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1.
J Med Virol ; 2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34411312

RESUMO

This study aimed to determine the frequency of SARS-CoV-2 RNA in serum and its association with the clinical severity of COVID-19. This retrospective cohort study performed at Toyama University Hospital included consecutive patients with confirmed COVID-19. The prevalence of SARS-CoV-2 RNAemia and the strength of its association with clinical severity variables were examined. Fifty-six patients were included in this study. RNAemia was detected in 19.6% (11/56) patients on admission, and subsequently in 1.0% (1/25), 50.0% (6/12), and 100.0% (4/4) moderate, severe, and critically ill patients, respectively. Patients with RNAemia required more frequent oxygen supplementation (90.0% vs. 13.3%), ICU admission (81.8% vs. 6.7%), and invasive mechanical ventilation (27.3% vs. 0.0%). Among patients with RNAemia, the median viral loads of nasopharyngeal (NP) swabs that were collected around the same time as the serum sample were significantly higher in critically ill (5.4 log10 copies/µl; interquartile range [IQR]: 4.2-6.3) than in moderate-severe cases (2.6 log10 copies/µl; [IQR: 1.1-4.5]; p = 0.030) and were significantly higher in nonsurvivors (6.2 log10 copies/µl [IQR: 6.0-6.5]) than in survivors (3.9 log10 copies/µl [IQR: 1.6-4.6]; p = 0.045). This study demonstrated a relatively high proportion of SARS-CoV-2 RNAemia and an association between RNAemia and clinical severity. Moreover, among the patients with RNAemia, the viral loads of NP swabs were correlated with disease severity and mortality, suggesting the potential utility of combining serum testing with NP tests as a prognostic indicator for COVID-19, with higher quality than each separate test.

2.
Sci Rep ; 11(1): 16535, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400739

RESUMO

Adaptive immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) dynamics remain largely unknown. The neutralizing antibody (NAb) levels in patients with coronavirus disease 2019 (COVID-19) are helpful for understanding the pathology. Using SARS-CoV-2 pseudotyped virus, serum sample neutralization values in symptomatic COVID-19 patients were measured using the chemiluminescence reduction neutralization test (CRNT). At least two sequential serum samples collected during hospitalization were analyzed to assess NAbs neutralizing activity dynamics at different time points. Of the 11 patients, four (36.4%), six (54.5%), and one (9.1%) had moderate, severe, and critical disease, respectively. Fifty percent neutralization (N50%-CRNT) was observed upon admission in 90.9% (10/11); all patients acquired neutralizing activity 2-12 days after onset. In patients with moderate disease, neutralization was observed at earliest within two days after symptom onset. In patients with severe-to-critical disease, neutralization activity increased, plateauing 9-16 days after onset. Neutralization activity on admission was significantly higher in patients with moderate disease than in patients with severe-to-critical disease (relative % of infectivity, 6.4% vs. 41.1%; P = .011). Neutralization activity on admission inversely correlated with disease severity. The rapid NAb response may play a crucial role in preventing the progression of COVID-19.


Assuntos
Imunidade Adaptativa , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/diagnóstico , SARS-CoV-2/imunologia , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/imunologia , COVID-19/sangue , COVID-19/imunologia , COVID-19/virologia , Teste de Ácido Nucleico para COVID-19 , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes de Neutralização/estatística & dados numéricos , Estudos Retrospectivos , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Fatores de Tempo
3.
Viruses ; 13(6)2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34205062

RESUMO

Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne bunyavirus that causes severe disease in humans with case fatality rates of approximately 30%. There are few treatment options for SFTSV infection. SFTSV RNA synthesis is conducted using a virus-encoded complex with RNA-dependent RNA polymerase activity that is required for viral propagation. This complex and its activities are, therefore, potential antiviral targets. A library of small molecule compounds was processed using a high-throughput screening (HTS) based on an SFTSV minigenome assay (MGA) in a 96-well microplate format to identify potential lead inhibitors of SFTSV RNA synthesis. The assay confirmed inhibitory activities of previously reported SFTSV inhibitors, favipiravir and ribavirin. A small-scale screening using MGA identified four candidate inhibitors that inhibited SFTSV minigenome activity by more than 80% while exhibiting less than 20% cell cytotoxicity with selectivity index (SI) values of more than 100. These included mycophenolate mofetil, methotrexate, clofarabine, and bleomycin. Overall, these data demonstrate that the SFTSV MGA is useful for anti-SFTSV drug development research.

4.
Virology ; 556: 124-132, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33561699

RESUMO

The heartland virus (HRTV) is a novel phlebovirus that causes severe infections in the USA and closely related to the severe fever thrombocytopenia syndrome virus (SFTSV), a causative agent for SFTS in Asia. The entry mechanisms of HRTV remain unclear. Here, we developed the pseudotyped vesicular stomatitis virus bearing the HRTV glycoprotein (GP) (HRTVpv), and the antigenicity and the entry mechanisms of HRTV were analyzed. HRTVpv was neutralized by anti-SFTSV Gc antibody, but not the anti-SFTSV Gn antibodies. Entry of HRTVpv to cells was inhibited by bafilomycin A1 and dynasore, and but it was enhanced in cells overexpressed with C-type lectins. Production of infectious HRTVpv and SFTSVpv was reduced by Nn-DNJ, α-glucosidase inhibitor. The entry of HRTV occurs via pH- and dynamin-dependent endocytosis. Furthermore, Nn-DNJ may be a possible therapeutic agent against HRTV and SFTSV.

5.
Virol J ; 18(1): 16, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33435994

RESUMO

BACKGROUND: SARS-CoV-2 is a novel coronavirus that emerged in 2019 and is now classified in the genus Coronavirus with closely related SARS-CoV. SARS-CoV-2 is highly pathogenic in humans and is classified as a biosafety level (BSL)-3 pathogen, which makes manipulating it relatively difficult due to its infectious nature. METHODS: To circumvent the need for BSL-3 laboratories, an alternative assay was developed that avoids live virus and instead uses a recombinant VSV expressing luciferase and possesses the full length or truncated spike proteins of SARS-CoV-2. Furthermore, to measure SARS-CoV-2 neutralizing antibodies under BSL2 conditions, a chemiluminescence reduction neutralization test (CRNT) for SARS-CoV-2 was developed. The neutralization values of the serum samples collected from hospitalized patients with COVID-19 or SARS-CoV-2 PCR-negative donors against the pseudotyped virus infection evaluated by the CRNT were compared with antibody titers determined from an enzyme-linked immunosorbent assay (ELISA) or an immunofluorescence assay (IFA). RESULTS: The CRNT, which used whole blood collected from hospitalized patients with COVID-19, was also examined. As a result, the inhibition of pseudotyped virus infection was specifically observed in both serum and whole blood and was also correlated with the results of the IFA. CONCLUSIONS: In conclusion, the CRNT for COVID-19 is a convenient assay system that can be performed in a BSL-2 laboratory with high specificity and sensitivity for evaluating the occurrence of neutralizing antibodies against SARS-CoV-2.


Assuntos
Anticorpos Neutralizantes/sangue , Teste Sorológico para COVID-19/métodos , COVID-19/sangue , Testes de Neutralização/métodos , SARS-CoV-2/imunologia , Glicoproteína da Espícula de Coronavírus/imunologia , Vírus da Estomatite Vesicular Indiana/genética , Animais , Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Linhagem Celular , Convalescença , Humanos , Concentração Inibidora 50 , Luminescência , SARS-CoV-2/genética , Glicoproteína da Espícula de Coronavírus/genética
6.
PLoS One ; 15(12): e0243597, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33296437

RESUMO

OBJECTIVE: To investigate the relationship between viral load and secondary transmission in novel coronavirus disease 2019 (COVID-19). METHODS: Epidemiological and clinical data were obtained from immunocompetent laboratory-confirmed patients with COVID-19 who were admitted to and/or from whom viral loads were measured at Toyama University Hospital. Using a case-control approach, index patients who transmitted the disease to at least one other patient were analysed as "cases" (index patients) compared with patients who were not the cause of secondary transmission (non-index patients, analysed as "controls"). The viral load time courses were assessed between the index and non-index symptomatic patients using non-linear regression employing a standard one-phase decay model. RESULTS: In total, 28 patients were included in the analysis. Median viral load at the initial sample collection was significantly higher in symptomatic than in asymptomatic patients and in adults than in children. Among symptomatic patients (n = 18), non-linear regression models showed that the estimated viral load at onset was higher in the index than in the non-index patients (median [95% confidence interval]: 6.6 [5.2-8.2] vs. 3.1 [1.5-4.8] log copies/µL, respectively). In adult (symptomatic and asymptomatic) patients (n = 21), median viral load at the initial sample collection was significantly higher in the index than in the non-index patients (p = 0.015, 3.3 vs. 1.8 log copies/µL, respectively). CONCLUSIONS: High nasopharyngeal viral loads around onset may contribute to secondary transmission of COVID-19. Viral load may help provide a better understanding of why transmission is observed in some instances, but not in others, especially among household contacts.


Assuntos
COVID-19 , Modelos Biológicos , Nasofaringe , SARS-CoV-2/metabolismo , Carga Viral , Adolescente , Adulto , Idoso , COVID-19/metabolismo , COVID-19/transmissão , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Nasofaringe/metabolismo , Nasofaringe/virologia
7.
Antiviral Res ; 182: 104926, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32882323

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS), an emerging viral infectious disease with a high case fatality rate, is caused by the SFTS virus (SFTSV). Although several cellular molecules involved in viral entry have been identified, the entry mechanisms of SFTSV remain unclear. In this study, we screened the protein kinase inhibitors in inhibitory effects on the infection of Vero cells with SFTSV using InhibitorSelect™ Protein Kinase Library Series (Merck & Co., Inc., Kenilworth, NJ, USA). Several types of inhibitors targeted to platelet-derived growth factor receptor ß (PDGFRß) inhibited the infection of Vero, Huh7, and NIH3T3 cells with SFTSV in a dose-dependent manner within the noncytotoxic range. In addition, these protein kinase inhibitors also inhibited the infection of the target cells with SFTSV glycoprotein (SFTSV-GP) pseudotyped virus (SFTSVpv). Activation of PDGFRß phosphorylation was detected in SFTSV-treated cells. The infectivities of SFTSVpv were specifically decreased not only in NIH3T3 cells treated with siRNA for PDGFRß but also in NIH3T3 cells treated with anti-PDGFRß neutralizing antibody in a dose-dependent manner. SFTSV growth and entry of SFTSVpv were also inhibited by Akt inhibitors. Activation of Akt phosphorylation was also detected in SFTSV-treated cells. These data indicate that PDGFRß is one of the important host factors in the entry steps of SFTSV.

8.
Drug Metab Dispos ; 47(11): 1270-1280, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511257

RESUMO

Endogenous substrates are emerging biomarkers for drug transporters, which serve as surrogate probes in drug-drug interaction (DDI) studies. In this study, the results of metabolome analysis using wild-type and Oct1/2 double knockout mice suggested that N 1-methyladenosine (m1A) was a novel organic cation transporter (OCT) 2 substrate. An in vitro transport study revealed that m1A is a substrate of mouse Oct1, Oct2, Mate1, human OCT1, OCT2, and multidrug and toxin exclusion protein (MATE) 2-K, but not human MATE1. Urinary excretion accounted for 77% of the systemic elimination of m1A in mice. The renal clearance (46.9 ± 4.9 ml/min per kilogram) of exogenously given m1A was decreased to near the glomerular filtration rates by Oct1/2 double knockout or Mate1 inhibition by pyrimethamine (16.6 ± 2.6 and 24.3 ± 0.6 ml/min per kilogram, respectively), accompanied by significantly higher plasma concentrations. In vivo inhibition of OCT2/MATE2-K by a single dose of 7-[(3R)-3-(1-aminocyclopropyl)pyrrolidin-1-yl]-1-[(1R,2S)-2-fluorocyclopropyl]-8-methoxy-4-oxoquinoline-3-carboxylic acid in cynomolgus monkeys resulted in the elevation of the area under the curve of m1A (1.72-fold) as well as metformin (2.18-fold). The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. The renal clearance of m1A in younger (21-45 year old) and older (65-79 year old) volunteers (244 ± 58 and 169 ± 22 ml/min per kilogram, respectively) was about 2-fold higher than the creatinine clearance. The renal clearances of m1A and creatinine were 31% and 17% smaller in older than in younger volunteers. Thus, m1A could be a surrogate probe for the evaluation of DDIs involving OCT2/MATE2-K. SIGNIFICANCE STATEMENT: Endogenous substrates can serve as surrogate probes for clinical drug-drug interaction studies involving drug transporters or enzymes. In this study, m1A was found to be a novel substrate of renal cationic drug transporters OCT2 and MATE2-K. N 1-methyladenosine was revealed to have some advantages compared to other OCT2/MATE substrates (creatinine and N 1-methylnicotinamide). The genetic or chemical impairment of OCT2 or MATE2-K caused a significant increase in the plasma m1A concentration in mice and cynomolgus monkeys due to the high contribution of tubular secretion to the net elimination of m1A. The plasma m1A concentration profile showed low diurnal and interindividual variation in healthy volunteers. Thus, m1A could be a better biomarker of variations in OCT2/MATE2-K activity caused by inhibitory drugs.


Assuntos
Adenosina/análogos & derivados , Interações Medicamentosas , Rim/metabolismo , Proteínas de Transporte de Cátions Orgânicos/fisiologia , Adenosina/metabolismo , Adulto , Idoso , Animais , Biomarcadores , Creatinina/metabolismo , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Camundongos , Camundongos Endogâmicos ICR , Pessoa de Meia-Idade
9.
Virology ; 535: 102-110, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31299486

RESUMO

Severe fever with thrombocytopenia syndrome (SFTS) is an infectious disease with a high fatality rate, caused by SFTS virus (SFTSV). Because little is known about the nature of SFTSV, basic studies are required for the developments of vaccines and effective therapies. In the present study, we identified the amino acid residue important for membrane fusion induced by the SFTSV glycoprotein (GP). Syncytium formations were observed in cells expressing the GPs of SFTSV Japanese strain (YG-1 and SPL030). In contrast, no or only weak syncytium formations were induced in cells expressing GP of SFTSV Chinese strain (HB29). The replacement of arginine at amino acid residue 962 with serine in HB29 GP (R962S) induced membrane fusion, while the replacement of serine at residue 962 with arginine in YG1 GP (S962R) did not. These data indicate that serine at residue 962 in the SFTSV-GP is critical for inducing membrane fusion and viral infection.


Assuntos
Phlebovirus/fisiologia , Proteínas Virais de Fusão/metabolismo , Internalização do Vírus , Substituição de Aminoácidos , Fusão Celular , Células Gigantes/citologia , Células Gigantes/virologia , Mutagênese Sítio-Dirigida , Phlebovirus/genética , Proteínas Virais de Fusão/genética
10.
Eur J Clin Pharmacol ; 75(3): 351-361, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30382297

RESUMO

BACKGROUND: Magnesium oxide (MgO) is often co-prescribed with L-dopa/carbidopa (LDCD) to improve constipation in Parkinson's disease patients. The mixing of L-dopa and MgO has been shown to degrade L-dopa; however, there is no interaction study on humans. We proposed mechanisms for the interaction between LDCD and MgO and conducted pharmacokinetic studies on rats and humans. To assess pharmacodynamic changes with the MgO treatment, we applied a model-based meta-analysis (MBMA). METHODS: The effects of MgO on the stabilities of L-dopa and carbidopa were evaluated in in vitro studies. We conducted pharmacokinetic interaction studies of MgO and LDCD on rats and healthy volunteers. A clinical study was conducted with an open-label, non-randomized, single-arm, and two-phase study. In MBMA, we constructed a population pharmacokinetic/pharmacodynamic model of L-dopa and predicted the effects of the MgO treatment on the pharmacodynamics of L-dopa. RESULTS: In vitro results suggested that carbidopa was unstable under alkaline pH conditions. Reductions in plasma LDCD concentrations were observed after oral-MgO/oral-LDCD, but not in oral-MgO/i.v.-LDCD treatments in rats, suggesting that the gastrointestinal tract is an interaction site. A healthy volunteer study showed that MgO was also associated with significant decreases of 35.3 and 80.9% in the AUC0-12 of L-dopa and carbidopa, respectively. A model-based simulation suggested that the MgO treatment was undesirable for the effectiveness of L-dopa. CONCLUSIONS: This is the first study to show a clear pharmacokinetic interaction between LDCD and MgO in humans. Further investigations to confirm the effects of MgO on the pharmacodynamics of L-dopa are required.


Assuntos
Antiparkinsonianos/sangue , Carbidopa/sangue , Levodopa/sangue , Óxido de Magnésio/farmacologia , Modelos Biológicos , Administração Oral , Adulto , Animais , Antiparkinsonianos/administração & dosagem , Carbidopa/administração & dosagem , Simulação por Computador , Combinação de Medicamentos , Interações Medicamentosas , Estabilidade de Medicamentos , Feminino , Voluntários Saudáveis , Humanos , Injeções Intravenosas , Levodopa/administração & dosagem , Óxido de Magnésio/administração & dosagem , Masculino , Ratos Wistar , Adulto Jovem
11.
Drug Metab Pharmacokinet ; 34(1): 78-86, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30528195

RESUMO

This study aimed to elucidate the impact of OATP1B1 genotype (*1b/*1b, *1b/*15, and *15/*15) on plasma concentrations of endogenous OATP1B1 substrates. Healthy volunteers with OATP1B1 *1b/*1b (n = 10), *1b/*15 (n = 7), or *15/*15 (n = 2) received oral administration of a cocktail of statins (atorvastatin, pitavastatin, rosuvastatin, and fluvastatin). Mean area under the plasma concentration of atorvastatin, pitavastatin, and rosuvastatin in OATP1B1 *15/*15 were 2.2, 1.7 and 1.58-times greater than the corresponding values in OATP1B1 *1b/*1b, respectively, whereas that of fluvastatin was identical to those in other OATP1B1 genotypes. OATP1B1 *15/*15 also showed higher mean plasma concentrations of OATP1B1 endogenous substrates compared with the other OATP1B1 genotypes, such as coproporphyrin I, glycochenodeoxycholate sulfate (GCDCA-S), lithocholate sulfate (LCA-S), glycolithocholate sulfate (GLCA-S) and taurolithocholate sulfate (TLCA-S), but not total or direct bilirubin, chenodeoxycholate-24-glucuronide, or ω-dicarboxylic long-chain fatty acids. Area under the plasma concentration-time curves of plasma coproporphyrin I and GLCA-S discriminated OATP1B1 genotype *15/*15 from the other genotypes. In combination with previously published clinical studies, these results support the notion that coproporphyrin I, and GLCA-S and GCDCA-S could be a surrogate probe for assessing human in vivo OATP1B1 activities.


Assuntos
Genótipo , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/sangue , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Adulto , Feminino , Voluntários Saudáveis , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/sangue , Especificidade por Substrato/fisiologia , Adulto Jovem
12.
Jpn J Clin Oncol ; 48(4): 350-355, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29447361

RESUMO

Objective: To delineate the association between characteristics of adult-onset laryngeal squamous cell papilloma and human papillomavirus (HPV) infection. Methods: Clinical records and paraffin-embedded specimens of 77 papilloma patients who had been treated between 1998 and 2014 were collected. Of the 77 cases, 34 were identified in the larynx, 28 in the oral cavity and 15 in the oropharynx. Specimens were investigated by polymerase chain reaction (PCR) to detect HPV 6, 11, 16, 18, 31, 33, 35, 52b and 58, and immunohistochemical (IHC) staining for anti-p16INK4a antibody. Results: In 21 cases (61.8%) with laryngeal squamous cell papilloma, various types of HPV were detected: 14 cases (41.2%) were positive of high-risk HPV, 18 (52.9%) were positive of low-risk HPV and 11 (32.4%) were positive of both high-risk HPV and low-risk HPV. Younger patients (<60 years) showed a higher rate of HPV infection than older patients. Among the 34 cases with laryngeal papilloma, no malignant transformation was observed during the study period. With IHC staining, positive expression of p16 was observed in 20 cases (58.8%). HPV infection and p16-expression were associated with the pathological finding of koilocytosis. Only four cases (14.3%) showed HPV-positivity in the oral cavity, and none of the 15 oropharyngeal cases were positive for HPV, and none of the oral cavity and oropharyngeal cases showed koilocytosis. Results of HPV-PCR and p16-IHC staining were significantly correlated each other. Conclusions: HPV infection is frequently associated with laryngeal squamous cell papilloma, and koilocytosis is a characteristic pathological finding. To the best of our knowledge, this is the first report which have described infections with multiple HPV types in laryngeal papilloma.


Assuntos
Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/virologia , Papiloma/patologia , Papiloma/virologia , Papillomaviridae/fisiologia , Adulto , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Laringe/patologia , Masculino , Pessoa de Meia-Idade , Boca/patologia , Boca/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Reação em Cadeia da Polimerase
13.
Auris Nasus Larynx ; 45(3): 540-545, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28648812

RESUMO

OBJECTIVES: Unlike glottic cancer, supraglottic cancer often presents with neck metastases. This different might be attributable to the location of the primary lesion. This study aimed to clarify the relationships between the sublocation of T1-2 supraglottic cancer, human papillomavirus (HPV) infection, neck metastasis, and prognosis of supraglottic cancer. METHODS: This retrospective clinical study investigated 55 Japanese patients with T1-2 supraglottic cancer treated between 1994 and 2015. RESULTS: Of 55 patients with T1-2 supraglottic cancer, neck metastasis was present at initial diagnosis in 14 patients (25.5%). Presence of neck metastasis was the only factor associated with worse prognosis of T1-2 supraglottic cancer (p=0.004). In multivariate analysis, age <70years (p=0.033) and sublocation of the primary lesion in the superior epilaryngeal portion (p=0.017) were significantly associated with presence of neck metastasis in multivariate analysis. Twelve (27.9%) of 43 patients showed positive results for human papillomavirus infection. However, human papillomavirus infection was not associated with prognosis, presence of neck metastasis, or primary lesion sublocation in T1-2 supraglottic cancer. CONCLUSION: Relatively young patients with supraglottic cancer at the superior epilaryngeal portion are more likely to show neck metastasis. Human papillomavirus infection was not associated with frequency of neck metastasis.


Assuntos
Carcinoma de Células Escamosas/epidemiologia , Neoplasias de Cabeça e Pescoço/epidemiologia , Neoplasias Laríngeas/epidemiologia , Linfonodos/patologia , Infecções por Papillomavirus/epidemiologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Japão/epidemiologia , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/terapia , Laringectomia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Esvaziamento Cervical , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida
14.
J Pharm Sci ; 106(9): 2542-2550, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28479364

RESUMO

Recent studies suggest that trimethylamine N-oxide (TMAO) is associated with the development of chronic kidney disease and heart failure. In this study, we investigated the importance of organic cation transporters (OCTs) in the clearance and tissue distribution of TMAO. The low-affinity and high-capacity transport of TMAO by mouse and human OCT1 and OCT2 was observed. Uptake and efflux of TMAO by the mouse hepatocytes as well as TMAO uptake into mouse kidney slices were significantly decreased by the addition of tetraethylammonium or Oct1/2 double knockout (dKO). Plasma concentrations of endogenous TMAO and TMAO-d9 given by intravenous infusion was 2-fold higher in Oct1/2 dKO than in wild-type mice due to significant decrease in its renal clearance. These results indicate that OCTs have a crucial role in the kinetics of TMAO in mice. In human, however, the OCT2-mediated tubular secretion in the urinary excretion of TMAO was insignificant because the renal clearance of TMAO was similar to that of creatinine in both young and elderly subjects, suggesting the species difference in the urinary excretion mechanisms of TMAO between mouse and human.


Assuntos
Metilaminas/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Adulto , Idoso , Animais , Transporte Biológico , Creatinina/química , Creatinina/metabolismo , Células HEK293 , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Cinética , Metilaminas/química , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Fator 1 de Transcrição de Octâmero/metabolismo , Transportador 2 de Cátion Orgânico/metabolismo , Tetraetilamônio/química , Tetraetilamônio/metabolismo , Distribuição Tecidual
15.
J Pharm Sci ; 106(9): 2688-2694, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28322941

RESUMO

The aims of this study were (1) to investigate the effects of atorvastatin (10 mg, therapeutic dose) and grapefruit juice (GFJ), inhibitors of OATP2B1, on the pharmacokinetics of substrates for OATP2B1 and BCRP under oral small-dosing conditions (300 µg sulfasalazine, 250 µg rosuvastatin, 300 µg glibenclamide, 1200 µg celiprolol, and 600 µg sumatriptan), and (2) to evaluate the contribution of SLCO2B1*3 and ABCG2 c.421C>A polymorphisms to the pharmacokinetics of the 5 test drugs in 23 healthy volunteers. In the 3 phases, the test drugs were administered to volunteers with either water (control phase), atorvastatin, or GFJ. GFJ but not atorvastatin reduced the exposure of the test drugs significantly more than the control phase, suggesting that all 5 test drugs are substrates for OATP2B1. The SLCO2B1*3 genotype had no effect on the pharmacokinetics of the test drugs. In contrast, the exposure of sulfasalazine and rosuvastatin was significantly higher in ABCG2 421C/A than in ABCG2 421C/C individuals at all 3 phases, even under small-dosing conditions.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Atorvastatina/farmacocinética , Citrus paradisi/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , Farmacogenética/métodos , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Adulto , Atorvastatina/química , Atorvastatina/metabolismo , Celiprolol/química , Celiprolol/farmacocinética , Relação Dose-Resposta a Droga , Interações Medicamentosas , Feminino , Interações Alimento-Droga , Genótipo , Glibureto/química , Glibureto/farmacocinética , Humanos , Absorção Intestinal , Masculino , Proteínas de Neoplasias/metabolismo , Rosuvastatina Cálcica/química , Rosuvastatina Cálcica/farmacocinética , Sulfassalazina/química , Sulfassalazina/farmacocinética , Sumatriptana/química , Sumatriptana/farmacocinética
16.
Sci Rep ; 6: 32299, 2016 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-27571936

RESUMO

A variant in the breast cancer resistance protein (BCRP) gene, 421C> A is a useful biomarker for describing large inter-individual differences in the pharmacokinetics of sulfasalazine (SASP), a BCRP substrate. However, large intra-genotypic variability still exists in spite of the incorporation of this variant into the pharmacokinetics of SASP. Since miR-328 negatively regulates BCRP expression in human tissues, we hypothesized that exosomal miR-328 in plasma, which leaks from the intestines, is a possible biomarker for estimating BCRP activity in the human intestines. We established an immunoprecipitation-based quantitative method for circulating intestine-derived miR-328 in plasma using an anti-glycoprotein A33 antibody. A clinical study was conducted with an open-label, non-randomized, and single-arm design involving 33 healthy participants. Intestine-derived exosomal miR-328 levels positively correlated (P < 0.05) with SASP AUC0-48, suggesting that subjects with high miR-328 levels have low intestinal BCRP activity, resulting in the high AUC of SASP. Circulating intestine-derived exosomal miR-328 in plasma has potential as a possible biomarker for estimating BCRP function in the human intestines.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Exossomos/genética , Mucosa Intestinal/metabolismo , MicroRNAs/genética , Proteínas de Neoplasias/genética , Sulfassalazina/farmacocinética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Anti-Infecciosos/sangue , Anti-Infecciosos/farmacocinética , Área Sob a Curva , Arilamina N-Acetiltransferase/genética , Arilamina N-Acetiltransferase/metabolismo , Biomarcadores/sangue , Exossomos/ultraestrutura , Expressão Gênica , Genótipo , Humanos , MicroRNAs/sangue , Microscopia Eletrônica de Transmissão , Proteínas de Neoplasias/metabolismo , Polimorfismo de Nucleotídeo Único , Sulfassalazina/sangue , Adulto Jovem
17.
Drug Metab Dispos ; 44(10): 1622-32, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27457785

RESUMO

Clopidogrel is reported to be associated with cerivastatin-induced rhabdomyolysis, and clopidogrel and its metabolites are capable of inhibiting CYP2C8 and OATP 1B1 in vitro. The objective of the present study was to identify the mechanism of clopidogrel-mediated drug-drug interactions (DDIs) on the pharmacokinetics of OATP1B1 and/or CYP2C8 substrates in vivo. A clinical cassette small-dose study using OATPs, CYP2C8, and OATP1B1/CYP2C8 probe drugs (pitavastatin, pioglitazone, and repaglinide, respectively) with or without the coadministration of either 600 mg rifampicin (an inhibitor for OATPs), 200 mg trimethoprim (an inhibitor for CYP2C8), or 300 mg clopidogrel was performed, and the area under the concentration-time curve (AUC) ratios (AUCRs) for probe substrates were predicted using a static model. Clopidogrel increased the AUC of pioglitazone (2.0-fold) and repaglinide (3.1-fold) but did not significantly change the AUC of pitavastatin (1.1-fold). In addition, the AUC of pioglitazone M4, a CYP2C8-mediated metabolite of pioglitazone, was reduced to 70% of the control by coadministration of clopidogrel. The predicted AUCRs using the mechanism-based inhibition of CYP2C8 by clopidogrel acyl-ß-glucuronide were similar to the observed AUCRs, and the predicted AUCR (1.1) of repaglinide using only the inhibition of OATP1B1 did not reach the observed AUCR (3.1). In conclusion, a single 300 mg of clopidogrel mainly inhibits CYP2C8-mediated metabolism by clopidogrel acyl-ß-glucuronide, but its effect on the pharmacokinetics of OATP1B1 substrates is negligible. Clopidogrel is expected to have an effect not only on CYP2C8 substrates, but also dual CYP2C8/OATP1B1 substrates as seen in the case of repaglinide.


Assuntos
Inibidores da Agregação Plaquetária/farmacologia , Ticlopidina/análogos & derivados , Área Sob a Curva , Clopidogrel , Citocromo P-450 CYP2C8/metabolismo , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Técnicas In Vitro , Masculino , Inibidores da Agregação Plaquetária/sangue , Inibidores da Agregação Plaquetária/farmacocinética , Quinolinas/farmacologia , Rifampina/farmacologia , Ticlopidina/sangue , Ticlopidina/farmacocinética , Ticlopidina/farmacologia , Trimetoprima/farmacologia
18.
Clin Pharmacol Drug Dev ; 4(3): 218-25, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-27140802

RESUMO

This randomized, two-way crossover study evaluated the bioavailability of elvitegravir administered as the new individual tablet containing 150 mg and a cobicistat 150 mg tablet, concomitantly with a fixed-dose combination tablet containing 200 mg of emtricitabine and 300 mg of tenofovir disoproxil fumarate (EVG + COBI + FTC/TDF), in comparison with a single-tablet regimen containing the same dose of each component (EVG/COBI/FTC/TDF). Twenty-four healthy Japanese male subjects received the two different elvitegravir treatments, the separate-tablet or single-tablet regimen, once-daily for 10 days in each. The pharmacokinetic parameters (Cmax , AUCtau , and Ctau ) of elvitegravir were investigated at Day 10 after each treatment, together with safety and tolerability. Relative to EVG/COBI/FTC/TDF, the geometric least-squares mean ratios (GMR) and 90% confidence intervals (CIs) for elvitegravir Cmax and AUCtau were within the boundary of 0.8-1.25, while the upper limit of the 90% CI of GMR for Ctau was narrowly below the lack of bioequivalence boundary (0.79). No deaths, serious AEs, or drug-related AEs occurred. In conclusion, Cmax and AUCtau of elvitegravir met the strict definition of bioequivalence, indicating that the two regimens were essentially bioequivalent. Treatment with both regimens for 10 days appeared to be safe and well tolerated.


Assuntos
Fármacos Anti-HIV/administração & dosagem , Fármacos Anti-HIV/farmacocinética , Cobicistat/administração & dosagem , Cobicistat/farmacocinética , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/administração & dosagem , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/farmacocinética , Quinolonas/administração & dosagem , Quinolonas/farmacocinética , Administração Oral , Adulto , Fármacos Anti-HIV/efeitos adversos , Área Sob a Curva , Cobicistat/efeitos adversos , Estudos Cross-Over , Esquema de Medicação , Quimioterapia Combinada , Combinação Elvitegravir, Cobicistat, Emtricitabina e Fumarato de Tenofovir Desoproxila/efeitos adversos , Voluntários Saudáveis , Humanos , Japão , Análise dos Mínimos Quadrados , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Modelos Biológicos , Quinolonas/efeitos adversos , Comprimidos , Equivalência Terapêutica , Adulto Jovem
19.
Clin Pharmacol Drug Dev ; 4(2): 99-104, 2015 03.
Artigo em Inglês | MEDLINE | ID: mdl-27128214

RESUMO

FSK0808, a biosimilar of filgrastim, is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharmaceuticals and Mochida Pharmaceutical Co., Ltd. We conducted a double-blind, randomized, crossover study in healthy Japanese men, comparing the number of CD34-positive cells (CD34(+) cells) after repeated subcutaneous administration of either FSK0808 or the reference filgrastim (Gran(®) ). As primary endpoints, we compared the maximum number of CD34(+) cells (CD34(+) Cmax ) and the time to reach CD34(+) Cmax (CD34(+) tmax ). As secondary endpoints, we compared the area under the curve for the number of CD34(+) cells over time at the 410 hours time point (CD34(+) AUC0-410 ), the parameters used to calculate the pharmacodynamic index of the absolute neutrophil count, and the pharmacokinetic parameters. Regarding the CD34(+) Cmax and the CD34(+) AUC0-410 values, the 95% confidence interval (CI) of the differences between the mean values for each drug was within the range of log(0.8)-log(1.25). With respect to the differences in the median values between drugs, the ratio against the reference filgrastim median value in the 95% CI was within the range of ± 0.2 for the CD34(+) tmax value. From these results, we considered that these drugs display equivalent pharmacodynamic and pharmacokinetic properties.


Assuntos
Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/farmacocinética , Filgrastim/administração & dosagem , Filgrastim/farmacocinética , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Adulto , Antígenos CD34/sangue , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Biomarcadores/sangue , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/sangue , Estudos Cross-Over , Método Duplo-Cego , Filgrastim/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/sangue , Voluntários Saudáveis , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Japão , Masculino , Equivalência Terapêutica , Resultado do Tratamento , Adulto Jovem
20.
Drug Dev Ind Pharm ; 41(3): 470-5, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24471477

RESUMO

FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200 µg/m(2)) and single subcutaneous dose (400 µg/m(2)) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration - time curve by 48 hours after administration (AUC0-48) in a single intravenous drip (IVD) study, and AUC0-48 and maximum blood concentration (Cmax) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34(+) cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC0-48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for Cmax and AUC0-48 were within the range of log(0.8)-log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)-log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.


Assuntos
Grupo com Ancestrais do Continente Asiático , Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/farmacocinética , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacocinética , Adulto , Estudos Cross-Over , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Masculino , Adulto Jovem
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