Cisplatin emetogenicity

Cisplatin administration requires adequate hydration and forced diuresis to prevent kidney damage. Cisplatin is intensely emetogenic and its use requires adequate antiemetic prophylaxis. Myelosuppression is less evident than with other alkylating agents. 

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. 

Several compounds affecting various 5-HT functional parameters (uptake inhibition (fluoxetine), metabolism (tranylcypromine) or synthesis (5-OH tryptophan, 5-HTP)) had no effect on subemetic doses of cisplatin [110]. In fact, tranylcypromine and 5-HTP antagonized emesis of cisplatin. Thus these results would favour an inhibitory role of 5-HT instead of emetogenic. It is conceivable that an excess of 5-HT may desensitize 5-HT3 receptors that may result in a reduced sensitivity to emetogenic stimuli. 

The initial 2 doses should be 2 mg/kg if highly emetogenic drugs such as cisplatin or dacarbazine are used alone or in combination. For less emetogenic regimens, 1 mg/kg/dose may be adequate. 

Antiemetic Aprepitant, in combination with other antiemetic agents, is indicated for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin. 

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,... 

Finally, the ability of aprepitant to block emesis, a therapeutically relevant endpoint for the ultimate clinical application of the drug, as discussed below, was tested in the presence of several emetogens in the ferret. This species is believed to be a valid animal model for cancer chemotherapy-induced emesis in humans. Aprepitant (1) effectively blocked retching and vomiting due to cisplatin, apomorphine, and morphine at a dose of 3.0 mg/kg p.o. and 0.3 mg/kg i.v. (in the case of cisplatin).8... 

One of the adverse effects of clinically used venlafaxine 10 is nausea that may be connected with its mixed serotonin/noradrenaline profile. The selective noradrenaline-reuptake inhibitor sila-velafaxime (R)-ll at oral administration effectively inhibited emetic episodes caused by emetogen (morphine) in the ferret emesis model (06BMCL2555). Intraperitoneally administered sila-venlafaxine (R)-ll was able to reduce cisplatin-induced acute and delayed emesis (08TAP369). 

Like carboplatin, oxaliplatin does not usually cause nephrotoxicity. In addition, both drugs are only moderately emetogenic, in contrast to cisplatin. The most important dose-limiting adverse effect of oxaliplatin is a sensory peripheral neuropathy, which has two different forms ... 

Nausea, vomiting, and diarrhea are common adverse effects of oxaliplatin and carboplatin, but they are generally mild to moderate, and both are less emetogenic than cisplatin. However, patients who have previously received cisplatin may be at greater risk of vomiting with carboplatin or oxaliplatin (1,8,9). 

Current published information describes the experience with aprepitant in highly emetogenic cisplatin-based chemotherapy regimens. The NCCN has also included aprepitant for prophylaxis of nausea and vomiting induced by moderately emetogenic chemotherapy regimens. This recommendation is not supported by the current literature and has been questioned by clinicians. 

Myelosuppression thrombocytopenia, neutropenia, anemia moderately emetogenic risk of hypersensitivity reactions, frequently delayed, after 5-E doses may necessitate discontinuation of carboplatin frequently results in cross-hypersensitivity to cisplatin... 

In the cat model, with cisplatin as emetogenic drug, A -THC, administered... 

Another organometallic platinum drug has been approved in the United States. It is a diammin platinum coordinate with 1,1-cyclobutanedicarboxylic acid named carboplatin (CBDA, Paraplatin). Its advantages over cisplatin are a lesser emetogenic effect as well as a possible decrease in nephro- and ototoxicity. 

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