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.

Cisplatin nephrotoxicity in male beagle dogs: next-generation protein kidney safety biomarker tissue expression and related changes in urine

“…17,25 CDDP accumulation in kidney proximal tubule epithelium is often followed by the formation of platinum complexes; and these platinum complexes ultimately lead to the inhibition of DNA synthesis; 26 increased kidney vascular resistance; and eventual tubular cell necroptosis with hallmark inflammation; 15,27 and endoplasmic stress-induced apoptosis. 29,30 In dogs, progressive CDDPinduced tubular injury may occur as early as 72 h post dose as indicated by remarkable increases in selected inflammatory cytokines and chemokines in urine, whereas increases in sCr concentrations were mostly insensitive, except when total individual animal kidney histopathology severity scores were above grade 4. 29,30 In dogs, progressive CDDPinduced tubular injury may occur as early as 72 h post dose as indicated by remarkable increases in selected inflammatory cytokines and chemokines in urine, whereas increases in sCr concentrations were mostly insensitive, except when total individual animal kidney histopathology severity scores were above grade 4.…”

Anti-nausea effects and pharmacokinetics of ondansetron, maropitant and metoclopramide in a low-dose cisplatin model of nausea and vomiting in the dog: a blinded crossover study

“…One day prior to cisplatin administration, a double lumen jugular catheter was implanted under general anesthesia using the methods described in Kenward et al [ 16 ].…”

“…All dogs were given 0.9% saline and mannitol infusions prior to the administration of cisplatin and an hourly saline bolus post cisplatin through the first lumen of the jugular catheter as described in Kenward et al [ 16 ] to reduce the nephrotoxic effects of cisplatin (Fig. 1 ).…”

“…It is highly emetogenic [ 12 ] and has been widely used experimentally to induce nausea and emesis in a variety of species including Suncus murinus [ 13 ], ferret [ 14 ] and the dog [ 15 ]. The low dose cisplatin model of nausea and emesis in the dog [ 16 ] induces significantly less emesis than previous models which utilise clinical doses of cisplatin [ 15 ]. The reduced emesis in the low dose model facilitates recognition of the behavioral signs of nausea and grading of its severity without the bias of frequent emetic events.…”

“…Potential nausea biomarkers, arginine vasopressin (AVP) and cortisol, have been identified as correlates of nausea behaviour in the dog [ 16 ]. Increased AVP has been positively correlated to self-reported nausea scores by volunteers, in which, motion sickness is induced [ 17 , 18 ].…”