Dithranol: An Insight into its Novel Delivery Cargos for Psoriasis Management.

OBJECTIVE: Dithranol (DTH) is a well-known moiety that has long been used promisingly to impede and treat skin disorders, particularly psoriasis. Nowadays, a rekindled interest in the use of DTH for this disorder has been observed. Side effects associated with conventional topical formulations of this moiety have aroused the interest of the scientific community in investigating novel cargos of DTH for psoriasis management. RESULTS: Previous research has evidenced the anti-inflammatory and anti-proliferating potential of DTH. Numerous studies have indicated that DTH inhibits polymorphonuclear (PMN) leucocyte, modulates epidermal cell receptors and promotes anti-psoriatic action. However, some deterrent factors like poor solubility, stability, toxicity, staining and skin irritation hamper its use as a potential therapeutic agent. With the adoption of novel drug delivery technologies, the above mentioned inherent limitations of DTH have been compensated to reestablish this drug moiety. CONCLUSION: This article reviews novel drug delivery aspects, safety concerns, clinical evidence, current status, and future opportunities of DTH in the management of psoriasis. Further, it will update researchers on this promising drug moiety, which is free from systemic adverse responses in comparison to other therapeutic molecules like steroids, for psoriasis treatment.

Treatment of chronic extensive alopecia areata by diphenylcyclopropenone alone versus in combination with anthralin.

Alopecia areata (AA) is a chronic inflammatory, recurrent, tissue-specific autoimmune disease, mediated by autoreactive CD8+ T cells, occurring in genetically predisposed individuals. Targeting intrabulbar and peribulbar lymphocytic infiltrate by using squaric acid dibutyl ester and diphenylcyclopropenone (DPCP) in contact immunotherapy is by far the best chemotherapy for AA. The aim of this work was to evaluate the efficacy and safety of combination therapy with DPCP and anthralin in chronic extensive AA. A total of 24 patients (12 were treated only with DPCP and 12 with DPCP and anthralin for at least 24 weeks) were evaluated. Complete hair regrowth was observed in 62.5 and 18.2% of the patients who received DPCP and combination therapy, respectively (p = .04). Hair regrowth duration was different in both groups. The DPCP therapy is superior to the combination therapy with DPCP and anthralin in terms of efficacy, the time of onset of hair regrowth, and the time of completion of hair regrowth, Moreover, combination therapy has more side effects in combination therapy group have been discussed in this work.

Efficacy and safety of anthralin in combination with diphenylcyclopropenone in the treatment of alopecia areata: a retrospective case series.

Contact immunotherapy with diphenylcyclopropenone (DPCP) and anthralin is considered the treatment option for extensive alopecia areata (AA) unresponsive to DPCP immunotherapy alone. Only one study has described the efficacy of combination therapy; therefore, we investigated whether topical DPCP and anthralin can promote hair regrowth in DPCP-non responders. In this retrospective case-series we analyzed the efficacy and side effects of DPCP with anthralin in AA patients who did not respond to several months of treatment with DPCP alone. Thirty-two DPCP-nonresponsive AA patients were treated with DPCP and anthralin for the average of 8.3 ± 3.8 (3-17) months. During the treatment, 40.62% of patients (13 patients out of 32) had terminal hair regrowth. The mean of hair regrowth rate was 41%; it was mainly as partial hair regrowth (˂ 50%) and 27.27% of cases achieved > 50% terminal hair regrowth. Treatment response strongly related to the duration of combination therapy (p value ˂ 0.001), but we did not find any relation with other demographic characteristics. The first signs of response to treatment were noticed 2-12 months (5.5 ± 3.4) after initiation of combination therapy while there was a positive correlation among the duration of treatment and percentage of hair regrowth (p < 0.001). The most common complication was bullae (25%), and the least frequent side effect was generalized pruritus (3.1%). The combination therapy with DPCP and anthralin could be effective to treat DPCP non-responder AA patients. Additionally, the higher treatment response could be achieved by longer treatment duration.

Dithranol-loaded nanostructured lipid carrier-based gel ameliorate psoriasis in imiquimod-induced mice psoriatic plaque model.

OBJECTIVE: The aim of this study was to formulate nanostructured lipid carriers (NLCs) of dithranol-loaded in gel for ease of application and to evaluate its anti-psoriatic efficacy vis-a-vis conventional ointment formulation. SIGNIFICANCE: This study will provide an insight about the use of nanocarriers, esp. NLCs loaded with dithranol for the effective treatment of psoriasis. METHODS: Dithranol-loaded NLCs were prepared by hot melt homogenization method and characterized for particle size and percentage entrapment efficiency. The optimized NLCs were loaded into gel and evaluated for drug release, spreadability, rheological behavior, and staining. Anti-psoriatic efficacy of the NLC gel was evaluated in imiquimod (IMQ) induced psoriatic plaque model in comparison with prepared conventional ointment formulation (1.15% w/w dithranol). RESULTS: NLCs were prepared with particle size below 300 nm, polydispersity index (PDI) below 0.3 and percentage entrapment efficiency of ∼100%. The prepared NLC gel was then compared with the ointment for drug release, staining property, and efficacy. Topical application of dithranol-loaded NLC gel on IMQ-induced psoriatic plaque model reduced the symptoms of psoriasis assessed by both Psoriasis area severity index (PASI) scoring and enzyme-linked immunosorbent assay. There was a significant reduction in disease severity and cytokines like Interleukins-17, 22, 23 and Tumor necrosis factor-α by the developed system in comparison to the negative control. CONCLUSIONS: To conclude dithranol-loaded NLCs in gel base was efficacious in management of psoriasis at the same drug concentration and also offer less cloth staining to that of the ointment product.

Recalcitrant alopecia areata responsive to leflunomide and anthralin-Potentially undiscovered JAK/STAT inhibitors?

Several treatment modalities are available for the management of alopecia areata (AA); however, no therapy is universally effective and treatment can be frustrating in severe cases, with low response and high recurrence rates. Recent studies show that the JAK/STAT pathway plays a central role in the pathogenesis of this disease by determining the crosstalk between the infiltrating CD8+ T cells and the hair follicles, suggesting a role of JAK inhibitors in the treatment of AA. However, reports on the off-label use of these more expensive targeted agents have shown variable results. We present a case of a child with recalcitrant ophiasis-pattern AA who had failed steroid therapy and was treated successfully with leflunomide and anthralin, possibly by the synergistic effect on the JAK/STAT pathway inhibition, and we propose this combination could be a cost-effective therapeutic option for recalcitrant AA.

Treatment of pediatric alopecia areata with anthralin: A retrospective study of 37 patients.

BACKGROUND/OBJECTIVES: Data on treatment options in pediatric alopecia areata are limited. Topical anthralin has been demonstrated to be an effective treatment option in adults and has minimal systemic toxicity. Prior results on its efficacy in children with alopecia areata have been mixed. METHODS: Medical records of 37 patients with alopecia areata who were started on topical anthralin before age 17 were reviewed for efficacy and safety data. Scalp regrowth was quantified by serial photography if available or by medical record documentation if photographs were unavailable. Mean duration of clinical follow-up was 2.5 years. RESULTS: Most patients were started on anthralin while continued on prior therapies, including topical corticosteroids, minoxidil, and/or intralesional corticosteroids. Twelve patients (32%) experienced complete scalp regrowth, while 25 patients (68%) experienced at least 50% maximal scalp regrowth with using anthralin. Of the patients with at least 50% scalp regrowth, mean time to first clinically observed response was 3.4 months. Mean time to maximal response was 15 months. Four patients stopped anthralin due to skin irritation. Relapses affected 64% of those with at least 50% maximal scalp regrowth. CONCLUSIONS: Topical anthralin provides children with alopecia areata an additional option that offers potential for significant scalp regrowth with minimal systemic effects. Treatment course may need to be continued for at least 1 year in order to achieve maximal efficacy. The efficacy of anthralin may be limited by high rate of recurrence and local adverse effects.

Use of topical therapies for pediatric psoriasis: A systematic review.

Psoriasis is one of the most common chronic skin diseases, affecting 1%-3% of the general population. It can have a significant negative impact on a patient's quality of life, and in approximately 30% of patients first symptoms can be traced back to childhood. We have performed a comprehensive literature search using the MEDLINE database in order to ascertain the efficacy and adverse reactions of topical treatments in pediatric psoriasis. A total of 13 relevant articles were identified on the following topical agents: corticosteroids, calcineurin inhibitors, vitamin D analogs, and dithranol. Corticosteroids achieved clearance in 72.7% of patients. Calcitriol lead to a 57.2%-100% mean improvement in severity, and calcipotriol to 52%-64%. Combination of calcipotriol and corticosteroids achieved an improvement in mean severity ranging between 32.1% and 80%. Treatment with tacrolimus lead to an >50% improvement. Finally, short contact dithranol lead to a variable response in clearance between different studies, ranging between 3.7% and 81%. No serious adverse reactions were documented, the most common local reaction being irritation. Pediatric psoriasis is a common and challenging condition with no easy and definitive solution. Topical agents are safe, easy to use, readily available and cheap. However, they need to be applied repeatedly, may cause skin irritation, and can be messy. Based on the results presented above, we recommend utilizing all the available topical options before escalating to systemic treatments.

Higher concentrations of dithranol appear to induce hair growth even in severe alopecia areata.

Alopecia areata (AA) is the commonest autoimmune cause of non-scarring alopecia. Topical treatments including corticosteroids and irritants maybe beneficial. Studies report variable hair regrowth with dithranol (anthralin) but all used low concentrations (0.1-1.25%) and inconsistent measurements of AA severity. We report retrospective data (2005-2014) of 102 patients who had failed ultra-potent topical steroids and were referred to a specialist hair clinic for treatment with dithranol up to 3%. The severity of alopecia areata tool was used and participants graded as mild (<25%), moderate (>25 to 75%), and severe (>75%) hair loss. Compared with baseline any and at-least 50% hair regrowth [72%, 68%, 50% and 61.5%, 48.4%, 37.5%, in mild, moderate and severe AA respectively] occurred in all groups (median treatment duration 12 months). Twenty-nine patients (28.4%) were discharged with complete regrowth; with no difference in proportions in severity groups (33.3%, 29%, and 21.9%) but in the period to discharge [7.9, 6.3, and 29.4 months (p-values <.05)] for mild, moderate, and severe AA. Treatment trials of 12 months with dithranol at higher concentrations may be an option in patients who failed potent topical or intra-lesional steroids) regardless of AA severity. Randomized trials (of less staining formulations) of dithranol are warranted.

Serum Fatty Acid-Binding Protein 4 is Increased in Patients with Psoriasis.

Psoriasis is associated with metabolic syndrome and cardiovascular disease. Fatty acid-binding proteins (FABP) have been recognized as predictors of these systemic disorders. The aim of this study was to assess correlations between levels of serum heart and adipocyte fatty acid-binding proteins (FABP3, FABP4) and disease severity, indicators of inflammation or metabolic disturbances, and topical treatment in psoriatic patients. Thirty-seven patients with relapse of plaque-type psoriasis and 16 healthy volunteers were recruited. Blood samples were collected before and after 14 days of therapy. Serum FABP concentrations were examined by enzyme-linked immunosorbent assay for correlation with Psoriasis Area and Severity Index (PASI), body mass index (BMI), inflammatory or metabolic parameters, and treatment used. The median FABP4 serum levels were significantly increased (p = 0.038) in psoriatic patients, while FABP3 levels did not differ (p = 0.47) compared to the controls. No significant correlations were noted between the proteins and PASI, C-reactive protein (CRP), BMI, or levels of glucose or lipids. FABP3 significantly correlated with white blood count (p = 0.03) and aspartate aminotransferase (p = 0.04). After topical treatment, there was no significant change in serum FABP3 [11.5 (4.9-30.3) vs. 12.9 (3.5-30.3) ng/ml] (p = 0.96), whereas FABP4 was decreased [27,286 (20,344-32,257) vs. 23,034 (18,320-29,874) pg/ml] (p = 0.12), losing its basal significance. FABP4 may be a marker of psoriasis, and FABP3 may be associated with inflammation or liver disorders in psoriatic patients. FABP do not appear to be useful for determining disease severity or the effectiveness of antipsoriatic treatment.

Topical Therapies for Psoriasis: Improving Management Strategies and Patient Adherence.

Psoriasis is a chronic disease that has a substantial effect on quality of life of patients and often needs long-term treatment. Topical treatments for psoriasis include corticosteroids, vitamin D derivatives, tazarotene, anthralin, tacrolimus, pimecrolimus, and newer formulations of tar. Although many of these treatments are effective, they must be prescribed appropriately and used consistently for a period of weeks to months before clinical evidence of improvement can be seen and patients perceive that the treatment is working. As such, medication dosage/schedule, choice of vehicle, and especially patient adherence to medication are key factors for a treatment to be effective. Addressing patient preferences about treatments and concerns about treatment-related toxicities and managing their expectations represent additional aspects of patient care. Therapies such as calcipotriene and betamethasone dipropionate (Cal/BD) fixed combination foam and new drugs and vehicles continuously enhance the treatment landscape for psoriasis. Because adherence to topical treatment can be a major difficulty, keeping the treatment regimen simple and using new and sophisticated treatment vehicles that are acceptable to patients can likely improve treatment outcomes.

Exploring the mode of action of dithranol therapy for psoriasis: a metabolomic analysis using HaCaT cells.

Psoriasis is a common, immune-mediated inflammatory skin disease characterized by red, heavily scaled plaques. The disease affects over one million people in the UK and causes significant physical, psychological and societal impact. There is limited understanding regarding the exact pathogenesis of the disease although it is believed to be a consequence of genetic predisposition and environmental triggers. Treatments vary from topical therapies, such as dithranol, for disease of limited extent (<5% body surface area) to the new immune-targeted biologic therapies for severe psoriasis. Dithranol (also known as anthralin) is a topical therapy for psoriasis believed to work by inhibiting keratinocyte proliferation. To date there have been no metabolomic-based investigations into psoriasis. The HaCaT cell line is a model system for the epidermal keratinocyte proliferation characteristic of psoriasis and was thus chosen for study. Dithranol was applied at therapeutically relevant doses to HaCaT cells. Following the optimisation of enzyme inactivation and metabolite extraction, gas chromatography-mass spectrometry was employed for metabolomics as this addresses central metabolism. Cells were challenged with 0-0.5 µg mL(-1) in 0.1 µg mL(-1) steps and this quantitative perturbation generated data that were highly amenable to correlation analysis. Thus, we used a combination of traditional principal components analysis, hierarchical cluster analysis, along with correlation networks. All methods highlighted distinct metabolite groups, which had different metabolite trajectories with respect to drug concentration and the interpretation of these data established that cellular metabolism had been altered significantly and provided further clarification of the proposed mechanism of action of the drug.

Novel psoriasis therapies and patient outcomes, part 1: topical medications.

In recent years, advances in our understanding of inflammatory mediators and the underlying pathogenesis of psoriasis and psoriatic arthritis have shed light on potential therapeutic targets, which has led to the development of several new promising treatments. In this article, key clinical trials, mechanisms of action, patient outcomes, and relevant safety information for these novel topical medications will be evaluated. This article is the first in a 3-part series on treatments presently in the pipeline for the management of psoriasis and psoriatic arthritis including topical agents, biologic treatments, and systemic therapies in phase 2 and phase 3 clinical trials. With novel approaches to the disease process, these therapies may afford more targeted individualized treatment regimens and offer hope to patients with psoriasis and psoriatic arthritis who have reported a suboptimal therapeutic response to conventional therapies.

Efficacy and safety of diphenylcyclopropenone alone or in combination with anthralin in the treatment of chronic extensive alopecia areata: a retrospective case series.

BACKGROUND: Some patients with chronic extensive alopecia areata (AA) may be refractory to topical immunotherapy. Combination therapy is recommended for such patients. Efficacy and safety of a combination therapy with diphenylcyclopropenone (DPCP) and anthralin in chronic extensive AA is unknown. OBJECTIVE: We sought to determine whether the combination therapy of DPCP and anthralin is superior to DPCP alone in chronic extensive AA. METHODS: We retrospectively analyzed the efficacy, side effects, and relapse rates of DPCP (alone or with anthralin) in chronic extensive AA. RESULTS: A total of 47 patients (22 were treated only with DPCP, and 25 with DPCP and anthralin for at least 30 weeks) were evaluated. Complete hair regrowth was observed in 36.4% and 72% of the patients who received DPCP and combination therapy, respectively (P = .01). Hair regrowth duration was shorter with combination therapy (P = .01). Regrowth rates of the eyebrows, eyelashes, and beard in patients on combination therapy were higher than those in patients on DPCP (P = .01). Side effects such as folliculitis, hyperpigmentation, and staining of skin, hair, and clothes were more common in combination therapy group. LIMITATIONS: The retrospective design and small number of patients are limitations. CONCLUSION: Combination therapy with DPCP and anthralin is superior to DPCP alone in chronic extensive AA.

The effectiveness and safety of short-contact dithranol therapy in paediatric psoriasis: a prospective comparison of regular day care and day care with telemedicine.

BACKGROUND: Evidence on the effectiveness and safety of short-contact dithranol therapy in paediatric psoriasis is sparse and based only on retrospective data. The best results are achieved in a time-consuming day-care setting. OBJECTIVES: To study prospectively the effectiveness and safety of short-contact dithranol therapy in paediatric psoriasis. In addition, the effectiveness, safety, duration of treatment and number of visits between regular day care and day care with telemedicine were compared. METHODS: Data were collected from the prospective observational Child-CAPTURE registry of children with psoriasis. Effectiveness was measured as the mean percentage improvement in Psoriasis Area and Severity Index (PASI). Safety was assessed by recording adverse events. The number of visits and duration of treatment were reported. RESULTS: For all patients a mean percentage reduction in PASI score of -69·3% was found, with no significant differences between regular day care and day care with telemedicine. The only adverse event reported was irritation of the skin. Neither the frequency of irritation during treatment nor the mean duration of treatment significantly differed between the two groups. Patients with telemedicine had significantly fewer visits. CONCLUSIONS: This first prospective observational study demonstrates that short-contact dithranol therapy in paediatric psoriasis is effective and safe. Regular day care and day care with telemedicine are equally effective. Telemedicine can be of additional value as it is less time consuming. We hope it will therefore make dithranol treatment appropriate for a larger number of children with psoriasis.

Hyperbranched dendritic nano-carriers for topical delivery of dithranol.

The purpose of the current investigation was to explore the potential of polypropylene imine (PPI) dendrimers to deliver dithranol (DIT) topically and to evaluate its encapsulation, permeation and skin irritation potential. PPI (5.0 generation, 5.0 G) dendrimers and DIT-loaded PPI (DIT-PPI) were prepared and characterized by spectroscopy and transmission electron microscopy. DIT encapsulation, in vitro skin permeation study, skin irritation studies, fluorescent studies and tape stripping studies were performed. Loading of DIT was found to be pH dependent with maximum encapsulation at acidic pH (1.0 ± 0.02, 17.2 ± 0.56 and 57.1 ± 1.32% at 7.4, 5.5 and 1.2 pH, respectively). DIT-PPI showed significantly enhanced permeation rate constant and lesser skin irritation (11.61 ± 1.80 µg/cm(2)/h and 1.0, respectively) when compared with the plain DIT solution (2.72 ± 0.31 µg/cm(2)/h and 2.3, respectively). Skin separation studies and confocal laser scanning microscope images showed that the dye-loaded dendrimers exhibits deposition of dye in pilosebaceous compartment. These studies demonstrate that PPI can be exploited to improve the topical bioavailability of the molecules in a controlled pattern. The enhanced accumulation of DIT via dendrimer carrier within the skin might help optimize targeting of this drug to the epidermal and dermal sites, thus creating new opportunities for well-controlled, modern topical application of DIT for the treatment of psoriasis.

Improving outcomes in patients with psoriasis.

Psoriasis is a heterogeneous inflammatory disorder that targets the skin and joints. It affects 1.3-2% of the population. The diagnosis of plaque psoriasis is usually straightforward, a helpful diagnostic clue is the tendency for silver scales to appear after gentle scratching of a lesion. Stress, streptococcal infection and drugs including beta-blockers, antimalarials and lithium may precipitate or exacerbate psoriasis. Psoriasis, especially when severe, predisposes to metabolic syndrome, and patients with psoriasis are at increased risk of ischaemic heart disease, hypertension, stroke, type 2 diabetes and hyperlipidaemia. Additionally, psoriasis sufferers appear at increased risk of uveitis, inflammatory boweldisease, lymphoma, non-melanoma skin cancer, COPD and venous thromboembolism. Psoriasis should be assessed on the basis of: severity, impact on physical, psychological and social wellbeing, symptoms of arthritis and the presence of comorbidities. Poor response to topical therapy may be as much to do with lack of compliance as with lack of efficacy. The number of treatments each day should be kept to a minimum, and patients should be reviewed after four weeks when initiating or changing topical therapy to improve adherence to treatment and assess response. The majority of patients with psoriasis can be managed in primary care, although specialist care may be necessary at some point in up to 60% of cases. Patients with erythrodermic or generalised pustular psoriasis should be referred for a same day dermatological opinion, and if psoriatic arthritis is suspected, early referral for a rheumatological opinion is recommended.

[Evaluation of effect of local administration of desoximetasone and ditranol in psoriatic lesion byapplying 20 MHz ultrasound].

INTRODUCTION: This prospective study was aimed at examining the modification of ultrasound characteristics of psoriatic plaques during desoximetasone and dithranol treatment. MATERIAL AND METHODS: The examination included 50 patients with chronic plaque-type psoriasis to whom 0.25% desoximetasone and dithranol was applied on the psoriatic lesions in the period of 21 days. The changes were measured before and every 7 days after the beginning of therapy by the combined application of A- and B-mode echosonography. RESULTS. At the beginning of the examination, the average values of the enter echo were 0.67 +/- 0.53 mm; hypoehogen shadow 0.30 +/- 0.11 mm, and dermis thickness 3.03 +/- 1.05 mm. On the first check up, the average values of the enter echo were 0.45 +/- 0.29 mm; hypoechogen shadow 0.23 +/- 0.08 mm and dermis thickness 2.65 +/- 0.97 mm. On the second check up, the average values of the enter echo were 0.30 +/- 0.18 mm; hypoechogen shadow 0.21 +/- 0.18 mm, dermis thickness 2.18 +/- 0.82 mm. On the third check up, the average values of the enter echo were 0.24 +/- 0.17 mm; hypoechogen shadow 0.18 +/- 0.17 mm, and dermis thickness 1.8 +/- 0.69 mm. DISCUSSION. The evaluation of the ultrasonographic characteristics revealed a significant reduction in the values in the course of the examination. Statistically significant differences were found before, during, and at the end of the examination by recording the ultrasound parameters of the epidermis and dermis and by following their modification. CONCLUSION. Precise determination of ultrasound parameters of epidermis and dermis and the possibility of recording their modification in a shorter or longer time interval can be used for monitoring and assessment of therapy effect of a medication.

[Children and adolescents with psoriasis. What therapy is recommended?]. / Kinder und Jugendliche mit Psoriasis. Welche Maßnahmen werden empfohlen?

Juvenile psoriasis shows a cumulative incidence of 1.76% until the 18th year of life and thus is important for both pediatricians and dermatologists. In contrast to psoriasis in adults, the main trigger factors are infections, mechanical trauma and stress factors and to a much lesser extent medical and recreational drugs. Apart from the classical predilection sites, the diaper area, scalp and face are mainly involved. Guttate psoriasis following streptococcal infections is a specific clinical manifestation in childhood and adolescence. Psoriasis arthritis of childhood falls into the group of juvenile idiopathic arthritis and typically presents before or simultaneously with skin symptoms. All recommended childhood vaccinations should be administered, ideally when the disease is under remission. Therapy relies heavily on topical agents like dithranol, corticosteroids, and alternatively topical calcineurin inhibitors in addition to individually adapted skin moisturizing measures. In severe cases which do not adequately respond to topical therapy, systemic treatment with classical immunomodulatory agents like methotrexate, cyclosporin, retinoids and fumarates may be initiated but all usage is off-label. The only agent licensed for the treatment of psoriasis in patients above the age of 8 years is etanercept if classical treatment has failed. Rehabilitative measures in mountain and seaside areas are reasonable for maintaining improvement and helping patient learn to deal with disease.