title: Comparative effects of the anti-platelet drugs, clopidogrel, ticlopidine, and cilostazol on aspirin-induced gastric bleeding and damage in rats.
abstract: OBJECTIVE
  The present study compared the effects of frequently used anti-platelet drugs, such as clopidogrel, ticlopidine, and cilostazol, on the gastric bleeding and ulcerogenic responses induced by intraluminal perfusion with 25 mM aspirin acidified with 25 mM HCl (acidified ASA) in rats.
  
  
  METHODS
  The stomach was perfused with acidified ASA at a rate of 0.4 ml/min for 60 min under urethane anesthesia, and gastric bleeding was measured as the concentration of hemoglobin in the luminal perfusate, which was collected every 15 min. Clopidogrel (10-100mg/kg), ticlopidine (10-300 mg/kg), or cilostazol (3-30 mg/kg) was given p.o. 24h or 90 min before the perfusion of acidified ASA, respectively.
  
  
  RESULTS
  Perfusion of the stomach with acidified ASA alone led to slight bleeding and lesions in the stomach. The pretreatment with clopidogrel, even though it did not cause bleeding or damage by itself, dose-dependently increased the gastric bleeding and ulcerogenic responses induced by acidified ASA. Ticlopidine also aggravated the severity of damage by increasing gastric bleeding, and the effects of ticlopidine at 300 mg/kg were equivalent to those of clopidogrel at 100mg/kg. In contrast, cilostazol dose-dependently decreased gastric bleeding and damage in response to acidified ASA.
  
  
  CONCLUSIONS
  These results demonstrated that clopidogrel and ticlopidine, P2Y12 receptor inhibitors, increased gastric bleeding and ulcerogenic responses to acidified ASA, to the same extent, while cilostazol, a phosphodiesterase III inhibitor, suppressed these responses. Therefore, cilostazol may be safely used in dual anti-platelet therapy combined with ASA, without increasing the risk of gastric bleeding.
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan; General Incorporated Association, Kyoto Research Center for Gastrointestinal Diseases, Karasuma-Oike, 671, Kyoto 604-8106, Japan. Electronic address: takeuchi@mb.kyoto-phu.ac.jp.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Takayama
authors.affiliation: Division of Pathological Sciences, Department of Pharmacology and Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto 607-8414, Japan.
authors.forename: Chitose
authors.initials: C
authors.lastname: Izuhara
mesh_terms: D000818:Animals; D001241:Aspirin / Q000009:adverse effects*; D000077407:Cilostazol; D000077144:Clopidogrel; D006454:Hemoglobins / Q000032:analysis; D006470:Hemorrhage / Q000139:chemically induced*; D008297:Male; D009195:Peroxidase / Q000032:analysis; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013272:Stomach Diseases / Q000139:chemically induced* / Q000473:pathology; D013777:Tetrazoles; D013988:Ticlopidine / Q000031:analogs & derivatives
chemical_list: D006454:Hemoglobins; D010975:Platelet Aggregation Inhibitors; D013777:Tetrazoles; D000077144:Clopidogrel; D009195:Peroxidase; D000077407:Cilostazol; D013988:Ticlopidine; D001241:Aspirin
keywords: Anti-platelet drug; Aspirin; Gastric bleeding; P2Y(12) receptor antagonist; PDE III inhibitor; Rat