Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration

The pharmacokinetics and haemodynamic effects of isosorbide dinitrate (ISDN) have been investigated following administration of single doses as a sublingual (SL) spray (2.5 mg), sublingual tablet (5 mg) and peroral tablet (10 mg) in a randomised, placebo-controlled double-blind cross-over trial in 16 healthy volunteers.After the sublingual spray C_max was higher (39.0 ng·ml^-1) and t_max was shorter (3.9 min) than after the sublingual (22.8 ng·ml^-1 and 13.8 min) and peroral (16.9 ng·ml^-1 and 25.6 min) tablets. The AUC of ISDN did not differ following any of the three formulations (1031; 879; 997 ng·ml^-1·min, for the spray, SL tablet and PO-tablet, respectively). Mononitrate metabolites of ISDN (IS-2-MN and IS-5-MN) and total nitrates in plasma increased in proportion to the administered dose. This indicates that the fraction of the dose absorbed was the same for all the formulations but that the extent of first-pass metabolism increased in the order sublingual spray < sublingual tablet < peroral tablet. Thus, compared to the spray, the relative bioavailability of ISDN was 48% and 28% from the sublingual and peroral tablets, respectively.The haemodynamic effects were quantified using the a/b ratio of the finger pulse wave and the systolic blood pressure and heart rate under orthostatic conditions. For the a/b ratio of the finger pulse, the maximal effect was higher (e_max=130%) and the time to e_max (t_emax) shorter (16.6 min) after the spray than the sublingual tablet (84.4% and 25.5 min) or peroral tablet (90.2 and 31.3 min). The onset of effect was within 3, 5 and 7.5 min after the spray, sublingual and peroral tablets, respectively. A larger change in the orthostatically-induced decrease in systolic blood pressure and increase in heart rate was obtained following peroral than sublingual administration despite the similar plasma concentrations of ISDN. This probably reflects the larger amount of pharmacodynamically active mononitrate metabolites formed after oral dosing. The integrated effect following administration of 2.5 mg ISDN as spray was similar to that of a sublingual tablet of 5 mg.     

复方丹参滴丸抗心绞痛临床观察

目的 观察复方丹参滴丸抗心绞痛的疗效和耐药性,并与消心痛的疗效进行比较。方法 将病人随机分为A组和B组,以双盲方式给药观察8周。A组口服复方丹参滴丸10粒／次、3次／d,B组口服消心痛10mg/次、3次／d。结果 心绞痛有效率,ECG有效率用药2周时两组无显著差异,用药后第4周、第6周和第8周A组优于B组。用药后第6周与第2周的有效率比较,A组无明显变化（P＞0．05）,B组显著下降（P＜0．05）。结论 与消心痛相比较,长期服用复方丹参滴丸的有效率高,疗效稳定,且不产生耐药性。     

单硝酸异山梨酯药动学和药效学特点及机制探讨

目的：对单硝酸异山梨酯药动学和药效学作用特点及其机制等方面进行评价,为该类药物的开发利用提供理论参考。方法：收集有关该药的国内外近期资料加以综合归纳。结果：较为系统的阐明了该药作用及作用机制在目前国内外研究状况,并提出将来的研究动态。结论：单硝酸异山梨酯具有疗效肯定、用途广泛、毒副作用小等特点     

Effects of molsidomine,nitroglycerin, and isosorbide dinitrate on the coronary circulation,myocardial oxygen consumption,and haemodynamics in anaesthetized dogs

Summary The effects of i.v. molsidomine administration on the coronary circulation, myocardial oxygen consumption, and haemodynamics were studied in open-chest dogs with non-constricted coronary arteries, and compared to those of nitroglycerin and isosorbide dinitrate. Molsidomine (50, 100, 250 g/kg) reduced coronary flow while nitroglycerin (5, 10, 20 g/kg) and isosorbide dinitrate (50, 100, 250 g/kg) augmented coronary flow indicating coronary dilatation. Coronary resistance remained unaffected by molsidomine but fell after both nitrates. Molsidomine decreased myocardial oxygen consumption whereas nitroglycerin and isosorbide dinitrate initially increased oxygen consumption followed by a reduction. A decrease in stroke work was calculated after all three drugs. Minute work fell after molsidomine and nitroglycerin but not after isosorbide dinitrate.Heart rate and contractility remained unchanged by molsidomine but were both significantly enhanced by both nitrates. Stroke volume and cardiac output fell after molsidomine but increased immediately after both nitrates when administered with a subsequent decrease. Peripheral resistance was unchanged by the low dose of molsidomine but significantly decreased by the two nitrates immediately after administration indicating precapillary vasodilatation. The fall in blood pressure after molsidomine followed the reduction in cardiac output as sequel of lowered preload and venous return to the heart. The same mechanism decreased heart work after both nitrates but in addition vasodilatation of the coronary arteries and arterial vessel occurred.The effects of the three compounds are mainly the consequence of extracardiac effects, i.e. increased capacity of postcapillary vessels (molsidomine) plus arteriolar vasodilatation of short (nitroglycerin) and long duration (isosorbide dinitrate), respectively. Whereas molsidomine exerts no effects on the heart and coronary circulation both nitrates dilate coronary arteries and change heart performance thus indicating direct effects on the entire heart.     

复方单硝酸异山梨醇酯缓释片人体生物等效性研究

目的 :评价试验制剂复方单硝酸异山梨醇酯缓释片 (T)与参比制剂单硝酸异山梨醇酯缓释片和阿司匹林肠溶片 (R)的生物等效性 ,以及缓释制剂释放特点、稳态血浓度和波动度。方法 :采用高效液相色谱法分别测定单剂和多剂交叉给药单硝酸异山梨醇酯和阿司匹林代谢物水杨酸经时血浓度 ,计算药物动力学参数 ,并进行方差分析和双单侧t检验。结果 :单剂给药试验制剂和参比制剂单硝酸异山梨醇酯半衰期 (t1 2 )分别为 8.3± 0 .6、8.2± 0 .6h ,血浓度峰值 (Cmax)分别为 0 .5 1± 0 .0 9、 0 .5 3±0 .0 9mg·L-1,达峰时间 (tmax)分别为 4 .8± 0 .4、4 .6± 0 .3h ,药时曲线下面积 (AUC0 -t)分别为 4 .90±0 .6 1、5 .2± 0 .8mg·h-1·L-1,相对生物利用度 (F)为(96 .1± 10 .8) % ;试验制剂和参比制剂阿司匹林代谢物水杨酸t1 2 分别为 2 .4± 0 .3、2 .5± 0 .3h ,Cmax分别为 3.4± 0 .5、3.0± 0 .4mg·L-1,tmax分别为 1.7±0 .2h和 4 .9± 0 .3h ,AUC0 -t分别为 13.4± 2 .5和13.0± 2 .5mg·h-1·L-1,以水杨酸计阿司匹林F为(10 3.6± 9.6 ) %。多剂给药试验制剂和参比制剂单硝酸异山梨醇酯Cmax 分别为 0 .6 8± 0 .14、0 .6 7±0 .13mg·L-1,Cmin 分别为 0 .17± 0 .0 3、 0 .17±0 .0 4mg·L-1,波动系数 (DF)     

麝香保心丸与硝酸异山梨酯联合治疗无症状性心肌缺血的效果研究

目的探讨无症状性心肌缺血患者使用麝香保心丸与硝酸异山梨酯联合治疗后的临床效果。方法选择来我院就诊的无症状性心肌缺血患者72例作为本次研究对象，随机分为两组。观察组（n=36）采用麝香保心丸联合硝酸异山梨酯进行治疗，对照组（n=36）采用硝酸异山梨酯进行治疗，对两组患者的心电图心肌缺血改善情况及血脂、血液动力学观察指标进行对比分析。结果观察组患者与对照组比较，心电图缺血改善情况中有效率明显较高，两组差异具有显著性（P〈0．05）。治疗后观察组患者的全血黏度高切值、全血黏度低切值、血浆比黏度、TG、TC均显著降低，与对照组治疗后比较改善情况明显较好（P〈0．05）。所有患者治疗后均未发现不良情况。结论无症状性心肌缺血患者在采用麝香保心丸联合硝酸异山梨酯治疗后能够收到较好的临床效果。可以在临床推广应用。     

Effects of Vehicles and Pressure Sensitive Adhesives on the Penetration of Isosorbide Dinitrate Across the Hairless Mouse Skin

The effects of various vehicles and adhesives on the percutaneous absorption of isosorbide dinitrate (ISDN) were evaluated. Lauroglycol ® FCC showed the highest flux among vehicles tested. The flux of ISDN from silicone and acrylic adhesive matrices was found to be higher than that from other types of adhesive matrices. No statistically significant relationship between the flux from acrylic PSA and the flux from a solution formulation was observed. A highly cross-linked acrylic adhesive gave higher permeation rates than the other acrylic adhesives examined. N-decylmethyl sulfoxide showed the highest enhancing effect on the flux of ISDN from acrylic adhesive. The relationship between the HLB values of vehicles and the measured flux showed a decrease of flux at HLB values greater than 12.     

中西医结合治疗冠心病劳力型心绞痛60例疗效分析

目的：比较分析中西医结合治疗与单纯西药治疗冠心病劳力型心绞痛的疗效,以为今后临床本病的治疗提供参考。方法114例冠心病合并劳力型心绞痛患者,随机分为中西医结合治疗组(观察组,60例)以及西药治疗组(对照组,54例),对照组给予单硝酸异山梨酯片治疗,观察组在对照组基础上联合自制中药汤剂治疗。观察两组疗效。结果观察组显效34例,有效18例,无效8例,总有效率为86.7%,对照组患者显效18例,有效20例,无效为16例,总有效率为70.4%,观察组总有效率明显高于对照组,差异具有统计学意义(P<0.05)。两组均有个别患者有副作用,经对应调节后副作用均消失,所有患者均坚持全程服药。结论中西医结合治疗冠心痛劳力型心绞痛疗效显著,值得临床应用推广。     

Pharmacokinetic Interaction of the Direct Renin Inhibitor Aliskiren with Furosemide and Extended‐Release Isosorbide‐5‐Mononitrate in Healthy Subjects

This study investigated the pharmacokinetics, safety, and tolerability of aliskiren administered alone or in combination with either the loop diuretic furosemide or an oral extended‐release formulation of isosorbide‐5‐mononitrate (ISMN). In separate studies, 22 healthy subjects (ages 18–45 years) received either ISMN 40 mg or furosemide 20 mg once‐daily for 3 days followed by a 3‐day washout. Subjects then received aliskiren 300 mg once‐daily for 7 days followed by combination therapy for 3 days. Pharmacokinetic assessments were taken at regular intervals over 24 h after dosing on the last day of each treatment period. At steady state, aliskiren AUC_τ was decreased by 7% (geometric mean ratio [90% CI], 0.93 [0.84, 1.04]), and C_max by 20% (0.80 [0.65, 0.97]) with furosemide coadministration compared with aliskiren administration alone. Aliskiren coadministration reduced furosemide AUC_τ by 28% (0.72 [0.64, 0.81]) and C_max by 49% (0.51 [0.39, 0.66]) compared with furosemide alone. Coadministration of aliskiren and ISMN was associated with only minor changes in the pharmacokinetic parameters of aliskiren (AUC_τ 1.03 [0.90, 1.18]; C_max 0.94 [0.69, 1.29]) and ISMN (AUC_τ 0.88 [0.71, 1.10]; C_max 0.94 [0.79, 1.13]). Headache and dizziness were the most common adverse events in both studies; dizziness and BP values below normal (SBP <90 and/or DBP <50 mmHg) were more frequent with aliskiren and ISMN coadministration than with either agent alone. Coadministration of aliskiren and ISMN had no clinically relevant effect on either aliskiren or ISMN pharmacokinetics. In conclusion, coadministration of aliskiren and furosemide reduced furosemide exposure and had a minor effect on aliskiren pharmacokinetics. The clinical significance of reduced systemic exposure to furosemide during coadministration of aliskiren is uncertain.     

Comparison of the antianginal efficacy of isosorbide dinitrate (ISDN) 40 mg and verapamil 120 mg three times daily in the acute trial and following two-week treatment

Fourteen male patients with exertion-related angina pectorisand reproducible ST-segment depression on stress testing wereeach treated with isosorbide dinitrate (ISDN) 40 mg three timesdaily, verapamil 120 mg three times daily and placebo threetimes daily for two weeks according to a double-blind cross-overprotocol. The mean improvement of exercise-induced ST-segment depressionamounted to 73% on the first day of ISDN treatment (P < 0.001)and to 54% following acute administration of verapamil (P <0.001). On the last day of continuous treatment, the antianginalefficacy of ISDN was somewhat mitigated (reduction of ST-segmentdepression: 54%; P<0.001), while the effect of verapamilremained unchanged (55%, P<0.001). The double product (heartrate x systolic blood pressure) at the end of stress testingdecreased most pronouncedly on day 1 of ISDN treatment ( - 21%;P<0.01). On chronic testing, both drugs similarly influencedthis parameter: 10–11% (P<0.05). The mean global ejectionfraction (EF) assessed by gated blood pool scintigraphy on day13 showed a stress-induced fall from 49 to 44% (P<0.05) afterthe administration of placebo. The respective values with ISDNwere 53% at rest and 52% on exercise (n.s.), and after givingverapamil 50% and47% (n.s.). Thus, ISDN 40 mg and verapamil 120 mg displayed beneficial anti-ischaemiceffects in patients with stable exertion-related angina pectorisafter acute and chronic administration. The efficacy of ISDNdeclined somewhat in the course of the two-week treatment, whereasthat of verapamil remained unchanged. Beneficial effects ofboth drugs were also demonstrated with regard to the rate pressureproduct. Isosorbide dinitrate 40 mg and verapamil 120 mg administeredthree times daily can be recommended for the acute and chronictherapy of patients with stable angina.