piperidines and Dermatitis--Atopic

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Dermatitis, Atopic; Humans; Interleukins; Janus Kinases; Lymphoma; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Nitriles; Piperidines; Purines; Pyrazoles; Pyrimidines; Signal Transduction; Skin Neoplasms; STAT Transcription Factors; Sulfonamides; Tumor Microenvironment

Tofacitinib citrate is an oral Janus kinase 1/3 inhibitor approved for rheumatoid arthritis, ulcerative colitis, and active psoriatic arthritis. Tofacitinib is being increasingly used off-label for dermatological conditions, with varying efficacy across recent studies. A review of these studies will be a helpful resource for dermatologists considering the use of tofacitinib for conditions refractory to first-line therapies.. MEDLINE, Embase, CINAHL Plus, Cochrane Library, Scopus, Web of Science, Clinicaltrials.gov, and the WHO International Clinical Trials Registry Platform were all searched for articles and trials mentioning the term 'tofacitinib', then manually reviewed to identify published data on off-label uses of tofacitinib. The article was structured according to the quality of the evidence available.. Tofacitinib appears to show strong efficacy for numerous dermatologic conditions. Randomized controlled trial data is available for atopic dermatitis, alopecia areata, and plaque psoriasis. Case report and case series data is available for numerous other dermatologic conditions.. While tofacitinib has a wide array of immunoregulatory properties, making it a possible candidate for treating many dermatologic conditions refractory to other treatments, further testing is needed to better characterize its efficacy and utility moving forward, as well as its safety and adverse effect profile.

Topics: Alopecia Areata; Arthritis, Psoriatic; Colitis, Ulcerative; Dermatitis, Atopic; Dermatology; Humans; Off-Label Use; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Randomized Controlled Trials as Topic

Atopic dermatitis (AD) is chronic, pruritic, inflammatory skin disease that affects a significant portion of the population in industrialized nations. For nonresponders to conventional therapies, AD can significantly reduce sleep quality and quality of life. AD pathogenesis is multifactorial and involves multiple immune pathways, with recent evidence of T helper (Th)2, Th17 and Th22 axis attenuation in various AD endotypes and racial subtypes. Inhibition of the conserved Janus kinase (JAK) signalling pathway represents a promising therapeutic avenue to reduce the activation of multiple proinflammatory mediators involved in AD pathogenesis. JAK inhibitors exist in both oral and topical forms with variable specificity for the receptor tyrosine kinases JAK1, JAK2, JAK3 and tyrosine kinase 2. Oral formulations include abrocitinib, upadacitinib, baricitinib and gusacitinib, and are most appropriate for patients with moderate to severe AD. Emerging topical formulation in development include ruxolitinib and deglocitinib, which may be used in patients with localized AD and also adjunctively with systemic therapy in patients with more severe disease. With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment to revolutionize the management of AD.

Topics: Acetonitriles; Administration, Oral; Administration, Topical; Adult; Azetidines; Child; Dermatitis, Atopic; Heterocyclic Compounds, 3-Ring; Humans; Janus Kinase 1; Janus Kinase 2; Janus Kinase 3; Janus Kinase Inhibitors; Nitriles; Piperidines; Purines; Pyrazoles; Pyridazines; Pyrimidines; Quality of Life; Safety; Severity of Illness Index; STAT1 Transcription Factor; Sulfonamides; Treatment Outcome; TYK2 Kinase

Atopic dermatitis (AD) is a widely acquired, relapsing inflammatory skin disease. Biologics are now widely used in patients with moderate-to-severe AD.. This work aims to summarize both label and off-label biologics on AD treatment in phase II and phase III stages, and compile evidence on the efficacy of the most-studied biologics.. We conducted a comprehensive literature search through PubMed, EMBASE, and ClinicalTrials.gov to identify all documented biological therapies for AD. The criteria were further refined to focus on those treatments with the highest evidence level for AD with at least one randomized clinical trial supporting their use. Only studies or articles published in English were enrolled in this study.. Primary searches identified 525 relevant articles and 27 trials. Duplicated articles and papers without a full text were excluded. Only completed trials were enrolled. We included 28 randomized controlled trials, 4 unpublished trials, 2 observational studies, and 1 meta-analysis. Eight kinds of biologics, including IL-4/IL-13 inhibitors, JAK inhibitors, anti-IL-13 antibodies, anti-IL-22 antibodies, anti-IL-33 antibodies, thymic stromal lymphopoietin inhibitor (TSLP), OX40 antibodies, and H4R-antagonists were included in this work. Dupliumab, as the most widely used and investigated biologic, was reported in 1 meta-analysis and 4 trials exploring its long-term use and application in both adults and pediatric patients. Besides dupilumab, four other IL-4/IL-13 inhibitors recruited were all randomized, clinical trials at phase 2-3 stage. Six different kinds of JAK inhibitors were summarized with strong evidence revealing their significant therapeutic effects on AD. There were 3 trials for nemolizumab, an anti-IL-13 antibody, all of which were in the phase 2 clinical trial stage. Results showed nemolizumab could be another alternative therapy for moderate-to-severe AD with long-term efficiency and safety.. The biological therapies with the most robust evidence on efficacy and long-term safety for AD treatment include dupilumab, barcitinib, abrocitinib, and delgocitinib. Most of the biologics mentioned in this review were still at the exploratory stage. This review will help practitioners advise patients seeking suitable biological therapies and offer experimental study directions for treatment.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azetidines; Biological Products; Carbamates; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Heterocyclic Compounds, 3-Ring; Humans; Nitriles; Piperidines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyrimidines; Pyrroles; Sulfonamides

Atopic dermatitis (AD) is the most common inflammatory skin disease driven by both terminal keratinocyte differentiation defects and type 2 immune responses, and this condition causes psychological and social morbidity. Although patients with severe AD require systemic immunotherapy, conventional agents including ciclosporin could not be used for several years due to side effects such as nephrotoxicity, hypertension and long-term risks of malignancy. It is well known that dupilumab, which blocks receptor binding of both IL-4 and IL-13, is remarkably efficacious in the treatment of AD. We have entered a new era when many novel topical and systemic agents that may have great potential in AD treatment are emerging through clinical trials. The purpose of this article is to summarize the efficacy and safety of the current topical and systemic therapies in AD by reviewing recently published papers regarding phase II/III clinical trials. It is revealed that topical phosphodiesterase 4 inhibitors and Janus kinase (JAK) inhibitors are promising treatments for AD. Moreover, systemic therapies such as biologics targeting IL-13 and oral JAK inhibitors show strong efficacy in AD.

Topics: Acrylamides; Administration, Topical; Antibodies, Monoclonal, Humanized; Biological Products; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dermatitis, Atopic; Humans; Immunotherapy; Interleukin-13; Janus Kinase Inhibitors; Molecular Targeted Therapy; Phosphodiesterase 4 Inhibitors; Piperidines; Pyridines; Pyrimidines; Pyrroles; Resorcinols; Stilbenes; TRPV Cation Channels

Janus kinase family (JAKs) has recently attracted the attention of many researchers, and several JAK inhibitor drugs have been developed targeting different members of the JAK family. Tofacitinib and ruxolitinib are US FDA approved drugs in this family for rheumatoid arthritis and myeloproliferative diseases, respectively. Dysregulation of JAK/STAT pathway is also involved in many skin diseases, specifically inflammatory disorders. The JAK/STAT signaling pathway and its involvement in skin diseases are overviewed in this study. We also review clinical studies of JAK inhibitors in field of dermatology, including psoriasis, atopic dermatitis, alopecia areata and vitiligo. Although the available evidence shows promising results, it is still too early to draw a firm conclusion about the place of these drugs in dermatological treatment.

Topics: Alopecia Areata; Azetidines; Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Piperidines; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases; Sulfonamides; Vitiligo

Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology.. We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Technical reports on tofacitinib from U.S. Food and Drug Administration and European Medical Agency were also included.. Forty-three papers were included in this review. We report current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata.. JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo. Despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies will have to determine the adequate risk-to-benefit ratio.

Topics: Administration, Oral; Alopecia Areata; Dermatitis, Atopic; Humans; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Psoriasis; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Vitiligo

New molecularly targeted therapeutics are changing dermatologic therapy. Janus kinase-signal transducer and activator of transcription (JAK-STAT) is an intracellular signaling pathway upon which many different proinflammatory signaling pathways converge. Numerous inflammatory dermatoses are driven by soluble inflammatory mediators, which rely on JAK-STAT signaling, and inhibition of this pathway using JAK inhibitors might be a useful therapeutic strategy for these diseases. Growing evidence suggests that JAK inhibitors are efficacious in atopic dermatitis, alopecia areata, psoriasis, and vitiligo. Additional evidence suggests that JAK inhibition might be broadly useful in dermatology, with early reports of efficacy in several other conditions. JAK inhibitors can be administered orally or used topically and represent a promising new class of medications. The use of JAK inhibitors in dermatology is reviewed here.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Azetidines; Clinical Trials as Topic; Dermatitis, Atopic; Dermatologic Agents; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Signal Transduction; Skin Diseases; Sulfonamides; Vitiligo

Topics: Alzheimer Disease; Animals; Asthma; Dermatitis, Atopic; Drug Design; Enzyme Inhibitors; Humans; Intramolecular Oxidoreductases; Leukodystrophy, Globoid Cell; Lipocalins; Muscular Dystrophies; Niacinamide; Piperidines; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyrimidines; Rhinitis, Allergic, Perennial; Spinal Cord Injuries; Thiazoles

We established a novel dermatitis model in mice earlobes and analyzed the roles of histamine using specific antagonists for histamine receptors. After sensitization with picryl chloride (PiCl) by painting it on the earlobes of cyclophosphamide-treated mice, 12-O-tetradecanoylphorbol 13-acetate (TPA) was painted twice at the same site, and then allergic inflammation was induced by painting with PiCl. Histamine antagonists and cyclosporin A were administered i.v. The application of TPA shifted the PiCl-induced allergic inflammation from a delayed-type response to a biphasic response and increased the infiltration of eosinophils and mast cells at the inflammatory site. In this model, the PiCl-induced increase in the thickness of the earlobe in the immediate phase was suppressed by the histamine H₁ antagonist pyrilamine. In contrast, the increase in the swelling in the late phase and the infiltration of eosinophils were suppressed by the H₃/H₄ antagonist thioperamide. The inhibitory effect of the combined treatment with pyrilamine and thioperamide on TPA-modified contact dermatitis was as potent as that of cyclosporin A. Histamine plays significant roles in early-phase swelling via H₁ receptors and in late-phase swelling via H₃/H₄ receptors in this TPA-modified allergic dermatitis model.

Topics: Animals; Cyclosporine; Dermatitis, Atopic; Disease Models, Animal; Drug Therapy, Combination; Histamine; Histamine Antagonists; Humans; Mice; Picryl Chloride; Piperidines; Pyrilamine; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H1; Receptors, Histamine H3; Receptors, Histamine H4; Tetradecanoylphorbol Acetate

Atopic dermatitis is a chronic eczematous, pruritic, inflammatory skin condition affecting children and adults. Tofacitinib is a Janus kinase inhibitor. The efficacy, safety, and pharmacokinetics of 2% tofacitinib ointment twice daily have been evaluated in a 4-week phase 2a multisite randomized, double-blind, vehicle-controlled, parallel-group study (NCT02001181) in adult patients with mild to moderate atopic dermatitis and 2% to 20% body surface area (BSA) involvement. Tofacitinib ointment demonstrated significantly greater efficacy versus vehicle for all efficacy end points and had an acceptable safety profile. Predose and postdose pharmacokinetic samples were collected in week 2 and week 4. The objective of this analysis was to assess if predicted mean tofacitinib concentrations with topical application at higher treated BSA across age groups would exceed relevant concentration thresholds based on oral doses of tofacitinib. In this analysis, the pharmacokinetic concentrations were characterized using a linear mixed-effects model. The model was used to predict concentrations for adults with higher (>20%) treatable BSA. Adult concentrations were used to extrapolate concentrations to a pediatric population (2 to 17 years) using allometric principles. The predicted systemic concentrations for 2% tofacitinib ointment in both adult and pediatric populations at treated BSA ≤50% for a mild to moderate atopic dermatitis population did not exceed those reported for the 10th percentile of observed oral tofacitinib 5-mg twice-daily doses in patients with moderate to severe plaque psoriasis. The methodology described will enable analysis and prediction of systemic concentrations for topical agents.

Topics: Adult; Dermatitis, Atopic; Double-Blind Method; Humans; Models, Biological; Ointments; Pediatrics; Piperidines; Pyrimidines; Pyrroles

ASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.. The objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily).. ASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE.. In patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation.

Topics: Acetonitriles; Adult; Biomarkers; Dermatitis, Atopic; Dose-Response Relationship, Drug; Double-Blind Method; Down-Regulation; E-Selectin; Female; Humans; Janus Kinase Inhibitors; Janus Kinases; Male; Middle Aged; Piperidines; Placebos; Pyridazines; Severity of Illness Index; Signal Transduction; Syk Kinase; Treatment Outcome; Young Adult

Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.. Tofacitinib, a small-molecule JAK inhibitor, was investigated for the topical treatment of AD.. In this 4-week, phase IIa, randomized, double-blind, vehicle-controlled study (NCT02001181), 69 adults with mild-to-moderate AD were randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily. Percentage change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end point. Secondary efficacy end points included percentage CFB in body surface area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response and CFB in patient-reported pruritus. Safety, local tolerability and pharmacokinetics were monitored.. The mean percentage CFB at week 4 in EASI score was significantly greater (P < 0·001) for tofacitinib (-81·7%) vs. vehicle (-29·9%). Patients treated with tofacitinib showed significant (P < 0·001) improvements vs. vehicle across all prespecified efficacy end points and for pruritus at week 4. Significant improvements in EASI, PGA and BSA were observed by week 1 and improvements in pruritus were observed by day 2. Safety/local tolerability were generally similar for both treatments, although more adverse events were observed for vehicle vs. tofacitinib.. Tofacitinib ointment showed significantly greater efficacy vs. vehicle across end points, with early onset of effect and comparable safety/local tolerability to vehicle. JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.

Topics: Adolescent; Adult; Dermatitis, Atopic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Ointments; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Treatment Outcome; Young Adult

This study investigated the efficacy and safety of masitinib, a selective tyrosine kinase inhibitor capable of downregulating mast cell functions, for treatment of canine atopic dermatitis (CAD). Dogs with confirmed CAD received masitinib at 12.5 mg/kg/day (n = 202) or control (n = 104) for 12 weeks. A reduction in CAD Extent and Severity Index (CADESI-02) score of ≥ 50% at week 12 was observed in 61% of masitinib-treated dogs versus 35% of control dogs (P < 0.001), according to the modified intent-to-treat population. For dogs resistant to ciclosporin and/or corticosteroids (60% of the study population), CADESI-02 response rates were 60 versus 31%, respectively (P = 0.004). The mean reduction in pruritus score of severely pruritic dogs was 46 versus 29%, respectively (P = 0.045). Furthermore, 65% of owners with severely pruritic dogs assessed masitinib efficacy as good/excellent versus 35% control (P = 0.05). Overall, 63% of investigators assessed masitinib efficacy as good/excellent versus 35% control (P < 0.001). Premature discontinuations from the modified intent-to-treat population (28.2% masitinib versus 26.0% control) were mainly due to adverse events (13.4 versus 4.8%, respectively) or lack of efficacy (12.4 versus 18.3%, respectively). In total, 13.2% dogs presented with severe adverse events (16.0% masitinib versus 7.7% control). Masitinib showed a risk of reversible protein loss, although regular surveillance of blood albumin and proteinuria allowed for discontinuation of treatment while the dog was still clinically asymptomatic. Masitinib proved to be an effective and mostly well-tolerated treatment of CAD, including severe and refractory cases, with medically manageable adverse effects.

Topics: Animals; Benzamides; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; Drug Administration Schedule; Female; Male; Piperidines; Prospective Studies; Protein Kinase Inhibitors; Pyridines; Severity of Illness Index; Thiazoles; Treatment Outcome

Although many antihistamines are now in clinical use, few studies directly compare their pharmacodynamic and sedative activities in humans in vivo. We designed a double-blind, placebo-controlled, crossover study to compare the inhibitory effects of bepotastine, cetirizine, fexofenadine, and olopatadine on histamine-induced flare-and-wheal response. Systemic sedative effects and impaired psychomotor activities by these drugs were also evaluated. Bepotastine (10 mg twice a day), cetirizine (10 mg once a day), fexofenadine (60 mg twice a day), and olopatadine (5 mg twice a day) or placebo was given in a double-blind manner to seven healthy volunteers before histamine challenge by iontophoresis. At 0, 1, 2, 4, 8, 12, and 24 h following the oral administration of these drugs, histamine iontophoresis-induced wheal-and-flare response was measured. Sedative effects by the drugs were also evaluated by a visual analogue scale for subjective sedation, and by word processor test for psychomotor activity. Each volunteer was tested with all of the drugs (including placebo), administered in a random order with a washout period of at least 1 week. Histamine iontophoresis induced marked wheal-and-flare response in all participants. Bepotastine, cetirizine, fexofenadine, and olopatadine yielded significant reduction of histamine-induced wheal-and-flare response compared to placebo (P < 0.01). Among the drugs, olopatadine and cetirizine suppressed most markedly and persistently histamine-induced wheal-and-flare response, while bepotastine and fexofenadine produced a significant, but less persistent suppression. Olopatadine, fexofenadine, and cetirizine showed a significant systemic sedative effect in this order with bepotastine showing the least sedative effect. Moreover, olopatadine affected psychomotor performance most markedly, which was followed by fexofenadine and cetirizine. These results indicate that bepotastine, cetirizine, fexofenadine, and olopatadine inhibit histamine-induced wheal-and-flare response of humans in vivo and induce a variable systemic sedative effect and impaired psychomotor activity. Although olopatadine and cetirizine showed the strongest and most persistent suppression of histamine-induced wheal-and-flare response, olopatadine showed a considerable sedative effect with impaired psychomotor performance.

Topics: Adult; Cetirizine; Cross-Over Studies; Dermatitis, Atopic; Dibenzoxepins; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Iontophoresis; Male; Olopatadine Hydrochloride; Piperidines; Psychomotor Performance; Pyridines; Sleep Stages; Terfenadine

Twenty-nine pruritic, atopic dogs were entered into a double-blind, placebo-controlled, crossover study to evaluate the efficacy of an investigational antiallergenic compound, AHR-13268. Fourteen dogs were evaluated by a veterinary dermatologist (at intervals) and the owner (daily). Fifteen dogs were evaluated only by the owner. The mean (+/- SE) owner scores for pruritus, erythema, and lesions with placebo treatment (higher score = worse signs) were 3.24 (+/- 0.12), 2.73 (+/- 0.12), and 2.61 (+/- 0.09), respectively. With drug treatment, the corresponding scores were 2.89 (+/- 0.12), 2.50 (+/- 0.12), and 2.25 (+/- 0.09). Scores for pruritus and lesions (but not erythema) were significantly better with drug treatment than with placebo treatment. Investigator scores showed similar trends, but the differences were not great enough to be statistically significant. Overall, 11/29 (38%) owners reported their dogs had moderate or better improvement from drug capsules, and 4/29 dogs (14%) improved on placebo capsules. A variety of adverse effects were reported following both drug (9/29 dogs) and placebo (8/29 dogs) capsule administration, but were mild and well tolerated. Results of this study indicate that AHR-13268 has potential for empiric treatment of allergic inhalant dermatitis in some dogs.

Topics: Analysis of Variance; Animals; Benzoates; Dermatitis, Atopic; Dog Diseases; Dogs; Double-Blind Method; Histamine H1 Antagonists; Piperidines; Pruritus; Regression Analysis; Surveys and Questionnaires

Topics: Administration, Cutaneous; Alkaloids; Animals; Benzodioxoles; Dermatitis, Atopic; Lipids; Liposomes; Mice; Mice, Inbred BALB C; Piperidines; Polyunsaturated Alkamides; Skin; Skin Absorption

Topics: Alopecia; Colitis, Ulcerative; Dermatitis, Atopic; Humans; Piperidines; Pyrimidines

Topics: Dermatitis, Atopic; Ectodermal Dysplasia; Ectodermal Dysplasia 1, Anhidrotic; Ectodysplasins; Humans; Mutation; Pedigree; Piperidines; Pyrimidines

Topics: Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Kimura Disease; Male; Middle Aged; Piperidines; Pyrimidines; Skin

In atopic diseases, the epithelium releases cytokines and chemokines that initiate skin inflammation. Atopic dermatitis (AD) is characterized by a disrupted epidermal barrier and is triggered or exacerbated by environmental stimuli such as house dust mite (HDM) allergens. The proinflammatory cytokine interleukin 33 (IL-33) plays an important role in the pathogenesis of AD, but how IL-33 production in keratinocytes is elicited by HDM is unknown. To that end, here we stimulated monolayer-cultured human keratinocytes and human living skin equivalents with Dermatophagoides pteronyssinus HDM extract to investigate its effects on IL-33 production from keratinocytes. The HDM extract induced intracellular expression of IL-33 and modulated its processing and maturation, triggering rapid IL-33 release from keratinocytes. Group 1 HDM allergen but not group 2 HDM allergen elicited IL-33 production. An ATP assay of keratinocyte culture supernatants revealed an acute and transient accumulation of extracellular ATP immediately after the HDM extract stimulation. Using the broad-spectrum P2 antagonist suramin, the specific purinergic receptor P2Y2 (P2RY2) antagonist AR-C118925XX, and P2RY2-specific siRNA, we discovered that the HDM extract-induced IL-33 expression was mainly dependent on extracellular ATP/P2Y2 signaling mediated by transactivation of epidermal growth factor receptor, followed by activation of the ERK kinase signaling pathway. Moreover, HDM extract-induced release of 25-kDa IL-33 from the keratinocytes depended on an extracellular ATP/P2 signaling-mediated intracellular Ca

Topics: Adenosine Triphosphate; Allergens; Antigens, Dermatophagoides; Cells, Cultured; Coculture Techniques; Dermatitis, Atopic; Extracellular Space; Fibroblasts; Furans; Humans; Immunity, Innate; Interleukin-33; Keratinocytes; Piperidines; Primary Cell Culture; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y2; RNA, Small Interfering; Signal Transduction; Skin; Tetrazoles

Topics: Arthritis, Rheumatoid; Azetidines; Betacoronavirus; Colitis, Ulcerative; Coronavirus Infections; COVID-19; Cytokines; Dermatitis, Atopic; Heterocyclic Compounds, 3-Ring; Humans; Immunomodulation; Janus Kinases; Nitriles; Pandemics; Piperidines; Pneumonia, Viral; Primary Myelofibrosis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; SARS-CoV-2; STAT Transcription Factors; Sulfonamides

Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation.. Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis.. 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis.. Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions.. JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

Topics: Cell Proliferation; Computer Simulation; Dermatitis, Atopic; Filaggrin Proteins; Humans; Imaging, Three-Dimensional; Intermediate Filament Proteins; Janus Kinase 1; Keratinocytes; Piperidines; Psoriasis; Pyrimidines; Pyrroles; Sensitivity and Specificity; STAT6 Transcription Factor

Topical Janus kinase (JAK) inhibition is a promising therapeutic target for several inflammatory skin diseases of humans.. To evaluate the anti-inflammatory effect of tofacitinib, a JAK 1/3 inhibitor, on immediate and late-phase skin reactions in dogs.. Five healthy laboratory beagle dogs.. Topical tofacitinib (total daily dosage: 0.5 mg/cm. The tofacitinib gel was well-tolerated; one dog developed mild erythema at Day 5 that resolved by the next application. Treatment with tofacitinib reduced histamine and anticanine-IgE global wheal scores (one-way ANOVA, P ≤ 0.005 for both) compared to baseline; there was no significant difference for the vehicle placebo (histamine; P = 0.163; IgE, P = 0.223). Late-phase reactions (LPRs) were markedly, but not significantly reduced after tofacitinib treatment (P = 0.071). A blinded histological evaluation of 6 h-anti-IgE-associated LPRs revealed a significant reduction in the total leucocyte superficial dermal cellularity (P = 0.022), as well as eosinophil (P = 0.022) and mast cell (P = 0.022) counts at tofacitinib-treated sides compared with pretreatment values. Post-treatment complete blood counts and serum chemistry profiles did not show relevant tofacitinib-induced changes.. Our observations suggest that topical tofacitinib exerts an inhibitory effect on activated canine skin-emigrating immune cells; this drug should be investigated further as a topical immunosuppressive drug in dogs.

Topics: Animals; Anti-Inflammatory Agents; Dermatitis, Atopic; Dog Diseases; Dogs; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Inflammation; Pilot Projects; Piperidines; Pyrimidines; Pyrroles

Topical administration of PR022, 0.05% hypochlorous acid (HOCl) in gel has been demonstrated to be beneficial in a chronic murine atopic dermatitis model. In a follow up study we tested a higher concentration (0.1%) of PR022 HOCl gel in comparison to the Janus kinase inhibitor tofacitinib, both of which are currently in clinical phase studies for treatment of human atopic dermatitis.. The effect of topically administered HOCl (0.1%) in gel was compared to a topical formulation of tofacitinib (0.5%) in a therapeutic setting on atopic dermatitis-like lesions in NC/Nga mice as well as itch behaviour. NC/Nga mice were sensitized with house dust mite allergen. After reaching visible lesions, mice were treated either topically with HOCl or tofacitinib or gel vehicle for 17 days. After termination of the study, dorsal root ganglia were isolated for ex vivo stimulation and skin samples were taken for cytokine determination in inflamed skin.. When administered onto lesional skin of NC/Nga mice, both HOCl and tofacitinib reduced lesions and scratching behaviour. The reduced inflammatory response by HOCl and tofacitinib treatment was demonstrated by diminished inflammatory cytokines in affected skin tissue from NC/Nga mice. Dorsal root ganglia neurons re-stimulated with a range of mediators of itch showed a reduced response compared to the vehicle control mice, when isolated from tofacitinib or HOCl treated mice.. These data indicate a similar beneficial potential of topical high dose PR022 HOCl (0.1%) in gel and tofacitinib, in a translational murine model of atopic dermatitis.

Topics: Administration, Topical; Animals; Cells, Cultured; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Female; Ganglia, Spinal; Hypochlorous Acid; Immunoglobulin E; Mice; Neurons; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin

Phosphatidylinositide 3-kinases (PI3Ks) are widely expressed enzymes involved in membrane signalization pathways. Attempts to administer inhibitors with broad activity against different isoforms have failed due to toxicity. Conversely the PI3Kδ isoform is much more selectively expressed, enabling therapeutic targeting of this isoform. Of particular interest PI3Kδ is expressed in human basophils and its inhibition has been shown to reduce anti-IgE induced basophil degranulation, suggesting that PI3Kδ inhibitors could be useful as anti-allergy drugs. Herein, we report for the first time the activity of compounds derived from chalcone scaffolds as inhibitors of normal human basophil degranulation and identified the most active compound with anti-PI3Kδ properties that was investigated in preclinical models. Compound 18, namely 1-[2-hydroxy-4,6-dimethoxy-3-(N-methylpiperidin-4-yl)phenyl]-3-(2,4,6-trimethoxyphenyl)-prop-2-en-1-one, was found to inhibit normal human basophil degranulation in a dose-dependent manner. In a murine model of ovalbumin-induced asthma, compound 18 was shown to reduce expiratory pressure while its impact on the inflammatory infiltrate in alveolar lavage and total lung was dependent on the route of administration. In a DNFB-induced model of atopic dermatitis compound 18 administered systemically proved to be as potent as topical betamethasone. These results support the anti-atopic and allergic properties of the title compound and warrant further clinical development.

Topics: Animals; Asthma; Basophils; Cell Degranulation; Chalcones; Dermatitis, Atopic; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Mice; Models, Molecular; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Piperidines; Protein Kinase Inhibitors

Topics: Adult; Alopecia Areata; Dermatitis, Atopic; Humans; Janus Kinase Inhibitors; Male; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Th2 Cells; Treatment Outcome; Vitiligo

The treatment of atopic dermatitis in adults is based on the use of topical steroids and emollients. When AD is resistant to a well-conducted topical treatment, phototherapy or systemic treatments can be used: ciclosporin, methotrexate, azathioprine or mycophenolate mofetil. The therapeutic landscape of adult AD is about to change and even be revolutionized by the imminent arrival of new treatments: topical phosphodiesterase 4 inhibitors, topical or systemic JAK inhibitors, anti-IL-4 and/or antiIL-13 biotherapies (dupilumab, tralokinumab, lebrikizumab), anti-IL-31 (nemolizumab), anti-TSLP.

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Azathioprine; Boron Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Methotrexate; Mycophenolic Acid; Piperidines; Pyrimidines; Pyrroles; Thalidomide; Ustekinumab

The histamine H4 receptor (H4R) was brought into focus as a new therapeutic target for the treatment of allergic disorders such as atopic dermatitis (AD). H4R antagonists have already been tested in several animal models of AD, but these studies have yielded conflicting results.. The development of ovalbumin-induced AD-like skin lesions was analysed in H4R(-/-) mice and in H4R antagonist (JNJ28307474)-treated mice.. H4R(-/-) mice showed a clear amelioration of the skin lesions, with a diminished influx of inflammatory cells and a reduced epidermal hyperproliferation at lesional skin sites. H4R(-/-) mice had a reduced amount of ovalbumin-specific IgE, a reduced number of splenocytes and lymph node cells with a decreased number of CD4+ T cells. The H4R modulated the cytokine secretion of CD4+ T cells and splenocytes and altered the cellular profile in the lymph nodes. The anti-inflammatory effect could only partially be mimicked by JNJ28307474 and only when the H4R antagonist was given during sensitization and challenge and not when JNJ28307474 was only given during the provocation phase of the allergic reaction.. The H4R modulates inflammation in a chronic allergic dermatitis setting. However, results of this study indicate that it is necessary to block the H4R during ontogeny and development of the allergic inflammation.

Topics: Animals; CD4-Positive T-Lymphocytes; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Epidermis; Female; Immunoglobulin E; Lymph Nodes; Mice; Mice, Knockout; Ovalbumin; Piperidines; Pyridines; Receptors, G-Protein-Coupled; Receptors, Histamine; Receptors, Histamine H4; Skin

Janus kinase (JAK) inhibitors have recently been developed for allergic diseases. We focused on the 2 different JAK inhibitors, tofacitinib (selective for JAK3) and oclacitinib (selective for JAK1 and 2), to clarify the mechanism of anti-inflammatory and anti-itching potency of these drugs. In the process of detecting anti-itching potency, we observed that tofacitinib treated mice showed aggression behaviour. The objective of the study reported here was to investigate the aggressive behaviour induced by tofacitinib by using a mouse model of allergic dermatitis and the resident-intruder test. For the allergic dermatitis model, female BALB/c mice were sensitised and challenged topically with toluene-2,4-diisocyanate (TDI). Vehicle, tofacitinib or oclacitinib, was administered orally 30 min before TDI challenge. Scratching, aggression and standing behaviours were monitored in the 60 min period immediately following challenge of TDI. Another group of male BALB/c mice treated with vehicle, tofacitinib or oclacitinib was evaluated in the resident-intruder test and brains were obtained to determine blood brain barrier penetration. In the allergic dermatitis model, a significant increase in aggression and standing behaviour was only obvious in the tofacitinib treatment group. There was no effect in non-sensitised mice, but similar aggression was also induced by tofacitinib in male resident-intruder test. Penetration of blood-brain barrier was observed both in tofacitinib and oclacitinib treated mice. These results suggest that aggression was induced by tofacitinib under some kind of stressful environment. This study indicates a possible role of the JAK-STAT pathway in modulation of aggression behaviour.

Topics: Administration, Oral; Aggression; Animals; Anti-Allergic Agents; Anti-Inflammatory Agents; Behavior, Animal; Brain; Dermatitis, Atopic; Disease Models, Animal; Female; Janus Kinases; Male; Mice, Inbred BALB C; Piperidines; Protein Kinase Inhibitors; Pruritus; Pyrimidines; Pyrroles; Stress, Psychological; Sulfonamides; Toluene 2,4-Diisocyanate

Treatment of moderate to severe atopic dermatitis (AD) is often inadequate.. We sought to evaluate the efficacy of the oral Janus kinase inhibitor tofacitinib citrate in the treatment of moderate to severe AD.. Six consecutive patients with moderate to severe AD who had failed standard treatment were treated with tofacitinib citrate. Response to treatment was assessed using the Scoring of AD index.. Decreased body surface area involvement of dermatitis and decreased erythema, edema/papulation, lichenification, and excoriation were observed in all patients. The Scoring of AD index decreased by 66.6% from 36.5 to 12.2 (P < .05) during 8 to 29 weeks of treatment. There were no adverse events.. Small sample size, lack of placebo control group, and the possibility of bias are limitations.. The oral Janus kinase inhibitor tofacitinib citrate may be beneficial in the treatment of moderate to severe AD.

Topics: Administration, Oral; Adolescent; Adult; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Janus Kinases; Male; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Risk Assessment; Sampling Studies; Severity of Illness Index; Treatment Outcome; Young Adult

Topics: Antifungal Agents; Attention Deficit Disorder with Hyperactivity; Boron Compounds; Botulinum Toxins, Type A; Bridged Bicyclo Compounds, Heterocyclic; Brimonidine Tartrate; Depression; Dermatitis, Atopic; Food Hypersensitivity; Humans; Immunologic Factors; Ivermectin; Phosphodiesterase Inhibitors; Phototherapy; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Quinoxalines; Skin Diseases; Societies, Medical; Thalidomide; Triazoles; United States

The Skindex-16 questionnaire was recently developed as a measure of dermatological health-related quality of life (HRQoL), including symptoms, emotions and functional aspects. Bepotastine besilate is a selective histamine H(1) -receptor antagonist and a second-generation non-sedating antihistamine to treat various dermatological disorders. We assessed changes of the HRQoL instrument (Skindex-16) on patients with pruritus, including those with atopic dermatitis (AD) over bepotastine treatment period. The patients' personal assessment of the intensity of pruritus was determined using the Visual Analog Scale (VAS) for pruritus. Patients answered the Skindex-16 at baseline and at week 4. Forty-eight of 51 enrolled dermatological patients completed the Skindex-16. Of the 48 patients, 11 had AD and 37 had other conditions. Improvement in the clinical evaluation and VAS score was significant in all patients, the AD group and the other disorders group between baseline and week 4. Skindex-16 showed significantly lower scores for each of the three scales (symptoms, emotions and functioning) and the global score at baseline compared to that at week 4 in all patients and the other disorders. In contrast, there was a significant reduction in the emotions and global score among the AD patients. We found a significant correlation between falls in emotions score of Skindex-16 and falls in VAS scores for pruritus in the AD group. Bepotastine could be effective in the management of patients' HRQoL and useful in patients suffering with pruritus. We suggested that pruritus of AD patients could exert a stronger emotional effect due to the skin condition compared to the symptomatic or functional effects.

Topics: Adolescent; Adult; Aged; Dermatitis, Atopic; Emotions; Female; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pruritus; Pyridines; Quality of Life; Surveys and Questionnaires; Young Adult

Aloperine has been shown to inhibit 2,4-dinitrofluorobenzene (DNFB) induced allergic contact dermatitis in BALB/c mice. In the present study, we further investigated the effect of aloperine on DNFB-induced atopic dermatitis-like skin lesions in NC/Nga mice. NC/Nga mice elicited atopic dermatitis-like skin lesions after the topical application of DNFB. Aloperine treatment significantly inhibited dermatitis index and ear thickness in DNFB-treated NC/Nga mice in a dose-dependent manner. Eosinophils, mast cells infiltration into the ears and plasma level of immunoglobulin (Ig) E were also suppressed by aloperine treatment. Finally, cytokine (interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-13, tumor necrosis factor (TNF)-α and interferon (IFN)-γ) productions in ear biopsies homogenates were significantly elevated after DNFB challenge. Topical application of aloperine increased the immunosuppressive cytokine IL-10 level, while it reduced other cytokines production in a dose-dependent manner. Taken together, these data suggest that aloperine may be one of the effective therapeutic agents for the treatment of atopic dermatitis.

Topics: Administration, Topical; Animals; Dermatitis, Atopic; Dinitrofluorobenzene; Down-Regulation; Ear; Female; Immunoglobulin E; Interleukin-10; Mast Cells; Mice; Piperidines; Quinolizidines; Th1 Cells; Th2 Cells; Up-Regulation

There is an on-going need to identify medications suitable for the long-term treatment of canine atopic dermatitis (CAD). Masitinib mesilate is a potent and selective tyrosine kinase inhibitor of the c-KIT receptor. A strong relationship exists between the SCF/c-KIT pathway and pathogenesis of CAD, suggesting that masitinib may potentially fulfil the above role. This study reports on an uncontrolled pilot study of masitinib in CAD. Masitinib was administered orally to 11 dogs at a mean dose of 11.0 +/- 1.83 mg/kg/day (free base) for 28 days. Treatment response was assessed by evolution of clinical appearance according to a modified version of the Canine Atopic Dermatitis Extent and Severity Index (mCADESI), pruritus scale and surface area of lesions. Masitinib improved CAD with a mean reduction in mCADESI of 50.7 +/- 29.8% (95% C.I. = 29.4-72.0; p = 0.0004) at day 28 relative to baseline, with 8/10, 8/10 and 4/10 dogs showing improvement of >or=33%, >or=40% and >or=50%, respectively. Improvement was further evidenced by a decrease in pruritus score and the surface area of lesions. No serious or severe adverse events occurred during this trial, although 6/11 dogs presented with mild to moderate treatment related adverse events. There is sufficient compelling evidence to warrant further investigation.

Topics: Animals; Benzamides; Dermatitis, Atopic; Dog Diseases; Dogs; Drug-Related Side Effects and Adverse Reactions; Pilot Projects; Piperidines; Pruritus; Pyridines; Severity of Illness Index; Skin; Thiazoles; Treatment Outcome

Sedation is the most frequent side effect of H(1)-antihistamines, and, sometimes, it may be life-threatening for patients. Evaluation of the sedative properties of H(1)-antihistamines is important to improve the patients' quality of life (QOL). Therefore, we carried out a large-scale surveillance quantified through a questionnaire using visual analog scale (VAS) from 1,742 patients. The results showed that the degree of sleepiness caused by some nonsedative second-generation antihistamines, including fexofenadine, olopatadine and cetirizine, was disease dependent. In atopic dermatitis, an unexpectedly low VAS score of sleepiness was obtained for the first-generation antihistamine d-chlorpheniramine, which is similar to those obtained for bepotastine and epinastine. d-Chlorpheniramine also showed a high VAS score in efficacy. Meanwhile, fexofenadine showed a higher VAS score of sleepiness in atopic dermatitis than those obtained in the other allergic diseases including allergic rhinitis, urticaria and asthma. In asthma, a higher VAS score of sleepiness was found for olopatadine, ebastine and cetirizine, when compared with d-chlorpheniramine. On the other hand, bepotastine showed the lowest VAS score for sleepiness. Our findings suggest the existence of unknown factors influencing the sedative properties of H(1)-antihistamines. Therefore, appropriate H(1)-antihistamines may need to be selected, depending on allergic diseases, to improve patients' QOL.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Asthma; Butyrophenones; Cetirizine; Child; Chlorpheniramine; Dermatitis, Atopic; Dibenzazepines; Dibenzoxepins; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Imidazoles; Japan; Male; Middle Aged; Olopatadine Hydrochloride; Pain Measurement; Piperidines; Population Surveillance; Psychomotor Performance; Pyridines; Quality of Life; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Sleep Stages; Surveys and Questionnaires; Terfenadine; Urticaria

Pruritus is the most severe problem in atopic dermatitis. Even though its mechanism is still not fully understood, antihistamines have been prescribed for atopic dermatitis.. To evaluate the effect of antihistamine on atopic dermatitis, we analyzed the scratching behavior in atopic dermatitis model NC/Nga mice.. BALB/c mice, in which scratching behavior was induced by intradermal injection of compound 48/80 (100 microg/100 microl/mouse), and NC/Nga mice, housed in a conventional environment and having developed spontaneous eczematous regions, were monitored with a SCLABA system after oral administration of bepotastine besilate. The number of eosinophils in the ear skin and the serum leukotriene B(4) (LTB(4)) levels were also evaluated.. Bepotastine at doses of 3 and 10 mg/kg effectively inhibited the compound 48/80-induced scratching behavior of BALB/c mice 1 h after oral administration, comparable with the blood T(max), which was reached within 0.8-1.6 h in humans. Bepotastine also significantly inhibited the scratching behavior of NC/Nga mice 1 h after oral administration. Even though 10 mg/kg bepotastine could not influence the number of tissue eosinophils, it effectively suppressed the serum LTB(4) levels, just comparable with the suppression of scratch behavior of NC/Nga mice.. Bepotastin effectively suppressed the scratch behavior of atopic dermatitis model mice, which may not simply be explained by the suppression of histamine but also by the suppression of other mediators like LTB(4). Bepotastine could be useful in the treatment of pruritus, especially early after oral administration.

Topics: Administration, Oral; Animals; Antipruritics; Behavior, Animal; Dermatitis, Atopic; Disease Models, Animal; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; p-Methoxy-N-methylphenethylamine; Piperidines; Pruritus; Pyridines

Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation.. Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion.. Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism.. These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

Topics: Anaphylaxis; Animals; Anti-Inflammatory Agents; Astemizole; Benzimidazoles; Cell Adhesion; Cell Adhesion Molecules; Cell Movement; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Endothelium, Vascular; Eosinophils; Guinea Pigs; Histamine H1 Antagonists; Humans; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred BALB C; Piperidines; Receptors, Histamine H1; Respiratory Hypersensitivity; Umbilical Veins; Vascular Cell Adhesion Molecule-1

Topics: Allergens; Animals; Dermatitis, Atopic; Dog Diseases; Dogs; Female; Male; Piperidines; Siphonaptera

Topics: Adult; Dermatitis, Atopic; Dermatitis, Contact; Humans; Male; Piperidines

Topics: Anti-Allergic Agents; Dermatitis, Atopic; Eczema; Histamine H1 Antagonists; Humans; Hypersensitivity; Piperidines; Pruritus; Skin Diseases; Tartrates