Iqi NK-i receptor antagonists

Substance P evokes neural excitation in the area postrema of the dorsal brainstem. The key role of this nucleus in the emetic reflex and its close proximity to the nucleus of the solitary tract, itself of fundamental importance in emetic pathways, raised the possibility that substance P or other tachykinins were important mediators of the emetic reflex. Administration of substance P evoked emesis in dogs and in the ferret; the prototypical tachykinin (NK1) receptor antagonist, CP-99,994 (33) inhibited the emetic response to cisplatin. NK1 receptor antagonists have a broad-spectrum antiemetic profile in a range of animals including dog, ferret, cat, pig, and shrew, preventing emetic responses to chemotherapeutic agents (both acute and delayed emetic responses), x-radiation, volatile and gaseous anesthetic agents, ipecacuanha, morphine, ethanol, and motion. Addition of the NK1 receptor antagonist, ezlopitant, to an antiemetic regime of granisetron and dexamethasone was superior to use of the 5HT3 receptor antagonist and steroid alone in cisplatin-induced emesis.90 Similar data were obtained with L-754,030 (35), an NK1 receptor antagonist that has been superceded by its prodrug, aprepitant. Aprepitant was as effective as ondansetron in controlling acute emesis to cisplatin, but was more effective than ondansetron in controlling delayed emesis.91 In a small study aimed at treatment of established PONV following gynecological surgery, the NK1 receptor antagonist vofopitant (37) was superior to placebo at controlling symptoms over a 24 h period.92 In a study of PONV prophylaxis following abdominal hysterectomy, the NK1 receptor antagonist CP-122,721 (34) was superior to treatment with a 5HT3 receptor antagonist.93 In studies of motion-induced nausea, vofopitant failed to control nausea at doses shown to be effective at controlling PONV.94

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