with the changed content of other metabolites, led to the conclusion that the mode of action of rafoxanide against F. hepatica in vivo is by uncoupling oxidative phosphorylation.
Adenosine Diphosphate↗
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.
Abomasum↗
Stability and partitioning of closantel and rafoxanide in ruminal fluid of sheep.
The stability and the partitioning of closantel and rafoxanide in ruminal fluid (RF) was examined in vitro. Stability was evaluated in two studies in a ruminal fluid-artificial saliva (RF-AS) mixture containing either drug. Drug concentrations were measured in samples collected sequentially from four batches of RF-AS fortified with either closantel or rafoxanide in one study and in four separately incubated aliquots of a RF-AS mixture of each drug in the second study at the start and at various intervals during a 24 h incubation period. The viability of the in vitro RF-AS incubation model was validated by the presence of digoxin degradation (T1/2 of 39,1 +/- 13 h) and by the absence of significant time related differences (P> 0,5) in volume of gas produced, pH and methylene blue reduction time of the RF-AS drug mixture. Partitioning of closantel and rafoxanide was determined by measuring the relative drug concentration of the fluid and particulate phases in RF fortified with either drug at different concentrations. Closantel and rafoxanide were shown to be stable in a RF-AS mixture and were not subjected to any significant biodegradation. An initial marked reduction in drug concentration measured in the RF-AS mixture during the first 2 h of incubation was attributed to the attachment of both drugs onto particulate matter. This was subsequently confirmed in the partitioning study. More than 80% of closantel and rafoxanide was shown to be associated with the particulate phase of RF
Animals↗
Differences in the oral bioavailability of three rafoxanide formulations in sheep.
The bioavailability of a modified rafoxanide oral suspension was compared to the original innovator product and a generic formulation in a single dose, randomised, parallel design study in sheep (n = 30). The area under the rafoxanide plasma concentration versus time curve (AUC), AUC extrapolated to infinity, and maximum plasma rafoxanide concentrations (Cmax), were used to compare the extent of absorption of the formulations. All 3 parameters were significantly (p < or = 0.01) smaller for both the modified and generic formulations relative to the original product. There were no significant (p > 0.05) differences between the modified and generic formulations. The mean point ratio % of the modified to original and modified to generic formulations for the 3 parameters were 36.4%, 35%, 45.9% and 70.9%, 70%, 79.7%, respectively. In terms of the calculated 90% confidence t-intervals of the mean % ratios, the modified and generic formulations were not bioequivalent to the original product, since they were substantially below the accepted range of 80-125%. No significant differences (p > 0.05) were noted for the time to Cmax and Cmax/AUC, both measurements of rate of absorption. A lag period before absorption of rafoxanide for all formulations of c 5 h was observed. The differences in oral bioavailability of rafoxanide and related anthelmintic formulations have implications for the efficacy and registration of generic products.
Administration, Oral↗
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.
Animals↗
Comparative efficacy of triclabendazole, nitroxynil and rafoxanide against immature and mature Fasciola hepatica in naturally infected cattle.
In two trials the fasciolicidal activities of triclabendazole, nitroxynil and rafoxanide were assessed in cattle naturally infected with predominantly immature stages of Fasciola hepatica. Tablets containing 900 mg triclabendazole were administered orally at a dose rate of 12 mg/kg bodyweight. Rafoxanide and nitroxynil were used at a dose rate of 10 mg/kg, rafoxanide being given orally and nitroxynil by subcutaneous injection. Based on faecal egg counts nine weeks after treatment the efficacies were calculated to be 100 per cent for triclabendazole and 95.0 per cent for nitroxynil in the first trial and 98.4 per cent for triclabendazole and 52.9 per cent for rafoxanide 15 weeks after treatment in the second trial. In the first trial five animals from each of the three groups were slaughtered and their fluke burdens counted. Compared with the untreated control group the reductions in the fluke burdens were 96.9 per cent in triclabendazole treated cattle and 76.4 per cent in the nitroxynil treated group.
Animals↗
Determination of rafoxanide and closantel in ovine plasma by high performance liquid chromatography.
A high performance liquid chromatographic method has been developed for the determination of rafoxanide and closantel in ovine plasma. Acetonitrile and chloroform were used for the extraction. The mean recoveries were 78.69% and 80.59% for rafoxanide and closantel, respectively. This method was applied to the characterization of rafoxanide plasma kinetics following oral administration of therapeutic doses to sheep.
Animals↗
A safety trial with rafoxanide in sheep.
Six groups of 6 lambs each were treated orally with rafoxanide at dosages ranging from 0 to 37,5 mg/kg live mass in multiples of 7,5 mg/kg. The lambs were slaughtered 27 to 31 d after treatment for post mortem examination. No clinical, ophthalmological or pathological changes attributable to treatment were detected in any of the lambs. Possible differential diagnoses and predisposing factors for rafoxanide toxicity are discussed. It is suggested that plasma-rafoxanide assay be used as a diagnostic tool.
Animals↗
Pharmacokinetics of rafoxanide in suckling and weaned lambs following oral administration.
The pharmacokinetics of rafoxanide administered orally at 15 mg kg-1 were compared in suckling lambs (n = 8), aged 5-8 weeks and weaned lambs (n = 8), aged 21-22 weeks. A significant difference (p < 0.0001) in area under the curve (AUC) and maximum plasma concentrations (Cmax) were observed between the different age groups. The bioavailability, as measured by AUC and Cmax, was 2.5-3 times greater in the suckling lambs compared to the weaned lambs. No significant differences (p > 0.05) in time to maximum plasma concentrations (Tmax), distribution half-life (T1/2 alpha), elimination half-life (T1/2 beta) and mean residence time (MRT) were observed. It was concluded that the pharmacokinetic differences observed between suckling and weaned lambs may result in an increased susceptibility of suckling lambs to the toxic effects of rafoxanide. Lambs younger than 8 weeks, should preferably not be treated with rafoxanide, or the dose must be reduced.
Aging↗
Incidence of experimental fascioliasis on hepatic disposition of [3H]tetracycline and [14C]rafoxanide in rats.
[7-3H]Tetracycline and [carbonyl-14C]rafoxanide were injected intravenously into anesthetized controls and rats in which experimental fascioliasis had been induced by 20 Fasciola hepatica metacercariae. The biliary excretion (1 and 3 h, respectively) of the radioactivity consisted of approximately 4% of the administered dose. In 4-week infested rats, biliary excretion of [3H]tetracycline and hepatic levels of radioactivity were decreased, whereas bile flow did not vary and plasma clearance of the antibiotic was significantly decreased in comparison with control animals. These differences could be the result of the fascioliasis-induced decrease in the hepatic uptake of tetracycline and the limited active transport for its output into bile canaliculi. No change in [14C]rafoxanide disposition was shown in infested rats.
Animals↗
The effects of rafoxanide and nitroxynil on the survival, growth and morphology of Fasciola hepatica in rabbits.
Two experiments were carried out to assess the effects of nitroxynil (10 mg/kg p.o.) and rafoxanide (6.7 mg/kg p.o.) against 2,4, 6 or 8 weeks old F. hepatica in rabbits. The results show that the efficacy and incidence of stunted and abnormal surviving flukes were directly related to the age of infection at treatment. Rafoxanide was the more potent compound against immature forms. The testes were the most consistently abnormal reproductive organs in flukes surviving treatment with both drugs and spermatogenesis per se was disrupted.
Age Factors↗
Effects of the anthelmintics clorsulon, rafoxanide, mebendazole and arprinocid on Echinostoma caproni in ICR mice [corrected and reapublished in J Helminthol 1996 Mar;70(1):95-6].
Female ICR mice, 5 to 6 weeks old, were exposed by stomach tube to 25 metacercarial cysts of Echinostoma caproni per mouse. At 14 days post-exposure, mice were fed by stomach tube clorsulon (1000 mg/kg, 500 mg/kg and 100 mg/kg) or rafoxanide (50 mg/kg, 25 mg/kg and 5 mg/kg) dissolved in dimethylsulphoxide (DMSO) carrier and mebendazole (1000 mg/kg and 500 mg/kg) or arprinocid (100 mg/kg and 50 mg/kg) suspended in a 2:1 polyethylene glycol (PEG)/DMSO carrier. All drugs were obtained from Merck Inc. (Rahway, New Jersey, USA) and only single dose regimes were used. Experimentally infected mice that served as controls received either DMSO or 2:1 PEG/DMSO carriers or were not given the carrier. Mice were necropsied 15v, 16, 18 and 20 days postexposure to worms. Doses of 100 mg/kg of clorsulon and 50 mg/kg of rafoxanide were 100% effective in eliminating the echinostomes on day 1 post-administration of the anthelmintics. Mebendazole and arprinocid were ineffective in eliminating worms at 1 or 2 days post drug administration.
Adenine↗
Effects of the anthelmintics clorsulon, rafoxanide, mebendazole and arprinocid on Echinostoma caproni in ICR mice.
Female ICR mice, 5 to 6 weeks old, were exposed by stomach tube to 25 metacercarial cysts of Echinostoma caproni per mouse. At 14 days post-exposure, mice were fed by stomach tube clorsulon (1000 mg/kg, 500 mg/kg and 100 mg/ kg) or rafoxanide (50 mg/kg, 25 mg/kg and 5 mg/kg) dissolved in dimethylsulphoxide (DMSO) carrier and mebendazole (1000 mg/kg and 500 mg/ kg) or arprinocid (100 mg/kg and 50 mg/kg) suspended in a 2:1 polyethylene glycol (PEG)/DMSO carrier. All drugs were obtained from Merck Inc. (Rahway, New Jersey, USA) and only single dose regimes were used. Experimentally infected mice that served as controls received either DMSO or 2:1 PEG/DMSO carriers or were not given the carrier. Mice were necropsied 15, 16, 18 and 20 days postexposure to worms. Doses of 100 mg/kg of clorsulon and 50 mg/kg of rafoxanide were 100% effective in eliminating the echinostomes on day 1 post-administration of the anthelmintics. Mebendazole and arprinocid were ineffective in eliminating worms at 1 or 2 days post drug administration.
Adenine↗