{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:55:23Z","timestamp":1767192923222,"version":"3.41.0"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,11,27]],"date-time":"2016-11-27T00:00:00Z","timestamp":1480204800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Merial Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vet Pharm &amp; Therapeutics"],"published-print":{"date-parts":[[2017,10]]},"abstract":"<jats:p>The safety profile of afoxolaner (an isoxazoline molecule) when combined with milbemycin oxime (a macrocyclic lactone) was evaluated according to the regulatory requirements when administered six times orally in a soft chewable formulation at a dose of at least 1\u00d7, 3\u00d7, or 5\u00d7 the maximum exposure dose in 8\u2010week\u2010old Beagle dogs. Thirty\u2010two healthy puppies (16 males and 16 females) were enrolled and allocated randomly to one of four treatment groups. Three doses were administered at 28\u2010day intervals (Days 0, 28, and 56), followed by three additional doses administered with 14\u2010day intervals (Days 84, 98, and 112). The study ended on Day 126. Treatment groups were as follows: Group 1: untreated, sham\u2010dosed control; Group 2: afoxolaner\/milbemycin oxime chews administered at a dose of at least 5 and 1\u00a0mg\/kg, respectively (1\u00d7); Group 3: afoxolaner\/milbemycin oxime chews administered at a dose of at least 15 and 3\u00a0mg\/kg, respectively (3); and Group 4: afoxolaner\/milbemycin oxime chews administered at a dose of at least 25 and 5\u00a0mg\/kg, respectively (5\u00d7). All dogs were examined for general health twice a day beginning on Day \u201014. Physical examinations, and blood collections for clinical pathology analysis and afoxolaner and milbemycin oxime plasma concentrations, were performed throughout the study. No afoxolaner\/milbemycin oxime treatment\u2010related changes were observed in growth, physical variables, clinical pathology variables, or tissues examined histologically. No clinically relevant or statistically significant health abnormalities related to the administration of afoxolaner\/milbemycin oxime were observed. No signs of macrocyclic lactone sensitivity were observed at any time during the study. Vomiting and diarrhea were observed sporadically across all groups including the controls. Based upon the results of this study, afoxolaner\/milbemycin oxime soft chewables were shown to be safe when administered repeatedly at up to 5\u00d7 the maximum exposure dose in dogs as young as 8\u00a0weeks of age.<\/jats:p>","DOI":"10.1111\/jvp.12375","type":"journal-article","created":{"date-parts":[[2016,11,28]],"date-time":"2016-11-28T04:26:40Z","timestamp":1480307200000},"page":"447-453","source":"Crossref","is-referenced-by-count":16,"title":["Safety evaluation of orally administered afoxolaner and milbemycin oxime in eight\u2010week\u2010old dogs"],"prefix":"10.1111","volume":"40","author":[{"given":"M.","family":"Drag","sequence":"first","affiliation":[{"name":"Merial Inc. Duluth GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Saik","sequence":"additional","affiliation":[{"name":"Formerly Merial Inc. Duluth GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J.","family":"Harriman","sequence":"additional","affiliation":[{"name":"Merial Inc. Duluth GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"L.","family":"Letendre","sequence":"additional","affiliation":[{"name":"Merial Inc. Duluth GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S.","family":"Yoon","sequence":"additional","affiliation":[{"name":"Merial Inc. Duluth GA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D.","family":"Larsen","sequence":"additional","affiliation":[{"name":"Merial Inc. 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