新型口服抗凝药在伴有慢性肾脏疾病的非瓣膜性房颤患者中抗凝的研究进展

心房颤动是常见的心律失常疾病,持续48 h即可形成血栓,血栓脱落可导致动脉栓塞,其中90%是缺血性脑卒中,而慢性肾脏疾病可进一步增加房颤患者的卒中和出血风险。因此,在伴有慢性肾脏疾病的非瓣膜性房颤患者中的抗凝尤为重要。华法林用于肾功能不全的房颤患者虽可减少血栓栓塞的发生率,但是随着肾功能的恶化,华法林可增加出血的风险,且维持国际标准化比值（INR）在目标范围的时间非常困难。与华法林相比,新型口服抗凝药物能显著地降低卒中、颅内出血和死亡风险。然而新型口服抗凝药物在轻度、中度、重度,甚至血液透析房颤患者的应用仍存在争议。     

1例心肌梗死合并肾功能不全患者使用低分子肝素引起出血的用药分析

1例75岁的男性患者,因急性ST段抬高型心肌梗死(STEMI)合并肾功能不全,抗凝和行连续性肾脏替代治疗(CRRT)过程中使用低分子肝素出现消化道出血,暂停抗凝、CR RT治疗后出现咯血症状,后抢救无效死亡.此病例提醒医务工作者虽然低分子肝素较之肝素较少引起出血,但在低分子肝素的临床使用中,尤其注意肾功能不全患者在抗凝治疗时的出血风险,行CRRT治疗的患者,在没有枸橼酸使用禁忌证时,CRRT抗凝剂可优先选择枸橼酸.     

下肢深静脉血栓合并慢性肾功能不全血液透析患者的药学监护

<正>深静脉血栓是常见的周围血管疾病,可能导致肺栓塞和(或)血栓后综合征,严重影响患者的生活质量和生命健康。终末期肾病患者机体凝血活性亢进、血小板功能活化,处于高凝状态,易形成血栓,但抗凝治疗时,受肾功能不全及并发症因素的影响,加剧抗凝药物的出血风险。透析患者深静脉血栓的发病率为8.4%,为普通患者深静脉血栓发病率的4.5倍,肺栓塞病死率升高至2.56倍,终末期肾病行血液透析合并深静脉血栓的患者,接受抗凝治疗时出血风险明显增加,     

新型抗凝药:XI因子抑制剂预防静脉血栓形成安全有效

<正>近日,一项Ⅱ期试验发现,一个新型的抗凝药物——Ⅺ因子抑制剂可有效降低全膝关节置换术后静脉血栓栓塞症的风险,并且不会增加出血风险。全膝关节置换术后患者的静脉血栓栓塞症的风险升高,而传统的预防治疗方法包括使用Xa因子抑制剂或凝血酶抑制剂,尽管这类药物很有效,但患者的出血风险也相应升高。     

重症监护病房肾功能不全患者个体化用药决策

肾功能不全患者的肾脏滤过功能受损,对经肾脏排泄的药物的滤过功能减弱,易致药物在体内蓄积而发生药物副反应.ICU患者中,肾功能不全发生率较高,临床药师在临床药学实践过程中,应重视肾功能不全患者的用药监护,及时参与肾功能不全患者个体化用药方案的决策和建议,为合理用药发挥积极作用. 1 ICU疾病特点及用药特点 ICU患者病情复杂、危重,常合并肝肾等多脏器功能异常,疾病进展快,病死率高.ICU患者用药一般以静脉给药为主,结合多途径给药;使用药物品种多,发生药物相互作用的几率大;患者病情严重,发生药物不良反应的几率高;用药反应监测很困难[1].常用药物包括抗感染药物、肠内外营养药物、血管活性药物、镇静镇痛药物、抗心律失常药物及抗高血压药物、止血药物及抗凝血药物及糖皮质激素等.     

伴有慢性肾脏疾病的心房颤动患者的抗凝治疗

慢性肾脏疾病是心房颤动的一个独立危险因素,伴有慢性肾脏疾病的心房颤动患者更易发生血栓栓塞疾病;但慢性肾脏疾病患者行抗凝治疗时,出血并发症的发生率增加。华法林在伴有慢性肾脏疾病的心房颤动患者抗凝治疗中对出血并发症的影响仍有争议,采用华法林抗凝应充分考虑药物的风险-效益比,进行个体化治疗,明确指征,避免用于高出血风险患者,并加强国际标准化比率监测。新型抗凝药物和左心耳封堵术在伴有慢性肾脏疾病的心房颤动患者的疗效还有待研究。     

细胞毒性药物在肝肾功能不全患者中的剂量调整

目的：探索细胞毒性药物在肝肾功能不全患者中的剂量调整。方法：以"细胞毒性药物","肝功能不全","肾功能不全"为关键词对Pubmed,EMbase,Cochrane Library,中国知网,万方,维普等数据库进行检索,以整理和归纳细胞毒性药物在肝肾功能不全患者中的剂量调整策略。结果：肝肾功能不全可影响药物的代谢动力学,进而影响药物的安全性和有效性。45种常见细胞毒性药物,当肝功能不全时,有41种药物需要进行剂量调整;当肾功能不全时,有33种药物需要进行剂量调整。结论：应重视细胞毒性药物在肝肾功能不全患者中的剂量调整,以保障患者用药的安全性和有效性。     

慢性肾功能不全合并非瓣膜房颤患者抗血栓药物治疗的有效性和安全性概述

摘 要约1/3的房颤（AF）患者伴发慢性肾脏疾病（CKD）。AF患者存在全身性栓塞风险,因抗凝药物的使用存在出血的风险。CKD,尤其是终末期CKD,增加了AF患者血栓栓塞以及大出血的风险。许多研究已评估了华法林在AF合并CKD,尤其是终末期CKD患者（包括血液透析患者）缺血性卒中,全身栓塞和大出血风险的影响,但研究结果不一致。新型口服抗凝药物（NOACs）已在Ⅲ期（中度）CKD患者中进行了研究,研究提示,经剂量调整后,NOACs可获得与华法林相近的预防血栓栓塞的疗效,并可明显减少致命性出血的风险。本文就CKD合并非瓣膜性AF患者使用华法林和NOACs的有效性和安全性做一综述。     

关注特殊人群抗菌药物应用的安全性

婴幼儿、妊娠及哺乳期妇女、肝肾功能不全患者及老年人等特殊人群存在不同程度的免疫功能不全,发生感染的概率高于其他人群,抗菌药物的使用率较高,而因其特殊的生理病理状态和药物代谢特点,发生不良反应的风险更大。因此,抗菌药物在特殊人群中应用的安全性应得到更多的关注。掌握特殊人群的病理生理特点和抗菌药物的药代动力学特点,加强对特殊人群抗菌药物处方的审核和点评,有助于提高抗菌药物合理用药水平,减少抗菌药物对特殊人群的伤害。     

口服抗凝药在心房颤动合并慢性肾脏病患者应用的研究进展

慢性肾脏病(CKD)在房颤患者中非常普遍,是卒中和死亡的危险因素,其发病机制十分复杂。无论是房颤还是CKD,均与脑卒中、心血管疾病发病率和病死率增加相关。两者亦具有密切的双向关系,且常常同时存在。相较于单独的房颤或CKD患者,同时患有两种疾病的患者脑卒中风险、血栓栓塞风险和病死率较高[1]。因此,如何有效治疗该类人群一直是当今医学界关注的热点。目前华法林用于肾功能不全的房颤患者虽可减少血栓栓塞的发生率,但其起效慢、出血风险高及需频繁监测INR等缺点限制了其使用。新型口服抗凝药物(NOACs)的出现克服了传统口服抗凝药(OACs)的弊端,但该类药物均经过肾脏代谢,肾功能不全使药物在体内蓄积导致出血风险增加。近年来,对于NOACs治疗该类人群的研究也越来越多。现将OACs在伴有CKD的非瓣膜性房颤患者中抗凝的有效性和安全性综述如下。     

肾功能不全癌症疼痛患者阿片类药物的应用

阿片类药物是控制癌症疼痛(简称癌痛)的重要药物,若品种及剂量使用不当,将会进一步造成肾脏损伤.癌症患者由于疾病本身或并发症的进展,可能会伴有肾功能不全.因此存在肾功能不全风险的癌痛患者,必须正确评估肾功能状态,结合疼痛程度和阿片类药物特性,正确选择药品品种和剂量.该文综述常用阿片类药物的药动学特征、肾功能不全患者和透析...     

原发性和转移性脑肿瘤患者抗凝治疗相关问题探讨

原发性和转移性脑肿瘤患者发生静脉血栓栓塞症和颅内出血的风险均会增加,因此,必须对这类患者抗凝治疗的潜在益处与颅内出血风险加以权衡。本文探讨了原发性和转移性脑肿瘤患者颅内出血的风险以及抗凝治疗的现有证据和近期研究。对于大多数原发性和转移性脑肿瘤患者,使用低分子肝素及新型口服抗凝药谨慎抗凝治疗不会进一步增加颅内出血的风险,应结合患者的具体情况选择合适的抗凝治疗方案,同时还需关注药物相互作用对出血风险的影响。     

Pharmacokinetics and dosage adjustment in patients with renal dysfunction

Introduction  Chronic kidney disease is a common, progressive illness that is becoming a global public health problem. In patients with kidney dysfunction, the renal excretion of parent drug and/or its metabolites will be impaired, leading to their excessive accumulation in the body. In addition, the plasma protein binding of drugs may be significantly reduced, which in turn could influence the pharmacokinetic processes of distribution and elimination. The activity of several drug-metabolizing enzymes and drug transporters has been shown to be impaired in chronic renal failure. In patients with end-stage renal disease, dialysis techniques such as hemodialysis and continuous ambulatory peritoneal dialysis may remove drugs from the body, necessitating dosage adjustment. Methods  Inappropriate dosing in patients with renal dysfunction can cause toxicity or ineffective therapy. Therefore, the normal dosage regimen of a drug may have to be adjusted in a patient with renal dysfunction. Dosage adjustment is based on the remaining kidney function, most often estimated on the basis of the patient's glomerular filtration rate (GFR) estimated by the Cockroft–Gault formula. Net renal excretion of drug is a combination of three processes: glomerular filtration, tubular secretion and tubular reabsorption. Therefore, dosage adjustment based on GFR may not always be appropriate and a re-evaluation of markers of renal function may be required. Discussion  According to EMEA and FDA guidelines, a pharmacokinetic study should be carried out during the development phase of a new drug that is likely to be used in patients with renal dysfunction and whose pharmacokinetics are likely to be significantly altered in these patients. This study should be carried out in carefully selected subjects with varying degrees of renal dysfunction. In addition to this two-stage pharmacokinetic approach, a population PK/PD study in patients participating in phase II/phase III clinical trials can also be used to assess the impact of renal dysfunction on the drug's pharmacokinetics and pharmacodynamics. Conclusion  In conclusion, renal dysfunction affects more that just the renal handling of drugs and/or active drug metabolites. Even when the dosage adjustment recommended for patients with renal dysfunction are carefully followed, adverse drug reactions remain common.     

Single-dose pharmacokinetics of felbamate in patients with renal dysfunction

Aims The purpose of this study was to evaluate the effects of renal impairment on the single-dose pharmacokinetics of the antiepileptic felbamate.
Methods Twelve subjects with three levels of renal dysfunction (creatinine clearance >30–80, >10–30 or 5–10  m  min⁻¹ ) and four controls with normal renal function (creatinine clearance >80  ml min⁻¹ were studied). Plasma and urine samples were obtained for 144  h following administration of a single 1200  mg dose.
Results Compared with controls, apparent total body clearance, renal clearance and urinary excretion of felbamate were decreased, and half-life, C _max and AUC values were increased in subjects with renal dysfunction. The magnitude of these changes was associated with the degree of renal dysfunction. Nonrenal clearance and apparent volume of distribution values were also lower in renal dysfunction subjects, but there was no association between the extent of these changes and degree of renal dysfunction. Renal clearance of felbamate accounted for approximately 30% of apparent total body clearance in the control group and from 9–22% in the renal failure patients. Renal clearance of felbamate was significantly correlated with creatinine clearance ( r ²=0.75; P <0.001).
Conclusions These data suggest that initial dosage and titration of felbamate may require adjustment in patients with renal dysfunction.     

血管紧张素转换酶基因多态性与重度子痫前期及肾功能损害的关系

目的 探讨血管紧张素转换酶(ACE)基因第16内含子插入/缺失(I/D)多态性与重度子痫前期和子病前期肾功能损害的关系.方法 采用聚合酶链反应(PCR)技术检测120例子痫前期(其中轻度67例,重度53例)和60例正常孕妇ACE基因I/D多态性.结果 重度子痫前期组分别与正常孕妇组和轻度子痫前期组比较,ACE基因型分布和等位基因频率均有显著差异(P＜0.01);子痫前期肾功能损害组与无肾功能损害组比较,ACE基因型分布有显著差异(P＜0.05).结论 ACE基因I/D多态性与子痫前期病情相关;ACE基因I/D多态性与子痫前期肾功能损害相关,DD基因型可能是子痫前期肾功能损害的危险因素.     

Effect of Renal or Hepatic Dysfunction on Neurotoxic Convulsion Induced by Ranitidine in Mice

We investigated the effect of acute renal and hepatic dysfunction on the neurotoxicity of ranitidine, a histamine H₂ receptor antagonist. Experimental acute hepatic and renal dysfunction in mice were produced by i.p. injection of uranyl nitrate (UN) and carbon tetrachloride (CT), respectively. Ranitidine was then constantly infused into the tail vein until the onset of clonic convulsion. When compared to control mice, UN treated mice had a significantly shorter onset time to clonic convulsion, lower total dose and higher plasma concentration at initiation of clonic convulsion. In contrast, the convulsive threshold concentration in the brain of UN treated mice was not significantly different from that of control mice. In CT treated mice, all pharmacokinetic and pharmacodynamic data described above were not significantly different from those of the control mice. No significant difference in the brain/plasma concentration ratio was observed between both disease models and the corresponding control mice. Finally, the effect of UN and CT treatment on the convulsive potency after intracerebral (i.e.) administration of ranitidine was investigated in mice. Potentiation of the intrinsic neurotoxic sensitivity to ranitidine could not be demonstrated for mice with renal or hepatic dysfunction. From these findings, we conclude that renal dysfunction is a risk factor for ranitidine neurotoxicity, and this increased risk results from increase in the drug concentration in plasma and brain as a result of impaired renal excretion. No apparent effect of acute hepatic dysfunction was observed on both the pharmacokinetic and pharmacodynamic behavior of the drug.     

抗癫痫药物在肝肾功能不全患者中使用的研究进展

临床常用抗癫痫药物根据其药动学特点可分为主要经肝代谢、主要经肾排泄和肝肾双通道清除。肝功能不全患者尽量选择主要经肾排泄的抗癫痫药物,如加巴喷丁、普瑞巴林,或评估肝功能不全的程度,适当的减少剂量。肾功能不全的患者尽量选择主要经肝代谢的抗癫痫药物,如丙戊酸钠、卡马西平、拉莫三嗪,或评估患者的肌酐清除率（CLcr）,根据CLcr进行剂量调整。对于透析的患者,结合血药浓度监测透析后补充剂量有助于个体化治疗。肝肾功能不全患者抗癫痫药物的选择、剂量调整应综合考虑患者肝肾功能情况、药物代谢特点、合并疾病、个体耐受性等因素,在抗癫痫药物使用过程中,加强对药物相互作用、药物不良反应等的监护,结合血药浓度监测,以提高临床用药的有效性与安全性。     

Dose optimization of piperacillin/tazobactam in patients with renal dysfunction based on population pharmacokinetic and pharmacodynamic simulations

In the present study, we aimed to investigate the optimal dosage regimens of piperacillin/tazobactam in patients with chronic kidney disease according to their different classes of renal function based on bacterial resistance. A total of 2700 simulationswere applied based on a published population pharmacokinetic and pharmacodynamic model using nonlinear mixed effects modeling (NONMEM) software. Permissible optimal dosage regimens were defined as those associated with a less than 10% of patients whose probabilities of target attainment (PTA) were not attain target. For patients with mild to moderate renal injury, 4/0.5 g of piperacillin/tazobactam every 12 h in 30 min intermittent infusion could attain the target. If the MIC (minimum inhibitory concentration) for the pathogen was 8 mg/L or 16 mg/L, either an 8-h or 6-h dosing interval or extended 2–6 h infusion regimen had to be used to achieve the outcome of the therapy. Regarding MIC was up to above 32 mg/L, a high dose of piperacillin (12–24 g/d) in continuous infusion was the only approach that could achieve the effective target in patients with renal dysfunction. A low dose with extended 4–6 h infusion regimen was recommended for patients with severe renal injury. Our study identified permissible optimal piperacillin/tazobactam dosage regimens for patients with renal dysfunction with an MIC up to 64 mg/L. The findings of this study would be helpful for precise administration of piperacillin/tazobactam in clinical practice.     

床边实时超声检查对指导脓毒症患者抗凝治疗的临床意义

目的 探讨床边实时超声在重症监护病房(ICU)脓毒症患者抗凝治疗过程中的指导意义, 为降低抗凝风险提供临床依据。方法 收集ICU病房中脓毒症患者212例, 根据修订Geneva量表评分系统, 将患者分为低危、中危和高危。90例低危患者中, 未进行抗凝治疗30例(A组), 随机抗凝治疗30例(B组), 经超声指导下抗凝30例(C组), 比较3组患者血小板减少和出血发生率、机械通气使用天数、患者病死率等。结果 3组患者病死率差异无统计学意义(P>0.05), 但B组造成的临床出血风险最高, 与A组和C组比较, 临床发生消化道、气道或泌尿道出血例数增加, 且差异有统计学意义(P<0.05)。治疗前, 3组病例血小板差异无统计学意义(P>0.05), 但经抗凝治疗后, B组造成的血小板下降最为明显, 与A组和C组比较, 差异有统计学意义(P<0.05), 对于患者机械通气使用天数, 以超声引导下抗凝组时间最短。结论 超声引导下抗凝治疗, 可明显降低ICU脓毒症患者机械通气天数, 减少患者出血风险, 但对于脓毒症患者病死率无明显影响。