Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, 12, 287-302 287 Classical to Current Approach for Treatment of : A Review

Mahfoozur Rahman1,*, Kainat Alam2, Mohammad Zaki Ahmad1, Gaurav Gupta3, Muhammad Afzal3, Sohail Akhter4, Imran Kazmi3,*, Jyoti1, Farhan Jalees Ahmad4 and Firoz Anwar3

1Dreamz College of Pharmacy, Himachal Pradesh, India; 2NIMS University, Jaipur; 3Siddhartha Institute of Pharmacy, Dehradun, Uttarakhand, India; 4Deptt of Pharmaceutics, Jamia Hamdard, New Delhi, India

Abstract: Psoriasis is a genetic predisposition with T-cell mediated autoimmune inflammatory skin disorder, characterized by cutaneous inflammation, increased epidermal proliferation, hyperkeratosis, angiogenesis, and abnormal keratinization that affects up to 2 – 3% of the population worldwide. Common therapies that are used for the treatment of psoriasis include topical, systemic, phototherapy, combination, herbal therapy and novel molecules. Topically used agents include Vit D, calcipotriol, corticosteroids, dithranol and retinoids etc. Systemically used agents include and cyclosporine etc. Phototherapy includes UV-B, Psoralen plus ultraviolet therapy and excimer laser etc. These therapies have a number of potential problems, such as limited in efficacy, inconvenience, organ toxicity, carcinogenic and broad- band . In natural treatment a variety of natural agents such as methanolic extracts of duzhong (Eucommia ulmoides Oliv.), yerba mate (Ilex paraguariensis,) linseed oil, fish oil, and Indigo naturalis etc., that modulates and cytokine action at various steps along with the pathogenic sequence have been developed. But till now there is no more in vivo, dose and its efficacy data has been established. Current therapy includes biologicals, small molecules inhibitor and enzyme inhibitors etc, which serve as novel therapeutic options for psoriasis treatment. All these avoid the side effects of the prebiologically developed systemic agents including hepatotoxicity, nephrotoxicity, and bone marrow suppression. Currently, Denilukin diftitox, , , and are approved by the FDA, and others molecules are at clinical stage. Patents issued by the US office are also included in current psoriasis treatment scenario. In the United States, biologicals are widely used for moderate-to-severe psoriasis. But because of the high cost of and their availability in injection form, it remains to be seen how widely these agents will be utilized worldwide. Still, developing countries prefer conventional drugs. Keywords: Conventional treatment, genetic factor, herbal drugs, novel molecules, patents, psoriasis.

INTRODUCTION include, dry or red patches of skin covered with silvery scales and red boarders. Additional symptoms include skin Psoriasis is the most common chronic and recurrent skin lesions, cracking of skin, inflammation, itching, joints pain, T- cell mediated multifactorial type-1autoimmune disorder. increased tearing in eyes and small scaly dots on the skin It is found generally from the teen age to 20 years. especially in children. In the last few years, it is recognized According to the US National Institute of Health, 2.7% as T-cell mediated/activated inflammatory disease. T-cell population of the world suffers from this disease. In Asia, activation breaks down into three steps 1) activation of T- near about 1% of the population is affected with psoriasis. It cell; 2) the migration of T-cell into the lesion skin; 3) release may affect many parts of the body or all parts of the skin. of cytokines by activated T-cell in the skin [6, 7]. Psoriatic But commonly seen on the skin of the trunk, elbows, knees, cell rich in inflammatory mediators, CD4+, CD8+ T-cell and scalps, in the finger nails and toe nails. Psoriasis may mostly infiltrating T-cell markers such as IL-2, IL-8 and be aggravated by infection, injury, irritation (cuts, burns, TNF-α receptors, resulting in keratinocyte hyperproliferation rashes or insect bites) and in those patients who already have and epidermal cell activation. Earlier, the exact origin of autoimmune disorders such as [1-5]. psoriasis was not well known. Many literatures have shown Healthy skin takes about a month for new skin cells to move predominance of cytotoxic CD8+ T cells in psoriatic lesion up from lower layers to come up on the surface of skin, but epidermis, whereas CD4+ cells are predominant type in psoriasis this process gets completed within few days, in psoriatic dermis. These dermis cells express CD45RO resulting in building up of dead skin cells and formation of on the surface, indicating their effectors/memory status thick scaly layer and induces keratinocyte hyper proliferation, as per psoriasis pathology [1, 8, 9]. Environmental stress, which is a characteristic of psoriasis. Symptoms of psoriasis microorganism/toxin etc, causes stimulation of T cell

receptor by the binding of major histocompatibility complex

(MHC I or II) on the presenting cell (APC), followed *Address correspondence to these authors at the Dreamz College of Pharmacy, by interaction of surface molecules such as CD2 on the T Himachal Pradesh, India; Tel: +91-9625218477; Fax: 911905248600; E-mail: [email protected] and Siddhartha Institute of pharmacy, cell with leukocyte function associated antigen (LFA)-1 on Dehra Dun, India; Tel: +91 8899814066/9690717533; the APC [10]. Over all formation of antigen MHC complexes Fax: 0135 2607784; E-mail: [email protected] with the surface of APCs, interaction with T cell receptors

2212-3873/12 $58.00+.00 © 2012 Bentham Science Publishers 288 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al. and CD4/CD8 co-receptors on the surface of T cells, conventional treatment than topical treatment [29]. resulting in generation of signal 1 for psoriasis [10]. Signal According to the “European Federations of Psoriasis 2, initiated by interactions between CD40 and CD40L, CD28 Association” psoriasis patient survey, among 17,990 patients and CD80, CD28 and CD86, and LFA3 with CD2. Signals 1 only 27% patients show satisfaction with conventional and 2, both are required to complete T cell activation. Its treatment. It is due to severe side effect, time consuming and activation provokes neo-angiogenesis in the dermis and ineffective therapy, which reflects the quality of life [29, 30]. proliferation of keratinocyte [10-12]. Currently, psoriasis is Therefore, from last 10 years, better understanding of firmly established as strong complex genetic background the pathogenesis of psoriasis has led to the development of along with environmental factor. Great progress has been novel molecules with potential fewer side effects. Among made to identify more than twenty genetic risk factors to practicing dermatologists, use of novel molecules such as date. Mostly genes for psoriasis are situated within the major biological, small molecule inhibitors, kinase inhibitors and histocompatibility complex class I region on chromosome -6 phosphodiestrease inhibitors is increasing day by day. Some [13]. Recently it is identified as Class I HLA-CW*0602 novel molecules are available in market and many are alleles. Class I HLA molecules present mostly on intracellular currently undergoing advanced clinical trials and have peptide antigen to CD8+ T cells. ERAPA and PSMA6 are the potential to become available within the next few years. genes which implicated as risk antigen for psoriasis on [1, 31, 32]. CD8+ T- cell [14]. Recently, ZAP70 has been recognized as a risk gene and also associated with carrier of HLA-cw6. TOPICAL TREATMENT ZAP70 gene encodes tyrosine kinase, which ultimately makes threshold for T-cell receptors activation [15]. Topical treatment is the first line treatment approach Dendritic cell and macrophages have played a key role in the prescribed for patients with mild to moderate inflammatory psoriasis, these are found in plenty of psoriatic lesions and disorders. It includes Vitamin D analog, corticosteroids, associated with both Cd4 and CD8 T-cell. Results express dithranol, tars retinoids, , Babchi oil and 8- the inducible isoform of nitric oxide synthase which release methoxypsoralen. Topical treatment reduces potential side large amount of nitric oxide, called as endothelium relaxing effects which are associated with systemic treatments. Skin factor (EDRF). It plays a key role in the regulation of is a site for both biosynthesis and a target organ for vitamin inflammation. Recently, Nos2 genes have been identified D action. Kragballe and kang et al., reported that vit D which encode iNOS, showing increased risk of psoriasis. inhibits keratinocyte differentiation and proliferation by Association of macrophages and dendritic cells with CD4 decreasing the production of -8 (Fig. 1). Its and CD8 T-cell are key sources of various cytokines, limited use in psoriasis is due to hypercalcemia. The active including IL-12, IL-23, TNF- α, β. IL-12 and IL-23. These metabolite of vit D is calcitriol, which is less irritating than inflammatory mediators regulate the generation and other vit D analogs and hence better tolerated for sensitive expansion of T- helper (Th1) cells and Th17/Th22 cells [16- skin like face and flexures. A synthetic analogue of vitamin 20]. Recently, many genetic polymorphisms have identified D is calcipotriol, its mechanism is similar to vit D. in the psoriasis such as IL-12 B, IL23 A and IL23R. All Drawbacks associated with calcipotriol is skin irritation, less these show increased risk of psoriasis. Tumor necrosis penetration in the skin layer and rapid metabolism. To factors α and β, control the transcription of a large number of overcome this problem, a calcipotriol loaded liposome gel pro-inflammatory genes, including REL, NFKBLA, TNIPA, has been reported that increases the amount of calcipotriol TNFAIP3 and FBXL19 and have been identified to accrual in viable epidermis of distorted skin and reduces the the risk of psoriasis. Epidermal structural protein is regulated skin irritation [33-37]. Recently double blind trial of by several genes such as LCE3C, LCE3B, CJB2 (Connexin calcipotriol (50µg/g) once in a day compared with twice in a 26) and SERPINB8 [21-23]. Moreover, other Susceptibility day with calcipotriol/clobetasone and calcipotriol with genes also involved in psoriasis include variants close to the betamethasone, the maximum effectiveness was found to be IL4/IL13 gene network, resulting in Th2/Th1-Th17 polarization in the case of calcipotriol with betamethasone. Topical and inducing (IFN) signaling such as IL28RA, corticosteroids remains the first line treatment for mostly IFIH1 and TYK2. Furthermore, they play a role in regulating mild to moderate plaque psoriasis, possible mechanism is to IL-17 signaling. Recently, more than two non human inhibit the formation of various inflammatory mediators like leukocyte antigen (HLA) related to gene STAT2/IL23A prostaglandin and (Fig. 1). The major problem and TNIP1 have been identified for psoriasis. These is tachyphylaxis, so for its prevention, it is recommended novels findings are beneficial for psoriasis via targeting to be frequently used with other drugs like betamethasone molecules [1, 24-26]. Conventional treatment for psoriasis plus dithranol, PUVA and with calcipotriol. Superpotent includes topical corticosteroids, tars, anthralin, vit D analogs, corticosteroids have been more effective than calcipotriol. tazarotene and salicylic acids. All of these have severe side When Betamethasone 0.1% ointment was compared with effects like hepatotoxicity, nephrotoxicity, associated with calcipotriol 0.005% ointment it resulted in an 86% and 62% methotrexate and cyclosporine, teratogenicity with oral mean reduction in psoriasis area and severity index (PASI) retinoids and skin cancers with photo/ [27, 28]. score respectively [38-40]. Topical dithranol is one of the Another conventional approach is herbal drugs, few in vivo oldest treatments for psoriasis; it produces therapeutic action and safety data have been reported, so more research by acting on IL-receptor of keratinocyte cell. Skin irritation regarding in vivo and its efficacy is needed. According to is one of the demerits associated, which depends on national psoriasis foundation survey only 26% of patients concentration of drug in skin. This problem overcomes in was satisfied with conventional treatment. A survey from two ways, first formulating a novel aqueous gel based UK has found that only 44% of patients prefer systemic liposome-entrapped formulation of dithranol, resulting in Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 289

Cell Membrane

Curcuma longa Corticosteroids _ _ Fish Oil Cytokines

Arachidonic acid COX-2 gene +

Cycloxygenase Lipoxygenase + _

_ Turmeric, Toxin, Stress Zingiber zerumbet Mahonia Prostaglandins Leukotrienes aquifolium

_

Keratinocyte Arginine Hyperproliferation NO + NF-k β + + iNOS

_ + + Rhizoma coptidis, Cytokines Psorolia corylifolia, Complement Eucommia ulmoides, Crotollaria emorglanella, components _ Yarba mate, Curcuma Indigo neutralis, Campotheca longa, Vit D analogues acuminate +

_ _

Fumaric acid Immunosuppressant and _ Biological agents Triptergium wilfordii

Serum Ag-Ab complex

Fig. (1). The various drug targets involved at the molecular level in the psoriasis cascade. better efficacy and tolerability, with respect to conventional the skin and may reduce the systemic toxicity, but major formulation. The second approach is given with calcipotriol disadvantages associated with Acitretin are irritation, and also with UVB [41, 42]. Topical tar is produced by coal erythema, peeling and burning. To overcome this problem, a by using high temperature (900-1200°C). Therapeutic action formulation is developed which explores the potential achieved due to suppression of DNA synthesis, reduces the benefits of nanostructured lipid carriers (NLCs) in improving cell division of basal layer in epidermis. Conventional topical the topical delivery of Acitretin. It was observed that formulations have many limitations, like skin irritation, cloth sustained release of drug for the entire period of study, staining, not confined to affected area and not easily enhanced the patient compliance, improved the therapeutic washable. To overcome this problem a novel formulation- response and reduced adverse effects as compared to the lipid based (lecithinized) self assembled system at micro or application of twice in a day of plain Act gel [45]. nano range, has been designed resulting in the release of the Tretinoin (TTN), is a natural retinoid, widely used in drug at the desired site, cover more affected surface area, various dermatological disorders such as, psoriasis and less irritating, less staining and not spread to uninvolved acne etc. For topical application, skin permeation is one of native tissues [43]. Topical retinoids like Acitretin (Act) or the major limitation, therefore efforts have been made to 13 cis-trans retinoic acid is a metabolite of vitamin A. develop solid lipid nanoparticles (SLNs), which have better Possible mechanism is to inhibit the keratinocyte hyper- permeation, lesser skin irritancy, greater occlusivity and proliferation and differentiation, but it has gained great sustained drug release activity [45]. Topical tazarotene is a potential due to its multitude of physiological effects such as retinoid, which has additional corticosteroid-sparing property. regulation of epithelial cell growth and differentiation, The most common side effect is skin irritation, for prevention, sebum production and collagen synthesis [44]. Oral Acitretin it is used with corticosteroid, resulting in the reduction is indicated for severe psoriasis, but its use is restricted of skin irritation, and skin atrophy, and accelerates the due to systemic side effects and teratogenicity. Topical therapeutic response by synergistic action. Tazarotene 0.1% application of Acitretin enhances local bioavailability in 290 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

Table 1. Topical treatments in psoriasis (reference noted in text).

Drugs Advantages Disadvantages

Vitamin D analogs Effective Short duration of remission necessitates constant treatment. (calcipotriol) Irritant, hypercalcemia.

Corticosteroids Effective Short duration of remission. Risk of cutaneous atrophy and rebound of psoriasis on discontinuation. myelosuppression, alopecia,teratogenic.

Dithranol (anthralin Effective Dithranol stains skin, clothing and skin Irritation.

Tar (crude coal tar) Effective long contact time required. Irritation, unpleasant odor, folliculitis, possible carcinogen.

Retinoids (tazarotene) Effective Irritant, teratogenic, Pruritis.

Calcineurin inhibitors Effective only on thin Should not be used with phototherapy or sun exposure. (tacrolimus) plaques (face and flexures) transient burning sensation

has been reported to have therapeutic effects against the action on nuclear receptor and reduces epidermal psoriasis [46, 47]. Tacrolimus is a immuno- hyperplasia in psoriasis. It is classified into first and second suppressant, biologically it is isolated from the fermentation generation, both are effective against psoriasis. All retinoids broth of Streptomyces tsukubaensis and is highly effective have common side effects including teratogenicity, hyper- against immune-inflammatory disorders [48]. Mechanism lipidemia, elevated liver enzymes and contraindicated in involves the binding of it to cytoplasmic receptor, which is fertile female [54]. To overcome this major problem, an Act FKBP-immunophilin and then associate it with NLCs (Act nanolipid carrier) gel has been developed that and inhibits its phosphates activity, resulting in inhibition of reduces the side effect associated with oral therapy [55]. T-lymphocyte activation (i.e. immunosuppression) [48]. The Etritinate is a second generation and highly lipophilic major adverse effect associated with tacrolimus is burning compound. A double blind placebo controlled trial clears sensation and pruritus at the site of application, risk of psoriasis in between 30-45%, while placebo only clears 6- cutaneous infections and long-term malignancy risk may be 8%. Inside the body, it is metabolized into acitretin which involved [49]. Presently, tacrolimus ointment is available, has the same efficacy like Etritinate, but both cause terato- but it is less effective due to poor penetration in psoriatic genicity. Due to lipophilic nature, it gets deposited in skin. Overall its efficacy is less than corticosteroids [50]. To fat, resulting in increased half life, one of the main reasons overcome from poor penetration problem, Tacrolimus- for producing toxicity [56]. Isotretinion (13-cis retinoic loaded lipid-nanoparticles (T-LN) were prepared, which results in reducing the adverse effect associated with acid) is the only natural retinoid which have oral clinical conventional ointment and highly beneficial in immune- application, but less effective than acitretin in psoriasis inflammatory disorders. Babchi oil (Psoralea corylifolia) is treatment [57]. Liarozole is a chemically synthetic imidazole used for the treatment of psoriasis, because its chief derivative, which inhibits the metabolism of retinoic acid by constituent is psoralen which is a photoactive furocoumarin action on P-450 dependent enzymes. Its side effects are similar to synthetic retinoids [58]. Methotrexate (MTX; 4- that binds to DNA, which form photoproducts with pyrimidine 10 base when exposed to UV light. This action inhibits DNA amino – N methyl pteroylglutamic acid), is a potent synthesis and decreases the keratinocyte hyper proliferation. immune modulating gold standard drug for severe, recalcitrant Poor permeation is a big demerit, may be overcome by psoriasis. It blocks the conversion of dihydrofolate to microemulsion gel which provides improved permeation of tetrahydrofolate, tetrahydrofolate is a cofactor for the the drug through the skin due to the presence of surfactant formation of De Nova synthesis. Recently, new mechanism and co-surfactant in microemulsion and also increase patient has been found, MTX inhibits aminoimidazole carboxamide compliance [51]. Methoxsalen (8-MOP) and its derivatives ribotide transformylase, resulting in accumulation of was used for the treatment of hyperproliferative skin adenosine, which is a T-lymphocyte toxin, which may be diseases, when used along with long wavelength UVA light. responsible for immunosuppressive action. The Methotrexate But due to certain limitations, it was developed into 8-MOP (MTX) can be administered as oral and parenteral routes. microemulsion gel form resulting in drug targeting, efficient However, various side effects including mucosal ulceration, promoter of the 8-MOP localization into the skin, reduces stomatitis, bone marrow suppression, loss of appetite with systemic side effect and increases patient compliance drug induced hepatic fibrosis and cirrhosis can occur [52, 53]. when applied over a long period. To reduce the adverse effects MTX is preferred in topical form, but the presence of stratum corneum does not permeate at required therapeutic SYSTEMIC TREATMENTS concentration to the basal layer of epidermis in order to Retinoid is a vit A, which is available in natural and exert its pharmacological action [59, 60]. To overcome synthetic form. Vit A deficiency in the body causes hyper- this problem, a novel formulation of MTX nanogels drug keratosis of the skin. Retinoid regulates gene transcription by delivery system was designed. Trotta et al., have formulated Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 291 the liposomes using phosphatidylcholine and surfactant available in psoralen plus UVA (PUVA), broadband UVB dipotassium glycyrrhizinate (KG) for dermal administration (BB-UVB), and narrowband UVB (NB-UVB) form and of MTX. The MTX amount permeated across porcine skin excimer laser [66]. UV-B is having a wavelength in the by using KG-containing liposomes showed 3–4-fold higher range of 290-320 nm, mostly it is given with the dose of than that of conventional liposomes [61]. Cyclosporine, is 300-313nm. Shorter wavelength causes erythema, for this an immunosuppressant drug and very effective against reason TL-01 UVB fluorescent tube which gives 83% of the psoriasis. It blocks T-cell activation by binding to cytosolic UV-emission at the 311±2 nm has been developed. Mostly it immunophilin. But it has major side effects, i.e., renal is given with TL-01 UVB± with PUVA. The other attractive impairment and hypertension. For long-term purpose, option is the use of narrow band UVB, which are best cyclosporine is an unattractive option for the patient [62]. tolerating and available at low cost. It lowers the long- term photo carcinogenic risk and is safe in pregnancy. Hydroxyurea, is metabolized in the body to produce a Narrowband (NB)-UVB is mostly applicable for large BSA free radical nitric oxide, which inhibits the DNA synthesis. It (body surface area) patients [67, 68]. Psoralen plus is effective in psoriasis, due to the inhibition of dividing ultraviolet A therapy consists of wavelength 320-400 nm and keratinocyte cell. Its common side effect is bone marrow its therapeutic effect is limited. For enhancing its therapeutic suppression [63]. Fumaric acid is a simple-structured effect, it is mostly given with photosensitizing psoralen dicarbonic acid, widely used in northern Europe for relapsing (PUVA). Antipsoriatic effect is produced due to the and refractory psoriasis. Inside the body it is metabolized to suppression of DNA synthesis by cross linking to DNA produce mono and , both these metabolites strand and conjugate protein. Treatment involves ingestion are called fumaderm which shows antipsoriatic activity. or application of psoralen (5-methoxy psoralen, 8-methoxy Possible mechanisms are: i) inhibiting the production psoralen or trioxalen), applied before UVA irradiation. Dose of proinflammatory cytokines and adhesion molecules of UVA depends on the presence or absence of erythema. expression ii) inhibiting the D-cell differentiation iii) The main drawback of long-term use of PUVA therapy is reducing intracellular free radical generation. Its major side skin cancer like squamous cell carcinoma and malignant effect is gastrointestinal complications [64]. Fish oil contains melanoma. Prevention from that B photo dermatology group both 20- and 22-carbon n-3 fatty acids, eicosapentaenoic acid recommends that exposure of PUVA should be less than (EPA) and docosahexaenoic acid (DHA). EPA can act as a 2 1000 J/cm [69]. In excimer laser, use of monochromatic competitive inhibitor of conversion of arachidonic acid into xenonchloride (excimer) laser and other phototherapeutic PGE2 and LTB4 (Fig. 1). With inhibition of T-cell, IFN-γ appliances, that delivers UVB radiation of 308 nm. Its and IL secretion also gets inhibited. Analogous of n-3 fatty treatment time is much shorter than traditional UVB and acids such as inclusion of the 20-carbon n-9 fatty acid output of the laser is far greater than from a fluorescent tube, eicosatrienoic acid in the diet also resulted in decreased one of the big advantage is that it can be directly focused on synthesis of LTB4. n -3 fatty acids are associated with skin affected area [70, 71]. significant reduction in the release of prostaglandins, leukotrienes B4 (LTB4) from stimulated neutrophil and interleukin 1(IL-1) from monocytes. Both these mediators NATURAL TREATMENT / HERBAL THERAPY play an inflammatory role in the psoriatic event. Benefits Herbal remedies are classical approach. But it has great may be related to the anti-inflammatory effects of fish structural diversity, which is not commonly seen with oil. The special omega-3 fatty acid content of fish oil may synthetic compounds. Different herbal constituents such as reduce abnormal inflammation in bodies, including the alkaloids, steroids, terpenoids, polyphenolics, phenylpro- inflammation connected with psoriasis and/or psoriatic panoids, fatty acids, lipids and various miscellaneous arthritis. Oil rich in EPA and DHA are fish oil, rapeseed oil, compounds, show immunosuppressive and anti-inflamma- walnut (both called as omega-3-egg), flaxseed oil and canola tory activity against psoriasis [72, 73]. It shows action oil. Orally, 1- 8 gm EPA/DHA per day is effective in against immune-inflammatory disorders by the targets on psoriasis and psoriatic arthritis [65]. various mediators like lipoxygenases (LOXs), arachidonic acid (AA) pathway, nitric oxide (NO), NF-kβ [74-76], PHOTOTHERAPY cytokines, chemokines and adhesion molecules (Fig. 1). Phototherapy is used when the involved body surface Herbal treatment includes Eucommia ulmoides Oliv. Yerba area is large and plaques are small and thin. Phototherapy is mate, Indigo naturalis, Curcuma longa, Zingiber officinalis,

Table 2. Systemic treatments in psoriasis (reference noted in text)

Drugs Advantages Disadvantages

Acitretin Effective, except in fertile women Slow onset of action, teratogenicity, and raised plasma lipids.

Methotrexate effective nausea, bone marrow suppression, hepatic fibrosis.

Cyclosporine Rapid action and highly effective Nephrotoxicity, immunosuppression Hypertension.

Hydroxycarbamide (hydroxyurea) effective Bone marrow suppression.

Fumaric acid esters effective GIT complications (flushing episodes, diarrhea) and lymphopenia (Usually mild).

292 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

Momordica charantia and Mahonia aquifolium etc which constituents such as plumbagin, linoleic acid, nonylnonanoate, have been reported against psoriasis. stigmasterol present in it [94]. Thespesia populnea Soland ex. Correa (Malvaceae) Annon et al., has demonstrated that Herbs extracts of duzhong (Eucommia ulmoides Oliv.), decoction of bark is very effective in skin disorder like and yerba mate (Ilex paraguariensis) extracts possess antipsoriatic action, by reducing the secretion of many pro- psoriasis, eczema and scabies. Furthermore, its leaves, flowers and fruits are also effective [95]. Rhizomes of inflammatory cytokines such as tumor necrosis factor-α, Zingiber zerumbet has been used for psoriasis, due to the interleukin (IL)-8, and IL-1b [77-79]. Indigo naturalis (or in presence of constituents such as zerumbone, 3-O-methyl Chinese, qing dai) is a dark-blue powder prepared from kaempferol kaempferol-3-O-(2, 4-di-O-acetyl-a-L-rhamno- leaves of plants such as Baphicacathus cusia, Polygonum pyranoside), that exerts anti inflammatory effect by tinctorium, Isatis indigotica and Indigofera tinctoria. Indirubin and indigo present as constituents inhibit the inhibiting the NO and PGE2 production [96]. Extract of the stem bark of Mahonia aquifolium (Oregon grape), contains hyperproliferation and abnormal differentiation of protoberberine alkaloid which inhibits the lipoxygenase keratinocyte cells [80-83]. Use of indigo naturalis as a novel and lipid hydroperoxide, reducing the growth of human topical ointment shows better therapeutic action against keratinocyte, both these mediators take crucial role for psoriasis [84, 85]. Turmeric is Curcuma longa, its rhizomes psoriasis and other inflammatory disorders (recently it is are widely use in Ayurveda and in traditional Chinese medicine for thousands of years against various filed for patent) [97]. Rind of the Aloe Vera leaf exerts anti- inflammatory, analgesic, antipruritic and wound healing inflammatory disorders. Its main constituent is curcumin, properties. Recently, 0.5% topical Aloe Vera extract cream which mediates antipsoriatic effect by targeting various has been used as an effective remedy for the treatment of transcription factors like (e.g., NF-KB, AP-1, and PPARγ), psoriasis. One of the major findings of this study is, it enzymes (e.g., COX2, 5-LOX, iNOS, and hemeoxygenase- significantly resolved psoriatic plaques and quite effective in 1), cell cycle proteins (e.g, cyclin D1 and p21), cytokines (e.g., TNF, IL-1, IL-6) and cell surface adhesion molecules healing patients suffering from psoriasis vulgaris [98]. Essential oils distilled from L. angustifolia, L. latifolia, L. [86, 87]. Ginger (Zingiber officinalis), also exhibits an stoechas and L.x intermedia have been used to relieve the antipsoriatic action like curcumin, due to the presence of 6- symptoms of skin disorder in psoriasis, dermatitis and gingerol, which is a natural analog of curcumin [88]. Many eczema, without any skin irritation and sensitization [99]. literatures have reported that Momordica charantia is Tuhuai mainly composed of flos sophorae, smilax glabra roxb widely used in the world for the treatment of psoriasis, dysmenorrhea, eczema, emmenagogue, antimalarial, galacta and Liquorice, its topical applications exhibit anti-proliferative and anti-inflammatory activities in psoriasis. It is relatively gogue, gout, jaundice, abdominal pain and kidney stone safe, effective and inexpensive [100]. Radix Angelicae [89]. dahuricae is a Chinese herb, that contain furocoumarins Linné (Compositae) and Asparagus cochinchinensis including imperatorin, isoimperatorin, and alloimperatorin, Merrill (Liliaceae) are traditional herbs, used to treat various which in the presence of UVA irradiation will combine with immune-related inflammatory disorders like psoriasis, the DNA and inhibits hyperproliferation just like psoralen rheumatism etc. Extracts have been found to contain seven compounds. Oral use of Radix Angelicae dahuricae with phytoconstituents including acacetin, apigenin and their ultraviolet light-A irradiation, is more effective than the use derivatives etc, which show anti-inflammatory properties of UVA irradiation alone and have milder side effects as [90]. Berberine is an alkaloid, isolated from Chinese compared to psoralen and UVA [101]. Other traditional medicine Rhizoma coptidis (RC), exerts anti inflammatory Chinese medicines Tripterygium wilfordii Hook and effect in psoriasis and in other inflammatory disorders by Triptergium hypoglaucum Hutch have immunosuppressive significantly inhibiting TNF-α via AP-1 blockade [91]. and anti-inflammatory properties that are effective against Aqueous extract of Hypoxis hemerocallidea Fisch. [‘African psoriasis and eczema with minimal side effects [102]. Potato’], contains phytosterols and sterolins, which show Camptotheca acuminate, is also called cancer tree. It anti-inflammatory, antinociceptive, and antidiabetic properties contains many alkaloids, such as camptothecin, 10-, 11-, or [92]. Taheebo (Tabebuia avellanedae), is an ancient 12-hydroxycamptothecin, 9-, 10- or 11-methoxycamptothecin, medicinal herb and has been used for over 1000 years in the 12-chlorocamptothecin, venoterpin, and deoxycamptothecin. South American rainforest to treat skin inflammatory Topical treatment of Camptotheca acuminate in a 0.03% diseases such as psoriasis, eczema and antifungal diseases concentration shows more anti-psoriatic activity than such as candidiasis, Pyorrhea and athlete’s foot. Mechanisms 1% hydrocortisone [103]. Crotalaria emarginella Vatke underlying for anti-inflammatory activity may block the (Leguminosae), its aerial parts are found to contain two production of NO, PGE2 and suppressed mRNA levels of triterpenes, such as 3a-hydroxy-arbor-12- ene-28-carboxylic COX-II and iNOS. Centella asiatica (L.) is a traditional anti- acid, known as crotalic acid (I), and 2b, 3b, 21-trihydroxy- psoriatic herbal medicine, in which the main constituent is arbor-12-ene-29-carboxylic acid, called as emarginellic acid pentacyclic triterpenes, mainly asiaticoside, madecassoside, (II). Crotalic acid at the dose of 10mg/kg exhibits a asiatic acid and madecossic acid. Recently, many literatures significant anti-inflammatory action in psoriasis [104]. reported pentacyclic triterpenes has been used for the treatment of psoriasis. Aqueous extract of Psoralea CURRENT APPROACH FOR PSORIASIS corylifolia L. (Leguminosae), contains phenolic glycosides which inhibits keratinocytes replication in psoriasis [93]. In the last ten years, researches at the molecular level Extracts of Plumbago zeylanica possess immunosuppressive have enhanced the understanding of immunologic basis of action in immune inflammatory disorders, due to several Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 293 psoriasis. Understanding the pathogenesis of psoriasis has recommends that platelets counts should be checked monthly led to the development and utilization of novel drugs for in the first three months and then on quarterly bases [109]. psoriasis, such as biologicals, small molecules inhibitors, Denilukin diftitox (ontak) is a fusion toxin made from the kinase inhibitors and specifically phosphodiestrease inhibitors. IL-2 gene and the enzymatically active ADP-ribosyltrans- It is administered as I.M or S.C. Presently, many novel ferase domain of diphtheria toxin. It acts on Il-2 receptor and molecules are available in market and many are undergoing thus decrease the number of pathogenic T-cell. The study clinical trials. Biological molecules have potentially fewer was conducted on 24 patients with plaque type psoriasis by side effects. Biological therapies are novel therapeutic administration of 2,4,6,9 mg/kg of Denilukin diftitox by i.v options in the treatment of moderate-to-severe psoriasis, route for five continuous days in a week up to 6 months. In unlike traditional systemic anti-psoriatic drugs, which are the end, Psoriasis Area and Severity Index (PASI) decreased chemically synthesized, these agents are unique in that they by 68% with respect to baseline. At higher dose > 50% are derived from living organisms, mostly these are proteins, reduction in PASI baseline was found in half of all patients. and hence are called ‘‘biologics’’. Highly specific molecular The treatment was associated with some moderate reactions, targets can avoid the side effects of traditional drugs but the most common one observed included fever, molecules including hepatotoxicity, nephrotoxicity and bone asthenia, vomiting and chills [110]. (Zenapax) is marrow suppression [1, 29, 105]. Still the conventional drugs a humanized monoclonal . It is FDA approved such as methotrexate and cyclosporine are being used in for acute renal transplant rejection and is currently under the developing countries. According to the information evaluation for the treatment of psoriasis. It acts against management system (IMS) data, in the United States, CD25, and deactivates the T-cell. In one multicenter study, dermatologists prescribe approximately 95% prescription 19-patients received a dose of 2mg/kg followed by 1mg/kg with novel biological agents, due to the fear of potential side for 8 weeks, in 30% of patient PASI score was less than effects of conventional agents. Recently, many examples earlier. Still no adverse effects associated with the use of such as (Alefacept, Denilukin diftitox and Etanercept etc) are daclizumab are known. Therefore, it acts as an effective currently approved by the United States Food and Drug therapy for patients with moderate to severe psoriasis [111]. Administration (FDA), In addition, some other biological (Simulect) is a chimeric agents such as Basiliximab, Daclizumab, and directed against the CD25 subunit of IL-2 and decreased the etc., are under clinical stage, which have been number of pathogenic T-cell. Till now no large clinical trials discussed below. The adequacy and efficacy of the biological data have been reported, only two cases of severe pustular agents are assessed with the help of psoriasis area and and plaque-type psoriasis have been successfully treated with severity index (PASI). PASI determination is based on the Basiliximab I.V. infusions. Some minor adverse reactions severity of erythema, desquamation as well as the extent of like myalgia were observed in treated patients [112]. Further involvement in four separate body areas. But Biological clinical trials are necessary to truly evaluate the effectiveness agents have only disadvantage i.e., their high cost and their of basiliximab in treating psoriasis. Siplizumab (Medimmune), availability in injection form [1, 29, 106]. is a humanized IgG1 monoclonal antibody, its action is Alefacept (Amevive) is a , consists of directed against CD2 and on decreasing the number of extracellular domain of LFA-3 fused with the CH2 and CH3 pathogenic T-cell. Currently, it is crossing phase II stage and domains of IgG1. It competitively binds to CD2 on T cells to available in the SC injections form. In an open label, dose- block its activation [107]. It was the first biological agent to escalation study, a case study on 26 patients of psoriasis at be approved for the treatment of psoriasis. A case study on the dose of 0.4-40% mg/kg for 8 weeks showed, 75% 553 psoriasis patients at the dose of 7.5mg of I.V bolus reduction from mean base line PASI in 50% of the patients. injection for a 12-week period causes a 75% reduction in Minor adverse reactions like lymphopenia, chills, and base line in 28% of patients after one course of treatment headache have been reported but no severe reactions were and in 40% of patients after second course of treatment. noted. The results of these studies suggest that multiple Clinical trial data shows well toleration without major organ courses of siplizumab may be an effective therapy for toxication and further no rebound occurred after complete psoriasis. Further evaluation on the duration of response treatment [107]. Efalizumab (Raptiva1) is a humanized to this agent and long-term safety data are needed [113]. monoclonal antibody, active against the T-cell surface TNF-α, is a proinflammatory cytokine found in increased molecule CD11a. Binding of efalizumab to CD11a blocks concentration in the joints and skin. Endogenous skin cells the interaction between LFA-1 and intracellular adhesion and activated leukocytes secrete TNF-α, which binds to molecule- 1 (ICAM-1), on the surface of antigen-presenting target receptor and plays an active role in leukocyte cells (APCs), vascular endothelial cells, and keratinocyte, recruitment, migration, and activation, resulting in the resulting in T-cell inhibition [108]. It is approved by the secretion of more cytokines which induce an inflammatory FDA in 2003, and is available as subcutaneous preparation. cascade. The biological agents that block TNF-α, include In the case of 556 patients, at the dose of 1mg/kg for etanercept, , and etc. Etanercept 12-week more than 75% reduction in the base line was (Enbrel1) is a fusion protein composed of two TNF receptor, found. PASI score increased with increased duration which are fused to the Fc portion of human IgG antibody. It of therapy. Unexpectedly, 2 out of 556 patients in the shows action against exogenous TNF receptorws preventing efalizumab safety data base developed thrombocytopenia excess of TNF binding to cell-bound receptors, resulting in (52,000 platelets per ml). No any evidence of organ toxicity reduction in the amount of active TNF and mitigation of was found. Although no definitive causal relationship TNF-mediated diseases, such as rheumatoid arthritis and of efalizumab and thrombocytopenia was known. FDA psoriasis (Fig. 2). In 2002, the FDA approved etanercept for 294 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

ETANERCEPT Pathogens TNF-α ADALIMUMAB TNFR1 INFLIXIMAB

TLR CERTOLIZUMAB

TNFAIP3 BMSS82949 Cell membrane B K

- FBXL19 pathway NF NFKBIA P38

Pro- inflammatory gene transcription

Fig. (2). Nuclear factor (NF-kβ) signal pathway serves as to mediate various inflammatory cascades, including tumor necrosis factor (TNF- α) and TLR signaling, affecting proinflammatory gene transcription which leads to psoriasis. Various novel molecules have been given in boxes. P38 mitogen –activated protein kinase pathway activated by passing signals through TNF-α, resulting in NF-kβ activation. One blocking agent BMS582949, is currently under stage II of clinical trial for psoriasis. psoriatic arthritis. In 2004, etanercept FDA approval was approved Adalimumab against rheumatoid arthritis. A case conducted for psoriasis [114]. A case study on 672 patients study on 148 patients of psoriasis at the dose of 40mg every of psoriasis with the dose of 25mg/kg for every week or 50 week for 12 weeks resulted in 75% reduction from base line mg/kg twice a week after observation showed a 75% PASI in 80% of the patients. As like etanercept, adverse reduction from base line PASI in 44% of the patients at effects are infection and development of anti-nuclear the25mg/kg of every week, 59% of the patients at the [119, 120]. So there is a need of studies for long- 50mg/kg twice a week [115]. Minor adverse effect such as term safety data. Oprelvekin (Neumega), antagonizes the mild-to-moderate injection site reaction was reported, cytokines mediators, currently, it has been at the Ist stage of furthermore, treated patients were at greater risk of clinical trial. Daily subcutaneous injections of 2.5 or 5 mg/kg developing antinuclear antibodies (ANA). At this time, of oprelvekin for 8 weeks reduced the PASI in 11 of 12 United States has widely used biological agent for psoriasis subjects in the range between 20% and 80%. No more [116]. Long-term data has reported that dosing can be adverse effects were observed. But long-term safety data was continuous over the years with good durable responses, needed [121]. RIL-10 (brand name: Tenovil), antagonizes if dosing flexibility offers the added convenience of the different cytokines mediators such as IL-4, IL-10 and IL- self administration at home, and unlike efalizumab and 11. In a small open-label study on 28 patients of psoriasis at etanercept may be discontinued without the risk of rebound the dose of 20 mg/kg s.c three times in a day for 12 week of psoriasis. Infliximab (Remicade) is also a monoclonal causes 35% reduction from baseline PASI. In another study, antibody, and act directly against TNF-a (Fig. 2). Presently, 10 psoriatic patients treated with subcutaneous rIL-10 over a it is available in i.v form. More than 430,000 rheumatoid 7-week period, resulted in improvement in 9 of the 10 arthritis and Crohn’s disease patients have been treated subjects with a mean decrease in PASI by 49% [122]. worldwide [117]. Currently, it is evaluated for the treatment To date, two human anti-p40 antibodies have been of psoriasis and psoriatic arthritis. A multicenter, double- reported against psoriasis, such as ustekinumab (CNTO- blind, placebo controlled trial case study on 249- patient with 1275, Stelara, Centocor, Horsham, PA) and the dose of 3.5mg/kg for 6 weeks was conducted for (ABT-874, Abbott, Abbott Park, IL). Ustekinumab was observation, resulting in 75% reduction from base line PASI recently approved by the United States Food and Drug in 72% of the patients at 3mg/kg, and 88% of the patients at Administration, it acts against p40 subunit. While briakinumab the 5mg/kg. Some minor side effects have been reported is currently at stage III of clinical trials. Ustekinumab such as headache and diarrhoea [118]. Adalimumab (Humira) (CNTO-1275), is a fully human interleukin- 12/23p40 is a fully human monoclonal antibody that act directly monoclonal antibody (Fig. 3). Therapeutically it is more against TNF-a (Fig. 2) [119]. In December 2002, the FDA Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 295 effective against moderate to severe plaque psoriasis. As Enzyme Inhibitors (EIs): Biological agents are main targets compared with other biological agents, clinical output with to soluble cytokines or cellular receptor, but EIs targets Ustekinumab treatment is linked with drug exposure (which the enzyme within a signaling pathway such as tyrosine may be affected by multiple factors, including dose, route of kinase, phosphodiestrese etc. EIs are well suited for oral administration and patient weight). Clinical trial on 903 administration with respect to biological agents and are patients started with dose of 45mg for 4 weeks, and other inexpensive to synthesize. Many EIs are under trial against with 90mg for 4 weeks, 75% reduction was found in psoriasis. EIs include: kinase inhibitors, (JAK), PASI score with 90mg dose. Some adverse reactions were Spleen tyrosine kinase, Mitogen activated protein kinase and observed such as injection site reaction and upper tract Phosphodiestrese inhibitor etc. Kinase inhibitors are serine respiratory infection [123-126]. Briakinumab (ABT874) is a threonine kinase, consisting of 10 isoenzyms. These are fully human monoclonal antibody. It acts against psoriasis by divided into three groups, first is conventional protein targeting on P40 subunit of IL-12 and IL-23. Resulting kinase (α, β II and γ form). Second is novel protein kinase downstream T-cell signal prevent binding of IL with T-cell (δ,ε,ή, and θ form) and the third one is atypical ζ form. (Fig. 3). Unlike ustekinumab, briakinumab is crossing stage All these contributed to several signal transduction cascades II of clinical trial. Multicenter, randomized, double-blinded, [1, 131-134]. Development of PKI named as AEB071 placebo-controlled dose finding trial conducted for an initial (Sotrastaurin), acts on inhibitory activity on 3 PKc isoform 12-week phase, followed by a 36-week. During the initial 12 (PKc θ, PKc α, PKc β). All these are important for T-cell weeks, 180 subjects were randomized into a group of 6 (n = signaling and critical for production of IFN-γ and IL-17. 32 30 per group) and received dose, one 200 mg dose at week 0, patients received 50-600 mg daily for 2 weeks, resulting in 100 mg every other week (EOW) for 12 weeks, 200 mg 69% PASI score [131]. Janus kinase (JAK) is member of weekly for 4 weeks, 200 mg EOW for 12 weeks, 200 mg intracellular signaling molecules that connect to several weekly for 12 weeks, or placebo. The aim of clinical output cytokine receptors and activate the various transcription of this trial was to achieve 75% reduction in psoriatic area pathways. JAK is composed of JAK 1, JAK 2, JAK3 and severity index. At stage III of clinical trial, briakinumab was tyrosine kinase -2. And all these key inflammatory molecules compared with etanercept and methotrexate with a dose of are of great interest in developing novel molecules that 200mg at weeks 0 and 4 followed by 100 mg at 8 week. inhibit all these mediators to resolve the psoriasis [135]. After 12 weeks 75% reduction in their clinical severity JAK-1-2 has a key role in IL and IFN- signaling, JAK-3 found, as measured by the psoriasis area severity index induces signal from IL-2, IL-7, IL-15 and IL-21, all these are (PASI) score (PASI-75) in 81% of the patient. The responsible for T-cell growth. Targeting on these pathways most common adverse event seen in patients receiving lead to the development of novel drugs such as CP-690550, briakinumab was injection site reaction occurring in 16.7%, targeting JAK1 and JAK3. ASP015k targets on JAK3. which is higher as compared to ustekinumab (CNTO-1275). INCB28050, acts on JAK1 and JAK2 [134]. Spleen tyrosine This event occurred in greater frequency with briakinumab kinase is a cytoplasmic tyrosine kinase that is critical (16.7%) versus ustekinumab in trials (1.2%-2%). Naso- for transducing signal for T-cell macrophage, neutrophil pharyngitis and upper respiratory tract infections were also and mast cell function. Fostamatinib is a prodrug, after experienced with briakinumab at greater frequency, followed absorption change into active metabolite, which inhibits by bronchitis and viral infection [123-126]. Currently, at spleen tyrosine kinase. Now it is under stage II of clinical IIIrd stage of clinical trial one major cardiovascular trial of psoriasis [136-138]. Mitogen activated protein kinase event was observed, which was recalled by the FDA. An (MAPK) plays a key role in many inflammatory diseases. alternative approach has been devloped which acts on P19 It is activated by reactive oxygen species (ROS), reactive subunit of IL-23 named as SCH900222, now it is under nitrogen species (RNS) and various growth factor receptors. clinical trial II. Another one is APG 2305 which is composed Its activation further leads to formation of many inflammatory of short sequence of peptide, that inhibits the IL-23 receptors cytokines including TNF-α and apoptosis signal regulating and currently at the stage of phase II trial [123-124]. kinase (ASK1), resulting in activation of p38 pathway via (AIN457), is a fully human antibody against cell division cycle 42 (CDC42). All these inflammatory IL-17A. IL-17 (Fig. 3) is produced by a number of cells such molecules play a role in inducing the keratinocyte hyper- as neutrophils, mast cells, CD8 (TL17) and CD4 (Th17) proliferation in psoriasis. Currently, BMS582949 is T-cell. In phase II stage, 36 patients received single infusion developed, which selectively inhibits p38- mitogen activated of secukinumab at 3mg/kg resulting in 63% reduction in protein kinase (Fig. 2), now it is under II stage of clinical PASI [127, 128]. Another biological agent LY2439821 is trial [1, 139-141]. Epidermal growth factor is composed of 7 a humanized anti-IL17 antibody (Fig. 3), now it is under members and has intrinsic tyrosine kinase activity, 5 clinical trial II. AMG827, is also a fully human antibody members elevated in psoriatic plaque. Erlotinib is tyrosine that blocks the IL-17 receptor and its three isoforms kinase inhibitor, now it is at stage II of clinical trial [142- IL-17A/F. Eight patients received I.V with the dose of 144]. Sphingosine -1- phosphate (SIP) is a lysophospholipid, 700mg, after a week 75% PASI reduction was observed in that mediates inflammation through G-protein coupled S1P 7% out of 8. Currently, it is at stage II of clinical trial [128]. 1-5 receptor, by oxidation of phospholipids. ACT-128800 Among cytokines, Il-22 plays a major role in epidermal and VB-201 were designed as a synthetic anti-inflammatory hyperproliferation. (ILV-094) is anti IL-22 agent. Currently, these are at stage II of clinical trial for monoclonal antibody, which is used during early treatment psoriasis [145-147]. Phosphodiestrese inhibitor; Phospho- of psoriasis [129]. is a humanized diestrese is an isoenzyme (I- IV). Isoenzyme IV plays a monoclonal antibody that acts against TNF-α (Fig. 2). Pegol key role in psoriasis and degrading the cycline adenosine is polyethylene glycol used for increasing its half life [130]. monophosphate (cAMP) in cell, resulting in activation of 296 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

DC

USTEKINUMAB USTEKINUMAB BRIAKINUMAB IL-12 IL 12B IL-23 BRIAKINUMAB SCH900222 IL-12A

IL12RB1 IL2RB1 JAK 2, TYK2 JAK2, TYK2 ALEFACEPT Th1 Th22 Th17 SECUKINUMAB IFN - γ IL - 22 IL - 17A/F LY2439821

Keratinocyte

TRAF3IP2

Nucleus Cell

Pro-inflammatory gene transcription

Fig. (3). Various genes involved in the activation of IL-12/IL-23/IL-17. Novel drugs given in boxes which block, IFN, IL, JAK, TRAF3IP2 etc., resulting in inhibition of pro-inflammatory gene transcription. inflammatory cytokines such as TNF-α, IFN-γ via T-cell 5,527,350 and 5,836,999 described pulse infra red laser activation. Apremilast is a PDE IV inhibitor. During a treatment and electromagnetic radiation used for treating clinical trial 19 patients received 20 mg for 29 days, resulting psoriasis. But the major drawback associated with them is in 74% of patients show an improvement in the PASI score the skin cancer [153, 154]. US patent number 5,858,372 [29, 148]. describes applications of hydrophilic ointment of extract from the leaves of wrightia tinctoria on skin, resulting in PATENT ON PSORIASIS TREATMENT keratolyse of the psoriatic skin part [155]. US patent no 4,772,591 discuses the use of D-glucosamine as in topical US patent number 4,483,845 describes topical agents form which shows antipsoriatic action by the mechanism of such as calcipotriene with salicylic acid effective in removing suppressing the production of cytokines, that resulting in the thick scales in psoriasis [149]. US patent number inhibition of inflammation. Combination of glucosamine 5,719,195 describes 11-cis-retinoic acid 0.001% cream, to with the extract of berberine and oleuropein shows synergetic suppress the inflammation in psoriasis and in combination action and is highly efficacious against moderate to severe with UV light gives more effective action with respect to psoriasis with non toxicity [156]. US patent number itself alone use [150]. US patent number 4,153,572 accounts 6,225,342 accounts on an extract of calendula officinalis on the application of natural sunlight and UV- radiation which shows effective action against psoriasis [157]. US therapy, which are beneficial for treatment of psoriasis [151]. patent number 0165136 discuses herbal composition having Other US patent number 4,558,700 described UVB (280- 1-2% w/w azadirachta indica seed oil, 0.1- 1% w/w linum 320 nm) radiation which is commonly used for the treatment usitatissimum seed oil, 0.5-10.25% w/w vitis vinefera seed of psoriasis and its efficacy improved by coating the skin oil, 0.5-1.25% w/w boswellia serrata gum resin extract, 3-5 with tar, which has emollient prior to the radiation. These % w/w almond oil and 75-80% w/w aloe vera shows agents are used for control of psoriasis, but these have more antipsoriatic activity [158]. But herbal preparation has few side effects than other therapies [152]. US patents number clinical data, and there is need of more research. Now novel Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 297

Table 3. Novel molecules in development of psoriasis.

Novel Molecules Mechanism Clinical Stage Manufacturer

Fezakinumab (Biological agent) Act against IL-22 I/II Pfizer

BMS582949 (small molecule inhibitor) P38 inhibitor II Bristol-Myers squibb

LY2439821(Biological agent) Act against IL-12/23 II Eli lilly

Certolizumab (Biological agent) Act against TNF-α II UCB

Apremilast (small molecule inhibitor) Anti T-cell III Celgene

Voclosporin ( Small molecule inhibitor) Calcineurin inhibitor III Isotechnika

Briakinumab (Biological agent) Act against IL-12/23 Withdrawn Abbott

Alefacept (Biological agent) Anti T- cell Approved Astellas

Infliximab (Biological agent) Act against TNF-α Approved Centocor

Adalimumab (Biological agent) Act against TNF-α Approved Abbott

Ustekinumab (Biological agent) Anti-IL-12/23 Approved Centocor

Etanercept (Biological agent) Anti TNF Approved Amgen

Fostamatinib (Small molecule inhibitor) Spleen tyrosine kinase inhibitor II A/Z Rigel

SCH900222 ( Biological agent) Act against IL-23 II Sanofi Pasteur MSD

Erlotinib (Small molecule inhibitor) Anti-EGFR II OSI Pharmaceuticals

APG2305 (Small molecule inhibitor) Antagonist of IL-23 receptor II Allostera pharma

AIN457 (Biological agent) Anti-IL-17 II Novartis

RWJ-445380 (Small molecule inhibitor) Cathepsin inhibitor II Johnson and Johnson

CP690,550 (Small molecule inhibitor) JAK inhibitor III Pfizer

AEB071 (Small molecule inhibitor) PKC inhibitor II Novartis

biologics gain popularity, US patents no 6,569,664 and plaques covered by salivary micaceous scale and epidermal 6,593,456 describe enbrel (etanercept), which is a chimeric hyper proliferation, leading to profound adverse effects on molecule, and it is a better therapeutic option for treatment of patient’s physical, social and mental well-being. Conventional psoriasis [159, 160]. US patents no 5,656,272 and 6,090,382 therapies including, topical therapies, calcipotriene, have discussed about TNF-α inhibitor like as infliximab, corticosteroids, tar, anthralin, ultraviolet B radiation (UVB) CDP571, CDP870 (a humanized monoclonal anti TNF- α and methoxsalen (psoralen) with ultraviolet A radiation IgG4 antibody fragment), CNT0148 (), and (PUVA) are commonly used. Systemic treatment includes adalimumab [161, 162]. Moreover, US patent no 6,593,458 drugs like methotrexate, cyclosporine and acitretin. Treatment describes lenercept and recombinant TNF binding protein with topical steroids suppresses the body’s such as r-TBP-I (serono) against psoriasis [163]. US patent when used for prolonged period of time, whereas other no 7,147,854 discuses about the antibodies which act systemic drugs like methotrexate and cyclosporine etc., can against IL-8, resulting in inhibition of keratinocyte hyper- impair vital organs, like liver and kidney functions. Another proliferation in psoriasis [164]. US patent no 6, 709, 654, treatment approach is herbal therapy. It presents great describes different monoclonal antibodies such as 7B6, structural diversity, which is not commonly seen in synthetic 16C10, 7C10 and 20C9. All these inhibit the B7:CD28 compounds. But very few researches have been done with pathway in autoimmune disease, resulting in keratinocyte herbal therapy in respect of in vivo, dose and efficacy, so hyperproliferation and decrease in psoriasis [165]. All these herbal therapy needs deep research to establish its efficacy biologicals are very effective against psoriasis and few and safety. Currently, novel molecules such as alefacept, insignificant adverse effects seen during clinical trials. efalizumab, etanercept, infliximab, ampremilast and adalimumab etc., are precisely targeted to interfere with the CONCLUSION pathogenesis of psoriasis. Further, clinical studies suggest these agents have good clinical efficacy and safety. The Psoriasis is a gene and immune mediated inflammatory relative efficacy of these novel agents when compared to skin disorder, affecting millions of people worldwide. conventional systemic agents, such as methotrexate and Clinically, it is characterized by erythematous, rounded cyclosporine etc, has been the subject of much speculation. 298 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

Even though there are no head-to-head comparisons Anwar, F. (2012) Insight into the Biomarkers as the Novel Anti- regarding their efficacy, alefacept appears to be safe as it has Psoriatic Drug Discovery Tool: A Contemporary Viewpoint. Curr. Drug Discov. Technols., 9, 48-62. no convincing side effects when given in depot injection. But [2] Lebwohl, M. (2003) Psoriasis. Lancet, 361, 1197-1204. still, long-term safety data is not yet available. Efalizumab [3] Krueger, J.G. (2002) The immunologic basis for the treatment of shows slightly better efficacy than alefacept. Developed psoriasis with new biologic agents. J. Am. Acad. Dermatol., 46, 1-23. countries like United States, utilize novel molecules. The [4] Christophers, E. (2001) Psoriasis epidemiology and clinical main reason for underutilization of prebiologically systemic spectrum. Clin. Exp. Dermatol., 26, 314-320. [5] Greaves, M.W. and Weinstein, G.D. (1995) Treatment of psoriasis. agents is the fear of major organ toxicity. Overall, the N. Engl. J. Med., 332, 581-588. introduction of novel molecules is the best hope as systemic [6] International psoriasis council IPC. Psoriasis Review, Focus on agents in treating moderate- to-severe psoriasis. Although it Asia-pacific, May 2010. is quite early to say about these agents how effective and [7] Nickoloff, B.J.; Xin, H.; Nestle, F.O. and Qin, J.Z. (2007) The cytokine and chemokines network in psoriasis. Clin. Dermatol., 25, safe they will be, and where they will fit into treatment 568-573. algorithms, it is evident that our range of options in treating [8] Res, P.C.; Piskin, G.; de Boer, O.J.; van der Loos, C.M.; Teeling, this often perplexing disease will greatly increase in future. P.; Bos, J.D. and Teunissen, M.B. (2010) Overrepresentation of IL- If the above mentioned herbal drugs are properly evaluated 17A and IL-22 producing CD8 T cells in lesional skin suggests in terms of efficacy, molecular mechanism and dose, then it their involvement in the pathogenesis of psoriasis. PLoS One, 5, e14108. may be possible in future to get an effective treatment for [9] Bos, J.D.; Hagenaars, C.; Das, P.K.; Krieg, S.R.; Voorn, W.J. and psoriasis with low cost, which will be very beneficial Kapsenberg, M.L. (1989) Predominance of "memory" T cells worldwide. (CD4+, CDw29+) over "naive" T cells (CD4+, CD45R+) in both normal and diseased human skin. Arch. Dermatol. Res., 281, 24-30. [10] Takai, T.; Nakamura, A. and Akiyama, K. (2003) Fc receptors as CONFLICT OF INTEREST potential targets for the treatment of allergy, autoimmune disease and cancer. Curr. Drug Targets Immun. Endocr. Metabol. Disord., The author(s) confirm that this article content has no 3, 187-197. conflicts of interest. [11] Wingren, A.G.; Parra, E.; Varga, M.; Kalland, T.; Sjögren, H.O.; Hedlund, G. and Dohlsten, M. (1995) T cell activation pathways:. B7, LFA-3, and ICAM-1 shape unique T cell profiles. Crit. Rev. ACKNOWLEDGEMENT Immunol., 15, 235-253. [12] Racke, M.K. and Stuart, R.W. (2002) Targeting T cell Declared none. costimulation in autoimmune disease. Expert Opin. Ther. Targets, 6, 275-289. [13] Elder, J.T.; Bruce, A.T.; Gudjonsson, J.E.; Johnston, A.; Stuart, ABBREVIATIONS P.E.; Tejasvi, T.; Voorhees, J.J.; Abecasi,s G.R. and Nair, R.P. AA = Arachidonic acid (2010) Molecular dissection of psoriasis: integrating genetics and biology. J. Invest. Dermatol., 130, 1213-1226. AP-1 = Activator protein-1 [14] Genetic Analysis of Psoriasis Consortium & the Wellcome Trust Case Control Consortium 2.; Strange, A.; Capon, F.; Spencer, C.C.; CD = Cluster of differentiation molecule Knight, J.; Weale, M.E.; Allen, M.H.; Barton, A.; Band, G.; Bellenguez, C.; Bergboer, J.G.; Blackwell, J.M.; Bramon, E.; COX = Cyclopxygenase Bumpstead, S.J.; Casas, J.P.; Cork, M.J.; Corvin, A.; Deloukas, P.; DHA = Docosahexaenoic acid Dilthey, A.; Duncanson, A.; Edkins, S.; Estivill, X.; Fitzgerald, O.; Freeman, C.; Giardina, E.; Gray, E.; Hofer, A.; Hüffmeier, U.; EPA = Eicosapentaenoic acid Hunt, S.E.; Irvine, A.D.; Jankowski, J.; Kirby, B.; Langford, C.; Lascorz, J.; Leman, J.; Leslie, S.; Mallbris, L.; Markus, H.S.; FKBP = FK-binding protein Mathew, C.G.; McLean, W.H.; McManus, R.; Mössner, R.; Moutsianas, L.; Naluai, A.T.; Nestle, F.O.; Novelli, G.; IFN = Interferon Onoufriadis, A.; Palmer, C.N.; Perricone, C.; Pirinen, M.; Plomin, R.; Potter, S.C.; Pujol, R.M.; Rautanen, A.; Riveira-Munoz, E.; IL = Interleukin Ryan, A.W.; Salmhofer, W.; Samuelsson, L.; Sawcer, S.J.; iNOS = Inducible nitric oxide synthase Schalkwijk, J.; Smith, C.H.; Ståhle, M.; Su, Z.; Tazi-Ahnini, R.; Traupe, H.; Viswanathan, A.C.; Warren, R.B.; Weger, W.; Wolk, LOX = Lipoxygenase K.; Wood, N.; Worthington, J.; Young, H.S.; Zeeuwen, P.L.; Hayday, A.; Burden, A.D.; Griffiths, C.E.; Kere, J.; Reis, A.; LT = Leukotrienes McVean, G.; Evans, D.M.; Brown, M.A.; Barker, J.N.; Peltonen, L.; Donnelly, P. and Trembath, R.C. (2010) A genome-wide a LTB4 = Leukotrienes B4 ssociation study identifies new psoriasis susceptibility loci and NF-kB = Nuclear factor-kB an interac- tion between HLA-C and ERAP1. Nat. Genet., 42, 985-990. NO = Nitric oxide [15] Picard, C.; Dogniaux, S.; Chemin, K.; Maciorowski, Z.; Lim, A.; Mazerolles, F.; Rieux-Laucat, F.; Stolzenberg, M.C.; Debre, M.; PASI = Psoriasis area and severity index Magny, J.P.; Le Deist, F.; Fischer, A. and Hivroz, C. (2009) Hypomorphic mutation of ZAP70 in human results in a late onset PG = Prostaglandins immunodeficiency and no autoimmunity. Eur. J. Immunol., 39, 1966-1976. PGE2 = Prostaglandin E2 [16] Fuentes-Duculan, J.; Suárez-Fariñas, M.; Zaba, L.C.; Nograles, TNF-a = Tumor necrosis factor-a K.E.; Pierson, K.C.; Mitsui, H.; Pensabene, C.A.; Kzhyshkowska, J.; Krueger, J.G. and Lowes, M.A. (2010) A subpopulation o f CD163-positive macrophages is classically activated in psoriasis. J. REFERENCES Invest. Dermatol., 130, 2412-2422. [17] Lowes, M.A.; Chamian, F.; Abello, M.V.; Fuentes-Duculan, J.; [1] Rahman, M.; Zaki, A.M.; Kazmi, I.; Akhter, S.; Beg, S.; Gupta, G.; Lin, S.L.; Nussbaum, R.; Novitskaya, I.; Carbonaro, H.; Cardinale, Afzal, M.; Saleem, S.; Ahmad, I.; Adil, S.M.; Jalees, A.F. and I.; Kikuchi, T.; Gilleaudeau, P.; Sullivan-Whalen, M.; Wittkowski, Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 299

K.M.; Papp, K.; Garovoy, M.; Dummer, W.; Steinman, R.M. and Results of a 1998 Natl Psoriasis Foundation Patient-Membership Krueger, J.G. (2005) Increase in TNF-alpha and inducible nitric Survey. Arch. Dermatol., 137, 280-284. oxide synthase-expressing dendritic cells in psoriasis and reduction [30] Richards, H.L.; Fortune, D.G.; O'Sullivan, T.M.; Main, C.J. and with efalizumab (anti-CD11a). Proc. Natl. Acad. Sci. USA, 102, Griffiths, C.E. (1999) Patients with psoriasis and their compliance 19057-19062. with medication. J. Am. Acad. Dermatol., 41, 581-583. [18] Abramson, S.B.; Amin, A.R.; Clancy, R.M. and Attur, M. (2001) [31] Schafer, P.H.; Parton, A.; Gandhi, A.K.; Capone, L.; Adams, M.; The role of nitric oxide in tissue destruction. Best Pract. Res. Clin. Wu, L.; Bartlett, J.B.; Loveland, M.A.; Gilhar, A.; Cheung, Y.F.; Rheumatol., 15, 831-845. Baillie, G.S.; Houslay, M.D.; Man, H.W.; Muller, G.W. and [19] Bettelli, E.; Carrier, Y.; Gao, W.; Korn, T.; Strom, T.B.; Oukka, Stirling, D.I. (2010) Apremilast, a cAMP phosphodiesterase-4 M.; Weiner, H.L.; Kuchroo, V.K. (2006) Reciprocal developmental inhibitor, demonstrates anti-inflammatory activity in vitro and in a pathways for the generation of pathogenic effector TH17 and model of psoriasis. Br. J. Pharmacol., 159, 842-855. regulatory T cells. Nature, 441, 235-238. [32] Mellor, H. and Parker, P.J. (1998) The extended protein kinase C [20] Zaba, L.C.; Cardinale, I.; Gilleaudeau, P. and Sullivan-Whalen, M. superfamily. Biochem. J., 332, 281-292 (2007) Suarez-Farinas M, Fuentes-Duculan J, et al. Amelioration o [33] Kragballe, K. and Wildfang, I.L. (1990) Calcipotriol (MC 903), a f epidermal hyperplasia by TNF inhibition is associated with novel vitamin D3 analogue, stimulates terminal differentiation and reduced Th17 responses. J Exp. Med., 204, 3183-3194. inhibits proliferation of cultured human keratinocytes. Dermatol. [21] de Cid, R.; Riveira-Munoz, E.; Zeeuwen, P.L.; Robarge, J.; Liao, Res., 282, 164-167. W.; Dannhauser, E.N.; Giardina, E.; Stuart, P.E.; Nair, R.; Helms, [34] Kragballe, K.; Gjertsen, B.T. and de Hoop, D. (1991) Calcipotriol, C.; Escaramís, G.; Ballana, E.; Martín-Ezquerra, G.; den Heijer, a novel principle in the treatment of psoriasis vulgaris, results of a M.; Kamsteeg, M.; Joosten, I.; Eichler, E.E.; Lázaro, C.; Pujol, double-blind, multicenter, right-left comparison with betamethasone R.M.; Armengol, L.; Abecasis, G.; Elder, J.T.; Novelli, G.; 17-valerate. Lancet, 337, 193-196. Armour, J.A.; Kwok, P.Y.; Bowcock, A.; Schalkwijk, J. and [35] Kragballe, K.; Barnes, L.; Hamberg, K.J.; Hutchinson, P.; Murphy, Estivill, X. (2009) Deletion of the late cornified envelope LCE3B F.P.; Ruzicka, T. and Van de Kerkhof, P.C.M. (1998) Calcipotriol and LCE3C genes as a susceptibility factor for psoriasis. Nat. cream with or without concurrent topical corticosteroid in psoriasis, Genet., 41, 211-215. tolerability and efficacy. Br. J Dermatol., 139, 649-654. [22] Stuart, P.E.; Nair, R.P.; Ellinghaus, E.; Ding, J.; Tejasvi, T.; [36] Masuda, S. and Jones, G. (2003) Vit D analogues drug design Gudjonsson, J.E.; Li, Y.; Weidinger, S.; Eberlein, B.; Gieger, C.; based on protein involved in Vit D signal transduction. Curr. Drug Wichmann, H.E.; Kunz, M.; Ike, R.; Krueger, G.G.; Bowcock, Target Immun. Endocr. Metab. Disord., 3, 43-66. A.M.; Mrowietz, U.; Lim, H.W.; Voorhees, J.J.; Abecasis, G.R.; [37] Kang, S.; Griffiths, C.E.M.; Fancher, L.; Hamilton, T.A. and Choi, Weichenthal, M.; Franke, A.; Rahman, P.; Gladman, D.D. and J.H. (1998) Calcipotriene-induced improvement in psoriasis is Elder, J.T. (2010) Genome-wide association analysis identifies associated with reduced interleukin-8 and increased interleukin-10 three psoriasis susceptibility loci. Nat. Genet., 42, 1000-1004. levels within lesions. Br. J. Dermatol., 138, 77-83. [23] Tejasvi, T.; Stuart, P.E.; Nair, R.P.; Voorhees, J.J. and Elder, J.T. [38] Molin, L.; Cutler, T.P.; Helander, I. and Nyfors, B.D.N. (1997) (2012) TNFAIP3 Gene Polymorphisms Are Associated with Comparative efficacy of calcipotriol (MC903) cream and Response to TNF Blockade in Psoriasis. J. Invest. Dermatol., 32, betamethasone 17-valerate cream in the treatment of chronic plaque 593-600. psoriasis. A randomized doubleblind, parallel group, multicenter [24] Sun, L.D.; Cheng, H.; Wang, Z.X.; Zhang, A.P.; Wang, P.G.; Xu, study. Br. J. Dermatol., 136, 89- 93. J.H.; Zhu, Q.X.; Zhou, H.S.; Ellinghaus, E.; Zhang, F.R.; Pu, X.M.; [39] Austad, J.; Bjerke, J.R.; Gjertsen, B.T.; Helland, S.; Livden, J.K.; Yang, X.Q.; Zhang, J.Z.; Xu, A.E.; Wu, R.N.; Xu, L.M.; Peng, L.; Morken, T. and Mork, N.K. (1998) Clobetasol propionate followed Helms, C.A.; Ren, Y.Q.; Zhang, C.; Zhang, S.M.; Nair, R.P.; by calcipotriol is superior to calcipotriol alone in topical treatment Wang, H.Y.; Lin, G.S.; Stuart, P.E.; Fan, X.; Chen, G.; Tejasvi, T.; of psoriasis. J. Eur. Acad. Dermatol. Venereol., 11, 19-24. Li, P.; Zhu, J.; Li, Z.M.; Ge, H.M.; Weichenthal, M.; Ye, W.Z.; [40] Lebwohl, M. (1997) Topical application of calcipotriene and Zhang, C.; Shen, S.K.; Yang, B.Q.; Sun, Y.Y.; Li, S.S.; Lin, Y.; corticosteroids, combination regimens. J. Am. Acad. Dermatol., 37, Jiang, J.H.; Li, C.T.; Chen, R.X.; Cheng, J.; Jiang, X.; Zhang, P.; S55-S58. Song, W.M.; Tang, J.; Zhang, H.Q.; Sun, L.; Cui, J.; Zhang, L.J.; [41] Seville, R.H. (1976) Relapse rate of psoriasis worsened by adding Tang, B.; Huang, F.; Qin, Q.; Pei, X.P.; Zhou, A.M.; Shao, L.M.; steroids to a dithranol regimen. Br. J. Dermatol., 95, 643-646. Liu, J.L.; Zhang, F.Y.; Du, W.D.; Franke, A.; Bowcock, A.M.; [42] Farkas, A.; Keemeny, L.; Szony, B. J.; Bata-Csorgo, Z.; Pivarcsi, Elder, J.T.; Liu, J.J.; Yang, S. and Zhang, X.J. (2010) Association A.; Kiss, M.; Szell, M.; Koreck, A. and Dobozy, A. (2001) analyses identify six new psoriasis susceptibility loci in the Chinese Dithranol upregulates IL-10 receptors on the cultured keratinocyte population. Nat. Genet., 42, 1005-1009. cell line HaCaT. Inflamm. Res., 2001, 50, 44-49. [25] Australo-Anglo-American Spondyloarthritis Consortium (TASC).; [43] Williams, R.E.; Tillman, D.M.; White, S.I.; Barnett, E.L. and Reveille, J.D.; Sims, A.M.; Danoy, P.; Evans, D.M.; Leo, P.; Mackie, R.M. (1992) Re-examining crude coal tar treatment for Pointon, J.J.; Jin, R.; Zhou, X.; Bradbury, L.A.; Appleton, L.H.; psoriasis. Br. J. Dermatol., 126, 608-610. Davis, J.C.; Diekman, L.; Doan, T.; Dowling, A.; Duan, R.; [44] Allen, J.G. and Bloxham, D.P. (1989) The pharmacology and Duncan, E.L.; Farrar, C.; Hadler, J.; Harvey, D.; Karaderi, T.; pharmacokinetics of the retinoids. Pharmacol. Ther., 40, 1-27. Mogg, R.; Pomeroy, E.; Pryce, K.; Taylor, J.; Savage, L.; [45] Shah, K.A.; Date, A.A.; Joshi, M.D. and Patravale, V.B. (2007) Deloukas, P.; Kumanduri, V.; Peltonen, L.; Ring, S.M.; Whittaker, Solid lipid nanoparticles (SLN) of tretinoin, potential in topical P.; Glazov, E.; Thomas, G.P.; Maksymowych, W.P.; Inman, R.D.; delivery. Int. J. Pharm., 345, 163-171. Ward, M.M.; Stone, M.A.; Weisman, M.H.; Wordsworth, B.P. and [46] Gerald, M.D. and Weinstein, D. (1997) Tazarotene gel: Efficacy Brown, M.A. (2010) Genome-wide association study of ankylosing and safety in plaque psoriasis. J. Am. Acad. Dermatol., 37, 33-38. spondylitis identifies non-MHC susceptibility loci. Nat. Genet., 42, [47] Scher, R.K.; Stiller, M. and Zhu, Y.I. (2001) Tazarotene 0.1 % gel 123-127. in the treatment of fingernail psoriasis, a double-blind, randomized, [26] Duerr, R.H.; Taylor, K.D.; Brant, S.R.; Rioux, J.D.; Silverberg, vehicle-controlled study. Cutis, 68, 355-358. M.S.; Daly, M.J.; Steinhart, A.H.; Abraham, C.; Regueiro, M.; [48] Rubins, A.; Gutmane, R.; Valdmane, N.; Stevenson, P.; Foster, C. Griffiths, A.; Dassopoulos, T.; Bitton, A.; Yang, H.; Targan, S.; and Undre, N. (2005) Pharmacokinetics of 0.1% Tacrolimus Datta, L.W.; Kistner, E.O.; Schumm, L.P.; Lee, A.T.; Gregersen, ointment after first and repeated application to adults with P.K.; Barmada, M.M.; Rotter, J.I.; Nicolae, D.L. and Cho, J.H. moderate to severe . J. Invest. Dermatol., 125, (2006) A genome-wide association study identifies IL23R as an 68-71. inflammatory bowel disease gene. Science, 314, 1461-1463. [49] Zahir, H.; Nand, R.A.; Brown, K.F.; Tattam, B.N. and Mclachlan, [27] Lebwohl, M. and Ali, S. (2001) Treatment of psoriasis Topical A.J. (2001) Validation of methods to study the distribution and therapy and phototherapy. J. Am. Acad. Dermatol., 45, 487-498. protein binding of tacrolimus in human blood. J. Pharmacol. [28] Lebwohl, M. and Ali, S. (2001) Part 2, Treatment of psoriasis Toxicol., 46, 27-35. Systemic therapies. J. Am. Acad. Dermatol., 45, 649-661. [50] Remitz, A.; Reitamo, S.; Erko, P.; Granlund, H. and Lauerma, A.I. [29] Krueger, G.; Koo, J.; Lebwohl, M.; Menter, A.; Stern, R.S. and (1999) Tacrolimus ointment improves psoriasis in a microplaque Rolstad, T. (2001) The Impact of Psoriasis on Quality of Life. assay. Br. J. Dermatol., 141, 103-107. 300 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

[51] Ali, J.; Akhtar, N.; Sultana, Y.; Baboota, S. and Ahuja, A. (2008) activity on arachidonate 5-lipoxygenase and 5-lipoxygenase/ Antipsoriatic microemulsion gel formulations for topical drug cyclooxygenase. Phytother. Res., 19, 81-102. delivery of babchi oil (Psoralea corylifolia). Exp. Clin. Pharmacol., [74] Schneider, I. and Bucar, F. (2005) Lipoxygenase inhibitors from 30, 277-285. natural plant sources. Part 1, Medicinal plants with inhibitory [52] Collins, P.; Wainwright, N.J.; Amorim, I.; Lakshmipathi, T. and activity on arachidonate 5-lipoxygenase and 5-lipoxygenase/ Ferguson, J. (1996) 8-MOP PUVA for psoriasis, a comparison of a cyclooxygenase. Phytother. Res., 19, 81-102. minimal phototoxic dose-based regimen with a skin-type approach. [75] Jachak, S.M. (2006) Cyclooxygenase Inhibitory Natural Products: Br. J. Dermatol., 135, 248-254. Current Status. Curr. Medici. Chem., 13, 659-678. [53] Baroli, B.; López-Quintela, M.A.; Delgado-Charro, M.B.; Fadda, [76] Calixto, J.B.; Otuki, M.F. and Santos, A.R.S. (2003) Anti- A.M. and Blanco-Méndez, J. (2000) Microemulsions for topical inflammatory compounds of plant origin. Part I. Action on delivery of 8-methoxsalen. J. Controlled Rel., 69, 209-218. arachidonic acid pathway, nitric oxide and nuclear factor-kB (NF- [54] Gottlieb, S.; Hayes, E.; Gilleaudeau, P.; Cardinale, I.; Gottlieb, kB). Planta Med., 69, 973-983. A.B. and Krueger, J.G. (1996) Cellular actions of etretinate in [77] Battagim, J.; de Souza, V.T. and Miyasaka N.R.S. (2011) psoriasis, enhanced epidermal differentiation and reduced cell- Comparative study of the effect of green and roasted water extracts mediated inflammation are unexpected outcomes. J. Cutan. of mate (Ilex paraguariensis) on glucosyltransferase activity of Pathol., 23, 404-418. Streptococcus mutans. J. Enzyme Inhib. Med. Chem., 27, 232-240. [55] Agrawal, Y.; Petkar, K.C. and Sawant, K.K. (2010) Development, [78] Deborah, H.B.; Luciane, A.S. and Rodrigo R.C. (2007) Phenolic evaluation and clinical studies of Acitretin loaded nanostructured Antioxidants Identified by ESI-MS from Yerba Maté (Ilex lipid carriers for topical treatment of psoriasis. Int. J. Pharm., 401, paraguariensis) and Green Tea (Camelia sinensis) Extracts. 93-102. Molecules, 12, 423-432. [56] Gollnick, H.P.M. (1996) Oral retinoids efficacy and toxicity in [79] Kleber, B. and Marcia, B. (2011) Chemical Composition and psoriasis. Br. J. Dermatol., 135, 6-17. Antioxidant Activity of Yerba-Mate (Ilex paraguariensis A.St. [57] Moy, R.L.; Kinston, T.P. and Lowe, N.J. (1985) Isotretinoin versus Hill., Aquifoliaceae) Extract as Obtained by Spray Drying. J. etretinate therapy in generalized pustular and chronic psoriasis. Agric. Food Chem., 21, 510, 640. Arch. Dermatol., 121, 1297-1301. [80] Liau, B.C.; Jong, T.T.; Lee, M.R. and Chen, S.S. (2007) LC-APCI- [58] Berth-Jones, J.; Todd, G.; Hutchison, P.E.; Thestrup-Pederson, K. MS method for detection and analysis of tryptanthrin, indigo, and and Vanhoutte, F.P. (2000) Treatment of psoriasis with oral indirubin in daqingye and banlangen. J. Pharmaceut. Biomed. liarozole, a doseranging study. Br. J. Dermatol., 143, 1170-1176. Anal., 43, 346-351. [59] Eskicirak, B.; Zemheri, E. and Cerkezoglu, A. (2006) The treatment [81] Lee, J.W.; Moon, M.J.; Min, H.Y.; Chung, H.J.; Park, E.J.; Park, of psoriasis vulgaris, 1% topical methotrexate gel, Int. J. Dermatol., H.J.; Hong, J.Y.; Kim, Y.C. and Lee, S.K. (2005) Induction of 45, 965-969. apoptosis by a novel indirubin-5-nitro-3_-monoxime, a CDK [60] Ali, M.F.; Salah, M.; Rafea, M. and Saleh, N. (2008) Liposomal inhibitor, in human lung cancer cells. Bio-Org. Medi. Chem. Lett., methotrexate hydrogel for treatment of psoriasis, preparation, 15, 3948-3952. characterization and laser targeting, Med. Sci. Monit., 14, 66-74. [82] Suzuki, K.; Adachi, R.; Hirayama, A.; Watanabe, H.; Otani, S.; [61] Trotta, M.; Peira, M.; Eugenia, M. (2004) Deformable liposomes Watanabe, Y. and Kasahara, T. (2005) Indirubin, a Chinese anti- for dermal administration of methotrexate. Int. J. Pharmaceut., leukaemia drug, promotes neutrophilic differentiation of human 270, 119-125. myelocytic leukaemia HL-60 cells. Br. J. Haemat., 130, 681-690. [62] Faerber, L.; Braeutigan, M.; Weidinger, G.; Mrowietz, U.; [83] Moon, M.J.; Lee, S.K.; Lee, J.W.; Song, W.K.; Kim, S.W.; Kim, Christophers, E.; Schulze, H.J.; Mahrle, G.; Meffert, H. and J.I.; Cho, C.; Choi, S.J. and Kim, Y.C. (2006) Synthesis and Dreshcler, S. (2001) Cyclosporine in severe psoriasis. Results of a structure-activity relationships of novel indirubin derivatives as meta-analysis in 579 patients. Am. J. Clin. Dermatol., 2, 41-47. potent anti-proliferative agents with CDK2 inhibitory activities. [63] Yarbro, J.W. (1969) Hydroxyurea in the treatment of refractory Bio-org. Medi. Chem., 14, 237-246. psoriasis. Lancet, 2, 846-847. [84] Lin, Y.K.; Wong, W.R.; Chang, Y.C.; Chang, C.J.; Tsay, P.K.; [64] Kolbach, D.N. and Niebor, C. (1992) Fumaric acid therapy in Chang, S.C. and Pang, J.H. (2007) The efficacy and safety of psoriasis, results and side effects of 2 years of treatment. J. Am. topically applied indigo naturalis ointment in patients with plaque- Acad. Dermatol., 27, 769-771. type psoriasis. Dermatology, 214, 155-161. [65] Gil, A. (2002) Polyunsaturated fatty acids and inflammatory diseases. [85] Lin, Y.K.; Wong, W.R. and Su Pang, J.H. (2007) Successful Biomed. Pharmacothe., 56, 388-396. treatment of recalcitrant psoriasis with Indigo naturalis ointment. [66] Krutmann, J. (1998) Therapeutic photoimmunology; photo- Clini. Exper. Dermatol., 32, 99-100. immunological mechanisms in photo(chemo)therapy. J. Photochem. [86] Matsuda, H.; Tewtrakul, S.; Morikawa, T.; Nakamura, A. and Photobiol. B. Biol., 44, 159-164. Yoshikawa, M. (2004) Anti-allergic principles from Thai zedoary: [67] Gordon, P.M.; Diffey, B.L.; Matthews, J.N.S. and Farr, P.M. structural requirements of curcuminoids for inhibition of (1999) A randomized comparison of narrow-band TL-01 photo- degranulation and effect on the release of TNF-alpha and IL-4 in therapy and PUVA photochemotherapy for psoriasis. J. Am. Acad. RBL-2H3cells. Bioorg. Med. Chem., 12, 5891-5898. Dermatol., 41, 728-732. [87] Heng, M.C.; Song, M.K. and Harker, J. (2000) Drug-induced [68] Racz, E.; Prens, E.P. and Kurek, D. (2011) Effective treatment of suppression of phosphorylase kinase activity correlates with psoriasis with narrow-band UVB phototherapy is linked to resolution of psoriasis as assessed by clinical, histological and suppression of the IFN and Th17 pathways. J. Invest. Dermatol., immunohistochemical parameters. Br. J. Dermatol., 143, 937-949. 131, 1547-1558. [88] Kim, S.O.; Kundu, J.K. and Shin, Y.K. (2005) 6-Gingerol inhibits [69] Gruss, C.; Behren, S.; Reuther, T.; Husebo, L.; Neumann, N.; COX-2 expression by blocking the activation of p38 MAP kinase Altmeyer, P.; Lehman, P. and Kerscher, M. (1998) Kinetics of and NF-kappa B in phorbol esterstimulated mouse skin. Oncogene, photosensitivity in bath-PUVA photochemotherapy. J. Am. Acad. 24, 2558-2567. Dermatol., 89, 443-446. [89] Takemoto, D.J.; Kresie, R. and Vaughn, D. (1980) Partial [70] Trehan, M. and Taylor, C.R. (2002) High-dose 308-nm excimer purification and characterization of a guanylate cyclase inhibitor laser for the treatment of psoriasis. J. Am. Acad. Dermatol., 46, with cytotoxic properties from the bitter melon (Momordica 732-737. charantia). Biochem. Biophys. Res. Commun., 94, 332-339. [71] Feldman, S.R.; Mellen, B.G.; Housman, T.S.; Fitzpatrick, R.E.; [90] Gao, M.H.; Li, H.; Zhang, L. and Xiao, S.X. (2008) Studies on Geronemus, R.G.; Friedman, P.M.; Vasily, D.B. and Morison, chemical constituents from flowers of Chrysanthemum indicum. W.L. (2002) Efficacy of the 308-nm excimer laser for treatment of Zhong Yao Cai., 31, 682-684. psoriasis; results of a multicenter study. J. Am. Acad. Dermatol., [91] Lee, D.U.; Kang, Y.J.; Park, M.K.; Lee, Y.S.; Seo, H.G.; Kim, 46, 900-906. T.S.; Kim, C.H. and Chang K.C. (2003) Effects of 13-alkyl- [72] Newman, D.J. and Cragg, G.M. (2007) Natural products as sources substituted berberine alkaloids on the expression of COX-II, TNF- of new drugs over the last 25 years. J. Nat. Prod., 70, 461-477. alpha, iNOS, and IL-12 production in LPSstimulated macrophages. [73] Schneider, I. and Bucar, F. (2005) Lipoxygenase inhibitors from Life Sci., 73, 1401-1412. natural plant sources. Part 1, Medicinal plants with inhibitory Classical to Current Approach for Treatment of Psoriasis Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 301

[92] Cunningham, A.B. (1997) An African wide overview of medicinal [113] Langley, R.; Roenigk, H.; McCall, C.; et al. (2001) Phase I results plant harvesting, conservation and health care. Non Wood For. of intravenous MEDI-507 an anti-T-cell antibody for the treatment Prod., 11, 116-129. of psoriasis. J. Invest. Dermatol., 117, 817. [93] Sampson, J.H.; Raman A.; Karlsen, G.; Navsaria, H. and Leigh, [114] Goffe, B. and Cather, J.C. (2003) Etanercept: an overview. J. Am. I.M. (2001) In vitro keratinocyte antiproliferant effect of Centella Acad. Dermatol., 49, 105-111. asiatica extract and triterpenoid saponins. Phytomedicine, 8, [115] Leonardi, C.L.; Powers, J.L.; Matheson, R.T.; Goffe, B.S.; Zitnik, 230-235. R.; Wang, A.; Gottlieb, A.B. and Etanercept Psoriasis Study Group. [94] Kefale, T.; Gebre-Mariam, T.; Asres, K.; Perry, F. and (2003) Etanercept as monotherapy in patients with psoriasis. N. Engidawork, E. (2008) Toxicity studies on dermal application of Engl. J. Med., 349, 2014-2022. plant extract of Plumbago zeylanica used in Ethiopian traditional [116] Kormeili, T.; Lowe, N.J. and Yamauchi, P.S. (2004) Psoriasis: medicine. J. Ethnopharmacol., 117, 236-248. immunopathogenesis and evolving immunomodulators and [95] Vasudevan, M.; Gunnam, K.K. and Parle, M. (2007) systemic therapies, U.S. experiences. Br. J. Dermatol., 151, 3-15. Antinociceptive and anti-inflammatory effects of Thespesia [117] Winterfield, L.S. and Menter, A. (2004) Infliximab. Dermatol. populnea bark extract. J. Ethnopharmacol., 109, 264-270. Ther., 17, 409-426. [96] Yob, N.J.; Jofrry, S.M.; Affandi, M.M.; The, L.K.; Salleh, M.Z. [118] Gottlieb, A.B.; Evans, R.; Li, S.; Dooley, L.T.; Guzzo, C.A.; Baker, and Zakaria, Z.A. (2011) Zingiber zerumbet (L.) Smith, A Review D.; Bala, M.; Marano, C.W. and Menter, A. (2004) Infliximab of Its Ethnomedicinal, Chemical, and Pharmacological Uses. Evid. induction therapy for patients with severe plaquetype psoriasis: a Based Complement Alternat Med., 2011, 543216. randomized, double-blind, placebocontrolled trial. J. Am. Acad. [97] Misik, V.; Bezakova, L.; Malekova, L. and Kotalova, D. (1995) Dermatol., 51, 534-542. Lipoxygenase inhibition and antioxidant properties of [119] Richard, B.W.; Christopher, E.M.G. (2009) Adalimumab for the protoberberine and aporphine alkaloids isolated from Mahonia Treatment of Psoriasis. Expert Rev. Dermatol., 4, 15-21. aquifolium. Planta Med., 61, 372-373. [120] Patel, T. and Gordon, K. (2004) Adalimumab: efficacy and safety [98] Tanweer, A.S.; Ahmad, S.A.; Albert, H.H.; Ahmad, S.A.; Ahmad, in psoriasis and rheumatoid arthritis. Dermatol. Ther., 17, 427-431. S.H. and Afzal, M. (1996) Management of psoriasis with Aloe Vera [121] Trepicchio, W.L.; Bozza, M.; Pedneault, G. and Dorner, A.J. extract in a hydrophilic cream, a placebo-controlled, double-blind (1996) Recombinant human IL-11 attenuates the inflammatory study. Trop. Medi. Int. Health, 1, 505-509. response through down-regulation of proinflammatory cytokine [99] Kim, H.M. and Cho, S.H. (1999) Levander oil inhibits immediate release and nitric oxide production. J. Immunol., 157, 3627-3634. type allergic reaction in mice and rats. J. Pharm. Pharmacol., 51, [122] Kimball, A.B.; Kawamura, T.; Tejura, K.; Boss, C.; Hancox, 221-226. A.R.; Vogel, J.C.; Steinberg, S.M.; Turner, M.L. and Blauvelt, A. [100] Man, M.Q.; Shi, Y.; Man, M.; Lee, S.H.; Demerjian, M.; Chang, (2002) Clinical and immunologic assessment of patients with S.; Feingold, K.R. and Elias, P.M. (2008) Elias Chinese herbal psoriasis in a randomized double-blind placebo-controlled trial medicine (Tuhuai extract) exhibits topical anti-proliferative and using recombinant human interleukin -10. Arch. Dermatol., 138, anti-inflammatory activity in murine disease models. Exp. Dermatol., 1341-1346. 17, 681-687. [123] Kimball, A.B.; Gordon, K.B.; Langley, R.G.; Menter, A.; Chartash, [101] Zhang, G.W.; Li, S.B. and Wang, H.J. (1980) Inhibition of Chinese E.K. and Valdes, J. (2008) Safety and efficacy of ABT-874, a fully herb medicine, Angelica Dahurica (Benth et Hook) and UVA on human /23 monoclonal antibody, in the treatment synthesis of DNA of lymphocytes in vitro. Chin. J. Dermatol., 13, of moderate to severe chronic plaque psoriasis: results of a 138-140. randomized, placebo-controlled, phase 2 trial. Arch. Dermatol., [102] Zhao-Li Zhou, Ya-Xi Yang, Jian Ding, Yuan-Chao Li and Ze- 144, 200-207. Hong Miao (2012) Triptolide: structural modifications, structure– [124] Lima, X.T.; Abuabara, K.; Kimball, A.B. and Lima, H. C. (2009) activity relationships, bioactivities, clinical development and Briakinumab. Expert Opini. Biological. Therapy, 9, 1107-1113. mechanisms. Nat. Prod. Rep., 29, 457-475. [125] Res, P.C.; Piskin, G.; de Boer, O.J.; van der Loos, C.M.; Teeling, [103] Koo, J. and Arain, S. (1998) Traditional Chinese Medicine for P.; Bos, J.D. and Teunissen, M.B. (2010) Overrepresentation of IL- the Treatment of Dermatologic Disorders. Arch. Dermatol., 134, 17A and IL-22 producing CD8 T cells in lesional skin suggests 1388-1393. their involvement in the pathogenesis o f psoriasis. PLoS One, 5, [104] Nishimoto, K.; Ito, M.; Natori, S. and Ohmoto, T. (1968) The e14108. structure of arundoin, cylindrin and fernenol, Triterpenoids of [126] Kimball, A.B.; Gordon, K.B.; Langley, R.G.; Menter, A.; Chartash, fernane and arborane groups of Imperata cylindrica var. koenigii. E.K. and Valdes, J. (2008) Safety and efficacy of ABT- 874, a fully Tetrahedron, 24, 735-752. human interleu- kin 12/23 monoclonal antibody in the treatment of [105] Spitaler, M. and Cantrell, D.A. (2004) Protein kinase C and moderate to se-vere chronic plaque psoriasis results of a beyond. Nat. Immunol., 5, 785-790. randomized placebo- controlled phase 2 trials. Arch. Dermatol., [106] da Silva, A.J.; Brickelmaier, M.; Majeau, G.R.; Li, Z.; Su, L.; Hsu, 144, 200-207. Y.M. and Hochman, P.S. (2002) Alefacept an immunomodulatory [127] Hueber, W.; Patel, D.D.; Dryja, T.; Wright, A.M.; Koroleva, I.; recombinant LFA-3/IgG1 fusion protein induces CD16 signaling Bruin, G.; Antoni, C.; Draelos, Z.; Gold, M.H.; Psoriasis Study and CD2/CD16-dependent apoptosis of CD2 (þ) cells. J. Immunol., Group.; Durez, P.; Tak, P.P.; Gomez-Reino, J.J.; Rheumatoid 168, 4462-4471. Arthritis Study Group.; Foster, C.S.; Kim, R.Y.; Samson, C.M.; [107] Krueger, G. (2003) Clinical response to alefacept results of a phase Falk, N.S.; Chu, D.S.; Callanan, D.; Nguyen, Q.D.; Uveitis Study 3 study of intravenous administration of alefacept in patients with Group.; Rose, K.; Haider, A. and Di Padova, F. (2010) Effects of chronic plaque psoriasis. J. Eur. Acad. Dermatol. Venereol., 17, AIN457, a fully human antibody to interleukin-17A, on psoriasis, 17-24. rheumatoid arthritis, and uveitis. Sci. Transl. Med., 2, 52-72. [108] Leonardi, C.L. (2003) Efalizumab: an overview. J. Am. Acad. [128] Russell, C.B.; Kerkof, K.; Bigler, J. and et al. (2011) Blockade of Dermatol., 49, 98-104. the IL-17R with AMG 827 leads to rapid reversal of gene [109] Gordon, K.B.; Papp, K.A.; Hamilton, T.K.; Walicke, P.A.; Dummer, expression and histopathologic abnormalities in psoriatic skin, W.; Li, N.; Bresnahan, B.W.; Menter, A. and Efalizumab Study Group. including substantial pathway-specific effects within one week. J. (2003) Efalizumab for patients with moderate to severe plaque Invest. Dermatol., 131, 11. psoriasis: a randomized controlled trial. JAMA, 290, 3073-3080. [129] Kopf, M.; Bachmann, M.F. and Marsland, B.J. (2010) Averting [110] Foss, F.M. (2005) DAB (389) IL-2 (, ONTAK) a inflammation by targeting the cytokine environment. Nat. Rev. new fusion protein technology. Clin. Lymphoma., 1, 27-31. Drug Discov., 9, 703-718. [111] Krueger, J.G.; Walters, I.B.; Miyazawa, M.; Gilleaudeau, P.; Hakimi, [130] Nesbitt, A.; Fossati, G.; Bergin, M.; Stephens, P.; Stephens, S.; J.; Light, S.; Sherr, A. and Gottlieb, A.B. (2000) Successful in vivo Foulkes, R.; Brown, D.; Robinson, M. and Bourne, T. (2007) blockade of CD25 (high-affinity receptor) on T cells Mechanism of action of certolizumab pegol (CDP870): in vitro by administration of humanized anti-Tac antibody to patients with comparison with other antietumor necrosis factor alpha agents. psoriasis. J. Am. Acad. Dermatol., 43, 448-458. Inflamm. Bowel Dis., 13, 1323-1332. [112] Owen, C.M. and Harrison, P.V. (2000) Successful treatment of [131] Skvara, H.; Dawid, M.; Kleyn, E.; Wolff, B.; Meingassner, J.G.; severe psoriasis with basiliximab, an interleukin-2 receptor Knight, H.; Dumortier, T.; Kopp, T.; Fallahi, N.; Stary, G.; monoclonal antibody. Clin. Exp. Dermatol., 25, 195-197. Burkhart, C.; Grenet, O.; Wagner, J.; Hijazi, Y.; Morris, R.E.; 302 Endocrine, Metabolic & Immune Disorders - Drug Targets, 2012, Vol. 12, No. 3 Rahman et al.

McGeown, C.; Rordorf, C.; Griffiths, C.E.; Stingl, G. and Jung, T. Sippel, V.; Steiner, B.; Strasser, D.; Treiber, A. and Weller, T. (2008) The PKC inhibitor AEB071 may be a therapeutic option for (2010) 2-imino-thiazolidin-4-one derivatives as potent, orally psoriasis. J. Clin. Invest., 118, 3151-3159. active S1P1 receptor agonists. J. Med. Chem., 53, 4198-4211. [132] Aytac, U. and Dang, N.H. (2004) CD26/dipeptidyl peptidase IV: a [146] Mendel, I.; Shoham, A.; Propheta-Meiran, O.; Ishai, E.; Halperin, regulator of immune function and a potential molecular target G.; Feige, E. and Breitbart, E. (2010) A Lecinoxoid, anoxidized fortherapy. Curr. Drug Targets Immun. Endocr. Metabol. Disord., phospholipids mall molecule, c on strains CNS autoimmuned 4, 11-18. disease. J. Neuroimmunol., 226, 126-135. [133] Tan, S.L.; Zhao, J.; Bi, C.; Chen, X.C.; Hepburn, D.L.; Wang, J.; [147] Feige, E.; Mendel, I.; George, J.; Yacov, N. and Harats, D. (2010) Sedgwick, J.D.; Chintalacharuvu, S.R. and Na, S. (2006) Modified phospholipids as anti-inflammatory compounds. Curr. Resistance to experimental autoimmune encephalomyelitis and Opin. Lipidol., 21, 525-529. impaired IL-17 production in protein kinase C theta-deficient mice. [148] Claveau, D.; Chen, S.L.; O'Keefe, S.; Zaller, D.M.; Styhler, A.; J. Immunol., 176, 2872-2879. Liu, S.; Huang, Z.; Nicholson, D.W. and Mancini, J.A. (2004) [134] Alves, N.L.; Arosa, F.A. and van Lier, R.A. (2007) Common gamma Preferential inhibition of T helper 1, but not T helper 2, cytokines chain cytokines: dissidence in the details. Immunol. Lett., 108, 113-120. in vitro by L-826,141 [4-[2-(3,4-Bisdifluromethoxyphenyl)- 2-[4- [135] Borie, D.C.; Si, M.S.; Morris, R.E.; Reitz, B.A. and Changelian, (1,1,1,3,3,3-hexafluoro-2-hydroxy propan-2-yl)-phenyl]- ethyl]3- P.S. (2003) JAK3 inhibition as a new concept for immune methylpyridine-1-oxide], a potent and selective phosphodiesterase suppression. Curr. Opin. Investig. Drugs, 4, 1297-1303. 4 inhibitor. J. Pharmacol. Exp. Ther., 310, 752-760. [136] Genovese, M.C.; Kavanaugh, A.; Weinblatt, M.E.; Peterfy, C.; [149] Diamond, J. (1984) Systemic treatment of psoriasis using certain DiCarlo, J.; White, M.L.; O'Brien, M.; Grossbard, E.B. and salicylates: US patent no 4, 483, 845. Magilavy, D.B. (2011) An oral syk kinase inhibitor in the treatment [150] Braiman, M. (1998) Treatment of psoriasis with 11-cis-retinoic of rheumatoid arthritis: a 3 month randomized placebo controlled acid: US patent no 5, 719,195. phase 2 study in patients with active RA who had failed biologic [151] Robert W. Wolfe (1979) Ultraviolet emitting CeYMg aluminate agents. Arthritis Rheum., 63, 337-345. fluorescent lamp phosphor for psoriasis treatment; US patent no [137] Braselmann, S.; Taylor, V.; Zhao, H.; Wang, S.; Sylvain, C.; 4153572. Baluom, M.; Qu, K.; Herlaar, E.; Lau, A.; Young, C.; Wong, B.R.; [152] Maximillion F. Mutzhas (1985) UV radiation device for Lovell, S.; Sun, T.; Park, G.; Argade, A.; Jurcevic, S.; Pine, P.; phototherapy of dermatoses especially psoriasis. US patent no Singh, R.; Grossbard, E.B.; Payan, D.G. and Masuda, E.S. (2006) 4,558,700. R406, an orally available spleen tyrosine kinase inhibitor blocks [153] Robert E. Grove, James Z. Holtz (1996) Pulsed infrared laser fc receptor signaling and reduces immune complex-mediated treatment of psoriasis. US patent no 5527350. inflammation. J. Pharmacol. Exp. Ther., 319, 998-1008. [154] Shimon Eckhouse, Michael Kreindel (1998) Method and apparatus [138] Weinblatt, M.E.; Kavanaugh, A.; Genovese, M.C.; Musser, T.K.; for treating psoriasis using pulsed electromagnetic radiation. US Grossbard, E.B. and Magilavy, D.B. (2010) An oral spleen tyrosine patent no 5836999. kinase (Syk) inhibitor for rheumatoid arthritis. N. Engl. J. Med., [155] George, Jacob (1999) Herbal medication for the treatment of 363, 1303-1312. psoriasis. US patent no 5858372. [139] Schieven, G.L. (2005) The biology of p38 kinase: a central role in [156] Lorraine F. Meisner (1988) Method for accelerated wound healing. inflammation. Curr. Top. Med. Chem., 5, 921-928. US Patent no 4772591. [140] Westra, J.; Doornbos-van der Meer, B.; de Boer, P.; van Leeuwen, [157] Solomon Habtemarium, William Howard Stimson, Alexander M.A.; van Rijswijk, M.H. and Limburg, P.C. (2004) Strong Irvine Gray, Chaman Lal Anand, Peter George Waterman (2001) inhisbition of TNF-alpha production and inhibition of IL-8 and Use of calendula glycosides for the treatment of psoriasis: US COX-2 mRNA expression in monocyte-derived macrophages by Patent number 6225342. RWJ 67657, a p38 mitogen-activated protein kinase (MAPK) [158] Uddagiri Venkannu Babu, Bhaidyanalh Mishra (2011) Novel inhibitor. Arthritis Res. Ther., 6, 384-392. herbal composition for treatment of psoriasis and other skin [141] Liu, C.; Lin, J.; Wrobleski, S.T.; Lin, S.; Hynes, J.; Wu, H.; disorders: US patent no 0165136A1. Dyckman, A.J.; Li, T.; Wityak, J.; Gillooly, K.M.; Pitt, S.; [159] Tetsuya Gatanaga, Gale A. Granger (2003) Native TNF receptor Shen, D.R.; Zhang, R.F.; McIntyre, K.W.; Salter-Cid, L.; Shuster, releasing enzyme: US patent no 6569664. D.J.; Zhang, H.; Marathe, P.H.; Doweyko, A.M.; Sack, J.S.; [160] Tetsuya Gatanaga, Gale A. Granger (2005) A system for Kiefer, S.E.; Kish, K.F.; Newitt, J.A.; McKinnon, M.; Dodd, J.H.; discovering and producing new tnf receptor releasing enzymes: US Barrish, J.C.; Schieven, G.L. and Leftheris, K. (2010) Discovery of patent no 6858402. 4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5- methyl-N- [161] Junming Le, Jan Vilcek, Peter Dadonna, John Ghrayeb, David propylpyrrolo [1,2-f][1,2,4]triazine-6-carboxamide (BMS-582949), Knight, Scott Seigal (1999) Methods of treating TNF.alpha.-mediated a clinical p38alpha MAP kinase inhibitor for the treatment of disease using chimeric anti-TNF-α: US patent no 5919452. inflammatory diseases. J. Med. Chem., 53, 6629-6639. [162] Jochen G. Salfeld, Deborah J. Allen, Hendricus R. J. M. [142] Johnston, A.; Gudjonsson, J.E.; Aphale, A.; Guzman, A.M.; Stoll, S.W. Hoogenboom, Zehra Kaymakcalan, Boris Labkovsky, John A. and Elder, J.T. (2011) EGFR and IL-1 signaling synergistically Mankovich, Brian T. McGuinness, Andrew J. Roberts, Paul promote kerat- inocyte antimicrobial defenses in a differentiation- Sakorafas, David Schoenhaut, Tristan J. Vaughan, Michael White, dependent manner. J. Invest. Dermatol., 131, 329-337. Alison J. Wilton (2000) Human antibodies that bind human TNF- [143] Lurje, G. and Lenz, H.J. (2009) EGFR signaling and drug α. US patent no 6090382. discovery. Oncology, 77, 400-410. [163] Rathjen, Deborah A. Aston, Roger (2009) Tumor necrosis factor [144] Giroux, L.E.; Friard, S. and Couderc, L.J. (2010) Improvement of binding ligand. US patent no 7,517,963. psoriasis in a lung cancer patient treated with erlotinib. Eur. J. [164] George Qing Wei Ye (2006) Topical treatment of psoriasis using Dermatol., 20, 243-244. neutralizing antibodies to interleukin-8. US patent no 7147854. [145] Bolli, M.H.; Abele, S.; Binkert, C.; Bravo, R.; Buchmann, S.; Bur, [165] Darrell R. Anderson, Peter Brams, Nabil Hanna, William S. D.; Gatfield, J.; Hess, P.; Kohl, C.; Mangold, C.; Mathys, B.; Shestowsky, Cheryl Heard 2004 Treatment of psoriasis using anti- Menyhart, K.; Müller, C.; Nayler, O.; Scherz, M.; Schmidt, G.; B7.1 (CD80) antibodies. US patent no 6709654.

Received: 07 December, 2011 Accepted: 22 March, 2012