Methotrexate produces delayed emesis in dogs: a potential model of delayed emesis induced by chemotherapy

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Abstract

We investigated the emetic effects of cisplatin and methotrexate in dogs, the effects of ondansetron on cisplatin-induced vomiting, and the effects of ondansetron, dexamethasone and a combination of the two on the vomiting induced by methotrexate. Ondansetron was administered 30 min before cisplatin administration. Ondansetron, dexamethasone or a combination of the two was administered 8, 24 and 48 h after methotrexate administration. Cisplatin (3 mg/kg, i.v.) induced acute vomiting but failed to induce delayed vomiting. The acute vomiting was markedly inhibited by ondansetron (3 mg/kg, p.o.; 1 mg/kg, i.v.). Methotrexate (2.5 mg/kg, i.v.) caused delayed vomiting, which was partly inhibited by ondansetron (1 mg/kg, i.v.) or dexamethasone (2.5 mg/kg, i.v.). The combination of the two agents was more effective. These results suggest that methotrexate-induced emesis in dogs would be useful for studying delayed emesis.

Introduction

In patients with cancer, nausea or vomiting is one of the most undesirable side-effects of chemotherapy, although the introduction of 5-HT3 receptor antagonists for the treatment of emesis evoked by cancer chemotherapy has made a significant improvement. Cisplatin chemotherapy induces a biphasic pattern of emesis, which is characterized by an acute phase and a delayed phase. Following the initial peak of intense emesis, which occurs within 8 h after cisplatin administration (De Mulder et al., 1990; Marty et al., 1990), there is a secondary, delayed emesis phase, which is defined as emesis or nausea occurring more than 24 h after cisplatin administration (Kris et al., 1985). The delayed emesis is severest at 48–72 h after drug administration (Kris et al., 1985). 5-HT3 receptor antagonists are highly effective for controlling the acute emesis induced by cisplatin. However, the delayed phase of emesis is not satisfactorily controlled by antiemetics. Although delayed emesis is less severe than acute emesis (Kris et al., 1985), it may adversely affect patients' quality of life and contribute to the occurrence of anticipatory nausea and emesis with further courses of chemotherapy. The control of delayed emesis, especially after cisplatin administration, remains an important therapeutic challenge.

Ferrets and piglets have been used as experimental models to elucidate the pathophysiology of delayed emesis. Rudd et al. (1994)recently developed a model of cisplatin-induced delayed emesis in the ferret: intraperitoneal administration of cisplatin at a low dose (5 mg/kg) causes an initial peak of emesis within the first 16 h, followed by a delayed emesis after 32–72 h. In the piglet, cisplatin (5.5 mg/kg, i.v.) induces both the acute and delayed phases of the emetic response without any lethality (Milano et al., 1995). Acute emesis is observed from 2–16 h after dosing; delayed emesis starts at 18 h after dosing and lasts until 58 h. The pattern of the acute and delayed emesis in ferrets and piglets is similar to that observed in humans (Kris et al., 1985). However, ferrets die within 1 week after intraperitoneal administration of cisplatin at doses of 5 mg/kg and above (Veyrat-Follet et al., 1997; Fukui and Yamamoto, unpublished data), suggesting that this model may be accompanied by general prostration before death. In the piglet, delayed emesis induced by cisplatin occurs at a non-lethal dose, but the emesis is completely inhibited by repetitive treatment with a 5-HT3 receptor antagonist, granisetron (Grélot et al., 1996). This complete inhibition by the 5-HT3 receptor antagonist is not the case in humans, as described above. Therefore, we considered that we needed a model of delayed emesis using another species to clarify the mechanism of delayed emesis and to find a new antiemetic agent. It is known that the dog is a species particularly sensitive to emetic stimuli. In the present study, we found that methotrexate, an anticancer drug, could cause delayed emesis in dogs, and we examined the suitability of canine methotrexate-induced delayed emesis as a model of the delayed emesis induced by chemotherapy in humans.

Section snippets

Animals

Thirty-six Beagle dogs of either sex weighing 6.9–13.0 kg were used. The dogs were housed in metal cages in an animal room under controlled conditions: room temperature, 20–26°C; relative humidity, 40–70%; and air exchange, 8–25 times/h. Each animal was given dog food (CD-5, Clea Japan) once daily, was allowed tap water ad libitum, and was fasted for at least 18 h before surgery or administration of methotrexate or cisplatin.

Vagotomy and greater splanchnic nerve section

Four dogs underwent surgery after pretreatment with atropine sulfate

Effects of ondansetron on acute vomiting induced by cisplatin

No animals receiving 3 mg/kg of cisplatin died within 2 weeks or longer after drug administration. The results are summarized in Table 1, and the pattern of vomiting following intravenous administration of cisplatin (3 mg/kg, n=6) is shown in Fig. 1. In the control animals, vomiting episodes began 1.1±0.2 h (mean±S.E., n=6) after cisplatin administration, and the most frequent vomiting episodes were observed from 1 to 3 h after dosing. No vomiting episodes were observed from 3.5 to 5 h after

Discussion

In the present study, consistent with our previous reports (Fukui et al., 1992, Fukui et al., 1993a, Fukui et al., 1993b; Fukui and Yamamoto, 1998), cisplatin at a non-lethal dose (3 mg/kg, i.v.) induced acute phase vomiting in dogs, up to around 3 h after dosing. Ondansetron administered orally (3 mg/kg) or intravenously (1 mg/kg) strongly inhibited the acute vomiting induced by cisplatin. In previous studies, we have demonstrated that, in dogs, other anticancer agents such as

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