巴马小型猪植入式遥测动物模型的建立及应用

目的 基于遥测技术建立适用于监测清醒自由活动状态下巴马小型猪心电、血压、体温等生理指标的动物模型,为其在安全药理学研究中的应用提供支持。方法 8只巴马小型猪（雌雄各半）经手术植入植入子,手术后恢复3~4周,经体格检查确认已完全恢复后,采用EMKA遥测系统连续监测至少24 h心电图、血压等生理指标,包括心率、PR间期、QRS间期、QT间期、校正QT （QTcv）间期、体温、收缩压（SBP）、舒张压（DBP）、平均动脉压（MBP）,并于次周重复监测1次。对巴马小型猪的24 h指标变化进行分析,并与Beagle犬和食蟹猴数据进行种属间比对分析。结果 巴马小型猪的心电数据和血压数据昼夜节律均不明显;体温呈现明显的昼夜节律,白天体温高,夜间体温低;动物的心率、血压和体温均受外界影响比较大,与动物的活动呈现明显的相关性;与Beagle犬和食蟹猴比较,巴马小型猪的心率和人类最为相似,SBP仅稍高于人类。结论 通过体内植入植入子,成功建立了巴马小型猪植入式遥测动物模型;与Beagle犬和食蟹猴比较,巴马小型猪更适合用于药物对心血管系统影响的评价。     

盐酸莫西沙星对清醒Beagle犬肢体Ⅱ导联心电图的影响

目的观察单次灌胃给予盐酸莫西沙星片对清醒Beagle犬肢体Ⅱ导联心电图(ECG-Ⅱ)各指标的影响,重点观察其引起的QT、QTc波动,为其作为验证心电图遥测系统阳性药物的可能性提供参考。方法取健康Beagle犬6只,雌雄各半,先后以10 mL·kg~(-1)的容积灌胃给予纯水和盐酸莫西沙星片药液(300 mg·kg~(-1));并用EMKA无创动物生理信号遥测系统记录清醒动物给药前和给药后约330min的ECG-Ⅱ数据,并每间隔30 min测定ECG-Ⅱ各指标1次。结果莫西沙星组动物给药后所有测量点的QT和QTc均明显延长(P<0.05,P<0.01),变化率为10%~40%,但其他指标没有明显改变(P>0.05)。结论盐酸莫西沙星片300 mg·kg-1可引起犬QT和QTc明显延长且具有良好的时间-反应趋势,可作为阳性药物用于ECG-Ⅱ检测设备的验证。     

莫西沙星致不良反应165例分析

摘 要 目的:探讨莫西沙星所致不良反应特点及相关因素,为临床合理用药提供参考。方法：在鼓楼医院2008年5月6日～2013年5月6日上报的不良反应报表中,检索由莫西沙星引起的不良反应,对患者用药情况、性别、年龄、不良反应表现等方面进行统计分析。结果：检索到莫西沙星引起的不良反应165例,其中口服莫西沙星片所致不良反应35例,莫西沙星针剂130例,涉及消化系统、神经系统、心血管系统等系统。结论：临床应重视莫西沙星发生的不良反应,用药时注意患者的临床表现,监测患者肝、肾功能。     

清醒Beagle犬呼吸和循环系统功能监测模型建立及生物学特性分析

目的:应用植入式遥测技术,建立Beagle犬清醒动物呼吸和循环系统功能检测模型,应用遥测技术对Beagle犬生理参数进行长时程采集和分析,为临床前药物安全性评价试验提供重要的生理基础参考值。方法:通过外科手术,在Beagle犬体内埋植TL11M3-D70-PCTP遥测传感器,以DSI遥测生理信号采集系统连续记录并分析Beagle犬在无束缚条件下24 h生理信号,分析其昼夜节律,并以特非那定作为阳性药物进行验证。结果:成功建立了Beagle犬植入式清醒动物模型,Beagle犬的生理活动具有明显的昼夜节律性,早上09:00左右是多项生理指标的最高点,特非那定能够明显延长Beagle犬的QTc间期。结论:试验获得了本中心GLP试验室饲养条件下动物的基础值,可为其在药物临床前试验中的应用提供重要的参考数据。     

2016—2019年东莞市人民医院莫西沙星不良反应分析

目的 了解南方医科大学附属东莞医院莫西沙星药品不良反应（ADR）的特点及有关因素,为莫西沙星的临床合理用药治疗提供一定的参考。方法 对南方医科大学附属东莞医院2016—2019年医院电子病历系统收录的莫西沙星的药品不良反应病例进行回顾性的分析总结,分析不良反应的规律及其相关因素。结果 共收集5 986例莫西沙星药物使用病例,关于不良反应的有132例;其中一般ADR出现119例（90.15%）,严重ADR出现13例（9.85%）;ADR主要发生在36～59岁和≥60岁的中老年患者;静脉给药的有129例（97.73%）,口服给药的有3例（2.27%）。ADR涵盖了皮肤及其附件系统、神经系统、消化系统、心血管系统;发生ADR后,患者停药处理后均痊愈或好转,无出现后遗症患者。结论 莫西沙星的ADR发生率较少,严重ADR发生率较低,但存在着新的ADR,临床医护人员应该有着足够的重视,确保安全、合理地使用该药。     

牛蒡子苷元注射液对清醒Beagle犬心血管系统和呼吸系统的影响

目的通过对预先埋植有DSI遥测植入子的清醒Beagle犬皮下注射给予牛蒡子苷元注射液(NBZGY),评价对Beagle犬心血管系统和呼吸系统产生的潜在影响。方法采用8只已经成功埋植DSI遥测植入子(TL11M2-D70-PCTR)的Beagle犬,皮下注射给予NBZGY(0.05~5 mg·kg-1),每只清醒Beagle犬将在4个独立的给药日分别给予溶媒及3个剂量的NBZGY,每次给药间隔(含给药日)为2天。通过生理信号遥测系统连续测量和记录给药前、给药后1、1.5、2、3、4、5、6、12、24 h的心电(RR间期、心率、T波振幅、ST段、QRS间期、PR间期、QT间期)、体温、血压(收缩压、舒张压、平均压)、呼吸(潮气量、呼吸频率)等指标。结果给药后1、2、24 h,部分指标与同期溶媒对照组相比具有统计学意义(P<0.05),但因差异无剂量依赖性,故无生物学意义。结论本实验条件下,Beagle犬皮下注射给予NBZGY,心血管系统和呼吸系统均未见与供试品相关的明显改变。     

基于遥测系统测定戊巴比妥钠对Beagle犬心血管及呼吸系统的影响

摘 要 目的：探讨戊巴比妥钠对Beagle犬麻醉状态下心血管及呼吸系统的影响。 方法: Beagle犬随机分为对照组和麻醉药组,每组4只,清醒状态下分别静脉注射生理盐水1 ml·kg-1和戊巴比妥钠30 mg·kg-1。给药后0.5,1,1.5,2,4 h分别使用emkaPACK 4G遥测系统测定心电图（QRS波群、QT间期）、心率、呼吸频率、收缩压、舒张压、平均压。 结果: 给药后0.5 h,麻醉药组呼吸频率指标低于对照组,QRS指标高于对照组,体现出麻醉药初期呼吸频率快速降低,并出现QRS间期延长;给药后1 h,麻醉药组呼吸频率、心率、QRS和QT指标均高于对照组;随着药物作用时间延长,呼吸频率明显提高,心率增加明显,同时出现QRS和QT延长;给药后1.5 h,麻醉药组QRS指标高于对照组;给药后2 h,麻醉药组平均压、QRS和QT指标高于对照组;给药后4 h,麻醉药组舒张压和QRS指标高于对照组(P<0.05)。 结论: 戊巴比妥钠会增加动物的血压,延长动物的QRS和QT间期;初期降低呼吸频率。对血压和QRS影响时间较长,大于4 h。     

盐酸苯海拉明/咖啡因复方的安全药理学研究

目的 观察盐酸苯海拉明/咖啡因复方对小鼠神经系统及Beagle犬心血管系统、呼吸系统的影响,为临床安全用药提供参考。方法 观察盐酸苯海拉明/咖啡因复方单次灌胃给药对小鼠爬杆能力的影响,以及对Beagle犬血压、心电图、呼吸频率和幅度的影响。结果 盐酸苯海拉明/咖啡因复方（盐酸苯海拉明与咖啡因之比为1:2.4）给药剂量在51、102、204mg/kg时,对小鼠的爬杆能力无明显影响。给药剂量雄性在14.2、28.3、56.6 mg/kg、雌性在5.66、14.2、28.3 mg/kg时,对Beagle犬收缩压、舒张压、平均动脉压、心率、ECG（P波电压、R波电压、T波电压、QRS时间、PR间期、QT间期）、呼吸频率和幅度无明显影响。结论 本实验条件下,单次灌胃给予盐酸苯海拉明/咖啡因复方对实验动物神经系统、心血管系统、呼吸系统无明显影响,提示盐酸苯海拉明/咖啡因复方具有较高的安全性。     

金丝桃苷的一般药理学研究

目的 观察金丝桃苷对实验动物中枢神经系统、呼吸系统、心血管系统的影响。方法 以低、中、高剂量(12.5、60.0、300.0 mg/kg)金丝桃苷ig给予BALB/c小鼠,观察小鼠的一般行为、自主活动、入睡只数、入睡时间和协调运动,考察其对小鼠中枢神经系统的影响;以低、中、高剂量(2、12、65 mg/kg)金丝桃苷对麻醉Beagle犬十二指肠给药,观察给药前后麻醉犬的呼吸频率、呼吸幅度、收缩压(SBP)、舒张压(DBP)、平均血压(MBP)、心率(HR)、Ⅱ导联心电图QT间期、QRS波群时间、PR间期、ST段偏移幅度等相关指标的变化,考察其对Beagle犬呼吸系统及心血管系统的影响。结果 与对照组比较,用药后各组小鼠中枢神经系统,Beagle犬呼吸幅度、呼吸频率、血压、心率、心电图均无明显变化。结论 金丝桃苷对小鼠中枢神经系统、Beagle犬呼吸系统及心血管系统均无明显影响,提示其不良反应小。     

戴蒙开颗粒对比格犬和小鼠的一般药理学研究

目的 观察戴蒙开颗粒对麻醉犬心血管系统、呼吸系统,对小鼠神经系统的影响。方法 戊巴比妥钠麻醉犬,经十二指肠给予戴蒙开颗粒,记录给药前及给药后30、60、120、180、210、240 min舒张压（SBP）、收缩压（DBP）、平均动脉压（MBP）、心率（HR）、心电图（T波振幅,ST段偏移,PR间期,QRS时限和QT间期）、呼吸频率、呼吸深度的变化。采用灌胃给药,观察戴蒙开颗粒对小鼠阈下睡眠剂量戊巴比妥钠催眠作用、协调运动、一般行为和自发活动的影响。结果 戴蒙开颗粒低、中、高等不同剂量组的比格犬SBP、DBP、MBP、HR、PR间期,QRS时限、QT间期、T波、呼吸频率和呼吸深度等指标均未见明显变化,与对照组相比,P>0.05。戴蒙开颗粒高剂量组和阳性对照组的翻正反射消失率均极显著性的升高（P<0.01）;各剂量、各时间点小鼠协调运动障碍的评级与阴性组比较均无显著性差异（P>0.05）;戴蒙开颗粒低剂量组在给药后90 min自发活动数显著性地降低（P<0.05）,戴蒙开颗粒高剂量组在给药后30、60、90 min自发活动数均极显著性地降低（P<0.01）。结论 戴蒙开颗粒对比格犬心血管系统、呼吸系统未见明显影响;戴蒙开颗粒中、低剂量对小鼠神经系统未见明显影响。     

QT PRODACT: sensitivity and specificity of the canine telemetry assay for detecting drug-induced QT interval prolongation

The purpose of this investigation was to define the sensitivity and specificity of the canine telemetry assay for detecting drug-induced QT interval prolongation. Data from twelve studies generated in the QT PRODACT project were used in this investigation. The study design was a 4x4 Latin square cross-over design and included the following drugs: MK-499, E-4031, terfenadine, haloperidol, cisapride, bepridil, propranolol, diphenhydramine, captopril, verapamil, amoxicillin, and ciprofloxacin. The estimated root squared error of the model, which estimated the slope of the QT-RR relationships for each animal, for all dogs during the pre-dosing period was 5.45%. Using the QT-RR model, the sensitivity and specificity in each cutoff value that judges QT prolongation were estimated based on the experiment errors and measurement errors in the 12 studies. When the cutoff value was 5%, the sensitivity in 10% prolongation was 0.978 and the specificity in 0% was 0.996. In conclusion, it was judged that a 5% cutoff value for changes in heart rate corrected QT interval using the canine telemetry assay is practical, and the sensitivity and specificity of the telemetry assay are very high when using the analytical method presented here. Based upon this information, the canine telemetry assay using the individual subject heart rate correction model is recommended as a sensitive test system for the in vivo assessment of risk for QT interval prolongation.     

Sensitivity and Reliability of Halothane‐anaesthetized Microminipigs to Assess Risk of Drug‐induced Long QT Syndrome

Using moxifloxacin and terfenadine, which are known to induce benign and malignant QT interval prolongation, respectively, we analysed whether halothane‐anaesthetized microminipigs are 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‐anaesthetized microminipigs (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 in microminipigs than those previously reported in dogs. These results indicate that halothane‐anaesthetized microminipigs would 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.     

清醒Beagle犬安全药理心血管呼吸遥测系统验证研究

目的选用呼吸系统阳性药对Beagle犬心血管呼吸遥测系统进行性能验证。方法 8只埋植植入子的清醒Beagle犬隔日依次静脉注射给予生理盐水、盐酸多沙普仑(4 mg·kg-1)、盐酸瑞芬太尼(4μg·kg-1)和盐酸索他洛尔(10 mg·kg-1)。实验时连续获取每次给药前至少2 h及给药后24 h内数据,包括血压、心电图、呼吸等指标。结果生理盐水对各参数无明显影响。呼吸兴奋药盐酸多沙普仑可导致动物呼吸频率和潮气量明显增加,伴有血压及心率的增加。呼吸抑制药盐酸瑞芬太尼可导致动物呼吸潮气量明显减少,对呼吸频率作用不明显。QT间期(QTcf)延长阳性药盐酸索他洛尔可导致动物心电图心率校正的QTcf明显延长,最大变化率约11%。结论本系统可灵敏检测到心血管、呼吸系统的相关变化,可用于清醒动物心血管呼吸系统安全药理学研究。     

Aclidinium bromide, a long-acting antimuscarinic, does not affect QT interval in healthy subjects

In this phase I trial, the effect of aclidinium, a novel, inhaled long-acting muscarinic antagonist, on QT interval was evaluated, and its cardiovascular safety was assessed in 272 healthy subjects. Aclidinium 200 μg, aclidinium 800 μg, matching placebo, or open-label moxifloxacin 400 mg was administered daily for 3 days. The primary outcome was mean change in individual heart rate-corrected QT interval (QTcI). Secondary measures included Bazett-corrected QT interval (QTcB), Fridericia-corrected (QTcF) intervals, 12-lead electrocardiogram (ECG) readings, and 24-hour 12-lead Holter ECG parameters. Adverse events, vital signs, and laboratory and pharmacokinetic parameters were also assessed. Maximum mean QTcI change from time-matched baseline on day 3 was -1.0 milliseconds at 2 hours for aclidinium 200 μg, -1.8 milliseconds at 5 minutes for 800 μg, +11.0 milliseconds at 4 hours for moxifloxacin, and -1.2 milliseconds at 23.5 hours for placebo. Aclidinium had no significant effects on secondary ECG measures. Aclidinium plasma concentrations were generally below the lower limit of quantitation (0.05 ng/mL) after 200 μg and were detected only up to 1 hour after the 800-μg dose in the majority of cases. It is concluded that aclidinium bromide, at doses up to 800 μg, has a favorable cardiovascular safety profile with no effect on QT interval.     

A Comparative Pharmacokinetic-Pharmacodynamic Study of the Electrocardiographic Effects of Epinastine and Terfenadine in Rats

The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective. Epinastine hydrochloride (1 or 3 mg kg^?1 h^?1) or terfenadine (5, 10 or 15 mg kg^?1 h^?1) was intravenously infused into rats anaesthetized with urethane and α-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner; its EC50 value was 792–1039 ng mL^?1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100–200 ng mL^?1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL^?1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man. We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.     

Improving the detection of subtle I(Kr)-inhibition: assessing electrocardiographic abnormalities of repolarization induced by moxifloxacin.

BACKGROUND: QT prolongation is an incomplete measure of drug-induced changes in repolarization. In this study, we investigated a novel, automatic ECG technique for describing ventricular repolarization morphology and we compared these results to corrected QT (QTc) prolongation for identifying ECGs of healthy individuals on moxifloxacin. METHODS: We analysed data from the US FDA ECG Warehouse involving 160 standard ECGs from 40 healthy subjects enrolled in a randomized, parallel, placebo-controlled, 'thorough QT' study. Computerized ECG analysis included a series of scalar and vectorial parameters describing duration of repolarization segments and T-wave/loop morphology including its symmetry, amplitude and shape. Binary logistic models for the identification of moxifloxacin-induced abnormalities of the repolarization were developed. RESULTS: Moxifloxacin induced significant changes in several ECG parameters including QT and QT apex and early repolarization duration (ERD)(30)(%), T-wave amplitude and slopes of the ascending and descending arm of the T-wave. The logistic model based only on T-wave morphology parameters outperformed the model based on QTc interval for identifying the presence of moxifloxacin. Combining information about repolarization interval duration with T-wave morphology significantly improved the detection of presence of moxifloxacin (p < 0.01). The increased sensitivity of our novel ECG method contributes to a >40% reduction in the sample size required to detect significant QTc prolongation induced by moxifloxacin. CONCLUSIONS: Repolarization morphology is significantly altered by moxifloxacin. The computerized ECG technique provides a novel method for quantifying morphological changes of repolarization segment. Our new parameters reflecting the morphology of the T-wave outperformed QTc measurements when identifying moxifloxacin-induced blockade of the outward rapid components of the delayed rectifier repolarizing potassium current (I(Kr)). These data indicate that the analysis of T-wave morphology could play a role in the assessment of drug toxicity.     

HR0905安全药理学研究

目的观察HR0905对小鼠神经系统、犬心血管系统及呼吸系统的影响。方法实验均分HR0905高、中、低剂量组及溶媒对照共4个组,小鼠实验给药组分别单次灌胃（ig）HR0905 30,100和300 mg/kg,观察药物对小鼠自发活动和爬杆能力的影响;犬实验给药组分别单次igHR0905 2、6、20 mg/kg,观察药物对犬血压、ECG、呼吸频率及节律的影响。结果与溶媒对照组相比,HR0905单次ig后高剂量组爬杆能力显著下降;给药后1.5 h开始动物自发活动有下降趋势,且3.5 h下降最多;HR0905单次ig后犬心率明显减慢。给药后2.0 h中剂量组及高剂量组Beagle犬收缩压、舒张压及平均动脉压有下降趋势,且4.0 h下降幅度最大。HR0905对Beagle犬ECG之P波电压、T波电压、QRS时间、PR间期、QT间期、ST段无明显影响;HR0905对呼吸频率、幅度和节律无明显影响。结论 HR0905对心血管和神经系统有一定的影响,可使犬心率减慢,犬收缩压、舒张压及平均动脉压有下降趋势,小鼠爬杆能力显著下降,自发活动有下降趋势。     

Development of telemetry system in the common marmoset--cardiovascular effects of astemizole and nicardipine

The purpose of this study was to evaluate a telemetry system for examining the cardiovascular system in the conscious common marmoset. Parameters obtained were blood pressure, heart rate, respiratory rate, ECG, body temperature and locomotor activity, and these were continuously recorded on a data recorder via the telemetry system and then processed by a computerized system. Diurnal rhythms of blood pressure, heart rate, body temperature and locomotor activity were observed in this system. We studied the effects of astemizole (antihistamine) and nicardipine (Ca2+ channel blocker) on cardiovascular parameters. Astemizole at 30 mg/kg (p.o.) and at 1 to 3 mg/kg (i.v.), prolonged QT interval and induced ventricular extrasystole. Torsades de pointes occurred in one of three cases at 3 mg/kg (i.v.) and 30 mg/kg (p.o.), while it did not affect the blood pressure, respiratory rate and body temperature. Nicardipine at 30 mg/kg (p.o.) caused sustained hypotension and tachycardia. These results demonstrate the usefulness of the telemetry system using the common marmoset for evaluating the cardiovascular effects of drugs under physiological conditions.