Emesis, antagonists cisplatin-induced

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. 

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. 

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... 

There are a few reports on possible sites of action of 5-HT3 antagonists. Low doses of zacopride administered directly into the fourth ventricle (i.c.v.) antagonized cisplatin (i.v.[-induced emesis in the cat [108]. A similar antagonism was demonstrated when routes of drug administration were interchanged. Similarly, GR 38032F, GR 65630 and MDL 72222, administered i.c.v. onto the area postrema at very low doses, antagonized cisplatin-induced... 

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... 

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. 

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. 

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. 

Domperidone [133], one of the most potent D2-dopamine blockers and antagonists of apomorphine-induced emesis with limited brain-blood barrier permeability, did not establish a position as an antiemetic, especially against cisplatin [134], Recently, the use of domperidone as a parenteral antiemetic has been discontinued because of serious cardiovascular toxicity. 

Currently, 5-HT, antagonists have found their greatest therapeutic value in the treatment of cancer chemotherapy-induced emesis (406). Release of 5-HT from the enterochro-mafhn cells in the gastrointestinal track often results from cancer chemotherapy with cytotoxic agents, such as cisplatin (446, 447). Blockade of 5-HT, receptors in the CNS or on peripheral vagal afferent fibers prevents the initiation of the vomit reflex. 

---