Mibefradil Research Articles

EXTH-41. COMBINATION TREATMENT OF CALCIUM CHANNEL ANTAGONIST MIBEFRADIL ENHANCES THE EFFECT OF HYDROXYUREA AT THERAPEUTIC RANGES IN HIGH-GRADE MENINGIOMA IN VITRO

Abstract High-grade meningiomas (MNs), WHO Grade II- III, are highly aggressive brain tumors that are difficult to treat. Standard chemotherapy agents are, at best, moderately effective in treating high-grade MNs. There is great interest in developing combinatorial drug treatment regimens to enhance the effects of standard chemotherapy. Many cancer types, including brain tumors, have an increase in the expression of voltage-gated calcium channels (VGCCs). These channels are involved in the regulation of cell cycle, proliferation, and apoptosis, among other functions. FDA-approved VGCC antagonists nimodipine (NIMO) and mibefradil (MIB) target two different VGCCs, L- and T-type channels, and have been of great interest for their use in combination therapy in other cancers. We sought to determine the efficacy of chemotherapy agents tested at clinically relevant concentrations for the treatment of high-grade MNs alone or in combination with NIMO or MIB. We cultured CH-157MN and IOMM-Lee MN cells and assessed their cell survival, apoptosis, and proliferation in the presence of temozolomide, octreotide, sunitinib, or hydroxyurea (HU). We confirmed that HU (150 µM) was the most efficacious chemotherapy agent, decreasing cell viability at therapeutic ranges. Monotherapy treatment with 2 or 4 µM MIB significantly decreased cell viability in both cell lines, whereas 1 µM NIMO only affected IOMM-Lee cells. The combination of HU and MIB further decreased cell viability but only in the most aggressive cell line, IOMM-Lee, whereas NIMO did not enhance HU’s ability to decrease cell survival. Remarkably, we detect an enhancement of HU’s effect by MIB when both agents are used within therapeutic ranges, as reported by pharmacokinetic studies. Here we demonstrate for the first time that T-type calcium channels play an important role in MN survival. The combination of HU and MIB suggests their use could be a promising treatment for high-grade MN.

Abstract P3-07-03: Targeting low voltage-activated calcium channels in HER2-positive breast cancer

Abstract Under physiological conditions low voltage-activated calcium channels (LVA, also called T-type channels) occur mostly in the brain, peripheral nervous system, smooth muscles, and pacemaker of the heart. However, LVA are often aberrantly expressed in various cancers and their overexpression is inversely correlated with outcomes. Active LVA contribute to proliferation, progression and resistance to therapy in several human cancers, including breast cancer (BC). The molecular mechanism of this activity is still not fully understood, and there is a lack of pre-clinical studies that target LVA in animal models of BC.Data from the Cancer Genome Atlas (TCGA) show a positive correlation between HER2 gene amplification and LVA channel overexpression, particularly of Cav3.1 (CACNA1G) subunit. The goal of this study is to identify functional links between HER2 receptor signaling and LVA channels, and validate LVA Ca2+ channels as a potential target for BC therapy. Inhibition of LVA, by small molecule antagonist mibefradil (MIB) or shRNA, significantly decreased the activity of PI3K/mTOR/AKT pathway in HER2-positive BC cell lines, blocked cell cycle progression, and at higher concentrations induced apoptotic cell death. Furthermore, LVA antagonist, mibefradil, sensitized cells to trastuzumab, lapatinib and paclitaxel, commonly used standard treatments for HER2-positive BC. To test the effects of LVA inhibition in vivo, the MMTV-PyMT mouse model of BC was used. In this model several features of HER2-positive BC are recapitulated, such as activation of PI3K/AKT/mTOR pathway, overexpression of HER2, BIRC5 and cyclin D1, and low expression of ERα, PGR and FOXA1. In PyMT animals palpable tumors can be detected at the age of 10-12 weeks, and 100% of animals will develop high tumor burden, including lung metastases, at the age of 15-20 weeks. Expression of CACNA1G subunit was detected in breast epithelial cells of 7 week old mice, and throughout the adult life, in both wild-type and PyMT animals, but CACNA1G was not expressed in lung or skeletal muscles. In in vitro experiments, cell lines derived from PyMT tumors were sensitive to MIB. In in vivo experiment, 5 to 7 weeks-old PyMT mice were fed either control or MIB-containing diet ad lib. Analysis of mouse serum revealed stable MIB concentration of ˜1500 ng/mL achieved within one week of treatment. In MIB-fed animals tumor appearance was delayed by 2 weeks, and the tumors were smaller as compared to control, thus suggesting a supporting role for LVA channels in breast tumor development and progression. Together, our observations provide new insights into the role of Ca2+ channels in HER2 driven BC and posit a future use of LVA channel antagonists for the treatment HER2-positive breast tumors. Citation Format: Dziegielewska B, Dunlap-Brown ME, Warnock WT, Dillon PM, Bouton AH, Dziegielewski J. Targeting low voltage-activated calcium channels in HER2-positive breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-07-03.

Plasmodium falciparum and Plasmodium vivax Demonstrate Contrasting Chloroquine Resistance Reversal Phenotypes.

ABSTRACTHigh-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.

Effects of T-type calcium channel inhibitors on monocrotaline-induced pulmonary arterial hypertension in rats

Objective To investigate the effects of T-type calcium channel inhibitors (ProTx-1, micromolar Ni2+ and Mibefradil) on Monocrotaline(MCT)-induced pulmonary arterial hypertension (PAH) in rats. Methods Forty male Sprague-Dawley rats were randomly divided into 5 groups: normal control group, MCT group, ProTx-1 group, micromolar Ni2+ group and Mibefradil group (8 cases in each group). The right ventricular systolic pressure (RVSP), the right ventricular hypertrophy index (RVHI), and the index of pulmonary vascular remodeling(MA%) were measured on day 28 after MCT-treatment.Western blot was used to detect the expression of proliferating cell nuclear antigen(PCNA) and Cleaved Caspase-3 in pulmonary artery. Results (1)RVSP and RVHI in MCT group were significantly higher than those in the other 4 groups (F=21.55, P 0.05). (2)MA% in normal control group[(23.43±1.95)%] was lower than that in MCT group[(80.42±4.30)%], ProTx-1 group[(60.35±3.83)%], micromolar Ni2+ group[(62.44±3.81)%] and Mibefradil group[(58.66±4.23)%](F=216.2, P 0.05), however, they were all signi-ficantly lower than that in MCT group.(3)The expression of PCNA in MCT group was higher than that in normal control group, meanwhile, 3 intervention groups were significantly lower than that in MCT group.The expression of Cleaved Caspase-3 in MCT group was higher than that in normal control group, nevertheless, 3 intervention groups showed no significant changes compared with MCT group, respectively. Conclusions T-type calcium channel inhibitors could ameliorate the progression of MCT-PAH in rats, mainly through suppressing the proliferation of pulmonary artery smooth muscle cells. Key words: Pulmonary arterial hypertension; Monocrotaline; Voltage dependent calcium channel; Proliferation; Apoptosis

Rebound depolarization of substantia gelatinosa neurons and its modulatory mechanisms in rat spinal dorsal horn

To investigate the rebound depolarization of substantia gelatinosa (SG) neurons in rat spinal dorsal horn and explore its modulatory mechanisms to provide better insights into rebound depolarization-related diseases. Parasagittal slices of the spinal cord were prepared from 3- to 5-week-old Sprague-Dawley rats. The electrophysiologic characteristics and responses to hyperpolarization stimulation were recorded using whole-cell patch-clamp technique. The effects of hyperpolarization-activated cyclic nucleotide gated cation (HCN) channel blockers and T-type calcium channel blockers on rebound depolarization of the neurons were studied. A total of 63 SG neurons were recorded. Among them, 23 neurons showed no rebound depolarization, 19 neurons showed rebound depolarization without spikes, and 21 neurons showed rebound depolarization with spikes. The action potential thresholds of the neurons without rebound depolarization were significantly higher than those of the neurons with rebound depolarization and spikes (-28.7∓1.6 mV vs -36.0∓2.0 mV, P<0.05). The two HCN channel blockers CsCl and ZD7288 significantly delayed the latency of rebound depolarization with spike from 45.9∓11.6 ms to 121.6∓51.3 ms (P<0.05) and from 36.2∓10.3 ms to 73.6∓13.6 ms (P<0.05), respectively. ZD7288 also significantly prolonged the latency of rebound depolarization without spike from 71.9∓35.1 ms to 267.0∓68.8 ms (P<0.05). The T-type calcium channel blockers NiCl2 and mibefradil strongly decreased the amplitude of rebound depolarization with spike from 19.9∓6.3 mV to 9.5∓4.5 mV (P<0.05) and from 26.1∓9.4 mV to 15.5∓5.0 mV (P<0.05), respectively. Mibefradil also significantly decreased the amplitude of rebound depolarization without spike from 14.3∓3.0 mV to 7.9∓2.0 mV (P<0.05). Nearly two-thirds of the SG neurons have rebound depolarizations modulated by HCN channel and T-type calcium channel.

NIMG-35RESULTS OF EXPLORATORY 18F-FLT PET IMAGING IN TEN RECURRENT HIGH-GRADE GLIOMA PATIENTS TREATED WITH THE SELECTIVE T-TYPE CALCIUM CHANNEL BLOCKER MIBEFRADIL FOLLOWED BY TEMOZOLOMIDE (ABTC TRIAL 1101)

BACKGROUND: Mibefradil (MIB) is a selective T-type calcium channel blocker that has shown preclinical impact on cell cycle activity, specifically arrest at G1/S in tumor cells, suggesting a potential chemo-sensitizing effect if given prior to chemotherapy. In our study, MIB was administered orally QID x 7 days prior to standard temozolomide (150-200 mg/m2 x 5/28d) in recurrent high-grade glioma (HGG) patients. 18F-FLT PET was used as an exploratory imaging biomarker to assess influence of MIB on overall tracer accumulation in tumor. METHODS: 18F-FLT PET was performed in 10 patients treated at the maximum tolerated dose of MIB (87.5 mg po QID) at 5 different institutions. Prior to MIB administration, 2 PET scans were performed as a double baseline to assess repeatability of PET measurements. A third scan was performed on day 7 of MIB treatment to assess 18F-FLT uptake for response. Tumor standardized uptake values (SUVs) were measured at a central laboratory by automatically positioning a 1mL sphere at the region of highest uptake (SUVpeak). RESULTS: The double baseline data indicated 95% limits of repeatability of 18.5% (6.7% within-patient coefficient of variation) for SUVpeak. Two of the 10 patients demonstrated a drop in SUVpeak after 7 days of MIB that exceeded these limits (-47% and -67%). No significant change between double baseline and day 7 of MIB was seen in the remaining 8 patients. CONCLUSIONS: In this first 18F-FLT PET imaging study within a multicenter HGG trial, 18F-FLT PET was found to be feasible and highly repeatable. The results suggest influence of MIB on tumor accumulation of the radiotracer, possibly in part due to alterations in cell cycle activity in a subset of patients, but the precise mechanism remains to be determined as tracer delivery/transport effects may also be contributing to the decline in signal observed in the two patients.

Timed-sequential therapy with mibefradil and temozolomide in patients with recurrent high-grade gliomas: A phase I Adult Brain Tumor Consortium study.

2033 Background: Mibefradil (MIB) is a selective T-type calcium channel blocker that had previously been approved for treatment of hypertension. MIB has shown significant preclinical activity in ma...

Sequential therapy with the selective T-type calcium channel blocker mibefradil and temozolomide in patients with recurrent high-grade gliomas: An Adult Brain Tumor Consortium phase I study (ABTC1101).

TPS2105 Background: Despite recent advances in their treatment, high-grade gliomas (HGG) carry a dismal prognosis. Treatment options at recurrence are particularly limited and a re-challenge with temozolomide (TMZ) frequently appears as the most appropriate systemic treatment option in patients whose progression occurred off TMZ. This study investigates the sequential treatment of mibefradil (MIB), a selective Cav3 calcium channel blocker, and standard dose TMZ. Preclinical data showed that Cav3 inhibitors such as MIB can slow tumor growth without significant effect on normal tissues and can induce cell cycle arrest in cancer cells at the G1/S-phase checkpoint. We hypothesize that withdrawal of MIB could synchronize and release cells into S-phase, thereby potentiating the cytotoxic effect of TMZ. Methods: This trial is an open-label, multicenter phase I study, structured into a dose escalation phase to determine the maximum tolerated dose of MIB (MTD; Primary Objective) and an expansion cohort of 10 patients at the MTD level. Adults with recurrent HGG (WHO grade 3 or 4) who have previously received standard adjuvant therapy with radiation (RT) and TMZ (last dose ≥ 3 months prior to enrollment) and who have not received other cytotoxic therapy (except for carmustine wafers) are eligible. Patients receive oral MIB for 7 days on a 4 x/day (QID) schedule, followed by standard dose TMZ at 150-200 mg/m2 for 5 days each 28-day cycle. Dose finding uses a modified 3+3 design, starting at MIB 25 mg po QID (100 mg/day) with dose increases of 25 mg/dose per dose level. The target dose-limiting toxicity (DLT) rate is ≤ 33%. Secondary Objectives: (1) safety and adverse event analysis (incl. cardiac monitoring during cycle 1), (2) pharmacokinetic profile of MIB, (3) response assessment (RANO criteria), and (4) assessment of the potential effect of MIB on tumor DNA synthesis as determined by fluorothymidine positron emission tomography (FLT PET; extension cohort). Enrollment status as of January 2013: cohort 1 completed without DLT; cohort 2 enrolling at MIB 200 mg/day. Clinical trial information: NCT01480050.

Impact of calcium channel antagonists for estrogen action on the endometrial carcinoma HEC-1A cells

To study the effects of nifedipine and mibefradil on the cell proliferation, apoptosis, migration on the HEC-1A in vitro and also study the mRNA and protein expression levels of the calcium channel alpha1D (Cav1.3) and calcium channel alpha1G (Cav3.1) to discuss the effects of the calcium antagonists on the mechanisms of the endometrial carcinoma. (1) Add 10 µmol/L nifedipine and mibefradil at 15 minutes before adding 10 µmol/L 17β-estradiol (17β-E(2)) and 100 µmol/L b-estradiol-6-(O-carboxymethyl)oxime (E(2)-BSA) to the HEC-1A in different time including 0, 5, 15, 30, 60, 120 minutes. Then the changes of mRNA and protein were detected by reverse transcripiton (RT)-PCR and western-blot. (2) Add 1.25, 2.5, 5, 10, 20, 40, 80, 100 µmol/L nifedipine and mibefradil to the HEC-1A at 24, 48, 96 hours to detect the cell proliferation by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) method. (3) Add 10 µmol/L nifedipine and mibefradil to the HEC-1A, then detect the apoptosis at 0 minute, 30 minutes, 1 hour, 6 hours, 24 hours and migration in vitro at 36 hours with transwell methods. (1) After the pretreated effect of the nifedipine before 17β-E(2), the mRNA express of Cav1.3 genes was lowest at 15 minutes, and returned to the control level after 30 minutes. The protein level didn't change very much in 30 minutes, but rose after 60 minutes. The Cav3.1 genes mRNA express was lowest at 5 minutes, rose at 30 minutes and returned to the 0 minute level gradually. (2) After the pretreated effect of the nifedipine before E(2)-BSA, the Cav1.3 genes mRNA was lowest at 5 minutes and returned at 15 minutes. The protein level rose gradually in 15 minutes but reduced after 15 minutes. The Cav3.1 mRNA and protein level were reduced at every time point. (3) After the pretreated effect of the mibefradil before 17β-E(2), there was no change of mRNA expression of Cav1.3 genes. The protein level rose at 15 and 60 minutes, there was no change in any other time. The Cav3.1 genes mRNA were gradually reduced and the protein level rose at 15 minutes, and there was no change in any other times. (4) After the pretreated effect of the mibefradil before E(2)-BSA, the mRNA and protein of Cav1.3 levels were reduced after 15 minutes. There was no mRNA expression of Cav3.1, while the protein level was lowest at 15 minutes. (5) Nifedipine and mibefradil affected HEC-1A proliferation depended on the different concentration and interval time points. There was significant difference than those in control group (P < 0.05). (6) There were statistical differences in apoptosis rate after adding nifedipine (P < 0.05), while rose at mibefradil treated the same time (24 hours: 8.41 ± 0.07, 0 minute: 3.74 ± 0.18; P < 0.05). (7) The numbers of stained cells after both nifedipine and mibefradil treated reduced more than control group. (1) Nifedipine and mibefradil could inhibit both the effect of the estrogen on the L-type and T-type calcium channel in short time, meanwhile the mibefradil effects last long time. (2) The inhibited effect of the mibefradil on the proliferation, apoptosis and migration of HEC-1A cells in vitro is more significant than that by nifedidipine.

The role of T-type calcium channel in lidocaine-induced neuronal cytotoxicity

Objective To investigate the role of T-type calcium channel in lidocaine-induced neuronal cytotoxicity. Methods SH-SY5Y cell line was a gift from cell biology laboratory of our medical university. The cells were cultured in DMEM liquid culture medium at 37 ℃ in incubator filled with 5 % CO2, and randomly divided into 4 groups （ n = 66 each） ： control group （group C）and M, L and ML groups were exposed to 5 μmol/L mibefradil （a T-type calcium channel blocker）, 10 mmol/L lidocaine and 5 μmol/L mibefradil ＋ 10 mmol/L lidocaine for 24 h. Cell morphology was examined by electronic microscopy at 24 h of drug exposure. Cell viability （by MTT） and neuronal apoptosis （by flow cytometry） were detected immediately before and at 1, 6, 12 and 24 h of exposure to mibefradil or/and lidocaine. Results In C and M groups, the cells demonstrated dendritic protrusions, enlarged nerve processes and dense lattice. After being exposed to lidocaine for 24 h, the dendritic protrusions disappeared, the cells decreased in size, shrinked and became round; the cell viability was significantly decreased while the neuronal apoptosis increased. The lidocaine-induced changes were significantly attenuated by co-incubation with mibefradil. Conclusion T-type calcium channel is involved in lidocaine-induced neuronal cytotoxicity. Key words: Lidocaine ; Calcium channel

Beneficial effects of mibefradil in the control of angina associated with the coronary slow flow phenomenon. A randomised, double-blind, placebo-controlled, crossover study

Beneficial effects of mibefradil in the control of angina associated with the coronary slow flow phenomenon. A randomised, double-blind, placebo-controlled, crossover study

Evidence for a sympatholytic effect of mibefradil in the pithed rat preparation.

The T-type prevalent calcium channel blocker mibefradil (MIB) was shown to possess N-type calcium channel blocking properties. As this particular type of calcium channel is known to be crucially involved in the neuronal release of noradrenaline, we have investigated whether MIB could be a sympatholytic drug. To evaluate the sympathoinhibitory action, the effects of 3 and 10 micromol/kg MIB on the tachycardic effect of electrical stimulation of the preganglionic cardioaccelerator nerves in the pithed rat were investigated. The effect of MIB on the dose-response curve of externally applied noradrenaline was also studied. To compare the results with a classic L-type calcium channel blocker, the experiments were repeated with 3 and 10 micromol/kg verapamil (VER). The maximal increase in heart rate in response to electrical nerve stimulation was 96 +/- 7 bpm (control, n = 6), 70 +/- 6 bpm (3 micromol/kg MIB, n = 8), 57 +/- 6 bpm (10 micromol/kg MIB, n = 5), 93 +/- 5 bpm (3 micromol/kg VER, n = 6) and 46 +/- 7 bpm (10 micromol/kg VER, n = 5). The tachycardic response to electrical stimulation at 1, 5 and 10 Hz was completely blocked by 5 mg/kg intravenous guanethidine. The maximal increase in heart rate in response to noradrenaline was 96 +/- 4 bpm (control, n = 6), 103 +/- 6 (3 micromol/kg MIB, n = 6), 42 +/- 9 bpm (10 micromol/kg MIB, n = 5), 73 +/- 5 bpm (3 micromol/kg VER, n = 5) and 40 +/- 7 bpm (10 micromol/kg VER, n = 6). Under control conditions and in the presence of 3 micromol/kg MIB and VER the maximal effect of noradrenaline was reached at 0.1 micromol/kg whereas in the presence of 10 micromol/kg MIB and VER it was reached at a dose of 1 micromol/kg. MIB at a dose of 3 micromol/kg was significantly more effective in reducing the chronotropic response to electrical stimulation compared with externally applied noradrenaline. For VER the opposite holds true. These differences were not observed with doses of 10 micromol/kg MIB and VER. Mibefradil, besides its direct effect on cardiac T- and L-type calcium channels, reduces the release of noradrenaline from sympathetic nerve endings, most probably by inhibition of presynaptic N-type calcium channels. In the model used this effect is only observable at relatively low concentrations, most probably because of the direct cardiodepressant action of MIB provoked by L-type channel blockade.

Comparison of effects of nitrendipine, lacidipine and mibefradil on postischaemic myocardial damage in isolated rat hearts.

During ischaemia and reperfusion increased cytosolic Ca2+ is one of the important causes for ischaemic-reperfusion myocardial injury. In the present study we compared effects of preferentially L-type Ca2+ antagonists nitrendipine (NT) and lacidipine (LP), and of mibefradil (MB) a Ca2+ antagonist with higher affinity to T- than to L-type channels on myocardial function during reperfusion. Coronary flow (CF), heart rate (HR), left ventricular pressure (LVP), lactate dehydrogenase (LDH) release rate and ECG were registered during 40 min of reperfusion following 30 min of global zero flow ischaemia in Langendorff's isolated rat hearts. Either NT (100 nmol/L) or LP (10 nmol/L) or MB (100 nmol/L) was added to Krebs-Henseleit solution 10 min before ischaemia till the end of experiments. All three drugs influenced CF, HR and LVP. All of them decreased LDH release rate (P < 0.05, in μkat/g.min) when compared with control hearts (53.2 ± 5.1): MB (19.4 ± 4.3) > LP (30.7 ± 6.6) > NT (43.3 ± 2.8). NT reduced the duration of continuous arrhythmias at the beginning of reperfusion (to 59.1 ± 6.1 % of ischaemic controls) as well as the number of single arrhythmic events arising during the whole period of reperfusion (to 26.1 ± 6.0 % of ischaemic controls). MB diminished only single arrhythmic events during reperfusion to 39.1 ± 17.3 % of ischaemic controls. LP did not affect the onset of arrhythmias. Results of our experiments indicate a relatively greater importance of T-type than of L-type Ca2+ channels in the arising of postischaemic myocardial damage.

Effects of mibefradil, a T-type calcium current antagonist, on electrophysiology of Purkinje fibers that survived in the infarcted canine heart.

We studied the effects of mibefradil (MIB), a nondihydropyridine T-type Ca2+ channel antagonist, on T- and L-type Ca2+ (I(CaT), I(CaL)) currents in Purkinje myocytes dispersed from the subendocardium of the left ventricle of normal (NZPC) and 48-hour infarcted (IZPC) hearts. Currents were recorded with Cs+- and EGTA-rich pipettes and in Na+-K+-free external solutions to eliminate overlapping currents. In all cells, I(Ca) was reduced by MIB (0.1 to 10 microM). No change in the time course of decay of peak I(Ca) was noted. Average peak T/L ratio decreased in NZPCs but not IZPCs with 1 microM MIB. Steady-state availability of I(CaL) was altered with 1 microM MIB in both cell types (mean +/- SEM) (V0.5 = -22 +/- 4 mV for NZPC and -25 +/- 5 mV for IZPC before drug; -63 +/- 9 mV for NZPC and -67 +/- 6 mV for IZPC after drug; P < 0.05). For I(CaT), V0.5 (-50 +/- 3 mV for NZPC and -52 +/- 1 mV for IZPC before drug) shifted to -60 +/- 2 mV (NZPC) and -62 +/- 3 mV (IZPC) (P < 0.05) after drug. We also determined the effects of MIB on spontaneously beating Purkinje normal fibers and on depolarized abnormally automatic fibers from the infarcted heart using standard microelectrode techniques. When NZPC and IZPC fibers were superfused with [K+]o = 2.7 mM, MIB 3 microM and 10 microM had no effect on rate or the maximum diastolic potential, but action potential plateau shifted to more negative values, the slope of repolarization phase 3 decreased, and action potential duration increased. MIB blocks L- and T-type Ca2+ currents in Purkinje myocytes but lacks an effect on either normal or abnormal automaticity in Purkinje fibers.

What lessons can be learnt from withdrawal of mibefradil from the market?

What lessons can be learnt from withdrawal of mibefradil from the market?

Two New Warnings Added to Labeling for Mibefradil

Two New Warnings Added to Labeling for Mibefradil

Effect of mibefradil (MIB) on daily ischemic episodes with and without increase in heart rate

Effect of mibefradil (MIB) on daily ischemic episodes with and without increase in heart rate

Effect of Mibefradil (MIB) on Daily Ischemic Episodes With and Without Increase in Heart Rate

Effect of Mibefradil (MIB) on Daily Ischemic Episodes With and Without Increase in Heart Rate

Mibefradil 'safe' and 'very well tolerated'

Mibefradil 'safe' and 'very well tolerated'