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A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research.

Sanger, GJ; Andrews, PLR (2018) A History of Drug Discovery for Treatment of Nausea and Vomiting and the Implications for Future Research. Front Pharmacol, 9. p. 913. ISSN 1663-9812 https://doi.org/10.3389/fphar.2018.00913
SGUL Authors: Andrews, Paul Lyn Rodney

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Abstract

The origins of the major classes of current anti-emetics are examined. Serendipity is a recurrent theme in discovery of their anti-emetic properties and repurposing from one indication to another is a continuing trend. Notably, the discoveries have occurred against a background of company mergers and changing anti-emetic requirements. Major drug classes include: (i) Muscarinic receptor antagonists-originated from historical accounts of plant extracts containing atropine and hyoscine with development stimulated by the need to prevent sea-sickness among soldiers during beach landings; (ii) Histamine receptor antagonists-searching for replacements for the anti-malaria drug quinine, in short supply because of wartime shipping blockade, facilitated the discovery of histamine (H1) antagonists (e.g., dimenhydrinate), followed by serendipitous discovery of anti-emetic activity against motion sickness in a patient undergoing treatment for urticaria; (iii) Phenothiazines and dopamine receptor antagonists-investigations of their pharmacology as "sedatives" (e.g., chlorpromazine) implicated dopamine receptors in emesis, leading to development of selective dopamine (D2) receptor antagonists (e.g., domperidone with poor ability to penetrate the blood-brain barrier) as anti-emetics in chemotherapy and surgery; (iv) Metoclopramide and selective 5-hydroxytryptamine3(5-HT3) receptor antagonists-metoclopramide was initially assumed to act only via D2 receptor antagonism but subsequently its gastric motility stimulant effect (proposed to contribute to the anti-emetic action) was shown to be due to 5-hydroxytryptamine4 receptor agonism. Pre-clinical studies showed that anti-emetic efficacy against the newly-introduced, highly emetic, chemotherapeutic agent cisplatin was due to antagonism at 5-HT3 receptors. The latter led to identification of selective 5-HT3 receptor antagonists (e.g., granisetron), a major breakthrough in treatment of chemotherapy-induced emesis; (v) Neurokinin1receptor antagonists-antagonists of the actions of substance P were developed as analgesics but pre-clinical studies identified broad-spectrum anti-emetic effects; clinical studies showed particular efficacy in the delayed phase of chemotherapy-induced emesis. Finally, the repurposing of different drugs for treatment of nausea and vomiting is examined, particularly during palliative care, and also the challenges in identifying novel anti-emetic drugs, particularly for treatment of nausea as compared to vomiting. We consider the lessons from the past for the future and ask why there has not been a major breakthrough in the last 20 years.

Item Type: Article
Additional Information: © 2018 Sanger and Andrews. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Keywords: 5-hydroxytryptamine3 receptor antagonists, drug discovery, histamine H1 receptor antagonists, metoclopramide, muscarinic receptor antagonists, nausea and vomiting, neurokinin1 receptor antagonists, olanzapine, nausea and vomiting, drug discovery, metoclopramide, histamine H-1 receptor antagonists, muscarinic receptor antagonists, 5-hydroxytryptamine(3) receptor antagonists, neurokinin(1) receptor antagonists, olanzapine, 1115 Pharmacology And Pharmaceutical Sciences
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Front Pharmacol
ISSN: 1663-9812
Language: eng
Dates:
DateEvent
4 September 2018Published
25 July 2018Accepted
Publisher License: Creative Commons: Attribution 4.0
PubMed ID: 30233361
Web of Science ID: WOS:000443597900001
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/110186
Publisher's version: https://doi.org/10.3389/fphar.2018.00913

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