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Proton Pump Inhibitors

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Proton Pump Inhibitors. Edited by Olbe L. (Pp 264; illustrated; sFr198.00.) Switzerland: Birkhäuser Verlag. 1999. ISBN 3 76435 897 1.

The history of the development of drugs to treat the so-called acid related diseases makes a fascinating story, and the publication of this book addresses a significant chapter in that story. Before 1976, treatment of peptic ulcer and gastroesophageal reflux disease was either inadequate medical therapy involving antacids, non-selective anticholinergic drugs, or surgery with its associated morbidity problems. The advent of cimetidine (Tagamet), the first of the histamine H2 receptor antagonists revolutionised the therapy of these diseases, and cimetidine became the first billion dollar drug. Subsequently, ranitidine (Zantac) superseded cimetidine as the world's most successful drug.

Despite their success, H2 antagonists had some limitations, particularly in the treatment of gastroesphageal reflux disease and the arrival of omeprazole, the first proton pump inhibitor, with its profound and sustained inhibitory action on acid secretion represented a further significant therapeutic advance.

While the discovery of cimetidine was based on systematic pharmacological analysis aimed at a known target, that of the first proton pump inhibitors was serendipitous, their target and mechanism of action being initially unknown, and those early days are excellently described in the first chapter of this volume. The story of the antisecretory is often one of “what might have been”, and this is illustrated by George Sachs in Chapter 2. He points out that SmithKline & French in Philadelphia instigated a programme for the regulation of gastric secretion by inhibiting the acid pump as early as 1968, but with the success of the H2 antagonist programme in the United Kingdom, work was abandoned in 1973. Would history have been different if they had continued?

Chapter 1 ends on an enigmatic note, the final sentence stating that despite demonstration of clinical efficacy in the first trials of omeprazole described in 1982, “new problems were waiting round the corner”. I assume this refers to the gastric carcinoid lesions found in long term toxicity tests on rat. At the time, this discovery generated genuine concern, and some hysteria, regarding the safety of proton pump inhibitors, and it certainly delayed the development and ultimate approval of omeprazole. However, the company involved, Astra, successfully convinced the regulatory authorities that it did not represent a problem for human studies, a position vindicated by the data presented by Werner Creuzfeldt in his key chapter. Interestingly, SmithKline & French and Glaxo took a different attitude when their long acting H2 antagonists led to similar carcinoid formation and stopped their development programmes—was this the right decision? Concerns about sustained hypergastrinaemia caused by the prolonged inhibition of acid secretion by proton pump inhibitors also prompted the search for reversible K+ competitive H+/K+ATPase inhibitors, examples of which entered the clinic, but these too have been largely discontinued because of the efficacy and safety of available drugs.

Given the fact that omeprazole has been on the market for a decade, and in the light of its clinical and commercial success, it is surprising that this volume represents the first book to address the proton pump inhibitors, and I am pleased to say it fills that gap admirably. Lars Olbe has gathered together an excellent team of authors to produce a volume that is comprehensive (I cannot identify any aspect of the subject that is missing) and scientifically rigorous, but at the same time eminently readable for both the basic scientist and the clinician. History is dealt with, mechanisms of action made clear and understandable, clinical efficacy demonstrated, and the chapters onHelicobacter pylori bring us bang up to date. In the socioeconomic section it would have been interesting to have some numbers (in ecus) to give an idea of the savings brought about by the use of proton pump inhibitors, but maybe this is unquantifiable. Most chapters have comprehensive bibliographies and the overall presentation of the book is good, although the index is a trifle thin—well, nothing can be perfect. It is difficult to judge the potential success of the book for a broad readership when the reviewer was actively involved in the field. As most reviewers say, I will certainly have this volume on my bookshelf, and it is not because I can keep my review copy.