药物基因组学模型对机械瓣膜置换术后华法林低强度抗凝治疗剂量预测效果的评价

目的 评价华法林药物基因组学模型对机械瓣膜置换术后华法林低强度抗凝治疗剂量预测效果。方法 按照设定的标准选取皖南医学院弋矶山医院2012年1月-2013年10月行心脏机械瓣膜置换术后接受华法林低强度抗凝治疗(目标国际标准化比值INR为1.6~2.5)患者107例,采用聚合酶链反应-限制性片段长度多态性方法(PCR-RFLP)和测序技术对CYP2C9和VKORC1基因进行检测。依据INR监测结果调整华法林至稳定剂量,并根据华法林实际稳定剂量将患者分为低剂量组(≤1.5 mg/d)、中剂量组(1.5~4.5 mg/d)和高剂量组(≥4.5 mg/d)。利用国际华法林药物基因组联合会(IWPC)模型计算华法林预测剂量,比较华法林预测剂量与实际稳定剂量的平均绝对误差(MAE),计算预测剂量位于理想剂量(实际稳定剂量20%界限)、高估和低估剂量患者比例,并以华法林预测剂量和实际稳定剂量拟合相关回归曲线R²评价该模型预测剂量的准确性。结果 华法林预测剂量与实际稳定剂量MAE为(0.89±0.62) mg/d,相关回归系数R²为0.325,预测剂量在理想剂量范围内的比例为42.06%,其中高剂量组位于理想剂量范围内比例为50.00%,高于中剂量组(43.75%)和低剂量组(11.11%)。结论 IWPC模型对中国汉族人群华法林剂量预测的效果有限,适合于中国汉族人华法林低强度抗凝治疗药物的基因组学模型仍需进一步大规模临床研究和验证。     

皖南地区汉族人群华法林稳定剂量模型预测准确性的评价与建立

目的:比较并评价4种华法林稳定剂量预测模型的预测准确性并建立华法林剂量预测模型。方法:收集483名服用华法林患者的临床资料,检测患者CYP2C9*3和VKORC1基因型,以预测百分比和平均绝对误差分析4种华法林稳定剂量预测模型的准确性;将纳入影响华法林稳定剂量的相关因素进行多元线性回归分析,得到相应的剂量预测模型。结果:CYP2C9*3/*3型患者华法林稳定剂量为(0.83±0.19) mg·d^-1,显著低于*1/*1型和*1/*3型患者(P＜0.05),VKORC1 GG型患者华法林稳定剂量为(4.17±1.49) mg·d^-1,显著高于AA型和GA型患者(P＜0.05);4种华法林剂量预测模型的预测剂量与实际剂量差异均显著相关(P＜0.01),IWPC模型的相关性最好,r=0.519;MAE最低的是TAN模型,为(0.70±0.53) mg·d^-1,指南模型的MAE最高,为(0.86±0.60) mg·d^-1;华法林稳定剂量模型建立结果D(mg·d^-1)=2.826-0.018×年龄+0.544×BSA-0.322×CYP2C9+0.482×VKORC1-0.336×胺碘酮-0.801×心房颤动。结论:CYP2C9和VKORC1基因多态性对华法林稳定剂量存在一定影响,构建的华法林剂量预测模型可较为准确地预测稳定剂量,优化给药方案,为临床个体化用药提供指导。     

基因指导新疆维吾尔族患者华法林日稳定剂量预测模型的建立及验证

目的：评价新疆维吾尔族患者临床特征及基因型分布,建立华法林日稳定剂量预测模型并验证准确性。方法：按照纳入排除标准选取接受华法林抗凝治疗并达稳定剂量的患者120例,分为建模组（90例）和验证组（30例）,应用PCR直接测序法检测VKORC1、CYP2C9基因多态性,记录华法林日稳定剂量、人口学资料、个人史、合并用药、合并疾病,采用多元线性回归方法建立华法林稳定剂量预测模型并进行准确性验证。结果：新疆维吾尔族患者华法林日稳定剂量预测公式为：Dose=3.642+0.910×VKORC1-1 173TC+1.774×VKORC1-1 173CC-2.660×CYP2C9CC+0.991×吸烟×0.02年龄（yr）;该预测模型在验证组患者中的预测剂量与实际剂量无统计学差异（P>0.05）;IWPC预测模型在验证组患者中预测剂量低于实际剂量比例为46.7%;Huang等预测模型在验证组患者中的预测剂量与实际剂量无统计学差异（P>0.05）,其中40%的患者为理想预测剂量;本预测模型在心脏瓣膜置换术后患者中预测剂量为理想预测剂量的百分比为70%。结论：本预测模型可预测新疆维吾尔族患者的华法林日稳定剂量,但样本量较少,该预测模型需要进一步的验证。     

3种华法林剂量预测模型与汉族人群的维持剂量相关性评价

目的：评价3种不同华法林剂量预测模型对汉族人群华法林每日维持剂量预测的准确性。方法：选取86例行VKORC1、CYP2C9基因多态性检测,华法林抗凝治疗且INR达标患者,收集患者平均每日华法林维持剂量、人口学信息及临床情况等;通过比较患者的实际剂量与预测剂量的差异,评价Gage模型、国际华法林药物基因组协会（IWPC）和药物作用靶点基因检测技术指南（指南）等推荐的华法林剂量预测模型的准确性。结果：Gage模型的预测剂量稍小于患者实际剂量,但没有统计学差异[（3.81±0.95）mg vs.（4.19±1.19） mg,P=0.199],预测准确率61.6%,而IWPC、指南模型的平均预测剂量均低于患者实际剂量[（3.48±0.85）mg,P=0.025和（3.38±0.66）mg,P=0.007）];预测准确率分别为48.8%和41.8%。结论：GAGE模型更适合威海地区汉族人群,但需大样本研究进一步验证其准确性。     

基于人工神经网络模型预测华法林服药者国际标准化比值

目的 探究CYP2C9*2、CYP2C9*3、CYP4F2、VKORC11173C>T基因多态性与华法林维持剂量之间的相关性,建立华法林服用者用药后国际标准化比值(international normalized ratio,INR)的人工神经网络预测模型,提高稳定剂量预测准确性。方法 回顾性研究2019—2021年收集的214例服用华法林达到稳定抗凝患者的临床资料与华法林药物基因数据,分析临床因素与各基因型对患者华法林稳态剂量的影响;建立机器学习预测模型,采用模拟输入患者华法林剂量计算INR靶值的方式来预测稳态剂量,与直接剂量预测方法以及多元回归模型对比准确性。结果 多元回归模型对数据集中患者稳态剂量的预测最佳准确度56.4%,机器学习的预测模型输入稳态剂量预测INR值时的平均绝对误差(mean absolute error, MAE)为0.40,R2为0.81,直接预测剂量时MAE为0.52,R2为0.68,在进行分组训练后误差能够降低20.4%,准确率提高7.3%。结论 通过模拟输入药物剂量预测INR的人工神经网络华法林模型能够更准确地预测患者稳态剂量,有利于实现个体化给药...     

基于CYP2C9*3和VKORC1-1639G＞A基因多态性指导房颤患者华法林稳定剂量预测模型的验证与评价

目的:验证评价4个基于CYP2C9*3和VKORC1-1639G＞A基因多态性的华法林稳定剂量预测模型的准确性。方法:收集太和县人民医院2020年1月至2022年7月进行CYP2C9*3和VKORC1-1639G＞A基因检测的非瓣膜性房颤患者,将CYP2C9*3和VKORC1基因型和患者基本信息代入华法林稳定剂量预测模型中得到预测剂量,以绝对误差均值和理想预测百分比作为准确性评价指标,应用SPSS 17.0软件进行统计分析。结果:88例房颤患者的CYP2C9*3、VKORC1-1639G＞A基因频率均符合Hardy-Weinberg平衡。模型1、2、3、4华法林预测剂量分别为(2.82±0.78),(2.80±0.85),(2.47±0.30),(1.99±0.82) mg·d^-1,实际剂量为(2.71±0.74) mg·d^-1;4个模型的绝对误差均值分别为0.11、0.09、-0.24、-0.72 mg·d^-1。4个模型理想预测百分比分别为72.73%、70.45%、61.36%、20.45%,模型1最高,模型4最低。散点图结果显示:模型2和模型1预测剂量与实际剂量的相关性较好。一致性检验结果显示:预测剂量与实际剂量一致性最高的是模型1,最低的为模型4。结论:模型1和模型2可以较好地预测房颤患者华法林给药剂量。     

钙腔蛋白（rs2290228）基因多态性与华法林稳定剂量的关系*

【摘要】目的 探讨钙腔蛋白（CALU,rs2290228）基因型在中国汉族人群中的分布情况及其基因多态性与瓣膜置换术后华法林稳定剂量的关系。方法 采用Snapshot技术检测226例研究对象CALU（rs2290228）位点基因型,研究其基因型及等位基因频率;比较其中176例行瓣膜置换术后抗凝稳态患者基因多态性与华法林稳定剂量的关系。结果 226例中CALU（rs2290228）位点基因型TT、CT 和CC分别为2例(0.9%)、88例(38.9%)和136例(60.2%), T和C等位基因的频率分别为20.4%和79.6%;176例服用华法林达稳定状态患者,华法林日维持剂量为TT型（2.75±0.35）mg/ d,CT型（3.37±0.81）mg/d,CC型（3.14±0.89）mg/d;3种基因型华法林日维持剂量、凝血酶原时间和抗凝强度预设国际标准化比值组间比较差异无统计学意义（P > 0.05）。结论 中国汉族人群CALU（rs2290228）基因多态性可能不是瓣膜置换术后华法林个体剂量差异的影响因素。     

基于CYP2C9和VKORC1基因多态性预测老年房颤患者使用华法林的稳定剂量

目的:探讨CYP2C9和VKORC1基因多态性对房颤患者华法林稳定剂量的影响,建立适合汉族人群老年房颤患者的华法林给药模型,指导华法林个体化抗凝治疗。方法:对200例口服华法林抗凝的老年患者进行CYP2C9和VKORC1基因分型,比较不同基因型房颤患者华法林日均稳定剂量的差异。采用多元线性回归分析法依据CYP2C9和VKORC1基因型、年龄、身高、体质量、合并用药建立华法林稳定剂量计算公式。结果:INR稳定在2.0～3.0之间时,CYP2C9*1/*1基因型患者日均使用华法林剂量(3.87±0.71)mg显著高于CYP2C9*3基因型患者(1.05±0.59)mg;VKORC1-1639AA基因型患者日均使用华法林剂量(2.94±1.03)mg显著低于VKORC1-1639GA/GG基因型患者(5.76±1.12)mg。通过多元线性回归分析得出华法林稳定剂量公式,建立的回归模型中包含年龄、体质量、合并用药、CYP2C9*3和VKORC1-1639基因型,该模型能解释约56.5%个体间华法林剂量差异。结论:基于CYP2C9和VKORC1基因多态性建立的华法林稳定剂量预测公式,能帮助指导华法林在老年房颤患者中的抗凝治疗。     

山西人群华法林基因多态性与其稳定剂量预测模型的研究

目的 建立适合山西人群的华法林稳定剂量预测模型。方法 选取符合入组标准的山西籍汉族患者,采用聚合酶链反应-限制性内切酶片段长度多态性(PCR-RFLP)技术检测基因VKOR复合体(VKORC1)、细胞色素P450(CYP)2C9、γ-谷氨酰羧化酶(GGCX)、环氧化物水解酶(EPHX1)多态性。记录患者临床信息,采用逐步多元回归分析法计算华法林稳定剂量预测模型公式。结果 华法林稳定剂量预测模型包括VKORC1、CYP2C9、GGCX、EPHX1及患者的身高等因素(R²=0.284);在模型中加入GGCX、EPHX1基因型后,模型的总体R²从0.257提升至0.284,GGCX、EPHX1基因型在模型中解释了2.7%的剂量差异。维生素K的日均摄入量未对华法林稳定剂量有显著影响,但是男性每天维生素K摄入量明显低于女性。将服用华法林患者国际标准化比值(INR)值分为低INR值组、正常组、高INR值组,显示随着INR值升高,患者日均维生素K摄入量降低。结论 基于6种基因多态性的剂量预测模型可以帮助预测山西汉族患者华法林稳定剂量。     

CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量影响及分析

摘要：目的:探讨CYP2C9和VKORC1基因多态性对老年房颤患者华法林稳定剂量的影响,建立适合汉族人群老年房颤患者的华法林给药模型,指导华法林个体化抗凝治疗。方法:对195例口服华法林抗凝的老年患者进行CYP2C9和VKORC1基因分型,比较不同基因型房颤老年患者华法林日均稳定剂量差异。采用多重线性回归分析法依据CYP2C9和VKORC1基因型、年龄、体表面积（BSA）、胺碘酮建立华法林稳定剂量计算公式。结果:国际标准化比值（INR）稳定在2.0～3.0之间时,CYP2C9*1/*1基因型患者日均华法林剂量（3.10±0.91） mg,显著高于CYP2C9*1/*3与CYP2C9*3/*3基因型患者的（2.10±0.89） mg和（1.25±0.00） mg; VKORC1-1639AA基因型患者日均华法林剂量（2.86±0.88） mg,显著低于VKORC1-1639GA/GG基因型患者的（3.68±0.88） mg和（6.38±0.91） mg（P<0.05）。通过多元线性回归分析得出华法林稳定剂量公式,建立的回归模型中包含年龄、BSA、胺碘酮、CYP2C9和VKORC1-1639基因型,该模型能解释约60.4%个体间华法林剂量差异。结论:基于CYP2C9和VKORC1基因多态性建立的华法林稳定剂量预测公式,能帮助指导华法林在老年房颤患者中的抗凝治疗。     

Validation of pharmacogenetic algorithms and warfarin dosing table in Egyptian patients

Background Warfarin remains a difficult drug to use due to the large variability in dose response. Clear understanding of the accuracy of warfarin pharmacogenetic dosing methods might lead to appropriate control of anticoagulation. Objective This study aims to evaluate the accuracy of warfarin dosing table and two pharmacogenetic algorithms, namely the algorithms of Gage et al. (Clin Pharmacol Ther 84:326?C331, 2008), and the International Warfarin Pharmacogenetics Consortium algorithm (IWPC) in a real Egyptian clinical setting. Additionally, three non-pharmacogenetic dosing methods (the Gage, IWPC clinical algorithms and the empiric 5?mg/day dosing) were evaluated. Setting Sixty-three Egyptian patients on a stable therapeutic warfarin dose were included. Patients were recruited from the outpatient clinic of the critical care medicine department. Methods CYP2C9 and VKORC1 polymorphisms were genotyped by real time PCR system. Predicted doses by all dosing methods were calculated and compared with the actual therapeutic warfarin doses. Results The Gage algorithm (adjusted R²?=?0.421, and mean absolute error (MAE)?=?3.3), and IWPC algorithm (adjusted R²?=?0.419, MAE?=?3.2) produced better accuracy than did the warfarin dosing table (adjusted R²?=?0.246, MAE?=?3.5), the two clinical algorithms (R²?=?0.24, MAE?=?3.7) and the fixed dose approach (MAE?=?3.9). However, all dosing models produced comparable clinical accuracy with respect to proportion of patients within 1?mg/day of actual dose (ideal dose). Non-pharmacogenetic methods severely over-predicted dose (defined as ??2?mg/day more than actual dose) compared to the three pharmacogenetic models. In comparison to non-pharmacogenetic methods, the three pharmacogenetic models performed better regarding the low dose group in terms of percentage of patients within ideal dose. In the high dose group, none of the dosing models predicted warfarin doses within ideal dose. Conclusion Our study showed that genotype-based dosing improved prediction of warfarin therapeutic dose beyond that available with the fixed-dose approach or the clinical algorithms, especially in the low-dose group. However, the two pharmacogenetic algorithms were the most accurate.     

Verification of five pharmacogenomics-based warfarin administration models

Objective:This study aims to screen and validate five individual warfarin dosing models (four Asian model algorithms, namely, Ohno, Wen, Miao, Huang, and the algorithm of International Warfarin Pharmacogenetic Consortium, namely IWPC algorithm) with the aim of evaluating their accuracy, practicality, and safety.Results:The prediction accuracies of the Huang and Wen models were the highest. In terms of clinical practicality, the Huang model rated the highest for the low-dose group, whereas the Ohno and IWPC models rated the highest for the middle-dose group. The models tended to markedly overpredict the doses in the low-dose group, especially the IWPC model. The Miao model tended to severely underpredict the doses in the middle-dose group, whereas no model exhibited severe overprediction.Conclusions:Since none of the models ranked high for all the three criteria considered, the impact of various factors should be thoroughly considered before selecting the most appropriate model for the region''s population.KEY WORDS: Mechanical heart valve replacement, model, pharmacogenomics, verification, warfarin     

低剂量华法林对心房颤动患者脑卒中和凝血指标的影响

目的 探讨心房颤动患者低剂量长期使用华法林对患者脑卒中和凝血指标的影响。方法 选择2016年1月—2018年12月喀什地区第一人民医院收治的心房颤动患者213例作为研究对象,按照随机数字表法将患者分为3组,每组各71例。对照组患者使用阿司匹林肠溶片,200 mg/d。华法林高剂量组患者在使用华法林钠片前测定抗凝强度国际化标准比率（INR）作为基础值,初始剂量为2.5 mg/d,每隔3~5 d复查IRN,根据IRN调整使用剂量,每次增加0.625 mg,直至复查INR达标,达标时IRN值为2.1~3.0。华法林低剂量组患者使用华法林初始量为1.25 mg/d,每隔3~5 d复查IRN,达标时IRN值为1.5~2.0。根据IRN调整使用剂量,如果INR<1.5,每次增加0.625 mg,直至复查INR达标;如果INR>2.1,将华法林剂量减少0.625 mg。INR不稳定时,连续达标2次后以该剂量作为维持剂量,每月复查1次,直至INR达标。3组均治疗随访18个月。观察并比较两组患者的脑卒中发生情况、凝血指标、华法林用量、达INR标准时间和不良反应发生情况。结果 随访后,华法林高剂量组脑卒中发生率为2.82%,华法林低剂量组为4.23%,均明显低于对照组的14.08%,组间差异具有统计学意义（P<0.05）。治疗后,3组活化部分凝血活酶时间（APTT）、凝血酶原时间（PT）均明显延长（P<0.05）,华法林高剂量和低剂量APTT、PT显著优于对照组,组间差异具有统计学意义（P<0.05）。华法林低剂量组华法林使用量和INR达标准值时间均明显低于华法林高剂量组（P<0.05）。治疗期间,华法林高剂量组出血、腹部不适等不良反应发生率为9.86%,华法林低剂量组为5.63%,均明显低于对照组的29.58%（P<0.05）。结论 心房颤动患者长期使用低剂量华法林能够有效的达到预防脑卒中的效果,其疗效与标准抗凝强度相当,且明显优于阿司匹林,具有较高的临床应用价值,可推广使用。     

A new warfarin dosing algorithm including VKORC1 3730 G > A polymorphism: comparison with results obtained by other published algorithms

Purpose

Warfarin dosing is affected by clinical and genetic variants, but the contribution of the genotype associated with warfarin resistance in pharmacogenetic algorithms has not been well assessed yet. We developed a new dosing algorithm including polymorphisms associated both with warfarin sensitivity and resistance in the Italian population, and its performance was compared with those of eight previously published algorithms.

Methods

Clinical and genetic data (CYP2C9*2, CYP2C9*3, VKORC1 –1639?G > A, and VKORC1 3730?G > A) were used to elaborate the new algorithm. Derivation and validation groups comprised 55 (58.2% men, mean age 69?years) and 40 (57.5% men, mean age 70?years) patients, respectively, who were on stable anticoagulation therapy for at least 3 months with different oral anticoagulation therapy (OAT) indications.

Results

Performance of the new algorithm, evaluated with mean absolute error (MAE) defined as the absolute value of the difference between observed daily maintenance dose and predicted daily dose, correlation with the observed dose and R² value, was comparable with or slightly lower than that obtained using the other algorithms. The new algorithm could correctly assign 53.3%, 50.0%, and 57.1% of patients to the low (≤25 mg/week), intermediate (26–44?mg/week) and high (≥ 45?mg/week) dosing range, respectively. Our data showed a significant increase in predictive accuracy among patients requiring high warfarin dose compared with the other algorithms (ranging from 0% to 28.6%).

Conclusions

The algorithm including VKORC1 3730?G > A, associated with warfarin resistance, allowed a more accurate identification of resistant patients who require higher warfarin dosage.     

Long-term efficacy and toxicity of high- and low-dose amiodarone regimens

Amiodarone is an effective antiarrhythmic drug for the control of potentially lethal and lethal ventricular arrhythmias (VA). In the United States, a high-dose regimen has been used at the expense of a high toxicity profile for the control of lethal VAs. Significant antiarrhythmic efficacy has also been established with low-dose regimens, which carry a low rate of intolerable side effects (5.4%) when compared with the high-dose regimen (16.7%). The high incidence of tolerable and intolerable adverse side effects is probably related to high amiodarone loading (31.92 g) and maintenance doses (520 mg/d). In contrast, the low-dose regimen uses much lower loading (7.2 g) and maintenance (280 mg/d) doses.     

VKORC1基因分型对华法林初始抗凝治疗的 影响和临床指导意义

目的:探索中国人群VKORC1-1639G>A基因多态性对华法林初始剂量和INR值的影响。方法:纳入2019年1月~6月在阜外医院行人工瓣膜置换术后服用华法林、并进行基因检测的患者,采用匹配病例对照研究的方法,至少携带一个VKORC1-1639G等位基因的患者为突变型组,匹配相同例数的VKORC1-1639AA型患者作为野生型组,评估VKORC1-1639G>A基因型对初始华法林响应和剂量的影响。两组患者均在华法林治疗前采用PCR-RFLP的方法检测VKORC1和CYP2C9的基因型,首次给予3 mg的剂量后每日根据INR值调整剂量。结果:共纳入患者60人,两组各30人。两组患者人口统计学和临床基线信息无显著性差异;突变型组前2天、前3天、前4天华法林总剂量显著高于野生型组(除前2天两组总剂量差异P<0.05外,其余P<0.01);突变型组第2天、第3天、第4天、第5天INR值显著低于野生型组(P<0.01)。结论:与VKORC1-1639AA型患者相比,携带至少1个VKORC1-1639G等位基因的患者,前5天服用较大剂量华法林,INR值仍持续较低。     

Sequential treatment for Helicobacter pylori eradication in duodenal ulcer patients: improving the cost of pharmacotherapy

BACKGROUND: Several studies have shown that Helicobacter pylori eradication rates with standard 7-day triple therapy are unsatisfactory. A novel 10-day sequential treatment regimen recently achieved a significantly higher eradication rate. To improve the pharmacotherapeutic cost, we evaluated whether an acceptable eradication rate could be achieved in peptic ulcer patients by halving the dose of clarithromycin. METHODS: In a prospective, open-label study, 152 duodenal ulcer patients with H. pylori infection, assessed by rapid urease test and histology, were enrolled. Patients were randomized to receive either a 10-day sequential treatment comprising rabeprazole 20 mg b.d. plus amoxicillin 1 g b.d. for the first 5 days, followed by rabeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. for the remaining 5 days (high-dose therapy), or a similar schedule with the clarithromycin doses halved to 250 mg b.d. (low-dose therapy). No further antisecretory drugs were offered. Four to six weeks after therapy, H. pylori eradication and ulcer healing rates were assessed by endoscopy. RESULTS: Similar H. pylori eradication rates were observed following high- and low-dose regimens for both per protocol (97.3% vs. 95.9%; P = N.S.) and intention-to-treat (94.7% vs. 92.2%; P = N.S.) analyses. No major side-effects were reported. At repeat endoscopy, peptic ulcer healing was observed in 93% and 93% of patients following high- and low-dose therapy, respectively. CONCLUSION: The cheaper low-dose sequential regimen may be suggested for H. pylori eradication in duodenal ulcer patients, even without continued proton pump inhibitor therapy after eradication treatment.     

Comparative effects of ranitidine and cimetidine on the pharmacokinetics and pharmacodynamics of warfarin in man

Summary Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H₂-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.