曲马多与华法林的相互作用增加出血风险及其处理

患血栓栓塞性疾病并伴有各种中度疼痛的患者,常联合华法林和曲马多用于防止凝血和缓解疼痛。近年研究发现,曲马多可增强华法林的抗凝作用,导致国际标准化比率(INR)升高,增加出血风险。临床若需该2药联用,华法林的剂量应减少,以避免危及生命的不良反应。     

Tricyclic antidepressant plasma levels after augmentation with citalopram: a case study

Summary In a depressed patient, the addition of citalopram 40–60 mg per day to treatment with amitriptyline 75 mg per day had no effect on the plasma levels of amitriptyline and nortriptyline, but it led to clinical improvement without the appearance of adverse effects.This and similar findings in four other patients comedicated with citalopram and amitriptyline (2 patients), clomipramine or maprotiline suggest that citalopram differs from other selective serotonin reuptake inhibitors, such as fluvoxamine and fluoxetine, which have been shown to increase tricyclic antidepressant plasma levels.     

Effect of the oral renin inhibitor aliskiren on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in healthy subjects

AIMS: To investigate the effects of aliskiren, an oral renin inhibitor, on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: In a single-blind, placebo-controlled, randomized, two-period crossover study, 15 healthy male and female subjects received a single oral dose of 25 mg racemic warfarin twice, once in the morning of the 8th day of treatment with 150 mg aliskiren and once at the same time point during treatment with placebo. Blood samples were collected for the measurement of prothrombin time (PT) and activated thromboplastin time (aPTT) and for determination of plasma concentrations of (R)- and (S)-warfarin. RESULTS: Aliskiren treatment had no effect on the blood coagulation parameters (PT, INR and aPTT). The ratios of least square means (90% CI) of pharmacokinetic parameters in the presence and absence of aliskiren for (R)- and (S)-warfarin were Cmax 0.89 (0.82, 0.96) and 0.88 (0.80, 0.97), AUC(0, infinity) 1.00 (0.94, 1.07) and 1.06 (0.96, 1.16) and t(1/2) 0.99 (0.92, 1.07) and 1.05 (0.96, 1.14). CONCLUSIONS: Multiple doses of aliskiren had no detectable effect on the pharmacokinetics or pharmacodynamics of a single dose of warfarin in healthy subjects.     

1例胺碘酮致华法林抗凝作用增强病例分析

目的 探讨临床药师在华法林抗凝治疗时联用胺碘酮引起国际标准化值(INR)异常升高的处理方法及药学监护。 方法 通过对照华法林与其他药物相互作用的情况,确定引起INR值异常波动的药物,及时调整华法林剂量,加强凝血功能的监测,并从华法林与胺碘酮的作用机制、相互作用、两药联用后抗凝作用与两药的剂量、浓度相关性等方面阐述胺碘酮对华法林抗凝作用的影响。 结果 INR异常波动为华法林与胺碘酮联用所致,两药联用可增强华法林的抗凝作用,增加出血风险,通过停用华法林3 d,INR恢复到目标值范围,继续给予华法林抗凝治疗,患者情况控制平稳,顺利出院。 结论 临床药师通过对患者有效的药学监护,可协助临床及时发现药物治疗相关问题。在使用与华法林有相互作用的药物时要考虑其对抗凝治疗的影响,一方面要充分了解药物合用时的药理学及药动学变化,另一方面要加强监测,以便及时调整用药方案,提高临床用药的安全性和合理性,更好地为患者提供药学服务。     

Interaction of sulphinpyrazone with warfarin

Summary The effect of sulphinpyrazone administration on the anticoagulant response was investigated in five patients receiving long-term treatment with warfarin. Sulphinpyrazone caused a rapid increase in prothrombin (PT) ratio in all five patients and warfarin dose had to be reduced by a mean of 46% to maintain the PT ratio in the therapeutic range. PT ratio and daily warfarin requirement returned to previous levels when sulphinpyrazone was ceased. Warfarin protein binding was not altered during sulphinpyrazone administration and sulphinpyrazone added to plasma in vitro did not increase warfarin free fraction. The average racemic plasma warfarin concentration over a dosage interval when adjusted for warfarin dose was not altered by sulphinpyrazone administration. The most likely mechanism for this drug interaction is a stereoselective effect of sulphinpyrazone on the metabolism of the warfarin enantiomers.     

1例小肠坏死患者的围术期营养支持与华法林相互作用的药学监护

目的 探讨营养支持治疗与华法林的药物相互作用。方法 通过对1例突发小肠坏死的二尖瓣置换术患者的围术期营养支持治疗进行病例分析和药学监护,探讨营养支持治疗对华法林疗效的影响。结果 营养配方的调整会影响INR值,而通过空肠造口给药,华法林的吸收也受到影响。在药师的药学监护下,通过对营养方案和华法林相互作用的分析和剂量调整,识别出可疑药物严重不良反应1例,避免了后续潜在的药物不良反应风险。结论 营养支持治疗对华法林疗效的影响需要综合多方面因素考虑,临床药师的工作有助于帮助识别和减少药物不良反应,促进临床合理用药。     

Effect of oral diuretics on chronic warfarin therapy: a retrospective study

Background: Limited clinical documentation is suggestive of a drug interaction between warfarin and diuretics.

Objective: To evaluate the effect on international normalized ratio (INR) when a daily oral diuretic is started or increased in patients on chronic stable warfarin therapy.

Methods: The medical records of all active patients of two hospital-based anticoagulation clinics were retrospectively reviewed to identify patients who were started on or received a dose increase of a daily oral diuretic while on stable warfarin therapy. The primary endpoint was the mean difference between an INR recorded within 30 days prior to the diuretic initiation (pre-INR) and an INR recorded within 30 days after diuretic initiation (post-INR).

Results: A total of 1254 patient charts were screened and a total of 123 patients met the study criteria. The mean difference in pre-INR and post-INR was 0.09 (95% CI -0.03 to 0.21, p = 0.12). Post-INR values were outside of the patient's therapeutic range in 39 patients (32%), but no major bleeding or thromboembolic events were reported.

Conclusion: Based on this retrospective study, diuretics did not result in a significant change in the INR in patients on stable warfarin therapy.     

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin

AIM: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin. METHODS: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment. RESULTS: Lasofoxifene had no clinically meaningful effect on R- or S-warfarin pharmacokinetics. The S-warfarin area under the plasma concentration-time curve (AUC) was 23% and 67% larger in subjects with *1/*2 and *1/*3 heterozygous mutations, relative to *1/*1, respectively. The mean PT AUC and Cmax ratio (90% confidence interval) was 91.9 (89.6, 94.2) and 84.2 (80.6, 87.8), respectively. INR results were similar. CONCLUSIONS: Lasofoxifene has no clinically meaningful effect on the pharmacokinetics of warfarin. Although the decrease in PT/INR may not be clinically meaningful, more frequent INR monitoring may be considered during lasofoxifene introduction and discontinuation, consistent with warfarin's label.     

药物临床试验电子信息化管理的分析与探讨

目的:探讨与分析电子信息化管理在药物临床试验中的应用。方法:通过设计及应用OA信息化管理系统与临床试验信息管理系统,对药物临床试验进行电子信息化管理。结果:通过电子信息系统平台及网络技术的应用,对相关数据进行处理和分析,有利于临床试验信息的融合,可衔接各科室与相关部门,提高了药物临床试验机构的管理效率。结论:药物临床试验的电子信息化管理方便、快捷、安全,已成为药物临床试验管理的大势所趋。     

药品不良反应224例报告分析

目的了解河南大学淮河医院药品不良反应（ADR）发生的特点,促进临床合理用药。方法对2007年1月—2009年12月收集到的224例ADR报告,分别从患者的性别、年龄、给药途径、药品类别、涉及器官或系统及主要临床表现等方面进行统计、分析。结果 224例ADR报告中,〉60岁的患者ADR发生率最高（占34.82%）;静脉给药方式是引发ADR的重要给药途径（占82.59%）;最易引起ADR的药品为抗感染药;最常见的临床表现为皮肤及其附件损害。结论应加强合理用药监测工作,减少或避免ADR发生。     

我院199例喹诺酮类药不良反应报告分析

目的:了解我院喹诺酮类药不良反应发生的特点,促进临床合理用药。方法:采用回顾性调查方法,对我院2004年5月～2007年12月收集到的喹诺酮类药所致的199例不良反应报告表,分别从患者性别、年龄、涉及药品、既往不良反应史、给药途径、临床表现等方面进行统计、分析。结果:199例不良反应涉及9种喹诺酮类药,其中左氧氟沙星引起的不良反应118例;既往有不良反应史者占16.1%;93.5%的患者通过静脉滴注给药;临床表现主要以皮肤及其附件和消化系统损害最为常见,严重不良反应7例。结论:应严格掌握药物使用适应证,尽可能采用口服给药方式,重视用药监护,以减少和避免不良反应的发生。     

Effect of gemfibrozil on the pharmacokinetics and pharmacodynamics of racemic warfarin in healthy subjects

AIMS: Case reports suggest that gemfobrozil can increase the anticoagulant effect of warfarin. Because gemfibrozil inhibits CYP2C9 in vitro, we studied its effects on the pharmacokinetics and pharmacodynamics of racemic warfarin. METHODS: In a randomized cross-over study, 10 healthy subjects ingested 600 mg gemfibrozil or placebo twice daily for 8 days. On day 3, they were administered a single dose of 10 mg racemic R-S-warfarin orally. The concentrations of R- and S-warfarin in plasma and thromboplastin time were monitored up to 168 h. RESULTS: Gemfibrozil decreased the mean (+/-SD) area under the plasma concentration-time curve [AUC((0-infinity))] of S-warfarin by 11%, from 19.9 +/- 5.2 mg l(-1) h to 17.6 +/- 4.7 mg l(-1) h (95% CI on the difference -3.7, -0.78; P < 0.01) and that of R-warfarin by 6% from 31.3 +/- 7.5 mg l(-1) h during the gemfibrozil phase to 29.5 +/- 6.9 mg l(-1) h during the placebo phase (95% CI -3.3, -0.33; P < 0.05). There were no significant differences in the elimination half-lives of S- or R-warfarin between the phases. Gemfibrozil did not alter the anticoagulant effect of warfarin. CONCLUSION: Unexpectedly, gemfibrozil slightly decreased the plasma concentrations of R- and S-warfarin. Displacement of warfarin from plasma albumin by gemfibrozil or its interference with the absorption of warfarin could explain the present findings. Usual therapeutic doses of gemfibrozil seem to have limited effects on the pharmacokinetics and pharmacodynamics of single dose warfarin in healthy subjects.     

Amoxicillin/clavulanic acid-warfarin drug interaction: a randomized controlled trial

AIMS

To investigate whether an interaction exists between amoxicillin/clavulanic acid (amoxiclav) and warfarin in patients treated with stable oral anticoagulant therapy.

METHODS

In a double-blind, cross-over, placebo-controlled study, 12 patients on stable warfarin therapy, received a 7 day amoxiclav regimen or placebo.

RESULTS

The mean maximum increase in INR observed was 0.22 ± 0.3 with amoxiclav vs. 0.24 ± 0.6 with placebo (P= 0.94). The day 7–day 1 factor II, R(–) and S(–) warfarin plasma concentrations were similar during the amoxiclav and placebo study periods (P= 0.81, P= 0.45, P= 0.75, respectively).

CONCLUSION

Amoxiclav did not modify anticoagulation in patients treated with stable warfarin therapy and without infection.     

药品不良反应个案报道的规范性报告

个案报道是临床研究报告的一种重要形式,其在报告罕见或严重不良反应事件方面具有明显优越性。本文从个案报道的概念、分类及报告规范等方面分别进行了阐述;依据不良反应个案报告的方法学特点,参考国际个案报道的撰写规范,提出并制定了不良反应个案研究建议报告条目,以供医疗领域的临床工作者及研究者参考使用。     

非诺贝特与华法林相互作用致血尿1例及文献复习

目的 探讨非诺贝特对华法林抗凝作用的影响、作用机制和处理方法。方法 1位78岁老年男性患者长期稳定服用华法林抗凝治疗,在服用非诺贝特2周后出现咳血、血尿和左下肢疼痛,急诊查INR值为5.9,予停用华法林、肌注维生素K1 10 mg处理后出院,随后根据INR值调整华法林周剂量下降40%后INR值达到稳定,半个月后患者因肌痛停用非诺贝特,INR值连续2周持续下降,调整华法林剂量至接近服用非诺贝特前。结果 患者在稳定的华法林治疗剂量基础上加用非诺贝特后,增加了华法林的抗凝效果。非诺贝特蛋白结合率高,可能把与白蛋白结合的华法林置换下来,导致抗凝效果增强;非诺贝特也是轻到中度的CYP2C9抑制剂,CYP2C9为S型华法林的代谢酶。这2种作用合起来可增强华法林的药效。结论 在长期华法林稳定抗凝治疗的情况下加用非诺贝特后,建议连续监测INR值并考虑经验性降低华法林剂量20%,之后根据INR值继续调整剂量至稳定。     

阿奇霉素对大鼠灌服华法林的药效学和药动学的影响

目的：研究抗生索阿奇霉素对大鼠灌服华法林的药效学指标凝血酶原时间（PT）和国际标准化比值（INR）以及药动学指标血药浓度的影响。方法：将SD大鼠随机分成两组：单用华法林组（A组）和华法林＋阿奇霉素合用组（B组）,每组大鼠灌胃给予华法林0．2mg·kg^-1,每日1次,连续613,其中B组大鼠在第6日最后1次灌胃给予华法林后立即腹腔注射阿奇霉素80mg·kg^-1,且开始计时,分别于0．25、0．5、1．5、2．5、3．5、5、7、10、13小时采血,测定PT,计算INR。并建立HPLC法,测定华法林血药浓度。结果：从5小时开始,B组大鼠的胛值较A组显著增大（P〈0．05）,INR值最高可达7．5;B组大鼠的华法林药动学参数咒。较A组显著延长（P〈0．01）,其他药动学参数无显著性差异;两组大鼠的INR-C曲线都呈逆时针走向,且B组的逆时针效应更甚。结论：阿奇霉素与华法林合用可发生药效学和药动学相互作用,增强华法林的抗凝作用,增加用药者的出血风险,故临床上两药合用时应密切监测用药者的INR值,避免严重不良反应的发生。