Potassium channel openers and blockers in coronary artery disease. Comparison to betablockers and calcium antagonists.

Potassium channel openers and blockers, which belong to a novel class of vasodilator drugs and to the class of specific bradycardic substances, are potential new antianginal drugs. Experimental findings in vivo suggest that bimakalim is a new substance characterized as ATP-sensitive K+ channel openers, since it exerts preferential vasodilation of the collateral circulation of the coronary vasculature and both leads to increase blood flow to ischemic areas and to attenuate the ST segment elevation caused by regional ischemia in the canine heart. Opening of KATP increases the conductivity of potassium ions which results in hyperpolarization of smooth muscle membranes, thus producing vasodilation. Tedisamil is a new bradycardic agent proven to exert antiischemic and antiarrhythmic effects by blockade of the cellular cardiac repolarization K+ currents as well as of multiple neuronal and vascular K+ currents (Ito, Ik, and K+ATP). Using right heart catheterization and exercise tolerance tests, we investigated the hemodynamic, antiischemic and neurohumoral effects of bimakalim and tedisamil in patients with angiographically proven coronary artery disease, stable angina pectoris and reproducible ST segment depression during exercise. In 50 patients with coronary artery disease, the hemodynamic and antiischemic effects of a single oral dose bimakalim of 0.1 mg, 0.3 mg and 0.6 mg were compared to placebo. In a dose-finding baseline-controlled study, a comparable collective was examined for the effects of acute i.v. administration of tedisamil 0.1, 0.2, 0.3 and 0.4 mg/kg bw. A subgroup of 8 patients receiving 0.3 mg/kg bw tedisamil i.v. was compared with a similar group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intra-individual comparison. Furthermore, in 48 patients, short-term (6 days) effects of tedisamil, 2 times 100 mg orally, were compared to 2 times 50 mg atenolol treatment. With a single oral dose of bimakalim antianginal and/or antiischemic effects were lacking, increased doses, however, induced changes in hemodynamics typical of vasodilation, i.e., a significant decrease in systolic blood pressure and a secondary chronotropic response. In contrast to bimakalim, tedisamil produced antiischemic effects and was found to have favorable hemodynamic, neurohumoral and antiischemic effects in comparison to the betablocker esmolol and atenolol in patients with coronary artery disease. Tedisamil induced a dose-dependent decrease in both heart rate and the index of myocardial oxygen consumption associated with an improvement in ST segment depression. Tedisamil as well as esmolol and atenolol showed almost equipotent antiischemic effects at the doses administered. Compared with gallopamil, both tedisamil and esmolol were superior in their effects on myocardial oxygen consumption and ST segment depression, whereas plasma lactate concentrations were more reduced by tedisamil and gallopamil.

Modulation of ventricular rate in permanent atrial fibrillation: randomized, crossover study of the effects of slow-release formulations of gallopamil, diltiazem, or verapamil.

BACKGROUND: The management of permanent atrial fibrillation (PAF) consists primarily of long-term anticoagulation with either aspirin or warfarin to prevent systemic embolization, and modulation of ventricular rate (VR) to improve cardiac function by prolonging the ventricular diastolic filling time. HYPOTHESIS: The effects of slow-release formulations of gallopamil (100 mg b.i.d.), diltiazem (120 mg b.i.d.), or verapamil (120 mg b.i.d.) on VR were evaluated in 18 patients with PAF without organic heart disease. METHODS: In all patients, each treatment was administered randomly, was compared with oral digoxin, and was assessed by 24-h Holter monitoring during daily life and by a 6-min walking test. RESULTS: There were no significant differences in mean and minimum VR recorded during 24-h Holter monitoring among the four treatments. Peak heart rates recorded during the 6-min walking test with digoxin treatment was 167 +/- 12 beats/min. This was significantly reduced by gallopamil (149 +/- 23 beats/min, p = 0.01), diltiazem (142 +/- 24 beats/min, p < 0.001), and verapamil (137 +/- 30 beats/min, p < 0.001). There were no significant differences in peak VR during the walking test among the three calcium antagonists. Pauses of > 3 s were observed in 3 of 18 (17%) patients who received digoxin (max 3.4 s) and in 5 of 18 (28%) patients who received diltiazem (max 3.4 s); p = NS. Periods of bradycardia < 30 beats/min were observed in 5 of 18 (28%) patients during digoxin treatment, and in 3 of 18 (17%) patients during treatment with gallopamil, diltiazem, and verapamil; p = NS. CONCLUSION: Gallopamil, diltiazem, or verapamil are superior to digoxin in controlling VR during mild exercise in patients with PAF without organic heart disease. The reduction of peak VR is obtainable without further slowing of resting VR. However, gallopamil appears to be the least effective calcium blocker at controlling resting and exercise VR; thus, there are no advantages over the other calcium blockers in its use in the clinical setting.

Comparison of the potassium channel blocker tedisamil with the beta-adrenoceptor blocker esmolol and the calcium antagonist gallopamil in patients with coronary artery disease.

BACKGROUND: Tedisamil is a new bradycardic agent proven to exert anti-ischemic and antiarrhythmic effects by blockade of the different cardiac and vascular K+ currents. HYPOTHESIS: It was the aim of the present study to compare the favorable anti-ischemic effects of tedisamil, with two long established representatives in the treatment of coronary artery disease (CAD), namely, the beta1 blocker esmolol and the Ca2 antagonist gallopamil. METHODS: The hemodynamic and neurohumoral effects of the new potassium channel blocker tedisamil, an agent with negative chronotropic and class III antiarrhythmic properties, were compared with the ultra-short-acting beta1-selective adrenoceptor blocker esmolol and the calcium antagonist gallopamil. A total of 22 patients with angiographically proven CAD and reproducible ST-segment depression in the exercise electrocardiogram was included in two studies with an almost identical design and inclusion criteria. The investigation was carried out using right heart catheterization and bicycle ergometry. A subgroup of 8 patients receiving 0.3 mg/kg body weight tedisamil intravenously (i.v.) in an open dose-finding study was compared with a group of 14 patients who had received esmolol (i.v. bolus of 500 micrograms/kg, maintenance dose 200 micrograms/kg/min) and gallopamil (initial dose 0.025 mg/kg, maintenance dose 0.0005 mg/kg/h) in a second intraindividual comparison. RESULTS: Tedisamil and esmolol reduced heart rate at rest by 13% (p < 0.001), and 6% (p < 0.05), and at maximum working levels by 8% (p < 0.01) and 9% (p < 0.05), respectively. Gallopamil increased heart rate at rest by 7% (p < 0.05), with only slight changes occurring during exercise. Corresponding findings for each drug were observed for cardiac output both at rest and during exercise [tedisamil: at rest -10% (NS), max. exercise -8%; esmolol: at rest -14% (NS), max. exercise -18% (NS); gallopamil: no significant changes]. Compared with tedisamil, stroke volume was reduced by esmolol [at rest and max. workload: -9% (NS)] and gallopamil [rest: -6% (NS), max. exercise: -2% (NS)]. Of the indirect parameters of ventricular function, that is, mean capillary wedge pressure (PCWPm) and right ventricular ejection fraction, only PCWPm demonstrated significant differences between tedisamil and gallopamil (+18% and -6% at rest, +17% and -21% during exercise, respectively; p < 0.001). Compared with gallopamil, both tedisamil and esmolol were superior in their effects on rate-pressure product, myocardial oxygen consumption, and ST-segment depression, whereas plasma lactate concentration was more reduced by tedisamil and gallopamil. Tedisamil led to a fall in norepinephrine levels in particular. CONCLUSION: Tedisamil and esmolol showed almost equipotent anti-ischemic effects at the doses administered. Tedisamil acts mainly by reductions in heart rate, and esmolol, though to a lesser degree, also by reductions in systolic blood pressure. The mechanism of gallopamil is to reduce afterload and to improve coronary perfusion. At the doses applied, however, it has lower antianginal potency compared with tedisamil and esmolol.

Systemic and regional hemodynamic effects of gallopamil in patients with essential hypertension.

Systemic and regional hemodynamics were assessed in 10 patients with uncomplicated mild to moderate essential hypertension before and during gallopamil therapy. Cardiac output was measured in triplicate with indocyanine dye. Plasma volume and renal blood flow were measured radioisotopically. Immediately following the initial dose of a slow-release (SR) formulation of gallopamil, a significant fall in arterial pressure associated with a decreased total peripheral resistance and a reflex increase in heart rate and cardiac output were seen. Then, after 8-12 weeks of treatment, arterial pressure and total peripheral resistance remained reduced, but heart rate and cardiac output returned to pretreatment levels. Gallopamil also produced significant reductions in renal and splanchnic vascular resistance. Plasma volume and total blood volume did not change. Thus, gallopamil reduced arterial pressure and vascular resistances without fluid retention or prolonged reflexive changes.

[Anti-ischemia effects of gallopamil and esmolol in an intra-individual comparison in patients with coronary heart disease]. / Antiischämische Auswirkungen von Gallopamil und Esmolol im intraindividuellen Vergleich bei Patienten mit koronarer Herzkrankheit.

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.

[The anti-ischemic effect of phosphodiesterase III inhibitors]. / Antiischämische Wirkung von PDE-III-Hemmern.

When enoximone is acutely administered to patients with stable angina and angiographically proven relevant coronary stenosis i.v. application of 0.75 mg/kg exhibits pronounced antiischemic effects. This could be observed in patients during exercise and in those in whom the ischemia was provoked by rapid cardiac stimulation. The antiischemic effects were documented by relief of symptoms, reduction of ST-depression, improvement of impaired myocardial wall motion, decrease to normalization of pathologically elevated filling pressure, amelioration of coronary blood flow as evidenced by myocard scintigraphy and washout time of an intracoronarily injected echo-contrast medium. There was also a definite improvement of ischemia-caused mitral regurgitation. Similar observations were found when the drug was injected in the diseased coronary arteries in a small dose (0.075 mg/kg) so that peripheral effects were not present. In comparison to the Ca(++)-blocker Gallopamil the antiischemic effects of Enoximone were more pronounced, a synergistic action was, however, observed. Negative dromotropic effects of Gallopamil could be abolished by Enoximone. With oral administration of the drug over a period of one week antiischemic effects could also be documented with Holter monitoring as well as during exercise. There was a reduction of ST-depression both at spontaneously occurring ischemic episodes and during exercise, in the number and duration of episodes of silent ischemia, particularly, however, a decrease in symptomatic episodes. In none of the patients under study proarrhythmic effects were observed.

Enantioselective gallopamil protein binding.

The protein binding of the enantiomers of gallopamil has been investigated in solutions of human serum albumin, alpha 1-acid glycoprotein and serum. Over the range of concentrations attained after oral gallopamil administration, the binding of both enantiomers to albumin, alpha 1-acid glycoprotein, and serum proteins was independent of gallopamil concentration. The binding to both human serum albumin (40 g/liter) [range of fraction bound (fb) R: 0.624 to 0.699; S: 0.502 to 0.605] and alpha 1-acid glycoprotein (0.5 g/liter) (range of fb R: 0.530 to 0.718; S: 0.502 to 0.620) was stereoselective, favoring the (R)-enantiomer (predialysis gallopamil concentrations 2.5 to 10,000 ng/ml). When the enantiomers (predialysis gallopamil concentration 10 ng/ml) were studied separately in drug-free serum samples from six healthy volunteers the fraction of (S)-gallopamil bound (fb: 0.943 +/- 0.016) was lower (P < 0.05) than that of (R)-gallopamil (fb: 0.960 +/- 0.010). The serum protein binding of both (R)- and (S)-gallopamil was unaffected by their optical antipodes (fb R: 0.963 +/- 0.011; S: 0.948 +/- 0.015) indicating that at therapeutic concentrations a protein binding enantiomer-enantiomer interaction does not occur. The protein binding of (R)- and (S)-gallopamil ex vivo 2 h after single dose oral administration of 50 mg pseudoracemic gallopamil (fb R: 0.960 +/- 0.010: predialysis [R] 6.9 to 35.3 ng/ml; S: 0.943 +/- 0.016: predialysis [S] 9.5 to 30.7 ng/ml) was comparable to that observed in vitro in drug-free serum. Gallopamil metabolites formed during first-pass following oral administration, therefore, do not influence the protein binding of (R)- or (S)-gallopamil.

[The anti-ischemic effect of gallopamil-retard in comparison with nifedipine-retard in stable angina pectoris]. / Antiischämische Wirkung von Gallopamil retard im Vergleich zu Nifedipin retard bei stabiler Angina pectoris.

To assess the antiischemic efficacy of slow-release (SR) gallopamil, 100 mg b.i.d., versus slow-release (SR) nifedipine, 20 mg b.i.d., 24 patients with chronic stable angina underwent symptom-limited bicycle ergometer exercise stress tests in a randomized, placebo-controlled, double-blind, cross-over protocol. Both medications caused a significant reduction in anginal attack frequency and nitroglycerin consumption as compared to placebo; similarly, exercise tolerance was augmented in association with a considerable reduction in ischemia-induced ST-segment depression. The antiischemic effect of gallopamil (SR) was marginally superior to that of nifedipine (SR). Since the incidence of adverse effects was also less with gallopamil (SR) this drug exhibited a more favorable risk-benefit ratio relative to nifedipine (SR).

[Long-term treatment of stable angina pectoris with gallopamil]. / Trattamento a lungo termine dell'angina pectoris stabile con gallopamil.

BACKGROUND: The effects of long-term treatment with gallopamil 50 mg t.i.d were assessed in 8 patients, 7 males and 1 female, aged 47-69 years, with stable angina pectoris, positive exercise tests, coronary artery disease and no previous myocardial infarction. METHODS: Clinical and ECG parameters as well as exercise testing, 24-hour Holter and echocardiography were assessed before treatment, after 3 months, after 1 and 2 years of treatment, and following final wash-out. RESULTS: Comparing each treatment period to baseline, a significant decrease in resting heart rate (from 66 +/- 9 beats/min at baseline to 56 +/- 7 beats/min after 3 months [p < 0.01], 59 +/- 8 beats/min after 1 year [p < 0.05] and 58 +/- 9 beats/min after 2 years [p < 0.05]), systolic (from 162 +/- 19 mmHg at baseline to 147 +/- 12 mmHg after 3 months [p < 0.05], 146 +/- 20 mmHg after 1 year [p < 0.01] and 146 +/- 27 mmHg after 2 years [p < 0.05]), and diastolic (from 89 +/- 6 mmHg to 82 +/- 7 after 3 months [p < 0.05], 82 +/- 4 after 1 year [p < 0.05] and 83 +/- 4 after 2 years [p < 0.05]) blood pressure was observed. Exercise time significantly improved (from 596 +/- 209 seconds to 802 +/- 66 seconds after 3 months [p < 0.01], 710 +/- 167 seconds after 1 year [p < 0.05] and 723 +/- 125 seconds after 2 year [p < 0.05]), while heart rate and rate-pressure product at peak exercise did not change. The number of ischemic episodes and the total ischemic time per 24 hours significantly decreased (from 35 +/- 15 min to 12 +/- 10 min after 3 months [p < 0.05], 10 +/- 8 min after 1 year [p < 0.05] and 11 +/- 9 min after 2 years [p < 0.05]). Ejection fraction increased (from 66 +/- 10% to 77 +/- 7% after 3 months [p < 0.01], 80 +/- 5% after 1 year [p < 0.01] and 80 +/- 3% after 2 years [p < 0.01]), while contractility, as expressed by the end-systolic stress/end systolic volume ratio remained unchanged. No serious side-effects or biochemical abnormalities developed. CONCLUSIONS: Gallopamil appears to be safe, well tolerated and effective in the long term control of angina pectoris; its effects are fully developed at 3 months and persist unchanged after 2 years. For its hypotensive action and the lack of significant effects on myocardial contractility, gallopamil appears to be potentially useful in patients with associated angina and hypertension and in patients with impaired left ventricular function.

[The effect of gallopamil on myocardial perfusion in angina of effort]. / Influenza del gallopamil sulla perfusione miocardica nell'angina da sforzo.

To value stress tolerance and stress myocardial perfusion before and after a week of oral therapy with gallopamil 150 mg daily, we studied 10 patients suffering from stable effort angina. We performed bicycle exercise stress testing and thallium scintigraphy (Tl) with planar technique in 3 projections (anterior-posterior and oblique left anterior at 45 and 70 degrees) according to the current standards. We valued systolic and diastolic blood pressure (SBP-DBP), heart rate (HR) and HR-SBP product at rest, at symptoms stress-induced and at the end of the procedure. Moreover we valued work threshold of chest discomfort and ischemia, the maximal work capacity and the perfusion defects according to a Tl score obtained dividing the 3 projections in 5 segments and fixing a value according to the observed perfusion from 0 = normal perfusion to 3 absent perfusion. We observed a significant reduction of basal HR (77 vs 71, p = 0.05), SBP (147 +/- 15 vs 131 +/- 15 mmHg, p = 0.001), DBP (91 +/- 6 vs 83 +/- 6 mmHg, p = 0.002). Work threshold of chest discomfort and ischemia significantly arose (8 +/- 3 vs 11 +/- 4 min., p = 0.002; 6 +/- 3 vs 10 +/- 4 min., p = 0.001). The HR-SBP product at the maximal work capacity and the Tl score significant decreased (31650 +/- 6239 vs 29406 +/- 5418, p = 0.003; 8 +/- 2 vs 5 +/- 1, p = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of inhaled gallopamil, a potent calcium channel blocker, on the late-phase response in subjects with allergic asthma.

The effect of gallopamil on the late-phase response to inhaled allergen was evaluated in six young adults with allergic asthma in a crossover manner. During 2 study days, subjects received 20 mg of inhaled gallopamil or placebo 30 minutes before challenge with the same dose of allergen. In addition, a histamine challenge was performed 1 1/2 hours before and 24 hours after allergen challenge. On 2 additional study days, in the absence of allergen, basal airway responsiveness to histamine was measured before and after gallopamil or placebo administration. During the early phase, the mean +/- SD decrease in FEV1 was 28.0% +/- 11.3% after placebo and 25.1% +/- 8.4% after gallopamil administration (p greater than 0.05; beta = 0.14). During the late phase, the maximum decrease in FEV1 was 26.9% +/- 11.9% after placebo and 25.3% +/- 10.3% after gallopamil administration (p greater than 0.05; beta = 0.21). Airway reactivity to histamine 24 hours after allergen challenge could not be measured in three subjects after gallopamil administration and in one subject after placebo administration because of persistent bronchospasm. In contrast, basal responsiveness to histamine in the absence of allergen was modestly decreased by gallopamil. Since gallopamil is one of the most potent calcium channel blockers when it is administered by the inhaled route, it is unlikely that this group of drugs will be clinically useful for allergic asthma.

Gallopamil slow release: a double blind study of twice daily versus once daily treatment in chronic stable angina.

The clinical efficacy of a new slow release preparation of the calcium antagonist gallopamil was assessed in 20 patients by diary cards and treadmill exercise tests. A single blind phase of two week periods of placebo, gallopamil 100 mg o.d. and gallopamil 100 mg b.i.d., blinded to the patient, was followed in 18 patients by a double blind comparison of gallopamil 100 mg od versus 100 mg b.i.d. Angina frequency and trinitrin consumption per week were both significantly less on high dose (2.7 and 1.7) than on low dose (5.4 and 3.4) respectively. Treadmill total exercise time was longer on high dose (523s) than low dose (449s). Other exercise test parameters showed similar improvements on high dose treatment. Gallopamil was well tolerated. PR interval correlated best with plasma gallopamil level, while exercise test parameters correlated best with the log plasma level of its major metabolite nor-gallopamil.

[4'-epidoxorubicin: its cardiotoxicity. Possible cardiac protection with gallopamil, a drug with calcium-antagonist action]. / La 4'-epidoxorubicina: sua cardiotossicità. Eventuale cardioprotezione con il gallopamil, farmaco ad azione calcioantagonista.

The 4'-EPI-doxorubicin (4'-EDX) has shown antitumoral activity against a broad spectrum of human tumors. The same clinical reports have shown therapeutic activity comparable to doxorubicin (adriamycin), but a lower cardiac toxicity. 4'-EDX cardiotoxicity appears after highest cumulative doses: 935 mg/m2 bs for 4'-EDX vs 550 mg/m2 bs for adriamycin. Moreover we have observed a protective action of the calcium antagonist gallopamil. We have found an improvement in ventricular performance after using gallopamil, and a reduction of 4'-EDX cardiotoxicity. Cardiac function was evaluated by EKS, STI, echography, myocardial scintigraphy course. Our result indicates the possibility of treating tumors without serious cardiotoxic by 4'-EDX and gallopamil.

The importance of stress-induced cardiac wall motion abnormalities in the evaluation of drug intervention.

Stress-induced wall motion abnormalities are a sensitive marker of myocardial ischaemia. Stress echocardiography has recently been the subject of increasing interest because of its improved feasibility and compatibility with new and effective alternative stresses. Transoesophageal atrial pacing (TAP) with 2-dimensional echocardiography (2-D echo) is a recently developed echo-cardiographic stress procedure that has been shown to be reliable and effective in both the diagnosis and evaluation of stress-induced myocardial ischaemia. TAP with 2-D echo was performed after treatment with placebo and intravenous gallopamil 0.03 mg/kg in 12 patients with stable, reproducible angina of effort. Compared with placebo, gallopamil treatment increased the time to 1 mm ST-segment depression (6.6 vs 5.3 minutes; p less than 0.05) and improved the ventricular wall motion score at a heart rate of 130 beats/min (17 vs 15; p less than 0.01) and 150 beats/min (13 vs 11; p = 0.07). Three patients who developed angina after placebo administration were symptom-free after gallopamil. Thus, gallopamil exerts a beneficial effect on atrial pacing-induced ischaemia, by increasing the pacing time to the ischaemic threshold and reducing the extent of dysfunctional myocardium during ischaemia.

Intracoronary gallopamil during percutaneous transluminal coronary angioplasty.

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.

Combined gallopamil and isosorbide-5-mononitrate in "mixed" angina pectoris.

The efficacy of combining gallopamil and isosorbide-5-mononitrate (IS-5-MN) was evaluated in 15 patients with "mixed" angina and documented coronary artery disease who participated in a 4-week, double-blind, double-dummy, crossover, placebo-controlled trial. After the first week of the placebo phase (single-blinded), all patients received in three different weeks IS-5-MN 20 mg three times daily, gallopamil 50 mg three times daily, and the same dosages of IS-5-MN and gallopamil three times daily. Exercise tolerance, and peak values of heart rate, systolic blood pressure, double product (DP/100), and ST-segment were evaluated with a treadmill test at the end of each phase. The improvement in exercise tolerance obtained by the combination of the two drugs was significantly greater (p < 0.01) than that achieved by IS-5-MN but not that by gallopamil monotherapy (NS). This effect was accompanied by significant (p < 0.05) reduction (-61%) in ST-segment and significant (p < 0.05) increment (+8%) in peak heart rate only after administration of the combination of the two drugs. The number of ST-depression (ST-) > 1 mm or ST-elevation (ST+) episodes on 24-h Holter monitoring lasting > or = 1 min were also noted in all patients at the end of each phase of the trial.(ABSTRACT TRUNCATED AT 250 WORDS)

Slow-release gallopamil in patients with stable effort angina.

Gallopamil (GSR) is a new calcium-channel blocker. The anti-ischemic activity of GSR was investigated in 12 patients with stable angina of effort, with fixed ischemic threshold (variations < 15%). After a 7-day washout period, patients were randomized to receive treatment with either GSR 100 mg or placebo twice daily for 7 days. Patients underwent maximal symptom-limited exercise test, 10 W/min on a bicycle, during washout (twice) and after the end of each treatment period. Patients were studied by electrocardiogram and the cuff method for determining systolic blood pressure. After treatment with GSR, ischemic and anginal thresholds were increased for at least 12 h in comparison with placebo (ischemic threshold: GSR 663 +/- 37, placebo 571 +/- 36, p < 0.01; anginal threshold: GSR 708 +/- 32, placebo 646 +/- 38, p < 0.05). Rate-pressure product was not changed at the same levels of exercise, but it was significantly increased during exercise at ischemic threshold. In conclusion, GSR possesses an anti-ischemic and antianginal activity lasting at least 12 h. This activity seems due to an increase of coronary blood flow to ischemic areas.

Slow-release gallopamil evaluated by exercise test and long-term electrocardiography.

The effects of slow-release gallopamil (100 mg b.i.d.) were studied on exercise-induced ST-segment depression as well as on spontaneous myocardial ischemia detected by long-term electrocardiography (ECG) monitoring for 48 h in 26 patients with coronary artery disease and angina pectoris. Eight patients had to be excluded (because of paroxysmal atrial fibrillation in four patients, development of unstable angina pectoris in three patients, and frequent ventricular premature beats in one patient). In the remaining 18 patients, gallopamil led to an increase of work load (W x min) evaluated by bicycle ergometry, paralleled by an increase of exercise duration until the occurrence of ST-segment depression of > or = 0.1 mV in the nonblinded part of the trial. The number of spontaneous episodes of myocardial ischemia during long-term ECG recording, ranging from 0 to 14 during control, decreased in patients with two or more episodes during control, paralleled by a decrease in the total duration of ischemic episodes and a decrease in the ischemic score (duration of episodes x maximal ST-segment depression). During long-term ECG monitoring, we observed asymptomatic episodes of spontaneous second degree atrioventricular block of the Wenckebach type in three patients. No other adverse effects of slow-release gallopamil were observed. Therefore, these preliminary results of the non-blinded protocol confirm the anti-ischemic effects of slow-release gallopamil given 100 mg b.i.d.; however, these promising results will have to be confirmed in the consecutive double-blind, placebo-controlled part of the trial.

Efficacy and tolerability of slow-release gallopamil in patients with stable exercise-inducible angina pectoris.

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.

Administration of gallopamil by long-term venous infusion in spontaneous angina. A single-blind, self-controlled study versus placebo.

In order to assess the efficacy and tolerability of gallopamil (D-600, CAS 16662-47-8) by long-term venous infusion in the treatment of spontaneous angina, 15 consecutive patients were studied in a single-blind, self-controlled trial versus placebo. Following a 24-h Holter ECG recording of the patients receiving a saline infusion (run-in phase), i.v. administration of gallopamil was started at a dose of 0.02 mg/kg/h preceded by a 0.03 mg/kg bolus. After 24 h, the dosage was increased to 0.03 mg/kg/h and the infusion was maintained for another 48 h. The Holter ECG recording was repeated in the last 24 h of treatment and after 6 h from withdrawal (washout phase). The reduction in the number of angina attacks, as shown by a comparison between the average of the two placebo periods (run-in and washout phases) and the three days of treatment, was 68.2%, 92.5%, and 87%, respectively. Consumption of glyceryl trinitrate decreased by 92.5% on each one of the three days of treatment. The reduction in the number of ischemic episodes (IEs) with symptomatic (-91.6%) and silent (-98.0%) ST elevation, and with symptomatic (-100%) and silent (-90%) ST depression, also proved significant. Heart rate decreased only moderately. One patient showed a mild first-degree heart block, while another suffered a transient episode of isorhythmic A-V dissociation. In conclusion, when administered by venous infusion, gallopamil has been found to be well tolerated and highly effective in the treatment of spontaneous angina.(ABSTRACT TRUNCATED AT 250 WORDS)