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1.
Expert Opin Drug Discov ; 14(5): 485-497, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30870037

RESUMO

INTRODUCTION: Chronic, nonhealing skin wounds claim >3% of the health-care budget in industrialized countries, and the incidence is rising. Currently, two parallel trends influence innovations within the field of wound healing: the need to reduce spread of antibiotic resistance and the emerging use of health economy and value-based models. Areas covered: This review focuses on the discovery of drug candidates and development of treatments aiming to enhance wound healing in the heterogeneous group of patients with nonhealing wounds. Expert opinion: Nonhealing wounds are multifaceted and recognized as difficult indications. The majority of products currently in use are medical device dressings, or concepts of negative pressure or hyperbaric oxygen treatment. Global best practice guidelines for the treatment of diabetic foot ulcers recommend debridement, redressing, as well as infection control, and are critical to the lack of coherent clinical evidence for many approved products in active wound care. To accelerate wound healing, there is an emerging trend toward biologics, gene therapy, and novel concepts for drug delivery in research and in the pipeline for clinical trials. Scientific delineation of the therapeutic mechanism of action is, in our opinion, vital for clinical trial success and for an increased fraction of medical products in the pharmaceutical pipeline.


Assuntos
Desenvolvimento de Medicamentos/métodos , Descoberta de Drogas/métodos , Cicatrização/efeitos dos fármacos , Administração Tópica , Pé Diabético/tratamento farmacológico , Pé Diabético/patologia , Sistemas de Liberação de Medicamentos , Humanos , Preparações Farmacêuticas/administração & dosagem , Ferimentos e Lesões/tratamento farmacológico , Ferimentos e Lesões/patologia
2.
Acta Physiol (Oxf) ; 214(2): 200-9, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25561022

RESUMO

AIM: Myeloid cells have been suggested to participate in angiogenesis and regulation of vascular function. Shb-deficient mice display both vascular and myeloid cell abnormalities with possible consequences for recovery after hindlimb ischaemia. This study was conducted in order to assess the contribution of Shb deficiency in myeloid cells to impaired vascular function in ischaemia. METHODS: Wild type and Shb-deficient mice were subjected to peritoneal vascular endothelial growth factor A (VEGFA) followed by intraperitoneal lavage, after which blood and peritoneal cells were stained for myeloid markers. VEGFA-induced leucocyte recruitment to cremaster muscle was investigated using intravital microscopy of both mouse strains. Blood flow after femoral artery ligation was determined on chimeric mice after bone marrow transplantation. RESULTS: No differences in neutrophil numbers or cell surface phenotypes were detected. Moreover, neutrophil extravasation in VEGFA-activated cremaster muscle was unaffected by Shb deficiency. However, blood and peritoneal CXCR4+ monocytes/macrophages were reduced in response to intraperitoneal VEGFA but not lipopolysaccharide (LPS) in the absence of Shb. Furthermore, the macrophage population in ischaemic muscle was unaffected by Shb deficiency after 2 days but reduced 7 days after injury. The bone marrow transplantation experiments revealed that mice with wild type vasculature showed better blood flow than those with Shb-deficient vasculature irrespective of leucocyte genotype. CONCLUSION: The observed aberrations in myeloid cell properties in Shb-deficient mice are likely consequences of an abnormal vascular compartment and are not responsible for reduced muscle blood flow. Structural vascular abnormalities seem to be the primary cause of poor vascular performance under provoked vascular stress in this genetic model.


Assuntos
Endotélio/irrigação sanguínea , Membro Posterior/irrigação sanguínea , Isquemia/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Movimento Celular/fisiologia , Células Endoteliais/metabolismo , Isquemia/fisiopatologia , Leucócitos/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Knockout , Neovascularização Patológica/metabolismo , Neovascularização Fisiológica , Proteínas Proto-Oncogênicas/deficiência , Transdução de Sinais/fisiologia
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