The Use of Herbal Medicine in the Treatment of Vitiligo: An Updated Review

Abstract

Vitiligo is a chronic disease of unknown etiology that causes progressive cutaneous depigmentation. Current pharmacological treatments have limited success and present significant risks. Many efforts have been made in recent years to explore new anti-vitiligo therapeutic strategies, including herbal-based therapies. The objective of the present review is to provide an updated overview on the most frequently used medicinal plants in the treatment of vitiligo. A bibliographical search was carried out in scientific databases Pubmed, Scifinder, Scopus, Google Scholar, and Medline up to October 2021 using the descriptors vitiligo, herbal, medicinal plants, and alternative therapies. In our search, the highest number of published studies comprise plants commonly used in traditional herbal medicine, highlighting the usefulness of ethnopharmacology in the discovery of new therapeutic agents. The review outlines current understanding and provides an insight into the role of psoralens and khellin (photosensitizing agents obtained from plants such as Cullen corylifolium or Ammi visnaga). The paper also describes other traditional herbs such as Ginkgo biloba, Phlebodium aureum, Piper nigrum, Picrorhiza kurroa, and Baccharoides anthelmintica that can likewise act as potential therapeutical agents. Based on our findings, photosensitizing agents in combination with phototherapy, the association of oral Phebodium aureum with phototherapies as well as oral G. biloba in monotherapy showed greater scientific evidence as therapeutic options. The research results emphasize that further investigation in this area is merited. More long-term follow up clinical trials and higher quality randomized trials are needed.

Key words

Vitiligo - medicinal plants - Cullen corylifolium - Ammi visnaga - Gingko biloba - Phlebodium aureum - Piper nigrum - Picrorhiza kurroa - Baccharoides anthelmintica

Publication History

Received: 13 January 2022

Accepted after revision: 02 May 2022

Article published online:
15 November 2022

• References

• 1 Ezzedine K, Eleftheriadou V, Whitton M, van Geel N. Vitiligo. Lancet 2015; 386: 74-84
• 2 Ezzedine K, Lim HW, Suzuki T, Katayama I, Hamzavi I, Lan CC, Goh BK, Anbar T, Silva de Castro C, Lee AY, Parsad D, van Geel N, Le Poole IC, Oiso N, Benzekri L, Spritz R, Gauthier Y, Hann SK, Picardo M, Taieb A. Revised classification/nomenclature of vitiligo and related issues: The vitiligo global issues consensus conference. Pigment Cell Melanoma Res 2012; 25: E1-E13
• 3 Taieb A, Alomar A, Böhm M, Dellʼanna ML, De Pase A, Eleftheriadou V, Ezzedine K, Gauthier Y, Gawkrodger DJ, Jouary T, Leone G, Moretti S, Nieuweboer-Krobotova L, Olsson MJ, Parsad D, Passeron T, Tanew A, van der Veen W, van Geel N, Whitton M, Wolkerstorfer A. Picardo M; Vitiligo European Task Force (VETF); European Academy of Dermatology and Venereology (EADV), Union Européenne des Médecins Spécialistes (UEMS). Guidelines for the management of vitiligo: The European Dermatology Forum consensus. Br J Dermatol 2013; 168: 5-19
• 4 Whitton ME, Pinart M, Batchelor J, Leonardi-Bee J, González U, Jiyad Z, Eleftheriadou V, Ezzedine K. Interventions for vitiligo (update). Cochrane Database Syst Rev 2015; (02) CD003263
• 5 Martis J, Bhat R, Nandakishore B, Shetty JN. A clinical study of vitiligo. Indian J Dermatol Venereol Leprol 2002; 68: 92-93
• 6 Whitton M, Pinart M, Batchelor JM, Leonardi-Bee J, Gonzalez U, Jiyad Z, Eleftheriadou V, Ezzedine K. Evidence-based management of vitiligo: Summary of a Cochrane systematic review. Br J Dermatol 2016; 174: 962-969
• 7 Elbuluk N, Ezzedine K. Quality of life, burden of disease, co-morbidities, and systemic effects in vitiligo patients. Dermatol Clin 2017; 35: 117-128
• 8 Bergqvist C, Ezzedine K. Vitiligo: A Review. Dermatology 2020; 236: 571-592
• 9 Kussainova A, Kassym L, Akhmetova A, Glushkova N, Sabirov U, Adilgozhina S, Tuleutayeva R, Semenova Y. Vitiligo and anxiety: A systematic review and meta-analysis. PLoS One 2020; 15: e0241445
• 10 Laddha NC, Dwivedi M, Mansuri MS, Gani AR, Ansarullah M, Ramachandran AV, Dalai S, Begum R. Vitiligo: interplay between oxidative stress and immune system. Exp Dermatol 2013; 22: 245-250
• 11 Colucci R, Dragoni F, Moretti S. Oxidative stress and immune system in vitiligo and thyroid diseases. Oxid Med Cell Longev 2015; 2015: 631927
• 12 Said-Fernandez SL, Sanchez-Domínguez CN, Salinas-Santander MA, Martinez-Rodriguez HG, Kubelis-Lopez DE, Zapata-Salazar NA, Vazquez-Martinez OT, Wollina U, Lotti T, Ocampo-Candiani J. Novel immunological and genetic factors associated with vitiligo: A review. Exp Ther Med 2021; 21: 312
• 13 Bergqvist C, Ezzedine K. Vitiligo: A focus on pathogenesis and its therapeutic implications. J Dermatol 2021; 48: 252-270
• 14 Forschner T, Buchholtz S, Stockfleth E. Current state of vitiligo therapy – evidence based analysis of the literature. J Dtsch Dermatol Ges 2007; 5: 467-475
• 15 Bae JM, Jung HM, Hong BY, Lee JH, Choi WJ, Lee JH, Kim GM. Phototherapy for vitiligo: a systematic review and meta-analysis. JAMA Dermatol 2017; 153: 666-674
• 16 Dillon AB, Sideris A, Hadi A, Elbuluk N. Advances in vitiligo: An update on medical and surgical treatments. J Clin Aesthet Dermatol 2017; 10: 15-28
• 17 Ezzedine K, Whitton M, Pinart M. Interventions for vitiligo. JAMA 2016; 316: 1708-1709
• 18 Rodrigues M, Ezzedine K, Hamzavi I, Pandya AG, Harris JE. Vitiligo Working Group. Current and emerging treatments for vitiligo. J Am Acad Dermatol 2017; 77: 17-29
• 19 Kubelis-López DE, Zapata-Salazar NA, Said-Fernández SL, Sánchez-Domínguez CN, Salinas-Santander MA, Martínez-Rodríguez HG, Vázquez-Martínez OT, Wollina U, Lotti T, Ocampo-Candiani J. Updates and new medical treatments for vitiligo (Review). Exp Ther Med 2021; 22: 797
• 20 Heinrich M, Barnes J, Prieto-Garcia J, Gibbons S, Williamson E. Fundamentals of Pharmacognosy and Phytotherapy. 3rd edition. Oxford: Elsevier; 2018: 184-232
• 21 Szczurko O, Boon HS. A systematic review of natural health product treatment for vitiligo. BMC Dermatol 2008; 8: 2
• 22 Gianfaldoni S, Wollina U, Tirant M, Tchernev G, Lotti J, Satolli F, Rovesti M, França K, Lotti T. Herbal compounds for the treatment of vitiligo: A review. Open Access Maced J Med Sci 2018; 6: 203-207
• 23 Hussain I. The Safety of medicinal plants used in the treatment of vitiligo and hypermelanosis: A systematic review of use and reports of harm. Clin Cosmet Investig Dermatol 2021; 14: 261-284
• 24 Khushboo PS, Jadhav VM, Kadam VJ, Sathe NS. Psoralea corylifolia Linn.–“Kushtanashini”. Pharmacogn Rev 2010; 4: 69-76
• 25 Khalil N, Bishr M, Desouky S, Salama O. Ammi visnaga L., a potential medicinal plant: A review. Molecules 2020; 25: 301
• 26 Usmani QI, Jahan N, Aleem M, Hasan SA. Aatrilal (Ammi majus L.), an important drug of Unani system of medicine: A review. J Ethnopharmacol 2021; 276: 1141-1144
• 27 McGovern TW, Barkley TM. Botanical dermatology. Int J Dermatol 1998; 37: 321-334
• 28 Pathak MA, Fitzpatrick TB. The evolution of photochemotherapy with psoralens and UVA (PUVA): 2000 BC to 1992 AD. J Photochem Photobiol B 1992; 14: 3-22
• 29 Wang PL, Yao ZH, Zhang FX, Shen XY, Dai Y, Qin L, Yao XS. Identification of metabolites of psoraleae fructus in rats by ultra-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry analysis. J Pharm Biomed Anal 2015; 112: 23-35
• 30 Mahendra CK, Tan LTH, Lee WL, Yap WH, Pusparajah P, Low LE, Tang SY, Chan KG, Lee LH, Goh BH. Angelicin-A furocoumarin compound with vast biologicalp. Front Pharmacol 2020; 11: 366
• 31 Hashim S, Marwat AJKB, Khan MA. Phytochemistry and medicinal properties of Ammi visnaga (Apiaceae). Pak J Bot 2014; 46: 861-867
• 32 National Center for Biotechnology Information. PubChem Compound Summary for CID 3828, Khellin. Accessed November 2, 2021 at: https://pubchem.ncbi.nlm.nih.gov/compound/Khellin
• 33 Sehgal VN. Effectiveness of trioxsalen therapy for vitiligo. Arch Dermatol 1974; 110: 957-958
• 34 Theodoridis A, Tsambaos D, Sivenas C, Capetanakis J. Oral trimethylpsoralen in the treatment of vitiligo. Acta Derm Venereol 1976; 56: 253-256
• 35 Monem El Mofty A. A preliminary clinical report on the treatment of leukoderma with Ammi majus Linn. J Am Acad Derma-Egypt Med Assoc 1948; 31: 651-665
• 36 Felsten LM, Alikhan A, Petronic-Rosic V. Vitiligo: A comprehensive overview Part II: Treatment options and approach to treatment. J Am Acad Dermatol 2011; 65: 493-514
• 37 Hermanson GT. The Reactions of Bioconjugation. In: Hermanson GT. ed. Bioconjugate Techniques. 3rd ed.. Cambridge: Academic Press; 2013: 229-258
• 38 Loutfy MA, Abu-Shady HA. Preparation and skin-photosensitizing activity of substituted psoralens. J Pharm Sci 1977; 66: 1623-1625
• 39 Wu CS, Lan CC, Wang LF, Chen GS, Wu CS, Yu HS. Effects of psoralen plus ultraviolet A irradiation on cultured epidermal cells in vitro and patients with vitiligo in vivo . Br J Dermatol 2007; 156: 122-129
• 40 Pacifico A, Leone G. Photochemotherapy for vitiligo. Photodermatol Photoimmunol Photomed 2011; 27: 261-277
• 41 El-Mofty M, Mostafa W, Esmat S, Youssef R, Bosseila M, Hegazy RA. Phototherapy in vitiligo: a comparative evaluation of various therapeutic modalities. J Egypt Womenʼs Dermatologic Soc 2012; 9: 123-135
• 42 Paro Vidolin A, Aurizi C, Leone G. Phototherapy for vitiligo, whatʼs new?. G Ital Dermatol Venereol 2017; 152: 474-488
• 43 Brickl R, Schmid J, Koss FW. Clinical pharmacology of oral psoralen drugs. Photodermatol 1984; 1: 174-186
• 44 Grundmann-Kollmann M, Tegeder I, Ochsendorf FR, Zollner TM, Ludwig R, Kaufmann R, Podda M. Kinetics and dose-response of photosensitivity in cream psoralen plus ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three standard preparations. Br J Dermatol 2001; 144: 991-995
• 45 Sun MC, Xu XL, Lou XF, Du YZ. Recent progress and future directions: The nano-drug delivery system for the treatment of vitiligo. Int J Nanomedicine 2020; 15: 3267-3279
• 46 Sinico C, Valenti D, Manconi M, Lai F, Fadda AM. Cutaneous delivery of 8-methoxypsoralen from liposomal and niosomal carriers. J Drug Deliv Sci Technol 2006; 16: 115-120
• 47 Kassem AA, Abd El-Alim SH, Asfour MH. Enhancement of 8-methoxypsoralen topical delivery via nanosized niosomal vesicles: Formulation development, in vitro and in vivo evaluation of skin deposition. Int J Pharm 2017; 517: 256-268
• 48 Doppalapudi S, Mahira S, Khan W. Development and in vitro assessment of psoralen and resveratrol co-loaded ultradeformable liposomes for the treatment of vitiligo. J Photochem Photobiol B 2017; 174: 44-57
• 49 Elsayed MM, Abdallah OY, Naggar VF, Khalafallah NM. Deformable liposomes and ethosomes as carriers for skin delivery of ketotifen. Pharmazie 2007; 62: 133-137
• 50 Garg BJ, Garg NK, Beg S, Singh B, Katare OP. Nanosized ethosomes-based hydrogel formulations of methoxsalen for enhanced topical delivery against vitiligo: Formulation optimization, in vitro evaluation and preclinical assessment. J Drug Target 2016; 24: 233-246
• 51 Farah FS, Kurban AK, Chaglassian HT. The treatment of vitiligo with psoralens and triamcinolone by mouth. Br J Dermatol 1967; 79: 89-91
• 52 Pathak MA, Mosher DB, Fitzpatrick TB. Safety and therapeutic effectiveness of 8-methoxypsoralen, 4,5′,8-trimethylpsoralen, and psoralen in vitiligo. Natl Cancer Inst Monogr 1984; 66: 165-173
• 53 Bedi KL, Zutshi U, Chopra CL, Amla V. Picrorhiza kurroa, an ayurvedic herb, may potentiate photochemotherapy in vitiligo. J Ethnopharmacol 1989; 27: 347-352
• 54 al-Aboosi MM, Ajam ZA. Oral photochemotherapy in vitiligo: Follow-up, patient compliance. Int J Dermatol 1995; 34: 206-208
• 55 Khalid M, Mujtaba G, Haroon TS. Comparison of 0.05 % clobetasol propionate cream and topical Puvasol in childhood vitiligo. Int J Dermatol 1995; 34: 203-205
• 56 Westerhof W, Nieuweboer-Krobotova L. Treatment of vitiligo with UV-B radiation vs. topical psoralen plus UV-A. Arch Dermatol 1997; 133: 1525-1528
• 57 Cestari TF, Dias M, Fernandes EI, Albaneze R. Comparative study of two psoralens in topical phototherapy for vitiligo. An Bras Dermatol 2001; 76: 683-692
• 58 Ermis O, Alpsoy E, Cetin L, Yilmaz E. Is the efficacy of psoralen plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? a placebo-controlled double-blind study. Br J Dermatol 2001; 145: 472-475
• 59 Cherif F, Azaiz MI, Ben Hamida A, Ben O, Dhari A. Calcipotriol and PUVA as treatment for vitiligo. Dermatol Online J 2003; 9: 4
• 60 Reyes E, Jaén P, de Las Heras E, Carrión F, Álvarez-Mon M, de Eusebio E, Alvare M, Cuevas J, González S, Villarrubia VG. Systemic immunomodulatory effects of Polypodium leucotomos as an adjuvant to PUVA therapy in generalized vitiligo: A pilot study. J Dermatol Sci 2006; 41: 213-216
• 61 El-Mofty M, Mostafa W, Esmat S, Youssef R, Azzam O, Hunter N, El Hanafi G, Fawzi M. Narrow band Ultraviolet B 311 nm in the treatment of vitiligo: Two right-left comparison studies. Photodermatol Photoimmunol Photomed 2006; 22: 6-11
• 62 Parsad D, Kanwar AJ, Kumar B. Psoralen-ultraviolet A vs. narrow-band ultraviolet B phototherapy for the treatment of vitiligo. J Eur Acad Dermatol Venereol 2006; 20: 175-177
• 63 Radmanesh M, Saedi K. The efficacy of combined PUVA and low-dose azathioprine for early and enhanced repigmentation in vitiligo patients. J Dermatolog Treat 2006; 17: 151-153
• 64 Bhatnagar A, Kanwar AJ, Parsad D, De D. Comparison of systemic PUVA and NB-UVB in the treatment of vitiligo: An open prospective study. J Eur Acad Dermatol Venereol 2007; 21: 638-642
• 65 Yones SS, Palmer RA, Garibaldinos TM, Hawk JL. Randomized double-blind trial of treatment of vitiligo: Efficacy of psoralen-UV-A therapy vs. Narrowband-UV-B therapy. Arch Dermatol 2007; 143: 578-584 Erratum in: Arch Dermatol 2007; 143: 906 Erratum in: Arch Dermatol 2007; 143: 906
• 66 El-Mofty M, Mostafa WZ, Bosseila M, Youssef R, Esmat S, El Ramly A, Fawzi M, Mahgoub D, Nagui N, Mashaly HM, El-Fangary M, Fathy M. A large scale analytical study on efficacy of different photo(chemo)therapeutic modalities in the treatment of psoriasis, vitiligo and mycosis fungoides. Dermatol Ther 2010; 23: 428-434
• 67 Sapam R, Agrawal S, Dhali TK. Systemic PUVA vs. narrowband UVB in the treatment of vitiligo: A randomized controlled study. Int J Dermatol 2012; 51: 1107-1115
• 68 El-Mofty M, Bosseila M, Mashaly HM, Gawdat H, Makaly H. Broadband ultraviolet A vs. psoralen ultraviolet A in the treatment of vitiligo: A randomized controlled trial. Clin Exp Dermatol 2013; 38: 830-835
• 69 Bansal S, Sahoo B, Garg V. Psoralen-narrowband UVB phototherapy for the treatment of vitiligo in comparison to narrowband UVB alone. Photodermatol Photoimmunol Photomed 2013; 29: 311-317
• 70 Singh S, Khandpur S, Sharma VK, Ramam M. Comparison of efficacy and side-effect profile of oral PUVA vs. oral PUVA sol in the treatment of vitiligo: a 36-week prospective study. J Eur Acad Dermatol Venereol 2013; 27: 1344-1351
• 71 Van TN, Minh TT, Huu DL, Huu SN, Thanh TV, Huu ND, Cam VT, Huyen ML, Hau KT, Trong HN, Gandolfi M, Satolli F, Feliciani C, Tirant M, Vojvodic A, Lotti T. Successful treatment of vitiligo Vietnamese patients with Vitilinex^® herbal bio-actives in combination with phototherapy. Open Access Maced J Med Sci 2019; 7: 283-286
• 72 Zabolinejad N, Maleki M, Salehi M, Ashrafi Z, Molkara S, Layegh P. Psoralen and narrowband UVB combination provides higher efficacy in treating vitiligo compared with narrowband UVB alone: A randomised clinical trial. Australas J Dermatol 2020; 61: e65-e69
• 73 Sakhiya J, Sakhiya D, Virmani N, Gajjar T, Kaklotar J, Khambhati R, Daruwala F, Dudhatra N. A Retrospective study of 3000 Indian patients with vitiligo treated with phototherapy or topical monotherapy. J Clin Aesthet Dermatol 2021; 14: 46-49
• 74 Liu Y, Flynn TJ. CYP3A4 inhibition by Psoralea corylifolia and its major components in human recombinant enzyme, differentiated human hepatoma HuH-7 and HepaRG cells. Toxicol Rep 2015; 2: 530-534
• 75 Carlie G, Ntusi NB, Hulley PA, Kidson SH. KUVA (khellin plus ultraviolet A) stimulates proliferation and melanogenesis in normal human melanocytes and melanoma cells in vitro . Br J Dermatol 2003; 149: 707-717
• 76 Abdel-Fattah A, Aboul-Enein MN, Wassel GM, El-Menshawi BS. An approach to the treatment of vitiligo by khellin. Dermatologica 1982; 165: 136-140
• 77 Ortel B, Tanew A, Hönigsmann H. Treatment of vitiligo with khellin and ultraviolet A. J Am Acad Dermatol 1988; 18: 693-701
• 78 Orecchia G, Perfetti L. Photochemotherapy with topical khellin and sunlight in vitiligo. Dermatology 1992; 184: 120-123
• 79 Orecchia G, Sangalli ME, Gazzaniga A, Giordano F. Topical photochemotherapy of vitiligo with a new khellin formulation: Preliminary clinical results. J Dermatol Treat 1998; 9: 65-69
• 80 Hofer A, Kerl H, Wolf P. Long-term results in the treatment of vitiligo with oral khellin plus UVA. Eur J Dermatol 2001; 11: 225-229
• 81 Valkova S, Trashlieva M, Christova P. Treatment of vitiligo with local khellin and UVA: comparison with systemic PUVA. Clin Exp Dermatol 2004; 29: 180-184
• 82 Saraceno R, Nisticò SP, Capriotti E, Chimenti S. Monochromatic excimer light 308 nm in monotherapy and combined with topical khellin 4 % in the treatment of vitiligo: a controlled study. Dermatol Ther 2009; 22: 391-394
• 83 de Leeuw J, Assen YJ, van der Beek N, Bjerring P, Martino Neumann HA. Treatment of vitiligo with khellin liposomes, ultraviolet light and blister roof transplantation. J Eur Acad Dermatol Venereol 2011; 25: 74-81
• 84 Nistico S, Cannarozzo G, Sannino M, Del Duca E, Bottoni U. 308 nm UV excimer light in monotherapy or combined to topical khellin 4 % and/or tacrolimus 0.1 % in the treatment of vitiligo. Glob Dermatol 2015; 2: 93-96
• 85 Fenniche S, Zaouak A, Tanfous AB, Jrad M, Hammami H. Successful Treatment of refractory vitiligo with a combination of khellin and 308-nm excimer lamp: An open-label, 1-year prospective study. Dermatol Ther (Heidelb) 2018; 8: 127-135
• 86 Carrascosa JM. Fototerapia y fotoquimioterapia. Actas Dermosifiliogr 2004; 95: 259-284
• 87 Lázaro TAC, Sánchez SMP. Vitiligo: Principales opciones terapéuticas. Med Cutan Iber Lat Am 2006; 34: 81-88
• 88 Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine: Expanded Commission E Monographs. Austin: American Botanical Council; 2000
• 89 Isah T. Rethinking Ginkgo biloba L.: Medicinal uses and conservation. Pharmacogn Rev 2015; 9: 140-148
• 90 McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of Ginkgo biloba in clinical and preclinical applications. Altern Ther Health Med 2001; 7: 70-86 88–90
• 91 Evans WC. Trease and Evans Pharmacognosy, 16th edition. Edinburgh: Saunders/Elsevier; 2009
• 92 Chan PC, Xia Q, Fu PP. Ginkgo biloba leave extract: biological, medicinal, and toxicological effects. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2007; 25: 211-244
• 93 Kaur S, Sharma N, Nehru B. Antiinflammatory effects of Ginkgo biloba extract against trimethyltin-induced hippocampal neuronal injury. Inflammopharmacology 2018; 26: 87-104
• 94 Achete de Souza G, de Marqui SV, Matias JN, Guiguer EL, Barbalho SM. Effects of Ginkgo biloba on diseases related to oxidative stress. Planta Med 2020; 86: 376-386
• 95 Bosch-Morell F, Villagrasa V, Ortega T, Acero N, Muñoz-Mingarro D, González-Rosende ME, Castillo E, Sanahuja MA, Soriano P, Martínez-Solís I. Medicinal plants and natural products as neuroprotective agents in age-related macular degeneration. Neural Regen Res 2020; 15: 2207-2216
• 96 Ude C, Schubert-Zsilavecz M, Wurglics M. Ginkgo biloba extracts: a review of the pharmacokinetics of the active ingredients. Clin Pharmacokinet 2013; 52: 727-749
• 97 Parsad D, Pandhi R, Juneja A. Effectiveness of oral Ginkgo biloba in treating limited, slowly spreading vitiligo. Clin Exp Dermatol 2003; 28: 285-287
• 98 Szczurko O, Shear N, Taddio A, Boon H. Ginkgo biloba for the treatment of vitiligo vulgaris: An open label pilot clinical trial. BMC Complement Altern Med 2011; 11: 21-30
• 99 Komen L, da Graça V, Wolkerstorfer A, de Rie MA, Terwee CB, van der Veen JP. Vitiligo Area Scoring Index and Vitiligo European Task Force assessment: Reliable and responsive instruments to measure the degree of depigmentation in vitiligo. Br J Dermatol 2015; 172: 437-443
• 100 Lu L, Wang S, Fu L, Liu D, Zhu Y, Xu A. Bilobalide protection of normal human melanocytes from hydrogen peroxide-induced oxidative damage via promotion of antioxidase expression and inhibition of endoplasmic reticulum stress. Clin Exp Dermatol 2016; 41: 64-73
• 101 Zhang S, Yi X, Su X, Jian Z, Cui T, Guo S, Gao T, Li C, Li S, Xiao Q. Ginkgo biloba extract protects human melanocytes from H₂O₂-induced oxidative stress by activating Nrf2. J Cell Mol Med 2019; 23: 5193-5199
• 102 Abu-Raghif AR, Ali NM, Farhood IG, Hameed MF, Sahib HB. Evaluation of a standardized extract of Ginkgo biloba in vitiligo remedy. Asian J Pharm Clin Res 2013; 6: 127-130
• 103 Ching-Hsiang L, Chiao-Wen H, Nan-Fu C, Wen-Sheng L, Ya-Fen H, Wen-Tung W. In vivo effects of Ginkgo biloba extract on interleukin-6 cytokine levels in patients with neurological disorders. Indian J Pharmacol 2012; 44: 118-121
• 104 Liu B, Xie Y, Mei X, Sun Y, Shi W, Wu Z. Reciprocal regulation of interleukin-17A and interleukin-22 secretion through aryl hydrocarbon receptor activation in CD4+ T cells of patients with vitiligo. Exp Ther Med 2021; 21: 158
• 105 Nguyen T, Alzahrani T. Ginkgo Biloba . In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021. Accessed September 3, 2021 at: https://www.ncbi.nlm.nih.gov/books/NBK541024/
• 106 Martínez-Solís I, Acero N, Bosch-Morell F, Castillo E, González-Rosende ME, Muñoz-Mingarro D, Ortega T, Sanahuja MA, Villagrasa V. Neuroprotective potential of Ginkgo biloba in retinal diseases. Planta Med 2019; 85: 1292-1303
• 107 Tracy TS. Ginkgo biloba. . In: Tracy TS, Kingston RL. eds. Herbal Products, Toxicology and Clinical Pharmacology. 2nd edition. New Jersey: Springer; 2007: 41-54
• 108 Mei N, Guo X, Ren Z, Kobayashi D, Wada K, Guo L. Review of Ginkgo biloba-induced toxicity, from experimental studies to human case reports. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 2017; 35: 1-28
• 109 Elmer GW, Lafferty WE, Tyree PT, Lind BK. Potential interactions between complementary/alternative products and conventional medicines in a medicare population. Ann Pharmacother 2007; 41: 1617-1624
• 110 Agbabiaka TB, Wider B, Watson LK, Goodman C. Concurrent use of prescription drugs and herbal medicinal products in older adults: A systematic review. Drugs Aging 2017; 34: 891-905
• 111 White HL, Scates PW, Cooper BR. Extracts of Ginkgo biloba leaves inhibit monoamine oxidase. Life Sci 1996; 58: 1315-1321
• 112 Tres JC. Interacción entre fármacos y plantas medicinales. An Sist Sanit Navar 2006; 29: 233-252
• 113 Segars K, McCarver V, Miller RA. Dermatologic applications of Polypodium leucotomos: A literature review. J Clin Aesthet Dermatol 2021; 14: 50-60
• 114 Parrado C, Juarranz A, Gilaberte Y, Philips N, González S. Fern Extract, Oxidative Stress and Skin Cancer. In: Preedy V, Patel VD. eds. Cancer: Oxidative Stress and Dietary Antioxidants. 2nd Edition. London, UK: Elsevier; 2021: 387-398
• 115 Padilla HC, Laínez H, Pacheco JA. A new agent (hydrophilic fraction of Polypodium leucotomos) for management of psoriasis. Int J Dermatol 1974; 13: 276-282
• 116 Gomes AJ, Lunardi CN, Gonzalez S, Tedesco AC. The anti-oxidant action of Polypodium leucotomos extract and kojic acid: reactions with reactive oxygen species. Braz J Med Biol Res 2001; 34: 1487-1494
• 117 Brieva A, Guerrero A, Pivel JP. Immunomodulatory properties of a hydrophilic extract of Polypodium leucotomos . Inflammopharmacology 2002; 9: 361-371
• 118 Parrado C, Mascaraque M, Gilaberte Y, Juarranzn A, Gonzalez S. Fernblock (Polypodium leucotomos Extract): Molecular mechanisms and pleiotropic effects in light-related skin conditions, photoaging and skin cancers, a review. Int J Mol Sci 2016; 17: 1026-1047
• 119 Nestor M, Bucay V, Callender V, Cohen JL, Sadick N, Waldorf H. Polypodium leucotomos as an adjunct treatment of pigmentary disorders. J Clin Aesthet Dermatol 2014; 7: 13-17
• 120 Middelkamp-Hup MA, Bos JD, Rius-Diaz F, Gonzalez S, Westerhof W. Treatment of vitiligo vulgaris with narrow-band UVB and oral Polypodium leucotomos extract: a randomized double-blind placebo-controlled study. J Eur Acad Dermatol Venereol 2007; 21: 942-950
• 121 Zurita G, Briones MC, Preciado V, Uraga R. Efecto del Polypodium leucotomos como adjuvante en la repigmentación inducida con UVB de banda estrecha en pacientes con vitiligo. Med Cutan Iber Lat Am 2013; 41: 205-209
• 122 Pacifico A, Vidolin AP, Leone G, Iacovelli P. Combined treatment of narrowband ultraviolet B light (NB-UVB) phototherapy and oral Polypodium leucotomos extract versus NB UVB phototherapy alone in the treatment of patients with vitiligo. J Am Acad Dermatol 2009; 60: AB154
• 123 Pacifico A, Damiani G, Iacovelli P, Conic RRZ. Young Dermatologists Italian Network (YDIN), Gonzalez S, Morrone A. NB-UVB plus oral Polypodium leucotomos extract display higher efficacy than NB-UVB alone in patients with vitiligo. Dermatol Ther 2021; 34: e14776
• 124 Speeckaert R, Dugardin J, Lambert J, Lapeere H, Verhaeghe E, Speeckaert MM, van Geel N. Critical appraisal of the oxidative stress pathway in vitiligo: A systematic review and meta-analysis. J Eur Acad Dermatol Venereol 2018; 32: 1089-1098
• 125 Guarneri F, Bertino L, Pioggia G, Casciaro M, Gangemi S. Therapies with antioxidant potential in psoriasis, vitiligo, and Lichen Planus. Antioxidants 2021; 10: 1087
• 126 Philips N, Smith J, Keller T, Gonzalez S. Predominant effects of Phlebodium aureum on membrane integrity, lipid peroxidation, and expression of elastin and matrixmetalloproteinase-1 in ultraviolet radiation exposed fibroblasts, and keratinocytes. J Dermatol Sci 2003; 32: 1-9
• 127 Nestor MS, Berman B, Swenson N. Safety and efficacy study of oral Polypodium leucotomos extract in healthy adult subjects. J Clin Aesthet Dermatol 2015; 8: 19-23
• 128 Gonzalez S, Alcaraz MV, Cuevas J, Perez M, Jaen P, Alvarez-Mon M, Villarrubia VG. An extract of the fern Polypodium leucotomos (Difur) modulates Th1/Th2 cytokines balance in vitro and appears to exhibit anti-angiogenic activities in vivo: pathogenic relationships and therapeutic implications. Anticancer Res 2000; 20: 1567-1575
• 129 Murbach TS, Béres E, Vértesi A, Glávits R, Hirkab G, Endresa JR, Clewella AE, Szakonyiné IP. A comprehensive toxicological safety assessment of an aqueous extract of Polypodium leucotomos (Fernblock^®). Food Chem Toxicol 2015; 86: 328-341
• 130 Sultan P, Jan A, Pervaiz Q. Phytochemical studies for quantitative estimation of iridoid glycosides in Picrorhiza kurroa Royle. Bot Stud 2016; 57: 7
• 131 Ma S, Wang X, Lai F, Lou C. The beneficial pharmacological effects and potential mechanisms of picroside II: Evidence of its benefits from in vitro and in vivo . Biomed Pharmacother 2020; 130: 110421
• 132 Basu K, Dasgupta B, Ghosal S. Structure of kutkin, the bitter glucoside of Picrorhiza kurroa Royle ex Benth. J Org Chem 1970; 35: 3159-3161
• 133 Singh GB, Bani S, Singh S, Kaul A, Khajuria A, Sharma ML, Gupta BD, Banerjee SK. Antiinflammatory activity of the iridoids kutkin, picroside-I and kutkoside from Picrorhiza kurroa . Phytother Res 1993; 7: 402-407
• 134 Sharma ML, Rao CS, Duda PL. Immunostimulatory activity of Picrorhiza kurroa leaf extract. J Ethnopharmacol 1994; 41: 185-192
• 135 Ray A, Chaudhuri SR, Majumdar B, Bandyopadhyay SK. Antioxidant activity of ethanol extract of rhizome of Picrorhiza kurroa on indomethacin induced gastric ulcer during healing. Indian J Clin Biochem 2002; 17: 44-51
• 136 Verma PC, Basu V, Gupta V, Saxena G, Rahman LU. Pharmacology and chemistry of a potent hepatoprotective compound Picroliv isolated from the roots and rhizomes of Picrorhiza kurroa Royle ex Benth. (kutki). Curr Pharm Biotechnol 2009; 10: 641-649
• 137 Sinha S, Bhat J, Joshi MK, Sinkar VP, Ghaskadbi SS. Hepatoprotective activity of Picrorhiza kurroa Royle Ex. Benth extract against alcohol cytotoxicity in mouse liver slice culture. Int J Green Pharm 2011; 5: 244
• 138 Soni D, Grover A. „Picrosides“ from Picrorhiza kurroa as potential anti-carcinogenic agents. Biomed Pharmacother 2019; 109: 1680-1687
• 139 Mehta S, Sharma AK, Singh RK. Advances in ethnobotany, synthetic phytochemistry and pharmacology of endangered herb Picrorhiza kurroa (Kutki): A comprehensive review (2010–2020). Mini Rev Med Chem 2021; 21: 2976-2995
• 140 Kumari I, Kaurav H, Chaudhary G. Ethnobotanical significance of Picrorhiza Kurroa (Kutki), a threatened species. IJRR 2021; 8: 363-375
• 141 Upadhyay D, Dash RP, Anandjiwala S, Nivsarkar M. Comparative pharmacokinetic profiles of picrosides I and II from kutkin, Picrorhiza kurroa extract and its formulation in rats. Fitoterapia 2013; 85: 76-83
• 142 Chander R, Kapoor NK, Dhawan BN. Picroliv, picroside-I and kutkoside from Picrorhiza kurroa are scavengers of superoxide anions. Biochem Pharmacol 1992; 44: 180-183
• 143 Chander R, Singh K, Visen PK, Kapoor NK, Dhawan BN. Picroliv prevents oxidation in serum lipoprotein lipids of Mastomys coucha infected with Plasmodium berghei . Indian J Exp Biol 1998; 36: 371-374
• 144 Rajkumar V, Guha G, Kumar RA. Antioxidant and anti-neoplastic activities of Picrorhiza kurroa extracts. Food Chem Toxicol 2011; 49: 363-369
• 145 Krupashree K, Hemanth Kumar K, Rachitha P, Jayashree GV, Khanum F. Chemical composition, antioxidant and macromolecule damage protective effects of Picrorhiza kurroa Royle ex Benth. S Afr J Bot 2014; 94: 249-254
• 146 Gupta A, Khajuria A, Singh J, Bedi KL, Satti NK, Dutt P, Suri KA, Suri OP, Qazi GN. Immunomodulatory activity of biopolymeric fraction RLJ-NE-205 from Picrorhiza kurroa . Int Immunopharmacol 2006; 6: 1543-1549
• 147 Hussain A, Shadma W, Maksood A, Ansari SH. Protective effects of Picrorhiza kurroa on cyclophosphamide induced immunosuppression in mice. Pharmacognosy Res 2013; 5: 30-35
• 148 Kumar R, Gupta YK, Singh S, Raj A. Antiinflammatory effect of Picrorhiza kurroa in experimental models of inflammation. Planta Med 2016; 82: 1403-1409
• 149 Picrorhiza kurroa. Monograph. Altern Med Rev 2001; 6: 319-321
• 150 Krishna AB, Manikyam HK, Sharma VK, Sharma N. Single dose oral toxicity study of Picrorhiza kurroa rhizome extract in Wistar rats. Fundam Toxicol Sci 2016; 3: 9-12
• 151 Shityakov S, Bigdelian E, Hussein AA, Hussain MB, Tripathi YC, Khan MU, Shariati MA. Phytochemical and pharmacological attributes of piperine: A bioactive ingredient of black pepper. Eur J Med Chem 2019; 176: 149-161
• 152 Takooree H, Aumeeruddy MZ, Rengasamy KRR, Venugopala KN, Jeewon R, Zengin G, Mahomoodally MF. A systematic review on black pepper (Piper nigrum L.): From folk uses to pharmacological applications. Crit Rev Food Sci Nutr 2019; 59: S210-S243
• 153 Plants of the World Online. Piper nigrum L. Accessed October 20, 2021 at: http://plantsoftheworldonline.org/taxon/urn:lsid:ipni.org:names:682369-1
• 154 Diniz do Nascimento L, Moraes AAB, Costa KSD, Pereira Galúcio JM, Taube PS, Costa CML, Neves Cruz J, de Aguiar Andrade EH, Faria LJG. Bioactive natural compounds and antioxidant activity of essential oils from spice plants: New findings and potential applications. Biomolecules 2020; 10: 988
• 155 Shamkuwar PB, Shahi SR, Jadhav ST. Evaluation of antidiarrhoeal effect of Black pepper (Piper nigrum L.). Asian J Plant Sci Res 2012; 2: 48-53
• 156 Dogra NK, Kumar S, Kumar D. Vernonia anthelmintica (L.) Willd. An ethnomedicinal, phytochemical, pharmacological and toxicological review. J Ethnopharmacol 2020; 256: 112777
• 157 Evans WC. Trease and Evans Pharmacognosy, 16th edition. Edinburgh: Saunders/Elsevier; 2009; 56: 503
• 158 Meghwal M, Goswami TK. Piper nigrum and piperine: An update. Phytother Res 2013; 27: 1121-1130
• 159 Heinrich M, Barnes J, Prieto-Garcia J, Gibbons S, Williamson E. Fundamentals of Pharmacognosy and Phytotherapy. 3rd edition. Oxford: Elsevier; 2018: 45
• 160 Ying X, Chen X, Cheng S, Shen Y, Peng L, Xu HZ. Piperine inhibits IL-β induced expression of inflammatory mediators in human osteoarthritis chondrocyte. Int Immunopharmacol 2013; 17: 293-299
• 161 Sunila ES, Kuttan G. Immunomodulatory and antitumor activity of Piper longum Linn. and piperine. J Ethnopharmacol 2004; 90: 339-346
• 162 Kapoor IP, Singh B, Singh G, De Heluani CS, De Lampasona MP, Catalan CA. Chemistry and in vitro antioxidant activity of volatile oil and oleoresins of black pepper (Piper nigrum). J Agric Food Chem 2009; 57: 5358-5364
• 163 Kim DW, Kim MJ, Shin Y, Jung SK, Kim YJ. Green Pepper (Piper nigrum L.) extract suppresses oxidative stress and LPS-induced inflammation via regulation of JNK signaling pathways. Appl Sci 2020; 10: 2519
• 164 Lin Z, Hoult JRS, Bennett DC, Raman A. Stimulation of mouse melanocyte proliferation by Piper nigrum fruit extract and its main alkaloid, piperine. Planta Med 1999; 65: 600-603
• 165 Venkatasamy R, Faas L, Young AR, Raman A, Hider RC. Effects of piperine analogues on stimulation of melanocyte proliferation and melanocyte differentiation. Bioorg Med Chem 2004; 12: 1905-1920
• 166 Lin Z, Liao Y, Venkatasamy R, Hider RC, Soumyanath A. Amides from Piper nigrum L. with dissimilar effects on melanocyte proliferation invitro . J Pharm Pharmacol 2007; 59: 529-536
• 167 Singh IP. Choudhary A. piperine and derivatives: Trends in structure-activity relationships. Curr Top Med Chem 2015; 15: 1722-1734
• 168 Soumyanath A, Venkatasamy R, Joshi M, Faas L, Adejuyigbe B, Drake AF, Hider RC, Young AR. UV irradiation affects melanocyte stimulatory activity and protein binding of piperine. Photochem Photobiol 2006; 82: 1541-1548
• 169 Faas L, Venkatasamy R, Hider RC, Young AR, Soumyanath A. In vivo evaluation of piperine and synthetic analogues as potential treatments for vitiligo using a sparsely pigmented mouse model. Br J Dermatol 2008; 158: 941-950
• 170 Vinod KR, Anbazhagan S, Santhosha D, Banji O, Banji D, Sandhya S. Effect of UV radiation in the antivitiligo therapy by piperine topical formulation. Arch Appl Sci Res 2010; 2: 165-169
• 171 Shafiee A, Hoormand M, Shahidi-Dadras M, Abadi A. The effect of topical piperine combined with narrowband UVB on vitiligo treatment: A clinical trial study. Phytother Res 2018; 32: 1812-1817
• 172 Mihăilăv B, Dinică RM, Tatu AL, Buzia OD. New insights in vitiligo treatments using bioactive compounds from Piper nigrum . Exp Ther Med 2019; 17: 1039-1044
• 173 Monograph: Black Pepper – Piper nigrum . Accessed June 3, 2022 at: http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monoReq.do?id=2836&lang=eng
• 174 Janakiraman K, Manavalan R. Studies on effect of piperine on oral bioavailability of ampicillin and norfloxacin. Afr J Tradit Complement Altern Med 2008; 5: 257-262
• 175 Acharya SG, Momin AH, Gajjar AV. Review of piperine as a bioenhancer. Am J Pharm Tech Res 2012; 2: 32-44
• 176 Butt MS, Pasha I, Sultan MT, Randhawa MA, Saeed F, Ahmed W. Black pepper and health claims: a comprehensive treatise. Crit Rev Food Sci Nutr 2013; 53: 875-886
• 177 Sharma S, Kalia NP, Suden P, Chauhan PS, Kumar M, Ram AB, Khan IA. Protective efficacy of piperine against Mycobacterium tuberculosis . Tuberculosis 2014; 94: 389-396
• 178 Niu C, Aisa HA. Upregulation of melanogenesis and tyrosinase activity: potential agents for vitiligo. Molecules 2017; 22: 1303
• 179 Zhou J, Shang J, Ping F, Zhao G. Alcohol extract from Vernonia anthelmintica (L.) willd seed enhances melanin synthesis through activation of the p38 MAPK signaling pathway in B16F10 cells and primary melanocytes. J. Ethnopharmacol 2012; 143: 639-664
• 180 Tuerxuntayi A, Liu YQ, Tulake A, Kabas M, Eblimit A, Aisa HA. Kaliziri extract upregulates tyrosinase, TRP-1, TRP2 and MITF expression in murine B16 melanoma cells. BMC Complement Altern Med 2014; 14: 166
• 181 Mamat N, Lu XY, Kabas M, Aisa HA. Potential anti-vitiligo properties of cynarine extracted from Vernonia anthelmintica (L.) Willd. Int J Mol Med 2018; 42: 2665-2675
• 182 Maimaiti Z, Turak A, Aisa HA. Two new compounds from the seeds of Vernonia anthelmintica . J Asian Nat Prod Res 2017; 19: 862-868
• 183 Wang JY, Chen H, Wang YY, Wang XQ, Chen HY, Zhang M, Tang Y, Zhang B. Network pharmacological mechanisms of Vernonia anthelmintica (L.) in the treatment of vitiligo: Isorhamnetin induction of melanogenesis via up-regulation of melanin-biosynthetic genes. BMC Syst Biol 2017; 11: 103-107
• 184 Huo SX, Wang Q, Liu XM, Ge CH, Gao L, Peng XM, Yan M. The effect of butin on the vitiligo mouse model induced by hydroquinone. Phytother Res 2017; 31: 740-746
• 185 Lai Y, Feng Q, Zhang R, Shang J, Zhong H. The great capacity on promoting melanogenesis of three compatible components in Vernonia anthelmintica (L.) Willd. Int J Mol Sci 2021; 22: 4073
• 186 Aobuli A, Maitusong J, Bakri M, Lu X, Maiwulanjiang M, Aisa HA. The effect of volatile oil from Vernonia anthelmintica seeds on melanin synthesis in B₁₆ cells and its chemical analysis by GC-QTOF-MS. Evid Based Complement Alternat Med 2018; 2018: 6291281
• 187 Turak A, Maimaiti Z, Ma HR, Aisa HA. Pseudo-disesquiterpenoids from seeds of Vernonia anthelmintica and their biological activities. Phytochem Lett 2017; 21: 163-168