Sikavica

Silybum marianum (L.) Gaertner,
Asteraceae

engl. milk thistle, marian thistle; fr. chardon-Marie, lait de Notre-Dame, chardon-argenté, chardon-marbré; njem. Mariendistelfrüchte, Marienkörner, Stechkörner, Frauendistelfrüchte.

BOTANIČKI PODACI

Sikavica je do 2 metra visoka, trnovita, zeljasta dvogodišnja biljka. Listovi su izmjenični, valovitih rubova i krpasto urezani ili trnovito nazubljeni, bijelo ožiljeni i s bijelim mrljama. Stabljika je uspravna i paučinasto dlakava. Crvenoljubičasti cjevasti cvjetovi združeni su u kuglaste glavice obavijene snažno trnovitim ovojnim listovima. Iz cvjetova se razvijaju tamno sivi do crni sjajni plodovi (roške) s čuperkom svilenkastih dlaka na vrhu, koje služe za rasprostranjivanje. Samonikla je u Sredozemlju, a uzgaja se u cijelom svijetu.

OFICINALNI DIJELOVI BILJKE

Oficininalan je plod biljke (cardui mariae fructus, fructus silybi mariae). Premda često korišten u tradicionalnoj fitoterapiji, list nije oficinalan (ESCOP, komisija E).

KEMIJSKI SASTAV (AKTIVNE TVARI)

Flavanolignani: kompleks "silimarin" 1,5-3% u kojeg ulaze silibin A i B, izo-silibin A i B, silikristin, silidianin, 3-dezoksisilikristin, izo-silikristin, izo-silibin, silihermin, neosilihermin A i B, 2,3-dehidro-silibin, oligomeri silibina (tri- i pentameri). Flavonoidi: taksifolin, kvercetol, dihidrokemferol, kemferol, apigenin, naringin, eriodictiol, krizoeriol. Fenoli: 5,7-dihidroksikromon, dihidrokoniferil alkohol. Trigliceridi s 60% linolne, 30% oleinske i 9% palmitinske kiseline. Drugi spojevi: tokoferoli (38mg/100g); steroli (630 mg/100g) - kolesterol, kampesterol, stigmasterol; albumin.

Sadržaj podložan razlicima u kemotipovima.

INDIKACIJE/DJELOVANJE

Komisija E: hepatitisi - adjuvantna terapija hepatitisa i ciroze.

ESCOP: ne navodi.

Druge primjene (klinička ispitivanja): hepatitis C, HIV/AIDS, neki tipovi karcinoma, toksični hepatitisi (trovanje gljivama, organskim otapalima), Alzheimerova bolest.

TIPOVI EKSTRAKATA

Suhi ekstrakt standardiziran na silimarin kompleks, obično definiran na sadržaj silibina (DAB, Ph.Fr. X).

Droga odobrena samo za dispepsije (slava topivost flavanolignana u vodi).

POSOLOGIJA

Komisija E: suhi ekstrakt koji sadrži 200-400mg silimarina dnevno.

Sugerirana doza: 400 -500mg dnevno.

Doze u kliničkim ispitivanjima: od 400mg do nekoliko desetaka grama dnevno.

KONTRAINDIKACIJE

Nepoznate (komisija E).

INTERAKCIJE S LIJEKOVIMA

Nepoznate (komisija E).

Jedna od rijetkih biljaka koja djeluje na rad jetre, a ne uzrokuje znatnije interakcije s lijeklovima.

osobna iskustvena praksa

Sikavica ima impresivan opus kliničkih istraživanja za cijeli splet indikacija, no najčešće za sve što je vezano uz bolesti jetre. Premda zbunjuje njegova farmakodinamika (nitko nije dao plauzibilni molekularni mehanizam djelovanja), djelotvornost sikavice se uopće više ne može opovrgnuti niti imati dvojbe oko njene upotrebe.

Najveći problem kod sikavice je doza. Gotovo je nevjerojatno da u vremenu kada se zna da je potrebna doza od preko 400 mg silimarina dnevno, još uvijek i poznati specijalisti i oppinion leaderi znaju propisivati samo stotinjak miligrama dnevno, što je za svaku osudu. Zamislite kakv bi bio skandal da liječnik umjesto 500mg azitromicina propiše 125 miligrama. Sa sikavicom vlada ista analogija. Ta je činjenica još nevjerojatnija kada znamo da ispitivane kliničke doze prelaze i nekoliko grama silimarina dnevno. Ovo je i kritika na neke proizvođače farmacetuskih oblika koji u ljekoviti oblik formuliraju relativno malu dozu (npr. 100mg).

Kod sikavice ugodno iznenađuje odsustvo nuspojava čak i kada se višestruko premaši doza od 400mg silimarina dnevno. Terapija u kroničnim bolestima također je kronična, čak i višegodišnja, bez štetnih nuspojava. U svojoj praksi nisam susreo niti jedan slučaj alergijske reakcije ili bilo koje, čak i najmanje nuspojave. Iskustvo me uči da ne utječe na INR kod antikoagulantne terapije varfarinom, što je prava rijetkost među biljkama koje djeluju na jetru. Najčešće ga propisujem kod:

• virusnog hepatitisa, kroničnog i aktunog
• toksičnog oštećenja jetre (alkohol, lijekovi, kemikalije)
• autoimunih bolesti jetre
• smanjene renalne funkcije
• masne degeneracije jetre
• ciroze jetre
• dislipidemija povezanih uz oštećenje i degenerativnih bolesti jetre

Odabir doze prije svega ovisi o nalazima jetrenih enzima (AST, ALT, GGT). Kod iznimno povišenih vrijednosti, te kod akutnog virusnog hepatitisa kao u primjeru hepatitisa izazvanog Esptein-Barrovim virusom (infektivna mononukleoza), dnevna doza zna biti i preko 1200mg silimarina dnevno, uzeta u tri manje doze uz obrok. Ta se doza kod kroničnog propisivanja smanjuje tijekom vremena na 400-800mg silimarina dnevno.

Za tipičnog pacijenta u Hrvatskoj koji su mahom navikli na kapsule i tablete, sikavica pokazuje dobar patient compliance, jer su djelotvorni upravo suhi standardizirani ekstrakti. Mljevene sjemenke, dekokt sjemenki sikavice, infuz lista sikavice, ne pokazuju potreban ljekoviti efekt. Sikavica djeluje na jetru, ali nije koleretik. To ima višestruko značenje:

• sikavica se smije koristiti kod kolelitijaze (žučnih kamenaca), za razliku od koleretičnih biljaka
• ona nije klasična drenažna biljka za jetru i žuč - želimo li "očistiti organizam", sikavica nije monoterapija, već ju udružujemo s koleretičnim biljkama poput artičoke ili korijena maslačka.

Kod virusnih hepatitisa, najčešće ju propisujem zajedno s oralnim pripravcima antivirusnih eteričnih ulja (ravintsara, čajevac, klinčićevac, mravinac kompaktni). Treba samo imati na umu da takve pripravke ne možemo davati godinama kao i sikavicu - idelano bi bilo kontrolirati kvantitativnim PCR-om ili bDNA analizama dolazi li do smanjenja viremije. Kod toksičnog oštećenja jetre, ciroze te smanjene renalne funkcije uglavnom ju kombiniram s alfa-lipoičnom kiselinom koja je također klinički ispitana u tim indikacijama. Jedna je od rijetkih biljaka koja djeluje kod toksičnih oštećenja izazvanog otrovima gljiva, kao što je zelena pupavka. U svijetu su za to formulirane čak i intravenski oblici silimarina. Kod masne degeneracije jetre i dislipidemija obično ju udružujem sa SIPF ekstraktom artičoke. Kod autoimunih bolesti jetre, najbolje ju je kombinirati s drugim prirodnim regulatorima imunološkog odgovora kao što je ulje crnog kima.

Sikavica je biljka bez koje se ne može zamisliti moderna fitoterapija, a njen potencijal tek otkrivamo. Nadam se da će ju ipak ponovno otkriti i kliničari, ovog puta u ispravnoj dozi.

REFERENCE

 

KLINIČKA ISPITIVANJA

Review i meta analize

The efficacy and safety of herbal medicines used in the treatment of hyperlipidemia; a systematic review. Hasani-Ranjbar S, Nayebi N, Moradi L, Mehri A, Larijani B, Abdollahi M. Curr Pharm Des. 2010;16(26):2935-47.

Milk thistle in liver diseases: past, present, future. Abenavoli L, Capasso R, Milic N, Capasso F. Phytother Res. 2010 Oct;24(10):1423-32. Review.

Silibinin--a promising new treatment for cancer. Cheung CW, Gibbons N, Johnson DW, Nicol DL. Anticancer Agents Med Chem. 2010 Mar;10(3):186-95. Review.

Cosmeceuticals and silibinin. Singh RP, Agarwal R. Clin Dermatol. 2009 Sep-Oct;27(5):479-84. Review.

A systematic review of the potential herbal sources of future drugs effective in oxidant-related diseases. Hasani-Ranjbar S, Larijani B, Abdollahi M. Inflamm Allergy Drug Targets. 2009 Mar;8(1):2-10. Review.

Multitargeted therapy of cancer by silymarin. Ramasamy K, Agarwal R. Cancer Lett. 2008 Oct 8;269(2):352-62. Epub 2008 May 9. Review.

Milk thistle (Silybum marianum): an ancient botanical medicine for modern times. Ross SM. Holist Nurs Pract. 2008 Sep-Oct;22(5):299-300. Review. No abstract available.

An updated systematic review with meta-analysis for the clinical evidence of silymarin. Saller R, Brignoli R, Melzer J, Meier R. Forsch Komplementmed. 2008 Feb;15(1):9-20. Review.

Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Rambaldi A, Jacobs BP, Gluud C. Cochrane Database Syst Rev. 2007 Oct 17;(4):CD003620. Review.

Future directions for research on Silybum marianum for cancer patients. Sagar SM. Integr Cancer Ther. 2007 Jun;6(2):166-73. Review.

Clinical applications of Silybum marianum in oncology. Greenlee H, Abascal K, Yarnell E, Ladas E. Integr Cancer Ther. 2007 Jun;6(2):158-65. Review.

Review of clinical trials evaluating safety and efficacy of milk thistle (Silybum marianum [L.] Gaertn.). Tamayo C, Diamond S. Integr Cancer Ther. 2007 Jun;6(2):146-57. Review.

Chemopreventive efficacy of silymarin in skin and prostate cancer. Deep G, Agarwal R. Integr Cancer Ther. 2007 Jun;6(2):130-45. Review.

Advances in the use of milk thistle (Silybum marianum). Post-White J, Ladas EJ, Kelly KM. Integr Cancer Ther. 2007 Jun;6(2):104-9. Review.

Silybin and silymarin--new and emerging applications in medicine. Gazák R, Walterová D, Kren V. Curr Med Chem. 2007;14(3):315-38. Review.

Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine. Pradhan SC, Girish C. Indian J Med Res. 2006 Nov;124(5):491-504. Review.

Anticancer potential of silymarin: from bench to bed side. Agarwal R, Agarwal C, Ichikawa H, Singh RP, Aggarwal BB. Anticancer Res. 2006 Nov-Dec;26(6B):4457-98. Review.

Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication. Crocenzi FA, Roma MG. Curr Med Chem. 2006;13(9):1055-74. Review.

Silymarin treatment of viral hepatitis: a systematic review. Mayer KE, Myers RP, Lee SS. J Viral Hepat. 2005 Nov;12(6):559-67. Review.

Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Rambaldi A, Jacobs BP, Iaquinto G, Gluud C. Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003620. Review. Update

Silymarin and skin cancer prevention: anti-inflammatory, antioxidant and immunomodulatory effects (Review). Katiyar SK. Int J Oncol. 2005 Jan;26(1):169-76. Review.

The use of silymarin in the treatment of liver diseases. Saller R, Meier R, Brignoli R. Drugs. 2001;61(14):2035-63. Review.

Milk thistle and the treatment of hepatitis. Giese LA. Gastroenterol Nurs. 2001 Mar-Apr;24(2):95-7. Review.

The use of silymarin in the treatment of liver diseases. Saller R, Meier R, Brignoli R. Drugs. 2001;61(14):2035-63. Review.

 

Farmakokinetika i formulacije

Patented bioavailability enhancement techniques of silymarin. Javed S, Kohli K, Ali M. Recent Pat Drug Deliv Formul. 2010 Jun 1;4(2):145-52. Review.

Quantitation of silibinin, a putative cancer chemopreventive agent derived from milk thistle (Silybum marianum), in human plasma by high-performance liquid chromatography and identification of possible metabolites. Hoh CS, Boocock DJ, Marczylo TH, Brown VA, Cai H, Steward WP, Berry DP, Gescher AJ. J Agric Food Chem. 2007 Apr 4;55(7):2532-5. Epub 2007 Mar 14.

Evaluation of hybrid liposomes-encapsulated silymarin regarding physical stability and in vivo performance. El-Samaligy MS, Afifi NN, Mahmoud EA. Int J Pharm. 2006 Aug 17;319(1-2):121-9. Epub 2006 Jun 9.

A review of the bioavailability and clinical efficacy of milk thistle phytosome: a silybin-phosphatidylcholine complex (Siliphos). Kidd P, Head K. Altern Med Rev. 2005 Sep;10(3):193-203. Review.

Efficacy of silymarin-phospholipid complex in reducing the toxicity of aflatoxin B1 in broiler chicks. Tedesco D, Steidler S, Galletti S, Tameni M, Sonzogni O, Ravarotto L. Poult Sci. 2004 Nov;83(11):1839-43.

Indikacije

A study of high-dose oral silybin-phytosome followed by prostatectomy in patients with localized prostate cancer. Flaig TW, Glodé M, Gustafson D, van Bokhoven A, Tao Y, Wilson S, Su LJ, Li Y, Harrison G, Agarwal R, Crawford ED, Lucia MS, Pollak M. Prostate. 2010 Jun 1;70(8):848-55.

Comparison of Silybum marianum (L.) Gaertn. with fluoxetine in the treatment of Obsessive-Compulsive Disorder. Sayyah M, Boostani H, Pakseresht S, Malayeri A. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Mar 17;34(2):362-5. Epub 2009 Dec 24.

Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. Hawke RL, Schrieber SJ, Soule TA, Wen Z, Smith PC, Reddy KR, Wahed AS, Belle SH, Afdhal NH, Navarro VJ, Berman J, Liu QY, Doo E, Fried MW; SyNCH Trial Group. J Clin Pharmacol. 2010 Apr;50(4):434-49. Epub 2009 Oct

Dietary supplementation of silymarin protects against chemically induced nephrotoxicity, inflammation and renal tumor promotion response. Kaur G, Athar M, Alam MS. Invest New Drugs. 2010 Oct;28(5):703-13. Epub 2009 Jul 10.

Combined therapy of silymarin and desferrioxamine in patients with beta-thalassemia major: a randomized double-blind clinical trial. Gharagozloo M, Moayedi B, Zakerinia M, Hamidi M, Karimi M, Maracy M, Amirghofran Z. Fundam Clin Pharmacol. 2009 Jun;23(3):359-65. Epub 2009 May 7.

A randomized controlled trial to assess the safety and efficacy of silymarin on symptoms, signs and biomarkers of acute hepatitis. El-Kamary SS, Shardell MD, Abdel-Hamid M, Ismail S, El-Ateek M, Metwally M, Mikhail N, Hashem M, Mousa A, Aboul-Fotouh A, El-Kassas M, Esmat G, Strickland GT. Phytomedicine. 2009 May;16(5):391-400. Epub 2009 Mar 19.

Clinical efficacy, safety and tolerability of BIO-C (micronized Silymarin) as a galactagogue. Di Pierro F, Callegari A, Carotenuto D, Tapia MM. Acta Biomed. 2008 Dec;79(3):205-10.

Complementary and alternative medicine use by patients chronically infected with hepatitis C virus. White CP, Hirsch G, Patel S, Adams F, Peltekian KM. Can J Gastroenterol. 2007 Sep;21(9):589-95.

A pilot and feasibility study on the effects of naturopathic botanical and dietary interventions on sex steroid hormone metabolism in premenopausal women. Greenlee H, Atkinson C, Stanczyk FZ, Lampe JW. Cancer Epidemiol Biomarkers Prev. 2007 Aug;16(8):1601-9.

The efficacy of Silybum marianum (L.) Gaertn. (silymarin) in the treatment of type II diabetes: a randomized, double-blind, placebo-controlled, clinical trial. Huseini HF, Larijani B, Heshmat R, Fakhrzadeh H, Radjabipour B, Toliat T, Raza M. Phytother Res. 2006 Dec;20(12):1036-9.

Effects of Silybum marianum on serum hepatitis C virus RNA, alanine aminotransferase levels and well-being in patients with chronic hepatitis C. Gordon A, Hobbs DA, Bowden DS, Bailey MJ, Mitchell J, Francis AJ, Roberts SK. J Gastroenterol Hepatol. 2006 Jan;21(1 Pt 2):275-80.

Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, Base W, Schneider B. J Hepatol. 1989 Jul;9(1):105-13.

PREDKLINIČKA ISPITIVANJA

Preventive effect of silymarin in cerebral ischemia-reperfusion-induced brain injury in rats possibly through impairing NF-κB and STAT-1 activation. Hou YC, Liou KT, Chern CM, Wang YH, Liao JF, Chang S, Chou YH, Shen YC. Phytomedicine. 2010 Oct;17(12):963-73.

Study on genes with altered expression in alpha-amanitin poisoned mice and evaluation on antagonistic effects of traditional Chinese medicines against toxicity of alpha-amanitin. Chen Q, Cao M, Xiang WL, Sun Q, Zhang J, Hou RT, Yan ZY, Yang ZR, Liu J, Zhao J. Acta Biol Hung. 2009 Sep;60(3):281-91.

Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T. Br J Pharmacol. 2009 Aug;157(7):1270-7. Epub 2009 Jun

Anti- and pro-mutagenic effects of silymarin in the Ames bacterial reverse mutation assay. Kaleeswaran S, Sriram P, Prabhu D; Chinnathambi; Vijayakumar, Mathuram LN. Phytother Res. 2009 Oct;23(10):1378-84.

Silibinin ameliorates oxidative stress induced aberrant crypt foci and lipid peroxidation in 1, 2 dimethylhydrazine induced rat colon cancer. Sangeetha N, Aranganathan S, Nalini N. Invest New Drugs. 2010 Jun;28(3):225-33. Epub 2009 Mar 10.

Protective effect of a mixture of Aloe vera and Silybum marianum against carbon tetrachloride-induced acute hepatotoxicity and liver fibrosis. Kim SH, Cheon HJ, Yun N, Oh ST, Shin E, Shim KS, Lee SM. J Pharmacol Sci. 2009 Jan;109(1):119-27.

Effects of silymarin on the resolution of liver fibrosis induced by carbon tetrachloride in rats. Tsai JH, Liu JY, Wu TT, Ho PC, Huang CY, Shyu JC, Hsieh YS, Tsai CC, Liu YC. J Viral Hepat. 2008 Jul;15(7):508-14. Epub 2008 Apr 4.

Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Turgut F, Bayrak O, Catal F, Bayrak R, Atmaca AF, Koc A, Akbas A, Akcay A, Unal D. Int Urol Nephrol. 2008;40(2):453-60.

Antioxidant and mitochondrial protective effects of silibinin in cold preservation-warm reperfusion liver injury. Ligeret H, Brault A, Vallerand D, Haddad Y, Haddad PS. J Ethnopharmacol. 2008 Feb 12;115(3):507-14. Epub 2007 Oct 24.

Immunosuppressive effect of silibinin in experimental autoimmune encephalomyelitis. Min K, Yoon WK, Kim SK, Kim BH. Arch Pharm Res. 2007 Oct;30(10):1265-72.

Effect of silymarin and vitamin E on gentamicin-induced nephrotoxicity in dogs. Varzi HN, Esmailzadeh S, Morovvati H, Avizeh R, Shahriari A, Givi ME. J Vet Pharmacol Ther. 2007 Oct;30(5):477-81.

Flavonolignans from Silybum marianum moderate UVA-induced oxidative damage to HaCaT keratinocytes. Svobodová A, Zdarilová A, Walterová D, Vostálová J. J Dermatol Sci. 2007 Dec;48(3):213-24. Epub 2007 Aug 3.

Silymarin, the antioxidant component of Silybum marianum, protects against burn-induced oxidative skin injury. Toklu HZ, Tunali-Akbay T, Erkanli G, Yüksel M, Ercan F, Sener G. Burns. 2007 Nov;33(7):908-16. Epub 2007 May 22.

Inhibition of T-cell inflammatory cytokines, hepatocyte NF-kappaB signaling, and HCV infection by standardized Silymarin. Polyak SJ, Morishima C, Shuhart MC, Wang CC, Liu Y, Lee DY. Gastroenterology. 2007 May;132(5):1925-36. Epub 2007 Feb 21.

Attenuation of UVA-induced damage to human keratinocytes by silymarin. Svobodová A, Zdarilová A, Malisková J, Mikulková H, Walterová D, Vostalová J. J Dermatol Sci. 2007 Apr;46(1):21-30. Epub 2007 Feb 7.

Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS. Biochem Biophys Res Commun. 2007 Mar 2;354(1):165-71. Epub 2007 Jan 2.

Influence of silymarin and its flavonolignans on H(2)O(2)-induced oxidative stress in human keratinocytes and mouse fibroblasts. Svobodová A, Walterová D, Psotová J. Burns. 2006 Dec;32(8):973-9. Epub 2006 Sep 29.

Protective effect of silymarin on oxidative stress in rat brain. Nencini C, Giorgi G, Micheli L. Phytomedicine. 2007 Feb;14(2-3):129-35. Epub 2006 Apr 25.

Phenolics-rich extracts from Silybum marianum and Prunella vulgaris reduce a high-sucrose diet induced oxidative stress in hereditary hypertriglyceridemic rats. Skottová N, Kazdová L, Oliyarnyk O, Vecera R, Sobolová L, Ulrichová J. Pharmacol Res. 2004 Aug;50(2):123-30.

Silibinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer cells. Thelen P, Jarry H, Ringert RH, Wuttke W. Planta Med. 2004 May;70(5):397-400.

Study of the hypoglycaemic activity of Fraxinus excelsior and Silybum marianum in an animal model of type 1 diabetes mellitus. Maghrani M, Zeggwagh NA, Lemhadri A, El Amraoui M, Michel JB, Eddouks M. J Ethnopharmacol. 2004 Apr;91(2-3):309-16.

Chemoprotective effect of plant phenolics against anthracycline-induced toxicity on rat cardiomyocytes. Part I. Silymarin and its flavonolignans. Chlopcíková S, Psotová J, Miketová P, Simánek V. Phytother Res. 2004 Feb;18(2):107-10.

Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: II. alterations in thymic differentiation correlate with changes in c-myc gene expression. Johnson VJ, Osuchowski MF, He Q, Sharma RP. Planta Med. 2002 Nov;68(11):961-5.

Immunostimulatory effect of Silybum Marianum (milk thistle) extract. Wilasrusmee C, Kittur S, Shah G, Siddiqui J, Bruch D, Wilasrusmee S, Kittur DS. Med Sci Monit. 2002 Nov;8(11):BR439-43.

Treatment of silymarin, a plant flavonoid, prevents ultraviolet light-induced immune suppression and oxidative stress in mouse skin. Katiyar SK. Int J Oncol. 2002 Dec;21(6):1213-22.

Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: I induction of transforming growth factor beta1 and c-myc in liver with marginal effects on other genes. He Q, Osuchowski MF, Johnson VJ, Sharma RP. Planta Med. 2002 Aug;68(8):676-9.

Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, Mori H. Int J Cancer. 2002 Oct 10;101(5):461-8.

Dietary silymarin suppresses 4-nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Yanaida Y, Kohno H, Yoshida K, Hirose Y, Yamada Y, Mori H, Tanaka T. Carcinogenesis. 2002 May;23(5):787-94.

[Effect of Silybum marianum oil and legalon on lipid peroxidation and liver antioxidant systems in rats intoxicated with carbon tetrachloride]. Batakov EA. Eksp Klin Farmakol. 2001 Jul-Aug;64(4):53-5. Russian.

Fetoprotectivity of the flavanolignan compound siliphos against ethanol-induced toxicity. Edwards J, Grange LL, Wang M, Reyes E. Phytother Res. 2000 Nov;14(7):517-21.

Effect of silymarin on serum cholesterol levels in rats. Skottová N, Krecman V, Walterová D, Ulrichová J, Kosina P, Simánek V. Acta Univ Palacki Olomuc Fac Med. 1998;141:87-9.

Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Krecman V, Skottová N, Walterová D, Ulrichová J, Simánek V. Planta Med. 1998 Mar;64(2):138-42.

[Anti-phalloidine activity of the silymarins silybine and disilybine]. Vogel VG, Trost W. Arzneimittelforschung. 1975 Mar;25(3):392-3. German.

The effects of silymarin on experimental phalloidine poisoning. Desplaces A, Choppin J, Vogel G, Trost W. Arzneimittelforschung. 1975 Jan;25(1):89-96.

Proceedings: Neutralization of the lethal effects of phalloidine and alpha-amanitine in animal experiments by substances from the seeds of Silybum marianum l. gaertn. Vogel G, Trost W. Naunyn Schmiedebergs Arch Pharmacol. 1974;282(Suppl):suppl 282:R102. No abstract available.

TOKSIČNOST I INTERAKCIJE

Anti- and pro-mutagenic effects of silymarin in the Ames bacterial reverse mutation assay. Kaleeswaran S, Sriram P, Prabhu D; Chinnathambi; Vijayakumar, Mathuram LN. Phytother Res. 2009 Oct;23(10):1378-84.

Clinical assessment of CYP2D6-mediated herb-drug interactions in humans: effects of milk thistle, black cohosh, goldenseal, kava kava, St. John's wort, and Echinacea. Gurley BJ, Swain A, Hubbard MA, Williams DK, Barone G, Hartsfield F, Tong Y, Carrier DJ, Cheboyina S, Battu SK. Mol Nutr Food Res. 2008 Jul;52(7):755-63.

Modulation of human cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) in Caco-2 cell monolayers by selected commercial-source milk thistle and goldenseal products. Budzinski JW, Trudeau VL, Drouin CE, Panahi M, Arnason JT, Foster BC. Can J Physiol Pharmacol. 2007 Sep;85(9):966-78.

Effect of milk thistle (Silybum marianum) and black cohosh (Cimicifuga racemosa) supplementation on digoxin pharmacokinetics in humans. Gurley BJ, Barone GW, Williams DK, Carrier J, Breen P, Yates CR, Song PF, Hubbard MA, Tong Y, Cheboyina S. Drug Metab Dispos. 2006 Jan;34(1):69-74. Epub 2005 Oct 12.

Herb-drug interactions: a literature review. Hu Z, Yang X, Ho PC, Chan SY, Heng PW, Chan E, Duan W, Koh HL, Zhou S. Drugs. 2005;65(9):1239-82. Review.

In vivo assessment of botanical supplementation on human cytochrome P450 phenotypes: Citrus aurantium, Echinacea purpurea, milk thistle, and saw palmetto. Gurley BJ, Gardner SF, Hubbard MA, Williams DK, Gentry WB, Carrier J, Khan IA, Edwards DJ, Shah A. Clin Pharmacol Ther. 2004 Nov;76(5):428-40. Erratum in: Clin Pharmacol Ther. 2005 May;77(5):456.

Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Zuber R, Modrianský M, Dvorák Z, Rohovský P, Ulrichová J, Simánek V, Anzenbacher P. Phytother Res. 2002 Nov;16(7):632-8.

An adverse reaction to the herbal medication milk thistle (Silybum marianum). Adverse Drug Reactions Advisory Committee. [No authors listed] Med J Aust. 1999 Mar 1;170(5):218-9. No abstract available.

[Pharmacodynamics, site and mechanism of action of silymarin, the antihepatoxic principle from Silybum mar. (L) Gaertn. 1. Acute toxicology or tolerance, general and specific (liver-) pharmacology]. Vogel G, Trost W, Braatz R, Odenthal KP, Brüsewitz G, Antweiler H, Seeger R. Arzneimittelforschung. 1975 Jan;25(1):82-9. German. No abstract available.