Pharmacogenetics and pharmacogenomics of thienopyridines: clinically relevant?

Pharmacogenetics have been touted as the future of personalized medicine where genetic biomarkers will guide therapeutic approach. The currently approved thienopyridines, prasugrel and clopidogrel, are prodrugs requiring conversion to active metabolite through the cytochrome P450 system. Genetic variation has been associated with the pharmacokinetic, pharmacodynamic, and clinical response to clopidogrel, but not to prasugrel. This review aims to summarize the recent pharmacogenetic findings associated with the response to thienopyridine treatment. Additionally, considerations for the incorporation of genetic biomarkers into clinical practice will be discussed in the context of thienopyridines.     

Interaction between statins and clopidogrel: is there anything clinically relevant?

Since their introduction several years ago, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors-the statins-have been widely used for hyperlipidemia and for the primary/secondary prevention of cardiovascular diseases. They have been shown to be safe as well as efficacious in a number of different clinical trials; however, studies have suggested that they can interact with other co-administered therapies. More recently, the thienopyridines have been successfully integrated with the conventional medical treatment of coronary disease as they showed effectiveness in reducing platelet activity both in stable and unstable settings. They also improve the outcome of patients treated with percutaneous coronary intervention. The potential interaction of statins and thienopyridines is a matter of concern. Despite some preclinical data suggesting an interaction between statins metabolized by the liver cytochrome P3A4-such as atorvastatin, lovastatin and simvastatin-and clopidogrel, there is no compelling clinical evidence to stop their co-administration.     

Do pulse checks delay semiautomatic defibrillation by EMT-Defibrillators?

Advanced cardiac life support (ACLS) guidelines from the American Heart Association (AHA) now recommend not checking for a pulse between the initial three defibrillations for pulseless patients in ventricular tachycardia or fibrillation. The AHA asserts that checking for a pulse needlessly delays defibrillation. This study was undertaken to determine if pulse checks delay defibrillation by EMT-Defibrillators (EMT-Ds) using a semiautomatic defibrillator (SAED). Twenty-seven EMT-Ds demonstrated delivery of three successive defibrillations during two test scenarios: once with and once without pulse checks after the first and second defibrillations. The time from the first to third defibrillation was recorded. The mean time to deliver the defibrillations was 60.2 ± 6.2 seconds with pulse checks and 57.5 ± 4.6 seconds without pulse checks. The difference, 2.7 ± 5.9 seconds, was statistically significant (P = 0.026). Pulse checks by EMT-Ds do delay administration of defibrillations, but consideration should be given to reinstating pulse checks as a part of the AHA guidelines, since this delay is of questionable clinical significance.     

Do soluble mediators cause ventilator-induced lung injury and multi-organ failure?

Background  

Significant advances in the management of patients with acute respiratory distress syndrome have been few in the recent past despite considerable efforts in clinical testing and experimental work. The biotrauma hypothesis of ventilator-associated lung injury (VALI), suggesting that mechanical ventilation induces the release of injurious mediators from the lung, implies that pharmaceutical interventions targeting these circulating pathogenic mediators would be clinically beneficial. Among the commonly reported classes of ventilation-associated mediators are cytokines, coagulation factors, hormones (e.g., angiotensin-II), lipid-derived mediators and oxidants, yet proof of their pathogenicity is lacking.     

Does electrode polarity alter the energy requirements for transthoracic biphasic waveform defibrillation? Experimental studies.

BACKGROUND: Electrode polarity may alter the success of biphasic shocks from implantable systems. Whether the electrode polarity influences the success of transthoracic biphasic defibrillation is unknown. We determined the effect of electrode polarity on biphasic transthoracic defibrillation in a porcine model. METHOD: In ten anesthetized adult pigs, 16-28 kg, electrode pads were placed in two different orientations on the chest wall; apex-right parasternal and sternal-vertebral column. Ventricular fibrillation (VF) was electrically induced and allowed to persist for 30 s. Truncated exponential biphasic shocks (5/3 ms) were delivered at 20, 30, 50, 70 and 100 J. Four shocks at each energy level were delivered to construct energy vs. % success curves for VF termination. Electrode polarity for the first pulse was varied so that the first pulse cathode was either the apex (for apex-parasternal) or sternum (for sternum-vertebral column), or the reverse. The second pulse polarity was always the opposite of the first. RESULTS: VF termination success rose from 0 to 86% as energy increased from 20 to 100 J. Varying the electrode polarity did not alter success rates at any energy level with either electrode pad placement. CONCLUSION: In this porcine model of transthoracic defibrillation, varying the biphasic shock electrode polarity did not alter transthoracic defibrillation success. Positional labeling of transthoracic biphasic defibrillation electrode pads may be unnecessary.     

Resuscitation fluids and endotoxin-induced myocardial dysfunction: is selection a load-independent differential issue?

ABSTRACT: Along with redistributive shock, myocardial dysfunction is now recognized as highly prevalent in early severe sepsis. Indeed, aside from their distinct loading potency, resuscitation fluids have been poorly investigated as to their specific molecular impact on myocardial dysfunction. The objective of this study was to evaluate the load-independent biological impact of different resuscitation fluids on endotoxin-induced myocardial dysfunction. Adult rats implanted with a central venous catheter were given an intraperitoneal injection of endotoxin (lipopolysaccharides [LPSs], Escherichia coli, 10 mg/kg) or normal saline (sham) and subsequently infused or not with similar "fluid potency" loading resuscitation fluid (normal saline, albumin [Alb], or hypertonic saline solution) for 6 to 24 h, followed by echocardiographic and hemodynamic monitoring together with biochemical and histopathologic evaluation. Intervention was to assess the selective influence of load-independent fluid infusion on the aforementioned parameters in groups of animals challenged or not with LPS. At comparative plasma volumes, Alb improved myocardial homeostasis after LPS challenge by (i) reducing left ventricular relative wall diastolic thickness, interstitial space enlargement, and endogenous Alb content; (ii) limiting cardiac apoptosis and sustaining extracellular signal-regulated mitogen-activated protein kinase activation; and (iii) enhancing the expression pattern of heme-oxygenase 1/inducible nitric oxide synthase. Hypertonic saline solution was also cardioprotective by early prevention of myocardial dysfunction and by reducing cardiac apoptosis. Fluid infusions have distinct load-independent structural/biological impacts on endotoxin-induced myocardial dysfunction. Albumin and hypertonic saline solution are the most pleiotropic fluids in protecting the heart after a "sepsis" hit.