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At least 19 recordsLinked to original sources
PubMed1989

Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells.

The calcium channel blocker verapamil has been shown to reverse multidrug resistance (T. Tsuruo et al., Cancer Res. 41: 1967-1972, 1981), but the mechanism of action of this agent has not been fully elucidated. A radioactive photoactive analogue of verapamil, N-[benzoyl-3,5-3H-(+/-)-5-[(3,4-dimethoxyphenetyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropyl-N-p-azidobenzoylpentylamine, was used to label the plasma membranes of a human myelogenous leukemia cell line (K562), a multidrug-resistant subline selected for resistance to Adriamycin (K562/ADM) and its revertant cell (R1-3). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled Mr 170,000-180,000 protein in the membranes from K562/ADM but not from the drug-sensitive parental K562 and revertant R1-3 cells. The Mr 170,000-180,000 verapamil acceptor was immunoprecipitated by monoclonal antibody MRK16 specific for P-glycoprotein associated with multidrug resistance, indicating that P-glycoprotein in the plasma membrane is a major target of verapamil in K562/ADM cells. The photolabeling of P-glycoprotein with N-[benzoyl-3,5-3H]-(+/-)-5-[(3,4-dimethoxyphenetyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropyl-N-p-azidobenzoylphentylamine was significantly blocked by other calcium channel blockers, nicardipine and diltiazem, that have been shown to overcome multidrug resistance. In addition, the photolabeling was partially blocked by Adriamycin, vincristine, and colchicine, suggesting that the specific binding sites for verapamil on P-glycoprotein are closely related to the binding sites for these calcium channel blockers and antitumor agents. To determine whether verapamil could be a substrate for P-glycoprotein, the cellular accumulation of [3H]verapamil into K562 and K562/ADM was evaluated. The accumulation of [3H]verapamil in the multidrug-resistant cells was 30% of K562 cells and increased when K562/ADM cells were treated with vincristine and nicardipine at 5 microM, indicating that the P-glycoprotein transports verapamil as well as other antitumor agents in the multidrug-resistant cells. These results suggest that verapamil enhances antitumor agent retention through competition for closely related binding sites on P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Treatment with verapamil during and after an acute myocardial infarction: a review based on the Danish Verapamil Infarction Trials I and II. The Danish Study Group on Verapamil in Myocardial Infarction.

The effect of verapamil on death and reinfarction after an acute myocardial infarction was studied in two double-blind, randomized, placebo-controlled multicenter trials, the Danish Verapamil Infarction Trials I and II (DAVIT I and II). The studies demonstrated that verapamil 360 mg/day from the 2nd week after an acute myocardial infarction, prevented death and reinfarction. Meta-analyses of the results of DAVITs I and II resulted in a reduction of pooled ratios of 22% (95% confidence limits 1-37, p = 0.04) for death, 21% (5-35, p = 0.02) for first major events (first reinfarction or death), and 27% (6-43, p = 0.02) for first reinfarctions. The effect of verapamil was to prevent myocardial ischemia and reduce sudden death and reinfarction. It is concluded that long-term treatment with verapamil after an acute myocardial infarction may be recommended with the object of reducing overall mortality, major events and reinfarction.

Arrhythmias, Cardiac↗
PubMed1992

Comparative efficacy, safety and pharmacokinetics of verapamil SR vs verapamil IR in hypertensive patients.

The antihypertensive effects of the regular immediate release formulation of verapamil (verapamil IR) and the newer sustained release formulation of verapamil (verapamil SR) were compared in Hispanic patients with untreated essential hypertension. Verapamil IR was given in 3 divided doses (80 or 160mg 3 times daily) and verapamil SR was given either as a single daily dose of 240mg or as 240mg every 12 hours. With both formulations there was a significant reduction in systolic (SBP) and diastolic blood pressure (DBP); a greater lowering of BP was observed with verapamil 480 mg/day than with 240 mg/day. With verapamil SR 480 mg/day, 91% of patients had reductions in SBP and DBP greater than 20 and 15mm Hg, respectively. In addition, 83% of patients reached normotension. With the lower dose (240mg once daily), 83% of patients had decreases in DBP greater than 10mm Hg and 73% of patients achieved normotension. Comparable effects were achieved with verapamil IR. With verapamil IR there was a more rapid fall in BP which peaked 3 to 4 hours postdose, whereas with verapamil SR a more gradual and sustained BP reduction was observed. Only small changes in heart rate (HR) were observed with verapamil IR and verapamil SR. For verapamil SR, the mean increase in HR was 5 beats/min (to 80 beats/min) and the mean decrease in HR was 13 beats/min (to 62 beats/min). Both verapamil SR and verapamil IR prolonged the PR interval of the ECG. An equal degree of PR prolongation was observed with 240 and 480 mg/day. The incidence of side effects (headache, palpitations, dizziness and flushing) was dose dependent, decreased with continuous treatment and was much higher with verapamil IR than with verapamil SR. Steady-state plasma verapamil concentrations were monitored. Compared with verapamil IR, verapamil SR produced a more gradual rise and a more sustained elevation of plasma verapamil and norverapamil concentrations. Comparable trough verapamil concentrations (Cmin) were observed with verapamil IR (98 micrograms/L) and SR (81 micrograms/L); morning Cmin verapamil concentrations were higher than daytime Cmin values. The normalised area under the plasma concentration-time curve (AUC) and maximum concentration (Cmax) were 10 to 20% greater for verapamil IR than SR. The 2-fold increase in oral dose produced a 2.2- and 2.4-fold increase in AUC for verapamil IR and SR, respectively, associated with a 20% reduction in metabolism to norverapamil. Fasting increased the rate and extent of absorption of verapamil.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Pressure↗
PubMed1989

Verapamil versus hydrochlorothiazide in the treatment of hypertension: results of long term double blind comparative trial. Verapamil versus Diuretic (VERDI) Trial Research Group.

OBJECTIVE: To compare the efficacy and tolerability of hydrochlorothiazide, sustained release verapamil, and their combination in patients with mild to moderate hypertension. DESIGN: Randomised multicentre trial of 48 weeks' duration with a double blind comparison of hydrochlorothiazide and verapamil followed by an open trial of combined treatment for patients not achieving the target diastolic blood pressure (less than 90 mm Hg) during treatment with a single drug. SETTING: Outpatient departments in 10 clinics and 10 private practices of general practitioners or internists. PATIENTS: 369 Hypertensive patients with a diastolic blood pressure of 95-120 mm Hg during a placebo run in period of two weeks. INTERVENTIONS: Initial treatment consisted of 12.5 mg hydrochlorothiazide (n = 187) or 120 mg sustained release verapamil (n = 182) once daily (regimen I). If the target diastolic blood pressure of less than 90 mm Hg was not achieved within four weeks doses were increased to 25 mg hydrochlorothiazide or 240 mg verapamil once (regimen II) and twice daily (regimen III). Patients not achieving target blood pressure were given the combination of hydrochlorothiazide and verapamil--that is, 25 and 240 mg once (regimen IV) and twice daily (regimen V). MAIN OUTCOME MEASURE: Blood pressure determined with a device permitting automatic repeated measurements with printouts. RESULTS: After eight weeks of treatment with a single drug 76 out of 178 (43%) and 101 out of 175 (58%) patients achieved the target blood pressure with hydrochlorothiazide and verapamil, respectively. During follow up until 48 weeks patients treated with verapamil reached the target blood pressure more often and at lower doses and were less likely to switch to combination treatment than patients randomised to hydrochlorothiazide treatment. Adding verapamil to hydrochlorothiazide was more effective than the addition of hydrochlorothiazide to verapamil. At the end of the study 42 out of 169 (25%) and 73 out of 163 (45%) patients initially randomised to hydrochlorothiazide and verapamil, respectively, were at target blood pressure without combination treatment. After adding verapamil to hydrochlorothiazide or hydrochlorothiazide to verapamil an additional 58 (34%) and 29 (18%) patients reached the target blood pressure, respectively. Altogether 92 out of 332 (28%) patients failed to achieve target blood pressure with regimen V. There were four, 10, seven, and seven withdrawals due to possible adverse effects to treatment with hydrochlorothiazide, verapamil, combining verapamil with hydrochlorothiazide, and combining hydrochlorothiazide with verapamil, respectively. CONCLUSIONS: In doses currently used in antihypertensive treatment verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension, whereas withdrawal rates caused by side effects possibly related to treatment were similar.

Adult↗
PubMed1975

The pharmacodynamics of orally taken verapamil and verapamil retard as judged by their negative dromotropic effects.

The widely recognized, negative dromotropic effects of alpha-isopropyl-alpha-[N-methyl-N-homaveratryl)-gamma-aminopropyl]-3-4-dimethoxyphenylacetonitrile (verapamil, Isoptin) on arterio-venous (A-V) nodal conductions were studied using long-term atrial stimulation (AS) in 7 healthy volunteers whose mean age was 30 years. A control group consisting of three of the volunteers who underwent long-term atrial stimulation without medication was established. Since an isolated, well-known drug effect was studied over a long period of time, it was felt that this was an acceptable method for reaching valid pharmacodynamic conclusions. Atrial stimulation was carried out at hourly intervals up to 14-16 h and continued to the highest possible rate without the occurrence of 2nd degree A-V block before and following oral application of verapamil, 240 mg. The stimulus-Q (S-Q) prolongation at increased pace rates was compared to the control. Verapamil retard was tested in a similar course of investigation the following day. The results clearly demonstrated that both forms of verapamil are effective when taken orally. Verapamil acts 2 h after oral application. The peak effectiveness of the drug is found at 5 h and at this point A-V block can occur at low atrial stimulated rates. The effect of verapamil retard is obvious only after 6 h but is still apparent after 14 h and it remains constant with no peak in effectiveness. Characteristics of the resulting regressions allow to distinguish the effect of verapamil on A-V conduction from influences that might be mediated by the diurnal changes in tone of the autonomic nervous system only. The effect of verapamil after oral application is more pronounced with higher heart rates. The pharmacodnaymics of verapamil evaluated with regard to a single well-known pharmacological effect, have not necessarily to be identical with the pharmacokinetics and the bioavailability of the drug.

Adult↗
PubMed1990

The anaerobic metabolism of verapamil in rat cecal contents forms nor-verapamil and thiocyanate.

The anaerobic metabolism of verapamil was studied to determine the role the intestinal flora may have on the disposition of verapamil. Metabolites produced by the flora could be the source of adverse reactions reported only with the p.o. controlled release formulations but not with immediate release formulations. Verapamil was found to be metabolized to thiocyanate, nor-verapamil and several more polar metabolites that were detected by either a specific assay for cyanide and thiocyanate or a high-performance liquid chromatography (HPLC) assay, respectively. The rate of thiocyanate formation with an initial substrate concentration of 2 mM verapamil was found to be 0.008 +/- 0.004 microgram/hr/ml of 1:10 cecal suspension. The N-demethylated metabolite, nor-verapamil, was detected in the cecal suspensions but it also disappeared with time. The rate of verapamil disappearance was dependent on the concentration of bacteria in the incubation mixture; the rate being most rapid with the highest concentration of bacteria. Acetonitrile and butyronitrile were also found to be metabolized by the cecal flora. Cyanide as well as thiocyanate were produced from both organo-nitriles. These results suggest that the cyano group of verapamil, acetonitrile and butyronitrile were all cleaved to form cyanide and/or thiocyanate. With verapamil, cleavage of the cyano group would form new chemical entities that could be pharmacologically active and serve as a source of some of the adverse reactions or side-effects reported.

Acetonitriles↗
PubMed1990

Secondary prevention with verapamil after myocardial infarction. The Danish Study Group on Verapamil in Myocardial Infarction.

The effect of verapamil on death and major events (i.e., death or reinfarction) after an acute myocardial infarction was studied in a double-blind, randomized, placebo-controlled, multicenter trial, the Danish Verapamil Infarction Trial II (DAVIT II). Eight hundred seventy-eight patients started treatment with verapamil 360 mg/day and 897 patients with placebo. Treatment continued for up to 18 months (mean 16 months). Ninety-five deaths and 146 major events occurred in the verapamil group and 119 deaths and 180 major events in the placebo group. Eighteen-month mortality rates were 11.1 and 13.8% (hazard ratio 0.80, 95% confidence limits 0.63 to 1.05, p = 0.108), and major event rates 18.0 and 21.6% (0.80, 0.64 to 0.99, p = 0.027) in the verapamil and placebo groups respectively. When combining the results of this trial with the results of the first Danish study on verapamil in myocardial infarction, the meta-analysis demonstrated that treatment with verapamil from the second week after an acute myocardial infarction resulted in a reduction of pooled odds ratios of 0.22 (95% confidence interval 0.01 to 0.37, p = 0.04) for death, 0.21 (0.05 to 0.35, p = 0.02) for major events, and 0.27 (0.06 to 0.43, p = 0.02) for first reinfarctions. It is concluded that long-term treatment with verapamil after an acute myocardial infarction is associated with a significant reduction in overall mortality as well as major event and reinfarction rates.

Cholesterol↗
PubMed1992

[Verapamil therapy improves the prognosis after acute myocardial infarction. A review over the Danish studies of verapamil therapy during and after acute myocardial infarction].

The effect of verapamil therapy in a dosage of 120 thrice daily on the mortality and re-infarction from the time of admission and for the subsequent six months was investigated in a double-blind, randomized, placebo-controlled, multicentre investigation (The Danish Verapamil Infarction Trial (DAVIT I)). Seven hundred and seventeen patients were treated with verapamil and 719 with placebo. The mortalities after six months were 12.8% in the verapamil group and 13.9% in the placebo group (NS) and re-infarction occurred in 7.0% and 8.3%, respectively (NS). The effect of verapamil on the mortality and major events, i.e. death or the first re-infarction from the second week after an acute myocardial infarction was investigated in a double-blind, randomized, placebo-controlled, multicentre investigation (DAVIT II) in which 878 patients commenced treatment with verapamil in a dosage of 360 mg daily and 897 patients received a placebo. This treatment was continued for up to 18 months, on an average for 16 months. Ninety-five patients died and 146 major events were registered in the verapamil group while 119 died and 180 major events occurred in the placebo group. The 18 months mortality rates were 11.1 and 13.8% (hazard ratio 0.80, 95% confidence limits 0.63-1.05, p = 0.11) and the major event rates were 18.0 and 21.6% (0.80, 0.64-0.99, p = 0.03) in the verapamil and placebo groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Denmark↗
PubMed1989

The relationship of dose to the antihypertensive response of verapamil-sustained release in patients with mild to moderate essential hypertension. The Verapamil-SR Study Group.

The dose-response relationship of verapamil-SR was studied in 221 hypertensive patients. This double-blind, parallel-group, placebo-controlled study compared placebo to 60 mg, 120 mg, 240 mg and 480 mg daily of verapamil-SR. After 6 weeks of therapy, peak diastolic blood pressure was similar in the placebo group and the verapamil-SR 60 mg group, 93.0 and 92.0 mmHg, respectively. The 120 mg, 240 mg and 480 mg verapamil-SR groups produced significantly lower diastolic blood pressure, 89.8, 85.3 and 83.7 mmHg (P less than 0.01), respectively. At trough, placebo and verapamil-SR 60 mg groups and 120 mg groups had diastolic blood pressures of 96.6, 97.0 and 97.1 mmHg, respectively. Diastolic blood pressure with the 240 mg dose (92.4 mmHg) was significantly lower than with the 120 mg dose (P less than 0.01). The 480 mg dose resulted in a diastolic blood pressure of 88.6 mmHg, which was significantly lower than the 240 mg dose (P less than 0.01). The responder rate with 240 mg at peak was 82%. The trough to peak ratio was 0.58. Plasma concentrations were highly correlated with dose (r greater than 0.8; P less than 0.01); but not with diastolic blood pressure (r greater than 0.4; P less than 0.01). Headache and constipation, although not significantly different from placebo, were the most commonly reported adverse reactions in the verapamil-SR groups, 6.3% (placebo--6.7%) and 5.1% (placebo--4.4%), respectively. Graded doses of verapamil-SR produced a dose-response curve in hypertensive patients with a greater than 80% responder rate at the 240 mg dose.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Pressure↗
PubMed1991

Hydrochlorothiazide and verapamil in the treatment of hypertension. The Verapamil Versus Diuretic (VERDI) Trial Research Group.

The efficacy and tolerability of hydrochlorothiazide, sustained-release verapamil, and their combination was compared in patients with mild to moderate hypertension. The design was a multicenter, randomized, double-blind clinical trial with a single-blind placebo baseline period of 2 weeks. Three hundred sixty-nine patients with a diastolic blood pressure of 95-120 mm Hg were included. Treatment consisted of 12.5 mg of hydrochlorothiazide once daily, then 25 mg once daily, and finally 25 mg twice daily; the other group received verapamil at a dose of 120 mg once daily, then 240 mg once daily, and finally 240 mg twice daily. Patients not achieving target blood pressure (less than 90 mm Hg diastolic) were given the combination of hydrochlorothiazide and verapamil, that is, 25 and 240 mg once daily and twice daily. During all time points during the study patients receiving verapamil achieved target blood pressure more often than patients receiving hydrochlorothiazide (after 8 weeks, 57.7 and 42.7%; after 24 weeks, 46.8 and 26.4%; and after 48 weeks, 44.8 and 24.7%, respectively). Adding verapamil to hydrochlorothiazide was more effective in lowering blood pressure than adding hydrochlorothiazide to verapamil. The number of treatment withdrawals was essentially the same with the two drugs. Therefore, in the doses currently used in antihypertensive treatment, verapamil was more effective than hydrochlorothiazide as a single agent and in combination in mild to moderate hypertension.

Adult↗
PubMed1991

Changes in calcium homoeostasis and bone formation in patients recovering from acute myocardial infarction: effect of verapamil treatment. Danish Study Group on Verapamil in Myocardial Infarction.

The effect of the calcium antagonist verapamil on calcium homoeostasis and bone metabolism has been investigated in a double-blind randomized placebo-controlled study. Ten patients randomized to verapamil 120 mg t.i.d. and 9 patients randomized to placebo in The Danish Verapamil Infarction Trial II took part in the study. Bone formation, estimated by 24-h whole body retention of diphosphonate (WBR), osteocalcin, alkaline phosphatase and calcium metabolic indices, was recorded before the start of medication and after 1 and 6 months of treatment. Baseline calcium metabolic variables were not significantly different between the two study groups. There were no significant differences in WBR (0.38 vs 0.37), osteocalcin level (8.2 vs 8.0 micrograms/l) or alkaline phosphatase (218 vs 200 U/l) after treatment for 6 months with verapamil compared to placebo. Serum PTH, calcium and phosphate levels were also not affected by verapamil. The results suggest that prolonged treatment with clinical doses of verapamil does not affect indices of calcium and bone metabolism in humans.

Alkaline Phosphatase↗
PubMed1990

Effect of verapamil on mortality and major events after acute myocardial infarction (the Danish Verapamil Infarction Trial II--DAVIT II)

The effect of verapamil on death and major events (i.e., death or reinfarction) after an acute myocardial infarction was studied in a double-blind, randomized, placebo-controlled multicenter trial. Eight hundred seventy-eight patients started treatment with verapamil, 360 mg/day, and 897 patients with placebo. Treatment started in the second week after admission and continued for up to 18 months (mean 16 months). Ninety-five deaths and 146 major events occurred in the verapamil group and 119 deaths and 180 major events in the placebo group. The 18-month mortality rates were 11.1 and 13.8% (p = 0.11, hazard ratio, 0.80; 95% confidence limits, 0.61 to 1.05), and major event rates 18.0 and 21.6% (p = 0.03, hazard ratio, 0.80; 95% confidence limits, 0.64 to 0.99) in the verapamil and placebo groups, respectively. In patients without heart failure in the coronary care unit the mortality rates were 7.7% in the verapamil group and 11.8% in the placebo group (p = 0.02, hazard ratio, 0.64; 95% confidence limits, 0.44 to 0.94), and major event rates 14.6 and 19.7% (p = 0.01, hazard ratio 0.70; 95% confidence limits (0.52 to 0.93). In patients with heart failure the mortality rates were 17.9 and 17.5% (p = 0.79, hazard ratio, 1.05; 95% confidence limits, 0.72 to 1.54), and major event rates 24.9 and 24.9% (p = 1.0, hazard ratio 0.98; 95% confidence limits 0.72 to 1.39). Long-term treatment with verapamil after an acute myocardial infarction caused a significant reduction in major events, and the positive effect was found in patients without heart failure.

Aged↗
PubMed1991

Treatment with verapamil after an acute myocardial infarction. Review of the Danish studies on verapamil in myocardial infarction (DAVIT I and II).

The effect of verapamil on death, reinfarctions, and major events, i.e. death or reinfarction after a myocardial infarction has been investigated in 2 Danish double-blind placebo-controlled verapamil infarction trials (DAVIT I and II). DAVIT I was an early intervention trial that demonstrated a statistically nonsignificant reduction in mortality and reinfarction after 6 months of treatment. DAVIT II was a later intervention trial that demonstrated a nonsignificant reduction in the 18-month mortality rate [p = 0.11, hazard ratio 0.80; 95% confidence limits (CL) 0.61 to 1.05], a significant reduction in the reinfarction rate (p = 0.04, hazard ratio 0.77; CL 0.58 to 1.03), and in the major event rate (p = 0.03, hazard ratio 0.80; CL 0.64 to 0.99) in the verapamil group compared with the placebo group. In patients without heart failure in the coronary care unit, a statistically significant reduction in the 18-month mortality rate (p = 0.02, hazard ratio 0.64; CL 0.44 to 0.94), the reinfarction rate (p = 0.02, hazard ratio 0.67; CL 0.46 to 0.97), and the major event rate (p = 0.01, hazard ratio 0.70; CL 0.52 to 0.93) was observed in the verapamil group compared with the placebo group. No significant differences were found in patients with heart failure. Meta-analyses of DAVIT I (for patients alive at day 8) and DAVIT II showed a statistically significant reduction in the odds ratio of mortality (22%), reinfarctions (27%), and the major event rate (21%) in verapamil-treated patients. It is concluded that long term treatment with verapamil after an acute myocardial infarction is associated with a significant reduction in overall mortality, major events, and reinfarctions, with the greatest effect in patients without heart failure.

Angina Pectoris↗
PubMed1991

Effect of verapamil on ischemia and ventricular arrhythmias after an acute myocardial infarction: prognostic implications. The Danish Verapamil Infarction Trial II Study Group.

This article is a review of presented subsets of the Danish Verapamil Infarction Trial II (DAVIT II) regarding the effect of verapamil on postinfarction ischemia, ventricular arrhythmias, and heart rate (HR), and the prognostic implications of these findings. Patients underwent Holter monitoring for 24-48 h at 1 week, i.e., before randomization to long-term treatment with placebo or verapamil, and after 1 month and about 1 year of study treatment. Ischemia: 18% of the patients had transient ST-segment deviation before randomization; 24% of the placebo- and 8% of the verapamil-treated patients (p = 0.04) showed ischemia after 1 month; and after 1 year, the figures were 26 and 4%, respectively (p = 0.02). The 18-month major event rate, i.e., first reinfarction or death, in patients with ischemia before randomization were 40 and 23.8% in patients without ischemia (p = 0.06). Arrhythmias: In the placebo group the prevalence and incidence of many ventricular ectopic beats (VEBs), i.e., more than 10 VEBs/h, increased significantly during the first years after infarction; this was not the case in the verapamil patients group. The mean HR was significantly reduced by verapamil treatment after 1 month and after 16 months of treatment. Multivariate analysis demonstrated the presence of more than 10 VEBs/h only early (i.e., 1 week) but not late (i.e., 1 month) after infarction, to be an independent predictor of major events during 18 months' follow-up observation. A HR above 80 beats/min independently predicted major events when appearing both early and late after infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1992

The significance of myocardial ischaemia and verapamil treatment on the prevalence of supraventricular tachyarrhythmias in patients recovering from acute myocardial infarction. Danish Study Group on Verapamil in Myocardial Infarction.

Twenty-four hour Holter monitoring and symptom-limited exercise testing were carried out prior to discharge in 157 patients recovering from acute myocardial infarction. Supraventricular arrhythmias (SVT) during Holter monitoring were recorded in 15%, and ST segment depression during exercise in 27%. No association between exercise-provoked ischaemia and SVT was found in the late hospital phase of myocardial infarction. After the tests, patients were double-blindly randomized to treatment with verapamil 120 mg t.i.d. or placebo. One month after randomization 24 h Holter monitoring was repeated in 125 patients (verapamil = 63, placebo = 62). At one month a significantly increased incidence of SVT was found in the placebo group (25%) compared to the verapamil-treated patients (9%) (P = 0.04). The increased prevalence in the placebo group was mainly due to an increased incidence of SVT in patients with exercise-induced ischaemia (P = 0.03). This increment was blurred in the verapamil group. In conclusion, the prevalence of SVT increases during the first month after myocardial infarction. The increase is most pronounced in patients with residual myocardial ischaemia and seemed to be prevented by treatment with verapamil.

Double-Blind Method↗
PubMed1992

Internally standardized simultaneous assay of verapamil and N-demethyl-verapamil enantiomers in human plasma by means of high performance liquid chromatography.

A high performance liquid chromatographic method with internal analog standardization for the simultaneous assay of the verapamil and N-demethyl-verapamil enantiomers in human plasma after administration of racemic verapamil is described. The method comprises extraction from alkalinized plasma into an n-hexane/2-propanol phase (95:5), separation of the optical antipodes on a chiral phase (Daicel OJ) and quantification by means of fluorescence detection. A detection limit of about 6 pmol was determined for all four enantiomers. Under routine conditions the limit of quantification (variation coefficient < 10%) was about 8 pmol for the (R)- and (S)-enantiomers. The determination method for verapamil and N-demethyl-verapamil enantiomers is not impaired by their known metabolites. The suitability of the method for clinical pharmacology studies is demonstrated with samples obtained from healthy subjects. First results of comparative kinetics studies in humans and various animal species show marked species-dependency with prevailing (R)-enantiomer levels in humans and dogs, and the opposite in rats.

Chromatography, High Pressure Liquid↗
PubMed1977

Determination of verapamil in human plasma by mass fragmentography using stable isotope-labelled verapamil as internal standard.

In the present investigation a mass fragmentographic procedure for the quantitative determination of verapamil in human plasma was developed which makes use of the principle of mass spectrometry and of isotopic dilution: a known amount of isotopically labelled standard ([13C, 2H2]-verapamil) is added to the plasma sample. After an effective extraction procedure the ratio of the main fragments of verapamil (m/e 303) and the labelled standard (m/e 306) is measured by mass fragmentography. The lower limit of detection is at 1 ng/ml for plasma and at 10 pg/injection for pure verapamil. The precision was found to be between 3.4% and 14.4%, depending on the range (32.7 ng/ml and 2.2 ng/ml, resp.) of the concentration of verapamil in plasma.

Chemical Phenomena↗
PubMed1992

Prevalence of transient myocardial ischaemia during the first year after a myocardial infarction. Effect of treatment with verapamil. The Danish Study Group on Verapamil in Myocardial Infarction.

DAVIT-II is a double-blind, randomized, multicentre, placebo-controlled study of long-term treatment with verapamil 360 mg per day administered to patients who have suffered an acute myocardial infarction (AMI). In the present study, comprising a subset of DAVIT-II, 48 h continuous ECG recordings demonstrated transient ST segment deviation indicative of myocardial ischaemia after one week, prior to randomization, in 18% (10 of 57) of the patients. After one month, 24% (11 of 46) of the placebo and 8% (3 of 39) of the verapamil-treated patients (P = 0.04) had myocardial ischaemia; after one year the figures were 26% (9 of 35) and 4% (1 of 27) (P = 0.02), respectively. At 18 months the 'major' event rate in patients who had had ischaemia before randomization was 40% and 23.8% in patients without ischaemia (P = 0.057). In the placebo group, 63% of 91 episodes of ST depression were recorded between 0600 h and 1800 h, and 62% of 26 episodes of ST elevation between 1800 h and 0600 h (P less than 0.001). Nine episodes of ST depression and no episode of ST elevation were recorded in the verapamil-treated patients. In conclusion, 20-25% of post-AMI patients have transient ischaemia; verapamil prevents ischaemia, and a pronounced circadian variation of ST segment deviations can be demonstrated.

Aged↗