title: The history and rationale of using carbonic anhydrase inhibitors in the treatment of peptic ulcers. In memoriam Ioan Puşcaş (1932-2015).
abstract: Carbonic anhydrase (CA, EC 4.2.1.1) inhibitors (CAIs) started to be used in the treatment of peptic ulcers in the 1970s, and for more than two decades, a group led by Ioan Puşcaş used them for this purpose, assuming that by inhibiting the gastric mucosa CA isoforms, hydrochloric acid secretion is decreased. Although acetazolamide and other sulfonamide CAIs are indeed effective in healing ulcers, the inhibition of CA isoforms in other organs than the stomach led to a number of serious side effects which made this treatment obsolete when the histamine H2 receptor antagonists and the proton pump inhibitors became available. Decades later, in 2002, it has been discovered that Helicobacter pylori, the bacterial pathogen responsible for gastric ulcers and cancers, encodes for two CAs, one belonging to the α-class and the other one to the β-class of these enzymes. These enzymes are crucial for the life cycle of the bacterium and its acclimation within the highly acidic environment of the stomach. Inhibition of the two bacterial CAs with sulfonamides such as acetazolamide, a low-nanomolar H. pylori CAI, is lethal for the pathogen, which explains why these compounds were clinically efficient as anti-ulcer drugs. Thus, the approach promoted by Ioan Puşcaş for treating this disease was a good one although the rationale behind it was wrong. In this review, we present a historical overview of the sulfonamide CAIs as anti-ulcer agents, in memoriam of the scientist who was in the first line of this research trend.
authors.affiliation: a Department of Gastroenterology , Ferencváros Health Centre , Budapest , Hungary and.
authors.forename: György M
authors.initials: GM
authors.lastname: Buzás
authors.affiliation: b Neurofarba Department , Sezione di Scienzie Farmaceutiche, Polo Scientifico, Università degli Studi di Firenze , Sesto Fiorentino, Firenze , Italy.
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D000897:Anti-Ulcer Agents / Q000737:chemistry / Q000266:history* / Q000627:therapeutic use*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000266:history* / Q000627:therapeutic use*; D016480:Helicobacter pylori / Q000187:drug effects / Q000201:enzymology; D049673:History, 20th Century; D006801:Humans; D010437:Peptic Ulcer / Q000188:drug therapy* / Q000266:history* / Q000382:microbiology; D013449:Sulfonamides / Q000737:chemistry / Q000266:history / Q000627:therapeutic use
chemical_list: D000897:Anti-Ulcer Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides
keywords: Acetazolamide; Helicobacter pylori; carbonic anhydrase; enzyme inhibitors; peptic ulcer