Pharmacology of Azapropazone: Potential Utility in the Treatment of Ischemia/Reperfusion Injury

Abstract

This article reviews the pharmacology of azapropazone and provides a likely link between its anti-inflammatory and myocardial cytoprotective efficacy in myocardial ischemidreperfusion injury.Azapropazone (AZP) is a chemically unique substituted benzotriazine nonsteroidal anti-inflammatory drug (NSAID). AZP was one of the early representatives of the class of NSAIDs to be introduced after phenylbutazone (PBZ) and indomethacin. Twenty years of clinical experience have been gained with AZP, which was developed and successfully introduced into a number of European countries for the treatment of a wide range of rheumatic conditions (47). Currently, AZP is under evaluation as a potential protective agent in different disease states involving neutrophil infiltration (1 3,25,29,32).This drug differs chemically from PBZ; a detailed comparison (structural, spectroscopic, and chemical) of AZP with PBZ reveals major differences (6,48). Although AZP undergoes enol formation (unlike PBZ), it is less acidic because of the differences in the restriction in rotation of AZP compared with the phenyl groups of PBZ. The dimethylamino substituent is present only in AZP and this markedly enhances its aqueous solubility by interaction of the nitrogen of this group with the hydroxyl moiety at low pH (such as in the stomach). There are also major differences in pharmacokinetics, metabolism, and pharmacodynamic actions of AZP compared to PBZ (48) (see reviews of Ref. 39). These considerations suggest that AZP should be classified separately from PBZ. It is important to note that the OH and = 0 groups in the formal structure of AZP depicted in Fig. 1 are interchangeable.