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1.
BMC Pulm Med ; 23(1): 312, 2023 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-37641057

RESUMO

BACKGROUND: During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. METHODS: This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. RESULTS: The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. CONCLUSIONS: We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.


Assuntos
COVID-19 , Diabetes Mellitus , Humanos , Masculino , Idoso , COVID-19/epidemiologia , Estudos Retrospectivos , Progressão da Doença , Diabetes Mellitus/epidemiologia , Obesidade/epidemiologia
2.
Gan To Kagaku Ryoho ; 50(8): 909-912, 2023 Aug.
Artigo em Japonês | MEDLINE | ID: mdl-37608419

RESUMO

A 79-year-old man was diagnosed with esophagogastric junction adenocarcinoma, cT3N3M0, cStage Ⅲ, including enlarged lymph node metastases(Bulky N)in the middle mediastinum and intraperitoneal. A total of 2 cycles of S-1 plus oxaliplatin(SOX)was administered. After neoadjuvant chemotherapy, the primary tumor and enlarged lymph nodes had greatly decreased in size. Subsequently, thoracoscopic subtotal esophagectomy and reconstruction with a gastric tube were performed. Histopathological examinations showed no residual cancer cells in the primary lesion and dissected lymph nodes (pathological complete response). Preoperative chemotherapy containing SOX could be a useful treatment strategy for patients with esophagogastric junction adenocarcinoma with enlarged lymph node metastasis.


Assuntos
Adenocarcinoma , Linfadenopatia , Masculino , Humanos , Idoso , Metástase Linfática , Terapia Neoadjuvante , Mediastino/cirurgia , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/cirurgia , Junção Esofagogástrica/cirurgia
3.
Int J Med Sci ; 19(5): 834-841, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35693744

RESUMO

Background: Mutations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may reduce the efficacy of neutralizing monoclonal antibody therapy against coronavirus disease 2019 (COVID-19). We here evaluated the efficacy of casirivimab-imdevimab in patients with mild-to-moderate COVID-19 during the Delta variant surge in Fukushima Prefecture, Japan. Methods: We enrolled 949 patients with mild-to-moderate COVID-19 who were admitted to hospital between July 24, 2021 and September 30, 2021. Clinical deterioration after admission was compared between casirivimab-imdevimab users (n = 314) and non-users (n = 635). Results: The casirivimab-imdevimab users were older (P < 0.0001), had higher body temperature (≥ 38°C) (P < 0.0001) and greater rates of history of cigarette smoking (P = 0.0068), hypertension (P = 0.0004), obesity (P < 0.0001), and dyslipidemia (P < 0.0001) than the non-users. Multivariate logistic regression analysis demonstrated that receiving casirivimab-imdevimab was an independent factor for preventing deterioration (odds ratio 0.448; 95% confidence interval 0.263-0.763; P = 0.0023). Furthermore, in 222 patients who were selected from each group after matching on the propensity score, deterioration was significantly lower among those receiving casirivimab-imdevimab compared to those not receiving casirivimab-imdevimab (7.66% vs 14.0%; p = 0.021). Conclusion: This real-world study demonstrates that casirivimab-imdevimab contributes to the prevention of deterioration in COVID-19 patients after hospitalization during a Delta variant surge.


Assuntos
Tratamento Farmacológico da COVID-19 , Pandemias , Anticorpos Monoclonais Humanizados , Humanos , SARS-CoV-2 , Resultado do Tratamento
4.
Cancer Sci ; 111(7): 2570-2578, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32350988

RESUMO

Using surgically resected tissue, we identified characteristic metabolites related to the diagnosis and malignant status of clear cell renal cell carcinoma (ccRCC). Specifically, we quantified these metabolites in urine samples to evaluate their potential as clinically useful noninvasive biomarkers of ccRCC. Between January 2016 and August 2018, we collected urine samples from 87 patients who had pathologically diagnosed ccRCC and from 60 controls who were patients with benign urological conditions. Metabolite concentrations in urine samples were investigated using liquid chromatography-mass spectrometry with an internal standard and adjustment based on urinary creatinine levels. We analyzed the association between metabolite concentration and predictability of diagnosis and of malignant status by multiple logistic regression and receiver operating characteristic (ROC) curves to establish ccRCC predictive models. Of the 47 metabolites identified in our previous study, we quantified 33 metabolites in the urine samples. Multiple logistic regression analysis revealed 5 metabolites (l-glutamic acid, lactate, d-sedoheptulose 7-phosphate, 2-hydroxyglutarate, and myoinositol) for a diagnostic predictive model and 4 metabolites (l-kynurenine, l-glutamine, fructose 6-phosphate, and butyrylcarnitine) for a predictive model for clinical stage III/IV. The sensitivity and specificity of the diagnostic predictive model were 93.1% and 95.0%, respectively, yielding an area under the ROC curve (AUC) of 0.966. The sensitivity and specificity of the predictive model for clinical stage were 88.5% and 75.4%, respectively, with an AUC of 0.837. In conclusion, quantitative analysis of urinary metabolites yielded predictive models for diagnosis and malignant status of ccRCC. Urinary metabolites have the potential to be clinically useful noninvasive biomarkers of ccRCC to improve patient outcomes.


Assuntos
Biomarcadores Tumorais , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/urina , Neoplasias Renais/diagnóstico , Neoplasias Renais/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Cromatografia Líquida , Comorbidade , Feminino , Humanos , Masculino , Metaboloma , Metabolômica/métodos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem
5.
J Infect Chemother ; 26(1): 132-135, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31350185

RESUMO

Aspergillosis is a rare fungal infection in newborns, and its morbidity and mortality are high. Voriconazole (VRCZ) is the first-line antifungal agent for invasive Aspergillus infection, but little data is available about its pharmacokinetics in infants. We report a case of a premature infant who developed ventriculitis due to Aspergillus fumigatus and received combination antifungal therapy including VRCZ. ß-D glucan and Aspergillus antigen index were elevated in the cerebrospinal fluid (CSF). We titrated the dose of VRCZ by monitoring plasma and CSF concentrations. The CSF to plasma concentration ratio of VRCZ ranged from 0.47 to 1.36 (median 0.71). While VRCZ adequately penetrates the blood-brain barrier, its concentration is highly variable in infants.


Assuntos
Antifúngicos , Aspergillus fumigatus , Ventriculite Cerebral/tratamento farmacológico , Neuroaspergilose/tratamento farmacológico , Voriconazol , Antifúngicos/sangue , Antifúngicos/líquido cefalorraquidiano , Antifúngicos/uso terapêutico , Monitoramento de Medicamentos , Humanos , Recém-Nascido , Masculino , Voriconazol/sangue , Voriconazol/líquido cefalorraquidiano , Voriconazol/uso terapêutico
6.
Endocr J ; 67(8): 841-852, 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32378529

RESUMO

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11ß-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.


Assuntos
Síndrome de Cushing/tratamento farmacológico , Imidazóis/uso terapêutico , Piridinas/uso terapêutico , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Imidazóis/administração & dosagem , Japão , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Piridinas/administração & dosagem , Resultado do Tratamento , Adulto Jovem
7.
Tohoku J Exp Med ; 252(1): 1-8, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32814720

RESUMO

Carbohydrate antigens are associated with carcinogenesis, cancer invasion, and metastasis and their expression reflect biological activities of various cancers. We previously reported that expression of disialosyl globopentaosyl ceramide (DSGb5), one of carbohydrate antigens, in radical prostatectomy specimens independently predicted biochemical recurrence (i.e., elevating serum prostate specific antigen without recurrent lesions in the image) after radical prostatectomy. However, it is important to evaluate the prognosis at the diagnosis. In this study we investigated DSGb5 expression in prostate biopsy specimens to develop a novel biomarker for providing appropriate management. Between 2005 and 2011, patients who underwent both prostate biopsy and radical prostatectomy in our institution were included. The median follow-up period was 88 months. DSGb5 expression was assessed by immunohistochemical staining and defined 116 patients as high DSGb5 expression (42 patients) or low DSGb5 expression (74 patients). High DSGb5 expression was significantly associated with lymphovascular invasion in radical prostatectomy specimens on both univariate and multivariable analyses (p = 0.028, 0.027). On multivariable analysis, Gleason Score in prostatectomy specimen, positive resection margin, and DSGb5 expression in the biopsy specimen were independently associated with biochemical recurrence-free survival following radical prostatectomy (p = 0.004, 0.008, 0.024). When targeting only patients with negative resection margin, DSGb5 expression was significantly associated with biochemical recurrence-free survival on both univariate and multivariable analyses (p = 0.006, 0.007). DSGb5 expression in prostate biopsy specimens is predictive of lymphovascular invasion and biochemical recurrence-free survival following radical prostatectomy. DSGb5 is a potential biomarker for preoperatively predicting oncological outcomes of prostate cancer.


Assuntos
Biomarcadores Tumorais/metabolismo , Globosídeos/metabolismo , Recidiva Local de Neoplasia/patologia , Próstata/metabolismo , Próstata/patologia , Prostatectomia , Idoso , Biópsia , Intervalo Livre de Doença , Humanos , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Próstata/cirurgia
8.
Arch Virol ; 164(8): 2179-2182, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31111258

RESUMO

We identified two novel circoviruses, HK02976 and HK00220, in oral swabs from bats. The size of their full genome was 2,010 nucleotides (nt). The full-genome sequence of our strains shared 96.1% nucleotide sequence identity with each other, and 39.9%-69.5% identity with bat-associated circoviruses (BatACVs)1-9. Based on the species demarcation threshold for viruses of the family Circoviridae, which is 80% genome-wide nucleotide sequence identity, we have tentatively named this group of viruses "bat-associated circovirus 10" (BatACV10).


Assuntos
Quirópteros/virologia , Circovirus/genética , Animais , Sequência de Bases/genética , Infecções por Circoviridae/virologia , Variação Genética/genética , Genoma Viral/genética , Japão , Fases de Leitura Aberta/genética , Filogenia
10.
Hinyokika Kiyo ; 64(2): 75-78, 2018 Feb.
Artigo em Japonês | MEDLINE | ID: mdl-29684954

RESUMO

A 59-year-old man presented with pain and swelling of the right scrotum. Magnetic resonance imaging revealed a mass withsignal intensity similar to background on an apparent diffusion coefficient (ADC)-map of the upper region of the right testis. Inflammation was considered, but a testicular tumor could not be ruled out. Right high orchidectomy and histopathological assessment revealed granulomatous orchitis. The cause, clinical course and treatment of rare granulomatous orchitis remain unknown. Granulomatous orchitis and testicular tumor are difficult to discriminate, and high orchidectomy is usually applied along with histopathological assessment to achieve a definitive diagnosis. On the other hand, some patients who were only medically treated for granulomatous orchitis have recovered. We recently found that diffusionweighted imaging and ADC values derived from magnetic resonance images can differentiate testicular tumor from orchitis. We suggest an algorithm for the diagnosis and treatment of granulomatous orchitis considering the present patient and previous reports.


Assuntos
Orquite/etiologia , Neoplasias Testiculares/complicações , Diferenciação Celular , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Orquiectomia , Orquite/diagnóstico por imagem , Orquite/patologia , Orquite/cirurgia , Neoplasias Testiculares/diagnóstico por imagem , Neoplasias Testiculares/patologia , Neoplasias Testiculares/cirurgia
11.
Int J Clin Pharmacol Ther ; 55(10): 798-806, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28766497

RESUMO

OBJECTIVES: Acid-reducing agents (ARAs) may affect drug exposure for orally-administered drugs exhibiting pH-dependent solubility. The aim of this research was to investigate factors predicting the effect of ARAs on drug exposure. Dose (mg)/250 mL/solubility at neutral pH and ratio of solubility at acidic pH to that at neutral pH were investigated as potential factors. MATERIALS AND METHODS: Drug-drug interaction (DDI) study results with ARAs were selected based on PubMed search from 2007 to 2016 and novel drug approvals at the US Food and Drug Administration (FDA) from 2014 to 2016. For the selected drugs, solubility data at acidic and neutral pH were obtained from publications, FDA and European Medicines Agency (EMA) review report, and Japanese interview form. RESULTS: 32 DDI study results with ARAs from 27 drugs having solubility data were obtained. The effect of ARAs on the Cmax or AUC ratio% (with/without ARAs) decreased with the increasing values of both factors, but the ratio of solubility showed higher values of squared correlation coefficient R2 (0.75 - 0.78) than the dose (mg)/250 mL/solubility at neutral pH (0.48 - 0.59). CONCLUSION: Ratio of solubility at acidic pH to that at neutral pH was a good predictor to estimate the effect of ARAs on drug exposure. Prediction of the effect of ARAs on drug exposure using solubility data would help to consider the necessity and timing for conducting a dedicated DDI study with ARAs and contribute to efficient drug development.
.


Assuntos
Secreções Corporais/efeitos dos fármacos , Interações Medicamentosas , Preparações Farmacêuticas/administração & dosagem , Substâncias Redutoras/uso terapêutico , Administração Oral , Descoberta de Drogas/métodos , Humanos , Concentração de Íons de Hidrogênio , Solubilidade , Estados Unidos , United States Food and Drug Administration
12.
Hinyokika Kiyo ; 63(12): 515-520, 2017 Dec.
Artigo em Japonês | MEDLINE | ID: mdl-29370662

RESUMO

Prostate cancer patients with initial PSA 100 ng/ml or greater who received transrectal ultrasoundguided prostate biopsy and were staged as M0 by imaging studies from 2011 to 2014 in seven hospitals, were enrolled in the study. Castration-resistant prostate cancer (CRPC)-free survival was compared between the two treatment groups : androgen deprivation therapy (ADT) alone and ADT plus local therapy. Of 142 prostate cancer patients with initial PSA 100 ng/ml or greater, 49 (34.5%) had no metastases and final analysis was performed on 46 patients. Thirty one M0 patients received ADT alone, and 15 received ADT plus local therapy. During follow-up (median 31 months, range 1-56 months) 13 patients (42%) in the ADT alone group progressed to CRPC. One- and two-year CRPC-free survival rates were 72.5 and 53%, respectively. No patients with ADT plus local therapy developed CRPC, and time to CRPC was prolonged significantly (p=0.002). On multivariate analysis for the group with ADT alone, PSA nadir of more than 0. 2 ng/ml and cN1 were independent predictors for progression to CRPC (p=0.009, 0.031). About one third of prostate cancer patients with initial PSA 100 ng/ml or greater had clinically no metastases. Local therapy to prostate combined with ADT may prolong time to CRPC compared with ADT alone. A subset of men with a PSA nadir of more than 0.2 ng/ml after ADT and cN1 could benefit from local therapy.


Assuntos
Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/terapia , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias de Próstata Resistentes à Castração/diagnóstico , Estudos Retrospectivos , Resultado do Tratamento
13.
Nihon Hinyokika Gakkai Zasshi ; 108(2): 64-68, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-29669978

RESUMO

(Objectives) To evaluate the outcomes of patients who were surgically treated for retroperitoneal liposarcoma in our hospital from February 2002 to August 2015. (Methods) Fifteen patients were surgically treated for retroperitoneal liposarcoma in our hospital during the study period. All patients were diagnosed with liposarcoma on pathological examination. The mean follow-up period was 46.7 months (range, 1-126 months). (Results) There was no difference in the sex distribution of the patients (7 men and 8 women). The median age was 67 years (range, 33-78 years). The median tumor diameter was 24 cm (range, 7.5-45 cm) and the median tumor weight was 1,959 g (range, 545-15,400 g). One patient's operation was unsuccessful, with incomplete tumor resection. The surgical margin was positive in two patients. The 5- and 10-year survival rates were 67% and 50%, respectively. There was a significant difference in the survival rate between complete resection and incomplete resection, including surgical margin-positive patients (p=0.0019). Moreover, there was a significant difference in the recurrence-free rate between complete resection and surgical margin-positive patients (p=0.013). There was no significant difference according to whether removal of the tumor with adjacent viscera or removal of the tumor only had been performed (p=0.09 and 0.90, respectively). (Conclusions) Surgery is the mainstay of treatment for retroperitoneal liposarcoma, and complete resection is necessary.

14.
Bioorg Med Chem ; 24(4): 759-67, 2016 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-26795112

RESUMO

Raloxifene, a selective estrogen receptor modulator (SERM), reduces fracture risk at least in part by improving the mechanical properties of bone in a cell- and estrogen receptor-independent manner. In this study, we determined that raloxifene directly interacts with the bone tissue. Through the use of multiple and complementary biophysical techniques including nuclear magnetic resonance (NMR) and Fourier transform infrared spectroscopy (FTIR), we show that raloxifene interacts specifically with the organic component or the organic/mineral composite, and not with hydroxyapatite. Structure-activity studies reveal that the basic side chain of raloxifene is an instrumental determinant in the interaction with bone. Thus, truncation of portions of the side chain reduces bone binding and also diminishes the increase in mechanical properties. Our results support a model wherein the piperidine interacts with bone matrix through electrostatic interactions with the piperidine nitrogen and through hydrophobic interactions (van der Waals) with the aliphatic groups in the side chain and the benzothiophene core. Furthermore, in silico prediction of the potential binding sites on the surface of collagen revealed the presence of a groove with sufficient space to accommodate raloxifene analogs. The hydroxyl groups on the benzothiophene nucleus, which are necessary for binding of SERMs to the estrogen receptor, are not required for binding to the bone surface, but mediate a more robust binding of the compound to the bone powder. In conclusion, we report herein a novel property of raloxifene analogs that allows them to interact with the bone tissue through potential contacts with the organic matrix and in particular collagen.


Assuntos
Matriz Óssea/efeitos dos fármacos , Colágeno/metabolismo , Fêmur/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Animais , Matriz Óssea/metabolismo , Colágeno/química , Cães , Durapatita/química , Fêmur/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Masculino , Piperidinas/química , Polilisina/química , Polilisina/metabolismo , Ligação Proteica , Cloridrato de Raloxifeno/metabolismo , Receptores de Estrogênio/metabolismo , Eletricidade Estática , Relação Estrutura-Atividade , Tiofenos/química
15.
Hinyokika Kiyo ; 62(6): 313-6, 2016 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-27452494

RESUMO

The patient was a 47 year-old female who had autosomal dominant polycystic kidney disease (ADPKD) with bilateral small renal cell carcinoma (RCC). We performed bilateral partial nephrectomy and radiofrequency ablation to the residual tumor. Pathological diagnosis was clear cell carcinoma,Fuhrman grade 3. Sunitinib therapy was started nine months after the operation because multiple liver metastases occurred. Twenty-six months after the operation,she died from rapid progression of liver metastasis.


Assuntos
Carcinoma de Células Renais/complicações , Neoplasias Renais/complicações , Rim Policístico Autossômico Dominante/complicações , Carcinoma de Células Renais/cirurgia , Ablação por Cateter , Evolução Fatal , Feminino , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Pessoa de Meia-Idade , Nefrectomia , Cuidados Paliativos , Rim Policístico Autossômico Dominante/cirurgia
16.
Int J Clin Pharmacol Ther ; 53(11): 955-62, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26365336

RESUMO

OBJECTIVES: The aim of the present study is to investigate factors affecting intrasubject variability of pharmacokinetic (PK) exposure, which affect the results of bioequivalence (BE) studies. We focused on two factors: absolute oral bioavailability (BA) and acidic nature of drugs. METHODS: Intrasubject coefficient of variation (CV) for Cmax and AUC was estimated based on the 90% confidence intervals (CIs) and the number of subjects from fasting BE study results for our investigation. Relationships between the intrasubject CV and the absolute oral BA as well as the acidic nature of the drugs were investigated. RESULTS: First, the relationship between absolute oral BA and intrasubject variability of PK exposure (Cmax and AUC) showed negative log-linear relationship in the BE studies following oral administration of 65 immediate-release drugs under fasted condition. Drugs with poor absolute oral BA of less than 5% showed high intrasubject CV in the range of 30-65%. In contrast, drugs with high absolute oral BA of more than 80% showed low intrasubject CV of less than 20%. Second, acidic drugs with pKa<6 had higher intrasubject CV of Cmax than AUC compared to other types of drugs. The intrasubject CV ratios of Cmax to AUC for acidic drugs with pKa<6 were significantly higher than those for other types of drugs. CONCLUSION: Results show that absolute oral BA is one of the major factors that predict the extent of intrasubject variability of PK exposure. Acidic nature of drugs is thought to be an additional factor increasing intrasubject variability of Cmax as compared to AUC.


Assuntos
Modelos Biológicos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Humanos , Concentração de Íons de Hidrogênio , Modelos Lineares , Preparações Farmacêuticas/química , Solubilidade
17.
Nihon Hinyokika Gakkai Zasshi ; 106(1): 53-8, 2015 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-26399133

RESUMO

A 44-year-old man discovered a swollen right testis more than 4 years earlier. He was brought to our hospital because of abdominal pain and vomiting. Enhanced computed tomography (CT) showed a swollen right testis, lung nodules, and swollen retroperitoneal and mediastinal lymph nodes. The swollen lymph nodes compressed the duodenum, causing ileus. HCG, HCG-ß, and AFP levels were normal, but the LDH level was high (2,933 IU/L). A diagnosis of testicular cancer with lung and lymph node metastases was made, and a right orchidectomy was performed. However, the pathological diagnosis was unclear, and it was necessary to consult another pathologist, but this took .6 weeks. While awaiting the pathological diagnosis, the patient was given chemotherapy with two 3-week courses of BEP. On pathological examination, the tumor consisted of small round cells with a rosette-like arrangement. Cartilage and keratinized tissues were also present. Immunohistochemical staining was positive for CD56, synaptophysin, vimentin, GFAP, and CD99 (MIC2), but negative for AE1/AE3, OCT-4, chromogranin, INI-1, and desmin. The patient was then diagnosed as having a primitive neuroectodermal tumor and teratoma. The metastatic lymph nodes decreased in size after chemotherapy; therefore, two further courses of BEP were added. However, CT showed disease progression. The patient refused further therapy and returned home. Eight months later, he was hospitalized because of swollen retroperitoneal and mediastinal lymph nodes and ileus. Despite treatment with radiation therapy, which resulted in decreased lymph nodes, the patient died. This was a very rare case, the first such case in Japan.


Assuntos
Tumores Neuroectodérmicos Primitivos/terapia , Neoplasias Testiculares/terapia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Evolução Fatal , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/secundário , Metástase Linfática , Masculino , Tumores Neuroectodérmicos Primitivos/secundário , Orquiectomia , Neoplasias Testiculares/patologia
18.
Cancer Sci ; 105(3): 347-53, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24405565

RESUMO

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, ß, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.


Assuntos
Aminopiridinas/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Morfolinas/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase , Adulto , Idoso , Aminopiridinas/efeitos adversos , Aminopiridinas/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Área Sob a Curva , Carcinoma de Células Escamosas/patologia , Neoplasias Colorretais/patologia , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Japão , Metástase Linfática , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Morfolinas/efeitos adversos , Morfolinas/farmacocinética , Resultado do Tratamento , Adulto Jovem
19.
Pathol Res Pract ; 260: 155379, 2024 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-38850876

RESUMO

Prostate cancer is one of the most common malignancies in men, and there is a need to explore novel biomarkers or therapeutic targets. Toll-like receptor 4 (TLR4) is expressed not only in antigen-presenting cells but also types of human malignancies, contributing to disease progression, although its clinical significance or functional role in prostate cancer remains unclear. Therefore, we immunolocalized TLR4 in 117 prostate cancer tissues to address its clinicopathological significance. Additionally, we performed in vitro assays to examine the effects of TLR4 on proliferation and migration of prostate cancer cell lines (LNCaP, DU-145 and PC-3). TLR4 immunoreactivity was predominantly detected in the cytoplasm of prostate cancer cells, and it was positively associated with proliferation and invasion abilities, as well as Gleason score. Subsequent in vitro experiments revealed that the inhibition of TLR4 by Sparstolonin B (SsnB) significantly suppressed the proliferation and migration of LNCaP, DU-145 and PC-3 cells. Therefore, we concluded that TLR4 was a potent prognostic factor associated with proliferation and invasion, and it might serve as a therapeutic target in prostate cancer.

20.
Nat Commun ; 15(1): 3493, 2024 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-38684653

RESUMO

Extraterrestrial minerals on the surface of airless Solar System bodies undergo gradual alteration processes known as space weathering over long periods of time. The signatures of space weathering help us understand the phenomena occurring in the Solar System. However, meteorites rarely retain the signatures, making it impossible to study the space weathering processes precisely. Here, we examine samples retrieved from the asteroid Ryugu by the Hayabusa2 spacecraft and discover the presence of nonmagnetic framboids through electron holography measurements that can visualize magnetic flux. Magnetite particles, which normally provide a record of the nebular magnetic field, have lost their magnetic properties by reduction via a high-velocity (>5 km s-1) impact of a micrometeoroid with a diameter ranging from 2 to 20 µm after destruction of the parent body of Ryugu. Around these particles, thousands of metallic-iron nanoparticles with a vortex magnetic domain structure, which could have recorded a magnetic field in the impact event, are found. Through measuring the remanent magnetization of the iron nanoparticles, future studies are expected to elucidate the nature of the nebular/interplanetary magnetic fields after the termination of aqueous alteration in an asteroid.

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