Current available data show that about 4% to 30% of patients treated with conventional doses of clopidogrel do not display adequate antiplatelet response. Clopidogrel resistance is a widely used term that remains to be clearly defined. So far, it has been used to reflect failure of clopidogrel to achieve its antiaggregatory effect. The interpatient variability in clopidogrel response is multifactorial. It can be due to extrinsic or intrinsic mechanisms. Among extrinsic mechanisms are the possibility of clopidogrel underdosing in patients undergoing stenting or with acute coronary syndrome, and drug-drug interactions involving CYP3A4. Intrinsic mechanisms include genetic polymorphisms of the P2Y(12) receptor and of the CYP3As, accrued release of adenosine diphosphate, or up-regulation of other platelet activation pathways. Presently, there is no definite demonstration of an association between low responsiveness to clopidogrel and thrombotic events. The optimal level of clopidogrel-induced platelet inhibition, which will correlate quantitatively with clopidogrel's ability to prevent atherothrombotic events is still lacking. Furthermore, because there is no single and validated platelet function assay to measure clopidogrel's antiplatelet effect, it is not justified to routinely look for clopidogrel resistance in the clinical setting. This review discusses currently available evidence surrounding the variability in the antiplatelet response to clopidogrel.

The assessment of platelet function inhibition by clopidogrel is highly test-specific. Decision to increase clopidogrel dosage may vary on the basis of the assay used, thus highlighting the need for unambiguous guidelines with respect to assay selection, as platelet function assays are not interchangeable. At present, platelet function testing evaluating clopidogrel efficacy cannot be recommended in routine clinical practice.

The emergence of point-of-care assays enabling bedside testing such as the VerifyNow P2Y12 system might prove useful in clinical settings. The aim of this study was to evaluate the ability of the VerifyNow P2Y12 assay to estimate the inhibition of platelet aggregation provided by clopidogrel in the absence of baseline off-drug aggregation data. Sixty-eight patients with coronary artery disease scheduled to initiate clopidogrel therapy underwent platelet aggregation testing by VerifyNow P2Y12 at baseline and after clopidogrel administration. The inhibition reported by the VerifyNow assay (relative to thrombin receptor activating peptide-induced platelet aggregation, serving as baseline) was compared with that calculated with the actual adenosine diphosphate-induced baseline obtained with the same methodology. The postclopidogrel thrombin receptor activating peptide-induced aggregation showed a great discordance with that induced by adenosine diphosphate before clopidogrel with a bias of 24 units (95% limits of agreement from -142 to 190 units). Moreover, the inhibition reported by the assay overestimated the standard before-and-after testing data by an average of 8% (95% limits of agreement from -49% to 65%), making its use without a true baseline comparator unsatisfactory. The VerifyNow P2Y12 assay fails to accurately quantify platelet inhibition achieved by clopidogrel compared with before-and-after testing. Further studies are required to establish the clinical usefulness of the VerifyNow P2Y12 assay to accurately predict the occurrence of major adverse cardiovascular events in patients with reduced clopidogrel efficacy before it can be implemented in clinical practice. At present, the use of this assay in clinical care cannot be recommended for monitoring clopidogrel therapy.

Biogenic silica has been considered as a potential feedstock for producing a variety of silicon-containing products. A new synthesis pathway of tetraethyl orthosilicate from silica that is contained in rice hull ash has been recently proposed. Requiring only one-step processing, it is expected to offer advantages over conventional routes which are derived from silicon metal. This study aims to investigate the optimal synthesis conditions for which this new technology can sustainably replace the conventional method. Experiments employing different reaction conditions are performed to provide the necessary information for a conceptual process design and an economic and environmental viability evaluation. The results obtained by comparison with a selected conventional process show that, under the optimal synthesis conditions, the new process can decrease the production cost and markedly reduce the high greenhouse gas emissions. The competitiveness of the new process is further examined with a sensitivity analysis considering fluctuations in key feedstock and utility prices and alternative sources of electricity supplied to the conventional process. The new synthesis technology shows high potential as a sustainable alternative to the conventional one.

The left ventricle hypertrophies in response to chronic pressure overload. To determine whether increased beta-adrenergic stimulation, wall mass, intrinsic contractility, or a combination of these factors is responsible for improved left ventricular (LV) pump function during early development of pressure-overload hypertrophy and whether hypertrophy normalizes peak-systolic wall stress, as is commonly believed, we induced pressure overload in intact-chest dogs by gradual constriction of one renal artery and implanted radiopaque markers, via a catheter, in the LV endocardium to measure dimensions. Changes in hemodynamics, LV dimensions, contractility indexes, and circumferential wall stress were measured before and after acute beta-blockade for 12 wk. LV function improved over time in the unblocked state, indicated by increased cardiac output, systolic pressures, stroke work, and maximal elastance (Emax). Acute beta-blockade reduced stroke work, Emax, and maximal LV rate of pressure over time (dP/dtmax) relative to the unblocked state but all still increased significantly over time. dP/dtmax and Emax did not vary with increases in LV mass, but stroke work was borderline dependent on LV mass. These results suggest that beta-adrenergic stimulation contributes to improved LV pump function and that the remaining improvements are due to both increased intrinsic contractility and wall mass. In contrast to accepted theory, LV systolic wall stresses decreased significantly over time. End-diastolic wall stress increased after renal artery constriction, then returned to baseline values as the heart hypertrophied. These results suggest that hypertrophy normalizes end-diastolic, not peak-systolic, wall stress.