OBJECTIVE: To evaluate the antidiarrheal effect of ethanol extract of Glycyrrhiza uralensis Fisch root (GFR) in vivo and jejunal contraction in vitro. METHODS: In vivo, 50 mice were divided into negative control, positive control (verapamil), low-, medium- and high-dose GFR (250, 500, 1,000 mg/kg) groups by a random number table, 10 mice in each group. The antidiarrheal activity was evaluated in castor oil-induced diarrhea mice model by evacuation index (EI). In vitro, the effects of GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) on the spontaneous contraction of isolated smooth muscle of rabbit jejunum and contraction of pretreated by Acetylcholine (ACh, 10 µmol/L) and KCl (60 mmol/L) were observed for 200 s. In addition, CaCl₂ was accumulated to further study its mechanism after pretreating jejunal smooth muscle with GFR (1 and 3 g/L) or verapamil (0.03 and 0.1 µmol/L) in a Ca²⁺-free-high-K⁺ solution containing ethylene diamine tetraacetic acid (EDTA). RESULTS: GFR (500 and 1,000 mg/kg) significantly reduced EI in castor oil-induced diarrhea model mice (P<0.01). Meanwhile, GFR (0.01, 0.03, 0.1, 0.3, 1, 3, and 10 g/L) inhibited the spontaneous contraction of rabbit jejunum (P<0.05 or P<0.01). Contraction of jejunums samples pretreated by ACh and KCl with 50% effective concentration (EC₅₀) values was 1.05 (0.71-1.24), 0.34 (0.29-0.41) and 0.15 (0.11-0.20) g/L, respectively. In addition, GFR moved the concentration-effect curve of CaCl₂ down to the right, showing a similar effect to verapamil. CONCLUSIONS GFR can effectively against diarrhea and inhibit intestinal contraction, and these antidiarrheal effects may be based on blocking L-type Ca²⁺ channels and muscarinic receptors.
Mice ; Rabbits ; Animals ; Antidiarrheals/adverse effects* ; Jejunum ; Glycyrrhiza uralensis ; Castor Oil/adverse effects* ; Calcium Chloride/adverse effects* ; Diarrhea/drug therapy* ; Plant Extracts/adverse effects* ; Verapamil/adverse effects* ; Muscle Contraction

Most diabetic patients experience diabetic mellitus (DM) urinary bladder dysfunction. A number of studies evaluate bladder smooth muscle contraction in DM. In this study, we evaluated the change of bladder smooth muscle contraction between normal rats and DM rats. Furthermore, we used pharmacological inhibitors to determine the differences in the signaling pathways between normal and DM rats. Rats in the DM group received an intraperitoneal injection of 65 mg/kg streptozotocin and measured blood glucose level after 14 days to confirm DM. Bladder smooth muscle contraction was induced using acetylcholine (ACh, 10⁻⁴ M). The materials such as, atropine (a muscarinic receptor antagonist), U73122 (a phospholipase C inhibitor), DPCPX (an adenosine A1 receptor antagonist), udenafil (a PDE5 inhibitor), prazosin (an α₁-receptor antagonist), papaverine (a smooth muscle relaxant), verapamil (a calcium channel blocker), and chelerythrine (a protein kinase C inhibitor) were pre-treated in bladder smooth muscle. We found that the DM rats had lower bladder smooth muscle contractility than normal rats. When prazosin, udenafil, verapamil, and U73122 were pre-treated, there were significant differences between normal and DM rats. Taken together, it was concluded that the change of intracellular Ca²⁺ release mediated by PLC/IP3 and PDE5 activity were responsible for decreased bladder smooth muscle contractility in DM rats.
Acetylcholine ; Animals ; Atropine ; Blood Glucose ; Calcium Channels ; Humans ; Injections, Intraperitoneal ; Muscle, Smooth* ; Papaverine ; Prazosin ; Protein Kinase C ; Rats* ; Receptor, Adenosine A1 ; Receptors, Muscarinic ; Streptozocin ; Type C Phospholipases ; Urinary Bladder* ; Verapamil

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.
Acetylcysteine ; Adult ; Animals ; Anti-Inflammatory Agents ; Biomarkers ; C-Reactive Protein ; Cyclooxygenase 2 ; Diclofenac ; Edema ; Humans ; Male ; Nitric Oxide Synthase ; Pain Measurement ; Rats ; Rats, Wistar ; Verapamil

PURPOSE: Although the economic and mortality burden of atrial fibrillation (AF) is substantial, it remains unclear which treatment strategies for rate and rhythm control are most cost-effective. Consequently, economic factors can play an adjunctive role in guiding treatment selection. MATERIALS AND METHODS: We built a Markov chain Monte Carlo model using the Korean Health Insurance Review & Assessment Service database. Drugs for rate control and rhythm control in AF were analyzed. Cost-effective therapies were selected using a cost-effectiveness ratio, calculated by net cost and quality-adjusted life years (QALY). RESULTS: In the National Health Insurance Service data, 268149 patients with prevalent AF (age ≥18 years) were identified between January 1, 2013 and December 31, 2015. Among them, 212459 and 55690 patients were taking drugs for rate and rhythm control, respectively. Atenolol cost $714/QALY. Among the rate-control medications, the cost of propranolol was lowest at $487/QALY, while that of carvedilol was highest at $1363/QALY. Among the rhythm-control medications, the cost of pilsicainide was lowest at $638/QALY, while that of amiodarone was highest at $986/QALY. Flecainide and propafenone cost $834 and $830/QALY, respectively. The cost-effectiveness threshold of all drugs was lower than $30000/QALY. Compared with atenolol, the rate-control drugs propranolol, betaxolol, bevantolol, bisoprolol, diltiazem, and verapamil, as well as the rhythm-control drugs sotalol, pilsicainide, flecainide, propafenone, and dronedarone, showed better incremental cost-effectiveness ratios. CONCLUSION: Propranolol and pilsicainide appear to be cost-effective in patients with AF in Korea assuming that drug usage or compliance is the same.
Amiodarone ; Atenolol ; Atrial Fibrillation ; Betaxolol ; Bisoprolol ; Compliance ; Cost-Benefit Analysis ; Diltiazem ; Flecainide ; Humans ; Insurance, Health ; Korea ; Markov Chains ; Mortality ; National Health Programs ; Propafenone ; Propranolol ; Quality-Adjusted Life Years ; Sotalol ; Verapamil

Bladder dysfunction is a common complication of diabetes mellitus (DM). However, there have been a few studies evaluating bladder smooth muscle contraction in DM in the presence of pharmacological inhibitors. In the present study, we compared the contractility of bladder smooth muscle from normal rats and DM rats. Furthermore, we utilized pharmacological inhibitors to delineate the mechanisms underlying bladder muscle differences between normal and DM rats. DM was established in 14 days after using a single injection of streptozotocin (65 mg/kg, intraperitoneal) in Sprague-Dawley rats. Bladder smooth muscle contraction was induced electrically using electrical field stimulation consisting of pulse trains at an amplitude of 40 V and pulse duration of 1 ms at frequencies of 2–10 Hz. In this study, the pharmacological inhibitors atropine (muscarinic receptor antagonist), U73122 (phospholipase C inhibitor), DPCPX (adenosine A₁ receptor antagonist), udenafil (PDE5 inhibitor), prazosin (α₁-receptor antagonist), verapamil (calcium channel blocker), and chelerythrine (protein kinase C inhibitor) were used to pretreat bladder smooth muscles. It was found that the contractility of bladder smooth muscles from DM rats was lower than that of normal rats. In addition, there were significant differences in percent change of contractility between normal and DM rats following pretreatment with prazosin, udenafil, verapamil, and U73122. In conclusion, we suggest that the decreased bladder muscle contractility in DM rats was a result of perturbations in PLC/IP₃-mediated intracellular Ca²⁺ release and PDE5 activity.
Animals ; Atropine ; Diabetes Mellitus ; Muscle, Smooth ; Phosphotransferases ; Prazosin ; Rats* ; Rats, Sprague-Dawley ; Streptozocin ; Type C Phospholipases ; Urinary Bladder* ; Verapamil

To evaluate the anti-cicatricial and anti-restenosis effect of verapamil on anterior urethral stricture.
 Methods: A total of 32 patients received anterior urethral stricture were enrolled in this study. They were divided into 4 blocks according to the duration of previous urethral operations and dilations. Every block was further randomly divided into an experimental group and a control group. Experimental groups received 2 mL injection of verapamil around the anastomosis site of urethra before and after the surgery (2, 4, 6, 8, and 10 weeks after the surgery), while the control groups only received the anastomosis surgery. After surgery, maximal urinary flow rate (Qmax) was examined for all patients once the catheter was removed. In addition, they were also conducted palpation of urethral scar range. The sum of long transverse diameters of urethral scar was measured, and the narrowest urethral inner diameter was examined. The Qmax was rechecked and the urethral scar range was assessed by penis color Doppler elastography after 12 weeks of surgery. The above 4 indexes were used to evaluate the inhibitory effect of verapamil on urethral scar.
 Results: The length of palpated urethral scar in the Block 1 to 4 of the experimental groups was (22.75±1.03), (21.25±0.25), (20.75±1.03), and (20.0±0.58) mm, respectively; and those in the control groups (26.00±0.82), (24.5±1.04), (25.75±1.65), and (28.25±1.75) mm, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.85±0.77), (11.33±0.81), (10.23±0.26), and (10.35±0.17) mL/s, respectively; and those in the control groups were (10.85±0.39), (10.50±0.76), (10.53±1.00), (12.60±0.39) mL/s, respectively. The Qmax rates in the Block 1 to 4 of the experimental groups were (11.73±0.87), (10.65±0.25), (10.23±0.19), and (10.35±0.29) mL/s, respectively; and those in the control groups were (8.05±0.28), (7.73±0.68), (7.53±0.92), and (9.60±0.32) mL/s, respectively. The narrowest diameters of urethral in the Block 1 to 4 of the experimental groups were (9.00±0.58), (7.50±2.89), (7.00±0.10), and (7.00±0.41) mm, respectively; and those in the control groups were (5.50±0.29), (5.00±0.41), (4.75±0.48), and (6.75±0.48) mm, respectively. The ultrasound strain ratio in the Block 1 to 4 of the experimental groups were 6.10±0.22, 6.10±0.17, 5.10±0.16, and 6.90±0.19, respectively; and those in the control groups were 8.00±0.25, 10.60±0.29, 11.30±0.16, and 8.90±0.33, respectively. Compared with the control groups, the experimental groups displayed smaller urethral scar range, less severe scarring, improved Qmax rates and wider inner diameters (all P<0.05).
 Conclusion: Urethral regional injection of verapamil intraoperatively or postoperatively can prevent overgrowth of urethral scar tissues after the transperineal anastomosis surgery, and reduce the tendency of postoperative restenosis of anterior urethral stricture.
Anastomosis, Surgical ; adverse effects ; Cicatrix ; diagnostic imaging ; drug therapy ; prevention & control ; Dilatation ; adverse effects ; Humans ; Male ; Penis ; diagnostic imaging ; Postoperative Complications ; diagnostic imaging ; drug therapy ; prevention & control ; Secondary Prevention ; Ultrasonography ; Urethra ; diagnostic imaging ; surgery ; Urethral Stricture ; prevention & control ; surgery ; Urination ; Urological Agents ; therapeutic use ; Verapamil ; therapeutic use

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.
Animals ; Arterial Pressure ; Calcium Channels ; Heart Rate ; Hemodynamics ; Humans ; Infusions, Intravenous ; Male ; Models, Animal* ; Poisoning ; Rats* ; Rats, Sprague-Dawley ; Therapeutic Uses ; Verapamil*

BACKGROUND/OBJECTIVE: This study was designed to investigate how a Portulaca oleracea L. extract (POE) stimulates insulin secretion in INS-1 pancreatic β-cells. MATERIALS/METHOD: INS-1 pancreatic β-cells were incubated in the presence of various glucose concentrations: 1.1 or 5.6, 16.7 mM glucose. The cells were treated with insulin secretagogues or insulin secretion inhibitor for insulin secretion assay using an insulin ELISA kit. In order to quantify intracellular influx of Ca2+ caused by POE treatment, the effect of POE on intracellular Ca2+ in INS-1 pancreatic β-cells was examined using Fluo-2 AM dye. RESULTS: POE at 10 to 200 µg/mL significantly increased insulin secretion dose-dependently as compared to the control. Experiments at three glucose concentrations (1.1, 5.6, and 16.7 mM) confirmed that POE significantly stimulated insulin secretion on its own as well as in a glucose-dependent manner. POE also exerted synergistic effects on insulin secretion with secretagogues, such as L-alanine, 3-isobutyl-1-methylxanthine, and especially tolbutamide, and at a depolarizing concentration of KCl. The insulin secretion caused by POE was significantly attenuated by treatment with diazoxide, an opener of the K+ ATP channel (blocking insulin secretion) and by verapamil (a Ca2+ channel blocker). The insulinotropic effect of POE was not observed under Ca2+-free conditions in INS-1 pancreatic β-cells. When the cells were preincubated with a Ca2+ fluorescent dye, Fluo-2 (acetoxymethyl ester), the cells treated with POE showed changes in fluorescence in red, green, and blue tones, indicating a significant increase in intracellular Ca2+, which closely correlated with increases in the levels of insulin secretion. CONCLUSIONS: These findings indicate that POE stimulates insulin secretion via a K+ ATP channel-dependent pathway in INS-1 pancreatic β-cells.
1-Methyl-3-isobutylxanthine ; Adenosine Triphosphate ; Alanine ; Calcium Channels ; Diabetes Mellitus ; Diazoxide ; Enzyme-Linked Immunosorbent Assay ; Fluorescence ; Glucose ; Insulin* ; Portulaca* ; Tolbutamide ; Verapamil

An 8-month old female presented with spontaneous subarachnoid hemorrhage and was treated successfully with endovascular coil embolization of the ruptured aneurysm. Transcranial Doppler ultrasound performed four days later demonstrated middle cerebral artery (MCA) velocities greater than 350 cm/sec on the right and greater than 200 cm/sec on the left, despite medical management. The patient demonstrated no focal neurological deficits, though examination was limited by our patient's sedation and intubation. Angiography revealed severe vasospasm of the supraclinoid internal carotid and MCA territories, bilaterally. The vasospasm was refractory to the administration of intra-arterial verapamil. Balloon angioplasty was attempted, but the device could not be advanced safely due to the small size of the patient's vessels and the stiffness of the device. A microcatheter (0.0165" diameter) was advanced over a J-shaped soft microwire (0.014" diameter) to perform mechanical angioplasty in the internal carotid artery and MCA vessels bilaterally. Dramatic improvement was seen angiographically and on transcranial Doppler, and no complications were seen.
Aneurysm ; Aneurysm, Ruptured ; Angiography ; Angioplasty ; Angioplasty, Balloon ; Carotid Artery, Internal ; Embolization, Therapeutic ; Female ; Humans ; Infant* ; Intubation ; Middle Cerebral Artery ; Subarachnoid Hemorrhage ; Ultrasonography ; Vasospasm, Intracranial* ; Verapamil

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.
Absorption ; Administration, Oral ; Animals ; Biological Availability ; Breast Neoplasms ; Carcinoma, Non-Small-Cell Lung ; Cell Line ; Daunorubicin ; In Vitro Techniques ; Ovarian Neoplasms ; P-Glycoprotein ; Paclitaxel* ; Pharmacokinetics ; Plasma ; Rats* ; Verapamil