Comparative effects of once-daily molsidomine in coronary patients from two distinct European ethnicities.

INTRODUCTION: Molsidomine, a direct nitric oxide donor, is frequently used in several European countries for the treatment of stable angina. The aim of this study was to compare the effects of a new once-daily 16-mg dose formulation, Coruno (Therabel Pharmaceuticals, Loughrea, Ireland), in patients with stable angina belonging to two distinct European ethnicities. METHODS: A total of 261 Hungarian and 267 Polish patients took part in this multicenter, randomized, double-blind, placebo-controlled clinical trial. Exercise testing was performed after the first administration of molsidomine and repeated after a 2-week treatment. Frequency of anginal attacks, short-acting nitroderivative tablet consumption, and incidence of adverse events were also evaluated. RESULTS: Demographic and clinical characteristics were significantly different in Hungarian compared with Polish patients. Hungarian patients had a lower proportion of males, were shorter in stature, had less previous smoking experience, consumed more alcohol, had less severe coronary disease (electrocardiographic evidence, rate of anginal crises, and nitroderivative consumption), and higher exercise capacity. However, molsidomine-related improvement in exercise capacity at start of the study was similar in both cohorts. After a 2-week treatment, improvement was fully maintained in Polish and only minimally reduced in Hungarian patients. Furthermore, molsidomine reduced significantly more anginal episodes and nitroderivative consumption in the more severely affected Polish cohort. Proportions of patients reporting drug-related adverse events were similar on placebo and molsidomine in both cohorts. Most of the adverse events were not severe and resolved spontaneously. Less myocardial ischemia and gender (including height, a confounding covariate) acted positively and negatively, respectively, on the higher exercise capacity of Hungarian versus Polish patients. CONCLUSION: The once-daily 16-mg molsidomine formulation is effective and has good tolerability in both patient cohorts. Molsidomine does not induce any meaningful tolerance issues in Hungarian or Polish patients with stable angina, despite significant demographic and clinical disparities.

Tolerability to 1-year treatment with once-daily molsidomine in patients with stable angina.

Prolonged-release molsidomine 16 mg once daily) QD (has proved effective in the short-term treatment of patients with stable angina. The purpose of this multicenter study was to assess its long-term tolerability and clinical effectiveness. A total of 320 patients with stable angina were treated for 1 year with molsidomine 16 mg QD administered open label as monotherapy or add-on therapy, when beta blockers and/or calcium antagonists were prescribed concomitantly) in 128 patients, ie, 40% of cases), depending on the severity of disease and/or local therapeutic policies. In all, 293 patients (91.6%) completed the study. The proportion of patients who reported drug-related adverse events (AEs) was 9.1%, which is not significantly different (P=.13) from the 5.9% observed during previous short-term (2-4 wk) treatment. Headache accounted for 80.6% of all drug-related AEs and required discontinuation of the drug in one quarter of patients who reported the symptom (ie, 1.9% of the 320 patients involved in the study). No serious drug-related AEs occurred during the study. Tolerability to molsidomine, evaluated with use of a visual analog scale (VAS), improved by 20% from beginning to end of 1-year follow-up. Two-by-two Bonferroni's comparisons were significant at the .05 level between the 2-month assessment and assessments performed at 8, 10, and 12 months. No age-time interaction was noted (P=.82). Heart rate, blood pressure, electrocardiogram, and blood parameters showed no statistically significant or clinically relevant changes during the study. Compliance with treatment was satisfactory throughout the follow-up period. There was no significant change in the weekly frequency of anginal attacks and consumption of short-acting nitroderivatives during the 1-year study (P=.07 and P=.12,respectively), but their frequency was significantly (ie, approximately 50%) lower than during a preceding short-term treatment period (P<.0001 and P=.014, respectively). Subjective clinical status, evaluated through an appropriate VAS, improved by 38% from start to end of 1-year follow-up. Bonferroni's comparisons between baseline and subsequent 2-month evaluations were all significant at the .05 level. No age-time interaction could be seen for frequency of anginal attacks and consumption of short-acting nitroderivatives, nor for clinical status )P=.10, P=.11, and P=.51, respectively). Neither tolerability to molsidomine nor effectiveness of the drug was biased by concomitant antianginal therapies, insofar as none of these parameters showed a significant treatment type (ie, molsidomine administered as monotherapy or add-on therapy)-time interaction (VAS for tolerability: P=.44; angina: P=.39; nitroderivatives: P=.72; VAS for clinical status: P=.62). Molsidomine 16 mg QD administered for 1 y to patients with stable angina was well tolerated and remained effective during the entire treatment period, independent of age and concomitant antianginal therapy.

Efficacy and safety of once- and twice-daily formulations of molsidomine in patients with stable angina pectoris: double-blind and open-label studies.

Molsidomine, a sydnonimine acting as a heterocyclic direct nitric oxide donor, has been used for many years in several European countries for the treatment of patients with stable angina pectoris. The efficacy and tolerability of a novel once-daily 16-mg formulation of molsidomine (M16) were compared with those of the currently used twice-daily 8-mg molsidomine tablet (M8) in 666 patients. Study 1, a multicenter, randomized, double-blind, placebo-controlled, twin crossover study, involved 533 patients given acute and 2-week treatment with each drug formulation. Study 2, a multicenter, open-label, sequential, add-on trial, compared M16 and M8 in 133 patients. Drug effects on exercise capacity (study 1 only), frequency of anginal attacks and consumption of short-acting itroderivatives, and incidence of adverse events (AEs) were evaluated. Compared with placebo, M16 increased exercise capacity by 15% (P<.001) at the start of study 1 and by 13% (P<.001) after 2 weeks' treatment, and was not inferior to M8. In terms of anginal attack frequency and nitroderivative consumption, M16 was not inferior to M8 in either study. Moreover, compared with M8, M16 produced a statistically and clinically significant reduction in the incidence of anginal attacks in elderly (>/=75 y) but not in younger patients (<75 y) (study 2), nor in patients from study 1. No significant difference from M8 was found in either study in short-acting nitroderivative consumption. No tolerance to M8 or M16 was observed after 2-week treatment. No statistically significant differences in incidences of all AEs and drug-related AEs were observed between M16 and M8 in either study. The same held true for proportions of patients experiencing AEs and drug-related AEs on M16 vs M8: in study 1-14.3% and 11.8% for all AEs (P=.218), 6.9% and 5.4% for drug-related AEs (P=.280); in study 2-1.3% and 1.3% for all AEs, 0% and 1.3% for drug-related AEs (P>.10) in young patients; and in the elderly, 3.6% and 0% for drug-related AEs (P>.10). Only the proportion of elderly patients with all AEs was significantly higher with M16 than with M8: 14.5% vs 1.8% (P=.039). M16 once daily was effective and well tolerated in investigated patients with stable angina pectoris, particularly the elderly, affording 24 hours of therapeutic activity. M16 was not inferior to M8 given twice daily in terms of efficacy, safety profile, and tolerability.

Comparative effect of nimesulide and ibuprofen on the urinary levels of collagen type II C-telopeptide degradation products and on the serum levels of hyaluronan and matrix metalloproteinases-3 and -13 in patients with flare-up of osteoarthritis.

BACKGROUND AND AIM: Because in vitro studies have shown that nimesulide not only preferentially inhibits COX-2 but also reduces the action/release of pro-inflammatory cytokines, down-regulates the synthesis and/or activity of collagenase(s), and releases reactive oxygen species and other toxic substances from neutrophils, this study investigated whether nimesulide and ibuprofen could affect levels of biochemical markers of joint inflammation and collagen catabolism in patients with flare-up of knee or hip osteoarthritis. METHODS: Ninety patients were included in this randomised, prospective, single- blind study. They received either nimesulide (n = 45) or ibuprofen (n = 45) for a 4-week treatment period. The following parameters were analysed by ELISA: urinary levels of C-terminal cross-linking telopeptide of type II collagen (CTX-II), a marker of type II collagen breakdown; serum levels of hyaluronan (HA), a marker of synovial inflammation and hyperplasia; and circulating levels of stromelysin-1 (matrix metalloproteinase-3 [MMP-3]), collagenase-1 (MMP-1) and collagenase-3 (MMP-13). Statistical analysis used was ANOVA. RESULTS: At the end of the treatment period, nimesulide but not ibuprofen markedly reduced the urinary levels of CTX-II (p < 0.001) and the serum levels of HA (p < 0.05), two markers known to prognosticate poor outcome of the osteoarthritis disease process. Nimesulide also reduced the serum levels of both MMP-3 (p < 0.05) and MMP-13 (p < 0.001). Furthermore, in the nimesulide group, the decrease in levels of CTX-II correlated significantly with the decrease in levels of HA and MMP-13. CONCLUSION: Although nonsteroidal anti-inflammatory drugs are effective in improving pain and disability in OA patients, to date it has been unclear to what extent these drugs could affect joint metabolism and hence joint structure. Patients with flare-up of their osteoarthritis disease process exhibit enhanced levels of markers of joint inflammation and cartilage collagen breakdown, which were markedly decreased by nimesulide but not by ibuprofen.

Efficacy and safety of molsidomine once-a-day in patients with stable angina pectoris.

BACKGROUND: The objective of this study was to compare the efficacy and tolerability of molsidomine prolonged-release 16 mg once-a-day (o.a.d.) with 8 mg twice-a-day (b.i.d.) and placebo in patients with stable angina pectoris. METHODS: After a run-in placebo period of 7 days, the two formulations were compared acutely and then chronically (2 weeks) using cycloergometric tests and a randomized, multicenter, double-blind, double-dummy, crossover design in 533 patients. The quality of life was assessed using the frequency of anginal crises and nitrate sublingual tablets consumption. RESULTS: Both formulations significantly improved exercise test parameters compared with placebo, being it after acute drug intake or after a 2-week treatment period and independently of spontaneous diurnal variation in exercise tolerance. Noninferiority of molsidomine 16 mg compared with 8 mg was demonstrated with a statistically significant superiority of the 16-mg formulation from 14 to 24 h postintake. Both treatments reduced incidence of anginal attacks and use of sublingual isosorbide dinitrate tablets. Tolerability of active drugs was satisfactory, the incidence of drug-related headache being not significantly different from placebo. Only hypotension was significantly more frequent with molsidomine 16 mg than with placebo, pretrial diastolic blood pressure being significantly lower in these patients than in those who did not develop hypotension during the study. CONCLUSIONS: Both molsidomine formulations were effective in controlling patients' angina, did not induce any habituation and were well tolerated. However, the once-daily 16-mg formulation tended to provide better 24-h protection against myocardial ischemia than the 8-mg b.i.d. formulation.

Effect of nimesulide on the serum levels of hyaluronan and stromelysin-1 in patients with osteoarthritis: a pilot study.

This prospective preliminary single-blind study was conducted in patients suffering from osteoarthritis (OA) and requiring non-steroidal anti-inflammatory drugs (NSAIDs) to determine to what extent nimesulide (200 mg/day) and ibuprofen (1200 mg/day) could induce significant changes in the serum levels of matrix metalloproteinase-3 (MMP-3), tissue inhibitor-1 of MMPs (TIMP-1), hyaluronan (HA) and YKL-40 after a therapeutic time period of 28 days. The four biochemical parameters were assessed by using immunoassays. Nimesulide significantly reduced the serum levels of both HA and MMP-3, whereas ibuprofen increased moderately but significantly the serum concentrations of MMP-3 and had no effect on the serum concentrations of HA. The two NSAIDs were unable to change the serum levels of both TIMP-1 and YKL-40. These results suggest that nimesulide might have a favourable effect on the metabolism of OA joints.

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.

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.