非洛地平和美托洛尔联用大鼠经皮给药的协同降压作用

目的：研究非洛地平和美托洛尔联用经皮给药对自发性高血压大鼠的协同降压作用，为其复方经皮给药系统的研制提供药理学依据。方法：50只自发性高血压大鼠随机分为10组（均为单次给药）：空白对照组，非洛地平-美托洛尔剂量分别为1-10、3—30、9—90mg／kg的复方透皮贴剂治疗组，非洛地平剂量分别为1、3、9mg／kg和美托洛尔剂量分别为10、30、90mg／kg的单方透皮贴剂治疗组。以无创性尾套法测定给药后大鼠的血压和心率，评价两药联用的协同降压作用。结呆：非洛地平和美托洛尔联用经皮给药对收缩压和舒张压的降低作用均显著高于两药各自单用（P〈0．05），对心率有降低作用但显著低于单用美托洛尔（P〈0．05）。单方与复方药物经皮给药对血压及心率的作用强度和持续时间均具有剂量依赖性（P〈0．05）。结论：作用机制不同的非洛地平和美托洛尔联用，协同和互补作用明确，该透皮给药复方制剂可以提高血压控制率、治疗安全性和病人用药依从性。     

非洛地平-美托洛尔复方经皮给药系统设计及其降压有效性评价

目的:设计制备非洛地平-美托洛尔复方经皮给药系统,评价其对自发性高血压大鼠的降压作用.方法:50只3月龄自发性高血压大鼠随机分为5组进行长期给药治疗试验:空白贴剂对照组、非洛地平(FEL)-美托洛尔(MET)口服混悬液组(FEL 1 mg·kg-1,MET 10 mg·kg-1,qd)及FEL-MET透皮贴剂低、中、高剂量组[剂量分别为:FEL 1 mg·kg-,MET 10 mg·kg-1;FEL 3 mg·kg-1,MET 30 mg·kg-1;FEL 9 mg·kg-1,MET90 mg·kg-,每隔2 d给药1次],共持续44 d.另设同月龄正常血压Wistar大鼠为正常对照组.以无创性尾套法测定给药后大鼠血压和心率,评价经皮给药系统的降压作用.结果:FEL-MET透皮贴剂降压作用起效快、持续时间长,无耐药趋势,强度具有剂量依赖性.FEL-MET透皮贴剂低、中、高剂量分别使收缩压下降27.3-39.2mmHg(14.78%～21.22%),34.2～49.7 mmHg(18.59%～27.01%)和50.8～68.6 mmHg(27.34%～36.92%);使舒张压下降19.8～32.6 mmHg(12.90%～21.24%),22.7～34.9 mmHg(15.30%～23.52%)和33.7～52.8mmHg(22.74%～35.63%);降压效果显著优于FEL和MET长期口服联用(P＜0.05).结论:FEL-MET经皮给药系统降压效果确切,作用平稳,持效时间长,使用方便,安全性高,适于高血压的长期药物治疗.     

非洛地平-美托洛尔复方贴剂的透皮吸收促进剂优化

目的：优化复合透皮吸收促进剂，制备非洛地平-美托洛尔复方贴剂，并对其外观、物理特性、体外药物释放和经皮渗透性能进行综合评价。方法：以药物体外释放速率和稳态透皮速率为指标，通过正交设计试验考察桉叶油醇、月桂氮[艹卓]酮和丙二醇体系对贴剂质量的影响，优选最佳复合透皮吸收促进剂构成。结果：优选的透皮吸收促进剂最佳含量分别为桉叶油醇5％、月桂氮[艹卓]酮3％和丙二醇12%，以该促透体系制备的贴剂药物体外释放速率和稳态透皮速率高，外观和理化特性较佳，物理黏性适宜，各指标均达到预期设计要求。结论：桉叶油醇-月桂氮[艹卓]酮-丙二醇（5：3：12）复合体系对非洛地平和关托洛尔的协同促透作用显著，且稳定可靠，是非洛地平关托洛尔复方贴剂的优良透皮吸收促进剂。     

非洛地平-美托洛尔复方经皮给药系统的制备及其兔体内生物利用度

制备了非洛地平-美托洛尔复方经皮给药系统，并研究其药剂学性质及经兔皮肤给药的药代动力学和生物利用度。先建立了同时测定贴剂和经皮渗透液中非洛地平与美托洛尔含量的RP-HPLC方法，以考察贴剂的药物体外稳态透皮速率和经皮渗透机制，并进行质量控制和评价；再以高灵敏度的GC-ECD方法分别测定非洛地平和美托洛尔的血药浓度，研究贴剂经皮给药后在兔体内的药代动力学和生物利用度。结果显示，该给药系统的复方药物体外透皮转运具有零级动力学特征，其含量均匀度检查符合2005版中国药典规定，稳定性好；经皮给药的血药浓度明显较口服平稳，且波动性小，达峰时间推后，持效时间延长，非洛地平与美托洛尔的相对生物利用度分别为275.37%和189.76%。以上结果表明，非洛地平-美托洛尔复方经皮给药系统具有明显缓释特征，可较长时间维持稳定有效的血药浓度。     

非洛地平/美托洛尔复方贴剂体外透皮特性及皮肤刺激性考察

目的 制备非洛地平/美托洛尔复方透皮贴剂,考察其对离体兔皮的经皮渗透性及对家兔皮肤的刺激性.方法 采用改良的Franz透皮扩散装置,以离体兔皮为渗透屏障,NS-乙醇(6040)为接受液,用HPLC法同时测定经皮渗透液中两药浓度并计算其渗透动力学参数.通过皮肤刺激性试验法考察该贴剂对家兔皮肤的刺激性.结果 非洛地平/美托洛尔复方透皮贴剂中非洛地平和美托洛尔48h内均以零级动力学经兔皮转运,并具一定同步性;该贴剂对家兔皮肤无刺激性.结论 非洛地平/美托洛尔复方透皮贴剂缓释长效特征明显,药物体外经皮渗透性较好且稳定,符合经皮给药系统应对皮肤无刺激性的设计要求.     

非洛地平-美托洛尔透皮贴剂与缓释片在兔体内药动学及生物利用度比较

目的：研究非洛地平-美托洛尔复方透皮贴剂与两药市售缓释片在兔体内药动学和生物利用度差异。方法：采用三周期随机交叉试验法，6只健康白兔随机分为3组，分别给予复方非洛地平-美托洛尔静脉注射液、透皮贴剂及两药市售缓释片各l片，以气相色谱-电子捕获法分别测定非洛地平和美托洛尔血药浓度，用DAS软件计算药动学参数和生物利用度，通过统计学检验评价不同剂型间差异。结果：透皮贴剂较口服缓释片药物吸收时间显著延长（P〈0.05），达峰时间显著推后（P〈0．05），血药浓度平稳，波动性小，体内作用时间长达2d-3d。贴剂中非洛地平和美托洛尔的生物利用度分别是其口服缓释片的114．30％和192．92％。结论：该贴荆缓释特征明显，达到了预期提高生物利用度、延长药物体内驻留时间、维持平稳血药浓度和方便用药的新剂型设计目的。     

复方比索洛尔硝酸异山梨酯透皮贴剂自发性高血压大鼠的心血管保护作用

探讨复方比索洛尔硝酸异山梨酯透皮贴剂对自发性高血压大鼠的心血管保护作用的优势.自发性高血压大鼠随机分为空白贴组、比索洛尔口服组(BP-FT,20.0 mg/kg)、比索洛尔贴剂组(BP-TP,20.0 mg/kg)、硝酸异山梨酯贴剂组(ISDN-TP,20.0 mg/kg)、联合给药组(BP,8 mg/kg;ISDN,12 mg/kg).观察42天治疗期内复方比索洛尔硝酸异山梨酯透皮贴剂对其血压的影响,测定与心血管保护有关的生化指标,并对心肌和血管结构进行了评定.BP和ISDN具有协同的抗压作用.联合给药对与单独给BP相比,有着相同的降低心率的作用,并且在控制血压波动方面有明显的优势.而ISDN的单独给药没有明显的抗压或降心率的作用.联合给药组能显著增加大鼠血液中心房钠肽和一氧化碳的含量,减少心肌组织中羟脯氨酸和内皮素-1的含量,降低血液中内皮素-1和丙二醛的浓度.同时,联合用药组还可以减轻心肌肥大,减小血管腔壁比,显著增强Ach诱导的内皮依赖性舒张反应.复方比索洛尔硝酸异山梨酯透皮贴剂长期给药不仅可明显降低血压,产生平稳的降压效果,且对心脏和血管产生明显的保护作用,这种协同作用可能在心血管保护的长期治疗中发挥优势.     

非洛地平-美托洛尔复方贴剂经不同动物皮肤的药物渗透性

目的制备非洛地平-美托洛尔复方透皮贴剂并研究经不同动物皮肤的体外药物渗透特性。方法采用改良的Franz透皮扩散装置,分别以离体小鼠、大鼠和兔皮肤为渗透屏障,生理盐水-乙醇(60:40)为接受液,用HPLC同时测定经皮渗透液中两药物的浓度,并计算渗透动力学参数。结果贴剂中,非洛地平和美托洛尔48 h内均以零级动力学经不同动物皮肤转运,并具一定同步性,动物皮肤对药物渗透性依次为:小鼠>大鼠>兔。结论非洛地平-美托洛尔复方透皮贴剂缓释长效特征明显,药物体外经皮渗透性稳定,各指标均可满足治疗血药浓度的要求。     

盐酸格拉司琼透皮贴剂对化疗药物致犬呕吐的预防作用

目的:观察盐酸格拉司琼透皮贴剂(GH透皮贴剂)对化疗药物诱导的犬呕吐的拮抗作用。方法:30只比格犬按体重随机分为5组,每组6只,分别为模型组、盐酸格拉司琼片剂组(0.1 mg.kg-1)、GH透皮贴剂0.150,.30和0.60 mg.kg-1组。GH透皮贴剂组给药24 h后以及片剂组给药1 h后,静脉注射顺铂3.0 mg.kg-1或环磷酰胺70 mg.kg-1诱导犬呕吐,观察呕吐和干呕次数、呕吐潜伏期和持续时间。结果:GH透皮贴剂0.15,0.30和0.60 mg.kg-1给药24 h后,均能显著减少顺铂和环磷酰胺引起的犬干呕及呕吐的次数,明显延长呕吐反应的潜伏期及缩短持续时间,剂量关系明确。结论:GH透皮贴剂对顺铂和环磷酰胺所致的犬呕吐有明显的拮抗作用。     

非洛地平-美托洛尔复方透皮贴剂的处方与工艺研究

目的:考察并筛选非洛地平-美托洛尔(FEL-MET)复方透皮贴剂的基础处方与制备工艺。方法:以聚丙烯酸树脂Eu-dragit E PO和Eudragit RL PO为复合压敏胶,采用流涎法制备非洛地平-美托洛尔复方透皮贴剂。通过单因素试验考察处方与制备工艺对贴剂外观、物理黏性、药物体外释放和经皮渗透性等指标的影响,初步确定贴剂处方和工艺条件。结果:较佳的处方构成和工艺条件:FEL和MET载药量分别为2%~3%和20%~30%,Eudragit E PO∶Eudragit RL PO为4∶6~6∶4,贴剂厚度为(1·0±0·1)~(2·0±0·1)mm,固化条件为70℃干燥30min。上述各因素对贴剂质量考察指标影响显著。结论:筛选处方合理,工艺稳定可行,制备的贴剂质量符合相关要求。     

A double-blind,placebo-controlled,dose-response study of the effectiveness and safety of enalapril for children with hypertension

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectively in 110 hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24-h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose-dependent manner. During a 2-week, double-blind, randomized, dose-response period, patients were stratified by weight (< 50 kg or > or = 50 kg), then assigned to one of three dosing groups: low(0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight-adjusted basis. On completion of the dose-response phase of the study, patients entered a 2-week, double-blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose-response relationship for enalapril had a negative slope and was linear over the chosen dosing range, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug orplacebo confirmed the antihypertensive effectiveness of enalapril in the middle- and high-dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well-tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing > 50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose-dependent fashion, with larger doses resulting in a greater reduction.     

非洛地平缓释片联合美托洛尔缓释片治疗中青年高血压病有效性的临床评价

目的 观察非洛地平缓释片联合美托洛尔缓释片联合用药对高血压患者的降压效果.方法 将160例高血压病患者随机分为治疗组和对照组.治疗组:80例用非洛地平缓释片联合美托洛尔缓释片治疗;对照组:80例非洛地平缓释片单药治疗,比较随访8周的血压达标率及安全性、耐受性情况.结果 (1)血压达标百分率:治疗组93.75％,对照组75％.(2)与药物相关的不良反应事件:治疗组(8.751％),对照组(7.5％).结论 非洛地平联合美托洛尔降压疗效确切,且安全性、耐受性好,依从性高.     

Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies

BAY 41-8543 is a novel non-NO-based stimulator of sGC. This study investigates the acute effects of BAY 41-8543 on haemodynamics in anaesthetized rats and dogs, its long-term effects in conscious hypertension rat models and its antiplatelet effects. In anaesthetized dogs, intravenous injections of BAY 41-8543 (3 - 100 microg kg(-1)) caused a dose-dependent decrease in blood pressure and cardiac oxygen consumption as well as an increase in coronary blood flow and heart rate. In anaesthetized normotensive rats, BAY 41-8543 produced a dose-dependent and long-lasting blood pressure lowering effect after intravenous (3 - 300 microg kg(-1)) and oral (0.1 - 1 mg kg(-1)) administration. A dose-dependent and long-lasting decrease in blood pressure was also observed in conscious spontaneously hypertensive rats with a threshold dose of 0.1 mg kg(-1) p.o. After 3 mg kg(-1) the antihypertensive effect lasted for nearly 24 h. After multiple dosages, BAY 41-8543 did not develop tachyphylaxis in SHR. BAY 41-8543 prolonged the rat tail bleeding time and reduced thrombosis in the FeCl(3) thrombosis model after oral administration. In a low NO, high renin rat model of hypertension, BAY 41-8543 prevented the increase in blood pressure evoked by L-NAME and reveals a kidney protective effect. In this model, the overall beneficial effects of BAY 41-8543 manifested as both antiplatelet effect and vasodilatation were reflected in a significant reduction in mortality. The pharmacological profile of BAY 41-8543 suggests therefore that this compound has the potential to be an important research tool for in vivo investigations in the sGC/cGMP field and it also has the potential of being a unique clinical utility for treatment of cardiovascular diseases.     

Endothelin antagonizes the hypotension and potentiates the hypertension induced by clonidine

Modification of clonidine-induced cardiovascular effects by endothelin-1 (ET-1) was studied in male Sprague-Dawley rats. A dose-dependent decrease in blood pressure and heart rate was produced by clonidine (100, 250 and 500 μg/kg i.v.). Lower doses produced only a fall in blood pressure (through central -adrenoceptors) while higher doses of clonidine produced an initial hypertensive response (through peripheral -adrenoceptors) and subsequent longer lasting hypotension and bradycardia. The hypotension and bradycardia induced by 100 and 250 μg/kg i.v. dose of clonidine were completely blocked by ET-1 (100 ng/kg i.v.) pretreatment. Conversely, the hypertensive response induced by high dose of clonidine (500 μg/kg i.v.) was significantly potentiated by ET-1 pretreatment. In cervical sectioned rats, i.v. administered clonidine failed to produce any hypotensive effect, indicating lack of central effect of clonidine. ET-1 significantly (P< 0.0005) potentiated the hypertensive response of a low dose (50μg/kg i.v.) of clonidine in cervical-sectioned rats. I.c.v administration of clodinine (1, 2, 4 and 6 μg) produced a dose-dependent decrease in blood pressure and heart rate. ET-1 pretreatment (25 ng i.c.v. transietly blocked the clonidine-induced decrease in blood pressure and heart rate for about 10 min but the hypotension and bradycardia was observed subsequently. Since the major site of action of clonidine is the ventral surface of medulla, clonidine was applied directly to the ventral surface of medulla and produced a decrease in blood pressure and heart rate. ET-1 pretreatment at the ventral surface of medulla blocked the clonidine-induced decrease in blood pressure and heart rate initially but the fall in blood pressure and heart rate was observed subsequently. To explore the possibility that transient antagonism of clonidine-induced effects is due to vasoconstriction, studies were performed with angiotensin II, a powerful vasoconstrictor. Angiotensin II (5 μg i.c.v.) pretreatment like ET-1 blocked the hypotensive and bradycardic effect of i.c.v. or i.v. administered clonidine. It is concluded that ET-1 blocks the hypotensive and potentiates the hypertensive effect of clonidine, possible mechanisms have been discussed.     

Can Garlic Lower Blood Pressure? A Pilot Study

A popular garlic preparation containing 1.3% allicin at a large dose (2400 mg) was evaluated in this open-label study in nine patients with rather severe hypertension (diastolic blood pressure ≥ 115 mm Hg). Sitting blood pressure fell 7/16 (± 3/2 SD) mm Hg at peak effect approximately 5 hours after the dose, with a significant decrease in diastolic blood pressure (p<0.05) from 5–14 hours after the dose. No significant side effects were reported. Our results indicate that this garlic preparation can reduce blood pressure. Further controlled studies are needed, particularly with more conventional doses (e.g., ≤ 900 mg/day), in patients with mild to moderate hypertension and under placebo-controlled, double-blind conditions.     

The effects of escalating doses of smoked cocaine in humans

This study examined the effects of escalating doses of smoked cocaine in non-treatment-seeking cocaine users. Cocaine sessions were conducted twice per day for 3 consecutive days. During each session, one group of participants smoked a 12 mg cocaine dose, followed by a 25 mg dose, followed by four 50 mg doses at 14 min intervals (escalating-dose group); another group of participants smoked six 50 mg cocaine doses at 14 min intervals (fixed-dosing group). Cocaine produced dose-dependent increases in heart rate (HR), blood pressure, ratings of positive drug effect, e.g., "good drug effect", and ratings of cocaine dose, e.g., "liking", in the escalating-dose group. The 50 mg dose also increased these measures in the fixed-dosing group to a level that was not different than that observed following the initial 50 mg dose in the escalating-dose group. The largest effects of 50 mg cocaine were observed following the initial dose, with the latter 50 mg doses maintaining but not increasing these effects in both groups. The effects of cocaine in both groups were consistent for most measures within a day and between days. Resting baseline heart rate, blood pressure and cocaine craving were lower during the first session and higher thereafter. These results demonstrate that increasing the dose of cocaine during a bout, i.e., "binge", of cocaine use can increment the effects of cocaine, but administering the same cocaine dose maintains, but does not increment the effects of cocaine.     

In vivo and in vitro activity of selective 5-hydroxytryptamine2 receptor antagonists

The abilities of ketanserin, ritanserin, R56413 and LY53857 to inhibit 5-hydroxytryptamine (5-HT) and noradrenaline-induced vasoconstrictor responses both in vitro and in vivo and to lower blood pressure in the rat, were compared. In the isolated perfused mesenteric artery preparation of the rat all of the compounds tested were found to be potent inhibitors of 5-HT-induced vasoconstrictor responses. Ritanserin was the most potent compound, producing more than 50% inhibition of a near maximal response to 5-HT at a concentration of 10(-11) M. All four compounds were found to be competitive antagonists of noradrenaline; ketanserin being the most potent with a pA2 value of 7.64 +/- 0.06. 5-HT-induced pressor responses in the pithed rat were inhibited by low doses (0.3-10 micrograms kg-1) of the four compounds. Ketanserin, at doses of 0.1-3.0 mg kg-1, resulted in rightward shifts of the control dose-response curve to noradrenaline in the pithed rat. None of the other compounds had any significant effect on the noradrenaline-induced pressor responses. Ketanserin (0.1-1 mg kg-1) produced a dose-dependent decrease in the mean arterial blood pressure of anaesthetized rats. The maximum decrease in blood pressure observed following a dose of 1 mg kg-1 ketanserin was 73.7 +/- 4.7 mmHg. The other compounds at doses of 1.0-3.0 mg kg-1 produced a decrease in blood pressure of a lesser magnitude than that following ketanserin. In addition, this effect did not appear to be dose-dependent. It is suggested that the acute hypotensive effect of ketanserin results predominantly from alpha 1-adrenoceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)     

不同剂量阿托伐他汀对高血压前期合并高脂血症患者血脂及血压的影响

目的:探讨不同剂量阿托伐他汀对高血压前期合并高脂血症患者血脂及血压的影响。方法:将体检发现的120例高血压前期合并高血脂患者随机均分为低剂量组、常规剂量组和对照组,并进行12周不同剂量阿托伐他汀药物干预性治疗。观察3组患者血脂及血压的变化及各组不良反应。结果:在改善血脂方面,常规剂量组优于低剂量组及对照组(P<0.05),低剂量组优于对照组(P<0.05)。在降低血压方面,常规剂量组优于低剂量组及对照组(P<0.05);低剂量组血压较对照组略有下降,但2组比较差异无统计学意义(P>0.05)。3组均未见明显不良反应。结论:常规剂量阿托伐他汀在有效降脂的同时,可进一步降低患者血压,且安全性较好。