Treatment Of Allergic Skin Diseases Research Articles

2023 AAHA Management of Allergic Skin Diseases in Dogs and Cats Guidelines.

These guidelines present a systematic approach to diagnosis, treatment, and management of allergic skin diseases in dogs and cats. The guidelines describe detailed diagnosis and treatment plans for flea allergy, food allergy, and atopy in dogs and for flea allergy, food allergy, and feline atopic skin syndrome in cats. Management of the allergic patient entails a multimodal approach with frequent and ongoing communication with the client. Obtaining a comprehensive history is crucial for diagnosis and treatment of allergic skin diseases, and the guidelines describe key questions to ask when presented with allergic canine and feline patients. Once a detailed history is obtained, a physical examination should be performed, a minimum dermatologic database collected, and treatment for secondary infection, ectoparasites, and pruritus (where indicated) initiated. The process of diagnosing and managing allergic skin disease can be prolonged and frustrating for clients. The guidelines offer recommendations and tips for client communication and when referral to a dermatologist should be considered, to improve client satisfaction and optimize patient outcomes.

Pharmacological activity cream of extract Salix alba and zinc for allergic contact dermatitis

Allergic dermatitis is the most common skin disease, manifested by classic factors in response to the external environment. Solving the problem of global prevalence and intensive growth of the frequency of allergic dermatitis requires improving the medical supply of the population of Ukraine with drugs for the effective treatment of allergic skin diseases. According to the literature, preparations based on white willow bark have a wide range of biological effects, which exhibit anti-inflammatory, anti-allergic, anti-pruritic, analgesic activity and have a positive effect on the immune system and are promising for the treatment and prevention of allergic dermatitis. Zinc takes part in metabolism and stabilization of cell membranes, is part of the main enzymes that take part in antioxidant biochemical reactions. The trace element has a regenerating effect, ensures the transmission of nerve impulses, promotes the synthesis of cortisol. 
 The purpose of our work was to study the effect of a cream based on white willow and Zn antigen-specific link of immune protection of animals on 3 experimental allergic dermatitis. 
 The study was conducted on сavia porcellus. Allergic contact dermatitis was modeled using 2,4-dinitrochlorobenzene. Phagocytic activity of granulocytic neutrophils in a suspension of leukocytes is determined for assessment of the activity of factors of non-specific immunity.
 It is important to determine the status of antigen-specific factors of immune protection, which are directly involved in all doses of the immune response. To assess the activity of factors of nonspecific immunity, the phagocytic activity of granulocytic neutrophils was determined in the suspension of leukocytes obtained from heparinized blood.
 The obtained data on the increase of F1 and F4 indicators in animals against the background of experimental dermatitis indicate the presence of a natural protective defense aimed at neutralizing the allergen and its subsequent removal from the body. In comparison with reference drugs it was found distinct antigen-specific effect, which exceeds Psoricap and is equal Fladex.
 On the model of allergic contact dermatitis in Cavia porcellus, the researched cream showed a pronounced immunotropic activity relative to a decrease in the phagocytic activity of cell.

The effects of oclacitinib treatment on antimicrobial usage in allergic dogs in primary practice: an Australia wide case-control study

BackgroundCanine allergic dermatitis is a common diagnosis in veterinary practices which can lead to secondary infections requiring treatment with antimicrobials. A previous study suggested that dogs treated with oclacitinib in an Australian referral hospital required fewer courses of antimicrobial therapy compared to dogs receiving other anti-pruritic treatments. This study aimed to quantify the effect of oclacitinib treatment on the use of antimicrobials and other therapies in general practice veterinary clinics across Australia. A retrospective case-controlled review of patient records was designed to investigate the number of courses of antimicrobials and other therapies in dogs that received oclacitinib (Apoquel®), compared with those who received an anti-pruritic treatment that was not oclacitinib.ResultsThe target population included canine patients with a presumptive diagnosis of allergic dermatitis presenting between 2008 and 2018 to general practices contributing to the VetCompass Australia database. Patient records of interest were identified using search terms relating to allergic dermatitis, resulting in over 700,000 observations. Multivariable logistic regression models were developed to determine whether cases were prescribed fewer antimicrobial courses than controls, after adjusting for the presence of concurrent skin infections or infectious agents in ears. Our results indicate that fewer antimicrobial courses were prescribed in the cases compared to the controls. After adjusting for the concurrent skin infections, there was a significant reduction in the use of cefovecin [OR:0.62(0.39–0.98), P = 0.043], chlorhexidine [OR:0.57(0.42–0.77), P < 0.001], neomycin [OR:0.4(0.28–0.56), P < 0.001] and amoxycillin clavulanic acid (AMC) [OR: 0.55(0.39–0.78), P = 0.001] in cases compared to controls.ConclusionThis study demonstrates a potential sparing effect of oclacitinib on the prescription of antimicrobials for the treatment of allergic skin diseases in dogs. This information may assist in the planning of treatment for canine allergic dermatitis, with consideration for antimicrobial stewardship.

Sarsasapogenin and fluticasone combination improves DNFB induced atopic dermatitis lesions in BALB/c mice

Objective Atopic dermatitis (AD) is a pruritic, chronic, relapsing inflammatory skin disease. The research aims to study the effects of Sarsasapogenin and its combination with Fluticasone in 2, 4-Dinitrofluorobenzene (DNFB) induced atopic dermatitis in BALB/c mice. Material and Methods Thirty male Balb/c mice were divided into 5 groups: (i) Normal control (NC), (ii) Disease control (DNFB), (iii) Sarsasapogenin (SG) (50 µg/mice), (iv) Fluticasone (FC) (50 µg/mice), (v) Sarsasapogenin + Fluticasone (SG + FC) combination (25 µg/mice). Dermatitis was induced by repeated application of DNFB in Balb/c mice. On topical application of SG, FC, and SG + FC combination on the ear and skin lesions, body weight, ear weight, ear thickness, erythema score, spleen weight, cytokines, immunoglobulin E (IgE) levels, nitric oxide (NO) level, hematological parameters, and oxidative stress markers were evaluated. Histological analysis of the ear tissue was also done. Results The results stated that SG and SG + FC treatment to mice considerably decrease the ear weight, ear thickness, spleen weight, serum IgE, cytokines, NO levels, and restoration of antioxidant stress markers with elevation in the hematological parameters. The observations were further confirmed by histopathological analysis of ear tissue. Conclusion These data specify that SG has been demonstrated as a probable therapy for the treatment of allergic skin diseases in combination with FC by decreasing its dose from 50 to 25 µg/mice to avoid the chronic side effects of FC. Hence, it can be concluded that SG and SG + FC combination significantly improved the AD-like symptoms in the DNFB sensitized mice through mitigating the production of proinflammatory mediators and restoration of oxidative stress markers.

Non-thermal plasma inhibits mast cell activation and ameliorates allergic skin inflammatory diseases in NC/Nga mice

Non-thermal plasma (NTP) has many functional activities such as, sterilization, wound healing and anti-cancer activity. Despite of its wide spread biomedical application, the effect of NTP on immune cells and allergic response has not been well studied. In this study, we determined whether NTP suppresses mast cell activation, which is important for allergic response, and ameliorates an atopic dermatitis (AD)-like skin inflammatory disease in mice. Exposure to NTP-treated medium during mast cell activation inhibited the expression and production of IL-6, TNF-α and suppressed NF-κB activation. We also investigated whether NTP treatment ameliorates house dust mite (HDM)-induced AD-like skin inflammation in mice. NTP treatment inhibited increases in epidermal thickness and recruitment of mast cells and eosinophils, which are important cell types in AD pathogenesis. In addition, Th2 cell differentiation was induced by application of HDM and the differentiation was also inhibited in the draining lymph node of NTP-treated mice. Finally, the expression of AD-related cytokines and chemokines was also decreased in NTP-treated mice. Taken together, these results suggest that NTP might be useful in the treatment of allergic skin diseases, such as AD.

MicroRNA-126 accelerates IgE-mediated mast cell degranulation associated with the PI3K/Akt signaling pathway by promoting Ca2+ influx.

Mast cells (MCs) have been reported to serve a crucial role in allergic diseases, including asthma, allergic rhinitis and anaphylaxis. A previous study revealed that microRNA-126 (miR-126) was associated with airway hyperresponsiveness induced by house dust mites, however the molecular mechanisms were unclear. The present study aimed to investigate the effect of miR-126 on immunoglobulin E (IgE)-regulated MC degranulation and explore its underlying mechanisms. miR-126 expression was quantified using a rat model in vivo and in rat peritoneal mast cells (RPMCs) in vitro. Overexpression or downregulation of miR-126 was established by transfection with miR-126 mimics or miR-126 inhibitors and MC degranulation was subsequently evaluated. The effect of miR-126 on protein kinase B (Akt) and phosphorylated Akt protein expression was examined by western blot analysis. The phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) was used to determine the role of the PI3K/Akt signaling pathway. In addition, cytosolic calcium (Ca2+) levels were measured by a fura-2 assay. The results demonstrated that miR-126 expression was upregulated in the ear tissues of rats with allergic contact dermatitis and IgE-activated MCs. The overexpression of miR-126 in RPMCs was established following miR-126 mimic transfection. The release of β-hexosaminidase and histamine, markers of MC degranulation, were significantly increased in cells with miR-126 overexpression. The phosphorylation of Akt was significantly increased following transfection with miR-126 mimics in stimulated cells, however the signaling activation was abrogated by LY294002. In addition, Ca2+ influx was significantly promoted in stimulated RPMCs overexpressing miR-126. These results indicate that miR-126 accelerated IgE-mediated MC degranulation associated with the PI3K/Akt signaling pathway by promoting Ca2+ influx. This suggests that miR-126 may be a promising therapeutic target for the treatment of allergic skin diseases.

Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-\u03baB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)

BackgroundHistamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.MethodsInterleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.ResultsHistamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 ± 2.50 μM and median lethal concentration (LC50) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.ConclusionTaken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.

ВПЛИВ МАЗІ, ЩО МІСТИТЬ СУХИЙ ЕКСТРАКТ КОРЕНЯ СОЛОДКИ, НА ФАГОЦИТАРНУ АКТИВНІСТЬ ГРАНУЛОЦИТАРНИХ НЕЙТРОФІЛІВ КРОВІ В МУРЧАКІВ З ЕКСПЕРИМЕНТАЛЬНИМ ДЕРМАТИТОМ

У статті наведено результати вивчення впливу мазі «Алерголік», що містить сухий екстракт кореня солодки, на фагоцитарну активність гранулоцитарних нейтрофілів крові мурчаків з експериментальним алергічним контактним дерматитом, викликаним 2,4-динітрохлорбензолом. Згідно з отриманими даними, мазь «Алерголік», що застосовувалась в умовах лікувально-профілактичного режиму, мала виражену імунотропну дію, яка полягала в достовірному зниженні, відносно групи контрольної патології, фагоцитарної активності гранулоцитарних нейтрофілів, чого не спостерігали в групі тварин, яких лікували препаратом порівняння «Фладекс».

The 'omics' revolution: redefining the understanding and treatment of allergic skin diseases.

To evaluate how the genomic, transcriptomic, and proteomic profiles of allergic skin diseases, like atopic dermatitis and allergic contact dermatitis, contribute to their understanding and promote their therapeutic development. The '-omics' revolution has facilitated the quantification of inflammatory skin diseases at the molecular level, expanding our understanding of disease pathogenesis. It has also greatly expanded once-limited treatment options and improved the ability to define posttreatment improvements, beyond clinical scores. The findings on the genomic/transcriptomic level are also complemented by proteomic data, contributing to the understanding of the later changes taking place in the final stages of protein formation. Atopic dermatitis is defined as a Th2/Th22 polarized disease with some contributions of Th17 and Th1 pathways. In atopic dermatitis, studies of biologics and small molecules, targeting specific pathways upregulated in atopic dermatitis, seem to provide well tolerated alternatives to conventional immunosuppressive therapies (i.e. corticosteroids and cyclosporine A), particularly for severe patients. Allergic contact dermatitis is defined as having Th1/Th17-centered inflammation, especially with nickel-induced disease, but additional pathways, including Th2 and Th22, are upregulated with other allergens (i.e. fragrance). Supplementing studies of allergic skin diseases with '-omics' approaches are transforming the pathogenic understanding, diagnosis and, perhaps, also the treatment of these diseases.

Effect of 6'-acetylpaeoniflorin on dinitrochlorobenzene-induced allergic contact dermatitis in BALB/c mice.

Allergic contact dermatitis (ACD) is a classical experimental model of allergic inflammatory skin disease, which is a delayed-type hypersensitivity reaction that is mediated by hapten-specific T lymphocytes. The goal of this study was to investigate the pharmacokinetic profiles of 6'-acetylpaeoniflorin (6-AP) and the effect of 6-AP on the ACD model. 6-AP was synthesized from paeoniflorin (Pae) via acetylation, and the structure was confirmed. There were statistically significant differences in the pharmacokinetic parameters including t 1/2α , t 1/2β , AUC, MRT and C max among the animals that were orally administered Pae and 6-AP. An ACD model was induced using immunization with dinitrochlorobenzene (DNCB) in BALB/c mice. The mice were orally administered 6-AP (35, 70 and 140mg/kg/d), Pae (70mg/kg/d) and prednisone (Pre, 5mg/kg/d) from day 1 to day 7 after immunization. The results indicated that the topical application of DNCB to the skin provoked obvious inflammatory responses. 6-AP significantly inhibited ear swelling and decreased inflammatory cell infiltration and epidermal keratinization. Additionally, 6-AP observably alleviated the hyperplasia of red pulp and germinal center appearance, decreased the spleen index and inhibited splenocyte proliferation in the ACD model compared to that of Pae. Furthermore, the study indicated that 6-AP could increase the IL-10 level, while simultaneously reducing the IL-17 level in splenocytes. In summary, these results suggest that 6-AP has a significantly higher anti-inflammatory effect than Pae and that 6-AP might be a candidate for the treatment of allergic skin diseases.

Synthesis and biological evaluation of novel orally available 1-phenyl-6-aminouracils containing dimethyldihydrobenzofuranol structure for the treatment of allergic skin diseases.

We have designed and efficiently synthesized novel 1-phenyl-6-aminouracils by replacing the chroman moiety in CX-659S, a nonsteroidal dermatologic candidate, with dimethyldihydrobenzofuranol to cancel CX-659S asymmetric center. Medicinal chemistry effort culminated in the discovery of 13d bearing a 3-methyl group at the 1-phenyl group as a promising compound. Compound 13d, having good in vitro ADME profile and moderate oral bioavailability in mice, showed potent anti-inflammatory activity against hapten-induced contact hypersensitivity reaction in mice following topical and oral administration. The effects of 13d were equipotent to that of tacrolimus or prednisolone. In addition, compound 13d, having potent hydroxyl radical-scavenging activity, showed more potent suppressive effect on substance P-induced pruritus in mice than oxatomide.

ID: 21: Ganoderma lucidum-derived triterpenes inhibit PAR2-mediated IL8 production by human keratinocytes

Crude extracts from Ganoderma lucidum, a medical mushroom, are popularly used for treatment of allergic diseases such as atopic dermatitis (AD). Triterpenes are the major active constituents of Ganoderma lucidum. Stimulation of protease-activated receptor-2 (PAR2) on cutaneous keratinocytes induces secretion of various immune and inflammatory cytokines including interleukin 8 (IL8), and thereby plays a role in the development of allergic skin inflammation. Thus, PAR2-mediated signaling has been suggested to be a therapeutic target for the treatment of allergic diseases. This study aimed to evaluate the inhibitory effects of Ganoderma triterpenes on PAR2-mediated IL8 secretion from human keratinocytes. Normal human epidermal keratinocytes (NHEK) were stimulated with PAR2-activating peptide (AP) in the presence or absence of Ganoderma triterpenes in vitro. IL8 secretion from NHEK cells was measured by enzyme-linked immunosorbent assay (ELISA). Chemical structures of triterpenes were determined based on spectroscopic evidence and mass spectral data. Among of Ganoderma triterpenes, ganolucidate F exhibited most potent inhibitory activity on PAR2-mediated IL8 secretion from keratinocytes (IC50 = 12.5 μ M). Ganolucidic acid γ a showed strong inhibitory activity with IC50 value of 29.1 μ M. In addition, ganoderic acid η and ganoderic acid θ showed remarkable inhibitory effects with IC50 values of 64.9 μ M and 109.5 μ M, respectively. Elucidation of relationships between chemical structure of triterpenes and inhibitory activity implied that substitution of hydroxy group at C-23, instead of a carbonyl group, may be a very important structural feature for inhibitory activity. Ganoderma lucidum-derived ganoderic acids could be a candidate drug for treatment of allergic skin diseases.

Chinese herbal medicine network and core treatments for allergic skin diseases: Implications from a nationwide database

Ethno-pharmacological relevanceChinese herbal medicine (CHM) is commonly used to treat skin diseases, but CHM prescription patterns are difficult to understand due to their complexity and inter-connections. This study aimed to demonstrate CHM core treatments and network for treatment of allergic skin diseases by analyzing a nationwide prescription database. Materials and methodsAll CHM prescriptions made for atopic dermatitis (with age limitation ≤12 years) and urticaria for the entire year of 2011 were included. Association rule mining (ARM) combined with social network analysis (SNA) were used to analyze CHM prescriptions and explore the CHM prescription pattern and network. ResultsA total of 27,350 and 97,188 prescriptions for atopic dermatitis and urticaria, respectively, were analyzed. Xiao-Feng-San (XFS) was the most commonly used CHM (32% of prescriptions for atopic dermatitis and 47.4% for urticaria) and was the core treatment for both diseases. Moreover, 42 and 82 important CHM–CHM combinations were identified to establish the CHM network, and XFS with Dictamnus dasycarpus Turcz was the most prevalent (6.4% for atopic dermatitis and 9.1% for urticaria). Traditional Chinese Medicine heat syndrome was most prevalent cause. Extensive anti-inflammation, anti-allergy, anti-oxidation, and anti-bacterial effects were also found among the CHMs. ConclusionsNetwork analysis on CHM prescriptions provides graphic and comprehensive illustrations regarding CHM treatment for atopic dermatitis and urticaria. The CHM network analysis of prescriptions is essential to realize the CHM treatments and to select suitable candidates for clinical use or further studies.

What's new in the topical treatment of allergic skin diseases.

To review recent literature on the topical treatment of allergic skin diseases to help clinicians make informed evidence-based decisions. Twenty-four publications were identified from a PubMed search of randomized controlled trials and systematic reviews of topical treatment of atopic dermatitis and allergic contact dermatitis published from 1 January 2013 to 31 January 2014. Studies on the topical treatment of atopic dermatitis largely supported the recommended use of topical corticosteroids and topical calcineurin inhibitors. Barrier therapy continues to play an important role without evidence supporting use of one emollient over another. Lipoxin A4, an eicosanoid with anti-inflammatory properties, and a 5% cis-urocanic acid emulsion cream were effective in the treatment of atopic dermatitis, although studies were small. Adjunct therapy with bleach baths, natural oils, and textiles all showed some benefit; however, studies are limited. Literature on topical treatment of allergic contact dermatitis was limited to one publication, providing evidence for a natural multicomponent cream as maintenance therapy after control of disease with a topical corticosteroid. There is strong evidence for the use of topical anti-inflammatory therapies in the treatment of atopic dermatitis. There is little evidence to suggest that one emollient is better than others.

Anti-inflammatory activities of Dictamnus dasycarpus Turcz., root bark on allergic contact dermatitis induced by dinitrofluorobenzene in mice

Ethnopharmacological relevanceThe root bark of Dictamnus dasycarpus Turcz. is widely used as a medicinal herb for treatment of skin diseases such as eczema, pruritus and urticaria in China, Japan and Korea. Materials and methodsWe investigated the effects of methanol extract of Dictamnus dasycarpus Turcz., root bark (MEDD) on ear thickness, ear weights, histopathological changes such as hyperplasia, edema, spongiosis and immune cell infiltration and cytokine productions in 1-fluoro-2,4-dinitrofluorobenzene (DNFB)-induced contact dermatitis (CD) mice. We also investigated its effects on degranulation of histamine and β-hexosaminidase and related mechanisms using RBL-2H3 cells. ResultsTopical application of MEDD effectively inhibited enlargement of ear thickness and weight (P<0.05). MEDD treatment also inhibited hyperplasia, edema and spongiosis induced by DNFB. Treatment with 300μg/ear of MEDD suppressed the increase in IFN-γ and TNF-α levels (P<0.05). In addition, treatment with >50μg/mL MEDD reduced the level of β-hexosaminidase release, while >100μg/mL MEDD lowered the level of histamine release in a dose-dependent manner (P<0.05). Finally, MEDD treatment prevented phosphorylation of p38 MAPK induced by phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187 in RBL-2H3 cells. ConclusionsThese data indicate that root bark of Dictamnus dasycarpus Turcz. has the potential for use in the treatment of allergic skin diseases. Furthermore, they suggest that root bark of Dictamnus dasycarpus Turcz. is involved in decreasing degranulation of MCs via inhibition of the p38 MAPK pathway as well as in the inhibition of Th1 skewing reactions.

Rutin suppresses atopic dermatitis and allergic contact dermatitis

Atopic dermatitis (AD) and allergic contact dermatitis (ACD) is a common allergic inflammatory skin disease caused by a combination of eczematous, scratching, pruritus and cutaneous sensitization with allergens. The aim of our study was to examine whether rutin, a predominant flavonoid having anti-inflammatory and antioxidative potential, modulates AD and ACD symptoms. We established an atopic dermatitis model in BALB/c mice by repeated local exposure of house dust mite (Dermatophagoides farinae) extract (DFE) and 2,4-dinitrochlorobenzene (DNCB) to the ears. In addition, 2,4-dinitroflourobenzene-sensitized a local lymph node assay was used for the ACD model. Repeated alternative treatment of DFE/DNCB caused AD symptoms. Topical application of rutin reduced AD based on ear thickness and histopathological analysis, in addition to serum IgE levels. Rutin inhibited mast cell infiltration into the ear and serum histamine level. Rutin suppressed DFE/DNCB-induced expression of interleukin (IL)-4, IL-5, IL-13, IL-31, IL-32 and interferon (INF)-γ in the tissue. In addition, rutin suppressed ACD based on ear thickness and lymphocyte proliferation, serum IgG2a levels, and expression of INF-γ, IL-4, IL-5, IL-10, IL-17 and tumour necrosis factor-α in ACD ears. This study demonstrates that rutin inhibits AD and ACD, suggesting that rutin might be a candidate for the treatment of allergic skin diseases.

THE EFFICIENCY OF LEVOCETIRIZINE IN TREATMENT OF ALLERGIC SKIN DISEASES

In the article the results of supervision over the patients with chronic urticaria (n=32) and atopic dermatitis (n=30), at the age from 2 till 55 years old treated with H^blocker levocetirizine, are presented. High clinical efficiency and safety of levocetirizine treatment of allergic skin diseases were confirmed.

The histamine H4 receptor as a new target for treatment of canine inflammatory skin diseases

Histamine is a well known mediator of allergic skin diseases and, with the discovery of the histamine H(4) receptor, the role of histamine is re-evaluated. There are only limited published data elucidating the role of the histamine H(4) receptor in dogs. Twelve beagles intradermally injected with histamine (0.25 micromol and 2.5 micromol/site) reacted with a classical wheal and flare reaction. None of the dogs showed signs of pruritus. The dogs reacted with a wheal and flare reaction after intradermal injection of histamine H(4) receptor agonist/H(3) receptor antagonist clobenpropit (0.1 micromol) and selective histamine H(4) receptor agonist VUF 8430 (1.5 micromol). Again, no scratching occurred in any of the dogs. The highly selective histamine H(4) receptor antagonist JNJ 7777120 reduced the histamine-induced wheal reaction in nine out of 12 dogs. To determine whether canine mast cells are susceptible to histamine H(4) receptor-mediated reactions, effects of clobenpropit and VUF 8430 were tested in canine mastocytoma cells (C2). Incubation with histamine H(4) receptor agonists (up to 10 micromol/L) induced a distinct calcium(2+) influx. C2 cells also responded with enhanced chemotaxis when stimulated with histamine, VUF 8430 and clobenpropit. Neither VUF 8430, nor clobenpropit (up to 10 micromol/L) led to a modulation of histamine concentration in supernatants of canine mastocytoma cells, whereas mastoparan, used as a positive control, enhanced histamine concentration in supernatants. For treatment of allergic skin diseases in dogs, a combination of H(1)R and H(4)R antagonists might be advantageous.

Topical Application of Sphingosine-1-Phosphate and FTY720 Attenuate Allergic Contact Dermatitis Reaction through Inhibition of Dendritic Cell Migration

Migration of Langerhans cells (LCs) from the skin to the lymph node is an essential step in the pathogenesis of allergic contact dermatitis (ACD). Therefore, inhibition of LC-migration could be a promising strategy to improve this skin disease. Effects of sphingosine-1-phosphate (S1P) and the immunomodulator FTY720 on LC trafficking is not well defined, yet. Thus, we investigated the action of topically administered S1P and FTY720 in a murine model of ACD. Most interestingly, FTY720 as well as S1P inhibited the inflammatory reaction in the elicitation phase of ACD. In the sensitization phase, FTY720, and S1P reduced the weight and cell count of the draining auricular lymph node, as well as immigrated dendritic cells provoked by repetitive topical administration of the hapten. Correspondingly, the density of LCs in the epidermis was higher in FTY720- and S1P-treated mice compared to vehicle treatment. A skin dendritic cell migration assay confirmed the significant inhibition of dendritic cell migration by FTY720 and S1P. These data supply conclusive evidence that the strategy of targeting the migratory response of LCs with locally acting S1P or FTY720 represents an emerging option in the treatment of allergic skin diseases like contact hypersensitivity and atopic dermatitis.

Effects of cyclosporin A and cilomilast on activated canine, murine and human keratinocytes

The calcineurin inhibitor cyclosporin A and the phosphodiesterase 4 inhibitor cilomilast exhibit potent immunomodulatory properties which make them interesting therapeutics for the treatment of skin disorders like canine and human atopic dermatitis. Cyclosporin A and phosphodiesterase 4 inhibitors have already demonstrated clinical efficacy in the therapy of canine and human atopic dermatitis. Their direct impact on keratinocytes, especially canine keratinocytes, is less obvious. Thus, an investigation was carried out to ascertain whether cyclosporin A and cilomilast modulate keratinocyte proliferation and secretion of proinflammatory mediators. Cyclosporin A inhibited canine and murine keratinocyte proliferation, whereas cilomilast had no affect. Cyclosporin A and cilomilast reduced the lipopolysaccharide-induced prostaglandin E2 synthesis in canine and murine keratinocytes. Both immunomodulators also inhibited the production of the CXC chemokine KC and CCL2 in the murine keratinocyte cell line MSC-P5. The two immunomodulators also significantly reduced the interferon-gamma-induced production of interferon-gamma-inducible protein 10 in human keratinocytes (HaCaT cells). Thus, cyclosporin A and cilomilast directly modulate keratinocyte functions which might contribute to the anti-inflammatory and immunomodulatory action of these compounds in the treatment of allergic skin diseases.