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C Minge - One of the best experts on this subject based on the ideXlab platform.
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anti ischemia effects of Gallopamil and esmolol in an intra individual comparison in patients with coronary heart disease
Zeitschrift Fur Kardiologie, 1994Co-Authors: Veselin Mitrovic, E Oehm, C Minge, P Thurmann, M SchlepperAbstract:: To compare the hemodynamic, antiischemic, metabolic, and neurohumoral effects of intravenous esmolol (beta 1 blocking agent) and Gallopamil (verapamil-like calcium channel blocker), 14 patients with angiographically proven CAD and reproducible ST segment depression were studied at rest and during exercise under control conditions and after an intravenous bolus injection of esmolol (0.5 mg/kg/1 min, followed by an infusion with 0.2 mg/kg/min) or Gallopamil (0.025 mg/kg/3 min). In contrast to Gallopamil, esmolol significantly reduced systolic blood pressure (175.7 vs. 160 mm Hg) and heart rate (107.4 vs. 96.9 min-1) during exercise as well as cardiac output (11.57 vs. 9.38 l/min) and significantly enhanced systemic vascular resistance both at rest (1241 vs. 1479 dynes.s.cm-5) and during exercise (805 vs. 947 dynes.s.cm-5). On the other hand, exercise filling pressures and lactate levels (3.66 vs. 3.05 mmol/l) were significantly reduced by Gallopamil only. Thus, the significant improvement of exercise tolerance by both esmolol and Gallopamil is based on different mechanisms of action: esmolol improves myocardial ischemia by appreciably reducing myocardial oxygen consumption, whereas Gallopamil primarily improves oxygen supply and ventricular performance. Plasma catecholamines, atrial natriuretic factor, and aldosterone levels as well as plasma renin activity were identically influenced by esmolol and Gallopamil, respectively. A reflex activation of the sympathetic system did not occur.
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Efficacy and tolerability of slow-release Gallopamil in patients with stable exercise-inducible angina pectoris.
Journal of cardiovascular pharmacology, 1992Co-Authors: H Kottkamp, H Gülker, K Emmerich, H P Koch, C MingeAbstract:The anti-ischemic properties and tolerability of a slow-release formulation (SR) of Gallopamil were investigated in 118 patients with exercise-inducible ST-segment depression and stable angina pectoris in this double-blind, randomized, placebo-controlled, multicenter study. After a placebo run-in period (A) of 2-7 days and a 7-day open therapy period (B) with Gallopamil SR, the patients were randomized to a double-blind 7-day period (C) to receive placebo or Gallopamil SR 100 mg twice a day. Each patient was submitted to gradual upright bicycle ergometry and electrocardiography (ECG) at rest on the last 2 days of each period at 6 and 12 h postadministration (p.a.) In period C, exercise time and exercise tolerance remained significantly prolonged at 6 and 12 h after Gallopamil SR administration in comparison with the placebo values. Additionally the sum of ST-segment depression and maximal ST-segment depression were significantly reduced by Gallopamil SR at 6 h p.a. as were the frequency of angina attacks and nitroglycerin consumption. Four patients were withdrawn from the study because of Gallopamil-related adverse events, which, however, were not serious. Constipation was noted in 2.5% of the patients. These data suggest that Gallopamil SR is effective in reducing exercise-inducible ST-segment depression and increasing exercise tolerance with no serious adverse effects in patients with stable angina pectoris.
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efficacy and tolerability of slow release Gallopamil in patients with stable exercise inducible angina pectoris
Journal of Cardiovascular Pharmacology, 1992Co-Authors: H Kottkamp, H Gülker, K Emmerich, H P Koch, C MingeAbstract:The anti-ischemic properties and tolerability of a slow-release formulation (SR) of Gallopamil were investigated in 118 patients with exercise-inducible ST-segment depression and stable angina pectoris in this double-blind, randomized, placebo-controlled, multicenter study. After a placebo run-in period (A) of 2-7 days and a 7-day open therapy period (B) with Gallopamil SR, the patients were randomized to a double-blind 7-day period (C) to receive placebo or Gallopamil SR 100 mg twice a day
H P Koch - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and tolerability of slow-release Gallopamil in patients with stable exercise-inducible angina pectoris.
Journal of cardiovascular pharmacology, 1992Co-Authors: H Kottkamp, H Gülker, K Emmerich, H P Koch, C MingeAbstract:The anti-ischemic properties and tolerability of a slow-release formulation (SR) of Gallopamil were investigated in 118 patients with exercise-inducible ST-segment depression and stable angina pectoris in this double-blind, randomized, placebo-controlled, multicenter study. After a placebo run-in period (A) of 2-7 days and a 7-day open therapy period (B) with Gallopamil SR, the patients were randomized to a double-blind 7-day period (C) to receive placebo or Gallopamil SR 100 mg twice a day. Each patient was submitted to gradual upright bicycle ergometry and electrocardiography (ECG) at rest on the last 2 days of each period at 6 and 12 h postadministration (p.a.) In period C, exercise time and exercise tolerance remained significantly prolonged at 6 and 12 h after Gallopamil SR administration in comparison with the placebo values. Additionally the sum of ST-segment depression and maximal ST-segment depression were significantly reduced by Gallopamil SR at 6 h p.a. as were the frequency of angina attacks and nitroglycerin consumption. Four patients were withdrawn from the study because of Gallopamil-related adverse events, which, however, were not serious. Constipation was noted in 2.5% of the patients. These data suggest that Gallopamil SR is effective in reducing exercise-inducible ST-segment depression and increasing exercise tolerance with no serious adverse effects in patients with stable angina pectoris.
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efficacy and tolerability of slow release Gallopamil in patients with stable exercise inducible angina pectoris
Journal of Cardiovascular Pharmacology, 1992Co-Authors: H Kottkamp, H Gülker, K Emmerich, H P Koch, C MingeAbstract:The anti-ischemic properties and tolerability of a slow-release formulation (SR) of Gallopamil were investigated in 118 patients with exercise-inducible ST-segment depression and stable angina pectoris in this double-blind, randomized, placebo-controlled, multicenter study. After a placebo run-in period (A) of 2-7 days and a 7-day open therapy period (B) with Gallopamil SR, the patients were randomized to a double-blind 7-day period (C) to receive placebo or Gallopamil SR 100 mg twice a day
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Effect of Gallopamil on Myocardial Ischaemia During Percutaneous Transluminal Coronary Angioplasty
Drugs, 1991Co-Authors: B Rauch, R Zimmermann, H P Koch, J. Neumann, G. Richardt, R. Kranzhöfer, R. Barth, H. Tillmanns, A. SchömigAbstract:This report summarises selected preliminary results from an ongoing study designed to investigate the effect of the calcium antagonist Gallopamil on myocardial ischaemia during percutaneous transluminal coronary angioplasty (PTCA). To date, 12 adult males with coronary artery disease and significant proximal stenosis of the left anterior descending coronary artery (LAD) have been randomly assigned to Gallopamil or placebo under double-blind conditions. Patients with recent myocardial infarction, apparent collateralisation of the LAD, myocardial failure, sinoatrial or atrioventricular block, severe hepatic disease or renal failure were excluded from the study. PTCA was performed using at least 2 balloon inflations, each of 2 minutes’ duration. Gallopamil 0.4mg or placebo (normal saline) were administered during the 10-minute interval between the 2 inflations. Blood samples were taken simultaneously from the coronary sinus and the femoral artery before and immediately after each inflation. Lactate concentration and the relative amount of activated neutrophils were selected for trend analysis. Furthermore, ECG changes were analysed by calculating the sum of the absolute ST-segment deviations (80 msec after J point, maximal T deviation) of leads I, II, III, V_2, V_4 and V_6. In the presence of Gallopamil, the degree of ST-segment/T-wave changes induced by balloon inflation was reduced. Additionally, Gallopamil attenuated myocardial lactate release and appeared to prevent the increase in activated neutrophils observed during control inflations. These preliminary results suggest a beneficial effect from intracoronary administration of Gallopamil during PTCA, achieved by attenuation of the ischaemic reaction during coronary occlusion.
R Zimmermann - One of the best experts on this subject based on the ideXlab platform.
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Effect of Gallopamil on neutrophil function: experimental and clinical studies.
Journal of cardiovascular pharmacology, 1992Co-Authors: F J Neumann, G Richardt, R Zimmermann, H Tillmanns, W Kübler, B RauchAbstract:The purpose of the study was to investigate whether Gallopamil interferes with neutrophil activation. In vitro, Gallopamil caused a dose-dependent reduction in phorbol myristate acetate-stimulated superoxide anion production by neutrophils as measured by the superoxide dismutase inhibited reduction of cytochrome C [concentration of 50% inhibition (IC50) = 9.5 x 10(-6) mol/L]. Furthermore, Gallopamil reduced the platelet-activating factor-induced loss of neutrophil deformation, which was assessed by filtrometry (IC50 = 4.3 x 10(-6) mol/L). The effect of Gallopamil was assessed in 24 patients during elective balloon angioplasty. Gallopamil (0.4 mg) or placebo (double-blind conditions) was administered by intracoronary application during the 10-min interval between the first two balloon inflations. In the placebo group, blood samples obtained simultaneously from the coronary sinus and from the femoral artery revealed an increase in the proportion of activated neutrophils in the coronary sinus blood after the second balloon inflation [nitro blue tetrazolium (NBT) score, NBT test: 15 +/- 9% relative coronary sinus and arterial blood difference, p < 0.05]; these changes in NBT score were similar to those after the first balloon inflation. In the Gallopamil-treated group, however, significant arterial and coronary sinus blood differences in NBT scores were not found after the second balloon inflation. Gallopamil may, thus, attenuate the local neutrophil activation during balloon angioplasty.
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Reduction of myocardial ischemia by Gallopamil: a dual-isotope study with thallium-201 and iodine-123 phenylpentadecanoic acid.
Journal of cardiovascular pharmacology, 1992Co-Authors: R Zimmermann, F J Neumann, B Rauch, H. Tillmanns, M Kapp, U Grethe, K Schlumpp, B Bubeck, W KüblerAbstract:The present study was performed for characterizing the effect of chronic oral treatment with the calcium antagonist Gallopamil on regional myocardial perfusion and free fatty acid utilization in poststenotic human myocardium. Twenty-two patients with angiographically documented coronary artery disease and stable angina pectoris underwent consecutive dual-isotope studies following simultaneous injection of 80 MBq thallium-201 and 200 MBq iodine-123 phenylpentadecanoic acid (IPPA) during a symptom-limited stress test. Radionuclide studies were performed after 1 week of placebo treatment (baseline), 4 weeks after oral treatment with 50 mg of Gallopamil t.i.d. and again after 1 week of double-blind treatment with Gallopamil or placebo. As compared to baseline, initial (poststress) uptake of both tracers in poststenotic myocardial segments was significantly improved after 4 weeks of treatment with Gallopamil [thallium-201, +9.0%; p < 0.001; 95% confidence interval (CI), 4.3-13.6%; IPPA, +11.8%; p = 0.003; 95% CI, 4.2-19.3%]. Poststenotic IPPA-clearance was likewise significantly increased (+28.2%; p < 0.001; 95% CI, 12.4-44.0%) indicating a considerably enhanced myocardial fatty acid oxidation after treatment. In the final double-blind phase, myocardial uptake of both tracers as well as IPPA clearance remained enhanced in the subgroup of patients receiving Gallopamil and returned to baseline values in patients receiving placebo. Thus, in poststenotic myocardium, chronic treatment with Gallopamil provokes an improvement of both regional myocardial perfusion (as demonstrated by an increased tracer uptake in poststress scintigrams) and regional myocardial fatty acid utilization (as demonstrated by an increased uptake and clearance of IPPA).
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Intracoronary Gallopamil during percutaneous transluminal coronary angioplasty.
Journal of cardiovascular pharmacology, 1992Co-Authors: B Rauch, R Zimmermann, W Kübler, G. Richardt, R. Barth, H. Tillmanns, A. Schömig, F J NeumannAbstract:The present study was designed to investigate the effect of the calcium-channel antagonist Gallopamil on myocardial ischemia during percutaneous transluminal coronary angioplasty (PTCA). Twenty-four adult patients with coronary artery disease and significant proximal stenosis of the left anterior descending coronary artery (LAD) were randomly assigned to receive Gallopamil or placebo under double-blind conditions. Patients with recent myocardial infarction, apparent collateralization of the LAD, myocardial failure, sinoatrial or atrioventricular block, severe hepatic disease, or renal failure were excluded from the study. PTCA was performed with use of at least two balloon inflations, each of 2 min in duration. Gallopamil (0.4 mg) or placebo (0.9% sodium chloride) was administered during the 10-min interval between the two inflations. For determination of myocardial lactate and hypoxanthine release, blood samples were taken simultaneously from the great cardiac vein and the femoral artery before and immediately after each inflation. Electrocardiogram changes were analyzed by measuring ST-segment deviations (80 ms after the J point) and maximal T-wave deviations of the leads I, II, III, and V2, V4, and V6. The most sensitive leads for identification of myocardial ischemia in the LAD area were V2 and V4. If compared to the first balloon inflation, the degree of ST-segment/T-wave changes induced by the second inflation was significantly reduced only in the presence of Gallopamil. Furthermore, if compared to placebo, ischemia-induced lactate and hypoxanthine release was decreased in the presence of Gallopamil. These results suggest that intracoronary application of Gallopamil attenuates myocardial ischemia during PTCA.
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effect of Gallopamil on neutrophil function experimental and clinical studies
Journal of Cardiovascular Pharmacology, 1992Co-Authors: Franzjosef Neumann, G Richardt, R Zimmermann, H Tillmanns, W Kübler, Bernhard H RauchAbstract:The purpose of the study was to investigate whether Gallopamil interferes with neutrophil activation. In vitro, Gallopamil caused a dose-dependent reduction in phorbol myristate acetate-stimulated superoxide anion production by neutrophils as measured by the superoxide dismutase inhibited reduction of cytochrome C [concentration of 50% inhibition (IC 50 )=9.5×10 -6 mol/L]. Furthermore, Gallopamil reduced the platelet-activating factor-induced loss of neutrophil deformation, which was assessed by filtrometry (IC 50 =4.3×10 -6 mol/L)
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intracoronary Gallopamil during percutaneous transluminal coronary angioplasty
Journal of Cardiovascular Pharmacology, 1992Co-Authors: Bernhard Rauch, G Richardt, R Zimmermann, H Tillmanns, W Kübler, R. Barth, A. Schömig, Franzjosef NeumannAbstract:The present study was designed to investigate the effect of the calcium-channel antagonist Gallopamil on myocardial ischemia during percutaneous transluminal coronary angioplasty (PTCA). Twenty-four adult patients with coronary artery disease and significant proximal stenosis of the left anterior descending coronary artery (LAD) were randomly assigned to receive Gallopamil or placebo under double-blind conditions. Patients with recent myocardial infarction, apparent collateralization of the LAD, myocardial failure, sinoatrial or atrioventricular block, severe hepatic disease, or renal failure were excluded from the study
Paul Benfield - One of the best experts on this subject based on the ideXlab platform.
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Gallopamil a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in ischaemic heart disease
Drugs, 1994Co-Authors: R N Brogden, Paul BenfieldAbstract:: Gallopamil is a methoxy derivative of verapamil. As is typical of the phenylalkylamine class of calcium antagonists, it acts on the vascular system, and on the heart and its nodal structures. In the treatment of stable angina pectoris, Gallopamil is at least as effective as nifedipine and diltiazem, though apparently better tolerated than nifedipine. Typical of calcium antagonists there is little or no tolerance to the antiischaemic effects of Gallopamil. Preliminary studies indicate that Gallopamil, like other calcium antagonists, has cardioprotective potential. However, further investigation is required to explore the clinical relevance of the improved myocardial regional perfusion and free fatty acid utilisation in reversibly ischaemic regions, and the potential of delayed ischaemia during angioplasty that is observed during Gallopamil administration. Gallopamil is well tolerated, exhibiting a low propensity for causing cardiovascular and gastrointestinal adverse effects, thus making it a suitable alternative to other calcium antagonists for the treatment of patients with ischaemic heart disease.
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Gallopamil
Drugs, 1994Co-Authors: R N Brogden, Paul BenfieldAbstract:Synopsis Gallopamil is a methoxy derivative of verapamil. As is typical of the phenylalkylamine class of calcium antagonists, it acts on the vascular system, and on the heart and its nodal structures. In the treatment of stable angina pectoris, Gallopamil is at least as effective as nifedipine and diltiazem, though apparently better tolerated than nifedipine. Typical of calcium antagonists there is little or no tolerance to the antiischaemic effects of Gallopamil. Preliminary studies indicate that Gallopamil, like other calcium antagonists, has cardioprotective potential. However, further investigation is required to explore the clinical relevance of the improved myocardial regional perfusion and free fatty acid utilisation in reversibly ischaemic regions, and the potential of delayed ischaemia during angioplasty that is observed during Gallopamil administration. Gallopamil is well tolerated, exhibiting a low propensity for causing cardiovascular and gastrointestinal adverse effects, thus making it a suitable alternative to other calcium antagonists for the treatment of patients with ischaemic heart disease. Pharmacodynamic Properties Gallopamil, a phenylalkylamine calcium antagonist, is typical of its class in acting on the vascular system, and the heart and its nodal structures. When administered at usual oral therapeutic dosages, Gallopamil generally caused little change in resting heart rate, reduced the gain in heart rate during exercise, and decreased systolic and diastolic blood pressure in patients with coronary artery disease, particularly those who developed ischaemia, both at rest and during exercise. The effect of Gallopamil on rate-pressure product has varied between studies, but this parameter decreased or remained unchanged more frequently than it increased. In animal studies, Gallopamil inhibited contraction of major extramural and peripheral arteries induced by potassium, acetylcholine or adrenaline (epinephrine), as well as autoregulatory constriction of peripheral resistance vessels, with a potency intermediate between those of verapamil and nifedipine. The concentration of Gallopamil required to relax potassium-induced contracture of canine veins was much lower than that required to relax arteries from the same body region. In patients with normal coronary arteries, intracoronary administration of Gallopamil 1.5 or 3 μg/kg produced dose-related coronary vasodilatation, while a 26% increase in the calibre of stenosed arteries followed intravenous administration of a 2mg dose. When administered orally or intravenously, Gallopamil does not significantly influence normal or mildly impaired left ventricular function in patients with coronary artery disease, and improves relaxation and left ventricular filling in patients with acute myocardial infarction or hypertrophic cardiomyopathy, reflecting improved left ventricular diastolic function. Changes in intracellular calcium may be a primary event in the sequence of metabolic and ionic changes that characterise acute ischaemia. In animal studies, Gallopamil attenuated the release of creatine phosphokinase and noradrenaline (norepinephrine) during reperfusion, maintained mitochondrial function, reduced microcirculatory changes induced by repetitive ischaemia, and limited the extent of myocardial necrosis when administered soon after the beginning of occlusion. Initial studies in patients with coronary artery disease suggest that oral treatment with Gallopamil 50mg 3 times daily improves regional myocardial perfusion and fatty acid utilisation, and myocardial microperfusion in previously ischaemic areas of left ventricle, similarly to verapamil 80mg, diltiazem 180mg and nifedipine 60mg (all 3 times daily). Electrophysiological investigations during His bundle electrocardiography revealed that within 20 minutes of intravenous administration of Gallopamil 0.06 mg/kg there was an increase in sinus rate, nodal conduction time, Wenckebach point, and functional and effective refractory period of the AV node. Sinoatrial node recovery time was prolonged only in patients thought to have sick-sinus syndrome. Oral administration of Gallopamil to obese males with hypertension and impaired glucose tolerance did not influence glucose metabolism, whereas Gallopamil 1mg intravenously delayed the release of insulin and C peptide after an oral glucose load in healthy volunteers. Pharmacokinetic Properties The pharmacokinetic properties of Gallopamil administered as the racemate have been studied in small groups of healthy volunteers and in patients with chronic stable angina pectoris. Single dose administration of Gallopamil 50 and 100mg as conventional tablets resulted in mean maximum plasma concentrations (C_max) of about 30 and 50 μg/L, respectively. Mean C_max values increased to 68.3 μg/L in healthy volunteers receiving 50mg 3 times daily for 12 days. In a comparison of single doses of conventional (50mg) and sustained release (SR) tablets (100mg), mean C_max and area under the plasma concentration-time curve (AUC) were 21.3 μg/L and 66.8 μg/L · h, respectively, after the conventional preparation, and 13 μg/L and 161.7 μg/L · h after the sustained release tablet. Mean trough plasma concentrations were 20.3 and 33.7 μg/L in patients treated twice daily with SR Gallopamil 75 and 100mg, respectively. Despite almost complete oral absorption, systemic availability is low at 15% after a single dose and about 23% after repeated doses, due to extensive first-pass hepatic metabolism. Protein binding of Gallopamil in vitro in serum of healthy volunteers is about 93% and independent of drug concentration over a range of 10 to 100 μg/L, but is influenced by pH. Gallopamil is largely eliminated by metabolism. The principal metabolite is norGallopamil, which is thought to be pharmacologically inactive. Mean total plasma clearance is 66 to 72 L/h after intravenous administration. Reported values for mean terminal elimination half-life were between 2.5 and 5.5 hours or between 4 and 8 hours after oral administration of conventional tablets, depending on assay method. Following administration of SR Gallopamil, elimination half-life was reported to be between 5.3 and 8 hours. After oral administration of radiolabelled Gallopamil, about 48 to 55% of cumulative ^14C excretion appeared in the urine and 40 to 50% in faeces in the form of metabolites. Only 0.2 to 2% of a dose was excreted unchanged in the urine. Preliminary studies in patients with liver cirrhosis given a single oral dose of Gallopamil indicated that total plasma clearance was reduced, absolute bioavailability increased, and elimination half-life prolonged to an extent suggesting the need for a dosage reduction in patients with liver cirrhosis. Therapeutic Efficacy The therapeutic efficacy of Gallopamil administered orally as a conventional or sustained release product has been studied in double- or single-blind short term trials involving generally small numbers of patients with confirmed coronary artery disease and stable exertional angina pectoris. Gallopamil 50mg 3 times daily or 100mg twice daily (SR) is more effective than placebo in improving exercise time and tolerance, delaying the ischaemic threshold and decreasing the extent of ST-segment depression at comparable and maximum workload during exercise tests. Relative to placebo, Gallopamil increased the duration of exercise by 9 to 44%, exercise tolerance by 24 to 57%, and decreased the ST-segment depression by 42 to 70%. Treatment with conventional or SR Gallopamil reduces the mean incidence of spontaneous asymptomatic as well as exercise-induced episodes of ischaemia during 24-hour ambulatory electrocardiographic monitoring. In small numbers of patients studied for periods of 1 to 4 weeks, the overall efficacy of Gallopamil 50mg 3 times daily was generally similar to that of nifedipine 10mg 3 times daily, although in one study Gallopamil tended to be more effective. SR Gallopamil (100mg twice daily) was superior to SR nifedipine 20mg twice daily in delaying the onset of ST segment depression. In some of the small number of crossover trials conducted, Gallopamil 50mg 3 times daily was more effective than diltiazem 60mg 3 times daily in improving exercise duration, the extent of ST-segment depression and anginal attack frequency. Long term noncomparative studies of up to 2 years’ duration indicated that objective and subjective improvement achieved in the first 1 to 3 months of Gallopamil therapy was maintained for the duration of the study. Preliminary studies suggest the potential of intravenously administered Gallopamil for the symptomatic control of unstable and variant angina. Tolerability In the treatment of patients with coronary artery disease, therapeutic dosages of Gallopamil have been well tolerated by most patients. In large short term noncomparative trials involving a total of over 33 000 patients, gastrointestinal symptoms, including nausea, constipation, epigastric pain and other complaints, occurred in 4.4 to 8.3% of patients. Orthostatic hypotension, flushing and peripheral oedema were reported in 2 to 2.4%. Other cardiovascular complaints included bradycardia (0.5%), first and second degree AV block (0.3%), and tachycardia (0.2%). Aggravation of existing heart failure occurred in only 0.03% of patients. Adverse effects necessitated withdrawal of Gallopamil in 1.4 to 3% of patients. Dosage and Administration The usual oral dosage of Gallopamil in the treatment of patients with chronic stable angina pectoris is 50mg 3 times daily when administered as a conventional tablet and 100mg once or twice daily as a sustained release preparation, although individualised dosages have ranged from 75 to 200mg and 100 to 200mg daily administered as conventional and sustained release preparations, respectively. In patients with unstable or variant angina, an intravenous bolus of Gallopamil 30 to 60 μg/kg has been followed by continuous intravenous infusion of 0.3 to 1 μg/kg/min. Dosage should be reduced in patients with liver cirrhosis.
Mario Mariani - One of the best experts on this subject based on the ideXlab platform.
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interaction between Gallopamil and cardiac ryanodine receptors
British Journal of Pharmacology, 1995Co-Authors: Riccardo Zucchi, Simonetta Roncatestoni, G Yu, Paola Galbani, G Ronca, Mario MarianiAbstract:1. In a sarcoplasmic reticulum fraction obtained from rat hearts, the analysis of equilibrium [3H]-ryanodine binding showed high and low affinity sites (KD = 1.3 nM and 2.8 microM, Bmax = 2.2 pmol mg-1 and 27.8 pmol mg-1). The dissociation rate constant increased at 1 microM vs 4 nM [3H]-ryanodine concentration, and micromolar ryanodine slowed the dissociation of nanomolar ryanodine. 2. The binding of 4 nM [3H]-ryanodine was not affected by Gallopamil, while the binding of 100 nM to 18 microM [3H]-ryanodine was partly displaced. Data analysis suggested that Gallopamil inhibited low affinity [3H]-ryanodine binding, with IC50 in the micromolar range. 3. Gallopamil decreased the dissociation rate constant of 1 microM [3H]-ryanodine. While Gallopamil alone did not affect the dissociation of 4 nM [3H]-ryanodine, Gallopamil and micromolar ryanodine slowed it to a greater extent than micromolar ryanodine alone. 4. Our results are consistent with the hypothesis that the ryanodine receptor is a negatively cooperative oligomer, which undergoes a sequential alteration after ryanodine binding. Gallopamil has complex actions: it inhibits ryanodine binding to its low affinity site(s), and probably modulates the cooperativity of ryanodine binding and/or the transition to a receptor state characterized by slow ryanodine dissociation. These molecular actions could account for the previously reported effect of Gallopamil on the sarcoplasmic reticulum calcium release channel.
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Effect of Gallopamil on cardiac sarcoplasmic reticulum.
Journal of cardiovascular pharmacology, 1992Co-Authors: Riccardo Zucchi, G Yu, Paola Galbani, G Ronca, S Ronca-testoni, U Limbruno, Mario MarianiAbstract:We investigated the effect of Gallopamil on cardiac sarcoplasmic reticulum (SR) function. Heavy SR was prepared from bovine ventricular muscle. Oxalate-supported calcium uptake was stimulated by Gallopamil at concentrations ranging from 10 to 300 nM, whereas higher concentrations were ineffective. Peak stimulation averaged 25-30% of control calcium uptake and was observed at free calcium concentrations ranging from 1 to 6 microM. Calcium uptake is actually the difference between active calcium transport by SR calcium-adenosine triphosphate (calcium-ATPase), and passive efflux through SR calcium-release channels. In the presence of 300 microM of ryanodine, a blocker of SR channels, calcium uptake increased by 43% under control conditions, but not further stimulation was produced by Gallopamil. SR calcium-ATPase was not affected by Gallopamil. Similar results were obtained when oxalate-supported calcium uptake was determined with use of unfractionated homogenate obtained from rat hearts. We conclude that Gallopamil acts on SR calcium-release channels and reduces the probability of channel opening and/or channel conductivity. The dose-response curve is bell shaped, and the maximum effect, which corresponds to 65% of the maximum effect of ryanodine, is achieved at therapeutic concentrations. Such action might contribute to the beneficial effect of Gallopamil in the treatment of myocardial ischemia.
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effect of Gallopamil on cardiac sarcoplasmic reticulum
Journal of Cardiovascular Pharmacology, 1992Co-Authors: Riccardo Zucchi, Simonetta Roncatestoni, G Yu, Paola Galbani, G Ronca, U Limbruno, Mario MarianiAbstract:We investigated the effect of Gallopamil on cardiac sarcoplasmic reticulum (SR) function. Heavy SR was prepared from bovine ventricular muscle. Oxalate-supported calcium uptake was stimulated by Gallopamil at concentrations ranging from 10 to 300 nM, whereas higher concentrations were ineffective. Peak stimulation averaged 2.5-30% of control calcium uptake and was observed at free calcium concentrations ranging from 1 to 6 μM
