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Quevedo, Joäo
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[PMID]:28284339
[Au] Autor:Comim CM; Freiberger V; Ventura L; Mina F; Ferreira GK; Michels M; Generoso JS; Streck EL; Quevedo J; Barichello T; Dal-Pizzol F
[Ad] Endereço:Research Group of Experimental Neuropathology, Laboratory of Experimental Neuroscience, Postgraduate Program in Health Sciences, University of South Santa Catarina, Palhoça, SC, Brazil. Electronic address: clarissamc@gmail.com.
[Ti] Título:Inhibition of indoleamine 2,3-dioxygenase 1/2 prevented cognitive impairment and energetic metabolism changes in the hippocampus of adult rats subjected to polymicrobial sepsis.
[So] Source:J Neuroimmunol;305:167-171, 2017 Apr 15.
[Is] ISSN:1872-8421
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection that may affect the brain. We investigated the role of indoleamine 2,3-dioxygenase (IDO-1/2) inhibition on long-term memory and energetic metabolism after experimental sepsis by caecal ligation and perforation (CLP). Experimental sepsis increased the activity of complexes I, II-III and IV at 24h after CLP, and IDO-1/2 inhibition normalized the activity of these complexes in the hippocampus. Wistar rats presented impairment of habituation and aversive memories 10days after CLP. Adjuvant treatment with the IDO inhibitor prevented long-term cognitive impairment triggered by sepsis.
[Mh] Termos MeSH primário: Transtornos Cognitivos/etiologia
Transtornos Cognitivos/metabolismo
Transtornos Cognitivos/prevenção & controle
Metabolismo Energético/fisiologia
Hipocampo/metabolismo
Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo
Sepse/complicações
[Mh] Termos MeSH secundário: Animais
Aprendizagem da Esquiva/efeitos dos fármacos
Modelos Animais de Doenças
Metabolismo Energético/efeitos dos fármacos
Comportamento Exploratório/efeitos dos fármacos
Hipocampo/efeitos dos fármacos
Antígenos de Histocompatibilidade/metabolismo
Inibição (Psicologia)
Injeções Intra-Articulares
Masculino
Ratos
Ratos Wistar
Sepse/etiologia
Sepse/microbiologia
Estatísticas não Paramétricas
Simpatomiméticos/farmacologia
Simpatomiméticos/uso terapêutico
p-Hidroxianfetamina/farmacologia
p-Hidroxianfetamina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histocompatibility Antigens); 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase); 0 (Sympathomimetics); FQR280JW2N (p-Hydroxyamphetamine)
[Em] Mês de entrada:1708
[Cu] Atualização por classe:170817
[Lr] Data última revisão:
170817
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170313
[St] Status:MEDLINE


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[PMID]:28115274
[Au] Autor:Feio-Azevedo R; Costa VM; Ferreira LM; Branco PS; Pereira FC; Bastos ML; Carvalho F; Capela JP
[Ad] Endereço:UCIBIO/REQUIMTE (Rede de Química e Tecnologia), Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Portugal. Electronic address: ritaffeio@gmail.com.
[Ti] Título:Toxicity of the amphetamine metabolites 4-hydroxyamphetamine and 4-hydroxynorephedrine in human dopaminergic differentiated SH-SY5Y cells.
[So] Source:Toxicol Lett;269:65-76, 2017 Mar 05.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Amphetamine (AMPH) is a psychostimulant used worldwide by millions of patients in the clinical treatment of attention deficit hyperactivity disorder, narcolepsy or even obesity, and is also a drug of abuse. 4-Hydroxynorephedrine (4-OHNE) and 4-hydroxyamphetamine (4-OHAMPH) are two major metabolites known to persist in the brain longer than AMPH. The contribution of AMPH metabolites for its neurotoxicity is undetermined. We evaluated the toxicity of AMPH and its metabolites 4-OHNE and 4-OHAMPH, obtained by chemical synthesis, in human dopaminergic differentiated SH-SY5Y neurons. Cells were exposed to AMPH (concentration range 0-5mM) or 4-OHAMPH or 4-OHNE (concentration range 0-10mM) for 24 or 48h, and the viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) leakage assays. Results showed that for both AMPH and the metabolites a concentration-dependent toxicity was observed. The toxic concentration 50% (TC ) for AMPH and 4-OHNE following 24h exposure was circa 3.5mM and 8mM, respectively. For 4-OHAMPH the TC was not reached in the tested concentration range. N-acetyl cysteine, cycloheximide, l-carnitine, and methylphenidate were able to reduce cell death induced by AMPH TC . Acridine orange/ethidium bromide staining showed evident signs of late apoptotic cells and necrotic cells following 24h exposure to AMPH 3.50mM. The 4-OHAMPH metabolite at 8.00mM originated few late apoptotic cells, whereas 4-OHNE at 8.00mM resulted in late apoptotic cells and necrotic cells, in a scenario similar to AMPH. In conclusion, the AMPH metabolite 4-OHNE is more toxic than 4-OHAMPH, nonetheless both are less toxic than the parent compound in vitro. The most toxic metabolite 4-OHNE has longer permanence in the brain, rendering likely its contribution for AMPH neurotoxicity.
[Mh] Termos MeSH primário: Anfetamina/toxicidade
Diferenciação Celular/efeitos dos fármacos
Neurônios Dopaminérgicos/efeitos dos fármacos
p-Hidroxianfetamina/toxicidade
p-Hidroxinorefedrina/toxicidade
[Mh] Termos MeSH secundário: Acetilcisteína/farmacologia
Anfetamina/química
Apoptose/efeitos dos fármacos
Carnitina/farmacologia
Linhagem Celular
Sobrevivência Celular/efeitos dos fármacos
Cicloeximida/farmacologia
Neurônios Dopaminérgicos/citologia
Relação Dose-Resposta a Droga
Seres Humanos
Dose Letal Mediana
Metilfenidato/farmacologia
Espécies Reativas de Oxigênio/química
p-Hidroxianfetamina/química
p-Hidroxinorefedrina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Reactive Oxygen Species); 207ZZ9QZ49 (Methylphenidate); 552-85-2 (p-Hydroxynorephedrine); 98600C0908 (Cycloheximide); CK833KGX7E (Amphetamine); FQR280JW2N (p-Hydroxyamphetamine); S7UI8SM58A (Carnitine); WYQ7N0BPYC (Acetylcysteine)
[Em] Mês de entrada:1703
[Cu] Atualização por classe:170321
[Lr] Data última revisão:
170321
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170125
[St] Status:MEDLINE


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[PMID]:25975097
[Au] Autor:Abe Y; Ota E; Harada H; Kanbe H; Kojima Y; Kanazawa T; Endo T; Murakami M; Kobayashi M
[Ti] Título:Species differences in the metabolism of ritobegron in vitro and assessment of potential interactions with transporters and cytochrome P450 enzymes.
[So] Source:Pharmazie;70(1):38-46, 2015 Jan.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:Ritobegron, a selective ß3-adrenoceptor agonist, is the prodrug of the active compound, KUC-7322. We investigated species differences in its metabolism in vitro and the potential for drug-drug interactions with ritobegron. In rat, dog, monkey, and human liver microsomes, ritobegron was not metabolized by cytochrome P450 enzymes (CYPs). KUC-7322 was the only metabolite observed. Hydrolysis of ritobegron to KUC-7322 was likely catalyzed by carboxylesterases in human liver microsomes. The maximum velocity of the reaction (V(max))/Michaelis-Menten constant (K(m)) for hydrolysis of ritobegron to KUC-7322 was much higher in rat serum than those in other species. There were also species differences in the conjugation of KUC-7322. Sulfate conjugates of ritobegron were detected in all species, whereas glucuronide and glutathione conjugates of KUC-7322 were only observed in rat liver subcellular fractions. Ritobegron and KUC-7322 did not affect the CYP-mediated metabolism of probe substrates in human liver microsomes and organic anion transporter 1 (OAT1)-, OAT2-, OAT3-, organic cation transporter 2 (OCT-2)-, OCT3-, or organic cation/carnitine transporter 1 (OCTN1)-mediated uptake of probe substrates in S2 cells. Ritobegron, but not KUC-7322, inhibited P-glycoprotein-mediated digoxin transport in Caco-2 cells. Significant uptake of KUC-7322 was observed in OAT3-expressing S2 cells. Therefore, CYP-mediated drug-drug interactions are not likely when ritobegron is administered with CYP substrates or inhibitors. Ritobegron may increase the plasma concentrations of P-glycoprotein substrates, such as digoxin, and the plasma concentration of KUC-7322 may increase when it is administered in combination with OAT inhibitors such as probenecid.
[Mh] Termos MeSH primário: Acetatos/farmacocinética
Agonistas de Receptores Adrenérgicos beta 3/farmacocinética
Proteínas de Transporte/metabolismo
Sistema Enzimático do Citocromo P-450/metabolismo
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Acetatos/farmacologia
Agonistas de Receptores Adrenérgicos beta 3/farmacologia
Animais
Proteínas de Transporte/efeitos dos fármacos
Sistema Enzimático do Citocromo P-450/efeitos dos fármacos
Cães
Interações Medicamentosas
Inibidores Enzimáticos/farmacologia
Haplorrinos
Seres Humanos
Técnicas In Vitro
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Microssomos Hepáticos/metabolismo
Ratos
Especificidade da Espécie
Frações Subcelulares/efeitos dos fármacos
Frações Subcelulares/enzimologia
Frações Subcelulares/metabolismo
p-Hidroxianfetamina/farmacocinética
p-Hidroxianfetamina/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Carrier Proteins); 0 (Enzyme Inhibitors); 9035-51-2 (Cytochrome P-450 Enzyme System); FQR280JW2N (p-Hydroxyamphetamine); LD86RKR53M (ritobegron)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:150515
[Lr] Data última revisão:
150515
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150516
[St] Status:MEDLINE


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[PMID]:25902102
[Au] Autor:Henchoz L; Reymond-Gruber S; Kawasaki A
[Ad] Endereço:Department of Ophthalmology, University of Lausanne, Hôpital Ophtalmique Jules Gonin and Asile des Aveugles, Lausanne, Switzerland.
[Ti] Título:Silent Horner Syndrome.
[So] Source:Klin Monbl Augenheilkd;232(4):482-3, 2015 Apr.
[Is] ISSN:1439-3999
[Cp] País de publicação:Germany
[La] Idioma:eng
[Mh] Termos MeSH primário: Anisocoria/diagnóstico
Blefaroptose/diagnóstico
Síndrome de Horner/diagnóstico
Imagem por Ressonância Magnética/métodos
p-Hidroxianfetamina/administração & dosagem
[Mh] Termos MeSH secundário: Diagnóstico Diferencial
Seres Humanos
Masculino
Meia-Idade
Midriáticos/administração & dosagem
Avaliação de Sintomas/métodos
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Mydriatics); FQR280JW2N (p-Hydroxyamphetamine)
[Em] Mês de entrada:1601
[Cu] Atualização por classe:150423
[Lr] Data última revisão:
150423
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150423
[St] Status:MEDLINE
[do] DOI:10.1055/s-0035-1545677


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[PMID]:25951660
[Au] Autor:Abe Y; Ota E; Endo T; Murakami M; Kobayashi M
[Ti] Título:Absorption, disposition, metabolism, and excretion of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, in rats.
[So] Source:Pharmazie;69(12):881-8, 2014 Dec.
[Is] ISSN:0031-7144
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:The pharmacokinetic profile of ritobegron, a novel, selective ß3-adrenoceptor agonist, was investigated in rats. Ritobegron, an ethyl ester prodrug of the active compound KUC-7322, or KUC-7322 itself was orally administered (10 mg/kg). Ethyl esterification resulted in a 10-fold increase in the area under the plasma concentration-time curve (AUC(0-t)), as compared to KUC-7322. Following intravenous administration of KUC-7322 (1 mg/kg), total blood clearance was 1.36 L/h/kg, suggesting that intrinsic hepatic clearance is the rate-limiting step in KUC-7322 excretion. When ritobegron was orally administered (0.3, 1, 3, and 10 mg/kg), plasma concentrations of KUC-7322 rapidly increased and reached a maximum concentration (C(max)) at 0.25 to 0.31 h. KUC-7322 levels rapidly decreased, with a half-life (t 1/2) of 0.42 to 1.37 h thereafter. AUC(0-t) did not show a dose-dependent increase. The bioavailability of KUC-7322 was estimated to be 4%. Following oral administration of [14C]ritobegron (3 mg/kg), radioactivity concentrations in tissues rapidly increased and declined in parallel with changes in plasma concentration. In most of tissues, excluding the liver, kidney, urinary bladder, stomach and small intestine, radioactivity concentrations were lower than that in plasma. In plasma, bile, urine, and feces, KUC-7322 and its glucuronide, sulfate, and glutathione conjugates were detected. The glucuronide conjugate of KUC-7322 was the predominant metabolite in bile, plasma, and urine, and KUC-7322 was predominant in feces. Ritobegron was not detected in any of the samples. The cumulative excretion of radioactivity in urine and feces were 28.7% and 68.3% of the dose, respectively, up to 120 h after administration.
[Mh] Termos MeSH primário: Acetatos/farmacocinética
Agonistas de Receptores Adrenérgicos beta 3/farmacocinética
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Acetatos/metabolismo
Agonistas de Receptores Adrenérgicos beta 3/metabolismo
Animais
Área Sob a Curva
Bile/metabolismo
Biotransformação
Fezes/química
Técnicas In Vitro
Absorção Intestinal
Masculino
Ligação Proteica
Ratos
Ratos Sprague-Dawley
Distribuição Tecidual
Bexiga Urinária Hiperativa/tratamento farmacológico
p-Hidroxianfetamina/metabolismo
p-Hidroxianfetamina/farmacocinética
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); FQR280JW2N (p-Hydroxyamphetamine); LD86RKR53M (ritobegron)
[Em] Mês de entrada:1506
[Cu] Atualização por classe:150508
[Lr] Data última revisão:
150508
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150509
[St] Status:MEDLINE


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[PMID]:23370415
[Au] Autor:Davagnanam I; Fraser CL; Miszkiel K; Daniel CS; Plant GT
[Ad] Endereço:Moorfields Eye Hospital, London, UK. indran_davagnanam@yahoo.co.uk
[Ti] Título:Adult Horner's syndrome: a combined clinical, pharmacological, and imaging algorithm.
[So] Source:Eye (Lond);27(3):291-8, 2013 Mar.
[Is] ISSN:1476-5454
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The diagnosis of Horner's syndrome (HS) can be difficult, as patients rarely present with the classic triad of ptosis, miosis, and anhydrosis. Frequently, there are no associated symptoms to help determine or localise the underlying pathology. The onset of anisocoria may also be uncertain, with many cases referred after incidental discovery on routine optometric assessment. Although the textbooks discuss the use of cocaine, apraclonidine, and hydroxyamphetamine to diagnose and localise HS, in addition to reported false positive and negative results, these pharmacological agents are rarely available during acute assessment or in general ophthalmic departments. Typically, a week is required between using cocaine or apraclonidine for diagnosis and localisation of HS with hydroxyamphetamine, leaving the clinician with the decision of which investigations to request and with what urgency. Modern imaging modalities have advanced significantly and become more readily available since many of the established management algorithms were written. We thus propose a practical and safe combined clinical and radiological diagnostic protocol for HS that can be applied in most clinical settings.
[Mh] Termos MeSH primário: Algoritmos
Diagnóstico por Imagem/métodos
Síndrome de Horner/diagnóstico
Midriáticos
[Mh] Termos MeSH secundário: Adulto
Angiografia Digital
Clonidina/análogos & derivados
Cocaína
Seres Humanos
Imagem por Ressonância Magnética
p-Hidroxianfetamina
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Mydriatics); 843CEN85DI (apraclonidine); FQR280JW2N (p-Hydroxyamphetamine); I5Y540LHVR (Cocaine); MN3L5RMN02 (Clonidine)
[Em] Mês de entrada:1308
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130202
[St] Status:MEDLINE
[do] DOI:10.1038/eye.2012.281


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[PMID]:23538508
[Au] Autor:Maruyama I; Yonekubo S; Tatemichi S; Maruyama K; Hoyano Y; Yamazaki Y; Kusama H
[Ad] Endereço:Kissei Pharmaceutical Co., Ltd., Japan. itaru_maruyama@pharm.kissei.co.jp
[Ti] Título:Effects of ritobegron (KUC-7483), a novel ß3-adrenoceptor agonist, on both rat bladder function following partial bladder outlet obstruction and on rat salivary secretion: a comparison with the effects of tolterodine.
[So] Source:J Smooth Muscle Res;48(5-6):115-24, 2012.
[Is] ISSN:1884-8796
[Cp] País de publicação:Japan
[La] Idioma:eng
[Ab] Resumo:The objective of this study was to investigate the effects of the ß3-adrenoceptor (AR) agonist ritobegron on rat bladder function following partial bladder outlet obstruction and on rat salivary secretion. In addition, the effects of ritobegron were compared with those of the anti-muscarinic agent tolterodine. After a 6-week partial bladder outlet obstruction (BOO), drug effects on bladder functions were evaluated using cystometrography. Effects on carbachol (CCh)-induced salivary secretion were evaluated in urethane-anesthetized rats. Ritobegron significantly decreased the frequency of non-voiding contractions (NVC), while both ritobegron and tolterodine each significantly decreased the amplitude of NVC. Ritobegron had no effect on either the micturition pressure (MP) or the residual volume (RV). In contrast, tolterodine dose-dependently decreased MP and increased RV. Ritobegron had no effect on CCh-induced salivary secretion, whereas tolterodine dose-dependently decreased it. Ritobegron decreased both the frequency and amplitude of NVC, which is similar to its effect on the contractions associated with detrusor overactivity (DO) in patients with an overactive bladder (OAB), without affecting MP, RV, or CCh-induced salivary secretion. Although tolterodine reduced the amplitude of NVC, it also markedly increased RV and significantly inhibited CCh-induced salivary secretion. These results suggest that use of ritobegron, a ß3-AR agonist, is unlikely to lead to the residual urine and dry mouth symptoms that are associated with anti-muscarinic drugs, and that ritobegron may hold promise as a safe and effective agent for OAB treatment.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Agonistas de Receptores Adrenérgicos beta 3/farmacologia
Compostos Benzidrílicos/farmacologia
Cresóis/farmacologia
Antagonistas Muscarínicos/farmacologia
Fenilpropanolamina/farmacologia
Saliva/secreção
Obstrução do Colo da Bexiga Urinária/tratamento farmacológico
Obstrução do Colo da Bexiga Urinária/fisiopatologia
Bexiga Urinária/fisiopatologia
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Animais
Feminino
Masculino
Ratos
Ratos Sprague-Dawley
Fatores de Tempo
Tartarato de Tolterodina
p-Hidroxianfetamina/farmacologia
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Benzhydryl Compounds); 0 (Cresols); 0 (Muscarinic Antagonists); 33RU150WUN (Phenylpropanolamine); 5T619TQR3R (Tolterodine Tartrate); FQR280JW2N (p-Hydroxyamphetamine); LD86RKR53M (ritobegron)
[Em] Mês de entrada:1309
[Cu] Atualização por classe:151119
[Lr] Data última revisão:
151119
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130330
[St] Status:MEDLINE


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[PMID]:22644105
[Au] Autor:Igawa Y; Schneider T; Yamazaki Y; Tatemichi S; Homma Y; Nishizawa O; Michel MC
[Ad] Endereço:Department of Continence Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. yigawa-jua@umin.ac.jp
[Ti] Título:Functional investigation of ß-adrenoceptors in human isolated detrusor focusing on the novel selective ß3-adrenoceptor agonist KUC-7322.
[So] Source:Naunyn Schmiedebergs Arch Pharmacol;385(8):759-67, 2012 Aug.
[Is] ISSN:1432-1912
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:This study aimed to characterize the ß-adrenoceptor (ß-AR) subtype mediating relaxation of isolated human bladder strips and to explore relaxation by the novel ß3-AR-selective agonist KUC-7322 for its relaxant effect on the human isolated detrusor and for its effect on the carbachol (CCh)-induced contractile response. In two parallel studies, relaxation of isolated human bladder strips was tested for the ß-AR agonists isoproterenol, clenbuterol, BRL 37344, and KUC-7322. For the isoproterenol and KUC-7322 responses, antagonism by CGP 20712A, ICI 118551, and SR59230A was determined. The potency and efficacy of the reference agonists for detrusor relaxation was in line with their known ß3-AR activity. KUC-7322 relative to isoproterenol was a full agonist with a pEC(50) of 5.95 ± 0.09 and 5.92 ± 0.11 in the two studies. SR59230A exhibited antagonism of the expected potency against isoproterenol (apparent pK (B) 7.2) but not against KUC-7322. Neither isoproterenol nor KUC-7322 nor forskolin significantly attenuated CCh-induced contraction. These results suggest that KUC-7322 displays full agonistic activity in relaxing the human detrusor without inhibiting the contraction induced by cholinergic stimulation. These characteristics, if proven in vivo, may be beneficial for the treatment of overactive bladder, as increased bladder capacity with a negligible effect on voiding contractions may be anticipated.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Agonistas de Receptores Adrenérgicos beta 3/farmacologia
Receptores Adrenérgicos beta/fisiologia
Bexiga Urinária/efeitos dos fármacos
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Agonistas Adrenérgicos beta/farmacologia
Antagonistas Adrenérgicos beta/farmacologia
Idoso
Carbacol/farmacologia
Interpretação Estatística de Dados
Relação Dose-Resposta a Droga
Feminino
Seres Humanos
Masculino
Agonistas Muscarínicos/farmacologia
Antagonistas Muscarínicos/farmacologia
Contração Muscular/efeitos dos fármacos
Relaxamento Muscular/efeitos dos fármacos
Parassimpatolíticos/farmacologia
Receptores Adrenérgicos beta/efeitos dos fármacos
Neoplasias da Bexiga Urinária/cirurgia
p-Hidroxianfetamina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Adrenergic beta-Agonists); 0 (Adrenergic beta-Antagonists); 0 (Muscarinic Agonists); 0 (Muscarinic Antagonists); 0 (Parasympatholytics); 0 (Receptors, Adrenergic, beta); 8Y164V895Y (Carbachol); FQR280JW2N (p-Hydroxyamphetamine); LD86RKR53M (ritobegron)
[Em] Mês de entrada:1211
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120531
[St] Status:MEDLINE
[do] DOI:10.1007/s00210-012-0763-x


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[PMID]:22552730
[Au] Autor:Maruyama I; Goi Y; Tatemichi S; Maruyama K; Hoyano Y; Yamazaki Y; Kusama H
[Ad] Endereço:Central Research Laboratory, Kissei Pharmaceutical Co., Ltd., Nagano, Japan. itaru_maruyama@pharm.kissei.co.jp
[Ti] Título:Bladder selectivity of the novel ß3-agonist ritobegron (KUC-7483) explored by in vitro and in vivo studies in the rat.
[So] Source:Naunyn Schmiedebergs Arch Pharmacol;385(8):845-52, 2012 Aug.
[Is] ISSN:1432-1912
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:We performed in vitro and in vivo experiments to evaluate the pharmacological profile of ritobegron and its effects on the bladder in rats. ß(3)-AR selectivity was assessed using CHO cells expressing various subtypes of the human ß-adrenoceptor (AR). Effects on isolated organs were evaluated using the organ-bath method. Effects on intravesical pressure, heart rate, and mean blood pressure were evaluated in urethane-anesthetized rats. Ritobegron increased cAMP accumulation in a concentration-dependent manner in CHO cells expressing any one of three human ß-AR, its selectivity for ß(3)-AR being 301-fold and 32-fold higher versus ß(1)-AR and ß(2)-AR, respectively. Ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50), 7.7 × 10(-8) mol/L; maximal relaxation, 97.0 %), and the ß(3)-AR antagonist SR58894A produced a parallel rightward-shift of this concentration-response curve without altering the maximal response [pK(B) value, 6.43]. Ritobegron concentration-dependently increased atrial rate and decreased myometrial contractions in vitro, and its selectivity for the bladder was 2,078-fold higher versus the atria and 14-fold higher versus the uterus. In vivo, ritobegron induced a dose-dependent decrease in intravesical pressure (ED(50) 0.4 mg/kg), without affecting heart rate and only slightly lowering mean blood pressure. Thus, ritobegron displayed potent and selective ß(3)-AR agonistic activity toward transfected human ß-AR and exhibited a high selectivity for the bladder versus other organs in rats. Moreover, it decreased intravesical pressure with minimal effects on the cardiovascular system in anesthetized rats. These results suggest that ritobegron shows promise as a potential agent for the treatment of overactive bladder.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Agonistas de Receptores Adrenérgicos beta 3/farmacologia
Bexiga Urinária/efeitos dos fármacos
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Antagonistas de Receptores Adrenérgicos beta 3/farmacologia
Agonistas Adrenérgicos beta/farmacologia
Animais
Células CHO
Colforsina/farmacologia
Cricetinae
Cricetulus
AMP Cíclico/metabolismo
Feminino
Frequência Cardíaca/efeitos dos fármacos
Seres Humanos
Técnicas In Vitro
Isoproterenol/farmacologia
Masculino
Relaxamento Muscular/efeitos dos fármacos
Especificidade de Órgãos
Ratos
Ratos Sprague-Dawley
Especificidade por Substrato
Bexiga Urinária Hiperativa/tratamento farmacológico
p-Hidroxianfetamina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Adrenergic beta-3 Receptor Antagonists); 0 (Adrenergic beta-Agonists); 0 (ritobegron ethyl); 1F7A44V6OU (Colforsin); E0399OZS9N (Cyclic AMP); FQR280JW2N (p-Hydroxyamphetamine); L628TT009W (Isoproterenol)
[Em] Mês de entrada:1211
[Cu] Atualização por classe:170920
[Lr] Data última revisão:
170920
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120504
[St] Status:MEDLINE
[do] DOI:10.1007/s00210-012-0755-x


  10 / 178 MEDLINE  
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[PMID]:22511202
[Au] Autor:Maruyama I; Tatemichi S; Goi Y; Maruyama K; Hoyano Y; Yamazaki Y; Kusama H
[Ad] Endereço:Central Research Laboratories, Kissei Pharmaceutical Co., Ltd., 4365-1, Kashiwabara, Hotaka, Azumino-City, Nagano-Pref. 399-8304, Japan. itaru_maruyama@pharm.kissei.co.jp
[Ti] Título:Effects of ritobegron (KUC-7483), a novel selective ß3-adrenoceptor agonist, on bladder function in cynomolgus monkey.
[So] Source:J Pharmacol Exp Ther;342(1):163-8, 2012 Jul.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:We evaluated the pharmacological profile of ritobegron [KUC-7483; (-)-ethyl 2-[4-(2-{[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino}ethyl)-2,5-dimethylphenyloxy]acetate monohydrochloride] and its effects on the bladder in cynomolgus monkeys by in vitro and in vivo experiments. In vitro, ritobegron decreased the resting tension of the isolated bladder in a concentration-dependent manner (EC(50) 8.2 ± 2.3 × 10(-7) M; maximal relaxation 88.7 ± 3.7%). The ß(3)-adrenoceptor (AR) antagonist 3-(2-allylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-(2S)-2-propanol hydrochloride (SR58894A) produced a rightward shift of this concentration-response curve without altering the maximal response (pK(B) value 6.56 ± 0.35). In isolated atria, ritobegron increased the atrial rate only at high concentrations (EC(50) 6.5 ± 1.2 × 10(-5) M). Ritobegron had no effect on tracheal contraction at concentrations from 10(-9) to 10(-4) M, and even at the highest concentration tested, 10(-3) M, the maximal relaxation it induced was only 26.7 ± 8.1%. Tests of the selectivity of ritobegron for the bladder gave values of 79.3- and 1200-fold higher versus atria and trachea, respectively. In the in vivo study ritobegron significantly decreased intravesical pressure (ED(50) 1.44 mg/kg) without affecting either mean blood pressure or heart rate. In conclusion, ritobegron displayed potent and selective ß(3)-AR agonistic activity and relaxed the monkey isolated bladder, and in vivo it decreased intravesical pressure without affecting cardiovascular parameters. These results suggest that ritobegron may be a promising potential agent for the treatment of overactive bladder.
[Mh] Termos MeSH primário: Acetatos/farmacologia
Agonistas de Receptores Adrenérgicos beta 3/farmacologia
Bexiga Urinária/efeitos dos fármacos
p-Hidroxianfetamina/análogos & derivados
[Mh] Termos MeSH secundário: Antagonistas de Receptores Adrenérgicos beta 3/farmacologia
Animais
Pressão Sanguínea/efeitos dos fármacos
Feminino
Átrios do Coração/efeitos dos fármacos
Frequência Cardíaca/efeitos dos fármacos
Macaca fascicularis
Masculino
Contração Muscular/efeitos dos fármacos
Relaxamento Muscular/efeitos dos fármacos
Traqueia/efeitos dos fármacos
Bexiga Urinária/fisiologia
Bexiga Urinária Hiperativa/tratamento farmacológico
p-Hidroxianfetamina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Acetates); 0 (Adrenergic beta-3 Receptor Agonists); 0 (Adrenergic beta-3 Receptor Antagonists); 0 (ritobegron ethyl); FQR280JW2N (p-Hydroxyamphetamine)
[Em] Mês de entrada:1211
[Cu] Atualização por classe:131121
[Lr] Data última revisão:
131121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:120419
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.112.191783



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