European field study of the efficacy and safety of the novel anthelmintic monepantel in sheep.

During 2007, a large-scale controlled, multicentre, blinded and randomised field study was conducted in Scotland, England and France to assess the efficacy and safety of monepantel, the first molecule to be developed from the recently discovered amino-acetonitrile derivatives class of anthelmintics, in sheep. Monepantel was administered orally, at a minimum dose of 2.5 mg/kg bodyweight, for the control of gastrointestinal nematodes in sheep maintained at pasture in a range of commercial production systems. Efficacy was measured by faecal egg count (FEC) reduction tests seven days after treatment and was demonstrated to be over 98 per cent against mixed-genus infections. The reduction in FEC of monepantel-treated sheep was statistically significantly greater than in untreated control sheep (P<0.0001). The efficacy of monepantel against mixed-genus natural field infections of the major gastrointestinal nematodes was in agreement with similar studies conducted in Australia and New Zealand. There were no treatment-related adverse events during the study, which included the use of a range of concomitant treatments.

Safety of an amino-acetonitrile derivative (AAD), monepantel, in ewes and their offspring following repeated oral administration.

AIM: To demonstrate the clinical and reproductive safety in ewes and their offspring of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at three times the proposed maximum recommended dose (MRD) over an entire reproductive cycle. METHODS: A randomised controlled blinded study design was used. One hundred and twelve primi- or multi-parous ewes and 28 rams were randomly allocated into control and treated groups (n=56 for groups of ewes, n=14 for groups of rams). Two control ewes and two treated ewes were randomly selected to form 28 subgroups. A control or treated ram was then randomly allocated to each subgroup, to form control ram/treated ewe, control ram/control ewe, treated ram/treated ewe, and treated ram/control ewe 'treatment/mating' units. Control animals were treated with saline, and treated animals given three times the MRD (11.25 mg/kg) of monepantel. Treatments were administered orally every 5 days during an entire reproductive cycle, including oestrus and mating, gestation, and post-lambing to weaning. Detailed recording at multiple time points were made of veterinary examinations; observations for adverse events; bodyweight measurements; faecal scores; and haematology, clinical chemistry and coagulation variables. Reproductive indices determined included percent pregnant, number of failed embryos, abortion percentage, number of lambs with teratogenic defects, length of gestation, percentage of stillbirths, number of ewes experiencing reproductive problems, lambing percentage, and pre-weaning mortality. Post-mortem examination, including measurement of organ weights, was performed on randomly selected ewes (n=40) and lambs (n=40) at the completion of the study. RESULTS: All ewes treated with monepantel and those in the control group thrived and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or gross post-mortem changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between ewes treated with monepantel and control ewes. No significant differences were observed in any of the reproductive indices measured. No significant clinical differences were noted between lambs born from treated ewes and those from controls. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated oral administration of monepantel at three times the MRD every 5 days over an entire reproductive cycle was not associated with any treatment-related adverse effects on the reproductive performance of ewes nor on the viability of their offspring, and was systemically very well tolerated. This study demonstrated that this population of ewes could tolerate accidental overdoses of up to three times the MRD of monepantel or prolonged repetitive administration of overdoses. Thus, those so treated entering a breeding programme would have normal reproductive indices, mating behaviour, and health, and their lambs would suffer no ill effects.

Safety of an amino-acetonitrile derivative ( AAD ), monepantel, in weaned lambs following repeated oral administration.

AIM: To demonstrate the safety in weaned lambs of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at the proposed maximum recommended dose (MRD) and three and five times the MRD over 24 weeks. METHODS: A randomised controlled blinded study design was used. Fifty-six weaned lambs were randomly allocated into a control group, the MRD (3.75 mg/kg) and three (11.25 mg/ kg) and five (18.75 mg/kg) times the MRD treatment groups (n=7 castrated males plus seven females each). Treatment doses of monepantel were calculated based on the MRD of 3.75 mg/ kg, and administered orally on eight occasions at intervals of approximately 21 days. Detailed recording at multiple time points were made of veterinary examinations, observations for adverse events, bodyweight measurements, faecal scores, and haematology, clinical chemistry and coagulation variables. Gross pathology (including measurement of organ weights) and histopathology were performed at the completion of the study. RESULTS: All lambs treated with monepantel and those in the control group thrived, grew and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or macroscopic or microscopic changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between lambs treated with monepantel and control lambs. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated oral administration of monepantel at the MRD and three and five times the MRD every 3 weeks for eight treatments was not associated with any treatment-related adverse effects and was systemically very well tolerated in weaned, growing lambs. This study demonstrated that this population of lambs could tolerate accidental overdoses of up to five times the MRD of monepantel or prolonged repetitive administration at recommended doses or overdoses.

Reproductive safety of an amino-acetonitrile derivative (AAD), monepantel, in rams following repeated oral administration.

AIM: To demonstrate the clinical and reproductive safety in rams of repetitive oral doses of monepantel, an amino-acetonitrile derivative (AAD), when administered at three times the proposed maximum recommended dose (MRD) over an entire spermatogenic cycle and during mating with ewes. METHODS: A randomised controlled blinded study design was used with 28 rams randomly divided into two groups. The control group was treated with saline, and the other group was given three times the MRD (11.25 mg/kg) of monepantel. Treatments were administered orally every 5 days, for 100 days, during an entire spermatogenic cycle and subsequent mating period. Detailed recording at multiple time points were made of veterinary examinations; observations for adverse events; bodyweight measurements; faecal scores; haematology, clinical chemistry and coagulation variables; semen indices; evaluation of serving capacity; and gross pathology (including measurement of organ weights) performed on 10 rams from each group at the completion of the study. RESULTS: All rams treated with monepantel and those in the control group thrived and behaved normally to the end of the study. No treatment-related, toxicologically relevant adverse events, clinical observations or macroscopic changes were observed. Furthermore, there were no significant differences in bodyweight or organ weights, and haematological, clinical chemistry or coagulation variables between rams treated with monepantel and control rams. No significant changes were observed in any semen variable measured in any rams, and the serving capacity of rams mated to ewes was unaffected. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated oral administration of monepantel at three times the MRD every 5 days over an entire spermatogenic cycle and during mating was not associated with any treatment-related adverse effects on the reproductive performance of rams and was systemically very well tolerated. This study demonstrated that this population of rams could tolerate accidental overdoses of up to three times the MRD of monepantel or prolonged repetitive administration at overdoses. Thus, those so treated entering a breeding programme would have normal sperm indices, mating behaviour, and health.

Pharmacokinetics of clomipramine in dogs following single-dose and repeated-dose oral administration.

OBJECTIVE: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages. ANIMALS: 9 male and 9 female Beagles. PROCEDURES: Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method. RESULTS: Dose-related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs. CONCLUSIONS AND CLINICAL RELEVANCE: Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethylclomipramine in dogs.