Evaluation of clorsulon against immature Fascioloides magna in cattle and sheep

Efficacy of clorsulon was evaluated against infection with immature Fascioloides magna in 24 cattle and 12 sheep. Infections were induced by oral administration of 600 metacercariae/host. In cattle, clorsulon at dosages of 7 and 21 mg/kg of body weight was 65 and 100% effective against 8-week-old flukes, and 20 and 74% effective against 16-week-old flukes, respectively. In sheep, clorsulon at a dosage of 21 mg/kg was 92% effective against 8-week-old flukes. Significantly (P less than 0.05) more F magna were recovered from untreated sheep than from untreated cattle.     

Comparative efficacy of clorsulon and albendazole against Fasciola hepatica in cattle

In a dosage-confirmation trial, anthelmintic activities of clorsulon and albendazole against Fasciola hepatica were evaluated and compared. Twenty-eight cattle (8 to 12 months old) with natural F hepatica infections were randomly allotted to 4 groups of 7 cattle each: group 1, no treatment (controls); group 2, clorsulon suspension given orally at 3.5 mg/kg of body weight; group 3, clorsulon suspension given orally at 7 mg/kg; and group 4, albendazole paste given orally at 10 mg/kg. At necropsies, performed 7 and 8 days after treatment, control cattle harbored a geometric mean of 133.2 F hepatica, 16.0 of which were immature. Clorsulon administered at 3.5 mg/kg or 7 mg/kg resulted in greater than 99% removal of F hepatica, including immatures. Albendazole treatment resulted in a 76% overall reduction in F hepatica, including a 91% reduction of immatures. Fascioloides magna also were found in the cattle, but neither clorsulon nor albendazole caused significant reductions of the parasite. Adverse reactions to the 2 drugs were not observed.     

Ineffectiveness of clorsulon against Nanophyetus salmincola in coyotes

Efficacy of clorsulon against the trematode Nanophyetus salmincola was evaluated in coyotes. Ten 16-week-old coyote pups were fed fish that contained metacercariae of N. salmincola. Twenty-one days later, 5 of the coyotes were given a suspension of clorsulon (approx 16 mg/kg of body weight, orally). Within 30 days after treatment, the numbers of fluke eggs in fecal specimens from the 5 treated coyotes had not decreased, and numbers of fluke eggs and flukes recovered from treated coyotes at necropsy did not differ from numbers of fluke eggs and flukes recovered from 5 untreated coyotes. Therefore, clorsulon at a dosage of 16 mg/kg was not effective against N. salmincola.     

Evaluation of the comparative efficacy of a moxidectin plus triclabendazole pour-on solution against adult and immature liver fluke, Fasciola hepatica, in cattle

The objective of this study was to evaluate the efficacy of a pour-on solution containing moxidectin plus triclabendazole (MOX plus TCBZ) against immature and adult stages of the liver fluke in cattle and compare the efficacy with other commercially available preparations. To this end, 104 male Holstein-Friesian calves aged between 3 and 4 months, were randomly allocated to 13 groups of eight animals each, and infected with approximately 500 Fasciola hepatica metacercariae. One group remained untreated, four groups were treated with MOX plus TCBZ at a dose rate of 0.1mL/kg, four other groups were treated with ivermectin (IVM) plus clorsulon injectable at a dose rate of 0.02mL/kg, and the remaining four groups were treated with IVM plus closantel pour-on at a dose rate of 0.1mL/kg. Each treatment was applied to one of the groups at 4 weeks, 6 weeks, 8 weeks and 12 weeks after the experimental infection. At necropsy (99-102 days after infection), all untreated animals were infected with a minimum of 30 flukes. The MOX plus TCBZ treated animals had significantly (P<0.0001) lower fluke counts compared to the untreated control animals at all time points after treatment. Efficacy against 8-week old and adult flukes was >99.5%. For 6-week old immature fluke, the efficacy was 98.0% and for 4-week old immature fluke the efficacy was 90.9%. The IVM plus closantel pour-on treated animals had significantly lower fluke counts compared to the untreated control animals for adult and 8-week old flukes (P<0.0001), and for 6-week old flukes (P=0.002). The efficacy was 26.8%, 68.2%, 90.6% and 99.3% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. The IVM plus clorsulon treated animals had significantly lower fluke counts compared to the untreated control animals for adult (P<0.0001) and 8-week old (P<0.05) flukes. The efficacy was 29.7%, 43.4%, 53.2% and 99.2% against 4-week, 6-week and 8-week old immature flukes, and adult flukes respectively. For treatments at 4, 6 and 8 weeks after infection, the fluke counts were significantly (P<0.0001) lower for the MOX plus TCBZ treatment than for IVM plus closantel or IVM plus clorsulon. The results confirm the high efficacy (>90%) of the MOX plus TCBZ pour-on combination against 4-week old to adult liver fluke in cattle. The IVM plus closantel pour-on combination was effective (>90%) against 8-week old and adult flukes, but had low efficacy against 4- and 6-week old fluke. The IVM plus clorsulon injectable combination was effective (>90%) against adult fluke only.     

Efficacy of clorsulon for the treatment of experimentally induced infections of Fasciola hepatica in goats

A dose titration study was undertaken to determine the efficacy of clorsulon against the adult stage of Fasciola hepatica in goats. Thirty-nine goats were experimentally infected with metacercariae of F hepatica. At 14 weeks after infection, each goat was assigned randomly to 1 of 5 groups. Goats in groups 1 to 4 received a single oral administration of clorsulon at dosages of 3.5, 7, 11, and 15 mg/kg of body weight, respectively. The fifth group of goats (control group) was infected with F hepatica, but were not treated with clorsulon. Postmortem examination of goats at 3 weeks after treatment revealed mean reductions in numbers of flukes of 83, 98, 99, and 100% for groups 1 to 4, respectively. Mean percentage of reduction in eggs following treatment of groups was 82, 98, 100, and 100%, respectively. The clinical effects of clorsulon in 24 goats that were not infected with F hepatica were studied. Goats in groups 1 to 3 received a single oral administration of clorsulon at dosages of 7, 21, and 35 mg/kg, respectively, every other day for a total of 3 doses/goat. Group-4 goats (control group) received a vehicle placebo. Goats in group 3 were subject to postmortem examination at 14 days after dosing. Abnormal signs or lesions that could be attributed to clorsulon were not found in any goat.     

Efficacy of clorsulon against mature, naturally acquired Fasciola hepatica infections in cattle and sheep

Clorsulon (3.5 or 7 mg/kg of body weight) was given orally to mature cows (dairy or beef) and to mature mixed-breed sheep harboring patent infections of Fasciola hepatica. Eighteen animals of each species were assigned to a control group (drug vehicle) or to 1 of 2 treatment (3.5 or 7.0 mg/kg) groups of 6 animals each. On posttreatment days 8 (cows) or 14 (sheep), the animals were slaughtered for recovery of flukes. In cows, the efficacy (P values for treatment groups vs control) of clorsulon against infections of mature F hepatica was 99.21% (P less than or equal to 0.0065) at 3.5 mg/kg and was 100% (P less than or equal to 0.0039) at 7 mg/kg. In sheep, the efficacy was 93.33% (P less than or equal to 0.0104) at 3.5 mg/kg and was 100% (P less than or equal to 0.0039) at 7 mg/kg. These results indicate that clorsulon is a highly effective compound for the treatment of mature F hepatica in cows and sheep.     

The efficacy of triclabendazole and other anthelmintics against Fasciola hepatica in controlled studies in cattle

In eight controlled tests 274 cattle were used to assess the efficacies of triclabendazole, albendazole, clorsulon, nitroxynil, oxyclozanide and rafoxanide against Fasciola hepatica. Against one-, two- and four-week-old early immature fluke the mean efficacies of triclabendazole given orally at 12 mg/kg were 88.1, 95.3 and 90.7 per cent, respectively. Clorsulon, nitroxynil and rafoxanide administered at recommended dose rates showed negligible activity against these stages of the parasite. Against six- and eight-week-old infections the mean efficacies of triclabendazole at 12 mg/kg were 87.5 per cent and 95.7 per cent, respectively. Against F hepatica aged six weeks, albendazole and oxyclozanide showed no activity and clorsulon, nitroxynil and rafoxanide had only slight to moderate activity. The efficacies of triclabendazole, clorsulon, nitroxynil and rafoxanide against 10- or 12-week-old parasites were 100, 99.0, 99.1 and 90.1 per cent, respectively. Albendazole and oxyclozanide showed poor efficacy against 12-week-old infections.     

Efficacy of clorsulon against Fascioloides magna infection in sheep

In a study to evaluate the efficacy of clorsulon against Fascioloides magna infection in sheep, 12 ewes were inoculated orally with 100 metacercariae of F magna, and 6 were treated with clorsulon (15 mg/kg of body weight) 8 weeks after inoculation. The sheep were euthanatized 16 weeks after inoculation, flukes were recovered, and the liver and other tissues were subjectively scored for the severity of lesions (0 to 4+). The number of flukes recovered from the clorsulon-treated group (3.8 +/- 1.2 flukes) was significantly (P = 0.025) lower than the number of flukes recovered from the group of untreated controls (10.0 +/- 6.6 flukes). The severity of lesions was significantly (P = 0.004) reduced (45.9%) in the treated group (2.0 +/- 1.1), compared with that in the untreated controls (3.7 +/- 0.5). In the untreated group, 3 sheep died and 1 became moribund 14 to 16 weeks after inoculation. The data suggested that a single treatment with clorsulon at a dosage of 15 mg/kg 8 weeks after inoculation was not effective in preventing F magna infection in sheep, because the survival of only a few F magna is potentially fatal in sheep within 6 months after infection.     

Efficacy of concomitant early summer treatment with fenbendazole and clorsulon against Fasciola hepatica and gastrointestinal nematodes in calves in Louisiana

The efficacy, safety, and compatibility of fenbendazole (FBZ) and clorsulon (CLN) were tested after oral administration of label recommended and of higher (5x) dosage rates to calves naturally infected with gastrointestinal nematodes and Fasciola hepatica. Results for 42 calves allotted to 4 treatment groups indicated a similar efficacy against mature F hepatica by FBZ (5 mg/kg of body weight) and CLN (7 mg/kg) in a combined oral suspension, compared with CLN (7 mg/kg) alone (100 vs 99% reduction). A lesser efficacy was observed against immature flukes (88.6 and 84.9% reduction, respectively). Calves given 25 mg of FBZ/kg and 35 mg of CLN/kg had nearly complete reduction of both mature (99.6%) and immature flukes (99.1%). Fasciola egg counts were reduced by greater than 99.5% in all treated groups. Against Ostertagia ostertagi, the percentage of efficacy of the combined FBZ (5 mg/kg) and CLN (7 mg/kg) treatment was 94.3% against adults and 81.3% against inhibited larvae. Efficacy against all other nematodes was 100%, except against Cooperia spp adults (98.3%) and immature Oesaphagostomum radiatum (88.0%). At 5 x dosage rates for FBZ and CLN, percentage of removal of adults and inhibited larvae of O ostertagi was 99.3 and 99.0%, respectively, and 99 to 100% for other nematodes. Results indicate that FBZ and CLN are compatible when mixed together and administered as an oral suspension to cattle and that the efficacy is similar to that of the drugs individually. On the basis of further results, we suggest that summer treatment may be superior in preventive value for gastrointestinal nematodes and F hepatica, compared with spring treatment, because of seasonal infection dynamics of the major cattle parasites in Louisiana.     

Interaction of Fasciola hepatica with albendazole and its metabolites

Adult Fasciola hepatica recovered from sheep 12 and 24 h after a single oral dose of albendazole (20 mg/kg) contained significant amounts of two oxidized metabolites of albendazole (ABZ), a sulphoxide (SX) and a sulphone (SO), but not ABZ. Flukes incubated in vitro with 10 microM SX or SO contained these metabolites at a level two to three times the level observed in flukes recovered from sheep 24 h after a curative oral dose of ABZ. The concentration of ABZ in flukes was 10-fold greater than either SX or SO after a 24 h in vitro incubation in 10 microM of the respective drug. Flukes exposed to ABZ in vitro contained two-fold higher SX levels than SX-treated flukes due to a combination of spontaneous oxidation in media and fluke-mediated oxidation of ABZ. Measurement of end-products of glucose metabolism following 24 h incubation in 10 microM of either ABZ, SX or SO did not show a significant difference between treated and untreated flukes.     

国产三氯苯咪唑驱除山羊肝片形吸虫效果试验

以国产三氯苯咪唑对自然感染肝片形吸虫的山羊进行了驱虫试验，并以硝氯酚为药物对照。结果表明，三氯本咪唑5mg/kg体重的剂量对肝片形吸虫成虫和童虫的驱虫率分别为99.3%和92.9%，驱净率为75％；三氯苯咪唑10mg/kg体重的剂量对肝片形吸虫成虫和童虫的驱虫率均为100％，驱净率为100％；硝氯酚5mg/kg体重剂量对肝片形吸虫成虫驱虫率为100％，但对童虫的仅为74.3%，而驱净率仅为60％。在整个试验期间试验羊均无不良反应。     

Prophylactic efficacy of clorsulon against Fasciola hepatica in calves and sheep

A daily oral 5 mg kg-1 dose of clorsulon for 28 days in calves given Fasciola hepatica cysts at 3, 5, and 7 days after initiation of treatment was highly effective in reducing worm burdens (98%) and preventing liver pathology. In similarly infected and treated sheep, clorsulon showed little effect as a prophylactic for delaying the onset of liver pathology. The size of flukes recovered from treated sheep was reduced. Although clorsulon prevented development of fascioliasis in treated calves, the host antibody response was qualitatively similar to that of untreated infected calves, but the magnitude of the response was reduced. Blood clorsulon levels in calves rose to 2.90 micrograms ml-1 within the first week of treatment then fluctuated between 2.65 and 2.90 micrograms ml-1 for the next two weeks. Clorsulon levels in sheep were 0.50-0.60 micrograms ml-1 lower than those in calf blood. The difference in bioavailability of clorsulon between sheep and calves may have contributed to differences in efficacy of the drug.     

Clorsulon pharmacokinetics in sheep and goats following oral and intravenous administration

Clorsulon was measured in plasma and urine of sheep and goats after administration of a single intravenous (i.v.) and after a single oral dose of 7 mg/kg. A three-compartment model with elimination occurring from the central compartment was determined to best describe the i.v. data, whereas a one-compartment model with a single exponential absorption phase best described the oral plasma data. The bioavailability of orally administered clorsulon was approximately 55% in goats and 60% in sheep. Peak plasma concentrations occurred at 14 h and 15 h after oral administration in goats and sheep, respectively. Absorption from the gastro-intestinal tract effectively prolonged the elimination of clorsulon by increasing the elimination half-life from 17 to 28 h in sheep and from 12 to 23 h in goats for the i.v. and oral routes, respectively. In both goats and sheep, approximately 50% of the i.v. dose was recovered in urine as parent drug at 48 h after administration, whereas 41% and 30% of the dose was recovered after oral administration for goats and sheep, respectively. The elimination rate constant (kel) in goats was nearly twice as large as the value determined in sheep, and the urea under the i.v. plasma curve in goats was only 63% of the value in sheep indicating that goats are more effective in their capacity to eliminate clorsulon than are sheep. These differences in drug disposition between sheep and goats may account for the reduced efficacy of clorsulon reported in goats.     

克洛素隆对小鼠的急性毒性试验

一次性口服或皮下给予小鼠不同剂量的克洛素隆,观察其急性毒性.结果:小鼠分别口服克洛素隆5251.9、6827.5、8875.7、11538.5、15000 mg/kg体重,肉眼未见毒副反应亦无死亡,属于实际无毒;分别皮下注射克洛素隆655.4、819.2、1024、1280、1600、2000、2500、3125mg/kg体重,其半数致死量为1 224.05 mg/kg体重.     

Efficacy of oral clorsulon in the treatment of Fasciola hepatica infections in calves

Twenty calves at each of 2 Arkansas locations were inoculated with infective Fasciola hepatica metacercariae. After 56 days, the calves at each site were randomly assigned by weight to 2 treatment groups of 10 calves/group; vehicle control or clorsulon at the rate of 7 mg/kg of body weight. All treatments were given orally as a suspension. Calves were killed 6 weeks after treatment and F hepatica counts were performed for all animals. At the 2 sites, mean levels of efficacy were 96% and 91%. Adverse reactions to clorsulon or the vehicle were not observed in the calves.     

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.     

The anthelmintic efficacy of netobimin against experimental infections of Fasciola hepatica in sheep

Netobimin (coded SCH 32481, Schering Corporation), a new broad-spectrum anthelmintic having both fasciolicidal and nematocidal properties was evaluated for efficacy against mature Fasciola hepatica infections in sheep. The trial was conducted with 30 cross-bred spring lambs, each experimentally infected with 250 F. hepatica metacercariae. A single treatment of netobimin was administered at 17 weeks post-infection (PI) by oral drench at 7.5 or 20 mg kg-1 body weight while 10 animals remained as untreated controls. At necropsy (either 1 or 2 weeks post-treatment), the mean number of adult flukes recovered from the control, 7.5 and 20 mg kg-1 groups were 94.7, 35.9 and 8.8, respectively. The resulting efficacies were 62% (P less than or equal to 0.05) and 90.7% (P less than or equal to 0.01), respectively. No clinical signs of fascioliasis were noted in any sheep during the trial. No signs of toxicosis nor any adverse reactions to the drug were observed.     

Effect of inoculum on the size and location of Fasciola hepatica subsequently recovered from the livers of rats

Two outbred strains of Sprague-Dawley rats were given, by intraperitoneal injection, 5, 10, 20, 30 or 50 newly excysted juvenile (NEJ) Fasciola hepatica. Ninety days post-infection all rats were killed and their livers teased apart under 10 X magnification for quantitation of the flukes present. There was no significant difference in worm numbers between the rat strains. However, several significant differences (P less than 0.05) between the various infection groups were observed. As the size of the infective dose was increased from 5 to 50 NEJ, the percentage of the infective dose recovered from the livers of the infected rats decreased from 36.7 to 12.1%. With the 5 and 10 NEJ infective doses, the worms recovered were large mature flukes (1.52 and 1.68 cm, respectively) and were found in the common bile ducts. In the rats receiving infections of 30 and 50 NEJ, the flukes were smaller (0.88 and 0.55 cm, respectively), immature, and were primarily located in the liver parenchyma. These findings are important in light of previous studies on the development of resistance in the rat to challenge infections in which immunity was based on both the size and the location of the flukes recovered. The results from our study indicate that in a primary infection of 20 or greater NEJ, many small immature flukes remain in the liver parenchyma, even after several months. When testing for resistance to F. hepatica in rats, these flukes may erroneously be thought to comprise a portion of the challenge infection.     

Plasma salicylate concentrations in immature dogs following aspirin administration: comparison with adult dogs

Aspirin disposition in immature and adult dogs, assessed by plasma salicylate concentrations following single doses of aspirin given orally (p.o.) and intravenously (i.v.), was compared. Using a cross-over design, four immature (12–16-weeks-old) and eight adult (1– 2-years-old) dogs were given a single dose of aspirin at 17.5 mg/kg body weight i.v. and a single dose of buffered aspirin at 35 mg/kg body weight p.o. Blood was collected from the jugular vein for 24 h following each dose. A fluorescence polarization immunoassay was used for determination of salicylate in plasma. Significant differences in aspirin disposition were identified between the two groups. Immature dogs had significantly shorter salicylate half-life, lower mean residence time, and more rapid salicylate clearance than adult dogs. The difference in volume of distribution between the two groups was not significantly different. Immature dogs had lower mean (± SD) peak plasma salicylate concentrations (64.5 ± 2.38 mg/L) than adult dogs (95.9 ± 12.2 mg/L) following a single oral dose of buffered aspirin at 35 mg/kg body weight. Predicted plasma salicylate concentration-time curves were constructed for various aspirin dosage regimens. This analysis showed that the previously recommended buffered aspirin dose for adult dogs of 25 mg/kg body weight p.o. every 8 h would be ineffective in maintaining plasma salicylate concentrations > 50 mg/L in immature dogs.     

Pharmacokinetics of albendazole sulfoxide enantiomers administered in racemic form and separately in rats

The pharmacokinetic behaviour of albendazole sulfoxide (ABZSO) enantiomers was studied in rats after the oral administration of 10 mg/kg of rac-ABZSO, 5 mg/kg of (-)-ABZSO or 5 mg/kg of (+)-ABZSO. The disposition profiles of ABZSO enantiomers were similar in all treatments, but the calculated area under the curve for the (-)-ABZSO was higher in all cases compared with (+)-ABZSO. The results suggest that there is no chiral inversion of ABZSO enantiomers. After the administration of rac-ABZSO, 17.2% of the total dose was recovered in urine as albendazole ABZ (0.1%), albendazole sulfone ABZSO(2) (0.3%), albendazole 2-aminosulfone (ABZ-SO(2)NH(2)) (3.1%) and ABZSO (13.7%). The ratio (+) to (-) was similar in urine (1.6) and blood (1.7).