Results of two controlled studies on antiemetic combination against vomiting induced by 5-fluorouracil

A group of 132 patients with different disseminated solid tumors entered two consecutive antiemetic trials in which 5-fluorouracil given in a 120-h continuous infusion was the emetogenic stimulus. The purpose of the trials was to investigate the validity of Peroutka and Snyder's hypothesis. These authors suggested that CNS receptors other than the classical dopamine D-2 (e.g., histamine H-1 and muscarinic cholinergic receptors) were involved in emetic response. Hence, a combination of a phenothiazine (an antidopaminergic drug) with an antihistaminic or a tricyclic antidepressant (H-1 and muscarinic cholinergic blockers) was suggested to be possibly superior to phenothiazine alone against antineoplastic chemotherapy-induced vomiting. The first study showed the antiemetic superiority of a phenothiazine (thiethylperazine) over placebo but failed to show a superiority of the combination of thiethylperazine and an antihistaminic (diphenhydramine) over thiethylperazine alone. In contrast, the second study proved the superiority of the combination of thiethylperazine and a tricyclic antidepressant (amitriptyline) over thiethylperazine alone. In conclusion, tricyclic antidepressants - but not antihistaminics - potentiate the antiemetic activity of thiethylperazine against 5-fluorouracil-induced vomiting.