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  • 1
    Electronic Resource
    Electronic Resource
    Comparison of the effects of two different galenical preparations of glyceryl trinitrate on pulmonary artery pressure and on the finger pulse curve (1993)
    Springer
    European journal of clinical pharmacology 44 (1993), S. 451-456 
    Details
    ISSN: 1432-1041
    Keywords: Glyceryl trinitrate spray ; pharmacokinetics ; a/b-ratio ; pulmonary artery diastolic pressure ; finger pulse curve ; bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary 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 PADd at rest (≥15 mm Hg). 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00315542
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  • 2
    Electronic Resource
    Electronic Resource
    Relationship between pharmacokinetics and hemodynamic tolerance to isosorbide-5-mononitrate (1990)
    Springer
    European journal of clinical pharmacology 38 (1990), S. S53 
    Details
    ISSN: 1432-1041
    Keywords: nitrates ; pharmacokinetics ; pharmacodynamics ; nitrate tolerance ; isosorbide-5-mononitrate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Healthy male volunteers received three different dose regimens of a controlled-release form of isosorbide-5-mononitrate (IS-5-MN; 60 mg per tablet). Dose regimen I consisted of a single daily dose of 60 mg given for 5 days. Dose regimen 11 was started with a dose of 60 mg, followed by 30 mg 12 h later and thereafter every 8 h. The last dose, on the 5th day was again 60 mg. In dose regimen III60 mg followed by 30 mg 6 h later were administered every day for 5 days. The peripheral arterial and venous effects of IS-5-MN during the first and last dosing interval were followed by changes in the finger pulse curve, standing systolic blood pressure, heart rate, and venous distensibility. Plasma concentrations of IS-5-MN were measured frequently following the first and the last dose. Following dose regimen I all hemodynamic effects produced by the first dose were maintained during the study. The maximal plasma concentrations were about 400 ng/ml and the trough value, lower than 100 ng/ml. Following dose regimen II the hemodynamic effects of IS-5-MN and sublingual glyceroltrinitrate were completely abolished on the 5th day. Trough plasma concentrations were approximately 300 ng/ml during the entire study period. Following dose regimen III pronounced hemodynamic effects were seen on the 1st day. However, a significant attenuation of the hemodynamic effects was measured on the 5th day, when trough plasma concentrations were between 100 and 230 ng/ml. There was a significant negative correlation between the magnitude of hemodynamic effect remaining on the 5th day (measured by the area under the finger pulse curve) and the trough plasma concentration. Thus, the maintenance of minimum plasma concentrations of IS-5MN of 300 ng/ml or higher produces a rapid development of hemodynamic nitrate tolerance, whereas no tolerance was found when the plasma concentrations were allowed to decline below 100 ng/ml before the next dose was given. A significant attenuation of hemodynamic effects was found when minimum plasma concentrations were between 100 and 230 ng/ml. The degree of attenuation in this concentration range increased with increasing trough plasma concentrations.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01417565
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  • 3
    Electronic Resource
    Electronic Resource
    Die Beziehung zwischen Pharmakokinetik und hämodynamischer Toleranz gegenüber isosorbid-5-Mononitrat (1991)
    Springer
    European journal of clinical pharmacology 40 (1991), S. S151 
    Details
    ISSN: 1432-1041
    Keywords: Nitrate ; Pharmakokinetik ; Pharmakodynamik ; Nitrattoleranz ; Isosorbid-5-Mononitrat
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Zusammenfassung Gesunde männliche Probanden erhielten Isosorbid-5-Mononitrat in einer Darreichungsform mit verzögerter Freisetzung (IS-5-MN; 60 mg pro Tablette) nach drei unterschiedlichen Dosierungsschemata. Dosierungsschema I bestand aus einer Einzeldosis von täglich 60 mg über eine Dauer von 5 Tagen. Dosierungsschema II begann mit einer Dosis von 60 mg, gefolgt von einer Dosis zu 30 mg 12 Std später und danach alle 8 Std. Die letzte Dosis, gegeben am fünften Tage, betrug wiederum 60 mg. Bei Dosierungsschema III folgte auf zunächst 60 mg jeweils 6 Std später eine Gabe von 30 mg. Diese Dosis wurde über eine Dauer von 5 Tagen täglich gegeben. Die peripheren arteriellen und venösen Wirkungen von IS-5-MN wurden während des ersten und des letzten Dosierungsintervalls anhand von Änderungen der Fingerpulskurve, des systolischen Blutdrucks im Stehen, der Herzfrequenz und der venösen Kapazität bestimmt. Die Plasmakonzentrationen von IS-5-MN wurden nach Verabreichung der ersten und der letzten Dosis mehrfach gemessen. Bei der nach Dosierungsschema I durchgeführten Behandlung blieben alle hämodynamischen Effekte, die durch die erste Dosis hervorgerufen worden waren, während der gesamten Studiendauer erhalten. Die maximale Plasmakonzentration betrug 400 ng/ml. Die minimalen Plasmaspiegel lagen unterhalb 100 ng/ml. Bei Dosierungsschema II war die hämodynamische Wirksamkeit von IS-5-MN oder sublingual gegebenem Glyzeroltrinitrat am fünften Behandlungstage vollständig aufgehoben. Die minimalen Plasmakonzentrationen betrugen während der gesamten Studienperiode ungefähr 300 ng/ml. Bei Dosierungsschema III wurden am ersten Tage deutliche hämodynamische Effekte gemessen. Jedoch wurde am fünften Tage eine signifikante Abschwächung dieser Effekte festgestellt, wobei die minimalen Plasmakonzentrationen zwischen 100 und 230 ng/ml lagen. Das Ausmaß der am fünften Tage verbliebenen hämodynamischen Wirkung (gemessen als Fläche unter der Fingerpulskurve) zeigte eine negative Korrelation mit der gemessenen minimalen Plasmakonzentration. Die Aufrechterhaltung von Plasmakonzentrationen von IS-5-MN von mindestens 300 ng/ml führt somit zu einer schnellen Entwicklung einer hämodynamischen Nitrat-Toleranz. Demgegenüber wurde keine Toleranz gesehen, wenn die minimalen Plasmakonzentrationen unter 100 ng/ml absinken konnten. Lagen die minimalen Plasmakonzentrationen zwischen 100 und 230 ng/ml, wurde eine signifikante Verminderung der hämodynamischen Effekte festgestellt. In diesem Konzentrationsbereich stieg das Ausmaß der Wirkungsabschwächung mit ansteigender minimaler Plasmakonzentration von IS-5-MN an.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01418412
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  • 4
    Electronic Resource
    Electronic Resource
    Haemodynamic effects of glyceryl trinitrate following repeated application of a transdermal delivery system with a phasic release profile (1991)
    Springer
    European journal of clinical pharmacology 41 (1991), S. 115-118 
    Details
    ISSN: 1432-1041
    Keywords: Glyceryl trinitrate ; nitroglycerin ; transdermal delivery stystem ; nitrate tolerance
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary The haemodynamic effects and plasma concentrations of glyceryl trinitrate (GTN) and its dinitrate metabolites were investigated in 8 healthy male volunteers during 5 days of application of a new transdermal delivery system (TDS) with time-dependent release characteristics, which were considered to prevent or to diminish development of nitrate tolerance. On the first and fifth day of administration the following haemodynamic parameters were determined: digital pulse ratio of height of systolic peak to height of dicrotic wave (i.e.a/b-ratio), heart rate and systolic blood pressure under orthostatic conditions. Peak plasma concentrations of GTN were 139 and 155 pg·ml−1 on the first and fifth day of treatment, and the corresponding trough concentrations (i.e. 24 h after administration) were 52.5 and 36.6 pg·ml−1, respectively. Compared to placebo, the area under the effect curve of the a/b-ratio of the digital pulse was increased on the first (25.6%) and fifth day (13%). A significant increase of heart rate and a decrease of systolic blood pressure were seen only on the first day of treatment. The haemodynamic effects of sublingual GTN 0.8 mg were reduced by 69% (a/b-ratio) and 52% (standing heart rate) on the fifth day compared to the pretreatment values. Thus, the phasic release of GTN from the new TDS can be demonstrated by the time course of the plasma concentrations of GTN and its metabolites. Nevertheless, following repeated administration the hemodynamic effects are blunted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00265902
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  • 5
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and haemodynamic effects of ISDN following different dosage forms and routes of administration (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 319-324 
    Details
    ISSN: 1432-1041
    Keywords: Isosorbide dinitrate ; route of administration ; isosorbide-5-mononitrate ; finger pulse wave ; pharmacokinetics ; haemodynamic effects ; plasma nitrates
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 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. For the a/b ratio of the finger pulse, the maximal effect was higher (emax=130%) and the time to emax (temax) 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00194399
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  • 6
    Electronic Resource
    Electronic Resource
    Pharmacokinetics and pharmacodynamics of ramipril and piretanide administered alone and in combination (1994)
    Springer
    European journal of clinical pharmacology 46 (1994), S. 545-550 
    Details
    ISSN: 1432-1041
    Keywords: Ramipril ; Piretanide ; pharmacokinetics ; pharmacodynamics ; healthy volunteers
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Abstract 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00196113
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