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1.
Biol Pharm Bull ; 44(5): 669-677, 2021 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-33612567

RESUMO

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Inibidores do Fator Xa/uso terapêutico , Ventrículos do Coração/efeitos dos fármacos , Hipertensão Arterial Pulmonar/tratamento farmacológico , Rivaroxabana/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Técnicas de Cultura de Células , Modelos Animais de Doenças , Células Endoteliais/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inibidores do Fator Xa/farmacologia , Humanos , Hipóxia , Indóis , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , NF-kappa B/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Hipertensão Arterial Pulmonar/fisiopatologia , Pirróis , Ratos Sprague-Dawley , Rivaroxabana/farmacologia
2.
J Obstet Gynaecol Res ; 45(2): 337-344, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30362203

RESUMO

AIM: To evaluate the safety, effect on breastfeeding and efficacy of a combination of pethidine and levallorphan (Pethilorfan) for pain relief during labor. METHODS: We compared maternal or neonatal morbidities, suckling difficulties in newborns and breastfeeding rates between 177 women who received 50-200 mg (as pethidine) of Pethilorfan during labor (Pethilorfan group) and 354 women who delivered their infants without analgesic drugs immediately before or after each woman in the Pethilorfan group (control group) from January 1, 2005 to December 31, 2016. We performed univariate and multivariate analyses for comparison between the two groups. We also evaluated the efficacy of Pethilorfan retrospectively. RESULTS: The Pethilorfan group included more women with prolonged and/or operative deliveries than the control group. Nevertheless, no significant differences were seen between the two groups in the rates of Apgar scores less than 7 at 1 or 5 min, composite neonatal morbidities, hyperbilirubinemia or respiratory disturbances. The incidence of suckling difficulties lasting over 24 h and the breastfeeding rates at discharge or after 1 month were also similar. Maternal adverse effects of Pethilorfan were generally mild and transient. The efficacy ratio of Pethilorfan was 83.6%, although its analgesic effect was usually incomplete. CONCLUSION: Pethilorfan can be used safely for labor pain relief without increasing maternal or neonatal morbidities, or impeding breastfeeding, if it is administered at a prudent dosage. Parenteral opioids including Pethilorfan should remain as an option for treating women in labor pain, particularly when epidural analgesia is not readily available or contraindicated.


Assuntos
Analgesia Obstétrica/métodos , Analgésicos Opioides/farmacologia , Dor do Parto/tratamento farmacológico , Levalorfano/farmacologia , Meperidina/farmacologia , Antagonistas de Entorpecentes/farmacologia , Complicações do Trabalho de Parto , Avaliação de Resultados em Cuidados de Saúde , Analgesia Obstétrica/efeitos adversos , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Combinação de Medicamentos , Feminino , Humanos , Recém-Nascido , Levalorfano/administração & dosagem , Levalorfano/efeitos adversos , Meperidina/administração & dosagem , Meperidina/efeitos adversos , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Complicações do Trabalho de Parto/induzido quimicamente , Gravidez
3.
J Pharmacol Exp Ther ; 363(2): 275-283, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28819070

RESUMO

A current bottleneck in the development of central nervous system (CNS) drugs is the lack of drug delivery systems targeting the CNS. The intercellular space between endothelial cells of the blood-brain barrier (BBB) is sealed by complex protein-based structures called tight junctions (TJs). Claudin-5 (CLDN-5), a tetra-transmembrane protein is a key component of the TJ seal that prevents the paracellular diffusion of drugs into the CNS. In the present study, to investigate whether CLDN-5 binders can be used for delivery of drugs to the CNS, we generated monoclonal antibodies (mAbs) specific to the extracellular domains of CLDN-5. In an in vitro model of the BBB, the anti-CLDN-5 mAbs attenuated trans-epithelial/endothelial electrical resistance and enhanced solute permeation. These anti-CLDN-5 mAbs are potential leads for the development of novel drug delivery systems targeting the CNS.


Assuntos
Barreira Hematoencefálica/metabolismo , Claudina-5/metabolismo , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Claudina-5/química , Claudina-5/imunologia , Espaço Extracelular/metabolismo , Feminino , Humanos , Masculino , Camundongos , Permeabilidade , Domínios Proteicos , Junções Íntimas/metabolismo
5.
J Obstet Gynaecol Res ; 33(5): 612-8, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17845317

RESUMO

AIM: We evaluated the efficacy of antepartum screening for cord presentation by trans-vaginal ultrasonography (TVS) on predicting and preventing umbilical cord prolapse (UCP) in term breech delivery. METHODS: We investigated every woman with a breech-presenting fetus for cord presentation by weekly TVS after 36 weeks of gestation since 1995. If the cord was found in advance of fetal presenting parts, we recommended her to undergo elective cesarean section to avoid UCP. We studied the incidence of cord presentation by TVS and the clinical courses of the cases with it for 198 women who delivered breech after 36 weeks from 1995 to 2005 (group A). Further, the incidence of UCP was compared between group A and another 230 women who delivered breech at term from 1983 to 1994 (group B). RESULTS: Cord presentation was detected by TVS at least once in eight (4%) group A patients. Seven of them underwent elective cesarean section and, in six of these (86%), cord presentation was still found at the time of operation. The eighth patient became free of cord presentation at the later examinations and delivered vaginally without UCP. A hundred and twenty-one (61%) women in group A and 159 (69%) women in group B delivered vaginally. No UCP occurred in group A, while it occurred in 10 (4%) cases of group B (P < 0.01), and one baby died of it. CONCLUSIONS: Detection of cord presentation by TVS has a potential to predict and reduce UCP in breech delivery at term.


Assuntos
Apresentação Pélvica/diagnóstico por imagem , Complicações do Trabalho de Parto/prevenção & controle , Cordão Umbilical/diagnóstico por imagem , Apresentação Pélvica/cirurgia , Cesárea , Feminino , Humanos , Recém-Nascido , Gravidez , Prolapso , Ultrassonografia Pré-Natal , Cordão Umbilical/patologia , Cordão Umbilical/cirurgia
6.
J Pharmacol Exp Ther ; 309(3): 884-93, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-14764657

RESUMO

The effects of various anthraquinone polyamines (AQP) were studied at recombinant N-methyl-d-aspartate (NMDA) receptors expressed in Xenopus laevis oocytes. The AQP derivatives had different numbers of methylene groups between the NH(2) (or NH) groups in their spermidine-like tail. Thus, we termed these derivatives AQ33, AQ34, etc. All AQP derivatives inhibited responses of NR1/NR2 receptors in oocytes voltage-clamped at -70 mV, with IC(50) values between 4 and 22 microM. The block was strongly voltage-dependent. AQ34 and AQ33b inhibited responses of NR1/NR2 receptors but did not inhibit responses of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors expressed from GluR1 or GluR2(Q), indicating that AQ34 and AQ33b are preferential NMDA antagonists. Results of experiments using mutant NR1 and NR2 subunits identified residues that influence block by AQ34 and AQ33b. These residues are located in the outer vestibule at the selectivity filter/narrowest constriction of the channel and in the inner vestibule below the level of the selectivity filter. The results with mutant NR1 and NR2 subunits are consistent with the idea that NR1(Asn616) and NR2B(Asn616), but not NR2B(Asn615), make the narrowest constriction of NMDA channel.


Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Oócitos/efeitos dos fármacos , Poliaminas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Aminoácidos/metabolismo , Animais , Antraquinonas/química , Antraquinonas/farmacologia , Antagonistas de Aminoácidos Excitatórios/química , Mutagênese Sítio-Dirigida , Oócitos/metabolismo , Poliaminas/química , Conformação Proteica , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/química , Receptores de N-Metil-D-Aspartato/química , Relação Estrutura-Atividade , Xenopus laevis
7.
Biol Pharm Bull ; 25(9): 1129-32, 2002 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12230102

RESUMO

The frequency of generation of multidrug-resistant mutants of Staphylococcus aureus was examined by selection with various antiseptics and fluoroquinolones and the mutated genes were characterized. Multidrug-resistant mutants with mutation of the region between the promoter and structural regions of the norA gene were generated more frequently during selective pressure with antiseptics than during selective pressure with FQs. We also obtained evidence for the existence of at least one other gene related to resistance to antiseptics and fluoroquinolones on the chromosome of S. aureus in addition to norA gene.


Assuntos
Anti-Infecciosos Locais/farmacologia , Anti-Infecciosos/farmacologia , Genes MDR/genética , Mutação/genética , Staphylococcus aureus/genética , Sequência de Aminoácidos/genética , Sequência de Bases/genética , Fluoroquinolonas , Genes MDR/efeitos dos fármacos , Testes de Sensibilidade Microbiana/estatística & dados numéricos , Dados de Sequência Molecular , Mutação/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos
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