LONDON, April 23, 2015 /PRNewswire/ -- Clopidogrel (Plavix) is an anti-platelet drug that is used to prevent the formation of a thrombus (clot) in vulnerable patients. However, a significant proportion of patients who receive clopidogrel remain at risk for subsequent death, myocardial infarction, stent thrombosis, and stroke because of insufficient clopidogrel-induced platelet inhibition. Using customized relational databases with the capacity to rapidly mine large volumes of data and identify previously-unknown relationships, McCormack Pharma provides a new insight into why some people fail to adequately respond to the life-saving effects of clopidogrel. Their report identifies free fatty acids as the final arbiter in determining the magnitude of clopidogrel resistance.
Clopidogrel is a prodrug for an active metabolite that blocks the platelet P2Y12 receptor. This metabolite is generated in the liver by the cytochrome P450 (CYP) enzyme system. Inadequate responses to clopidogrel may be caused by polymorphisms in one or more of the cytochrome P450 enzymes, notably CYP2C19. However, when the mechanisms of clopidogrel resistance are explored across studies, polymorphisms in the CYP2C19 gene only partially explain the correlation with suboptimal clopidogrel response.
Conversion of clopidogrel to the active metabolite is limited in patients who carry CYP2C19 loss-of-function polymorphisms. Insufficient amounts of active metabolite mean that some platelet P2Y12 receptors will remain functional. McCormack's report defines points of convergence for potential augmentation of signalling from these remaining functional P2Y12 receptors by elevated levels of free fatty acids. This newly-characterized phenomenon fulfils requirements as a mechanism for non-linear augmentation of platelet activation. Additionally, McCormack's analysis shows how, even with 100% blockade of the P2Y12 receptor pool, elevated free fatty acids can activate the platelet by mimicking the downstream events of P2Y12 signalling, and also by inducing the expression upon the platelet surface of a clopidogrel-insensitive pool of P2Y12 receptors.
In clinical practice, these new findings offer an affordable solution for maximizing clopidogrel efficacy given that the use of inexpensive generic versions of clopidogrel is forecast to rise dramatically, in both developed and emerging nations. The report argues that in at-risk patient groups, the effects of an increased loading dose of clopidogrel are significantly attenuated by free fatty acids when above some critical concentration-dependent threshold.
"In these patients attempts to maximize clopidogrel efficacy through stepping up the dose may be likened to a futile effort to slow a speeding vehicle through use of the brakes while the throttle remains wide open; concomitant lowering of free fatty acids levels is a straightforward solution ......arguably, modulation of signalling by free fatty acids represents a highly-coordinated and teleologically-conserved failsafe mechanism for maintaining signalling fidelity." comments Dr Keith McCormack, founder and Head of Research at McCormack Pharma.
Dr McCormack emphasizes that McCormack Pharma's conclusions and recommendations require validation before new guidelines are implemented. The complete version of the report is available on McCormack's website at the URL below.
About McCormack Pharma and CEME
The systems of correlation and association that formed the basis of McCormack's data analysis platform CEME (Cutting-Edge Medical Education), were first created in 1983 by Keith McCormack. Today, CEME has evolved as a proprietary technology that is unique within the pharmaceutical industry. CEME describes the use of desktop methods that incorporate customized relational databases with the capacity to rapidly mine data and discover previously-unknown relationships between product data and data for a licensed indication. These novel outputs constitute new teachings that, by enhancing patient management provide the means for enhanced brand awareness and increased sales. More details are available at www.mccormackpharma.com