莫索尼定与可乐定对肾性高血压大鼠动脉压及心率作用的比较

背景：莫索尼定是高选择性的第二代中枢性降压药，而可乐定是第一代中枢降压药．用于临床治疗高血压，但副作用较多。 目的：比较莫索尼定与可乐定对肾性高血压大鼠的作用特点。 设计：随机对照动物实验。 单位：南通大学医学院药理学教研室。 材料：实验于2004-09／12在南通医学院完成。选择SD大鼠110只，鼠龄60d，体质量（180&;#177;30）g。 方法：SD大鼠左侧肾动脉用0．2mm或0．25mm内径的银夹狭窄，右侧肾脏不触及，造成二肾一夹型（two—kidney one—clip，2K—IC）肾性高血压模型。①采用尾动脉间接测压法，一次或连续口服给药，分别测定清醒肾性高血压大鼠血压及其心率变化。一次口服给药的降压实验：大鼠随机分成5组，每组10只，盐酸莫索尼定1mg／kg组、3mg／kg组、10mg／kg组、盐酸可乐定（1mg／kg）组作阳性对照、生理盐水组作阴性对照。根据盐酸奠索尼定对血压作用特点，测定给药后1,4，24，48,72h时间点的血压，分别与给药前或生理盐水作用相比较。连续每天1次口服给药降压实验：分组同上，连续给药7d，1次／d，测定每天给药前、给药后1h血压及心率的变化，停药后观察3d。人拟推荐剂量为盐酸莫索尼定0．4mg／kg左右，按动物体表面积换算，大鼠口服剂量约为0．04mg／kg左右。②采用颈动脉插管直接测压法测定麻醉肾性高血压大鼠血压及其心率变化：以0．2mg／kg的药液灌胃，大鼠随机分5组，每组10只，分别为盐酸莫索尼组、0．13mg／kg组、0．4mg／kg组、1．3mg／kg组、盐酸可乐定0．13mg／kg组及生理盐水对照组，测定给药前及给药后不同时间的平均动脉压。 主要观察指标：一次或连续口服给药情况下清醒和麻醉肾性高血压大鼠血压及其心率变化。 结果：在实验过程中，各组大鼠无脱失，全部进入结果分析。①清醒肾性高血压大鼠一次大剂量口服莫索尼定降压与心率减慢作用呈剂量依赖性，其10倍剂量与可乐定作用相近；连续小剂量口服莫索尼定降压百分率与可乐定相仿，心率减慢作用弱而短暂。②麻醉肾性高血压大鼠，一次口服莫索尼定降压作用与剂量相关；莫索尼定3～10倍剂量与可乐定降压百分率差异无显著性意义（P〉0．05）。 结论：大剂量一次口服给药，莫索尼定对清醒肾性高血压大鼠的降压作用呈剂量依赖性，其10倍剂量与可乐定作用相当；对麻醉肾性高血压大鼠莫索尼定3-10倍剂量与可乐定降压相当。小剂量连续口服给药，莫索尼定和可乐定等剂量对肾性高血压大鼠的降压作用相当。     

莫索尼定降压及逆转左室肥厚的临床效果观察

目的探讨莫索尼定降压效果和逆转患者左室肥厚的作用。方法将80例高血压合并左室肥厚患者分为莫索尼定(治疗)组和卡托普利(对照)组治疗,观察6个月,比较两组血压(BP)和左心室肥厚的变化。结果莫索尼定治疗使BP从(163.5/80.7±16.7/10.5)mmHg降至(125.7/71.3±13.6/8.53)mmHg(P<0.05),左心室质量指数(LVMI)从(145.8±13.0)g/m2降至(122.3±11.8)g/m2(P<0.05),但治疗组的BP和LVMI变化与对照组之间比较无差异。结论莫索尼定具有显著降压作用,长期使用能够显著逆转左心室肥厚。     

莫索尼定及福辛普利钠对阿霉素肾病肾组织TNF-α影响的对比研究

目的探讨肿瘤坏死因子-α(TNF-α)及血小板源性生长因子-BB(PDGF-BB)在大鼠阿霉素肾病发病中的可能作用及对比研究莫索尼定及福辛普利钠对其影响。方法采用二次给药法尾静脉注射0.2%的盐酸阿霉素诱导肾病模型,随机等分3组(10只/组):治疗组给予莫索尼定1.5mg/(Kg·d)或福辛普利钠10mg/(Kg·d),肾病组给等量不含药物的食物丸;10只大鼠尾静脉注射等量生理盐水做为对照组。12周测血压、尿蛋白、血去甲肾上腺素(NE)、血管紧张素Ⅱ(AngⅡ)、TNF-α水平,肾组织行HE、Masson染色及电镜观察,免疫组化法测定肾组织TNF-α、PDGF-BB蛋白表达。结果肾病组24h蛋白尿、血生化指标、肾组织损伤形态学指标及TNF-α和PDGF-BB蛋白表达明显高于对照组(P<0.01),两治疗组上述损伤指标轻于肾病组(P<0.01)。结论TNF-α及PDGF-BB在ADR肾组织内高表达,可能参与肾组织损伤,莫索尼定及福辛普利钠可能通过下调TNF-α及PDGF-B蛋白表达而起肾保护作用。     

高血压大鼠降压及肾损伤保护作用研究

目的：观察决明子蒽醌苷对两肾一夹（2K1C）高血压大鼠的降压及肾损伤保护作用。方法复制2K1C高血压大鼠动物模型,随机分为模型组和决明子蒽醌苷高（0.4 g/kg）、低（0.2 g/kg）剂量组。另取10只大鼠作为假手术组。各组大鼠连续日一次灌胃给药6周,每周末检测大鼠尾动脉收缩压。末次给药后次日颈椎脱臼处死大鼠,肾组织苏木素-伊红及弹力纤维染色切片,显微镜下测量小叶间动脉、入球小动脉中膜厚度与管腔直径比值。计数高倍镜下每视野肾小管蛋白质管型数、肾间质淋巴细胞数,计算全片的均值。结果决明子蒽醌苷能明显降低2 K1 C高血压大鼠尾动脉收缩压（ P〈0.01或0.05）。决明子蒽醌苷能减缓2K1C高血压大鼠肾内小动脉重塑,小叶间动脉、入球小动脉中膜厚度与管腔直径比值较模型组明显降低（ P〈0.01或0.05）。决明子蒽醌苷能明显减弱2K1C高血压大鼠肾脏损伤程度,每高倍镜视野蛋白管型数及肾间质淋巴细胞数较模型组均明显减少（ P〈0.01或0.05）;决明子蒽醌苷高剂量组降压及肾保护作用较低剂量组明显（ P〈0.01或0.05）。结论决明子蒽醌苷能明显降低2K1C高血压大鼠尾动脉收缩压且对高血压大鼠肾脏具有保护作用。     

恒定磁场对不同高血压模型大鼠的选择性作用

目的探讨不同高血压种类和程度用磁疗康复的疗效评价 . 方法在恒定弱磁场的作用下观察正常大鼠、去甲肾上腺素引起血压升高的大鼠及肾性高血压模型大鼠血压及心率的变化 . 结果该磁场对正常 Wistar大鼠的血压、心率均无影响 ; 对去甲肾上腺素引起的中、轻度高血压有较好的抑制作用 , 且降压程度与时间、剂量呈正相关 ; 对肾性高血压模型大鼠则没有影响 . 结论恒定弱磁场对大鼠血压的生物学效应取决于实验动物的功能状态 . 提示高血压患者应用磁疗进行的保健和康复效果应与高血压种类和程度有关 .     

植物提取剂紫苏油对大鼠血压及心率的影响

目的:研究紫苏油对大鼠血压的影响,为紫苏油的应用开发提供合理的实验依据。方法:以Sprague-Dawley大鼠为实验动物,随机将大鼠分为6组:正常对照组、模型组、牛黄降压丸组和紫苏油高(9.00g/kg)、中(4.50g/kg)、低(2.25g/kg)剂量组。对照组每天饮自来水,其余各组均饮20g/L盐水;剂量组每天给相应剂量的紫苏油,牛黄降压丸组给牛黄降压丸,对照组和模型组给生理盐水(各组均灌胃给药)。连续给药15d后,测量各组大鼠尾动脉收缩压和心率的变化。结果:高、中剂量紫苏油组和模型组尾动脉收缩压分别为(120.8±11.6),(123.3±9.31),(141.7±13.7)mmHg。F检验显示,高(9.00g/kg)、中(4.50g/kg)剂量紫苏油组的血压与对照组比无显著差异(P值分别为0.799与0.506),却显著低于模型组(P值分别为0.007与0.018),而对心率的影响不大。结论:紫苏油有抗高血压作用。     

可乐定术前用药对平衡麻醉时的血流动力学效应

目的：观察术前口服可乐定对麻醉期间循环功能的影响。方法：４０例ＡＳＡ１－２级的择期胸外科患者随机分成对照组（组Ⅰ，n=20)和可乐定组（组Ⅱ，n=20)，可乐定组患者在术前９０min口服可乐定５ug/kg。两组患者均采用二氢埃托啡、依托咪酯和琥碧胆碱诱导插管，Ｎ2O-O2持续吸入、二氢埃托啡持续静脉滴注及异氟醚间断吸入维持麻醉，观察并记录麻醉诱导和维持阶段的血压、中心静脉压和心率，患者入手术室后的意识状况以及术后疼痛的严重程度。结果：患者的一般情况和基础生命体征无显著差异。麻醉诱导前，可乐定产生明显的镇静作用。全麻诱导后气管插管前，两组患者的一般情况和基础生命体征无显著差异。麻醉诱导前，可乐定产生明显的镇静作用。全麻诱导后气管插管前，两组患者均有明显的血压下降，气管插管后，两组患者均出现血压升高和心率增快，但可乐定组的升高明显小于对照组。结论：以上结果提示可乐定术前口服具有良好的镇静作用。术前口服５ug/kg体重可乐定能阻断全麻诱和气管插管时的血压升高和心率增快。可乐定也许能成为有效的术前药。     

可乐定术前用药对平衡麻醉时的血流动力学效应

目的：观察术前口服可乐定对麻醉期间循环功能的影响。方法：40例ASA1～2级的择期购外科患者随机分成对照组（组Ⅰ,n＝20）和可乐定组（组Ⅱ,n＝20）,可乐定组患者在术前90min口服可乐定5μg／kg。两组患者均采用二氢埃托啡、依托咪酯和琥珀胆碱诱导插管,N2O－O2持续吸入、二氧埃托啡持续静脉滴往及异氟醚间断吸入维持麻醉。观察并记录麻醉诱导和维持阶段的血压、中心静脉压和心率,患者入手术室后的意识状况以及术后疼痛的严重程度。结果：患者的一般情况和基础生命体征无显著差异。麻醉诱导前,可乐定产生明显的镇静作用。全麻诱导后气管插管前,两组患者均有明显的血压下降。气管插管后,两组患者均出现血压升高和心率增快,但可乐定组的升高明显小于对照组。结论：以上结果提示可乐定术前口服具有良好的镇静作用。术前口服5μg／kg体重可乐定能阻断全麻诱导和气管插管时的血压升高和心率增快。可乐定也许能成为有效的术前药。     

盐酸特拉唑嗪治疗慢性肾脏病合并高血压42例疗效观察

目的观察盐酸特拉唑嗪片对临床慢性肾脏病(chronic kidney disease,CKD)合并高血压患者常规降压药物使用后疗效仍欠佳的高血压的疗效。方法盐酸特拉唑嗪片首剂2mg,睡前口服,以后视血压逐渐增加剂量,最大剂量:8 mg/日,可以4 mg bid口服。4周为一疗程,同时设自身对照组对比。结果降压有效率85.7%,以降低舒张压为主。结论盐酸特拉唑嗪对慢性肾脏病合并高血压的降压疗效确切。     

菊延保康冲剂对吗啡依赖大鼠戒断治疗的作用评价

目的:观察菊延保康冲剂对吗啡依赖大鼠戒断综合征的控制效果,旨在为戒毒康复研究提供药效学依据。方法:Wister种大鼠100只,雄雌兼用,体质量180～220g。以剂量递增法形成大鼠吗啡依赖模型,其中50只于第15天做催促戒断试验,随机分为阴性(NS)对照组、阳性对照组(可乐定,0.2mg/kg,灌胃),菊延保康冲剂Ⅰ、Ⅱ、Ⅲ组(以每kg体质量1.4g,2.4g,4.0g灌胃)后用纳洛酮(4mg/kg)催促,记录各组1h内大鼠的戒断反应。另50只大鼠于第29天早上做自然戒断试验,分成5组,每组10只,阴性(NS)对照组给予等容量生理盐水3次/d灌胃,阳性对照组(给予可乐定1mg/kg灌胃),菊延保康冲剂Ⅰ、Ⅱ、Ⅲ组分别给予每次0.7g/kg,1.4g/kg,2.4g/kg灌胃,给药连续1周。治疗前1d及治疗期间每天给药前称大鼠体质量。结果:菊延保康冲剂3个剂量组的戒断症状分值小于NS组,差异有非常显著性意义(P<0.01)。戒断症状分值大于可乐定组,但大、中剂量组与可乐定组比较差异无显著性意义(P>0.05)。菊延保康冲剂3个剂量组的体质量下降百分率低于NS组和可乐定组。吗啡依赖大鼠自然戒断试验结果显示菊延保康冲剂小剂量和中剂量组在治疗前3d对体质量下降均有显著的控制作用(P<0.05～P<0.01)。大剂量组从第3天开始体质量没有恢复,并继续下降。可乐定组完全不能控制吗啡依     

Pharmacological characterization of alpha adrenoceptors involved in the antinociceptive and cardiovascular effects of intrathecally administered clonidine

The effects on nociception, blood pressure and heart rate of clonidine administered intrathecally to the lumbar level were determined in conscious rats and in rats anesthetized lightly with pentobarbital. In anesthetized rats, intrathecal (i.t.) clonidine (3.2-32.0 micrograms) inhibited the nociceptive tail-flick reflex and had biphasic effects on blood pressure; lesser doses (1.0-10.0 micrograms) produced depressor effects, whereas a greater dose (32.0 micrograms) produced a marked pressor response. Clonidine also produced biphasic effects on blood pressure in conscious rats, with the dose-response function shifted upward and to the left of that observed in anesthetized rats. The depressor and antinociceptive effects of 3.2 micrograms of clonidine were antagonized by pretreatment with yohimbine (30.0 micrograms i.t.) but not by prazosin (30.0 micrograms i.t.) or by yohimbine (0.1 mg/kg i.v.). Thus, these effects of clonidine are mediated by spinal alpha-2 adrenoceptors. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was accompanied by marked bradycardia, and similar cardiovascular effects were observed when this dose of clonidine was administered either i.v. or to the cervical level of the spinal cord. The pressor response to 32.0 micrograms of clonidine (i.t., lumbar) was not reduced significantly by i.t. pretreatment with yohimbine (30.0 micrograms) or prazosin (30.0 micrograms), but was diminished significantly by i.v. pretreatment with yohimbine (1.0 mg/kg), prazosin (0.1 mg/kg) or phentolamine (2.0 mg/kg). Neither chlorisondamine (2.5 mg/kg i.v.) or the V1-vasopressin receptor antagonist [1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 2-(o-methyl)tyrosine]Arg8-vasopressin (10.0 micrograms/kg i.v.) reduced the clonidine-produced pressor response. After i.t. injection of 32.0 micrograms of [3H]clonidine, peak levels of radioactivity in the blood were observed at 2 min and corresponded to a blood concentration of 38.8 ng/ml. Injection of an i.v. bolus dose (2.5 micrograms/kg) sufficient to produce these blood levels resulted in a transient pressor response. These results suggest that after i.t. administration of greater doses of clonidine, sufficient amounts of the drug are rapidly redistributed systemically to produce pressor effects by stimulation of vascular alpha adrenoceptors.     

Withdrawal of clonidine: effects of varying dosage or duration of treatment on subsequent blood pressure and heart rate responses.

The influence of the dosage or duration of treatment on the incidence and severity of clonidine withdrawal responses was examined in normotensive rats. Clonidine (0.01 or 0.1 mg/kg i.m.) was administered either in single doses, or twice daily for 3 days or 3 weeks. Rats were then anesthetized and arterial catheters were inserted. Significant overshoots in blood pressure and heart rate, reaching peak values 16 to 26 hr after the last injection, occurred in all clonidine-treated rats, but in no control rats. The overshoots after single injections of clonidine were as great as those after suspension of sustained treatment. Moreover, withdrawal responses were as great after the low dose as they were after the 10-fold greater dose. Only plasma renin activity showed a significantly greater elevation during withdrawal of the high dose of clonidine. Since ganglionic blockade reduced blood pressures and heart rates to the same levels in rats with clonidine withdrawal hypertension as in control rats, the withdrawal overshoots appear to be nervously mediated. Neither the dosage nor the duration of treatment could be shown to determine the magnitude of the response to withdrawal of clonidine.     

Thoracic epidural clonidine attenuates haemodynamic responses induced by endobronchial intubation

Laryngoscopy and endobronchial intubation usually cause transient hypertension and tachycardia. We investigated whether thoracic epidurally injected 3 microg/kg clonidine attenuates cardiovascular responses to intubation compared with 2 microg/kg fentanyl and 1 mg/kg lidocaine. Epidural catheterization was performed at the T6-T7 or T7-T8 intervertebral space, and saline or clonidine in saline was injected 20 min before anaesthetic induction. Anaesthesia was induced using 5 mg/kg thiopental sodium and 0.1 mg/kg vecuronium. Laryngoscopy and endobronchial intubation were performed 2 min later. Mean blood pressure and heart rate were measured throughout anaesthetic induction. In the control group and the fentanyl group, mean blood pressure and heart rate 3 min after endobronchial intubation were elevated significantly compared with baseline. In the clonidine group, however, mean blood pressure and heart rate did not increase compared with baseline. The control group had higher mean blood pressure and heart rate than the clonidine group 3 min after endobronchial intubation. Thoracic epidural clonidine may attenuate the haemodynamic response to endobronchial intubation.     

复方黄精口服液对心力衰竭大鼠心肌肌球蛋白重链变化的作用

背景阿霉素是蒽环类抗肿瘤药,对多种恶性肿瘤有抑制作用.但由于其毒性大,可引起与剂量依赖性的心脏毒性,严重者可致心力衰竭.复方黄精口服液能抗自由基损伤,有望用于心力衰竭的辅助治疗.目的探讨复方黄精口服液抗心力衰竭疗效及其作用机制.设计随机对照观察.单位福建省医科大学附属第一医院中医科、福建省中医学院及福建省中医学院.材料实验于2000-08/2001-05在福建省高血压研究所完成,选用66只雄性SD大鼠.方法采用阿霉素损伤大鼠心肌致心力衰竭为模型,66只大鼠随机分为6组,每组11只.正常组腹腔注射等体积生理盐水.阿霉素组于实验开始后第2,4天腹腔注射阿霉素1 mg/kg;第6,8天腹腔注射2 mg/kg;第10,12天腹腔注射3 mg/kg;第14,16天腹腔注射4 mg/kg,16 d累计用药量达20 mg/kg.阿霉素+复方黄精口服液2 mL(小剂量组).阿霉素+复方黄精口服液4 mL(中剂量组).阿霉素+复方黄精口服液6 mL(大剂量组).小、中、大剂量组于实验开始后分别每日用复方黄精口服液灌胃.阿霉素的剂量用法同阿霉素单用组.阿霉素+天保宁(天保宁组)天保宁450 mg/kg隔日灌服共8 d.阿霉素的剂量用法同阿霉素单用组.主要观察指标观察各组大鼠心系数,α-肌球蛋白重链,β-肌球蛋白重链的变化.结果纳入实验动物数66只,在整个实验期间阿霉素组有5只大鼠,小剂量组4只大鼠,中剂量组2只大鼠,大剂量组3只大鼠,天保宁组3只大鼠死于明显的充血性心力衰竭,进入结果分析47只.与正常组比较,阿霉素组的α-肌球蛋白重链下降20.88%(P＜0.01),β-肌球蛋白重链上升50.93%(P＜0.01),心系数升高33.83%(P＜0.01).经给药治疗后,心肌β-肌球蛋白重链向α-肌球蛋白重链转化,与阿霉素组比较,各药物治疗组α-肌球蛋白重链上调(P＜0.01),β-肌球蛋白重链下降(P＜0.01),心系数均有不同程度下降(P＜0.01或P＜0.05),以上变化以中剂量组作用最佳.结论复方黄精口服液能减轻阿霉素致心力衰竭的毒性反应,其机制与复方黄精口服液可提高心肌α-肌球蛋白重链的转化有关,且呈剂量依赖性.     

Effects of the I(1) imidazoline/alpha(2)-adrenergic receptor agonist moxonidine in comparison with clonidine in the formalin test in rats

Moxonidine is a mixed I(1) imidazoline/alpha(2)moxonidine=morphine. The I(1) imidazoline preferring antagonist efaroxan produced a dose-dependent antagonism of both moxonidine (5.0 mg/kg) and clonidine (0.5 mg/kg). In addition, the alpha(2)-adrenergic receptor antagonist yohimbine produced a dose-related antagonism of moxonidine, but only partially antagonized clonidine. Prazosin failed to block the effects of either moxonidine or clonidine, indicating a lack of involvement of alpha(1) as well as alpha(2B) and alpha(2C) receptors. The present results suggest that alpha(2)-adrenergic receptors play an important role in mediating the effects of moxonidine in producing antinociception in the formalin test. Further, the present results demonstrate that the mechanism of action of moxonidine and clonidine differ in that clonidine, but not moxonidine, produces an antinociceptive effect through a yohimbine-insensitive mechanism in the formalin test.     

硝苯地平对自发性高血压大鼠血管内皮细胞的保护作用

背景研究表明,硝苯地平能够改善血管内皮细胞功能,而对于其扩张血管的机制,目前仍在进一步的研究中. 目的观察硝苯地平控释剂对自发性高血压大鼠(SHR)一氧化氮(NO)及诱导性一氧化氮合酶(iNOS)的影响.设计以实验动物为研究对象的观察对比研究.单位一所医学院的动物实验中心.材料本实验于2002-04/2002-05在山东大学医学院动物实验中心完成.实验动物为近交SHR大鼠21只,体质量(300±20)g,由山东大学医学院实验动物中心提供,清洁级.随机分为3组,即对照组、正常剂量组、低剂量组,每组7只. 方法对照组、正常剂量组和低剂量组分别灌胃生理盐水10 mL/kg、硝苯地平控释剂(拜新同)溶液(0.3 g/L)10 mL/kg和3 mL/kg,1次/d,连续15 d.末次给药后摘眼球取血并取大鼠心、肺分别测定血清NO和iNOS的含量.主要观察指标各组大鼠的NO含量、iNOS活性比较.结果灌胃15 d后,正常剂量组的NO含量与对照组、低剂量组比较,差异均有显著性意义(P<0.01);正常剂量组心、肺组织块中iNOS活性降低,与对照组和低剂量组比较差异均有显著性意义(P<0.01,P<0.05).结论硝苯地平可在降低血压的同时,提高血清NO的含量,并且能对抗血压增高所造成的iNOS的活性增强(或二者互为因果).     

Diurnal blood pressure in patients with mild-to-moderate hypertension treated with once-daily benazepril hydrochloride

This study evaluated the blood pressure effects of administration of once daily oral benazepril hydrochloride, a new angiotensin-converting enzyme (ACE) inhibitor, for mild-to-moderate hypertension. After a 2 to 4 week placebo baseline period, patients with diastolic blood pressure between 95 and 114 mm Hg, were randomized to receive either placebo or benazepril hydrochloride, 5, 10, 20, or 40 mg, once daily in double-blind fashion for 28 days. Blood pressure was measured predose and at 1, 2, 3, 4, 6, 8, 12, 16, 20, and 24 hours after the dose during inpatient observation days at the end of the placebo baseline period, and on the first and last day of the double-blind treatment period; and 24 hours after the dose at weekly outpatient visits. All doses of benazepril hydrochloride resulted in clinically important reductions in diastolic and systolic blood pressures that lasted between 12 and 24 hours after both the first dose, and following the last dose after 4 weeks of treatment. The findings indicate that benazepril hydrochloride may be clinically useful as once-daily monotherapy in many patients with hypertension.     

Effect of moxonidine monotherapy and in combination with melatonin on hemodynamic parameters in patients with arterial hypertension

Fifty patients (mean age 53.8 +/- 3.45) with arterial hypertension were examined. They were divided into 2 randomized groups, 25 patients each. One group received moxonidine, 40 mg, alone in the morning, the other had moxonidine in the same dose in combination with melatonin, 3 mg, overnight. The treatment lasted 14 days. Monitoring of blood pressure (BP), heart rate (HR), EchoCG was made before and after treatment. The studies indicated that moxonidine had a pronounced antihypertensive effect by slightly lowering BP overnight and that the chronostructure of BP and HR rhythms was impaired. Addition of melatonin to the moxonidine therapy with greater antihypertensive effects made the chronostructure of circadian BP and HR rhythms normal.     

Unexplained high fever in an elderly patient treated with clonidine,duloxetine, and atorvastatin

Background: Drug-induced fever is a clinical diagnosis and should always be considered when the fever is constant and high without a clear source of infection. Although drug-induced fever has been reported with other centrally acting antihypertensive drugs such as methyldopa, published reports of this adverse effect with clonidine in humans were not identified in a search of the literature.Case summary: A 66-year-old institutionalized white female with a history of morbid obesity (body mass index, 40 kg/m2), Alzheimer's dementia, hypertension, and depression presented to a hospital in Boston, Massachusetts (Caritas Saint Elizabeth's Medical Center) with generalized weakness and shortness of breath and was found to have a non-ST segment elevation myocardial infarction. Before hospitalization, the patient was taking memantine 10 mg PO BID, donepezil 10 mg PO once daily, duloxetine 60 mg PO once daily, clonidine 0.1 mg PO TID, metoprolol 50 mg PO BID, and amlodipine 10 mg PO once daily. On admission, the patient was initiated on aspirin 325 mg, atorvastatin 80 mg, and clopidogrel 75 mg PO daily. Her dose of clonidine was increased to 0.2 mg PO TID to optimize blood pressure control, and metoprolol and amlodipine were continued at the same doses. The patient developed fever on the third day after the cardiac catheterization. The fever ranged from 99.0°F to 102.7°F. The physical examination, laboratory data analysis, multiple blood cultures, urinalysis, chest radiograph, and a computed tomography of the head, chest, abdomen, and pelvis did not reveal any source of infection. On the sixth day after admission, clonidine was reduced to the baseline dose of 0.1 mg PO TID and on the ninth day it was stopped. The patient was afebrile on the twelfth day and remained so for the duration of her hospitalization. Naranjo scores for her newly initiated concomitant medications were as follows: aspirin, 1; atorvastatin, 3; clonidine, 6; and clopidogrel, 1. The rating of 6 for clonidine suggests that it was probably associated with the fever in this patient.Conclusion: We describe a case of drug-induced fever probably associated with clonidine administration. The higher dose of clonidine alone or in interaction with duloxetine and atorvastatin may have contributed to the development of drug-induced fever.     

Dose-dependent pharmacokinetics of itraconazole after intravenous or oral administration to rats: intestinal first-pass effect

The dose-dependent pharmacokinetics of itraconazole after intravenous (10, 20, or 30 mg/kg) and oral (10, 30, or 50 mg/kg) administration and the first-pass effects of itraconazole after intravenous, intraportal, intragastric, and intraduodenal administration at a dose of 10 mg/kg were evaluated in rats. After intravenous administration at a dose of 30 mg/kg, the area under the plasma concentration-time curve from time zero to infinity (AUC(0- infinity )) was significantly greater than those at 10 and 20 mg/kg (1,090, 1,270, and 1,760 micro g. min/ml for 10, 20, and 30 mg/kg, dose-normalized at 10 mg/kg). After oral administration, the AUC(0- infinity ) was significantly different for three oral doses (380, 687, and 934 micro g. min/ml for 10, 30, and 50 mg/kg, respectively, dose-normalized at 10 mg/kg). The extent of absolute oral bioavailability (F) was 34.9% after an oral dose at 10 mg/kg. The AUC(0- infinity ) (or AUC(0-8 h)) values were comparable between intravenous and intraportal administration and between intragastric and intraduodenal administration, suggesting that the hepatic and gastric first-pass effects were almost negligible in rats. However, the AUC(0-8 h) values after intraduodenal and intragastric administration were significantly smaller than that after intraportal administration, approximately 30%, suggesting that the intestinal first-pass effect was approximately 70% of that of an oral dose of 10 mg/kg. The low F after oral administration of itraconazole at a dose of 10 mg/kg could be mainly due to the considerable intestinal first-pass effect.