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Five novel complexes of nickel (II)(1), zinc (II)(2), zirconium (IV)(3), lanthanum (III)(4), thorium (IV)(5), with the dithranol (Dithr) ligand and glycine (Gly) were synthesized and characterized. Their structures were investigated using elemental analysis, molar conductance (Λ), magnetic studies (μeff), spectroscopic methods (FT‐IR, UV–Vis., 1H NMR, XRD), mass spectrometry, TG/DTG and DTA. Findings revealed that Dithr was chelated via two hydroxyl oxygen atoms and carbonyl group while, Gly chelated through carboxylic oxygen and nitrogen atom. All complexes appeared with molar ratio 1:1:1 (M:Dithr:Gly) and were electrolytes with 1:1 for (1), (2) and (3) complexes, 1:2 for (4) complex, and 1:3 for (5) complex according to elemental analysis and molar conductivity data. All metal‐chelates, except Th (IV)‐complex, were confirmed to have lattice water molecules based on their thermal behavior. Average crystalline size of all compounds was calculated using XRD analysis and found in the range 35.50–55.57 nm, indicating the compounds existed as nanocrystalline structure, except zirconium (IV) complex. Then, we studied cytotoxic effects of our synthetic drugs on the survival of an aggressive‐breast‐cancer‐histotype"66cl‐4." Given its involvement in cancer‐metastasis, matrix‐metalloproteinase‐(MMP)‐9 protein expression was evaluated using western‐blotting‐assays. Th(IV)‐complex emerged as the most effective option in inhibiting cancer‐cells‐proliferation (IC50: 9.39 μM), and suppressed expression MMP‐9 levels by 86%, at 25 μM dose, and drug‐binding‐affinity was interpreted via molecular modeling. [ABSTRACT FROM AUTHOR]

(1) Introduction: Topical dithranol is still commonly used today as an effective treatment for psoriasis. Dithranol treatment is often supplemented with balneotherapy, which has been shown to increase effectiveness and reduce side effects. The inorganic salts (sulfhide, selenium, zinc) are usually thought to be responsible for the effect. The antioxidant effect of the waters is thought to be behind the therapeutic effect, for which inorganic substances (sulfides, selenium, zinc) are thought to be responsible. The organic matter content of medicinal waters is also particularly important, as humic acids, which are often found in medicinal waters, have antioxidant effects. (2) Methods: In this short-term experiment, we aimed to test the possible protective effect of Szigetvár medicinal water and its organic matter isolate on HaCaT cells exposed to dithranol. Malondialdehyde levels were measured, and RT-qPCR was used to investigate the gene expression of selected cytokines relevant in the oxidative stress response (IL-6, IL-8, TNF-α, GM-CSF) and the expression of microRNA-21. (3) Results: Szigetvár medicinal water and the organic isolate prevented the increase in malondialdehyde levels caused by dithranol treatment. The cytokine gene expressions elevated by dithranol exposure were reduced by the treatment. (4) Conclusions: Szigetvár medicinal water and organic substances alone may have a protective effect on patients' healthy skin surfaces against dithranol damage. We also demonstrated that the organic compounds are also responsible for the protective effect. [ABSTRACT FROM AUTHOR]

(1) Introduction: Topical dithranol is still commonly used today as an effective treatment for psoriasis. Dithranol treatment is often supplemented with balneotherapy, which has been shown to increase effectiveness and reduce side effects. The inorganic salts (sulfhide, selenium, zinc) are usually thought to be responsible for the effect. The antioxidant effect of the waters is thought to be behind the therapeutic effect, for which inorganic substances (sulfides, selenium, zinc) are thought to be responsible. The organic matter content of medicinal waters is also particularly important, as humic acids, which are often found in medicinal waters, have antioxidant effects. (2) Methods: In this short-term experiment, we aimed to test the possible protective effect of Szigetvár medicinal water and its organic matter isolate on HaCaT cells exposed to dithranol. Malondialdehyde levels were measured, and RT-qPCR was used to investigate the gene expression of selected cytokines relevant in the oxidative stress response (IL-6, IL-8, TNF-α, GM-CSF) and the expression of microRNA-21. (3) Results: Szigetvár medicinal water and the organic isolate prevented the increase in malondialdehyde levels caused by dithranol treatment. The cytokine gene expressions elevated by dithranol exposure were reduced by the treatment. (4) Conclusions: Szigetvár medicinal water and organic substances alone may have a protective effect on patients’ healthy skin surfaces against dithranol damage. We also demonstrated that the organic compounds are also responsible for the protective effect.

Psoriasis is a chronic autoimmune skin disorder characterized by the rapid overproduction of skin cells, resulting in the formation of red, inflamed, and scaly patches or plaques on the skin. Dithranol, also known as anthralin, is a very effective topical medication used in the treatment of psoriasis, with several shortcomings like photo-instability; staining skin, clothing, and bedding; and causing skin irritation. Antiproliferative dithranol is frequently used in combination therapy with keratolytic salicylic acid. We have therefore proposed a novel topical antipsoriatic prodrug comprising dithranol and salicylic acid joined together with an ester bond, specifically 8-hydroxy-9-oxo-9,10-dihydroanthracen-1-yl-2-hydroxybenzoate. An ester bond is cleavable by endogenous esterase hydrolyzing this bond and releasing dithranol and salicylic acid in a 1:1 stoichiometric ratio. We performed an exhaustive theoretical analysis of this molecule using the reliable computational methods of quantum chemistry and ADME in silico studies to investigate its biological and pharmacokinetic activities. We found its molecular structure, vibrational spectra, molecular orbitals, MEP (molecular electric potential), UV-VIS spectra, and TDOS (total density of states), and we performed an RDG (reduced density gradient) analysis. The obtained results may be useful for the understanding of its properties, which may assist in the synthesis and further experimental study of this possible antipsoriatic dual-action prodrug with reduced adverse effects and enhanced therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Dithranol is one of the oldest and most efficient drugs used in the treatment of psoriasis. One of the challenges with using dithranol is its photostability, because it easily degrades when exposed to light. This study investigated the potential of coaxial core-sheath PCL/PVA nanofibers as a dual-functional system for enhancing dithranol photostability and remote-controlled drug delivery for psoriasis therapy. We have shown that coaxial nanofibers with titanium oxide nanoparticles (reflecting and absorbing ultra-violet light) in the PVA-based sheath part of the nanofibers can increase dithranol photostability. Incorporation of dithranol and magnetic nanoparticles into a PCL-based core of the nanofibers enables dithranol release control via an external radio-frequency field. The application of a radio-frequency field generates heat that can be used to control the release rate of drugs. Our approach therefore offers a non-invasive and remotely controlled drug release system that hold promise for the development of new topical formulations for psoriasis treatment using dithranol. [ABSTRACT FROM AUTHOR]

Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate the living skin in all its complexity; thus, to date, excised human skin is considered the gold standard for in vitro permeation studies. However, skin explants have a limited life span. In an attempt to overcome this problem, we used an innovative bioreactor that allowed us to achieve good structural and functional preservation in vitro of explanted human skin for up to 72 h. This device was then used to set up an in vitro inflammatory model by applying two distinct agents mimicking either exogenous or endogenous stimuli: i.e., dithranol, inducing the contact dermatitis phenotype, and the substance P, mimicking neurogenic inflammation. Our in vitro system proved to reproduce inflammatory events observed in vivo, such as vasodilation, increased number of macrophages and mast cells, and increased cytokine secretion. This bioreactor-based system may therefore be suitably and reliably used to simulate in vitro human skin inflammation and may be foreseen as a promising tool to test the efficacy of drugs and cosmetics. [ABSTRACT FROM AUTHOR]

Background/Aim: This study aimed to research the effects of Harkány healing water on oxidative stress. The study was performed in a randomized, placebo-controlled, double-blind setup. Patients and Methods: Twenty patients with psoriasis who underwent a 3-week-long inward balneotherapy-based rehabilitation were enrolled. Psoriasis Area and Severity Index (PASI) score and Malondialdehyde (MDA) - a marker of oxidative stress - were determined, on admission and before discharge. Patients were treated with dithranol. Results: The mean PASI score - determined on admission and before discharge - decreased significantly after the 3-week-long rehabilitation 8.17 vs. 3.51 (p<0.001). The baseline MDA value of patients with psoriasis was significantly higher compared to controls (3.0±3.5 vs. 8.4±7.4) (p=0.018). MDA levels of patients receiving placebo water increased significantly compared to MDA levels of patients receiving healing water (p=0.049). Conclusion: The effectiveness of dithranol resides in the formation of reactive oxygen species. No increased oxidative stress was found in the patients treated with healing water, thus healing water seems to be protective against oxidative stress. However, further research is needed to confirm these preliminary results. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic autoimmune skin disorder characterized by the rapid overproduction of skin cells, resulting in the formation of red, inflamed, and scaly patches or plaques on the skin. Dithranol, also known as anthralin, is a very effective topical medication used in the treatment of psoriasis, with several shortcomings like photo-instability; staining skin, clothing, and bedding; and causing skin irritation. Antiproliferative dithranol is frequently used in combination therapy with keratolytic salicylic acid. We have therefore proposed a novel topical antipsoriatic prodrug comprising dithranol and salicylic acid joined together with an ester bond, specifically 8-hydroxy-9-oxo-9,10-dihydroanthracen-1-yl-2-hydroxybenzoate. An ester bond is cleavable by endogenous esterase hydrolyzing this bond and releasing dithranol and salicylic acid in a 1:1 stoichiometric ratio. We performed an exhaustive theoretical analysis of this molecule using the reliable computational methods of quantum chemistry and ADME in silico studies to investigate its biological and pharmacokinetic activities. We found its molecular structure, vibrational spectra, molecular orbitals, MEP (molecular electric potential), UV-VIS spectra, and TDOS (total density of states), and we performed an RDG (reduced density gradient) analysis. The obtained results may be useful for the understanding of its properties, which may assist in the synthesis and further experimental study of this possible antipsoriatic dual-action prodrug with reduced adverse effects and enhanced therapeutic efficacy.

Dithranol is one of the oldest and most efficient drugs used in the treatment of psoriasis. One of the challenges with using dithranol is its photostability, because it easily degrades when exposed to light. This study investigated the potential of coaxial core-sheath PCL/PVA nanofibers as a dual-functional system for enhancing dithranol photostability and remote-controlled drug delivery for psoriasis therapy. We have shown that coaxial nanofibers with titanium oxide nanoparticles (reflecting and absorbing ultra-violet light) in the PVA-based sheath part of the nanofibers can increase dithranol photostability. Incorporation of dithranol and magnetic nanoparticles into a PCL-based core of the nanofibers enables dithranol release control via an external radio-frequency field. The application of a radio-frequency field generates heat that can be used to control the release rate of drugs. Our approach therefore offers a non-invasive and remotely controlled drug release system that hold promise for the development of new topical formulations for psoriasis treatment using dithranol.

Skin is a major administration route for drugs, and all transdermal formulations must be tested for their capability to overcome the cutaneous barrier. Therefore, developing highly reliable skin models is crucial for preclinical studies. The current in vitro models are unable to replicate the living skin in all its complexity; thus, to date, excised human skin is considered the gold standard for in vitro permeation studies. However, skin explants have a limited life span. In an attempt to overcome this problem, we used an innovative bioreactor that allowed us to achieve good structural and functional preservation in vitro of explanted human skin for up to 72 h. This device was then used to set up an in vitro inflammatory model by applying two distinct agents mimicking either exogenous or endogenous stimuli: i.e., dithranol, inducing the contact dermatitis phenotype, and the substance P, mimicking neurogenic inflammation. Our in vitro system proved to reproduce inflammatory events observed in vivo, such as vasodilation, increased number of macrophages and mast cells, and increased cytokine secretion. This bioreactor-based system may therefore be suitably and reliably used to simulate in vitro human skin inflammation and may be foreseen as a promising tool to test the efficacy of drugs and cosmetics.

Lingyun Wu,1,2,* Guoyan Liu,2,* Wenyu Wang,1 Ruobing Liu,1 Lingyan Liao,1 Ni Cheng,1 Wentong Li,3 Weifen Zhang,1 Dejun Ding1 1College of Pharmacy, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China; 2Department of Dermatology, Affiliated Hospital of Weifang Medical University, Weifang 261031, People’s Republic of China; 3Department of Pathology, Weifang Medical University, Weifang, Shandong 261053, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weifen Zhang; Dejun DingCollege of Pharmacy, Weifang Medical University, 7166# Baotong West Street, Weifang, Shandong 261053, People’s Republic of ChinaTel/Fax +(86)-0536-8462051Email zhangwf@wfmc.edu.cn; dejunding@wfmc.edu.cnPurpose: Reactive oxygen species (ROS)-induced oxidative stress plays a key role in the pathogenesis and progression of psoriasis by causing inflammation. Antioxidative strategies eradicating ROS may serve as effective and easy treatment options for psoriasis, while nanozymes with intrinsic antioxidant enzyme-like activity have not been explored for psoriasis treatment. The aim of this study is to fabricate β-cyclodextrins (β-CDs)-modified ceria nanoparticles (β-CDs/CeO2 NPs) with drug-loaded and multimimic-enzyme activities for combinational psoriasis therapy.Methods: The β-CDs/CeO2 NPs were synthesized by a hydrothermal method using unmodified β-CDs as a protecting agent. The structure, size and morphology were analyzed by dynamic light scattering, transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy. Considering the superoxide dismutase (SOD)- and catalase-mimetic activities, the in vitro antioxidant activity of the β-CDs/CeO2 NPs was investigated. After dithranol (DIT) was loaded, the drug-loading capacity and release profile were determined by UV-visible light spectrophotometer and high-performance liquid chromatography. The anti-psoriatic efficacy was studied in the imiquimod (IMQ)-induced mouse model on the basis of morphological evaluation, psoriasis area and severity index calculation (PASI), and inflammatory cytokine expression.Results: The average particle size of the blank β-CDs/CeO2 NPs was 60.89± 0.32 nm with a polydispersity index (PDI) of 0.12, whereas that of the DIT-loaded NPs was 79.38± 1.06 nm with a PDI of 0.27. TEM results showed the as-prepared NPs formed a uniform quasi-spherical shape with low polydispersity. XPS indicates synthesized NPs have a mixed Ce3+/Ce4+ valence state. FTIR spectroscopy confirmed the presence of β-CDs and DIT in the NPs. Inhibition of superoxide anion rate by NPs could be reached to 79.4% in the presence of 200 μg/mL, and elimination of H2O2 efficiency reached about 50% in the presence of 40 μg/mL, demonstrating excellent superoxide dismutase- and catalase-mimicking activities, thereby providing remarkable cryoprotection against ROS-mediated damage. Furthermore, β-CDs on the surface endowed the NPs with drug-loading function via host–guest interactions. The entrapment efficiency and drug loading of DIT are 94.7% and 3.48%, respectively. The in vitro drug release curves revealed a suitable release capability of DIT@β-CDs/CeO2 NPs under physiological conditions. In IMQ-induced psoriatic model, the DIT@β-CDs/CeO2 NPs exhibited excellent therapeutic effect.Conclusion: This study may pave the way for the application of nanozyme β-CDs/CeO2 NPs as a powerful tool for psoriasis therapy.Keywords: ceria nanoparticles, reactive oxygen species, mimic-enzyme, dithranol, anti-psoriatic, drug delivery

Background: Hair is susceptible to exogenous sources of discoloration. There are several exogenous etiologies for yellow hair discoloration, including tobacco.Purpose: We describe the clinical features of five men with tobacco-associated yellow discoloration of their mustache, a condition known as "smoker's mustache." We also review the characteristics of men with tobacco-associated yellow discoloration of their scalp or mustache hair.Materials and methods: The features of five men with smoker's mustache are presented. Using PubMed, the following terms were searched and relevant citations assessed: 4-4'-methylenedianiline, acid, dithranol, MDA, mustache, nicotine, picric, resorcin, smoker, tar, tobacco, and yellow. In addition, the literature on smoker's mustache is reviewed.Results: Smoker's mustache was an incidental finding and not the reason for patients presenting for medical attention. The condition was asymptomatic. In our patients, 60% (3 of 5) also had tobacco-related clinical findings on the distal soft tissue and/or nails of their fingers.Conclusion: Smoker's mustache refers to tobacco-associated discoloration of the hair of the upper lip of men. It is an asymptomatic condition that usually presents as an incidental finding. Indeed, patients tend to be unaware of the condition until it is brought to their attention. In addition to hair manifestations, patients may also demonstrate other tobacco-associated skin and nail findings, particularly brown or yellow-brown discoloration of their fingertip and/or fingernail. We postulate that discontinuation of smoking would eventually result in spontaneous resolution of the condition. However, all of our patients were determined to continue smoking.

Despite the introduction of biologics, topical dithranol (anthralin) has remained one of the most effective anti-psoriatic agents. Serial biopsies from human psoriatic lesions and both the c-Jun/JunB and imiquimod psoriasis mouse model allowed us to study the therapeutic mechanism of this drug. Top differentially expressed genes in the early response to dithranol belonged to keratinocyte and epidermal differentiation pathways and IL-1 family members (i.e. IL36RN) but not elements of the IL-17/IL-23 axis. In human psoriatic response to dithranol, rapid decrease in expression of keratinocyte differentiation regulators (e.g. involucrin, SERPINB7 and SERPINB13), antimicrobial peptides (e.g. ß-defensins like DEFB4A, DEFB4B, DEFB103A, S100 proteins like S100A7, S100A12), chemotactic factors for neutrophils (e.g. CXCL5, CXCL8) and neutrophilic infiltration was followed with much delay by reduction in T cell infiltration. Targeting keratinocytes rather than immune cells may be an alternative approach in particular for topical anti-psoriatic treatment, an area with high need for new drugs.

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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. [ABSTRACT FROM AUTHOR]

Abstract: 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. [ABSTRACT FROM AUTHOR]

Background:Pathogenesis of psoriasis involves epidermal growth factor (EGF) that participates in keratinocyte proliferation, angiogenesis and cell differentiation through binding to soluble epidermal growth factor receptor (sEGFR). It is synthesised by, among others, keratinocytes, especially within psoriatic skin. Objective:To evaluate EGF and sEGFR plasma concentrations during topical psoriatic treatment. Methods:Blood samples were collected from 51 patients with plaque psoriasis. EGF and sEGFR plasma concentrations were examined with immunoenzymatic method prior and 14 days after topical treatment. The outcomes were analyzed with respect to PASI. Results:Mean EGF concentration was higher in the plasma of psoriatic patients compared to the control group (p = .401) while mean sEGFR concentration was over twofold lower compared to the control group (p < .001). After the therapy, an insignificant decrease in EGF plasma concentration (p = .835) and a significant increase in sEGFR concentration (p = .017) compared to initial values were observed. The coefficient of EGF/sEGFR concentration calculated for each individual had similar values before and after the treatment (p = .009), both of which were significantly higher compared to control group (respectivelyp < .001,p < .008). Conclusion:Epidermal growth factor and its soluble receptor may be a useful markers in monitoring clinical course of psoriasis and the effectiveness of therapy. [ABSTRACT FROM PUBLISHER]

Background Psoriasis is an inflammatory skin disease with aberrant keratinocyte proliferation, presumably as a result of immune cell activation. Th17 cytokines like IL-17A and IL-22 are critically implicated in epidermal thickening, altered keratinocyte differentiation and production of innate factors such as antimicrobial peptides. Psoriasis treatment options include modern targeted therapies using anti-cytokine antibodies and traditional non-targeted treatments like anthralin (dithranol). While the mode of action of anti-cytokine antibodies is defined, the effects of topical anthralin on psoriatic skin are not fully understood. Objective This study aims to unravel the direct effects of anthralin on keratinocyte proliferation, differentiation and production of psoriasis-associated factors. Methods We tested the effects of anthralin on cell proliferation, cytokeratin expression and changes in the expression of antimicrobial peptides using primary keratinocytes and 3D psoriasis tissue models with and without stimulation of the psoriasis-promoting cytokines IL-17A and IL-22. Moreover, we compared the findings derived from monolayer and multilayer cultures to data derived from lesional skin of patients with psoriasis before and under treatment with anthralin. Results Our study shows that anthralin directly induces cell apoptosis in vitro in monolayer cultures but not in 3D psoriasis tissue models treated with IL-17A and IL-22. Yet, keratinocyte proliferation as determined by Ki-67 staining is impaired by anthralin in vivo . In lesional skin but not in 3D psoriasis tissue models anthralin rapidly normalizes cytokeratin (CK)16 expression. Furthermore, anthralin directly inhibits DEFB4 expression in vitro and in vivo , while other antimicrobial peptides and cytokines studied like IL-6 and IL-8 are regulated differently in vitro and in vivo . Conclusions Our results show that anthralin directly regulates DEFB4A expression. However, its beneficial effects on psoriasis cannot be explained by direct effects on keratinocyte differentiation or cytokine expression. [ABSTRACT FROM AUTHOR]

Irritant contact dermatitis (ICD) is an inflammatory skin condition characterized by severe eczematous lesions. Nanoparticulate drug delivery is the most predominant way to improve dermal penetration and have gained remarkable recognition for targeted delivery of therapeutic payload and reduced off-target effects. Therefore, the current work aimed to fabricate polyelectrolyte complex nanoparticles (PENPs) containing two natural biodegradable polymers namely; chitosan (CS) and hyaluronic acid (HA) to deliver the non steroidal anti-inflammatory drug etoricoxib (ETX) to the deeper skin layers to alleviate any systemic toxicity and improve its therapeutic efficacy against ICD. ETX loaded-PENPs were prepared and optimized utilizing three independent variables; CS: HA mass ratio, chitosan solution pH and molecular weight of chitosan. Following the various physicochemical optimizations, the optimum ETX-loaded PENPs formulation (N1 0.15 %) exhibited spherical nature with an average diameter of 267.9 ± 9.4 nm, Polydispersity index of 0.366 ± 0.02, and positive zeta potential (+32.9 ± 0.47 mV). The drug was successfully entrapped and the entrapment efficiency reached 95 ± 0.2 %. N1 0.15 % formula showed efficient dermal targeting by significantly enhanced percentage of ETX permeated and retained in the various skin layers in comparison to ETX conventional gel during the ex-vivo skin permeation experiments. Furthermore, N1 0.15 % exhibited superior anti-inflammatory properties in vivo compared to ETX conventional gel in dithranol induced mice ear dermatitis. Conclusively, ETX-loaded PENPs could be a promising therapeutic approach for effecient management of ICD. [ABSTRACT FROM AUTHOR]

Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 μM·min−1 and Km = 65.1 μM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis.

This study describes a 3² full factorial experimental design to optimize the formulation of dithranol (DTH) loaded solid lipid nanoparticles (SLN) by the pre-emulsion ultrasonication method. The variables drug: lipid ratio and sonication time were studied at three levels and arranged in a 3² factorial design to study the influence on the response variables particle size and % entrapment efficiency (%EE). From the statistical analysis of data polynomial equations were generated. The particle size and %EE for the 9 batches (R1 to R9) showed a wide variation of 219-348 nm and 51.33- 71.80 %, respectively. The physical characteristics of DTH-loaded SLN were evaluated using a particle size analyzer, differential scanning calorimetry and X-ray diffraction. The results of the optimized formulation showed an average particle size of 219 nm and entrapment efficiency of 69.88 %. Ex-vivo drug penetration using rat skin showed about a 2-fold increase in localization of DTH in skin as compared to the marketed preparation of DTH.Este estudo descreve o planejamento factorial 3² para otimizar a formulação de nanopartículas lipídicas sólidas (SLN) carregadas com ditranol (DTH) pelo método da ultrassonificação pré-emulsão. As variáveis como proporção de fármaco:lipídio e o tempo de sonicação foram estudados em três níveis e arranjados em planejamento fatorial 3² para estudar a influência nas variáveis de resposta tamanho de partícula e eficiência percentual de retenção do fármaco (%EE). Pela análise estatística, geraram-se equações polinomiais. O tamanho da partícula e a %EE para os 9 lotes (R1 a R9) mostraram ampla variação, respectivamente, 219-348 nm e 51,33-71,80%. As características físicas das SLN carregadas com DTN foram avaliadas utilizando-se analisador de tamanho de partícula, calorimetria de varredura diferencial e difração de raios X. Os resultados da formulação otimizada mostraram tamanho médio de partícula de 219 nm e eficiência de retenção do fármaco de 69,88%. A penetração ex vivo do fármaco utilizando pele de rato mostrou aumento de, aproximadamente, duas vezes na localização de DTH na pele, comparativamente à preparação de DTH comercializada.

Purpose TNF-like weak inducer of apoptosis (TWEAK) mediates not only apoptosis, but also inflammation, cell growth and angiogenesis. The role of TWEAK in psoriasis remains unknown. The aim of the study was to assess serum levels of TWEAK in psoriatic patients before and after topical treatment with dithranol in relation to the clinical activity of the disease. Material and methods Serum samples were collected from 40 patients with plaque type psoriasis before and after topical treatment with dithranol. The concentrations of serum TWEAK were measured by ELISA and next compared with 16 healthy controls. The data were analyzed with respect to Psoriasis Area and Severity Index (PASI). Results Baseline serum TWEAK concentrations of psoriatic patients (685 ± 166 pg/ml) were significantly greater compared to healthy controls (565 ± 110 pg/ml). Topical treatment resulted in further increase in serum TWEAK (749 ± 179 pg/ml; p < 0.01). In case of patients with initial serum TWEAK concentrations above the median, PASI after topical treatment was lower compared to the individuals with initial TWEAK below the median. Conclusion According to the study, serum Tweak was increased in psoriasis patients compared with controls. Moreover, dithranol topical treatment caused further increase in serum TWEAK. Also, a higher effectiveness of topical treatment was observed in case of patients with higher initial TWEAK concentrations. The results suggest a potential role of TWEAK in psoriasis therapy. [ABSTRACT FROM AUTHOR]

Selective alkylation of the antipsoriatic drug dithranol (DTR) at C-10 with tert -butyl bromoacetate, followed by acid-mediated deprotection, produced the corresponding carboxylic acid 4 which was coupled with selectively protected polyamines (PAs), such as putrescine (PUT), spermidine (SPD) and spermine (SPM), dopamine and aliphatic amines and substituted benzylamines producing a series of DTR–PA hybrids, after acid-mediated deprotection, as well as simple amides. The compounds were tested as antioxidants and inhibitors of lipoxygenase (LOX). The amides 4,4′-dimethoxybenzhydrylamide 13 (86% and 95%), 2,4-dimethoxybenzylamide 12 (87% and 81%) and dodecylamide 9 (98% and 74%), and the hybrid DTR–SPM ( 7 ) (93% and 87%), showed the highest antioxidant activity in the DPPH and AAPH assays, whereas the most potent inhibitors of LOX were amide 13 (IC 50 = 7 μM), the benzylamide 10 (IC 50 = 7.9 μM) and the butylamide 8 (IC 50 = 10 μM). Molecular binding studies showed that binding of these derivatives into the hydrophobic domain blocks approach of substrate to the active site, inhibiting soybean LOX. Amide 13 presented the highest anti-inflammatory activity (79.7%). The DTR moiety was absolutely necessary for securing high anti-inflammatory potency. Ethyl ester 3 (IC 50 = 0.357 μM) and the amides 9 (IC 50 = 0.022 μM) and 13 (IC 50 = 0.56 μM) exhibited higher antiproliferative activity than DTR (IC 50 = 0.945 μM) on HaCaT keratinocytes whereas amide 13 generally presented better cytocompatibility. Amide 13 is a very promising lead compound for further development as an anti-inflammatory and antiproliferative agent. [ABSTRACT FROM AUTHOR]

Context: Phyllanthus simplex Retz. (Phyllanthaceae) , Crotolaria juncea Linn. (Leguminosae), Leucas aspera Linn. (Lamiaceae), and Vitex glabrata R.Br. (Verbenaceae) are well-known Indian medicinal plants. Different parts of these plants are used for healing purposes traditionally in the treatment of psoriasis and various other disorders. This prompted us to assess the antipsoriatic activities of these plants. Objectives: Petroleum ether and ethanol extracts of the selected plants, i.e., P. simplex (whole plant), C. juncea (seeds), L. aspera (aerial parts), and V. glabrata (leaves) were investigated for their in vitro antipsoriatic activity. Materials and methods: Antipsoriatic activity of the extracts was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, using HaCaT cells. About 200 µl of different concentrations (25, 50, 100, 200, and 400 µg/ml) of test samples were prepared in the cell culture medium and incubated for 24 h before MTT assay to determine the viable cells. The effect of these extracts on nitric oxide (NO) production and lipid peroxidation was also evaluated. Results: Our findings revealed that these plants showed promising skin keratinocyte antiproliferative activity. However, the petroleum ether extract of C. juncea (CJPE) and ethanol extract of L. aspera (LAEE) were found to exhibit significant activity (IC50 value = 45.45 and 55.36 µg/ml, respectively). Discussion and conclusions: The inhibitory action against NO production and lipid peroxidation in HaCaT cells suggested that the antipsoriatic activity of the extracts was mediated by an antioxidant mechanism . These findings validate the claims of the use of these plants in the treatment of psoriasis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Dithranol is a very effective drug for the topical treatment of psoriasis. However, it has some adverse effects such as irritation and stain in the skin that make its application and patient adherence to treatment difficult. The aims of this work were to prepare and characterize dithranol-loaded nanocapsules as well as to evaluate the photostability and the irritation potential of these nanocarriers. Lipid-core nanocapsules containing dithranol (0.5 mg/mL) were prepared by interfacial deposition of preformed polymer. EDTA (0.05%) or ascorbic acid (0.02%) was used as antioxidants. After preparation, dithranol-loaded lipid-core nanocapsules showed satisfactory characteristics: drug content close to the theoretical concentration, encapsulation efficiency of about 100%, nanometric mean size (230–250 nm), polydispersity index below 0.25, negative zeta potential, and pH values from 4.3 to 5.6. In the photodegradation study against UVA light, we observed a higher stability of the dithranol-loaded lipid-core nanocapsules comparing to the solution containing the free drug (half-life times around 4 and 1 h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing EDTA, respectively; half-life times around 17 and 7 h for the dithranol-loaded lipid-core nanocapsules and free drug solution containing ascorbic acid, respectively). Irritation test by HET-CAM method was conducted to evaluate the safety of the formulations. From the results it was found that the nanoencapsulation of the drug decreased its toxicity compared to the effects observed for the free drug. [ABSTRACT FROM AUTHOR]

Treatment of 10-bromoanthralin (1) with several thiophenols (2) gave the corresponding 10-arylthioanthralins (3) in high yields. Oxidation of thioanthralins (3a-c) and (3k-m) using an excess of m-chloroperbenzoic acid gave the corresponding sulfones (4a-c) and (4k-m) in good yields. Oxidation of thioanthralins (3d-f) gave a mixture of the corresponding sulfones (4d-f) and anthralin-10,10'-dehydrodimer (5). Oxidation of thioanthralins (3g-j) afforded only anthralin-10,10'-dehydrodimer (5) with no evidence of sulfone.

Highlights: [•] New model of drug transport was presented. [•] Two methods for solving transport equation were used. [•] Dithranol transport through a DDC membrane was investigated. [•] Photoacoustic profilometry of drug distribution in membrane was performed. [Copyright &y& Elsevier]

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/cm2/h and 1.0, respectively) when compared with the plain DIT solution (2.72 ± 0.31 μg/cm2/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. [ABSTRACT FROM AUTHOR]

Psoriasis is a common, chronic and relapsing inflammatory skin disease. It affects approximately 2% of the western population and has no cure. Combination therapy for psoriasis often proves more efficacious and better tolerated than monotherapy with a single drug. Combination therapy could be administered in the form of a co-drug, where two or more therapeutic compounds active against the same condition are linked by a cleavable covalent bond. Similar to the pro-drug approach, the liberation of parent moieties post-administration, by enzymatic and/or chemical mechanisms, is a pre-requisite for effective treatment. In this study, a series of co-drugs incorporating dithranol in combination with one of several non-steroidal anti-inflammatory drugs, both useful for the treatment of psoriasis, were designed, synthesized and evaluated. An ester co-drug comprising dithranol and naproxen in a 1:1 stoichiometric ratio was determined to possess the optimal physicochemical properties for topical delivery. The co-drug was fully hydrolyzed in vitro by porcine liver esterase within four hours. When incubated with homogenized porcine skin, 9.5% of the parent compounds were liberated after 24 h, suggesting in situ esterase-mediated cleavage of the co-drug would occur within the skin. The kinetics of the reaction revealed first order kinetics, Vmax = 10.3 μM.min-1 and Km = 65.1 μM. The co-drug contains a modified dithranol chromophore that was just 37% of the absorbance of dithranol at 375 nm and suggests reduced skin/clothes staining. Overall, these findings suggest that the dithranol-naproxen co-drug offers an attractive, novel approach for the treatment of psoriasis. [ABSTRACT FROM AUTHOR]

Objectives Dithranol, one of the most successful topical agents for the treatment of psoriasis, has been shown to exert its therapeutic effect by inducing keratinocyte apoptosis. To gain further insights into dithranol-induced apoptotic events in vitro, a detailed investigation of its time- and dose-dependent effects has been performed through the evaluation of selected apoptotic markers, using a human keratinocyte cell line ( HaCaT) as a model. Methods The time- and dose-dependent effects of dithranol on a human keratinocyte cell line ( HaCaT) were investigated through the evaluation of a series of apoptotic markers; morphological changes (electron microscopy), phosphatidylserine externalisation (flow cytometry), and caspase-3/7 activation. Key findings The dithranol-induced apoptotic cascade was found to follow a well-defined dose and time-course, with the concentration and the period of exposure to the drug acting as the two major factors influencing the events and nature of cell death. The earliest apoptotic event detected was caspase activation (after 6 h), followed by the occurrence of phosphatidylserine externalisation (after 9 h) and subsequently the morphological characteristics associated with early and late stage apoptosis/necrosis (after 12 h). Conclusions This study has elucidated the dose- and time-response effects of dithranol-induced apoptosis in human keratinocytes in vitro. [ABSTRACT FROM AUTHOR]

The purpose of this study was to improve the stability of dithranol, an effective drug for topical treatment of psoriasis. Solid lipid nanoparticles (SLNs) were prepared by pre-emulsion followed by ultrasonication technique to investigate whether the inclusion in the lipid matrix could increase stability of the drug. Physicochemical characterization of the particles by differential scanning calorimetry (DSC) revealed that homogenization followed by ultrasonication is a suitable approach for dithranol-loaded SLN preparation. Preparation of SLNs was based on the previous part of this study. Mass-spectrometric determinations of dithranol and its degradation product were performed. The obtained average particle size was 219 nm; up to 69.88 % of drug was entrapped in the SLNs. The results showed that the inclusion of dithranol in SLNs reduced the rate of drug degradation. [ABSTRACT FROM AUTHOR]

Background: In childhood psoriasis, physicians aim for an effective and safe treatment such as with dithranol. This study presents the largest study of dithranol-treated patients described in the literature. Objective: The aim of the study was to determine the position of dithranol in the treatment strategy for psoriasis. Methods: All juvenile patients receiving dithranol treatment at our center were evaluated retrospectively. Results: Sixty patients (with 82 treatment episodes in total) were included. The mean age at the start of dithranol treatment was 11.1 years (range: 3.7–17.9 years). The result of the treatment was: excellent (3.7%), good (69.5%), moderate (8.5%), reasonable (13.4%) or disappointing (4.9%). Mild irritation was seen in 39%, and severe irritation in 63% of the patients. Conclusions: Dithranol can be regarded as an efficacious and safe topical therapy for the treatment of childhood psoriasis. It is a valuable alternative topical treatment which should not be disregarded in the treatment regimen for childhood psoriasis and should be commenced before ultraviolet or systemic treatments are initiated. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Various methods exist for research into the penetration process in the human nail plate and for investigation of dermal drug delivery. Application of spectroscopic methods in this scientific field is gaining importance. However, no method meets all demands of the large variety of applications. An alternative optical technique for the characterisation of samples is the photothermal spectroscopy. Photoacoustic techniques, photothermal radiometry, and photothermal beam deflection spectroscopy (PDS) are non-destructive analytical techniques that take advantage of the so-called photoacoustic and photothermal phenomena. PDS, in conjunction with an appropriate scanner, allows for depth profiling and is a promising technique for studies of three-dimensional drug diffusion into artificial and biological membranes. The objective of this article is to demonstrate the use of PDS imaging for pharmaceutical applications and drug delivery studies, with two experiments being used as examples: the follow-up of lateral dithranol penetration into an artificial membrane and depth-resolved measurement of the distribution of a model drug within a keratin membrane from bovine hoof. [Copyright &y& Elsevier]

The purpose of this study was to improve the stability of dithranol, an effective drug for topical treatment of psoriasis. The influence of several formulations (microemulsions, O/W emulsion, gel emulsion, and gel) on the photodegradation kinetics of dithranol was investigated. The photodegradation rate was found to be related with the initial drug concentration and the nature of the vehicle. Solid lipid nanoparticles (SLN) were prepared by solvent injection technique to investigate whether the inclusion in the lipid matrix could increase the stability of the drug. Physicochemical characterization of the particles by optical microscopy, photon correlation spectroscopy (PCS) and differential scanning calorimetry (DSC) revealed that solvent injection is a suitable approach for dithranol-loaded SLN preparation. The obtained particle sizes were between 230 and 270 nm; up to 92% of drug was entrapped in the SLN. The photodegradation kinetic constants (kc) of dithranol in SLN were related with the medium in which the particles were dispersed. The stability over time of dithranol was also investigated storing the samples at 25°C and the results showed that the drug inclusion in SLN dispersed in gel emulsion reduced its rate of degradation. [ABSTRACT FROM AUTHOR]

Abstract: Reactions of anti-psoriasis drug dithranol with 1-alkynyl Fischer carbene complexes (CO)5Me:glyph name="tbnd" />CPh (M=Cr, W) were investigated under controlled conditions in which triethylamine-promoted C-addition, O-addition, electrophilic aromatic substitution, and cyclization consecutively occurred at up to five positions of dithranol. A remarkable solvent effect led to selective formation of polyphenolic organic and organometallic mono- and triscarbene complexes which were efficiently demetalated to the potentially bioactive aromatic polyketides with pyridine-N-oxide. All the organic and organometallic products were characterized by methods including X-ray single crystal structural determinations. These results have revealed the novel multiple reactivities of dithranol which might be associated to its clinical side effect, providing a new synthetic methodology to functionalize dithranol for medical purposes, and chemically synthesize aromatic polyketides. [Copyright &y& Elsevier]