Pharmacology and clinical assessment of cariporide for the treatment coronary artery diseases.
Myocardial protection through pharmacological approaches represents a large therapeutic challenge and is an important therapeutic strategy in patients with coronary artery disease, particularly after myocardial infarction. Extensive animal experiments have repeatedly demonstrated the efficacy of sodium-hydrogen exchange (NHE) inhibition as a potent cardioprotective approach. The heart possesses primarily the NHE1 isoform which has led to the development of NHE1 specific inhibitors for cardiovascular therapeutics. Cariporide (HOE 642) is the first of such agents to have been developed and subjected to clinical trial. Preclinical studies with cariporide revealed excellent protection against necrosis, apoptosis, arrhythmias and mechanical dysfunction in hearts subjected to ischaemia and reperfusion. Cariporide has recently been evaluated in a large dose-finding Phase II/Phase III clinical trial (GUARDIAN) to assess its efficacy in patients with acute coronary syndromes. Overall results failed to demonstrate protection but sub-group analysis revealed significant risk reductions with the highest cariporide dose (120 mg t.i.d.) especially in high risk patients undergoing coronary artery bypass surgery. This suggests that insufficient dosage may have accounted, at least in part, for the less than optimum results. Another NHE1 inhibitor, eniporide, is currently in Phase II clinical trial (ESCAMI) in patients with acute myocardial infarction (MI) who are given angioplasty or thrombolysis. Although the study has not been completed interim findings appear positive. Both drugs were well-tolerated and produced no excess side effects compared with placebo. Further studies are needed to confirm the efficacy of NHE1 inhibitors for the treatment of coronary heart disease, even so initial results are encouraging.
Karmazyn
M
M
Department of Pharmacology and Toxicology, University of Western Ontario, London, Ontario N6A 5C1, Canada. mkarm@julian.uwo.ca
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D003327:Coronary Disease / Q000188:drug therapy* / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology* / Q000627:therapeutic use*; D006333:Heart Failure / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide