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The discovery and development of the proton pump inhibitor

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Book cover Proton Pump Inhibitors

Part of the book series: Milestones in Drug Therapy MDT ((MDT))

Abstract

In 1967 research director Ivan Östholm initiated an innovative research project in the gastrointestinal field at Astra Hässle. The aim was to develop an antisecretory drug to be used in peptic ulcer disease. Lars Olbe was appointed as an external consultant. The first idea was to block the release of the gastric acid stimulating hormone gastrin. This is released from the antrum of the stomach during meals and is a physiologically important stimulus of gastric acid secretion. It was known from animal experiments that local anesthesia of the antrum blocked the release of gastrin. The aim was to synthesize a local anesthetic drug that could be orally administrated and active in the antrum. All available local anesthetics were, however, protonated in an acidic environment and therefore inactive. The goal was therefore to change the chemical structure of lidocain — the established local anesthetic of Astra — into a nonbasic compound. The gastric fistula rat (the pylorus-ligated Shay rat) was used as a screening model. A large number of new chemical compounds were synthesized. It was found that the anesthetic property of selected compounds induced toxic effects in safety studies. The chemical development finally ended with antisecretory compounds, including carbamates, which were devoid of local anesthetic properties. The carbamates were found to be very effective as inhibitors of gastric acid secretion in the rat model [1–3] but rather ineffective in the dog. The most effective and nontoxic carbamate compound — H 81/75 – (Fig. 1) had no local anesthetic properties. It was finally tested in human volunteers in 1971–1972. It was found to be completely ineffective in human.

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Author information

Authors and Affiliations

  1. ASTRA AB, R & D, S-15185, Södertälje, Sweden

    Sven Erik Sjöstrand

  2. Gastroent. lab. Dept. of Surgery, University of Göteborg, Sweden

    Lars Olbe

  3. The Swedish Environmental Protection Agency, S-106 48, Stockholm, Sweden

    Erik Fellenius

Authors
  1. Sven Erik Sjöstrand
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  2. Lars Olbe
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  3. Erik Fellenius
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Editor information

Editors and Affiliations

  1. Centre for Gastroenterological Research, University of Göteborg, S-41345, Göteborg, Sweden

    Lars Olbe

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© 1999 Springer Basel AG

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Sjöstrand, S.E., Olbe, L., Fellenius, E. (1999). The discovery and development of the proton pump inhibitor. In: Olbe, L. (eds) Proton Pump Inhibitors. Milestones in Drug Therapy MDT. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8795-3_1

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  • DOI: https://doi.org/10.1007/978-3-0348-8795-3_1

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9777-8

  • Online ISBN: 978-3-0348-8795-3

  • eBook Packages: Springer Book Archive

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