[Therapy of heart failure with calcium channel blockers?].
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Calcium Channel Blockers↗
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Reassuring data on calcium channel blockers and cancer.
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Calcium Channel Blockers↗
Calcium channel blockers in perspective.
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Calcium Channel Blockers↗
N,N-dialkyl-dipeptidylamines as novel N-type calcium channel blockers.
Selective N-type voltage sensitive calcium channel (VSCC) blockers have shown utility in several models of stroke and pain. We are especially interested in small molecule N-type calcium channel blockers for therapeutic use. Herein, we report a series of N,N-dialkyl-dipeptidylamines with potent functional activity at N-type VSCCs and in vivo efficacy. The synthesis, SAR, and pharmacological evaluation of this series are discussed.
Animals↗
Inhibition of human mesangial cell proliferation by calcium channel blockers.
Human mesangial cells in culture proliferate in response to platelet-derived growth factor (PDGF) and thrombin. Both of these agents also induce changes in cytosolic calcium that are dependent on both mobilization of intracellular calcium and influx of extracellular calcium. We hypothesized that calcium channel blockers, by preventing influx of extracellular calcium, may inhibit proliferation induced by these mitogens. We found that three different calcium channel blockers, diltiazem, nifedipine, and verapamil, were able to significantly inhibit [3H]thymidine incorporation into human mesangial cells induced by either PDGF or thrombin. The inhibitory effect of these agents was significant at 10(-5) M. The calcium channel blockers also attenuated the increases in cell number and percentage of labeled nuclei induced by these mitogens. In contrast, dantrolene, an inhibitor of intracellular calcium mobilization, had no significant effect on [3H]thymidine incorporation by PDGF or thrombin. Finally, the calcium channel agonist, Bay K 8644 was found to stimulate [3H]thymidine incorporation into mesangial cells. Although the mechanisms for these effects of calcium channel blockers are not proven, these studies suggest that influx of extracellular calcium is an important signal in mitogen-induced mesangial proliferation and that these agents can be beneficial in preventing or attenuating renal diseases characterized by proliferation of these cells.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Synthesis and biological evaluation of substituted 4-(OBz)phenylalanine derivatives as novel N-type calcium channel blockers.
Selective N-type Voltage Activated Calcium Channel (VACC) blockers have shown utility in several models of stroke and pain. In the process of searching for small molecules as N-type calcium channel blockers, we have identified a series of N,N-dialkylpeptidylamines (e.g., PD 175069) with potent functional activity at N-type VACC. Further modification of the leucine moiety of PD 175069 with a cyclized ring structure provides a series of novel molecules. Syntheses and pharmacological evaluation of the series are presented.
Calcium Channel Blockers↗
[Gingival hyperplasia induced by calcium channel blockers. Rare or frequent in Norway?].
Sales statistics indicate that the number of Norwegians treated with calcium channel blockers increased from about 50,000 in 1986 to about 83,000 in 1991 (last year: nifedipine 39%, verapamil 27%, amlodipine 21%, diltiazem 10% and felodipine 3%). In spite of widespread use, only one report on gingival hyperplasia induced by calcium channel blockers has been received by the Norwegian Adverse drug reaction committee. The incidence of this adverse reaction is uncertain, but the few controlled studies that have been performed indicate that it may be as high as 15% in patients on long-term treatment, at least with nifedipine. This corresponds to nearly 5,000 cases among the about 32,000 users of nifedipine. Norwegian physicians and dentists are asked to report cases of gingival hyperplasia induced by calcium channel blockers. Although the voluntary report system is fraught with uncertainty, it is hoped that, in a relatively small and surveyable drug market as the Norwegian, the reporting may provide some relevant information, e.g. to allow comparison of the potential of the various calcium channel blockers to induce this adverse effect. A Norwegian controlled study on gingival conditions among long-term users of calcium channel blockers is in its initial stage. It may be of interest to compare the results of this study with the indications obtained from the spontaneous reporting on the incidence of this adverse effect, which is relatively easy to diagnose.
Adult↗
Effects of calcium channel blockers on bupivacaine-induced toxicity.
The purpose of this study was to investigate the influence of calcium channel blockers on bupivacaine-induced acute toxicity. For each of the three tested calcium channel blockers (diltiazem, verapamil and bepridil) 6 groups of mice were treated by two different doses, i.e. 2 and 10 mg/kg/i.p., or an equal volume of saline for the control group (n = 20); 15 minutes later, all the animals were injected with a single 50 mg/kg/i.p. dose of bupivacaine. The convulsant activity, the time of latency to convulse and the mortality rate were assessed in each group. The local anesthetic-induced mortality was significantly increased by the three different calcium channel blockers. The convulsant activity of bupivacaine was not significantly modified but calcium channel blockers decreased the time of latency to obtain bupivacaine-induced convulsions; this effect was less pronounced with bepridil.
Animals↗
Effect of calcium-channel blockers and salbutamol on the isolated mare uterus--interaction with the calcium agonist Bay K 8644.
The effects of nifedipine, verapamil and diltiazem were investigated in the isolated mare uterus in comparison with salbutamol. All the calcium-channel blockers and salbutamol inhibited the spontaneous, KC1- and electrically induced contractions; nifedipine and salbutamol were the most potent compounds. The calcium agonist Bay K 8644 (10(-8)-10(-6) mol/l) competitively antagonized the inhibitory effect of nifedipine (pA2 value = 8.54 +/- 0.06), whereas it was only slightly or totally ineffective against verapamil, diltiazem and salbutamol. These results indicate that calcium-channel blockers are potent inhibitors of mare uterine motility in vitro and emphasize the importance of Ca2+-related mechanisms in the control of uterine smooth-muscle contractility. Moreover, the validity of Bay K 8644 as a tool to distinguish classes of calcium-channel antagonists is confirmed.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
Using medication history to measure confounding by indication in assessing calcium channel blockers and other antihypertensive therapy.
Reported findings of elevated risk of adverse events associated with calcium channel blocker use in hypertensives may be due partly to unmeasured confounding by indication. To determine if such confounding occurs, we conducted a retrospective cohort analysis of 77 196 Pennsylvania Medicaid recipients aged 18 to 61 who were treated with antihypertensive medication between 1990 and 1992. All diagnoses and dispensed prescriptions during the year prior to study entry were examined. Prior recipients of multitherapy (n = 18 763) were more likely to have had previously diagnosed risk factors (OR = 1.31 [95% CI, 1.30-1.33]) than subjects with prior monotherapy (n = 11141). New initiators (n = 47292) were less likely to have had previously diagnosed risk factors (OR = 0.48 (95% CI, 0.47-0.49)) than previous users (n = 29904). The likelihood of being prescribed calcium channel blocker rather than other monotherapy was significantly higher for subjects diagnosed during the previous week with arteriosclerotic cardiovascular disease OR = 7.78 (95% CI, 2.72-22.28), P < 0.0001; angina OR = 2.92 (95% CI, 1.77-4.83), (P < 0.0001); diabetes OR = 1.49 (95% CI, 1.07-2.06), (P = 0.0004); and hypertension OR = 1.57 (95% CI 1.35-1.82), (P < 0.0001). Calcium channel blockers were selectively prescribed to subjects at elevated risk of adverse events. Confounding by indication was found in this large indigent population. Unmeasured confounding may contribute to overestimated relative risk of adverse events associated with calcium channel blocker therapy vs diuretics or beta-blockers. At least 1 full year of subjects' medical and prescription drug history should be examined prior to study entry; shorter observation periods will miss clinically relevant information about risk.
Adolescent↗
Ziconotide, a new N-type calcium channel blocker, administered intrathecally for acute postoperative pain.
BACKGROUND AND OBJECTIVES: Voltage-sensitive calcium channel conductance is essential for the nervous system to signal a painful event. However, intrathecal administration of L-type calcium channel blockers does not provide analgesia. The present investigation was designed to assess the safety and analgesic efficacy of ziconotide, a new N-type calcium channel blocker, when administered intrathecally to patients with acute postoperative pain. METHODS: This randomized, double-blind, pilot study included patients undergoing elective total abdominal hysterectomy, radical prostatectomy, or total hip replacement. After intrathecal injection of local anesthetic and before surgical incision, a continuous intrathecal infusion of either placebo or 1 of 2 doses of ziconotide (0.7 microg/h or 7.0 microg/h) was started and continued for 48 to 72 hours postoperatively. Primary and secondary efficacy variables were the mean daily patient controlled analgesia (PCA) morphine equivalent consumption and visual analog pain intensity (VASPI) scores, respectively. RESULTS: Thirty patients received study drug; 26 were evaluable for efficacy. Mean daily PCA morphine equivalent consumption was less in patients receiving ziconotide than in placebo-treated patients, and the difference was statistically significant between 24 and 48 hours (P = .040). VASPI scores during the first 8 hours postoperatively were markedly lower in ziconotide-treated than in placebo-treated patients. In 4 of 6 patients receiving the high-dose of ziconotide (7 microg/h), adverse events, such as dizziness, blurred vision, nystagmus, and sedation contributed to study drug being discontinued after 24 hours. After ziconotide discontinuation, these symptoms resolved. CONCLUSIONS: Ziconotide showed analgesic activity, as shown by decreased PCA morphine equivalent consumption and lower VASPI scores. Because of a favorable trend of decreased morphine consumption with an acceptable side-effect profile in the low-dose ziconotide group, 0.7 microg/h may be closer to the ideal dose than 7 microg/h. Large-scale studies are required to clarify this issue.
Acute Disease↗
The effects of calcium channel blockers on blood fluidity.
Although vasodilation, direct cardiac actions, or both represent the main properties of calcium channel blockers, there are further pharmacologic effects that may be therapeutically relevant. For example, hemorrheological effects, which have been demonstrated for a variety of calcium antagonists, have received relatively little attention to date. Hemorrheology describes the mechanics of blood and its components. It is of particular interest in the context of cardiovascular disease, as it has been shown that under certain conditions (reduced pump function, impaired vasomotor reserve), parameters of blood fluidity may be crucial for tissue perfusion. Whole-blood viscosity is the dominating factor in large arteries. For geometrical reasons, plasma viscosity and the rheological properties of blood cells may become of paramount importance at the microcirculatory level. In ischemic states, erythrocytes may be depleted of ATP, which they need for maintenance of normal shape and for transformation. This results in rigidification of the red blood cell and hindrance of its passage in the microcirculatory bed. Hence, blood flow deteriorates with the consequence of further unfavorable changes of the "milieu interieur," leading to the induction of a vicious cycle. Although effects on several hemorrheological parameters, for example, whole-blood viscosity, plasma viscosity, and red cell aggregation, can be demonstrated for various calcium channel blockers, the main rheological effects of these compounds are believed to consist in the improvement of erythrocyte deformability. When the ATP-dependent calcium pump is impaired in ischemia, calcium channel blockers may inhibit the slow inward transmembrane calcium flux and prevent the accumulation of intracellular calcium.
Blood Viscosity↗
Calcium channel blockers and terbutaline--a positive interaction.
The role of two calcium channel blockers, nifedipine and verapamil was investigated in patients of bronchial asthma. Both the drugs given orally produced an insignificant rise in PEFR, FEF25-75% and FEV1. Given along with terbutaline, however, these drugs produced significantly greater increase in PEFR, FEF25-75% and FEV1 as compared to patients receiving terbutaline alone. The two calcium channel blockers also inhibited the terbutaline induced tremors and palpitation.
Adult↗
Tricyclic antidepressants and calcium channel blockers: interactions at the (-)-desmethoxyverapamil binding site and the serotonin transporter.
The activity of various calcium channel blockers at the serotonin transporter, as determined by their effects on imipramine binding and serotonin uptake, was investigated in rat brain and human platelets. In addition, the effect of tricyclic antidepressants on the binding of calcium channel blockers was evaluated. Verapamil was found to be a competitive inhibitor of both imipramine binding and serotonin uptake in brain and platelets. The inhibitory activity of verapamil was calcium-independent. Chronic verapamil treatment resulted in a significant decrease (28%) in [3H]imipramine binding in the rat hypothalamus but had no effect on [3H]imipramine binding to cerebral cortex membranes or on [3H]serotonin uptake in these two brain regions. Tricyclic antidepressants inhibited (-)-[3H]desmethoxyverapamil binding but did not affect [3H]nitrendipine binding to rat cerebral cortex membranes. Chronic imipramine treatment induced a non-significant increase (34%) in (-)-[3H]desmethoxyverapamil binding but did not alter [3H]nitrendipine binding in rat cerebral cortex. These interactions may be relevant to an understanding of the beneficial effects of verapamil in major affective disorders and may suggest an involvement of calcium channels in the pharmacological activity of tricyclic antidepressants.
Animals↗
Calcium channel blockers in current medical practice: an update for 1993.
Calcium channel blocking drugs (CCB) have been used to lower blood pressure since 1970. Three classes are currently available, the phenylalkylamines, the benzothiazepines, and the dihydropyridines. The structure of the L-type, voltage dependent calcium channel has been elucidated with molecular techniques and the different binding sites of the various CCB described. CCB have specific effects at the site of target organs. In the kidney, all classes produce natriuresis. Their action appears independent of the level of salt intake. CCB may favorably influence the course of chronic renal disease; the results of a trial comparing nifedipine to the converting enzyme inhibitor captopril showed no difference between the two drugs. CCB may impede the progression of atherosclerosis in the coronary arteries; a prospective study of nifedipine on coronary artery morphology supports this view. In the brain, nimodipine improves the outcome of patients with stroke from subarachnoid hemorrhage. Positive effects on patients with ischemic stroke have not been corroborated. CCB are approved primary treatment for patients with hypertension and are readily combined with other antihypertensive agents. They are well tolerated and have no adverse metabolic side effects. The advent of molecular pharmacology will advance current efforts to develop new CCB, which are highly selective in their site and mode of action.
Brain↗
Association between cardiovascular outcomes and antihypertensive drug treatment in older women.
CONTEXT: Diuretic-based therapy is at least as effective as newer classes of agents for hypertension. However, many patients with hypertension require treatment with more than 1 drug class to achieve blood pressure control. The relative benefits or risks of 2-drug-class combinations are not well known. OBJECTIVE: To prospectively evaluate if there are differences in cardiovascular mortality among postmenopausal women with hypertension but no history of cardiovascular disease (CVD) treated with different classes of antihypertensive agents, singly or in combination. DESIGN, SETTING, AND PARTICIPANTS: Women with hypertension enrolled in the Women's Health Initiative Observational Study, a longitudinal multicenter cohort study of 93 676 women aged 50 to 79 years at baseline (1994-1998), assessed for a mean of 5.9 years. MAIN OUTCOME MEASURES: Relationship between baseline use of ACE inhibitors, beta-blockers, calcium channel blockers, or diuretics, or a combination of these, and incidence of coronary heart disease, stroke, and CVD mortality. RESULTS: Among 30,219 women with hypertension but no history of CVD, 19,889 were receiving pharmacological antihypertensive treatment, of whom 11,294 (57%) [corrected] were receiving monotherapy with an ACE inhibitor, beta-blocker, calcium channel blocker, or diuretic, and 4493 (23%) were treated at baseline with a combination of diuretic plus either ACE inhibitor, beta-blocker, or calcium channel blocker or ACE inhibitor plus calcium channel blocker. Monotherapy with calcium channel blockers vs diuretics was associated with greater risk of CVD death (hazard ratio, 1.55; 95% confidence interval, 1.02-2.35), controlling for multiple covariates. Women treated with a diuretic plus a calcium channel blocker had an 85% greater risk of CVD death vs those treated with a diuretic plus a beta-blocker, after adjustment for age, race, smoking, high cholesterol levels requiring medication, body mass index, physical activity, use of hormone therapy, and diabetes. After exclusion of women with diabetes the hazard ratio was 2.16 (95% confidence interval, 1.16-4.03). Analyses adjusting for propensity to be receiving a particular treatment did not change the results. For morbid events of coronary heart disease or stroke, diuretics plus ACE inhibitors or calcium channel blockers did not differ from diuretics plus beta-blockers. CONCLUSIONS: Among women with hypertension but no history of CVD, a 2-drug-class regimen of calcium channel blockers plus diuretics was associated with a higher risk of CVD mortality vs beta-blockers plus diuretics. Risks were similar for ACE inhibitors plus diuretics and beta-blockers plus diuretics. Monotherapy with diuretics was equal or superior to other monotherapy in preventing CVD complications of high blood pressure.
Adrenergic beta-Antagonists↗
Effect of calcium channel blockers on norepinephrine release and modulation by prejunctional D2 dopamine receptors.
Influx of calcium through voltage-dependent N-type calcium channels promotes the release of norepinephrine from nerve terminals. Contributions by L- and N-type calcium channels at different levels of nerve stimulation were examined in perfused rat tail arteries loaded with [3H]norepinephrine. Nifedipine had no effect while omega-conotoxin reduced tritium efflux by 69 to 82% depending on the stimulation intensity. Thus, N-type calcium channels predominated in the control of norepinephrine release, and the relative contribution of L- and N-type channels did not change when stimulation intensity was altered. We also explored the effect of calcium channel blockers on modulation of norepinephrine release by D2 dopamine receptors. Inhibition of stimulation-evoked tritium efflux by the D2 agonist N-0923 was similar in the absence and presence of nifedipine and/or omega-conotoxin. We conclude that D2 dopamine receptors are not coupled to L-type calcium channels; however, the role of N-type calcium channels requires further investigation.
Animals↗
Lead discovery and optimization of T-type calcium channel blockers.
A series of compounds were designed as T-type calcium channel blocker containing 6 or 5 pharmacophore features from structure-based virtual screening. To optimize the suggested structure, over 130 derivatives were synthesized and their inhibitory activities on T-type calcium channel were assayed using in vitro screening system with alpha1(G) and alpha1(H) clones. For the compounds with higher activities in FDSS assay system, the efficacy was measured by patch-clamp method. Among the library with 5 features, alkaneamide derivatives (7b, 9j, 11b, 11g, 11h) with 4-arylsubstituted piperazine showed better IC(50) values than Mibefradil.
Alkanes↗