Cosolvency of Dimethyl Isosorbide for Steroid Solubility

Dimethyl isosorbide (DMI), which is currently under investigation for its potential use as a pharmaceutical vehicle and drug permeation enhancer, is a water-miscible liquid with relatively low viscosity. The solubilization behavior of DMI as a cosolvent for nonpolar drugs was characterized via dielectric constant measurements of binary solvent systems containing DMI and either water, propylene glycol (PG), or polyethylene glycol (PEG). Evidence from the dielectric constant profiles and NMR studies suggest that DMI undergoes complexation with water and PG, but not with PEG, through hydrogen bonding interactions. The solvent complexation exhibited a major effect on the solubilities of prednisone, dexamethasone, and prednisolone in the mixed solvent systems. Maximum solubility of each drug was found to occur near a DMI/water or DMI/PG concentration ratio of 1:2. In the DMI–PEG mixed system, while there is no apparent interaction between DMI and PEG molecules, the solubility of prednisone was found to increase with decreasing dielectric constant.     

单硝酸异山梨酯联合磷酸川芎嗪治疗不稳定型心绞痛临床观察

目的观察单硝酸并山梨酯联合磷酸川芎嗪治疗不稳定型心绞痛的临床疗效。方法将80例患者随机分为两组。对照组在常规治疗的基础上加用单硝酸异山梨酯治疗，治疗组在常规治疗基础上，加用磷酸川芎嗪治疗。观察治疗前后心绞痛发作次数、心绞痛持续时间、发作间隔时间、Holter24h缺血总时间等变化。结果治疗组总有效率90．0％。优于时照组的77．5％（P〈0．05），且治疗组在心绞痛发作次数、持续时间、发作间隔时间及Hoher 24h缺血总时间改善方面优于对照组（P〈0．05）。结论单硝酸异山梨酯联合磷酸川芎嗪治疗不稳定型心绞痛疗效确切。     

5-单硝异山梨酯缓释剂治疗老年单纯收缩期高血压疗效观察

目的 观察5-单硝异山梨酯缓释剂（ISMN）对老年单纯收缩期高血压（ISH）患者降压治疗的疗效。方法 80例ISH患者随机分为对照组39例和治疗组41例，对照组给予氨氯地平5mg，吲达帕安2．5mg每日1次口服，治疗组在上述治疗的基础上给予5-单硝异山梨酯缓释剂40mg每日1次口服，疗程4周。结果 （1）治疗组从第一周开始收缩压（SBP）下降幅度即大于对照组，先于对照组于第二周降至正常，差异有显著性（P〈0．05）；（2）从第一周开始治疗组舒张压（DBP）下降幅度即小于对照组（P〈0．05），第三周开始差距加大，差异有非常显著性（P〈0．01），整个观察期内治疗组DBP下降幅度始终小于对照组，且从第二周开始处于相对稳定状态；（3）第一周开始治疗组脉压（PP）下降幅度即大于对照组（P〈0．05），第二周开始差距进一步加大，差异有非常显著性（P〈0．01）。结论 硝酸酯类药物能降低ISH患者的SBP,而对DBP影响不大，使PP减小，对ISH患者降压治疗有益。     

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.     

Role of pentobarbitone anaesthesia and sympathetic tone in the haemodynamic effects of isosorbide dinitrate in rats with cirrhosis

The haemodynamic effects of nitrovasodilators and their mechanisms of action on portal hypertension remain unclear. The splanchnic and systemic haemodynamic response to the infusion of isosorbide dinitrate (100 μg/kg per min), a nitrovasodilator, was investigated in cirrhotic rats. The role of the conscious state in the haemodynamic response to isosorbide dinitrate was examined using rats that were anaesthetized with pentobarbitone. The role of sympathetic tone in the haemodynamic response to isosorbide dinitrate was examined using rats pretreated with the ganglion blocker hexamethonium. Isosorbide dinitrate had no haemodynamic effects in conscious, unblocked normal and cirrhotic rats. Isosorbide dinitrate had no haemodynamic effects in normal and cirrhotic rats treated with hexamethonium. In normal anaesthetized rats, isosorbide dinitrate significantly decreased systemic vascular resistance (414±25 vs 290±26 dyn.s/cm⁵ per 100 g). In cirrhotic anaesthetized rats, isosorbide dinitrate significantly decreased mean arterial pressure (98±6 vs 79±7 mmHg), systemic vascular resistance (318±30 vs 207±10 dyn.s/cm⁵ per 100 g), portal pressure (14.0±1.0 vs 11.3±0.9 mmHg) and portal territory vascular resistance (1362±163 vs 1031±182 dyn.s/cm⁵ per 100 g). In conclusion, this study shows that the portal hypotensive effects of isosorbide dinitrate depend upon the alterations of vascular tone by pentobarbitone.     

Blood volume and right heart haemodynamics in abrupt hypotension following sublingual isosorbide dinitrate in acute myocardial infarction

Arterial blood pressure and heart rate were measured in 43 patientswith acute myocardial infarction and a systolic blood pressure120 mmHg during sublingual administration of 5 mg of isosorbidedinitrate. In 25 of them right heart haemodynamics were alsomeasured. Severe (25%) hypotension developed in 12 patients(Group 1, systolic blood pressure 158 ± 28 to 78 ±17 mmHg, mean ± SD) but not in the remaining 31 (Group2) and was accompanied by a fall in heart rate (82 ±20 to 70 ± 22beats min^-1, P<0.05), in cardiac output(4.3 ± 0.3 to 3.2 ± 0.4l mm^-1, P<0.02, n =5) and in systemic vascular resistances (2326 ± 463 to1532 ± 442 dynes sec^-1 cm^-5, P<0.02) not present inGroup 2. The reduction in right (Group 1,8 ± 3 to 3 ±1, vs. Group 2,10 ± 3 to 6± 3 mmHg, V <0.005)and in left ventricular filling pressures (Group 1,15 ±4 to 8 ± 2, vs. Group 2,18 ± 6 to 13 ±5 mmHg, P<0.001) was more remarkable in Group 1. In thisgroup there was also a high incidence of anterior infarction(9/12, 75%). Blood volume measured in 30 patients was lowerin Group 1 but differences were not significant. A second doseof 5 mg of isosorbide dinitrate 36–48 h later producedneither symptomatic hypotension (Group 1, 147 ± 29 to129 ± 24 mmHg) nor a fall in cardiac output in any patient,whereas changes infilling pressures were comparable to thoseof the first dose. Thus, severe isosorbide dinitrate-induced hypotension in myocardialinfarction is limited to the acute phase and seems more prevalentin anterior infarction but can not be clearly predicted fromresting haemodynamic or blood volume measurements, at leastin non-hypotensive patients. Moreover, it appears to be causedby an excessive ventricular emptying due to a striking venousand arterial vasodilation, probably during a stage of a particularlydepressed ventricular compliance.     

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。     

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.     

HPLC用于复方单硝酸异山梨酯-阿司匹林缓释片的质量分析

 目的建立用HPLC分析复方单硝酸异山梨酯-阿司匹林缓释片质量的方法。方法用高效液相色谱法检测复方单硝酸异山梨酯缓释片中药物的含量和释放度。色谱条件为：Hypersil C₁₈柱；甲醇-水(30∶70)加1‰磷酸调节pH值至3.0为流动相；流速为1 mL·min^-1；UV检测波长为235 nm。以乙腈为溶剂配制对照品溶液及样品溶液。结果复方中两种成分及阿司匹林水解产物水杨酸在20 min内达到良好分离。单硝酸异山梨酯、阿司匹林的线性范围分别为16.0～112.0 μg·mL^-1(r=0.999 9)，20.0～140.0 μg·mL^-1(r=0.999 9)。平均回收率分别为100.4%(RSD=0.66%)和100.7%(RSD=0.69%)。结论本法简便、快速，结果准确，可用于同类药品的质量标准研究和质量检验。     

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)