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1.
Int Heart J ; 61(2): 254-262, 2020 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-32173714

RESUMO

The effect of post-cardiac arrest care in children with out-of-hospital cardiac arrest (OHCA) has not been adequately established, and the long-term outcome after pediatric OHCA has not been sufficiently investigated. We describe here detailed in-hospital characteristics, actual management, and survival, including neurological status, 90 days after OHCA occurrence in children with OHCA transported to critical care medical centers (CCMCs).We analyzed the database of the Comprehensive Registry of Intensive Care for OHCA Survival (CRITICAL) study, which is a multicenter, prospective observational data registry designed to accumulate both pre- and in-hospital data on OHCA treatments. We enrolled all consecutive pediatric patients aged <18 years who had an OHCA and for whom resuscitation was attempted and who were transported to CCMCs between 2012 and 2016.A total of 263 pediatric patients with OHCA were enrolled. The average age of the patients was 6.3 years, 38.0% were aged < 1 year, and 60.8% were male. After hospital arrival, 4.9% of these pediatric patients received defibrillation; 1.9%, extracorporeal life support; 6.5%, target temperature management; and 88.2% adrenaline administration. The proportions of patients with 90-day survival and a pediatric cerebral performance category (PCPC) score of 1 or 2 were 6.1% and 1.9%, respectively. The proportion of patients with a PCPC score of 1 or 2 at 90 days after OHCA occurrence did not significantly improve during the study period.The proportion of pediatric patients with a 90-day PCPC score of 1 or 2 transported to CCMCs was extremely low, and no significant improvements were observed during the study period.

3.
Geriatr Gerontol Int ; 19(11): 1088-1095, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31622019

RESUMO

AIM: The purpose of this study was to evaluate the out-of-hospital cardiac arrest (OHCA) characteristics of patients stratified by age who had resuscitation attempted and were transported to tertiary emergency medical institutions in Osaka Prefecture, Japan; especially those of advanced age. METHODS: A prospective, population-based, observational review was carried out of consecutive OHCA patients with emergency responder resuscitation attempts from July 2012 to December 2016 in Osaka, Japan. Patients were classified into four groups: (i) 18-64 years; (ii) 65-74 years; (iii) 75-84 years; and (iv) ≥85 years. Patient, event and treatment characteristics were examined for patients with presumed cardiac etiology of OHCA. The primary outcome was the 1-month survival with a neurologically favorable outcome. RESULTS: A total of 4636 patients with OHCA of presumed cardiac origin were transported to tertiary emergency medical institutions. The number of patients in the four groups was as follows: (i) 1290 (27.8%); (ii) 1102 (23.8%); (iii) 1420 (30.6%); and (iv) 824 (17.8%). The 1-month survival with a neurologically favorable outcome was: (i) 207 (16.0%); (ii) 96 (8.7%); (iii) 60 (4.2%); and (iv) seven (0.85%). In a multivariate analysis for 1-month survival with a neurologically favorable outcome, increased age was a significant prognostic factor (≥85 years; adjusted odds ratio 0.08, 95% confidence interval 0.03-0.23) for poor outcomes. CONCLUSIONS: In this population, advanced age (≥85 years) was strongly associated with poor outcomes. Further discussion of policies directed at resuscitation of very elderly OHCA patients is required, considering limited medical resources and the rapidly aging population in Japan. Geriatr Gerontol Int 2019; 19: 1088-1095.

4.
Lung Cancer ; 135: 188-195, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31446994

RESUMO

OBJECTIVES: Most lung cancer diagnoses occur in elderly patients, who are underrepresented in clinical trials. We present a pooled analysis of safety and efficacy in elderly patients (≥75 years) who received pembrolizumab (a programmed death 1 inhibitor) for advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1)‒positive tumors. METHODS: The pooled analysis included patients aged ≥18 years with advanced NSCLC with PD-L1-positive tumors from the KEYNOTE-010 (NCT01905657), KEYNOTE-024 (NCT02142738), and KEYNOTE-042 (NCT02220894) studies. In KEYNOTE-010, patients were randomized to pembrolizumab 2 or 10 mg/kg every 3 weeks (Q3W) or docetaxel, as second- or later-line therapy. In KEYNOTE-024 and KEYNOTE-042, patients were randomized to first-line pembrolizumab 200 mg Q3W or platinum-based chemotherapy. Overall survival (OS) was estimated by the Kaplan-Meier method, and safety data were summarized in elderly patients (≥75 years). RESULTS: The analysis included 264 elderly patients with PD-L1-positive tumors (PD-L1 tumor proportion score [TPS] ≥1%); among these, 132 had PD-L1 TPS ≥ 50%. Pembrolizumab improved OS among elderly patients with PD-L1 TPS ≥ 1% (hazard ratio [HR], 0.76 [95% CI, 0.56-1.02]) and PD-L1 TPS ≥ 50% (HR, 0.40 [95% CI, 0.25-0.64]). Pembrolizumab as first-line therapy also improved OS among elderly patients with PD-L1 TPS ≥ 50% (from KEYNOTE-024 and KEYNOTE-042) compared with chemotherapy (HR, 0.41 [95% CI, 0.23‒0.73]). Pembrolizumab was associated with fewer treatment-related adverse events (AEs) in elderly patients (overall, 68.5% vs 94.3%; grade ≥3, 24.2% vs 61.0%) versus chemotherapy. Immune-mediated AEs and infusion reactions were more common with pembrolizumab versus chemotherapy (overall, 24.8% vs 6.7%; grade 3‒4: 9.4% vs 0%; no grade 5 events). CONCLUSIONS: In this pooled analysis of elderly patients with advanced NSCLC with PD-L1‒positive tumors, pembrolizumab improved OS versus chemotherapy, with a more favorable safety profile. Outcomes with pembrolizumab in patients ≥75 years were comparable to those in the overall populations in the individual studies.

5.
Resuscitation ; 143: 165-172, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302105

RESUMO

OBJECTIVES: This study aimed to evaluate whether intra-aortic balloon pump (IABP) use in nontraumatic out-of-hospital cardiac arrest (OHCA) patients who achieved return of spontaneous circulation (ROSC) is associated with favorable neurological outcome after OHCA. BACKGROUND: The association between the IABP use in OHCA patients and favorable neurological outcome has not been extensively evaluated. METHODS: The Comprehensive Registry of Intensive Cares for OHCA Survival (CRITICAL) study, a multicenter, prospective observational registry in Osaka, Japan, included consecutive nontraumatic OHCA patients aged ≥18 years who achieved ROSC from July 2012 to December 2016. The primary outcome was 1-month survival with favorable neurological outcome. Logistic regression analysis was used to evaluate the association between the IABP use or non-IABP use and favorable neurological outcome using one-to-one propensity score (PS) matching analysis. RESULTS: Among the 2894 eligible patients, 10.4% used IABP, and 89.6% did not use IABP. In all patients, the proportion of 1-month survival with favorable neurological outcome was higher in the IABP use group than in the non-IABP use group (30.7% [92/300] vs. 13.2% [342/2594]). However, in PS-matched patients, the proportions of 1-month survival with favorable neurological outcome were almost consistent, and there were no significant differences between the IABP use group and the non-IABP use group (37.3% [59/158] vs. 41.1% [65/158]; adjusted odds ratio, 0.97; 95% confidence interval, 0.48-1.96). CONCLUSIONS: In this population, the current PS matching analysis did not reveal any association between the IABP use and 1-month survival with favorable neurological outcome among adult patients with ROSC after OHCA.

6.
Eur Heart J Acute Cardiovasc Care ; : 2048872619848883, 2019 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-31081678

RESUMO

BACKGROUND: Little is known about the association between serum potassium level on hospital arrival and neurological outcome after out-of-hospital cardiac arrest (OHCA). We investigated whether the serum potassium level on hospital arrival had prognostic indications for patients with OHCA. METHODS: This prospective, multicenter observational study conducted in Osaka, Japan (CRITICAL study) enrolled consecutive patients with OHCA transported to 14 participating institutions from 2012 to 2016. We included adult patients aged ⩾18 years with OHCA of cardiac origin who achieved return of spontaneous circulation and whose serum potassium level on hospital arrival was available. Based on the serum potassium level, patients were divided into four quartiles: Q1 (K ⩽3.8 mEq/L), Q2 (3.8< K⩽4.5 mEq/L), Q3 (4.5< K⩽5.6 mEq/L) and Q4 (K >5.6 mEq/L). The primary outcome was one-month survival with favorable neurological outcome, defined as cerebral performance category scale 1 or 2. RESULTS: A total of 9822 patients were registered, and 1516 of these were eligible for analyses. The highest proportion of favorable neurological outcome was 44.8% (189/422) in Q1 group, followed by 30.3% (103/340), 11.7% (44/375) and 4.5% (17/379) in the Q2, Q3 and Q4 groups, respectively ( p<0.001). In the multivariable analysis, the proportion of favorable neurological outcome decreased as the serum potassium level increased ( p<0.001). CONCLUSIONS: High serum potassium level was significantly and dose-dependently associated with poor neurological outcome. Serum potassium on hospital arrival would be one of the effective prognostic indications for OHCA achieving return of spontaneous circulation.

7.
Cancer Sci ; 110(3): 1012-1020, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30618179

RESUMO

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD-1), has been shown to improve overall survival (OS) in patients with previously treated advanced non-small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE-025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD-L1 TPS ≥1% and had received ≥1 platinum-doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD-L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD-L1 TPS ≥50%. Thirty-eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41-78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3-5 treatment-related adverse events (AE); 9 patients (24%) experienced immune-mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD-L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6-61). Among evaluable patients with PD-L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10-38). Median (95% CI) progression-free survival and OS were 3.9 (2.0-6.2) months and 19.2 (8.0-26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD-L1-expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE-010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Grupo com Ancestrais do Continente Asiático , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino
8.
Resuscitation ; 133: 82-87, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30316953

RESUMO

BACKGROUND: It has been insufficiently investigated whether neurological function after out-of-hospital cardiac arrest (OHCA) would differ by 1 °C change in ordered target temperature of 33-36 °C among patients undergoing targeted temperature management (TTM) in the real-world setting. METHODS: This nationwide hospital-based observational study (The Japanese Association for Acute Medicine-OHCA Registry) conducted between June 2014 and December 2015 in Japan included OHCA patients aged ≥18 years who were treated with TTM. The primary outcome was one-month survival with neurologically favorable outcomes defined by cerebral performance category 1 or 2. To investigate the effect of TTM by 1 °C change in ordered target temperature of 33-36 °C on each outcome, random effects logistic regression analyses were performed. RESULTS: The final analysis included 738 patients. The proportion of patients with neurologically favorable outcome was 30.4% (7/23), 31.7% (175/552), 28.9% (11/38), and 30.4% (38/125) in the 33 °C, 34 °C, 35 °C, and 36 °C groups, respectively. In the multivariable logistic regression analysis, no group had a higher proportion of neurologically favorable outcome compared with the 34 °C group (vs. 33 °C group, adjusted odds ratio [AOR] 0.90; 95% confidence interval [CI] 0.25-3.12, vs. 35 °C group, AOR 1.17; 95% CI 0.44-3.13, vs. 36 °C group, AOR 1.26; 95% CI 0.78-2.02). CONCLUSIONS: In this population, we evaluated the difference in outcomes after adult OHCA patients received TTM by 1 °C change in ordered target temperature of 33-36 °C and demonstrated that there was no statistically significant difference in neurologically favorable outcomes after OHCA irrespective of target temperature.


Assuntos
Hipotermia Induzida/métodos , Parada Cardíaca Extra-Hospitalar/terapia , Temperatura Ambiente , Adulto , Idoso , Reanimação Cardiopulmonar/métodos , Feminino , Humanos , Japão , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Parada Cardíaca Extra-Hospitalar/epidemiologia , Sistema de Registros , Estudos Retrospectivos
9.
Cancer Chemother Pharmacol ; 79(4): 651-660, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28283736

RESUMO

PURPOSE: This phase I b study evaluated the safety and anti-tumor activity of pembrolizumab in Japanese patients with advanced melanoma. METHODS: Pembrolizumab (2 mg/kg) was given every 3 weeks (Q3W) for up to 2 years or until confirmed progression or unacceptable toxicity. The tumor response was assessed as per the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) by both investigator review and central review. RESULTS: Forty-two patients with advanced melanoma received pembrolizumab. A primary cutaneous histology was observed in 34 patients (81.0%), while a primary mucosal histology was observed in 8 patients (19.0%). Thirty-four patients (81.0%) experienced treatment-related adverse events (AEs). The most common treatment-related AEs were pruritus, maculopapular rash, malaise, and hypothyroidism. Grade 3-5 treatment-related AEs occurred in 8 patients (19.0%). The only grade 3-5 treatment-related AE reported in at least two patients was anemia. There were two treatment-related deaths (unknown cause and cerebral hemorrhage). Among the 37 evaluable patients, the confirmed overall response rates (ORRs) determined by central review were 24.1% (95% CI 10.3-43.5) for cutaneous melanoma and 25.0% (95% CI 3.2-65.1) for mucosal melanoma. The responses were durable, and the median duration of response was not reached in either population. The median overall survival (OS) was not reached, with a 12-month OS of 82.7% for cutaneous melanoma and 51.4% for mucosal melanoma. CONCLUSION: The safety profile of pembrolizumab in Japanese patients was similar to that reported in the previous clinical studies. Pembrolizumab provided promising anti-tumor activity in Japanese patients with advanced melanoma.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Melanoma/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Análise de Sobrevida
10.
Invest New Drugs ; 34(3): 347-54, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27000274

RESUMO

Background This phase I study evaluated the safety and tolerability, pharmacokinetics and pharmacodynamics, immunogenicity, and antitumor activity of pembrolizumab in Japanese patients with advanced solid tumors. Methods Following an initial dose and a 28-day rest (cycle 1), pembrolizumab was administered as an intravenous infusion at escalating doses (2 or 10 mg/kg) every 2 weeks (Q2W) until disease progression or unacceptable toxicity. Adverse events (AEs) were assessed using CTCAE v4.0, and tumor response was assessed using both RECIST v1.1 and immune-related response criteria (irRC). Full pharmacokinetic sampling was performed during cycle 1. Results Three patients received pembrolizumab at 2.0 mg/kg and seven at 10 mg/kg. No dose-limiting toxicities were observed during cycle 1. Eighty percent of patients experienced drug-related AEs (mostly grade 1 or 2); the most common drug-related AEs were nausea, malaise, pyrexia, and aspartate aminotransferase/alanine transaminase (AST/ALT) elevations (n = 2 each). No drug-related grade 4 or 5 AEs occurred. Immune-related AEs comprised grade 3 ALT elevation (n = 1), grade 3 AST elevation (n = 1), grade 1 pneumonitis (n = 1), and grade 1 thyroid-stimulating hormone elevation (n = 1). The safety and pharmacokinetic profiles of Japanese patients were similar to those previously reported for Caucasian patients. A partial tumor response was observed in one patient with non-small-cell lung cancer (NSCLC) and in one patient with melanoma. Conclusions Pembrolizumab at both 2 and 10 mg/kg Q2W was well tolerated in Japanese patients with advanced solid tumors and showed encouraging anti-tumor activity against melanoma and NSCLC.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Grupo com Ancestrais do Continente Asiático , Neoplasias/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/farmacocinética , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Progressão da Doença , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
11.
Cancer Chemother Pharmacol ; 76(2): 409-16, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26104654

RESUMO

PURPOSE: MK-2206 is an oral, highly selective inhibitor of AKT. The safety, tolerability, pharmacokinetics (PK), and anti-tumor activity of MK-2206 was evaluated in Japanese patients with advanced solid tumors. METHODS: Patients received a single oral dose of MK-2206 according to an every other day (QOD) dosing schedule or a once weekly (QW) dosing schedule in repeating 28-day treatment cycles, with a 7-day rest after only the first cycle. The dose-limiting toxicities (DLTs) were evaluated during Cycle 1. Full PK sampling was performed during Cycle 1. RESULTS: Twenty-four patients were treated at 45 mg (n = 3) or 60 mg (n = 9) QOD or at 135 mg (n = 3) or 200 mg (n = 9) QW. One patient experienced a DLT at 60 mg QOD, and three patients experienced DLTs at 200 mg QW. No DLTs were observed at 45 mg QOD or at 135 mg QW. The DLTs included mucosal inflammation, hyponatremia, face edema, erythema multiforme, and hyperglycemia. Common adverse events related to MK-2206 included rash, an elevated insulin c-peptide level, stomatitis, pyrexia, eosinophilia, leukopenia, and hyperglycemia. PK differences in MK-2206 exposure were observed between Japanese patients and non-Japanese patients. The higher exposure in Japanese patients was likely caused by the relatively lower weight of Japanese patients versus non-Japanese patients. No tumor responses were observed, but six patients exhibited stable disease lasting longer than 4 months. CONCLUSIONS: MK-2206 has an acceptable safety profile in Japanese patients with advanced solid tumors and warrants further investigation.


Assuntos
Antineoplásicos/farmacocinética , Compostos Heterocíclicos com 3 Anéis/farmacocinética , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Administração Oral , Adulto , Idoso , Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Feminino , Neoplasias Gastrointestinais/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Leiomiossarcoma/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Neoplasias do Colo do Útero/tratamento farmacológico
12.
Cancer Chemother Pharmacol ; 72(3): 643-52, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23921573

RESUMO

PURPOSE: The safety, tolerability, and pharmacokinetic (PK) interactions of MK-0646 in combination with cetuximab and irinotecan were investigated in Japanese patients with advanced colorectal cancer. METHODS: Twenty patients were treated in the following study arms in combination with cetuximab and irinotecan: A [MK-0646 (10 mg/kg) weekly starting on Day 22], B [MK-0646 (15 mg/kg) on Day 8, followed by 7.5 mg/kg every 2 weeks], or C [MK-0646 (10 mg/kg) on Day 1 and weekly starting on Day 22]. Dose limiting toxicities (DLTs) were evaluated during a prespecified 4-week period in arms A and B. Full PK sampling was performed to evaluate the PK interactions. RESULTS: One of the 6 evaluable patients in arm A developed a DLT (grade 3 hyperglycemia); no DLTs occurred in the 6 patients in arm B. Common treatment-related adverse events included leukopenia, neutropenia, dermatitis acneiform, paronychia, nausea, stomatitis, diarrhea, and decreased appetite. The co-administration of cetuximab and irinotecan with MK-0646 increased the MK-0646 AUC0-168h by 25 %, with MK-0646 accumulation from the previous dose contributing to the observed increase. The co-administration of MK-0646 with cetuximab and irinotecan did not affect the PK of cetuximab and irinotecan, but reduced the C max (from 16.8 to 13.0 ng/mL) and the AUC0-24h (by 13 %) of SN-38, the active metabolite of irinotecan. CONCLUSIONS: The triple combination of MK-0646, cetuximab, and irinotecan was well tolerated in Japanese patients with advanced colorectal cancer. These results indicate a minimal potential for PK interactions between MK-0646 and cetuximab and between MK-0646 and irinotecan/SN-38.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Receptor IGF Tipo 1/imunologia , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Área Sob a Curva , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Cetuximab , Neoplasias Colorretais/patologia , Interações de Medicamentos , Feminino , Humanos , Irinotecano , Japão , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Resultado do Tratamento
13.
J Crit Care ; 28(4): 536.e1-7, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23561945

RESUMO

PURPOSE: Disuse atrophy of the lower limbs of patients with consciousness disturbance has often been recognized as "an unavoidable consequence," such that the mechanism was not investigated diligently. In this study, we examined the preventive effects of electrical muscle stimulation (EMS) against disuse atrophy of the lower limbs in patients in coma after stroke or traumatic brain injury in the intensive care unit. MATERIALS AND METHODS: We evaluated changes in cross-sectional area of lower limb muscles weekly with computed tomography in 6 control group patients and 9 EMS group patients. Electrical muscle stimulation was performed daily from day 7 after admission. We evaluated the anterior thigh muscle compartment, posterior thigh muscle compartment, anterior leg muscle compartment, and posterior leg muscle compartment. RESULTS: In the control group, the decrease in cross-sectional area progressed in all compartments every week (P < .0001). Cross-sectional areas of all compartments at day 14 were significantly decreased in the control group compared with those in the EMS group at day 7 (P < .001). We were able to limit the rate of muscle atrophy as measured in the cross-sectional areas to within 4% during the period of EMS (days 7-42) in 5 patients. The difference between the control and the EMS groups was statistically significant (P < .001). CONCLUSION: Electrical muscle stimulation is effective in the prevention of disuse muscle atrophy in patients with consciousness disorder.


Assuntos
Transtornos da Consciência/fisiopatologia , Terapia por Estimulação Elétrica , Unidades de Terapia Intensiva , Perna (Membro)/fisiopatologia , Atrofia Muscular/fisiopatologia , Atrofia Muscular/reabilitação , Transtornos Musculares Atróficos/fisiopatologia , Transtornos Musculares Atróficos/reabilitação , Idoso , Análise de Variância , Feminino , Humanos , Perna (Membro)/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Atrofia Muscular/diagnóstico por imagem , Atrofia Muscular/etiologia , Transtornos Musculares Atróficos/diagnóstico por imagem , Transtornos Musculares Atróficos/etiologia , Radiografia , Resultado do Tratamento
14.
Int J Clin Oncol ; 18(1): 87-95, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22234637

RESUMO

BACKGROUND: Control of epigenetic changes using histone deacetylase inhibitors (HDACi) is thought to be a promising target in therapy of gastrointestinal (GI) cancer. In this study, we evaluated the safety, pharmacokinetics, and efficacy of two dosing regimens of vorinostat, an oral HDACi, in patients with GI tumors. METHODS: Patients received either vorinostat 300 mg bid for 3 consecutive days followed by 4 rest days per cycle (n = 10) or vorinostat 400 mg qd for 21 consecutive days per cycle (n = 6). Pharmacokinetic parameters were assessed for the first treatment cycle. Efficacy was determined through evaluation of tumors and assessment of treatment response. RESULTS: The median treatment duration of 300 mg bid was 52.0 days and of 400 mg qd was 51.5 days. The most common drug-related adverse events were anorexia, nausea, fatigue, and hyperglycemia. Two patients taking 400 mg qd had dose-limiting toxicities (DLTs) of thrombocytopenia. No patients taking 300 mg bid experienced DLT. Five patients taking 300 mg bid and 2 patients taking 400 mg qd maintained stable disease for >8 weeks, with the maximum duration of 245 days. Mean drug exposure (±SD) was generally higher with 400 mg qd (area under the curve [AUC(0-∞)] of 7.75 ± 2.79 µM h on Day 1 post-dose) compared with 300 mg bid (AUC(0-∞) of 3.94 ± 1.56 µM h on Day 1 post-dose). CONCLUSIONS: Vorinostat 300 mg bid for 3 consecutive days followed by 4 days of rest was better tolerated in patients with GI cancer than a higher once daily dose. Additionally, there were patients in both groups who achieved stable disease, most maintaining it for longer than 8 weeks, suggesting vorinostat as a possible active agent in the treatment of GI cancer.


Assuntos
Neoplasias Gastrointestinais/tratamento farmacológico , Inibidores de Histona Desacetilases/administração & dosagem , Ácidos Hidroxâmicos/administração & dosagem , Idoso , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/induzido quimicamente , Feminino , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/patologia , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/sangue , Inibidores de Histona Desacetilases/farmacocinética , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/sangue , Ácidos Hidroxâmicos/farmacocinética , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vorinostat
15.
J Dermatol ; 39(10): 823-8, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22506596

RESUMO

A phase I study was conducted to evaluate the safety, tolerability, pharmacokinetics (PK) and efficacy of the oral histone deacetylase (HDAC) inhibitor vorinostat in Japanese patients with relapsed or refractory cutaneous T-cell lymphoma (CTCL). Six patients received vorinostat (400 mg p.o., once daily). Dose-limiting toxicities (DLT) were evaluated in all six patients during the 28 days of the first cycle. One of the six patients who received vorinostat developed a DLT (grade 4 thrombocytopenia). The most common drug-related adverse events included nausea (4/6, 67%), thrombocytopenia (4/6, 67%), hyperbilirubinemia (3/6, 50%) and vomiting (3/6, 50%). Most of these events were reversible and were resolved by supportive care and/or the interruption of vorinostat treatment. The safety and PK profiles of vorinostat in Japanese patients with CTCL did not appear to differ from those previously observed in non-Japanese and Japanese patients with advanced solid tumors. None of the patients achieved an objective response in this study. However, one unconfirmed partial response and two cases of sustained stable disease for 12 weeks or longer were observed among the six patients in the study. One of the three evaluable patients experienced pruritus relief. Vorinostat was well tolerated at a dose of 400 mg p.o. once daily and showed potential efficacy in Japanese patients with CTCL, warranting further investigation.


Assuntos
Antineoplásicos/farmacocinética , Inibidores de Histona Desacetilases/farmacocinética , Ácidos Hidroxâmicos/farmacocinética , Linfoma Cutâneo de Células T/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Grupo com Ancestrais do Continente Asiático , Inibidores de Histona Desacetilases/efeitos adversos , Humanos , Ácidos Hidroxâmicos/efeitos adversos , Ácidos Hidroxâmicos/uso terapêutico , Hiperbilirrubinemia/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Trombocitopenia/induzido quimicamente , Vômito/induzido quimicamente , Vorinostat
16.
Appl Opt ; 51(7): 898-904, 2012 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-22410893

RESUMO

A high precision, polarization-independent optical circulator was developed for high accuracy Faraday depolarization lidar. Glan laser prisms and other novel optics were utilized in the circulator optics, resulting in a high extinction ratio of polarization of >30 dB. High accuracy is needed to detect a small rotation angle in the polarization plane of the propagating beam. It is generated by the Faraday effect due to the lightning discharge. The developed circulator delivered high performance of insertion loss and isolation as laser transmitter and echo receiver in the inline lidar optics.

17.
Cancer Chemother Pharmacol ; 69(4): 1099-105, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22143378

RESUMO

PURPOSE: Ridaforolimus is a non-prodrug mTOR inhibitor. The safety, pharmacokinetics (PK), and antitumor activity of oral ridaforolimus were assessed in Japanese patients with refractory solid tumors. METHODS: Ridaforolimus (20 or 40 mg) was administered as a single dose on Day 1, followed by once daily dosing five times a week for a 3-week cycle beginning on Day 8. Full PK sampling was performed on Days 1 and 26. RESULTS: Thirteen patients (7 at 20 mg and 6 at 40 mg) were enrolled. The median treatment duration was 82 days. The most common drug-related adverse events were stomatitis, hypertriglyceridemia, and proteinuria. Two patients had dose-limiting toxicities (grade 3 stomatitis at 20 mg, and grade 3 anorexia and vomiting at 40 mg). Four patients had grade 1 interstitial pneumonitis. Ridaforolimus in the whole blood was rapidly absorbed and slowly eliminated with a half-life of approximately 56-58 h after a single dose. Two patients (with non-small cell lung cancer and angiosarcoma, respectively) achieved a partial response, and five patients (one with thymic cancer and four with soft tissue sarcomas) had a stable disease for ≥ 16 weeks. CONCLUSIONS: Ridaforolimus was well tolerated up to a dose of 40 mg in Japanese patients. Preliminary evidence of antitumor activity was observed for patients with solid tumors. Further investigation at this dose is warranted.


Assuntos
Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Sirolimo/análogos & derivados , Adulto , Idoso , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/patologia , Inibidores de Proteínas Quinases/farmacocinética , Sirolimo/efeitos adversos , Sirolimo/farmacocinética , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
18.
Artif Organs ; 36(2): 130-8, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22171966

RESUMO

We clarified the effect of exchange transfusion with liposome-encapsulated hemoglobin (neo red cells, NRCs) with low O2 affinity (P50O2 = 50 mm Hg) on O2 metabolism. Rabbits were randomly assigned to receive serial exchange transfusions with NRC (NRC group, n = 5), shed blood diluted 1:1 with saline (red blood cell (RBC) group, n = 5), or saline alone (plasma group, n = 4) under hemodynamic monitoring. Cardiac tamponade was then induced and successively reversed to determine relationships between O2 consumption (VO2) and O2 delivery (DO2) using the dual-line method. Mean values of Hb concentration after exchange transfusion were 5.7 (NRC), 6.0 (RBC), and 1.5 (plasma) g/dL. The plasma group could not even survive the initial exchange hemodilution due to a critical decrease in DO2. The NRC, but not the RBC group, developed progressive metabolic acidosis and lactatemia, as well as increases in PaCO2 and decreases in tissue PO2 in skeletal muscle after exchange transfusion. Nonetheless, systemic O2 uptake indices obtained from an analysis of the VO2/DO2 relationship in the NRC and RBC groups were comparable. These findings suggested that systemic O2 uptake was maintained in rabbits after exchange transfusion with NRC, although progressive tissue hypoxia with systemic acidosis is indicative of inadequate peripheral circulation and insufficient aerobic metabolism during extended hemodilution in which 86% of the circulating blood is replaced.


Assuntos
Substitutos Sanguíneos/uso terapêutico , Transfusão Total , Oxigênio/metabolismo , Animais , Substitutos Sanguíneos/administração & dosagem , Transfusão Total/métodos , Feminino , Hemodiluição/métodos , Hemodinâmica , Lipossomos , Oxigênio/sangue , Consumo de Oxigênio , Coelhos , Distribuição Aleatória
19.
Resuscitation ; 82(4): 481-6, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21251746

RESUMO

PURPOSE: Despite the use of animal models to study post-cardiac-arrest resuscitation, the effects of hypothermia on physiological circulatory parameters are still not fully understood. In this study, using a gerbil model of global ischaemia/reperfusion, we aimed to assess the effects of hypothermia on physiological parameters and evaluated the optimal timing for the induction of hypothermia to achieve a better survival rate. METHODS: Survival rates at 72 h after reperfusion were evaluated by varying the degree of hypothermia and/or duration of ischaemia, and then examined by varying induction timing and/or extending the duration of ischaemia. Physiological parameters were measured using an intravital microscopy system. RESULTS: Under normothermic cerebral ischaemia, the survival rate was dramatically decreased by the induction of 15-20 min of ischaemia. Induction of hypothermia significantly improved the survival rate only when it occurred less than 10 min after ischaemic onset. In the hypothermia-treated groups, post-ischaemic hyperperfusion was significantly suppressed, and post-ischaemic vasoconstriction of the pial arteriole was prevented. CONCLUSIONS: Hypothermia-induced suppression of post-ischaemic hyperperfusion and the prevention of vasoconstriction of the pial arteriole play an important role in improving the survival rate after global ischaemia/reperfusion, but the time window for induction of hypothermia remains relatively narrow.


Assuntos
Reanimação Cardiopulmonar/métodos , Parada Cardíaca/terapia , Hipotermia Induzida , Isquemia/mortalidade , Animais , Modelos Animais de Doenças , Seguimentos , Gerbillinae , Parada Cardíaca/mortalidade , Parada Cardíaca/fisiopatologia , Isquemia/fisiopatologia , Masculino , Ratos , Taxa de Sobrevida/tendências , Fatores de Tempo
20.
Shock ; 32(6): 593-600, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19295486

RESUMO

After crush injury, patients often experience multiple organ dysfunction syndrome. In this study, we focused on vascular endothelial damage, which is believed to be a possible cause of multiple organ dysfunction syndrome, and revealed a pathological condition of distant organ failure. In particular, the lung is an especially prone target organ at the time of systemic inflammatory invasion after crush injury. We ascertained the effect of antithrombin (AT), which has recently attracted attention for its endothelial protective effects. Using a rat model of crush syndrome, we assessed severity of systemic inflammation and vascular endothelial damage through a blood test and degree of lung injury and centrally focused on morphological analysis of endothelium over time. Crush injury significantly elevated the blood concentration of tissue plasminogen activator-plasminogen activator inhibitor 1 complex, monocyte chemoattractant protein 1, and IL-6. Accumulation of active inflammatory cells (OX-42-positive cells) and expression of von Willebrand factor and vascular cell adhesion molecule 1 significantly increased in the lung 24 h after releasing crush. After 48 h, disarray of alveolar structure and alveolar hemorrhage appeared. Antithrombin administration significantly suppressed accumulation of inflammatory cells, expression of von Willebrand factor and vascular cell adhesion molecule 1, and mortality rate. Our research demonstrates that crush injury induces acute lung injury as distant organ failure, and it would seem that AT administration diminishes vascular endothelial damage and is effective against crush injury.


Assuntos
Antitrombinas/metabolismo , Síndrome de Esmagamento/metabolismo , Endotélio Vascular/citologia , Pulmão/metabolismo , Animais , Coagulação Sanguínea , Quimiocina CCL2/biossíntese , Inflamação , Interleucina-6/biossíntese , Masculino , Ratos , Ratos Wistar , Fatores de Tempo , Ativador de Plasminogênio Tecidual/biossíntese , Resultado do Tratamento
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