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1.
Nihon Hoshasen Gijutsu Gakkai Zasshi ; 79(3): 241-251, 2023 Mar 20.
Artigo em Japonês | MEDLINE | ID: mdl-36724920

RESUMO

The present study investigated how effective an L-shaped shield was, depending on its position, in reducing a doctor's exposure to radiation during catheterization to access the transradial approach (TRA). The shield's effectiveness was evaluated by measuring the air kerma where the doctor stood under four conditions: with and without the shield, and with and without the shield in conjunction with conventional protection. To enable the shield to be positioned correctly in clinical practice, an illustrated instruction decal affixable to the shield's doctor-facing surface was produced, and the effectiveness of the decal was verified by means of a crossover test in which, as subjects of the study, different nurses set up the shield with and without the decal affixed to it. In the test, in which a human body phantom was used, the C-arm set at the PA angle, and the shield positioned 10 cm from the axilla of the phantom, the shield's effectiveness at 100 cm, 130 cm, and 160 cm above the floor where the doctor stood was 55%, 77%, and 47%, respectively. The effectiveness increased when the shield was positioned closer to the axilla. A significant difference in the positioning of the shield by the subjects was observed depending on whether or not the decal was affixed ( p<0.05, Wilcoxon signed-rank test), indicating that the use of the decal improved the positioning. It was concluded that, positioned correctly, the shield could effectively reduce the doctor's exposure to radiation during TRA.


Assuntos
Exposição Ocupacional , Proteção Radiológica , Humanos , Proteção Radiológica/métodos , Radiologia Intervencionista , Exposição Ocupacional/prevenção & controle , Equipamentos de Proteção , Imagens de Fantasmas , Doses de Radiação
2.
J Appl Clin Med Phys ; 23(12): e13851, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36448537

RESUMO

This study aims to investigate the effects of the position correction of size-specific dose estimates (SSDE) on patient dose estimation in cone beam computed tomography (CBCT). The relationship between the phantom position and absorbed dose in the right breast was studied using optically stimulated luminescence dosimeters and a simulated human body phantom. The effect of position correction for CT dose index (CTDI) on SSDE was investigated in 51 patients who underwent right breast irradiation by comparing the SSDE with position correction and SSDE without position correction. The absorbed dose in the right breast tended to decrease by 10.2% as the phantom was placed away from the center of CBCT. The mean and standard deviation of SSDE were 2.54 ± 0.29 and 2.92 ± 0.30 mGy with and without position correction, respectively. The SSDE with position correction was 13.1% lower than that without position correction (p < 0.05). SSDE was different when the patient's torso center was located at the isocenter of CBCT, and when it was not. The same tendency was seen in the case of the breast. Therefore, if the center of the patient is not at the acquisition center of the CT scanner, position correction is required when estimating SSDE.


Assuntos
Mama , Tomografia Computadorizada de Feixe Cônico , Humanos , Doses de Radiação , Tomografia Computadorizada de Feixe Cônico/métodos , Tomógrafos Computadorizados , Imagens de Fantasmas
3.
Cancers (Basel) ; 14(16)2022 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-36010853

RESUMO

Stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer (NSCLC) leads to recurrence in approximately 18% of patients. We aimed to extract the radiomic features, with which we predicted clinical outcomes and to establish predictive models. Patients with primary non-metastatic NSCLC who were treated with SBRT between 2002 and 2022 were retrospectively reviewed. The 358 primary tumors were randomly divided into a training cohort of 250 tumors and a validation cohort of 108 tumors. Clinical features and 744 radiomic features derived from primary tumor delineation on pre-treatment computed tomography were examined as prognostic factors of survival outcomes by univariate and multivariate analyses in the training cohort. Predictive models of survival outcomes were established from the results of the multivariate analysis in the training cohort. The selected radiomic features and prediction models were tested in a validation cohort. We found that one radiomic feature showed a significant difference in overall survival (OS) in the validation cohort (p = 0.044) and one predicting model could estimate OS time (mean: 37.8 months) similar to the real OS time (33.7 months). In this study, we identified one radiomic factor and one prediction model that can be widely used.

4.
Commun Biol ; 5(1): 571, 2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35681099

RESUMO

Ribonucleotide reductase (RNR) is composed of two non-identical subunits, R1 and R2, and plays a crucial role in balancing the cellular dNTP pool, establishing it as an attractive cancer target. Herein, we report the discovery of a highly potent and selective small-molecule inhibitor, TAS1553, targeting protein-protein interaction between R1 and R2. TAS1553 is also expected to demonstrate superior selectivity because it does not directly target free radical or a substrate binding site. TAS1553 has shown antiproliferative activity in human cancer cell lines, dramatically reducing the intracellular dATP pool and causing DNA replication stress. Furthermore, we identified SLFN11 as a biomarker that predicts the cytotoxic effect of TAS1553. Oral administration of TAS1553 demonstrated robust antitumor efficacy against both hematological and solid cancer xenograft tumors and also provided a significant survival benefit in an acute myelogenous leukemia model. Our findings strongly support the evaluation of TAS1553 in clinical trials.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Ribonucleotídeo Redutases , Animais , Antineoplásicos/farmacologia , Replicação do DNA , Inibidores Enzimáticos/farmacologia , Humanos , Proteínas Nucleares/metabolismo , Ribonucleotídeo Redutases/antagonistas & inibidores
5.
J Appl Clin Med Phys ; 22(6): 262-267, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34048143

RESUMO

This study aims to investigate the influence of the phantom position on weighted computed tomography dose index (CTDIw ) in cone beam computed tomography (CBCT) when assuming breast irradiation. Computed tomography dose index (CTDI) was measured by the x-ray volume imaging of CBCT using parameters for image-guided radiation therapy (IGRT) in right breast irradiation. The measurement points of CTDI ranged from 0 (center) to 16 cm in the right-left (RL) direction, and from 0 (center) to 7.5 cm in the anterior-posterior (AP) direction, which assumed right breast irradiation. A nonuniform change exists in the relative value of CTDIw when the phantom deviated from the isocenter of CBCT. The CTDIw was ~30% lower compared with the value at the isocenter of CBCT when the phantom deviated 7.5 and 16 cm at the AP and RL directions, respectively. This study confirmed the influence of the phantom position on the CTDI values of CBCT. The CTDI measured at the isocenter of CBCT overestimates that measured at the irradiation center of the breast.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Radioterapia Guiada por Imagem , Humanos , Imagens de Fantasmas , Dosagem Radioterapêutica , Raios X
6.
Cancer Sci ; 112(1): 422-432, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33140501

RESUMO

Deficiency in DNA repair proteins confers susceptibility to DNA damage, making cancer cells vulnerable to various cancer chemotherapies. 5-Fluorouracil (5-FU) is an anticancer nucleoside analog that both inhibits thymidylate synthase (TS) and causes DNA damage via the misincorporation of FdUTP and dUTP into DNA under the conditions of dTTP depletion. However, the role of the DNA damage response to its antitumor activity is still unclear. To determine which DNA repair pathway contributes to DNA damage caused by 5-FU and uracil misincorporation, we examined cancer cells treated with 2'-deoxy-5-fluorouridine (FdUrd) in the presence of TAS-114, a highly potent inhibitor of dUTPase that restricts aberrant base misincorporation. Addition of TAS-114 increased FdUTP and dUTP levels in HeLa cells and facilitated 5-FU and uracil misincorporation into DNA, but did not alter TS inhibition or 5-FU incorporation into RNA. TAS-114 showed synergistic potentiation of FdUrd cytotoxicity and caused aberrant base misincorporation, leading to DNA damage and induced cell death even after short-term exposure to FdUrd. Base excision repair (BER) and homologous recombination (HR) were found to be involved in the DNA repair of 5-FU and uracil misincorporation caused by dUTPase inhibition in genetically modified chicken DT40 cell lines and siRNA-treated HeLa cells. These results suggested that BER and HR are major pathways that protect cells from the antitumor effects of massive incorporation of 5-FU and uracil. Further, dUTPase inhibition has the potential to maximize the antitumor activity of fluoropyrimidines in cancers that are defective in BER or HR.


Assuntos
Reparo do DNA/efeitos dos fármacos , Floxuridina/farmacologia , Pirimidinas/farmacologia , Pirofosfatases/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Galinhas , Dano ao DNA/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Células HeLa , Humanos , Timidilato Sintase/antagonistas & inibidores
7.
Microb Genom ; 5(7)2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31215859

RESUMO

Enterohaemorrhagic Escherichia coli (EHEC) is an important human pathogen worldwide. Although serotype O157 is currently the most dominant and important EHEC strain, serotypes O26, O111, O91, O103 and O121 are also recognized as serious pathogens that affect public health. EHEC outbreaks often occur in nurseries and elderly care facilities. In 2012, a nursery outbreak of EHEC O121 occurred during which the bacterium acquired a plasmid-borne extended-spectrum ß-lactamase (ESBL) gene. ESBL-producing E. coli O86 was concurrently isolated from one of the EHEC patients. Therefore, we investigated the isolates by whole-genome sequence (WGS) analysis to elucidate the transmission dynamics of the EHEC strains and the ESBL plasmid. According to WGS-based phylogeny, all 17 EHEC O121 isolates were clonal, while E. coli O86 was genetically distant from the EHEC O121 isolates. The complete sequence of an ESBL plasmid encoding the CTX-M-55 ß-lactamase was determined using S1-PFGE bands, and subsequent mapping of the WGS reads confirmed that the plasmid sequences from EHEC O121 and E. coli O86 were identical. Furthermore, conjugation experiments showed that the plasmid was capable of conjugative transfer. These results support the hypothesis that EHEC O121 acquired an ESBL-producing plasmid from E. coli O86 during the outbreak. This report demonstrates the importance of implementing preventive measures during EHEC outbreaks to control both secondary infection and the spread of antimicrobial resistance factors.


Assuntos
Surtos de Doenças , Escherichia coli Êntero-Hemorrágica/classificação , Escherichia coli Êntero-Hemorrágica/genética , Infecções por Escherichia coli/epidemiologia , Infecções por Escherichia coli/microbiologia , Proteínas de Escherichia coli/genética , beta-Lactamases/genética , Adulto , Pré-Escolar , Feminino , Humanos , Lactente , Japão , Masculino , Berçários para Lactentes , Filogenia , Plasmídeos
8.
Nihon Hoshasen Gijutsu Gakkai Zasshi ; 73(12): 1238-1243, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-29269619

RESUMO

The purpose of this study was to evaluate the performance of active collimator by changing acquisition parameters and obtaining dose profiles in z-axis direction. Dose profiles along z-axis were obtained using XRQA2 Gafchromic film. As a result, the active collimator reduced overranging about 55% compared to that without the active collimator. In addition, by changing the combination of X-ray beam width (32 mm, 40 mm), pitch factor (1.4, 0.6), and the X-ray tube rotation time (0.5 s/rot, 1.0 s/rot), the overranging changed from 19.4 to 34.9 mm. Although the active collimator is effective for reducing overranging, it is necessary to adjust acquisition parameters by taking the properties of the active collimator for acquisition parameters, especially setting beam width, into consideration.


Assuntos
Tomografia Computadorizada por Raios X/métodos , Doses de Radiação , Tomografia Computadorizada por Raios X/instrumentação
9.
Cancer Chemother Pharmacol ; 80(3): 527-533, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28711984

RESUMO

PURPOSE: Irinotecan (CPT-11) is used to treat advanced colorectal cancer. The drug is activated by carboxylesterases and rendered inactive by CYP3A4. Recently, the efficacy of combining CPT-11 and anti-epidermal growth factor receptor (EGFR) agents was confirmed in patients with KRAS wild-type metastatic colorectal cancer. Clarithromycin (CAM) is a strong CYP3A inhibitor often used to prevent rash associated with anti-EGFR therapy. The objective of this study was to evaluate the risk of increased neutropenia and diarrhea in combining CPT-11 and CAM. METHODS: Retrospective analyses were conducted at Osaka National Hospital (Osaka, Japan) on the records of colorectal cancer patients treated with a CPT-11-containing regimen between November 2006 and January 2014. The incidence of neutropenia and diarrhea was compared between patients who received CPT-11 and CAM and patients who received CPT-11 without CAM. RESULTS: One-hundred and twenty-eight patients were included in this study, of whom 21 were concomitantly treated with CAM and 107 were not. There was no difference in the incidence of grade 3-4 neutropenia between the CAM co-administration group (10%) and the non-CAM group (16%) [Odds ratio: 0.56 (95% confidence interval: 0.12-2.62), p = 0.45]. No difference in the incidence of grade 3-4 diarrhea was found between the CAM co-administration group (0%) and the non-CAM group (4%) (p = 0.37). CONCLUSIONS: This study did not identify an increase in CPT-11 toxicity by co-administration with CAM.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Camptotecina/análogos & derivados , Claritromicina/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/farmacologia , Camptotecina/administração & dosagem , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Claritromicina/administração & dosagem , Claritromicina/farmacologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Sci Total Environ ; 592: 178-186, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28319705

RESUMO

Nitrous acid (HONO) plays an important role in the formation of OH radicals, which are involved in photochemical oxidation. HONO concentrations in ambient air at urban sites have previously been measured, but very few studies have been performed in central Tokyo. In this study, HONO concentrations in ambient air in southeast central Tokyo (near Tokyo Bay) in winter were determined by incoherent cavity enhanced absorption spectroscopy. The O3, NO, NO2, and SO2 concentrations were simultaneously determined. The NO concentrations were used to classify the parts of the study period into types I (high pollution), II (medium pollution), and III (low pollution). The maximum HONO concentrations in the type I, II, and III periods were 7.1, 4.5, and 3.0ppbv, respectively. These concentrations were comparable to concentrations previously found in other Asian megacities. The mean HONO concentration varied diurnally, and HONO was depleted between 00:00 and 03:00 each day. The sampling site is surrounded by roads with high traffic loads, but vehicular emissions were estimated to contribute <10% of the HONO concentrations. Two positive and negative relative humidity dependences of the HONO to NO2 ratio were confirmed, implying the existence of the two different secondary formation process of HONO. The NO2 to HONO conversion rates at night in the type I, II, and III periods were 6.3×10-3, 7.6×10-3, and 4.2×10-3h-1, respectively.


Assuntos
Poluentes Atmosféricos/análise , Ácido Nitroso/análise , Estações do Ano , Emissões de Veículos/análise , Tóquio
11.
Bioorg Med Chem ; 24(14): 3207-17, 2016 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-27255177

RESUMO

Peripherally selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Herein, we describe our medicinal chemistry approach to discover peripheral-selective noradrenaline reuptake inhibitors to avert the risk of P-gp-mediated DDI at the blood-brain barrier. We observed that steric shielding of the hydrogen-bond acceptors and donors (HBA and HBD) of compound 1 reduced the multidrug resistance protein 1 (MDR1) efflux ratio; however, the resulting compound 6, a methoxyacetamide derivative, was mainly metabolized by CYP2D6 and CYP2C19 in the in vitro phenotyping study, implying the risk of PK variability based on the genetic polymorphism of the CYPs. Replacement of the hydrogen atom with a deuterium atom in a strategic, metabolically hot spot led to compound 13, which was mainly metabolized by CYP3A4. To our knowledge, this study represents the first report of the effect of deuterium replacement for a major metabolic enzyme. The compound 13, N-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-[(2H(3))methyloxy]acetamide hydrochloride, which exhibited peripheral NET selective inhibition at tested doses in rats, increased urethral resistance in a dose-dependent manner.


Assuntos
Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos , Inibidores da Captação de Neurotransmissores/síntese química , Ratos , Relação Estrutura-Atividade
12.
Bioorg Med Chem ; 24(16): 3716-26, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27325446

RESUMO

Peripheral-selective inhibition of noradrenaline reuptake is a novel mechanism for the treatment of stress urinary incontinence to overcome adverse effects associated with central action. Here, we describe our medicinal chemistry approach to discover a novel series of highly potent, peripheral-selective, and orally available noradrenaline reuptake inhibitors with a low multidrug resistance protein 1 (MDR1) efflux ratio by cyclization of an amide moiety and introduction of an acidic group. We observed that the MDR1 efflux ratio was correlated with the pKa value of the acidic moiety. The resulting compound 9 exhibited favorable PK profiles, probably because of the effect of intramolecular hydrogen bond, which was supported by a its single-crystal structure. The compound 9, 1-{[(6S,7R)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepan-6-yl]methyl}-2-oxo-1,2-dihydropyridine-3-carboxylic acid hydrochloride, which exhibited peripheral NET-selective inhibition at tested doses in rats by oral administration, increased urethral resistance in a dose-dependent manner.


Assuntos
Inibidores da Captação de Neurotransmissores/química , Inibidores da Captação de Neurotransmissores/farmacologia , Norepinefrina/metabolismo , Animais , Células CHO , Cricetulus , Cristalografia por Raios X , Avaliação Pré-Clínica de Medicamentos , Feminino , Humanos , Ligação de Hidrogênio , Espectrometria de Massas , Estrutura Molecular , Inibidores da Captação de Neurotransmissores/síntese química , Espectroscopia de Prótons por Ressonância Magnética , Ratos , Ratos Sprague-Dawley
13.
Cardiovasc Intervent Radiol ; 39(9): 1343-6, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27164971

RESUMO

There are many treatment options in high-flow priapism. Those mentioned most often are watchful waiting, Doppler-guided compression, endovascular highly selective embolization, and surgery. We present a case of high-flow priapism in a 57-year-old man treated by percutaneous direct puncture embolization of a post-traumatic left cavernosal arteriovenous fistula using N-butyl-cyanoacrylate. Erectile function was preserved during a 12-month follow-up. No patients with percutaneous direct puncture embolization for high-flow priapism have been reported previously. Percutaneous direct puncture embolization is a potentially useful and safe method for management of high-flow priapism.


Assuntos
Fístula Arteriovenosa/terapia , Embolização Terapêutica/métodos , Embucrilato/administração & dosagem , Priapismo/terapia , Angiografia , Fístula Arteriovenosa/complicações , Fístula Arteriovenosa/diagnóstico por imagem , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Pênis/diagnóstico por imagem , Priapismo/complicações , Priapismo/diagnóstico por imagem , Punções , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia , Ferimentos não Penetrantes/complicações
14.
Kansenshogaku Zasshi ; 90(6): 792-7, 2016 Nov.
Artigo em Japonês | MEDLINE | ID: mdl-30277370

RESUMO

In 2013, two outbreaks of enterohemorrhagic Escherichia coli (EHEC) occurred in Saitama city. According to reports from each of the medical institutions that detected the EHEC isolates, the isolates seemed to differ in their production of Vero Toxin (VT / Shiga Toxin: Stx) since one isolate produced only Stx1 and the other produced both Stx1 and Stx2. However, a patient survey conducted by a public health center revealed that common foodstuffs had been consumed in both outbreaks. Because, the two EHEC isolates were newly detected from two people in one patient's family, we analyzed the phenotypic and genetic relationships among four isolates in total. All the isolates were serotyped as O157: H-, and both stx1 and stx2 were detected. Subsequently, all four isolates were shown to have the same pulsed-field gel electrophoresis (PFGE) banding pattern. The findings suggested that these isolates belonged to the same strain group. Among these cases, the isolates had stx2c which is one of the stx2 subtypes. Reportedly, some cases with the Stx2 subtype can not be detected using conventional tests for toxin. In addition, Stx2 can be overlooked as a result of this limitation of Stx-production tests. Both epidemiological research by public health centers and genetic analysis by prefectural and municipal public health institutes (PHIs) are very important for clarifying possible relationships among outbreaks, as in the present cases. Moreover, collaborations and networks among medical institutions, PHIs and public health centers should be further strengthened to prevent the spread of infections.


Assuntos
Proteínas de Bactérias/genética , Surtos de Doenças , Infecções por Escherichia coli/microbiologia , Escherichia coli O157/genética , Toxina Shiga II/genética , Infecções por Escherichia coli/epidemiologia , Feminino , Humanos , Japão , Masculino
15.
Jpn J Infect Dis ; 69(1): 28-32, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-25971326

RESUMO

Vibrio parahaemolyticus is an important pathogen that causes gastroenteritis in humans, generally associated with the consumption of contaminated seafood, particularly raw shellfish. There are many serotypes in V. parahaemolyticus resulting from a combination of O and K antigens. Among them, O3:K6 and their variants, which represent the pandemic clone, are the most widespread strains worldwide. In this study, we examined V. parahaemolyticus isolated from a gastroenteritis patient's stool at a hospital in Saitama City, Japan in 2013. Serotyping of the O and K antigens identified the strain as O10:K60. To our knowledge, this is the first reported case of a V. parahaemolyticus strain with this antigen combination in Japan. Subsequently, we used PCR to assay for pathogenicity-associated genes, and found that it was positive for tdh, T3SS1, and T3SS2α genes. Antibiotic susceptibility tests showed that the strain was susceptible to all selected antibiotics except ampicillin. Moreover, we detected specific marker genes for the pandemic clone with two kinds of PCR assay. Our results suggest that the isolate O10:K60 is a newly emerging serotype that belongs to the pandemic clone.


Assuntos
Gastroenterite/diagnóstico , Gastroenterite/microbiologia , Sorogrupo , Vibrioses/diagnóstico , Vibrioses/microbiologia , Vibrio parahaemolyticus/classificação , Vibrio parahaemolyticus/isolamento & purificação , Adolescente , Antibacterianos/farmacologia , Antígenos de Bactérias/análise , Antígenos de Superfície/análise , Feminino , Humanos , Japão , Testes de Sensibilidade Microbiana , Antígenos O/análise , Reação em Cadeia da Polimerase , Vibrio parahaemolyticus/efeitos dos fármacos , Vibrio parahaemolyticus/genética , Fatores de Virulência/genética
16.
Bioorg Med Chem ; 23(15): 5000-5014, 2015 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26051602

RESUMO

Centrally acting noradrenaline reuptake inhibitor (NRI) is reportedly effective for patients with stress urinary incontinence (SUI) by increasing urethral closure in the clinical Phase IIa study with esreboxetine. Noradrenaline transporters are expressed in both central and peripheral nervous systems and the contribution of each site to efficacy has not been clarified. This report describes the development of a series of peripheral-selective 7-phenyl-1,4-oxazepane NRIs to investigate the contribution of the peripheral site to increasing urethral resistance in rats. (6S,7R)-1,4-Oxazepane derivative 7 exhibited noradrenaline transporter inhibition with high selectivity against inhibitions of serotonin and dopamine transporters. A replacement of hydroxyl with acetamide group contributed to enhancement of peripheral selectivity by increasing molecular polarity. Compound 12, N-{[(6S,7R)-7-(3,4-dichlorophenyl)-1,4-oxazepan-6-yl]methyl}acetamide 0.5 fumarate, which showed effectively no brain penetration in rats, increased urethral resistance in a dose-dependent manner and exhibited a maximal effect on par with esreboxetine. These results demonstrate that the urethral resistance-increasing effects of NRI in rats are mainly caused by the inhibition of noradrenaline transporters in the peripheral sites.


Assuntos
Desenho de Fármacos , Compostos Heterocíclicos/química , Inibidores da Recaptação de Serotonina e Norepinefrina/síntese química , Animais , Córtex Cerebral/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/uso terapêutico , Humanos , Conformação Molecular , Morfolinas/uso terapêutico , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/química , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas da Membrana Plasmática de Transporte de Serotonina/química , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Inibidores da Recaptação de Serotonina e Norepinefrina/química , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Estereoisomerismo , Relação Estrutura-Atividade , Incontinência Urinária por Estresse/tratamento farmacológico
17.
Int J Oncol ; 46(6): 2327-34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25901475

RESUMO

Trifluridine (FTD) and 2'-deoxy-5-fluorouridine (FdUrd), a derivative of 5-fluorouracil (5-FU), are antitumor agents that inhibit thymidylate synthase activity and their nucleotides are incorporated into DNA. However, it is evident that several differences occur in the underlying antitumor mechanisms associated with these nucleoside analogues. Recently, TAS-102 (composed of FTD and tipiracil hydrochloride, TPI) was shown to prolong the survival of patients with colorectal cancer who received a median of 2 prior therapies, including 5-FU. TAS-102 was recently approved for clinical use in Japan. These data suggest that the antitumor activities of TAS-102 and 5-FU proceed via different mechanisms. Thus, we analyzed their properties in terms of thymidine salvage pathway utilization, involving membrane transporters, a nucleoside kinase, a nucleotide-dephosphorylating enzyme, and DNA polymerase α. FTD incorporated into DNA with higher efficiency than FdUrd did. Both FTD and FdUrd were transported into cells by ENT1 and ENT2 and were phosphorylated by thymidine kinase 1, which showed a higher catalytic activity for FTD than for FdUrd. deoxyUTPase (DUT) did not recognize dTTP and FTD-triphosphate (F3dTTP), whereas deoxyuridine-triphosphate (dUTP) and FdUrd-triphosphate (FdUTP) were efficiently degraded by DUT. DNA polymerase α incorporated both F3dTTP and FdUTP into DNA at sites aligned with adenine on the opposite strand. FTD-treated cells showed differing nuclear morphologies compared to FdUrd-treated cells. These findings indicate that FTD and FdUrd are incorporated into DNA with different efficiencies due to differences in the substrate specificities of TK1 and DUT, causing abundant FTD incorporation into DNA.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Neoplasias Colorretais/genética , DNA de Neoplasias/química , Fluoruracila/farmacologia , Timidina Quinase/metabolismo , Trifluridina/farmacologia , Uracila/análogos & derivados , Antimetabólitos Antineoplásicos/farmacocinética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Combinação de Medicamentos , Transportador Equilibrativo 1 de Nucleosídeo/metabolismo , Transportador Equilibrativo 2 de Nucleosídeo/metabolismo , Fluoruracila/farmacocinética , Células HCT116 , Humanos , Masculino , Pirofosfatases/metabolismo , Pirrolidinas , Especificidade por Substrato , Timina , Trifluridina/farmacocinética , Uracila/farmacocinética , Uracila/farmacologia
18.
Cancer Chemother Pharmacol ; 75(2): 273-9, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25432775

RESUMO

BACKGROUND: Irinotecan (CPT-11), a highly effective chemotherapeutic agent, can cause severe neutropenia and diarrhea. The area under the curve of plasma levels over time of SN-38, an active metabolite of CPT-11, was previously reported to correlate with the pre-treatment serum total bilirubin level (PTB). However, there are no established criteria for selecting CPT-11 dose on the basis of PTB. Therefore, we evaluated PTB as an indicator for the optimal CPT-11 dose. METHODS: Retrospective analyses were conducted in patients administered CPT-11 as a single agent at the Osaka National Hospital from June 2006 to July 2013. Data obtained during the first 28 days following CPT-11 administration were analyzed to compare PTB between patients with and without grade 3-4 neutropenia and grade 3-4 diarrhea. Receiver operating characteristics (ROC) curve analysis was performed to determine the optimal PTB cutoff value for PTB-associated toxicity. Subgroup analysis was performed comparing the incidence of toxicity in patients with PTB values below or above the cutoff value. RESULTS: Although PTB incidence was significantly higher in patients who developed grade 3-4 neutropenia than in those who did not, PTB was not associated with grade 3-4 diarrhea. The PTB cutoff value for association with grade 3-4 neutropenia occurrence was set at 0.8 mg/dL. The incidence of febrile neutropenia (FN) significantly elevated to 21% in patients with PTB ≥0.8 mg/dL, whereas that of patients with PTB <0.8 mg/dL was 4%. In the subgroup analysis, no difference was found in the neutropenia incidence between patients treated with a dose below 80 mg/m(2) and those treated on a weekly schedule. CONCLUSIONS: PTB can be used as a predictive marker of CPT-11-induced severe neutropenia and FN. In patients with PTB ≥0.8 mg/dL, the CPT-11 dose should be reduced to less than 80 mg/m(2) with weekly dosing.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/uso terapêutico , Bilirrubina/sangue , Biomarcadores/sangue , Camptotecina/análogos & derivados , Neoplasias/tratamento farmacológico , Neoplasias/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Fitogênicos/efeitos adversos , Camptotecina/administração & dosagem , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Feminino , Genótipo , Glucuronosiltransferase/genética , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Valor Preditivo dos Testes , Estudos Retrospectivos
19.
Kansenshogaku Zasshi ; 88(4): 430-7, 2014 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-25199376

RESUMO

A Shiga toxin 2 producing enterohemorrhagic Escherichia coli (EHEC) O121: H19 was isolated from a 2-year-old child who attending a nursery. An EHEC O121 outbreak in two nurseries (A, B), involving a total of 17 infected persons including 12 children, was revealed through contact investigation. The symptoms of all infected persons were almost all mild, and no one developed the hemolytic uremic syndrome. The combination use of desoxycholate-hydrogen sulfide-lactose (DHL) and CHROMagar STEC as selective isolation media was employed for efficient fecal examination. Nursery A and nursery B were combined as one group after the outbreak in nursery A was confirmed. As a result, EHEC O121 infected persons were also detected in children from nursery B. The 17 strains of EHEC O121 obtained from the total population showed almost the same pulsed-gel electrophoresis (PFGE) pattern, suggesting that these strains were very closely related. However, 13 of these 17 strains obtained from nursery A were susceptible to cefotaxime, whereas the remaining 4 strains obtained from nursery B showed cefotaxime resistance. A cefotaxime resistant Escherichia coli (E. coli) O86 strain was isolated in the stool specimen from a child who had been infected with the cefotaxime resistant EHEC O121. Both the cefotaxime resistant EHEC O121 and E. coli O86 had the same drug resistant gene (bla(CTX-M-1) group). The child was the index case of these 4 later cases and had received no antibiotics therapy prior to the laboratory examination. These findings suggested the possibility that an EHEC O121 strain had acquired a drug resistant gene from E. coli O86 in the digestive tract of the child.


Assuntos
Antibacterianos/uso terapêutico , Cefotaxima/uso terapêutico , Surtos de Doenças/prevenção & controle , Infecções por Escherichia coli/tratamento farmacológico , Escherichia coli/isolamento & purificação , Pré-Escolar , Suscetibilidade a Doenças , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/diagnóstico , Fezes/microbiologia , Feminino , Humanos , Masculino , Berçários para Lactentes
20.
Gan To Kagaku Ryoho ; 41(2): 211-4, 2014 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-24743199

RESUMO

In Europe and the United States, beginning steroid treatment on the day before docetaxel(DTX)administration is recommended to reduce edema and/or hypersensitivity symptoms. In this study, we investigated the usefulness of starting steroid treatment on the day before DTX administration. Patients with breast cancer who received 4 or more cycles of DTX with or without trastuzumab or DTX and cyclophosphamide(TC)with or without trastuzumab as pre- or post-operative chemotherapy in our hospital between January 2010 and May 2012 were analyzed in this retrospective study. Patients were classified as those who started taking steroids on the day of DTX administration(GroupA: 62 patients)and those who started taking steroids on the day before DTX administration(GroupB: 47 patients). The incidence of edema and/or hypersensitivity was retrospectively compared between these groups after the completion of 4 cycles of chemotherapy. The incidence of edema was significantly lower in GroupB (n=12, 25.5%)than in GroupA (n=28, 45.2%; p=0.04). The onset of edema also tended to be later in GroupB. The incidence of hypersensitivity tended to be lower in GroupB(n=3, 6.4%)than in GroupA (n=8, 12.9%), although this difference was not statistically significant. These results suggest the benefit of steroid treatment started on the day before DTX administration in preventing the development of edema. Results also suggest that the onset of edema could be delayed by this administration method. We recommend that steroid premedication, which can lead to a reduction in adverse drug reactions to DTX, be used to help maintain patients' quality of life(QOL)and to support treatment continuation.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Dexametasona/efeitos adversos , Edema/prevenção & controle , Esteroides/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/administração & dosagem , Dexametasona/administração & dosagem , Edema/induzido quimicamente , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Trastuzumab , Resultado do Tratamento
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