piperidines and Skin-Diseases

The Janus kinase and Signal Transducer and Activator of Transcription protein (JAK/STAT) pathway is known to be involved in inflammatory and neoplastic skin diseases, like psoriasis, atopic dermatitis, alopecia areata, vitiligo and melanoma. Improved knowledge of the components of this pathway has allowed the development of drugs, which act by inhibiting the pathway, blocking specific components. This offers new therapeutic opportunities. Although evidence on the use of JAK/STAT blockades in dermatological diseases is growing, none have been approved for use in treating skin diseases. The aim of this study is to develop an a priori protocol to broadly review the available evidence on the use of drugs targeting the JAK/STAT pathway in the treatment of dermatological diseases.. For the conduction of the scoping review protocol, we will employ an established scoping review methodology described in the Joanna Briggs Institute manual. This methodology outlines a five-stage approach: (1) identify the research question; (2) identify relevant studies; (3) select studies; (4) chart the data and (5) collate, summarise and report the results, with an optional consultation exercise. Finally, we will use the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews to present the results.. Since this is a review of the literature, ethics approval is not indicated. We will disseminate the findings from this study in publications in peer-reviewed journals as well as presentations at relevant national and international conferences.

Topics: Humans; Janus Kinase Inhibitors; Janus Kinases; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases; STAT Transcription Factors

Tremendous progress has been made in the clinical landscape of advanced-stage. Targeted therapy with BRAF plus MEK inhibitors has become the standard of care for patients with advanced-stage

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Azetidines; Benzimidazoles; Carbamates; Fever; Humans; Imidazoles; Indoles; Melanoma; Mitogen-Activated Protein Kinase Kinases; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Skin Diseases; Sulfonamides; Vemurafenib

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

Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions.. Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases.. This is a systematic review of PubMed and ClinicalTrials.gov.. One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections.. It was not possible to perform a meta-analysis of the results.. This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.

Topics: Alopecia Areata; Anti-Inflammatory Agents; Antineoplastic Agents; Azetidines; Dermatologic Agents; Drug Eruptions; Humans; Janus Kinases; Molecular Targeted Therapy; Nitriles; Piperidines; Protein Kinase Inhibitors; Psoriasis; Purines; Pyrazoles; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Signal Transduction; Skin Diseases; Sulfonamides

Over the last year there has been major publications related to therapeutic trials in infectious dermatology, not only with regard to Herpes zoster subunit vaccine but also for the treatment of uncomplicated abscesses or scabies. In addition, biological treatments continue to be on the forefront, not only in the treatment of psoriasis but also in other chronic inflammatory dermatologic diseases such as atopic dermatitis and hidradenitis suppurativa, two diseases that significantly impact quality of life and for which there are to date, few therapeutic alternatives in moderate to severe forms. In addition, the treatment of cyclin-resistant papulopustular rosacea was also the subject of a large French controlled randomized controlled trial that could modify our therapeutic approach by the use of isotretinoin. Finally, the prevention of rashes induced by erlotinib with oral doxycyline is also part of this 2016 "what's new in dermatological therapeutics".

Topics: Adalimumab; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Dermatologic Agents; Dermatology; Erlotinib Hydrochloride; Herpes Zoster Vaccine; Humans; Interleukin 1 Receptor Antagonist Protein; Isotretinoin; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Diseases; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Ethanolamines; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Phenothiazines; Piperazines; Piperidines; Skin Diseases

PLD is a standard treatment in patients with recurrent platinum-resistant or refractory ovarian cancer. Vandetanib is an oral once daily administered inhibitor of VEGFR-, EGFR- and RET-signaling with activity in combination with chemotherapy in some solid tumours. We aimed to establish a feasible combination therapy of PLD and vandetanib in ovarian cancer.. Eligible patients were treated with PLD 50 mg/m(2) q28 and vandetanib 100 mg/d po. It was planned to recruit at least 10 patients evaluable for toxicity over 2 treatment cycles. Primary endpoints were tolerability and safety; secondary endpoint was efficacy.. Fourteen of 15 registered patients started treatment and were evaluable for toxicity. Three patients (21%) stopped after first cycle (PD, withdrawal of consent, nausea/vomiting). The remaining 11 patients were treated for at least 2 cycles. Dose reductions of PLD and vandetanib were indicated in 4 (29%) and 5 patients (36%), respectively. The following G3/4 toxicities occurred per patient: 2 (14%) elevated liver enzymes G3, 2 (14%) neutropenia G3/4, 5 (36%) PPE G3/4, 2 (14%) mucositis G3. Tyrosine kinase inhibitor attributed side effects like hypertension or bowel perforations were not reported. Toxicity led to cessation of treatment in 4 patients (29%). Ten patients were evaluable for response: PR 1, SD 4. The median PFS was 6.7 months and median OS was 11.1 months.. The combination of PLD 50 mg/m(2)q28 and vandetanib 100 mg/d is feasible, but may be intolerable due to reported toxicity.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Middle Aged; Ovarian Neoplasms; Piperidines; Polyethylene Glycols; Protein Kinase Inhibitors; Quinazolines; Skin Diseases

The administration of histamine with iontophoresis is an alternative method to skin prick tests or intradermal injections. Skin reactions obtained with this method can be recorded with laser Doppler flowmetry (LDF) and previous studies with this method have shown histamine-induced laser Doppler changes in the wheal area.. In order to compare the influence of two H1 receptor antagonists (cetirizine 10 mg vs. ebastine 10 mg) on the skin vascular responses to histamine introduced by iontophoresis, we designed a double-blind, randomized, two-period crossover trial in which 18 volunteers were randomized.. Before and 2, 5 and 7 h after drug administration, iontophoresis (30 s, 1.4 mA/cm2) of histamine 10% was performed and followed by (1) monitoring of skin vascular responses with LDF at the administration site and at 1 cm from it, and (2) wheal and flare area measurements.. 2, 5 and 7 h after intake of the antihistaminic drug, there were significant differences between both drugs. Concerning LDF recordings, we noted at the histamine administration site an increase in perfusion unit (PU) values which is an effect known to be in proportion to the degree of inhibition of wheal reaction, and at 1 cm distal to the histamine administration site, there was a decrease in PU values. These changes were more marked under cetirizine. A greater suppressive effect of cetirizine on the wheal and flare reaction was consistently observed at all time points during the study, demonstrating its superior efficacy.. We conclude that (1) cetirizine demonstrated a stronger antihistaminic effect compared to ebastine at all time points; (2) iontophoresis appears to be an appropriate method to study specific microvascular changes at the delivery site of histamine and hence to detect the earliest changes occurring at the site of agonist-antagonist competition in the skin.

Topics: Adult; Butyrophenones; Cetirizine; Cross-Over Studies; Double-Blind Method; Female; Histamine; Histamine H1 Antagonists; Humans; Iontophoresis; Laser-Doppler Flowmetry; Male; Piperidines; Skin; Skin Diseases; Skin Tests; Time Factors

The new antihistamine, HC20-511 (Sandoz), was compared with Dimetinden (Fenistil retard) in a single-blind comparative study in 42 patients with dermatoses, 28 of whom suffered from chronic urticaria. HC20-511 had a better effect, especially in chronic urticaria, where pruritus, erythema and papules quickly disappeared. The effect appeared somewhat faster than and lasted as long as that of Dimetinden, although HC20-511 is not a retard-preparation unlike the Dimetinden preparation used for comparison. HC20-511 also caused less side effects.

Topics: Adolescent; Adult; Aged; Chronic Disease; Clinical Trials as Topic; Dimethindene; Drug Therapy, Combination; Female; Fumarates; Histamine H1 Antagonists; Humans; Male; Middle Aged; Piperidines; Pruritus; Skin Diseases; Thiophenes; Urticaria; Vomiting

Progressive nodular histiocytosis is a rare variant of non-Langerhans cell histiocytosis that affects the skin and mucous membranes and displays a progressive clinical course and poor response to treatment. We describe a case of severe progressive nodular histiocytosis harboring a KRAS p.G12S mutation in a 9-year-old boy, refractory to chemotherapy, who was successfully treated with the MEK inhibitor cobimetinib. This is the first report of the use of MEK inhibition for this histiocytosis subtype in a pediatric patient.

Topics: Azetidines; Child; Histiocytosis; Histiocytosis, Langerhans-Cell; Humans; Male; Piperidines; Skin Diseases

Topics: Amyloidosis; Humans; Piperidines; Pyrimidines; Skin Diseases

High incidence of cutaneous toxicity ranging from 29.2% to 71.2% has been reported during clinical use of vandetanib, which is a multi-target kinase inhibitor indicated for the treatment of unresectable medullary thyroid carcinoma. The cutaneous toxicity of vandetanib has limited its clinical benefits, but the underlying mechanisms and protective strategies are not well studied. Hence, we firstly established an in vivo model by continuously administrating vandetanib at 55 mg/kg/day to C57BL/6 for 21 days and verified that vandetanib could induce skin rash in vivo, which was consistent with the clinical study. We further cultured HaCaT and NHEK cells, the immortalized or primary human keratinocyte line, and investigated vandetanib (0-10 μM, 0-24 h)-caused alteration in cellular survival and death processes. The western blot showed that the expression level of apoptotic-related protein, c-PARP, c-Caspase 3 and Bax were increased, while the anti-apoptotic protein Bcl2 and MCL1 level were decreased. Meanwhile, vandetanib downregulated mitochondrial membrane potential which in turn caused the release of Cytochrome C, excessive production of reactive oxygen species and DNA damage. Furthermore, we found that 5 μM bisdemethoxycurcumin partially rescued vandetanib-induced mitochondria pathway-dependent keratinocyte apoptosis via activation of autophagy in vivo and in vitro, thereby ameliorated cutaneous toxicity. Conclusively, our study revealed the mechanisms of vandetanib-induced apoptosis in keratinocytes during the occurrence of cutaneous toxicity, and suggested bisdemethoxycurcumin as a potential protective drug. This work provided a potentially promising therapeutic strategy for the treatment of vandetanib-induced cutaneous toxicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Autophagy; Diarylheptanoids; Disease Models, Animal; DNA Damage; HaCaT Cells; Humans; Keratinocytes; Membrane Potential, Mitochondrial; Mice, Inbred C57BL; Mitochondria; Piperidines; Protein Kinase Inhibitors; Quinazolines; Reactive Oxygen Species; Skin; Skin Diseases

Topics: Administration, Oral; Aged; Biopsy; Female; Humans; Janus Kinases; Lung; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoidosis; Sarcoidosis, Pulmonary; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors; Tomography, X-Ray Computed; Treatment Outcome

Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome is a rare autoinflammatory disorder. Cutaneous manifestations of CANDLE syndrome include characteristic recurring violaceous annular plaques comprised of an immature dermal mononuclear cell infiltrate. In CANDLE syndrome, deleterious genetic mutations inhibit proteasome-immunoproteasome function, resulting in cellular accumulation of ubiquitinated waste proteins that activate type I interferon signaling to drive inflammation. We describe a report of successful treatment of a 12-year-old girl with CANDLE syndrome with tofacitinib.

Topics: Child; Female; Fever; Humans; Immunologic Deficiency Syndromes; Lipodystrophy; Piperidines; Pyrimidines; Skin Diseases; Sweet Syndrome

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Protein Kinase Inhibitors; Skin; Skin Diseases

Erdheim-Chester disease (ECD) is a rare multisystemic disease characterised by an infiltration of various organs by CD68. We report the case of a 71-year-old woman with ECD which was revealed by neurological and cutaneous manifestations. The diagnosis was confirmed by skin biopsy and the BRAFV600E mutation was identified in skin tissue, leading to the use of combined therapy targeting the RAS-RAF-ERK-MEK pathway. This therapy allowed an improvement of cutaneous manifestations but neurological manifestations lead to death, underlying their notable severity.. Our case report shows the persistent diagnostic difficulty of the ECD and the particular gravity of neurologic involvement.

Topics: Aged; Azetidines; Drug Therapy, Combination; Erdheim-Chester Disease; Female; Humans; Mitogen-Activated Protein Kinase Kinases; Molecular Targeted Therapy; Nervous System Diseases; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Rare Diseases; Skin Diseases; Vemurafenib

Vandetanib is a wide spectrum tyrosine kinase inhibitor used for the treatment of metastatic medullary thyroid cancer (MTC) and various other cancer types. Although it is usually well-tolerated ıt has been linked to a variety of severe dermatologic reactions. Our study aimed was to investigate adenosine 5'-triphosphate (ATP) on vandetanib-induced skin damage.. A total number of 18 rats were divided into three equal groups as vandetanib group (VDB), vandetanib plus ATP group (VAT), and healthy group (HG); 25 mg/kg ATP was injected intraperitoneally (ip) to the VAT group. Normal saline was given to the HG and VDB groups as solvent via intraperitoneally. One hour later, 25 mg/kg vandetanib was applied orally via an orogastric catheter in the VAT and VDB groups. This procedure was repeated once daily for 4 weeks. After that period, all animals were sacrificed and their skin tissues removed. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS) levels in rats' skin tissues were evaluated with histopathological analyses.. MDA and TOS levels measured higher in the VDB group compared to the VAT and HG groups (. We demonstrated that adenosine triphosphate can prevent vandetanib-induced skin toxicity in rats for the first time. The promising results denote that further studies testing this agent in other animal models and in humans are warranted.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Glutathione; Male; Malondialdehyde; Piperidines; Protein Kinase Inhibitors; Quinazolines; Rats, Wistar; Skin; Skin Diseases

LiTCTP is a toxin from the Translationally Controlled Tumor Protein (TCTP) family identified in

Topics: Animals; Biomarkers, Tumor; Cimetidine; Cromolyn Sodium; Dose-Response Relationship, Drug; Hypersensitivity; Inflammation; Injections, Intraperitoneal; Injections, Intravenous; Mast Cells; Mice; Phosphoric Diester Hydrolases; Piperidines; Promethazine; Rabbits; Rats; Skin Diseases; Spider Venoms; Tumor Cells, Cultured; Tumor Protein, Translationally-Controlled 1

Topics: Aged; Benzimidazoles; Eosinophilia; Histamine Antagonists; Humans; Male; Piperidines; Skin; Skin Diseases

Topics: Adrenal Cortex Hormones; Adult; Aged, 80 and over; Azetidines; Bone Diseases; Dermatologic Agents; Female; Histiocytosis, Langerhans-Cell; Humans; Male; Middle Aged; Off-Label Use; Piperidines; Skin Diseases; Thalidomide

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) are among the cornerstones of metastatic melanoma therapy demonstrating excellent response rates with duration of 7-12 m. Long-term benefit from these agents was reported in patients with normal lactate dehydrogenase (LDH) and less than three disease sites. However, a treatment-dependent marker for long-term efficacy is lacking. Data suggest that immune-related adverse events (irAEs) are associated with clinical benefit in patients treated with immunotherapy and that response to BRAF/MEK therapy may have an underlying immune mechanism. We hypothesised that AEs with an underlying immune mechanism may be associated with a durable response to targeted therapy. We retrospectively identified a cohort of 78 BRAF V600-mutant metastatic melanoma patients treated with BRAFi or BRAFi + MEKi between November 2010 and November 2013. Four treatment-related AEs including vitiligo, uveitis, erythema nodosum and keratitis sicca were defined as irAEs of interest. Retrospective analysis of AEs in relationship to progression-free survival (PFS), disease burden and LDH levels was performed. Median PFS (mPFS) for all patients was 7.5 months with responses ongoing in eight patients as of April 2017. Ten patients were identified with the AEs defined previously. Cox regression analysis revealed a very strong association between those AEs and PFS; mPFS was 42.8 m in patients with at least one AE versus 6.1 m in those without an AE (hazard ratio [HR] 0.22, p = 0.002). This association was independent of LDH levels and disease burden (HR 0.24, p = 0.035). This analysis demonstrates a strong association between immune AEs and durable response to targeted therapy and may provide a treatment-related biomarker to estimate the outcome of therapy.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Arthralgia; Azetidines; Female; Humans; Imidazoles; Kaplan-Meier Estimate; Male; MAP Kinase Kinase 1; Melanoma; Middle Aged; Mutation; Neoplasm Metastasis; Oximes; Piperidines; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retrospective Studies; Skin Diseases; Skin Neoplasms; Vemurafenib; Young Adult

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).

Topics: Female; Humans; Immunohistochemistry; Janus Kinases; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction; Sarcoidosis; Sarcoidosis, Pulmonary; Sequence Analysis, RNA; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors

Topics: Adult; Aged; Female; Humans; Hypereosinophilic Syndrome; Janus Kinase Inhibitors; Male; Middle Aged; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Skin Diseases

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

Halofuginone, isolated from Dichroa febreifuga, is a potent inhibitor of skin collagen in chronic graft-versus-host disease (GVHD). To evaluate the effect of halofuginone on the development of cutaneous GVHD, we developed a murine model based on BALB/c (H-2d) as recipients with transplantation of C57BL/6(H-2b) bone marrow plus splenocytes. Halofuginone or its vehicle dimethyl sulfoxide (DMSO) was given introperitoneally at a dose of 5 ug/mouse daily from one day before transplantation until 20 days post-transplantation. Halofuginone-treated recipients showed only very mild appearance of cutaneous GVHD, whereas DMSO-treated recipients rapidly showed manifestation of severe cutaneous GVHD, indicating a protective effect of halofuginone in cutaneous GVHD. After injected with halofuginone, we observed a decrease in the number of CD4(+) interleukin (IL)-17(+) cells and a parallel increase in that of CD4(+) interferon (IFN)-gamma(+) cells in peripheral blood. This shift between CD4(+) IL-17(+) cells and CD4(+) IFN-gamma(+) cells developed through modulation of cytokine profile indicated by a marked increase in the levels of IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-6. The level of IL-10 was not changed obviously. Mechanistically, we demonstrate that severe tissue damage was associated with the production of IL-17 and expansion of CD4(+)IL-17(+) cells during this disorder. Specific inhibition of Th17 differentiation by halofuginone reduced disease severity. Our results indicate a significant role of halofuginone in suppressing cutaneous GVHD, apparently through effect on inhibition of Th17 cells differentiation.

Topics: Angiogenesis Inhibitors; Animals; Bone Marrow Transplantation; Cell Differentiation; Chronic Disease; Cytokines; Female; Graft vs Host Disease; Male; Mice; Mice, Inbred BALB C; Piperidines; Quinazolinones; Skin Diseases; Th17 Cells; Time Factors; Transplantation, Homologous

The end point of pathogenic events in scleroderma is fibrosis of the skin and internal organs. Fibrosis in scleroderma results from the over synthesis and deposition of collagen in the connective tissue. The morbidity and mortality of the scleroderm is very high and presently there is no specific treatment. Halofuginone is a drug with great potential for the treatment of scleroderma since it inhibits the synthesis of collagen type I by fibroblasts. We have studied the in vivo effect of halofuginone in tight skin (TSK) mice that spontaneously develop a scleroderma-like disease due to a genetic defect. Our results demonstrate that halofuginone prevented the occurrence of skin sclerosis when administered to newborn mice and reduced cutaneous hyperplasia when administered in adult TSK mice. These effects correlated with a decreased number of cells synthesizing collagen gene transcripts and a reduction in the level of autoantibodies specific for human target antigens. These results indicate that halofuginone may have use as a therapeutic in the treatment of fibrotic disease.

Topics: Animals; Animals, Newborn; Collagen; Disease Models, Animal; Fibrosis; Humans; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Piperidines; Protein Synthesis Inhibitors; Quinazolines; Quinazolinones; Scleroderma, Systemic; Skin Diseases

Halofuginone is a drug that has been shown to have an antifibrotic property in vitro and in vivo. Whereas halofuginone shows promise as a therapeutic agent for a variety of diseases including scleroderma, liver cirrhosis, cystic fibrosis, and certain types of cancer, the mechanism of action remains unknown. Using the tight skin mouse (TSK) model for scleroderma, we evaluated the ability of halofuginone to inhibit spontaneous development of dermal fibrosis. We found that administration of a low dose of halofuginone both in adult and newborn animals for 60 d prevented the development of cutaneous hyperplasia (dermal fibrosis). In vitro halofuginone was found to reduce the amount of collagen synthesized by fibroblasts. This effect was due to a reduction in the promoter activity of the type-I collagen genes as treatment of fibroblast cultures with 10(-8) M halofuginone reduced the level of alpha2(I) collagen message detectible by northern blot and greatly reduced the activity of a reporter construct under control of the -3200 to +54 bp alpha2(I) collagen promoter. In addition, analysis of transforming growth factor beta signaling pathways in fibroblasts revealed that halofuginone inhibited transforming-growth-factor-beta-induced upregulation of collagen protein and activity of the alpha2(I) collagen promoter. Further we found that halofuginone blocked the phosphorylation and subsequent activation of Smad3 after transforming growth factor beta stimulation. Apparently the inhibitory property was specific to Smad3 as there was no inhibitory effect on the activation of Smad2 after stimulation with transforming growth factor beta. Our results demonstrate that halofuginone is a specific inhibitor of type-I collagen synthesis and may elicit its effect via interference with the transforming growth factor beta signaling pathway.

Topics: Animals; Cells, Cultured; Collagen; Collagen Type I; DNA-Binding Proteins; Fibroblasts; Gene Expression; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Mutant Strains; Piperidines; Quinazolines; Quinazolinones; Receptors, Transforming Growth Factor beta; Sclerosis; Signal Transduction; Skin; Skin Diseases; Smad3 Protein; Trans-Activators; Transforming Growth Factor beta

1. The possibility that tachykinin NK1 receptors are involved in the plasma extravasation evoked by intradermal (i.d.) injection of Phoneutria nigriventer venom (PNV) in rat dorsal skin in vivo has been investigated. 2. Local oedema formation induced by the i.d. injection of test agents was measured by the extravascular accumulation of intravenously (i.v.) injected 125I-labelled human serum albumin over a 30 min period. 3. The tachykinin NK1 agonist, GR73632 (30 pmol per site), induced local oedema formation which was potentiated by co-injection with the neuropeptide vasodilator, calcitonin gene-related peptide (CGRP, 10 pmol per site). The non-peptide tachykinin NK1 receptor antagonist, SR140333 (0.03-1 nmol per site co-injected, i.d.) significantly inhibited (0.3 nmol per site, P < 0.05; 1 nmol per site, P < 0.001) local oedema formation induced by GR73632 with CGRP but not that induced by histamine (10 nmol per site) with CGRP. 4. PNV (0.03-0.3 microgram per site) injected i.d. induced dose-dependent local oedema formation. SR140333 (1 nmol per site, co-injected i.d.) inhibited oedema formation; with complete inhibition observed at doses of 0.03 microgram (P < 0.05) and 0.1 microgram (P < 0.001); and partial inhibition (50%) observed with the highest dose of PNV, 0.3 microgram (P < 0.05). 5. Local oedema formation induced by PNV was not affected by systemic pretreatment with the bradykinin B2 receptor antagonist, Hoe 140 (80 nmol kg-1, i.v.), which was used at a dose which significantly inhibited oedema formation by bradykinin (1 nmol per site). 6. Local oedema formation induced by PNV was significantly inhibited (P < 0.01) by co-injection of the histamine H1 receptor antagonist, mepyramine (2.5 nmol per site), together with the 5-hydroxytryptamine (5-HT) antagonist, methysergide (2.8 nmol per site). 7. In the presence of all three antagonists (mepyramine 2.5 nmol per site; methysergide, 2.8 nmol per site and SR140333 1 nmol per site), the plasma extravasation induced by PNV was further significantly inhibited (P < 0.001, when compared with PNV injected i.d. alone; P < 0.05 when compared with PNV co-injected with mepyramine and methysergide and P < 0.01, when compared with PNV co-injected with SR140333). 8. These results suggest that oedema formation evoked by i.d. PNV in rat skin may be partially mediated via a mechanism involving tachykinin NK1 receptors and that this effect is independent of histamine and 5-HT.

Topics: Animals; Edema; Male; Methysergide; Neurokinin-1 Receptor Antagonists; Peptide Fragments; Piperidines; Pyrilamine; Quinuclidines; Rats; Rats, Wistar; Receptors, Neurokinin-1; Skin Diseases; Spider Venoms; Substance P

SR 140333, the first member of a newly developed neurokinin-1 (NK1) receptor antagonist series, inhibited in a dose-dependent manner oedema formation in rat skin when administered i.d. premixed with [Arg6,Sar9,Met(O2)11]substance P(6-11) (NK1 ago), a selective agonist of the NK1 receptor or substance P (SP) (ED50 values = 0.9 +/- 0.3 and 0.8 +/- 0.2 nmol/site, respectively) (n = 9). SR 140333 protected rats from NK1 ago- or SP-induced plasma extravasation with ED50 values of 35 +/- 7 and 43 +/- 6 micrograms/kg, respectively, when given i.v. 15 min before the challenge. In ovalbumin-presensitized rats, SR 140333, premixed with the allergen, inhibited in a dose-dependent manner plasma exudation (ED50 = 0.18 +/- 0.04 nmol/site, i.d.) (n = 15). Intravenous injection of SR 140333 inhibited allergen-induced vascular permeability (ED50 = 87 +/- 14 micrograms/kg). These results therefore show that NK1 plays a major role in the development of cutaneous anaphylaxis and that SR 140333 may be an effective prophylactic drug.

Topics: Allergens; Animals; Edema; Male; Neurokinin-1 Receptor Antagonists; Piperidines; Quinuclidines; Rats; Rats, Sprague-Dawley; Receptors, Neurokinin-1; Skin Diseases; Substance P

To describe a novel treatment for perianal excoriation in an infant receiving a promotility agent.. A 2-month-old boy with reflux, and regurgitation was treated with cisapride. Shortly after cisapride therapy he developed a rash on his buttocks and anal irritation that progressed in severity despite the use of numerous topical products and extended diaper-free periods. A topical cholestyramine ointment compound was prepared and administered, resulting in complete resolution within 3 days.. Cisapride can decrease the gastrointestinal transit time, which can lead to less time for bile acid reabsorption in the distal ileum. If high concentrations of bile acids are contained in the stool, they can irritate the anus and buttocks in a manner similar to the skin irritation experienced by patients with ostomies. Cholestyramine, a bile acid sequestrant, can irreversibly bind the bile when applied topically and bring relief to the patient.. Topical cholestyramine ointment may be a safe and efficacious treatment option for perianal irritation due to bile acids.

Topics: Antipruritics; Buttocks; Cholestyramine Resin; Cisapride; Drug Eruptions; Humans; Infant; Male; Ointments; Piperidines; Skin Diseases; Sympathomimetics

Topics: Administration, Topical; Anti-Inflammatory Agents; Humans; Piperidines; Prednisolone; Skin Diseases

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Piperidines; Skin Diseases

Topics: Bridged-Ring Compounds; Bromides; Exanthema; Humans; Hypnotics and Sedatives; Incidence; Piperidines; Skin Diseases; Urea

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

Topics: Cholinergic Antagonists; Parasympatholytics; Piperidines; Skin Diseases

Topics: Dairy Products; Humans; Muscarinic Antagonists; Parasympatholytics; Piperidines; Skin Diseases

Topics: Central Nervous System Stimulants; Piperidines; Pruritus; Skin Diseases; Tripelennamine

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Piperidines; Skin Diseases

Topics: Dermatology; Humans; Parasympatholytics; Piperidines; Skin Diseases

Topics: Anti-Allergic Agents; Histamine H1 Antagonists; Piperidines; Skin Diseases

Topics: Bridged-Ring Compounds; Dermatitis; Humans; Pharmaceutical Preparations; Piperidines; Purpura; Skin Diseases; Urea