逆转达比加群酯抗凝活性的研究进展和处理建议

达比加群酯是一种直接抑制凝血酶的新型口服抗凝药,具有较好的抗凝疗效和安全性,出血是其最常见的不良反应,发生率略低于或类似于华法林和依诺肝素。当服用达比加群酯的患者发生大出血,或者需进行手术或侵入性处理时,常须紧急逆转其抗凝活性。目前尚未研发出达比加群酯特异性解药,临床上应根据患者的出血部位和严重程度,进行综合治疗。监测凝血酶凝固时间（TT）和蛇静脉酶凝结时间（ECT）等指标有助于判断逆转达比加群酯活性的疗效。     

Determination of dabigatran in dog plasma by LC-MS/MS and its application to a pharmacokinetic study of dabigatran etexilate nanosuspension

In this study, a sensitive and rapid LC-MS/MS method was developed and validated to determine dabigatran in plasma of beagle dogs after oral administration of dabigatran etexilate nanosuspension (DABE-NS). The analytes (dabigatran) and sertraline hydrochloride (internal standard, IS) were separated on a Kromasil C₁₈ column using gradient elution consisting of methanol and formate buffer at a flow rate of 0.4 mL/min in 20 min. Detection and quantitation were carried out by multiple reaction monitoring following the transitions: m/z 472.17→289.07 and 305.98→275.00 for dabigatran and IS at positive ion mode, respectively. The calibration curves were linear from 1.0 to 500.0  ng/mL for dabigatran with r  = 0.9995. The accuracy of each analyte ranged from 94.8% to 107.1%, and the precision was within 6%. Besides, this method was successfully applied in the investigation of the pharmacokinetic profile of dabigatran in beagle dogs after oral administration ofDABE-NS. The maximum concentration and the areas under curves of dabigatranfor DABE-NS were significantly higher than those of control formulation, indicating improved oral absorption.     

达比加群酯用于非瓣膜性房颤抗凝治疗的不良反应分析

目的:了解我院达比加群酯致药品不良反应发生的规律和特点,为临床安全合理使用达比加群酯提供参考依据.方法:采用回顾性分析方法,对我院2015年2月-2019年12月上报国家ADR监测中心的19例达比加群酯ADR报告进行统计分析.结果:19例达比加群酯ADR报告中,男女比例为1:1.7;61～70岁患者最多(42.11％)...     

达比加群酯联合阿司匹林在非瓣膜性房颤治疗中的应用效果及安全性评价

目的 分析非瓣膜性心房颤动(房颤)患者使用达比加群酯联合阿司匹林进行治疗的临床疗效及安全性.方法 120例非瓣膜性房颤患者,根据随机数字表法分为对照组和实验组,各60例.对照组患者采用常规抗凝治疗,实验组患者采用达比加群酯联合阿司匹林治疗.对比两组患者的治疗效果及不良反应发生情况.结果 实验组患者的治疗总有效率为93....     

Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin

AIMS

This study examined the effects of the CYP3A/P-glycoprotein inducer, rifampicin, on the pharmacokinetics of dabigatran following oral administration of the prodrug, dabigatran etexilate.

METHODS

This was an open-label, fixed-sequence, four-period study in healthy volunteers. Subjects received a single dose of dabigatran etexilate 150 mg on day 1, rifampicin 600 mg once daily on days 2–8, and single doses of dabigatran etexilate on days 9, 16 and 23.

RESULTS

Twenty-four subjects were treated, of whom 22 received all treatments. Relative to the reference (single dose of dabigatran etexilate alone; treatment A), administration of dabigatran etexilate following 7 days of rifampicin (treatment B) decreased the geometric mean (gMean) area under the concentration–time curve (AUC_0–∞) and maximal plasma concentration (C_max) of total dabigatran by 67 and 65.5%, respectively. The time to peak and the terminal half-life were not affected. The gMean ratio for the primary comparison (treatment B vs. treatment A) was 33.0% (90% confidence interval 26.5, 41.2%) for AUC_0–∞ and 34.5% (90% confidence interval 26.9, 44.1%) for C_max, indicating a significant effect on total dabigatran exposure (total pharmacologically active dabigatran represents the sum of nonconjugated dabigatran and dabigatran glucuronide). After a 7 day (treatment C) or 14 day washout (treatment D), the AUC_0–∞ and C_max of dabigatran were reduced by 18 and 20%, and by 15 and 20%, respectively, compared with treatment A, which was considered not clinically relevant. The overall safety profile of all treatments was good.

CONCLUSIONS

Administration of rifampicin for 7 days resulted in a significant reduction in the bioavailability of dabigatran, which returned almost to baseline after 7 days washout.     

The evolving role of dabigatran etexilate in clinical practice

Introduction: Stroke and venous thromboembolism (VTE) affect millions of patients. The vitamin K antagonist, warfarin, has been the main oral anticoagulant used to treat these conditions despite many limitations associated with its use. Recently, multiple novel oral anticoagulants have been approved and are reshaping how patients with atrial fibrillation (AF) at risk of stroke and patients with VTE are treated. The direct thrombin inhibitor, dabigatran etexilate, is among these novel agents that have been developed to overcome limitations with warfarin.

Areas covered: In this article, authors describe the pharmacokinetic and pharmacodynamic properties of dabigatran etexilate and summarize the clinical evidence and controversy surrounding its use in the US, Canada and Europe.

Expert opinion: Dabigatran has demonstrated similar efficacy and safety to enoxaparin for VTE prevention in patients undergoing hip and knee arthroplasty, and to warfarin for the treatment of VTE. Dabigatran (110 mg) is noninferior and dabigatran (150 mg) is superior to warfarin for stroke prevention in patients with nonvalvular AF, with a lower rate of intracranial hemorrhage reported at both doses. Apixaban, rivaroxaban and edoxaban provide alternate anticoagulant options to dabigatran. While there are many similarities, there are also significant differences to consider in agent selection based on patient-specific characteristics.     

达比加群酯联合替格瑞洛对老年心房颤动合并不稳定型心绞痛患者的治疗效果

目的 探讨在治疗老年心房颤动合并不稳定型心绞痛时使用达比加群酯联合替格瑞洛对其凝血功能及临床疗效的影响.方法 120例老年心房颤动合并不稳定型心绞痛患者,按照入院的先后顺序分成观察组和对照组,每组60例.对照组在常规治疗的基础上口服华法林、替格瑞洛进行治疗,观察组在常规治疗的基础上加用达比加群酯联合替格瑞洛进行治疗.比...     

心房颤动合并冠心病冠状动脉介入治疗术后达比加群酯 抗凝治疗的有效性及安全性研究

目的 研究达比加群酯(dabigatran etexilate)在心房颤动(房颤)合并冠心病冠状动脉介入治疗(PCI)术后抗凝治疗中的有效性及安全性。方法 选取2015年3月至2016年3月安徽医科大学第二附属医院收治的房颤合并冠心病冠状动脉介入治疗病人90例,采用随机数字表法分为观察组和对照组,每组45例。观察组每天两次口服达比加群酯110 mg;对照组予以华法林治疗,调节国际标准化比值(INR)至2.0~3.0之间;同时两组均予以阿司匹林100 mg/d。观察随访12个月,比较两组病人实验室指标变化、新发急性心肌梗死、急性脑梗死、非中枢神经系统栓塞、出血事件及不良反应的发生率。结果 观察组中栓塞事件发生率(8.9%)与对照组(17.8%)相比差异无统计学意义(χ²=1.538,P=0.215);达比加群酯在降低与血栓形成有关的实验室指标上较华法林更优,同时观察组出血事件发生率低于对照组(χ²=4.406,P=0.036);两组在不良反应事件发生率上均差异无统计学意义(P>0.05)。结论 达比加群酯在房颤合并冠心病PCI术后病人抗凝治疗中与华法林的疗效相似,且达比加群酯的安全性更高,是此类病人抗凝治疗的理想选择。     

A three-step stacking capillary electrophoresis of field-amplified sample injection,sweeping, and micellar collapse for determination of dabigatran and its active metabolite in human plasma

A three-step stacking capillary electrophoresis (CE) composed of field-amplified sample injection, sweeping, and analyte focusing by micellar collapse (FASI-sweeping-AFMC) was developed to determine dabigatran (D) and its major active metabolite, dabigatran acyl-beta-d-glucuronide (DAG), in human plasma. After optimization and validation, this novel approach was further applied to monitor 5 real samples, and the 25.2–186.8 ng mL⁻¹ D could be observed among those. Based on these results, the novel CE stacking strategy was successfully applied for the analysis of D and DAG in human plasma and could be served as a tool for clinical assays.     

The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects

AIMS: The novel direct thrombin inhibitor (DTI), dabigatran etexilate (Boehringer Ingelheim Pharma GmbH & Co. KG), shows potential as an oral antithrombotic agent. Two double-blind, randomized trials were undertaken to investigate the pharmacokinetics (PK), pharmacodynamics (PD) and tolerability of orally administered dabigatran etexilate in healthy male subjects. METHODS: Dabigatran etexilate or placebo was administered orally at single doses of 10-400 mg (n = 40) or at multiple doses of 50-400 mg three times daily for 6 days (n = 40). Plasma and urine samples were collected over time to determine the PK profile of dabigatran. PD activity was assessed by its effects on blood coagulation parameters: activated partial thromboplastin time (aPTT), prothrombin time (PT), reported as international normalized ratio (INR), thrombin time (TT), and ecarin clotting time (ECT). All adverse events were recorded. RESULTS: Dabigatran etexilate was rapidly absorbed with peak plasma concentrations of dabigatran reached within 2 h of administration. This was followed by a rapid distribution/elimination phase and a terminal phase, with associated estimated half-lives of 8-10 h and 14-17 h with single and multiple dose administrations, respectively. Dabigatran exhibited linear PK characteristics with dose-proportional increases observed in maximum plasma concentration and area under the curve. Steady-state conditions were reached within 3 days with multiple dosing. The mean apparent volume of distribution during the terminal phase (V(z)/F) of 1860 l (range 1430-2400 l) and the apparent total clearance after oral administration (CL(tot)/F) of 2031 ml min(-1) (range 1480-2430), were dose independent. Time curves for aPTT, INR, TT and ECT paralleled plasma concentration-time curves with values increasing rapidly and in a dose-dependent manner. At the highest dose of 400 mg administered three times daily, maximum prolongations over baseline of 3.1 (aPTT), 3.5 (INR), 29 (TT) and 9.5-fold (ECT) were observed. Dabigatran underwent conjugation with glucuronic acid to form pharmacologically active conjugates that accounted for approximately 20% of total dabigatran in plasma. Overall, variability in PK parameters was low to moderate, with an average interindividual coefficient of variation (CV) of approximately 30% and variability in PD parameters was low, with CV < 10%. Of the four assays, TT and ECT exhibited the greatest sensitivity and precision within the anticipated therapeutic dose range. Bleeding events were few and were mild-to-moderate in intensity, occurring only in the higher, multiple dose groups. CONCLUSIONS: These data suggest that dabigatran etexilate is a promising novel oral DTI with predictable PK and PD characteristics and good tolerability. Further investigation of dabigatran etexilate for the treatment and prophylaxis of patients with arterial and venous thromboembolic disorders, acute coronary syndromes and other medical conditions is warranted.     

Glucagon-like peptide 1 receptor plays a critical role in geniposide-regulated insulin secretion in INS-1 cells

Aim:

To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells.

Methods:

Rat INS-1 insulinoma cells were cultured. The content of insulin in the culture medium was measured with ELISA assay. GLP-1R gene in INS-1 cells was knocked down with shRNA interference. The level of GLP-1R protein in INS-1 cells was measured with Western blotting.

Results:

Geniposide (0.01–100 μmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner. Geniposide (10 μmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose. Blockade of GLP-1R with the GLP-1R antagonist exendin (9–39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 μmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L).

Conclusion:

Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells.     

A dabigatran etexilate phospholipid complex nanoemulsion system for further oral bioavailability by reducing drug-leakage in the gastrointestinal tract

Dabigatran etexilate (DE) is insoluble at neutral pH values but soluble at low pH values due to protonation, which is the major cause for the poor bioavailability of commercial DE products. Here, we first developed a DE nanoemulsion system and improved dissolution in simulated intestinal fluids by encapsulating DE into an oil phase, but 35.8% of the drug still leaked out. Further, we prepared a DE-phospholipid complex (DE-PC) to enhance lipophilicity and solubility of DE. The resulting DE-PC nanoemulsions significantly (P < 0.05) reduced drug leakage and subsequent precipitation. As a result, the relative bioavailability of DE-PC nanoemulsions increased to 147.3% and 606.6% compared to DE nanoemulsions and commercial DE products, respectively. Thus, the presently developed drug-phospholipid complex nanoemulsion system is a promising drug delivery system for improving the oral bioavailability of pH-dependent soluble drugs.     

A novel drug interaction between the quinolone antibiotic ciprofloxacin and a chiral metabolite of pentoxifylline

Pentoxifylline (PTX), a methylxanthine derivative, is metabolized to seven compounds in vivo, with metabolites 1 and 5 possessing biologic activity. Metabolite-1 is a chiral molecule and its S-enantiomer is selectively formed during PTX metabolism in vivo. We have developed a reproducible method of synthesizing a racemic mixture of the chiral metabolite-1 (M-1) of PTX. In this study, we examined the kinetics of racemic M-1 in mice compared to PTX. An interaction between PTX and the quinolone antibiotic ciprofloxacin has been demonstrated. A goal of this study was to determine if a similar interaction occurs between ciprofloxacin and M-1 in vivo. M-1 and PTX had similar absorption and elimination rates. M-1 was rapidly converted to PTX, while very little PTX was converted to M-1 in vivo. The peak concentration of biologically active drug (PTX+M-1) was 36% higher when M-1 was administered compared to PTX. Combination of ciprofloxacin and PTX significantly increased serum concentrations of both PTX and M-1 (2-fold) compared to controls. The combination of M-1 and ciprofloxacin significantly increased serum concentration of M-1 (3-fold) and PTX (2-fold). The ciprofloxacin/M-1 combination produced a significantly higher sera concentration of bioactive drug compared to all other groups suggesting that this combination may enhance the anti-fibrogenic effect.     

GLP-1 receptor plays a critical role in geniposideinduced expression of heme oxygenase-1 in PC12 cells

Aim:

To explore the role of activation of glucagon-like peptide 1 receptor (GLP-1R) and its relative cell signaling pathway in the cytoprotection of geniposide.

Methods:

Cell viability was determined by MTT assay. Knockdown of the Glp-1r gene was carried out with shRNA. The levels of HO-1 protein and cAMP response element binding protein (CREB) phosphorylation were measured by Western blotting.

Results:

Geniposide protected PC12 cells from oxidative damage induced by 3-morpholinosydnonimine hydrochloride (SIN-1) by enhancing the expression of heme oxygenase 1 (HO-1) via the cAMP-PKA-CREB signal pathway. After transfecting PC12 cells with the AB1 enhancer from the HO-1 gene, luciferase activity induced by geniposide increased in a dose-dependent manner, but not in the PC12 cells whose Glp-1r gene was disrupted. Additionally, inhibition of HO-1 activity by Sn-protoporphyrin IX (SnPP) or shRNA-mediated knockdown of Glp-1r decreased the neuroprotection of geniposide in PC12 cells.

Conclusion:

GLP-1R plays a critical role in geniposide-induced HO-1 expression to attenuate oxidative insults in PC12 cells.     

A critical role of COX-2 in the progression of neointimal formation after wire injury in mice

Background: Inflammation plays an important role in neointimal hyperplasia after vascular injury. COX-2 is a key mediator of inflammation and contributes to several inflammatory diseases. Although selective COX-2 inhibitors affect pathological conditions in inflammatory diseases, little is known about the effects on vascular remodeling after mechanical injury. Methods: To clarify the role of COX-2 in vascular remodeling after arterial injury, we made a wire-injury model using C57BL/6J mice. These mice were orally administrated a selective COX-2 inhibitor twice a day. COX-2 mRNA expression was analyzed in injured femoral arteries. Results: COX-2 expression was markedly enhanced in the arterial wall on day 7; the expression was gradually decreased from day 14. In histopathological analyses, the COX-2 inhibitor significantly suppressed the progression of neointimal formation in comparison with non-treated mice. In an in vitro study, RNA was collected from macrophages after stimulation. The stimulation resulted in enhanced expression of IL-6 compared with the control, and the COX-2 inhibitor decreased this expression. Conclusion: COX-2 is enhanced in the neointima after mechanical injury, and inhibition attenuated this. Therefore, regulation of COX-2 may be useful for preventing neointimal formation after coronary intervention.     

Platelet activating factor receptor binding plays a critical role in jet fuel-induced immune suppression

Applying military jet fuel (JP-8) or commercial jet fuel (Jet-A) to the skin of mice suppresses the immune response in a dose-dependent manner. The release of biological response modifiers, particularly prostaglandin E2 (PGE2), is a critical step in activating immune suppression. Previous studies have shown that injecting selective cyclooxygenase-2 inhibitors into jet fuel-treated mice blocks immune suppression. Because the inflammatory phospholipid mediator, platelet-activating factor (PAF), up-regulates cyclooxygenase-2 production and PGE2 synthesis by keratinocytes, we tested the hypothesis that PAF-receptor binding plays a role in jet fuel-induced immune suppression. Treating keratinocyte cultures with PAF and/or jet fuel (JP-8 and Jet-A) stimulates PGE2 secretion. Jet fuel-induced PGE2 production was suppressed by treating the keratinocytes with specific PAF-receptor antagonists. Injecting mice with PAF, or treating the skin of the mice with JP-8, or Jet-A, induced immune suppression. Jet fuel-induced immune suppression was blocked when the jet fuel-treated mice were injected with PAF-receptor antagonists before treatment. Jet fuel treatment has been reported to activate oxidative stress and treating the mice with anti-oxidants (Vitamins C, or E or beta-hydroxy toluene), before jet fuel application, interfered with immune suppression. These findings confirm previous studies showing that PAF-receptor binding can modulate immune function. Furthermore, they suggest that PAF-receptor binding may be an early event in the induction of immune suppression by immunotoxic environmental agents that target the skin.     

Lack of pharmacokinetic interaction between ropinirole and theophylline in patients with Parkinson's disease

Objective: Ropinirole and theophylline have the potential to interact, because they use the same hepatic cytochrome P450 (CYP1A2) as their major metabolic pathway. The present study investigated the effect of steady-state oral theophylline on the pharmacokinetics of ropinirole at steady state and the effect of steady-state ropinirole on the pharmacokinetics of a single intravenous (i.v.) dose of theophylline, both in patients with idiopathic Parkinson's disease (PD). Methods: Pharmacokinetic parameters (AUC and C_max) for i.v. theophylline were compared before and after a 4-week period of oral treatment with ropinirole (2 mg t.i.d.) in 12 patients with PD. Patients were then maintained at this dose of ropinirole, and oral theophylline was co-administered at doses of up to 300 mg b.i.d. The parameters AUC, C_max and t_max for ropinirole were compared before, during and after oral theophylline co-treatment. Results: Co-administration of ropinirole did not significantly change the pharmacokinetics of i.v. theophylline (mean AUC with and without ropinirole: 68.6 μg · h⁻¹ · ml⁻¹ and 70.0 μ· h⁻¹ · ml⁻¹, respectively; mean C_max with and without ropinirole: 11.07 μ g · ml⁻¹ and 11.83 μg · ml⁻¹, respectively). Similarly, there were no significant changes in ropinirole pharmacokinetics when the drug was co-administered with oral theophylline (mean AUC for ropinirole with and without theophylline: 21.91 ng · h⁻¹ · ml⁻¹ and 22.09 ng · h⁻¹ · ml⁻¹, respectively; mean C_max for ropinirole with and without theophylline: 5.65 ng · ml⁻¹ and 5.54 ng · ml⁻¹, respectively; median t_max for ropinirole with and without theophylline: 2.0 h and 1.5 h, respectively). Conclusion: These results suggest a lack of significant pharmacokinetic interaction between the two drugs at current therapeutic doses. Received: 10 August 1998 / Accepted in revised form: 27 January 1999