Advanced glycation end-product cross-link breakers. A novel approach to cardiovascular pathologies related to the aging process.
Advanced glycation end product (AGE) formation that occurs with aging and diabetes leads to the cross-linking of proteins and subsequent changes in the physicochemical properties of tissues. Cellular responses to AGE that lead to either pathological conditions or removal of AGE are mediated by a number of receptors that have been identified on various cell types such as macrophages, endothelial cells, and smooth-muscle cells. Mechanisms by which AGE affect the cardiovascular system include AGE cross-linking of long-lived proteins such as collagen and elastin and altered cellular responses. Alagebrium (3-phenacyl-4,5-dimethylthiazolium chloride, ALT-711) is the first drug in a new class of thiazolium therapeutic agents that break established AGE cross-links between proteins. In animal studies, alagebrium was effective in reducing large artery stiffness, slowing pulse-wave velocity, enhancing cardiac output, and improving left ventricular diastolic distensibility. In human studies to determine safety and efficacy, alagebrium was safe and well tolerated. In the first phase 2 clinical study, alagebrium improved arterial compliance in elderly patients with vascular stiffening. In two subsequent phase 2 clinical studies, one addressing diastolic heart failure and the other addressing systolic hypertension, alagebrium was effective in improving cardiac function and uncontrolled systolic blood pressure, particularly in more severely affected patients. Additional clinical studies to determine the utility of alagebrium in treating cardiovascular disorders associated with aging are in progress.
Bakris
George L
GL
Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois 60612, USA. George_Bakris@rush.edu
Bank
Alan J
AJ
Kass
David A
DA
Neutel
Joel M
JM
Preston
Richard A
RA
Oparil
Suzanne
S
D000375:Aging / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001808:Blood Vessels / Q000378:metabolism / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000378:metabolism* / Q000503:physiopathology; D018849:Controlled Clinical Trials as Topic; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use
D002317:Cardiovascular Agents; D017127:Glycation End Products, Advanced; D013844:Thiazoles; C406794:alagebrium