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PubMed1984

Calcium channel blocker enhancement of anticancer drug cytotoxicity--a review.

A review of the pharmacological background and clinical activity of different Ca2+ channel blockers concerning reversal of anticancer drug resistance in tumors suggests that verapamil and trifluoperazine may be the most immediate candidates. Reversal of resistance to anthracyclines and vinca alkaloids originally observed in mouse experimental leukemia cell lines has now been extended to other animal cell lines and human tumors as well. Evidence is available that resistance to drugs of other classes such as dactinomycin, etoposide, and mitoxantrone can be reversed by various calcium channel blockers. Apart from enhancing retention of anticancer drugs in tumor cells, little is actually known of the mechanism(s) by which this phenomenon occurs. There is inconclusive evidence for the role of Ca2+ ions and Ca2+ channel receptors in the process, and, furthermore, there is no evidence that Ca2+ channel blocking activity per se is necessary for the reversal of drug resistance.

Animals↗
PubMedDate not supplied

Clinical evaluation of marginal parodontium condition in patients after kidney graft treated with calcineurine inhibitors and calcium channel blockers.

Renal transplantation is a method of treating the chronic renal failure. Gingival overgrowth is a common side effect of immunosuppressive treatment with cyclosporine A. Calcium channel blockers also cause gingival overgrowth or intensify it. Tacrolimus is a new inhibitor of calcineurine used as an alternative to cyclosporine A. 124 patients were treated with cyclosporine A, and 38 patients were given tacrolimus. At the same time, patients were given calcium channel blockers. Impact of age, sex, calcineurine inhibitors dosage, sort of calcium channel blocker used as well as treatment duration on gingival overgrowth were studied. Also, periodontal status: oral cavity hygiene, gingivitis degree as well as extent and level of gingival overgrowth were evaluated. Gingival overgrowth of different degree was present in 58 patients (46.7%) treated with CsA and in none of the patients treated with tacrolimus. Hygiene and inflammation indices were significantly higher in the group of patients with gingival overgrowth as compared to the group without gingival overgrowth treated with CsA. In the group of patients treated with tacrolimus, these indices were the lowest, and the gingivae were sort of shrunk and paler. Patients with risk factors in gingival overgrowth and patients with severe overgrowth should be converted to tacrolimus treatment.

Adult↗
PubMed1992

OPC-13340, a new dihydropyridine calcium channel blocker attenuates rapid vascular smooth muscle cell growth in spontaneously hypertensive rats.

We investigated the mechanism of the antimitotic effects of calcium channel blockers in vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR). VSMC from SHR exhibited rapid proliferation through a quick transition from the G0/G1 to the DNA synthetic (S) phase and from the S to the G2/mitotic (M) phase, whereas the DNA synthetic rate itself was equal to that of Wistar-Kyoto rats (WKY). OPC-13340, a new dihydropyridine calcium channel blocker, dose-dependently decreased incorporation of [3H]thymidine into the DNA fragments in randomly cycling VSMC in SHR. Cell cycle analysis showed that the rapid transition from the S to the G2/M period was restored by OPC-13340 to the control level in WKY, whereas the quick transition from G0/G1 to S was unaffected. This antimitotic effect of OPC-13340 was reflected by attenuation of enhanced cellular protein synthesis during the G2/M period. Protein synthesis in the G0/G1 period was not influenced by OPC-13340. Thus, these data indicate that the calcium channel blocker OPC-13340 mitigates the enhanced proliferation observed in randomly cycling VSMC from SHR and that this effect is primarily due to normalization of the premature mitosis during the G2/M period.

Animals↗
PubMed2001

Effects of calcium channel blockers on pentylenetetrazol drug discrimination in rats.

The effects of the dihydropyridine L-type calcium channel blockers nitrendipine and nimodipine on the pentylenetetrazol (PTZ) drug discrimination, an operant model of anxiety, were investigated. Male Long-Evans rats were trained to discriminate PTZ (16 mg/kg, i.p.) from saline. Both nitrendipine (5.0-25 mg/kg, i.p.) and nimodipine (5.0-25 mg/kg, i.p.) partially substituted for the PTZ discriminative stimulus. However, pretreatment with nitrendipine (25 mg/kg, i.p.) or nimodipine (25 mg/kg, i.p.) produced no change in the PTZ dose-effect function. Rats were given a nutritionally balanced liquid diet containing 6.5% ethanol for 10 days. Rats selected the PTZ drug lever during withdrawal. Subchronic coadministration of nitrendipine (1.25-5.0 mg/kg, i.p., b.i.d.) with ethanol failed to dose-dependently reduce PTZ-lever responding, but it did reverse withdrawal signs. Acute administration of nitrendipine (5, 10, and 20 mg/kg, i.p.) produced marked suppression of lever responding, but it failed to significantly reduce levels of PTZ-lever responding. Although calcium channel blockers reduce signs of ethanol withdrawal, they also markedly reduce rates of behavior and produce no clear effects on anxiety-like behaviors induced by ethanol withdrawal.

Animals↗
PubMed1997

Binding and distribution of three prototype calcium channel blockers in perfused rat liver.

This work represents a study of the binding and distribution of three different calcium channel blockers in the Sprague-Dawley rat liver, using an in situ perfusion technique. For this purpose, [3H] desmethoxyverapamil, [3H] PN200-110 (isradipine) and [3H] azidopine were used as binding probes interacting with calcium channels. The perfusion steps of the liver involved both portal vein and thoracic inferior vena cava cannulations as inlet and outlet respectively. The subhepatic inferior vena cava was ligated to prevent leakage of the perfusate. Buffer, containing the tracer drug, was administered via the portal vein at a rate of 1 mL/min and perfusate collected at the same rate within specified time intervals during 50 min. The concentration of the tracer solutes in the perfusate's outlet increased with time, and steady state was observed for all tracers at > or = 40 min. The effect of adding cold isradipine to tracer desmethoxyverapamil, or cold verapamil to tracer PN200-110 were also assessed. First order rate constants for hepatocellular influx, efflux and calcium channel binding of the tracer substances were obtained using a simplified model from Goresky et al. These constants were mathematically manipulated and changed into permeability constants, second order binding constants, and residency times. Tracer solute influx across hepatocellular membranes is solubility-diffusion controlled, is inversely related to the molecular weights and is different in value from the efflux constants. Cold isradipine reduced the binding constant of desmethoxyverapamil by 36%, while cold verapamil reduced the binding constant of PN200-110 by 23%. Azidopine cellular distribution was low, however, binding to its receptor was analogous to desmethoxyverapamil and PN200-110. Moreover, PN200-110 had the highest residency time with no effect of cold verapamil on its receptor binding, while desmethoxyverapamil had the lowest residency time which significantly increased in the presence of cold isradipine.

Animals↗
PubMed2003

Endothelium, atherosclerosis and calcium channel blockers.

Probably the most significant advance in cardiovascular medicine over the last two decades has been the identification of endothelial cells as a vasoactive organ. The endothelium plays a primary autocrine/paracrine regulatory role by secreting substances that control both vascular tone and structure. The dysfunctioning endothelium, which is characteristic of essential hypertension and most of the cardiovascular risk factors, is a major promoter for atherothrombosis and, consequently, cardiovascular treatment. One of most relevant mechanisms of endothelial dysfunction is oxidative stress production, which causes nitric oxide breakdown. The clinical manifestations of atherosclerosis are by far the prevailing cause of morbidity and mortality in hypertensive patients. Various clinical studies have shown the beneficial effects of calcium channel blockers on endothelial dysfunction. The potential mechanism by which calcium channel antagonists could exert their beneficial activity on endothelial dysfunction is very unlikely to be a calcium-dependent mechanism since endothelial cells do not express voltage-operated calcium channels. Experimental evidence suggests that calcium channel antagonists exert an anti-oxidant effect and therefore could protect endothelial cells against free-radical injury. Nifedipine is the calcium channel blocker, which improves endothelial nitric oxide availability, antagonises endothelin 1, restores endothelial permeability and low-density lipoprotein deposition. Calcium antagonists have demonstrated anti-atherogenic properties in various dinical studies. Calcium antagonists--in addition to their primary action in lowering blood pressure influence numerous cellular process involved in early atherogenesis. All calcium channel blockers do not offer same benefit of reversal of endothelial dysfunction. Amlodipine does not seem to be as effective as nifedipine in terms of atheroprotection. With nifedipine, the overall risk of cardiovascular events decreased significantly. Therefore, nifedipine (long-acting formulation) remains the first choice calcium channel blocker in cardiovascular therapeutics--today and tomorrow.

Antihypertensive Agents↗
PubMed1983

Interaction of verapamil and other calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors.

To determine the specificity of the previously demonstrated competition of verapamil with radioligand binding to alpha-adrenergic receptors, we examined the interaction of calcium channel blockers with alpha 1- and alpha 2-adrenergic receptors on several tissues. Verapamil competed for [3H] prazosin binding to alpha 1-adrenergic receptors and for [3H]yohimbine binding to alpha 2-adrenergic receptors in several tissues (human platelets, rat kidney and heart, and cultured muscle cells) with dissociation constants of 0.6-6 microM. The calcium channel blockers D600, D591, fendiline, and prenylamine--which are structural analogues of verapamil--also competed for [3H]yohimbine binding to human platelets. Two other calcium channel blockers, diltiazem and nifedipine, did not compete for [3H] yohimbine binding to human platelets or [3H]prazosin binding to membranes prepared from rat ventricles. We used [3H]nitrendipine binding to identify putative calcium channels on rat myocardial membranes. Nifedipine and verapamil blocked these [3H]nitrendipine-binding sites on ventricular membranes, but epinephrine and prazosin did not, indicating that the ventricular alpha 1 receptors and calcium channels are distinct. We found no specific [3H]nitrendipine binding to human platelets. We conclude that the interaction of verapamil with alpha-adrenergic receptors is not receptor subtype or tissue specific, that interaction with alpha-adrenergic receptors is not a property of all calcium channel blockers, and that the interaction of verapamil with alpha-adrenergic receptors and its interaction with calcium channels occur at at least two distinct sites.

Animals↗
PubMed1992

Effects of calcium channel blockers on formalin-induced nociception and inflammation in rats.

The possible anti-inflammatory and antinociceptive effects of nitrendipine, nicardipine, diltiazem and verapamil were examined with formalin test in the rat paw. Pretreatment with these calcium channel blockers 1 h before formalin injection diminished formalin-induced inflammatory changes and nociceptive responses. Formalin-induced nociceptive responses were inhibited 20-90% by the calcium channel blockers. Nitrendipine and nicardipine were found to be highly effective in inhibiting the inflammatory changes, whereas the effects of verapamil and diltiazem were partial. Administration of naloxone affected neither the inflammatory changes and nociceptive responses induced by formalin nor the antiinflammatory and antinociceptive effects of the calcium channel blockers. The results suggest the possible anti-inflammatory and naloxone-insensitive antinociceptive properties of calcium channel blockers.

Analgesics↗
PubMedDate not supplied

When lithium does not help: the use of anticonvulsants and calcium channel blockers in the treatment of bipolar disorder in the older person.

Although anticonvulsant agents and calcium channel blockers do not have any clear advantages over lithium, they do offer patients who cannot (or will not) take lithium another treatment option. It is not yet clear from the literature who will respond best to which drug or combination of drugs. The nurse should be supportive to the patients and family, in what may be a drawn out process, to find the best treatment. Optimism is justified because a lack of response to one drug is not indicative of nonresponse to other drugs. It is important to actively treat bipolar disorder because each episode of mania increases the risk of progression of the illness, with increasingly severe episodes occurring closer together. Bipolar disorder has high social costs (legal, financial, and relationship problems) that make improvements in treatment important for the patient and society. Anticonvulsant agents and calcium channel blockers may also be useful in treating depression. The number of people whose depressive symptoms respond is far less (25% to 30%) than the number who respond to the anti-manic effects, but this is an option when antidepressants and electroconvulsive therapy are not effective.

Age Factors↗
PubMed2001

Influence of chronic treatment of rats with isoprenaline and calcium channel blockers on response of isolated right ventricle to noradrenaline.

Influence of chronic treatment of rats with and calcium channel blockers (CCBs) and isoprenaline (ISP) on responses to noradrenaline (NA) was investigated on electrically--driven isolated right ventricle preparations. The ventricles were obtained from animals treated with chronic ISP or CCBs alone and chronic nifedipine, verapamil, diltiazem or nimodipine plus chronic ISP. A decreased response to NA as evidenced by an increase in EC50 for contraction which was observed in chronic ISP- treated preparations may be due to development of desensitisation (down-regulation) of beta-adrenoceptors. In chronic CCB-treated preparations there was a significant decrease in the EC50 of NA and decreased contractile response suggesting an increase in the beta-adrenoceptors and decreased availability of calcium, respectively. In chronic CCBs + ISP treated preparations further decreases in the EC50 values were observed suggesting that the voltage gated L-type Ca2+ channels may be affected directly or indirectly by change in beta-adrenoceptor activity. By the above results a proposed mechanism of interrelationship of beta-adrenoceptors with voltage gated L-type calcium channels in cardiac muscle is supported.

Animals↗
PubMed2003

The L-type calcium channel blocker nimodipine mitigates "learned helplessness" in rats.

We assessed the effect of nimodipine, an L-type calcium channel blocker, on the escape deficit induced by prior exposure to inescapable shock in rats in four experiments. In Experiment 1, we injected rats at each of three time points (i.e., before shock exposure, after shock exposure, and before shuttle escape testing) with one of four doses of nimodipine (0, 0.5, 2.5, 5.0 mg/kg). The 5.0-mg/kg dose was most effective, acting to reduce shuttle escape latencies of inescapably shocked rats to a level comparable with nonshocked controls. No benefit occurred in Experiment 2, however, when nimodipine was administered at only one of the three time points used in the first experiment. Moreover, escape performance did not improve when rats received injections of nimodipine on the 2 days prior the experiment, and then one additional injection at one of the three time points identified above in Experiment 3. Finally, administration of nimodipine at two of the three time points did improve escape responding, but only when injected immediately prior both to shock exposure and the shuttle escape test.

Animals↗
PubMed1991

The devapamil-binding site of the purified skeletal muscle receptor for organic-calcium channel blockers is modulated by micromolar and millimolar concentrations of Ca2+.

The interaction of 2,7-dimethyl-3-(3,4-dimethoxyphenyl)-3-cyan-7-aza-9-(3- methoxyphenyl) nonahydrochloride (devapamil), a stereospecific analog of (3-[2-(3,4-dimethoxyphenyl)ethyl]- methylaminopropyl-3,4-dimethoxy-(1-methylethyl)benzeneacetonitr ile (verapamil), with the purified skeletal muscle receptor for calcium channel blockers (CaCB) was studied at 4 degrees C and 30 degrees C in the absence and presence of calcium. The purified CaCB receptor bound 0.9 mol devapamil/mol calcium-channel alpha 1 subunit, with an apparent Kd of 13 +/- 2.6 nM at 4 degrees C in the presence of 0.4 microM Ca2+. The affinity, and not the density, of the devapamil-binding site was decreased by lowering the pH from 8.5-6.5, or by increasing the Ca2+ concentration from 0.4 microM to 100 mM. The same results were obtained at 30 degrees C, although the ligand-receptor complex was not stable at Ca2+ concentrations below 10 microM. These binding data were confirmed by kinetic experiments. The rate constants calculated for a pseudo-first-order and a second-order reactions were identical and yielded fourfold lower k-1/k+1 (KD) values than the equilibrium experiments performed using 1 nM and 0.4 microM Ca2+, but the same values using 1 mM Ca2+. 1 mM Ca2+ increased the k-1/k+1 (KD) by decreasing 10-fold the association rate at 4 degrees C. The dissociation rate was increased about 10-fold by 5 microM devapamil or 100 microM D-cis-diltiazem, suggesting that the high affinity site is negatively regulated allosterically by millimolar Ca2+ concentrations and by the occupation of a second low-affinity site. Incubation of the CaCB receptors in the absence of Ca2+ and devapamil at 30 degrees C, but not at 4 degrees C, resulted in an apparent loss of devapamil-binding sites. The decrease in binding sites was caused by a reduced affinity. This apparent loss of binding sites was prevented by the addition of Ca2+ with an apparent median effective concentration of 0.4 microM. The apparent half-maximal inactivation times of the devapamil-binding site were 90 s and 12 min in the presence of 1 nM and 0.4 microM Ca2+, respectively. These results show that micromolar Ca2+ concentrations stabilize the CaCB receptor in a conformation which allows high-affinity binding of phenylalkylamines. Millimolar Ca2+ concentrations induce a low-affinity state of the devapamil-binding site on a stable CaCB receptor.

Animals↗
PubMed2005

Pharmacokinetic interactions between indinavir plus ritonavir and calcium channel blockers.

BACKGROUND: Hypertension is an important modifiable cardiac risk factor in human immunodeficiency virus (HIV)-infected patients. Calcium channel blockers are substrates of cytochrome P450 3A and are commonly prescribed for hypertension. We evaluated potential bidirectional pharmacokinetic interactions between calcium channel blockers and coadministered indinavir and ritonavir. METHODS: Healthy HIV- seronegative subjects received 120 mg diltiazem daily or 5 mg amlodipine daily for days 1 to 7 and 20 to 26. All subjects received 100 mg ritonavir and 800 mg indinavir every 12 hours on days 8 to 26. Twenty-four-hour pharmacokinetic collection was performed on days 7 and 26, with 12-hour collection on day 19. RESULTS: Indinavir plus ritonavir increased the median amlodipine area under the curve from 0 to 24 hours (AUC) by 89.8%, from 122 to 230 ng.h/mL (n = 18, P < .0001), and increased the median diltiazem AUC by 26.5%, from 800 to 1060 ng.h/mL (n = 13, P = .06). Of 13 subjects, 2 (15%) had greater than 4-fold increases in diltiazem AUC. Desacetyldiltiazem AUC increased by 102.2% (P = .001), and desmethyldiltiazem AUC decreased by 27.4% (P = .01). Neither amlodipine nor diltiazem affected steady-state AUCs of the protease inhibitors. No serious cardiovascular adverse effects were observed. CONCLUSIONS: Indinavir plus ritonavir increases the AUCs of both amlodipine and diltiazem, which may result in an increased response. If coadministration is indicated, amlodipine or diltiazem should be initiated at low doses with careful titration to response and side effects.

Adolescent↗
PubMed2000

Diltiazem, nifedipine, nimodipine or verapamil for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) is a potentially disfiguring movement disorder of the orofacial region often caused by use of neuroleptic drugs. A wide range of strategies have been used to help manage TD and, for those who are unable to have their antipsychotic medication stopped or substantially changed, the calcium-channel blocking group of drugs (diltiazem, nifedipine, nimodipine, verapamil) has been suggested as a useful adjunctive treatment. OBJECTIVES: To determine the clinical efficacy of calcium-channel blockers in people with neuroleptic-induced tardive dyskinesia (TD) and schizophrenia or other chronic mental illnesses. SEARCH STRATEGY: Electronic searches of Biological Abstracts (1982-1995), Cochrane Schizophrenia Group's Register of trials (1995), EMBASE (1980-1995), LILACS (1982-1996), MEDLINE (1966-1995), PsycLIT (1974-1995), and SCISEARCH were undertaken. References of all identified studies were searched for further trial citations. Principal authors of trials were contacted. SELECTION CRITERIA: The inclusion criteria for all relevant randomised studies were that they should focus on people with schizophrenia or other chronic mental illnesses, with neuroleptic-induced TD and compare the use of calcium-channel blockers to placebo or no intervention. DATA COLLECTION AND ANALYSIS: No data could be extracted from the two randomised controlled trials that are currently awaiting assessment. The authors have been contacted to provide the relevant information. MAIN RESULTS: No studies met the entry criteria. No data were synthesized. REVIEWER'S CONCLUSIONS: Based on currently available information, no confident statement can be made about the effectiveness of calcium-channel blockers for treating people with neuroleptic-induced tardive dyskinesia. Before evaluation of these drugs in larger randomised controlled trials, clinicians should carefully weigh up their possible benefits against their potential adverse effects.

Antipsychotic Agents↗
PubMed2004

Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients.

OBJECTIVE: To demonstrate that calcium channel blockers can improve insulin resistance clinically, we investigated the effects of the calcium channel blockers, amlodipine, manidipine and cilnidipine on serum levels of steroid hormones and insulin. SUBJECTS AND METHODS: Thirty hypertensive obese patients [15 men and 15 women; mean age 55.9 years, mean body mass index (BMI) 27.6] were divided into three groups and treated with either 5 mg of amlodipine, 20 mg of manidipine or 10 mg of cilnidipine. Blood pressure (BP), fasting plasma glucose (FPG), HbA1c, fasting serum immunoreactive insulin (F-IRI), insulin resistance index [as assessed by the homeostasis model assessment (HOMA-R)], serum DHEA, serum DHEA-S, plasma ACTH, serum cortisol, plasma renin activity (PRA), and serum aldosterone, were measured before and after 1, 2, 3 and 6 months of treatment. RESULTS: In all three groups, BP decreased significantly after 1 month and F-IRI and HOMA-R decreased significantly after 2-3 months. A concurrent rise in serum DHEA and DHEA-S levels was also observed, however, the differences were not significant. No changes in FPG, HbA1c, ACTH, cortisol, PRA or aldosterone levels were observed during treatment. CONCLUSIONS: We conclude that amlodipine, manidipine and cilnidipine all improve insulin resistance and consequently increase serum levels of DHEA and DHEA-S.

Aged↗