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1.
Drug Metab Pharmacokinet ; 48: 100474, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36529053

RESUMO

TAK-123, a combination of sodium phenylacetate (NaPA) and sodium benzoate (NaBZ), is an intravenously administered drug developed for the treatment of acute hyperammonemia in infants, children, and adults with urea cycle enzyme deficiencies. The aim of the current study was to evaluate the pharmacokinetics, safety, and tolerability after intravenous infusion of TAK-123 in Japanese healthy adult volunteers. Ten volunteers received a 3.75 g/m2 loading dose of TAK-123 over a period of 1.5 h followed by a maintenance infusion of the same dose over 24 h. Phenylacetate (PA) and benzoate (BZ) and their respective metabolites, phenylacetylglutamine (PAG) and hippurate (HIP) were measured over a 24-h period using a high-performance liquid chromatography/tandem mass spectrometry method. Non-compartmental analysis was performed using WinNonlin® Professional. During the loading dose, plasma levels of both PA and BZ peaked at 1.5 h. Plasma PA levels plateaued and were maintained up to 6.5 h, whereas plasma BZ levels declined rapidly after switching to maintenance infusion. Urinary excretion ratios of PAG and HIP at 48 h after the administration were 99.3% and 104%, respectively, suggesting that almost all NaPA and NaBZ were metabolized and excreted into urine. Overall, TAK-123 was well-tolerated in healthy Japanese adults.


Assuntos
Hiperamonemia , Benzoato de Sódio , Adulto , Criança , Lactente , Humanos , Benzoato de Sódio/uso terapêutico , População do Leste Asiático , Hiperamonemia/tratamento farmacológico , Fenilacetatos/metabolismo , Fenilacetatos/urina , Benzoatos/uso terapêutico , Benzoatos/urina , Voluntários Saudáveis
2.
Sensors (Basel) ; 22(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36433254

RESUMO

A new type of soil moisture sensor using spatial frequency domain transmissometry (SFDT) was evaluated. This sensor transmits and receives ultrawideband (1 to 6 GHz) radio waves between two separated antennas and measures the propagation delay time in the soil related to the dielectric constant. This method is expected to be less affected by air gaps between the probes and the soil, as well as being less affected by soil electrical conductivity (EC), than typical commercial sensors. The relationship between output and volumetric water content (θ), and the effects of air gaps and EC were evaluated through experiments using sand samples and the prototype SFDT sensor. The output of the SFDT sensor increased linearly with θ and was not affected by even a high salt concentration for irrigation water, such that the EC of the pore water was 9.2 dS·m-1. The SFDT sensor was almost unaffected by polyethylene tapes wrapped around the sensor to simulate air gaps, whereas a commercially available capacitance sensor significantly underestimated θ. Theoretical models of the SFDT sensor were also developed for the calibration equation and the air gaps. The calculation results agreed well with the experimental results, indicating that analytical approaches are possible for the evaluation of the SFDT sensor.


Assuntos
Solo , Água , Água/análise , Condutividade Elétrica , Capacitância Elétrica , Modelos Teóricos
3.
Proc Natl Acad Sci U S A ; 119(35): e2207531119, 2022 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-35994639

RESUMO

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.


Assuntos
Estimulantes do Sistema Nervoso Central , Narcolepsia , Receptores de Orexina , Adulto , Animais , Ataxina-3/genética , Ataxina-3/metabolismo , Cataplexia/tratamento farmacológico , Cataplexia/genética , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Modelos Animais de Doenças , Humanos , Camundongos , Narcolepsia/tratamento farmacológico , Narcolepsia/genética , Neurônios/metabolismo , Receptores de Orexina/agonistas , Receptores de Orexina/genética , Receptores de Orexina/metabolismo , Receptores de Orexina/uso terapêutico , Orexinas/genética , Orexinas/metabolismo , Fenótipo , Vigília/efeitos dos fármacos , Vigília/genética
4.
Plant J ; 110(2): 470-481, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35061931

RESUMO

The nonexpressor of pathogenesis-related (NPR) gene family is well known to play a crucial role in transactivation of TGA transcription factors for salicylic acid (SA)-responsive genes, including pathogenesis-related protein 1 (PR1), during plants' immune response after pathogen attack in the model dicot Arabidopsis thaliana. However, little is known about NPR gene functions in monocots. We therefore explored the functions of NPRs in SA signaling in the model monocot Brachypodium distachyon. BdNPR1 and BdNPR2/3 share structural similarities with A. thaliana AtNPR1/2 and AtNPR3/4 subfamilies, respectively. The transcript level of BdNPR2 but not BdNPR1/3 appeared to be positively regulated in leaves in response to methyl salicylate. Reporter assays in protoplasts showed that BdNPR2 positively regulated BdTGA1-mediated activation of PR1. This transactivation occurred in an SA-dependent manner through SA binding at Arg468 of BdNPR2. In contrast, BdNPR1 functioned as a suppressor of BdNPR2/BdTGA1-mediated transcription of PR1. Collectively, our findings reveal that the TGA-promoted transcription of SA-inducible PR1 is orchestrated by the activator BdNPR2 and the repressor BdNPR1, which function competitively in B. distachyon.


Assuntos
Arabidopsis , Brachypodium , Arabidopsis/genética , Arabidopsis/metabolismo , Brachypodium/genética , Brachypodium/metabolismo , Regulação da Expressão Gênica de Plantas/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ácido Salicílico/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Ativação Transcricional/genética
5.
Intern Med ; 61(9): 1337-1343, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-34645759

RESUMO

Objective To evaluate the safety profile of ixazomib combined with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM) in clinical practice in Japan through an all-case post-marketing surveillance. Methods This was a nationwide non-interventional observational study conducted in Japan. The study included all patients who received ixazomib from May 24 to September 24, 2017. Ixazomib was administered to RRMM patients according to the Japanese package insert. All enrolled patients were observed until the completion of the sixth treatment cycle or until ixazomib discontinuation. The patient treatment course, including adverse events (AEs), was reported. Results The safety analysis set included 741 patients; the median age was 71 (range 35-92) years old, and the median number of prior treatment lines was 3 (range 1-30). Adverse drug reactions (ADRs) occurred in 572 (77.2%) patients, most commonly being thrombocytopenia (49.9%), diarrhea (29.2%), and nausea (12.4%). Serious ADRs occurred in 193 (26.0%) patients, most commonly being thrombocytopenia (9.9%) and diarrhea (5.9%). Thrombocytopenia, severe gastrointestinal disorders, infections, skin disorders, and peripheral neuropathy were prespecified as ADRs of clinical importance; the frequency of these ADRs (grade ≥3) were 28.5%, 9.4%, 7.4%, 2.2%, and 1.3%, respectively. Treatment discontinuation was most common with thrombocytopenia and severe gastrointestinal disorders (49 and 43 patients, respectively). Eleven patients died due to ADRs (16 events). Conclusion These results suggest that ixazomib has a tolerable safety profile in clinical practice in Japan. However, close AE management for thrombocytopenia and gastrointestinal disorders should be considered.


Assuntos
Leucopenia , Mieloma Múltiplo , Trombocitopenia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Compostos de Boro , Dexametasona/uso terapêutico , Diarreia/induzido quimicamente , Diarreia/epidemiologia , Glicina/análogos & derivados , Humanos , Japão , Leucopenia/induzido quimicamente , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/etiologia , Vigilância de Produtos Comercializados , Talidomida/uso terapêutico , Trombocitopenia/induzido quimicamente , Trombocitopenia/tratamento farmacológico , Trombocitopenia/epidemiologia
7.
Cell Rep Med ; 2(6): 100311, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34027498

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic is a major global public health concern. Although rapid point-of-care testing for detecting viral antigen is important for management of the outbreak, the current antigen tests are less sensitive than nucleic acid testing. In our current study, we produce monoclonal antibodies (mAbs) that exclusively react with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and exhibit no cross-reactivity with other human coronaviruses, including SARS-CoV. Molecular modeling suggests that the mAbs bind to epitopes present on the exterior surface of the nucleocapsid, making them suitable for detecting SARS-CoV-2 in clinical samples. We further select the optimal pair of anti-SARS-CoV-2 nucleocapsid protein (NP) mAbs using ELISA and then use this mAb pair to develop immunochromatographic assay augmented with silver amplification technology. Our mAbs recognize the variants of concern (501Y.V1-V3) that are currently in circulation. Because of their high performance, the mAbs of this study can serve as good candidates for developing antigen detection kits for COVID-19.


Assuntos
Anticorpos Monoclonais/imunologia , Proteínas do Nucleocapsídeo de Coronavírus/imunologia , Epitopos/imunologia , Imunoensaio/métodos , SARS-CoV-2/metabolismo , Animais , Reações Antígeno-Anticorpo , COVID-19/patologia , COVID-19/virologia , Proteínas do Nucleocapsídeo de Coronavírus/genética , Proteínas do Nucleocapsídeo de Coronavírus/metabolismo , Humanos , Imunização , Camundongos , Camundongos Endogâmicos BALB C , Fosfoproteínas/genética , Fosfoproteínas/imunologia , Fosfoproteínas/metabolismo , Sistemas Automatizados de Assistência Junto ao Leito , SARS-CoV-2/isolamento & purificação , Prata/química
8.
J Oral Sci ; 63(2): 157-162, 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33597337

RESUMO

PURPOSE: This study aimed to examine novel techniques using prototype endodontic obturators to obturate a resin-based sealer. METHODS: Powder-liquid ratios of MetaSEAL Soft were changed to obtain suitable root canal sealing, and the physical properties for various powder-liquid ratios were analyzed according to ISO-6876. Tensile bond strength was also examined. Prototype endodontic obturators with a combination of thread numbers and pitch angles were analyzed for sealing ability after MetaSEAL Soft was obturated in simulated root canals. RESULTS: Powder-liquid ratios of 1.0:1, 1.1:1, 1.2:1, and 1.3:1 showed suitable physical properties; however, flow for 1.4:1 was below a standard value. Tensile bond strength increased gradually when the powder-liquid ratio changed from 1.0:1 to 1.3:1, and 1.3:1 and 1.4:1 showed the highest and lowest bond strengths, respectively. Sealing ability increased when pitch angles of the obturators were 5°, 8°, and 11°; 11° showed the best results. Similarly, sealing ability increased when the thread number was 12, 17, and 22 pitches; 22 showed the best results. CONCLUSION: These findings suggest that the prototype endodontic obturator can be useful for obturating MetaSEAL Soft, and a powder-liquid ratio of 1.3:1 MetaSEAL Soft may be the most suitable for achieving excellent sealing.


Assuntos
Materiais Restauradores do Canal Radicular , Resinas Epóxi , Pós , Obturação do Canal Radicular , Resistência à Tração
9.
Front Public Health ; 9: 690006, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-35155329

RESUMO

Background: Epidemiological contact tracing is a powerful tool to rapidly detect SARS-CoV-2 infection in persons with a close contact history with COVID-19-affected patients. However, it remains unclear whom and when should be PCR tested among the close contact subjects. Methods: We retrospectively analyzed 817 close contact subjects, including 144 potentially SARS-CoV-2-infected persons. The patient characteristics and contact type, duration between the date of the close contact and specimen sampling, and PCR test results in PCR positive and negative persons were compared. Results: We found that male gender {adjusted odds ratio 1.747 [95% confidence interval (CI) 1.180-2.608]}, age ≥ 60 [1.749 (95% CI 1.07-2.812)], and household contact [2.14 (95% CI 1.388-3.371)] are independent risk factors for close contact SARS-CoV-2 infection. Symptomatic subjects were predicted 6.179 (95% CI 3.985-9.61) times more likely to be infected compared to asymptomatic ones. We could observe PCR test positivity between days 1 and 17 after close contact. However, no subject could be found with a Ct-value <30, considered less infective, after day 14 of close contact. Conclusions: Based on our results, we suggest that contact tracing should be performed on the high-risk subjects between days 3 and 13 after close contacts.


Assuntos
COVID-19 , Busca de Comunicante , Humanos , Masculino , Estudos Retrospectivos , Fatores de Risco , SARS-CoV-2
10.
J Neuroinflammation ; 17(1): 312, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33081813

RESUMO

BACKGROUND: The existence of referred pain and ectopic paresthesia caused by tooth pulp inflammation may make definitive diagnosis difficult and cause misdiagnosis or mistreatment; thus, elucidation of that molecular mechanism is urgent. In the present study, we investigated the mechanisms underlying ectopic pain, especially tongue hyperalgesia, after tooth pulp inflammation. METHODS: A rat model with mandibular first molar tooth pulp exposure was employed. Tooth pulp exposure-induced heat and mechanical-evoked tongue hypersensitivity was measured, and immunohistochemical staining for Iba1, a marker of active macrophages, IL-1ß, IL-1 type I receptor (IL-1RΙ), and toll-like receptor 4 in the trigeminal ganglion was performed. In addition, we investigated the effects of injections of liposomal clodronate Clophosome-A (LCCA), a selective macrophage depletion agent, lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS, a toll-like receptor 4 antagonist), IL-1ß, or heat shock protein 70 (Hsp70, a selective agonist of toll-like receptor 4), to examine changes in tongue hypersensitivity and in the regulation of IL-1RΙ, toll-like receptor 4, and transient receptor potential vanilloid 1 (TRPV1) biosynthesis. RESULTS: At day 1 after tooth pulp exposure, obvious tooth pulp inflammation was observed. Tooth pulp exposure-induced heat and mechanical tongue hypersensitivity was observed from days 1 to 3 after tooth pulp exposure. The production of IL-1ß in activated macrophages and toll-like receptor 4 and IL-1RΙ expression were significantly increased in trigeminal ganglion neurons innervating the tongue following tooth pulp exposure. Intra-trigeminal ganglion injection of LCCA significantly suppressed tongue hypersensitivity; however, toll-like receptor 4 and IL-1RΙ expression in trigeminal ganglion neurons innervating the tongue was not significantly altered. Intra-trigeminal ganglion injection of LPS-RS significantly suppressed tongue hypersensitivity and reduced IL-1RΙ expression in the trigeminal ganglion neurons innervating the tongue following tooth pulp exposure. Intra-trigeminal ganglion injection of recombinant Hsp70 significantly promoted tongue hypersensitivity and increased IL-1RI expression in trigeminal ganglion neurons innervating the tongue in naive rats. Furthermore, intra-trigeminal ganglion injection of recombinant IL-1ß led to tongue hypersensitivity and enhanced TRPV1 expression in trigeminal ganglion neurons innervating the tongue in naive rats. CONCLUSIONS: The present findings suggest that the neuron-macrophage interaction mediated by toll-like receptor 4 and IL-1RI activation in trigeminal ganglion neurons affects the pathogenesis of abnormal tongue pain following tooth pulp inflammation via IL-1RI and TRPV1 signaling in the trigeminal ganglion. Further research may contribute to the establishment of new therapeutic and diagnostic methods.


Assuntos
Polpa Dentária/metabolismo , Macrófagos/metabolismo , Dor/metabolismo , Receptores Tipo I de Interleucina-1/metabolismo , Receptor 4 Toll-Like/metabolismo , Língua/metabolismo , Animais , Polpa Dentária/patologia , Macrófagos/patologia , Masculino , Dor/patologia , Medição da Dor/métodos , Pulpite/metabolismo , Pulpite/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Língua/patologia
11.
Viruses ; 12(2)2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-32013144

RESUMO

The A(H1N1)pdm09 virus emerged in 2009 and continues to circulate in human populations. Recent A(H1N1)pdm09 viruses, that is, A(H1N1)pdm09 viruses circulating in the post-pandemic era, can cause more or less severe infections than those caused by the initial pandemic viruses. To evaluate the changes in pathogenicity of the A(H1N1)pdm09 viruses during their continued circulation in humans, we compared the nucleotide and amino acid sequences of ten A(H1N1)pdm09 viruses isolated in Japan between 2009 and 2015, and experimentally infected mice with each virus. The severity of infection caused by these Japanese isolates ranged from milder to more severe than that caused by the prototypic pandemic strain A/California/04/2009 (CA04/09); however, specific mutations responsible for their pathogenicity have not yet been identified.


Assuntos
Sequência de Aminoácidos , Sequência de Bases , Vírus da Influenza A Subtipo H1N1/genética , Vírus da Influenza A Subtipo H1N1/patogenicidade , Infecções por Orthomyxoviridae/virologia , Animais , Feminino , Humanos , Influenza Humana/epidemiologia , Influenza Humana/virologia , Japão/epidemiologia , Camundongos , Camundongos Endogâmicos BALB C , Mutação , Pandemias , Filogenia , RNA Viral/genética , Índice de Gravidade de Doença , Virulência
12.
J Diabetes Investig ; 11(2): 373-381, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31389201

RESUMO

INTRODUCTION: To investigate the efficacy and safety of trelagliptin 25 mg in patients with type 2 diabetes mellitus with severe renal impairment or end-stage renal disease. MATERIALS AND METHODS: This multicenter, randomized, phase 3 study comprised a 12-week double-blind phase followed by a 40-week open-label phase. Patients had type 2 diabetes mellitus with severe renal impairment (creatinine clearance <30 mL/min) or end-stage renal disease (undergoing hemodialysis), and were receiving diet and/or exercise therapy with/without one antidiabetic drug. RESULTS: Patients were randomized to trelagliptin (A/A, n = 55) or placebo (P/A, n = 52; double-blind phase). Both groups received trelagliptin in the open-label phase. The least square mean change (95% confidence interval [CI]) from baseline in hemoglobin A1c at the end of the double-blind phase was -0.71% (95% CI -0.885, -0.542) and 0.01% (95% CI -0.170, 0.183) in the A/A and P/A groups, respectively (intergroup least square means difference -0.72%, 95% CI -0.966, -0.473; P < 0.0001). Mean hemoglobin A1c decreased after trelagliptin treatment in the P/A group to similar levels observed in the A/A group and remained comparable in both groups versus baseline up to week 52. In the double-blind phase, the incidence of treatment-emergent adverse events (TEAEs) was 72.7% and 61.5% in the A/A and P/A group, respectively; most TEAEs were mild-to-moderate, except in one patient (P/A group), who experienced two severe TEAEs. The incidence of serious TEAEs was 7.3% and 3.8% in the A/A and P/A group, respectively. CONCLUSIONS: Once-weekly trelagliptin 25 mg was efficacious, with no major safety concerns, and represents a meaningful treatment option in this patient population.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Hipoglicemiantes/uso terapêutico , Falência Renal Crônica/complicações , Insuficiência Renal/complicações , Uracila/análogos & derivados , Idoso , Povo Asiático , Diabetes Mellitus Tipo 2/complicações , Dietoterapia , Método Duplo-Cego , Terapia por Exercício , Feminino , Hemoglobinas Glicadas/análise , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Uracila/uso terapêutico
13.
Nat Microbiol ; 4(8): 1268-1273, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31036910

RESUMO

Here, we developed hCK, a Madin-Darby canine kidney (MDCK) cell line that expresses high levels of human influenza virus receptors and low levels of avian virus receptors. hCK cells supported human A/H3N2 influenza virus isolation and growth much more effectively than conventional MDCK or human virus receptor-overexpressing (AX4) cells. A/H3N2 viruses propagated in hCK cells also maintained higher genetic stability than those propagated in MDCK and AX4 cells.


Assuntos
Células Madin Darby de Rim Canino/virologia , Orthomyxoviridae/genética , Orthomyxoviridae/isolamento & purificação , Animais , Antígenos CD/metabolismo , Linhagem Celular , Cães , Humanos , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/crescimento & desenvolvimento , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana , Mutação , Receptores Virais/genética , Receptores Virais/metabolismo , Sialiltransferases/genética , Sialiltransferases/metabolismo , beta-Galactosídeo alfa-2,3-Sialiltransferase
14.
Euro Surveill ; 24(6)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30755292

RESUMO

BACKGROUND: Influenza A(H3N2) virus rapidly evolves to evade human immune responses, resulting in changes in the antigenicity of haemagglutinin (HA). Therefore, continuous genetic and antigenic analyses of A(H3N2) virus are necessary to detect antigenic mutants as quickly as possible. AIM: We attempted to phylogenetically and antigenically capture the epidemic trend of A(H3N2) virus infection in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons. METHODS: We determined the HA sequences of A(H3N2) viruses detected in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons to identify amino acid substitutions and the loss or gain of potential N-glycosylation sites in HA, both of which potentially affect the antigenicity of HA. We also examined the antigenicity of isolates using ferret antisera obtained from experimentally infected ferrets. RESULTS: Influenza A(H3N2) viruses belonging to six clades (clades 3C.2A1, 3C.2A1a, 3C.2A1b, 3C.2A2, 3C.2A3 and 3C.2A4) were detected during the 2016/17 influenza season, whereas viruses belonging to two clades (clades 3C.2A1b and 3C.2A2) dominated during the 2017/18 influenza season. The isolates in clades 3C.2A1a and 3C.2A3 lost one N-linked glycosylation site in HA relative to other clades. Antigenic analysis revealed antigenic differences among clades, especially clade 3C.2A2 and 3C.2A4 viruses, which showed distinct antigenic differences from each other and from other clades in the antigenic map. CONCLUSION: Multiple clades, some of which differed antigenically from others, co-circulated in Yokohama, Japan during the 2016/17 and 2017/18 influenza seasons.


Assuntos
Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Vírus da Influenza A Subtipo H3N2/genética , Vírus da Influenza A Subtipo H3N2/isolamento & purificação , Influenza Humana/diagnóstico , RNA Viral/genética , Epidemias , Variação Genética , Hemaglutininas/genética , Humanos , Influenza Humana/epidemiologia , Japão/epidemiologia , Dados de Sequência Molecular , Filogenia , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estações do Ano , Análise de Sequência de DNA
15.
Clin J Am Soc Nephrol ; 14(3): 354-363, 2019 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-30755452

RESUMO

BACKGROUND AND OBJECTIVES: Imarikiren is a novel, potent, and selective direct renin inhibitor that has shown high oral availability during clinical development for the treatment of diabetic nephropathy. We evaluated the efficacy and safety of imarikiren in patients with type 2 diabetes mellitus and microalbuminuria. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This was a randomized, multicenter, placebo-controlled, double-blind, phase 2, dose-finding trial. A total of 415 patients were randomized to imarikiren 5, 20, 40, or 80 mg; placebo; or candesartan cilexetil 8 mg treatment for 12 weeks. The primary end point was change in log-transformed urine albumin-to-creatinine ratio from baseline to the end of treatment analyzed using analysis of covariance and a fixed sequence testing procedure. Secondary efficacy end points included urine albumin-to-creatinine ratio at each assessment point and remission and progression rates. Exploratory efficacy end points included eGFR and sitting BP before dosing. RESULTS: Changes in the urine albumin-to-creatinine ratio from baseline to the end of treatment were 16% (placebo), -16% (imarikiren 5 mg), -27% (imarikiren 20 mg), -38% (imarikiren 40 mg), -39% (imarikiren 80 mg), and -31% (candesartan cilexetil 8 mg). Urine albumin-to-creatinine ratio reductions from baseline were statistically significant in all imarikiren groups versus placebo (P<0.001 each) as well as for candesartan cilexetil 8 mg versus placebo (P<0.001). Remission rates (urine albumin-to-creatinine ratio <30 mg/g creatinine and decreased ≥30% from baseline) were higher in all imarikiren groups versus the placebo group. Incidence of adverse events was higher in the imarikiren 80-mg group (52%) versus placebo (42%) and candesartan cilexetil (43%) groups. Incidence of adverse events for the other imarikiren groups ranged from 33% to 42%. Adverse events were mild or moderate in severity. All imarikiren doses were well tolerated. CONCLUSIONS: Imarikiren resulted in a dose-dependent improvement in albuminuria compared with placebo, and it was well tolerated in patients with type 2 diabetes mellitus and microalbuminuria.


Assuntos
Albuminúria/tratamento farmacológico , Benzimidazóis/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/tratamento farmacológico , Morfolinas/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Renina/antagonistas & inibidores , Adulto , Idoso , Albuminúria/diagnóstico , Albuminúria/etiologia , Benzimidazóis/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Proteases/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
J Biotechnol ; 294: 67-72, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30772329

RESUMO

This study focused on a culture system of aerial microalgae with the decomposition of casein protein for obtaining bioactive compounds such as peptides with inhibitory activity against angiotensin-converting enzyme (ACE). The aerial microalga Vischeria helvetica exhibited growth in Bold's basal medium supplemented with casein protein as nitrogen source. The algal cells secreted protease and amino oxidase into the medium, and ammonium ions as a nitrogen source was produced by the conjugated-enzyme reaction. Furthermore, a bioactive peptide with ACE-inhibitory activity was efficiently produced from casein protein by the proteases secreted under light conditions. The results presented will facilitate the development of production systems for useful materials from photosynthetic microorganisms and casein protein in a culture medium.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/metabolismo , Caseínas/metabolismo , L-Aminoácido Oxidase/metabolismo , Microalgas/metabolismo , Oligopeptídeos/metabolismo , Peptídeo Hidrolases/metabolismo , Estramenópilas/metabolismo , Proteínas de Algas/metabolismo , Hidrólise , Peptidil Dipeptidase A/metabolismo
17.
J Oral Sci ; 60(4): 493-499, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30587684

RESUMO

Pulpitis often causes referred pain in opposing teeth. However, the precise mechanism underlying ectopic pain associated with tooth-pulp inflammation remains unclear. We performed the present study to test the hypothesis that functional interactions between satellite glial cells (SGCs) and trigeminal ganglion (TG) neurons are involved in ectopic orofacial pain associated with tooth-pulp inflammation. Digastric muscle electromyograph (D-EMG) activity elicited by administration of capsaicin into the upper second molar pulp (U2) was analyzed to evaluate noxious reflex responses. D-EMG activity was significantly increased in rats with lower first molar (L1) inflammation relative to saline-treated rats. Significantly increased expression of glial fibrillary acid protein (GFAP), a marker of activated glial cells, and connexin 43 (Cx43), a gap-junction protein, was observed in activated SGCs surrounding U2-innervating TG-neurons after L1-pulp inflammation. Daily administration of Gap26, a Cx43-inhibiting mimetic peptide, into the TG significantly suppressed capsaicin-induced D-EMG activity enhancement and reduced the percentage of fluorogold-labeled (U2-innervated) cells that were surrounded by GFAP-immunoreactive (IR) and Cx43-IR cells after L1-pulp inflammation. These findings indicate that tooth-pulp inflammation induces SGC activation and subsequent spread of SGC activation in the TG via Cx43-containing gap junctions. Thus, remote neuron excitability becomes enhanced in the TG following tooth-pulp inflammation, resulting in ectopic tooth-pulp pain in the contralateral tooth.


Assuntos
Conexina 43/metabolismo , Neuroglia/metabolismo , Dor Referida , Pulpite/metabolismo , Gânglio Trigeminal/metabolismo , Animais , Capsaicina/administração & dosagem , Eletromiografia , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Dente Molar , Peptídeos/farmacologia , Ratos , Ratos Sprague-Dawley
18.
Int Heart J ; 59(6): 1352-1358, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30369564

RESUMO

Although beta-blockade itself is not a first choice for chronic kidney disease (CKD) patients, alpha-beta-blockers (ABB) do improve their prognoses. This study's aim was to evaluate the effect of beta-selective-blockers (BSB) and ABB on circadian cardiac autonomic activity in CKD patients.The study consisted of 496 non-diabetic individuals who underwent 24-hour Holter monitoring (149 CKD patients and 347 controls without CKD). Using heart rate variability analysis, we evaluated the proportion of NN50 and the high-frequency component (reflecting parasympathetic activity), and low- to high-frequency ratio (reflecting sympathovagal balance). These indices were evaluated by regression analysis incorporating gender, age, related comorbidities, and medications. BSB increased vagal activity only in the day-time and not the night-time in controls. In CKD patients, BSB was significantly related to higher vagal activity throughout the day and with lower sympathovagal balance at night. The night sympathovagal balance of CKD patients taking ABB was significantly higher than that of CKD patients taking BSB, which was the only significant difference between the effects of BSB and ABB.The sympatholytic therapy effect is different depending on CKD presence and whether patients are treated with BSB or ABB. In CKD patients without severe heart failure, BSB could be associated with higher parasympathetic activity and lower sympathovagal balance compared to ABB.


Assuntos
Antagonistas Adrenérgicos alfa/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Sistema Nervoso Autônomo/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Insuficiência Renal Crônica/tratamento farmacológico , Simpatolíticos/farmacologia , Nervo Vago/efeitos dos fármacos , Antagonistas Adrenérgicos alfa/uso terapêutico , Antagonistas Adrenérgicos beta/uso terapêutico , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Insuficiência Renal Crônica/fisiopatologia , Estudos Retrospectivos , Simpatolíticos/uso terapêutico
19.
Clin Drug Investig ; 38(11): 1041-1051, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30194585

RESUMO

BACKGROUND AND OBJECTIVE: Imarikiren hydrochloride (TAK-272; SCO-272) is a novel direct renin inhibitor. The objective of this study was to determine the effects of renal impairment (RI) or hepatic impairment (HI) on the pharmacokinetics and safety of imarikiren. METHODS: This phase I, open-label, parallel-group comparative study evaluated the pharmacokinetics and safety of a single 40 mg oral dose of imarikiren in RI [mild, moderate, severe, or end-stage renal disease (ESRD), and on hemodialysis] or HI (mild or moderate) subjects compared with subjects with normal renal or hepatic function. RESULTS: Following administration of a single 40 mg oral imarikiren dose, the geometric mean imarikiren area under the plasma concentration-time curve from time zero to infinity (AUC∞) and maximum observed plasma concentration (Cmax) in subjects with mild, moderate, and severe RI (including non-hemodialysis and ESRD), and hemodialysis subjects compared with normal renal function subjects were approximately 0.5-, 1.2-, 2.7-, and 1.8-fold, respectively, for AUC∞; and approximately 0.6-, 0.8-, 2.1-, and 1.4-fold, respectively, for Cmax. The mean fraction of excretion of imarikiren in dialysate was ~ 3% during the 4 h dialysis period. The geometric mean imarikiren AUC∞ and Cmax in mild and moderate HI subjects compared with normal hepatic function subjects were approximately 1.0- and 1.4-fold, respectively, for AUC∞, and approximately 0.9- and 1.3-fold, respectively, for Cmax. No deaths or serious adverse events were observed; all adverse events were mild or moderate in intensity. CONCLUSIONS: RI and HI are associated with limited changes in imarikiren pharmacokinetics. Imarikiren was safe and well-tolerated, regardless of the severity of RI or HI. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02367872.


Assuntos
Benzimidazóis/administração & dosagem , Benzimidazóis/farmacocinética , Falência Renal Crônica/metabolismo , Hepatopatias/metabolismo , Morfolinas/administração & dosagem , Morfolinas/farmacocinética , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Adulto , Idoso , Área Sob a Curva , Benzimidazóis/efeitos adversos , Fármacos Cardiovasculares/administração & dosagem , Fármacos Cardiovasculares/efeitos adversos , Fármacos Cardiovasculares/farmacocinética , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Falência Renal Crônica/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Piperidinas/efeitos adversos , Diálise Renal/tendências
20.
Nucleic Acids Res ; 46(13): 6761-6772, 2018 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-29762762

RESUMO

(6-4) Photolyases ((6-4)PLs) are flavoenzymes that repair the carcinogenic UV-induced DNA damage, pyrimidine(6-4)pyrimidone photoproducts ((6-4)PPs), in a light-dependent manner. Although the reaction mechanism of DNA photorepair by (6-4)PLs has been intensively investigated, the molecular mechanism of the lesion recognition remains obscure. We show that a well-conserved arginine residue in Xenopus laevis (6-4)PL (Xl64) participates in DNA binding, through Coulomb and CH-π interactions. Fragment molecular orbital calculations estimated attractive interaction energies of -80-100 kcal mol-1 for the Coulomb interaction and -6 kcal mol-1 for the CH-π interaction, and the loss of either of them significantly reduced the affinity for (6-4)PP-containing oligonucleotides, as well as the quantum yield of DNA photorepair. From experimental and theoretical observations, we formulated a DNA binding model of (6-4)PLs. Based on the binding model, we mutated this Arg in Xl64 to His, which is well conserved among the animal cryptochromes (CRYs), and found that the CRY-type mutant exhibited reduced affinity for the (6-4)PP-containing oligonucleotides, implying the possible molecular origin of the functional diversity of the photolyase/cryptochrome superfamily.


Assuntos
Reparo do DNA , DNA/química , Desoxirribodipirimidina Fotoliase/química , Proteínas de Xenopus/química , Animais , Arginina/química , Criptocromos/química , DNA/metabolismo , Desoxirribodipirimidina Fotoliase/genética , Desoxirribodipirimidina Fotoliase/metabolismo , Mutação , Ligação Proteica , Proteínas de Xenopus/genética , Proteínas de Xenopus/metabolismo , Xenopus laevis
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