Pegasti Badelj

Pegasti badelj – Silybum marianum Gaertn

PEGASTI BADELJ – Silybum marianum Gaertn

Pegasti badelj izvira iz južne Evrope, Male Azije in severne Afrike. Raste tudi v centralni Evropi. Prilagodil se je podnebju v Ameriki in na jugu Avstralije.  Raste v globoki zemlji, v vlažnih, z dušikom bogatih tleh na mediteranskem področju, ob vznožju zidov, ob robu poti, na neobdelanih območjih. Cveti pozno spomladi in zgodaj poleti, nabira pa se jeseni. Pri nabiranju se najprej odreže socvetja in nato pobere plodove. Znan tudi pod imenom: osat svete Marije, Marijin osat, mlečni osat, pegasti osat, bodika, ostropes, bodečnica.

I. Uporabni deli

Plod. Včasih, čeprav zelo redko, listje in korenine.

II. Aktivne sestavine

  • Flavonoidi: Med njimi izstopa podskupina kromonov, katerih mešanica se imenuje silimarin (1,5 do 3%), to je mešanica različnih derivatov flavanonov (flavanolignanov), ki se nahaja izključno v povrhnjici plodu. Glavne sestavine omenjene mešanice so silibin (oziroma silibinin), silikristin in silidianin. Prav tako so prisotni derivati 3-deoksi silidianina (imenovani silimonin) in silikristina, kot tudi izosilikristina, izosilibina in njegovega derivata 3-deoksi silandrina, derivata 3-deoksi silihermina, neosilihermina A in B, 2,3-dehidrosilibin in tri- tetra- in pentameri silibina (silibinomeri). Vsebuje tudi flavonoide kot so: taksifolin, kvercetin, kvercetol, dihidrokemferol, kemferol, apigenin, naringin, naringenin, eriodiktiol, krizoeriol, 5,7-dihidroksi kromon in alkohol dihidro koniferil.
  • Sluzi
  • Amini: tiramin, agmatin in histamin.
  • Lipidi in maščobna olja (20-30%), ki vsebujejo visok delež kislin: linolne (približno 60%), oleinske (pribl. 30%) in palmitinske (pribl. 9%) v svojih trigliceridih; tokoferol (0,04%).
  • Fitosteroli (0,6%), kot: holesterol, kampesterol, stigmasterol in sitosterol.
  • Organske kisline
  • Proteini (20-30%)
  • Saponozidi
  • Sledovi eteričnih olj
  • Vitamini (C, E, K) in minerali (krom, železo, magnezij, mangan, fosfor, selen in cink).
  • Grenčine
  • Drugo: smola, itd.

III. Farmakološko delovanje

  1. Notranja uporaba:
  • Ščiti jetra (silimarin). Terapevtska učinkovitost silimarina temelji na več mehanizmih delovanja: lahko spodbuja rast jetrnih celic, jih varuje pred celično smrtjo, zavira toksine in preprečuje vnetja.

a.) Spreminja strukturo zunanje celične membrane hepatocitov tako, da preprečuje vdor hepatotoksičnih snovi v celico. Silimarin kaže izrazit jetrni tropizem in deluje kot antagonist proti številnim hepatotoksičnim snovem. Obstajajo številni poskusi na laboratorijskih živalih, ki dokazujejo inhibicijo peroksidacije membran hepatocitos tem, da se znižuje zvišane stopnje AST, ALT in LDH, ki so posledica jetrne zastrupitve s tioacetamidom, lantanidi, ogljikovim tetrakloridom, galaktozaminom, alkoholom, tetraciklini, in hepatotoksičnim virusom FV3, značilnim za hladnokrvne živali. Podobno silimarin in silibin preprečujeta zastrupitev s faloidinom in a-amanitinom (načelo zastrupitve pri zastrupitvi s falotoksini zelene mušnice). Profilaktično zdravljenje je bolj učinkovito kot terapevtsko, ko že pride do poškodbe jeter. Učinkovitost je maksimalna, če se zdravljenje izvede 6 ur preden začne delovati toksin (faloidin), medtem ko je ob uporabi silimarina 30 minut po toksinu učinkovitost manjša. Če silimarin damo s še večjim zamikom, pa ni nobenega učinka.

b.) Zmanjša aktivnost Kupfferjevih celic, (zmanjša nastanek superoksidnih radikalov, dušikovega oksida in levkotrienov), in poveča proizvodnjo glutationa, ob enem pa zmanjša njegovo oksidacijo. Silimarin v jetrnih celicah poveča količino glutationa, ki je naravni znotrajcelični antioksidant bistvenega pomena za jetra, želodec in črevesje, zelo pomemben za preprečevanje mutacij DNA in RNA. Zdi se, da je antioksidantno delovanje silimarina 10-krat močnejše od vitamina E. Poveča se tudi količina encima superoksid dizmutaze. Ta encim je skupaj z encimom glutation peroksidazo ključnega pomena pri razstrupljanju in regeneraciji jetrnih celic.

c.) Spodbuja delovanje RNA polimeraze in jedrc, s čimer se povečuje ribosomska sinteza beljakovin v jetrnih celicah, tako da to spodbuja regenerativne sposobnosti parenhima jeter in proizvodnjo novih jetrnih celic. Silimarin ne stimulira rasti malignega jetrnega tkiva. Stopnja smrtnosti med bolniki s cirozo, ki jemljejo silimarin, je znatno upadla, še posebej v primerih alkoholne ciroze.

Številne klinične študije pri odraslih bolnikih s hepatitisom kažejo, da je lahko ena od specifičnih komponent silimarina koristna pri nadzorovanju kroničnega virusnega hepatitisa. Obstajajo znanstveni dokazi, ki dokazujejo izboljšanje simptomov kroničnih jetrnih bolezni, kot so: slabost, slabotnost, zmanjšan apetit, utrujenost in bolečine v trebuhu. Dokazano je tudi, da se pri bolnikih s hudim obolenjem jeter zniža umrljivost.

  • Antioksidant (flavolignani, silimarin, silibin). Antiradikalna aktivnost je posledica stabilizacijskega delovanja silimarina na biološke membrane. Številne hepatoksične snovi ustvarjajo proste radikale v gladkem ER, kar posledično sproži tvorbo novih prostih radikalov, ki povzročajo nastanek lipidnih peroksidov na področju membran. Na tej ravni silimarin in silibin delujeta tako, da ujameta proste radikale, na ravni proizvajanja reaktivnih kisikovih zvrsti (ROS), in jih nevtralizirata, s čimer ustavitakaskadno produkcijsko verigo prostih radikalov, še zlasti lipoperoksidov. Zavirajo encim lipoksigenazo, ki katalizira reakcijo za nastanek oksidiranih polinenasičenih maščob, ki so za jetra škodljive.

Dokazano antihepatoksično delovanje je verjetno povezano tudi z antioksidativnim delovanjem in lovljenjem prostih radikalov, značilnih za silimarin in njegovo delovanje na “stabilizacijo membran”, ki se je dejansko opazovalo pri celicah kvasovk, poškodovanih z nistatinom. Klinično je bilo v dvojno slepi študiji dokazano, da silimarin (3 x 40 mg na dan) bistveno znižuje umrljivost pri bolnikih s cirozo jeter zaradi alkohola.

Silimarin tudi pri visokih odmerkih ni strupen (20,0 g/kg oralno pri podganah). Pri človeku, ko se presnovi v telesu, se v glavnem izloča z žolčem (20-40% v 24 urah) in preko ledvic (3-7%) v obliki sulfatov ali glukornatov. Ne prihaja do kopičenja. Koncentracije silibina najdemo v žolču, ob jemanju terapevtskih odmerkov, ki se določajo glede na učinkovitosti zdravila. Zato je farmakokinetično obnašanje silibina v človeku v skladu s terapevtsko učinkovitostjo.

  • Holeretik in holagog, kar pomeni, da stimulira proizvodnjo žolča in njegovo izločanje iz žolčnika (flavanolignani: silimarin in silibin, eterično olje, smola). Silibin ima dokazano antiholestatično delovanje.
  • Zmerno zvišuje krvni tlak in izboljša tonus srca (tiramin).
  • Diuretik (flavonoidi).
  • Protivneten. Silimarin ima zaviralni učinek na sintezo levkotrienov z inhibicijo 5-lipoksigenaze (5-LOX).
  • Antialergen (flavanolignani).
  • Znižuje raven lipidov in holesterola (silimarin). V študijah se je izkazalo, da ima silimarin pri podganah velik hipolipemičen učinek-, saj zmanjšuje vsebnost holesterola v jetrih in zvišuje raven  holesterola HDL-C.
  • Antitumorski (silimarin, silibin). Silibin je pokazal antitumorsko delovanje v študijah in vitro na človeških rakavih celičnih linijah jajčnikov in dojk. Prav tako je pokazal sinergistično delovanje s ciplastinom in doksorubicinom.
  • Aperitiv in digestiv (flavonoidi, grenčine).
  • Hemostatičen strjevanje krvi (flavonoidi).
  • Drugo: nekateri avtorji mu pripisujejo zmožnost blagega zniževanja vročine (antipiretik), blago hipoglikemično delovanje (krom, pomemben za regulacijo ravni sladkorja v krvi), imunostimulant (poveča proizvodnjo T-celic in interferona), venotoničen.

2. Zunanja uporaba:

  • Protivneten. Silimarin ima zaviralni učinek na sintezo levkotrienov z inhibicijo 5-lipoksigenaze (5-LOX).
  • Antitumorski (silimarin, silibin). Silimarin je ob topikalni administraciji v študijah tumorjev, ki jih pri podganah povzroča UV sevanje, pokazal zaščitni učinek pred tvorbo tumorjev kot tudi zmanjšanje njihove pojavnosti, množičnosti in velikosti.

IV. Indikacije

  1. Notranja uporaba:
  • Preprečevanje in zdravljenje bolezni jeter: hepatobiliarna insuficienca, akutni in kronični hepatitis, ciroza jeter, jetrna steatoza (zamaščena jetra), diskinezija žolčnika in vodov, kronične degenerativne bolezni jeter, jetrna nekroza, itd.
  • Zaščita jeter, predpisujejo se dolgotrajna zdravljenja, dolga vsaj 40 dni. Potem, ko že pride do poškodbe jeter, je profilaktično zdravljenje preventivno  s silimarinom bolj učinkovito od terapevtskega.
  • Bolezni žolčnika in žolčevodov: diskinezija žolčnika, žolčni kamni, holelitiaza, holangitis, holestaza.
  • Alkoholizem.
  • Zastrupitev s toksini (zelena mušnica), zdravili (kot so paracetamol, fenitoin in fenotiazini), alkoholom in strupi.
  • Ljudje, ki jemljejo zdravila, ki so potencialno škodljiva za jetra (hepatotoksična zdravila).
  • Izguba apetita, hiposekretorna dispepsija, napenjanje in vetrovi.
  • Krvavitve: hematurija, epistaksa ali krvavitev iz nosu, metroragije.
  • Vrtoglavica in bruhanje na potovanjih.
  • Alergične reakcije kot so seneni nahod, koprivnica in astma.
  • Drugo: gripa, prehlad, vnetje mehurja, ledvični kamni, oligurija, glavoboli in nevralgija, izčrpanost in astenija ali utrujenost, diabetes, itd.

2. Zunanja uporaba:

  • Eritemi in staranje kože.
  • Hemoroidi, krčne žile in razjede na nogah.

V. Kontraindikacije

  • Preobčutljivost na pegasti badelj ali druge vrste iz družine nebinovk.
  • Arterijska hipertenzija.
  • Zdravljenje z antidepresivi MAOI (inhibitorji monoaminooksidaze, encima, ki v telesu uničuje strukturo aminov kot so adrenalin, noradrenalin in serotonin). Ker vsebuje tiramin, lahko sproži hipertenzivno krizo pri bolnikih po antidepresivnem zdravljenju z MAOI.
  • Hude bolezni ledvic.
  • Biliarne obstrukcije. Pegasti badelj lahko sproži žolčne kolike in poslabša obstrukcijo zaradi holeretičnega/holagogičnega učinka
  • Nosečnost. Pegasti badelj se ne sme uporabljati med nosečnostjo zaradi pomanjkanja podatkov, ki bi podprli njegovo varnost. Izvedli so študije na različnih živalskih vrstah, v katerih so uporabili nekajkrat višje doze kot pri človeku, in niso ugotovili embriotoksičnih ali teratogenih učinkov; kljub temu pa ni bilo nobenih kliničnih testiranj na ljudeh, zato je zdravljenje s pegastim badljem dovoljeno le, če ni varnejših terapevtskih alternativ.
  • Dojenje. Pegasti badelj se ne sme uporabljati med dojenjem zaradi pomanjkanja podatkov, ki bi podprali njegovo varnost. Če ne upoštevamo, da se učinkovine pegastega badlja v znatnih količinah izločajo v materino mleko, bi to lahko vplivalo na otroka. Priporočljivo je, da prenehate z dojenjem ali jemanjem pegastega badlja.

VI. Opozorila in interakcije z zdravili

Opozorila:

  • Ker vsebuje tiramin, lahko sproži hipertenzivno krizo pri bolnikih, ki se zdravijo z antidepresivi zaviralci monoaminooksidaze (MAOI).
  • Žolčni kamni. Pegasti badelj uporabljajte previdno, saj lahko zaradi holeretičnega/holagogičnega učinka povzroči premikanje žolčnih kamnov.

Interakcije z zdravili:

  • Butirofenoni. Sočasna uporaba silimarina in butirofenonov zmanjša peroksidacijo lipidov.
  • Fenotiazini. Sočasna uporaba silimarina in fenotiazinov zmanjša peroksidacijo lipidov. Johimbin. Silimarin zmanjša učinek johimbina. V primeru sočasne uporabe je treba doze johimbina prilagoditi.
  • Peroralna kontracepcijska sredstva (estrogeni). Silibinin lahko zavira bakterijski encim β-glukuronidazo, ki sodeluje pri presnovi peroralnih kontraceptivov, tako da lahko teoretično zmanjša njihovo učinkovitost.
  • Fentolamin. Silimarin zmanjša učinke fentolamina. V primeru sočasne uporabe je treba prilagoditi odmerke fentolamina.
  • Dekstrametorfan. Silibinin je zaviralec citokroma P450, kar lahko poveča plazemske koncentracije dekstrometorfana in tako ojača njegove terapevtske in stranske učinke.
  • Nifedipin. Silibinin je zaviralec citokroma P450, kar lahko poveča plazemske koncentracije nifedipina in tako ojača njegove terapevtske in stranske učinke.
  • Peroralni antikoagulanti. Silibinin je zaviralec citokroma P450 in zato lahko poviša plazemske ravni peroralnih antikoagulantov, kar lahko povzroči krvavitve.

Kot navaja nek članek, silimarin lahko poveča ali okrepi delovanje določenih zdravil:

  • Metadon.
  • Zdravila za srce: flekainid, propafenon.
  • Antibiotiki: eritromicin, rifampin.
  • Antikonvulzijska zdravila: karbamazepin.
  • Antidepresivi: šentjanževka, bupropion, paroksetin, fluoksetin, fluvoksetin, nefazodon, sertralin, in venlafaksin.
  • Antihistaminiki: astemizol, terfenadin.
  • Antimikotiki: itrakonazol, ketokonazol.
  • Snovi, ki spodbujajo peristaltiko prebavil: cisaprid.
  • Zdravila z ergot alkaloidi: ergotamin.
  • Antipsihotiki: klozapin, pimozid.
  • Pomirjevala in uspavala: zolpidem, triazolam, midazolam, lorazepam.
  • Zdravila za zniževanje lipidov (statini): fluvastatin, lovastatin, pravastatin, simvastatin in cerivastatin.
  • Zdravila po presaditvi: ciklosporin, takrolimus.
  • Zdravila proti parazitom oz. antimalariki: atovakvon.

VII. Sekundarni učinki in toksičnost

Ob uporabi priporočenih terapevtskih odmerkov ni zabeleženih nikakršnih nezaželenih učinkov. Pri večjih odmerkih, kroničnih zdravljenjih ali pri posebej občutljivih posameznikih pa lahko pride do sledečih reakcij:

  • Alergije: Sveža rastlina lahko povzroči kontaktni dermatitis.
  • Prebavne motnje. Redko pride do blagih prebavnih motenj kot je diareja.

Silimarin tudi pri večjih količinah ni toksičen (20,0 g/kg oralno pri podganah).

 

Viri

Klinične študije:

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*Tedesco D, Domeneghini C, Sciannimanico D, Tameni M, Steidler S, Galletti S. Department of Veterinary Science and Technology for Food Safety, Faculty of Veterinary Medicine, University of Milan, Via Celoria 10, 20133, Milan, Italy. Silymarin, a possible hepatoprotector in dairy cows: biochemical and histological observations. J Vet Med A Physiol Pathol Clin Med. 2004 Mar;51(2):85-9. PMID: 15153078 [PubMed-in process].

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*Fiebig   M,   Wagner   H.   New   antihepatotoxic   effects   of flavonolignans of a white flowering variety of Silybum. Planta Med. 1984 Aug;50(4):310-3. PMID: 6095354 [PubMed-indexed for MEDLINE].

*Fintelmann V. Medizinische Abteilung B, Krankenhaus Rissen, Hamburg, Federal Republic of Germany. Modern phytotherapy and its uses in gastrointestinal conditions. Planta Med. 1991 Oct;57(7):S48-52. PMID: 1956958 [PubMed-indexed for MEDLINE].

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*Velussi M, Cernigoi AM, De Monte A, Dapas F, Caffau C, Zilli M. Anti-Diabetes Centre, Monfalcone Hospital, Gorizia, Italy. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic  diabetic  patients.  J  Hepatol.  1997  Apr;26(4):871-9.  PMID:9126802 [PubMed-indexed for MEDLINE].

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*Kittur S, Wilasrusmee S, Pedersen WA, Mattson MP, Straube- West K, Wilasrusmee C, Lubelt B, Kittur DS. Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture. J Mol Neurosci. 2002 Jun;18(3):265-9. PMID: 12059045 [PubMed-indexed for MEDLINE].

*Wang MJ, Lin WW, Chen HL, Chang YH, Ou HC, Kuo JS, Hong JS, Jeng KC. Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan. Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation. Eur J Neurosci. 2002 Dec;16(11):2103-PMID: 12473078 [PubMed-indexed for MEDLINE].

*Thelen P, Jarry H, Ringert RH, Wuttke W. Department of Urology, Georg-August-University, Gottingen, Germany. Silibinin down-regulates prostate epithelium-derived Ets transcription factor in LNCaP prostate cancer  cells.  Planta  Med.  2004  May;70(5):397-400. PMID:  15124082 [PubMed-in process].

*Thelen P, Wuttke W, Jarry H, Grzmil M, Ringert RH. Department of Urology, Institute of Human Genetics, Georg-August-University, Gottingen, Germany. Inhibition of telomerase activity and secretion of prostate specific antigen by silibinin in prostate cancer cells. J Urol. 2004 May;171(5):1934-8. PMID: 15076315 [PubMed-indexed for MEDLINE].

*Hannay  JA,  Yu  D.  The  University  of  Texas,  M.D.  Anderson Cancer Center; Houston, Texas USA. Silibinin: a thorny therapeutic for EGF-R expressing tumors?. Cancer Biol Ther. 2003 Sep-Oct;2(5):532-3. PMID: 14614321 [PubMed-indexed for MEDLINE].

*Dhanalakshmi S, Agarwal P, Glode LM, Agarwal R. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, CO 80262, USA. Silibinin sensitizes human prostate carcinoma DU145 cells  to  cisplatin- and  carboplatin- induced growth inhibition and apoptotic death. Int J Cancer. 2003 Sep 20;106(5):699-705. PMID: 12866029 [PubMed-indexed for MEDLINE].

*Ladas EJ, Kelly KM. Division of Pediatric Oncology, Columbia University, New York, NY, USA. Milk thistle: is there a role for its use as an adjunct therapy in patients with cancer?. J Altern Complement Med. 2003 Jun;9(3):411-6. PMID: 12816629 [PubMed-indexed for MEDLINE].

*Tyagi A, Bhatia N, Condon MS, Bosland MC, Agarwal C, Agarwal R. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. Antiproliferative and  apoptotic effects of  silibinin in  rat  prostate cancer cells. Prostate. 2002 Nov 1;53(3):211-7. PMID: 12386921 [PubMed-indexed for MEDLINE].

*Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, Mori H. First Department of Pathology, Kanazawa Medical University, Ishikawa, Japan. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. Int J Cancer. 2002 Oct 10;101(5):461-8. PMID: 12216075 [PubMed-indexed for MEDLINE].

*Yanaida Y, Kohno H, Yoshida K, Hirose Y, Yamada Y, Mori H, Tanaka  T.  Department  of  Laboratory  Sciences,  School  of  Health Sciences, Faculty of Medicine, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa 920-0942, Japan. Dietary silymarin suppresses 4- nitroquinoline 1-oxide-induced tongue carcinogenesis in male F344 rats. Carcinogenesis. 2002 May;23(5):787-94. PMID: 12016151 [PubMed- indexed for MEDLINE].

*Manna SK, Mukhopadhyay A, Van NT, Aggarwal BB. Department of  Molecular  Oncology,  Cytokine  Research  Laboratory,  University  of Texas M. D. Anderson Cancer Center, Houston 77030, USA. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol. 1999 Dec 15;163(12):6800-9. PMID: 10586080 [PubMed-indexed for MEDLINE].

*Singh RP, Agarwal R. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Cancer Center, 4200 East Ninth Avenue, Denver, CO 80262, USA. Prostate cancer prevention by silibinin. Curr Cancer Drug Targets. 2004 Feb;4(1):1-11. PMID: 14965263 [PubMed-in process].

*Kang  SN,  Lee  MH,  Kim  KM,  Cho  D,  Kim  TS.  College  of Pharmacy, Chonnam National University, Kwangju 500-757, Republic of Korea. Induction of human promyelocytic leukemia HL-60 cell differentiation into monocytes by silibinin: involvement of protein kinase C. Biochem Pharmacol. 2001 Jun 15;61(12):1487-95. PMID: 11377378 [PubMed-indexed for MEDLINE].

*Neese S, La Grange L, Trujillo E, Romero D. Department of Behavioral Sciences, New Mexico Highlands University, 117 Hewett Hall, Las Vegas, NM 87701, USA. The effects of ethanol and silymarin treatment during gestation on spatial working memory. BMC Complement Altern Med. 2004 Feb 12;4(1):4. PMID: 15018621 [PubMed-in process]. * Reid C, Edwards J, Wang M, Manybeads Y, Mike L, Martinez N, La Grange L, Reyes E. Department of Behavioral Sciences, New Mexico Highlands University, Las Vegas, USA. Prevention by a silymarin/phospholipid compound of ethanol-induced social learning deficits in rats. Planta Med. 1999 Jun;65(5):421-4. PMID: 10418328 [PubMed-indexed for MEDLINE].

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*Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, Anzenbacher P. Faculty of Chemical Technology, University of Pardubice, Nam. Cs. Legii 565, 532 10 Pardubice, Czech Republic. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Phytother Res. 2002 Nov;16(7):632-8. PMID: 12410543 [PubMed-indexed for MEDLINE].

*Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, Bocker RH, Beckurts  KT,  Lang  W,  Hunz  M,  Fuhr  U.  Institute  for  Pharmacology, Clinical Pharmacology, University of Koln, Germany. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes. Pharmacol Toxicol. 2000 Jun;86(6):250-6. PMID: 10895987 [PubMed- indexed for MEDLINE].

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*Mourelle   M,   Favari   L.   Departmento   de   Farmacologia   y Toxicologia, Centro de Investigacion y de Estudios Avanzados del I.P.N., Mexico, D.F. Silymarin improves metabolism and disposition of aspirin in cirrhotic rats. Life Sci. 1988;43(3):201-7. PMID: 3398694 [PubMed- indexed for MEDLINE].

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*Khayyal MT, el-Ghazaly MA, Kenawy SA, Seif-el-Nasr M, Mahran LG, Kafafi YA, Okpanyi SN. Department of Pharmacology, Faculty of Pharmacy, Cairo University, Cairo, Egypt. Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination. Arzneimittelforschung. 2001;51(7):545-53. PMID: 11505785 [PubMed- indexed for MEDLINE].

*Alarcon de la Lastra AC, Martin MJ, Motilva V, Jimenez M, La Casa   C,   Lopez   A.   Departamento   de   Farmacia   y   Tecnologia Farmaceutica, Facultad  de  Farmacia, Sevilla,  Spain.  Gastroprotection induced by silymarin, the hepatoprotective principle of Silybum marianum in ischemia-reperfusion mucosal injury: role of neutrophils. Planta Med. 1995 Apr;61(2):116-9. PMID: 7753916 [PubMed-indexed for MEDLINE].

*Cruz T, Galvez J, Crespo E, Ocete MA, Zarzuelo A. Effects of silymarin on the acute stage of the trinitrobenzenesulphonic acid model of rat colitis. Planta Med. 2001 Feb;67(1):94-6. PMID: 11270735 [PubMed- indexed for MEDLINE].

*Gil’miiarov EM, Radomskaia VM, Kretova IG, Vinogradova LN, Babichev AV, Ponomareva LA, Samykina LN, Sheshunov IV, Gil’miiarov EM. Biologically active additive from milk thistle in the solution of public health problems. Vopr Pitan. 1998;(3):33-5. PMID: 9752670 [PubMed- indexed for MEDLINE].

*Rui YC. College of Pharmacy, Second Military Medical University, Shanghai, China. Advances in pharmacological studies of silymarin. Mem Inst Oswaldo Cruz. 1991;86 Suppl 2:79-85. PMID: 1842018 [PubMed- indexed for MEDLINE].

*Allain H, Schuck S, Lebreton S, Strenge-Hesse A, Braun W, Gandon JM, Brissot P. Laboratoire de Pharmacologie Experimentale et Clinique, Faculte de Medecine, Universite de Rennes I, Rennes, France. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer’s disease. Dement Geriatr Cogn Disord. 1999 May- Jun;10(3):181-5. PMID: 10325444 [PubMed-indexed for MEDLINE].

*L  Pitzel,  C  Castillo  Robles,  J  Tresguerres,  S  Taubert,  V Christoffel, W Wuttke. Effects of estradiol (E2) and some phytoestrogens (PEs) containing plant extracts on differentiated 3T3-L1 fat cells. Exp Clin Endocrinol Diabetes. DOI: 10.1055/s-2004-819223

*No authors listed. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Adverse Drug Reactions Advisory Committee.  Med  J  Aust.  1999  Mar  1;170(5):218-9. PMID:  10092919 [PubMed-indexed for MEDLINE]

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