Cisplatin-induced emesis

H]spiperone binding test) and in vivo (catalepsy induction, and antagonism of apomorphine-induced stereotypy in rats antagonism of apomorphine-induced emesis in dogs). On the other hand, antagonism of cisplatin-induced emesis in the dog and ferret was retained. Several representative /J-keto, ji-hydroxy and / -methoxy analogues are shown in Table 7.1. 

In general, ketones, alcohols and ethers of formula (3) showed comparable protection against cisplatin-induced emesis in the dog and ferret with that of metoclopramide. Erythro (cis) alcohols (3c, 3g, 3i) were found to be more potent than the corresponding threo-(trans) isomers (3d, 3h, 3j). Optical isomer (.R) (3e) was found to be somewhat more potent than its (S )-enantiomer (3f) as an antagonist of cisplatin-induced emesis in the ferret. In the dog, both isomers showed similar activity. A number of heterocyclic analogues were also studied but with the exception of (3k), all were inferior in potency as antiemetic agents compared with other compounds (3) shown in Table 7.1. Lead compound, BMY 25801, batanopride, (3a) is presently under clinical investigation. 

Table 7.1. ANTAGONISM OF CISPLATIN-INDUCED EMESIS BY 2-SUBSTITUTED ANALOGUES (3) OF METOCLOPRAMIDE...

Another approach combined modification of the 2-substituent yielding dihy-drobenzofuran and pyrrolidinemethyl side-chain with unsubstituted (secondary) nitrogen to give ADR 851 (24) and ADR 847 (25) [18]. Both were reported to be somewhat more effective than metoclopramide as antagonists of cisplatin-induced emesis in the dog. In addition, ADR 847 enhanced gastric emptying [19]. 

Parallel with the developments in the benzamide area, progress was also made in several nonbenzamide series of compounds. MDL 72222 (26) [20], atropine ester of 3,5-dichlorobenzoic acid, was the first selective 5-HT3 receptor antagonist and a potent antagonist of cisplatin-induced emesis in the ferret [21]. ICS 205-930 (27) [22,23 ], the tropine ester of 3-indolecarboxylic acid, exhibited similar pharmacological and antiemetic profiles. 

Ablation of AP did not prevent radiation-induced emesis in cats, while abdominal vagotomy did [68]. In contrast, the cisplatin-induced emesis required the intact AP in the same species [69]. 

Metoclopramide, administered at doses higher than those required to inhibit apomorphine-induced emesis, was more effective than haloperidol in antagonizing cisplatin-induced emesis in dogs [80]. This was observed despite the fact that metoclopramide was considerably weaker than haloperidol as a D2-dopamine antagonist [43]. Subsequently, antiemetic efficacy of metoclopramide administered at high doses has been reported in cancer patients... 

Inhibition of Bezold-Jarisch reflex in rats. h Antagonism of cisplatin-induced emesis in ferrets and dogs. c L.M. Pinkus, personal communication. 

Involvement of endogenous 5-HT in emesis was investigated. It was found that reserpine, p-chlorophenylalanine (PCPA) and fenfluramine antagonized cisplatin-induced emesis in the ferret [109]. The real role of 5-HT was difficult to assess, as all these agents with a possible exception of PCPA, depleted 5-HT, dopamine (DA) and noradrenaline (NE), unselectively. Cisplatin, the potent emetogenic agent, moderately increased brain levels of DA and decreased NE, while it had no significant effect on 5-HT or 5-hydroxyindoleacetic acid. 

ZO330 Sharma, S. S., V. Kochupillai, S. K. Gupta, S. D. Seth, and Y. K. Gupta. Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs. J Ethnopharmacol... 

Augments the antiemetic activity of the 5-HT3-receptor antagonist ondansetron and the corticosteroid dexamethasone and inhibits both the acute and delayed phases of cisplatin-induced emesis... 

Highly effective against cisplatin-induced emesis... 

Fleming GF, Yokes EE, McEvilly JM, Janisch L, Francher D, Smaldone L. Double-blind, randomized crossover study of metoclopramide and batanopride for prevention of cisplatin-induced emesis. Cancer Chemother Pharmacol 1991 28(3) 226-7. 

Manusirivithaya S, Chareoniam V, Isariyodom P, Sungsab D. Comparison of ondansetron-dexamethasone-lorazepam versus metoclopramide-dexamethasone-lorazepam in the control of cisplatin induced emesis. J Med Assoc Thai 2001 84(7) 966-72. 

Campos D, Pereira JR, Reinhardt RR, Carracedo C, Poli S, Vogel C, Martinez-Cedillo J, Erazo A, Wittreich J, Eriksson LO, Carides AD, Gertz BJ. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granise-tron and dexamethasone or with dexamethasone alone. J Clin Oncol 2001 19(6) 1759-67. 

Kwiatkowska M, Parker LA, Burton P, Mechoulam R (2004) A comparative analysis of the potential of cannabinoids and ondansetron to supress cisplatin-induced emesis in the Suncus murinus (house musk shrew). Psychopharmacology (Berl). 174 254-259... 

Heron JP, Goedhals L, Jordaan JP, et al. Oral granisetron alone and in combination with dexamethasone A double-blind randomized comparison against high-dose metoclopramide plus dexamethasone in prevention of cisplatin-induced emesis. Ann Oncol 1994 5 579-584. 

Hesketh PJ, Gralla RJ, Webb RT, et al. Randomized phase II smdy of the neurokinin 1 receptor antagonist CJ-11,974 in the control of cisplatin-induced emesis. J CUn Oncol 1999 17 338-343. 

Navari RM, Reinhardt RR, Gralla RJ, et al. Reduction of cisplatin-induced emesis by a selective neurokinin-1-receptor antagonist. N Engl J Med 1999 340 190-195. 

Litoxetine is a new selective and potent inhibitor of serotonin receptors that has antiemetic effects against cisplatin-induced emesis. The clinical use of the majority of sero-toninergic antidepressants such as fluoxetin and fluvoxamine is associated with gastrointestinal discomfort which appears to be due to stimulation of 5-HT3 receptors. Litoxetine, by antagonizing 5-HT3 receptors, may limit nausea and vomiting associated with fluoxetin or fluvoxamine (see also Figure 73). 

Darmani, N.A. (2001b) Delta-9-tetrahydrocannabinol differentially suppresses cisplatin-induced emesis and indices of motor function via cannabinoid CB] receptors in the least shrew, Pharmacol. Biochem. Behav. 69 239-249. 

Darmani, N.A. (1998) Serotonin 5-HT3 receptor antagonists prevent cisplatin-induced emesis in Cryptotis parva a new experimental model of emesis, J. Neural Trans. 105 1143-1154. 

Hesketh, P. K., Van BeUe, S., Aapro, M., et al. (2003) Differential involvement of neurotransmitters through the time course of cisplatin-induced emesis as revealed by therapy with specific receptor antagonists. Eur. J. Cancer 39, 1074-1080. 

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