Login Register Cart 0
Generic placeholder image

Applied Drug Research, Clinical Trials and Regulatory Affairs

Editor-in-Chief

ISSN (Print): 2667-3371
ISSN (Online): 2667-338X

Back
Journal Home About Journal Editorial Board Current Issue Volumes/Issues
Subscribe
Review Article

Clinical and Regulatory Status of Silymarin

Author(s): Tanya Ralli, Vivekanandan Kalaiselvan, Ritu Tiwari, Shatrunajay Shukla and Kanchan Kholi*

Volume 8, Issue 2, 2021

Published on: 02 December, 2021

Article ID: e121121197923 Pages: 8

DOI: 10.2174/2667337108666211112153807

Price: $65

Abstract

Introduction: Silymarin is a mixture of 9 different active flavanolignans extracted from the seeds of the milk thistle (Silybum marianum) plant. It has been extensively used by local people and medicinal practitioners in European countries from around 2,000 years for the treatment of liver and biliary-related disorders.

Aims: This review article documents and critically assesses, for the first time, up to date the regulatory status of the silymarin extract for the treatment of hepatic and other diseases.

Methods: Information was collected systematically from electronic scientific databases including Google Scholar, Science Direct, PubMed, Web of Science, ACS Publications, Elsevier, SciFinder, and Wiley Online Library, as well as other literature sources (e.g., books). Additionally, various regulatory authority websites have been searched for exploring the data.

Key Findings: Silymarin has been approved in different doses for the treatment or adjuvant therapy for liver disorders by the regulatory authorities of different countries. But, silymarin has still been used as a dietary supplement in the US, despite its high sales. The potential of silymarin to be approved for various other indications has been proved by assessing its efficacy in human patients. In addition to efficacy, it is found to be safe and well-tolerated.

Conclusion: Phytochemical and pharmacological studies have demonstrated that silymarin is an important medicinal herb with prominent bioactivities. Thus, there is a need to conduct clinical trials in a larger number of patients to get approval for use in diseases like metabolic syndrome, diabetes mellitus, cancer, and many more.

Keywords: Silymarin, milk thistle, Silybum marianum, silybin, silibinin, hepatoprotectant

Graphical Abstract

[1]
Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res 2010; 24(10): 1423-32.
[http://dx.doi.org/10.1002/ptr.3207] [PMID: 20564545]
[2]
Surai PF. Silymarin as a natural antioxidant: An overview of the current evidence and perspectives. Antioxidants 2015; 4(1): 204-47.
[http://dx.doi.org/10.3390/antiox4010204] [PMID: 26785346]
[3]
Ladas E, Kroll DJ, Kelly KM. Milk thistle (Silybum marianum) Encyclopedia of Dietary Supplements. New York, NY: Marcel Dekker 2005.
[4]
Federico A, Dallio M, Loguercio C. Silymarin/silybin and chronic liver disease: A marriage of many years. Molecules 2017; 22(2): 191.
[http://dx.doi.org/10.3390/molecules22020191] [PMID: 28125040]
[5]
Mamalis A, Nguyen D-H, Brody N, Jagdeo J. The active natural anti-oxidant properties of chamomile, milk thistle, and halophilic bacterial components in human skin in vitro. J Drugs Dermatol 2013; 12(7): 780-4.
[PMID: 23884490]
[6]
Di Pierro F, Bellone I, Rapacioli G, Putignano P. Clinical role of a fixed combination of standardized Berberis aristata and Silybum marianum extracts in diabetic and hypercholesterolemic patients intolerant to statins. Diabetes Metab Syndr Obes 2015; 8(1): 89-96.
[http://dx.doi.org/10.2147/DMSO.S78877] [PMID: 25678808]
[7]
Mohammadi H, Hadi A, Arab A, Moradi S, Rouhani MH. Effects of silymarin supplementation on blood lipids: A systematic review and meta-analysis of clinical trials. Phytother Res 2019; 33(4): 871-80.
[http://dx.doi.org/10.1002/ptr.6287] [PMID: 30834633]
[8]
Tao L, Qu X, Zhang Y, Song Y, Zhang SX. Prophylactic therapy of silymarin (milk thistle) on antituberculosis drug-induced liver injury: A meta-analysis of randomized controlled trials. Can J Gastroenterol Hepatol 2019; 2019: 3192351.
[http://dx.doi.org/10.1155/2019/3192351] [PMID: 30733935]
[9]
Gupta SC, Prasad S, Aggarwal BB, Eds. Neha; Jaggi, A.S.; Singh, N., Silymarin and its role in chronic diseases. Drug Discovery from Mother Nature. Cham, Switzerland: Springer 2016; pp. 25-44.
[10]
Chambers CS, Holečková V, Petrásková L, et al. The silymarin composition… and why does it matter??? Food Res Int 2017; 100(Pt 3): 339-53.
[http://dx.doi.org/10.1016/j.foodres.2017.07.017] [PMID: 28964357]
[11]
Mengs U, Pohl RT, Mitchell T. Legalon® SIL: The antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharm Biotechnol 2012; 13(10): 1964-70.
[http://dx.doi.org/10.2174/138920112802273353] [PMID: 22352731]
[12]
Luangchosiri C, Thakkinstian A, Chitphuk S, Stitchantrakul W, Petraksa S, Sobhonslidsuk A. A double-blinded randomized controlled trial of silymarin for the prevention of antituberculosis drug-induced liver injury. BMC Complement Altern Med 2015; 15(1): 334.
[http://dx.doi.org/10.1186/s12906-015-0861-7] [PMID: 26400476]
[13]
Marjani M, Fahim F, Sadr M, et al. Evaluation of Silymarin for management of anti-tuberculosis drug induced liver injury: A randomized clinical trial. Gastroenterol Hepatol Bed Bench 2019; 12(2): 138-42.
[PMID: 31191838]
[14]
Heo E, Kim DK, Oh SH, Lee J-K, Park J-H, Chung HS. Effect of prophylactic use of silymarin on anti-tuberculosis drugs induced hepatotoxicity. Tuberc Respir Dis (Seoul) 2017; 80(3): 265-9.
[http://dx.doi.org/10.4046/trd.2017.80.3.265] [PMID: 28747959]
[15]
Momeni A, Hajigholami A, Geshnizjani S, Kheiri S. Effect of silymarin in the prevention of Cisplatin nephrotoxicity, a clinical trial study. J Clin Diagn Res 2015; 9(4): OC11-3.
[http://dx.doi.org/10.7860/JCDR/2015/12776.5789] [PMID: 26046020]
[16]
Shahbazi F, Sadighi S, Dashti-Khavidaki S, et al. Effect of silymarin administration on cisplatin nephrotoxicity: report from a pilot, randomized, double-blinded, placebo-controlled clinical trial. Phytother Res 2015; 29(7): 1046-53.
[http://dx.doi.org/10.1002/ptr.5345] [PMID: 25857366]
[17]
Elyasi S, Shojaee FSR, Allahyari A, Karimi G. Topical silymarin administration for prevention of capecitabinea induced hand- foot syndrome: A randomized, double-blinded, placebo-controlled clinical trial. Phytother Res 2017; 31(9): 1323-9.
[http://dx.doi.org/10.1002/ptr.5857] [PMID: 28635153]
[18]
Vidlar A, Vostalova J, Ulrichova J, et al. The safety and efficacy of a silymarin and selenium combination in men after radical prostatectomy - a six month placebo-controlled double-blind clinical trial. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010; 154(3): 239-44.
[http://dx.doi.org/10.5507/bp.2010.036] [PMID: 21048810]
[19]
Ebrahimpour-Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M. Lower glycemic indices and lipid profile among type 2 diabetes mellitus patients who received novel dose of Silybum marianum (L.) Gaertn. (silymarin) extract supplement: A Triple-blinded randomized controlled clinical trial. Phytomedicine 2018; 44(1): 39-44.
[http://dx.doi.org/10.1016/j.phymed.2018.03.050] [PMID: 29895491]
[20]
Ebrahimpour Koujan S, Gargari BP, Mobasseri M, Valizadeh H, Asghari-Jafarabadi M. Effects of Silybum marianum (L.) Gaertn. (silymarin) extract supplementation on antioxidant status and hs-CRP in patients with type 2 diabetes mellitus: A randomized, triple-blind, placebo-controlled clinical trial. Phytomedicine 2015; 22(2): 290-6.
[http://dx.doi.org/10.1016/j.phymed.2014.12.010] [PMID: 25765835]
[21]
Voroneanu L, Nistor I, Dumea R, Apetrii M, Covic A. Silymarin in type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials. J Diabetes Res 2016; 2016(1): 5147468.
[http://dx.doi.org/10.1155/2016/5147468] [PMID: 27340676]
[22]
Di Pierro F, Putignano P, Villanova N, Montesi L, Moscatiello S, Marchesini G. Preliminary study about the possible glycemic clinical advantage in using a fixed combination of Berberis aristata and Silybum marianum standardized extracts versus only Berberis aristata in patients with type 2 diabetes. Clin Pharmacol 2013; 5(1): 167-74.
[http://dx.doi.org/10.2147/CPAA.S54308] [PMID: 24277991]
[23]
Hussain SA-R. Silymarin as an adjunct to glibenclamide therapy improves long-term and postprandial glycemic control and body mass index in type 2 diabetes. J Med Food 2007; 10(3): 543-7.
[http://dx.doi.org/10.1089/jmf.2006.089] [PMID: 17887949]
[24]
Rastegarpanah M, Malekzadeh R, Vahedi H, et al. A randomized, double blinded, placebo-controlled clinical trial of silymarin in ulcerative colitis. Chin J Integr Med 2015; 21(12): 902-6.
[http://dx.doi.org/10.1007/s11655-012-1026-x] [PMID: 22528757]
[25]
Hussain SA, Jassim NA, Numan IT, Al-Khalifa II, Abdullah TA. Anti-inflammatory activity of silymarin in patients with knee osteoarthritis. A comparative study with piroxicam and meloxicam. Saudi Med J 2009; 30(1): 98-103.
[PMID: 19139781]
[26]
Hussain SA, Mortada AH, Jasim NA, Gorial FI. Silibinin improves the effects of methotrexate in patients with active rheumatoid arthritis: Pilot clinical study. Oman Med J 2016; 31(4): 263-9.
[http://dx.doi.org/10.5001/omj.2016.52] [PMID: 27403238]
[27]
Shavandi M, Moini A, Shakiba Y, et al. Silymarin (Livergol®) decreases disease activity score in patients with rheumatoid arthritis: A non-randomized single-Arm clinical trial. Iran J Allergy Asthma Immunol 2017; 16(2): 99-106.
[PMID: 28601049]
[28]
Bakhshaee M, Jabbari F, Hoseini S, et al. Effect of silymarin in the treatment of allergic rhinitis. Otolaryngol Head Neck Surg 2011; 145(6): 904-9.
[http://dx.doi.org/10.1177/0194599811423504] [PMID: 21952357]
[29]
Balouchi S, Gharagozloo M, Esmaeil N, Mirmoghtadaei M, Moayedi B. Serum levels of TGFβ, IL-10, IL-17, and IL-23 cytokines in β-thalassemia major patients: the impact of silymarin therapy. Immunopharmacol Immunotoxicol 2014; 36(4): 271-4.
[http://dx.doi.org/10.3109/08923973.2014.926916] [PMID: 24945737]
[30]
Hagag A. Therapeutic value of combined therapy with Deferiprone and Silymarin as iron chelators in Egyptian Children with Beta Thalassemia major. Infect Disord Drug Targets 2015; 15(3): 189-95.
[31]
Moayedi B, Gharagozloo M, Esmaeil N, Maracy MR, Hoorfar H, Jalaeikar M. A randomized double-blind, placebo-controlled study of therapeutic effects of silymarin in β-thalassemia major patients receiving desferrioxamine. Eur J Haematol 2013; 90(3): 202-9.
[http://dx.doi.org/10.1111/ejh.12061] [PMID: 23278124]
[32]
Abenavoli L, Izzo AA, Milić N, Cicala C, Santini A, Capasso R. Milk thistle (Silybum marianum): A concise overview on its chemistry, pharmacological, and nutraceutical uses in liver diseases. Phytother Res 2018; 32(11): 2202-13.
[http://dx.doi.org/10.1002/ptr.6171] [PMID: 30080294]
[33]
Qi Z, Kelley E. The WHO traditional medicine strategy 2014-2023: A perspective. Science 2014; 346(6216): S5-6.
[34]
Organization WH. National policy on traditional medicine and regulation of herbal medicines: Report of a WHO global survey. In World Health Organization 2005.
[35]
In Indian Pharmacopoeia: 2018. Available from: https://www.indianpharmacopoeia.in/
[36]
In British Pharmacopoeia: 2019. Available from: https://www.pharmacopoeia.com/
[37]
In United State Pharmacopoeia: 2017. Available from: https://www.usp.org/
[38]
Soleimani V, Delghandi PS, Moallem SA, Karimi G. Safety and toxicity of silymarin, the major constituent of milk thistle extract: An updated review. Phytother Res 2019; 33(6): 1627-38.
[http://dx.doi.org/10.1002/ptr.6361] [PMID: 31069872]
[39]
Mayer KE, Myers RP, Lee SS. Silymarin treatment of viral hepatitis: A systematic review. J Viral Hepat 2005; 12(6): 559-67.
[http://dx.doi.org/10.1111/j.1365-2893.2005.00636.x] [PMID: 16255756]
[40]
Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine Expanded Commission E monographs. Massachusetts: Integrative Medicine Communications 2000.
[41]
Hung J-H, Chu C-J, Sung P-L, et al. Lamivudine therapy in the treatment of chronic hepatitis B with acute exacerbation during pregnancy. J Chin Med Assoc 2008; 71(3): 155-8.
[http://dx.doi.org/10.1016/S1726-4901(08)70009-1] [PMID: 18364269]
[42]
Fraschini F, Demartini G, Esposti D. Pharmacology of silymarin. Clin Drug Investig 2002; 22(1): 51-65.
[http://dx.doi.org/10.2165/00044011-200222010-00007]
[43]
The ABC clinical guide to herbs. Available from: http://cms.herbalgram.org/ABCGuide/GuidePDFs/Milk_Thistle.pdf (Accessed on 11 August).
[44]
CDSCO Drugs. Available from: https://cdscoonline.gov.in/CDSCO/Drugs (Accessed on 10 August).
[45]
Therapeutic goods administration. Available from: https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=5C1B805656659C42CA25843100422F45&agid=(PrintDetailsPublic)&actionid=1 (Accessed on 09 August).
[46]
Therapeutic goods administration. Available from: https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=D79E179ABD1E8BFBCA2581FE003C9DB4&agid=(PrintDetailsPublic)&actionid=1 (Accessed on 12 August).
[47]
Find product information about medicines. Available from: http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con117535.pdf (Accessed on 15 August).
[48]
Therapeutic goods administration. Available from: https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=95A874ACF86E042ECA257A3600422E73&agid=(PrintDetailsPublic)&actionid=1 (Accessed on 14 August).
[49]
Therapeutic goods administration. Available from: https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=24308771FFD4D562CA257D1000422AA9&agid=(PrintDetailsPublic)&actionid=1 (Accessed on 30 August).
[50]
Therapeutic goods administration. Available from: https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=24DC6922E15F5A8BCA257A87004233E2&agid=(PrintDetailsPublic)&actionid=1 (Accessed on 17 August).
[51]
Health-products Canada. Available from: https://health-products.canada.ca/dpd-bdpp/dispatch-repartition.do (Accessed on 01 August).
[52]
Health-products Canada. Available from: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=65028 (Accessed on 02 August).
[53]
Health-products Canada. Available from: https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=61734 (Accessed on 21 August).
[54]
Latest general sales product information. Available from: https://www.hpra.ie/img/uploaded/swedocuments/latest_general_sales_list.pdf (Accessed on 07 August).
[55]
Latest general sales product information. Available from: https://www.hpra.ie/img/uploaded/swedocuments/latest_general_sales_list.pdf (Accessed on 19 August).
[56]
European medicines agency. Available from: https://www.ema.europa.eu/en/documents/herbal-report/final-assessment-report-silybum-marianum-l-gaertn-fructus_en.pdf (Accessed on 22 August).

Rights & Permissions Print Cite
Article Metrics
12
© 2024 Bentham Science Publishers | Privacy Policy