Effects Of Verapamil Research Articles

Effect of Verapamil as an Adjuvant to Levobupivacaine in Supraclavicular Brachial Plexus Block.

Background:Many adjuvants have been used with local anesthetics to reduce the time of onset and prolong the duration of analgesia in brachial plexus blocks. However, few studies are there using verapamil as an adjuvant with levobupivacaine.Aims:This study aims to study the effects of verapamil as adjuvant to levobupivacaine in supraclavicular block for upper extremity surgery.Methods:In this double-blinded clinical trial, 60 American Society of Anesthesiologist Class I and II patients posted to undergo upper extremity surgery were divided into 2 different groups randomly. In Group A, the patients received 30 ml levobupivacaine 0.5% plus 2 ml normal saline and Group B patients received 30 ml levobupivacaine 0.5% plus 5 mg verapamil diluted to 2 ml normal saline for supraclavicular block. Time of request for rescue analgesia, onset and duration of sensory motor blocks and changes in hemodynamic parameters were studied and analyzed. P < 0.001 was considered statistically significant.Results:Time for a request for rescue analgesia was 425.80 ± 90.46 min in Group B and 366.13 ± 70.42 min in Group A which was clinically significant. The mean of sensory and motor block onset time in Group B was less than in Group A, the difference between the two groups being statistically significant (P < 0.001). In Group A, mean duration of sensory block was 316.13 ± 91.08 min and in Group B was 375.83 ± 114.48 min, which was statistically significant (P < 0.001).Conclusion:The addition of verapamil as an adjuvant to levobupivacaine in brachial plexus blockade delayed the requirement of rescue analgesia with decreased onset time and prolonged duration of sensory and motor block characteristics.

A Comparison of Gene Expression of Decorin and MMP13 in Hypertrophic Scars Treated With Calcium Channel Blocker, Steroid, and Interferon: A Human-Scar-Carrying Animal Model Study

The formation of hypertrophic scaring (HSc) is an abnormal wound-healing response. In a previous study, an animal model with human scar tissue implanted into nude mice (BALB/c) has been successfully established. The effects of verapamil as well as combination therapy with verapamil and kenacort have been studied and compared. To treat persistent hypertrophic scars, local injection of drugs composed of steroids, calcium channel blockers (CCBs), and interferon might be a good method. What is the best dose of the regimen and what are the mechanisms are also a worthwhile study. Scar specimens were harvested from patients with HSc or Keloid resulting from burn injury, and then implanted to BALB/c-nu nude mice for 4 weeks. Before implantation, the specimen was either injected with or without drugs such as steroids (kenacort), CCBs (verapamil), and interferons (INFα2b), respectively. After the removal of implants, quantitative gene expressions of decorin and collagenase (MMP13) were measured using a real-time polymerase chain reaction to detect their mRNAs. Two way-ANOVA and Post Hoc were used for statistical analysis using the software SPSS 15.0. All drug-treated groups increased the expressions of decorin and MMP13 in comparison with those in noninjected group (p < .001) in a dose-dependent manner. Comparing equal amounts of individual drugs, gene expression of decorin was increased with increasing injection amount, and the best result in low amount of injection (0.02 mL of each) was shown in the group injected with INFα2b followed by kenacort and verapamil. However, the results were changed while injection amount was up to 0.04 mL and the strongest decorin gene expression was found in kenacort injection. Regarding MMP-13 expression, low-amount injection (0.02 mL) of INFα2b has strongest gene expression followed by kenacort and verapamil, but in the large-amount regimes (0.04 mL), verapamil had strongest gene expression followed by INFα2b and kenacort. This study showed that the kenacort, verapamil, and INFα2b all inhibited HSc in a dose-dependent manner through the evidence of gene expression of decorin and MMP13. In comparison with the injections between small amounts of drugs, INFα2b potentiated the strongest decorin and MMP13 expression. On the contrary, among the large-amount injection regimes, kenacrot was more effective on decorin expression as verapamil to MMP13 expression. To decrease side effects from the drugs and produce promising results for the clinical practice, it is suggested to maintain the dose of INFα2b along with an increased dose of verapamil for HSc improvement.

Effect of Verapamil on the formation of adhesions in aseptic peritonitis

Objective. An experimental study of verapamil new properties, such as the regulation of the connective tissue formation. Materials and мethods. The study was conducted in an aseptic inflammation of the peritoneum both on the body and cell culture in simulating haemoperitoneum in rats. The optimal dose (0,1 mg/kg body weight) for intraperitoneal verapamil administration was fixed, which did not provoke significant and reliable changes in cardio- and hemodynamics. Results. It was revealed that verapamil injected intraperitoneally at a dose of 0,1 mg/kg demonstrates a pronounced pharmacological effect against excessive production of the connective tissue in hemoperitoneum. Conclusion. It was proved (in vivo and in vitro) the possibility of drug-induced modulating of the proliferative drug and collagen-producing fibroblast functions by regulating the calcium metabolism in these cells with verapamil.

Antiepileptic effect of calcium channel blockers alone and in combination with phenytoin on MES induced epilepsy in rats

Background: The currently available antiepileptic drugs have a low therapeutic index, and provide satisfactory seizure control in only 60-70% of patients. Calcium channel blocker has shown potentials of a useful add-on drug for the existing antiepileptic drugs. Objectives: To study the effect of calcium channel blockers (CCBs) nifedipine and verapamil on maximal electroshock (MES)-induced convulsions and also to evaluate their effect in combination with Phenytoin. Methods: For this study, Male Wistar rats were used. Effects of nifedipine (5 mg/kg), verapamil (20mg/kg) alone and in combination with phenytoin (25mg/kg) were studied in MES model. Abolition of hind limb tonic extension and reduction of duration of tonic extension was considered as the index for antiepileptic activity in MES. Results: Verapamil and nifedipine produced significant antiepileptic effect alone. Verapamil and nifedipine potentiated the antiepileptic effect of phenytoin sodium. Conclusion: Dose of phenytoin sodium can be reduced in epileptic patients receiving verapamil or nifedipine for some other clinical conditions. Verapamil and nifedipine can also be used alone in the treatment of generalized tonic clonic seizures. However it needs further confirmation to establish clinical utility of calcium channel blockers. KEY WORDS: Nifedipine, verapamil, phenytoin, MES seizure rats.

Effects of Propranolol and Verapamil on Changes in TQ and ST Segment Potentials During Graded Coronary Flow Reduction in a Porcine Myocardial Ischemia Model.

Acute myocardial ischemia causes TQ depression and ST elevation. However, the effects of cardioprotective drugs such as β-blockers and Ca++-antagonists on the extent of TQ depression, ST elevation, and myocardial ischemic injury are not fully understood.We created a carotid-coronary shunt in 30 pigs, and extracellular K+ ([K+]e), TQ, and ST segments were recorded simultaneously with K+-selective plunge electrodes placed in the left anterior descending artery (LAD) distribution during graded LAD flow reduction before and after administration of propranolol or verapamil. Unipolar DC-coupled electrograms were recorded from the reference pole of the K+-selective plunge electrodes. The microvolt readings from the K+-selective electrodes were converted to [K+]e and then to the changes in potassium equilibrium potential (ΔEK). The shunted LAD flow was reduced in a stepwise fashion at 5-minute intervals.segment depression at the similar ΔEK was not affected by propranolol or verapamil. However, ST segment elevation was reduced by propranolol but exacerbated by verapamil at the similar ΔEK.TQ-ST changes recorded by AC coupled ECG are not a reliable index of ischemia and therefore cannot be used to evaluate the effects of drugs that might affect the electrophysiologic properties of ischemic myocardium.

Сравнительное влияние бисопролола и верапамила на центральное и периферическое АД у больных артериальной гипертензией

Сравнительное влияние бисопролола и верапамила на центральное и периферическое АД у больных артериальной гипертензией

Coronary Flow Parameters Assessed by Transesophageal Echocardiography in Patients with Coronary Artery Ectasia Baseline Measurements and the Effects of Intravenous Verapamil

Background and rationale: Coronary artery ectasia (defined as luminal dilatation 1.5 to 2 times the adjacent healthy coronary artery or the diameter of the corresponding coronary artery in the control group in case of diffuse ectasia) is an uncommon disorder, usually associated with underlying myocardial ischemia. Micro-circulatory dysfunction has been demonstrated as one possible mechanism to explain ischemia in this disorder. Calcium antagonists have been proven to relieve microvascular spasm. Aim of the study: To test the hypothesis that relieving microvascular spasm in patients with coronary artery ectasia, through intravenous administration of verapamil, may result in improvement of microvascular coronary flow as reflected by coronary flow parameters assessed by transesophageal echocardiography (TEE). Patients and methods: Thirty patients with angiographically documented coronary artery ectasia of the left anterior descending artery were prospectively enrolled in the current study. Ten patients with normal coronary arteries were included as controls. All forty patients underwent TEE using pulsed wave Doppler (PWD) to measure peak systolic and diastolic velocities (m/sec); systolic, diastolic and total velocity time integrals (cm); and the systolic, diastolic and total coronary blood flow (cm³/min) in the proximal LAD before and after intravenous injection of verapamil (0.1 mg/kg). Results: Resting systolic, diastolic, and total coronary blood flow (cm³/min) were significantly higher in patients with ectasia compared to normal subjects (60.83 ± 27.7 cm³/min versus 25.31 ± 9.01 cm³/min, p<0.001; 126.89 ± 49.22 cm³/min versus 53.15 ± 18.30 cm³/min, p<0.001; and 188.02 ± 70.36 cm³/min versus 78.46 ± 25.97 cm³/min, p<0.001). There was a trend, not reaching statistical significance, towards higher basal peak velocities in normal subjects compared to patients with ectasia. In patients with coronary artery ectasia, intravenous injection of verapamil resulted in an increase in all observed coronary flow parameters including: peak systolic velocity (m/sec) from 0.19 ± 0.05 to 0.21 ± 0.04, p=<0.05, peak diastolic velocity (m/sec) from 0.39 ± 0.11 to 0.48 ± 0.15, p=<0.001, systolic velocity time integral (cm) from 3.0 ± 1.05 to 3.38 ± 0.78, p=<0.05, diastolic velocity time integral (cm) from 6.22 ± 1.97 to 8.42 ± 2.09, p=<0.001; total velocity time integral (cm) from 9.22 ± 2.73 to 11.8 ± 2.64, p=<0.001, systolic coronary blood flow (cm³/min) from 60.83 ± 27.7 to 69.0 ± 22.7, p=<0.05, diastolic coronary blood flow (cm³/min) from 126.89 ± 49.22 to 173.01 ± 62.4 p=<0.001, and total coronary blood flow (cm³/min) from 188.02 ± 70.36 to 242.0 ± 81.82, p=<0.001. Conclusion: Intravenous administration of verapamil resulted in statistically significant improvement of coronary flow parameters in patients with coronary artery ectasia. Further studies are needed to confirm whether continued treatment with verapamil translates to symptomatic improvement in the clinical setting.

Kinetic Aspects of Verapamil Binding (On-Rate) on Wild-Type and Six hKv1.3 Mutant Channels

Background/Aims: The human-voltage gated K_v1.3 channel (hK_v1.3) is expressed in T- and B lymphocytes. Verapamil is able to block hK_v1.3 channels. We characterized the effect of verapamil on currents through hK_v1.3 channels paying special attention to the on-rate (k_on) of verapamil. By comparing on-rates obtained in wild-type (wt) and mutant channels a binding pocket for verapamil and impacts of different amino acid residues should be investigated. Methods: Using the whole-cell patch clamp technique the action of verapamil on currents through wild-type and six hK_v1.3 mutant channels in the open state was investigated by measuring the time course of the open channel block in order to calculate k_on of verapamil. Results: The on-rate of verapamil to block current through hK_v1.3_T419C mutant channels is similar to that obtained for hK_v1.3_wt channels whereas the on-rate of verapamil to block currents through hK_v1.3_L417C and hK_v1.3_L418C mutant channels was ∼ 3 times slower compared to in wt channels. The on-rate of verapamil to block currents through hK_v1.3_L346C and the double mutant hK_v1.3_L346C_L418C channel was ∼ 2 times slower compared to that obtained in the wt channel. The hK_v1.3_I420C mutant channel reduced the on-rate of verapamil to block currents ∼ 6 fold. Conclusions: We conclude that position 420 in hK_v1.3 channels maximally interferes with verapamil reaching its binding site to block the channel. Positions 417 and 418 in hK_v1.3 channels partially hinder verapamil reaching its binding site to block the channel whereas position 419 may not interfere with verapamil at all. Mutant hK_v1.3_L346C and hK_v1.3_L346C_L418C mutant channels might indirectly influence the ability of verapamil reaching its binding site to block current.

Selective and Irreversible Induction of Necroptotic Cell Death in Lung Tumorspheres by Short-Term Exposure to Verapamil in Combination with Sorafenib.

The presence of highly resistant cancer cells and the toxicity to normal cells are key factors that limit chemotherapy. Here, we used two models of highly resistant lung cancer cells: (1) adherent cells growing under prolonged periods of serum starvation (PPSS) and (2) cells growing as floating tumorspheres (FTs) to evaluate the effect of Verapamil (VP) in combination with Sorafenib (SF). Compared to cells growing under routine culture conditions (RCCs), PPPS cells or FTs were highly sensitive to short-term exposure (24 h) to VP 100 μM + SF 5 μM (VP100 + SF5). Recovery experiments exposing cells to VP100 + SF5 for 24 h followed by incubation in drug-free media for 48 h demonstrated that while PPSS as well as FT cells were unable to recover, cancer cells and the noncancerous cell line Beas-2B growing under RCCs were less sensitive and were also able to recover significantly. VP100 + SF5 induced significant changes in the expression of protein associated with apoptosis, autophagy, and to a lesser extent necroptosis. Coincubation experiments with z-VAD-FMK, necrostatin 1, or chloroquine showed evidence that necroptosis played a central role. Our data demonstrates that highly resistant cancer cells can be selectively eliminated by VP + SF and that necroptosis plays a central role.

Effect of calcium channel blockers on primary cultured human urethra scar fibroblasts

To investigate effects of verapamil on primary cultured human urethral scar fibroblasts (USFs) and to provide basis for protecting the formation of urethra scar. Methods: The cell proliferation was evaluated with the cell counting kit (CCK)-8 method after USFs were incubated various verapamil concentrations (50, 100, 150, 200, or 250 μmol/L) or solvent for 12, 24, or 48 h. The protein level of matrix metalloproteinase (MMP) was evaluated with ELISA after cells were incubated with verapamil (100 μmol/L) or solvent (control cells) for 24 h. Results: The proliferation of USFs was obviously suppressed after verapamil treatment, which was in a dose-dependent and time-dependent manner. Meanwhile, the protein levels of MMP-2 and MMP-9 in the verapamil treatment group increased obviously compared with those of the control groups (P<0.05). Conclusion: Calcium channel blockers may prevent the excessive formation of urethra scar by inhibiting the proliferation of urethral scar fibroblasts and enhancing the activity of MMP.

Lipid Emulsion Inhibits Apoptosis Induced by a Toxic Dose of Verapamil via the Delta-Opioid Receptor in H9c2 Rat Cardiomyoblasts.

The goals of this study were to investigate the effects of lipid emulsion (LE) on apoptosis induced by a toxic dose of verapamil in H9c2 cells and to elucidate the associated cellular mechanism. The effects of LE alone and combined with an inhibitor on the decreases in cell counts and viability induced by verapamil and diltiazem were examined using the MTT assay. The effects of verapamil alone, combined LE and verapamil treatment, and combined inhibitor, LE and verapamil treatment on cleaved caspase-3, caspase-8 and Bax expression, were examined using Western blotting. The effects of verapamil alone and combined with LE on the number of TUNEL-positive H9c2 cells were also examined. LE attenuated the decreases in cell counts and viability induced by verapamil and diltiazem. However, the magnitude of the LE-mediated attenuation of decreased cell viability was enhanced by verapamil compared with diltiazem treatment. Naloxone, naltrindole hydrochloride, LY294002 and MK-2206 inhibited the LE-mediated attenuation of increased cleaved caspase-3 and caspase-8 expression induced by verapamil. LE attenuated the increase in the number of TUNEL-positive cell induced by verapamil. These results suggest that LE attenuates apoptosis induced by verapamil via activation of the delta-opioid receptor, phosphoinositide 3-kinase and Akt.

Comparative effect and safety of verapamil in keloid and hypertrophic scar treatment: a meta-analysis.

BackgroundKeloids and hypertrophic scars are the most common types of pathological scarring. Traditionally, keloids have been considered as a result of aberrant wound healing, involving excessive fibroblast participation that is characterized by hyalinized collagen bundles. However, the usefulness of this characterization has been questioned. In recent years, studies have reported the appropriate use of verapamil for keloids and hypertrophic scars.MethodsSearches were conducted on the databases Medline, Embase, Cochrane, PubMed, and China National Knowledge Infrastructure from 2006 to July 2016. State12.0 was used for literature review, data extraction, and meta-analysis. Treatment groups were divided into verapamil and nonverapamil group. Nonverapamil group includes steroids and intense pulsed light (IPL) therapy. Total effective rates include cure rate and effective rate. Cure: skin lesions were completely flattened, became soft and symptoms disappeared. Efficacy: skin lesions subsided, patient significantly reduced symptoms. Inefficient definition of skin was progression free or became worse. Random-effects model was used for the meta-analysis.ResultsSix studies that included 331 patients with keloids and hypertrophic scars were analyzed. Analysis of the total effective rate of skin healing was performed. The total effective rates in the two groups were 54.07% (verapamil) and 53.18% (nonverapamil), respectively. The meta-analysis showed that there was no difference between the two groups. We also compared the adverse reactions between the verapamil treatment group and the steroids treatment group in two studies, and the result indicated that the verapamil group showed less adverse reactions.ConclusionThere were no differences between the application of verapamil and nonverapamil group in keloids and hypertrophic scars treatment. Verapamil could act as an effective alternative modality in the prevention and treatment of keloid and hypertrophic scars. A larger number of studies are required to confirm our conclusion.

Effects of Verapamil on Bone Cancer Cells in vitro

Effects of Verapamil on Bone Cancer Cells in vitro

Current statins show calcium channel blocking activity through voltage gated channels.

BackgroundStatins are used for treatment of hypercholestremia. Common adverse reports associated with use of statins are generalized bodyache, rhabdomyolysis, muscles weakness and gastrointestinal disorders. The current work is an attempt to explain how smooth muscles of gastrointestinal tissues are affected by the current statins (Simvastatin, atorvastatin, fluvastatin and rosuvastatin).MethodsEffects of the current statins were studied on spontaneous activity of isolated rabbits’ jejunal preparations. Different molar concentrations (10−12–10−2M) of the statins were applied on spontaneously contracting rabbits’ jejunal preparations. As statins relaxed spontaneous activity, so we tested the statins on KCl (80 mM) induced contractions in similar test concentrations. Positive relaxant statins were tested again through construction of Calcium Concentration Response Curves (CCRCs) in the absence and presence of the statins using verapamil, a standard calcium channel blocker. CCRCs of statins were compared with CCRCs of verapamil.ResultsSimvastatin, atorvastatin, fluvastatin and rosuvastatin relaxed the spontaneous and KCl-induced contractions. IC50 for simvastatin on spontaneous rabbit’s jejunal preparations is −5.08 ± 0.1 Log 10 M. Similarly, IC50 for KCl-induced contractions is −4.25 ± 0.01 Log 10 M. Mean IC50 (Log 10 M) for atorvastatin on spontaneous rabbit’s jejunal preparations and KCl-induced contractions are −5.19 ± 0.07 and −4.37 ± 0.09, respectively. Fluvastatin relaxed spontaneous activity of rabbits’ jejunal preparations with an IC50 (Log 10 M) −4.5 ± 0.03. Rosuvastatin relaxed spontaneous as well as KCl (80 mM) induced contractions with respective IC50 (Log 10 M) −3.62 ± 0.04 and −4.57 ± 0.06. In case of CCRCs, tissues pre-treated with 4.6 μg/ml of simvastatin, have IC50 = −1.84 ± 0.03 [log (Ca++) M] vs control IC50 = −2.54 ± 0.04 [log (Ca++) M]. Similarly, atorvastatin, fluvastatin and rosuvastatin produced significant right shift in IC50 for CCRCs (P ≤ 0.05). In case of verapamil, IC50 for control curves is −2.45 ± 0.06 [log (Ca ++) M], while IC50 in presence of verapamil (0.1 μM) is −1.69 ± 0.05 [log (Ca ++) M]. Statins produced right shift in the IC50 of CCRCs. The effects of statins are like that of effects of verapamil, a standard calcium channel blocker.ConclusionsOur findings suggest that current statins have calcium antagonistic effects that act on voltage gated calcium channels that may provide a rationale for cause muscle weakness and gastrointestinal disorders.

Sex-specific pharmacological modulation of autophagic process in human umbilical artery smooth muscle cells

Sex has largely been neglected in cell studies. Therefore, we investigated the occurrence of sexual dimorphism in human umbilical artery smooth muscle cells (HUASMCs). In particular, we investigated the existence of sex differences in basal and in drug-induced autophagy, a process involved in cardiovascular diseases.HUASMCs were isolated from healthy and normal weight male and female newborns (MHUASMCs and FHUASMCs, respectively). Expression of the primary molecules involved in the autophagic process [beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)], and PmTOR were detected using western blotting in basal conditions, after serum starvation, rapamycin and verapamil treatments.The level of constitutive autophagy, measured as the LC3II/I ratio, was similar in male and female HUASMCs in the basal condition. Serum starvation promoted autophagy in both cell types, but the increase was more pronounced in FHUASMCs, while 250nM rapamycin induced autophagy only in female cells. Moreover, the level of verapamil-induced autophagy was not different between the two sexes. Notably, in the basal condition, Beclin-1 was more elevated in MHUASMCs than in FHUASMCs, and the difference disappeared after serum starvation and exposure to rapamycin. After exposure to verapamil, the differences in Beclin-1 increased, with more elevated expression levels in female cells. PmTor did not differ in basal conditions, but it was significantly down-regulated by starvation only in FHUASMCs and by rapamycin both in male and female cells. Finally, a strong negative correlation was observed between the newborn’s weight and basal autophagy in female cells and between the newborn’s weight and the LC3II/I ratio in male verapamil-treated cells.These results indicate that sex-differences begin in utero, are parameter-specific and drug specific suggesting that HUASMCs are a suitable model for the screening of drugs and to study the influence of sex. The sex differences in the autophagy suggest sexually different pharmacodynamics effects of verapamil and rapamycin.

Verapamil, a Calcium-Channel Blocker, Improves the Wound Healing Process in Rats with Excisional Full-Thickness Skin Wounds Based on Stereological Parameters.

Calcium can play noticeable roles in the wound-healing process, such as its effects on organization of F-actinin collagen bundles by fibroblasts at the injury site. In addition, calcium-channel blockers such as verapamil have antioxidant activity by increasing nitric oxide production that promotes angiogenesis, proliferation of fibroblasts, and endothelial cells in the skin-regeneration process. Therefore, in this study, the authors' objective was to investigate the effects of verapamil on the process of wound healing in rat models according to stereological parameters. In this experimental study, 36 male Wistar rats were randomly divided into 3 groups (n = 12): the control group that received no treatment, gel-base-treated group, and the 5% verapamil gel-treated group. Treatments were done every 24 hours for 15 days. Wound closure rate, volume densities of the collagen bundles and the vessels, vessel's length density and mean diameter, and fibroblast populations were estimated using stereological methods and were analyzed by the Kruskal-Wallis and Mann-Whitney U tests; P < .05 was considered statistically significant. The verapamil-treated group showed a faster wound closure rate in comparison with control and gel-base groups (P = .007 and P = .011). The numerical density of fibroblasts, volume density of collagen bundles, mean diameter, and volume densities of the vessels in the verapamil group were significantly higher than those in the control and the base groups (P < .005). The authors showed that verapamil has the ability to improve wound healing by enhancing fibroblast proliferation, collagen bundle synthesis, and revascularization in skin injuries.

Abstract 4683: Verapamil and tamoxifen modulate ABCB1 expression in multidrug-resistant cells and resensitize them to conventional chemotherapy

Abstract Multidrug-resistant (MDR) tumors are an increasingly important obstacle in cancer treatment, wherein many cases are associated with the overexpression of P-glycoprotein 1 (P-gp1, ABCB1). Previous efforts to sensitize ABCB1-expressing tumor cells to anti-cancer drugs were associated with severe side effects, so interest in clinical trials using these drugs has dwindled. Studies have shown P-glycoprotein-overexpressing cells to be hyper sensitive (or collaterally sensitive) to a diverse group of non-toxic compounds. Given earlier results demonstrating a significant increase in ABCB1 expression post-chemotherapeutic treatment of cancer patients (e.g., breast, ovarian, myeloma, and acute myeloid leukemia), and the role of ABCB1 in drug resistance, it was determined that targeting ABCB1-expressing tumor cells with effective collateral sensitivity drugs should increase the effectiveness of current chemotherapeutic treatments. In this report, it was of interest to determine the effect of the collateral sensitivity drugs verapamil and tamoxifen on P-glycoprotein 1 expression at the level of cells and individual cell clones. Clones from P-gp1-overexpressing Chinese hamster ovarian cell lines (CHRC5) or triple negative breast cancer cells (MDA-MB-231/400 nM doxo) were treated with varying levels of collateral sensitivity drugs and ABCB1 expression was determined by Western blots and ELISAs. The sensitivity of each cell clone to anti-cancer or collateral sensitivity drugs was determined using cytotoxicity assays. Our results demonstrate a drop in ABCB1 expression in each clone, together with decreased collateral sensitivity and overall increased sensitivity to anti-cancer drugs in cell lines selected with verapamil and tamoxifen. Work is in progress to study the various mechanisms responsible for this drop in ABCB1 expression and its impact on treatment outcome. Citation Format: Georgia Limniatis, Elias Georges. Verapamil and tamoxifen modulate ABCB1 expression in multidrug-resistant cells and resensitize them to conventional chemotherapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4683.

The effects of verapamil on the pharmacokinetics of curculigoside in rats

Context: Clarifying the potential mechanism of the poor oral bioavailability of curculigoside would be helpful for for investigating pharmacological effects and clinical applications.Objective: To clarify the main mechanism for poor oral bioavailability.Materials and methods: First, the pharmacokinetics of curculigoside (20 mg/kg) in rats with and without pretreatment with verapamil (10 mg/kg) was determined using a sensitive and reliable LC-MS method. Then the effects of verapamil on the transport and metabolic stability of curculigoside were investigated using Caco-2 cell transwell model and rat liver microsome incubation systems.Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 60.17 ng/mL to 93.66 ng/mL) and AUC0−t (from 289.57 to 764.02 ng·h/mL) of curculigoside. The Caco-2 cell experiments indicated that the efflux ratio of curculigoside was 3.92 (PappAB 6.43 ± 0.57 × 10 −7 cm/s; PappBA 2.52 ± 0.37 × 10 −36 cm/s), P-gp might be involved in the transport of curculigoside, and verapamil could inhibit the efflux of curculigoside and increase the absorption of curculigoside significantly in the Caco-2 cell monolayer. Additionally, the rat liver microsome incubation experiments indicated that verapamil could significantly decrease the intrinsic clearance rate of curculigoside (from 38.8 to 23.6 μL/min/mg protein).Discussion and conclusion: These results indicated that verapamil could significantly change the pharmacokinetic profiles of curculigoside in rats, the poor absorption due to P-gp mediated efflux in intestine and high intrinsic clearance rate in rat liver may be the main reason for the poor oral absolute bioavailability of curculigoside.

Hypoxia can impair doxorubicin resistance of non-small cell lung cancer cells by inhibiting MRP1 and P-gp expression and boosting the chemosensitizing effects of MRP1 and P-gp blockers.

Non-small cell lung cancers (NSCLCs) frequently exhibit resistance to therapeutic drugs, which seriously hampers their treatment. Here, we set out to assess the roles of the multidrug resistance protein 1 (MRP1) and P-glycoprotein (P-gp) in the doxorubicin (DOX) resistance of NSCLC cells, as well as the putative therapeutic efficacy of MRP1 and P-gp blockers on DOX-treated NSCLC cells. The impact of DOX on cell survival, DOX efflux and MRP1 and P-gp expression was assessed in 5 different NSCLC-derived cell lines (parental CH27, A549, H1299, H460, and DOX resistant CH27) in the absence or presence of MK571 (MRP1 inhibitor) or Verapamil (P-gp inhibitor), under both normoxic and hypoxic conditions. We found that in response to DOX treatment, NSCLC cells that express high levels of MRP1 and P-gp (such as CH27) showed a better DOX efflux and a higher DOX resistance. MK571 and Verapamil were found to abolish DOX resistance and to act as chemosensitizers for DOX therapy in all cell lines tested. We also found that hypoxia could inhibit MRP1 and P-gp expression in a HIF-1α-dependent manner, abolish DOX resistance and boost the chemosensitizer effect of MK571 and Verapamil on DOX treatment of all the NSCLC cells tested, except the DOX-resistant CH27 cells. From our data we conclude that MRP1 and P-gp play critical roles in the DOX resistance of the NSCLC cells tested. MRP1 and P-gp targeted therapy using MK571, Verapamil, CoCl2 or ambient hypoxia appeared to be promising in abolishing the DOX efflux and DOX resistance of the NSCLC cells. The putative therapeutic efficacies of MRP1 and/or P-gp blockers on NSCLC cells are worthy of note.

Hyperoxaluria-induced tubular ischemia: the effects of verapamil on the antioxidant capacity of the affected kidneys.

To evaluate the potential protective effects of a calcium channel blocker (Verapamil) on the oxidative stress related changes with an emphasis on the antioxidant capacity of the kidneys an experimental study in rats was performed. A total of 44 rats have been included. Hyperoxaluria was induced in Group 1 by continuous administration of ethylene glycol (EG). Animals in Group 2 received Verapamil in addition to EG. Animals in Group 3 constituted the control group. In addition to the evaluation of tissue and serum levels of three scavenging enzymes, NO, MDA and T-AOC; the presence and degree of crystal formation in renal parenchyma were evaluated in all animals after 7 and 28days. Our data demonstrated that in addition to the lower level of all three scavenging enzymes (SOD, CAT and GSH) particularly during late phase evaluation (4weeks); the total antioxidant capacity (T-AOC) of these kidneys were also higher when compared with the animals receiving EG only. Tissue and serum levels of both NO and MDA indicated the preventive effect of Verapamil on the oxidative stress induced changes. Very limited or no crystallization in the kidneys treated with verapamil during early and late phase examination was observed when compared with considerable crystal formation in Group 2 animals. Verapamil treatment may preserve the oxidant capacity of the kidneys and subsequently limit the crystal deposition induced by hyperoxaluria. Verapamil could therefore be considered in the management of kidney stone formation particularly in cases with recurrent kidney stone disease.