Milk Thistle/ In HCV & HIV

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Milk Thistle/ In HCV & HIV

Milk Thistle Silibinin Extracts Inhibit HCV Polymerase in Laboratory Study

SUMMARY: Silibinin and related biologically active compounds from the milk thistle plant demonstrated direct inhibition of hepatitis C virus (HCV) polymerase in laboratory cell culture experiments, according to a report published in the March 2010 issue of Gastroenterology. It did not, however, act as an HCV protease inhibitor.

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By Liz HighleymanThe milk thistle plant, Silybum marianum, is widely used in traditional herbal medicine as a treatment for liver disease. While milk thistle and its components are most often studied as a potential anti-fibrosis or liver-protective therapy, it may also have direct activity against HCV.Abdelhakim Ahmed-Belkacem and colleagues from France and Germany used different laboratory models to evaluate whether active compounds in silymarin could inhibit the function of HCV enzymes, similar to the effects of the novel directly-targeting antiviral therapies now making their way through the development pipeline.Silymarin is a mixture of several milk thistle "flavonolignans" (a type of plant component) including silibinin A, silibinin B, isosilibinin A, isosilibinin B, silicristin, and silidianin, the study authors noted

as background. Past research has shown that silibin inhibits HCV replication in laboratory replicons, and intravenous infusion leads to dose-dependent reduction in HCV RNA viral load in patients.The researchers tested the inhibitory activity of silymarin components against the HCV RNA-dependent RNA polymerase and NS3/4A protease enzymes, which play crucial roles in viral replication. They looked at the compounds' ability to interfere with HCV enzyme activity, and to inhibit replication in an HCV genotype 1b replicon model and a genotype 2a JFH1 infectious HCV cell culture model.ResultsSilibinin A, silibinin B, their water-soluble dihydrogen succinate forms, and Legalon SIL -- a commercially available intravenous silibinin preparation -- all inhibited HCV polymerase function.50% inhibitory concentrations (IC50) were around 75-100 muM.None of these compounds inhibited HCV

protease function.Silibinin A and silibinin B inhibited HCV replication in both the genotype 1b replicon and in the JFH1 cell culture model."Silibinin A and silibinin B, as well as Legalon SIL, inhibit HCV replicon and JFH1 replication in cell culture," the study authors concluded. "This effect is at least partly explained by the ability of these compounds to inhibit HCV RNA-dependent RNA polymerase activity.""Our results provide a basis for the optimization and subsequent development of members of the flavonoid family as specific HCV antivirals," they added.Research Team "Pathophysiology and Therapy of Chronic Viral Hepatitis," INSERM U955, Créteil, France; Institut de Biologie de Lille (CNRS UMR8161), Université de Lille I and II and Institut Pasteur de Lille, Lille, France; Department of Virology, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France; Rottapharm/Madaus, Cologne, Germany; National Reference Center for Viral

Hepatitis B, C and Delta, Department of Virology, Hôpital Henri Mondor, Université Paris 12, Créteil, France.4/6/10ReferenceA Ahmed-Belkacem, N Ahnou, L Barbotte, and others. Silibinin and Related Compounds are Direct Inhibitors of Hepatitis C Virus RNA-Dependent RNA Polymerase. Gastroenterology 138(3): 1112-1122 (Abstract). March 2010.

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Milk thistle and other medications

Below is a short list of some other medications that are processed through the CYP3A4 enzyme. Based on the effect of milk thistle on liver enzymes in the lab, it is possible that levels of these medications may increase if taken by people who are also using milk thistle.

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This list is not exhaustive:

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Heart drugs – Tambocor (flecainide), Rythmol (propafenone)

Antibiotics – erythromycin, rifampin

Anti-seizure drugs – carbamazepine (Tegretol)

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Antidepressants –Zyban/Wellbutrin (bupropion), Paxil (paroxetine), Prozac (fluoxetine), Luvox (fluvoxetine). Serzone (nefazodone), Zoloft (sertraline), Effexor (venlafaxine) St. ’s wort.

Antihistamines – Hismanal (astemizole), Seldane (terfenadine)

Antifungals – itraconazole (Sporanox), ketoconazole (Nizoral)

Gastrointestinal motility agents – Prepulsid (Cisapride)

Ergot drugs – Ergonovine, Ergomar (ergotamine)

Anti-psychotics – Clozaril (clozapine), Orap (pimozide)

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Sedatives/sleeping pills –Ambien (zolpidem), Halcion (triazolam), Versed (midazolam)

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Erectile dysfunction drugs – Viagra (sildenafil),

Lipid-lowering drugs (statins) –Lescol (fluvastatin), Mevacor (lovastatin), Pravachol (pravastatin), Zocor (simvastatin)

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Transplant drugs –cyclosporine (Neoral, Sandimmune), ProGraf (tacrolimus).

Milk thistle also has the potential to lower levels of the following drugs in the blood: anti-parasite drugs – Mepron (atovaquone) sedatives/sleeping pills – Ativan (lorazepam) hormones – estrogen

The research by the scientists in Pittsburgh and at the NIH should emphasize to readers that simply because a product is “natural†it does not mean it is safe when taken with other substances. This research also highlights the need to conduct further research on herb-drug interactions on liver cells as well as in people. Such studies may find combinations of herbs and drugs that can be safely used together. The Pittsburgh researchers noted that “patients and health care professionals must be encouraged to discuss the use of herbs and be educated about the potential interactions between herbs and drugs.†This cannot be stressed enough. Contraindications: milk thistle is not recommended for use during pregnancy or breastfeedingCaution: Milk Thistle and Protease Inhibitors

A caution for HIV patients, because many medications taken by individuals diagnosed with HIV/AIDS (PHAs) - such as protease inhibitors and non-nukes are processed by the liver enzyme CYP3A4 which is decreased by Silymarin. If Milk Thistle is taken by someone using protease inhibitors or non-nukes, it has the potential to raise levels of these drugs. This should not be a concern as long as levels of these drugs are monitored closely and dosage is adjusted to reach the desired levels.

Warnings 1. Milk thistle and anti-HIV medications Researchers at the University of Pittsburgh have suspected that milk thistle can slow down or reduce the activity of enzymes in the liver. What does this have to do with HIV? Enzymes in the liver break down many of the substances that we eat and drink, including medications. If the activity of these enzymes is reduced, then drugs remain in the blood longer than they otherwise might. This could lead to higher-than-expected levels of drugs in the body, causing side effects or intensifying already-existing side effects. Alternatively, if the activity of enzymes is increased, then the level of drugs in blood may fall to less-than-normal levels. This could help HIV resist the effect of the drugs you are taking and reduce your future treatment options.Many medications taken by PHAs, such as protease inhibitors and non-nukes, are processed by this liver enzyme. If milk thistle is taken by someone using protease inhibitors or non-nukes, it has the potential to affect the levels of these medications.To find out if milk thistle affects indinavir (Crixivan) levels in people, researchers at the National

Institutes of Health (NIH) in Bethesda, land, conducted a study. They used healthy, HIV negative subjects taking the protease inhibitor indinavir at a dose of 800 mg three times daily on an empty stomach. Milk thistle was taken at a dose of 175 mg three times daily with food. Overall, the researchers found that the total amount of indinavir that entered their blood was decreased by only 9% with use of milk thistle. Perhaps more significant were the changes in trough levels of indinavir.“Trough levels†refers to the lowest level to which a drug in the blood falls over time. It’s easiest for HIV to develop resistance when drug levels are at their lowest — at the trough. Levels of indinavir are at their lowest just before it’s time to take the next dose — eight hours after the last dose was taken. In the study, milk thistle lowered indinavir trough levels by about 25% compared to their levels when indinavir alone was taken. This

change was statistically significant, that is, not likely due to chance alone. In one subject, trough levels decreased by as much as 60%.A decrease of 25% in trough levels may be a concern for some people who are using only one protease inhibitor in their treatment regimen. However, in North America and the European Union, more doctors are increasingly prescribing indinavir with another PI — ritonavir (Norvir). This is because Ritonavir can significantly increase and maintain high levels of indinavir. For the same reason, ritonavir is also used to boost other PIs including the following:amprenavir (Agenerase)lopinavir (in Kaletra)saquinavir (Fortovase or Invirase) When taken with ritonavir, because it is such a powerful booster, indinavir levels may not be significantly affected by the dose of milk thistle used in the NIH study.The precise effect of milk thistle on other single protease inhibitors without the ritonavir boost, and on non-nukes, until studied, is not clear.

http://Hepatitis Cnewdrugs.blogspot.com/2010/05/cautionmilk-thistle-in-hcv-and-hiv.html