Botanicals in Dermatology: An Evidence-based Review

Juliane Reuter; Irmgard Merfort; Christoph M. Schempp

Disclosures

Am J Clin Dermatol. 2010;11(4):247-267. 

In This Article

2. Inflammatory Skin Diseases

2.1 Atopic Dermatitis

Traditional herbal treatment of atopic dermatitis (AD) has to consider the actual stage of the disease. Acute, oozing eczema is covered (but not occluded) with cold wet packs made from oak bark (Quercus spp.), witch hazel (H. virginiana), black tea (Camellia sinensis), or chamomile (M. recutita) decoctions. In subacute stages and intervals, ointments or creams with antiphlogistic and antipruritic drugs like balloon vine (Cardiospermum halicacabum), bittersweet (S. dulcamara), witch hazel (H. virginiana), or oat straw are recommended. Oils from borage (Borago officinalis) or evening primrose (Oenotherabiennis) are rich in γ-linoleic acid and used for systemic and topical application. Bacterial superinfections are treated topically with chamomile tea or oil from St John's wort (H. perforatum)[23,24] [LOE-D].

2.1.1 Topical Application For most of these traditionally used herbal treatments there is limited evidence from clinical studies (an overview of clinical studies in AD is given in table III). A randomized, partially double-blind study was carried out as a half-side comparison of a cream containing chamomile (M. recutita) extract from the variety 'Manzana' versus hydrocortisone 0.5% cream and the vehicle cream as placebo in 72 patients with medium-degree AD. After 2 weeks of treatment the chamomile cream displayed only a marginal superiority compared with hydrocortisone 0.5% and was not superior to placebo[25] [LOE-A].

Since bacterial colonization plays a role in the pathogenesis of AD, antimicrobial activity of a medical skin care product for AD would be beneficial. Recently, the antimicrobial property of a distillate of witch hazel (H. virginiana) and urea, formulated as a topical dermatologic preparation that contains both active ingredients, has been investigated in vivo by using the simple occlusion test in 15 healthy volunteers. The test revealed a significant antimicrobial activity of the product[46] [LOE-C]. Thus, formulations containing Hamamelis distillate have mainly anti-inflammatory, hydrating, and barrier-stabilizing effects, which may be beneficial in AD maintenance therapy. However, Hamamelis is not efficient enough to treat severe AD, as shown in a randomized, double-blind, paired trial in patients with moderately severe AD. Seventy-two patients were treated with a Hamamelis distillate cream compared with the corresponding drug-free vehicle and hydrocortisone 0.5% cream over a period of 14 days. The Hamamelis preparation was not superior to the vehicle[26] [LOE-A].

In contrast, both antimicrobial activity and therapeutic efficacy have been demonstrated for St John's wort (H. perforatum) extract.[27,47] A medical skin care product in the form of a cream distributed in European countries was tested in a randomized, double-blind, placebo-controlled, half-side comparison study in 28 patients with AD. The efficacy of the Hypericum cream was significantly superior to its vehicle. The skin tolerance and cosmetic acceptability of the Hypericum cream was excellent[27] [LOE-A]. In addition to antimicrobial activity, one possible mode of action of St John's wort and its major metabolite hyperforin might be inhibition of the antigen-presenting capacity of epidermal Langerhans cells[48] [LOE-D].

Another placebo-controlled study with only seven AD patients was performed with Shiunko, a typical Japanese Kampo drug made fromherbal extracts. The clinical effectiveness and the changes in bacterial species and cell numbers on the skin were evaluated in test areas treated with Shiunko, salt water, or petrolatum. Bacterial counts were reduced with Shiunko in four of seven patients (57%) compared with one of seven patients (14%) treated with petrolatum or salt water[28] [LOE-B].

No effect superior to placebo could be demonstrated in the following trials: a randomized, double-blind, placebo-controlled trial with 53 patients with mild to intermediate AD using cream containing sea buckthorn (Hippophae rhamnoides) 20%and 10%[29] [LOE-A]; a randomized, double-blind, placebo-controlled study with 20 AD patients using an ointment containing black seed (Nigella sativa) oil 15%[30] [LOE-A]; and a randomized, double-blind, placebo-controlled, parallel-group trial with 151 AD patients including children investigating the efficacy and tolerability of oral high-dosage treatment with borage oil, which contains a high concentration of γ-linolenic acid[31] [LOE-A].

Besides displaying antimicrobial activity due to berberine and other constituents, Oregon grape root (Mahonia aquifolium) inhibits proinflammatory cytokines. A cream containing Mahonia extract ('psorberine') 10%has recently been evaluated in an open-label trial in 42 adult AD patients treated three times daily over a period of 12 weeks. There was a significant improvement of the Eczema Area and Severity Index score[32] [LOE-B].

An open-label, non-controlled study of 27 children with AD was conducted with an over-the-counter herbal ointment containing 5% of homeopathic mother tinctures of each of the botanicals Oregon grape root (M. aquifolium), pansy (Viola tricolorhortensis), and gotu kola (Centella asiatica). Within the 2- to 4-week observation period, the symptoms resolved completely in 22% of the patients, with an additional 60% reporting marked improvement[33] [LOE-B]. In a previously conducted randomized, double-blind, clinically vehicle-controlled, half-side comparison with 88 adult patients with mild to moderate AD, the same ointment was not superior to the vehicle after 4 weeks of treatment. However, a subanalysis indicated that the cream might be effective under conditions of cold and dry weather[34] [LOE-A].

Glycyrrhetinic acid, as the most important compound from licorice, has been shown to possess pronounced anti-inflammatory activity in tetradecanoylphorbol acetate-induced mouse ear edema[49] [LOE-D]. A standardized extract of licorice (G. glabra) in the form of a 1% and 2% gel has been investigated in the treatment of AD. In a double-blind, vehicle-controlled phase II trial, 2% licorice gel was more effective than 1%gel and the vehicle in reducing the scores for erythema, edema, and itching after 2 weeks of treatment (90 patients; 30 in each group)[35] [LOE-A].

A new phytotherapeutic creamavailable in pharmacies for the treatment of AD contains glycyrrhetinic acid 2%, an extract of the leaves of grape vine (Vitis vinifera), allantoin, and telmesteine (3-ethylhydrogen-3,4-thiazolidine-dicarboxylate). In a small randomized, double-blind, vehicle-controlled trial with 20 subjects, this cream was superior to the vehicle in improving the sodium lauryl sulfate-induced irritant contact dermatitis as measured by parameters such as the transepidermal water loss and blood flow (cited in Abramovits et al.[37]) [LOE-A]. A European, randomized, double-blind, vehicle-controlled, 5-week study of 30 adultADpatients with mild tomoderateADrevealed that this cream is safe and effective in the treatment of AD[38] [LOE-A]. This study was followed by a randomized, multicenter, vehicle-controlled clinical study over a period of 50 days with 218 adult AD patients in the US, which confirmed the results of the pilot study, demonstrating highly significant superiority over placebo in all test parameters[36] [LOE-A]. The efficacy of the same ointment was assessed in 142 children aged 6 months to 12 years in a randomized, vehicle-controlled study. The ointment was applied three times daily to the affected areas. After 22 days the test preparation was statistically more effective than vehicle cream in all endpoints tested[39] [LOE-A].

2.1.2 Oral Administration Oolong tea, a variety of black tea (C. sinensis) orally administered (1000mL divided into three serving sizes per day), seems to be effective in the treatment of recalcitrant AD.[40] In an open-label study conducted over a period of 6 months with 121 patients, 63% of the subjects showed moderate to marked improvement of the skin after 1 month of treatment. Good treatment response was still observed in 54% of the patients after 6 months. The therapeutic efficacy of oolong tea in AD is attributed to the antiallergic properties of the oolong tea polyphenols[40] [LOE-B].

Japanese Kampo medicines have been investigated for efficacy and safety in 95 patients with recalcitrant AD[41] [LOE-C]. The most commonly used Kampo formula was Hochu-ekki-to containing Astragalus root (Astragalus membranaceus), licorice (G. glabra), jujube (Ziziphus zizyphus), ginseng(Panax ginseng), white Atractylodes rhizome (Atractylodes macrocephalae), fresh ginger (Zingiber officinale), andChinese Angelica root (Angelicasinensis). Since Kampomedicines are individually formulated for each patient it was not possible to choose a defined Hochu-ekkito formula as treatment for all types of AD in a randomized controlled study. The outcome of the study with 95 AD patients showed a slight (38% of the patients) to moderate (35% of the patients) or marked effect (20% of the patients) on the suppression of AD. The formula was ineffective in 4% of the patients[41] [LOE-C].

Japanese herbal medicine is thought to be useful as an alternative therapy for intractable AD in association with diet. It has been shown that increased blood eosinophil counts in patients with recalcitrant AD decreased significantly and the serum IgE levels also showed a tendency to decrease after administration of Hochu-ekki-to[42] [LOE-D].

Traditional Chinese herbal medicines (TCHMs) have been used to treat AD for many years and their efficacy has attracted public attention. Several clinical trials have demonstrated the efficacy of TCHMs. Recently, a randomized, double-blind, placebo-controlled trial of 85 children with AD has been conducted with twice-daily dosing of three capsules of either TCHM or placebo for 12 weeks.[43] The daily dose corresponded to 9g of a herbal formula consisting of Lonicerae flos (Jinyinhua) 2 g, Menthae herba (Bohe) 1 g, Moutan cortex (Danpi) 2 g, Atractylodisrhizoma (Cangzhu) 2 g, and Phellodendri cortex (Huangbai) 2 g. The results of this study suggested that the TCHM concoction is efficacious in improving quality of life and reducing topical corticosteroid use in children with moderate to severe AD. However, there was no significant difference in the improvement of symptoms as determined by the SCORing of Atopic Dermatitis (SCORAD) score[43] [LOE-A]. Another double-blind, crossover, placebo-controlled trial investigated a formulation of ten orally administered Chinese medicinal plant extracts (Clematisarmandii, Dictamnus dasycarpus, G. glabra, Ledebouriellasaseloides, Lophatherum gracile, Rehmannia glutinosa, Paeonialactiflora, Potentilla chinensis, Tribulus terrestris, and Schizonepetatenuifolia) in 40 adult patients.[44] Patients had to drink 200mL of a freshly prepared decoction once a day, corresponding to 10g of this blend or to a placebo blend of plants not expected to be helpful for AD. The extent and severity of erythema and surface damage was significantly reduced with the medicinal plant extract compared with placebo. A subjective improvement in itching and sleep was noted during the treatment phase[44] [LOE-A]. The symptoms were significantly improved and stabilized during the 1-year follow-up[50] [LOE-A].

A randomized, double-blind, placebo-controlled trial with 49 patients could not demonstrate that oral administration of a tri-herbal combination of Siberian ginseng (Eleutherococcussenticosus), yarrow (Achillea millefolium), and white deadnettle (Lamium album) in addition to topical treatments has an advantage over placebo in the treatment of AD[45] [LOE-A].

2.1.3 Summary Good scientific data are scarce for most traditionally used botanical treatments of AD, but their application seems justified by long-term clinical experience and theoretical considerations based on their active ingredients. However, their efficacy depends on good knowledge of drug quality, adequate preparation, and correct application. Therefore, it would be desirable for more standardized preparations to be developed and clinically proven. Of the plant species reported here, St John's wort, Oregon grape root, licorice, and some traditional Chinese medicines clearly warrant further study.

2.2 Psoriasis

2.2.1 Plant-derived Standard Therapies Standard psoriasis therapy includes topical preparations containing salicylic acid, originally derived from white willow bark (Salix alba) [see table I]. Salicylic acid is ubiquitously found in plants where it functions as a phenolic phytohormone. Salicylic acid-containing preparations have exfoliative effects on hyperkeratotic skin lesions and are, therefore, beneficial to 'prepare' psoriatic skin for an anti-inflammatory treatment.

One of the most important topical psoriasis treatments is dithranol (in Germany: cignolin, in the US: anthralin). Nowadays synthetically manufactured, dithranol was derived in former days from chrysarobin, a constituent of the bark of the araroba tree (Andira araroba) or goa tree found in the rain forests of the Amazon. Dithranol inhibits the release of proinflammatory cytokines and the growth of keratinocytes. Recently, a randomized multicenter study with 106 patients revealed that topical dithranol, although difficult to use in an outpatient setting, is superior to other established topical psoriasis drugs such as the vitamin D3 analog calcipotriene (calcipotriol) in a day-care setting[51] [LOE-A].

The abnormal growth of keratinocytes is also inhibited by psoralens in combination with UVA irradiation (PUVA). The most potent psoralen is methoxsalen (8-methoxypsoralen or 8-MOP, a furocoumarin from Ammi majus). Psoralens are photosensitizers that occur in different plant families such as Apiaceae, Rutaceae and Moraceae[52] [LOE-D]. While PUVA was widely used as a systemic therapy in the US and Europe, various studies have recently confirmed the antipsoriatic efficacy ofmethoxsalen as a bath additive or creamin combinationwith phototherapy for the topical treatment of psoriasis[53,54] [LOE-A].

Traditional oral treatment of psoriasis with depurative teas has no scientific evidence. The following antipsoriatic drugs are all applied topically.

2.2.2 Topical Application Oregon grape root (M. aquifolium or B. aquifolium) is not only used for the treatment of acne but also for psoriasis.Amonograph on three open-label clinical trials using M. aquifolium cream and a review of earlier clinical data with M. aquifoliumfor the treatment of plaque psoriasis have indicated that this botanical is a safe and possibly effective treatment for patients with mild to moderate psoriasis[55] [LOE-B]. A recent randomized, double-blind, placebo-controlled study in 200 patients yielded statistical proof for the efficacy and safety of a topical Mahonia 10% cream standardized to berberine 0.1% in the treatment of psoriasis, with improvement in the Psoriasis Area and Severity Index (PASI) as well as in the Quality of Life Index[56] [LOE-A] (table IV).

Avocado oil combined with vitamin B12 in a cream has been shown in a randomized, prospective, clinical trial to be equally beneficial as calcipotriene in the topical treatment of psoriasis without any adverse effects, especially with regard to long-term treatment[57] [LOE-A].

A double-blind, placebo-controlled clinical trial with 197 patients has shown that capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), the main ingredient in cayenne pepper (Capsicumfrutensis), applied as a 0.025%creamfour times daily for 6 weeks, significantly decreases symptoms in psoriasis. The psoriasis severity score combined from scaling, thickness, erythema, and pruritus was different between treatment groups from week 4 to week 6 (p = 0.03)[58] [LOE-A]. These observations have already been established in a previous double-blind, placebo-controlled study in 44 patients during a 6-week treatment with topical capsaicin in moderate and severe psoriasis vulgaris; there was no difference in efficacy between 0.01% and 0.025%capsaicin cream but significant superiority of both to placebo[59] [LOE-A]. Transient burning at the site of application was the most frequent adverse effect reported in both trials. However, capsaicin is contraindicated on injured skin and should not be used on the face. Moreover, the duration of application should be limited.

The efficacy of bitter melon (Momordica charantia), another botanical that has been traditionally used for the treatment of psoriasis[66] [LOE-D], has not been proven yet in controlled clinical studies.

Aloe vera (Aloe barbadensis) is utilized as an ingredient in a myriad of health and cosmetic products, principally due to its valuable moisturizing emollient effects. Scientific literature yields conflicting reports on the efficacy of aloe vera in the treatment of psoriasis. A randomized, double-blind, placebo-controlled study with 60 patients treated with aloe vera extract 0.5% in a hydrophilic creamthree times daily for up to 4 weeks showed the cream to be more effective than placebo without any adverse effects. Only 2 of 30 patients in the placebo group, but 25 of 30 in the treatment group, were rated as cured after 4 weeks, and the PASI score decreased from8.9 to 8.2 in the placebo group, and from9.7 to 2.2 under active treatment[60] [LOE-A]. In contrast, another double-blind, placebo-controlled study with 41 patients with slight to moderate psoriasis showed only a modest effect of a commercial, aloin-free aloe vera gel that was not superior to placebo. However, the high response rate of the placebo gel indicated a possible effect of the placebo in its own right, which could havemade the aloe vera gel appear less effective[61] [LOE-A]. The difference may also be due to the presence or absence of aloin, belonging to the anthranoids, which are known to have beneficial effects on psoriasis.

A double-blind, placebo-controlled, pilot study with 30 patients was conducted to determine the effectiveness of the oil of the kukui nut tree (Aleurites moluccana) as a topical treatment for psoriasis. No significant beneficial effect of the oil could be demonstrated [LOE-A], although anecdotal reports existed from psoriasis patients visiting Hawaii who seemed to benefit from topical kukui nut oil.[62]

In the treatment of psoriasis, TCHMs are commonly used. Randomized controlled clinical trials to assess the efficacy of Chinese herbs are difficult to undertake becauseTCHMs, similar to Japanese Kampo medicines, consist of a mixture of herbs individually formulated for oral intake by the patient. The specific combination utilized is often changed over timeaccording to the clinical status of the patient. Therefore, scientific literature yields little with regard to controlled clinical trials to substantiate the effects of those herbalmixtures. However, a great number of uncontrolled studies have been performed with TCHMs in psoriasis. In these trials, a total of 174 Chinese herbs have been used. The ten most commonly used herbs are Rhemannia glutinosa,A. sinensis, Salvia miltiorhiza, D. dasycarpus, Smilaxglabra, Oldenlandia diffusa, Lithospermum erythrorhizon,P. lactiflora, Carthamnus tinctorius, and Glycyrrhiza uralensis. Most of the key actions of these botanicals that are relevant to reducing psoriatic symptoms reflect anti-inflammatory activities, modulation of cytokine production, or inhibition of angiogenesis[67] [LOE-D]. More experimental studies are needed to elucidate the exact mode of action of the specific herbs.

One recent TCHM study investigated the effect of a new Pulian ointment (NPLO), consisting of two primary herbs, Radix Scutellariae (HuangQin) andCortexPhellodendri (Huang Bai). NPLO was applied twice daily in 108 psoriasis patients in addition to individual TCHM oral formulations. The effect of NPLO was assessed in a randomized, single-blind, vehicle-controlled study. After 4 weeks the NPLO was significantly superior (45%clearing) to the vehicle (12%clearing)[63] [LOE-A].

Indigo naturalis (Qing Dai) is a blue powder that is extracted from the stems and leaves of the plant Baphicacanthus cusia. In a prospective, non-randomized, half-side comparison study, indigo naturalis 20% ointment was compared with vehicle in 14 patients with chronic plaque psoriasis. After 8 weeks, marked improvement was seen in 80% of the plaques treated with indigo naturalis, whereas no improvement was seen with the vehicle[64] [LOE-B]. In a subsequent randomized, vehicle-controlled, observer-blind, intra-patient comparison study with 42 patients, these findings were confirmed (about 74% clearing of the indigo-ointment treated lesions)[65] [LOE-A].

India madder root (Rubia cordifolia) is a Chinese herb with antiproliferative properties. There is evidence that induction of apoptosis of keratinocytes is the underlying mechanism for the observed antiproliferative action of Radix Rubiae. Experimental results suggest that this drug is a promising source from which a herb-based topical agent could be developed for the treatment of psoriasis[68] [LOE-D].

2.2.3 Summary There are some promising herbal treatments for psoriasis, which is a difficult-to-treat and chronic disease requiring a number of well tolerated alternatives for individual therapy. In addition to the well established plant-derived molecules, Oregon grape root and capsaicin are interesting candidates, and it is definitely reasonable to conduct more controlled clinical trials to substantiate the positive effects of TCHM in the treatment of psoriasis. However, psoriasiswill require combination rather than monotherapy, and tolerability and cosmetic effects of botanical formulations are nearly as important as their therapeutic potency.

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