Regioselectivity significantly impacts microsomal glucuronidation efficiency of R/S-6, 7-, and 8-hydroxywarfarin

1. Coumadin (R/S-warfarin) metabolism plays a critical role in patient response to anticoagulant therapy. Several cytochrome P450s oxidize warfarin into R/S-6-, 7-, 8-, 10, and 4′-hydroxywarfarin that can undergo subsequent glucuronidation by UDP-glucuronosyltransferases (UGTs); however, current studies on recombinant UGTs cannot be adequately extrapolated to microsomal glucuronidation capacities for the liver.

2. Herein, we estimated the capacity of the average human liver to glucuronidate hydroxywarfarin and identified UGTs responsible for those metabolic reactions through inhibitor phenotyping. There was no observable activity toward R/S-warfarin, R/S-10-hydroxywarfarin or R/S-4′-hydroxywarfarin.

3. The observed metabolic efficiencies (V_max/K_m) toward R/S-6-, 7-, and especially 8-hydroxywarfarin indicated a high glucuronidation capacity to metabolize these compounds.

4. UGTs demonstrated strong regioselectivity toward the hydroxywarfarins. UGT1A6 and UGT1A1 played a major role in R/S-6- and 7-hydroxywarfarin glucuronidation, respectively, whereas UGT1A9 accounted for almost all of the generation of the R/S-8-hydroxywarfarin glucuronide.

5. In summary, these studies expanded insights to glucuronidation of hydroxywarfarins by pooled human liver microsomes, novel roles for UGT1A6 and 1A9, and the overall degree of regioselectivity for the UGT reactions.

     

脊柱后路内固定术后硬膜外血肿的预防与护理体会

目的 探讨脊柱后路内固定术后硬膜外血肿的预防与护理体会。方法 遵照回顾性分析法选择我院2013年2 月～2018 年2 月纳入的60 例脊柱后路内固定术患者，依照不同理疗方式进行分组。其中30 例给予常规药物治疗作为对照组，另30 例除了常规治疗之外实施综合护理作为研究组，记录两组硬膜外血肿、腰椎术后血肿及颈椎术后血肿发生率，分别在干预前后进行生活质量评分（QOL）调查，出院时发放满意度调查问卷表，对比两组干预结果。结果 研究组血肿发生率为6.67%，明显低于对照组的20.00%（P＜0.05）。干预前两组的食欲、精神、睡眠、疼痛及日常生活评分相比差异无统计学意义（P＞0.05），干预后研究组的各项评分均高于对照组（P＜0.05）。研究组对干预效果的满意度为90.00%，明显高于对照组的76.67%（P＜0.05）。结论 护理干预运用于脊柱后路内固定中效果显著，能够有效减少硬膜外血肿的发生率，提升生活质量，促进病情稳定，患者满意度较高，可维持良好医患关系。     

老年慢性非瓣膜房颤患者的抗凝治疗

目的比较肠溶阿司匹林和结晶华法林对慢性非瓣膜房颤的老年患者预防缺血性脑卒中的疗效。方法老年慢性非瓣膜性房颤患者431例,年龄>65岁,随机分为阿司匹林、华法林两组对照试验,服用2年,观察脑卒中和出血的发生率。结果年龄65～74岁没有危险因素的房颤患者脑卒中的发生率肠溶阿司匹林组为2.9%、华法林组为1.7%,差异无明显性(P>0.05);年龄65～74岁有危险因素的房颤患者脑卒中的发生率肠溶阿司匹林组为5.2%,明显高于华法林组2.1%。年龄≥75岁没有危险因素的患者,脑卒中发生率阿司匹林组4.9%明显高于华法林组2.3%;年龄≥75岁有危险因素的患者,脑卒中发生率阿司匹林组6.7%,明显高于华法林组2.2%(P<0.05)。出血并发症发生率阿司匹林3.06%、华法林组2.76%,两组比较差异无显著性(P>0.05)。结论年龄65～74岁没有危险因素的非瓣膜房颤患者可服用阿司匹林预防脑卒中。而对于年龄≥75岁以及所有有危险因素的患者须服用华法林预防脑卒中,华法林在抗凝同时没有增加出血的并发症。     

A review of the practical advantages of low molecular weight heparin in the treatment of cancer-related venous thromboembolism

Patients with cancer, particularly those with metastatic cancer, are at high risk of venous thromboembolism (VTE), which places a huge burden on healthcare resources and can adversely affect patients' prognosis. In addition, VTE can have a negative impact on quality of life and increase the management challenges faced by physicians and nurses. Conventional long-term treatment using vitamin K antagonists, such as warfarin, presents many practical problems for cancer patients including frequent monitoring and dose adjustment, drug interactions, and disruption of anticoagulation for invasive procedures. The aim of this article is to review the potential advantages of using low molecular weight heparin (LMWH) in the treatment of cancer-related VTE in comparison to conventional therapy with warfarin or standard heparin. The potential advantages were determined via a literature review. LMWH is at least as effective as standard heparin or warfarin, and has been shown to have several benefits over warfarin in cancer patients. The simplicity of this therapy enables patients to be treated at home, and has been shown to have a positive impact on overall quality of life. The use of LMWH provides a treatment alternative to patients with cancer offering them hope and optimism regarding their care.     

2013年北京医院门诊老年患者华法林处方不合理用药分析

目的:了解北京医院(以下简称"我院")华法林的使用情况,探讨其用药合理性。方法:从我院信息系统中筛选出2013年门诊60岁及以上患者使用华法林的处方1 621张,对处方用药的合理性进行点评、分析。结果:1 621张处方中,需要关注的问题处方有840张,占51.82%。其中,处方中存在药物不良相互作用的问题最为突出;其次为联合用药不适宜、用法与用量不适宜等。结论:应加强华法林在临床的合理应用,以提高治疗效果,减少不良反应的发生。     

临床药师参与1例心脏瓣膜置换术后合并肝功能异常患者华法林个体化抗凝治疗

目的：探讨临床药师在华法林个体化抗凝治疗中的作用。方法：回顾分析临床药师参与1例心脏瓣膜置换术后合并肝功能异常患者华法林抗凝治疗的全过程。结果：临床药师从患者基因型、肝功能及药物相互作用角度分析华法林抗凝过量原因,对患者实施华法林个体化抗凝治疗,并对其进行药学监护。结论：临床药师参与患者的个体化抗凝治疗,可提高抗凝治疗成功率,降低患者抗凝风险。     

质子泵抑制剂对华法林抗凝效果影响的研究进展

临床联用华法林与质子泵抑制剂的情况很多,鉴于华法林的治疗窗较窄,联用是否会影响华法林抗凝作用和增加出血风险,目前尚无定论。本文通过整合和分析国内外相关临床研究的证据,探讨各种质子泵抑制剂与华法林相互作用的机制和细胞色素P450（cytochrome P450）的CYP2C19基因多态性对两者相互作用的影响,发现华法林与泮托拉唑、雷贝拉唑联用相对较安全,但各研究对兰索拉唑、奥美拉唑、埃索美拉唑与华法林的相互作用是否具有临床意义仍存在争议,亟须进行前瞻性的多中心、随机、双盲、对照研究。     

服用华法林而致咯血患者的药学监护

目的探讨服用华法林导致出血不良事件的药学监护内容以及临床药师参与药物治疗的模式。方法对服用华法林而致出血的病例,临床药师协助临床医师寻找出血原因,并对其治疗全过程进行监护。结果经药师仔细询问该患者用药史建立用药与INR时间表后,判断出血受药物相互不良作用影响较大,并进行治疗药物优化建议和密切监护出血情况后,患者康复出院。结论临床药师积极参与临床实践,作为药物治疗团队中的一员,可利用药学特长协助临床医师做出药物相关性疾病的诊断,共同监护药物治疗的有效性、安全性和依从性,体现了临床药师价值。     

Cost-effectiveness of edoxaban for the treatment of venous thromboembolism based on the Hokusai-VTE study

Objective: Venous thromboembolism (VTE) is associated with almost 300,000 deaths per year in the United States. Novel oral anticoagulants (NOACs) offer an alternative to warfarin-based therapy without monitoring requirements and with fewer drug and food interactions. Edoxaban, a direct Xa inhibitor, is approved by the Food and Drug Administration (FDA), based upon results of the Hokusai-VTE Phase 3 trial. The trial demonstrated that edoxaban administered once daily after initial treatment with heparin was non-inferior in reducing the risk of VTE recurrence and caused significantly less major and clinically relevant non-major (CRNM) bleeding compared to warfarin. The objective of this study was to evaluate the cost-effectiveness of edoxaban versus warfarin for the treatment of adults with VTE. Methods: A cost-effectiveness model was developed using patient-level data from the Hokusai-VTE trial, clinical event costs from real-world databases, and drug acquisition costs for warfarin of $0.36 and edoxaban of $9.24 per tablet. Results: From a U.S. health-care delivery system perspective, the incremental cost-effectiveness ratio (ICER) was $22,057 per quality adjusted life year (QALY) gained. Probabilistic sensitivity analysis showed that edoxaban had an ICER <$50,000 per QALY gained relative to warfarin in 67% of model simulations. The result was robust to variation in key model parameters including the cost and disutility of warfarin monitoring. Conclusion: Despite its higher drug acquisition cost, edoxaban is a cost-effective alternative to warfarin for the treatment of VTE.     

老年心房颤动患者应用华法林个体化剂量的研究

目的 探讨老年心房颤动(房颤)患者应用华法林的个体化剂量.方法 41例老年房颤患者,给予华法林抗凝治疗,治疗初始阶段每日监测国际标准化比值(INR),目标抗凝强度INR1.6～2.5.观察患者年龄、性别、身高、体质量等人口统计学指标以及合并用药、并存疾病等临床指标,测定血清白蛋白水平、INR等实验室指标,记录华法林剂量.结果 单因素分析显示,个体华发林剂量分别与以下指标相关:年龄(r=-0.535,P＜0.01)、性别(rs=-0.494,P＜0.01)、身高(r=0.484,P＜0.01)、体质量(r=0.453,P＜0.01)、体表面积(r=0.388,P＜0.05)、磺脲类降糖药物(rs=-0.446,P＜0.01)、白蛋白(r=0.520,P＜0.01);多元逐步回归分析中,年龄、白蛋白、性别、磺脲类依次进入回归方程,个体化剂量回归方程式可以解释65.4%的华法林个体剂量的变异(R-0.808,R2=65.4%).结论 老年房颤患者应用华法林抗凝治疗的个体化剂量可在治疗的初始阶段,根据患者的年龄、性别、是否合用磺脲类降糖药物及血清白蛋白水平等因素预测得到.