Diltiazem

地尔硫
  • 文章类型: Journal Article
    本研究旨在评估静脉注射地尔硫卓和美托洛尔在快速心室率房颤(AF)患者的心率控制中的相关性。重点关注心率控制疗效和血流动力学不良事件。遵循系统审查和荟萃分析(PRISMA)指南的首选报告项目,在Embase进行了电子搜索,PubMed,和Cochrane中央控制试验登记册(中央),直到2024年2月20日。主要结果是实现心室率控制<110/min。次要结果包括新的低血压(收缩压<90mmHg)和心动过缓(心率<60/min)。该荟萃分析包括19项研究(3项随机对照试验和16项观察性研究)。汇总分析显示,与地尔硫卓相比,静脉注射美托洛尔的心率控制率降低了39%(OR:0.61;95%CI:0.44至0.84;p=0.002)。两组之间的心动过缓(OR:0.51;95%CI:0.22至1.22;p=0.13)或低血压风险(OR:1.08;95%CI:0.72至1.61;p=0.72)没有显着差异。在快速心室率的房颤患者中,静脉地尔硫与美托洛尔相比具有更好的心率控制功效。然而,在安全性结果方面没有观察到显著差异,即,心动过缓和低血压。
    This study aims to assess the association between intravenous diltiazem and metoprolol in rate control for atrial fibrillation (AF) patients with rapid ventricular rate, focusing on rate control efficacy and hemodynamic adverse events. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, electronic searches were conducted in Embase, PubMed, and Cochrane Central Register of Controlled Trials (CENTRAL) until February 20, 2024. The primary outcome was achieving ventricular rate control < 110/min. Secondary outcomes included new hypotension (systolic blood pressure < 90 mm Hg) and bradycardia (heart rate < 60/min). Nineteen studies (three randomized controlled trials and 16 observational studies) were included in this meta-analysis. Pooled analysis showed intravenous metoprolol resulted in a 39% lower rate control attainment compared to diltiazem (OR: 0.61; 95% CI: 0.44 to 0.84; p = 0.002). There were no significant differences in bradycardia (OR: 0.51; 95% CI: 0.22 to 1.22; p = 0.13) or hypotension risk (OR: 1.08; 95% CI: 0.72 to 1.61; p = 0.72) between the two groups. Intravenous diltiazem demonstrated superior rate control efficacy compared to metoprolol in AF patients with rapid ventricular rate. However, no significant differences were observed in safety outcomes, namely, bradycardia and hypotension.
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  • 文章类型: Comparative Study
    地尔硫卓,房颤患者常用的心室率控制药物,抑制阿哌沙班和利伐沙班的消除,可能导致抗凝过度.
    比较阿哌沙班或利伐沙班的新使用者与地尔硫卓或美托洛尔治疗的房颤的严重出血风险。
    这项回顾性队列研究包括年龄在65岁或以上的房颤患者的Medicare受益人,他们在2012年1月1日至2020年11月29日期间开始使用阿哌沙班或利伐沙班,并开始使用地尔硫卓或美托洛尔治疗。到2020年11月30日,对患者进行了365天的随访。对2023年8月至2024年2月的数据进行了分析。
    地尔硫和美托洛尔。
    主要结局是出血相关住院和死亡的复合结果,最近有出血证据。次要结果为缺血性卒中或全身性栓塞,主要缺血性或出血性事件(缺血性卒中,全身性栓塞,颅内或致命的颅外出血,或最近有出血迹象的死亡),和没有最近出血证据的死亡。危险比(HR)和比率差异(RD)进行了校正,以重叠加权的协变量差异。
    该研究包括204155名美国医疗保险受益人,其中53275人接受地尔硫治疗,150880人接受美托洛尔治疗。研究患者(平均[SD]年龄,76.9[7.0]年;52.7%为女性)进行了90927人年(PY)的随访(中位数,120[IQR,59-281]天)。接受地尔硫治疗的患者主要结局的风险增加(RD,每1000日元10.6[95%CI,7.0-14.2];HR,1.21[95%CI,1.13-1.29])及其出血相关住院的组成部分(RD,每1000日元8.2[95%CI,5.1-11.4];HR,1.22[95%CI,1.13-1.31])和近期出血证据的死亡(RD,每1000日元2.4[95%CI,0.6-4.2];HR,1.19[95%CI,1.05-1.34])与接受美托洛尔的患者相比。初始剂量超过120mg/d的主要结局风险(RD,每1000日元15.1[95%CI,10.2-20.1];HR,1.29[95%CI,1.19-1.39])大于低剂量(RD,每1000日元6.7[95%CI,2.0-11.4];HR,1.13[95%CI,1.04-1.24])。剂量超过120mg/d时,严重缺血或出血事件的风险增加(HR,1.14[95%CI,1.02-1.27])。在没有近期出血证据的情况下,两个剂量组缺血性卒中或全身性栓塞或死亡的风险均无显著变化。当直接比较接受高剂量和低剂量地尔硫治疗的患者时,主要结局的HR为1.14(95%CI,1.02-1.26).
    在接受阿哌沙班或利伐沙班治疗的房颤患者中,地尔硫与美托洛尔相比,严重出血的风险更大,特别是地尔硫卓剂量超过120毫克/天。
    Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation.
    To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol.
    This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024.
    Diltiazem and metoprolol.
    The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting.
    The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26).
    In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.
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  • 文章类型: Randomized Controlled Trial
    在过去,腰方阻滞(QLB)主要用于患者的术后镇痛,很少有麻醉师在手术过程中使用无阿片类药物麻醉(OFA)。因此,目前尚不清楚仰卧位的QLB是否能在OFA策略下提供完美的镇痛和抑制麻醉应激。观察超声引导下OFA仰卧位腰方肌阻滞(US-QLB)用于下腹部及盆腔手术的临床疗效。选取2021年3月至2022年7月在万宁市人民医院行下腹部或盆腔手术的患者122例,按随机数字表法分为腰方肌阻滞组(Q组,n=62)和对照组(C组,n=60)。两组均采用仰卧位全麻联合QLB。镇静后,根据手术领域的需要,在局部麻醉下,基于类似于"人眼"和"摇篮中婴儿"的图像,通过超声引导前路进行单侧或双侧QLB.Q组,每侧注射20ml稀释在生理盐水(NS)中的0.50%利多卡因和0.20%罗哌卡因。C组,将20ml的NS注射到每一侧。BP的值,HR,SPO2,SE,RE,SPI,NRS,管家得分,异丙酚的剂量,右美托咪定,和罗库溴铵,需要瑞芬太尼的患者数量,异丙酚,或者地尔硫卓,穿刺点,块平面,麻醉持续时间,导管拔除,并监测手术期间的清醒情况。一般数据无显著差异,需要额外瑞芬太尼的病例数量,异丙酚,或者地尔硫治疗,两组穿刺点和穿刺平面比较(P>0.05)。HR,SBP,T1时Q组DBP值高于C组;HR,SPI,SE,而在T3,SE时,Q组的RE值低于C组,在T4和T5时,Q组Steward评分高于C组,差异有统计学意义(P<0.05)。Q组拔管时间和清醒时间均低于C组,差异有统计学意义(P<0.05)。TheSE,RE,T1、T2、T3和T4时的SPI值低于T0时的SPI值。Q组T4和T5时Steward评分高于C组,均低于T0时,差异有统计学意义(P<0.05)。两组在t1、t3、t4时的术后镇痛效果比较,差异均有统计学意义(P<0.05)。OFA仰卧位的US-QLB对下腹部或骨盆手术患者有效,术中生命体征稳定,完全恢复和更好的术后镇痛。
    In the past, quadratus lumborum block (QLB) was mostly used for postoperative analgesia in patients, and few anesthesiologists applied it during surgery with opioid-free anesthesia (OFA). Consequently, it is still unclear whether QLB in the supine position can provide perfect analgesia and inhibit anesthetic stress during surgery under the OFA strategy. To observe the clinical efficacy of ultrasound-guided quadratus lumborum block (US-QLB) in the supine position with OFA for lower abdominal and pelvic surgery. A total of 122 patients who underwent lower abdominal or pelvic surgery in People\'s Hospital of Wanning between March 2021 and July 2022 were selected and divided into a quadratus lumborum block group (Q) (n = 62) and control group (C) (n = 60) according to the random number table method. Both groups underwent general anesthesia combined with QLB in the supine position. After sedation, unilateral or bilateral QLB was performed via the ultrasound guided anterior approach based on images resembling a \"human eye\" and \"baby in a cradle\" under local anesthesia according to the needs of the operative field. In group Q, 20 ml of 0.50% lidocaine and 0.20% ropivacaine diluted in normal saline (NS) were injected into each side. In group C, 20 ml of NS was injected into each side. The values of BP, HR, SPO2, SE, RE, SPI, NRS, Steward score, dosage of propofol, dexmedetomidine, and rocuronium, the number of patients who needed remifentanil, propofol, or diltiazem, puncture point, block plane, duration of anesthesia, catheter extraction, and wakefulness during the operation were monitored. There were no significant differences in the general data, number of cases requiring additional remifentanil, propofol, or diltiazem treatment, as well as puncture point and puncture plane between the two groups (P > 0.05). HR, SBP, and DBP values were higher in group Q than in group C at T1; HR, SPI, and SE, while RE values were lower in group Q than in group C at T3, SE, and RE; the Steward score was higher in group Q than in group C at T4 and T5, and the difference was statistically significant (P < 0.05). The extubation and awake times were lower in group Q than in group C, and the difference was statistically significant (P < 0.05). The SE, RE, and SPI values were lower at T1, T2, T3, and T4 than at T0. The Steward scores at T4 and T5 were higher in group Q than in group C, and were lower than at T0, with a statistically significant difference (P < 0.05). There were significant differences in the effectiveness of postoperative analgesia between the two groups at t1, t3 and t4 (P < 0.05). US-QLB in the supine position with OFA is effective in patients undergoing lower abdominal or pelvic surgery with stable intraoperative vital signs, complete recovery and better postoperative analgesia.
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  • 文章类型: Meta-Analysis
    抗凝相关的消化道出血(GIB)可能有许多预测因子,但直到现在,对证据确定性的系统评价和评估尚未公布。我们进行了系统评价,以确定抗凝相关GIB的所有危险因素,以告知抗凝相关GIB管理的风险预测。
    进行了系统评价和荟萃分析,以搜索PubMed,EMBASE,WebofScience,和CochraneLibrary数据库(从成立到2022年1月21日)使用以下搜索词:抗凝剂,肝素,华法林,达比加群,利伐沙班,阿哌沙班,DOAC,消化道出血,风险因素。根据纳入和排除标准,确定了抗凝相关GIB的危险因素研究.抗凝相关GIB的危险因素被用作本综述的结果指标。
    我们在分析中纳入了34项研究。对于抗凝剂相关的GIB,中度确定性证据显示可能与年龄有关,肾病,同时使用阿司匹林,同时使用抗血小板药,心力衰竭,心肌梗塞,便血,肾功能衰竭,冠状动脉疾病,幽门螺杆菌感染,社会风险因素,酒精使用,吸烟,贫血,睡眠呼吸暂停的病史,慢性阻塞性肺疾病,国际标准化比率(INR),肥胖等。其中一些因素不包括在当前的GIB风险预测模型中。比如贫血,吉非贝齐的共同给药,联合使用维拉帕米或地尔硫卓,INR,心力衰竭,心肌梗塞,等。
    研究发现贫血,吉非贝齐的共同给药,联合使用维拉帕米或地尔硫卓,INR,心力衰竭,心肌梗死等。与抗凝相关的GIB,这些因素不在现有的预测模型中。这项研究提供了抗凝剂相关GIB的风险预测,它还为GIB预防和未来研究提供了指导.
    There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify all risk factors for anticoagulant-associated GIB to inform risk prediction in the management of anticoagulation- related GIB.
    A systematic review and meta-analysis were conducted to search PubMed, EMBASE, Web of Science, and Cochrane Library databases (from inception through January 21, 2022) using the following search terms: anticoagulants, heparin, warfarin, dabigatran, rivaroxaban, apixaban, DOACs, gastrointestinal hemorrhage, risk factors. According to inclusion and exclusion criteria, studies of risk factors for anticoagulation-related GIB were identified. Risk factors for anticoagulant-associated GIB were used as the outcome index of this review.
    We included 34 studies in our analysis. For anticoagulant-associated GIB, moderate-certainty evidence showed a probable association with older age, kidney disease, concomitant use of aspirin, concomitant use of the antiplatelet agent, heart failure, myocardial infarction, hematochezia, renal failure, coronary artery disease, helicobacter pylori infection, social risk factors, alcohol use, smoking, anemia, history of sleep apnea, chronic obstructive pulmonary disease, international normalized ratio (INR), obesity et al. Some of these factors are not included in current GIB risk prediction models. such as anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction, etc.
    The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.
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  • 文章类型: Randomized Controlled Trial
    背景:目前,手术期间没有监测有害刺激的黄金标准,手术面积指数(SPI)只是众多监测方法中的一种。它通常用于常规阿片类麻醉的监测,但其在无阿片类药物麻醉(OFA)中的有效性尚未评估。因此,本研究的目的是观察手术面积指数在无阿片类药物麻醉下腹部或盆腔手术患者中的指导价值.
    方法:选取2021年3月至2022年7月在我院行下腹部或盆腔手术的患者122例,按随机数字表法平均分为OFA(F)组和对照组(C)。两组均根据手术野采用超声引导下仰卧位单侧/双侧腰方肌阻滞。F组,每侧注射0.50%利多卡因和0.20%罗哌卡因(在20mL的0.9%生理盐水中)。C组,每侧注射20mL0.9%生理盐水。F组接受无阿片类药物的全身麻醉,C组接受阿片类药物的全身麻醉。BP,脉搏氧饱和度,PETCO2,反应熵,状态熵,和SPI值;Steward评分;丙泊酚剂量,右美托咪定,罗库溴铵,监测两组的拔管时间和清醒时间。
    结果:两组一般资料比较差异无统计学意义(P>.05)。在T0,T1,T2,T3,T4和T5的SPI值或需要额外瑞芬太尼的病例数没有显着差异,异丙酚,两组间地尔硫(P>.05)。状态熵,反应熵,在T4和T5时,F组的Steward评分高于C组,而F组的拔管和清醒时间低于C组(P<0.05)。T3时,F组心率和SPI低于C组(P<0.05)。
    结论:SPI在OFA中的指导价值与其在阿片类麻醉中的应用相似。其临床疗效确切,生命体征稳定,快速启用,完全恢复意识。
    BACKGROUND: Currently, there is no gold standard for monitoring noxious stimulation during surgery, and the surgical pleth index (SPI) is only one of many monitoring methods. It is commonly used in the monitoring of conventional opiate anesthesia, but its effectiveness in opioid-free anesthesia (OFA) has not been evaluated. Therefore, the aim of this study was to observe the guidance value of the surgical pleth index in opioid-free anesthesia for patients undergoing lower abdominal or pelvic surgery.
    METHODS: A total of 122 patients who underwent lower abdominal or pelvic surgery in our hospital between March 2021 and July 2022 were selected and equally divided into OFA (F) and control (C) groups according to the random number table method. Both groups underwent ultrasound-guided unilateral/bilateral quadratus lumborum block in the supine position according to the surgical field. In group F, 0.50% lidocaine and 0.20% ropivacaine (in 20 mL of 0.9% normal saline) were injected on each side. In group C, 20 mL 0.9% normal saline was injected on each side. Group F received general anesthesia without opioids and group C received general anesthesia with opioids. BP, pulse oxygen saturation, PETCO2, reactionentropy, stateentropy, and SPI values; Steward score; dosage of propofol, dexmedetomidine, rocuronium, and diltiazem; extubation time; and awake time were monitored in both groups.
    RESULTS: There were no significant differences in the general data between the 2 groups (P > .05). There were no significant differences in SPI values at T0, T1, T2, T3, T4, and T5 or the number of cases requiring additional remifentanil, propofol, and diltiazem between the 2 groups (P > .05). The stateentropy, reactionentropy, and Steward scores were higher in group F than in group C at T4 and T5, while the extubation and awake times were lower in group F than in group C (P < .05). The heart rate and SPI of group F were lower than that of group C at T3 (P < .05).
    CONCLUSIONS: The guiding value of SPI in OFA was similar to its use in opiated anesthesia. Its clinical efficacy is exact, vital signs are stable, enabling rapid, and complete regaining of consciousness.
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  • 文章类型: Journal Article
    暂无摘要。
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  • 文章类型: Letter
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  • 文章类型: Clinical Trial
    在这项研究中,作者试图研究镁单独或与地尔硫卓和/或胺碘酮联合使用在预防非体外循环冠状动脉旁路移植术(CABG)后房颤(AF)中的作用。
    CABG后房颤是常见的,并导致发病率和死亡率。各种药理预防措施,包括镁,胺碘酮,地尔硫卓,已尝试联合治疗以降低AF的发生率。大多数研究是在接受常规泵上CABG的患者中进行的。在这场不受控制的审判中,在接受非体外循环CABG的患者中,研究了单独使用镁或与胺碘酮和/或地尔硫卓联合使用的疗效.
    将150例接受非体外循环CABG的患者分为3组,M组(n=21)在中线胸骨切开术后1小时内接受30mg/kg的术中镁输注;MD组(n=78)在整个术中期间以类似的方式输注镁,并以0.05μg/kg/hr的剂量输注地尔硫卓;AMD组(n=51)接受术前口服胺碘酮,每天三次,持续3天,然后每天200mg,然后每天两次,再进行200mg持续超过10分钟或需要医疗干预的AF被认为是AF。
    术后房颤总发生率为12.6%,AMD组为11.7%,M组19%,MD组为11.5%,这没有统计学意义。
    得出的结论是,除了镁之外,胺碘酮和/或地尔硫卓的使用并未导致降低AF发生率的额外益处。
    In this study the authors have tried to examine the role of magnesium alone or in combination with diltiazem and / or amiodarone in prevention of atrial fibrillation (AF) following off-pump coronary artery bypass grafting (CABG).
    AF after CABG is common and contributes to morbidity and mortality. Various pharmacological preventive measures including magnesium, amiodarone, diltiazem, and combination therapy among others have been tried to lower the incidence of AF. Most of the studies have been performed in patients undergoing conventional on-pump CABG. In this uncontrolled trial, efficacy of magnesium alone or in combination with amiodarone and / or diltiazem has been studied in patients undergoing off-pump CABG.
    One hundred and fifty patients undergoing off-pump CABG were divided into 3 groups, Group M (n=21) received intraoperative magnesium infusion at 30mg/ kg over 1 hour after midline sternotomy; Group MD (n=78) received magnesium infusion in similar manner with diltiazem infusion at 0.05 μg/kg/hr throughout the intraoperative period; Group AMD (n=51) received preoperative oral amiodarone at a dose of 200 mg three times a day for 3 days followed by 200 mg twice daily for another 3 days followed by 200 mg once daily till the day of surgery along with magnesium and diltiazem infusion as in other groups. AF lasting more than 10 min or requiring medical intervention was considered as AF.
    The overall incidence of postoperative AF was 12.6% with 11.7% in group AMD, 19% in group M, and 11.5% in group MD, which was not statistically significant.
    It is concluded that the use of amiodarone and/or diltiazem in addition to magnesium did not result in additional benefit of lowering the incidence of AF.
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  • 文章类型: Case Reports
    氯氮平可能与显着的副作用和耐受性问题有关。由于氯氮平具有显著的抗胆碱能活性,多汗症的发生率较低,临床医生无法预料。
    一名34岁女性夜间发展氯氮平,在初始滴定至400mg/天之后的全身性多汗症。剂量减少不会降低副作用。由于便秘,无法开始抗胆碱能药物治疗。用β受体阻滞剂治疗导致哮喘恶化。用钙通道阻滞剂治疗,地尔硫卓CD180毫克/天,导致多汗症的显著减少。
    该案例支持使用钙通道阻滞剂来减少氯氮平诱导的多汗症,并提供了可能对氯氮平耐受性产生负面影响的抗胆碱能药物的替代方案。
    UNASSIGNED: Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of clozapine\'s significant anticholinergic activity.
    UNASSIGNED: A 34-year-old female developed clozapine-induced nocturnal, generalized hyperhidrosis following initial titration to 400 mg/day. Dose reduction did not decrease the side effect. Treatment with an anticholinergic medication could not be initiated because of constipation. Treatment with a beta blocker resulted in worsening of asthma. Treatment with a calcium channel blocker, diltiazem CD 180 mg/day, resulted in a significant reduction in hyperhidrosis.
    UNASSIGNED: This case supports the use of calcium channel blockers to reduce clozapine-induced hyperhidrosis and offers an alternative to anticholinergic medications that may negatively impact clozapine tolerability.
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  • 文章类型: Journal Article
    Encorafenib是BRAFV600突变激酶的有效和选择性ATP竞争性抑制剂,已被批准用于BRAF突变黑色素瘤和结直肠癌患者。Encorafenib主要在体外被细胞色素P450(CYP)3A4代谢,当与CYP3A抑制剂或诱导剂共同给药时,可能对药物-药物相互作用敏感。主要目的是评估强CYP3A抑制剂泊沙康唑(第1部分)和中度CYP3A和P-gp抑制剂地尔硫卓(第2部分)对健康志愿者在单次50mg剂量后恩科拉非尼药代动力学的影响。共有32名参与者参加(第1部分和第2部分各16名)。曲线下面积外推到无穷大(AUCinf)和最大血浆浓度(Cmax)几何平均值恩科拉非尼增加了183%和68.4%,分别,与泊沙康唑共同给药时。当与泊沙康唑共同给药时,恩科非尼的表观清除率从26.0L/h降低到9.2L/h,恩可拉非尼的血浆终末半衰期(t½)从4.3小时增加到7.3小时。恩可拉非尼的AUCinf和Cmax几何平均值分别增加了83.0%和44.7%,分别,与地尔硫卓共同给药时。同样,与地尔硫卓共同给药时,表观恩科非尼清除率从29.0L/h降低至16.0L/h,恩可拉非尼的血浆t½从6.6小时增加到7.9小时。没有死亡,严重不良事件(AE),或由于第1部分或第2部分的AE而导致的患者停药。最常报告的治疗相关AE是第1部分的红斑(n=14;88%)和头痛(n=11;69%)以及第2部分的头痛(n=7;44%)。这项研究的结果表明,应避免恩可拉非尼与强或中度CYP3A4抑制剂的共同给药。
    Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUCinf ) and maximum plasma concentration (Cmax ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t½ ) of encorafenib increased from 4.3 to 7.3 h. The AUCinf and Cmax geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t½ of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.
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