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At least 19 recordsLinked to original sources
PubMed1998

Vasorelaxant and negative inotropic effects of gallopamil and LU49700, a metabolite of gallopamil, on isolated rat aorta and guinea-pig ventricular myocardium.

The effects of LU49700 (CAS 116759-60-5), the main metabolite of gallopamil (CAS 16662-47-8) on the mechanical response of isolated rat aortic and guinea-pig ventricular papillary muscle preparations were compared with those of gallopamil. Gallopamil and LU49700 inhibited the 64 mmol/l KCl-induced contraction of rat aorta in a concentration-dependent manner. The vasorelaxant potency of LU49700 was 244 times weaker than that of gallopamil. Gallopamil and LU49700 produced concentration-dependent negative inotropic effects on isolated right ventricular papillary muscles. The negative inotropic potency of LU49700 was 418 times weaker than that of gallopamil. These findings indicate that LU49700 has a weaker cardiovascular depressant potency than gallopamil. Therefore, LU49700 may not mediate the effects of gallopamil for treating subjects with cardiovascular diseases.

Animals↗
PubMed1997

Pharmacokinetics and pharmacodynamics of the enantiomers of gallopamil.

The pharmacokinetics and pharmacodynamics of the enantiomers of the calcium antagonist gallopamil have been investigated in six healthy volunteers. Each subject was studied on five occasions after receiving, in randomized order: placebo, 25 mg of (R)-gallopamil, 25 mg of (S)-gallopamil, 50 mg of pseudoracemic [25 mg of deuterated (S)-gallopamil and 25 mg of (R)-gallopamil] and 100 mg of (R)-gallopamil HCl orally. After separate administration, the apparent oral clearances of both enantiomers were similar [(R), 15.1 +/- 9.9 liters/min; (S), 11.0 +/- 6.0 liters/min], indicating that gallopamil first-pass metabolism is not stereoselective. After coadministration, the apparent oral clearance of each enantiomers decreased [(R), 5.9 +/- 2.8 liters/min; (S), 5.8 +/- 2.66 liters/min], suggesting that a partial saturation of first-pass metabolism occurs because the dose was twice as high than for the single enantiomers. Serum protein binding and renal elimination of gallopamil are stereoselective, favoring (S)-gallopamil. Analysis of urine samples revealed a marked degree of stereoselectivity in the formation of O- and N-dealkyl metabolites. Because these showed opposite stereoselectivity, canceling out each other, the net result was no or only marginal stereoselectivity. Twenty-five milligrams of (S)-gallopamil prolonged the PR interval in all subjects; however, a greater effect was elicited by 50 mg of (RS)-gallopamil. (R)-Gallopamil (100 mg) did not significantly alter the PR interval, although higher concentrations were attained than after the pseudoracemate. Based on a consideration of (S)-gallopamil serum concentrations, a comparable relationship between (S)-gallopamil level and effect occurred after (S)- and (RS)-gallopamil, indicating that the pharmacological effect produced by the racemate could be totally accounted for by the higher concentrations of (S)-gallopamil attained.

Adult↗
PubMed1993

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.

Administration, Oral↗
PubMed1998

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.

Adrenergic beta-Antagonists↗
PubMed1989

Objective evaluation of gallopamil in patients with chronic stable angina. Exercise testing, Holter monitoring, cross-sectional echocardiography and plasma levels.

In this double-blind, randomized placebo-controlled study the effects of two dosages of gallopamil on exercise tolerance were evaluated in 12 patients with stable effort angina. After a pre-study screening aimed at assessing the reproducibility of the exercise response, the patients entered the study which consisted of three 7-day consecutive periods during which placebo or gallopamil 50 mg t.i.d. or gallopamil 75 mg t.i.d. were administered according to a randomized sequence. 24-hour Holter monitoring and cross-sectional echocardiography were performed on the 6th and 7th day of each treatment period, respectively. On the 7th day of each treatment period, patients underwent an exercise test 2 and 8 h after the last administration of gallopamil or placebo. Blood samples for plasma gallopamil concentrations were taken just before each exercise test. The results were analysed using a three-way analysis of variance; intergroup differences were evaluated by the Newman-Keuls test. At 2 h, 11 patients with placebo and three with gallopamil experienced angina; both dosages of gallopamil significantly prolonged exercise time and -1 mm time and also reduced ST segment depression and the rate-pressure product at submaximal workload. No significant change in the rate-pressure product was observed either on the appearance of 1 mm ST depression or at peak exercise. At 8 h, 11 patients with placebo and gallopamil 50 mg t.i.d. and 10 with gallopamil 75 mg t.i.d. experienced angina; although exercise time was significantly prolonged by both dosages of gallopamil, the increase in -1 mm time and reduction of ST segment depression at submaximal workload did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1987

Effects of the calcium antagonist gallopamil (D600) upon excitation-contraction coupling in toe muscle fibres of the frog.

1. The effects of the Ca2+ antagonist gallopamil (D600) upon force development in short skeletal muscle fibres (m. lumbricalis digiti IV) of the frog were investigated under voltage-clamp control, using two flexible internal micro-electrodes (temperature = 6-7 degrees C). 2. In the presence of 5-100 microM-gallopamil muscle fibres developed one normal phasic contracture when they were depolarized from a holding potential of -90 to 0 mV. Subsequent depolarizations caused no mechanical response (paralysis). However, the ability to contract could be restored by hyperpolarizing the membrane to potentials between -120 and -150 mV. 3. In the absence of gallopamil, mechanical refractoriness could be fully reversed within 5-7 s by repolarizing the fibre from 0 to -120 mV. In the presence of 100 microM-gallopamil, no detectable restoration occurred within the first minute at -120 mV, and 45 to 100% of maximum force was eventually reached after 6 min of restoration. 4. The potential V at which the 'steady state' 50% of maximum force of a refractory fibre was restored shifted from -51 mV under normal conditions to -83 and -90 mV in the presence of 5 and 100 microM-gallopamil, respectively. 5. Paralysis in the presence of gallopamil and recovery from paralysis during hyperpolarization could also be observed when 2 mM-Cd2+ was applied to the external solution, i.e. when most Ca2+ channels in the T-tubular system were blocked. 6. Gallopamil shifted the threshold for activation of force to more negative potentials. Fibres developed force when they were depolarized to membrane potentials between -60 and -80 mV, whereby a fast phase of activation was followed by a slower one. Upon repolarization relaxation likewise occurred in a fast and a slow phase. 7. High concentrations of gallopamil (greater than 500 microM) caused a slowly developing contracture, independent of membrane potential (-90 or 0 mV). 8. It is proposed that gallopamil binds to a receptor at the force-controlling system in the T-tubular membrane (potential sensor) with a high affinity in the depolarized state and a lower affinity at negative potentials. Therefore association of gallopamil mainly leads to stabilization of the inactive state (paralysis) but can also stabilize the active state.

Action Potentials↗
PubMedDate not supplied

Efficacy and pharmacokinetics of gallopamil in patients with coronary artery disease.

We prospectively studied 10 patients with stable exertional ischaemia, selected from a larger group of patients referred for suspected coronary artery disease or to detect residual ischaemia after myocardial infarction, to evaluate pharmacokinetic changes during chronic treatment with gallopamil and its correlation with clinical efficacy in patients with coronary artery disease. Our study consisted of a 1-week run-in single-blind placebo treatment and a 4-week single-blind gallopamil treatment. At the end of the run-in period patients underwent two different exercise tests, the first 2 hours and the second 7 hours after placebo administration. During active treatment all patients underwent two different exercise tests, the first 2 hours and the second 7 hours after gallopamil (50 mg) administration on the 1st and 28th days of gallopamil therapy. On the same days in eight of the patients we evaluated gallopamil pharmacokinetic changes. Our data revealed a rapid increase of unchanged gallopamil and its metabolite (norgallopamil) in the plasma, and a peak concentration of these substances about 2 hour after oral administration on both the 1st and 28th day of observation. Moreover, our results demonstrated an increase between the first and 28th day of treatment in peak concentration of unchanged gallopamil in the plasma, and of AUC 0-infinity and AUC o-c values during chronic treatment with gallopamil. Our clinical data showed an improvement in exercise results during gallopamil therapy related to increased concentration of the drug.

Aged↗
PubMedDate not supplied

Effect of gallopamil on myocardial microperfusion in patients with stable effort angina: a randomized, cross-over, double-blind, placebo-controlled trial.

We evaluated the efficacy and safety of daily administration of gallopamil 150 mg/day and its effects on myocardial perfusion in a medium-term, randomized, double-blind, cross-over, placebo-controlled trial. We studied 19 patients (17 males and 2 females; mean age 57 +/- 6.8 years) with stable effort angina, angiographically documented coronary artery disease and reversible perfusion defects during exercise thallium-201 myocardial scintigraphy of at least one segment of the left ventricle. After 2 weeks of a single-blind placebo run-in period, during which each patient underwent at least 2 exercise tests and a 48-hour Holter ECG recording, all patients were treated with either placebo or gallopamil 50 mg t.i.d. for 28 days. At the end of this period, patients crossed over to the alternate regimen. This phase was double blind. After treatment with placebo or gallopamil, patients underwent exercise tests, 24-hour Holter ECG recording and thallium-201 myocardial scintigraphy. Weekly angina frequency and trinitroglycerin (TNT) consumption and safety were also evaluated. No patients dropped out of the study because of major side effects. The number of total ischemic and symptomatic events recorded at 24-hour ECG monitoring, weekly angina frequency and TNT consumption were significantly reduced during gallopamil treatment. After gallopamil administration, exercise duration significantly increased (run-in: 419 +/- 116 s, placebo: 420 +/- 118 s, gallopamil: 511 +/- 144 s; p < 0.05), and ST segment depression was significantly reduced (run-in: -1.3 +/- 0.3 mm, placebo: -1.3 +/- 0.3 mm, gallopamil: -0.94 +/- 0.68 mm; p < 0.01), while heart rate, systolic blood pressure and rate-pressure product were unchanged at rest, at submaximal and at peak exercise. Qualitative and quantitative evaluation of myocardial perfusion and the myocardial uptake percentage of thallium-201 in ischemic zones were significantly improved by gallopamil treatment. These findings demonstrate that gallopamil can improve myocardial perfusion and reduce myocardial oxygen consumption.

Aged↗
PubMed1993

Ovine tracheal muscle contraction in vitro: inhibition by calcium channel blockers gallopamil and verapamil.

We compared the inhibitory effects of calcium channel blockers, gallopamil and verapamil on acetylcholine (Ach)-induced contractions of ovine tracheal muscle in vitro. Adult sheep were sacrificed and tracheal strips were obtained by cutting the single tracheal rings from the mid-trachea. Tracheal strips were suspended in Krebs-Henseleit solution and isometric tension measured upon stimulation with cumulative doses of Ach (10(-7) to 10(-4) M) without and after pretreatment with gallopamil (10(-7) to 10(-6) M) or verapamil (10(-6) to 10(-5) M). In untreated tissues, the mean concentration of Ach required to produce 50% of maximal response (EC50) was 4.3 x 10(-6) M Ach. Both gallopamil and verapamil inhibited the Ach-induced contractions of ovine tracheal smooth muscle, by shifting the dose-response curves to Ach to the right. EC50 Ach for gallopamil (10(-6) M) and verapamil (10(-6) M) was 2.6 x 10(-5) and 5.2 x 10(-6) M, respectively. Dose ratio defined as postantagonist EC50 Ach/control EC50 Ach, was 7.7 for gallopamil and 2.0 for verapamil. Thus, the inhibitory effect of gallopamil was approximately 4-fold more potent than that of verapamil. Gallopamil was 17-fold more potent than verapamil in relaxing precontracted tracheal strips. The dose of calcium antagonists required to produce 25% relaxation (EC25) of tracheal strips precontracted with 10(-4) Ach was 3.7 x 10(-5) M for verapamil and 2.2 x 10(-6) M for gallopamil. These results indicate that gallopamil is effective against Ach-induced contractions of ovine trachealis muscles, and is more potent than verapamil.

Acetylcholine↗
PubMed1997

Haemodynamic and metabolic effects of gallopamil as additive to calcium-containing and calcium-free cardioplegic solutions in mature pig hearts.

Myocardial haemodynamic and metabolic effects of the calcium-channel blocker gallopamil as additive to calcium-containing (St Thomas Hospital, STH) and calcium-free (Bretschneider procaine-containing, BRT) crystalloid cardioplegic solutions were evaluated. Adult pig hearts (weight 0.033 kg) were randomized to four groups and perfused with 1 litre of cold (4 degrees C) cardioplegic solution; group A: BRT without gallopamil, n = 9, group B: BRT with gallopamil (0.4 microM), n = 8, group C: gallopamil-free STH, n = 8, and group D: STH with gallopamil (0.4 microM), n = 8. After storage at 4 degrees C for 6 hours the hearts were reperfused with blood/Ringer solution in a modified Langendorff model for 60 min. Developed left ventricular pressure, rate-pressure product and +dP/dt were lower in gallopamil-treated hearts during reperfusion (p < 0.05), as were oxygen extraction and oxygen uptake (p < 0.05) and lactate release (p < 0.05). Myocardial blood flow was greater in gallopamil-treated hearts (p < 0.05). In hearts comparable in size and anatomy to the human heart, gallopamil added to both cardioplegic solutions reduced cardiac function and oxygen uptake despite increased myocardial blood flow. The findings suggest reduced myocardial protection after addition of gallopamil to cardioplegic solutions.

Animals↗
PubMed1987

Gallopamil binding to human serum proteins.

We have determined the extent and variability in the binding of gallopamil to human serum proteins. Binding was determined by equilibrium dialysis in healthy volunteer serum, human serum albumin (45 g.l-1), and alpha-1 acid glycoprotein (AAG) (600 mg.l-1) at a pH of 7.4. Nonlinear regression analysis of gallopamil binding over a wide range of concentrations (10(-9) to 10(-4) M) in healthy volunteer serum suggested two classes of binding sites (kass.1 = 4.7 x 10(5)M-1, kass.2 = 4.1 x 10(4)M-1). These values were in close agreement with those obtained from binding to AAG and human serum albumin. Gallopamil free fraction over the concentration range of 10 to 100 ng.ml-1 was independent of concentration. The free fraction in 20 volunteers was 0.075 at a concentration of 10 ng.ml-1. Gallopamil free fractions were also determined in human serum albumin, to which various concentrations of AAG were added. Bound/free ratios correlated with AAG. As we changed the pH of the serum from 7.0 to 8.0, the free fraction changed from 0.1 to 0.05. Verapamil, lignocaine, procainamide, propranolol, 40 H-propranolol, MEGX, and NAPA all caused an increase in the free fraction of gallopamil in serum. However, tocanide, quinidine, diltiazem, GX, norverapamil, D620, D617, and desacetyl diltiazem had no effect on gallopamil binding. Therefore, the data strongly suggest AAG as the high affinity, low capacity binding site and albumin as the low affinity, high capacity binding site for gallopamil, variability in gallopamil binding can be explained by alterations in AAG concentrations, pH, and the presence of other drugs and their metabolites.

Blood Proteins↗
PubMed1988

Inhibition of antigen-induced bronchoconstriction by a new calcium antagonist, gallopamil: comparison with cromolyn sodium.

We have previously demonstrated partial attenuation of antigen-induced bronchoconstriction by aerosolized verapamil (Chest 1985;88:176-80). In the present investigation, we studied the effect of a new calcium antagonist, gallopamil, on allergic bronchial reactivity and compared it to that of cromolyn sodium. Nine asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma were studied on 4 different days, without and after pretreatments with aerosolized placebo, gallopamil (10 mg), or cromolyn sodium (20 mg) solution, in a single-blind, randomized, crossover design. Bronchial reactivity was measured as the cumulative provocative dose of ragweed antigen in breath units (PD35) that caused a 35% decrease in specific airway conductance (SGaw). Baseline SGaw was comparable on control, placebo-, gallopamil- and cromolyn sodium-treatment days. The airway deposition dose of gallopamil and cromolyn sodium was calculated at 1.05 mg and 2.1 mg, respectively. Neither cromolyn sodium nor gallopamil had a significant effect on mean SGaw. Mean +/- PD35 on control and placebo-treatment days was 0.54 +/- 0.95 and 0.23 +/- 0.17 breath units, respectively. Aerosolized gallopamil and cromolyn sodium increased the mean PD35 to 56 +/- 41 and 24 +/- 35 breath units, respectively (p less than 0.05). Gallopamil completely inhibited the antigen-induced bronchoconstriction in six (67%) subjects, whereas cromolyn sodium was totally effective in two of the nine (22%) subjects. These results demonstrate that aerosolized gallopamil inhibits allergic bronchial reactivity with efficacy comparable or better than cromolyn sodium.

Adult↗
PubMed1992

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.

Administration, Inhalation↗
PubMed2000

Pharmacokinetics and pharmacodynamics of R- and S-gallopamil during multiple dosing.

AIMS: Using a stable isotope technique we investigated the pharmacokinetics and pharmacodynamics of gallopamil after administration of 50 mg pseudoracemic gallopamil every 12 h for 7 doses (72 h). METHODS: Six male healthy volunteers were studied. After the seventh dose the pharmacokinetics and pharmacodynamics were assessed. Serum levels of gallopamil were measured by gas chromatography/mass spectrometry. Effects of gallopamil were measured by ECG recording. RESULTS: The apparent oral clearances (R: 4.8 l min-1 (95% CI: 2.9-6.8); S: 5.5 l min-1 (95% CI: 2.5-8.5)) and half-lives (R: 6.2 h; S: 7.2 h) of R- and S-gallopamil were similar (P >0.05). The serum protein binding (fu R: 0.035 (95% CI: 0.026-0. 045); S: 0.051 (95% CI: 0.033-0.069)) and the renal elimination (% of dose R: 0.49%; S: 0.71%) were enantioselective. Gallopamil had a potent effect on the PR interval (% prolongation 35.7% (95% CI: 14. 0-57.3)). No changes in other electrocardiographic or cardiovascular parameters were observed. CONCLUSIONS: The pharmacokinetics and bioavailability of the racemic drug gallopamil are not stereoselective at steady-state and are therefore not substantially altered compared with the single dose administration of gallopamil.

Area Under Curve↗
PubMed1999

Identification of human cytochrome P-450 isoforms involved in metabolism of R(+)- and S(-)-gallopamil: utility of in vitro disappearance rate.

Isoforms of cytochrome P-450 (CYP) involved in the metabolism of gallopamil enantiomers were identified by measuring the disappearance rate of parent drug from an incubation mixture with human liver microsomes and recombinant human CYPs. Mean (+/- S.D.) intrinsic clearances (CL(int)) of R(+)- and S(-)-gallopamil in human liver microsomes were 0.320 +/- 0.165 and 0.205 +/- 0.107 ml/min/mg protein, respectively. These values were highly correlated with the 6beta-hydroxylation activity of testosterone, a marker substrate of CYP3A4 (r = 0.977 and 0.900 for R(+)- and S(-)-gallopamil, respectively, p <.001). Ketoconazole and troleandomycin, selective inhibitors of CYP3A4, and polyclonal antibodies raised against CYP3A4/5 markedly reduced the CL(int) of gallopamil enantiomers in human liver microsomes. Among the 10 recombinant human CYP isoforms, CYP3A4 exhibited the highest CL(int) of gallopamil enantiomers, and CYP2C8 and CYP2D6 also exhibited appreciable activity. When the contribution of CYP3A4 to the total metabolic clearance of gallopamil enantiomers in human liver microsomes was estimated by relative activity factor, the mean (+/- S.D.) contributions were 92 +/- 18 and 68 +/- 19% for R(+)- and S(-)-gallopamil, respectively. These values were comparable to the rates of immunoinhibition by antibodies raised against CYP3A4/5 observed in human liver microsomes. The present study suggests that CYP3A4 is a major isoform involved in the overall metabolic clearance of gallopamil enantiomers in the human liver, and that the present approach based on disappearance rate may be applicable to identify major isoforms of CYP involved in the metabolism of a drug in human liver microsomes.

Cytochrome P-450 Enzyme System↗
PubMed1992

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.

Adult↗
PubMed1991

Interspecies differences in the effect of pH on gallopamil protein binding to albumin and alpha 1-acid glycoprotein.

There is little information about the factors which influence drug protein binding between species. We have therefore investigated the role of pH on the binding of gallopamil, a calcium channel antagonist known to exhibit pH-sensitive binding, among four species, human, baboon, bovine, and canine. We used pure protein solutions of alpha 1 acid glycoprotein (AAG) (60 mg.l-1), albumin (45 gm.l-1), and their combination and three values of pH, 7.0, 7.4, and 8.0. Gallopamil protein binding was determined over a concentration range of 2.0 x 10(-7) mol.l-1 to 2.1 x 10(-3) mol.l-1 using equilibrium dialysis. Gallopamil binding in all solutions was best described using a two binding site model in the combination solution and a one binding site model in the pure solutions. pH did not affect the number of identical binding sites. However, the influence of pH on gallopamil binding was species specific. Increasing the pH from 7.0 to 8.0 influenced binding affinity differently between species. There were directionally similar changes in unbound fraction at a gallopamil concentration of 2 x 10(-7) mol.l-1 as pH increased, although there were species differences in the degree of change. In protein solutions containing both AAG and albumin a reduction in pH from 7.4 to 7.0 resulted in species-specific increases in the unbound fraction. Increasing the pH from 7.4 to 8.0 again resulted in species-specific reductions in the unbound fraction of gallopamil. Similar changes were seen when pure AAG or albumin solutions were used, indicating species variance in both gallopamil protein binding and the effect of pH on binding.

Acid-Base Equilibrium↗
PubMed1988

Duration of protection of calcium channel blockers against exercise-induced bronchospasm: comparison of oral diltiazem and inhaled gallopamil.

The present study was conducted to determine the duration of the positive effect of oral diltiazem and inhaled gallopamil in mild asthmatic volunteers, ages 18-37 years, with a history of exercise-induced asthma and a 25-56% decrease in FEV1 after a standardized exercise challenge. Oral diltiazem 120 mg, inhaled gallopamil 10 mg, and placebo were administered in a double blind, randomized, crossover manner on different days 48 h apart. Diltiazem was administered 90 min and gallopamil 30 min before the first exercise challenge. Challenges were then repeated 3 and 6 h later. Neither diltiazem nor gallopamil significantly altered baseline FVC, FEV1, or FEF25-75. The mean maximum decrease in FEV1 after the first challenge was 16.8% after gallopamil, 25.2% after diltiazem and 30.1% after placebo. The mean post-exercise decrease in FEV1 after gallopamil was significantly smaller than after placebo. There were no significant differences in the post-exercise decreases in FEV1 between the three treatment regimens 3 and 6 h later. Thus, inhaled gallopamil provided significant protection against exercise-induced bronchospasm, but the beneficial effect was modest and short in duration.

Administration, Inhalation↗