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PubMed2005

High-dose insulin therapy for calcium-channel blocker overdose.

OBJECTIVE: To evaluate the evidence for using high-dose insulin therapy with supplemental dextrose and potassium in calcium-channel blocker (CCB) overdose. DATA SOURCES: Evidence of efficacy for high-dose insulin therapy with supplemental dextrose and potassium was sought by performing a search of MEDLINE and Toxline between 1966 and July 2004 using combinations of the terms calcium-channel blocker, overdose, poisoning, antidote, and insulin. Abstracts from the North American Congress of Clinical Toxicology for the years 1996-2003 were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Identified articles, including animal studies, case reports, and case series, were evaluated for this review. No clinical trials were available. DATA SYNTHESIS: Animal models of CCB overdose demonstrate that high-dose insulin with supplemental dextrose and potassium was a more effective therapy than calcium, glucagon, or catecholamines. High-dose insulin appears to enhance cardiac carbohydrate metabolism and has direct inotropic effects. Published clinical experience is limited to 13 case reports where insulin was used after other therapies were failing; 12 of these patients survived. High-dose insulin therapy was beneficial for CCB-induced hypotension, hyperglycemia, and metabolic acidosis. Bradycardia and heart block resolved in some patients, but persisted in others. CONCLUSIONS: Based on animal data and limited human experience, as well as the inadequacies of available alternatives for patients with significant poisoning, high-dose insulin therapy warrants further study and judicious use in patients with life-threatening CCB poisoning.

Adolescent↗
PubMed2005

Inhibition of in vitro contractions of human myometrium by mibefradil, a T-type calcium channel blocker: support for a model using excitation-contraction coupling, and autocrine and paracrine signaling mechanisms.

OBJECTIVE: To investigate the importance of T-type calcium channels in human myometrial contractility and to refine a model of contractility. METHODS: We performed in vitro muscle bath experiments on human myometrial tissue strips while simultaneously monitoring bioelectrical activity with loose-contact electrodes. Tissue was obtained by myometrial biopsy from term pregnant women at the time of cesarean delivery and studied after 1 to 7 days in organ culture. Tissue strips were exposed to 5 nM oxytocin to obtain regular contractions. Tissue was then exposed to the T-type calcium channel blocker mibefradil (1 microM), the L-type calcium channel blocker nifedipine (5 nM), or the cyclooxygenase (COX) inhibitor indomethacin (30 microM). All study drugs reduced the strength of contractions. Data were analyzed using a model composed of two phases of force production--an electrical phase (E), which encompassed the first 3 seconds of each contraction, and a paracrine phase (P), which continued until the peak of the contraction. For each phase, the relative force reduction was calculated by the ratio of forces measured after and before drug exposure (RE and RP, respectively). For each drug, experiments were performed in at least triplicate. RESULTS: Myometrial contractions and bioelectrical signals were routinely observed following oxytocin exposure. Spike-like bioelectrical signals occurred only at the beginning of each contraction. Nifedipine and indomethacin slightly modulated the bioelectrical signals, but mibefradil appeared to block the spike component. Mibefradil caused a similar reduction of E and P (RE = 58 +/- 10%, RP = 62 +/- 22%). Nifedipine also reduced E and P, although P was reduced more than E (RE = 72 +/- 12%, RP = 38 +/- 8%, P = .006). Indomethacin yielded variable results, with some experiments showing similar RE and RP values, while other experiments showed RP > RE. CONCLUSION: Mibefradil inhibition of the bioelectrical signal and uterine contractile forces suggest that T-type calcium channels are important in the initiation of each contraction. Some results using indomethacin suggest that for a specific tissue or under some conditions, autocrine stimulation by prostaglandins may be important for recruitment of myocytes in the electrical phase. Stimulation by prostaglandins is likely important in the paracrine phase. Enhanced inhibition by nifedipine in the paracrine phase suggests the mechanism of action of nifedipine tocolytic effect is block of prostaglandin F2alpha (PGF2alpha) paracrine stimulation. Our initial model proposed at least two mechanisms (electrical and nonelectrical) for the recruitment of myocytes. Our modified model suggests that the electrical phase contains a prostaglandin autocrine mechanism in addition to excitation-contraction coupling, and the mechanism in the nonelectrical phase is prostaglandin paracrine signaling.

Adult↗
PubMed1983

Dihydropyridines as potent calcium channel blockers in neuronal cells.

Nicardipine, one of the dihydropyridine derivatives, in a nanomolar concentration range suppressed the high K+ -induced neurotransmitter release from cultured neuronal cells (chick embryonic neural retina cells and clonal rat pheochromocytoma cells). The high K+ -induced Ca2+ uptake into pheochromocytoma cell was also blocked by nicardipine in the same concentration range. [3H]Nitrendipine, another dihydropyridine derivative, bound specifically to pheochromocytoma cell homogenate in a saturable manner. We concluded that dihydropyridines block and bind to the high K+ -sensitive Ca2+ channels in neuronal cells.

Adrenal Gland Neoplasms↗
PubMed1999

Calcium-channel blockers and the progression of renal disease.

Effective blood pressure (BP) reduction is now generally recognized as a clinically proven strategy to retard the seemingly inexorable downhill progression of patients with diabetic and nondiabetic chronic renal disease. Although calcium-channel blockers (CCBs) are effective antihypertensive agents, the available experimental and clinical data are quite contradictory as to whether BP reduction achieved with CCBs provides the expected renoprotection. Blockade of the "L" type, voltage-gated Ca channels that mediate the BP reduction also concurrently impairs renal autoregulatory responses of the preglomerular vasculature. Because these renal autoregulatory resistance changes provide the primary protection against the transmission of systemic hypertension to the renal microvasculature, the adverse effects of CCBs on renal autoregulation counteract the beneficial effects on BP reduction. The degree of renoprotection achieved, therefore, depends on the balance between these two opposing effects. The data also indicate that there are probably important and clinically relevant differences between the classes of CCBs, with the dihydropyridine (DHP) CCBs most likely to have consistent deleterious effects on renal autoregulation. However, the available data also indicate that the adverse effects of DHP CCBs are not likely to be observed if BP is lowered well into the normotensive range, possibly through the use of combination therapies. Even when used as adjunctive therapy, close monitoring may be advisable to ensure BP normalization and the absence of any untoward effects on proteinuria and renal function.

Animals↗
PubMed1991

Role of calcium-channel blockers in preventing acute and chronic renal injury.

Calcium-channel blockers (CCBs) have been shown to afford protection against acute (ARF) and chronic renal failure (CRF). The effects of CCBs against acute renal injury occur at both the vascular and tubular epithelial level. At the vascular level, experimental ARF-associated loss of renal autoregulation and hypersensitivity to renal nerve stimulation has been shown to be reversed by CCBs. These beneficial vascular effects of CCBs occur on the background of the finding that renal ischemic injury is associated with an increase in cellular Ca2+ concentration. A rise in tubular epithelial Ca2+ concentration also occurs very early after a renal ischemic insult. This effect of ischemia is associated with evidence of membrane depolarization, opening of slow calcium channels, increased cellular Ca2+ uptake, and reversal by CCBs. There is evidence that the increased cellular Ca2+ uptake activates phospholipases, which prolong and increase membrane damage. Experimental CRF is also associated with increased renal cellular Ca2+ concentration, an effect that can be attenuated by CCBs. The CCBs probably slow progression of CRF by both cytoprotective and antihypertensive effects. These findings of vascular and tubular effects of CCBs in experimental ARF and CRF have led to their clinical use to prevent initial dysfunction of cadaveric kidney transplants, cyclosporine nephrotoxicity, radiocontrast-induced ARF, and progression of CRF. Randomized clinical studies are necessary to further examine the efficacy of CCBs in ARF and CRF.

Acute Kidney Injury↗
PubMed1990

Treatment with conotoxin, an 'N-type' calcium channel blocker, in neuronal hypoxic-ischemic injury.

Therapeutic efficacy of calcium channel blockers in stroke remains controversial, but previously used agents bind almost exclusively to L-type calcium channels. The newly-discovered N-type calcium channel is specific to neurons, and therapy involving blockade of this site has not been previously attempted. We assessed the neuroprotective effect of omega-conotoxin GVIA (CgTx), a blocker of N-type calcium channels, using both in vitro hypoxic injury to rat cortical neurons and an in vivo model of reversible spinal cord ischemia in the rabbit. In cell cultures, CgTx inhibited hypoxia-induced 45Ca accumulation and neuronal injury minimally, compared to the NMDA antagonist ketamine. In vivo, the duration of spinal cord ischemia which produced permanent paraplegia in 50% of control animals (ET50) was 24.0 +/- 2.6 min. Animals treated 2 h prior to ischemia with 0.5 nmol CgTx in the subarachnoid space had an ET50 of 26.9 +/- 1.8 min (P = 0.36). Animals treated 24 h prior to ischemia (all had persistent systemic tremor) had a ET50 of 28.9 +/- 1.8 min (P = 0.13). We conclude that pharmacologic modulation of the N-type calcium channel does not provide a significant protective effect against neuronal hypoxic-ischemic injury.

Animals↗
PubMed1997

Calcium channel blockers and hypertension: evolving perspective--1996.

In recent years, calcium channel blockers (CCBs) have been used extensively in the United States and elsewhere as antihypertensive agents, and their availability has been an important advance in the management of hypertension. As antihypertensive agents, the CCBs thus appear considerably more versatile than most previous vasodilators. The available studies indicate that CCBs are metabolically neutral and do not exacerbate dyslipidemia or impair glucose tolerance. In contrast to diuretics and beta-blockers, CCBs do not appear to alter insulin sensitivity. The CCBs also differ from previous vasodilators because of their favorable accompanying effects on the heart and kidney. Despite the attributes of CCBs enumerated earlier, a number of recent retrospective analyses by Psaty et al. (JAMA 1995;274:620-625) have suggested that CCBs may be detrimental and may promote adverse cardiovascular events. I have recently reviewed the results of Psaty's meta-analysis and report (Arch Intern Med 1995;155: 2150-2156). I have emphasized that it is the rate of drug delivery into the systemic circulation that produces profound effects on the hemodynamic and neurohumoral responses to a dihydropyridine CCB drug. During chronic treatment with dihydropyridines, major fluctuations in blood pressure (rapid onset and offset of antihypertensive effects) during the dosing interval may persist for drugs and formulations that are short acting. In contrast, slow-release formulations of otherwise rapidly absorbed dihydropyridines achieve a more gradual and sustained antihypertensive effect. It is probable that newer CCB formulations that do not provoke intermittent sympathetic activation and do not evoke a cardioacceleratory response would not be expected to promote adverse cardiovascular events.

Antihypertensive Agents↗
PubMed1999

Evidence of sex related differences in the effects of calcium channel blockers on neuroleptic-induced catalepsy in mice.

1. Calcium channel blockers (CCBs) are reported to affect extrapyramidal motor behavior in mammals. Since sex related differences are a common feature in the pharmacological properties of several centrally active drugs, the authors decided to investigate the effects of verapamil (VER), flunarizine (FLU) and nimodipine (NIM), three pharmacologically different CCBs, on neuroleptic-induced catalepsy in male and female albino mice. 2. Catalepsy was induced with haloperidol (0.75 mg/kg, i.p.) and measured at 30-min intervals by means of a bar test. Drugs (or appropriate vehicle, for the controls) were injected i.p. 20 min before haloperidol, with each animal being used only once. 3. VER (1, 5 and 10 mg/kg) did not significantly affect catalepsy in male mice. In females, however, a significant attenuation of catalepsy was found at the two higher doses. 4. FLU (1, 5 and 10 mg/kg) did not significantly affect catalepsy in male mice, whilst a significant attenuation was observed in females with the doses of 1 and 5 mg/kg (but not with the dose of 10 mg/kg). 5. NIM (3, 10 and 30 mg/kg) potentiated neuroleptic-catalepsy in males at the doses of 10 and 30 mg/kg. In females, however, only the higher dose of NIM caused a potentiation of catalepsy. 6. These results demonstrate the existence of sex related differences in the extrapyramidal effects of CCBs in mice. Further, this sex related effect might depend, among other factors, on the particular channel involved.

Animals↗
PubMed1999

Calcium channel blockers, apoptosis and cancer: is there a biologic relationship?

Calcium channel blockers (CCBs) represent a chemically and pharmacologically diverse group of agents that are widely used for the treatment of hypertension and angina. A small number of retrospective, observational analyses have raised concern about a potential causal link between CCB use and an increased risk for cancer development. Despite the absence of cancer findings in extensive preclinical studies, it has been proposed that CCBs may work differently in humans by interfering with apoptosis, leading to an increased potential for abnormal cell proliferation and tumor growth. This biologic hypothesis has attracted considerable attention in the medical community but has not been critically evaluated. An analysis of the basic and clinical literature was conducted to examine biologic relationships among cell Ca2+ modulation, apoptosis, and cancer. In addition to a comprehensive review of the cellular and animal data, the results of large observational studies were included in this analysis. Results of this review demonstrated that the effects of CCBs on apoptosis are complex as both increases and decreases in intracellular Ca2+ have been linked to this form of programmed cell death. Most studies show that an effect (either positive or negative) of CCBs on apoptosis requires doses in the supra-pharmacologic range, and are therefore not clinically relevant. Results of large and methodologically robust observational studies fail to provide support for the hypothesis that CCB use is associated with an increased susceptibility for cancer incidence. A comprehensive analysis of the basic and clinical evidence does not support a causal relationship between the therapeutic use of CCBs and an increased incidence of cancer development as a result of interfering with apoptosis.

Animals↗
PubMed1997

Subacute cutaneous lupus erythematosus arising in the setting of calcium channel blocker therapy.

After 6 months to 5 years of calcium channel blocker (CCB) therapy for arterial hypertension, nine patients developed photoinduced annular or papulosquamous eruptions consonant clinically with subacute cutaneous lupus erythematosus (SCLE). Four patients were receiving diltiazem, four received verapamil, and one was taking nifedipine. Serology showed antinuclear antibodies (ANA) in seven of nine patients, anti-Ro antibodies in five, and anti-La antibodies in five, with three patients having only anti-La antibodies. Skin biopsy specimens in all nine patients were held to be characteristic of SCLE based on light microscopy, direct, and indirect immunofluorescence. The CCB was discontinued in all; in 8 patients in whom the CCB was stopped, the eruption resolved. A proposed mechanism by which the CCBs may have precipitated the eruptions is offered.

Aged↗
PubMed1996

The calcium channel blocker controversy.

A major controversy about the safety of calcium channel blockers (CCBs) has arisen since the publication of a case-control study showing that hypertensives who suffered an acute myocardial infarction (MI) were more likely than hypertensives who had not had an MI to be taking one of these (short-acting) agents than other antihypertensive agents. This study was accompanied by a republication of older studies showing that large doses of short-acting nifedipine given to post-MI patients increased their mortality rate. The danger of massive doses of short-acting nifedipine in a post-MI patient is real but irrelevant to current practice. On the other hand, the putative dangers of short-acting CCBs in the treatment of hypertension do not apply to the current use of long-acting CCBs. Therefore the scare over their use is both irrational and unfortunate.

Calcium Channel Blockers↗
PubMed2005

Calcium channel blocker class heterogeneity: select aspects of pharmacokinetics and pharmacodynamics.

Calcium channel blockers (CCBs) comprise a heterogeneous group of compounds with unique structures and pharmacologic characteristics. These agents are employed in the treatment of hypertension, coronary ischemia, and/or supraventricular arrhythmias. CCBs are both substrates for, and in the instance of verapamil and diltiazem inhibitors of, cytochrome P450 3A4. In the case of verapamil and diltiazem, this inhibitory effect increases the likelihood of drug-drug interactions with other compounds similarly metabolized by cytochrome P450 3A4. Much of the debate with reference to a cardiovascular risk for CCBs has been quieted with the advent of sustained-release delivery systems that offer a more gradual rate of drug delivery. The most common side effects with CCBs are vasodilatory in nature and include peripheral edema, flushing, and headache. Despite the potential for side effects with CCBs, their potent blood pressure-lowering effect makes them a prerequisite for blood pressure control in many patients.

Biological Availability↗
PubMed1987

Effect of calcium channel blockers on human CFU-GM with cytotoxic drugs.

Calcium channel blockers (CCBs) such as verapamil and nitrendipine are capable of increasing drug sensitivity in resistant murine and human tumor cells. This finding has potential value in the treatment of acquired drug resistance in human malignancies. Thus, we tested the ability of CCBs of two different structural classes to enhance the toxicity of doxorubicin (DOX), vinblastine (VBL), and vincristine (VCR) for normal myeloid and macrophage colony formation (marrow colony forming units-granulocyte-monocyte [CFU-GM]). Drug effects on colony formation from 35 normal volunteer marrows and from seven patient marrows in the recovery phase after cytotoxic chemotherapy were determined. No enhancement of toxicity was mediated by verapamil or nitrendipine when these drugs were co-incubated with the cytotoxic drugs for one hour or 24 hours before plating marrow cells in a semisolid agar system.

Adolescent↗
PubMed1992

Benzazepinone calcium channel blockers. 4. Structure-activity overview and intracellular binding site.

We have synthesized a series of benzazepinones (2) in order to determine the structure-activity relationships (SAR) for calcium channel blockers related to diltiazem. A prerequisite for calcium channel blocking activity in vitro and in vivo is the presence of two pharmacophores: a 4'-aryl methyl ether and a basic substituent appended to N1 with a pKa in the physiological range. When these constraints are satisfied, a wide variety of substitution is tolerated at C6, C7, and C3. The presence of an electron-withdrawing group at C6 appears to enhance potency in vitro and in vivo. For such benzazepinones, activity is primarily dependent upon lipophilicity, as measured by log P. We believe these compounds must partition into the cell membrane in order to access their receptor. The quaternary methiodide 15k was used to demonstrate that the binding site for benzazepinones is on the intracellular face of the membrane. This work represents the first comprehensive SAR of diltiazem-like calcium channel blockers.

Benzazepines↗
PubMed2001

Effects of mibefradil, a T- and L-type calcium channel blocker, on cardiac remodeling in the UM-X7.1 cardiomyopathic hamster.

Abnormalities of T-type calcium channel function reported to occur in the transition phase to heart failure in the hamster cardiomyopathy may contribute to progression of the disease. We tested the hypothesis that chronic exposure to mibefradil, a selective T-type calcium channel blocker, improves the deleterious cardiac remodeling observed in this condition. In the present study, 40 normal (N) and 40 UM-X7.1 cardiomyopathic hamsters (CMH), aged 180 days, were treated daily by gavage for 21 days with mibefradil (30 mg/Kg). Eight to 10 animals from each group were sacrificed at the end of the treatment period while the remainder were followed for an additional 30 days without treatment (washout period). Hearts were harvested, fixed with 10%-buffered paraformaldehyde and then cut in half down the middle. Several slices were dehydrated, embedded in paraffin and stained with Masson Trichrome. Wall thickness and dilatation index of the left ventricle were estimated by planimetry. Myocardial capillary density was also computed. The greater heart weight/body weight ratio seen in untreated CMH (7.7 +/- 0.4 vs 5.5 +/- 0.2 in N, p < 0.05) was improved with mibefradil. The dilatation index averaged 0.504 +/- 0.04 in N was increased in untreated CMH (0.566 +/- 0.03) and ameliorated in mibefradil-treated CMH. The 1-month washout period led to further deterioration of the dilatation index in untreated and mibefradil-treated CMH. Capillary density averaged 10,000 +/- 781 per mm2 in hearts from untreated N hamsters and 8,830 +/- 795 per mm2 in untreated CMH (p = NS). Chronic exposure to mibefradil resulted in a significant reduction of capillary density in both N and CMH hearts. Following the 1-month washout period, the change in myocardial capillary density associated with mibefradil was no longer detectable. In conclusion, chronic exposure to mibefradil, a T- and L-type calcium channel blocker, exerts opposite effects during the transition phase to heart failure in CMH, improving the deleterious left ventricular remodeling in UM-X7.1 hamsters and reducting myocardial capillary density independently of the disease process.

Animals↗
PubMed1990

[Use of calcium-channel blockers in cirrhotic patients with portal hypertension].

Four calcium-channel blockers (CCB)-nifedipine (NIF), verapamil (VER), cinnarizine (CIN) and tetrandrine (TET)-are currently available and widely used at home and abroad for the treatment of cardiovascular diseases. To confirm any effects of CCBs on cirrhotic patients with portal hypertension, the esophageal variceal pressure (EVP) during routine gastroscopy, hemodynamic study, portal venous pressure and rebleeding rate of esophageal varices after 18 months were measured and compared in 321 patients from 23 hospital. The results demonstrated that the CCBs could significantly reduce the EVP, portal venous pressure and the portal blood flow in cirrhotic patients with portal hypertension. Furthermore, we found that neither heart rates nor blood pressure showed any significant change in spite of pressures and flow reduction. The proportion of patients free of recurrent gastrointestinal bleeding 18 months after inclusion in this study was 87.9% in the TET group, which was much higher than in the other 4 groups (p less than 0.05). The results of this study suggest that TET seems to be more appropriate for cirrhotic patients with portal hypertension at the present time.

Adolescent↗
PubMed1991

[Influence of muscarinic receptors and calcium channel blockers on bronchial reactivity and ventilation parameters in patients with obstructive lung diseases].

In 9 patients with obstructive lung disease as influence of ipratropium bromide (Atrovent) - muscarine receptors blocker and verapamil - calcium channel blocker on bronchial reactivity was evaluated. In the study was documented that verapamil decreased the bronchial reactivity and didn't change static ventilation parameters. Atrovent in observed patients improved their ventilation. On the other hand, verapamil didn't change a mode and efficiency of Atrovent action.

Bronchial Hyperreactivity↗
PubMed1992

Reduction of exercise-induced regional contractile dysfunction in dogs using a novel calcium channel blocker (Ro 40-5967).

Ro 40-5967 is a calcium channel blocker with a novel chemical structure. The purpose of this study was to evaluate the effects of Ro 40-5967 on systemic hemodynamics and regional contractile function in a canine model of chronic coronary artery stenosis in which no contractile dysfunction is observed at rest, but dynamic exercise elicits regional myocardial ischemia and contractile dysfunction. Thirteen dogs were chronically instrumented with sonomicrometers for the measurement of wall thickness in the anterior and posterior left ventricular walls, a micromanometer for measuring left ventricular pressure (LVP) and its first derivative (dP/dt), and a catheter in the aorta for measuring systemic arterial pressure. An ameroid constrictor on the left circumflex coronary artery produced gradual constriction of the vessel such that treadmill exercise elicited regional contractile dysfunction. Runs were repeated 3 hours later after the administration of Ro 40-5967 (0.3 mg/kg, IV). During the control run, regional systolic wall thickening in the posterior wall fell from 25.5 +/- 6.3% (SD) to 15.9 +/- 5.1% (p less than 0.05). Ro 40-5967 did not change resting function in the poststenotic myocardium (26.9 +/- 8.4%) but improved regional function during the run to 18.2 +/- 6.2% (p less than 0.05). This improvement was associated with a slight decrease in the exercise heart rate (213 +/- 18 vs. 200 +/- 16 bpm, NS), no change in peak ventricular pressure (156 +/- 22 vs. 157 +/- 20 mmHg), mean aortic pressure (123 +/- 19 vs. 118 +/- 20 mmHg), dP/dt (5129 +/- 1143 vs. 5288 +/- 1120 mm Hg/sec), or systolic wall thickening in a distant control region.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗