达比加群酯对患者凝血功能的影响及相关影响因素分析

目的：调查患者使用达比加群酯治疗后凝血状况的变化,以及肝肾功能变化对凝血指标和出血情况的影响,为临床更好地使用达比加群酯提供参考依据。方法：收集中日友好医院2017年4月1日至2018年3月31日住院期间使用达比加群的患者信息,进行回顾性分析。通过分析患者的凝血指标、肝肾情况、出血情况,分析达比加群酯对这些指标的影响。结果：共收集患者247例,男性139例（56.28%）,女性108例（43.72%）,平均（72.11±29.26）岁。共有189例患者测定了便潜血,其中免疫法检测阳性或弱阳性患者32例（16.93%）,化学法检测阳性或弱阳性患者30例（15.87%）。共有220例患者测定了尿红细胞（高倍镜）,其中阳性患者30例（13.64%）。患者服用达比加群前后TT、APTT值变化十分明显。肾功能对APTT的影响无显著性差异。CrCL>50 mL·min^-1的患者免疫法、化学法便潜血阳性的患者比例分别为16.77%,15.48%,尿红细胞阳性患者比例为1.08%;30 ≤ CrCL ≤ 50 mL·min^-1的患者免疫法、化学法便潜血阳性的患者比例均为25.00%,尿红细胞阳性患者比例为9.52%;CrCL<30 mL·min^-1的患者免疫法、化学法便潜血阳性的患者比例均为22.00%,尿红细胞阳性患者比例为25.00%。肾功能损伤的患者出血风险增加,应注意应密切监测。ALT或AST一项或两项均升高组的患者服用达比加群后,免疫法、化学法便潜血阳性的患者比例均为29.17%,尿红细胞阳性患者比例为26.93%。相比于正常组患者分别升高了2倍和2.03倍,而尿红细胞阳性患者比例升高了2.22倍。结论：高龄、有出血史等高危患者使用达比加群时注意凝血功能监测,当APTT升高2倍以上时,注意是否有隐匿性出血。肾功能对APTT无明显影响,肝酶异常时APTT延长。肝肾异常患者使用达比加群时出血风险增大,注意监测。     

达比加群酯不良反应文献的分析

通过检索PubMed、中国知网数据库和维普数据库关于达比加群酯不良反应的文献并对其进行回顾性分析和总结。达比加群酯致ADR的个案报道共73例;其性别分布男性44例（60.3%）,女性29例（39.7%）;年龄分布以70岁以上较多（59例,80.8%）;多发生在用药后6个月内（60例,82.2%）;达比加群酯致ADR临床表现以消化系统损害（50.7%）、血液系统损害（15.1%）和心血管系统损害（11.0%）多见。临床使用达比加群酯过程中应重点考量患者肾功能、年龄、体重和性别等危险因素,并重点监测和防治其ADR,避免ADR的发生。     

达比加群酯抗凝治疗合理性和安全性评价

目的：调查住院患者接受达比加群酯治疗情况,了解该药的应用现状和不良反应并分析其危险因素,为临床更好的使用达比加群酯提供参考依据。方法：收集中日友好医院2017年4月1日至2018年3月31日住院期间使用达比加群的患者信息,进行回顾性分析。通过分析患者适应证、肝肾情况、凝血指标、不良反应、药物转换及合并用药情况,评价达比加群酯使用的合理性和安全性。结果：共收集患者247例,其中男139例（56.28%）,女108例（43.72%）。年龄29~91岁,平均（72.11±29.26）岁。使用达比加群的患者中老年人有207例（83.80%）,因房颤及房扑入院的患者有184例（74.49%）,占比最大。患者因CrCL<30 mL·min^-1禁忌使用达比加群的情况下仍使用的有10例（4.05%）。19例（7.69%）患者住院期间使用达比加群出现不良反应,出血有14例（73.68%）。服用达比加群期间进行药物转换的患者32例（12.96%）。由华法林向达比加群转换22例（68.75%）,使用错误率为36.36%。由达比加群向华法林转换6例（18.75%）,使用错误率为100%。合用药物中联合使用抗血小板药37例（14.98%）,联合使用胺碘酮16例（6.48%）,临床使用期间应该加强监测。结论：达比加群临床常用于老年非瓣膜性房颤患者,使用前应注意肝肾功能监测,常见不良反应为出血,合并使用抗血小板药和胺碘酮时多注意监护。达比加群与华法林药物转换时错误较多,是药学监护的重点。     

达比加群酯相关严重不良事件文献病例分析

目的:探讨达比加群酯相关严重不良事件（AE）的临床特点。方法:检索中国知网、万方、PubMed、Embase数据库（截至2020年10月31日）,收集报道达比加群酯相关严重AE的病例报告类文献,提取患者相关信息（国籍,性别,年龄,体重,达比加群酯应用情况,合并疾病和合并用药情况,AE的发生、处置及转归等）进行描述性统计...     

达比加群酯不良反应的文献调查分析

目的分析达比加群酯不良反应的发生规律和特点。方法通过检索CNKI、万方、VIP、PubMed、Web of Science、Science Direct、Scifinder等数据库,对国内外所有达比加群酯不良反应的个案报道、临床试验和研究进行回顾性分析。结果共收集17例案例。达比加群酯所致不良反应主要为出血(47.1%)和皮疹(41.2%),且ADR多发生于2周内(78.6%)。结论使用达比加群酯时,在服药的2周内,应加强对患者的临床观察和实验室检查,同时加强对患者的用药教育,尽可能降低其ADR发生率。     

甲磺酸达比加群酯的合成

目的:研究和改进甲磺酸达比加群酯的合成工艺。方法:以4-甲氨基-3-硝基苯甲酸(2)和3-(吡啶-2-基氨基)丙酸乙酯(3)为原料,经酰氯化、酰胺化、中和成盐和还原制得重要中间体3-[[3-氨基-4-(甲氨基)苯甲酰基](吡啶-2-基)氨基]丙酸乙酯(5)。5再与N-(4-氰基苯基)甘氨酸经酰胺化、闭环、中和成盐、成脒、酰化,进而与甲磺酸成盐制得甲磺酸达比加群酯。结果:中间体及目标化合物经质谱、核磁共振谱、红外光谱等确证,整个工艺的总收率为33.9%。结论:本路线操作简便、成本较低、条件温和、步骤少,适合工业化生产。     

达比加群酯的合成工艺改进

目的 改进达比加群酯的合成工艺,提高反应收率并简化操作。方法 以4-甲胺基-3-硝基苯甲酸为原料,与3-（吡啶-2-基氨基）丙酸乙酯缩合后,经催化氢化、酰胺化后闭环、成脒、与氯甲酸正己酯反应得到达比加群酯。结果与结论 目标化合物的结构经核磁共振氢谱、质谱确证。改进后的合成方法与原工艺相比,环境友好,收率提高了16.4%,总收率为33.75%(以4-甲胺基-3-硝基苯甲酸计)。     

达比加群酯致吞咽困难1例

<正>达比加群酯(dabigatran etexilate)获得美国食品和药物管理局(FDA)批准用于预防非瓣膜性房颤患者卒中和全身性栓塞,是一种直接凝血酶抑制剂,口服经胃肠道吸收后迅速在肝及血浆中被酯酶水解释放出达比加群,后者选择性、可逆性地结合于凝血酶的纤维蛋白特异结合位点,阻止纤维蛋白原裂解为纤维蛋白,同时抑制凝血酶,阻止其介导的血小板活化、聚集和血栓形成,从而发挥     

达比加群酯的合成

4-甲胺基-3-硝基苯甲酸(2)经酰氯化后和3-(吡啶-2-基氨基)丙酸乙酯缩合,得3-[(4-甲胺基-3-硝基苯甲酰基)(吡啶-2-基)氨基]丙酸乙酯,再在Fe-Al-Cu复合催化剂作用下经水合肼还原、酰胺化后闭环、成脒及酰化反应等制得抗凝血药达比加群酯,总收率约33.6％(以2计).     

达比加群酯降解杂质的合成

目的 为了更好的控制甲磺酸达比加群酯的质量,合成达比加群酯的5个降解杂质。方法 以N-[2-[[(4-氰基苯基)氨基]甲基]-1甲基-1H-5-苯并咪唑]羰基]-N-2-吡啶基-β-氨基丙酸乙酯为原料,经过成脒反应、酰胺反应、水解反应制备了杂质A~E。结果 所得产物经¹H-NMR,LC-MS和¹³C-NMR初步确证了结构,收率≥65%。结论 该合成路线反应条件温和,产品纯度高。     

Fatal amiodarone-induced hepatotoxicity: a case report and literature review

OBJECTIVE: To report a fatal case of amiodarone-induced acute hepatotoxicity after intravenous amiodarone administration and similar fatal cases review. CASE SUMMARY: A 72-year-old woman with a history of hypertension, prior cardiovascular disease, atrial fibrillation and diabetes mellitus was admitted to the hospital with acute pyelonephritis and transferred to the intensive care unit due to cerebral infarction. An antidiabetic drug, a low dose of aspirin and intravenous amiodarone therapy was started. After receiving a second dose of amiodarone (1,200 mg; injection rate 1 mg/min), the woman developed ascites, jaundice, high levels of serum transaminases, decreased prothrombin time, and finally became unconscious. Immediately after treatment was discontinued, her extremely high hepatic parameters returned to normal. According to the Naranjo probability scale, this adverse reaction was highly probable. DISCUSSION: The occurrence of acute liver damage after intravenous amiodarone is rare but harmful. It can be induced by polysorbate 80, a solubilizer, by immunomediated centrilobular necrosis, or by the presence of a functional PPAR-I+/- gene. CONCLUSION: Amiodarone is an effective antiarrhythmic agent for preventing and treating atrial and ventricular arrhythmias. The molecular mechanism causing acute hepatic damage after amiodarone treatment is not clear. Therefore, amiodarone must be administered with care, and liver function should be monitored closely in patients treated with this drug.     

奥司他韦致结膜炎1例及文献复习

奥司他韦(oseltamivir)是一种神经氨酸酶抑制剂,通过抑制病毒从被感染细胞中释放,从而减少甲型或乙型流感病毒的播散,用于治疗成人和1岁以上儿童的甲型和乙型流感,以及用于预防成人和13岁及以上青少年的甲型和乙型流感[1].奥司他韦常见的不良反应主要有胃肠系统损害(呕吐、恶心、腹泻、腹痛)、神经系统紊乱(睡眠障碍、...     

Hemopericardium in a patient treated with dabigatran etexilate

Dabigatran etexilate is a new oral anticoagulant used for the prevention of systemic thromboembolism in patients with atrial fibrillation. Acute bleeding episodes are known to occur with dabigatran etexilate therapy; however, only a few case reports in the literature describe such events. We describe a 70-year-old man treated with dabigatran etexilate for newly diagnosed, nonvalvular atrial fibrillation who developed a large hemopericardium that appeared to be temporally related to dabigatran etexilate administration. One month after starting the drug, an incidental finding of a small pericardial effusion was found on echocardiography. One month later, the patient came to his pulmonologist's office complaining of shortness of breath; a large pericardial effusion was found on a noncontrast computed tomographic scan, and the patient was admitted to the hospital. Laboratory monitoring of his coagulation status was limited due to the lack of assays available to directly monitor the therapeutic effects of dabigatran. The internal laboratory was able to perform a dilute thrombin time (DTT) test as part of a quality improvement project aiming to validate an assay for monitoring patients receiving dabigatran therapy. A DTT was therefore performed in conjunction with routine coagulation assays to evaluate the patient's coagulation status. After pericardiocentesis, the patient recovered without incident and was discharged without anticoagulant therapy. Although the Naranjo adverse reaction probability scale only indicated a possible relationship (score of 1) between the patient's development of hemopericardium and dabigatran etexilate therapy, investigation into the patient's clinical course, comorbidities, and laboratory results led us to conclude that dabigatran etexilate was responsible for the hemopericardium. To our knowledge, this report is the first to describe a case of potentially life-threatening pericardial bleeding that was temporally related to starting dabigatran etexilate therapy. Although we found that the DTT was a viable method of monitoring coagulation status in a patient receiving dabigatran etexilate therapy, the assay lacks approval by the United States Food and Drug Administration, which limits its clinical utility and widespread use at this time. Clinicians should be aware of the potential for life-threatening bleeding with use of this agent and the difficulty associated with monitoring and reversing this therapy in the setting of acute bleeding.     

硫唑嘌呤相关急性白血病1例报告与文献回顾

1例78岁男性特发性肺间质纤维化患者,应用泼尼松、硫唑嘌呤及雷公藤总苷联合治疗.给予硫唑嘌呤150 mg/d,共用19个月,总量93 g.2年后,患者出现发热、呼吸困难.入院查血常规:WBC 0.83×109/L,N 0.06,L 0.86,M 0.18～0.39,PLT 74×109/L,Hb 121 g/L;骨髓涂片:有核细胞增生活跃,分类不明细胞占50%,该类细胞呈深灰色,中等偏大,有伪足,胞浆中充满紫红色细小颗粒,未见Auer小体;骨髓活检:增生低下,三系细胞减少;血细胞染色:过氧化物酶呈阴性或弱阳性,碱性磷酸酶90%阳性.入院76 d复查骨髓象:有核细胞增生明显活跃,幼稚单核细胞占56%,三系细胞增生受抑.皮下注射阿糖胞苷200 mg/d,连用2 d.效果不佳,于入院后128 d死亡.     

Elevated hepatic transaminases associated with telithromycin therapy: a case report and literature review.

PURPOSE: A case of mild hepatocellular injury associated with the administration of telithromycin in a patient with no risk factors for hepatotoxicity is presented. SUMMARY: A 44-year-old man with no significant past medical history arrived at the emergency room after six days of high fever, chills, headache, neck stiffness, and back pain. Five days earlier, he visited a family medicine clinic for his symptoms and oral telithromycin 800 mg daily was prescribed for a suspected upper-respiratory-tract infection. The patient stopped taking the drug after three days due to persistent symptoms. On admission, the patient's laboratory tests revealed an aspartate transaminase (AST) concentration of 68 units/L, an alanine transaminase (ALT) value of 155 units/L, and an erythrocyte sedimentation rate of 40 mm/hr. The patient was not taking any long-term medications, had taken only aspirin for his fever, and denied the use of alcohol and illegal drugs. The patient was admitted to the general medical unit with a diagnosis of possible viral hepatitis. His urine culture was negative, and serology tests later revealed no evidence of hepatitis A, B, or C. Ibuprofen, pantoprazole, and enoxaparin were prescribed. On hospital day 2, the patient's AST and ALT concentrations had decreased to 50 and 110 units/L, respectively. By day 3, the patient's symptoms had improved and he remained afebrile. His AST and ALT values had further decreased to 41 and 105 units/L, respectively. He was then diagnosed with acute viral upper-respiratory-tract infection with mild hepatotoxicity associated with telithromycin and was discharged home with orders for follow-up at the family medicine clinic. CONCLUSION: A patient without risk factors for hepatotoxicity developed mild elevations in hepatic transaminases after receiving telithromycin for the treatment of a suspected upper-respiratory-tract infection.     

Bladder tumor associated with phenacetin abuse: a case report and a review of the literature

We herein report the case of a bladder tumor in an 85-year-old man who had been engaged in phenacetin abuse. He had been taking phenacetin owing to migraine headaches since he was 45 year of age. His total intake of phenacetin was approximately 7.3 to 11.5 kg over a period of years. He visited the Department of Urology in our hospital due to gross hematuria and pain on urination. IVP and a pelvic CT scan revealed a tumor mass on the right lateral wall of the urinary bladder. TUR-BT was performed. A histopathological examination of the resected specimen was diagnosed as urotherial carcinoma, grade 2～3, pT2N0M0. To our acknowledge, only 24 cases of urotherial tumors owing to phenacetin abuse have been previously reported in the Japanese literature, making this the 25 th such case to be reported in Japan.     

Possible heart failure exacerbation associated with rosiglitazone: case report and literature review

Increasing evidence suggests that neurohumoral manifestations of heart failure may lead to insulin resistance, predisposing patients with heart failure to the development of glucose intolerance or worsening of existing diabetes. Theoretically, insulin-sensitizing thiazolidinediones (TZDs) should be beneficial in this patient population. A 74-year-old man with well-compensated systolic dysfunction and longstanding type 2 diabetes mellitus treated with glyburide began therapy with rosiglitazone 4 mg/day, which was increased to 8 mg/day after 1 month. Two weeks later he was seen with a 5-kg weight gain, shortness of breath, bibasilar rales, +S3 gallop, and increased jugular venous distention. Twelve days later symptoms worsened, with pulmonary edema on chest radiograph, continued weight gain, and +4 pitting edema resistant to oral diuretics. The patient was admitted to the hospital for exacerbation of heart failure. Five days after discharge he was readmitted for similar symptoms, including an 11.8-kg weight gain. He reported adherence to drug therapy and diet. Rosiglitazone was immediately discontinued and 11 days later the man's weight stabilized to 79 kg and remained between 79 and 80 kg 2 and 3 months after discharge. This case demonstrates that TZDs may precipitate weight gain and pulmonary and peripheral edema in patients with stable heart failure. Earlier reports documented similar symptoms in patients without a history of heart failure. Although current recommendations state that TZDs should not be administered to patients with New York Heart Association class III or IV disease, practitioners should be aware that these adverse effects also may occur in patients with milder forms heart failure as well as those without heart failure.     

Fatal propafenone overdoses: case reports and a review of the literature

First synthesized in 1970, propafenone is a frequently used 1C antiarrhythmic drug metabolized into two major metabolites, 5-hydroxypropafenone and norpropafenone. Paradoxically, fatal intoxication is rarely described, and only six cases have been reported in the literature. We report our experience with two patients found dead of self-inflicted poisoning where the propafenone blood concentration was very high (one concentration to our knowledge is one of the highest reported in the literature). At autopsy, no evidence of significant pathological disease were found. Propafenone was detected in blood by gas chromatography-mass spectrometry and by high-performance liquid chromatography using a diode-array detector, respectively, as propafenone artifact and propafenone. Blood propafenone concentrations were 4180 ng/mL and 9123 ng/mL. The literature regarding propafenone pharmacokinetic and intoxication is reviewed, and we discuss the low death rate attributed to this drug in contrast to its frequent use.