Idiopathic left fascicular ventricular tachycardia in children and adolescents / Taquicardia ventricular fascicular izquierda idiopática en niños y adolescentes

Abstract Background: Idiopathic ventricular tachycardia (VT) in children with structurally normal hearts is generally unrelated to the risk of sudden arrhythmic death. Still, it may be associated with deterioration in the quality of life. VT involving the fascicular conduction system is the most typical form of idiopathic left VT. In this retrospective study, we describe the experience of the clinical presentation, catheter ablation, and long-term follow-up of left fascicular VT in children. Methods: An electrophysiological study was performed on consecutive children at a single tertiary center. Clinical fascicular left VT was induced by programmed stimulation, and catheter ablation was guided searching for Purkinje potentials. Results: We included 18 patients (0.8 patients/year): 14 (77.8%) males and four females. The mean age of the first VT episode was 8.5 ± 5 years. Intravenous verapamil administration was effective for paroxysmal fascicular VT but not for prevention of recurrences. The mean age at the time of catheter ablation was 11.1 ± 3.8 years (8 months-16 years). The mean weight was 36.8 ± 16.4 kg (8.7-58 kg). A 100% success rate was observed with catheter ablation after repeated procedures without major complications. Mean follow-up was 2.0 ± 1.2 years (1.0-4.0 years, median 1.5), with permanent success in all patients and no antiarrhythmic drug administration. Conclusions: Fascicular VT has an adverse clinical course in children. In most cases, this condition is drug refractory. Catheter ablation is successful and safe treatment and should represent the first-line approach in symptomatic children.

Resumen Introducción: La taquicardia ventricular (TV) idiopática en niños con corazón estructuralmente normal generalmente no se relaciona con el riesgo de muerte súbita arrítmica, pero puede asociarse con deterioro de la calidad de vida. La TV que involucra el sistema de conducción fascicular es la forma más común de TV izquierda idiopática. En este estudio retrospectivo se describe la experiencia de presentación clínica, ablación con catéter y seguimiento a largo plazo de TV fascicular en niños. Métodos: Se llevó a cabo un estudio electrofisiológico en niños consecutivos en un centro terciario. La TV fascicular clínica se indujo mediante la estimulación programada y la ablación con catéter fue guiada buscando el registro de potenciales de Purkinje. Resultados: Se incluyeron 18 pacientes (0.8 pacientes/año): 14 (77.8%) de sexo masculino y cuatro de sexo femenino. La media de edad a la cual ocurrió el primer episodio fue de 8.5 ± 5 años. La administración intravenosa de verapamilo fue eficaz para la TV fascicular paroxística, pero no para prevención de recurrencias. La media de edad de la ablación con catéter fue de 11.1 ± 3.8 años (8 meses-16 años). La media del peso fue 36.8 ± 16.4 kg (8.7-58 kg). Se observó el 100% de éxito con la ablación con catéter después de procedimientos repetidos sin complicaciones mayores. La media de seguimiento fue de 2.0 ± 1.2 años (1.0-4.0, mediana de 1.5 años) con éxito permanente en todos los pacientes y sin administración de fármacos antiarrítmicos. Conclusiones: En niños, el curso clínico de la TV fascicular es adverso. Además, en la mayoría de los casos, esta condición es refractaria a fármacos. La ablación con catéter resulta exitosa y segura y debe representar el abordaje de primera línea en niños sintomáticos.

Preparation and in vitro evaluation of fused deposition modeling 3D printed verapa-mil hydrochloride gastric floating formulations / 北京大学学报(医学版)

OBJECTIVE@#To explore the feasibility of preparing gastric floating formulations by fused de-position modeling (FDM) 3D printing technology, to evaluate the in vitro properties of the prepared FDM 3D printed gastric floating formulations, and to compare the influence of different external shapes of the formulation with their in vitro properties.@*METHODS@#Verapamil hydrochloride and polyvinyl alcohol (PVA) were used as the model drug and the excipient, respectively. The capsule-shaped and hemisphere-shaped gastric floating formulations were then prepared by FDM 3D printing. The infill percentages were 15%, the layer heights were 0.2 mm, and the roof or floor thicknesses were 0.8 mm for both the 3D printed formulations, while the number of shells was 3 and 4 for capsule-shaped and hemisphere-shaped formulation, respectively. Scanning electron microscopy (SEM) was used to observe the morpho-logy of the surface and cross section of the formulations. Gravimetric method was adopted to measure the weights of the formulations. Texture analyzer was employed to evaluate the hardness of the formulations. High performance liquid chromatography method was used to determine the drug contents of the formulations. The in vitro floating and drug release behavior of the formulations were also characterized.@*RESULTS@#SEM showed that the appearance of the FDM 3D printed gastric floating formulations were both intact and free from defects with the filling structure which was consistent with the design. The weight variations of the two formulations were relatively low, indicating a high reproducibility of the 3D printing fabrication. Above 800.0 N of hardness was obtained in two mutually perpendicular directions for the two formulations. The drug contents of the two formulations approached to 100%, showing no drug loss during the 3D printing process. The two formulations floated in vitro without any lag time, and the in vitro floating time of the capsule-shaped and hemisphere-shaped formulation were (3.97±0.41) h and (4.48±0.21) h, respectively. The in vitro release of the two formulations was significantly slower than that of the commercially available immediate-release tablets.@*CONCLUSION@#The capsule-shaped and hemisphere-shaped verapamil hydrochloride gastric floating formulations were prepared by FDM 3D printing technology successfully. Only the floating time was found to be influenced by the external shape of the 3D printed formulations in this study.

Aspirin plus verapamil relieves angina and perfusion abnormalities in patients with coronary microvascular dysfunction and Chagas disease: a pilot non-randomized study

Abstract INTRODUCTION: Most patients with chronic cardiomyopathy of Chagas disease (CCCD) harbor a secondary cause of coronary microvascular dysfunction (CMD), for which there is no evidence-based therapy. We evaluated the impact of verapamil plus aspirin on symptoms and perfusion abnormalities in patients with CCCD and CMD. METHODS: Consecutive patients with angina pectoris, who had neither coronary artery obstructions nor moderate-severe left ventricular dysfunction (left ventricular ejection fraction > 40%) despite showing wall motion abnormalities on ventriculography, were referred for invasive angiography and tested for Chagas disease. Thirty-two patients with confirmed CCCD and ischemia on stress-rest SPECT myocardial perfusion scintigraphy (MPS) were included. Clinical evaluation, quality of life (EQ-5D/ Seattle Angina Questionnaire), and MPS were assessed before and after 3 months of treatment with oral verapamil plus aspirin (n=26) or placebo (n=6). RESULTS: The mean patient age was 64 years, and 18 (56%) were female. The ischemic index summed difference score (SDS) in MPS was significantly reduced by 55.6% after aspirin+verapamil treatment. A decrease in SDS was observed in 20 (77%) participants, and in 10 participants, no more ischemia could be detected. Enhancements in quality of life were also detected. No change in symptoms or MPS was observed in the placebo group. CONCLUSIONS: This low-cost 3-month treatment for patients diagnosed with CCCD and CMD was safe and resulted in a 55.6% reduction in ischemic burden, symptomatic improvement, and better quality of life.

New Therapeutical Procedures of Peyronie’s Disease: Transfer Capacitive Resistive Energy in Association with Hydroelectrophoresis with Verapamil

Introduction: Efficacy evaluation of a new treatment, improving the symptoms of Peyronie’s disease (PD) inpatients with a curvature deformity < 30° and with an onset of symptoms of at least 6 months before the treatment.We investigated the effects of Transfer Capacitive Resistive Energy (TCARE) therapy accompanied byhydroelectrophoresis (HEP), a new electromotive system, for the transcutaneous delivery of Verapamil in menwith PD. Materials and Methods: Sixty-one patients affected by PD were enrolled. They were randomly dividedinto two groups: Group 1 (n. 30 patients, median age 56, range 49-62 yrs) was assigned to receive only TCARE;Group 2 (n. 31 patients; median age 58, range 51-60 yrs) received both TCARE and HEP. Every patientunderwent 16 treatment sessions, 2 sessions a week for each group. TCARE was performed with resistive energyand each treatment lasted 15 minutes. In Group 2 TCARE was also followed by HEP (with Hydro4and apparatus,Swiss4Med SA, Morbio Inferiore, Switzerland). HEP delivered 10 mg/4ml of Verapamil per session (2 ampoulesof Verapamil 5mg/2ml each; Isoptin, BGP products, Rome, Italy) for a 20-minute lasting. The endpoints were: apain increase in erection, the International Index of Erectile Function questionnaire (IIEF-15) scale score, andpenile curvature (in degrees). They were evaluated at the beginning of the study, at the end and three months afterthe discontinuation of the treatment. The pain was measured by using the Numeric Rating Scale (NRS) for pain1-10 and the erectile function by IIEF15. The penile curvature was measured instead by using photography, apersonal paper protractor after injection of PGE1 10 mcg. Some side effects during or immediately after thetreatment were recorded. Statistical analysis was performed using ANOVA for repeated measurements, correctedwith Bonferroni. The side effects were compared between the two groups using the Chi-square Test (test χ2).Results: The pain, the erectile function, and the penile curvature were all significantly improved with bothtreatments (p<0.001). In Group 2 (TCARE + HEP) the improvement was greater than Group 1 (p<0.001 for IIEFand curvature; p <0.05 for pain). The amelioration was maintained until three months after the end of treatment.No relevant side effects were observed or indicated by the patients. Conclusions: TCARE followed by Verapamiladministration by HEP is an effective and safe treatment for PD.

Evaluating the efficacy of intralesional verapamil over intralesional triamcinolone in management of keloid: an evidence based case report

Author present a case of 22-year-old female with keloid due to previous trauma three years prior. Keloids are excessive fibroblast growth present in pathological scars. Therapy for keloids still remain a challenge requiring an effective intervention. While the first line has always been the use of intralesional triamcinolone, recently intralesional verapamil has also been known to reduce growth of keloids. Aim of the study was to evaluate the efficacy of both of these drug options. Literature searching was performed from three databases namely PubMed, Cochrane library and Science Direct. Findings were systematically narrowed down through inclusion and exclusion criteria into four relevant randomized controlled trials. Selected studies were critically appraised for its validity, importance, and applicability using tools from Oxford Center of Evidence-Based Medicine. Both intralesional triamcinolone and verapamil show their own benefit and risk. Triamcinolone is more effective in reducing keloid with faster improvement as seen in scar height reduction, vascularity, pigmentation and pliability. However, verapamil has fewer side effects which serve as a safer treatment option. More clinical trials in the future may be needed to obtain more conclusive result.

Diethylmorphine effect on action potential and calcium ion current of neonatal rat cardiomyocytes in vitro / 中国组织工程研究

BACKGROUND: Opioids can regulate the changes of membrane potential and Ca2+ current in cardiomyocytes, but whether diacetylmorphine can induce the changes of cardiac rhythm, cell action potential and Ca2+ current has not been reported. OBJECTIVE: To explore the effect of diacetylmorphine on action potential and calcium current of isolated cardiomyocytes from neonatal Sprague-Dawley rats. METHODS: Five concentrations of diacetylmorphine (0, 10-2, 10-3, 10-4, 10-5 mol/L) and 20 mol/L verapamil were used to treat the cardiomyocytes of neonatal Sprague-Dawley rats cultured in vitro. The cells were divided into control group, diacetylmorphine group, diacetylmorphine+verapamil group. The latter two groups were treated with diacetylmorphine and diacetylmorphine+verapamil (20 μmol/L), respectively, while the control group was treated with the same amount of PBS. The study protocol was approved by the Animal Ethics Committee of the First Affiliated Hospital of Xinjiang Medical University on May 21, 2018 with approval No. IACUC201805-K1. RESULTS AND CONCLUSION: At 24 hours of culture with different concentrations of diacetylmorphine, the number of cardiomyocytes with abnormal morphology increased significantly in a dose-dependent manner. When the concentration of diacetylmorphine increased, the number of survived cells decreased, with a reduction in the size of cytoplasm and number of pseudopods, the cell membrane was shrunk and the nuclear structure was blurred. Compared with the control group, when diacetylmorphine was added to intervene with the cardiomyocytes, there was a significant difference in the spontaneous beating frequency and rhythm of cardiomyocytes. The negative value of resting membrane potential decreased, while the time course of action potential increased significantly, and the amplitude of action potential decreased significantly. Compared with the control group, the number of cells with changes in the membrane potential significantly increased in the diacetylmorphine group. The addition of verapamil reduced the number of cells with changes in the membrane potential. Compared with the control group, the number of cells with variation of membrane potential was increased to some extents. These findings suggest that diacetylmorphine can induce cardiomyocyte morphological abnormality, increase the spontaneous beating frequency and rhythm of cardiomyocytes, and change the membrane potential and action potential of cardiomyocytes. Verapamil acts as a calcium channel blocker that can improve the rhythm abnormality of cardiomyocytes induced by diacetylmorphine.

Simultaneous determination of verapamil and its metabolite norverapamil in human plasma by liquid chromatography-tandem mass spectrometry / 药学学报

A sensitive and simple high-performance liquid chromatographic tandem mass spectrometric (LC-MS/MS) method for the determination of verapamil and norverapamil in human plasma was established and utilized in a pharmacokinetic study in healthy patients. Protein was precipitated by methanol in plasma samples, and the analytes and internal standard were separated on an Agilent Zorbax Eclipse C18 column (50 mm×4.6 mm, 5 μm) with a gradient procedure using methanol-acetonitrile (50∶50) as the organic phase and 0.1% formic acid - 5% acetonitrile - 10 mmol·L-1 ammonium formate solution as the mobile phase at flow rate of 0.5 mL·min-1. Electrospray ionization (ESI) and multiple reaction monitoring (MRM) detection modes were used for quantitative detection of verapamil, norverapamil and verapamil-d6 (IS). In the mode of multiple reaction monitoring of positive-ions, the monitoring ion pairs of verapamil, norverapamil and the verapamil-d6 were m/z 445.0→165.2, m/z 441.0→165.2 and m/z 461.1→165.2, respectively. The quantitative lower limit (LLOQ) for the determination of verapamil and norverapamil concentrations in human plasma can reach 0.1 ng·mL-1 in this assay. The calibration curve concentration ranged from 0.1 to 50 ng·mL-1 with high linearity (r2 > 0.997). The matrix effect of verapamil and norverapamil was 99.2%-100% and 101%-102%, respectively. The recovery of verapamil and norverapamil was 86.8%-95.9% and 87.4%-94.8%, respectively. This method has good specificity and high sensitivity. The determination of the verapamil and norverapamil was not subject to the matrix effect and stable extraction recovery was achieved in this assay. This method could be used to determine the concentration of verapamil and norverapamil in human plasma and suitable for human pharmacokinetic studies after approved by ethics committee.

The reversal of tumor drug resistance by liposomes containing docetaxel and verapamil / 药学学报

To study the reversal effect of docetaxel (DTX) and verapamil (VRP) liposome (DTX-VRP LP) on multidrug resistance of human breast cancer chemotherapy, DTX-VRP LP was prepared by thin film dispersion method. The particle size and zeta potential were measured by laser particle sizer. The drug loading, entrapment efficiency and the cumulative release rate of liposomes in phosphate buffer saline solution (PBS) with pH 7.4 and 6.8 were determined by ultrafiltration and dynamic dialysis, respectively. With DTX resistant human breast cancer cells (MCF-7/DTX) to study on the pharmacodynamics of liposomes in vitro and in vivo. The animal experiments were approved by the Animal Research Ethics Committee of School of Medicine of Shanghai Jiao Tong University (No. 2019-06-172). The average particle size and zeta potential of DTX-VRP LP were about 140.9 nm and -28.7 mV, respectively. The entrapment efficiency and drug loading of DTX and VRP in DTX-VRP LP were (81.7 ± 3.9)%, (2.9 ± 0.3)% and (59.6 ± 0.6)%, (1.6 ± 0.5)%, respectively. The cumulative release rate of the group of DTX-VRP LP was about 40% and 70% within 0-4 h in pH 7.4 and 6.8 PBS, respectively. It was slightly slower compared with other experimental groups. In vitro pharmacodynamics experiments, the value of IC50 of DTX solution, DTX LP and DTX-VRP LP were 3.19 ± 0.6, 1.46 ± 0.48 and 1.12 ± 0.33 μmol·L-1 on human breast cancer cells (MCF-7), respectively. The results showed the data was not much difference between the other groups and all experimental groups had strong cytotoxicity on MCF-7. However, on the MCF-7/DTX, the IC50 values of the other groups were greater than 10 μmol·L-1 while DTX-VRP LP group 7.4 ± 2.86 μmol·L-1. The results showed DTX-VRP LP had obvious cytotoxicity with the concentration dependent reversal of multidrug resistance (MDR) of breast cancer MCF-7/DTX cells (P<0.05), the other experimental groups had no effect on MCF-7/DTX cells. The inhibitory effect of MCF-7/DTX in vivo is consistent with that in vitro. In conclusion, DTX-VRP LP could reverse the MDR of MCF-7/DTX cells.

An Improved Lc-Ms/Ms Method Development And Validation For The Determination Of Trandolapril And Verapamil In Human Plasma

Objective: A simple, sensitive and rapid LC-MS/MS technique was developed for the quantitation of trandolapril (TDL) and verapamil (VPL) in a biological matrix and validated. Methods: Sample preparation processed by SPE (Solid Phase extraction) on phenomenex cartridge using Ledipasvir as an internal standard. Two drugs were eluted on waters symmetry-RP18 (5µ, 150 mm×4.0 mm) column with the mobile composition of 10 mmol ammonium formate and ACN(acetonitrile) in the ratio of 70:30 %V/V. Detection and quantitation were processed by electrospray ionization in positive ionization mode. Results: The quantification approach was validated in 5-1500 ng/ml linear concentration range for TDL and 1-2000 ng/ml for VPL. The intraday and inter-day precision and accuracy were found to be 0.58% to 5.69% and 93% to 104% for two drugs. The average recoveries for TDL and VPL were found to be 92.9% and 93.5% respectively. Conclusion: The developed work was validated and can be applicable to the routine analysis of TDL and VPL simultaneously in a biological matrix.

Rapid-onset supraventricular tachycardia following clozapine initiation and its management with verapamil: a case report

Clozapine is the drug of choice for treatment-resistant schizophrenia. However, the use of clozapine is limited by its serious adverse effects, which often underlie its discontinuation. The cardiovascular side effects that raise safety concerns include tachycardia, myocarditis and cardiomyopathy. The development of clozapine-induced tachycardia is usually observed on higher dosage especially at early stages of treatment. Here, author presented the case of a patient with treatment-resistant schizophrenia who developed asymptotic supraventricular tachycardia despite low dose of clozapine at the second day of treatment. Additionally, author explored the possibility of clozapine re-challenge in combination with verapamil treatment.

Effect of Acori Tatarinowii Rhizoma on Intestinal Absorption of Ginsenosides in Dingzhi Xiaowan / 中国实验方剂学杂志

Objective: To explore the effect of Acori Tatarinowii Rhizoma on intestinal absorption of ginsenosides in Dingzhi Xiaowan,and reveal the mechanism of Acori Tatarinowii Rhizoma acting as " adjuvant drug" in this formula. Method: The contents of ginsenoside Rg1,Re and Rb1 were measured by UPLC-MS/MS and the absorption of three ginsenosides in different intestine segments was investigated by rat single pass intestinal perfusion in situ,including absorption rate constant(Ka) and apparent permeability coefficient(Papp).Everted intestinal sac model was used to investigate the absorption dosage of three ginsenosides affected by volatile oil from Acori Tatarinowii Rhizoma and verapamil[Ver,a P-glycoprotein(P-gp) inhibitor]. Result:Papp values of three ginsenosides were ≤ 0.191×10-3 cm·min-1 in Dingzhi Xiaowan when lack of Acori Tatarinowii Rhizoma.Compared with lack of Acori Tatarinowii Rhizoma in Dingzhi Xiaowan group,the Ka and Papp values of lack of volatile oil from Acori Tatarinowii Rhizoma in Dingzhi Xiaowan group slightly increased without significant difference in the four intestinal segments,but when the prescription had Acori Tatarinowii Rhizoma,the Ka increased by 3.97-8.35 fold and the Papp increased by 3.99-8.49 fold.The results of everted intestinal sac test showed that volatile oil of Acori Tatarinowii Rhizoma could significantly promote the intestinal absorption of ginsenoside Rg1,Re and Rb1,but there was no dose-dependent. Conclusion:Volatile oil of Acori Tatarinowii Rhizoma can promote the intestinal absorption of three ginsenosides in Dingzhi Xiaowan,and the mechanism may be related to the inhibiting function on P-gp.

Antinociceptive and anti-inflammatory effects of N-acetylcysteine and verapamil in Wistar rats / 대한통증학회지

BACKGROUND: Antinociceptive anti-inflammatory drugs have many adverse effects. The goal of this investigation is to study the probable anti-inflammatory and analgesic effects of verapamil and N-acetylcysteine (NAC) in experimental rats. METHODS: Adult male Wistar rats were randomly divided into 4 groups in the antinociceptive study, each containing 6 rats; the normal control group, which received saline (1 mL/kg); the diclofenac group, which received diclofenac sodium (5 mg/kg); the NAC group, which received NAC (125 mg/kg); and the verapamil group, which received verapamil (8 mg/kg). In the anti-inflammatory study, 5 groups were used, the 4 previous groups with the addition of an edema control group, received saline and were subjected to formalin test. Hot plate latency time was recorded for antinociceptive evaluation. Paw edema thickness and biochemical parameters were recorded for anti-inflammatory evaluation. RESULTS: Administration of NAC showed significant prolongation of hot plate latency time at 1 hour when compared to the control group while verapamil showed a significant prolongation of hot plate latency time at 1 and 2 hours when compared to the control group and NAC group values. Administration of NAC and verapamil significantly decreased paw edema thickness at 2, 4, and 8 hours when compared to edema control values. Regarding biochemical markers, NAC and verapamil significantly decreased serum nitric oxide synthase, C-reactive protein, and cyclooxygenase-2 levels compared to the edema control value. In accordance, a marked improvement of histopathological findings was observed with both drugs. CONCLUSIONS: NAC and verapamil have antinociceptive and anti-inflammatory effects comparable to diclofenac sodium.

The Effect of Intravenous Lipid Emulsion in a Rat Model of Verapamil Toxicity

PURPOSE: Intravenous lipid emulsion (ILE) has been shown to have significant therapeutic effects on calcium channel blocker overdose in animal studies and clinical cases. In this preliminary experiment, we investigated the hemodynamic changes and survival in a rat model of verapamil intoxication. METHODS: Fourteen male Sprague-Dawley rats were sedated and treated with ILE or normal saline (control), followed by continuous intravenous infusion of verapamil (20 mg/kg/h). Mean arterial pressure and heart rate of rats were monitored during the infusion. In addition, the total dose of infused verapamil and the duration of survival were measured. RESULTS: Survival was prolonged in the ILE group (32.43±5.8 min) relative to the control group (24.14±4.3 min) (p=0.01). The cumulative mean lethal dose of verapamil was higher in the ILE group (4.3±0.7 mg/kg) than in the control group (3.2±0.5 mg/kg; p=0.017). CONCLUSION: ILE pretreatment prolonged survival and increased the lethal dose in a rat model of verapamil poisoning.

The impact of Verapamil addition to Ketamine and Lidocaine Intravenous regional Anesthesia: A Randomized controlled study.

Background: The use of adjuncts along with Lidocaine during intravenous regional anesthesia (IVRA) decreases tourniquet pain and prolongs post-operative analgesia. Addition of ketamine reduces the time for onset of block, delays the onset of tourniquet pain and reduces postoperative analgesic requirement. Verapamil potentiates the effect of neuromuscular blocking agents. This study was designed to evaluate the effect of adding Verapamil (2.5 mg) to Lidocaine plus Ketamine (0.5 mg/kg) in comparison with lidocaine plus ketamine IVRA. Materials and methods: Hundred and twenty patients, aged 18–50 years, ASA physical status I and II undergoing elective hand or forearm surgery under Bier’s Block lasting one to one and half hours were included in this double-blinded, randomized and controlled study. Patients were divided into two groups of 60 patients each. Group- I (control group) received 40 ml of 0.5% Lidocaine plus ketamine (0.5 mg/kg) and Group- II received an addition of 2.5 mg of verapamil IVRA. Sensory and motor block onset and recovery time were noted. After the tourniquet deflation: pain, sedation values, time to first analgesic requirement and side effects were evaluated over a period of 12 hours. Results: Significant postoperative hemodynamic changes, sedation score, pain score and delayed first request for analgesia was observed in-group II when compared to group I. Sensory and motor block characteristics were significant in-group II as against group I. The side effect profile of verapamil (2.5mg) was minimal with a few episodes of hypotension and bradycardia, which were clinically managed by ephedrine and atropine respectively.

Research progress on correlation between ATP binding cassette transports and multidrug resistance of liver cancer / 上海预防医学

Multidrug resistance (MDR) is a major problem in the current treatment of liver cancer.ATP binding cassette (ABC) transports induce drug effluxes in cancer cells, thus contributing to MDR.ABCB1 is a main subtype of ABC transports that mediates the MDR of liver cancer.The expression of ABCB1 is related to the stemness characteristics of liver cancer cells.The key molecules of a variety types of signaling pathways related to inflammation and cancer collaborate with one another and adjust the expression of ABC transports.Verapamil can reverse the MDR of liver cancer through inhibiting ABCB1.Further investigations of the relation between ABC transporters and the MDR in liver cancer can improve treatment strategy for cancer and reduce mortality.

Effect of verapamil on expression of K+·Cl-cotransporter 2 in spinal dorsal horns during remifentanil-induced hyperalgesia in a rat model of incisional pain / 中华麻醉学杂志

Objective To evaluate the effect of verapamil on the expression of K+-Cl-cotransporter 2 (KCC2) in spinal dorsal horns during remifentanil-induced hyperalgesia in a rat model of incisional pain.Methods Thirty-two pathogen-free healthy adult male Sprague-Dawley rats,aged 6-7 weeks,weighing 250-300 g,were divided into 4 groups (n=8 each) using a random number table:control group (group C),incisional pain group (group Ⅰ),incisional pain plus remifentanil plus verapamil group (group I+R+ V) and incisional pain plus remifentanil group (group I+R).Normal saline was subcutaneously infused in group C.A 1 cm long incision was made in the plantar surface of the right hindpaw in anesthetized rats in group Ⅰ.Verapamil 5 mg/kg was intraperitoneally injected at 10 min before establishment of the incisional pain model in group I+R+V.In I+R and I+R+V groups,the model of incisional pain was established,and remifentanil was subcutaneously infused for 30 min at a rate of 80 μg · kg-1 · h-1 simultaneously.The mechanical paw withdrawal threshold (MWT) to yon Frey filament stimulation was measured at 1 day before establishment of the model (T0) and 2,6,24 and 48 h after establishment of the model (T1-4).The rats were sacrificed after measurement of MWT at T4,and the lumbar enlargement segments of the spinal cord were harvested for determination of the expression of KCC2 by immunofluorescence.Results Compared with group C,the MWT was significantly decreased at T1-4,and the expression of KCC2 was down-regulated in the other groups (P＜0.05).Compared with group Ⅰ,the MWT was significantly decreased at T1-4,and the expression of KCC2 was down-regulated in group I+R (P＜0.05).Compared with group I+R,the MWT was significantly increased at T1-4,and the expression of KCC2 was up-regulated in group I+R+V (P＜0.05).Conclusion The mechanism by which verapamil reduces remifentanil-induced hyperalgesia is related to up-regulation of the expression of KCC2 in spinal dorsal horns in a rat mnodel of incisional pain.

Effect of super selective intra-arterial infusion of verapamil for the treatment of cerebral vasospasm after subarachnoid hemorrhage:an efficacy analysis / 中国脑血管病杂志

Objective To investigate the efficacy of super selective intra-arterial infusion of verapamil for the treatment of cerebral vasospasm (CVS) after subarachnoid hemorrhage (SAH).Methods From January 2013 to February 2016,the clinical data of 15 patients with subarachnoid hemorrhage (SAH) who had CVS after intracranial aneurysm clipping (n=8) or endovascular treatment (n=7) were analyzed retrospectively.All patients received whole brain digital subtraction angiography (DSA).Microcatheter super selection to spastic arteries was used and verapamil (11.1±3.4 mg) was infused.The findings of whole brain DSA before and after treatments were compared.The blood pressure and heart rate were collected during the treatment and the findings of transcranial Doppler ultrasonography were recorded.The patients were followed up for 6 months and the Glasgow outcome scale (GCS) scores were obtained.Results (1) A total of 20 intra-arterial infusion treatments were performed in 15 cases.They were compared before and after perfusion.CVS was improved on DSA in 14 cases,there was no significant change in on cases.(2) Transcranial Doppler ultrasonography showed that the mean blood flow velocity (mBFV) of the middle cerebral artery was decreased from 181±4 cm/s before the super selective intra-arterial infusion to 126±4 cm/s within 1 hour after treatment.There was significant difference (t=42.46,P0.05).(4) All patients were followed up for 6 months.The GOS score at 6 months:good recovery in 9 cases,moderate disability but could take care of themselves in 3 cases,severe disability and could not take care of themselves in 3 cases,no persistent vegetative state or death.Conclusion Super selective intra-arterial infusion of verapamil can effectively improve the treatment of aneurysmal SAH caused CVS.At the same time,it has no obvious effect on blood pressure and heart rate.

Arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells: comparison of vasorelaxant effects of verapamil and phentolamine

Mitochondria are morphologically dynamic organelles which undergo fission and fusion processes. Our previous study found that arterial constriction was always accompanied by increased mitochondrial fission in smooth muscle cells, whereas inhibition of mitochondrial fission in smooth muscle cells was associated with arterial relaxation. Here, we used the typical vasorelaxants, verapamil and phentolamine, to further confirm the coupling between arterial constriction and mitochondrial fission in rat aorta. Results showed that phentolamine but not verapamil induced vasorelaxation in phenylephrine (PE)-induced rat thoracic aorta constriction. Verapamil, but not phentolamine, induced vasorelaxation in high K(KPSS)-induced rat thoracic aorta constriction. Pre-treatment with phentolamine prevented PE- but not KPSS-induced aorta constriction and pre-treatment with verapamil prevented both PE- and KPSS-induced aorta constriction. Transmission electron microscopy (TEM) results showed that verapamil but not phentolamine inhibited KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells, and verapamil prevented both PE- and KPSS-induced excessive mitochondrial fission in aortic smooth muscle cells. Verapamil inhibited KPSS-induced excessive mitochondrial fission in cultured vascular smooth muscle cells (A10). These results further demonstrate that arterial relaxation is coupled to inhibition of mitochondrial fission in arterial smooth muscle cells.

Therapeutic effects of sodium nitroprusside combined verapamil for no-reflow during percutaneous coronary intervention / 心血管康复医学杂志

Objective:To explore therapeutic effects of sodium nitroprusside (SNP) combined verapamil on no-reflow during percutaneous coronary intervention (PCI).Methods: A total of 106 patients, who suffered from no-reflow during PCI in our department from Jan 2011 to Dec 2013, were selected.According to random number table method, patients were divided into SNP group (n=55, received SNP based on routine treatment) and combined treatment group (n=51, received verapamil based on SNP group).Cardiac troponin I (cTnI) level before and 16h~18h after PCI, cardiac function indexes after 12-month follow-up, incidence of major adverse cardiovascular events (MACE) were measured and compared between two groups.Results: Compared with before PCI, there were significant rise in cTnI level in both groups on 16~18h after PCI, P=0.001 both;compared with SNP group, there were significant reductions in cTnI level [(1.31±0.44)μg/L vs.(0.11±0.02)μg/L] and percentage of cTnI>0.10μg/L (94.5% vs.54.9%) in combined treatment group, P=0.001 both.Compared with SNP group after 12 months, there was significant rise in left ventricular ejection fraction [(62.29±3.06)% vs.(65.65±3.94)%], and significant reductions in left ventricular end-diastolic dimension[(50.24±3.73)mm vs.(47.60±4.72)mm] and left ventricular end-systolic dimension [(33.29±2.11)mm vs.(31.00±4.33)mm] in combined treatment group, P<0.05 all.There were no significant adverse reactions during hospitalization and follow-up in both groups.Conclusion: When no-reflow occurs during PCI, intracoronary injection of SNP combined verapamil can improve cardiac function, and its safety is good, which is worth extending.

Effects of Adamantyl Derivatives on Pharmacokinetic Behavior of Paclitaxel in Rats

Paclitaxel (PTX) is one of the most frequently used anticancer agent for treating refractory ovarian cancer, metastatic breast cancer and non-small cell lung cancer. However, its oral administration is impeded by very low bioavailability (<5%) due to the P-glycopprotein (P-gp) efflux pump effect. This study investigated in vitro and in vivo P-gp inhibitory effects of adamantyl derivatives AC-603 and AC-786 in rats. Two adamantyl derivatives tested in this study increased the cytotoxicity of daunomycin (DNM) in P-gp overexpressed cell line by inhibiting P-gp efflux function. Pharmacokinetics of PTX with orally co-administered P-gp inhibitors were assessed in rats to improve PTX absorption. The pharmacokinetic parameters of PTX were determined in rats after intravenous (2 mg/kg) or oral (25 mg/kg) administration in the presence or absence of verapamil (a positive control), AC-603 or AC-786 (0.5 mg/kg or 5 mg/kg). Compared to control group (PTX alone), experimental groups (PTX with AC-603 or AC-786) significantly increased the area under the plasma concentration-time curve of PTX following oral administration by 1.7–2.2 fold. The volume of distribution and total clearance of PTX were decreased, while other parameters were not significantly changed. In conclusion, co-administration of AC-603 or AC-786 enhanced the relative bioavailability of orally administered PTX as compared to control.