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PubMed1985

Lipoprotein and protein binding of the calcium channel blocker diltiazem.

The plasma protein binding properties of the calcium channel blocker diltiazem were studied using a three-chamber equilibrium dialysis system. Diltiazem is 81% bound to human sera with significant inter-individual variation. The relative binding of diltiazem by lipoproteins and alpha 1-acid glycoprotein was higher than by albumin. The binding to low density lipoprotein was strong and appeared not to be associated with the surface apoprotein.

Benzazepines↗
PubMed2000

Calcium channel blocker ingestions in children.

UNLABELLED: Limited data exists regarding toxicity of calcium channel blockers (CCBs) in children. The purpose of this study was to determine the frequency, the range of toxicity, the appropriate observation time, and to assess effective interventions for CCB ingestions in children. A 6-year retrospective review of CCB ingestions in children younger than 7 years of age reported to one regional poison center was undertaken. Patients with coingestants with recognized cardiovascular or central nervous system (CNS) effects were excluded. Two hundred eighty-three patients met criteria for review. The mean age was 27 months with 52% of all patients being boys. Nifedipine (38%), verapamil (34%), and amlodipine (14%) were most commonly ingested. Seventy-five percent of ingestions reportedly involved < or =1 pill. Symptoms occurred in 16/283 (6%): 4 had vomiting, and 12 had CNS or cardiovascular effects. The mean time to onset of symptoms for regular-release and for sustained-release (SR) CCB preparations were 1.5 hours (range 0.5 to 3 hr) and 4.5 hours (range 1 to 14 hr) respectively. OUTCOME: 74% of patients had no clinical effects, 4% minor effects, 2% moderate effects, and 20% other. No deaths or major effects were reported. TREATMENT: 88% of patients evaluated in an emergency department received gastric decontamination, usually one dose of charcoal. Calcium chloride was given in three verapamil SR cases. Five of six patients had reversal of hypotension with IV fluids and decontamination alone. Most pediatric CCB ingestions involve ingestions of small amounts of drug with no effects. Asymptomatic children in this study group who were known to have ingested <12 mg/kg of verapamil SR or <2.7 mg/kg of nifedipine SR could have been monitored at home. Of the children requiring evaluation and monitoring in a health care facility, an observation period for regular-release and SR-CCBs for 3 and 14 hours respectively would have been appropriate. There were insufficient cases with symptoms to draw conclusions for optimal therapeutic interventions.

Biotransformation↗
PubMed1993

Improvement of the energy status of hypoxic hepatocytes by calcium channel blockers.

Isolated hepatocytes from rat liver in primary culture rapidly lost viability under hypoxic conditions. Hypoxic injury was significantly decreased by the calcium channel blockers nifedipine (5 microM) and diltiazem (10 microM). The concentrations of the inhibitors which afforded maximum protection also produced the maximum increase in the energy level of the hypoxic hepatocytes, as evidenced by their ATP, ADP, AMP, and total adenine nucleotide content and by their energy charge. The increased hypoxic energy level caused by these calcium channel blocking agents was not due to an increased rate of anaerobic glycolysis; nifedipine did not have any effect on lactate production while diltiazem slightly decreased its rate. During the first 2 h under hypoxic conditions the cytosolic Ca2+ concentration remained constant around 100 nM, subsequently increasing to 400 nM first slowly and later more rapidly. The calcium channel blockers delayed the Ca2+ increase by about 1 h but were without any effect on the rate of this increase. The results suggest that the well-known beneficial effects of calcium channel blockers on hypoxic liver injury are due in large measure to an improved energetic situation of the hepatocytes rather than to the increase in the cytosolic Ca2+ concentration being blocked.

Adenine Nucleotides↗
PubMed1986

Effects of calcium channel blockers on the female genital tract.

Contractile activity and vascular resistance in the female genital tract are influenced by several smooth muscle tissues with individual mechanisms for control of mechanical activation. Calcium channel blockers have potent relaxant effects on preparations of human myometrium. The myometrial arteries utilize multiple sources of calcium for contractile activation, and excitation-contraction coupling in isolated vessels from non-pregnant uteri seems comparatively less sensitive to nifedipine than in corresponding myometrial preparations. Contractile activation of myometrial and placental arteries at term is inhibited by nitrendipine and nifedipine. Human oviductal smooth muscle depends on superficially bound calcium for mechanical activation, but only phasic contractions can be abolished by nifedipine, while tonic contractions induced by various agents are more resistant to the calcium channel blocker. Menstrual uterine contractions and pain are effectively counteracted by nifedipine in normal and dysmenorrhoeic women. Such therapy may represent an alternative principle in the treatment of dysmenorrhea. Nifedipine has potent relaxant effects on the mid-term pregnant and the post-partum uterus and calcium channel blockers may prove useful in the treatment of premature labor. Nifedipine and related compounds may further show effective in the treatment of pregnancy-associated hypertension. Whether such treatment in late pregnancy involves maintained or even improved placental perfusion could be assumed from in vitro data but needs further studies.

Animals↗
PubMed2003

Has the role of calcium channel blockers in treating hypertension finally been defined?

Several large, prospective, randomized, clinical outcome trials have shown that calcium channel blockers are effective and safe antihypertensive drugs compared with placebo and reduce the cardiovascular morbidity and mortality of treated patients. In other studies, when compared with conventional antihypertensive drugs, they demonstrated similar blood pressure-lowering effects and similar reductions in cardiovascular morbidity and mortality, with the exception of a higher incidence of heart failure and fatal myocardial infarction in some studies. However, considering all the evidence available today, these drugs should be considered safe for the treatment of the uncomplicated hypertensive patient in combination with other drugs. They can also be used as first-line therapy for older, stroke-prone hypertensive patients. In addition, when a calcium channel blocker is indicated for better blood pressure control, its use should not be withheld for safety concerns.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Ultrastructural evidence for protection of the outer hair cells of the inner ear during intense noise exposure by application of the organic calcium channel blocker diltiazem.

Outer hair cells could be protected during intense noise exposure by the application of the calcium channel blocker diltiazem given before and after noise treatment. After various experimental approaches, the ultrastructural morphology was analysed for the different animal populations in the basal part of the second turn of the cochlea, which was the most destroyed area after an acute noise trauma caused by a gun shot (sound pressure at the ear drum 156 dB, frequency maximum between 4 and 6 kHz). Compared to untreated control specimens (experimental animal group I), the outer hair cells in the basal part of the second turn of the cochlea were mostly destroyed without any diltiazem application but after intense noise exposure (group II) or when the calcium channel blocker was given only before (group III) or only after an intense noise exposure (group IV). Only cellular debris of these receptor cells could be identified within this region of the cochlea at the electron-microscopic level. After diltiazem application before and after the intensive noise exposure (group V), the general morphology of the tissue was much better conserved and almost no destroyed outer hair cells were found. But nevertheless, the electron-microscopic analysis revealed that the cellular fine structure was altered. Compared to untreated control specimens, small invaginations were sometimes seen in the basolateral membranes of outer hair cells, and also the cuticular structures of the Deiters cells forming the lamina reticularis bulged into the outer hair cells. To get more information about possible physiological alterations, the amounts of precipitable calcium within the outer hair cells were determined by an image-processing system for the five different populations (groups I-V). The values obtained were compared to the calcium content in specimens which had received diltiazem without any additional noise exposure (group VI) and with an animal population which was exposed to a pure tone for 5 min at 90 dB (group VII). The results are discussed in respect of outer hair cell protection preventing morphological damage and/or physiological alterations.

Acute Disease↗
PubMed1999

Immunomodulating effects of second-generation calcium channel blockers on experimental heart transplantation.

The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypothesized that exposure to clinically relevant concentrations may have a significant immunomodulatory potential. The effects of various second-generation CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation of the donor heart, allograft recipients were exposed to felodipine (31 microg/kg/day), amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other allograft recipients were treated with low-dose cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 microg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given daily by gavage. Median survival time of untreated cardiac allografts was 6.5 days. When given alone, not all the second-generation CCBs elicited a positive effect: the dihydropyridines felodipine and amlodipine were ineffective (median survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzothiazepine clentiazem produced the most significant result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 days), while clentiazem had a significant positive effect. These data indicate that second-generation CCBs differ in their immunomodulatory potential. These observations of pharmacodynamic specificity appear to be related to differences in their chemical structure as well as their interaction with other sites than the calcium channel.

Adjuvants, Immunologic↗
PubMed2000

Drug interactions with calcium channel blockers: possible involvement of metabolite-intermediate complexation with CYP3A.

The inhibitory effects of six commonly used calcium channel blockers on three major cytochrome P-450 activities were examined and characterized in human liver microsomes. All six compounds reversibly inhibited CYP2D6 (bufuralol 1'-hydroxylation) and CYP2C9 (tolbutamide methyl hydroxylation) activities. The IC(50) values for the inhibition of CYP2D6 and CYP2C9 for nicardipine were 3 to 9 microM, whereas those for all others ranged from 14 to >150 microM. Except for nifedipine, all calcium channel blockers showed increased inhibitory potency toward CYP3A activities (testosterone 6beta-hydroxylation and midazolam 1'-hydroxylation) after 30-min preincubation with NADPH. IC(50) values for the inhibition of testosterone 6beta-hydroxylase obtained in the NADPH-preincubation experiment for nicardipine (1 microM), verapamil (2 microM), and diltiazem (5 microM) were within 10-fold, whereas those for amlodipine (5 microM) and felodipine (13 microM) were >200-fold of their respective plasma concentrations reported after therapeutic doses. Similar results also were obtained based on midazolam 1'-hydroxylase activity. Unlike the observations with mibefradil, a potent irreversible inhibitor of CYP3A, the NADPH-dependent inhibition of CYP3A activity by nicardipine and verapamil was completely reversible on dialysis, whereas that by diltiazem was partially restored (80%). Additional experiments revealed that nicardipine, verapamil, and diltiazem formed cytochrome P-450-iron (II)-metabolite complex in both human liver microsomes and recombinant CYP3A4. Nicardipine yielded a higher extent of complex formation ( approximately 30% at 100 microM), and was a much faster-acting inhibitor (maximal inhibition rate constant approximately 2 min(-1)) as compared with verapamil and diltiazem. These present findings that the CYP3A inhibition caused by nicardipine, verapamil, and diltiazem is, at least in part, quasi-irreversible provide a rational basis for pharmacokinetically significant interactions reported when they were coadministered with agents that are cleared primarily by CYP3A-mediated pathways.

Aryl Hydrocarbon Hydroxylases↗
PubMed2001

Calcium channel blockers in the management of preterm labor and hypertension in pregnancy.

Calcium channel blockers (CCBs) have the ability to inhibit contractility in smooth muscle cells. CCBs have an already established role in the treatment of non-pregnant hypertension and angina pectoris. Some epidemiological studies found an association between the use of CCBs and an increase in cardiovascular mortality, malignancy, and gastrointestinal bleeding. More recent studies with many more patients and a longer follow-up did not find these associations. In obstetrics CCBs have become increasingly popular for the management of preterm labor and pregnancy-induced hypertensive disorders. Meta-analysis shows that use of nifedipine in comparison with betamimetics is associated with a more frequent successful prolongation of pregnancy in case of preterm labor, resulting in significantly fewer admissions of newborns to the neonatal intensive care unit (NICU), and is associated with a lower incidence of respiratory distress syndrome. No adverse fetal side effects in humans have been reported with the use of nifedipine for obstetric indications. Nifedipine is an effective and safe drug to use when tocolytic therapy is indicated for preterm labor. In preeclampsia nifedipine effectively lowers blood pressure and can be a good alternative for (di) hydralazine.

Breast Feeding↗
PubMed2006

The L-type calcium channel blocker nimodipine mitigates cytoskeletal proteins phosphorylation in dichlorvos-induced delayed neurotoxicity in rats.

The present investigation was carried out to assess the protective efficacy of nimodipine against dichlorvos-induced organophosphate induced delayed neurotoxicity (OPIDN). Single subcutaneous dose of dichlorvos (200 mg/kg body weight) led to a consistent increase in the activity of both microtubule associated protein kinases viz. Ca2+/Calmodulin-dependent and cAMP dependent protein kinases, at all post exposure intervals (day 7, 15 and 21) as compared to that of controls. Autoradiography followed by microdensitometric studies demonstrated enhanced phosphorylation of 55 kDa and 280 kDa proteins in dichlorvos-exposed animals. These two proteins were confirmed to be tubulin and microtubule associated protein-2 (MAP-2) by western blotting. The hyperphosphorylation of these two proteins was shown to interfere with the assembly of neuronal microtubules as shown by electron microscopic studies that may eventually lead to possible disruption of neuronal cytoarchtecture resulting in axonal degeneration. Administration of nimodipine along with dichlorvos brought about a significant reduction in the activities of both the kinases as well as the extent of microtubule associated protein phosphorylation. This indicates that nimodipine, a centrally acting calcium channel blocker, may contribute to the amelioration of dichlorvos induced neurotoxicity by attenuation of calcium mediated disruption of cytoskeletal proteins and hence, calcium channel blockers like nimodipine have great future as new therapeutic agents for OPIDN.

Animals↗
PubMed1996

Optic nerve head circulation after topical calcium channel blocker.

PURPOSE: Our purpose was to investigate the effects of the calcium channel blocker verapamil on intraocular pressure and blood circulation in the human optic nerve head. METHODS: The effects of three different concentrations of topical verapamil (0.063%, 0.125%, and 0.25%) on intraocular pressure and optic nerve head capillary blood speed were measured in 12 healthy normal subjects. In a randomized, double-masked design, each subject received one drop of either verapamil or placebo in one eye and the opposite treatment in the fellow eye. Anterior optic nerve circulation was assessed at baseline and 90 min after instillation of the drops using the laser Doppler technique. RESULTS: The intraocular pressure was significantly reduced compared with baseline in both verapamil- and placebo-treated eyes at each concentration. The reductions of intraocular pressure were greater in verapamil-treated eyes (12-17%) than in placebo-treated eyes (9-12%). No systemic effect on heart rate or blood pressure was detected after administration of topical verapamil. The capillary blood speed in the optic nerve head was increased in both verapamil- and placebo-treated eyes at each concentration, although the only statistically significant increases were with the 0.25% concentration. The mean +/- SEM increase compared with baseline at the 0.25% concentration was 10.4 +/- 3.6% in verapamil-treated eyes (p = 0.017), and 11.6 +/- 4.4% in placebo-treated eyes (p = 0.026). CONCLUSIONS: These results indicate that topical administration of verapamil lowers the intraocular pressure and increases the capillary blood speed in the optic nerve head in normal subjects. Changes measured in verapamil-treated eyes were also observed in placebo-treated eyes, indicating a crossover effect.

Administration, Topical↗
PubMed1998

Safety of long-acting dihydropyridine calcium channel blockers in hypertensive patients.

Issues raised recently concerning the safety of calcium channel blockers (CCBs) prompted an analysis of the occurrence of cardiovascular events and death in the Pfizer Inc. hypertension clinical trial databases for amlodipine (Norvasc) and nifedipine in the gastrointestinal therapeutic system (GITS) formulation (Procardia XL). Prospectively defined analyses of data from comparative and noncomparative trials of amlodipine and nifedipine GITS were conducted. Outcome measures included cardiovascular and noncardiovascular deaths, and adverse cardiovascular events including new/worsened angina, myocardial infarction (MI), serious arrhythmia, stroke, congestive heart failure, and bleeding. Among all amlodipine-treated patients (n = 32,920), the incidence rates for all-cause death, MI, and new/worsened angina were 3.0, 3.3, and 1.6/1,000 patient-years of exposure, respectively. Among those in comparative trials alone (n = 4,126), the all-cause death rate was 4.1/1,000 patient-years, which was comparable to that of other non-CCB agents and significantly less than that of other CCBs (23.8/1,000 patient-years, p = 0.015), although the difference in rates represents only 2 deaths. Among all nifedipine-GITS-treated patients (n = 2,645), the rate of all-cause death was 4.1/1,000 patient-years, of MI 6.5/1,000 patient-years, and of new/ worsened angina 5.7/1,000 patient-years. The incidence rates for MI and other cardiac events were low in these hypertension trials, and did not differ among treatment groups in either the amlodipine or nifedipine GITS comparative analyses. In the clinical trial databases analyzed, there is no signal suggesting excessive risk of death or cardiovascular events for hypertensive patients treated with amlodipine or nifedipine GITS.

Amlodipine↗
PubMed1984

Calcium channel blockers: an intraoperative and postoperative trial in women.

This study analyzes the effects of intraoperative and postoperative calcium channel blockers on myocardial protection, postoperative arrhythmias, perioperative infarctions, and survival. Thirty-nine women undergoing consecutive coronary artery bypass operations were placed either in a control group (N = 23), in which standard cold potassium cardioplegia was used, or in a verapamil-nifedipine group (N = 16), in which verapamil (1 mg per liter) was added to the standard cardioplegic solution and nifedipine was instituted postoperatively. The verapamil-nifedipine group showed a significant reduction in postoperative levels of creatine phosphokinase (p less than 0.05). Levels of aspartate aminotransferase were also reduced (74 IU/L) compared with those for the control group (114 IU/L). In the control group, there were 3 early deaths secondary to abrupt ventricular fibrillation, but no patient in the verapamil-nifedipine group died or had serious early ventricular arrhythmias. Late hemodynamic variables were similar in both groups. We conclude that calcium channel blockers enhance myocardial protection during ischemic arrest and may diminish the incidence of fatal early postoperative ventricular arrhythmias in women undergoing coronary revascularization.

Arrhythmias, Cardiac↗
PubMed2002

Dietary phytoestrogens and their synthetic structural analogues as calcium channel blockers in human platelets.

Phytoestrogens have been shown to inhibit platelet activation by blocking platelet calcium channels. This study examined the effect of several synthetic derivatives of trans-resveratrol, genistein, and daidzein on platelet free intracellular calcium ([Ca2+]i) elevation in thrombin-activated platelets and the possible mechanisms of this inhibitory effect. Studies were conducted on fresh human platelets from healthy volunteers. The fluorescent dye fura-2 was used to monitor [Ca2+]i in platelets. At 10 microM-resveratrol, triacetyl-trans-resveratrol, and trimethoxy-trans-resveratrol produced, respectively, 57 +/- 4%, 40 +/- 4%, and 21 +/- 1% inhibition; genistein, acetylgenistein, and dihydrogenistein produced 51 +/- 10%, 26 +/- 7%, and 16 +/- 2% inhibition, respectively; daidzein and diacetyldaidzein produced 56 +/- 5% and 45 +/- 10% inhibition of thrombin-induced [Ca2+]i elevation. The inhibitory effect was immediate and appeared to directly affect the calcium influx channels. Phytoestrogen action on [Ca2+]i did not cause alteration in nitric oxide signaling. Tyrosine phosphorylation was not involved in the inhibition of [Ca2+]i elevation by phytoestrogens, because the percent inhibition produced by the tyrosine kinase inhibitor genistein and its inactive analogue daidzein on thrombin-induced and thapsigargin-induced [Ca2+]i elevation was not significantly different for either compound at any concentration tested. Structure-activity relationship studies on this limited set of compounds reveal the requirements for the stilbene pharmacophore for the calcium-blocking activity.

Adult↗