[Treatment of myocardial ischemia with molsidomine].
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Angina Pectoris↗
Biomedical subjects
W Rudolph
Publications and source records attributed to W Rudolph.
[Effectiveness of various combination therapies in patients with coronary heart disease].
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)
Adrenergic beta-Antagonists↗
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.
Administration, Cutaneous↗
[Nitrates in the treatment of heart failure].
Organic nitrates were the first peripherally-active vasodilators to be used for the treatment of heart failure. Currently, three nitrate derivatives, glycerol trinitrate, isosorbide dinitrate and isosorbide 5-mononitrate as well as the nitrate-like substance molsidomine are employed clinically. For treatment of heart failure, the decisive hemodynamic effect is a meaningful reduction in ventricular filling pressures with maintenance or even a slight increase in cardiac output. The individual response to nitrates is variable. An important indicator for the effect achievable for a certain dose or for the necessary dosage to affect a defined reduction in ventricular filling pressures, is the magnitude of right atrial pressure. It can be assumed that the latter statement is also valid for the nitrate-like substance molsidomine. An inherent problem with any long-term treatment with nitrates is the incurrence of tolerance. This can be expected with any dosing regimen which leads to nitrate cumulation in the plasma or to nearly-constant, high, plasma concentrations as rendered by multiple daily administration of orally-active nitrates or with continuous transdermal or intravenous nitrate administration. The cause of nitrate tolerance is regarded as an insufficient or absent stimulation of guanylate cyclase and, consequently, inadequate generation of cyclic GMP due to availability of thiol substrate. Since the nitrate-like substance molsidomine appears to be able to stimulate guanylate cyclase independent of thiol groups, tolerance development may not be a limiting factor with this agent. Comparable reduction of diastolic pulmonary artery pressure after acute administration and at the end of one week of treatment with 4 mg molsidomine four times daily has been reported.(ABSTRACT TRUNCATED AT 250 WORDS)
Dose-Response Relationship, Drug↗
[Can sudden cardiac death be prevented by treatment with anti-arrhythmia drugs?].
Sudden cardiac death is defined as death due to a primary cardiac cause or mechanism, occurring within one hour of the onset of acute illness in a person thought to be free of, or with symptomatically mild, heart disease, or simply prehospital death. Of persons dying suddenly, 90% have coronary artery disease, less commonly, dilated cardiomyopathy or hypertrophic cardiomyopathy, preexcitation syndrome, long QT-syndrome, conduction disturbances, congenital or valvular heart disease as well as cardiac tamponade are responsible. In the USA, the incidence of sudden cardiac death is approximately 450,000 per year, in the Federal Republic of Germany the number lies at about 70,000 to 80,000. The most important risk factors for sudden cardiac death are impaired left ventricular ejection fraction, myocardial ischemia and arrhythmias. In general, sudden cardiac death is caused by ventricular fibrillation which arises mainly by degeneration of ventricular tachycardia (VT). The terminal arrhythmia, it is assumed, is precipitated by premature ventricular beats originating in an arrhythmogenic substrate. MEDICAL ANTIARRHYTHMIC TREATMENT IN PATIENTS WITH CORONARY ARTERY DISEASE AFTER MYOCARDIAL INFARCTION: STUDIES WITH CLASS I DRUGS: The results of nine large, randomized , controlled studies are available in which the mortality of patients on antiarrhythmic treatment has been studied (Table 1). Two studies each were carried out with aprindine, phenytoin, mexiletine and tocainide as well as one study with endainide, flecainide or morizicine. With the exception of the CAST study, no study showed a significant difference between treated patients and the control group with respect to mortality or incidence of sudden cardiac death. The CAST study was terminated after ten months because the administration of flecainide and encainide led to overall mortality of 7.7% vs. 3.0% in the control group and the rate of sudden cardiac death at 4.5% was significantly higher in the treatment group than the 1.2% incidence found in controls (Table 2). For nearly all of the studies described, the patient groups were not sufficiently large and subgrouping according to patient characteristics was not carried out such that possibly, inhomogeneity of the entire collective may not have been recognized precluding identification of some individuals who may have shown benefit from antiarrhythmic treatment. The necessity for treatment in many of those receiving drugs is questionable since generally the rhythm profile of the patients was not taken into consideration for the decision to treat. Proarrhythmic effects, accordingly, were also not assessed. Individual treatment and dosage adjustment by monitoring with effectiveness criteria was carried out in one study only in which, even here, criteria for effectiveness were arbitrarily capable of eliciting antiarrhythmic actions. Calculation of mortality rates was carried out on the basis of the total number of deaths in the respective groups without taking into consideration that by the end of the study, in the treatment group the medication had been discontinued in up to 40% of the patients. STUDIES WITH CLASS II DRUGS: For treatment with beta-receptor blockers there are 15 large, controlled, randomized, long-term studies available in which total mortality and the incidence of sudden cardiac death were studied.(ABSTRACT TRUNCATED AT 400 WORDS)
Anti-Arrhythmia Agents↗
[Pathophysiologic and diagnostic aspects of heart failure].
Ventricular dysfunction due to an abnormality of the heart which is associated with typical hemodynamic, renal and hormonal reactions, characterizes the clinical syndrome heart failure. The traditional definition of heart failure as the inability to pump an amount of blood sufficient to cover the metabolic needs of the body in the presence of adequate venous return, emphasizes mainly the reduction in cardiac output but not the increase in intracardiac pressures. Pressure or volume overload, decreased contractility, loss of muscle mass or restricted filling represent the most important pathological processes leading to heart failure. The disturbance of systolic ventricular function due to pressure or volume overload or diminished contractility is characterized by a decrease in the ejection fraction, the disturbance in diastolic ventricular function associated with restricted filling is characterized by elevated chamber stiffness. Decreased contractility is most commonly responsible for the development of heart failure. Impairment of diastolic ventricular function can only be regarded as the dominant mechanism leading to heart failure in the presence of a small noncompliant ventricle. Impairment of diastolic ventricular function in an enlarged heart is always associated with an impairment of systolic ventricular function and is, then, relegated to a subordinate role. Common causes of heart failure are coronary artery disease, hypertension, cardiomyopathies, valvular heart diseases and congenital heart diseases, for the incidence of which coronary artery disease is most frequently responsible. Most of these diseases lead to heart failure not via a single, but rather several of the specified pathophysiological processes. Possible mechanisms for loss of contractility include structural changes as well as alterations in excitation-contraction coupling. Possible mechanisms responsible for impaired diastolic ventricular function encompass, in addition to altered calcium flux, structural changes such as fibrosis and hypertrophy and factors such as asynchrony and abnormal loading conditions. With increasing derangement of cardiac function, there is recruitment of the compensatory mechanisms: hypertrophy of the cardiac muscle, Frank-Starling mechanism, activation of the sympathetic nervous system, the renin-angiotensin-aldosterone system and the arginine-vasopressin system. The goal is maintenance of adequate blood pressure and cardiac output whereby blood flow is redistributed in favor of the heart and brain and away from the skin, musculature and visceral organs. Activation of the neurohumoral system can lead to excessive vasoconstriction as well as sodium and water retention resulting in an undesired elevation of preload and afterload which, in turn, leads to further worsening of the heart failure.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiac Output↗
[Treatment of heart failure with calcium antagonists].
Vasodilators have a well-established role in the treatment of congestive heart failure. By virtue of their vasodilating properties, the calcium channel blockers have been advocated for use in the treatment of heart failure, in particular, in consideration of the fact that the left ventricular dysfunction in 60 to 70% of the patients with this condition is due to ischemic heart disease, the primary disorder for which the calcium channel blockers are intended to treat. The net hemodynamic effect of calcium channel blockade is the result of two opposing actions: negative inotropy and systemic vasodilation with reflex-induced sympathetic stimulation. The balance is dependent on the prevailing cardiovascular status prior to administration of the drug. In the presence of no or only mild-to-moderate left ventricular dysfunction and intact adrenergic reflexes, a small amount of negative inotropy is readily offset by afterload reduction and adrenergic stimulation. In the presence of severe left ventricular dysfunction sufficiently extensive to lead to heart failure, a condition in which homeostatic reflexes are already attenuated, even a slight amount of negative inotropy can lead to unequivocal deterioration of hemodynamics. Of the three conventional calcium channel blockers, verapamil exerts the most marked negative inotropic effects. Even verapamil, however, has been shown to lead to hemodynamic improvement in some patients, at least after acute administration. Apparently, the cut-off point between beneficial and adverse actions lies at an ejection fraction between 30 and 40% and a pulmonary capillary pressure of about 20 mm Hg. In patients beyond these limits, if treated with verapamil, worsening of heart failure is not uncommon.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium Channel Blockers↗
[Spontaneous variability in ischemic episodes during everyday conditions. Role of ST-Holter monitoring in assessment of therapy].
To analyze the daily spontaneous variability of ischemic ST-segment changes and to derive criteria for statistical documentation of a therapeutic antiischemic effect, in 30 patients with coronary artery disease, with the aid of Holter monitoring the frequency of episodes E1 and E2 during everyday activities without medication was registered for two consecutive 24-hour periods. The spontaneous variability of the ischemic episodes of an individual patient was defined as the frequency distribution of the respective percent changes [(E2-E1)/E1].100 = (E2/E1-1).100 from day to day. To fit the curve to a normal distribution, logarithmic transformation was performed: [formula: see text] where i designates the number of patients. The constant 0.01 serves to correct for the event of episode frequency = 0. From the standard deviation sd of this logarithmic quotient, by retransformation, the one- and two-sided confidence limits K for the percent spontaneous variability are derived from the equation K = -(10-z alpha.sd-1).100; z alpha = 1.65 or 1.96. A statistically significant therapeutic effect can be assumed if, on paired comparison of 24-hour registrations with and without treatment, the limits are exceeded. Possible aggravation by the drug must be ruled out with the one-sided confidence interval. From the standard deviation sd, the standard deviation sd/square root of n for the collective of n = 5 ... to n = 30 patients was calculated and, analogously to the individual patient, the corresponding one- and two-sided 95% confidence limits for a significant therapeutic effect are defined.(ABSTRACT TRUNCATED AT 250 WORDS)
Activities of Daily Living↗
[Treatment of symptomatic and asymptomatic myocardial ischemia using 120 mg delayed-action 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)
Coronary Disease↗
[Echocardiographic and Doppler echocardiographic characterization of left ventricular diastolic function].
For noninvasive assessment of diastolic ventricular function, in addition to echocardiography, more recently, in particular, Doppler echocardiography has been employed. M-mode echocardiogram velocity curves for diameter changes as well as Doppler-echocardiographically registered velocity curves of mitral flow characterize the temporal changes of diastolic flow into the left ventricle. They represent the overall result of factors which influence diastolic filling and are functions of the temporal course of the pressure difference between left atrium and left ventricle. Registration of M-mode and Doppler echocardiograms: For determination of M-mode parameters which should describe left ventricular diastolic function, in addition to the motion of the mitral valve, the left ventricular contours of septum and posterior wall between mitral leaflets and papillary muscles are recorded together with the ECG. For evaluation of the index of atrial emptying, an M-mode registration is obtained from the region of the aortic root. Determination of the Doppler echocardiographic parameters is based on analysis of the blood flow velocity in the region of the mitral valve in the apical four-chamber view with the pulsed Doppler method. Additionally, simultaneous to the Doppler curve, a phonocardiogram is registered or, alternatively, a continuous-wave Doppler registration is obtained which delineates the left ventricular outflow signal and the artefact of mitral valve opening. Parameters for characterization of left ventricular diastolic filling: The first peak of the velocity curve of the diameter change in the M-mode echocardiogram corresponds with the maximal diameter change resulting from early-diastolic filling and the second peak with the maximal diameter change of the left ventricle associated with atrial filling. From this curve as well as the diameter curve relative to time and the mitral valve motion, the times for isovolumetric relaxation as well as the rapid, slow and atrial filling phase which characterize the ventricular filling and the diameter changes of the left ventricle during these time intervals can be derived. The maximal velocity of the diastolic diameter change (PFR) is used to characterize the maximal early diastolic flow. The atrial emptying index characterizes the fraction of filling volume in the first third of diastole with respect to total filling volume of the left ventricle. As an indirect parameter for description of the early-diastolic filling, the steepness of the early-diastolic closure of the anterior mitral leaflet is used. From Doppler velocity profiles of the mitral inflow, early and late diastolic maximal velocities and their velocity time integrals as well as the relationships of these parameters to each other are determined.(ABSTRACT TRUNCATED AT 400 WORDS)
Blood Flow Velocity↗
Limits of ultrashort pulse generation in cw mode-locked dye lasers.
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Journal Article↗
[Long-term therapy with nitrates. How can continuous effectiveness be achieved?].
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.
Administration, Cutaneous↗
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.
Administration, Cutaneous↗
[Influence of occlusion on head posture during prolonged phases of clenching].
The influence of divergent splint-adjusted maximum intercuspation on head posture during prolonged phases of clenching was studied in five subjects. During clenching in maximum intercuspation profound changes of head posture were observed, if intercuspation was not harmonized with an upright posture of head and body. Since the interrelation between occlusion and head posture is established a comprehensive approach of orthopedic, physiotherapeutic, and dental measures, in particular for the therapy of myoarthropathy patients with cervical spine symptoms seems appropriate. Occlusal corrections and determination of occlusal relations must always be made or at least checked in the upright relaxed patient with the head straight.
Bruxism↗
[Hemodynamics and gas exchange in acute lung embolism].
The main hemodynamic consequence of pulmonary embolism is the acute mechanical reduction of the pulmonary vascular cross-sectional area. This results in a sudden increase of the pulmonary vascular resistance, and if the cardiac output is to be maintained, in an increase in pulmonary artery pressure and right ventricular work. The extent of hemodynamic changes in pulmonary embolism are determined primarily by the size of the emboli and whether or not the patient has underlying cardiopulmonary disease. Although humoral factors and neural reflexes play a role in determining the severity of hemodynamic responses to pulmonary embolism in experimental animals, their role in patients is uncertain. In patients free of preembolic cardiopulmonary disease, the extent of embolic obstruction can be related directly to the mean pulmonary artery pressure. Accordingly, either the extent of obstruction or the mean pulmonary artery pressure may be used as a measure of right ventricular afterload. Obstruction of 25 to 40% leads to an increase in mean pulmonary artery pressure of 20 to 30 mm Hg, massive obstruction over 75% to a pressure of 40 to 45 mm Hg. Continuous hemodynamic monitoring helps to estimate the speed of the resolution of emboli and to a certain extent the adequacy of treatment. Right arterial pressure is consistently elevated by a mean pulmonary artery pressure over 30 mm Hg and provides also a rough estimate of the degree of pulmonary vascular obstruction. A previously normal right ventricle will dilate at a mean pulmonary artery pressure of 40 to 45 mm Hg. which may result in acute tricuspid insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)
Heart Atria↗
[The diagnosis of lung embolism].
An accurate diagnosis of pulmonary embolism is essential to prevent excessive mortality and morbidity from lack of therapy or inappropriate anticoagulation. The clinical diagnosis is highly nonspecific because none of the symptoms or signs of pulmonary embolism is unique and all may be caused by other cardiorespiratory disorders. The diagnosis of pulmonary embolism is unlikely, however, if patients do not have dyspnea, tachypnea, evidence of deep vein thrombosis, or a recognized predisposition to thromboembolic disease. Objective testing is mandatory to either confirm or exclude a diagnosis of pulmonary embolism. The electrocardiogram, chest X-ray and the echocardiogram may assist by excluding other potential diagnoses. Routine laboratory studies and lung function testing including blood gas analysis will not be of much help in the differential diagnosis. The hemodynamic investigation with a floating catheter is of diagnostic value especially in those cases where it is not possible to obtain the definitive diagnosis immediately; this method as well as echocardiography can provide a rough estimate of the degree of pulmonary vascular obstruction and are thus able to guide therapy. Methods such as DSA, CT, MR, SPECT, or radiolabelled thrombus scanning are promising but require more extensive validation before routine use. Lung scanning, with its high sensitivity but low specificity is a very useful procedure but cannot be considered to have diagnostic significance independent of the clinical situation. Pulmonary angiography provides the greatest diagnostic certainty of any test available. Based on current knowledge, a diagnostic approach for the management of clinically suspected pulmonary embolism is proposed. Ventilation-perfusion lung scanning is the appropriate next step after ECG, chest X-ray and echocardiogram. The finding of a normal perfusion scan rules out clinically significant embolism and anticoagulation is withheld. Segmental or lobar perfusion defects with normal ventilation in an appropriate clinical setting is sufficiently indicative of pulmonary embolism to proceed with therapy in patients without contraindications. Ventilation-perfusion scans of low or indeterminate probability for pulmonary embolism neither confirm nor exclude the presence of embolism and pulmonary angiography would then be the definitive procedure. As an alternative approach instrumental examination of the leg veins (with venography, impedance plethysmography, or ultrasound) is proposed (Figure 1). If these tests confirm the presence of deep venous thrombosis, anticoagulation can be commenced without the need to perform pulmonary angiography.(ABSTRACT TRUNCATED AT 400 WORDS)
Cardiac Catheterization↗
Spontaneous and mitogen-induced RNA synthesis by blood lymphocytes from bovine leukemia virus-infected and normal cows.
Peripheral blood lymphocytes (PBL) from normal and bovine leukemia virus (BLV)-infected cattle were prepared by density gradient technique and incubated with and without phytohaemagglutinin (PHA) and pokeweed mitogen (PWM). RNA synthesis was determined at different periods of incubation by 3H-uridine incorporation. PBL from BLV-infected cows with persistent lymphocytosis (PL) showed the highest spontaneous RNA synthesis. PBL from BLV-infected cows with normal lymphocyte counts synthesized more RNA than cells from normal animals. Decreased mitogen responses were observed in PBL from infected cows with PL in comparison to normal and BLV-infected cattle without PL. PHA and PWM did not show significant differences in their degree of stimulation of RNA synthesis.
Animals↗
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.
Administration, Cutaneous↗