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.

Endothelins: a possible mechanism of cytostatics-induced cardiomyopathy.

Endothelium responds to physical and chemical stimuli by synthesis and release of a variety of vasoactive and signal molecules. Cardiac performance is regulated by cardiac endothelial cells in a paracrine manner, analogous to vascular endothelial control of vascular tone. Endothelin-1 (ET-1), one of the most potent vasoconstrictor peptides, which is synthetized and released by endothelial cells. The role of ET-1 in some special pathological state is still unclear. Authors have investigated the effect of anthracyclines (maximal dose: 450 mg/bodysurface m2) on left ventricular systolic and diastolic function and on the level of plasma ET-1, in 31 (13 male, aged 19-70 years, mean: 38.9) patients suffered from Hodgkin (24) and Non-Hodgkin (7) lymphomas. They have also studied the association between plasma ET-1 concentration and echocardiographic parameters. Serum ET-1 was measured by ELISA method. Left ventricular function analyzed by echocardiography: ejection fraction (EF), time velocity integral (VTI), E and A waves, E/A ratio, deceleration time (DT), Doppler index were assessed. Statistical analysis was made by the Wilcoxon rank test. ET-1 plasma level decreased significantly after therapy (5.6 +/- 3.5 vs. 3.1 +/- 0.9 pg/ml, P < 0.0006). EF (56.4 +/- 5.0% vs. 48.7 +/- 5.1%, P < 0.0001) decreased, and DT (168.1 +/- 36.8 ms vs. 206.5 +/- 58.8 ms, P < 0.0073) increased significantly after administration of anthracycline, showing that both systolic and diastolic left ventricular performance was deteriorated. There was no difference in other echocardiographic parameters before and after therapy. In conclusion, decrease of serum ET-1 concentration might be a result of anthracyclin's direct cytotoxic effect and the decreasing level of ET-1 may play a role in the reduction of the EF. More studies are needed to evaluate the presence and severity of endothelial damage, and long-term follow-up may reveal the importance of low ET-1 level and may show the time is needed for the restoration of the ET-1 concentration to the basic level after cessation of cytostatic therapy.

Endothelin-1 and cardiac function in anthracycline-treated patients: a 1-year follow-up.

Anthracyclines are widely used chemotherapeutic agents in the treatment of lymphomas known to induce cardiomyopathy in more than 20% of patients. There is increasing experimental evidence that cardiac endothelial cells regulate cardiac performance and that endothelin-1 (ET-1) is a central substance in this regulatory mechanism. Twenty (seven male, aged 20-68 years) patients with Hodgkin's or non-Hodgkin's lymphoma treated with anthracycline were followed-up for 1 year. At baseline, after cessation of anthracycline treatment and at 1 year, the plasma ET-1 level was measured by enzyme-linked immunosorbent assay and cardiac function was estimated by echocardiographic measurement of the ejection fraction, the E/A ratio and the deceleration time. The ET-1 level decreased significantly after therapy (5.47 +/- 3.34 pg/mL versus 3.44 +/- 0.69 pg/mL, P < 0.02), and remained significant at 1 year (3.43 +/- 0.57 pg/mL, P < 0.008). The ejection fraction (57.80 +/- 4.73% versus 48.05 +/- 5.65%, P < 0.0001) and the E/A ratio (1.35 +/- 0.40 versus 1.15 +/- 0.40, P < 0.01) decreased, and the deceleration time (177.00 +/- 44.96 ms versus 209.50 +/- 66.25 ms, P < 0.04) increased significantly after therapy, showing that both systolic and diastolic left ventricular performance were deteriorated. Compared with the baseline, the same significant changes were found at 1 year (ejection fraction, 50.65 +/- 8.87%, P < 0.0007; E/A ratio, 1.10 +/- 0.34, P < 0.003; deceleration time, 223.25 +/- 46.85 ms, P < 0.002). The decrease of the ET-1 concentration might be a result of anthracyclines' direct cytotoxic effect and the decreasing level of ET-1 may play a role in the ejection fraction reduction. The results of 1-year follow-up suggest that, although anthracycline toxicity occurs shortly after treatment, the undesirable effect remains.

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.

[Double-blind peer review]. / Kettós vak lektorálás.

The peer review process in medical sciences is much debated. The method is not yet evidence based. Who are the reviewers and how do they perform? They are "independent" experts. As such they are bound to be involved in research similar to that outlined in the manuscript. Very often they are contestant in the same race. That is why the author consider the double blind method, where the author is blinded and the reviewer masked from each other's identity, the best choice. Nevertheless in very many scientific journals of high quality and envied impact factors do not blind the identity of the authors. Science is a race for fame, self accomplishment and also a means to get grants for pursuing the scientific research. Only success is able to provide resources for expensive scientific research. There is no fail-safe method against bias in grant giving and editorial process. In the tidal wave of electronic information it is mandatory to help in differentiating between signal and noise in science. Peer review is the best method to protect readers from the trash of uncontrolled publications in medical science.