Incorrect review of Milk thistle interaction article and refs

[Guest guest]

Analysis of Milk Thistle Potential Interactions

the analysis review below of the study of Indinavir & milk thistle in healthy volunteers appears INCORRECT, it says that the study found a 25% reduction in 'blood levels' in one place in the article & then in another says a 25% reduction in trough levels was statistically significant. According to the published report which i previously distributed & follows these comments immediately below says the reduction is in trough not AUC & is NOT statistically significant. However, this review raises several concerns about a potential effect on PI levels by milk thistle. One, the study they conducted used 480 mg dose of milk thistle 7 the authors suggested that if a higher dose were used perhaps a significant interaction could occur. Second, the authors say "Silymarin also may alter drug absorption, distribution, and elimination through inhibition of P-glycoprotein P-glyco-protein is an active drug transporter, has a wide substrate range, and is abundant in the apical membrane of many pharmacologically important barriers such as intestinal epithelium, and the blood-brain, blood-nerve, blood-testis, and maternofetal barriers.[7] Flow cytometric analysis confirmed significant P-gp expression in both CD4+ and CD8+ cells; therefore, in addition to playing a role in limiting drug bioavailability, P-gp may limit brain, testis, fetal, and intracellular penetration of drugs". In a separate report I distributed concerns were raised about the effect of milk thistle on ant-cancer drugs as a result of milk thistle's effect on p-gp. In the study below the authors say "More study is necessary before concluding that an herbal supplement with P-gp-inhibitory properties, such as milk thistle, will not increase intracellular or potential viral sanctuary site concentrations of indinavir". Immediately below is the published study I had distributed & it is posted on the NATAP website, and following it below is the apparent review with a different & apparently incorrect conclusion.

Jules Levin

NATAP - http://www.natap.org

Coadministration of Milk Thistle and Indinavir in Healthy Subjects

DiCenzo, Pharm.D., Mark Shelton, Pharm.D., Jordan, Pharm.D., Koval, M.D., Alan Forrest, Pharm.D., Reichman, M.D., Gene Morse, Pharm.D.

Pharmacotherapy 23(7):866-870, 2003. © 2003 Pharmacotherapy Publications

Posted 08/06/2003

Abstract and Introduction

Abstract

Study Objective: To determine if milk thistle (silymarin) alters the pharmacokinetics of indinavir.

Design: Sequential crossover trial.

Setting: General clinical research center.

Subjects: Ten healthy subjects.

Intervention: Indinavir 800 mg 3 times/day was given for four doses on days 1 and 2. Silymarin 160 mg 3 times/day was given on days 3-15. On day 16 and for one dose on day 17, both drugs were given at the same dosages.

Measurements and Main Results: Indinavir's pharmacokinetic parameters were evaluated at steady state both before and after administration of 14 days of silymarin. Blood samples were collected -0.25, 0.5, 1, 2, 3, 4, and 5 hours after indinavir dosing and assayed by high-performance liquid chromatography. The final pharmacokinetic model had first-order absorption after a lag time, and two compartments with first-order elimination from the central compartment. When given alone and combined with silymarin, respectively, the geometric mean (95% confidence interval [CI]) steady-state indinavir area under the plasma concentration-time curve was 20.7 hrmg/L (15.3-28.2 hrmg/L) and 19.4 hrmg/L (15.8-23.6 hrmg/L) and the trough plasma concentration was 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L).

Conclusion: Silymarin has no apparent effect on indinavir plasma concentrations.

Introduction

As complementary alternative medicine (CAM) is practiced increasingly among adults infected with human immunodeficiency virus (HIV), it is ever more necessary to know if CAM will influence antiretroviral therapy. A recent survey of 118 HIV-infected patients receiving highly active antiretroviral therapy (HAART) showed that 38% of respondents were taking CAM. Of particular concern is that physicians were unaware of this in 67% of patients taking herbal products.[1]

Approximately one third of HIV infected patients are coinfected with hepatitis C virus (HCV). Hepatitis C infection can progress to liver failure, and this progression may be especially rapid in coinfected patients.[2] Milk thistle, an herbal supplement, is purported to decrease the risk of developing liver failure; therefore, a number of HIV-infected patients who are also infected with HCV are interested in taking the supplement.[3]

The active component of milk thistle is thought to be silymarin. Silymarin has the potential to influence drug metabolism by decreasing the metabolic activity of cytochrome P450 (CYP) 3A4, a ubiquitous enzyme responsible for hepatic and intestinal metabolism of many antiretroviral agents, including indinavir.[4, 5] Silymarin also may alter drug absorption, distribution, and elimination through inhibition of P-glycoprotein (P-gp).[6] P-glyco-protein is an active drug transporter, has a wide substrate range, and is abundant in the apical membrane of many pharmacologically important barriers such as intestinal epithelium, and the blood-brain, blood-nerve, blood-testis, and maternofetal barriers.[7] Flow cytometric analysis confirmed significant P-gp expression in both CD4+ and CD8+ cells; therefore, in addition to playing a role in limiting drug bioavailability, P-gp may limit brain, testis, fetal, and intracellular penetration of drugs.[8]

Indinavir belongs to the protease inhibitor class of antiretroviral drugs and is an effective component of HAART. It is also a substrate of both CYP450 and P-gp.[5, 7, 9] The purpose of this trial was to determine if silymarin influences the pharmacokinetics of indinavir.

Methods

This sequential, crossover trial was conducted in healthy men and women not of childbearing potential (bilateral tubal ligation, hysterectomy, menopause) between 18 and 55 years of age who had a negative HIV test, normal clinical laboratory blood tests, and normal physical examination. Exclusion criteria were smoking in the past year, ingestion of milk thistle within 30 days, use of agents known to influence CYP450, use of herbal supplements, and active or history of liver disease.

All outpatient and inpatient procedures were performed in the General Clinical Research Center (GCRC) at the University of Rochester Medical Center. Subjects received indinavir (Crixivan; Merck & Co., Inc., Whitehouse Station, NJ) 800 mg at 8 A.M., 4 P.M., and midnight on day 1. The first dose was administered in the GCRC and subjects reported back to the center that evening for the first of two overnight stays. On day 2 subjects received indinavir 800 mg in the fasted state (no food within 8 hours) at 8 A.M.; plasma samples were drawn -0.25, 0.5, 1, 2, 3, 4, and 5 hours after this dose. Subjects received a standard breakfast consisting of 4 ounces of skim milk, 3/4 ounce of corn flakes, and 4 g of sugar 1 hour after the morning dose and were discharged after the last blood draw. They were instructed not to drink alcohol or citrus beverages on days 1, 2, 16, and 17. On day 3 subjects began taking silymarin 160 mg (standardized milk thistle; General Nutrition Corp., Pittsburgh, PA) 3 times/day. On day 16 they began taking indinavir with silymarin in the same dosages, and returned to the GCRC in the evening for their second overnight stay. On day 17 subjects took their last doses of silymarin 160 mg and indinavir 800 mg. Plasma sampling times and meals were identical to those for day 2. After the last blood draw on day 17 subjects were discharged from the GCRC. They returned to the center between days 42 and 56 for a physical examination, when blood was drawn for clinical laboratory tests and an HIV test.

Each blood sample was centrifuged for 10 minutes at 800 x g. Plasma was separated into three aliquots and stored at -70°C until shipped to the University at Buffalo Adult AIDS Clinical Trials Group Pharmacology Support Laboratory, Buffalo, NY. Indinavir plasma concentrations were quantified by a validated high-performance liquid chromatography (HPLC) assay with ultraviolet detection. Indinavir interassay coefficients of variation (CVs) were 3.2% at 75 ng/ml and 2.8% at 3500 ng/ml, and intraassay CVs were 1.7-8.5% at 75 ng/ml and 0.3-3.4% at 3500 ng/ml. Lower limit of quantification for the assay was 12.5 ng/ml.

Before subject enrollment, 10 milk thistle capsules were assayed for silymarin content by a validated HPLC method (Research Triangle Laboratories, Inc., Raleigh, NC). The amount of silymarin was 173 mg/capsule, and all milk thistle dispensed during this study was from the same lot number.

Indinavir plasma concentrations were first modeled in Adapt II using maximum likelihood.[10, 11] For all modeling methods, observed data were weighted by the inverse of the fitted variance. The variance model assumed a linear relationship between standard deviation and fitted concentration. Model discrimination was performed using Akaike's information criterion. Once the structural model was developed, final pharmacokinetic estimates were calculated by a MAP Bayesian approach using iterative two-stage analysis. Indinavir concentrations 8 hours after dose administration (Cmin) were computed as the fitted Cmin 8 hours after the dose. Maximum concentration during the dosing interval (Cmax) was determined by visual inspection. Ten subjects were required to have 80% power to detect a 50% difference in indinavir area under the plasma concentration-time curve (AUC0-8) using a two-sided paired t test with an a error of 0.05 assuming a 40% CV.[12] Confidence intervals (CIs) were constructed on results of analyses of variance of each pharmacokinetic parameter or its log transform. Bioequivalence was defined as the 90% CI of the geometric mean ratio of AUC0-8 or Cmax being within Food and Drug Administration (FDA) guidelines (0.80-1.25). All statistical analyses were conducted using SAS system, version 8 (SAS Institute, Cary, NC).

Results

Ten subjects (seven men) completed the trial. Mean ± SD age and weight were 32.5 ± 10.0 years and 83.6 ± 20.1 kg, respectively. All subjects were serum negative for HIV-1 and HIV-2 antibodies, and all women had negative serum pregnancy tests both before and after receiving study agents. Indinavir and milk thistle were well tolerated. One subject had elevated fasting blood glucose levels on both pharmacokinetic sampling days; however, this subject's fasting blood glucose concentrations were elevated before and after receiving study drug. One subject had an elevated alanine aminotransferase level before receiving study drug that decreased to normal by the end of the study. No other laboratory tests showed clinically significant deviation from normal. One subject reported very mild gastric reflux and another reported an episode of malaise while receiving indinavir. An episode of mild nausea and mild headache was reported by one subject receiving both indinavir and milk thistle. No adverse events were reported while receiving milk thistle alone. One subject took hydrochlorothiazide, one took estradiol and medroxyprogesterone, and three took multivitamins throughout the study.

The final pharmacokinetic model had two compartments, first-order absorption following a lag time, and first-order elimination from the central compartment. Individual pharmacokinetic parameters are shown in Table 1. Indinavir geometric mean (95% CI) steady-state AUC0-8 when given alone and with silymarin was 20.7 hrmg/L (15.3-28.2 hrmg/L) and 19.4 hrmg/L (15.8-23.6 hrmg/L), respectively (Figure 1). The difference [95% CI] between the geometric mean AUC0-8 for indinavir given alone and with silymarin (1.38 hrmg/L [0.79-1.48 hrmg/L]) was not significant (p=0.64), and changes in AUC0-8 did not follow an apparent trend (Figure 2). The geometric mean [95% CI] difference in Cmax (1.0 mg/L [0.88-1.4 mg/L]) also was not significant (p=0.30).

Neither the geometric mean ratio [90% CI] of indinavir AUC0-8 (0.93 hrmg/L [0.72-1.2 hrmg/L]) nor the geometric mean ratio [90% CI] of indinavir Cmax (0.89 mg/L [0.72-1.1 mg/L]) met the FDA definition of bioequivalence. This was most likely due to small sample size and intrasubject and intersubject variability in exposure, as this study was not powered to determine bioequivalence.

Milk thistle did not significantly influence indinavir trough concentrations. Geometric mean (95% CI) indinavir Cmins when given alone or with silymarin were 0.340 mg/L (0.232-0.497 mg/L) and 0.232 mg/L (0.129-0.419 mg/L), respectively. When comparing indinavir administered alone versus with silymarin, indinavir geometric mean [95% CI] apparent oral volume of distribution (54.1 mg/L [27.9-104.6 mg/L] vs 58.6 mg/L [40.4-85.6 mg/L]) and half-life (3.1 hrs [1.2-8.5 hrs] vs 3.1 hrs [1.3-7.2 hrs]) were not significantly different.

Discussion

Milk thistle extract is a common herbal supplement. Milk thistle is a biennial herb that consists of a mixture of flavonolignans that are present in the fruit, seeds, and leaves of the plant. Flavonolignans are produced in plants through coupling of a flavonoid and a phenylpropanoid. Silymarin, a mixture of flavonolignans (silybin, silydianin, silychristin), is primarily composed of silybin, and typical extracts of milk thistle contain 70-80% silymarin.[3] Milk thistle is considered a hepatoprotectant, and purported to be active against acute or chronic viral hepatitis, toxin- and drug-induced hepatitis and cirrhosis, and alcoholic liver disease. Silymarin is reported to inhibit nitric oxide production, increase levels of glutathione in liver and intestines, scavenge free radicals, prevent lipid peroxidation, and stimulate ribosomal RNA polymerase and subsequent protein synthesis.[3, 13-15]

Preliminary data suggest that silymarin may influence the metabolic capacity of CYP3A4, a CYP isoenzyme responsible for hepatic and intestinal metabolism of many important classes of drugs.[4, 5] Most protease inhibitors, including indinavir, are primarily metabolized by CYP3A4. In vitro it is both an inhibitor and substrate for P-gp, an active drug transporter of the adenosine triphosphate-binding cassette transporter family. Both infection of T cells with HIV-1 and administration of zidovudine to HIV-infected T cells resulted in elevated expression of P-gp.[16, 17] Since P-gp limits the bioavailability and the brain, testis, intracellular, and fetal penetration of drugs, effective inhibition of P-gp may increase the concentration of indinavir in blood and possibly in viral sanctuary sites. The importance of investigating potential herbal-antiretroviral drug interactions is further highlighted by trials in which St. 's wort significantly decreased indinavir plasma concentrations, and garlic significantly decreased plasma concentrations of the protease inhibitor saquinavir in healthy adults.[18, 19]

Administration of silymarin failed to influence either indinavir AUC0-8 or Cmax; therefore, at the dosage given in this study it does not appear to have a significant influence on CYP3A4-mediated hepatic or intestinal metabolism of indinavir. With the same indinavir dosage, others also failed to detect an influence of silymarin on the pharmacokinetics of indinavir in healthy adults.[20] Although neither the geometric mean ratio [90% CI] of AUC0-8 (0.93 mg/L [0.72-1.2 mg/L]) nor Cmax (0.89 mg/L [0.72-1.1 mg/L]) met the definition of bioequivalence, this study was not powered to test for bioequivalence. We also saw no apparent trend in the intersubject variability of AUC0-8 regardless of silymarin coadministration; therefore, the most likely reasons for failing to claim bioequivalence appear to be small sample size and intrasubject and intersubject variability in indinavir exposure.

The Cmin or trough value of a protease inhibitor such as indinavir may be an important marker for clinical outcome. Interest in this relationship is highlighted by the mounting body of evidence suggesting that Cmin or ratio of Cmin to viral genotypic, phenotypic, or virtual phenotypic results may be an important predictor of clinical outcome.[21-23] Milk thistle administration failed to influence indinavir Cmin.

Limitations of this trial include small sample size, no evaluation of the effect of higher dosages of silymarin on indinavir pharmacokinetics, omission of assaying silymarin blood concentrations, and the fact that indinavir is now commonly administered with drugs that inhibit its metabolism so as to provide a pharmacokinetic boosting effect. Although the trial had only 10 subjects, pharmacokinetic parameters were almost identical between the agents, and it is doubtful that even a large trial would find a clinically relevant difference.

The dosage we administered approximates the recommended hepatoprotectant dosage of silymarin at the time this trial was designed (480 mg/day) and falls within the range of common milk thistle extract dosages (300-600 mg/day).[3, 24] However, we cannot conclude that silymarin would not have influenced the pharmacokinetics of indinavir at higher dosages. Milk thistle is poorly absorbed after oral administration (bioavailability 23-47%); therefore, silymarin blood concentrations may have been too low to achieve an appreciable effect on either CYP3A4 or P-gp.[25] Although the silymarin content in the capsules was determined before administration, in the absence of silymarin blood samples we cannot rule out the possibility that inadequate silymarin absorption led to the observed absence of effect. Furthermore, protease inhibitors are commonly administered with drugs that alter CYP3A4-dependent metabolism; therefore, we cannot rule out the possibility that milk thistle may alter the pharmacokinetics of indinavir indirectly by influencing the pharmacokinetics of concomitant drugs.

Finally, although this trial failed to show an influence of silymarin on the pharmacokinetics of indinavir, it was not designed to examine P-gp-dependent alterations in the distribution of indinavir to potential viral sanctuary sites. More study is necessary before concluding that an herbal supplement with P-gp-inhibitory properties, such as milk thistle, will not increase intracellular or potential viral sanctuary site concentrations of indinavir.

In summary, silymarin 160 mg 3 times/day failed to influence the pharmacokinetics of indinavir in healthy subjects. Concomitant administration of milk thistle at this dosage would not be expected to alter indinavir AUC, Cmax, or Cmin to clinically significant extents.

Table 1. Indinavir Pharmacokinetic Parameters

                        AUC(hrmg/L)         Cmax (mg/L)     Cmin (mg/L)     Half-life (hrs)

Indinavir         20.7 (15.3-28.2)        8.85 (7.17-10.9)     0.34 (0.23-0.50)      3.1 (1.2-8.5)

IDV + silym.   19.4 (15.8-23.6)        7.85 (6.55-9.30)     0.23 (0.13-0.42)     3.1 (1.3-7.2)

Data are geometric mean (95% CI).

AUC = area under the plasma concentration-time curve; Cmax = maximum plasma concentration after dose administration; Cmin, minimum plasma concentration after dose administration.

I thought I remembered Steve Piscitelli reporting a study on Milk Thistle. The following review form CATIE a couple of years ago also references additional studies, though ritonavir-boosting would overcome the indivavir reductions reported.

Simon

HIV Treatment Bulletin Vol3 No9 November 2002

PHARMACOKINETICS

Milk thistle can reduce levels of indinavir in the blood Hosein SR, for CATIE TreatmentUpdate

Background and summary

Some people with HIV/AIDS (PHAs) use vitamins, supplements and herbs to complement          their drug-based therapy. One complementary therapy that is popular is the herb milk thistle. Traditionally, this herb has been used for the treatment of liver disorders such as jaundice (yellowing of the skin and whites of the eyes). Recent laboratory research on cells suggests that milk thistle extracts may be useful in helping the liver and kidneys recover from damage caused by certain drugs and alcohol.

A concern with herbal supplements is that they may interact with medications by either raising or lowering levels of medications used to treat HIV/AIDS and other conditions. Interactions can occur because many drugs are processed by enzymes in the liver. Herbs and drugs can speed up or slow down the activity of these enzymes, raising or lowering drug levels.

If an interaction raises drug levels, new or intensified side effects may occur. Similarly, if drug levels are lowered, the effectiveness of treatments will also be reduced. In the case of therapies for HIV/AIDS, this could lead to the development of drug-resistant HIV and reduced treatment options in the future.

This concern is not just a theory. The plant St 's wort, often used for managing anxiety and mild depression, can interact with many drugs, including two classes used for the treatment of HIV/AIDS:

protease inhibitors (PIs)

non-nucleoside reverse transcriptase inhibitors (non-nukes or NNRTIs)

In laboratory experiments with cells, researchers found that extracts from milk thistle          significantly reduced the activity of certain liver enzymes, specifically those used to process PIs and non-nukes. In theory, these extracts could raise levels of PIs and non-nukes in the blood.

To find out if this was the case in people, researchers at the National Institutes of Health in Bethesda, land, conducted a small study. They found that, overall, milk thistle reduced levels of the PI indinavir (Crixivan) in the blood by about 9%. They also found that just before it was time to take the next dose of indinavir, in subjects using indinavir and milk thistle, blood levels of this drug fell 25% lower than they normally should. The implications of these findings are discussed later in this report.

Study          details

Researchers enrolled 10 healthy, HIV negative subjects (four females, six males) whose          average age was 35 years. At different times over a period of six weeks, subjects received the following regimens:

indinavir 800 mg every eight hours on an empty stomach

indinavir and milk thistle

milk thistle only

The brand of milk thistle used in the study was Thisilyn, made by Nature's Way. This product contained 80% silymarin - one of the compounds responsible for the herb's beneficial effect. Subjects received 175 mg three times daily with meals.

A note about drug levels

The highest level a drug reaches in the blood is called the "peak" and          the lowest level the "trough." The level of a drug in the          blood usually reaches the trough level when it's time to take the          next scheduled dose. If viral resistance is to develop, it often occurs          when drug levels are at their lowest - the trough.

Results: indinavir and milk thistle

Overall, the total amount of indinavir that entered the blood was decreased by only 9% with the use of milk thistle. Perhaps more significant were the changes in trough levels of indinavir. Levels of this drug are at their lowest just before it's time to take the next dose - eight hours          after the last dose was taken. Milk thistle lowered indinavir trough levels by about 25% compared to their levels when indinavir was taken alone. This change was statistically significant, that is, not likely due to chance alone. In one subject, trough levels decreased by about 60%.

Results: side effects

Milk thistle was "generally well tolerated"; subjects using indinavir reported "an odd taste in their mouth" and nausea.

Why these results?

That milk thistle interacted with indinavir to cause a decrease in that drug's level in the blood of people is surprising because experiments with cells suggested the opposite. The reasons for this difference may be due to the following:

not using identical ingredients in both sets of studies (test-tube and people)

using a concentration of substances in the lab that is much higher than that used in people

experiments based solely on what's happening in a test tube don't always reflect the complexity of the organs and systems found in a body

Milk thistle and HIV/AIDS drugs

A decrease of 25% in trough levels may be a concern for some people who are using only one protease inhibitor in their HIV drug combination. However, in North America and perhaps the European Union, more doctors are increasingly prescribing indinavir along with another PI, ritonavir (Norvir). This is because ritonavir increases or boosts the level of indinavir in the          blood and maintains this level for prolonged periods. As a result, ritonavir-indinavir need only be taken twice daily. Similarly, ritonavir is 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 are not likely to be significantly affected by the dose of milk thistle used in this study.

The effect of milk thistle on unboosted protease inhibitors and non-nukes, until studied, is not clear.

References

Venkataramanan R, Ramachandran V, Komoroski BJ, et al. Milk thistle, an herbal supplement, decreases the activity of CYP 3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Drug Metabolism and Disposition 2000;28(11):1270-1273.

Sonnenbichler J, Scalera F, Sonnenbichler I and Weyhenmeyer R. Stimulatory effects of silibinin and silicristin from the milk thistle Silybum marianum on kidney cells. Journal of Pharmacology and Experimental Therapeutics              1999;290(3):1375-1383.

Flora K, Hahn M, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. American Journal of Gastroenterology 1998 February; 93(2):139-143.

Piscitelli SC, Formentini E, Burstein AH, et al. Effect of milk thistle on the pharmacokinetics of indinavir in healthy volunteers. Pharmacotherapy 2002;22(5):551-556.

PL, Brundage RC, Kakuda TN and Fletcher CV. CD4 response is correlated with peak plasma concentrations of indinavir in adults with undetectable human immunodeficiency virus ribonucleic acid. Clinical Pharmacokinetics 2002;71:280-285.

PL and Fletcher CV. Clinical Pharmacological considerations for HIV-1 protease inhibitors. Current Infectious Disease Reports 2001;3:381-387 [Medline].

Source:

CATIE TreatmentUpdate 2002 Sept/Oct Volume 14 Issue 7

--

Simon

HIV i-Base

http://www.i-Base.info

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[Guest guest]

At 04:15 PM 1/6/2006, you wrote:

>Analysis of Milk Thistle Potential Interactions

>

>the analysis review below of the study of Indinavir & milk thistle in

>healthy volunteers appears INCORRECT, it says that the study found a 25%

>reduction in 'blood levels' in one place in the article & then in another

>says a 25% reduction in trough levels was statistically significant.

>According to the published report which i previously distributed & follows

>these comments immediately below says the reduction is in trough not AUC &

>is NOT statistically significant. However, this review raises several

>concerns about a potential effect on PI levels by milk thistle.

Yet their conclusion is " In summary, silymarin 160 mg 3 times/day failed to

influence the pharmacokinetics of indinavir in healthy subjects.

Concomitant administration of milk thistle at this dosage would not be

expected to alter indinavir AUC, Cmax, or Cmin to clinically significant

extents. "

Look at how quickly they hurried up and said proton-pump inhibitors were

just Jim Dandy after interaction studies showed much more serious potential

interactions.

They are saying--and other studies concur--that there is no clinical

relevance to the changes observed, such as they are. From what I've seen of

people using milk thistle on combination therapy, there does not appear to

be any particular impact on viral activity. Still, even the slightest

concern is part of the reason FIAR/Mount Sinai team is doing the milk

thistle study in actual people with HIV on meds.

>One, the study they conducted used 480 mg dose of milk thistle 7 the

>authors suggested that if a higher dose were used perhaps a significant

>interaction could occur.

Generally, higher doses aren't used. ly, I think it's a tempest in a

teapot. I think the demonstrated hepatotoxicity of ARV lends a rationale to

milk thistle use. I think the issue of Hepatitis Coinfection and

liver-related mortality lends a rationale to determining if milk thistle

can at least ameliorate the damage. I think African Americans need more

agents like this given halved or less in terms of outcome with peg-IFN/riba

therapy.

I think also milk thistle alone won't do the trick entirely--other agents

like NAC, alpha lipoic acid, whey proteins--all these may help.

I think we need more clinical studies and data on a lot of these

agents. That's why FIAR was born.

M.

www.fiar.us