Background-We observed that the prodrug clopidogrel was less effective in inhibiting platelet aggregation with coadministration of atorvastatin during point-of-care platelet function testing. Because atorvastatin is metabolized by cytochrome P450 (CYP) 3A4, we hypothesized that clopidogrel might be activated by CYP3A4. Methods and Results-Platelet aggregation was measured in 44 patients undergoing coronary artery stent implantation treated with clopidogrel or clopidogrel plus pravastatin or atorvastatin, and in 27 volunteers treated with clopidogrel and either erythromycin or troleandomycin, CYP3A4 inhibitors, or rifampin, a CYP3A4 inducer. Atorvastatin, but not pravastatin, attenuated the antiplatelet activity of clopidogrel in a dose-dependent manner. Percent platelet aggregation was 34Ϯ23, 58Ϯ15 (Pϭ0.027), 74Ϯ10 (Pϭ0.002), and 89Ϯ7 (Pϭ0.001) in the presence of clopidogrel and 0, 10, 20, and 40 mg of atorvastatin, respectively. Erythromycin attenuated platelet aggregation inhibition (55Ϯ12 versus 42Ϯ12% platelet aggregation; Pϭ0.002), as did troleandomycin (78Ϯ18 versus 45Ϯ18% platelet aggregation; PϽ0.0003), whereas rifampin enhanced platelet aggregation inhibition (33Ϯ18 versus 56Ϯ20% platelet aggregation, Pϭ0.001). Conclusions-CYP3A4 activates clopidogrel. Atorvastatin, another CYP3A4 substrate, competitively inhibits this activation. Use of a statin not metabolized by CYP3A4 and point-of-care platelet function testing may be warranted in patients treated with clopidogrel. (Circulation. 2003;107:32-37.)Key Words: drugs Ⅲ pharmacology Ⅲ platelets Ⅲ statins C lopidogrel inhibits platelet aggregation. 1 It decreases the incidence of coronary artery stent thrombosis and is approved for reduction of myocardial infarction, stroke, and vascular death in patients with atherosclerotic vascular disease. [2][3][4] Clopidogrel is an inactive thienopyridine prodrug that requires in vivo conversion in the liver to an active metabolite that exerts its antiplatelet effect by forming an inactivating disulfide bond with the platelet P2Yac (P2Y12) adenosine diphosphate (ADP) receptor. [5][6][7][8] The P2Yac ADP receptor is a guanosine triphosphate (GTP)-coupled 7 transmembrane protein that mediates platelet aggregation by inhibiting adenyl cyclase. 8 In rats, it has been suggested that clopidogrel is activated by cytochrome P450 1A2, 6 whereas an analogue of clopidogrel, CS-747, is speculated to be activated by human cytochrome P450 3A4 (CYP3A4). 9 In humans, it is not known how clopidogrel is activated.Atorvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor widely used to treat hypercholesteremia. It is metabolized by CYP3A4, 10 the most abundant cytochrome P450 in human liver. Patients with atherosclerotic disease are frequently treated for hypercholesteremia with both clopidogrel and atorvastatin or another statin.During the course of evaluating the effect of clopidogrel on platelet function using a novel bedside platelet aggregometer, it was noted that the antiplatelet activity of clopidogrel...

The authors observed the incidence of grade 3 MV to be 1.4%, similar to studies with the same definition of difficult MV. Presence of a beard is the only easily modifiable independent risk factor for difficult MV. The mandibular protrusion test may be an essential element of the airway examination.

Children may become agitated after general anesthesia. This study describes several factors that may increase the risk for agitation. These data are important in planning anesthesia care for young children.