Different Mechanisms in Formation and Prevention of Indomethacin-induced Gastric Ulcers
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Different Mechanisms in Formation and Prevention of Indomethacin-induced Gastric Ulcers Halis Suleyman,1,4 Abdulmecit Albayrak,1 Mehmet Bilici,2 Elif Cadirci,3 and Zekai Halici1
Abstract—Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with antiinflammatory, analgesic, and antipyretic effects. Indomethacin became the first-choice drug to produce an experimental ulcer model as a result of having a higher ulcerogenic potential than other non-steroidal anti-inflammatory drugs (NSAIDs). There have been several conflicting reports about the ulcerogenic mechanism of indomethacin; the mechanism is still unclear. It has been suggested that indomethacin induces gastric damage via inhibiting the release of protective factors like cyclooxygenase-1 (COX-1), prostaglandin E2 (PGE2), bicarbonate, and mucus; increasing aggressive factors like acid; and increasing oxidant parameters while decreasing antioxidant parameters. Classic antiulcer drugs are known to produce antiulcer effects by activating against indomethacin (increasing PGE2, mucus, and bicarbonate production; inhibiting acid secretion; decreasing oxidant parameters; and increasing antioxidants). However, some antiulcer drugs have been shown to inhibit indomethacin-induced ulcers without affecting acid and mucus secretion or oxidant parameters, as well as to inhibit the production of protective factors like COX-1, PGE2, and bicarbonate, and to reduce antioxidant parameters. In order to resolve the contradictions in the abovementioned data, this review hypothesized a relationship between indomethacin-induced ulcers and α 2 adrenergic receptors. It is suggested that blockage of α 2 adrenergic receptors may be responsible for the increase in the aggressive factors induced by indomethacin, and stimulation of α 2 adrenergic receptors may be responsible for the increase of protective factors induced by antiulcer drugs. KEY WORDS: indomethacin; ulcer; adrenergic receptors.
known that the inhibition potencies of non-steroidal antiinflammatory drugs (NSAIDs) on cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes are different [5]. It is believed that while inhibition of COX1 by NSAIDs causes side effects as a result of reduced prostaglandin (PG) synthesis, inhibition of COX-2 is related to their anti-inflammatory effect [5–7]. Indomethacin potently damages PG synthesis by inhibiting both the COX-1 and COX-2 enzymes [1, 8]. Inhibition of the COX-1 and COX-2 enzymes is necessary for gastric damage to occur [9]. Indomethacin and similar NSAIDs, which inhibit both isoforms of the COX enzyme, produce more severe damage in gastric tissue, even gastrointestinal bleeding when combined with antithrombotic agents [10]. Inhibition of the COX-2 enzyme is thought to be responsible for indomethacin’s anti-inflammatory effect, while inhibition of COX-1 is responsible for its gastrointestinal system (GIS) side effects [10, 11].
INTRODUCTION Indomethacin is an indol derivative, non-steroidal, anti-inflammatory drug with anti-inflammatory, analgesic, and antipyretic eff
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