Increasing nitroglycerin release from patches enables circumvention of early nitrate tolerance.

Continuous treatment with transdermal nitroglycerin leads to tolerance development within the first day of application. Effective long-term therapy can be provided by interval treatment with nightly patch removal, but even during the hours of intermittent patch application there is rapid attenuation of initial effects. To assess whether an unattenuated antiischemic and antianginal efficacy during the hours of intermittent dosing can be maintained, a modified drug-release profile with increasing plasma concentrations was evaluated using a double-blind, placebo-controlled crossover protocol. Eleven patients with documented coronary artery disease received, in a randomized order, a total of four low-dose nitroglycerin patches (5 mg/24 h each) or placebo, respectively, at intervals of 3 hours. After a treatment interval of 12 hours, all patches were removed for an equally long patch-free interval prior to renewed application of one patch the next morning. At a comparable workload, reductions of ST-segment depression of 65%, 63%, and 56% were found at 2.5 hours, 8 hours, and 12 hours after application of the first patch on day 1, respectively (all significant vs. placebo; 2.5 hours vs. 12 hours, n.s.). On day 2, the comparable reduction of 63% at 2.5 hours after renewed application indicates prevention of tolerance development during subchronic treatment. Effects on exercise capacity and angina pectoris paralleled those on exercise-induced ST-segment depression. Plasma concentrations of nitroglycerin increased from 223 pg/mL to 558 and 803 pg/mL on day 1 and amounted to 205 ng/mL at 2.5 hours on day 2. Thus, interval therapy with increasing nitroglycerin concentrations provides unattenuated antiischemic and antianginal efficacy during the hours of treatment and circumvention of early tolerance during subchronic application. This modified pharmacokinetic profile can be regarded as a model for an improved dosage regimen in nitrate interval therapy.

Infusions with molsidomine and isosorbide-5-mononitrate in congestive heart failure: mechanisms underlying attenuation of effects.

The use of nitrates for treatment of heart failure is encumbered by tolerance, caused by whatever mechanism, which has been reported only in a few instances with sydnonimines. Accordingly, we compared molsidomine (6 mg/h) and isosorbide-5-mononitrate (3.75 mg/h) with respect to maximal hemodynamic effects, rapidity and extent of attenuation, and underlying mechanisms by means of constant infusions over 24 h each in 15 patients with chronic congestive heart failure (NYHA II-III) with a placebo-controlled, double-blind, randomized, crossover protocol. Hemodynamic measurements and determinations of neurohormones were performed at baseline and at 2, 8, and 24 h after the beginning of infusions. With molsidomine, reductions of diastolic pulmonary artery pressure by 29% (p < 0.001), by 24% (p < 0.01), and by 24% (p < 0.01) versus placebo were found at 2, 8, and 24 h, which amounted to 19% (p < 0.01), 10% (NS), and 14% (NS) with the nitrate. Cardiac output was meaningfully affected only with molsidomine (+5%, NS, at 2 h; +9%, p < 0.05, at 8 h; and +15%, p < 0.05, at 24 h), as was systemic vascular resistance (-13%, p < 0.05; -9%, NS; and -18%, p < 0.01) at the corresponding times. Increases in renin activity amounted to 130% (p < 0.001), 117% (p < 0.001), and 112% (p < 0.001) with molsidomine, and to 14, 16%, and 0 (each NS) with the nitrate at the corresponding times. Hematocrit was reduced by 5% (p < 0.001), 7% (p < 0.001), and 12% (p < 0.01) with molsidomine and by 5% (NS), 5% (p < 0.05), and 5% (NS) with the nitrate. We conclude that neurohumoral counterregulation or fluid shift, which is even more pronounced with molsidomine despite longer-lasting effects, has no essential role in nitrate-tolerance development. With molsidomine, such a role cannot be ruled out, although alternatively, a fluid shift from arterial to the low-pressure arm of circulation during the later course of infusion would be even more likely.

Clinical comparison of antiischemic efficacy of isosorbide dinitrate and molsidomine.

In 16 patients with documented coronary artery disease, the extent and duration of acute antiischemic and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate once daily and 8 mg of sustained-release molsidomine 3 times daily were compared according to a randomized, double-blind, cross-over and placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST) at an identical workload and determination of plasma concentrations of both substances. Up to 8 h after dosing in the morning, more marked and sustained effects were observed with the nitrate (ST at 2 h, -82%; p < 0.001; at 8 h, -64%; p < 0.01) than with molsidomine (2 h, -68%; p < 0.001; at 8 h, -9%; NS). At 12 h, no more meaningful actions were detectable with isosorbide dinitrate (-13%, NS) despite plasma concentrations still within a range otherwise considered therapeutically effective, whereas with molsidomine, at 4 h after renewed dosing, this parameter was reduced by 38% (p < 0.01). However, therapeutic coverage over a 24-h period could be demonstrated on neither regimen, in the case of the nitrate because of the development of early tolerance, and in the case of molsidomine with its meaningfully shorter half-life because of the necessity of increasing the dosing frequency even further. No meaningful adverse effects were observed with either regimen. Nonresponders, overall a minority on one treatment, responded completely to the alternative regimen and vice versa.

Anti-ischemic effects of first and second dose of 20 mg isosorbide dinitrate administered 5 hours apart: attenuation of effects despite rising plasma concentration.

Based on evidence that there may be early tolerance development even within the first daily cycle of treatment, this study was undertaken to evaluate the duration and extent of the antiischemic effects of two 20 mg doses of isosorbide dinitrate as used in a well-established regimen documented to maintain effectiveness during long-term treatment. Ischemia parameters were analyzed at 2 and 4 1/2 hours after the first dose as well as at 2 and 7 hours after the second dose given 5 hours later. The studies were performed in 10 male patients with documented coronary artery disease using bicycle ergometry and a double-blind, randomized, placebo-controlled, crossover protocol. ST-segment depression was reduced by 59% (p < 0.0005) at 2 hours and by 42% (p < 0.01) at 4 1/2 hours after the first tablet and by 38% (p < 0.005) at 2 hours and by 15% (p < 0.05) at 7 hours after the second tablet. Increments in ischemia-free workload capacity amounted to 112% (p < 0.005) and to 41% (p < 0.05) after the first tablet and 68% (p < 0.05) and 38% (p < 0.05) at 2 and 7 hours after the second tablet. At 2 and 4 1/2 hours after the first tablet, plasma concentrations of isosorbide dinitrate were 8.4 and 5.9 ng/ml, and those of isosorbide-5-mononitrate were 166.6 and 130.3 ng/ml. At 2 and 7 hours after the second tablet, the concentrations of isosorbide dinitrate were 9.1 and 5.9 ng/ml, and those of isosorbide-5-mononitrate were 224.5 and 148.1 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemodynamic evaluation of two regimens of molsidomine in patients with chronic congestive heart failure.

We investigated the extent and duration of the haemodynamic effects of two regimens of molsidomine, i.e. two tablets of a standard regimen consisting of 4 mg given 6 h apart and one tablet of 16 mg in sustained-release form once daily in 13 patients with chronic congestive heart failure using a placebo-controlled, randomized, double-blind and crossover protocol over a period of 12 h. Both regimens significantly affected systolic, mean and diastolic pulmonary arterial pressure (reductions of up to 15%), right atrial pressure (reductions of up to 35%) and total pulmonary resistance (reductions of up to 18%). The lower dose achieved its maximum action after about 1 h and remained effective for 2 h, whereas the higher dose in sustained-release form showed maximal efficacy at 2 h and remained active even at 12 h. In contrast, only minor changes in arterial blood pressure, systemic vascular resistance and cardiac output were observed on both regimens, almost exclusively at 2 h. Heart rate was not affected by either of the regimens tested. Neither regimen led to any untoward adverse effects. Thus, molsidomine is a potent vasodilating agent which, apart from its effects on preload, also acts on pulmonary arterial and right atrial pressures, leaving systemic circulation largely unaffected on the regimens tested. Administered on its own, it is therefore suitable for treatment of congestive heart failure.

Pharmacokinetics and additional anti-ischaemic effectiveness of amlodipine, a once-daily calcium antagonist, during acute and long-term therapy of stable angina pectoris in patients pre-treated with a beta-blocker.

Amlodipine 10 mg was evaluated for additional anti-ischaemic and anti-anginal efficacy in 14 patients pre-treated with a beta-blocker who had documented coronary artery disease, stable angina pectoris, and > or = 2 mm of exercise-induced ST segment depression. For 2 days the patients received open-label amlodipine and then, according to a randomized, placebo-controlled, cross-over and double-blind protocol, they were treated with amlodipine or placebo, respectively, once a day for 3 weeks each. Exercise tests and blood sampling for plasma concentrations of amlodipine were performed at 8 and at 24 h after dosing on both days of acute testing as well as on day 18 of chronic treatment. During chronic treatment, when plasma concentrations fluctuated between 23.5 ng.ml-1 at 8 h and 14 ng.ml-1 at 24 h post-dosing, ST segment depression at an individually comparable workload was significantly decreased by 28% compared with placebo (P < 0.005) at both points in time. Increases in ischaemia-free workload capacity amounted to 76% (P < 0.005) and to 81% (P < 0.01) at 8 and at 24 h, respectively. The number of anginal attacks was reduced by 39% (P < 0.05). Conversely, after initial dosing, i.e. when plasma concentrations declined from 4.7 ng.ml-1 to 3.9 ng.ml-1, influences upon ischaemic parameters compared to control values were markedly less at 24 h as opposed to 8 h. There were no untoward side effects observed at any point in time.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced effectiveness of combined sustained-release forms of isosorbide dinitrate and diltiazem for stable angina pectoris.

In 14 patients with documented coronary artery disease, the extent and duration of acute anti-ischemic, antianginal and hemodynamic effects of monotherapies with 120 mg of sustained-release isosorbide dinitrate and diltiazem were compared; their combined therapy administered once daily in the morning with diltiazem given again in the evening were also compared according to a randomized, double-blind, crossover, placebo-controlled protocol including exercise testing for assessment of ST-segment depression (ST decreases) at an identical work load, exercise capacity and determination of plasma concentrations of both substances. Comparison of individual substances revealed more marked and sustained effects of isosorbide dinitrate (ST decreases at 2 hours, -66%; at 6 hours, -50%; p less than or equal to 0.05 for both), remaining statistically significant up to 12 hours (-24%) than of diltiazem (2 hours, -30%; 6 hours, -16%; p less than 0.05). Combined therapy resulted in increased effects (ST decreases at 2 hours, -80%; 6 hours, -76%; 12 hours, -30%; p less than or equal to 0.05) as opposed to individual substances for a period of up to 12 hours. However, therapeutic coverage over 24 hours could not be demonstrated, even with renewed administration of sustained-release diltiazem in the evening. Plasma concentrations of isosorbide-5-mononitrate were greater than 250 ng/ml for 12 hours on days when isosorbide dinitrate was given, decreasing to less than 100 ng/ml at 24 hours. On days when diltiazem was given, plasma levels greater than 50 ng/ml were detected only at 2 and at 6 hours, and at 24 hours only after a second tablet was given.

[Effectiveness of various combination therapies in patients with coronary heart disease]. / Effektivität verschiedener Kombinationstherapien bei Patienten mit koronarer Herzerkrankung.

There is only a limited number of studies available comparing the effectiveness of various combinations of anti-ischemic and antianginal substances in the same patients with coronary artery disease and stable angina pectoris and even these are restricted to either only a few drugs or a single point in time for testing. Accordingly, this study was undertaken to determine to what extent the combination of two or three drugs with different anti-ischemic mechanisms of action such as the long-acting form of the beta-blocker metoprolol and isosorbide dinitrate (ISDN) in sustained-release form as well as the calcium channel blockers nisoldipine and diltiazem in sustained-release form, which previously have not been tested in combination, are capable of enhancing effectiveness and prolonging duration of action. In a double-blind, randomized, crossover study in eleven patients with documented coronary artery disease and stable angina pectoris the effects of monotherapy with 200 mg metoprolol in long-acting form were compared with those of combined treatment with 120 mg ISDN sustained-release or 10 mg nisoldipine or 120 mg diltiazem sustained-release as well as ISDN and nisoldipine and finally, ISDN and diltiazem by means of an intraindividual analysis. For assessment of anti-ischemic and antianginal effects, symptom-limited exercise testing was carried out before as well as three, eight, twelve and 24 hours after medication. The parameters analyzed were ST-segment depression at the highest comparable workload, ischemia-free and symptom-free exercise capacity (one minute prior to ST-segment depression of 1 mm or onset of angina pectoris) as well as the systolic blood pressure--heart rate product at the highest comparable workload and at the highest ischemia-free workload, that is one minute prior to an ischemic reaction of 1 mm. Based on the ST-segment depression, all combinations of two drugs (metoprolol and ISDN at three hours; metoprolol and diltiazem at eight hours) led to a significant or at least relative increase of effectiveness. On comparison of the various double combinations, those with nisoldipine showed an early dissipation of action which, twelve hours after administration, was significantly less marked than those with diltiazem. Of the two tested triple combinations, metoprolol, ISDN and diltiazem was either significantly more effective than the various double combinations (metoprolol and ISDN or metoprolol and nisoldipine, both at eight and twelve hours; metoprolol and diltiazem, twelve hours) or relatively more effective and showed clear prolongation of the effects in excess of twelve hours.(ABSTRACT TRUNCATED AT 400 WORDS)

[Treatment of symptomatic and asymptomatic myocardial ischemia using 120 mg delayed-action ISDN]. / Behandlung der symptomatischen und asymptomatischen myokardialen Ischämie mit 120 mg retardiertem ISDN.

Most episodes of myocardial ischemia in patients with coronary artery disease are incurred asymptomatically during everyday physical activities. While the necessity for medical treatment of angina pectoris is clearly established, the indication for treatment of asymptomatic ischemia is based on prevention of structural myocardial damage or malignant arrhythmias and on the implication of improvement in prognosis. In this regard, however, no reliable data is available. Additionally, only relatively few controlled studies have been carried out to investigate the influence of medical treatment on the ischemic episodes. Moreover, on assessment of treatment with Holter monitoring, as opposed to standardized ergometric testing, the substantial spontaneous variability of the frequency of ischemic episodes from day to day must be taken into consideration. Accordingly, in 25 patients with documented coronary artery disease, using a double-blind, randomized, placebo-controlled protocol with two periods of 48 hours of Holter monitoring each, we analyzed the effects of 120 mg isosorbide dinitrate in sustained-release form on the frequency, duration and extent as well as the circadian variation of transient myocardial ischemia during everyday physical activities and differentiated these from the spontaneous day-to-day fluctuations. During the placebo phase, 277 episodes with ST-segment depression greater than 1 mm were detected, 81% of which were asymptomatic. During treatment with 120 mg isosorbide dinitrate in sustained-release form, the number of episodes was reduced significantly (p less than 0.05) to 119 (-57%) where the decrease in symptomatic and asymptomatic episodes of 54% and 58%, respectively, was comparable (Figure 1).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-acting, marked antiischemic effect maintained unattenuated during long-term interval treatment with once-daily isosorbide-5-mononitrate in sustained-release form.

In 18 patients with documented coronary artery disease, the antiischemic effect of 50 and 100 mg isosorbide-5-mononitrate (IS-5-MN) in sustained-release (SR) form was investigated using a randomized, double-blind, crossover, placebo-controlled protocol. After the initial administration of both dosages, compared to placebo there were significant reductions in exercise-induced ST-segment depression and significant increases in ischemia-free exercise time at all times of testing. At 12 hours, the 100-mg dosage still amounted to greater than 50% of its maximum and was significantly more marked than the 50 mg dose. Accordingly, the 100-mg dosage can be assumed to confer a longer duration of action. At the end of 3 weeks of long-term treatment, the significant antiischemic effects were not diminished versus those observed after initial administration. There was no evidence of tolerance development with either dosage. The IS-5-MN plasma concentration during long-term administration displayed, within the 24-hour treatment cycle, a clear decrease to low baseline values and a marked 5- to 7-fold increase after the daily dose in accordance with the response known to be prerequisite to successful interval treatment. Thus, the once-daily administration of IS-5-MN SR with dosages of 50 mg and, more markedly, 100 mg, provides effective antiischemic protection throughout the daily period of most physical activities in patients with stable angina pectoris.

Nitrate therapy in patients with coronary artery disease--preparations and doses with and without development of tolerance.

Rapid tolerance development with respect to hemodynamic, anti-anginal and anti-ischemic effects is a relevant clinical problem associated with any longterm treatment with nitroglycerin, isosorbide dinitrate or isosorbide 5-mononitrate. Tolerance occurs with any dosing regimen that results in nitrate accumulation in the plasma or nearly-constant plasma concentrations, as is the case with multiple daily doses of oral nitrates or continuous application of transdermal patch systems. Nitrate tolerance can be prevented by the interval treatment. This encompasses incorporation of an application-free interval which prevents meaningful nitrate accumulation such that, from a low baseline level, renewed drug administration leads to an increase in the nitrate plasma concentration greater than 2.5-fold. From controlled studies, dosing regimens for interval treatment proven to be effective have been designated for isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin patch systems. The early attenuation of nitroglycerin, seen within the first 12 h of its use, according to the results of a recently completed study, can be counteracted through continuously increasing plasma concentrations during this period. Interval treatment does not enable 24-h therapeutic protection. Studies with ST-Holter monitoring, however, have shown that adequate coverage can be provided for the period during which the vast majority of ischemic episodes occur. Clinically-relevant rebound phenomena do not occur during interval treatment. Pharmacological approaches to prevent nitrate tolerance, on the basis of the limited and, in part, conflicting data available, do not provide an alternative to interval treatment.

[Long-term therapy with nitrates. How can continuous effectiveness be achieved?]. / Langzeittherapie mit Nitraten. Wie ist eine anhaltende Effektivität zu gewährleisten?

Due to rapidly occurring tolerance, "continuous" administration of nitrates can no longer be considered justified. The development of tolerance can be avoided and, thus, the antiischemic effect maintained during long-term treatment only by providing a nitrate-free interval. Dosing regimens with documented effectiveness in long-term controlled studies are available for both isosorbide dinitrate and isosorbide 5-mononitrate as well as for transdermal nitroglycerin systems.

Effectiveness of interval nitrate therapy in angina pectoris.

Because of rapid tolerance development, the use of multiple daily doses of oral nitrates or continuous application of transdermal nitrate systems can no longer be considered justified. Only with an interval treatment, which prevents nitrate accumulation in the plasma such that, from low baseline values, renewed administration of the drug results in a marked increase in plasma concentration, is it possible to utilize the antianginal and antiischaemic effects of nitrates for meaningful long-term treatment. For isosorbide dinitrate and isosorbide 5-mononitrate, as well as for transdermal nitroglycerin systems, interval treatment dosing regimens with maintained effectiveness documented in controlled studies have been delineated. To some degree, the principle of interval treatment can be achieved with continuously applied transdermal patches designed for discontinuous release of their content, which yield maintained though somewhat attenuated effects. Recent studies have shown that the tolerance to nitroglycerin, which develops within the first 12h of contact with currently available transdermal patches, can be prevented by gradually increasing the plasma concentration during this period of time. Evidence for clinically relevant rebound phenomena during interval treatment has not been observed.

When does nitrate tolerance develop? What dosages and which intervals are necessary to ensure maintained effectiveness?

To address the issues of tolerance development and its circumvention during long-term treatment with nitrates, several controlled studies have been performed. In patients with coronary artery disease, during long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form at dosages of 20 mg t.i.d., 40 mg t.i.d. and 60 mg t.i.d., both the rate of anginal attacks and the ischaemic reaction to exercise were unaffected. After a marked acute anti-ischaemic effect to 40 mg ISDN in nonsustained-release form, during chronic administration of the same dose four times daily, in association with continuously-high nitrate plasma concentrations, similarly, there were no significant effects. On use of nitroglycerin (NTG) transdermal patches delivering 10 mg, 15 mg and 30 mg per 24 hours, respectively, renewed patch application after 24 hours was not met with the same marked response observed after initial application. Clearly attenuated effects could be seen within 8 to 12 hours. These results show that tolerance development is incurred when the incrementation in plasma concentration after a repeated nitrate dose is of relatively limited magnitude with respect to baseline values. The observation of rapid reversibility of nitrate tolerance lead to the concept of interval treatment which on daily use incorporates a sufficiently long period without nitrate administration. On use of a nitrate-free treatment interval employing a regimen of 20 mg ISDN nonsustained-release form twice daily in the morning and at midday, 120 mg ISDN sustained-release form once daily or 50 or 100 mg isosorbide 5-mononitrate once daily, maintained effectiveness has been documented, as it has also been shown for treatment with NTG patches delivering 10 mg per 24 hours on incorporation of a 12-hour patch-free interval. The currently available patch system with discontinuous NTG delivery does not incur a complete loss of action but a considerable attenuation of its effects indicates the need for further refinements. Thus interval treatment guarantees maintenance of nitrate effects, albeit with the limitation that 24-hour therapeutic coverage is not enabled.

[Discontinuous drug release as an alternative to interval therapy in the treatment of coronary heart disease with nitroglycerin patches]. / Diskontinuierliche Wirkstofffreisetzung als Alternative zur Intervalltherapie bei der Behandlung der koronaren Herzerkrankung mit Nitroglycerinpflastern.

In ten patients with angiographically-documented coronary artery disease, according to a double-blind, placebo-controlled protocol, the antiischemic and antianginal actions of a new transdermal nitroglycerin patch system with discontinuous drug release (7.5 mg/24 hours, two-thirds of which is released within the first twelve hours) were assessed on three consecutive days to determine whether effective longterm treatment is possible (Figure 1). At 2.5 hours after initial application, as compared with placebo, the active drug led to a reduction in exercise-induced ST-segment depression of 55.9% (p less than 0.001; Figure 2), the exercise capacity to onset of 1 mm ST-segment depression increased 129% (p less than 0.05; Figure 3), angina pectoris during exercise was incurred in only 20% of the patients (Figure 4). At twelve hours, the corresponding effects were attenuated at -44%, +114% and +60%. 24 hours after patch application, an appreciable effect could no longer be detected. After renewed patch application on the second day, as compared with the initial application, the actions on ST-segment depression and exercise capacity were diminished about 20%. Similarly, there was an increase in the number of patients who developed angina during exercise. At twelve hours, there was more marked attenuation of the effects on all three parameters than that which had already been observed on the first day. At 24 hours, there were no significant effects. At 2.5 hours after renewed patch application on the third day, the effects on ST-segment depression, exercise capacity and incurrence of angina pectoris were essentially similar those seen after the second application.(ABSTRACT TRUNCATED AT 250 WORDS)

[Interval therapy in effective treatment of angina pectoris using nitroglycerin patch systems. A controlled study with determination of nitroglycerin plasma levels]. / Intervalltherapie zur effektiven Behandlung der Angina pectoris mit Nitroglycerin-Pflastersystemen. Kontrollierte Studie mit Bestimmung der Nitroglycerin-Plasmaspiegel.

In ten patients with angiographically-documented coronary artery disease, stable angina pectoris and reproducible exercise-induced ST-segment depression, the extent and duration of antiischemic and antianginal effects of transdermal nitroglycerin patches delivering 10 mg/24 hours were investigated according to a double-blind, crossover, placebo-controlled protocol. Exercise testing and blood sampling for determination of nitroglycerin plasma concentrations were carried out at 2.5 and twelve hours after initial application, at 2.5, twelve and 24 hours after renewed application subsequent to a twelve-hour treatment pause as well as at 2.5 hours after application of a third patch (Figure 1). At 2.5 hours after initial application there was a reduction in exercise-induced ST-segment depression from 2.7 mm +/- 0.19 (SEM) to 0.75 +/- 0.2 (-72%; p less than 0.001) (Figure 2). The exercise capacity to onset of 1 mm ST-segment depression increased from 117 Watt X min +/- 34 (SEM) to 361 Watt X min +/- 84 (+210%; p less than 0.001) (Figure 3). At twelve hours, exercise-induced ST-segment depression was reduced only from 2.5 mm +/- 13 to 1.77 +/- 0.2 (-32%; p less than 0.01) and the increase in exercise capacity to onset of 1 mm ST-segment depression was narrowed from 136 Watt X min +/- 28.5 to 215 Watt X min +/- 43 (+59%; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[Avoidance of tolerance development to long term therapy with nitrates through correct dosage]. / Vermeidung einer Toleranzentwicklung bei Langzeittherapie mit Nitraten durch korrekte Dosierung.

Tolerance development to organic nitrates, with respect to blood pressure reduction and precipitation of headache, had been assumed for almost a century but it was not until 1980 that the anti-ischemic effect was proven to be subject to this phenomenon, in a placebo-controlled, double-blind study carried out by our group exemplarily employing long-term treatment with isosorbide dinitrate (ISDN) in sustained-release form. Subsequent studies showed that tolerance development was also incurred during administration of ISDN, nonsustained-release form, 40 mg q.i.d. and on application of transdermal nitroglycerin patch systems. Both changes in the pharmacokinetics and activation of counter-regulatory mechanisms can be excluded as meaningful etiologic factors for the development of nitrate tolerance. It must be assumed that intracellular changes in the target organ which are associated with a diminished responsiveness for guanylate cyclase activation are at the basis of tolerance development. Prerequisite, according to laboratory experiments and clinical observations, are high concentrations of nitrates. After development of tolerance, on allowing a nitrate-free interval to intervene, the attenuated effects rapidly resume. Consequently, we investigated the hypothesis that tolerance could be avoided by an intermittent administration of nitrates which prevented accumulation of high serum concentrations. This was confirmed in two placebo-controlled, double-blind studies. Both during treatment with 20 mg ISDN in the morning and at midday as well as with the once-daily administration of 120 mg ISDN sustained-release form in the morning, there was an unequivocal anti-ischemic effect without tolerance development together with a significant reduction in the rate of anginal attacks and nitrate consumption.(ABSTRACT TRUNCATED AT 250 WORDS)

[Therapy of coronary heart disease with nitroglycerin patches. Behavior of anti-ischemic effectiveness in continuous administration and following patch free interval]. / Therapie der koronaren Herzerkrankung mit Nitroglycerinpflastern. Verhalten der antiischämischen Wirksamkeit bei kontinuierlicher Verabreichung und nach "pflasterfreiem" Intervall.

Subsequent to the finding of a rapidly attenuated anti-ischemic effect on use of high-dose nitroglycerin patch treatment in patients with coronary artery disease as well as contradictory results obtained with low-dose patch treatment, there are still no reliable guidelines for the use of transdermal nitroglycerin patch therapy. Accordingly, this study was carried out in ten patients with angiographically-documented coronary artery disease, stable exercise-induced angina pectoris and reproducible ST-segment depression, to assess the extent and duration of antianginal and anti-ischemic action of nitroglycerin patch treatment at an intermediate dosage of 15 mg/24 hours after the initial application, after renewed patch application on the second day and after patch application on the third day which had been preceded by a ten-hour patch-free interval in the night. At 2.5 hours after initial application of the nitroglycerin patch there was a 64% reduction in exercise-induced ST-segment depression from 2.6 mm +/- 0.21 (SEM) to 0.93 mm +/- 0.29 (p less than 0.001) (Figures 1 and 2). The exercise capacity to onset of 1 mm ST-segment depression was increased 132% from 191 watt X min +/- 15 (SEM) to 442 watt X min +/- 47 (p less than 0.001), (Figure 3). Eight hours after the initial patch application, exercise-induced ST-segment depression was reduced 37% from 2.6 mm +/- 0.19 to 1.65 mm +/- 0.18 (p less than 0.01); the exercise capacity to onset of 1 mm ST-segment depression was increased 39% from 178 watt X min +/- 18 to 245 watt X min +/- 19 (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

[High-dose transdermal nitroglycerin therapy: loss of effect within 24 hours?]. / Hochdosierte transdermale Nitroglycerintherapie: Wirkungsverlust innerhalb von 24 Stunden?

Within a relatively short period of time, nitroglycerin patches have come into widespread use for treatment of coronary artery disease in the absence of sufficient clinical data in support of their efficacy. Presently, there is still considerable controversy regarding the extent and duration of action as well as the dosage requirements. Accordingly, a study was carried out in six patients with angiographically-documented coronary artery disease, stable exercise-induced angina pectoris and reproducible ST-segment depression to analyze the effects of nitroglycerin patches, formulated to deliver 5 mg, 10 mg, 20 mg as well as 30 mg per 24 hours, respectively, on the extent of ST-segment depression. In a further study, the extent and duration of antianginal and anti-ischemic effects of nitroglycerin patches delivering 30 mg/24 hours were investigated in ten patients according to a randomized, double-blind, crossover placebo-controlled protocol. In seven of these patients, testing was again performed at 2.5 hours after repeated application (second application at 24 hours) (Figure 1). Nitroglycerin patches delivering 5 mg, 10 mg, 20 mg as well as 30 mg/24 hours, respectively, led to significant reductions in ST-segment depression at 2.5 hours of 59% (range 25 to 100%; p less than 0.025), 63% (0 to 100%, p less than 0.01), 77% (50 to 100%, p less than 0.001) as well as 82% (50 to 100%, p less than 0.005) as compared with control values (Figure 2).(ABSTRACT TRUNCATED AT 250 WORDS)

[Long-term therapy of stress angina pectoris by a single daily administration of 120 mg isosorbide dinitrate in retard form. Comparison of monotherapy and combination therapy with atenolol and nifedipine]. / Langzeittherapie der Belastungs-Angina-pectoris durch einmal tägliche Verabreichung von 120 mg Isosorbiddinitrat in retardierter Form. Vergleich von Monotherapie und Kombinationstherapie mit Atenolol und Nifedipin.

This study was undertaken to determine whether an effective antianginal treatment without tolerance development can be carried out with intermittent nitrate administration on a regimen with a single daily dose of 120 mg isosorbide dinitrate (ISDN) in sustained-release form (SR), as well as whether the concomitant administration of 100 mg atenolol or 100 mg atenolol and 20 mg nifedipine renders an additive antiischemic effect. In two independently performed investigations, the duration of action of a single dose of 120 mg ISDN SR was assessed after its initial administration in addition to the anti-ischemic effect during long-term treatment, each according to a randomized, double-blind, crossover, placebo-controlled protocol in a total of 15 patients with angiographically-documented coronary artery disease, stable angina pectoris and reproducible ST-segment depression during exercise. The test phases of four weeks each were separated by one week placebo phases. After completion of the study, for a further eight weeks, 120 mg ISDN SR was given together with 100 mg atenolol in the morning. Exercise testing was carried out after four weeks of treatment in a control period before and at two hours after administration of 120 mg ISDN SR with 100 mg atenolol as well as after another four weeks in a control period before and after concomitant administration of 120 mg ISDN SR, 100 mg atenolol and 20 mg nifedipine in sustained release form.(ABSTRACT TRUNCATED AT 250 WORDS)