Article (Scientific journals)
A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations
Messin, R.; Fenyvesi, T.; Carreer-Bruhwyler, F. et al.
2003In European Journal of Clinical Pharmacology, 59 (3), p. 227-232
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Keywords :
molsidomine; stable angina pectoris; exercise testing
Abstract :
[en] Objectives. A new once-a-day (o.a.d.) formulation of molsidomine (16 mg) was evaluated in patients with stable angina pectoris. The aims were to characterize its pharmacokinetics after a single dose, to demonstrate its clinical efficacy and safety versus placebo and to investigate correlations between pharmacokinetics and pharmacodynamics. Methods. Forty-two patients were recruited in a double-blind, crossover, randomized placebo-controlled trial. The pharmacokinetics of molsidomine and SIN-1, its active metabolite, were determined at specific time points (3, 6, 10, 14, 18, 22 and 24 h) after the administration of a single dose of molsidomine 16 mg o.a.d. in all patients distributed into seven groups. Twenty-eight of these 42 patients showed a positive baseline cycloergometric exercise test response during the run-in placebo period and were used to compare the efficacy of molsidomine to placebo. Relationships between plasma concentration in molsidomine or SIN-1 and ischemic threshold were assessed in 16 of the 28 patients with a positive exercise test at baseline. Indeed, the censored variable ischemia-limited tolerance to exercise could not be evaluated in those patients who did not show exercise-induced ischemia anymore under molsidomine 16 mg o.a.d. Pharmacokinetic-pharmacodynamic relationships were evaluated using regression models and correlation coefficients. Results. The highest average concentration in molsidomine and SIN-1 occurred after 6 h, then a plateau of 15-20 ng/ml molsidomine and 0.8-3.0 ng/ml SIN-1 was maintained for at least 8 h and the mean residual molsidomine concentration 24 h post-drug intake was around 8 ng/ml, still in the effective range of 5-10 ng/ml. A significant increase in total workload (+52 W min, P=0.009), total exercise time (+32 s, P=0.003) and time to angina (+25 s, P=0.016) was measured with molsidomine 16 mg o.a.d. relative to placebo. Using linear regression, significant correlation coefficients were determined between molsidomine plasma concentrations (but not SIN-1) and exercise test improvements (r=0.827, P<0.001 for the total workload; r=0.772, P<0.001 for the total exercise time; and r=0.566, P=0.028 for the time to 1 mm ST-segment depression). Conclusion. The pharmacokinetics of molsidomine 16 mg in patients with stable angina pectoris is compatible with a o.a.d. dosage regimen. This o.a.d. formulation is effective and well-tolerated, providing a 24-h therapeutic control of myocardial ischemia. A positive and significant linear relationship between molsidomine plasma concentration and the increase in exercise tolerance was observed.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Messin, R.
Fenyvesi, T.
Carreer-Bruhwyler, F.
Crommen, Jacques ;  Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Chiap, Patrice ;  Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Hubert, Philippe  ;  Université de Liège - ULiège > Chimie analytique
Dubois, C.
Famaey, J. P.
Geczy, J.
Language :
English
Title :
A pilot double-blind randomized placebo-controlled study of molsidomine 16 mg once-a-day in patients suffering from stable angina pectoris: correlation between efficacy and over time plasma concentrations
Publication date :
July 2003
Journal title :
European Journal of Clinical Pharmacology
ISSN :
0031-6970
eISSN :
1432-1041
Publisher :
Springer-Verlag, New York, United States - New York
Volume :
59
Issue :
3
Pages :
227-232
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 10 March 2009

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