Simvastatin potentiates the anti-hepatitis B virus activity

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Ted Badera, ,  and Brent Korbab,

a Section of Gastroenterology, Department of Medicine, University of Oklahoma Health Sciences Center, VA Medical Center, Mailstop 111H, 921 NE 13th Street, Oklahoma City, OK 73104, USA

b Department of Microbiology, Georgetown University Medical Center, 3900 Reservoir Road, NW, Med-Dent. Building, Room SW319, Washington, DC 20057, USA

Received 25 November 2009;  revised 28 January 2010;  accepted 26 February 2010.  Available online 6 March 2010.

Abstract
Statins are 3-hydroxyl-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors used for the treatment of hypercholesterolemia. We report that a particular statin, simvastatin (SIM), exhibits strong in vitro anti-HBV activity. Moreover, a combination of SIM with each of the individual nucleos(t)ide analogues lamivudine (LMV), adefovir (ADV), tenofovir (TEN) and entecavir (ETV), showed synergistic antiviral activity. Combination drug treatments were performed in the HepG2.2.15 cell line. Compound combinations were centered on a mixture designed to deliver approximately equipotent (not necessarily equimolar) concentrations of each agent, based on the ninety percent viral inhibition monotherapy values. SIM interacted favorably with all four licensed anti-HBV nucleos(t)ide analogues, especially at molar ratios that approximate combinations likely to be used clinically. As the relative concentration of SIM was raised to an excess, the overall favorability of the interactions progressively increased.

SIM displayed about equal degrees of synergy with ADV and TDF. The highest degree of synergy was observed at the 300:1 combination of SIM with ETV. Interactions with LMV were the least favorable. The in vitro potential shown here may greatly augment anti-HBV therapy clinically.

Keywords: Hepatitis B virus; Simvastatin; Mevalonate; Entecavir; Tenofovir

Abbreviations: HBV, hepatitis B virus; HCC, hepatocellular carcinoma; IFN, pegylated alfa-interferons; NA, nucleoside analogue; HBeAg, hepatitis B “e” antigen; ALT, alanine aminotransferase; HBV DNA, hepatitis B virus deoxyribonucleic acid; DNA, deoxyribonucleic acid; FDA, Food and Drug Administration (USA); HMG CoA, 3-hydroxy-3-methylglutaryl-coenzyme A; RNA, ribonucleic acid; HBsAg, hepatitis B surface antigen; SIM, simvastatin; LMV, lamivudine; ADV, adefovir; TDF, tenofovir; ETV, entecavir; NIAID, National Institute of Allergy and Infectious Diseases (USA); HBcAg, hepatitis B core antigen; EC50, fifty percent viral inhibition; EC90, ninety percent viral inhibition; CC50, 50% cell cytotoxicity; SI, selectivity index; AST, aspartate aminotransferase; HBx, “x” protein for hepatitis B virus

Article Outline
1. Introduction
2. Materials and methods
2.1. Agents
2.2. Cell cultures
2.3. Calculations
3. Results
3.1. Anti-HBV activity
3.2. Mevalonate addition
4. Discussion
5. Conclusions
Acknowledgements
References




Fig. 1. Two types of evaluations are presented for combination effect of SIM with each of the NA drugs. (A) LMV, (B) ETV, (C) TDF, and (D) ADV. The left hand panels present CI-Fa (combination index-fraction (of virus) affected) plots). For these plots, a combination index [CI] greater than 1.0 indicates antagonism and a CI less than 1.0 indicates synergism. Evaluations of synergy, additivity (summation), or antagonism at different levels of virus inhibition (e.g. 5% (Fa = 0.5) to 99% (Fa = 0.99)) are provided by the plotted lines and points. The outer lines denote 1.96 standard deviations for significance evaluations. The right hand panels present conventional isobolograms. For these plots, ED50, ED75, and ED90 (50%, 75%, and 90% effective antiviral dose) values for the combination treatments are displayed as single points. Three convex curves connecting the axes denote the expected (e.g. additive) EDC50, EDC75, and EDC90 values for drug combinations as calculated from the monotherapies. ED50, ED75, and ED90 values for the combinations that plot to the left (e.g. less than) of the corresponding lines indicate synergy, and values plotting to the right (e.g. greater than) of the corresponding lines indicate antagonism.

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Fig. 2. Collation of best molar combinations for drugs with simvastatin shown in Fig. 1 for comparison. See explanation under Fig. 1 as to description of left-sided and right-sided panels. SIM = simvastatin LMV = lamivudine, ENT = entecavir, ADV = adefovir, TDF = tenofovir.

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Table 1.
HBV antiviral activity of four nucleoside analogues alone and added to simvastatin.



EC50 – μM causing 50% reduction, EC90 = μM causing 90%. The ratios indicate the relative molar amount of the compounds used for each combination. EC50 and EC90 values for combinations are expressed in units of SIM. Additional details on the types of interactions for the different combinations are presented in [Fig. 1] and [Fig. 2].


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Table 2.
Observations of effect of mevalonate upon simvastatin and lamivudine.



CC50 = dose of compound causing 50% cytotoxicity, EC50 – μM causing 50% reduction, EC90 = μM causing 90%, SI = selectivity index = CC50/EC90.

LMV values differ slightly in [Table 1] and [Table 2] because they are from separate experiments.


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Corresponding author at: VA Medical Center, Mailstop 111H, 921 NE 13th Street, Oklahoma City, OK 73104, USA. Tel.: +1 405 456 5313; fax: +1 405 456 5946.



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lemonades

来自意大利人stefano170669的介绍。
他一直跟踪着最新的科研成果

战战兢兢

Simvastatin是一种降低胆固醇常用药物。具有抗乙肝病毒的效果。
这种老药新用的情况，如果老药过了专利保护期，没有商业利益的助推，后面的研究特别是临床试验，不知道美国是怎么样来推动的。想象中，这难免会成为盲点。
按照中国主要以仿造药物的现状来推论，中国本来适合这种事，但这很可能是一片痴心幻想，因为过去多年的经验教训证明，指望不大，或者说基本没有指望。

[ 本帖最后由 战战兢兢 于 2010-4-29 09:11 编辑 ]

走遍四方

原帖由 战战兢兢 于 2010-4-29 09:06 发表
Simvastatin是一种降低胆固醇常用药物。具有抗乙肝病毒的效果。
这种老药新用的情况，如果老药过了专利保护期，没有商业利益的助推，后面的研究特别是临床试验，不知道美国是怎么样来推动的。想象中，这难免会成为盲点。
按照 ...

我问过瑞金医院的医生，TDF何时在中国上市，她大致说TDF在中国还没有做临床，还早着呢。。。

lemonades

原帖由 战战兢兢 于 2010-4-29 09:06 发表
Simvastatin是一种降低胆固醇常用药物。具有抗乙肝病毒的效果。
这种老药新用的情况，如果老药过了专利保护期，没有商业利益的助推，后面的研究特别是临床试验，不知道美国是怎么样来推动的。想象中，这难免会成为盲点。
按照 ...

这篇文章应该是为了混文章和做科研的，也许不打算应用于临床，不过也说不定，毕竟他们才发表，兴许会有后续的研究也说不好。

体内显示跟恩替有很好的协同作用。这篇文章其实很好，有空大家仔细看下。老药，安全，体外显示有协同，很多战友胆固醇也的确偏高。

天行健君

Simvastatin应用中有转氨酶急剧升高的现象,这个文章好象没讲到怎么安全应用,同时使用恩替的话转安酶也会升高吗

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原帖由 天行健君 于 2010-5-2 18:20 发表
Simvastatin应用中有转氨酶急剧升高的现象,这个文章好象没讲到怎么安全应用,同时使用恩替的话转安酶也会升高吗

就前一部分展开讲讲？给个出处？谢谢

天行健君

辛伐他汀说明书:
【禁    忌】（1）对任何成分过敏者。
（2）活动性肝炎或无法解释的持续血清氨基转移酶升高者。
（3）与四氢萘酚类钙通道阻滞剂米贝地尔合用
个人理解,这个无法解释的应该就是抗病毒起作用了吧.
那怎么监测呢,恩替本身抗病毒很强了

天行健君

【注意事项】1.......。2.肝脏反应。本药应慎用在大量饮酒和/或有肝病历史的病人。有活动性肝病或无法解释的氨基转移酶升高者应禁用辛伐他汀。在临床实验中，有少数服用辛伐他汀的患者有显著的血清氨基转移酶持续升高(超过正常值3倍以上)的现象。但停药后，则氨基转移酶可回复至治疗前水平，但无黄疸或其它有关的临床症状或体征，亦无过敏现象。建议在治疗前对于氨基转移酶有升高现象的患者应加强检查并多加留意。
如果病人的氨基转移酶有继续升高的表现，特别是氨基转移酶升高超过正常值3倍以上并保持持续，则应予停药。与其它降脂药相同，应用辛伐他汀治疗的患者氨基转移酶中等程度升高(低于正常值3倍的情况)亦有报道。这些变化通常在应用辛伐他汀治疗后不久即有出现，但一般为一过性且不伴随任何症状，所以不必停药。
3.肌肉反应。应用辛伐他汀治疗的患者普遍有肌酸激酶(CK，来自骨骼肌)轻微的一过性升高，但这些并无任何临床意义。对于有弥漫性的肌痛、肌软弱或/和显著的肌酸激酶(CK)升高(大于正常值十倍以上)的情况应考虑为肌病，因此应要求病人若发现有不可解释的上述肌病征象应立即告诉医生。若发现肌酸激酶(CK)显著上升或诊断或怀疑肌痛，应立即停止辛伐他汀的治疗。对于有急性或严重的条件暗示的肌病及有因横纹肌溶解而导致二次急性肾衰竭倾向的病人应停止甲基羟戊二酰辅酶A(HMG-CoA)还原酶抑制剂的治疗

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原帖由 天行健君 于 2010-5-3 11:24 发表
辛伐他汀说明书:
【禁    忌】（1）对任何成分过敏者。
（2）活动性肝炎或无法解释的持续血清氨基转移酶升高者。
（3）与四氢萘酚类钙通道阻滞剂米贝地尔合用
个人理解,这个无法解释的应该就是抗病毒起作用了吧.
那怎么监测呢, ...

联用恩替的时候，如果不出现alt持续升高，肝脏无损伤的话也就不用管单独用药会怎样了。

这个的理论基础是，HBV表面抗原的制造过程需要胆固醇，降低胆固醇可能会降低病毒。