Pharmacogenetic and clinical predictors of response to clopidogrel plus aspirin after acute coronary syndrome in Egyptians.

OBJECTIVES: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel reduces the risk for recurrent cardiovascular events after acute coronary syndrome (ACS). However, there is significant variation in response to DAPT that may be influenced by both genetic and nongenetic factors. This study aimed to assess the effect of genetic polymorphisms in PON-1, PEAR-1, P2Y12, CES1, and CYP2C19, along with clinical, demographic, and social factors, on variation in response to DAPT in Egyptians. PARTICIPANTS AND METHODS: This study included 230 Egyptians treated with clopidogrel 75 mg/day and aspirin 81 mg/day for at least 12 months following their first ACS. Simple and multivariable logistic regression analyses were carried out to identify factors associated with major adverse cardiovascular events (MACE), defined as the occurrence of recurrent ACS, ischemic stroke, stent-related revascularization, or death, in clopidogrel-treated participants. RESULTS: Using multivariable logistic regression analysis, the CYP2C19*2 polymorphism was the only genetic predictor of MACE [odds ratio (OR): 2.23, 95% confidence interval (CI): 1.15-4.33, P=0.01]. In addition, proton pump inhibitor use (OR: 4.77, 95% CI: 1.47-15.54, P=0.009) and diabetes (OR: 1.83, 95% CI: 1.03-3.26, P=0.03) were associated with higher cardiovascular risk, whereas statin use was associated with lower risk (OR: 0.43, 95% CI: 0.25-0.76, P=0.003). The contribution of these four genetic and nongenetic factors explained 19% of the variability in risk for MACE in Egyptians treated with DAPT. CONCLUSION: These results highlight that CYP2C19*2, along with diabetes, and use of proton pump inhibitor and statin are important factors jointly associated with variability in clinical response to DAPT following ACS in Egyptians.

Involvement of serotoninergic 5-HT1A/2A, alpha-adrenergic and dopaminergic D1 receptors in St. John's wort-induced prepulse inhibition deficit: a possible role of hyperforin.

Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.

Proapoptotic and prepulse inhibition (PPI) disrupting effects of Hypericum perforatum in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. AIM OF THE STUDY: Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. MATERIALS AND METHODS: The effects of acute (500 mg/kg) and chronic (200mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. RESULTS: Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. CONCLUSIONS: The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.