Cisplatin 4- -receptor antagonists

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. 

Aprepitant (Emend) [Centrally Acting Antiemetic] Uses Pre-vents N/V assoc w/ emetogenic CA chemo (eg, cisplatin) (use in combo w/ other antiemetics) Action Substance P/neurokinin l(NKi) receptor antagonist Dose 125 mg PO day 1, 1 h before chemo, then 80 mg PO qAM days 2 3 Caution [B, /-] Contra Use w/ pimozide, Disp Caps SE Fatigue, asthenia, hiccups Interactions T Effects W/ clarithromycin, diltiazem, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, troleandomycin T effects OF alprazolam, astem-izole, cisapride, dexamethasone, methylprednisolone, midazolam, pimozide, terfe-nadine, triazolam, chemo agents, eg, docetaxel, etoposide, ifosfamide, imatinib, irinotecan, paclitaxel, vinblastine, vincristine, vinorelbine i effects W/ paroxetine,... 

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... 

Metoclopramide (Reglan, and others) is both a serotonin- and dopamine-receptor antagonist. Given alone, it is less effective than TV ondansetron. Given concurrently with dexamethasone and either the antianxiety agent lorazepam (Ativan, and others) or the antihistamine diphenhydramine (Benadryl, and others), it can control emesis due to high-dose cisplatin (120 mg/m2) in older adults. One study in older patients, however, found metoclopramide, dexamethasone, and diphenhydramine less effective than IV ondansetron combined with dexamethasone in patients taking > 50 mg/m2... 

Kris MG, Radford JE, Pizzo BA, et al. Use of a NK-1 receptor antagonist to prevent delayed emesis following cisplatin. J Natl Cancer Inst 1997 89 53-54. 

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. 

Ondansetron, a serotonin (5-HT3)-receptor antagonist (0.15 mg/kg IV with the first dose taken infused every 15 minutes before the start of chemotherapy), is used in the prevention of nansea and vomiting associated with initial and repeat conrses of emetogenic cancer chemotherapy, including high-dose cisplatin (see Figure 73). 

The dose-limiting toxicity of oxaliplatin is peripheral neuropathy. An acute form often is triggered by exposure to cold, and manifests as paresthesias and/or dysesthesias in the upper and lower extremities, mouth, and throat. A second type of peripheral neuropathy is more closely related to cumulative dose and similar to that seen with cisplatin 75% of patients receiving a cumulative dose of 1560 mg/mf experience some neurotoxicity. Hematologic toxicity is mild to moderate, and nausea is well controlled with 5-HT receptor antagonists. Oxaliplatin is unstable in the presence of chloride or alkaline solutions. 

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. 

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