Statin
and Diabetes Drug Show Activity against Hepatitis B Virus
in Laboratory Studies
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| SUMMARY:
Simvastatin (Zocor), a medication used to lower
blood cholesterol, had a synergistic effect against
hepatitis B virus (HBV) when combined with antiviral
drugs in a laboratory study, researchers reported
last month at the 60th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD
2009) in Boston. In another study, the diabetes
drug rosiglitazone also demonstrated in vitro
activity against HBV. |
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By
Liz Highleyman
Typically,
drugs studied for hepatitis B treatment were designed or
selected for their antiviral activity, but researchers sometimes
also test other types of commonly used agents.
Simvastatin
In
the first study, investigators from the University of Oklahoma
and Georgetown University Medical Center looked at interactions
between simvastatin -- which is widely used to manage elevated
cholesterol -- and the nucleoside/nucleotide anti-HBV drugs
lamivudine
(Epivir-HBV), adefovir
(Hepsera), entecavir
(Baraclude), and tenofovir
(Viread).
Combinations
of these agents were tested in a laboratory study using
cultures of 2.2.15 cells. The combinations were designed
to deliver equipotent (equal potency), though not equimolar,
concentrations of each agent, based on the EC90 (90% effective
concentration) of the drugs when used as monotherapy.
The researchers found that simvastatin interacted favorably
overall with all 4 anti-HBV drugs, especially at dose ratios
that resemble combinations likely to be used clinically.
As the relative concentration of simvastatin increased to
an excessive level, however, the favorability of the interactions
progressively decreased.
Simvastatin
demonstrated approximately equal degrees of synergy with
tenofovir (3:1) and adefovir (10:1), and the highest degree
with the 300:1 combination of simvastatin plus entecavir;
interactions with lamivudine (100:1) were the least favorable.
In all combinations, the addition of the nucleoside/nucleotide
agents did not increase the cytotoxicity (propensity to
damage cells) of simvastatin.
Rosiglitazone
In
the second study, researchers from Tohoku University School
of Medicine in Sendai, Japan, evaluated the suppressive
effect on HBV replication of bezafibrate, used to treat
elevated blood lipids, and rosiglitazone (Avandia), used
to manage diabetes.
Prior
research has indicated that peroxisome proliferator activated
receptors (PPARs) -- which play a role in glucose and lipid
metabolism -- may also influence immune response against
viruses; therefore, agents that activate PPARs may stimulate
this response.
In
this laboratory study, the investigators assessed the effects
and toxicity of bezafibrate (a PPAR-alpha agonist) and rosiglitazone
(a PPAR-gamma agonist) added (24 hours later) to cultures
of HepG2 cells infected with a genotype HBV genome with
no mutations in the core promotor or precore regions.
The
50% cytotoxicity concentration of rosiglitazone was almost
150 mcM and that of bezafibrate was almost 250 mcM; lamivudine
demonstrated no cytotoxicity at concentrations less than
1 mcM.
HBV
DNA levels decreased when the bezafibrate concentration
was greater than 200 mcM, but at this level it had considerable
cytotoxicity. In contrast, rosiglitazone decreased HBV DNA
at 5 mcM with no cytotoxicity. On this basis, the EC50 (50%
effective concentration) of rosiglitazone was calculated
as 9.8 mcM. Rosiglitazone also suppressed replication of
HBV strains with core promoter and/or precore mutations
in addition to the wild type strain.
"In
this study, it was suggested that the replication of HBV
was inhibited by rosiglitazone," the researchers concluded.
"The mechanism is uncertain and is being investigated
now."
12/4/09
References
T
Bader, B Korba, and M Bronze. Simvastatin has significant
antiviral synergism in vitro with anti-HBV drugs. 60th Annual
Meeting of the American Association for the Study of Liver
Diseases (AASLD 2009). Boston. October 30-November 1, 2009.
Abstract 408.
Y
Wakui, J Inoue, Y Ueno, and others. Rosiglitazone suppresses
the replication of hepatitis B virus in HepG2 cells. 60th
Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD 2009). Boston. October 30-November
1, 2009. Abstract 444.
