Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients

Moltó, José; Valle, Marta; Miranda, Cristina; Cedeño, Samandhy; Negredo, Eugènia; Clotet, Bonaventura

doi:10.1128/aac.00025-12

Cited by 24 publications

(13 citation statements)

References 44 publications

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“…99 In vitro, Echinacea , garlic, ginkgo biloba, ginseng, silymarin, and St John's wort have been shown to inhibit or induce enzymes or transporters involved in the metabolism or disposition of boceprevir and telaprevir. 99 In vivo , Echinacea 100,101 and silymarin 102,103 do not substantially alter HIV protease inhibitor exposures, but garlic and ginseng reduce CYP3A substrates by 44–51%. 104,105 Reductions of a similar magnitude could result in subtherapeutic boceprevir or telaprevir exposures, thus use of garlic and ginseng supplements should be avoided.…”

Section: Specific Drug Interactionsmentioning

confidence: 99%

Drug–drug interactions during antiviral therapy for chronic hepatitis C

Kiser

Burton²,

Everson³

2013

Nat Rev Gastroenterol Hepatol

123

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The emergence of direct-acting antiviral agents (DAAs) for HCV infection represents a major advance in treatment. The NS3 protease inhibitors, boceprevir and telaprevir, were the first DAAs to receive regulatory approval. When combined with PEG-IFN and ribavirin, these agents increase rates of sustained virologic response in HCV genotype 1 to ~70%. However, this treatment regimen is associated with several toxicities. In addition, both boceprevir and telaprevir are substrates for and inhibitors of the drug transporter P-glycoprotein and the cytochrome P450 enzyme 3A4 and are, therefore, prone to clinically relevant drug interactions. Several new DAAs for HCV are in late stages of clinical development and are likely to be approved in the near future. These include the protease inhibitors, simeprevir and faldaprevir, the NS5A inhibitor, daclatasvir, and the nucleotide polymerase inhibitor, sofosbuvir. Herein, we review the clinical pharmacology and drug interactions of boceprevir, telaprevir and these investigational DAAs. Although boceprevir and telaprevir are involved in many interactions, these interactions are manageable if health-care providers proactively identify and adjust treatments. Emerging DAAs seem to have a reduced potential for drug interactions, which will facilitate their use in the treatment of HCV.

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Section: Specific Drug Interactionsmentioning

confidence: 99%

Drug–drug interactions during antiviral therapy for chronic hepatitis C

Kiser

Burton²,

Everson³

2013

Nat Rev Gastroenterol Hepatol

123

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“…In viral hepatitis C patients, highdosage studies were performed with silymarin, and silymarin did not show any toxicity (36) and still decreased progression from fibrosis to cirrhosis (37). Furthermore, the coadministration of silymarin with darunavir/ritonavir seems to be safe in HIV-infected patients (38). There are no known collateral effects of silymarin that could raise doubt on the safety of this drug in schistosomiasis, but still, our study in mice raised no concern on the safety of silymarin in schistosomiasis, representing a first step toward future human tests.…”

Section: Discussionmentioning

confidence: 99%

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Hilton

Dutra

Rocha

et al. 2014

Antimicrob Agents Chemother

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In chronic schistosomiasis, hepatic fibrosis is linked to the portal hypertension that causes morbidity in Schistosoma mansoni infection. Silymarin (SIL) is a hepatoprotective and antioxidant medicament largely prescribed against liver diseases that has previously been shown to prevent fibrosis during acute murine schistosomiasis. Here we employed silymarin to try to reverse established hepatic fibrosis in chronic schistosomiasis. Silymarin or vehicle was administered to BALB/c mice every 48 h, starting on the 40th (80 days of treatment), 70th (50 days), or 110th (10 days) day postinfection (dpi). All mice were sacrificed and analyzed at 120 dpi. Treatment with silymarin reduced liver weight and granuloma sizes, reduced the increase in alanine aminotransferase and aspartate aminotransferase levels, and reduced the established hepatic fibrosis (assessed by hydroxyproline contents and picrosirius staining). Treatment with silymarin also reduced the levels of interleukin-13 (IL-13) in serum and increased the gamma interferon (IFN-␥)/IL-13 ratio. There was a linear correlation between IL-13 levels in serum and hydroxyproline hepatic content in both infected untreated and SIL-treated mice, with decreased IL-13 levels corresponding to decreased hydroxyproline hepatic contents. Treatment with either SIL or N-acetylcysteine reduced both proliferation of fibroblast cell lines and basal/IL-13-induced production of collagen I, indicating that besides inhibiting IL-13 production during infection, SIL antioxidant properties most likely contribute to inhibition of collagen production downstream of IL-13. These results show that silymarin interferes with fibrogenic cytokines, reduces established fibrosis, and inhibits downstream effects of IL-13 on fibrogenesis, indicating the drug as a safe and cheap treatment to liver fibrotic disease in schistosomiasis. Schistosomiasis is a chronic disease of high prevalence and wide distribution around the world (1) caused by worms that parasitize the vascular system. The morbidity in schistosomiasis is associated with the arrival of worm eggs to the liver and the stimulation of a granulomatous reaction (2). Chronic liver pathology is closely associated to the nature of the host inflammatory response. The immunological progression of this disease is frequently divided in distinct phases: prepostural acute Th1 phase, postural acute Th2 phase, and chronic Th2 downmodulated phase (3). The control of this Th response throughout the chronic phase may be associated with the reduction of morbidity in schistosomiasis. During acute murine infection, administration of antioxidant drugs such as curcumin (4), resveratrol (5), n-acetylcysteine (6), artemether (7), and silymarin (8) is used to reduce morbidity and prevent hepatic fibrosis. The reversal of established hepatic fibrosis at the chronic stage is directly linked to the portal hypertension, the major cause of morbidity in Schistosoma mansoni infection, and was not attained in any of these previous works. Currently, there is no medical treatmen...

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“…In this trial, 15 males were under treatment with darunavir–ritonavir at the doses of 600 and 100 mg twice a day. Silymarin tolerated well and was safe in combination with darunavir and ritonavir (Moltó et al, ).…”

Section: Safety and Adverse Reactions Of Oral Silymarin In Humansmentioning

confidence: 99%

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

Soleimani

Delghandi

Moallem

et al. 2019

Phytotherapy Research

155

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Milk thistle (Silybum marianum) is a medicinal plant from the Asteraceae family. Silymarin is the major constituent of milk thistle extract and is a mixture of some flavonolignans such as silybin, which is the most active component of silymarin. It is most commonly known for its hepatoprotective effect. Also, studies have shown other therapeutic effects such as anticancer, anti‐Alzheimer, anti‐Parkinson, and anti‐diabetic, so its safety is very important. It has no major toxicity in animals. Silymarin was mutagen in Salmonella typhimurium strains in the presence of metabolic enzymes. Silybin, silydianin, and silychristin were not cytotoxic and genotoxic at concentration of 100 μM. Silymarin is safe in humans at therapeutic doses and is well tolerated even at a high dose of 700 mg three times a day for 24 weeks. Some gastrointestinal discomforts occurred like nausea and diarrhea. One clinical trial showed silymarin is safe in pregnancy, and there were no anomalies. Consequently, caution should be exercised during pregnancy, and more studies are needed especially in humans. Silymarin has low‐drug interactions, and it does not have major effects on cytochromes P‐450. Some studies demonstrated that the use of silymarin must be with caution when co‐administered with narrow therapeutic window drugs.

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Effect of Milk Thistle on the Pharmacokinetics of Darunavir-Ritonavir in HIV-Infected Patients

Cited by 24 publications

References 44 publications

Drug–drug interactions during antiviral therapy for chronic hepatitis C

Drug–drug interactions during antiviral therapy for chronic hepatitis C

Silymarin Reduces Profibrogenic Cytokines and Reverses Hepatic Fibrosis in Chronic Murine Schistosomiasis

Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review

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