title: Reproductive safety of an amino-acetonitrile derivative (AAD), monepantel, in rams following repeated oral administration.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Novartis Animal Health Australasia Pty Limited, Yarrandoo R&D Centre, 245 Western Road, Kemps Creek, New South Wales 2178, Australia. nick.malikides@novartis.com
authors.forename: N
authors.initials: N
authors.lastname: Malikides
authors.forename: R
authors.initials: R
authors.lastname: Helbig
authors.forename: R
authors.initials: R
authors.lastname: Mahoney
authors.forename: B
authors.initials: B
authors.lastname: George
authors.forename: K
authors.initials: K
authors.lastname: Baker
authors.forename: K
authors.initials: K
authors.lastname: Vanhoff
authors.forename: K
authors.initials: K
authors.lastname: Spencer
authors.forename: C
authors.initials: C
authors.lastname: Hall
authors.forename: R
authors.initials: R
authors.lastname: Debenedetti
authors.forename: G A
authors.initials: GA
authors.lastname: Strehlau
mesh_terms: D000284:Administration, Oral; D000607:Aminoacetonitrile / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000871:Anthelmintics / Q000009:adverse effects* / Q000627:therapeutic use; D004311:Double-Blind Method; D006374:Helminthiasis, Animal / Q000188:drug therapy; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D012098:Reproduction / Q000187:drug effects* / Q000502:physiology; D012756:Sheep / Q000097:blood / Q000502:physiology*; D012757:Sheep Diseases / Q000188:drug therapy; D013094:Spermatozoa / Q000187:drug effects* / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology
chemical_list: D000871:Anthelmintics; D000607:Aminoacetonitrile; C533978:monepantel