Base de dados : MEDLINE
Pesquisa : G07.690.773.992.910 [Categoria DeCS]
Referências encontradas : 1329 [refinar]
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[PMID]:28619258
[Au] Autor:Shimizu Y; Koyama R; Kawamoto T
[Ad] Endereço:Biomolecular Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: yuuji.shimizu@takeda.com.
[Ti] Título:Rho kinase-dependent desensitization of GPR39; a unique mechanism of GPCR downregulation.
[So] Source:Biochem Pharmacol;140:105-114, 2017 Sep 15.
[Is] ISSN:1873-2968
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:GPR39, a G-protein-coupled receptor activated by zinc, reportedly activates multiple intracellular signaling pathways via Gs, Gq, G12/13, and ß-arrestin, but little is known about downregulation of the receptor upon its activation. To our knowledge, this is the first report on the mechanism of feedback regulation of GPR39 function determined in GPR39-expressing HEK293 cells (HEK293-GPR39) as a model cell system. In HEK293-GPR39 cells, GPR39-C3, which is a positive allosteric modulator, activated cAMP production (downstream of Gs), IP1 accumulation (downstream of Gq), SRF-RE-dependent transcription (downstream of G12/13), and ß-arrestin recruitment. GPR39-C3 induced dose- and time-dependent loss of response in cAMP production by second challenge of the compound. This functional desensitization was blocked by the Rho kinase (ROCK) inhibitor, Y-27632, but not by Gq or Gs-pathway inhibitors or inhibition of ß-arrestin recruitment. In the receptor localization assay, GPR39-C3 induced internalization of GFP-tagged GPR39. This internalization was also inhibited by Y-27632, which suggested that ROCK activation is critical for internalization and desensitization of GPR39. A novel biased GPR39 positive allosteric modulator, 5-[2-[(2,4-dichlorophenyl)methoxy]phenyl]-2,2-dimethyl-1,3,5,6-tetrahydrobenzo[a]phenanthridin-4-one (GSB-118), which activated cAMP responses and ß-arrestin recruitment but showed no effect on SRF-RE-dependent transcription, did not induce desensitization. These results revealed a unique mechanism of desensitization of GPR39.
[Mh] Termos MeSH primário: AMP Cíclico/metabolismo
Retroalimentação Fisiológica
Receptores Acoplados a Proteínas-G/antagonistas & inibidores
Sistemas do Segundo Mensageiro
Taquifilaxia
Zinco/metabolismo
Quinases Associadas a rho/metabolismo
[Mh] Termos MeSH secundário: Regulação Alostérica/efeitos dos fármacos
Amidas/farmacologia
Retroalimentação Fisiológica/efeitos dos fármacos
Regulação da Expressão Gênica/efeitos dos fármacos
Genes Reporter/efeitos dos fármacos
Proteínas de Fluorescência Verde/genética
Proteínas de Fluorescência Verde/metabolismo
Células HEK293
Seres Humanos
Cinética
Ligantes
Microscopia de Fluorescência
Fenantridinas/farmacologia
Inibidores de Proteínas Quinases/farmacologia
Transporte Proteico/efeitos dos fármacos
Piridinas/farmacologia
Pirimidinas/farmacologia
Receptores Acoplados a Proteínas-G/agonistas
Receptores Acoplados a Proteínas-G/genética
Receptores Acoplados a Proteínas-G/metabolismo
Proteínas Recombinantes de Fusão/metabolismo
Proteínas Recombinantes/química
Proteínas Recombinantes/metabolismo
Sistemas do Segundo Mensageiro/efeitos dos fármacos
Sulfonamidas/farmacologia
beta-Arrestinas/metabolismo
Quinases Associadas a rho/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Amides); 0 (GPR39 protein, human); 0 (GPR39-C3); 0 (GSB-118); 0 (Ligands); 0 (Phenanthridines); 0 (Protein Kinase Inhibitors); 0 (Pyridines); 0 (Pyrimidines); 0 (Receptors, G-Protein-Coupled); 0 (Recombinant Fusion Proteins); 0 (Recombinant Proteins); 0 (Sulfonamides); 0 (beta-Arrestins); 138381-45-0 (Y 27632); 147336-22-9 (Green Fluorescent Proteins); E0399OZS9N (Cyclic AMP); EC 2.7.11.1 (rho-Associated Kinases); J41CSQ7QDS (Zinc)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170818
[Lr] Data última revisão:
170818
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170617
[St] Status:MEDLINE


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[PMID]:27811173
[Au] Autor:Svensson KA; Heinz BA; Schaus JM; Beck JP; Hao J; Krushinski JH; Reinhard MR; Cohen MP; Hellman SL; Getman BG; Wang X; Menezes MM; Maren DL; Falcone JF; Anderson WH; Wright RA; Morin SM; Knopp KL; Adams BL; Rogovoy B; Okun I; Suter TM; Statnick MA; Gehlert DR; Nelson DL; Lucaites VL; Emkey R; DeLapp NW; Wiernicki TR; Cramer JW; Yang CR; Bruns RF
[Ad] Endereço:Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana (K.A.S., B.A.H., J.M.S., J.P.B., J.H., J.H.K., M.R.R., M.P.C., S.L.H., B.G.G., X.W., M.M.M., D.L.M., J.F.F., W.H.A., R.A.W., S.M.M., K.L.K., B.L.A., T.M.S., M.A.S., D.R.G., D.L.N., V.L.L., R.E., N.W.D., T.R.W., J.W.C., C.R.Y., R
[Ti] Título:An Allosteric Potentiator of the Dopamine D1 Receptor Increases Locomotor Activity in Human D1 Knock-In Mice without Causing Stereotypy or Tachyphylaxis.
[So] Source:J Pharmacol Exp Ther;360(1):117-128, 2017 Jan.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Allosteric potentiators amplify the sensitivity of physiologic control circuits, a mode of action that could provide therapeutic advantages. This hypothesis was tested with the dopamine D1 receptor potentiator DETQ [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one]. In human embryonic kidney 293 (HEK293) cells expressing the human D1 receptor, DETQ induced a 21-fold leftward shift in the cAMP response to dopamine, with a K of 26 nM. The maximum response to DETQ alone was ∼12% of the maximum response to dopamine, suggesting weak allosteric agonist activity. DETQ was ∼30-fold less potent at rat and mouse D1 receptors and was inactive at the human D5 receptor. To enable studies in rodents, an hD1 knock-in mouse was generated. DETQ (3-20 mg/kg orally) caused a robust (∼10-fold) increase in locomotor activity (LMA) in habituated hD1 mice but was inactive in wild-type mice. The LMA response to DETQ was blocked by the D1 antagonist SCH39166 and was dependent on endogenous dopamine. LMA reached a plateau at higher doses (30-240 mg/kg) even though free brain levels of DETQ continued to increase over the entire dose range. In contrast, the D1 agonists SKF 82958, A-77636, and dihydrexidine showed bell-shaped dose-response curves with a profound reduction in LMA at higher doses; video-tracking confirmed that the reduction in LMA caused by SKF 82958 was due to competing stereotyped behaviors. When dosed daily for 4 days, DETQ continued to elicit an increase in LMA, whereas the D1 agonist A-77636 showed complete tachyphylaxis by day 2. These results confirm that allosteric potentiators may have advantages compared with direct-acting agonists.
[Mh] Termos MeSH primário: Comportamento Animal/efeitos dos fármacos
Técnicas de Introdução de Genes
Isoquinolinas/farmacologia
Locomoção/efeitos dos fármacos
Receptores de Dopamina D1/genética
Receptores de Dopamina D1/metabolismo
Taquifilaxia
[Mh] Termos MeSH secundário: Adamantano/análogos & derivados
Adamantano/farmacologia
Regulação Alostérica/efeitos dos fármacos
Animais
Benzopiranos/farmacologia
Relação Dose-Resposta a Droga
Feminino
Células HEK293
Seres Humanos
Isoquinolinas/efeitos adversos
Masculino
Camundongos
Transporte Proteico/efeitos dos fármacos
Receptores de Dopamina D1/agonistas
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzopyrans); 0 (DETQ compound); 0 (Isoquinolines); 0 (Receptors, Dopamine D1); 145307-34-2 (A 77636); JGX76Y85M6 (isoquinoline); PJY633525U (Adamantane)
[Em] Mês de entrada:1705
[Cu] Atualização por classe:170526
[Lr] Data última revisão:
170526
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161105
[St] Status:MEDLINE


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[PMID]:28076566
[Au] Autor:Gokce G; Durukan AH; Koylu MT; Kucukevcilioglu M
[Ad] Endereço:Department of Ophthalmology, Kayseri Military Hospital, Kayseri, Turkey.
[Ti] Título:Efficacy of aflibercept on exudative age-related macular degeneration in patients exhibiting complete ranibizumab resistance and tachyphylaxis.
[So] Source:Arq Bras Oftalmol;79(6):384-389, 2016 Nov-Dec.
[Is] ISSN:1678-2925
[Cp] País de publicação:Brazil
[La] Idioma:eng
[Ab] Resumo:Purpose:: The present study compared the efficacy of aflibercept for neovascular age-related macular degeneration (NV-AMD) in patients with complete ranibizumab resistance and tachyphylaxis. Methods:: Forty-four eyes of 38 neovascular age-related macular degeneration patients were evaluated. Eyes were divided into a complete resistance group (n=23 eyes) and tachyphylaxis group (n=21 eyes). Results:: After three injections, eight (38.1%) patients in the tachyphylaxis group and nine (39.1%) in the complete resistance group presented with macular dryness. After the first injection of aflibercept, the mean visual acuity improved significantly in the tachyphylaxis group (p=0.018) but remained unchanged in the complete resistance group (p=0.37). There was a non-significant trend towards improved mean visual acuity in both groups after the second and third injections relative to the acuity at the final visit for ranibizumab treatment. In the tachyphylaxis group, the presence of subfoveal pigmented epithelium detachment (PED) decreased significantly after intravitreal aflibercept treatment. Conclusions:: Although treatment with aflibercept yielded generally positive anatomical results in both groups, no significant increase in visual acuity was achieved.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/uso terapêutico
Degeneração Macular/tratamento farmacológico
Ranibizumab/uso terapêutico
Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico
Proteínas Recombinantes de Fusão/uso terapêutico
Taquifilaxia
Acuidade Visual/efeitos dos fármacos
[Mh] Termos MeSH secundário: Idoso
Idoso de 80 Anos ou mais
Resistência a Medicamentos
Seres Humanos
Injeções Intravítreas
Degeneração Macular/complicações
Meia-Idade
Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagem
Proteínas Recombinantes de Fusão/administração & dosagem
Descolamento Retiniano/tratamento farmacológico
Descolamento Retiniano/etiologia
Epitélio Pigmentado da Retina/efeitos dos fármacos
Líquido Sub-Retiniano/secreção
Tomografia de Coerência Óptica
Resultado do Tratamento
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Recombinant Fusion Proteins); 15C2VL427D (aflibercept); EC 2.7.10.1 (Receptors, Vascular Endothelial Growth Factor); ZL1R02VT79 (Ranibizumab)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170918
[Lr] Data última revisão:
170918
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170112
[St] Status:MEDLINE


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[PMID]:27895464
[Au] Autor:Hardin EA; Chin KM
[Ad] Endereço:Department of Internal Medicine, Division of Cardiology.
[Ti] Título:Selexipag in the treatment of pulmonary arterial hypertension: design, development, and therapy.
[So] Source:Drug Des Devel Ther;10:3747-3754, 2016.
[Is] ISSN:1177-8881
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Pulmonary arterial hypertension is characterized by abnormalities in the small pulmonary arteries including increased vasoconstriction, vascular remodeling, proliferation of smooth muscle cells, and in situ thrombosis. Selexipag, a novel, oral prostacyclin receptor agonist, has been shown to improve hemodynamics in a phase II clinical trial and reduce clinical worsening in a large phase III clinical trial involving patients with pulmonary arterial hypertension. In this paper, we describe the prostacyclin signaling pathway, currently available oral prostanoid medications, and the development and clinical use of selexipag.
[Mh] Termos MeSH primário: Acetamidas
Ensaios Clínicos como Assunto
Hipertensão Pulmonar/tratamento farmacológico
Pirazinas
[Mh] Termos MeSH secundário: Acetamidas/química
Acetamidas/farmacocinética
Acetamidas/uso terapêutico
Administração Oral
Anti-Hipertensivos/química
Anti-Hipertensivos/farmacocinética
Anti-Hipertensivos/uso terapêutico
Epoprostenol/análogos & derivados
Epoprostenol/farmacocinética
Epoprostenol/uso terapêutico
Hipertensão Pulmonar Primária Familiar
Seres Humanos
Pirazinas/química
Pirazinas/farmacocinética
Pirazinas/uso terapêutico
Taquifilaxia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Acetamides); 0 (Antihypertensive Agents); 0 (Pyrazines); 5EXC0E384L (selexipag); DCR9Z582X0 (Epoprostenol)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:161130
[St] Status:MEDLINE


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[PMID]:27230954
[Au] Autor:Alves FL; Oliveira VX; Miranda A
[Ad] Endereço:Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, SP, Brazil. pelopes2@yahoo.com.br.
[Ti] Título:Angiotensin II analogues with N-terminal lactam bridge cyclization: an overview on AT receptor activation and tachyphylaxis.
[So] Source:Chem Biol Drug Des;88(5):677-682, 2016 Nov.
[Is] ISSN:1747-0285
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Angiotensin II (AngII) is the final active product of the renin enzymatic cascade, which is responsible for sustaining blood pressure. To investigate the effect of N-terminal cyclization on AT activation and tachyphylaxis, we designed conformationally constrained analogues with an i-(i + 1) lactam bridge. All analogues presented the same binding coefficient and tachyphylactic index, but some of them such as Cyclo (0-1a) [Glu , endo-(Lys )]-AngII and Cyclo (0-1a) [Asp , endo-(Orn )]-AngII showed higher potency. The same tachyphylactic index presented by AngII and cyclic analogues was surprising. We expected a variation after the modification of AngII N-terminal region.
[Mh] Termos MeSH primário: Angiotensina II/análogos & derivados
Lactamas/química
Receptor Tipo 1 de Angiotensina/metabolismo
[Mh] Termos MeSH secundário: Sequência de Aminoácidos
Angiotensina II/síntese química
Angiotensina II/metabolismo
Angiotensina II/farmacologia
Animais
Células CHO
Dicroísmo Circular
Cricetinae
Cricetulus
Ciclização
Fundo Gástrico/efeitos dos fármacos
Fundo Gástrico/fisiologia
Ligantes
Camundongos
Camundongos Endogâmicos C57BL
Peptídeos/síntese química
Peptídeos/química
Peptídeos/farmacologia
Ligação Proteica
Estrutura Secundária de Proteína
Receptor Tipo 1 de Angiotensina/química
Receptor Tipo 1 de Angiotensina/genética
Taquifilaxia/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Lactams); 0 (Ligands); 0 (Peptides); 0 (Receptor, Angiotensin, Type 1); 11128-99-7 (Angiotensin II)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170619
[Lr] Data última revisão:
170619
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160528
[St] Status:MEDLINE
[do] DOI:10.1111/cbdd.12795


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[PMID]:26678602
[Au] Autor:Amadio M; Govoni S; Pascale A
[Ad] Endereço:Dept. of Drug Sciences, Section of Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy. Electronic address: amadio@unipv.it.
[Ti] Título:Targeting VEGF in eye neovascularization: What's new?: A comprehensive review on current therapies and oligonucleotide-based interventions under development.
[So] Source:Pharmacol Res;103:253-69, 2016 Jan.
[Is] ISSN:1096-1186
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Roughly ten years ago the FDA approved most of the presently used anti-VEGF drugs for the treatment of neovascular AMD and other eye pathologies characterized by ocular neoangiogenesis. However, the recent findings on the physiologic activities of VEGF isoforms impose to reconsider the inhibitory effects of pan-VEGF antagonists and the concept that to face pathological alterations at ocular level is possible only through the full block of all VEGF isoforms. In fact, although pan-VEGF agents rapidly and effectively contrast ocular neovascularization, vascular leakage, and other pathological changes, in the long-term the inhibition of all VEGF isoforms likely may result in the loss of the physiologic effects exerted by VEGF121 and the anti-angiogenic VEGF165b. Notably, selective inhibitors of VEGF165a, such as pegaptanib, spare these targets. Moreover, preclinical and clinical evidence suggests that also systemic side effects, secondary to intraocular treatment with non-selective anti-VEGF drugs, may be reinterpreted in light of these recent findings, which may be useful to clinicians for the choice of the most appropriate anti-VEGF agent. Another aspect that should be considered is the involvement of VEGF-independent pathways in ocular neovascularization, therefore a combined therapy can represent a more effective pharmacological approach that might help also to counteract tachyphylaxis, an important issue in anti-VEGF treatment. This complex picture and the recent findings on current anti-VEGF drugs should be therefore taken into account to guide the development of novel agents targeting VEGF and/or other key factors involved in the pathogenesis of neovascular ocular diseases along the signaling pathways stimulated by the various isoforms. Accordingly, this review also reports on novel pharmacological molecules targeting VEGF at ocular level and currently under development, with a special attention to oligonucleotide-based interventions.
[Mh] Termos MeSH primário: Inibidores da Angiogênese/uso terapêutico
Neovascularização Patológica/tratamento farmacológico
Oligonucleotídeos/uso terapêutico
Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores
[Mh] Termos MeSH secundário: Inibidores da Angiogênese/efeitos adversos
Inibidores da Angiogênese/farmacologia
Animais
Olho/irrigação sanguínea
Seres Humanos
Neovascularização Patológica/terapia
Taquifilaxia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; REVIEW
[Nm] Nome de substância:
0 (Angiogenesis Inhibitors); 0 (Oligonucleotides); 0 (Vascular Endothelial Growth Factor A)
[Em] Mês de entrada:1612
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151219
[St] Status:MEDLINE


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[PMID]:26358179
[Au] Autor:Kongsgaard UE; Werner MU
[Ad] Endereço:Department of Anaesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital and Medical Faculty, University of Oslo, Oslo, Norway.
[Ti] Título:Tachyphylaxis to local anaesthetics. What is the clinical evidence? A systematic review.
[So] Source:Acta Anaesthesiol Scand;60(1):6-14, 2016 Jan.
[Is] ISSN:1399-6576
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Tachyphylaxis or acute tolerance to local anaesthetics has been reported, but the prevalence in clinical analgesia is obscure, and the mechanisms behind this phenomenon remain unclear. We sought to examine the clinical significance of tachyphylaxis from the available literature. METHODS: We performed a systematic review of the literature utilising the databases PubMed and Embase employing the search terms [Tachyphylaxis AND Local Anaesthetics AND Human] AND [Tolerance AND Local Anaesthetics AND Human]. RESULTS: A total of 66 records were identified. Thirty-four articles were assessed in full text for eligibility. Twenty studies were considered relevant for qualitative analyses, but only six studies were randomised controlled trials. Because of the heterogeneity of the randomised controlled trials, it was not possible to conduct a meta-analysis. CONCLUSION: Studies documenting tachyphylaxis with clinical use of local anaesthetics are surprisingly scarce, and the mechanisms behind it remain unclear.
[Mh] Termos MeSH primário: Anestésicos Locais/efeitos adversos
Taquifilaxia
[Mh] Termos MeSH secundário: Seres Humanos
Prevalência
Ensaios Clínicos Controlados Aleatórios como Assunto
[Pt] Tipo de publicação:JOURNAL ARTICLE; META-ANALYSIS; REVIEW
[Nm] Nome de substância:
0 (Anesthetics, Local)
[Em] Mês de entrada:1610
[Cu] Atualização por classe:161230
[Lr] Data última revisão:
161230
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150912
[St] Status:MEDLINE
[do] DOI:10.1111/aas.12631


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[PMID]:26219196
[Au] Autor:Ross EL; Reiter PD; Murphy ME; Bielsky AR
[Ad] Endereço:Department of Pharmacy, Children's Hospital Colorado, 13123 East 16th Ave Campus Box 375, Aurora, CO, USA. Electronic address: emma.ross16@gmail.com.
[Ti] Título:Evaluation of prolonged epidural chloroprocaine for postoperative analgesia in infants.
[So] Source:J Clin Anesth;27(6):463-9, 2015 Sep.
[Is] ISSN:1873-4529
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:STUDY OBJECTIVE: To describe the use and adverse effects of chloroprocaine for epidural analgesia in young infants for infusion durations greater than 3.5 hours. DESIGN: A retrospective cohort review of the electronic medical record over a 14-month period. SETTING: The level IV neonatal intensive care unit of a 414-bed free-standing children's hospital. PATIENTS: Eighteen infants (mean age, 1.7 ± 1.8 months [0.03-6.3]; mean weight, 3.8 ± 1.3 kg [1.56-6.9]; n = 10 [55%] males) received 1% chloroprocaine for epidural analgesia postoperatively for up to 96-hour duration and met criteria for inclusion. MEASUREMENTS: Dosing requirements, placement of epidural catheter, supplementary analgesic therapy, respiratory support, vital signs, and incidence of adverse events associated with local anesthetics were collected. MAIN RESULTS: Epidural catheter placement was caudal (n = 8), lumbar (n = 6), or thoracic (n = 4). Mean operative time was 2.48 ± 1 hour (1-5). Initial chloroprocaine dose was 1.3 ± 0.5 mL/h (0.4-2.5) (3.5 ± 1 mg/kg per hour [1.4-5]) with a maximum dose of 1.5 ± 0.6 mL/h (0.4-3) (4.2 ± 1.1 mg/kg per hour [2.2-6.1]). Duration of epidural analgesia was 48.3 ± 21.5 hours (10-96). Duration of epidural infusion did not influence dosing requirement, suggesting the absence of drug tachyphylaxis. All patients received intermittent doses of opioid and nonopioid pain medications while receiving chloroprocaine. Two mechanically ventilated patients required continuous infusion of opioids. No adverse events were directly attributed to chloroprocaine use. CONCLUSION: Epidural 1% chloroprocaine, in doses of 0.4-3 mL/h (1.5-6.1 mg/kg per hour), was well tolerated in both mechanically ventilated and spontaneously breathing infants for up to 96 hours with no identified adverse effects or tachyphylaxis.
[Mh] Termos MeSH primário: Analgesia Epidural/métodos
Anestésicos Locais/uso terapêutico
Dor Pós-Operatória/tratamento farmacológico
Procaína/análogos & derivados
[Mh] Termos MeSH secundário: Analgésicos Opioides/uso terapêutico
Anestesia Epidural
Anestésicos Locais/administração & dosagem
Anestésicos Locais/efeitos adversos
Pré-Escolar
Estudos de Coortes
Feminino
Seres Humanos
Lactente
Recém-Nascido
Unidades de Terapia Intensiva Neonatal
Masculino
Gravidez
Procaína/administração & dosagem
Procaína/efeitos adversos
Procaína/uso terapêutico
Respiração Artificial
Estudos Retrospectivos
Taquifilaxia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics, Opioid); 0 (Anesthetics, Local); 4Z8Y51M438 (Procaine); 5YVB0POT2H (chloroprocaine)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:150924
[Lr] Data última revisão:
150924
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150730
[St] Status:MEDLINE


  9 / 1329 MEDLINE  
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[PMID]:26218540
[Au] Autor:Morentin Gutierrez P; Gyte A; deSchoolmeester J; Ceuppens P; Swales J; Stacey C; Eriksson JW; Sjöstrand M; Nilsson C; Leighton B
[Ad] Endereço:AstraZeneca R&D, Mereside, Alderley Park, Macclesfield, SK10 4TG, UK.
[Ti] Título:Continuous inhibition of 11ß-hydroxysteroid dehydrogenase type I in adipose tissue leads to tachyphylaxis in humans and rats but not in mice.
[So] Source:Br J Pharmacol;172(20):4806-16, 2015 Oct.
[Is] ISSN:1476-5381
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND AND PURPOSE: 11ß-hydroxysteroid dehydrogenase type I (11ß-HSD1), a target for Type 2 diabetes mellitus, converts inactive glucocorticoids into bioactive forms, increasing tissue concentrations. We have compared the pharmacokinetic-pharmacodynamic (PK/PD) relationship of target inhibition after acute and repeat administration of inhibitors of 11ß-HSD1 activity in human, rat and mouse adipose tissue (AT). EXPERIMENTAL APPROACH: Studies included abdominally obese human volunteers, rats and mice. Two specific 11ß-HSD1 inhibitors (AZD8329 and COMPOUND-20) were administered as single oral doses or repeat daily doses for 7-9 days. 11ß-HSD1 activity in AT was measured ex vivo by conversion of (3) H-cortisone to (3) H-cortisol. KEY RESULTS: In human and rat AT, inhibition of 11ß-HSD1 activity was lost after repeat dosing of AZD8329, compared with acute administration. Similarly, in rat AT, there was loss of inhibition of 11ß-HSD1 activity after repeat dosing with COMPOUND-20 with continuous drug cover, but effects were substantially reduced if a 'drug holiday' period was maintained daily. Inhibition of 11ß-HSD1 activity was not lost in mouse AT after continuous cover with COMPOUND-20 for 7 days. CONCLUSIONS AND IMPLICATIONS: Human and rat AT, but not mouse AT, exhibited tachyphylaxis for inhibition of 11ß-HSD1 activity after repeat dosing. Translation of observed efficacy in murine disease models to human for 11ß-HSD1 inhibitors may be misleading. Investigators of the effects of 11ß-HSD1 inhibitors should confirm that desired levels of enzyme inhibition in AT can be maintained over time after repeat dosing and not rely on results following a single dose.
[Mh] Termos MeSH primário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/antagonistas & inibidores
Tecido Adiposo/enzimologia
Benzoatos/farmacologia
Dipeptídeos/farmacologia
Pirazóis/farmacologia
[Mh] Termos MeSH secundário: 11-beta-Hidroxiesteroide Desidrogenase Tipo 1/metabolismo
Animais
Benzoatos/sangue
Benzoatos/farmacocinética
Dipeptídeos/sangue
Dipeptídeos/farmacocinética
Seres Humanos
Masculino
Camundongos
Pirazóis/sangue
Pirazóis/farmacocinética
Ratos
Taquifilaxia
[Pt] Tipo de publicação:COMPARATIVE STUDY; CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-(4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl)benzoic acid); 0 (Benzoates); 0 (Dipeptides); 0 (Pyrazoles); 74075-33-5 (compound 20); EC 1.1.1.146 (11-beta-Hydroxysteroid Dehydrogenase Type 1)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:161215
[Lr] Data última revisão:
161215
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150729
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1111/bph.13251


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[PMID]:26144851
[Au] Autor:Singh SK; Nasir F
[Ad] Endereço:Department of Dermatology and Venereology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Utter Pradesh, India.
[Ti] Título:The reservoir effect of topical steroids in vitiliginous skin: A cross-sectional study.
[So] Source:Indian J Dermatol Venereol Leprol;81(4):370-5, 2015 Jul-Aug.
[Is] ISSN:0973-3922
[Cp] País de publicação:India
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Prolonged and frequent use of topical steroids may lead to decrease in efficacy as well as many local adverse effects. Stratum corneum has a unique property of reservoir effect. AIMS: To study the reservoir effect of topical steroids in a steroid-responsive condition which may enable a decrease in the dosing frequency of topical steroids. METHODS: A cross-sectional study design was used. Patients with at least three vitiliginous patches of more than 2 cm 2 present over the trunk or limbs were included. Exclusion criteria were topical or systemic corticosteroid use within the previous 4 weeks, antihistamine use within the previous 7 days, history of any allergy in the past and immunosuppression. Clobetasol propionate cream was applied on the first vitiliginous area (site A) and fluticasone propionate ointment was applied on the second vitiliginous area (site B). The third vitiliginous area, site C (control site) was left without applying any medication. Histamine-induced wheal suppression test was performed on each site, at the same time of the day, on every consecutive day following steroid application, until the values obtained at sites A and B approached those obtained at site C. SPSS software for Windows, version 16.0 was used for statistical analysis. The mean and standard deviation of the various studied parameters were calculated for various treatment groups and compared using analysis of variance (ANOVA) test. RESULTS: Forty patients were included in the study. The average wheal volumes and average erythema sizes at sites A and B were significantly smaller than the corresponding values at site C for up to 5 days after applying medication (P < 0.001). LIMITATIONS: The presence of a cutaneous reservoir of topical steroid was confirmed based on its suppressive effect on the wheal and flare response to histamine. It is not certain that the concentration that suppresses histamine-induced wheal and flare is sufficient for therapeutic efficacy in vitiligo. CONCLUSION: The reservoir effect of topical clobetasol propionate and fluticasone propionate persisted for 5 days in vitiliginous skin. Hence, it may be possible to reduce the frequency of topical steroid application in vitiligo.
[Mh] Termos MeSH primário: Anti-Inflamatórios/metabolismo
Clobetasol/metabolismo
Fluticasona/metabolismo
Vitiligo/tratamento farmacológico
Vitiligo/metabolismo
[Mh] Termos MeSH secundário: Administração Cutânea
Adolescente
Adulto
Anti-Inflamatórios/administração & dosagem
Clobetasol/administração & dosagem
Estudos Transversais
Feminino
Fluticasona/administração & dosagem
Histamina/farmacologia
Seres Humanos
Masculino
Meia-Idade
Pomadas/administração & dosagem
Pomadas/metabolismo
Pele/efeitos dos fármacos
Creme para a Pele/administração & dosagem
Creme para a Pele/metabolismo
Taquifilaxia
Adulto Jovem
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Anti-Inflammatory Agents); 0 (Ointments); 820484N8I3 (Histamine); ADN79D536H (Clobetasol); CUT2W21N7U (Fluticasone)
[Em] Mês de entrada:1603
[Cu] Atualização por classe:150706
[Lr] Data última revisão:
150706
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150707
[St] Status:MEDLINE
[do] DOI:10.4103/0378-6323.159933



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