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。     

速效抗晕胶囊的安全性药理研究

目的：观察速效抗晕胶囊对Beagle犬心血管系统、呼吸系统和小鼠神经系统的影响。方法：Beagle 犬实验分为低、中、高3个剂量和空白对照组,给药组分别单次给予速效抗晕胶囊5, 10和20 mg?kg-1（ig）,观察血压、心电图以及呼吸频率和节律。小鼠实验也分为低、中、高3个剂量和空白对照组,给药组分别单次给予速效抗晕胶囊20, 40和80 mg?kg-1（ig）,观察动物的自发活动、爬杆能力以及对阈下剂量戊巴比妥钠的协同作用。结果：速效抗晕胶囊5, 10和20 mg?kg-1单次给药对Beagle犬的收缩压、舒张压、平均动脉压、心率、心律、ECG的P波电压、T波电压、QRS时间、PR间期、QT间期、ST段、节律和幅度均无明显影响。与空白对照组相比,高剂量组犬60～120 min呼吸频率明显加快。速效抗晕胶囊20, 40和80 mg?kg-1单次给药对小鼠爬杆能力无明显影响,对阈下剂量戊巴比妥钠无明显协同作用。与空白对照组相比,高剂量组小鼠60～120 min自发活动明显增加。结论：速效抗晕胶囊对呼吸系统和神经系统有一定影响,20 mg?kg-1剂量可使犬呼吸频率加快,80 mg?kg-1剂量可使小鼠自发活动增加。     

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。     

欧前胡素急性毒性和安全药理学研究

目的观察欧前胡素对大、小鼠的急性毒性,以及对小鼠神经系统和犬心血管系统、呼吸系统的影响。方法通过腹腔内注射给药（ip）和灌胃给药（培）研究欧前胡素对小鼠的急性毒性,以及培对大鼠的急性毒性实验。安全药理学实验中以50、100、200mg／kg分别单次培给予小鼠欧前胡素,观察对小鼠神经系统的影响（包括小鼠自发活动、爬杆能力、小鼠阈下剂量戊巴比妥钠催眠协同实验）;以25、50、100mg／kg分别单次口服给药（po）欧前胡素,观察对犬心血管系统和呼吸系统的影响（包括心电图、血压、心率,以及呼吸频率、幅度、节律等指标）。结果欧前胡素培对小鼠的LD50为988．5mg/kg;ip对小鼠的LD50为603．3mg／kg;ig对大鼠的LD50为3188．7mg／kg。欧前胡素单次ig对小鼠神经系统无明显影响;单次po对犬心血管系统指标和呼吸系统指标无明显影响。结论欧前胡素安全范围较大,毒性较容易控制,且对正常动物（包括小鼠、大鼠和犬）的降压作用不显著,因此具有较大的临床应用可能性。     

原藜芦碱A对大鼠心血管系统和呼吸系统的影响

目的 观察藜芦主要成分原藜芦碱A对大鼠的心血管和呼吸系统的影响.方法 实验分低、中、高和空白对照组共4组,每组10只,雌雄各半,给药组分别单次ig原藜芦碱A 0.25,0.50和1.00 mg/kg,麻醉后行颈动脉插管术,观察原藜芦碱A对大鼠血压、ECG、呼吸频率及节律的影响.结果 原藜芦碱A给药后可降低大鼠收缩压、舒张压、平均动脉压,减慢心率,延长QTc间期;可使大鼠呼吸频率减慢,呼吸幅度加大.上述变化均存在量效关系,给药150 min内均可逐渐恢复.结论 原藜芦碱A对心血管和呼吸系统有一定的影响,能降低血压、减慢心率、延长QTc间期,能使呼吸频率减慢、呼吸幅度加大.     

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。     

重组人脑利钠肽安全药理学研究

目的:观察重组人脑利钠肽(rhBNP)对大鼠心血管、呼吸系统和对小鼠神经系统的影响。方法:大鼠实验分低、中、高3个剂量及空白对照共4个组,给药组分别单次静脉注射(iv)rhBNP 22．5,45．0和90．0μg·kg~(-1),对血压、心电图(ECG)、呼吸频率及节律进行观察。小鼠实验分低、中、高3个剂量及空白对照共4个组,给药组分别单次iv rhBNP 45．0,90．0和180．0μg·kg~(-1),对动物自发活动和爬杆能力进行观察。结果:rhBNP使大鼠收缩压、舒张压、平均动脉压降低,且存在量效关系,2h内上述指标基本恢复正常,对心率、心律、ECG之QRS时间、T波、ST段、呼吸频率、节律和幅度无明显影响。对小鼠自发活动和爬杆能力无明显影响。结论:rhBNP对心血管系统有一定影响,可使收缩压、舒张压、平均动脉压降低。     

蛇葡萄素钠的一般药理学研究

目的观察蛇葡萄素钠(sodiuum ampelopsin,AMP-Na)在不同剂量下对实验动物神经系统、呼吸系统、心血管系统的影响。方法小鼠iv AMP-Na 200,260和320 mg.kg-1,观察其对神经系统的影响;麻醉犬iv AMP-Na 45,82.2和150 mg.kg-1,观察其对呼吸系统、心血管系统的影响。结果 3个剂量组的AMP-Na分别对小鼠神经系统及犬呼吸系统无明显影响;45 mg.kg-1组对犬心血管系统亦无明显影响;但82.2和150 mg.kg-1(相当于临床患者用量15倍以上)可短暂性降低犬血压,尤其是舒张压,且减慢心率;150 mg.kg-1给药时可短暂缩短犬QRS群间期。结论 AMP-Na在药效剂量应用时比较安全,在大剂量应用时应注意对血压、心率的影响。     

亚硫酸氢钠穿心莲内酯的一般药埋学研究

目的观察亚硫酸氢钠穿心莲内酯对动物的一般药理作用。方法用抖笼法、爬杆法、游泳耗竭法及麻醉家犬静脉滴注等方法,观察亚硫酸氢钠穿心莲内酯对动物中枢神经系统、心血管及呼吸系统的影响。结果给小鼠静脉推注亚硫酸氢钠穿心莲内酯250、500mg/kg后,小鼠的自发活动明显减少。爬杆试验等级数和游泳耗竭时间与对照组比较无明显差异。小鼠静脉推注亚硫酸氢钠穿心莲内酯后加腹腔注射戊巴比妥钠(40mg/kg),500mg/kg组可缩短戊巴比妥钠入睡时间,250、500mg/kg组可延长睡眠持续时间。麻醉家犬静脉滴注亚硫酸氢钠穿心莲内酯后,对血压、心率、心律及心电图各波形未见有临床意义的改变,呼吸频率和深度也未见明显影响。结论亚硫酸氢钠穿心莲内酯对小鼠中枢神经系统具有明显的镇静作用,对小鼠的协调运动无明显影响,与戊巴比妥钠催眠作用有协同作用,麻醉家犬静脉滴注亚硫酸氢钠穿心莲内酯对心血管及呼吸系统均无明显影响。     

重组人甲状旁腺激素安全性药理学研究

目的:观察重组人甲状旁腺激素(rh-PTH)对大鼠心血管、呼吸系统和对小鼠神经系统的影响。方法:大鼠实验分高、中、低3个剂量及空白对照共4个组,给药组分别单次及连续7d皮下注射rh-PTH 160,80和40μg·kg~(-1),对血压、心电图(ECG)、呼吸频率及节律进行观察。小鼠实验分高、中、低3个剂量及空白对照共4个组,给药组分别单次及连续7d皮下注射rh-PTH 320,160,和80μg·kg~(-1),对动物自发活动和爬杆能力进行观察。结果:单次及连续7d皮下注射rh-PTH使大鼠收缩压、舒张压、平均动脉压降低,心率增加,且存在量效关系,但2h后上述指标基本恢复正常。对心律、ECG之QRS时间、T波、ST段、呼吸频率、节律和幅度无明显影响。对小鼠自发活动和爬杆能力无明显影响。结论:rh-PTH对心血管系统有一定影响,可使收缩压、舒张压、平均动脉压降低,心率增加。     

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.     

Effects of Combined Treatment with Sildenafil and Itraconazole on the Cardiovascular System in Telemetered Conscious Dogs

Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantlyenhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.     

Effects of combined treatment with sildenafil and itraconazole on the cardiovascular system in telemetered conscious dogs

Sildenafil, a potent PDE5 inhibitor, is widely prescribed as a treatment of erectile dysfunction. Itraconazole is an inhibitor of CYP3A4, a metabolic enzyme of sildenafil. In the current study, we investigated the effects of single treatment with sildenafil and combined treatment with sildenafil and itraconazole on blood pressure, heart rate, and QT interval in conscious beagle dogs. After a transmitter was implanted to beagle dogs for conscious state experiments, a single oral dose of sildenafil was administered to the beagle dogs at dose levels of 3, 15, and 30 mg/kg. Blood pressure, heart rate, and lead II ECG were measured prior to dosing and at 0.5, 1, 2, 4, 6, and 24 h postdosing. In the study of combined treatment with sildenafil and itraconazole, the 100 mg/kg dose of itraconazole was orally administered 1 h prior to oral administration of sildenafil. No changes in blood pressure were observed at any doses in animals receiving either single treatment with sildenafil or combined treatment with sildenafil and itraconazole. Increased heart rate from 0.5 h to 6 h postdosing and decreased QT interval were observed in animals receiving single treatment with sildenafil at 15 or 30 mg/kg. When 30 mg/kg of sildenafil was coadministered with 100 mg/kg of itraconazole, drug-related effects such as increased heart rate and decreased QT interval were significantly enhanced as compared to sildenafil-alone administration at 6 h postadministration. These results demonstrated that increased heart rate and decreased QT interval, the adverse effects of sildenafil, were enhanced and prolonged when sildenafil was coadministered with itraconazole. Therefore, caution should be taken when sildenafil is coadministered with itraconazole, a CYP3A4 inhibitor, or when administered to elderly patients or patients with hepatic or renal impairment who cannot metabolize and excrete sildenafil normally.     

Differential effects of human ether-a-go-go-related gene (HERG) blocking agents on QT duration variability in conscious dogs

The effects of drugs that inhibit human ether-a-go-go-related gene (HERG) related cardiac potassium channels on the variability of QT duration as a sign of repolarisation instability were evaluated in conscious telemetered dogs. QT duration variability was determined using a beat-to-beat analysis before and after the infusions of HERG channel blocking agents. Variability was evaluated as increased mean width (P(width)) and length (P(length)) of Poincaré plots of 100 consecutive beats. As HERG channel blockers which are associated with arrhythmias of the torsades de pointes (TdP) type, dofetilide and sotalol were infused. Verapamil was used as an HERG channel blocker that is not associated with TdP. Dofetilide (0.01 and 0.03 mg/kg) dose-dependently prolonged QT(c) duration (12% and 16%). Dofetilide also induced an increase of QT variability that reached statistical significance for P(length) at the higher dose (64%). A dose of 3 mg/kg sotalol neither prolonged QT(c) duration nor QT duration variability. In contrast, at 10 mg/kg sotalol prolonged QT(c) duration (15%) and increased P(length) (33%). Doses of 0.1 and 0.3 mg/kg verapamil did not increase QT(c) duration nor QT time variability. QT duration variability in conscious dogs may be a useful preclinical marker to discriminate pro-arrhythmogenic and non-arrhythmogenic activities of HERG blocking agents.     

QT-prolonging effects of sparfloxacin, a fluoroquinolone antibiotic, assessed in the in vivo canine model with monophasic action potential monitoring

Sparfloxacin, a fluoroquinolone antibacterial agent, prolongs cardiac repolarization, which may predispose to torsades de pointes. This study was designed to assess simultaneously the hemodynamic and electrophysiologic effects of sparfloxacin using the halothane-anesthetized, closed-chest in vivo canine model (n = 6). Sparfloxacin was intravenously administered in the following two doses with a pause of 20 min, a clinically relevant dose of 3.0 mg/kg/10 min and a 10 times higher dose of 30 mg/kg/10 min. After the low dose of sparfloxacin, cardiac output increased, heart rate decreased, and ventricular repolarization and refractory periods were prolonged. After the high dose, cardiac output increased, whereas heart rate and mean blood pressure decreased, and ventricular repolarization and effective refractory periods were prolonged. The increment was greater in repolarization than in refractoriness, indicating an increase of electrical vulnerability. Because sparfloxacin prolonged repolarization in a reverse use-dependent manner, its negative chronotropic effect may have potentiated the QT prolongation. Left ventricle preload, left ventricular contraction, and AV nodal as well as intraventricular conduction were minimally affected. These results suggest that caution should be used when administering sparfloxacin to patients having risk factors for QT prolongation.     

The cardiovascular and pharmacokinetic profile of dofetilide in conscious telemetered beagle dogs and cynomolgus monkeys

BACKGROUND AND PURPOSE: The effects of dofetilide were studied in monkeys and dogs. Pharmacokinetic data were generated together with the monitoring of cardiovascular changes in order to compare effects relative to human exposure. EXPERIMENTAL APPROACH: Beagle dogs and cynomolgus monkeys were telemetered to collect arterial blood pressure, heart rate and ECG for 6 h after selected oral doses of dofetilide. Pharmacokinetic parameters were determined for each dose. KEY RESULTS: Dogs: increases in the QT(c) interval reached 56 ms in dogs dosed with 0.3 mg kg(-1) of dofetilide. Premature ventricular contractions and right bundle branch block were evident at this dose, without changes in cardiovascular parameters. The mean C(max) values were 3.35 and 60.15 ng mL(-1) at doses of 0.03 and 0.3 mg kg(-1), respectively. Monkeys: increases in QT(c) intervals reached 40-50 ms after 0.03 mg kg(-1). T-wave changes were observed after 0.03 mg kg(-1) without changes in cardiovascular parameters. The mean C(max) values following oral doses of 0.01 and 0.03 mg kg(-1) were 0.919 ng mL(-1) and 1.85 ng mL(-1), respectively. CONCLUSIONS AND IMPLICATIONS: Despite dofetilide exposure comparable to that in humans, QT(c) responses in dogs were greater than those reported in humans. A comparable human dose used in the monkey achieved only half of the exposure but was associated with twofold greater increases in QT(c). Our data support the view that safety risk assessments of new drugs in animal models should ensure that the clinical therapeutic range of exposure is achieved and any untoward effects interpreted accordingly.     

Cardiovascular and bronchial actions of famotidine in anesthetized dogs

The effects of famotidine (Gaster; CAS 76824-35-6) and cimetidine on cardiovascular and bronchial functions were investigated in anesthetized dogs. Famotidine did not affect heart rate, blood pressure, left ventricular pressure (LVP), max. dLVP/dt, cardiac output or coronary blood flow at i.v. doses of 1 to 30 mg/kg in open-chest dogs anesthetized with pentobarbital or a combination of nitrous oxide, oxygen and halothane (GOF). No hemodynamic changes were either observed after famotidine in pentobarbital anesthetized dogs whose cardiac function was depressed by propranolol (1 mg/kg i.v.). On the contrary, cimetidine dose-dependently decreased heart rate and blood pressure at doses greater than 3 mg/kg, and left ventricular pressure, cardiac output and coronary blood flow at the dose of 30 mg/kg. Regarding the electrocardiogram (ECG), famotidine did not produce any remarkable change at doses up to 30 mg/kg with the exception of a transient increase or decrease in the T-wave amplitude at a dose of 30 mg/kg. Cimetidine prolonged Q-T intervals of ECG in addition to changing the T-wave at a dose of 30 mg/kg. Neither famotidine nor cimetidine showed any effect on resting and histamine-increased bronchoresistance at doses up to 30 mg/kg. It is concluded that famotidine is superior to cimetidine with regard to safety because famotidine has no significant effects on cardiovascular functions in anesthetized dogs.