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PubMed1984

[Reversal of acquired resistance to vinca alkaloids and anthracycline antibiotics by calcium channel blockers and calmodulin inhibitors].

One of the major causes of failure in cancer chemotherapy is the selection and proliferation of specific drug-resistant tumor cells during treatment. The mechanism of acquired resistance of tumor cells to some agents is related to intracellular drug accumulation and retention. For example, in vincristine (VCR)- and adriamycin (ADM)-resistant tumor cell sublines, these agents can be shown to enter the cell but are actively transported to the outside. This results in a relatively low intracellular level of drug and thus to low cytotoxicity. These observations suggest that if we could control the VCR- and ADM-efflux function of resistant tumor cells appropriately, then we could expect a reversal of acquired resistance to these drugs in drug resistant tumor cells. We found that calcium channel blockers and calmodulin inhibitors enhance the intracellular level of vincristine and adriamycin in tumor cells, especially in drug-resistant mouse and human tumor cells by inhibiting their outward transport. The approach using calcium modifiers has the following advantages. (1) Reversal of acquired resistance to vinca alkaloids and anthracyclic antibiotics can be attained. Calcium channel blockers, such as verapamil, diltiazem, nicardipine, niludipine and nimodipine, at doses of 30 to 125 mg/kg administered daily for 10 days with VCR (10-200 micrograms/mg) enhanced the chemotherapeutic effect of VCB (40-50% increase in life span) in P388/VCR-bearing mice. The calcium channel blockers also enhanced the therapeutic effect of ADM in ADM resistant P388 bearing mice. (2) The approach is also effective for the reversal of the inherent resistance of tumor cells to anticancer agents. Less sensitive tumor cells became more susceptible to VCR and the heterogeneity in drug sensitivity among tumor clones has been circumvented. (3) The approach with these calcium modifiers is also effective against other antitumor agents which are transported outside the cells by the similar mechanisms. As one of the mechanisms of cross-resistance is explained by the enhanced drug efflux from resistant tumor cells, antitumor agents which show cross-resistance to VCR and ADM become effective against resistant tumor cells by this approach. The mechanism of this approach is now under investigation. These calcium modifiers enhance the cellular level of antitumor agents by inhibiting their outward transport. The functions of cellular calcium and calmodulin in the membrane architecture and membrane functions might be involved in this process. Clinical evaluation is now under progress by using diltiazen, nicardipine and verapamil.

Animals↗
PubMed1996

Calcium channel blockers and hypertension: 1. New trials.

The long-term benefits and risks of using calcium channel blockers to treat hypertension have been called into question by reports of increased incidence of myocardial infarction and death among patients taking these drugs. There is now a worldwide effort, involving more than 30 countries and 100,000 patients, to provide a comprehensive data-base for making informed decisions.

Calcium Channel Blockers↗
PubMed1998

Amlodipine overdose causes prolonged calcium channel blocker toxicity.

Amlodipine is a relatively new agent that has the longest half-life of all calcium channel blockers. This report describes a severe overdose that resulted in prolonged and severe hemodynamic compromise for up to 10 days, but responded to aggressive therapy with calcium, glucagon, and other vasoactive medicines.

Aged↗
PubMed1992

The effect of nilvadipine, a dihydropyridine type calcium channel blocker, on local cerebral blood flow in rats.

The effect of nilvadipine, a dihydropyridine type calcium channel blocker, on local cerebral blood flow (lCBF) was investigated using the autoradiographic iodo[14C]antipyrine technique in rats. In control rats, lCBF in cortical areas and in the superior colliculus and inferior colliculus was higher than that in the hippocampus, septal nucleus, globus pallidus and substantia nigra. Nilvadipine (32 micrograms/kg, i.v.) increased lCBF in all structures (significantly in 11 of 21 structures) in spite of a 33% reduction in mean arterial blood pressure. These results confirm that nilvadipine has the ability to increase cerebral blood flow.

Animals↗
PubMed1983

The temperature-sensitivity of slow channel calcium blockers in relation to their effect upon the calcium paradox.

The isolated perfused rat heart preparation was used to investigate the interrelationship between temperature and the ability of calcium antagonists to reduce protein leakage in the calcium paradox. Exploiting the fact that although the calcium depletion phase of calcium paradox-injury is highly temperature sensitive, the calcium repletion phase, during which time the injury is manifested, is temperature independent. Verapamil (4 mumol l-1) included in a 10 min period of calcium depletion (37 degrees C) and a 20 min period of calcium repletion (37 degrees C) was known to reduce cumulative protein leakage by 22 +/- 3%. With calcium depletion again at 37 degrees C but repletion at 21 degrees C verapamil failed to achieve any reduction in protein leakage despite the fact that leakage in the 21 degrees C control group did not differ significantly from that in the 37 degrees C control group. Temperature-response studies (repletion temperature of 4, 10, 21, 23, 25, 28, 31, 34 and 37 degrees C) revealed an abrupt loss of drug effect below 25 degrees C. Studies with D600 (10 mumol l-1), nifedipine (4 mumol l-1), terodiline (4 mumol l-1) fendiline (20 mumol l-1) and diltiazem (2 mumol l-1) revealed that while all of these drugs reduced protein leakage at 37 degrees C (24 +/- 3%, 31 +/- 2%, 31 +/- 3%, 23 +/- 3% and 29 +/- 3%, respectively), like verapamil they had no effect at 21 degrees C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Effects of intrathecal L- and N-type calcium channel blockers on the antinociception evoked by opioid agonists in the rat tail flick test.

The effects of intrathecal administration of nimodipine or omega-conotoxin GVIA (L- and N-type calcium channel blockers, respectively) alone or followed by DAMGO, DADLE or bremazocine (mu-, delta- and kappa-opioid agonists, respectively) were studied on the rat tail flick test. The N- (16 to 64 pmoles), but not the L-type blocker (60 to 240 pmoles) produced a dose and time-dependent increase in the latency for the tail-flick reflex. DAMGO (30 to 120 pmoles) or bremazocine (190 to 560 pmoles), but not DADLE (50 to 200 pmoles), produced a dose-dependent increase in the latency for the tail-flick reflex. The effect of the highest dose of DAMGO was smaller, while the effects of DADLE and bremazocine were not changed after nimodipine (60 pmoles). The effects of DADLE were significantly potentiated, while the effects of DAMGO and bremazocine were not changed after omega-conotoxin GVIA (16 pmoles). The intrathecal administration of an N-type calcium channel blocker with a delta-opioid agonist seems to be the most effective combination to produce antinociception in the rat tail flick test.

Analgesics↗
PubMedDate not supplied

[The effect of calcium channel blockers on animal behavior in tests to study their anxiolytic activity].

The anxiolytic activity of calcium channel blockers (verapamil, nifedipine, cinnarizine, fendiline, and diltiazem) versus diazepam (relanium) was tested in experiments on male [correction of female] mice. Only verapamil (1 mg/kg) and nifedipine (5 mg/kg) were found to increase the number of transitions and reduced the animals' stay in the dark compartment. All the agents in the used doses failed to substantially affect the animals' behavior in the plus-maze. It is suggested that conditions for modelling pathological anxiety rather than natural states are required in the experiments where antianxiety properties are studied. The model of pathological anxiety states is possible in the examination of the action of agents on the effects of routine anxiogenic agents.

Animals↗
PubMedDate not supplied

The costs and effects of switching calcium channel blockers: evidence from Medicaid claims data.

This study used Medicaid claims data from Pennsylvania to examine the costs and effects of changing calcium channel blocker therapies. Specifically, we compared Procardia XL with Adalat CC. They are the only once-daily-dosed, extended-release forms of nifedipine available. These drugs were interesting to compare for several reasons. First, because the frequency of treatment regimens has been shown to be the most important determinant of long-term compliance with calcium channel blocker medications, it was desirable to compare drugs having identical dosing regimens. Second, switching from one to the other should be quite feasible in most patients. Third, Adalat CC is priced (ie, average wholesale price) less than Procardia XL. The results indicate that prescription prices were lower when patients were switched from Procardia XL to Adalat CC, with no apparent effects on blood pressure control, the incidence of adverse drug reactions, or nonprescription health care costs. The potential savings to Medicaid from switching patients from Procardia XL to Adalat CC appears to be large, more than $2.5 million annually for Procardia XL-treated Medicaid patients in the state of Pennsylvania. Our study also demonstrates that large retrospective databases can be used to evaluate economic and clinical outcomes for specific therapy alternatives. Such evaluations are increasingly relevant to third-party payers, health maintenance organizations, and other parties involved in managed care.

Cohort Studies↗
PubMed1995

Calcium channel blockers for heart rate control in atrial fibrillation complicated by congestive heart failure.

OBJECTIVES: To review the safety and efficacy of verapamil and diltiazem with respect to ventricular response in atrial fibrillation (AF) in the setting of left ventricular (LV) systolic dysfunction. DATA SOURCES: Pertinent articles were identified through a MEDLINE search of the English language literature from 1984 to 1993, followed by a manual search of the bibliographies of pertinent articles. STUDY SELECTION: Studies selected were case reports, controlled trials, review articles and editorials. DATA EXTRACTION: Effects of verapamil and diltiazem on hemodynamics, ventricular response in AF, clinical parameters and mortality were reviewed. DATA SYNTHESIS: There are limited data about the effects of verapamil and diltiazem on ventricular function in patients with congestive heart failure. In vitro diltiazem has fewer negative inotropic effects than verapamil. Clinically there are some reports of hemodynamic and clinical deterioration in patients with significant LV dysfunction given verapamil although most patients improve with verapamil. There are more data concerning diltiazem in the setting of AF complicated by congestive heart failure. The drug does not appear to exacerbate heart failure, although hypotension can result. In chronic AF complicated by heart failure, there is concern that diltiazem may increase mortality. Options for therapy are digoxin, beta-blockers and atrioventricular node ablation. CONCLUSIONS: Calcium channel blockers may have a role in the acute reduction of ventricular response in patients with AF complicated by congestive heart failure; however, their safety in chronic heart rate control remains to be proven.

Atrial Fibrillation↗
PubMed1991

Effects of TA-3090, a new calcium channel blocker, on myocardial substrate utilization in ischemic and nonischemic isolated working fatty acid-perfused rat hearts.

Experimental studies have shown that calcium channel blockade has a protective effect on the ischemic myocardium. Although these agents may act by decreasing intracellular Ca2+ accumulation during reperfusion or to reduce oxygen requirements by decreasing myocardial work load, recent evidence suggests that calcium blockers may also favorably alter energy substrate metabolism in ischemic and reperfused myocardium. In this study, TA-3090, a new calcium channel blocker with minimal effect on myocardial work load, was used to study the effect of calcium channel blockade on both myocardial substrate utilization and reperfusion recovery of ischemic hearts. Isolated working rat hearts were perfused at an 11.5 mm Hg preload and an 80 mm Hg afterload with Krebs-Henseleit buffer containing 11 mM glucose, 1.2 mM palmitate, and 500 microunits/ml insulin. In aerobically perfused spontaneously beating hearts, a 0.5 microM dose of TA-3090 had a mild depressant effect on heart rate but no effect on peak systolic pressure development. In paced hearts (250 beats/min), 0.5 microM TA-3090 had no effect on either peak systolic pressure development or contractility. Fatty acid and glucose oxidation was determined by measuring 14CO2 production in hearts perfused with either [14C]palmitate or [14C]glucose, respectively, whereas glycolysis was determined by measuring 3H2O production from [3H]glucose. Under aerobic conditions, fatty acid oxidation was not altered by TA-3090, but a significant decrease in glucose oxidation and glycolytic rates was observed. If hearts were subjected to a 30-minute period of no-flow ischemia, the addition of 0.5 microM TA-3090 to the perfusate before ischemia significantly improved reperfusion recovery of mechanical function. The protective effects of TA-3090 were not observed if TA-3090 was added at the time of reperfusion and were not related to a depression of function before ischemia. TA-3090, added before ischemia, significantly reduced glycogen and ATP depletion during no-flow ischemia and also significantly decreased glycolytic rates in hearts subjected to low-flow ischemia (coronary flow = 0.5 ml/min). Combined, our data suggest that the beneficial effects of calcium channel blockade on the ischemic myocardium are not related solely to a decrease in myocardial work load or metabolic demand before ischemia, but rather may in part be related to a decrease in myocardial energy demand during ischemia itself, resulting in preservation of ATP and a decrease in glycolysis. The decrease in glycolytic rates during ischemia may also result in a reduction of glycolytic product accumulation during ischemia.

Aerobiosis↗
PubMed1990

Interactions between analgesics and calcium channel blockers.

1. The findings, derived from different experimental models, examined in this review, provide evidence that the calcium channel blockers and related drugs possess analgesic effects. 2. The antinociceptive action that some analgesic drugs exhibit may be related to calcium channel blockade. 3. Evidence from a variety of biochemical and pharmacological experimental approaches, support the existence of an interelation between the calcium modulators and the opioid drugs. 4. This idea agrees with the novel neuropharmacological hypothesis that a common very high affinity binding site for multiple neurotransmitters could exist, as has been proposed by Pasternak and Wood (1986). 5. This hypothesis could be extended to the neuromodulators or other neuromediators.

Analgesics↗
PubMed1994

Calcium channel blockers in kidney transplantation.

PURPOSE: To review the question as to whether treatment with a calcium channel blocker (CCB) influences the course and outcome of cadaveric renal transplantation in recipients treated with cyclosporin A. METHODS: Computer-assisted search (Medline) and manual search of the literature. Odds ratio, Mantel-Haenszel test, Fischer's test and Chi 2 test. RESULTS: Two Randomised, placebo-controlled studies, 12 randomised, open studies, 3 retrospective studies, 1 study using a historic control group and 3 studies only reported in abstract form were identified. In the randomised, open studies treatment with CCB reduced the rate of delayed graft function but had no effect on the rate of rejection and graft survival. The effect on graft function was equivocal. In the blind, placebo-controlled studies no beneficial effects of treatment with CCB were found. Treatment with CCB reduced the dose of CyA needed to reach target whole blood level of CyA in nearly all studies. CONCLUSION: Results are conflicting. Further studies are needed.

Cadaver↗
PubMedDate not supplied

Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine.

The efficacy of dihydropyridine calcium channel blockers for treating hypertension appears to be similar, but a variety of factors, including patient characteristics, tolerability and pharmacokinetic properties, may influence treatment adherence and outcome. We aimed to evaluate treatment adherence in clinical practice among older hypertensive adults (50+ years) prescribed amlodipine or felodipine for the first time as part of the California Medicaid (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design. Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue study treatment than those prescribed felodipine. Discontinuation tended to occur early, with 20% and 30% of amlodipine and felodipine patients, respectively, discontinuing treatment after one prescription. A non-significant difference in favour of amlodipine was demonstrated for anti-anginal medication use among patients taking these drugs at baseline. This study suggests that use of amlodipine may be associated with improved adherence, compared with felodipine, among older out-patients in the Medi-Cal program.

Aged↗
PubMed1993

Pharmacokinetic evaluation of drug interactions with anti-human immunodeficiency virus drugs. VI. Effect of the calcium channel blocker nimodipine on zidovudine kinetics in monkeys.

Coadministration of zidovudine (AZT) and nimodipine, a calcium-channel blocker, is a potential therapeutic regimen in acquired immunodeficiency syndrome patients based on the report that nimodipine can prevent human immunodeficiency virus-induced neurotoxicity in vitro. An evaluation of the pharmacokinetics of AZT and its glucuronide metabolite 3'-azido-3'-deoxy-5'-O-beta-D-glucopyranurosylthymidine (GAZT) in the presence and absence of nimodipine in monkeys was undertaken. After 20 mg/kg of AZT given i.v. in the presence and absence of nimodipine, nimodipine caused a significant reduction (41%) in the volume of distribution of AZT at steady state and a 22% decrease in total clearance. The disposition of GAZT was also influenced by nimodipine, causing a large increase in its area under the plasma concentration-time curve. Renal excretion data for AZT and GAZT, although inconclusive, suggested nimodipine caused a decrease in the renal clearance of AZT with a minimal change in the renal clearance of GAZT. The combined effects of nimodipine on the clearance of AZT and volume of distribution at steady state produced no change in its elimination half-life.

Animals↗
PubMedDate not supplied

Cardiovascular effects of OPC-13340, a potent, long-acting 1,4-dihydropyridine calcium channel blocker, in dogs.

The cardiovascular effects of OPC-13340, a newly developed 1,4-dihydropyridine calcium channel blocker, were examined in several canine preparations. In conscious normotensive and DOCA-salt hypertensive dogs, OPC-13340, at doses of 10 to 30 micrograms/kg, i.v., and 0.3 to 3 mg/kg, p.o., exerted an hypotensive action in a dose-dependent manner. The hypotensive action of OPC-13340 was longer lasting and more potent than that of nicardipine and nifedipine. In conscious, normotensive instrumented dogs, OPC-13340, at doses of 1 and 3 mg/kg, p.o., dose-dependently decreased total peripheral resistance and mean blood pressure and increased heart rate, cardiac output and left ventricular contractility. In anesthetized open-chest dogs, OPC-13340, at doses of 1 to 30 micrograms/kg, i.v., increased coronary blood flow and decreased mean blood pressure, heart rate, coronary vascular resistance, arteriovenous oxygen difference and myocardial oxygen consumption. In contrast to OPC-13340, nicardipine did not change the myocardial oxygen consumption. From these results it was concluded that OPC-13340 lowered blood pressure and improved coronary circulation in dogs and that the duration of these actions was longer lasting than that of nifedipine and nicardipine. These actions of OPC-13340 may be useful in the treatment of hypertension and angina pectoris.

Anesthesia↗
PubMed1991

Multiattribute evaluation in formulary decision making as applied to calcium-channel blockers.

The use of multiattribute utility theory (MAUT) to make a formulary decision involving calcium-channel blockers (CCBs) is described. The MAUT method is a procedure for identifying, characterizing, and comparing the many variables that may affect a decision. Although applications in pharmacy have been infrequent, MAUT should be particularly appealing to formulary committees. The steps of the MAUT method are (1) determine the viewpoint of the decision makers, (2) identify the decision alternatives, (3) identify the attributes to be evaluated, (4) identify the factors to be used in evaluating the attributes, (5) establish a utility scale for scoring each factor, (6) transform the values for each factor to its utility scale, (7) determine weights for each attribute and factor, (8) calculate the total utility score for each decision alternative, (9) determine which decision alternative has the greatest total score, and (10) perform a sensitivity analysis. The viewpoint of a formulary committee in a health maintenance organization was simulated to develop a model for using the MAUT method to compare CCBs for single-agent therapy of chronic stable angina in ambulatory patients for one year. The attributes chosen were effectiveness, safety, patient acceptance, and cost and weighted 36%, 29%, 21%, and 14%, respectively, as contributions to the evaluation. The rank order of the decision alternatives was (1) generic verapamil, (2) brand-name verapamil, (3) diltiazem, (4) nicardipine, and (5) nifedipine. The MAUT method provides a standardized yet flexible format for comparing and selecting among formulary alternatives.

Calcium Channel Blockers↗
PubMed1987

Comparative effects of some calcium-channel blockers on human peripheral arteries and veins.

We investigated the effects of five different calcium-channel blockers (CCBs), verapamil, nifedipine, diltiazem, flunarizine and lidoflazine, on contractions evoked in vitro by noradrenaline (NA) in small human arteries and veins from the epigastric region. Vessels were obtained from patients without obvious vascular diseases undergoing surgery because of inguinal hernias. The human superficial epigastric artery has previously been shown to contain mainly alpha 1-adrenoceptors, whereas in the vein alpha 2-adrenoceptors predominate. In experiments where NA (10(-5) M) was added non-cumulatively, it was found that nifedipine was the most potent relaxant agent in both arteries and veins, but that this drug showed no preference for any type of vessel. In contrast verapamil (10(-6) M) and (10(-5) M) diltiazem, flunarizine and lidoflazine inhibited the NA-induced contractions to a significantly greater extent in the arteries than in the veins. Comparison between diltiazem and nifedipine on contractions induced by cumulative addition to NA showed that both drugs had significantly more depressive effects on arteries than on veins if the vessels were contracted by relatively high concentrations of NA (10(-6) and 10(-5) M). The results thus confirm the clinical finding that CCBs have more pronounced effects on the arterial than on the venous side of the circulation. They do not support the view that CCBs are more effective inhibitors of alpha 2- than alpha 1-adrenoceptor mediated contraction in isolated human blood vessels.

Adult↗
PubMed2002

Effects of the long-acting calcium channel blocker barnidipine hydrochloride on 24-h ambulatory blood pressure.

The effect of the long acting calcium channel blocker, barnidipine hydrochloride (barnidipine) on 24-h ambulatory blood pressure (ABP) was evaluated in J-MUBA (Japanese Multicentre Study on Barnidipine with Ambulatory Blood Pressure Monitoring). Following an observation period of two weeks, antihypertensive treatment with barnidipine was continued for at least six months. At the end of each period, ABP were measured. The patients were divided into high- and low-range groups based on ABP measurement. Throughout the 24 h, barnidipine exerted an excellent antihypertensive effect in the high-range group, but not in the low-range group. Barnidipine had comparable effects in the daytime and nighttime in inverted dippers and non-dippers, but it was more effective on daytime ABP than on nighttime ABP in dippers and in extreme dippers. Morning blood pressure before and after waking was evaluated before and after barnidipine administration in 233 patients. Barnidipine inhibited increases in blood pressure before and after waking, especially in surge-type patients whose blood pressure increased rapidly after waking. A positive correlation among 24-h ABP, daytime and night time ABP, morning blood pressure, and clinic blood pressure during the observation period and the antihypertensive effect of barnidipine was observed, with barnidipine exhibiting stronger antihypertensive effects in patients with persistently high blood pressure. It was concluded that the antihypertensive effects of barnidipine are maintained for 24 h but it has no excessive hypotensive effects on lower blood pressure and is thus a safe antihypertensive agent.

Blood Pressure↗