Sensitivity and reliability of halothane-anesthetized microminipigs to assess risk for drug-induced long QT syndrome
Sensitivity and reliability of halothane-anesthetized microminipigs to assess risk for drug-induced long QT syndrome
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氟烷麻醉微型猪评估药物引起的长 QT 综合征风险的敏感性和可靠性
DOI：
10.1111/bcpt.12838
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发表时间：
2017
影响因子：
3.1
通讯作者：
Sugiyama A
中科院分区：
文献类型：
--
作者：
Cao X;Wada T;Nakamura Y;Matsukura S;Izumi-Nakaseko H;Ando K;Naito AT;Sugiyama A
使用已知可分别诱导良性和恶性QT间期延长的利多卡因和特非那定，我们分析了氟烷麻醉的微型猪是否是评估药物诱导的长QT综合征风险的合适模型。莫西沙星（0.03、0.3和3 mg/kg）和特非那定（0.03、0.3和3 mg/kg）静脉输注10 min。暂停20分钟。氟烷麻醉的微型猪（每种药物n = 4）。莫西沙星可降低心率，但以剂量相关方式升高血压。它还以剂量相关方式延长PR间期和QT/QTc，而不改变QRS宽度。特非那定可降低心率和血压，但以剂量相关方式延长PR间期、QRS宽度和QT/QTc。特非那定显著延长了QT间期的逐搏变异性，反映了其潜在的促心律失常作用，而阿氟沙星未观察到这一点。给药3 mg/kg后，在微型猪体内的达峰血药浓度分别为4.81和10.15 μg/mL，均比先前报道的犬体内的达峰血药浓度低1.5倍。这些结果表明，氟烷麻醉的微型猪可用于检测药物诱导的心血管反应，以及区分良性和恶性QT间期延长（如犬），尽管这些动物之间的药代动力学特征可能存在一些差异。
Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane‐anaesthetizedmicrominipigsare an appropriate model for assessing the risk of drug‐induced long QT syndrome. Moxifloxacin (0.03, 0.3 and 3 mg/kg) and terfenadine (0.03, 0.3 and 3 mg/kg) were intravenously infused over 10 min. with a pause of 20 min. to the halothane‐anaesthetizedmicrominipigs(n = 4 for each drug). Moxifloxacin decreased the heart rate, whereas it increased the blood pressure in a dose‐related manner. It also prolonged the PR interval and QT/QTc in a dose‐related manner without altering the QRS width. Terfenadine decreased the heart rate and blood pressure, whereas it prolonged the PR interval, QRS width and QT/QTc in a dose‐related manner. Terfenadine significantly prolonged the beat‐to‐beat variability of QT interval reflecting its pro‐arrhythmic potential, which was not observed with moxifloxacin. The peak plasma concentrations of moxifloxacin and terfenadine after doses of 3 mg/kg were 4.81 and 10.15 μg/mL, respectively, which were both 1.5 times less inmicrominipigsthan those previously reported in dogs. These results indicate that halothane‐anaesthetizedmicrominipigswould be useful for detecting drug‐induced cardiovascular responses as well as differentiating benign from malignant QT interval prolongation like dogs, although there may be some differences in pharmacokinetic profile between these animals.