Reviews 1447

Topically Used Herbal Products for the Treatment of Psoriasis – Mechanism of Action, Drug Delivery, Clinical Studies

Authors Anna Herman1, Andrzej P. Herman 2

Affiliations 1 Faculty of Cosmetology, The Academy of Cosmetics and Health Care, Warsaw, Poland 2 Laboratory of Molecular Biology, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland

Key words Abstract several electronic databases and literature refer- l" Psoriasis ! ences were used to summarize the current l" herbal products Psoriasis is a chronic inflammatory skin disease knowledge acquired on the basis of animal stud- l" keratinocyte hyper- characterized histologically by hyperproliferation ies and clinical trials regarding herbal products proliferation and aberrant differentiation of epidermal kerati- used to treat psoriasis topically. This review dis- l" inflammatory reaction l" skin barrier nocytes. A wide range of conventional medical cusses the mechanisms of herbal products activ- l" herbal drug delivery systems therapies to treat psoriasis is established, from ities through (1) inhibition of the keratinocyte hy- topical therapies and systemic medications perproliferation and inducing apoptosis, (2) inhi- through to phototherapy or combinations of bition of immune-inflammatory reaction, (3) those. However, most of these therapies have a suppression of phosphorylase kinase (PhK) activ- limited efficacy and may cause a number of side ity, and (4) inhibition of the hedgehog (Hh) sig- effects, including cutaneous atrophy, organ toxic- naling pathway. Moreover, the penetration of ity, carcinogenicity, and broadband immunosup- herbal products through the psoriatic skin barrier, pression, which are restricting their long-term novel herbal drug delivery systems in psoriasis use. Therefore, it would be desirable to use herbal treatment, and possible adverse effects of herbal products as an alternative treatment for psoriasis therapy are discussed. that causes fewer side effects. For this purpose,

Introduction treatment of psoriasis causes its remission after ! finishing the treatment or only relieves the pa- Psoriasis is a chronic autoimmune human skin tientʼs condition. Moreover, psoriasis is often ac- disorder that is characterized by excessive prolif- companied by other diseases, such as depressive received May 23, 2016 revised July 31, 2016 eration of keratinocytes, scaly plaques, severe in- illness, cardiovascular disease, and a seronegative accepted August 8, 2016 flammation, and erythema [1]. A wide range of arthritis known as psoriatic arthritis [5]. There- conventional medical therapies to treat psoriasis fore, the invention of new alternative treatments Bibliography This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. DOI http://dx.doi.org/ is established, from topical therapies [steroids, vi- for psoriasis causing fewer side effects would be 10.1055/s-0042-115177 tamin D analogues, psoralen, 5-aminolevulinic desirable. It seems that several herbal drugs can Published online August 30, acid, salicylates, fumaric acid esters, anthralins meet these requirements and have to be seen as 2016 (dithranol), tacrolimus, retinoids – e.g tazarotene] promising new agents for psoriasis treatment [6]. Planta Med 2016; 82: and systemic medications (methotrexate, cyclo- Herbal products are greatly accepted by patients 1447–1455 © Georg Thieme Verlag KG Stuttgart · New York · sporine, retinoids, 6-thioguanine, mycophenolate because they are believed to be safer than conven- ISSN 0032‑0943 mofetil, troglitazone and new biologic agents, tional therapeutics. Moreover, herbal products such as adalimumab, alefacept, efalizumab, eta- present a great structural diversity and multi- Correspondence Anna Herman, PhD, DSc, Prof. nercept, infliximab), through to phototherapy or directional mechanisms of action, which is not Faculty of Cosmetology combinations of those [2]. However, most of these commonly seen in synthetic compounds. Herbal The Academy of Cosmetics and therapies cause a number of side effects, and lim- drugs may become an effective treatment for Health Care Podwale 13 street ited in efficacy, inconvenience, cutaneous atro- psoriasis, causing lower costs and less side- or 00–252 Warsaw phy, organ toxicity (hepatotoxicity, nephrotoxic- toxic effects in comparison to other therapies. Poland ity, teratogenicity), carcinogenicity, and broad- Therefore, researchers are still looking for novel Phone: + 48226355009 Fax: + 482 26357362 band immunosuppression, which are limiting herbal products and/or their active constituents, [email protected] their long-term use [3,4]. In turn, a short-term

Herman A, Herman AP. Topically Used Herbal… Planta Med 2016; 82: 1447–1455 1448 Reviews

which potentially could be used for the treatment of psoriasis in- Proinflammatory cytokines produced by these cells, including tu- stead of synthetic drugs. mor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin- The goal of this review is to summarize the knowledge based on 17 (IL-17), IL-20, IL-22, IL-23, IL-12, and IL-1b, have been linked animal studies and clinical trials regarding herbal products used to the pathogenesis of psoriasis through causing keratinocytes for the topical treatment of psoriasis and to characterize their hyperproliferation [7]. Moreover, IFN-γ and IL-15 seem to in- mechanisms of action. Penetration of herbal products through crease the apoptotic resistance of the keratinocytes [15,16]. Also the psoriatic skin barrier, novel herbal drug delivery systems in growth factors and genetic factors like transforming growth fac- psoriasis treatment, and possible adverse effects of herbal ther- tor (TGF)-β, toll-like receptor (TLR)-2, signal transducer and acti- apy are also discussed. vator of transcription (STAT-3), coiled-coil alpha-helical rod pro- tein 1 (CCHCR1), steroidogenic acute regulatory protein (StAR), and vitamin D receptor (VDR) are suggested to be the most crit- Methods ical factors governing the exacerbation of psoriasis [17,18]. The ! essential transcription factor in psoriasis, nuclear factor kappa B Search strategy (NF-κB), has been shown to be a key regulatory element occur- PubMed, Scopus and Google Scholar were searched for articles ring in a variety of immune and inflammatory pathways, in cellu- published from 1995 up to the present. Search terms included lar proliferation and differentiation, and in apoptosis [19]. An im- “herbal products and psoriasis”, “herbal treatments for psoriasis”, balance between the proapoptotic and antiapoptotic activities of “topical herbal medication for psoriasis”,and“herbal drug deliv- NF-κB proteins has been demonstrated to cause differentiation ery systems in psoriasis treatment”. References from reviews and hyperproliferation in psoriatic lesions rather than in normal about herbal products and psoriasis were examined for addition- cells [20]. al articles and case reports. A manual search was also conducted, based on citations in scientific literature. Topically Used Herbal Products for the Treatment of Psoriasis Inclusion and exclusion criteria Many herbal topical formulations have been marketed world- Selection criteria included articles which are examining herbal wide to prevent psoriasis [21]. There are many advantages of us- products used for the topical treatment of psoriasis by means of ing natural drugs, including patient compliance, less side-effects, animal studies and clinical trials, and are comparing herbal prod- easy availability, low-costs, and more than one mode of biochem- ucts treatment vs. control treatments (placebo or active therapy). ical action for psoriasis treatment. Therefore, researchers are Other forms of psoriasis treatment than topical administration of searching for new herbal products, which have the potential to herbal products (e.g. oral, systemic) were excluded from the be an alternative for synthetic drugs in psoriasis therapy. study. Also publications in languages other than English were ex- cluded. Animal-based studies Herbal products with an anti-psoriasis potential tested in animal- Pathology of Psoriasis based studies are summarized in l" Table 1. Most of the in vivo The pathophysiology of psoriasis involves both skin cells and im- studies performed in animals are based on a mouse tail model of mune cells. Psoriasis is typically characterized as inflamed skin psoriasis, introduced by Jarrett and Spearman [22]. The model is with surface scales, thickening of the epidermis (acanthosis; based on the induction of orthokeratosis in those parts of the granular layer is reduced or absent) caused by parakeratosis, adult mouse tail, which have normally a parakeratotic differenti- which is a consequence of nuclei retention in SC keratinocytes ation. Antipsoriatic drug activity is defined by the percentage in- caused by abnormal differentiation and hyperproliferation of epi- crease of orthokeratotic regions after topical drug treatment of a dermal keratinocytes [1,7]. Some scientific reports consider ni- mouse tail. Ethanolic extract of Aloe vera leaf gel [23], ethanolic tric oxide (NO), released from keratinocytes at high concentra- extract of Nigella sativa [24], ethanolic extract of Rubia cordifolia tions, as a key inhibitor of cellular proliferation and inducer of cell [25], methanol extract of Smilax china and the isolated flavonoid differentiation in vitro. Although a high-output NO synthesis is quercetin [26], Thespesia populne extract [27], hydro alcoholic ex- suggested by the expression of inducible NO synthase (iNOS), tract of Wrightia tinctoria [28], and baicalin isolated from Scutel- mRNA, and proteins in psoriasis lesions, the pronounced hyper- laria baicalensis [29] were assessed for their antipsoriatic activity

proliferation of psoriatic keratinocytes may indicate that iNOS ac- using the mouse tail model. All of them exhibited a significant This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. tivity is too low to effectively deliver antiproliferative NO concen- percentage reduction of relative epidermal thickness, promoted trations [8]. As a consequence, the impairment of corneocyte dif- epidermal differentiation and normal keratization of keratino- ferentiation, including an impaired formation and secretion of cyte, produced significant orthokeratosis, and exhibited a higher lamellar body contents and the processing of lamellar body con- antipsoriatic activity as the positive control (tretinoin 0.05%, ta- tents into lamellar bilayers, causes a reduction in the psoriatic zarotene 0.1%, dithranol 1%, tacrolimus 0.03%, retinoic acid). skin barrier function [9]. Moreover, skin barrier problems in A topically administered ointment containing methanol extract psoriasis are not only the excessive growth and aberrant differen- of Kigelia africana induced a significant and dose-dependent in- tiation of corneocytes but also almost absent normal moisturiz- crease in orthokeratosis in parakeratotic areas of albino mouse ing factors (NMFs) like water, an imbalance of skin lipids (rise in tails, with significant effects on the epidermal thickness com- the levels of cholesterol and fall in the levels of ceramides), and pared to the vehicle control [30]. dry and sensitive skin [10]. Only two studies were based on an UVB-induced model of psori- The role of the immune system and its interactive network of leu- asis. UVB-induced photodermatitis in rats has been proposed as kocytes and cytokines in disease pathogenesis was also described an experimental model for Psoriasis vulgaris by Nagakuma et al. [11,12]. Psoriatic lesions are highly infiltrated with immune cells, [32]. The model is based on the induction of dark-brown scale on most notably CD3+ T cells and CD11c+ dendritic cells [13,14]. the erythematous lesion after UVB irradiation. Singhal and Kan-

Herman A, Herman AP. Topically Used Herbal … Planta Med 2016; 82: 1447–1455 Reviews 1449

Table 1 Herbal products used for the topical treatment of psoriasis – animal studies.

Plant Animal Model of Pharmacological data Effect Ref. the study Cassia tora albino UVB- methanolic C. tora extract (0.05%, 0.1%, 0.2%) in O/W creams; O/W creams with extracts exhibited a [31] mice induced positive control: tretinoin (0.05%) in base cream; significant reduction in percentage of psoriasis treatment: single dose of creams with different concentrations relative epidermal thickness as compared of extract/tretinoin/cream base/crude extract to tretinoin Kigelia albino mouse tail ointments containing 200, 100 and 50 mg/ml of methanol stem methanol extracts induced ortho- [30] africana mice model of extracts from stem, leaves, and fruit of K. africana; keratosis in parakeratotic areas of mouse (sausage psoriasis control: vehicle and placebo; tail with significant effects on epidermal tree) treatment: 0.1 ml of the ointment, contact time of 2–3h, thickness once daily for 2 weeks Nigella sativa albino mouse tail 95% ethanolic extract of N. sativa desolved in water; ratio 1:2; extract produced equivalent epidermal [24] mice model of control: placebo; differentiation in degree of orthokerato- psoriasis positive control: tazarotene gel (0.1%); sis as tazarotene treatment: once daily for 14 days, contact with the skin for 2 h Rubia BALB/c mouse tail ethanolic extract was fractioned sequentially with hexane, EA fraction dose-dependently increased [25] cordifolia mice model of ethyl acetate (EA), n-butanol, and water; granular layer and epidermal thickness; psoriasis 1%, 2% and 5% EA fraction of extract was formulated into gel; potency of keratinocyte differentiation control: placebo; 5% EA fraction is similar to that of dithra- positive control: 1% w/w dithranol in gel; nol gel treatment: twice a day, 7 times a week for 4 consecutive weeks Scutellaria BALB/c mouse tail creams with 1%, 3% and 5% baicalin isolated from S. baicalensis; creams with baicalin inhibit CHS reaction [29] baicalensis mice model of control: placebo; at a less significant magnitude than that psoriasis negative control: 2,4-dinitrofluorobenzene-induced contact of tacrolimus ointment; hypersensitivity (CHS); 5% baicalin cream promotes epidermal positive control 1: 0.1% tazarotene cream; differentiation and normal keratization positive control 2: 0.03% tacrolimus ointment; of keratinocyte in mouse similar to that treatment: twice daily for 4 weeks of tazarotene cream Smilax china Swiss mouse tail methanol extract and isolated flavonoid quercetin; flavonoid quercetin shows significant [26] albino model of positive control: retinoic acid orthokeratosis, anti-inflammatory, and mice psoriasis maximum antiproliferant activities Thespesia Wistar mouse tail cream with 100 mg of each extract (ethanolic, pet-ether, bu- pet-ether extract and TpF-2 increased [27] populne rats model of tanolic, ethyl acetate) and 50 mg of each isolated compound orthokeratotic region psoriasis (TpF-1 and TpF-2 as flavonoids, TpS-2 as sterole); positive control: 0.05% tretinoin cream; treatment: once daily, 5 times a week for 2 weeks Wrightia tinc- albino mouse tail hydro alcoholic extract of W. tinctoria leaves; extract produced significant degree of [28] toria mice model of control: vehicle; orthokeratosis compared to isoretinoic psoriasis positive control: isoretinoic acid; acid and increased the epidermal thick- treatment: once daily for 14 days ness compared to control

sara [31] showed antipsoriatic activities of O/W creams contain- oil [38] showed significantly greater improvements in psoriatic ing methanolic extract of Cassia tora leaves as well as of the crude treatment compared with calcipotriol and fluticasone propionate extract, by using UVB-induced psoriasis in rats. Both of them ex- mixture, hydrocortisone, triamcinolone acetonide, and calcipo- hibited a significant percentage reduction of relative epidermal triol ointment, respectively. In turn, Aloe vera cream [39], Baphi- thickness and spleen index as compared to 0.05% tretinoin as cacanthus cusia ointment [40], Camptotheca acuminata nut ex- positive control. Also irradiated rat skin treated with SUEX GEL tract in tincture/gel/ointment [41], Curcuma longa microemulgel containing aqueous extract of the bark of Pongamia pinnata [42], Hypericum perforatum ointment [43], Indigo naturalis oint- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. showed a significant reduction in the total epidermal thickness ment [44], Indigo naturalis extract in oil [45], Mahonia aquifolium and retention of the Stratum granulosum compared to ointment cream [46], Mahonia aquifolium bark extract ointment [47], Stro- base and placebo group [33]. However, there is no animal model bilanthes formosanus ointment [48], and cream with capsaicin that could replace clinical studies. Moreover, positive results of from Capsicum frutescens [49] were found to be significantly animal-based studies are not always proved in clinical trials. They more effective than the vehicle control group. There are also liter- can only help in the initial determination of new herbal products, ature data showing no significant difference between herbal which may proceed to further stages of clinical trials and become products and drug/placebo treatment. The effect of Mahonia useful drugs for the treatment of psoriasis in the future. aquifolium ointment appears to be less potent than that of dithra- nol [50]. Aleurites moluccana (Kukui nut) oil [51], Aloe vera gel Clinical studies [52], as well as ointment and lotion containing 20% kunzea oil Herbal products with anti-psoriasis potential tested in clinical [53] showed no significant difference compared to a placebo studies are listed in l" Table 2. Topical application of cream with psoriasis treatment. 10% Mahonia aquifolium extract [34], 0.03% Camptotheca acumi- The clinical studies presented in l" Table 2 contain some short- nata nut [35], Aloe vera extract [36], oleoresin from Copeifera comings, which ultimately do not diminish the value of these langsdorffii (5%) ointment [37], and cream with Persea americana limited research works. l" Table 2 reports 10 clinical trials, which

Herman A, Herman AP. Topically Used Herbal… Planta Med 2016; 82: 1447–1455 1450 Reviews

Table 2 Herbal products used for the topical treatment of psoriasis – clinical studies.

Plant Type of clinical study Participants Treatments Effect Ref. Aloe vera placebo-controlled, 60 patients " A. vera extract (0.5%) in hydrophilic A. vera cream had cured 25/30 pa- [39] double-blind clinical (18–50 years) with cream (n = 30); tients compared to the placebo trial slight to moderate " base cream (n = 30); cure rate of 2/30 resulting in sig- chronic plaque psori- 3 times daily (without occlusion) nificant clearing of the psoriatic asis and PASI scores for 5 consecutive days per week for plaques and decreased PASI score between 4.8–16.7 16 weeks to a mean of 2.2 Aloe vera randomized, compara- 80 patients with mild " A. vera cream (70% aloe mucilage) A. vera cream was found to be [36] tive, double-blind clini- to moderate plaque (n = 40); more effective than triamcinolone cal trial psoriasis " 0.1% triamcinolone acetonide cream acetonide cream (n = 40); twice daily for 8 weeks Baphicacan- vehicle-controlled 14 patients with " indigo naturalis ointment significant reduction of psoriasis [40] thus cusia clinical trial chronic plaque (20% B. cusia powder); compared to control psoriasis " vehicle ointment; once daily for 8 weeks Capsicum comparative, vehicle- 44 patients with " cream with capsaicin isolated from capsaicin cream was found to be [49] frutescens controlled, double- moderate to severe C. frutescens; significantly more effective than blind clinical trial psoriasis " vehicle cream; control once a day for 6 weeks Curcuma longa randomized, prospec- 40 patients " turmeric (hydroalcoholic C. longa progressive reduction of thickness, [42] tive intra-individual, (18–60 years) with extract) microemulgel; followed by decrease erythema, right–left comparative, mild to moderate " vehicle; pruritus, resulting in moderate to placebo-controlled, plaque psoriasis twice a day for 9 weeks acceptable improvement; double blind clinical trial in some cases, significant resolu- tion of psoriatic lesions Hypericum per- right–left comparative, 10 patients " H. perforatum (5%) ointment; improvement in clinical scores [43] foratum vehicle- controlled, (20–55 years) with " vehicle ointment; was reported with H. perforatum single blinded (only mild plaque psoriasis twice daily for 4 weeks ointment compared with placebo patients were blinded) group clinical trial Indigo naturalis randomized, vehicle- 31 patients with sym- " refined I. naturalis extract in oil reduction of NAPSI scores for the [45] controlled, observer- metrically compara- (Lindioil); Lindioil group was superior to the blind clinical trial ble psoriatic nails " olive oil; reduction in the control group twice daily for the first 24 weeks Mahonia placebo-controlled, 200 patients with " cream with 10% M. aquifolium significant improvements in PASI [46] aquifolium double-blind clinical mild to moderate extract; and QLI in the Mahonia-treated trial psoriasis " placebo; group compared with the control twice a day for 12 weeks group Strobilanthes randomized, vehicle- 42 patients with " indigo naturalis (1.4%) ointment; 31 of 42 patients experienced [48] formosanus controlled, observer- chronic plaque " vehicle ointment; clearance or near clearance of blind clinical trial psoriasis once a day for 12 weeks psoriasis after herbs ointment treatment Persea randomized, prospec- 13 patients (10 men " cream with vitamin B12 and avocado cream with vitamin B12 and avo- [38] americana tive, right–left compar- and 3 women) with oil; cado oil was effective as calcipo- " (Avocado) ative clinical trial chronic plaque psori- vitamin D3 analog calcipotriol; triol cream with regard to PASI asis twice daily for 12 weeks score

PASI – Psoriasis Area and Severity Index; QLI – Quality of Life Index; NAPSI – Nail Psoriasis Severity Index This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

were carried out on groups consisting of 10–20 patients (3/10), with mild chronic plaque psoriasis (1/10), mild to moderate 30–50 patients (4/10), 60–80 patients (2/10), and more than 100 chronic plaque psoriasis (4/10), moderate to severe chronic patients (1/10). In practice, the first phase of clinical trials in- plaque psoriasis (1/10), and chronic plaque psoriasis without de- volved usually 100–500 participants, because only studies car- termining psoriasis area (4/10) were condensed in clinical trials. ried out with more than 100 patients provide the opportunity Plaque psoriasis, also known as Psoriasis vulgaris, affects about for statistical analyses. Only one of the above described clinical 90% of all cases of psoriasis, which makes the described research trials was performed on 200 subjects. The participants in this potentially useful to treat this type of psoriasis. These clinical randomized, double-blind, placebo-controlled study used either studies included randomized trials (5/10), vehicle-controlled the topical cream Reliéva (a homeopathic product containing a (8/10), comparative (5/10), observer-blind (2/10), single-blind proprietary M. aquifolium extract) or control (placebo) [46]. Oth- (1/10), and double-blind clinical trials (5/10). It is known that on- er clinical trials included a nonrepresentative number of partici- ly well-controlled double-blind clinical trials can prove the effi- pants and therefore the conclusions of these studies cannot be cacy of herbal products in psoriasis treatment. Moreover, such generalized to the entire population affected by psoriasis. More- research is expensive, long lasting and requires a special permis- over, participants (men and women) aged from 18 to 60 years sion from the regulatory authorities. Also compared to multi-

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directional synthetic drug studies, clinical and toxicological stud- topical delivery of capsaicin, to allow for an effective therapy of ies to prove the efficacy and safety of herbal products are rare. psoriasis [69]. Several factors might contribute to the explanation of such dis- crepancies, for example a lack of standardization and quality con- Mechanisms of Action of Herbal Products Used trol of the herbal products used in clinical trials, the use of differ- in Psoriasis Treatment ent dosages of herbal medicines, inadequate randomization in In general, herbal products used in the treatment of psoriasis most studies and an improper selection of patients, the numbers work by (1) inhibition of the keratinocyte hyperproliferation of patients in most trials are insufficient for the attainment of sta- and induction of apoptosis, (2) inhibition of immune-inflamma- tistical significance, wide variations in the duration of treatments tory reactions, (3) suppression of phosphorylase kinase (PhK) ac- using herbal medicines, and lacking or insufficient results of tox- tivity, (4) inhibition of the hedgehog (Hh) signaling pathway. icological studies. Unfortunately, the most of the above-men- A number of studies show that the inhibition of keratinocyte hy- tioned factors can be related to the clinical trials described in perproliferation, induction of apoptosis, and modulation of kera- l" Table 2. tinocyte differentiation have been considered as targets of anti- psoriatic strategies. Animal-based studies support the efficacy of Herbal Products Penetration Through Psoriasis Skin the herbal products for the treatment of psoriasis via inhibition of Novel drug delivery systems such as liposome, niosome, etho- keratinocyte hyperproliferation. The ethanolic extract of Aloe ve- some, microemulsion, nanoemulsion, solid lipid nanoparticles ra leaf gel showed antipsoriatic activity by a significant differen- (SLNs), and nanostructured lipid carrier systems (NLCs) present tiation of the epidermis, seen as orthokeratosis as well as an in- desirable attributes for the use in extremely dehydrated and crease in the relative epidermal thickness when compared with thickened psoriatic skin that has a lipid imbalance and is sensi- the control group in mice [23]. The ethanolic extract of Nigella tive to irritants [54,55]. They offer an enhanced penetration sativa seeds extract produced a significant epidermal differentia- through skin with less toxic effects compared to free drugs (lipo- tion from its degree of orthokeratosis comparable to tazarotene somes), slow down drug release and reduce systemic toxicity gel (0.1%) in albino mice [24]. However, most desired for the (niosomes), enable drugs to reach the deep skin layers and/or treatment of psoriasis are herbal products that inhibit epidermal the systemic circulation (ethosomes), provide long-term stability hyperplasia and inflammation simultaneously. Tuhuai extract re- and high solubilization capacity for hydrophilic and lipophilic duced epidermal hyperplasia and inflammation in normal hair- drugs (microemulsions), prolonge action on the skin and protect less mice, which makes it a valuable drug for treatment of psoria- the drug from instability (nanoemulsions), cause only negligible sis [70]. Baicalin isolated from Scutellaria baicalensis acts by in- skin irritation, and ensure the compatibility of the drugs (NLCs) hibiting inflammatory reactions and inducing the differentiation [54]. Moreover, topical drug delivery systems with herbal formu- of keratinocytes at the same time [29]. Moreover, baicalin cream lations enhance the therapeutic effects of herbal drugs and facili- (5%) promotes epidermal differentiation and normal keratization tate their penetration through the skin [56,57]. of keratinocyte in mouse skin similar to tazarotene cream (0.1%). Studies performed on liposomal vesicles (combination of metho- The flavonoid quercetin from the rhizome of Smilax china shows trexate and menthol) incorporated in vesicular gel base [58], significant orthokeratosis, reduction in epidermal thickness, elastic liposomal formulation of colchicine isolated from Colchi- anti-inflammatory, and maximum antiproliferant activities com- cum autumnale and Gloriosa superb [59], and capsaicin-contain- pared to mice treated with retinoic acid [26]. The treatment of ing liposomes, niosomes and emulsomes [60] confirmed their psoriasis by inhibition of keratinocyte hyperproliferation potential to enhance skin accumulation, prolong drug release, through herbal products was also confirmed in clinical studies. and improve the site-specificity of active constituents as effective Indigo naturalis ointment modulates the proliferation and differ- drugs in the treatment of psoriasis. Niosomes loaded with am- entiation of keratinocytes in the epidermis as well as inflamma- monium glycyrrhizinate from Glycyrrhiza glabra showed no tox- tory reactions by inhibiting the infiltration of T lymphocytes in icity, good skin tolerability and improved the drugʼs anti-inflam- patients with chronic plaque psoriasis [40]. Analysis of biopsies matory activity in mice and human [61]. Psoralen from Fructus taken from patients after I. naturalis ointment treatment showed psoraleae loaded in ethosomes increased the lipid fluidity and that the expressions of proliferating marker Ki-67 and inflamma- cell membrane penetrability, which made it possible to enhance tory marker CD3 were decreased, while differentiation markers, the skin deposition in vitro and in vivo and can be used to cure such as filaggrin, were increased in the epidermis. Moreover, psoriasis [62]. Microemulsion gel-based systems of babchi oil I. naturalis as well its major active constituent induribin inhibited This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. (Psoralea corylifolia) and chitosan-coated microemulsions are a the proliferation and abnormal differentiation of epidermal kera- potential vehicle for the topical delivery of psoralen and tinocytes through decreasing proliferating cell nuclear antigen methoxypsoralen (extracted from Ammi majus) for the treatment (PCNA) and increasing involucrin at both mRNA and protein lev- of psoriasis [63,64]. Microemulsion systems of 5% tea tree oil dis- els in patients with psoriatic lesions [71]. tilled from Melaleuca alternifolia are promising vehicles for a Some studies show that the inhibition of fibroblast-secreted cy- transdermal drug delivery [65]. Skin delivery of nanoemulsion tokines could regulate keratinocyte proliferation and differentia- system loaded turmeric oil (15%) from Curcuma longa [66], nano- tion as well slow down the process of inflammation in psoriasis emulsion O/W containing rice bran oil [67], and nanoemulsion [72]. Ethanolic extracts from Alpinia galanga, Curcuma longa and with glycyrrhetic acid from Glycyrrhiza glabra [68] significantly Annona squamosa showed effects on the downregulation of NF- increased the transdermal permeability of these compounds, κB signaling molecules in the HaCaT keratinocyte cell line, re- showed anti-inflammatory activities and a low irritation poten- flecting their potential use in treating diseases with inflamma- tial, and so can be used for psoriasis treatment. NLCs and SLNs tion and hyperproliferation such as psoriasis [73]. Copeifera showed a good ability to increase the drug accumulation in vari- langsdorffii oleoresin, also known as Copaiba balsam, exhibits an ous skin layers. NLCs may as well be a more potent carrier for the anti-inflammatory activity through inhibiting NF-κB nuclear translocation and secreting proinflammatory cytokines [37]. Pre-

Herman A, Herman AP. Topically Used Herbal… Planta Med 2016; 82: 1447–1455 1452 Reviews

incubation of LPS-stimulated human THP-1 monocytes with in- in O/W creams was safe up to a dose of 2000 mg/kg [31]. More- creasing concentrations of the oleoresin purified fraction re- over, for human safety reasons the assessment of new substances duced the release of proinflammatory cytokines (IL-1β, IL-6, is still evaluated for irritant potentials by application to animals TNF-α) and counteracts LPS-driven NF-κB nuclear translocation. followed by observation of visible changes such as erythema and Water-soluble polysaccharide (GP‑I) purified from Gynostemma oedema [81]. Testing for skin irritation in animals is not always pentaphyllum showed a significant antiproliferative effect and predictive for humans, but is still the most widely used method decreased TNF-α, a vital proinflammatory cytokine in psoriasis in toxicity research for herbal extracts applied topically. It is well [74]. Extracts of Acanthus mollis, Achillea ligustica, Artemisia known that some herbal remedies may cause allergic reactions, arborescens, and Inula viscosa inhibited 5-LOX and COX-1 activity erythema, and edema and several can be responsible for photo- as well as NF-κB activation [75]. Moreover, A. ligustica, sensitization [82,83]. Some herbal preparations can cause organ A. arborescens, and A. mollis increased the biosynthesis of 15(S)- toxicity, hitting liver, kidneys, heart, and other organs [84–86], or HETE, an anti-inflammatory eicosanoid. Herbal products treat- possess cancerogenic properties [87]. Moreover, herbal products ment of psoriasis through inhibition of cytokines was also con- are often mislabeled (unknown purity and standardization of ac- firmed in animal-based studies. The topical application of a mix- tive constituents) and may contain additives or contaminants ture of herbal extracts (Tinospora cordifolia, Curcuma longa, (heavy metals, pesticides) that are not listed in formulation [88– Celastrus paniculatus, Aloe vera) lead to the downregulation of 90]. Some herbal products may interact with conventional drugs overexpressed cytokines in mice, initially induced with psoria- and some are toxic if used improperly or at to high doses [91]. sis-like dermatitis through topical application of imiquimod [17]. Moreover, there are no regulations governing which herbal prod- Some research found that phosphorylase kinase (PhK) enzyme is ucts can be marketed for various ailments as well as no author- expressed on a significantly higher level in psoriatic epidermis as ities register adverse effects [92]. An increasing number of herbal in normal epidermis [76]. PhK integrates multiple calcium/cal- formulation available for sale should prompt governments to in- modulin-dependent signaling pathways including those involved troduce regulations on research which should be carried out be- in cell migration and cell proliferation. Therefore, a modulation of fore such products are released to the market. PhK activity by drugs/herbal products may be an effective treat- ment of psoriasis. Curcumin is a selective PhK inhibitor [77]. It Challenges and Perspectives for the Treatment was observed that the PhK activity was highest in active un- of Psoriasis by Herbal Products treated psoriasis, lower in the calcipotriol and curcumin treated The review of the literature shows that a great growth has taken group, and lowest in normal skin. A decreased PhK activity in place in the worldwide interest in the potential of herbal medi- curcumin and calcipotriol treated psoriasis patients was associ- cines for the treatment of psoriasis over the last 20 years. Parallel ated with corresponding decreases in keratinocyte transferrin re- to various synthetic medicines used topically (corticosteroids, vi- ceptor expression, severity of parakeratosis, and density of epi- tamin D analogues, retinoids) and systemic (methotrexate, reti- dermal CD8+ T cells. noids, cyclosporin), or targeted (biological) therapies (e.g. alefa- Some reports suggest that the Hh pathway is activated in lesional cept, efalizumab, etanercept) also herbal products play an impor- psoriatic skin, and that treatment with the Hh pathway antago- tant role as therapeutic agents for psoriasis treatment [93–95]. nist cyclopamine may lead to a rapid resolution of the disease The long tradition of herbal products used in the treatment of [78]. Cyclopamine isolated from Veratrum californicum was many diseases is not sufficient to consider them as effective and found to be more effective than topical clobetasol-17 propionate safe drugs. To confirm their effectiveness as new promising alter- in the treatment of guttate and plaque type psoriasis [79]. Be- native agent for the therapy of psoriasis a lot of research must be sides, inflammatory cells including CD4+ lymphocytes were performed. Studies showing antiproliferative activity of herbal found to disappear rapidly after the treatment with cyclopamine products and their ability to modulate cell differentiation in as well as hedgehog/smoothened signaling was inhibited. On the HaCaT cell lines [96–101] do not provide sufficient evidence that other hand, some research found that the Hh pathway is not acti- these herbal products will be effective in the treatment of psoria- vated in psoriasis [80]. It was observed that Hh target genes sis. Also promising results obtained in the studies performed on (PTCH1 and GLI1), whose expression is elevated in response to animals are not always consistent with the results of clinical tri- Hh signaling, were downregulated in lesional skin. Therefore, als. Therefore, only well-controlled double-blind clinical trials the proposed use of Hh antagonists as antipsoriatic agents is very and toxicological studies can prove the efficacy and safety of

questionable. herbal products in psoriasis treatment. In general, numerous dif- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. ficulties associated with the evaluation of the efficacy and safety Adverse Effects of Herbal Therapy of herbal medicines, standardization of plant materials, and qual- The risk of adverse events increases with the topical administra- ity of herbal products cause that only a few herbal drugs have tion and the long-term use of herbal-based formulations. Only been approved for clinical applications so far, and finally reach few of the animal-based and clinical studies discussed above in- the market [102]. Unfortunately, until now there are no approved cluded a safety profile of herbal products. No side-effects or ad- herbal drugs dedicated for the treatment of psoriasis. However, in verse events were reported for the psoriasis treatment with my opinion, the great progress in herbal medicine should make it Aleurites moluccana oil [51], Curcuma longa microemulgel [42], possible that the first highly efficient and completely safe herbal Hypericum perforatum ointment [43], Indigo naturalis extract in product designed for the therapy of psoriasis will be available on oil [45], and Strobilanthes formosanus ointment [48] in patients the world market in the near future. Herbal products can make participating in clinical trials. Local adverse events, mainly drying substantial contributions to drug innovation by providing novel up, stinging, and itching of the skin on test areas, were observed chemical structures and/or multidirectional mechanisms of ac- after the topical application of Aloe vera gel [36,52]. The only clin- tion, which are not commonly seen in synthetic compounds. ical trial which verified the possibility of acute dermal toxicity The development of topical drug delivery systems facilitates showed that methanolic Cassia tora leaves extract incorporated plant extract penetration through the skin and enhances the

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