ENHANCEMENT OF CYTOTOXICITY OF ANTICANCER DRUGS BY VERAPAMIL
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当教室で樹立した人培養腎癌細胞株 (NUR) および人正常腎細胞 (PHK) を用い, ビンクリスチン (VCR), アドリアマイシン (ADM), シスプラチン (CDDP) に対する verapamil の効果増強作用について検討した. 殺細胞効果については, 細胞の増殖曲線, 3H-thymidine incorporation 法で検討した. また細胞内における3H-VCR, 3H-daunomycin の取り込みを経時的に測定し, 取り込みおよび放出に対する verapamil の影響をみた. verapamil の濃度は細胞毒性を示さない1.0μg/mlとした. verapamil は NURcell の増殖曲線, 3H-thymidine incorporation のいずれにおいてもADM, VCR, CDDPの殺細胞効果を増強させ, 3H-thymidine incorporation の抑制でみるとIC50 (drug concentration for 50% inhibition) は各々制癌剤単独で0.095, 4.81, 1.01μg/mlであったものが, verapamil 1.0μg/mlの併用で, 0.039, 1.29, 0.508μg/mlとなった. またNUR cell に対し, ADMの効果増強を生じる verapamil の最小濃度は, 約0.1μg/mlであり, その増強効果は濃度依存性に高められた. 3H-VCR, 3H-daunomycin のNUR cell への取り込みは verapamil によって, いずれも増加した. しかし細胞外放出に対しては, 3H-VCRは verapamil によって抑制される傾向を示したが, 3H-daunomycin については, その影響を認めなかった. PHK cell についても 3H-thymidine incorporation によってVCR, ADM, CDDPに対する verapamil の影響を検討したが, いずれも軽度であった. また, PHK cell への3H-VCR, 3H-daunomycin の取り込みに対する verapamil の影響も極軽度であった.Keywords:
Thymidine
IC50
瞄准：在人的阴茎海绵体在试管内上评估 verapamil 的弛缓的效果并且为可勃起的机能障碍(编辑) 作为一个处理估计这药的潜力。方法：人的阴茎海绵体的准备从最近被获得有正常的死亡的年轻人可勃起的功能。当 10 micromol/L 脱羟肾上腺素导致的收缩被 verapamil 或车辆控制(无菌的水) 的不同剂量减少时，等轴的紧张和详细曲线被记录。人的阴茎海绵体准备的紧张在增加 verapamil 或车辆前被描述为他们的最高的紧张的一个百分比。ANOVA 和最少的有效差量测试被用于统计分析。结果：1 micromol/L， 10 micromol/L 和 100 micromol/L verapamil 的剂量导致了松驰(35.28+/-7.96 )% ，(55.91+/-6.41 )% ，(85.68+/-4.16 ) 在 30 min 以后的 % 分别地。车辆控制同时削尖生产松驰(-0.06+/-10.57)%(P<0.05 ) 。结论：Verapamil 在放松脱羟肾上腺素在试管内导致的正常人的语料库多孔的平滑肌是显著地有效的，弛缓的效果取决于 verapamil 的集中。
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IC50
Derivative (finance)
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Context: Oridonin has been traditionally used in Chinese treatment of various cancers, but its poor bioavailability limits its therapeutic uses. Verapamil can enhance the absorption of some drugs with poor oral bioavailability. Whether verapamil can enhance the bioavailability of oridonin is still unclear.Objective: This study investigated the effect of verapamil on the pharmacokinetics of oridonin in rats and clarified its main mechanism.Materials and methods: The pharmacokinetic profiles of oral administration of oridonin (20 mg/kg) in Sprague-Dawley rats with two groups of six animals each, with or without pre-treatment of verapamil (10 mg/kg/day for 7 days) were investigated. The effects of verapamil on the transport and metabolic stability of oridonin were also investigated using Caco-2 cell transwell model and rat liver microsomes.Results: The results showed that verapamil could significantly increase the peak plasma concentration (from 146.9 ± 10.17 to 193.97 ± 10.53 ng/mL), and decrease the oral clearance (from 14.69 ± 4.42 to 8.09 ± 3.03 L/h/kg) of oridonin. The Caco-2 cell transwell experiments indicated that verapamil could decrease the efflux ratio of oridonin from 1.67 to 1.15, and the intrinsic clearance rate of oridonin was decreased by the pre-treatment with verapamil (40.06 ± 2.5 vs. 36.09 ± 3.7 µL/min/mg protein).Discussion and conclusions: These results indicated that verapamil could significantly change the pharmacokinetic profile of oridonin in rats, and it might exert these effects through increasing the absorption of oridonin by inhibiting the activity of P-gp, or through inhibiting the metabolism of oridonin in rat liver. In addition, the potential drug-drug interaction should be given special attention when verapamil is used with oridonin. Also, the dose of oridonin should be carefully selected in the clinic.
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当教室で樹立した人培養腎癌細胞株 (NUR) および人正常腎細胞 (PHK) を用い, ビンクリスチン (VCR), アドリアマイシン (ADM), シスプラチン (CDDP) に対する verapamil の効果増強作用について検討した. 殺細胞効果については, 細胞の増殖曲線, 3H-thymidine incorporation 法で検討した. また細胞内における3H-VCR, 3H-daunomycin の取り込みを経時的に測定し, 取り込みおよび放出に対する verapamil の影響をみた. verapamil の濃度は細胞毒性を示さない1.0μg/mlとした. verapamil は NURcell の増殖曲線, 3H-thymidine incorporation のいずれにおいてもADM, VCR, CDDPの殺細胞効果を増強させ, 3H-thymidine incorporation の抑制でみるとIC50 (drug concentration for 50% inhibition) は各々制癌剤単独で0.095, 4.81, 1.01μg/mlであったものが, verapamil 1.0μg/mlの併用で, 0.039, 1.29, 0.508μg/mlとなった. またNUR cell に対し, ADMの効果増強を生じる verapamil の最小濃度は, 約0.1μg/mlであり, その増強効果は濃度依存性に高められた. 3H-VCR, 3H-daunomycin のNUR cell への取り込みは verapamil によって, いずれも増加した. しかし細胞外放出に対しては, 3H-VCRは verapamil によって抑制される傾向を示したが, 3H-daunomycin については, その影響を認めなかった. PHK cell についても 3H-thymidine incorporation によってVCR, ADM, CDDPに対する verapamil の影響を検討したが, いずれも軽度であった. また, PHK cell への3H-VCR, 3H-daunomycin の取り込みに対する verapamil の影響も極軽度であった.
Thymidine
IC50
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Pharmacodynamics
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A case of sick sinus syndrome with two different ventricular tachyarrythmias prevented by verapamil.
心室性頻脈性不整脈に対してverapamilが有効であるという報告は少い。我々は洞不全症候群を有し, 臨床電気生理学的検査により誘発された心室性頻拍 (VT) に対しverapamilが有効でかつその慢性経口投与が心室性頻脈性不整脈の予防に有効と考えられた症例を経験したので報告する。48歳男, 明らかな基礎心疾患を認めない。心電図上洞性徐脈, 洞停止, 接合部性補充調律, 心室性期外収縮, 心室粗動, slow VTがみられた。臨床電気生理学的検査ではQRS波形と心拍数の異る2種類のVTが誘発され, verapami1は両者に対して予防効果を認めた。洞結節回復時間は2, 060 msecでverapamil投与後さらに延長したためVVIのペースメーカーを植込み, さらにverapamil 320mg/日を服用させ, 以後1年間頻脈発作を認めない。この予防効果はペースメーカーによる徐脈予防およびverapamilによるものと考えられるが, VTに対するverapamilの慢性経口投与の有効性が示唆された。
Sick sinus syndrome
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The aim of this work was to determine the influence of ethanol on the antiarrhythmic activity of verapamil in the model of calcium arrhythmia in rats non-dependent and dependent on ethanol. The results of the experiment show that a combined, single administration of ethanol and verapamil attenuates in a statistically significant manner the antiarrhythmic effect of verapamil. Ethanol administered repeatedly together with verapamil does not diminish the antiarrhythmic activity of verapamil.
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Objective To evaluate the activity and synergistic cytotoxicity of adriamycin in combination with verapamil to OS732 tumor cell in vitro. Methods The activity of adriamycin with different grades concenstration and its synergistic cytoxicity with verapamil to OS732 after 24 h, 48 h and 72 h culture were surveyed by colorimetric MTT test. The CD95 level was detected by FCM. Results The cytotoxicity of adriamycin against OS732 has a dose\|dependant relation, but its cytotoxicity doesn't increase equally as the time elapsed. Verapamil with a dose without any cytotoxicity also can enhance the cytotoxicity of adriamycin and increase the expression level of CD95. Conclusion The mechanism of verapamil to adriamycin in OS732 may be differs from its reverse effect to multidrug resistance.
MTT assay
Efflux
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Abstract We have investigated the effect of quercetin on the pharmacokinetics of verapamil and its major metabolite, norverapamil, in rabbits. Pharmacokinetic parameters of verapamil and norverapamil were determined after the oral administration of verapamil (10 mg kg−1) to rabbits in the presence and absence of quercetin (5.0 and 15 mg kg−1). While co-administration of quercetin concurrently was not effective to enhance the oral exposure of verapamil, pretreatment of quercetin 30 min before verapamil administration significantly altered the pharmacokinetics of verapamil. Compared with the control group (given verapamil alone), the Cmax and AUC of verapamil increased approximately twofold in the rabbits pretreated with 15 mg kg−1 quercetin. There was no significant change in Tmax and terminal plasma half-life (t½) of verapamil in the presence of quercetin. Consequently, absolute and relative bioavailability values of verapamil in the rabbits pretreated with quercetin were significantly higher (P<0.05) than those from the control group. Metabolite-parent AUC ratio in the rabbits pretreated with quercetin decreased by twofold compared with the control group, implying that pretreatment of quercetin could be effective to inhibit the CYP3A4-mediated metabolism of verapamil. In conclusion, pretreatment of quercetin significantly enhanced the oral exposure of verapamil. This suggested that concomitant use of quercetin or a quercetin-containing dietary supplement with verapamil requires close monitoring for potential drug interaction.
Active metabolite
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