三维有序大孔淀粉材料改善达比加群酯的溶出行为

目的 制备三维有序大孔淀粉材料（three-dimensional ordered macroporous starch material,3DOMS）,改善难溶性药物达比加群酯（dabigatran etexilate,DBET）的溶出度。方法 通过硬模板法制备3DOMS;溶剂挥发法进行载药;借助X射线衍射法、差示扫描量热法和傅里叶红外光谱法表征考察药物存在状态;溶出度实验验证DBET溶出度改善情况。结果 3DOMS具有三维有序的纳米级连通孔道结构,借助其纳米级空间抑制效应能够有效抑制难溶性药物的结晶度,载药样品（DBET-3DOMS）中DBET以无定形态存在,体外溶出度实验表明药物溶出效果明显改善。结论 3DOMS能够有效改善DBET的溶出,作为生物可降解材料在改善难溶性药物水溶性方面具有较大潜力。     

Phase IIa study of dabigatran etexilate in children with venous thrombosis: pharmacokinetics,safety, and tolerability

Essentials

• Dabigatran etexilate may provide a new treatment option for pediatric venous thromboembolism.
• Children aged 1 to < 12 years were given dabigatran etexilate in an open‐label, single‐arm study.
• The pharmacokinetic–pharmacodynamic relationship was similar to that seen in adult patients.
• There were no serious adverse events, bleeding events or recurrent venous thromboembolism.

Summary

Background

The current standard‐of‐care treatments for pediatric venous thromboembolism (VTE) have limitations. Dabigatran etexilate (DE), a direct thrombin inhibitor, may offer an alternative therapeutic option.

Objectives

To assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of a DE oral liquid formulation (OLF) in pediatric patients with VTE.

Patients/Methods

Patients who had completed planned treatment with low molecular weight heparin or oral anticoagulants for VTE were enrolled in two age groups (2 to < 12 years and 1 to < 2 years), and received a DE OLF based on an age‐adjusted and weight‐adjusted nomogram. Originally, patients were to receive a DE OLF twice daily for 3 days, but the protocol was amended to a single dose on day 1. The primary endpoints were pharmacokinetics/pharmacodynamics‐related: plasma concentrations of DE and its metabolites; activated partial thromboplastin time (APTT), ecarin clotting time (ECT), and dilute thrombin time (dTT); and pharmacokinetic (PK)–pharmacodynamic (PD) correlation. Safety endpoints included incidence rates of bleeding events and all other adverse events (AEs).

Results

Eighteen patients entered the study and received the DE OLF (an exposure equivalent to a dose of 150 mg twice daily in adults). The projected steady‐state dabigatran trough concentrations were largely comparable between pediatric patients and adults. The PK/PD relationship was linear for ECT and dTT, and non‐linear for APTT. No serious or severe AEs, bleeding events, or recurrent VTEs were reported. Mild AEs were reported in three patients in the single‐dose group (screening period) and in one patient in the multiple‐dose group (on‐treatment period).

Conclusion

The current study supports the further evaluation of DE OLFs in pediatric patients with VTE.     

The risk of gastrointestinal bleeding in patients receiving dabigatran etexilate: a systematic review and meta-analysis of the literature

Background: Evidence on the risk of gastrointestinal (GI) bleeding associated with dabigatran etexilate (DE) is contrasting. We performed a meta-analysis of literature to address this issue.

Methods and Results: Studies on GI bleeding risk in patients receiving DE or vitamin-K antagonists (VKA) were systematically searched. Twenty-three studies (26 datasets) showed no difference in the GI bleeding risk between the 250,871 patients treated with DE and the 460,386 receiving VKA (OR: 1.052, 95% CI: 0.815, 1.359). Similar results were obtained when pooling together adjusted ORs/HRs, obtained by means of multivariate analysis (OR: 1.06, 95% CI: 0.914, 1.222). Compared with VKA, DE use was associated with a significantly lower risk of upper GI (OR: 0.742, 95% CI: 0.569, 0.968), but not of lower GI bleedings (OR: 1.208, 95% CI: 0.902, 1.619). Furthermore, no significant difference in the GI bleeding risk was found when data on DE 110?mg and DE 150?mg twice-daily were separately compared with VKA.

Conclusions: No difference in GI bleeding risk was found between DE and VKA. These results were confirmed for both dosages of DE and when specifically analyzing lower GI bleeding. In contrast, the risk of upper GI bleeding was lower with DE than with VKA.

• KEY MESSAGES

• No difference in the risk of gastrointestinal (GI) bleeding can be found between dabigatran etexilate (DE) and vitamin K-antagonists (VKA).

• These results are confirmed for both dosages of DE.

• The risk of upper GI bleeding is lower with DE than with VKA.

     

胺碘酮联合达比加群酯治疗非瓣膜性心房颤动的疗效和安全性分析

目的探讨胺碘酮联合达比加群酯治疗非瓣膜性心房颤动的疗效和安全性。方法将2014年1月至2014年7月收治的76例非瓣膜性心房颤动患者随机分为治疗组和对照组,治疗组予以胺碘酮联合达比加群酯治疗,对照组予以胺碘酮联合华法林,观察凝血指标变化,心电图、生化指标变化和不良反应等情况。结果与治疗前相比,治疗后两组凝血酶原时间(PT)、凝血活酶时间(APTT)、国际标准化比值(INR)、凝血酶时间(TT)均升高(P0.05)。治疗后,两组间各凝血指标比较,差异无统计学意义(P0.05),两组患者心率明显降低(P0.05),其他心电图表现均无明显变化(P0.05)。治疗组发生消化道反应9例(23.7%),高于对照组的5.3%(P0.05)。而治疗组栓塞或血栓以及出血的发生率均低于对照组(P0.05)。结论胺碘酮联合达比加群酯治疗非瓣膜性心房颤动安全有效,值得在临床推广。     

新型口服抗凝药预防非瓣膜性心房颤动相关性脑卒中的应用进展

非瓣膜性心房颤动(房颤)相关性脑卒中的临床后果严重,是房颤致残、致死的最主要原因。口服华法林是预防房颤患者发生脑卒中事件的有效措施,但华法林的抗凝治疗窗窄,显效慢,疗效易受食物和药物的影响,故需反复检测凝血功能并根据国际标准化比值调整使用剂量,从而降低了患者的用药依从性。以凝血酶抑制剂及Ⅹa因子抑制剂为代表的新型口服抗凝剂较华法林能显著降低房颤相关性脑卒中的发病率和出血风险,有望成为房颤患者抗凝治疗的新选择。     

Recurrent pheochromocytoma with catecholamine cardiomyopathy and left ventricular thrombus: a case report

Pheochromocytoma is a rare and usually benign tumor of the adrenal glands. We report a case of a 40-year-old woman with recurrent pheochromocytoma and catecholamine cardiomyopathy. She had no history of other types of tumors or connective tissue disease. She had already undergone surgery twice to remove the pheochromocytoma, which had now recurred for the second time. A thrombus in the left ventricle was also noted upon imaging examination, which dissipated after anticoagulation therapy using dabigatran, allowing the patient to opt for an elective third surgery. This paper describes the clinical outcome of using the anticoagulant dabigatran to treat left ventricular thrombosis in this rare case of recurrent pheochromocytoma, and thus further contributing to the knowledge of the clinical management of this rare and complicated disease.     

Direct‐acting oral anticoagulants: pharmacology,indications, management,and future perspectives

In recent years, several direct‐acting oral anticoagulants (DOAC) have become available for use in Europe and other regions in indications related to prophylaxis and treatment of venous and arterial thromboembolism. They include the oral direct thrombin inhibitor dabigatran etexilate (Pradaxa^®, Boehringer Ingelheim) and the oral direct FXa inhibitors rivaroxaban (Xarelto^®, Bayer HealthCare), apixaban (Eliquis^®, Bristol‐Myers Squibb), and edoxaban (Lixiana^®/Savaysa^®, Daiichi‐Sankyo). The new compounds have a predictable dose response and few drug–drug interactions (unlike vitamin k antagonists), and they do not require parenteral administration (unlike heparins). However, they accumulate in patients with renal impairment, lack widely available monitoring tests for measuring its anticoagulant activity, and no specific antidotes for neutralization in case of overdose and/or severe bleeding are currently available. In this review, we describe the pharmacology of the DOAC, the efficacy, and safety data from pivotal studies that support their currently approved indications and discuss the postmarketing experience available. We also summarize practical recommendations to ensure an appropriate use of the DOAC according to existing data. Finally, we discuss relevant ongoing studies and future perspectives.     

Use of direct-acting oral anticoagulants in solid organ transplantation: A systematic review

The use of direct-acting oral anticoagulants (DOACs) has increased secondary to the mounting evidence for comparable efficacy and potentially superior safety to vitamin K antagonists (VKAs) in the general population. However, insufficient data regarding DOAC use in solid organ transplant (SOT) recipients and numerous pharmacokinetic and pharmacodynamic considerations limit their use in this highly selected patient population. A systematic review of recent clinical evidence on the safety and efficacy of DOACs compared to VKAs in SOT recipients was conducted. Additional considerations including transplant-specific strategies for DOAC reversal and common pharmacokinetic/pharmacodynamic concerns were also reviewed. Although current evidence is limited to single-center retrospective analyses, DOACs, especially apixaban, appear to be a safe and effective alternative to VKAs for SOT recipients with stable graft function and without drug-drug interactions. Reliable data on DOAC reversal at the time of transplant surgery are lacking, and clinicians should consider idarucizumab, andexanet alfa, and other non-specific reversal agents on an individual patient basis. There is no evidence supporting deviations from the Food and Drug Administration labeling recommendations for DOAC dosing in the setting of drug-drug interactions, obesity, and renal function, especially in patients on hemodialysis.