Clinical pharmacological equivalence of a novel FCH-free GTN spray with low ethanol content vs a FCH-containing GTN spray

The overall therapeutic equivalence of a fluorochlorohydrocarbon (FCH)-free glyceryl trinitrate (GTN) pump spray with a low ethanol content (TL) was investigated relative to an FCH-containing GTN spray (Nitrolingual; R), in terms of: (1) pharmacokinetic bioavailability, (2) pharmacodynamic responses as assessed by digital plethysmography (DPG), and (3) clinical perception upon application.Pharmacokinetically, the time courses of the plasma concentrations of GTN and its dinitrate metabolites, 1,2- and 1,3-GDN, subsequent to the sublingual administration of 0.8 mg GTN showed somewhat lower bioavailability of GTN and its metabolites than to the reference. Pharmacodynamically, the changes in the DPG signals after the application of 0.8 mg GTN with TL were biostatistically euivalent with R (estimated ratio TL/R for the maximum decrease of the ratio between the systolic a wave and c incisure: 0.98; 90% CI: 0.84–1.14; and for the average decrease of the c: a ratio: 0.97; 90% CI: 0.80–1.16). The time of occurrence of the maximum effect of TL was not significantly different from that of R (estimated difference TL-R: -2.25 min; 95% CI:-9.5 min to 2 min).In contrast, after the administration of an FCH-free GTN spray with a higher ethanol content (TH, active control), the effect had a slightly earlier onset (TH-R:-6 min, 95% CI: -9.5 to -2 min) and there was a higher average response (TH/R: 1.12: 90% CI: 0.95 to 1.34). However, TH was consistently judged to cause an extremely unpleasant burning sensation in the mouth and thus was perceived as distinctly different from R. In contrast, TL was well tolerated and could not be distinguished from R.Therefore only TL met the criteria of overall therapeutic equivalence to R.     

Comparative vasodilator effects of nitroglycerin,pentaerythritol trinitrate and biometabolites,and other organic nitrates

Previous studies in man have shown pentaerythritol (PE) trinitrate, given either sublingually or orally, produces a prolonged hypotensive effect. The coronary vasodilator and systemic vasoddepressor activities of PE trinitrate and its metabolites, PE dinitrate, PE mononitrate and PE, were evaluated in dogs to determine whether the metabolites were active and contributory. Coronary vasodilator activity was estimated with a flow transducer placed on the left anterior descending artery, and reduction of arterial pressure was determined directly via the femoral artery. Quantitative comparisons were made from dose—response curves established for nitroglycerin (NG), PE nitrates, and other common organic nitrates after intrajugular administration. Increase of coronary blood flow and reduction of arterial pressure were proportionally related, and the proportionality was the same for all drugs. Relative to NG, the potency of PE trinitrate was about 20%, erythrityl tetranitrate 12%, and isosorbide dinitrate 3.5%. The ratios of vasodilator activity of PE trinitrate and its metabolites were: PE trinitrate 100; PE dinitrate 1.5; PE mononitrate 0.5; and PE 0. Tachyphylaxis was observed after close-order injections of NG or PE trinitrate. In addition, there was cross tolerance between NG and PE trinitrate and also between PE trinitrate and its less active metabolites.     

NADPH-diaphorase activity and Fos expression in brain nuclei following nitroglycerin administration

Organic nitrates are considered nitric oxide donors in that they have been shown to form nitric oxide in vitro and in vivo. Nitroglycerin is an organic nitrate which possesses peculiar activities mediated, to some extent, by the central nervous system via the noradrenergic system. Previous reports have shown that systematic nitroglycerin is able to induce Fos expression in brain nuclei which are known to contain also the nitric oxide synthesizing enzyme. Neuronal NADPH-diaphorase has been shown to be a nitric oxide synthase. Thus, in this study we used NADPH-diaphorase histochemistry to evaluate the distribution of Fos-immunoreactive cells within neurons which contain nitric oxide synthase. The data obtained showed co-localization of Fos with NADPH-diaphorase activity in numerous neurons of the paraventricular and supraoptic nuclei of the hypothalamus. In the brainstem, a few neurons were doubly labeled for Fos and NADPH-diaphorase activity, but NADPH-diaphorase positive fibers and Fos-immunoreactive neurons were consistently co-distributed in the locus coeruleus, parabrachial nucleus, nucleus tractus solitarius and spinal trigeminal nucleus caudalis. These findings demonstrate that nitroglycerin administration activates a selective group of neurons which are a source of nitric oxide or which are in close proximity with neuronal processes containing nitric oxide synthase, and suggest that the nitric oxide synthesizing pathway may be involved at various levels in the central effect of nitroglycerin.     

Dissociation of increases in cyclic GMP from relaxation of arterial smooth muscle

Glyceryl trinitrate increased the cyclic GMP content of epinephrine-contracted aortic strips from glyceryl trinitrate-tolerant rats in a dose-dependent manner. Glyceryl trinitrate (.05 millimicron/ml) at a concentration that caused to relaxation of aortas from tolerant animals but a 42.4 3.7% relaxation of control aortas, elevated cyclic GMP levels in both groups approximately 3-fold. The results are not consistent with the hypothesis that cyclic GMP is involved in the relaxation of arterial smooth muscle.     

米力农与硝酸甘油治疗心绞痛急性发作临床对照研究

目的评价米力农治疗心绞痛急性发作的疗效及安全性。方法选择心绞痛急性发作患者60例,随机分为2组,每组30例。2组均给予相同基础治疗,对照组加用硝酸甘油,治疗组加用米力农,均为静脉滴注,1~2次/d,连用3 d。用药前后观察2组临床总有效率、心率、血压、左室舒张末期内径(LVEDD)、左室射血分数(LVEF),以及并发症和不良反应情况。结果 2组临床总有效率比较,差异无统计学意义。治疗后2组患者心率、血压、LVEDD及LVED均较治疗前明显改善,但米力农组改善情况优于对照组,差异有统计学意义。米力农组无停药及死亡病例,对照组发生2例停药及2例死亡病例,且米力农组并发症及不良反应发生率高于对照组。结论米力农治疗心绞痛急性发作疗效确切、安全可靠。     

盐酸乌拉地尔控制老年高血压患者拔牙术中血压升高的疗效

目的:评价高血压患者拔牙术中出现血压明显升高时给予静脉注射盐酸乌拉地尔控制血压的疗效.方法:选择60例拔牙术中血压明显升高的高血压患者,随机均分为观察组和常规治疗组,观察组予静脉注射乌拉地尔,常规治疗组静脉点滴硝酸甘油,分别比较两组在5 min、10 min、20min和30 min时的降压有效率和心率的变化以及出现头...     

Inhalation of nebulized nitroglycerin, a nitric oxide donor, for the treatment of pulmonary hypertension induced by high pulmonary blood flow

This study explores the effect and mechanisms of inhalation of nebulized nitroglycerin (Neb-NTG) on pulmonary hypertension induced by high pulmonary blood flow. An aortocaval shunt was produced in rats. Twelve weeks after the operation, rats started to inhale Neb-NTG. After 15 weeks, pulmonary and systemic hemodynamics as well as pathological changes were measured in all animals. Inhalation of Neb-NTG was able not only to markedly attenuate pulmonary artery pressure without impacting systolic pressure but also to ameliorate muscularization of small pulmonary arteries. The relaxation response of pulmonary artery ring to acetylcholine in shunt rats and Neb-NTG-treated rats was decreased. However, Neb-NTG did not impact the relaxation response of pulmonary artery ring to both nitroprusside and nitroglycerin (NTG). Neb-NTG successfully inhibited the increased expression of pulmonary artery smooth muscle cell (PASMC) proliferative cell nuclear antigen, collagen I, and collagen III, as well as pulmonary artery urotensin-II in shunt rats with high pulmonary blood flow. Neb-NTG selectively ameliorated pulmonary hypertension as well as pulmonary vascular structural remodeling induced by high pulmonary blood flow.     

硝酸甘油耐受加重缺血再灌注所引起的主动脉损伤及其机制的实验研究

目的研究硝酸甘油耐受对缺血再灌注动脉损伤的影响及其机制。方法雄性SD大鼠尾静脉给予硝酸甘油(60μg·kg-1·h-1)或生理盐水12 h,测量平均动脉压和离体血管张力以确定硝酸甘油耐受是否产生。耐受大鼠的离体动脉随机接受以下处理:(1)模拟缺血再灌注,(2)模拟缺血再灌注+还原型谷胱甘肽(GSH,终浓度0.1 mmol/L),(3)对照处理(n=16-18)。未产生耐受的大鼠随机接受模拟缺血再灌注或对照处理(n=16-18)。为了确定硝酸甘油耐受对缺血再灌注血管损伤和内皮功能的影响,检测各组再灌注液中一氧化氮含量、肌酸激酶(CK)和乳酸脱氢酶(LDH)活性,并观测血管收缩功能和对乙酰胆碱的反应。免疫组化标记血管中的硝基化酪氨酸(过氧亚硝基阴离子标志物),灰度扫描分析标记强度。结果与其他各组相比,接受模拟缺血再灌注处理的硝酸甘油耐受血管内皮功能(乙酰胆碱舒张反应和合成一氧化氮能力)显著下降,组织损伤明显增加(CK、LDH活性增加,血管收缩功能降低),血管内硝基化酪氨酸含量显著升高。GSH显著抑制了硝酸甘油耐受的血管损伤作用。结论实验结果显示硝酸甘油耐受显著增加了缺血再灌注诱导的血管损伤,这种作用可能是过氧亚硝基阴离子介导的。此外,我们的结果还表明GSH不仅降低了硝酸甘油耐受的血管损伤作用,而且抑制了血管内过氧亚硝基阴离子的形成。     

预防桡动脉痉挛的前瞻性随机双盲研究

目的在使用维拉帕米的基础上,观察维拉帕米加量或联用硝酸甘油预防经桡动脉介入诊疗中桡动脉痉挛（rad ial artery spasm,RAS）的效果。方法前瞻性入选经桡动脉冠状动脉介入治疗的患者,按照随机、双盲原则将患者分为A组（维拉帕米200μg）、B组（维拉帕米1 mg）和C组（维拉帕米200μg＋硝酸甘油200μg）。在动脉鞘管置入后,随机给予不同药物。使用造影证实的临床RAS定义。记录并比较各组患者RAS和不良反应的发生率。结果共入选患者621例,其中A组205例、B组206例、C组210例。三组患者的基线资料比较,差异均无统计学意义。单因素方差分析显示,A组患者RAS发生率高于B组（17.1%比10.2%,P=0.045）和C组（17.1%比9.5%,P=0.029）,B组和C组间差异无统计学意义（10.2%比9.5%,P=0.870）。Logistic回归分析显示,B组和C组比A组发生RAS相对风险分别降低了32.1%（P=0.038）和43.8%（P=0.017）。不良反应A组和C组相似,均较少。B组不良反应发生率高于A组（9.7%比2.4%,P=0.003）和C组（9.7%比3.8%,P=0.019）。结论在经桡动脉介入诊疗中,推荐国人使用维拉帕米200μg＋硝酸甘油200μg预防RAS,该剂量安全、有效,且不良反应较少。     

硝酸甘油微量注射器持续泵注治疗重症充血性心力衰竭临床观察

目的：观察治疗重症充血性心力衰竭（CHF）的疗效方法。方法：选择50例充血性心力衰竭心功能Ⅲ～Ⅳ级住院患者,均进行病因和对症治疗并按CHF常规处理,包括低盐饮食,在应用洋地黄、利尿剂和血管紧张素转换酶抑制剂（ACEI）的基础上,应用硝酸甘油微量注射器以2～7mg/h持续泵注,连续7d。动态观察血压、临床症状、体征。结果：治疗1周后,总有效率为94%。结论：硝酸甘油注射液可有效治疗重症CHF,能明显改善患者心脏功能,短期应用副作用少、安全性好。