Table 1.

The major pharmaceutical companies involved in the discovery of anti-emetic drugs during the period covered by this review and a summary of their key contribution to the area.

Rhône-Poulenc Laboratories

•Rapidly focussed on the therapeutic potential of the newly-discovered “antihistamines,” searching libraries of compounds originally synthesized for another use. The first antihistamine to treat anaphylaxis and allergic reactions was phenbenzamine, introduced into the clinic in 1942. •Re-examination of the antihistamines to optimize the “anti-shock” property led to synthesis in 1946 of chlorpromazine (4560-R.P). This compound had low antihistamine activity but in 1951 the company demonstrated its ability to prevent emesis evoked by apomorphine in dogs.

G.D. Searle & Co

•Introduced the “antihistamine” dimenhydrinate (Dramamine), a combination of diphenhydramine and 8-chlorotheophylline (a mild stimulant and derivative of theophylline) as a counter measure against the drowsiness, somnolence, and sedation caused by H1 receptor antagonism within the brain.

Burroughs Wellcome

•Developed the “antihistamine” cyclizine, in 1947, subsequently taken on the Apollo moon missions as a treatment for space sickness.

Laboratoires Delagrange

•Identified metoclopramide in the mid-1950s, during a programme aimed at improving the properties of procainamide, a cardiac anti-arrhythmic and local anesthetic drug derived from procaine. The drug had negligible local anesthetic or cardiac anti-arrhythmic activity but an ability to inhibit emesis in dogs evoked by multiple stimuli. Soon after, metoclopramide was also found to stimulate GI motility and reduce symptoms associated with various upper GI disorders.

Janssen Pharmaceutica

•Among the antipsychotic compounds the company had developed in the mid-1950s, some were effective antagonists at the dopamine receptors in the chemoreceptor trigger zone, an area of brain outside the blood-brain barrier, involved in regulation of vomiting. Domperidone was identified in 1974 as an antagonist which did not cross the blood-brain barrier and hence, less likely to evoke the extrapyramidal side-effects.

Merrell Dow

•Synthesized MDL72222 from the chemical template of cocaine, the first selective 5-HT3 receptor antagonist, originally aimed at the treatment of migraine. A later compound (MDL73147 or dolasetron) was marketed for the control for chemo-radiotherapy-induced emesis.

Beecham Pharmaceuticals

•Identified the anti-emetic activity of the 5-HT3 receptor antagonists, developing its own molecule (BRL43694 or granisetron, launched by SmithKline Beecham for the control of chemoradiotherapy-induced emesis) and successfully filed a patent to cover the anti-emetic use of Glaxo's compound (GR38032F or ondansetron), originally designed for treatment of “a variety of disorders including migraine” before being specifically patented for treatment of depression, schizophrenia, anxiety, and cognitive disorders.

Glaxo

•Identified ondansetron for the treatment of migraine and a variety of CNS disorders. Subsequent marketing as an anti-emetic drug incurred royalty payments to Beecham/SmithKline Beecham who owned the patent covering the anti-emetic use of this drug.

Sandoz

•Identified the 5-HT3 receptor antagonist ICS 205-930 (tropisetron), originally for treatment of migraine, subsequently sponsoring research to characterize its anti-emetic activity and “re-purpose” for treatment of chemoradiotherapy-induced emesis.

Merck

•Aprepitant introduced in 2003, following initial characterization for treatment of depression and emesis and a long history of failure of other NK1 receptor antagonists to treat pain.

Syntex Discovery Research

•Synthesized and characterized palonosetron (RS 25259-197), licensed to Eisai and Helsinn for co-marketing in the USA in 2003 (the same year as aprepitant).

See text for further details.