title: Medicinal Chemistry Approaches of Controlling Gastrointestinal Side Effects of Non-Steroidal Anti-Inflammatory Drugs. Endogenous Protective Mechanisms and Drug Design.
abstract: BACKGROUND
  Non-steroidal anti-inflammatory drugs are the oldest and most widely used medicines. However, their untoward effects, especially gastrointestinal toxicity, remain the main obstacle to their application. Because of their mechanism of action, cycloxygenase (COX) inhibition, in combination with the weekly acidic character of most of them, major protective mechanisms of the gastrointestinal system are suppressed and deregulated.
  
  
  OBJECTIVE
  In this review, several compounds designed to retain anti-inflammatory activity, but devoid of gastrointestinal side effects, are presented. Thus, gastro-protective drugs, selective COX-2 inhibitors, nitric monoxide- and hydrogen sulphide-releasing agents, prodrugs, lipoxygenase (LOX) inhibitors and dual COX/LOX inhibitors are presented. Their mechanism of action, as well as their advantages and disadvantages are discussed.
  
  
  CONCLUSIONS
  Efforts, aiming to the development of safe non-steroidal anti-inflammatory agents, are evolving, however there are still several problems concerning gastro-protection to be efficiently solved, thus, design of effective and safe agents for the treatment of inflammatory conditions still remains a major challenge.
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Tziona
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Theodosis-Nobelos
authors.affiliation: Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotelian University of Thessaloniki, Thessaloniki 54124, Greece.
authors.forename: Eleni A
authors.initials: EA
authors.lastname: Rekka
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002626:Chemistry, Pharmaceutical; D003106:Colon / Q000187:drug effects / Q000473:pathology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005753:Gastric Mucosa / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010437:Peptic Ulcer / Q000517:prevention & control*; D011355:Prodrugs / Q000494:pharmacology; D020011:Protective Agents / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016859:Lipoxygenase Inhibitors; D020030:Nitric Oxide Donors; D011355:Prodrugs; D020011:Protective Agents; D009569:Nitric Oxide; D006862:Hydrogen Sulfide
keywords: COX/LOX inhibitors; Gastrointestinal toxicity; H2S releasing agents; NO donors; gastroprotective mechanisms; molecular modifications; non-steroidal anti-inflammatory drugs