• Journal of Pharmaceutical Investigation
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• v.37 no.2
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• pp.107-111
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• 2007

Epigallocatechin gallate (EGCC), a flavonoid, is the main component of green tea extracts. EGCG has been reported to be an inhibitor of P-glycoprotein (P-gp) and cytochrom P450 3A(CYP3A4). This study investigated the effect of long-term administration of EGCG on the pharmacokinetics of verapamil in rats. Pharmacokinetic parameters of verapamil were determined after oral administration of verapamil (9 mg/kg) in rats pretreated with EGCG (7.5 mg/hg) for 3 and 9 days. Compared to oral control group, the presence of EGCG significantly (p<0.01) increased the area under the plasma concentration-time curve (AUC) of verapamil by 102% (coad), 83.2% (3 days) and 52.3% (9 days), and the peak concentration $(C_{max})$ by 134% (coad), 120% (3 days) and 66.1% (9 days). The absolute bioavailability (A.B.%) of verapamil was significantly (p<0.01) higher by 8.4% (coad), 7.7% (3 days), 6.4% (9 days) compared to control (4.2%), and presence of EGCG was no significant change in the terminal half-life $(t_{1/2})$ and the time to reach the peak concentration $(T_{max})$ of verapamil. Our results indicate that EGCG significantly enhanced oral bioavailability of verapamil in rats, implying that presence of EGCG could be effective to inhibit the CYP3A4-mediated metabolism and P-gp efflux of verapamil in the intestine. Drug interactions should be considered in the clinical setting when verapamil is coadministrated with EGCG or EGCG-containing dietary.

• Biomedical Science Letters
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• v.2 no.2
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• pp.153-158
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• 1996

Verapamil, a potent calcium channel blocker, has been proved to be one of the modulators to overcome drug resistance in cancer chemotherapy. In the present experiment, the possibility of verapamil as a MDR modulator was investigated by using MTT assay. Sole treatment of verapamil on the HeLa and Caski cervical cancer cell line revealed dose dependent cytotoxicity within a range of tested dose. Combined treatment of verapamil with 5-FU, DDP on two human cervical cancer cell line led to a significant synergistic cytotoxicity. Therefore , these studies showed that verapamil had a possibility to be applicable to cancer chemotherapy in gynecological oncology.

• Archives of Pharmacal Research
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• v.28 no.4
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• pp.483-487
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• 2005

The aim of this study was to investigate the pharmacokinetic changes of verapamil and its major metabolite, norverapamil, after oral administration of verapamil (10 mg/kg) in rabbits with slight, moderate and severe hepatic failure induced by carbon tetrachloride. The plasma verapamil concentrations in all groups of hepatic failure were significantly higher (p<0.01) than the control. However, the plasma norverapamil concentrations in severe hepatic failure were significantly higher (p<0.05) than the control. The peak concentrations ($C_{max}$) and the areas under the plasma concentration-time curve (AUC) of verapamil in the rabbits were significantly (p<0.01) higher than the control. The absolute bioavailability ($F_{A.B}$) and the relative bioavailability ($F_{R.B}$) of verapamil in the rabbits with hepatic failure were significantly higher ($13.6-22.2\% and 150-244\%$, respectively) than the control ($9.1\% and 100\%$, respectively). Although the AUC and $C_{max}$ of its major metabolite, norverapamil, in slight, moderate hepatic failure were not significantly lower than the control, the metabolite-parent AUC ratio in all groups of hepatic failure was decreased significantly (p<0.05, in slight group; p<0.01, in moderate and severe group) than the control. This could be due to decrease in metabolism of verapamil in the liver because of suppressed hepatic function in the hepatic failure groups because verapamil is mainly metabolized in the liver. From our data, it would seem appropriate that in patients with liver disease, doses of verapamil should be decreased by degree of hepatic failure.

• Tuberculosis and Respiratory Diseases
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• v.40 no.3
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• pp.223-235
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• 1993

Background: Superoxide anion which was produced by macrophage and neutrophil has a defensive role to kill invasive microorganisms and also an injurious role to produce self lung damage. Production of oxygen free radicals including superoxide is a main mechanism of acute lung injury caused by bacterial endotoxin. Endotoxin is known to activate alveolar macrophage to produce increased oxygen free radicals after the stimulation with various biological materials (priming effect). Calcium is a very important intracellular messenger in that cellular process of superoxide production. Method: This experiment was performed to elucidate the effects of endotoxin and calcium on superoxide production by phorbol myristate acetate-stimulated alveolar macrophage and the effect of verapamil on priming effect of endotoxin. Results: 1) Preincubation of macrophages with endotoxin (E. coli 055-B5) primed the cells to respond with increased superoxide production after the stimulation with PMA. Priming with endotoxin ($10^{-1}$ug/ml) produced a maximal enhancement of superoxide production (43%). 2) Verapamil could inhibit the superoxide production by PMA stimulated macrophage regardless of the presence of extracellular calcium. This means that the inhibitory effect of verapamil is caused by a mechanism independent of blocking calcium influx. 3) Verapamil could inhibit the priming effect of endotoxin on alveolar macrophage (from 30% increment to 13% increment) and could inhibit the superoxide production by PMA-stimulated macrophage preincubated with endotoxin. Conclusion: We concluded that verapamil could inhibit the superoxide production by PMA-stimulated rat alveolar macrophage and also inhibit the priming effect of endotoxin on alveolar macrophage. These inhibitory effects of verapamil could be one of the mechanisms of verapamil effects on endotoxin induced lung injury.

• BMB Reports
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• v.29 no.4
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• pp.314-320
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• 1996

The effects of non-cytotoxic concentrations of tamoxifen, verapamil, and trifluoperazine on doxorubicin cytotoxicity in five human breast cancer cell lines were studied. A non-cytotoxic concentration of tamoxifen resulted in enhanced doxorubicin cytotoxicity in HTB-123, HTB-26, and MCF-7. In these three cell lines, a combination of tamoxifen with verapamil resulted in even more increased doxorubicin cytotoxicity. Addition of verapamil or trifluoperazine alone did not influence the doxorubicin cytotoxicity significantly. Only in HTB-19 did coincubation with verapamil increase the doxorubicin cytotoxicity. In HTB-123, combination of tamoxifen with trifluoperazine increased the doxorubicin cytotoxicity significantly. In the cell lines where co-incubation with tamoxifen increased doxorubicin sensitivity, high estrogen receptor expression was detected. However, HTB-20, where tamoxifen did not enhance doxorubicin action, was also estrogen receptor positive. None of the cell lines had multidrug resistance related drug efflux and drug retention was not increased by the treatment with tamoxifen and verapamil. Cell cycle traverses were not altered by incubation with tamoxifen, verapamil or combinations thereof. These observatlons suggest mechanism of non-cytotoxic concentrations of tamoxifen and verapamil on doxorubicin cytotoxicity may involve one or more other cellular processes besides those of interference of estrogen binding to its receptor, cell cycle perturbation, or drug efflux blocking.

• The Korean Journal of Pharmacology
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• v.22 no.2
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• pp.135-143
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• 1986

This study was designed to investigate the role of calcium in the function of an isolated perfused rabbit kidney and its effect on the diuretic action of furosemide. The administrations of hydralazine and verapamil produced remarkable diuretic actions mainly by decreasing renal resistance. The administration of furosemide in combination with hydralazine or verapamil produced remarkable diuretic action and there was no difference between the two groups. The administration of quinidine produced a diuretic action in spite of vasoconstriction and potentiated the diuretic action of furosemide. In the calcium-free perfusion medium, the administration of calcium produced a marked diuretic action in spite of vasoconstriction and potentiated significantly the diuretic action of furosemide. The administration of quinidine did not alter renal function and the diuretic action of furosemide, but the combined administration of quinidine and calcium showed antidiuretic effect due to excessive vasoconstriction in the calcium-free perfusion medium. Although the administration of verapamil produced a slight diuretic action in the calcium-free perfusion medium, verapamil did not alter the diuretic action of calcium as well as the diuretic actions of furosemide alone and in combination with calcium. The results of this experiment show that calcium, verapamil and quinidine produced diuretic actions and calcium potentiates the diuretic action of furosemide.

• Journal of Pharmaceutical Investigation
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• v.24 no.4
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• pp.289-295
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• 1994

Pharmacokinetic drug interaction between phenytoin and verapamil was investigated following i.v. administration of two drugs concomitantly to rabbits. Verapamil was coadministered with phenytoin (5 mg/kg) to rabbits at the doses of 0.5,1 and 2 mg/kg, respectively. Plasma concentration and AUC of phenytoin were increased significantly, but volume of distribution and total body clearance were decreased significantly (p<0.05) at doses of 1mg and 2mg/kg of verapamil, respectively. From the results of this experiment, it is desirable that dosage regimen of phenytoin should be adjusted and that therapeutic drug monitoring should be performed for reduction of side or toxic effect when phenytoin should be administered with verapamil in clinical practice.

• Bulletin of the Korean Chemical Society
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• v.32 no.7
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• pp.2274-2278
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• 2011

Verapamil is a calcium channel blocker and is classified as a class IV anti-arrhythmic agent. It is used in the control of supra ventricular tachyarrhythmias, and in the management of classical and variant angina pectoris. It is also used in the treatment of hypertension and used as an important therapeutic agent for angina pectoris, ischemic heart disease, hypertension and hypertrophic cardiomyopathy. Verapamil commonly co-administered with NSAIDs (non-steroidal anti-inflammatory drugs) i.e. diclofenac sodium, flurbiprofen, Ibuprofen, mefanamic acid and meloxicam. A simple and rapid RP-HPLC method for simultaneous determination and quantification of verapamil and NSAIDs was developed and validated. The mobile phase constituted of acetonitrile: water (55:45) whose pH was adjusted at 2.7 and pumped at a flow rate of 2.0 mL $min^{-1}$ at 230 nm. The proposed method is simple, precise, accurate, low cost and least time consuming for the simultaneous determination of verapamil and NSAIDs which can be effectively applied for the analysis of human serum.

• Archives of Plastic Surgery
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• v.32 no.5
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• pp.625-635
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• 2005

In this study, the effects of verapamil on growth rate, apoptosis, production of transforming growth factor (TGF-${\beta}$) and fibronectin were evaluated in keloid and normal human dermal fibroblasts. Both fibroblasts were primarily cultured from earlobe keloids of three female patients and treated with various concentrations of verapamil. Cell toxicity was assessed by MTT assay, growth rate and apoptosis by FACS, and the production of TGF-${\beta}$ and fibronectin by ELISA and Western blot, respectively. In the $MTT_{50}$, the cell growth was more suppressed in keloid fibroblasts. In the $MTT_{90}$, cell growth was more stimulated in normal fibroblasts. No significant effect appeared on TGF-${\beta}$ expression but an increase in extracellular fibronectin secretion was found in keloid fibroblasts. Keloid fibroblasts responded to verapamil more sensitively, and the percentage of apoptosis was higher at the $MTT_{50}$l. In brief, verapamil had growth-inhibitory effect with inducing apoptosis at the $MTT_{50}$, but rather growth-stimulatory effect at the $MTT_{90}$. The biphasic effect of verapamil depending on the dose might explain one of the reasons of relapse after keloid treatment with verapamil. Clinical application with high concentration (2.5 mg/ml) is advised unless excessive dosage is used.

• The Korean Journal of Pain
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• v.32 no.4
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• pp.256-263
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• 2019

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.