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本帖最后由 风雨不动 于 2012-4-14 16:12 编辑
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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