title: Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.
abstract: Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.
authors.affiliation: Department of Comparative Biomedical Sciences, Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Herts, AL9 7TA, UK, hkenward@rvc.ac.uk.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kenward
authors.forename: Ludovic
authors.initials: L
authors.lastname: Pelligand
authors.forename: Jonathan
authors.initials: J
authors.lastname: Elliott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D001127:Arginine Vasopressin / Q000097:blood; D002945:Cisplatin / Q000009:adverse effects*; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006098:Granulocytes / Q000473:pathology; D006854:Hydrocortisone / Q000097:blood; D016014:Linear Models; D008297:Male; D009325:Nausea / Q000097:blood / Q000139:chemically induced* / Q000473:pathology; D011863:Radioimmunoassay; D013997:Time Factors; D064232:Visual Analog Scale; D014839:Vomiting / Q000097:blood / Q000139:chemically induced* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001127:Arginine Vasopressin; D003404:Creatinine; D002945:Cisplatin; D006854:Hydrocortisone