title: Cyclooxygenase inhibitors: From pharmacology to clinical read-outs.
abstract: Acetylsalicylic acid (aspirin) is a prototypic cyclooxygenase (COX) inhibitor. It was synthesized serendipitously from a natural compound, i.e., salicylic acid, with known analgesic activity. This chemical modification, obtained for the first time in an industrial environment in 1897, endowed aspirin with the unique capacity of acetylating and inactivating permanently COX-isozymes. Traditional nonsteroidal anti-inflammatory drugs (tNSAIDs) were developed to mimic the pharmacological effects of aspirin, using aspirin-sensitive experimental models of pain and inflammation as the template for screening new chemical entities. Among the tNSAIDs, some were endowed with moderate COX- selectivity (e.g., diclofenac), but no studies of sufficient size and duration were performed to show any clinically relevant difference between different members of the class. Similarly, no serious attempts were made to unravel the mechanisms involved in the shared therapeutic and toxic effects of tNSAIDs until the discovery of COX-2. This led to characterizing their main therapeutic effects as being COX-2-dependent and their gastrointestinal (GI) toxicity as being COX-1-dependent, and provided a rationale for developing a new class of selective COX-2 inhibitors, the coxibs. This review will discuss the clinical pharmacology of tNSAIDs and coxibs, and the clinical read-outs of COX-isozyme inhibition. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."
authors.affiliation: Center of Excellence on Aging and Department of Neuroscience, Imaging and Clinical Sciences, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Patrignani
authors.affiliation: Department of Pharmacology, Catholic University School of Medicine, Rome, Italy. Electronic address: carlo.patrono@rm.unicatt.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Patrono
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D002317:Cardiovascular Agents / Q000627:therapeutic use; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use; D016861:Cyclooxygenase Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use*; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000201:enzymology; D006331:Heart Diseases / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D007527:Isoenzymes; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000517:prevention & control; D012307:Risk Factors; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D016588:Anticarcinogenic Agents; D002317:Cardiovascular Agents; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2
keywords: Aspirin; COX-1; COX-2; Coxib; NSAID