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2.
Acta Derm Venereol ; 100(10): adv00131, 2020 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-32250439

RESUMO

Isatis tinctoria L. (woad) has been used in medicine for centuries and has demonstrated anti-inflammatory effects. However, to date, no well-defined extracts with precise analysis of active substances have been developed. The aim of this study was to develop novel extracts of Isatis tinctoria L., and to characterize their active ingredients and anti-inflammatory properties. Various extracts of Isatis tinctoria L. were analysed for their active ingredients, and screened for anti-inflammatory effects using cyclooxygenase-2 activity assays. A petroleum ether extract was found to have the best effects, and was tested in a mouse model of acute allergic contact dermatitis. In the mouse model the petroleum ether extract resulted in significantly reduced ear swelling, oedema and inflammatory cell density. In mouse skin and human keratinocyte cultures, petroleum ether extract inhibited pro-inflammatory cytokine expression. Furthermore, human mast cell degranulation was significantly inhibited in LAD2 cell cultures. In conclusion, novel woad extracts were developed and shown to have anti-inflammatory properties in a contact hypersensitivity animal model and human keratinocytes. The production of such extracts and further characterization of their specific properties will enable determination of their potential dermatological effects in the treatment of inflamed and irritated skin.


Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Alérgica de Contato/tratamento farmacológico , Isatis , Fitoterapia , Extratos Vegetais/uso terapêutico , Administração Tópica , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/imunologia , Células Cultivadas , Dermatite Alérgica de Contato/imunologia , Fármacos Dermatológicos/administração & dosagem , Fármacos Dermatológicos/imunologia , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Orelha , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Interleucina-33/antagonistas & inibidores , Interleucina-33/imunologia , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Estabilizadores de Mastócitos/administração & dosagem , Estabilizadores de Mastócitos/imunologia , Estabilizadores de Mastócitos/uso terapêutico , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Camundongos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia
3.
J Invest Dermatol ; 140(1): 203-211.e4, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31276675

RESUMO

Neurophysiological mechanisms leading to chronicity of pruritus are not yet fully understood and it is not known whether these mechanisms diverge between different underlying diseases of chronic pruritus (CP). This study aimed to detect such mechanisms in CP of various origins. A total of 120 patients with CP of inflammatory origin (atopic dermatitis), neuropathic origin (brachioradial pruritus), and chronic prurigo of nodular type, the latter as a model for chronic scratching, as well as 40 matched healthy controls participated in this study. Stimulation with cowhage induced a more intensive itch sensation compared with stimulation with other substances in all patient groups but not in healthy controls, arguing for sensitization of cutaneous mechano- and heat-sensitive C-fibers in CP. All patient groups showed a decreased intraepidermal nerve fiber density compared with controls. A decreased condition pain modulation effect was observed in all patient groups compared with controls, suggesting a reduced descending inhibitory system in CP. In sum, CP of different etiologies showed a mixed peripheral and central pattern of neuronal alterations, which might contribute to the chronicity of pruritus with no differences between pruritus entities. Our findings may contribute to the development of future treatment strategies targeting these pathomechanisms.


Assuntos
Dermatite Atópica/diagnóstico , Fibras Nervosas/patologia , Prurigo/diagnóstico , Prurido/diagnóstico , Pele/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Alérgenos/imunologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mucuna/imunologia , Dor , Sistema Nervoso Periférico , Adulto Jovem
4.
Acta Derm Venereol ; 99(7): 668-674, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30938826

RESUMO

Chronic pruritus (CP) is often accompanied by paresthetic sensations like warmth, burning and stinging. The aim of this study was to analyze, whether divergent sensations are linked to structural and functional skin alterations in clinically diagnosed CP patients. Clinical responses to capsaicin, histamine, and to thermal and mechanical stimulation, intraepidermal nerve fiber density, and epidermal expression of transient receptor potential (TRP)-channels were investigated in healthy controls, and in CP patients, reporting either warmth (CP-W) or neuropathic sensations (CP-N). In CP-W, pinprick hyperalgesia and increased sensitivity to capsaicin were aligned with increased epidermal TRPV1 expression, while smaller histamine axon reflex erythema matched with significantly reduced intraepidermal nerve fiber density. CP-N showed earlier onset of sensations after capsaicin stimulation, significantly increased warmth detection threshold, and higher epidermal expression of TRPV4 compared to healthy controls. The present study contributes to the neurobiological understanding of the divergence of sensory sensations in CP, indicating new treatment targets.


Assuntos
Hiperalgesia/metabolismo , Nervos Periféricos/patologia , Prurido/metabolismo , Prurido/patologia , Canais de Cátion TRPV/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antipruriginosos/farmacologia , Capsaicina/farmacologia , Estudos de Casos e Controles , Doença Crônica , Feminino , Histamina/farmacologia , Agonistas dos Receptores Histamínicos/farmacologia , Temperatura Alta , Humanos , Hiperalgesia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Estimulação Física , Prurido/fisiopatologia , Tempo de Reação , Pele/inervação
5.
J Med Chem ; 60(6): 2526-2551, 2017 03 23.
Artigo em Inglês | MEDLINE | ID: mdl-28218838

RESUMO

In order to develop novel κ agonists restricted to the periphery, a diastereo- and enantioselective synthesis of (4aR,5S,8aS)-configured decahydroquinoxalines 5-8 was developed. Physicochemical and pharmacological properties were fine-tuned by structural modifications in the arylacetamide and amine part of the pharmacophore as well as in the amine part outside the pharmacophore. The decahydroquinoxalines 5-8 show single-digit nanomolar to subnanomolar κ-opioid receptor affinity, full κ agonistic activity in the [35S]GTPγS assay, and high selectivity over µ, δ, σ1, and σ2 receptors as well as the PCP binding site of the NMDA receptor. Several analogues were selective for the periphery. The anti-inflammatory activity of 5-8 after topical application was investigated in two mouse models of dermatitis. The methanesulfonamide 8a containing the (S)-configured hydroxypyrrolidine ring was identified as a potent (Ki = 0.63 nM) and highly selective κ agonist (EC50 = 1.8 nM) selective for the periphery with dose-dependent anti-inflammatory activity in acute and chronic skin inflammation.


Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Dermatite/tratamento farmacológico , Quinoxalinas/química , Quinoxalinas/uso terapêutico , Receptores Opioides kappa/agonistas , Pele/efeitos dos fármacos , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Dermatite/patologia , Desenho de Fármacos , Cobaias , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Quinoxalinas/farmacocinética , Quinoxalinas/farmacologia , Ratos Wistar , Pele/patologia
6.
Exp Dermatol ; 26(8): 739-742, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-27892633

RESUMO

Chronic pruritus is difficult to treat. Current treatment options are frequently ineffective and new therapeutic approaches are urgently needed. Avenanthramides are active substances in oats that exhibit anti-inflammatory effects. Their potential to interrupt pruritus mechanisms was investigated in this study. It was found that the synthetic analog dihydroavenanthramide D (DHAvD) can interact with the neurokinin-1 receptor (NK1R) and inhibit mast cell degranulation. DHAvD also affects inflammatory processes and reduces secretion of the cytokine interleukin-6. Our findings indicate that DHAvD may act as a NK1R inhibitor and could be a promising candidate for topical treatments of chronic pruritus.


Assuntos
Mastócitos/efeitos dos fármacos , Prurido/tratamento farmacológico , Receptores da Neurocinina-1/metabolismo , ortoaminobenzoatos/uso terapêutico , Animais , Sinalização do Cálcio/efeitos dos fármacos , Linhagem Celular , Doença Crônica , Avaliação Pré-Clínica de Medicamentos , Humanos , Ratos , Substância P , ortoaminobenzoatos/farmacologia
8.
Acta Derm Venereol ; 95(3): 266-71, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25136974

RESUMO

The complex nature and difficult-to-establish aetiology of chronic pruritus (CP) makes it challenging to provide medical care for patients with CP. This challenge can only be met with a multidisciplinary approach. The first multidisciplinary Itch Centre in Germany was established at the University of Münster in 2002 to meet the needs of this patient population. More than 2,500 outpatients and 400 inpatients are diagnosed and receive treatment each year. To ensure evidence-based medical care, an electronic system for medical documentation and patient-reported outcomes was established. Automated data transfer to a research database enables comprehensive data analysis. Our translational research has characterized peripheral and central itch mechanisms, provided novel clustering of CP patients, and identified novel target-specific therapies (e.g. neurokinin 1 receptor-antagonist). The multidisciplinary approach, combined with basic, clinical and translational research, enables comprehensive medical care of patients as well as implementation of high-quality experimental and clinical studies.


Assuntos
Comportamento Cooperativo , Comunicação Interdisciplinar , Ambulatório Hospitalar/organização & administração , Equipe de Assistência ao Paciente/organização & administração , Prurido , Antipruriginosos/uso terapêutico , Doença Crônica , Registros Eletrônicos de Saúde/organização & administração , Alemanha/epidemiologia , Humanos , Modelos Organizacionais , Valor Preditivo dos Testes , Prognóstico , Desenvolvimento de Programas , Prurido/diagnóstico , Prurido/tratamento farmacológico , Prurido/epidemiologia , Prurido/fisiopatologia , Fatores de Risco , Pesquisa Translacional Biomédica/organização & administração , Fluxo de Trabalho
9.
J Dtsch Dermatol Ges ; 12(7): 557-9, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24862239

RESUMO

Pruritus is an unpleasant sensation of the skin, which triggers a desire to scratch or rub. The chronic form (≥6 weeks' duration) often occurs as a side effect of many diseases and is usually accompanied by a high loss in quality of life for patients, especially in cases in which the symptom is chronic without adequate treatment options. In recent years, the situation improved continuously, guidelines for chronic pruritus have been defined and standard medications have been proposed. For many reasons, there are still patients who are unable to obtain relief. New therapeutic approaches are therefore urgently needed. Blocking the neuropeptide substance P is a promising strategy; substance P mediates clinically relevant pro-inflammatory effects by binding to the neurokinin 1 receptor (NK-1R). This led us to hypothesize that NK-1R antagonists are promising therapeutic options for chronic pruritus. Several international case series have meanwhile proven the antipruritic effect of the NK-1R antagonist aprepitant for various forms of chronic pruritus. Initiation of clinical trials with new NK-1R-antagonists as a new therapeutic option continues this trend.


Assuntos
Anti-Inflamatórios/uso terapêutico , Citocinas/imunologia , Fármacos Dermatológicos/uso terapêutico , Prurido/tratamento farmacológico , Prurido/imunologia , Pele/imunologia , Substância P/imunologia , Doença Crônica , Medicina Baseada em Evidências , Humanos , Modelos Imunológicos , Pele/efeitos dos fármacos
10.
Dermatology ; 227(4): 353-60, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24281309

RESUMO

BACKGROUND: In the treatment of atopic dermatitis, pimecrolimus has high antipruritic effects. OBJECTIVE: To investigate the efficacy of 1% pimecrolimus cream in comparison to 1% hydrocortisone cream in non-atopic prurigo nodularis (PN). METHODS: A randomized, controlled, double-blind study with intraindividual randomization was done in 30 patients (17 females, 13 males; mean age 58.5 years) with PN. RESULTS: Pruritus intensity decreased significantly (p < 0.001) on both treated sides as early as after 10 days of treatment; scratch lesions improved (p < 0.001). Quality of life as assessed by the Dermatology Life Quality Index improved significantly. However, a significant advantage of pimecrolimus over hydrocortisone was not found. CONCLUSION: The results suggest that the non-steroid pimecrolimus is an effective alternative for PN treatment.


Assuntos
Fármacos Dermatológicos/administração & dosagem , Neuropeptídeos/metabolismo , Prurigo/tratamento farmacológico , Prurido/tratamento farmacológico , Tacrolimo/análogos & derivados , Administração Cutânea , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Biomarcadores/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prurigo/complicações , Prurigo/metabolismo , Prurido/etiologia , Prurido/metabolismo , Qualidade de Vida , Tacrolimo/administração & dosagem
11.
Expert Opin Investig Drugs ; 22(9): 1167-79, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23815605

RESUMO

INTRODUCTION: Chronic pruritus (CP), defined as itch lasting for > 6 weeks, is a burdensome symptom of several different diseases, dermatological and systemic, with a high negative impact on the quality of life of patients. Given the manifold aetiologies of CP, therapy is often difficult. In recent years, however, novel substances have been developed for treatment of certain CP entities and identified targets. AREAS COVERED: In this review, the authors present a survey of targets currently believed to be promising (H4R, IL-31, MOR, KOR, GRPR, NGF, NK-1R, TRP channels) and related investigational drugs that are in the preclinical or clinical stage of development. Some substances have already undergone clinical testing, but only one of them (nalfurafine) has been licensed so far. Many of them are most likely to exert their effects on the skin and interfere there with the cutaneous neurobiology of CP. EXPERT OPINION: Currently, the most promising candidates for new therapeutic agents in CP are neurokinin-1 receptor antagonists and substances targeting the kappa- or mu-opioid receptor, or both. They have the potential to target the neuronal pathway of CP and are thus of interest for several CP entities. The goal for the coming years is to validate these concepts and move forward in developing new drugs for the therapy of CP.


Assuntos
Drogas em Investigação/uso terapêutico , Terapia de Alvo Molecular , Prurido/tratamento farmacológico , Animais , Doença Crônica , Desenho de Fármacos , Drogas em Investigação/farmacologia , Humanos , Qualidade de Vida , Pele/efeitos dos fármacos , Pele/metabolismo
12.
Acta Derm Venereol ; 92(5): 555-60, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22504709

RESUMO

Chronic pruritus is frequently refractory to currently available treatments. Studies suggest that pruritus may arise from an imbalance of the mu- and kappa-opioid receptor system activity in either the skin or the central nervous system. Stimulation of kappa-opioid receptors by their agonists inhibits pruritus in both animals and humans. The antipruritic effect of kappa-opioid receptors agonists can currently be assumed to be related to their binding to kappa-opioid receptors on keratinocytes and cutaneous and/or central itch neurones. To date, several case reports and 2 controlled trials have demonstrated a beneficial effect of systemic kappa-opioid receptor agonists in the treatment of uraemic pruritus, prurigo nodularis, paraneoplastic and cholestatic pruritus. Nalfurafine hydrochloride (Remitch(®)), a selective kappa-opioid receptor agonist, is approved for the treatment of chronic pruritus in Japan. The aim of this review is to provide an overview of the promising role of kappa- opioid receptors and their agonist in the pathophysiology and treatment of pruritus.


Assuntos
Antipruriginosos/uso terapêutico , Prurido/tratamento farmacológico , Receptores Opioides kappa/agonistas , Animais , Butorfanol/uso terapêutico , Doença Crônica , Humanos , Morfinanos/uso terapêutico , Prurido/diagnóstico , Prurido/metabolismo , Receptores Opioides kappa/metabolismo , Compostos de Espiro/uso terapêutico , Resultado do Tratamento
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