Bioequivalence of a sustained-release isosorbide dinitrate formulation at steady-state

Isosorbide 2,5-dinitrate and its pharmacologically active metabolites, isosorbide 2-nitrate and isosorbide 5-nitrate, in plasma accumulated to the predicted steady-state after five consecutive oral doses of sustained-release tablets containing 40 mg isosorbide dinitrate at 12-h intervals and after five consecutive oral doses of reference standard-release tablets containing 20 mg at 6-h intervals to 12 subjects in a crossover study. The comparative bioavailability of isosorbide dinitrate, isosorbide 2-nitrate and isosorbide 5-nitrate from the sustained-release tablet was 110 per cent (p greater than 0.05), 89 per cent (p greater than 0.05), and 89 per cent (p less than 0.05), respectively, of that from the reference standard-release tablet. The isosorbide dinitrate plasma level data were the more variable, as expected for a drug of low systemic availability subject to extensive first-pass elimination. The posterior probability that the true bioavailability of isosorbide dinitrate was included within the usually accepted limits of 80-120 per cent was 0.74, a value which is probably insufficient to justify claims of bioequivalence with the reference formulation in respect of extent of availability. In contrast, the posterior probability that the bioavailability of the metabolites isosorbide 2- and 5-nitrate was included within these limits was 0.90 and 0.98, respectively. On the basis of the mononitrate data, these two formulations may be judged bioequivalent in respect of extent of availability despite a formal statistically significant formulation-related effect in the analysis of variance of the isosorbide 5-nitrate bioavailability data. Claims of bioequivalence of isosorbide dinitrate sustained-release formulations may be more economically justified by analysis of the mononitrate plasma concentrations, although concentrations of the formulated parent dinitrate should also be known.     

Measurement of plasma concentrations of isosorbide dinitrate

Concentrations of the vasodilator isosorbide dinitrate (ISDN) in human plasma can be measured with good sensitivity (about 0·2–0·5 ng ml^?1) using electron-capture gas chromatography after a one-stage extraction. The mean recovery of ISDN from plasma was 83 per cent ± 9 standard deviation (S.D.). The precision of the method for the measurement of ISDN in plasma ranged from ± 14 per cent at 1 ng ml^?1 to ± 7 per cent at 5 ng ml^?1 to ± 4 per cent at 50 ng ml^?1. The 95 per cent confidence limits of the least-squares regression calibration line forced through the origin were ± 100 per cent at 1 ng ml^?1, ± 11 per cent at 10 ng ml^?1, and ± 8 per cent at 30 ng ml^?1. The method has been used to assay many samples withdrawn after doses of drug at therapeutic levels to normal subjects.     

Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5·0 mg h^?1 for 150 min and after single equal oral doses of 12·5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml^?1 and 514 ng ml^?1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9–10 min. After oral doses, peak plasma levels of 26·6 ng ml^?1 and 12·7 ng ml^?1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0·32 1 min^?1 and 0·161 min^?1 were unexpectedly low for a drug of reported high liver extraction ratio.     

Influence of exercise on plasma concentrations of isosorbide dinitrate

Summary As the fall in hepatic blood flow caused by exercise is expected to decrease the elimination of high extraction drugs, the influence of exercise on the fate of the anti-anginal drug isosorbide dinitrate has been assessed.Isosorbide dinitrate 10 mg was given orally, after an overnight fast, on 2 different days to 7 healthy volunteers and the plasma concentrations of the parent compound and its mononitrate metabolites were measured.Heavy bicycle exercise from the 45 th to the 105 th min after intake of the drug on one of the experimental days did not change the plasma isosorbide dinitrate concentrations as compared to those on the rest day. The concentrations of both mononitrates were lower on the exercise day, but the difference was already present before the exercise started.     

Plasma concentrations and relative bioavailability of naftidrofuryl from different salt forms

The relative bioavailability of the vasodilator naftidrofuryl from formulations containing its oxalate or citrate salt has been estimated using a specific HPLC assay, and a less specific fluorimetric assay, to measure plasma drug concentrations. The conclusions of the study were the same irrespective of the assay employed. The relative rate, but not the extent, of bioavailability of naftidrofuryl from the citrate salt (peak 1096 ng ml-1 at 0.76 h) was marginally greater (p = 0.003) than that from the oxalate salt (peak 922 ng ml-1 at 0.94 h). The degree of intersubject variability was similar after administration of either salt form. The mean half-life of naftidrofuryl was 1.8 h and its mean residence time was 2.5 h.     

Plasma disposition and hemodynamic effects of a single oral dose of isosorbide dinitrate in human males and females.

The goal of the present work was to determine the plasma disposition and hemodynamic effects of isosorbide dinitrate (ISDN) in human males and females. Fourteen healthy human volunteers took part in the study; seven males, 21.7 +/- 2.5 y (SD), and seven females, 20.7 +/- 3.4 y. Measurements of forearm blood flow (FBF), vascular conductance (FVC), and venous capacitance (Cv) were obtained by venous occlusion plethysmography, whereas blood pressure was measured by automatic sphygmomanometry. Blood samples were taken through a catheter placed in the antecubital vein at 0, 15, 30, 45, 60, 90, 120, 360, 480, 720, and 1440 min following a single 10 mg oral dose of ISDN. Plasma concentrations of ISDN and its mononitrate metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN), were determined by large bore capillary column gas-liquid chromatography. Hemodynamic measurements were made at corresponding experimental times up to 480 min. No differences were observed in the disposition of ISDN, 2-ISMN or 5-ISMN between the male and female volunteers. In addition, the plasma concentrations of ISDN and its mononitrate metabolites did not consistently correlate with the hemodynamic changes of the individual subjects. Diastolic blood pressure was significantly decreased for a 0.5 h period starting at 30 min, which was the time at which plasma ISDN concentrations peaked, and which preceded the time when the plasma concentrations of 2-ISMN and 5-ISMN were maximal. These observations indicate that, for a single 10 mg oral dose of ISDN, there were no gender-dependent differences in the plasma disposition of the parent drug or its mononitrate metabolites, and the vascular changes responsible for the decrease in diastolic blood pressure in these volunteers occurred in vascular beds other than those of skeletal muscle as represented by forearm blood flow.     

Bioavailability of bemetizide and triamterene from a combination formulation

The bioavailability of the thiazide diuretic bemetizide from a tablet containing 25 mg of this drug and 50 mg of the chemically unrelated diuretic triamterene was lower than, and significantly different (P < 0.01) from that from a tablet containing 25mg bemetizide alone. The mean peak plasma level of bemetizide after administration of the combination tablet (68.3ngml^?1) was lower than that after administration of bemetizide alone (87.9 ngml^?1), although the times of occurrence of the peak levels were similar. The bioavailability of triamterene from the combination tablet was greater than, but not significantly different from that after administration of a capsule containing 50 mg triamterene alone. The mean peak plasma level of triamterene after administration of the combination tablet (44.6 ng ml^?1) was higher than and significantly different (p< 0.001) from that after administration of triamterene alone (15.7 ng ml^?1). Although bemetizide is unstable in urine, measurement of the apparent excretion of unchanged drug in the 24 h post-dose urine (less than 4 per cent of the dose) agreed with the estimate of drug bioavailability from the plasma level data. Less than 2 per cent of the dose of triamterene was excreted unchanged in the 24 h post-dose urine, but the urinary excretion data also agreed with the bioavailability estimates from the plasma level data. The results of this study and those reported in the literature suggest that because of their physicochemical properties, the bioavailability of some thiazides and triamterene needs to be evaluated when new formulations of these drugs are produced. However, with respect to the combination formulation reported in this paper, the difference in bioavailability of the thiazide component did not detectably effect the diuretic activity of the formulation.     

舒芬太尼或芬太尼复合硝酸异山梨酯预防老年高血压患者气管插管反应

目的观察舒芬太尼或芬太尼复合硝酸异山梨酯对老年高血压患者全麻诱导期应激反应的影响。方法选择20例60～70岁拟于全身麻醉下行手术治疗的患者,随机分为实验组：舒芬太尼组（I）和对照组：芬太尼组（II）。两组患者在麻醉诱导时分别应用舒芬太尼和硝酸异山梨酯或芬太尼和硝酸异山梨酯,观察两组患者诱导前（T0）、插管前（T1）、插管后即刻（T2）以及插管后5min（T3）、10min（T4）时点的收缩压（DBP）、舒张压（SBP）、心率（HR）值以及血浆中去甲肾上腺素（NE）、心钠素（ANP）的浓度。结果与诱导前（T0）相比,两组患者插管后即刻（T2）血压无明显变化。舒芬太尼组（I）,插管后5min（T3）、10min（T4）血压低于T0点,插管后即刻（T2）及5min（T3）,舒芬太尼组（I）血压低于芬太尼组（II）。与插管前（T1）比较,两组患者插管后即刻（T2）心率均升高。舒芬太尼组（I）,插管后即可（T2）及5min（T3）,血浆中去甲肾上腺素浓度均低于芬太尼组。两组比较,血浆心钠素浓度无差别。结论舒芬太尼组和芬太尼组均能有效抑制诱导期应激反应,舒芬太尼组更有效。     

Assay of glyceryl trinitrate, isosorbide dinitrate, and their metabolites in plasma by large-bore capillary column gas-liquid chromatography

Two large-bore capillary columns, one with dimethyl polysiloxane (HP-1) as the stationary phase and the other with phenyl (50 per cent) methyl (50 per cent) polysiloxane (DB-17), were used to develop gas-liquid chromatographic (GLC) assays for measuring isosorbide dinitrate (ISDN), glyceryl trinitrate (GTN), and their metabolites. ISDN, isosorbide-2-mononitrate (2-ISMN), and isosorbide-5-mononitrate (5-ISMN) in plasma, ranging in concentration from 1 to 300 nM, and GTN, glyceryl-1,2-dinitrate (1,2-GDN), and glyceryl-1,3-dinitrate (1,3-GDN), ranging in concentration from 3 to 60 nM in plasma, were analysed on both columns. GLC analysis yielded baseline resolution of the analytes. The method using the dimethyl polysiloxane column gave a lower limit of detectability for GTN of 0.75 nM (signal/noise (s/n) = 2), and the procedure using the phenyl-methyl column provided a lower limit of detectability for ISDN of 81 pM (s/n = 2). The large-bore column GLC procedures exhibited shorter retention times for both ISDN and GTN than those previously reported for capillary-column assays. The chromatographic resolution of analytes and column efficiency of the large-bore capillary columns were comparable to the results previously found using capillary-column GC. The assays for ISDN and GTN have been shown to be appropriate for pharmacokinetic studies in volunteers and patients. We determined that the HP-1 column is appropriate for the analysis of GTN and metabolites, and the DB-17 column is suitable for analysis of ISDN and its metabolites. We conclude that the use of large-bore capillary columns provides rapid and reliable GLC assays for organic nitrates.     

硝酸异山梨酯缓释微丸处方及工艺优化

目的制备硝酸异山梨酯缓释微丸,优化处方及制备过程。方法采用粉末层积法和流化床喷雾法制备膜控缓释微丸,用单因素考察实验优化处方及工艺,采用HPLC法测定缓释微丸的累积释放度。结果确定以Eudragit RS30D和Eudragit RL30D混合分散体为包衣材料,Eudragit RS30D与Eudragit RL30D的比例是4∶1,包衣增重为5%,热处理温度、时间为40℃、24小时,抗静电剂、增塑剂分别占包衣聚合物量的0.5%、20%。在体外释放度实验中,微丸累积释放硝酸异山梨酯百分率,0.5小时为10.71%,2小时为45.80%,8小时90.79%,24小时为99.14%。结论体外释放度实验中,Eudragit RS30D与Eudragit RL30D的比例对微丸累积释放度的影响较大,随着包衣量增加,释放度略有降低。本制剂为膜控制剂。     

Concentrations of the vasodilator isosorbide dinitrate and its metabolites in the blood of human subjects

Summary An oral dose of 5 mg of¹⁴C-isosorbide dinitrate was rapidly absorbed, biotransformed and excreted by human subjects. Peak whole blood concentrations of radioactivity were reached after 1.5 to 2 hours and declined relatively slowly. The radioactivity in whole blood mainly represented metabolites, isosorbide mononitrates. The peak concentrations found were 4.5, 11.7 and 34.3 ng/ml of isosorbide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate, respectively, in the blood of one subject and 5.9, 15 and 61.3 ng/ml, respectively, in the blood of another subject. However, concentrations of the metabolites declined relatively slowly during 6 h after the oral dose. Up to 99% of an oral dose of isosorbide dinitrate was excreted during 5 days, mainly in the urine of the first day (ca. 78%). The results showed that isosorbide mononitrates were available to contribute to the pharmacological action.     

Electron beam irradiation: a novel technology for the development of transdermal system of isosorbide dinitrate

The development of a transdermal delivery system for isosorbide dinitrate (ISDN) using electron beam irradiation was studied. The solid state stability of the drug to irradiation was assessed. The drug was dissolved in 2-ethylhexylacrylate (EHA)-acrylic acid (AA) system and this solution was directly irradiated on a backing membrane (Scotchpak^®1006) at different doses to get transdermal patches. The developed systems were evaluated for residual monomer content, equilibrium weight swelling ratios (EWSR), differential scanning calorimetry (DSC), weight uniformity, thickness uniformity, drug content and content uniformity, peel strength, in vitro release, skin permeation kinetics and skin irritation potential. The developed system possessed excellent adhesive properties. Increase in the irradiation doses did not have a significant effect on the peel strength values. The systems exhibited promising skin permeation kinetics and no skin irritating potential, both of which are important properties for transdermal drug delivery. The ISDN-EHA-AA system developed at an irradiation dose of 50 kGy showed a higher skin permeation profile as compared to an internationally marketed transdermal matrix system of ISDN.     

Determination of isosorbide dinitrate biotransformation in various tissues of the rabbit by capillary column gas-liquid chromatography

A selective and sensitive capillary column gas-liquid chromatographic procedure has been developed for the simultaneous determination of isosorbide dinitrate (ISDN) and its mononitrate metabolites in rabbit blood and tissue homogenates. The method has a limit of detection of 0.1 ng ml-1 for ISDN, 1 ng ml-1 for isosorbide 5-mononitrate (5-ISMN), and 2 ng ml-1 for isosorbide 2-mononitrate (2-ISMN). The day-to-day coefficients of variation were 2.5, 6.8, and 11.3 per cent for ISDN, 5-ISMN, and 2-ISMN, respectively. The within-day coefficients of variation were 2.7, 4.9 and 6.5 per cent for ISDN, 5-ISMN, and 2-ISMN, respectively. The procedure was used to determine the biotransformation of ISDN (2 X 10(-7) M) to 5-ISMN and 2-ISMN by various rabbit tissue homogenates. The relative rate of biotransformation of ISDN was liver greater than lung approximately equal to intestine greater than kidney greater than blood approximately equal to skeletal muscle, with the lung and intestine homogenates being about two-thirds as active as liver homogenates. These results indicate that extrahepatic biotransformation of ISDN, especially by lung and intestine, may contribute to the systemic clearance of ISDN in the rabbit.     

硝酸异山梨酯对大鼠膀胱逼尿肌的舒张作用

目的:研究硝酸异山梨酯(ISDN)对大鼠离体膀胱逼尿肌螺旋条的舒张作用及可能机制。方法:采用离体逼尿肌螺旋条浴槽实验方法,以硝苯地平为对照,测定ISDN(10-6～10-4 mol/L)对氯化钾(4×10-2 mol/L)和乙酰胆碱(10-4 mol/L)预收缩离体膀胱逼尿肌条的平均张力、收缩幅度和频度的影响。用标准试剂盒测定膀胱组织经ISDN(10-4 mol/L)孵育1h后组织中一氧化氮(NO)和一氧化氮合酶(NOS)的活性。结果:ISDN的中剂量组和高剂量组(10-5 mol/L和10-4 mol/L)对乙酰胆碱预收缩肌螺旋条的平均张力、收缩幅度和频度均明显降低(P<0.05);ISDN各剂量组对高钾预收缩膀胱逼尿肌条的平均张力、收缩幅度和频度均没有明显影响(P>0.05)。另外,膀胱组织经ISDN孵育后NO的含量和NOS的活性明显升高(P<0.05)。结论:ISDN对乙酰胆碱预收缩的膀胱逼尿肌条有一定舒张作用,其机制可能与ISDN激活NOS,升高NO的含量有关。     

硝酸异山梨酯注射液联合血栓通注射液治疗不稳定型心绞痛的疗效观察

目的观察硝酸异山梨酯注射液联合血栓通注射液治疗不稳定型心绞痛的临床疗效。方法将60例不稳定型心绞痛患者随机分为治疗组和对照组,每组30例。在常规治疗的基础上,治疗组给予硝酸异山梨酯注射液联合血栓通注射液治疗,对照组给予硝酸异山梨酯注射液治疗,疗程均为14d。观察2组心绞痛、心电图疗效,并检测治疗前后血液流变学变化情况。结果治疗组心绞痛症状总有效率为96.67%高于对照组的83.33%,差异有统计学意义（P〈0.05）。治疗组心电图总有效率为83.33%高于对照组的73.33%,差异有统计学意义（P〈0.05）。治疗组治疗后红细胞压积、全血黏度、血浆黏度、纤维蛋白原和红细胞变形指数均低于治疗前,差异有统计学意义（P〈0.05）;治疗组治疗后以上指标均低于对照组,差异有统计学意义（P〈0.05）。结论硝酸异山梨酯注射液联合血栓通注射液治疗不稳定型心绞痛有较好的临床疗效。     

Differential effects of the novel NO-donating drug pirsidomine and isosorbide dinitrate on the venous vascular bed

Sixteen healthy male subjects were investigated on four occasions when they received either placebo, 10 mg isosorbide dinitrate (ISDN), or 2.5 or 10 mg pirsidomine, a novel NO-donating drug.A constant-rate iv. infusion of a subsystemic dose (average 42 ng·min^-1, SD 20.5) of noradrenaline in a dorsal hand vein was begun 1 h before drug treatment. It did not cause systemic changes but reduced the venous hand vein diameter by about 50%. This venoconstrictor response was approximately halved by 10 mg ISDN. Pirsidomine, in contrast, did not affect the in situ venoconstrictor responses to noradrenaline.ISDN and pirsidomine reduced systemic resting blood pressure. ISDN and 10 mg pirsidomine were approximately equipotent in reducing systolic blood pressure, both in terms of the duration and the extent of the effect (maximum average reduction of ISDN -6.7, 95% CI -10.3 to -3.0; and 10 mg pirsidomine -7.6, 95% CI -11.3 to -4.0 mmHg, respectively); 2.5 mg pirsidomine was less effective (-4.1, 95% CI -7.8 to -0.5). ISDN and 10 mg pirsidomine were also similarly effective in reducing diastolic blood pressure (ISDN -8.4 mmHg, 95% CI -10.5 to -6.2; 10 mg pirsidomine -6.0 mmHg, 95% CI -8.2 to -3.9; 2.5 mg pirsidomine -2.8 mmHg, 95% CI -5.0 to -0.6) but the effects of ISDN were longer lasting.Although similar with regard to their putative mechanism(s) of action and likely arterial/arteriolar effects, pirsidomine and ISDN seem to affect the venous vascular bed in distinctly different ways.     

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.     

Plasma concentrations of isosorbide dinitrate after oral administration of a sustained-release formulation to human subjects

1. A peak of mean plasma concentrations of isosorbide dinitrate of 5.8 ng/ml was reached at 0.5 h after a single oral dose of 5 mg in a standard tablet formulation. Thereafter mean concentrations declined with a half-life of about 48 min. 2. A peak of mean concentrations of isosorbide dinitrate of 3.2 ng/ml was reached at 2--4 h after a single oral dose of 20mg in a sustained-realease capsule formulation (Iso Mack Retard). Thereafter mean concentrations declined by about twofold during 6 h and were still detectable at 12 h after dosing. 3. When corrected by dose/bodyweight variations, the mean area under the isosorbide dinitrate plasma concentration curve from the sustained-release capule was 76% of that from the standard tablet and this formulation-related difference in bioavailability was statistically significant (p less than 0.05). 4. The results showed that sustained-release formulation is a useful way to maintain plasma concentrations of isosorbide dinitrate for several hours.     

Fate of isosorbide dinitrate and mononitrates in patients with renal failure

Summary Isosorbide dinitrate 10 mg, isosorbide 5-mononitrate 5 mg and isosorbide 2-mononitrate 5 mg were administered orally to subjects with and without renal failure, and the plasma concentrations of isosorbide dinitrate and of both the mononitrates were measured. There was no striking difference in plasma concentration as a function of time between subjects with and without renal failure, except for a somewhat higher isosorbide 5-mononitrate concentration after administration of this metabolite to uraemic patients.