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Pentaerythritol tetranitrate (PETN) has raised a great deal of interest in recent years, because it is probably the only organic "tolerance-sparing" nitrate. However, some clinicians doubt whether this drug is really effective in reducing angina and ischemia. The aim of this study, therefore, was to evaluate the clinical efficacy and adverse effects (AEs) of PETN in two doses: 50 mg (PETN-50) and 100 mg (PETN-100), after single ingestion. Twenty-five male patients (pts) with stable angina were enrolled in a randomized, double-blind and placebo (P) controlled study. Ten of them received PETN-50 or P and fifteen of them PETN-100 or P. Antianginal efficacy of the drugs was evaluated by analyzing the parameters of tolerance of effort and coronary reserve taken from serial exercise stress tests on the treadmill performed before single oral ingestion, then after 2h and 6h. Simple hemodynamic parameters were also evaluated at rest and during exercise. In comparison to P, PETN-50 did not change any parameter of tolerance of effort and coronary reserve, nor any simple hemodynamic parameter (all values statistically not significant - n.s.). However, in comparison to P, PETN-100 significantly improved the mean total walking time after 2h by 20.8% (p < 0.01) and also after 6h by 11.3% (p < 0.05). Similarly, PETN-100 improved walking time to angina after 2h by 18.8% (p < 0.05) and after 6h by 10.5% (p < 0.05). The drug also improved walking time to ischemia after 2h by 32.5% (p < 0.01) and after 6h by 13.8% (p < 0.05). PETN-100 did not significantly change the resting heart rate, but it decreased resting systolic blood pressure in both positions 6h after ingestion: in supine by 6.1% (p < 0.05) and in standing by 5.9% (p < 0.05). No postural hypotension in any pt occurred. Diastolic blood pressure significantly decreased only in standing position by 6.8% (p < 0.05) after 6h. During maximal exercise no significant reduction of systolic blood pressure occurred, but there was a significant reduction in diastolic blood pressure 6h after ingestion only. This study shows the good clinical tolerance and safety of PETN in both doses. There were no AEs after single ingestion of PETN-50 and AEs after ingestion of PETN-100 included headaches in 3 pts only (in 1 pt after P) in the group of 15 pts. Thus no clinical activity of PETN-50 was shown. However, our investigations suggest that PETN-100 is an active coronary drug, effective not less than 6 h after ingestion, and well tolerated by pts. Further studies are needed to evaluate the efficacy of PETN in long-term therapy.

Objectives: The revascularization procedures become more and more popular to treat coronary artery disease, in many countries. Some patients are free of angina after revascularization, without any documented re-stenosis present with recurrent angina symptoms after a period of time. The aim of this work was to assess the efficacy of trimetazidine in the subpopulation of patients with a history of PTCA or CABG, who were included in the TRIMPOL II study., Methodology: A subgroup of 94 patients was retrospectively analysed from the TRIMPOL II study, a multicentre, double-blind randomised placebo-controlled trial in 426 patients with stable effort angina. These patients have a history of revascularization for coronary artery disease, and they are still symptomatic after 6 months despite a treatment with metoprolol (50 mg twice daily). They were randomly allocated to receive either trimetazidine (20 mg 3 times daily) or placebo for 12 weeks, on top of the beta-blocker. Exercise test parameters, clinical efficacy and safety were assessed. Results were analysed using the Student test, the Mann-Whitney test or the Shapiro-Wilk test., Results: Compared to placebo, the 12-week treatment with trimetazidine significantly improved: time to 1 mm ST segment depression (385.1 s +/- 144.6 s versus 465.0 s +/- 143.8 s [p < 0.01]); exercise test duration (466.9 s +/- 144.8 s versus 524.4 s +/- 131.5 s [p = 0.048]), total workload (9.0 m.e. +/- 2.4 m.e versus 10.1 m.e. +/- 2.4 m.e [p = 0.035]) as well as time to onset of angina (433.6 s +/- 164 s versus 508.1 s +/- 132.4 s [p = 0.031]). Weekly number of angina attacks and nitrate consumption were significantly reduced in the trimetazidine group when compared to placebo. Three mild gastro-intestinal side-effects were reported in the trimetazidine group., Conclusion: These results show that trimetazidine provides anti-anginal efficacy in post-revascularized patients with recurrent angina despite a monotherapy with metoprolol. The treatment was well accepted.

The aim of this study was to evaluate clinical efficacy and adverse effects of nitroglycerin 15 mg in slow-release form (N-15) after single ingestion. In randomized, double-blind and placebo (P) controlled with cross-over design study 15 male patients with stable angina received N-15 or P. Antianginal efficacy of the drug was evaluated by analysing the parameters of tolerance of effort and coronary reserve taken from serial exercise stress tests on treadmill performed preceding single oral ingestion, 2 hours and 6 hours after. Simple hemodynamic parameters were also evaluated in the rest and during exercise. N-15 significantly improved in comparison to P: total walking time both after 2 hours by 34.3% (p < 0.01) and 6 hours by 23.1% (p < 0.01); walking time to angina after 2 hours by 34.8% (p < 0.01) and 6 hours by 21.7% (p < 0.05), and walking time to ischemia after 2 hours by 66.1% (p < 0.01) and 6 hours by 39.0% (p < 0.05). N-15 significantly increased the rest heart rate in standing position 2 hours after ingestion by 12.3% (p < 0.01) and decreased rest systolic blood pressure in both positions 2 hours after ingestion: in supine by 12.9% (p < 0.01) and standing by 16.3% (p < 0.01) and after 6 hours: in supine by 9.1% (p < 0.05) and standing by 10.0% (p < 0.05). No postural hypotension in any patient occurred. Diastolic blood pressure was significantly decreased only in standing position 2 hours after N-15 ingestion by 12.3% (p < 0.01) and after 6 hours by 9.1% (p < 0.05). During maximal exercise significant reduction of systolic blood pressure occurred 2 hours after ingestion and significant reduction of diastolic blood pressure occurred both 2 hours and 6 hours after ingestion. Adverse effects after single ingestion of N-15 were the few: the headaches were presented only in 4 patients (27%), and in 53% patients any adverse effect occurred. Nitroglycerin 15 mg in slow-release form is an active coronary drug, effective not less than 6 hours after ingestion, and its adverse effects are the few.

The aim of the work was an individual assessment of the effect on coronary reserve exerted by the widely used drug from the group of nitrates--isosorbide dinitrate (ISDN) in conventional and slow-release (SR) presentations, in various doses. The patients--38 males with stable coronary disease were given orally, by randomised double blind method, conventional isosorbide dinitrate (ISDN) in 10 and 20 mg doses, and slow-release isosorbide dinitrate in 20 mg SR, 40 mg SR, 80 mg SR and 120 mg SR doses, or placebo for the first time and for 7 days: four times daily, three times daily (with a 12-hour break), twice daily (with an 18-hour break) and once daily. In each of the therapeutic methods, walking times were analysed during exercise test six hours following drug administration, that is total time (TT), time to angina (TA) and time to ischaemia (TI). A prolongation by > or = 20% of walking times after ISDN administration as compared to placebo in > 50% of patients was accepted as significant improvement. Six hours after the first administration, a significant improvement of TT, TA and TI as compared to placebo was observed in the case of ISDN 20 mg, 40 mg SR, 80 mg SR and 120 mg SR. After administration of the drugs four times daily no significant improvement was observed after any dose. After administration of the drugs thrice daily, significant improvement was found in the case of TA (80 mg SR) and TI (20 mg SR, 40 mg SR and 120 mg SR), after twice daily administration--in the case of TI (40 mg SR and 80 mg SR) and after once daily administration--in the case of TT (80 mg SR), TA (120 mg SR) and TI (40 mg SR, 80 mg SR and 120 mg SR). In > 50% of patients, the coronary activity of ISDN in higher doses persists for six hours in the case of the first time administration; continuous therapy leads to tolerance development and intermittent therapy makes possible to avoid it. Tolerance does not depend on patients' sensitivity to nitrates.

Unlabelled: The aim of this study was the comparative evaluation of antianginal efficacy and the adverse effects of 3 nitrates in oral doses: isosorbide dinitrate 80 mg in slow release form (ISDN-80), nitroglycerin 15 mg--slow release (NITRO-15) and pentaerythritol tetranitrate 100 mg in normal tablets (PENTA-100) in patients (pts) with stable angina pectoris. In a randomized, double-blind, cross-over and placebo (P) controlled study 15 men, with mean age 54.8 +/- 8.0 years, with stable angina, received single doses of: ISDN-80, NITRO-15, PENTA-100 or P. Clinical efficacy of the drugs was evaluated by analysis of the walking times: total (TT), to angina (TA), and to ischemia (TI) on treadmill during stress tests performed 2 and 6 hours (h) after drug ingestion; the adverse effects were registered during 6 h follow up., Results: 2 h after ingestion all 3 study drugs improved significantly: TT, TA and TI in comparison to P. After 6 h the same parameters were improved by: ISDN-80 and NITRO-15, but PENTA-100 improved only TT and TA. After 6 h ISDN-80 significantly improved in comparison to NITRO-15: TT by 19.7% (p < 0.01), TA by 21.2% (p < 0.01) ant TI by 25.0% (p < 0.05), and in comparison to PENTA-100: TT by 32.1% (p < 0.001), TA by 33.4% (p < 0.001) and TI by 41.1% (p < 0.01). After 6 h NITRO-15 significantly improved TI in comparison to PENTA-100 by 13.1% (p < 0.05). The headaches, the most frequent adverse effects, occurred after ingestion of ISDN-80 in 6 pts, NITRO-15 in 4 pts, PENTA-100 in 3 pts and P in 1 pt. Among three evaluated nitrates ISDN-80 significantly improved the effort tolerance and the coronary reserve in the strongest way, NITRO-15 was intermediate in the clinical efficacy, but PENTA-100, the drug with the weakest antianginal efficacy, was the reason of the least number of the adverse effects.

Aims: To assess the antiischaemic efficacy and tolerability of the metabolic agent trimetazidine in combination with metoprolol in patients with stable effort angina., Methods: This was a randomized, multicentre, double-blind, placebo-controlled parallel group study. A total of 426 male and female patients with stable, effort-induced angina and documented coronary artery disease received either placebo or trimetazidine 20 mg three times daily in addition to metoprolol 50 mg twice daily. Treadmill exercise tests were performed at weeks (-1), 0, 4 and 12., Results: After 12 weeks, there were significantly greater improvements in the metoprolol + trimetazidine group than in the metoprolol + placebo group in: time to 1 mm ST segment depression, total workload, time to onset of angina, maximum ST segment depression, mean weekly number of angina attacks, mean weekly nitrate consumption, and grade of anginal pain. There was no evidence of any development of tolerance to trimetazidine. The tolerability of trimetazidine was excellent., Conclusions: Therapy with trimetazidine plus metoprolol produced significant improvements in exercise stress tests and the symptoms of angina relative to metoprolol alone. With its metabolic effect, devoid of any haemodynamic action, trimetazidine is useful for combination therapy in patients with stable angina insufficiently controlled by monotherapy with a beta-blocker., (Copyright 2001 The European Society of Cardiology.)

Introductions: The organic nitrates are effective anti-anginal drugs during initial treatment, but their therapeutic value is compromised by the rapid development of tolerance during sustained therapy. The only widely accepted method of preventing tolerance is the use of intermittent administration, but without specifying to what extent the length of interval is dependent on type and dose of nitrate. The aim of this study was to evaluate how long periods free of nitrates are sufficient to prevent tolerance in long-term therapy with oral sustained-release isosorbide dinitrate (ISDN)., Material and Methods: In a double-blind study, 38 patients with stable angina, received ISDN: 40 mg, 80 mg and 120 mg or placebo in the first ingestion (1st) and in long-term therapy in four 7 day phases: 4-times-daily (4x), 3-times-daily (3x) with 12 h nitrate-free interval, twice-daily (2x) with 18 h interval and once-daily (1x). After 1st and on the last day of each long-term phases, exercise tests with the analysis of walking times: total, to angina and to ischaemia (WTI) were performed: preceding ingestion, 2 h and 6 h after., Results: Six hours after 1st all doses WTI improved significantly in comparison to placebo (p < 0.0001): 40 mg by 52.5%, 80 mg by 66.0% and 120 mg by 58.4%. None of the ISDN doses improved significantly WTI in 4x phase; in 3x, only 40 mg by 12.1% (p < 0.05); in 2x, only 80 mg by 22.3% (p < 0.05) and in once-daily, 80 mg by 27.2% and 120 mg by 36.2% (p < 0.01)., Conclusion: 12 h nitrate-free interval is sufficient in order to prevent tolerance in long-term treatment of sustained-release ISDN with 40 mg dose, 18 h with 80 mg and 24 h with 120 mg doses.

In a randomized, double-blind, placebo (P) controlled with cross-over design study 38 male patients with stable angina and angiographically proven coronary artery disease, received isosorbide dinitrate (ISDN) in various single doses: 10 mg, 20 mg, 20 mg slow-release (-SR), 40 mg-SR, 80 mg-SR and 120 mg-SR. Evaluation of antianginal efficacy and the effect of ISDN on the simple hemodynamic parameters was performed by analysis of walking times on the treadmill: total, to angina and to ischemia (WTI) as well as: heart rate and systolic blood pressure at rest and during exercise. Exercise stress tests on the treadmill were performed: preceding drug administration, 2 hours and 6 h after. 6 h after taking the drug all doses of ISDN improved significantly all three analysed walking times on the treadmill, for example WTI in comparison to P (p < 0.001): 10 mg by 34.6%, 20 mg by 49.6%, 20 mg-SR by 42.9%, 40 mg-SR by 52.5%, 80 mg-SR by 66.0%, and 120 mg-SR by 58.4%. ISDN 20 mg was more active antianginally than 10 mg, but was connected with more severe orthostatic hypotension and headaches. ISDN 20 mg-SR was weaker in the improvement of coronary reserve than ISDN 20 mg, but it gave less adverse effects. The elevation of ISDN-SR dose was effective in the improvement of coronary reserve up to 80 mg-SR (without further benefits after 120 mg-SR). The antianginal efficacy of doses: 40 mg-SR, 80 mg-SR and 120 mg-SR was not significantly different.

Unlabelled: The aim of the study was to evaluate whether tolerance to oral isosorbide dinitrate in sustained-release form (ISDN-SR) may be related to reduction in hematocrit (HCT)--an indirect indicator of plasma volume expansion., Methods: In a double blind, cross-over and placebo (P) controlled study 38 men, with mean age 52.5 +/- 7.4 years, with stable angina and angiographically proven coronary artery disease, received ISDN-SR 120 mg or P as initial dose and after 7 days of therapy: 4-times-daily (ISDN-SR 480 mg a day) and once-daily (ISDN-SR 120 mg a day). Venous HCT was measured: before treatment and after each of the 3 long-term phases. Antianginal efficacy of ISDN-SR 120 mg was evaluated by analysis of walking time to ischemia (WTI) on treadmill during stress tests performed 2 and 6 hours after drug ingestion in acute and long-term therapy., Results: 6 hours after first ingestion of ISDN-SR 120 mg the mean walking time to ischaemia WTI was significantly improved in comparison to P by 58.4% (p < 0.0001) and after 7 days of once-daily treatment by 36.2% (p < 0.01) but not after the 4-times-daily period (NS). HCT fell from mean 43.2 +/- 3.6% before and 42.0 +/- 3.4% (NS) after P phase, to 40.5 +/- 3.0% (p < 0.05) after 4-times-daily period, but HCT remained unchanged after one week of once-daily treatment (NS)., Conclusions: Significant reduction in hematocrit--an indirect indicator of plasma volume expansion--during oral ISDN-SR 120 mg in long-term therapy 4-times-daily, when tolerance occurred, but not once-daily (without tolerance), may contribute to the mechanism of attenuation of antianginal activity of nitrates.