Pharmacokinetics of tilidine in terminal renal failure.

The aim of the present study was to investigate the pharmacokinetics of tilidine and its metabolites during the dialysis procedure and in the dialysis-free interval. Tilidine is a prodrug that is metabolized presystemically into the active metabolite nortilidine. Nortilidine is degraded thereafter to bisnortilidine and several polar metabolites. Nine patients with a creatinine clearance < 5 ml/min were treated in a crossover design with single oral doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interval. Blood samples were taken frequently and analyzed for tilidine, nortilidine, and bisnortilidine. Drug and metabolite concentrations were also measured in aliquots of dialysate collected during dialysis. Only negligible amounts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The presystemic apparent clearance of the prodrug tilidine was decreased significantly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteers. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function seems not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis.

Effect of lysine clonixinate on the pharmacokinetics and anticoagulant activity of phenprocoumon.

The effect of the non-steroidal anti-inflammatory drug lysine clonixinate ([2-(3-chloro-o-toluidino)nicotinic acid]-L-lysinate, CAS 55837-30-4) on the pharmacokinetics and anticoagulant activity of phenprocoumon (4-hydroxy-3-(1-phenylpropyl)-coumarin, CAS 435-97-2) was investigated in an open, randomised, two-fold, cross-over study in 12 healthy male volunteers. These subjects received a single dose of 18 mg phenprocoumon without or with concomitant treatment with lysine clonixinate (125 mg five times a day for 3 days before and 13 days after ingestion of a single dose of phenprocoumon). Pharmacokinetic parameters of phenprocoumon following oral administration were: CL/f: 0.779 +/- 0.157 ml/min, half-life of elimination: 147.2 +/- 19.9 h; free fraction in serum: 0.51 +/- 0.20%. These parameters were not significantly altered by concomitant treatment with lysine clonixinate. Prothrombin time increased from 13.3 +/- 1.3 s (at time 0) to 17.7 +/- 2.7 s following phenprocoumon and from 13.3 +/- 1.2 s to 18.0 +/- 2.2 s following combined administration. Prothrombin time returned to the pretreatment values 240 h after administration of phenprocoumon. The integrated effect (AUEC0-288 h) was identical following both treatments (4.303 +/- 461 and 4.303 +/- 312 s x h for phenprocoumon alone and phenprocoumon with lysine clonixinate, respectively). Thus, lysine clonixinate administered in therapeutic doses does not affect the pharmacokinetics and anticoagulant activity of phenproxoumon.

Comparison of the initial hemodynamic effects of immediate-release versus sustained-release isosorbide-5-mononitrate following single oral doses.

In this double-blind, randomized, placebo-controlled cross-over study, the authors investigated the initial time course of effects of isosorbide-5-mononitrate (IS-5-MN) on hemodynamic parameters in 15 healthy male volunteers after administering a single oral dose of either an immediate-release formulation (IS-5-MN 20 mg) or of a sustained-release formulation (IS-5-MN 50 mg). The latter formulation released 15 mg IS-5-MN immediately, while 35 mg of the dose was sustained release. The onset of effect on the a/b-ratio of the finger pulse curve (20 minutes after administration) and on heart rate following orthostatic challenge (30 minutes) was not different following ingestion of either the immediate-release or the sustained-release formulation. Only the systolic blood pressure following orthostatic challenge was affected earlier after ingestion of the immediate-release form of IS-5-MN (10 vs. 30 minutes). There was no statistically significant difference in the maximum effect on the measured hemodynamic parameters between the two formulations. There was no significant difference with respect to the effect per dose between both of the active treatments (i.e., IS-5-MN 20 mg immediate release and IS-5-MN 50 mg sustained release) within 6 hours after administration. The hemodynamic findings were consistent with the observed rates of the increase of plasma concentrations of IS-5-MN following both formulations. Thus, the administration of the sustained-release formulation of IS-5-MN 50 mg caused similar maximum effects when compared with an immediate-release formulation (20 mg). While the onset of effect of IS-5-MN on the a/b-ratio of the finger pulse curve and on heart rate following orthostasis was similar after administration of either the immediate- or the sustained-release formulation, the onset of effect of the sustained-release formulation on systolic blood pressure orthostasis was determined slightly later. However, the latter difference seems to be of minor clinical relevance.

Age-dependent differences in the anticoagulant effect of phenprocoumon in patients after heart valve surgery.

OBJECTIVE: An enhanced response to warfarin and an increased risk of major bleeding has been observed in older patients. The reason for this increase in sensitivity remains unknown. It could be due to pharmacodynamic reasons, pharmacokinetic reasons, or both. METHODS: We therefore followed an anticoagulant regimen with phenprocoumon in 19 older (76 years) and 19 younger patients (50 years) following heart valve replacement. INR values were determined frequently. At the 4th and around the 24th day after starting treatment with phenprocoumon, we also measured the total and unbound plasma concentration of phenprocoumon. RESULTS: The dose requirement to obtain the desired anticoagulant effect was significantly lower in the older patients than in the younger patients (26.3 vs. 37.3 micrograms.kg-1.day-1). The total plasma concentration (2.19 vs. 2.43 micrograms.ml-1), the percentage unbound drug in the plasma (0.61 vs. 0.64%) and the unbound plasma concentration (13.8 vs. 15.1 ng.ml-1) did not differ significantly between older and younger patients. The dose-adjusted INR (INR/dose) was higher in the older patients (110 vs. 67) but the INR adjusted for the unbound plasma concentration (INR/Cuss) which reflects the intrinsic sensitivity to the drug, was not significantly different (192 vs. 173). However, the older patients had an about 30% significantly lower metabolic clearance based on unbound drug (84 vs. 115 ml.kg-1.h-1). CONCLUSIONS: Older patients (> 70 years) require a dose approximately 30% lower than younger patients (< 160 years). Pharmacokinetic reasons (reduced metabolic clearance) are mainly responsible for the lower dose requirement of the older patients after heart valve surgery.

Short-term hemodynamic, anti-ischemic, and antianginal effects of pirsidomine, a new sydnonimine.

Pirsidomine is a new sydnonimine compound in clinical development. As a prodrug, it is transformed into a nitric oxide-releasing metabolite in vivo. In animal tests there were no signs of tolerance with repeated administration. The short-term effects of 10, 20, and 40 mg of the drug on pulmonary hemodynamics and ischemic parameters were examined at rest and during exercise in a double-blind, randomized, placebo-controlled study. The study included 48 patients with documented coronary artery disease and exercise-induced ST-segment depression. Compared with the baseline test, there was a reduction of diastolic pulmonary artery pressure with pirsidomine at rest (placebo: -0.4 +/- 0.5 mm Hg; 10 mg: - 1.5 +/- 2.4 mm Hg; 20 mg: - 1.4 +/- 1.1 mm Hg; 40 mg: - 2.3 +/- 1.3 mm Hg [p < 0.05 ]) and at the highest comparable workload (placebo: -2.8 +/- 1.9 mm Hg; 10 mg: -7.3 +/- 6.8 mm Hg; 20 mg: -8.4 +/- 7.9 mm Hg [p <0.05]; 40 mg: -13.8 +/- 7.1 mm Hg [p <0.05]). ST-segment depression decreased at the highest comparable workload (placebo: -0.33 +/- 0.49 mm; 10 mg: -1.33 +/- 1.37 mm [p <0.05]; 20 mg: -1.33 +/- 0.83 mm [p <0.05]; 40 mg: -1.96 +/- 0.86 mm [p <0.05]) and total exercise time increased (placebo: 15 +/- 48 s; 10 mg: 98 +/- 126 s; 20 mg: 165 +/- 251 s [p <0.05]; 40 mg: 155 +/- 174 s [p <0.05]). Of 40 patients who complained of angina pectoris symptoms in the baseline test, 15 became free of angina pectoris with pirsidomine. Compared with placebo, blood pressure, heart rate during exercise, and cardiac output during exercise showed no significant change. Plasma concentration response relations of the metabolite revealed concentrations that caused a half-maximum effect of 6 ng/ml, 13 ng/ml, 20 ng/ml, and 28 ng/ml in reduction of ST-segment depression, reduction of diastolic pulmonary artery pressure, relief of angina pectoris symptoms, and an increase in exercise duration, respectively. Thus, pirsidomine is an effective anti-ischemic and antianginal agent. A significant preload reduction was obtained with plasma metabolite concentrations lower than those necessary to achieve a satisfactory antianginal effect.

A pharmacodynamic and pharmacokinetic comparison of intravenous quinaprilat and oral quinapril.

Quinaprilat is the active metabolite of quinapril, an orally active angiotensin-converting enzyme (ACE) inhibitor. The dose-response and duration-of-effect after single intravenous doses of quinaprilat and placebo (part A) and after administration of oral quinapril solution and intravenous quinaprilat (part B) were assessed in a randomized, crossover study of two groups of 12 healthy volunteers. Pharmacodynamic effects of quinaprilat and oral quinapril were assessed by measurement of blood pressure changes after an infusion of angiotensin I (A-I) at a dose previously determined to produce an increase in diastolic blood pressure of 25 mmHg under standardized conditions (A-I pressor response). A clear dose-response relationship was demonstrated for quinaprilat in this pharmacodynamic model, with 0.5 mg as the lowest effective dose. Doses of 1.0 mg and higher partially suppressed A-I pressor response for at least 6 hours. Onset of action was observed within 15 minutes of intravenous administration of quinaprilat and was independent of dose, whereas peak effect and duration of action appeared to be dose related. Quinaprilat doses of 2.5 mg and 10 mg achieved approximately 50% and > 80% inhibition of the A-I pressor response, respectively. In part B, these doses of intravenous quinaprilat were compared with oral doses of quinapril previously found to produce 50% (2.5 mg) and 90% (10 mg) inhibition of the A-I pressor response. The magnitude of effect was similar after administration of 20 mg quinapril orally and 10 mg quinaprilat intravenously. Duration of action was longer, however, after administration of intravenous quinaprilat (10 mg) than after oral quinapril (20 mg), due to the higher maximum plasma concentration (Cmax) of quinaprilat. Mean area under the plasma concentration-time curve extrapolated to infinity (AUC0-infinity) of quinaprilat was similar after the 10-mg dose of intravenous quinaprilat and the 20-mg dose of oral quinapril. Based on the concentrations of quinaprilat observed in this study, the absolute bioavailability of quinapril was approximately 50%; intravenous quinaprilat should therefore produce a pharmacodynamic response similar to that obtained with oral quinapril at approximately half the dose.

Digital pulse plethysmography as a non-invasive method for predicting drug-induced changes in left ventricular preload.

OBJECTIVE: Changes in the contour of the plethysmographically recorded digital pulse curve after nitrate ingestion are well known, but it has not been fully established whether these changes reflect nitrate action on left ventricular (LV) preload or afterload. Therefore, we compared the pulse wave contour after administration of equieffective doses of nitroglycerin and nifedipine. METHODS: In 20 patients with coronary artery disease we measured aortic blood pressure curve in the aorta ascendens, digital volume pulse curve with a photoelectric pulse pickup, Riva Rocci blood pressure and heart rate after administration of either 0.8 mg nitroglycerin or 10 mg nifedipine. RESULTS: Peak plasma concentrations of nitroglycerin and nifedipine were achieved 5 min and 20 min after ingestion of the drugs. Systolic aortic blood pressure decreased after both nitroglycerin and nifedipine to 19.4 mmHg, but diastolic blood pressure decreased only after nifedipine by 10.5 mmHg (P < 0.05). Riva Rocci blood pressures showed a similar time course. Heart rate increased from 67.4 to 70.9 beats.min-1 after nitroglycerin and from 58.9 to 69.4 beats.min-1 after nifedipine. The calculated a/b ratio of the aortic pressure curve increased after both medications (nitroglycerin, from 1.66 to 1.99; nifedipine, from 1.66 to 1.93) and its time course mimicked that of the systolic blood pressure. The a/b ratio of the digital pulse curve did not change after nifedipine, but showed a pronounced rise after nitroglycerin from 1.29 to 1.84. With regard to pharmacological actions, nitroglycerin causes a reduction in LV preload and afterload, whereas nifedipine has only LV-afterload-reducing activity. CONCLUSION: We conclude, that the reduction in afterload did not cause the typical changes in wave contour of the peripheral pulse curve which occur with organic nitrates. Most likely changes in the a/b ratio reflect changes in LV preload.

Prolongation of the PQ interval as a measure of therapeutic inequivalence between two formulations of diltiazem.

We studied the use of atrioventricular (AV) conduction time to assess the therapeutic equivalence of two diltiazem formulations in 20 volunteers in a double-blind, cross-over trial. ECG recording was carried out before and at several intervals after drug administration, and prolongation of the PQ interval (delta PQ) was taken as a pharmacodynamic response. In addition, diltiazem plasma concentrations were determined in 8 subjects. The effect of diltiazem increased proportionally with the plasma concentration and could be detected up to 10 h after administration. The area under the effect-time curve (AUEC(0-10)), the peak effect (Emax), and the effect mean residence time (MRTE) showed significant differences. In contrast to the pharmacodynamics, the pharmacokinetic profiles of diltiazem do not vary to the same extent. We conclude that the formulations are therapeutically different. Furthermore, at the administered dose, delta PQ appears to be a sensitive measure for assessing the electrophysiological properties of diltiazem.

Determination of the anti-ischemic activity of nebivolol in comparison with atenolol.

The anti-ischemic effect of 5 mg nebivolol o.i.d., a newly developed beta 1-selective adrenoceptor blocking drug with vasodilating properties, was compared with that of atenolol (100 mg o.i.d.) following a treatment period of 6 days. The study was performed in 24 patients with documented coronary artery disease and stable angina pectoris according to a double-blind randomized study, designed using conventional symptom-limited exercise testing. Exercise testing 3 h after the first dose showed a more marked ST-segment reduction by atenolol than by nebivolol (59% vs. 18%). ST-segment depression measured 24 h after administration of the penultimate dose was statistically significantly reduced by nebivolol (from 0.19 +/- 0.07 to 0.13 +/- 0.07 mV; P = 0.0059) but not by atenolol (from 0.17 +/- 0.06 to 0.14 +/- 0.10 mV; P = 0.0703). Approximately 3 h after the last dose, the reduction was comparable (45% and 38% by nebivolol and atenolol, respectively). Exercise duration, exercise time necessary to produce ST-segment depression by 0.1 mV and exercise time to the onset of angina were also prolonged following administration of both drugs. Thus, at steady-state single daily doses of 100 mg atenolol and 5 mg nebivolol were about equieffective when measured at time of maximal effect (i.e. 3 h after drug administration). However, duration of action with respect to the ST-segment depression seems to be slightly longer for nebivolol.

Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination.

The pharmacokinetics and pharmacodynamics of single oral doses of 5 mg ramipril and 6 mg piretanide administered separately and in combination were determined in a single blind, randomised, 3-period cross-over study in 24 healthy male volunteers. The peak plasma concentrations of ramipril and ramiprilat increased slightly (from 11.9 to 14.8 ng/ml, and from 6.39 to 8.96 ng/ml, respectively) as did the area under the plasma concentration-time curve of ramipril (0-4 h) and ramiprilat (0-24 h) (from 15.8 to 19.8 ng.ml-1.h, and from 63.4 to 74.6 ng.ml-1.h, respectively). The urinary excretion of ramiprilat also rose (from 6.82 to 7.73% of dose) following simultaneous treatment with piretanide. These effects were probably due to reduced first-pass metabolism of ramipril/ramiprilat to inactive metabolites. The blood pressure lowering effect, the time course of inhibition of ACE activity in plasma and the concentration-response relationship for the inhibition of plasma ACE activity were not affected by piretanide. The peak plasma concentration of piretanide was somewhat reduced (from 285 to 244 ng/ml) following simultaneous treatment with ramipril. No other pharmacokinetic parameter was affected. Piretanide increased urine flow, and sodium, chloride and potassium excretion, especially during the first 2 hours following administration. These pharmacodynamic parameters were not affected by ramipril. Thus, simultaneous administration of single oral doses of ramipril and piretanide caused modest changes in the peak and average plasma concentrations of both drugs, which did not lead to detectable alterations in the pharmacodynamic parameters measured in healthy volunteers.

[Clinico-pharmacologic aspects of therapy with enoximone]. / Klinisch-pharmakologische Aspekte der Therapie mit Enoximon.

Enoximone is an imidazole derivative which proved to be a selective inhibitor of the isoenzymes III/IV of the cAMP-specific phosphodiesterase. It has been shown in various experimental models that the drug exerts both positive inotropic and vasodilating properties which can be attributed to the proposed mode of action. A marked dose-dependent improvement in left ventricular pump performance was observed, with only minor changes in heart rate or systemic blood pressure, if enoximone was administered as i.v. -bolus to patients with moderate to severe congestive heart failure. These effects coincided with vasodilatory effects as determined by decreases in systemic vascular resistance and pulmonary capillary wedge pressure. Enoximone is eliminated by intensive metabolism, predominantly in the liver, with enoximone sulfoxide being the major metabolite in man. Enoximone exhibits a marked firstpass metabolism following oral administration. There is evidence in the literature that the metabolism can be saturated either during long-term administration or by increasing the dose of enoximone. In experimental settings, the metabolite exerts weak positive inotropic effects, too, and reconversion to the parent compound enoximone has been demonstrated in addition. The half-life of elimination of enoximone seems to be about 1 h in healthy volunteers and approximately 3 to 7 h in patients with congestive heart failure, with marked inter-individual differences. In patients with renal failure mainly enoximone sulfoxide accumulates in plasma depending on the degree of renal impairment. The elimination of enoximone seems to be impaired in these patients, too, which might be caused by enhanced reconversion due to the high plasma concentrations of the metabolite.(ABSTRACT TRUNCATED AT 250 WORDS)

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 Cmax was higher (39.0 ng.ml-1) and tmax 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of the interaction of 3S-hydroxy-10,11-dihydroquinidine on the pharmacokinetics and pharmacodynamics of warfarin.

The investigational antiarrhythmic drug LNC-834 ((9S)-10,11-dihydro-6'-methoxy-cinchonan-3,9-diol hydrogen sulfate pentahydrate, CAS 85405-59-0) is structurally related to quinidine. It was investigated, if concurrent administration of LNC-834 affects the single dose pharmacokinetics and pharmacodynamics of warfarin (CAS 81-81-2). The study was performed as an open, randomized two-way cross-over, controlled investigation in 10 healthy volunteers. In treatment A, 2 tablets of LNC-834 (350 mg of hydrated salt corresponding to 226 mg anhydrous free base each) were ingested twice daily for a period of 9 days in total. On the 4th study day, 2 h after the application of LNC-834 in the morning, the volunteers received a mean dose of 0.36 +/- 0.03 mg/kg warfarin orally. In treatment B only warfarin was administered. Pharmacokinetics of warfarin and anticoagulant effect (prothrombin complex activity) were determined from plasma samples withdrawn up to 144 h after administration; LNC-409 (free base of LNC-834) and the metabolite LNC-253 (2'-oxo-analog) were monitored for check of compliance over the same time period. Concurrent administration of LNC-834 decreased significantly the area under the plasma concentration-time curve of warfarin (117,889 +/- 25,010 (A) vs. 125,294 +/- 22,314 ng/ml.h (B); p = 0.0488). Thus, a significant increase in apparent oral clearance (CL/f) of warfarin in the presence of LNC-834 was determined (3.98 +/- 0.63 vs. 3.71 +/- 0.50 ml/min; p = 0.0488). All other pharmacokinetic parameters determined (apparent volume of distribution (V/f), Cmax, tmax, terminal half-life of elimination) were not altered by concurrent treatment with LNC-834.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetics of cyclosporine and steady-state aspirin during coadministration.

Anecdotal reports from clinical trials assessing the use of cyclosporine in the treatment of rheumatoid arthritis suggest an association between enhanced renal impairment and combined use of cyclosporine with nonsteroidal anti-inflammatory drugs. To explore possible pharmacokinetic contributions to this phenomenon, a randomized, two-period crossover investigation was performed in 24 healthy volunteers in which a single oral dose of 300 mg cyclosporine was administered alone and on day 10 of multiple oral dosing of aspirin 960 mg three times daily. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a steady-state dosing interval for aspirin on day 9 (aspirin alone) and day 10 (coadministration of cyclosporine and aspirin). Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay and plasma concentrations of acetylsalicylic acid and metabolites by high-performance liquid chromatography. Lack of a pharmacokinetic interaction was conclusively demonstrated for the rate and extent of cyclosporine and acetylsalicylic acid absorption and for the rate and extent of salicylic acid formation after a single dose of cyclosporine was coadministered during steady-state aspirin dosing. If a clear association between enhanced renal impairment and the combined use of cyclosporine and aspirin is substantiated, the underlying mechanism appears to be pharmacodynamic rather than pharmacokinetic.

Effect of concomitantly administered cimetidine or ranitidine on the pharmacokinetics of the 5-HT2-receptor antagonist ritanserin.

The effects of concurrent administration of either cimetidine 800 mg once daily or ranitidine 300 mg once daily on the single-dose pharmacokinetics of ritanserin 10 mg were investigated in an open, randomized three-way cross-over, controlled investigation in 9 healthy volunteers. Concurrent administration of cimetidine had no significant effect on the area under the plasma concentration-time curve of ritanserin compared with control experiments. The maximum plasma concentration of ritanserin was decreased significantly (105.0 +/- 9.2 versus 125.0 +/- 13.8 ng/mL; P = .0039), whereas time to reach maximal concentration (tmax) of ritanserin was only slightly but not significantly increased, if the subjects were pretreated with cimetidine. After concurrent ingestion of ranitidine, only a trend to a decrease in the maximum plasma concentration of ritanserin was observed. Time to achieve the maximum plasma concentration, terminal half-life of elimination, and the total area under the plasma concentration-time curve of ritanserin were not altered in comparison with control experiments. The results of the study show that concurrent treatment with cimetidine 800 mg once daily or ranitidine 300 mg once daily has no apparent effect on the systemically available amount of ritanserin after a single oral dose of 10 mg. Both H2-antagonists cause a significant (cimetidine) or borderline significant (ranitidine) decrease of the maximum plasma concentration of ritanserin and a slight but not significant increase in tmax (cimetidine). These effects are of minor clinical importance and seem most likely be due to a decrease of the rate of absorption of ritanserin during concurrent administration of cimetidine/ranitidine.

Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve.

The time course and the magnitude of the effect of glyceryl trinitrate (GTN) on central venous (pulmonary artery diastolic pressure-PAPd) and peripheral arterial (a/b-ratio of the finger pulse wave) haemodynamics were compared in a randomized double-blind cross-over study in 12 patients suffering from congestive heart failure (NYHA II-III) with elevated PAPd at rest (> or = 15 mmHg). The data were obtained in a bioavailability study of two sprays of glyceryl trinitrate, which differed in their galenical characteristics and in the dose of GTN (0.4 mg vs. 0.8 mg). Following sublingual administration of each spray, PAPd, a/b-ratio and the plasma concentrations of GTN and its metabolites were measured up to 30 min. The relative bioavailability of GTN of the test preparation was estimated to be 157%, 161% and 147%, when calculated from the plasma concentration-time data or the integrated effect of GTN on a/b-ratio or PAPd, respectively. The mean time courses of the decrease in PAPd and the increase in the a/b-ratio of the finger pulse curve were mirror images. Thus, there was a strong correlation between the mean values of PAPd and a/b-ratio following the administration of glyceryl trinitrate. Since the slope of the relationship differed considerably between the patients, the magnitude of effect of GTN on PAPd in the individual patient could not be predicted from the changes in a/b-ratio.

Plasma profile and haemodynamic tolerance to isosorbide-5-mononitrate in controlled-release form.

1. Plasma concentrations and some haemodynamic parameters known to be affected by nitrates, were monitored in healthy volunteers who received three different dose regimens of isosorbide-5-mononitrate (5-ISMN) over 5 day study periods. 2. No haemodynamic tolerance was found in the 60 mg once-daily dose schedule which produced high plasma concentrations during the daytime but concentrations no greater than 100 ng ml-1 at night. In contrast, a dose regimen of 60 mg followed by 30 mg 12 h later and thereafter every 8 h until the fifth day induced complete haemodynamic tolerance. With this dose regimen the minimum plasma concentrations were never below 300 ng ml-1. A significant attenuation of haemodynamic effects was also found with the third dose regimen, 60 mg followed by 30 mg 6 h later for 5 days, which produced minimum plasma concentrations of between 100 ng ml-1 to 300 ng ml-1; the degree of attenuation rose as trough plasma concentrations increased. 3. In conclusion, 60 mg 5-ISMN in a controlled-release (Durules) preparation given once daily was the only dose regimen not inducing nitrate tolerance.

Pharmacodynamic and pharmacokinetic evaluation of a new transdermal delivery system with a time-dependent release of glyceryl trinitrate.

The pharmacokinetics of glyceryl trinitrate (GTN) and its main metabolites as well as the hemodynamic effects of a new transdermal delivery system (TDS) were investigated in ten healthy male volunteers using a single blind, placebo-controlled study design with an application period of active drug of 4 successive days. The adhesive-type matrix system contains 20-mg GTN and released about 75% in a time-dependent manner. The plasma concentrations of GTN and its metabolites 1-2- and 1-3 glyceryl dinitrate reflected the time-dependent release with higher plasma concentrations during the first 12 hours than during the second 12 hours. Continuous administration of the TDS, which released 15 mg GTN/day, caused an accumulation of GTN in the plasma (about 70% greater AUC at the fourth day in comparison with the first day). The total effect per dose on the a/b-ratio of the digital pulse (height of the peak of the systolic wave divided by height of the peak of the dicrotic wave) and the reflex tachycardia were diminished by about 50% and 37%, respectively, at the fourth treatment day. The effect on systolic blood pressure measured under orthostatic conditions was blunted already 8 hours after the first application. The effect of sublingually administered GTN on digital pulse was attenuated during administration and also 1 hour after removal of the last TDS. The effect was restored 8 to 12 hours after removal of the TDS. Thus, the discontinuous release of GTN from the new system does not prevent the decline of hemodynamic efficacy during continuous therapy.

Differences in the antiischaemic effects of molsidomine and isosorbide dinitrate (ISDN) during acute and short-term administration in stable angina pectoris.

The acute and short-term effects of treatment with 10 consecutive doses of isosorbide dinitrate 40 mg t.i.d. and molsidomine 8 mg t.i.d. in slow release formulations were investigated in 10 patients with angiographically documented coronary artery disease and stable angina pectoris according to a randomized, double-blind, double-dummy, cross-over study design using conventional symptom-limited exercise testing. Acute exercise testing 3 h following the first dose of ISDN and molsidomine showed a significant reduction of maximal ST segment depression and of the area above the ST segments. Time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance increased significantly. On the fourth treatment day with ISDN and molsidomine an attenuation of these antiischaemic effects was seen. The mean effects on ST segment depression, area above ST segments, time to occurrence of 0.1 mV ST segment depression, exercise duration, time to onset of angina and exercise tolerance were reduced by 40%, 44%, 47%, 58%, 54% and 65%, respectively, in patients administered ISDN and by 33%, 48%, 58%, 59%, 45% and 60% in those given molsidomine. Thus, following sustained short-term therapy the antiischaemic effects of both drugs seem to be attenuated. In this report no marked differences were found between ISDN and molsidomine.