The aim of the study is to explore the contribution of genetic factors related either to drug metabolism (cytochrome P450 2C9) or to drug target (vitamin K epoxide reductase) to variability in the response to acenocoumarol among 222 healthy volunteers after a single oral dose. Associations between a pharmacodynamic index (reduction in factor VII activity and international normalized ratio [INR] change) and several genetic polymorphisms (VKORC1: ؊4931T>C, ؊4451C>A, ؊2659G>C, ؊1877A>G, ؊1639G>A, 497C>G, 1173C>T, and CYP2C9*3) were investigated using haplotype and univariate analyses. VKORC1 haplotypes were associated with the pharmacologic response, and this association can be explained only by the effect of the ؊1639G>A polymorphism (or alternatively by 1173C>T, which is in complete association with it). Indeed, it explains about one third of the variability of the pharmacologic response (37% of factor VII decrease and 30% of INR change). Moreover, the previously observed effect of the CYP2C9*3 allele is independent of the VKORC1 gene effect. These 2 polymorphisms account for up to 50% of the interindividual variability. The simple genotyping of 2 single-nucleotide polymorphisms (SNPs), VKORC1 ؊1639G>A or 1173C>T and the CYP2C9*3 polymorphisms, could thus predict a high risk of overdose before initiation of anticoagulation with acenocoumarol, and provide a safer and more individualized anticoagulant therapy. (Blood. 2005;106:135-140)

This study assessed the minimum dose of clonidine required to prolong the duration of both anesthesia and analgesia after axillary brachial plexus blockade. Eighty patients scheduled for elective hand surgery were divided into eight groups in a randomized, double-blind fashion. An axillary brachial plexus block was performed with 40 mL 1% mepivacaine plus 1:200,000 epinephrine. The control group received no clonidine. In the other groups, increasing doses of clonidine (0.1, 0.2, 0.3, 0.4, 0.5, 1, and 1.5 micrograms/kg) were added to the local anesthetic solution. Onset time, duration of anesthesia and analgesia, postoperative pain score, intake of analgesics, and adverse effects were recorded. The eight groups were comparable in terms of onset time, postoperative pain score, and analgesic requirement. The minimum dose of clonidine required to significantly prolong the duration of analgesia and anesthesia was, respectively, 0.1 and 0.5 microgram/kg. No side effects (sedation, drowsiness, bradycardia, arterial hypotension) were reported. We conclude that the dose of clonidine required to prolong significantly the duration of both anesthesia and analgesia after axillary brachial plexus blockade is 0.5 microgram/kg and that, at this dose, clonidine may be used without important reported side effects even in outpatients.

International Normalized Ratio (INR), which standardizes prothrombin time (PT) during oral anticoagulation, has been extended to standardize PT in liver diseases and is included in prognostic models such as the Model for End stage Liver Disease (MELD). However, mechanisms of PT prolongation in liver diseases differ from those involved in oral anticoagulation, and the thromboplastin reagents differ in their sensitivities to these 2 mechanisms. Our aim was to determine whether, in the calibration model for thromboplastins proposed by the World Health Organization, the use of plasmas from patients with liver diseases instead of plasmas from patients on oral anticoagulation could lead to a new INR specific for liver diseases (INR "LD"), achieving a real standardization of PT. First, 5 thromboplastins were calibrated against an international reference using 60 plasmas of patients with liver failure and, in a second step, the variation of PT reported as seconds, the ratio of patient PT to normal PT, See Editorial on Page 295 P rothrombin time (PT) is the usual test for monitoring oral anticoagulation by vitamin K antagonists 1 and is widely adopted to assess the severity of acute and chronic liver injury. 2 PT is the recalcification time of citrated plasma in the presence of a thromboplastin reagent. 3 The term thromboplastin refers to a complex mixture of tissue factor and phospholipids prepared from tissue extracts of animal or human origin. Recent thromboplastins contain recombinant tissue factor. PT is influenced by the levels of the following coagulation factors: I (fibrinogen), II, V, VII, and X, all factors being synthesized by the liver and, among them, 3 (II, VII, and X) being vitamin K dependent. Thromboplastins can vary markedly in their responsiveness to the defects induced by vitamin K antagonist therapy. As a result, the poor agreement between PT in different laboratories whatever the methods of reporting results 4 has led to important differences in oral anticoagulant dosing. 5,6 Standardization of PT reporting in patients on oral anticoagulation has been improved by the calibration model for thromboplastins proposed by the World Health Organization (WHO). 7 This system defines, for a specific thromboplastin reagent, the International Sensitivity Index (ISI) obtained by a calibration using plasmas of patients on stable oral anticoagulant doses, against a WHO international reference thromboplastin. 7 The ISI is a numerical value that reflects the responsiveness of a given thromboplastin to reduction of the vitamin K-dependent coagulation factors; the lower the ISI value, the greater the sensitivity of the reagent. The recommended scale of reporting PT results is