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1.
Adv Ther ; 40(3): 934-950, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36547809

RESUMO

INTRODUCTION: A framework that extracts oncological outcomes from large-scale databases using artificial intelligence (AI) is not well established. Thus, we aimed to develop AI models to extract outcomes in patients with lung cancer using unstructured text data from electronic health records of multiple hospitals. METHODS: We constructed AI models (Bidirectional Encoder Representations from Transformers [BERT], Naïve Bayes, and Longformer) for tumor evaluation using the University of Miyazaki Hospital (UMH) database. This data included both structured and unstructured data from progress notes, radiology reports, and discharge summaries. The BERT model was applied to the Life Data Initiative (LDI) data set of six hospitals. Study outcomes included the performance of AI models and time to progression of disease (TTP) for each line of treatment based on the treatment response extracted by AI models. RESULTS: For the UMH data set, the BERT model exhibited higher precision accuracy compared to the Naïve Bayes or the Longformer models, respectively (precision [0.42 vs. 0.47 or 0.22], recall [0.63 vs. 0.46 or 0.33] and F1 scores [0.50 vs. 0.46 or 0.27]). When this BERT model was applied to LDI data, prediction accuracy remained quite similar. The Kaplan-Meier plots of TTP (months) showed similar trends for the first (median 14.9 [95% confidence interval 11.5, 21.1] and 16.8 [12.6, 21.8]), the second (7.8 [6.7, 10.7] and 7.8 [6.7, 10.7]), and the later lines of treatment for the predicted data by the BERT model and the manually curated data. CONCLUSION: We developed AI models to extract treatment responses in patients with lung cancer using a large EHR database; however, the model requires further improvement.


The use of artificial intelligence (AI) to derive health outcomes from large electronic health records is not well established. Thus, we built three different AI models: Bidirectional Encoder Representations from Transformers (BERT), Naïve Bayes, and Longformer to serve this purpose. Initially, we developed these models based on data from the University of Miyazaki Hospital (UMH) and later improved them using the Life Data Initiative (LDI) data set of six hospitals. The performance of the BERT model was better than the other two, and it showed similar results when it was applied to the LDI data set. The Kaplan­Meier plots of time to progression of disease for the predicted data by the BERT model showed similar trends to those for the manually curated data. In summary, we developed an AI model to extract health outcomes using a large electronic health database in this study; however, the performance of the AI model could be improved using more training data.


Assuntos
Inteligência Artificial , Neoplasias Pulmonares , Humanos , Teorema de Bayes , População do Leste Asiático , Registros Eletrônicos de Saúde
2.
Jpn J Clin Oncol ; 49(7): 676-686, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31008509

RESUMO

OBJECTIVE: Post-marketing surveillance (PMS) was performed in Japan to obtain information on the safety and efficacy of crizotinib. METHODS: Target patients included almost all patients with anaplastic lymphoma kinase-positive non-small cell lung cancer who were administered crizotinib. The observation period was 52 weeks. In the present study, we focused on the treatment status and safety of crizotinib therapy and analyzed the real-world data obtained by this PMS (ClinicalTrials.gov: NCT01597258). RESULTS: The safety analysis set included 2028 Japanese patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of adverse drug reactions (ADRs) was 91.6%, and common ADRs (incidence ≥15%) were nausea (32.2%), diarrhea (24.3%), photopsia (18.9%), vomiting (17.5%) and dysgeusia (16.8%). Many patients (623 patients) discontinued treatment of crizotinib because of adverse events within 12 weeks after therapy initiation, which tended to frequently occur in the following cases: (1) elderly, (2) body weight <40 kg, (3) body surface area <1.2 m2 (4) ECOG PS 2-4, (5) higher Brinkman index and (6) history of occupational/environmental exposure such as asbestos/pneumoconiosis. The proportions of patients remaining on crizotinib therapy were 68.2% for 3 months, 55.2% for 6 months and 36.1% for 12 months, with a median duration of 7.9 months. Multivariate analysis with a Cox proportional hazard model identified 10 statistically significant patient background factors influencing the duration of crizotinib therapy. CONCLUSIONS: No new safety concerns were observed in this PMS study. Our results provide useful information regarding the status of crizotinib therapy in the clinical setting.


Assuntos
Quinase do Linfoma Anaplásico/metabolismo , Povo Asiático , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Crizotinibe/efeitos adversos , Crizotinibe/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Idoso , Crizotinibe/farmacologia , Feminino , Humanos , Japão , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento , Suspensão de Tratamento
3.
Jpn J Clin Oncol ; 49(4): 354-360, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30834940

RESUMO

BACKGROUND: In an interim analysis of a Phase II trial in Japanese patients with pancreatic neuroendocrine tumors (panNETs), sunitinib demonstrated antitumor activity with an objective response rate (ORR) of 50% (95% confidence interval [CI], 21-79) and a median progression-free survival (PFS) of 16.8 months (95% CI, 9.3-26.2). Here, we report the final analyses of efficacy and safety, as well as additional analyses, from this Phase II study. METHODS: This was a multicenter, open-label, Phase II trial (NCT01121562) of sunitinib in Japanese patients with panNETs. Patients received oral sunitinib 37.5 mg/day on a continuous daily dosing schedule. Dose modifications were permitted. The primary endpoint was clinical benefit rate (CBR). Secondary endpoints included ORR, PFS, overall survival (OS), safety and pharmacokinetics. RESULTS: Of 12 patients enrolled and treated, all discontinued treatment-the majority (n = 8) owing to disease progression. Most patients were male (n = 8), <65 years of age (n = 11) and had a non-functional tumor (n = 10). The median (range) number of days on drug was 323.5 (22-727). The CBR (95% CI) was 75.0% (42.8-94.5). ORR (95% CI) was 50.0% (21.1-78.9). Median (95% CI) PFS was 16.8 (9.3-26.2) months; however, median (95% CI) OS was not reached (22.0-not estimable). Most common adverse events (AEs; all-causality) were diarrhea (n = 10; 83.3%), hand-foot syndrome (n = 8; 66.7%) and hypertension (n = 8; 66.7%). CONCLUSIONS: These results support the efficacy and safety of sunitinib in Japanese patients with panNETs. Appropriate AE management through dose reduction and interruption may prolong sunitinib treatment and maximize its efficacy.


Assuntos
Antineoplásicos/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Sunitinibe/uso terapêutico , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Intervalo Livre de Progressão
5.
Cancer Chemother Pharmacol ; 83(1): 201-207, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30413868

RESUMO

BACKGROUND: Sunitinib is approved for the treatment of progressive, well-differentiated pancreatic neuroendocrine tumors (pNETs) in patients with unresectable, locally advanced or metastatic disease. Safety and efficacy data in Japanese patients are limited. We report outcomes from a post-marketing surveillance study of sunitinib treatment in Japanese patients. METHODS: Sunitinib 37.5 mg once daily was orally administered in Japanese patients aged ≥ 15 years with pNETs. The primary endpoints included adverse events (AEs) occurring during the observation period of 168 days and objective response rate (ORR). RESULTS: Sunitinib was administered in 62 patients with pNETs. The median duration of treatment was 165 days. At 168 days from the start of treatment, 31 patients were still receiving sunitinib treatment and treatment continuation rate was 50.0%. Of the 31 patients who discontinued treatment, 18 (58.1%) discontinued because of AEs and 16 (51.6%) patients discontinued due to insufficient clinical effect. Of the 18 patients who discontinued due to AEs, 10 did so within 42 days of treatment initiation. The most common all-grade AEs were platelet count decreased (33.9%), diarrhea (29.0%), neutrophil count decreased (27.4%), hypertension (24.2%), and palmar-plantar erythrodysesthesia syndrome (24.2%). In the 51 patients eligible for the efficacy analysis, ORR was 13.7% (95% confidence interval, 5.7-26.3) and clinical benefit rate was 70.6%. CONCLUSIONS: There were no new safety concerns in real-world use of sunitinib in Japanese patients with pNETs. The short treatment duration likely led to low tumor response. Appropriate AEs management through dose interruption/reduction is essential for sunitinib treatment success in this patient population.


Assuntos
Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Tumores Neuroendócrinos/tratamento farmacológico , Vigilância de Produtos Comercializados , Sunitinibe/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/patologia , Prognóstico
6.
J Thorac Oncol ; 14(4): 672-682, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30521972

RESUMO

INTRODUCTION: The study objective was to determine the incidence and characteristics of drug-induced interstitial lung disease (ILD) associated with an orally available small-molecule tyrosine kinase inhibitor, crizotinib, in a real-world clinical setting. METHODS: Post-marketing surveillance was performed in Japan to obtain information on the safety and efficacy of crizotinib. Target patients included all patients with anaplastic lymphoma kinase-positive NSCLC who received crizotinib during the enrollment period between May 2012 and December 2014. The observation period was 52 weeks. Expert analysis of the ILD incidence was performed by an ILD independent review committee composed of five medical specialists. RESULTS: The safety analysis set included 2028 patients, and more than half of the patients (56.4%) were nonsmokers. The incidence of ILD associated with crizotinib therapy was 5.77%; and 3.45% patients showed grade 3 or greater. Pulmonary edema-like shadows with or without diffuse alveolar damage pattern were observed in crizotinib-associated ILD (incidence: 0.39%), but a causal relationship with the prognosis could not be identified. ILD developed within 4 weeks from initiation of crizotinib administration in 41.9% and within 8 weeks in 69.2% of the patients. Age 55 years or older, Eastern Cooperative Oncology Group performance status 2-4, smoking history, previous or concomitant ILD, and comorbid pleural effusion were statistically determined as significant risk factors for crizotinib-induced ILD. CONCLUSIONS: Crizotinib therapy should be applied to the NSCLC patients with any of above risk factors under a cautious monitoring for ILD occurrence, and clinicians should pay attention to the risks of severe ILD.


Assuntos
Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/induzido quimicamente , Crizotinibe/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Neoplasias Pulmonares/induzido quimicamente , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Criança , Pré-Escolar , Crizotinibe/farmacologia , Feminino , Humanos , Japão , Doenças Pulmonares Intersticiais/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
7.
Cancer Res Treat ; 50(3): 691-700, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28701030

RESUMO

PURPOSE: Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. MATERIALS AND METHODS: This analysis evaluated previously treated and untreated patients in two randomized, openlabel phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention-to-treat and "as-treated" populations for efficacy and safety endpoints, respectively. RESULTS: In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363 to 0.762; p < 0.001 and hazard ratio, 0.442; 95% confidence interval, 0.302 to 0.648; p < 0.001, respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p < 0.05). The most common treatment-emergent adverse events (any grade)with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. CONCLUSION: These data, currently the only analysis showing Asian and non-Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Pemetrexede/administração & dosagem , Pirazóis/administração & dosagem , Piridinas/administração & dosagem , Receptores Proteína Tirosina Quinases/genética , Taxoides/administração & dosagem , Quinase do Linfoma Anaplásico , Carcinoma Pulmonar de Células não Pequenas/genética , Crizotinibe , Docetaxel , Esquema de Medicação , Feminino , Humanos , Análise de Intenção de Tratamento , Estimativa de Kaplan-Meier , Neoplasias Pulmonares/genética , Masculino , Pemetrexede/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Análise de Sobrevida , Taxoides/efeitos adversos , Resultado do Tratamento
8.
Jpn J Clin Oncol ; 45(11): 1016-22, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26373318

RESUMO

OBJECTIVE: This study was conducted to expand the sunitinib safety database in Japanese imatinib-resistant/-intolerant gastrointestinal stromal tumor patients. Retrospective analyses investigated common adverse events as potential prognostic markers. METHODS: Four hundred and seventy patients who received sunitinib between June 2008 and November 2009 were analyzed for safety, progression-free survival and overall survival; 386 for objective response rate; 88% received sunitinib on Schedule 4/2 starting at 50 mg/day. RESULTS: No unexpected safety issues occurred. Grade ≥ 3 adverse events occurred in 70%, most commonly thrombocytopenia (33%), neutropenia (22%) and leukopenia (15%). Objective response rate was 20% (95% confidence interval 16-24). Median progression-free survival was 22.4 weeks (95% confidence interval, 21.7-24.0). The overall survival rate at 24 weeks was 91% (95% confidence interval, 88-94). Higher relative dose intensity (≥70 vs. <70%) during the first 6 weeks and better Eastern Cooperative Oncology Group performance status (0 vs. ≥1) were associated with longer progression-free survival (24.0 vs. 20.1 weeks; P = 0.011; and 24.1 vs. 16.9 weeks; P < 0.001) and higher 24-week overall survival rate (94 vs. 83%; P < 0.001; and 96 vs. 83%; P < 0.001). Increased progression-free survival and overall survival rates were associated with specific adverse events. Cox proportional hazard modeling adjusted for relative dose intensity and performance status established hand-foot syndrome (hazard ratio = 0.636; 95% confidence interval, 0.456-0.888) and leukopenia (hazard ratio = 0.683; 95% confidence interval, 0.492-0.948) occurring within 12 weeks were significantly correlated with increased progression-free survival. CONCLUSION: Sunitinib showed good efficacy and tolerable safety. Factors associated with greater efficacy were relative dose intensity, performance status and specific early adverse events.


Assuntos
Antineoplásicos/uso terapêutico , Povo Asiático/estatística & dados numéricos , Neoplasias Gastrointestinais/tratamento farmacológico , Tumores do Estroma Gastrointestinal/tratamento farmacológico , Indóis/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Intervalo Livre de Doença , Feminino , Síndrome Mão-Pé/epidemiologia , Síndrome Mão-Pé/etiologia , Humanos , Incidência , Indóis/administração & dosagem , Indóis/efeitos adversos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Neutropenia/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Sunitinibe , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Resultado do Tratamento
10.
J Infect Chemother ; 19(5): 951-5, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23322394

RESUMO

The efficacy of fluoroquinolones (FQs) correlates with the pharmacokinetic/pharmacodynamic (PK-PD) parameter, AUC/MIC. To our knowledge, however, no prospective studies have reported the relationship between FQ efficacy and PK-PD parameters in intraabdominal infection; therefore, we prospectively investigated the relationship between the efficacy of intravenous ciprofloxacin (CPFX IV) and PK-PD parameters. The study included 16 patients diagnosed with peritonitis between 2006 and 2008: 14 patients infected with a single organism and 2 patients infected with more than one organism. Each patient was treated with CPFX IV (300 mg twice daily). The response rate was 56% (9 responders and 7 non-responders). Non-responders were infected with Escherichia coli, Pseudomonas aeruginosa, and Bacteroides fragilis (6 patients were infected with a single organism and 1 with more than one organism). Plasma drug concentrations were measured 1 h and 2 or 4 h after administration of CPFX IV. AUC for 24 h (AUC(0-24))/MIC values was calculated. The range of AUC(0-24)/MIC values in responders [95.3-3628.4 (geometric mean, 521.6)] was significantly different from that in non-responders [7.0-45.2 (geometric mean, 16.5)] (p = 0.001). The target AUC/MIC value of CPFX IV would be considered to be 45-95 in patients with peritonitis.


Assuntos
Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/metabolismo , Ciprofloxacina/administração & dosagem , Ciprofloxacina/farmacocinética , Infecções Intra-Abdominais/tratamento farmacológico , Infecções Intra-Abdominais/metabolismo , Idoso , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Bactérias/efeitos dos fármacos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade
11.
Invest New Drugs ; 31(5): 1265-74, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23269537

RESUMO

BACKGROUND: Pancreatic neuroendocrine tumors (NETs) are rare but are frequently diagnosed at advanced stages and require systemic therapy. PATIENTS AND METHODS: This multicenter, open-label, phase II study evaluated sunitinib in Japanese patients with well-differentiated pancreatic NET. Patients received sunitinib 37.5 mg/day on a continuous daily dosing (CDD) schedule. The primary endpoint was clinical benefit rate (CBR; percentage of complete responses [CRs] plus partial responses [PRs] plus stable disease [SD] ≥ 24 weeks). Secondary endpoints included objective response rate (ORR), tumor shrinkage, progression-free survival (PFS) probability, safety, pharmacokinetics, and biomarkers. RESULTS: Twelve patients received treatment. The CBR was 75 % (95 % confidence interval [CI], 43-94) and included 6 patients with a PR and 3 with SD. The ORR was 50 % (95 % CI, 21-79). PFS probability was 91 % (95 % CI, 54-99) at 6 months and 71 % (95 % CI, 34-90) at 12 months. Commonly reported treatment-emergent (all-causality), any-grade adverse events included diarrhea (n=10), hand-foot syndrome and hypertension (both n=8), fatigue and headache (both n=7), and neutropenia (n=6). No deaths on study were reported; one death due to disease progression occurred >28 days after end of treatment. Sunitinib on a CDD schedule resulted in sustained drug concentrations without accumulation across cycles. Tumor responses in all 12 patients did not appear to correlate with decreases in chromogranin A levels. CONCLUSIONS: Sunitinib 37.5 mg/day on a CDD schedule demonstrated antitumor activity in Japanese patients with unresectable, well-differentiated pancreatic NET. Commonly reported adverse events were consistent with the known safety profile of sunitinib.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Indóis/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Pirróis/uso terapêutico , Adulto , Idoso , Inibidores da Angiogênese/sangue , Inibidores da Angiogênese/farmacocinética , Povo Asiático , Biomarcadores Tumorais/sangue , Cromogranina A/sangue , Feminino , Gastrinas/sangue , Humanos , Indóis/sangue , Indóis/farmacocinética , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Tumores Neuroendócrinos/sangue , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/sangue , Neoplasias Pancreáticas/patologia , Pirróis/sangue , Pirróis/farmacocinética , Sunitinibe , Resultado do Tratamento
12.
Invest New Drugs ; 30(6): 2352-63, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22249430

RESUMO

BACKGROUND: Dacomitinib (PF-00299804) is an oral, irreversible, small molecule inhibitor of human epidermal growth factor receptor-1, -2, and -4 tyrosine kinases. METHODS: This phase I, open-label, dose-escalation study (clinicaltrials.gov: NCT00783328) primarily evaluated the safety and tolerability of dacomitinib by dose-limiting toxicity (DLT), and determined the clinically recommended phase II dose (RP2D) in Japanese patients with advanced solid tumors. Dacomitinib was administered orally at three dose levels (15, 30, or 45 mg once daily [QD]). Patients initially received a single dose, and after 9 days of follow-up, continuously QD in 21-day cycles. Endpoints included pharmacokinetics (PK) and antitumor activity. RESULTS: Thirteen patients were assigned to the three dose levels (15 mg cohort: n = 3; 30 mg cohort: n = 3; 45 mg cohort: n = 7) according to a traditional '3 + 3' design. None of the treated patients experienced a DLT. Toxicities were manageable and similar in type to those observed in other studies. PK concentration parameters increased with dose over the range evaluated, with no evidence of accumulation over time. Of 13 evaluable patients, one with NSCLC (adenocarcinoma) had a partial response and nine patients had stable disease. CONCLUSIONS: Dacomitinib 45 mg QD was defined as the RP2D and demonstrated preliminary activity in Japanese patients with advanced solid tumors.


Assuntos
Antineoplásicos/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Quinazolinonas/administração & dosagem , Administração Oral , Adulto , Idoso , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Povo Asiático , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Esquema de Medicação , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores de Proteínas Quinases/sangue , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas p21(ras) , Quinazolinonas/sangue , Quinazolinonas/farmacocinética , Carga Tumoral/efeitos dos fármacos , Proteínas ras/genética
13.
Invest New Drugs ; 30(2): 639-46, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20960028

RESUMO

BACKGROUND: Sunitinib is an oral multitargeted tyrosine kinase inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptors, as well as of other receptor types. We have performed a feasibility study to investigate the safety of sunitinib in combination with pemetrexed for treatment of advanced refractory solid tumors. METHODS: Sunitinib was administered once daily on a continuous daily dosing (CDD) schedule (37.5 mg/day) or a 2-weeks-on, 1-week-off treatment schedule (50 mg/day, Schedule 2/1) in combination with pemetrexed at 500 mg/m(2) on day 1 of repeated 21-day cycles. RESULTS: Twelve patients were enrolled in the study: six on the CDD schedule and six on Schedule 2/1. None of the treated patients experienced a dose-limiting toxicity. Toxicities were manageable and similar in type to those observed in monotherapy studies of sunitinib and pemetrexed. Pharmacokinetic analysis did not reveal any substantial drug-drug interaction. One patient with squamous cell lung cancer showed a partial response and five patients had stable disease. CONCLUSIONS: Combination therapy with sunitinib administered on Schedule 2/1 (50 mg/day) or a CDD schedule (37.5 mg/day) together with standard-dose pemetrexed (500 mg/m(2)) was well tolerated in previously treated patients with advanced solid tumors.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias/tratamento farmacológico , Idoso , Inibidores da Angiogênese/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Esquema de Medicação , Estudos de Viabilidade , Feminino , Glutamatos/administração & dosagem , Guanina/administração & dosagem , Guanina/análogos & derivados , Humanos , Indóis/administração & dosagem , Japão , Masculino , Pessoa de Meia-Idade , Neoplasias/enzimologia , Neoplasias/patologia , Pemetrexede , Inibidores de Proteínas Quinases/administração & dosagem , Pirróis/administração & dosagem , Sunitinibe , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
J Infect Chemother ; 18(1): 127-9, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21814800

RESUMO

The pharmacokinetics-pharmacodynamics (PK-PD) breakpoint of piperacillin/tazobactam (PIPC/TAZ) for hospital-acquired pneumonia (HAP) and Pseudomonas aeruginosa-induced bacteremia is controversial, since the susceptibility of P. aeruginosa to PIPC/TAZ is known to be lower than that set by the Clinical Laboratory Standards Institute (CLSI), ≤64 mg/L. The association between MIC levels and bacterial eradication after various PIPC/TAZ treatments was investigated. In all, 61 and 17 Japanese patients from the microbiology laboratory database with HAP and P. aeruginosa-induced bacteremia, respectively, who were treated with PIPC/TAZ (4.5 g, b.i.d., t.i.d., or q.i.d.) between 2008 and 2009 were retrospectively analyzed. Pertinent clinical data were retrieved from medical records. The MIC level was determined using the microdilution method. Appropriate empirical therapy with PIPC/TAZ was selected for all patients within 24 h of positive culture results. The microbiological effect after treatment was used to determine the efficacy of each PIPC/TAZ administration method. In PIPC/TAZ-treated HAP patients (4.5 g, t.i.d.), the microbiological efficacy was 93.3% (28/30) when the MIC was ≤16 mg/L, while it was 50.0 (5/9) and 0% (0/3) with MICs of 32 (p < 0.05) and 64 mg/L, respectively. In PIPC/TAZ-treated bacteremia patients (4.5 g, t.i.d. or q.i.d.), the microbiological efficacy was 100% (11/11) when the MIC was <16 mg/L, while it was 33.3 (1/3) and 0% (0/3) with MICs of 32 (p < 0.05) and ≥64 mg/L, respectively. The present CLSI susceptibility breakpoints do not necessarily predict clinical outcomes. The appropriateness evaluation of the current CLSI resistance breakpoint of PIPC/TAZ and the PK-PD breakpoint determination warrant further studies.


Assuntos
Antibacterianos/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Antibacterianos/farmacocinética , Bacteriemia/tratamento farmacológico , Bacteriemia/microbiologia , Infecção Hospitalar/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Ácido Penicilânico/análogos & derivados , Ácido Penicilânico/farmacocinética , Ácido Penicilânico/farmacologia , Piperacilina/farmacocinética , Piperacilina/farmacologia , Combinação Piperacilina e Tazobactam , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Infecções por Pseudomonas/microbiologia , Estudos Retrospectivos
15.
Invest New Drugs ; 30(4): 1548-56, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21748299

RESUMO

OBJECTIVES: The insulin-like growth factor (IGF) signaling pathway has been implicated in the pathogenesis of numerous tumor types, including non-small cell lung cancer (NSCLC). Figitumumab is a fully human IgG2 monoclonal antibody against IGF-1 receptor (IGF-1R). METHODS: This phase I, open-label, dose-escalation study (ClinicalTrials.gov: NCT00603538) assessed the safety and tolerability of figitumumab (6, 10 and 20 mg/kg) in combination with carboplatin (area under the curve: 6 mg·min/mL) and paclitaxel (200 mg/m(2)) in Japanese patients (N = 19) with chemotherapy-naïve, advanced NSCLC. Treatments were administered intravenously on day 1 of a 21-day cycle for four to six cycles. Pharmacokinetics, biomarkers, and antitumor activity were also evaluated. RESULTS: Figitumumab in combination with carboplatin and paclitaxel was well tolerated at doses up to 20 mg/kg; no dose-limiting toxicities were observed at this dose level. When given in combination, figitumumab plasma exposure increased in an approximately dose-proportional manner. The approximate 2-fold accumulation following repeated administration supported the 21-day regimen as appropriate for figitumumab administration. Serum total IGF-1 and IGF binding protein-3 concentrations increased following figitumumab dosing, but a clear dose-dependent relationship was not demonstrated. Seven of 18 evaluable patients experienced a partial response. CONCLUSIONS: Figitumumab 20 mg/kg in combination with carboplatin and paclitaxel was well tolerated in chemotherapy-naïve Japanese patients with NSCLC. Further analysis of biomarker data is necessary for the development of figitumumab therapy.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Povo Asiático , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Paclitaxel/uso terapêutico , Adulto , Idoso , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/sangue , Anticorpos Monoclonais/farmacocinética , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Biomarcadores Tumorais/sangue , Carboplatina/efeitos adversos , Carboplatina/sangue , Carboplatina/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imunoglobulinas Intravenosas , Japão , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/efeitos adversos , Paclitaxel/sangue , Paclitaxel/farmacocinética , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
16.
J Infect Chemother ; 18(3): 313-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22020630

RESUMO

Mycoplasma genitalium has been shown to be one of the pathogens responsible for uterine cervicitis by many studies. However, there are no clinical recommendations for treating M. genitalium-positive uterine cervicitis. Our study retrospectively investigated the antimicrobial efficacies of several antibiotics against uterine cervicitis caused by M. genitalium. We studied a total of 257 women with M. genitalium-positive uterine cervicitis, except for those with chlamydial and gonococcal infections, who were treated with one of the following antibacterial therapies: azithromycin extended release formulation (AZM-SR) 2 g single dose, azithromycin (AZM) 1 g single dose, clarithromycin (CAM) 400 mg/day for 7 days, CAM 400 mg/day for 14 days, moxifloxacin (MFLX) 400 mg/day for 7 days, MFLX 400 mg/day for 14 days, levofloxacin (LVFX) 500 mg/day for 7 days, LVFX 500 mg/day for 14 days, sitafloxacin (STFX) 200 mg/day for 7 days, and STFX 200 mg/day for 14 days. A PCR-based assay was performed to evaluate the microbiological efficacy of eradication in these patients. M. genitalium was eradicated from the uterine cervix in 19 of the 21 (90.5%) patients treated with AZM-SR 2 g single dose, in 38 of the 42 (90.5%) patients treated with MFLX 400 mg/day for 7 days, in 42 of the 42 (100%) patients treated with MFLX 400 mg/day for 14 days, and in 12 of the 13 (92.3%) patients treated with STFX 200 mg/day for 14 days. In conclusion, AZM-SR 2 g single dose, MFLX 400 mg/day for 14 days, and STFX 200 mg/day for 14 days would each be an effective treatment for M. genitalium infection.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Mycoplasma/tratamento farmacológico , Mycoplasma genitalium/isolamento & purificação , Cervicite Uterina/tratamento farmacológico , Adolescente , Adulto , Antibacterianos/efeitos adversos , Compostos Aza/efeitos adversos , Compostos Aza/uso terapêutico , Azitromicina/efeitos adversos , Azitromicina/uso terapêutico , Feminino , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/uso terapêutico , Humanos , Testes de Sensibilidade Microbiana , Moxifloxacina , Infecções por Mycoplasma/microbiologia , Mycoplasma genitalium/genética , Reação em Cadeia da Polimerase , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Estudos Retrospectivos , Cervicite Uterina/microbiologia
17.
Jpn J Antibiot ; 63(2): 93-104, 2010 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-20919495

RESUMO

The prevalence of female sexually transmitted infection (STI) in Japan is in the decreasing tendency after 2002, however it still actualizes as a social problem. Azithromycin, which is 15-member macrolide antimicrobial agent, has indication to treat the chlamydia STI in a single dose of 1 g. In April 2009, a single dose of 2 g of azithromycin extended release (ER) formulation, which is improved formulation by the viewpoint of pharmacokinetics-pharmacodynamics, was approved and has indications to treat not only chlamydial STI but also gonococcal STI. We considered the clinical application of azithromycin ER to treat female STI, including our new our own experiences because the clinical studies of azithromycin ER for STI had not been conducted. In conclusion, azithromycin ER was suggested theoretically becoming one of the choices of new treatment STI caused by not only chlamydia but also gonococcus, more clinical consideration to treat STI will be necessary in the future.


Assuntos
Azitromicina/administração & dosagem , Doenças Bacterianas Sexualmente Transmissíveis/tratamento farmacológico , Anexos Uterinos/metabolismo , Azitromicina/efeitos adversos , Azitromicina/farmacocinética , Azitromicina/farmacologia , Chlamydia trachomatis/efeitos dos fármacos , Preparações de Ação Retardada , Diarreia/induzido quimicamente , Diarreia/prevenção & controle , Método Duplo-Cego , Farmacorresistência Bacteriana , Feminino , Humanos , Japão/epidemiologia , Neisseria gonorrhoeae/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Doenças Bacterianas Sexualmente Transmissíveis/diagnóstico , Doenças Bacterianas Sexualmente Transmissíveis/epidemiologia , Distribuição Tecidual
18.
Jpn J Antibiot ; 63(2): 171-7, 2010 Apr.
Artigo em Japonês | MEDLINE | ID: mdl-20919497

RESUMO

Administrations of antimicrobial agent influence human intestinal flora, and sometimes lead to cause Clostridium difficile colitis (CDC). It has been well known that antimicrobial agents, such as clindamycin (CLDM), ampicillin (ABPC) and cephems, frequently cause C. difficile colitis, however, recently some respiratory quinolones, such as garenoxacin (GRNX) and moxifloxacin (MFLX), have paid to attention. Bifidobacterium species would be highly associated with the preservation of normal intestinal flora, while C. difficile would be associated with diarrhea related with antibiotics administration. We investigated antimicrobial activity of GRNX, MFLX and levofloxacin (LVFX) by agar dilution methods based on CLSI recommendations. Forty-seven strains Bifidobacterium species isolated from healthy human intestinal flora and 51 strains of C. difficile isolated from C. difficile colitis patients between 2004 and 2006 were subjected to this study. MIC ranges of Bifidobacterium species for GRNX, MFLX and LVFX were 0.5-16, 0.06-2, and 0.5-8 microg/mL, respectively. MIC50 s of GRNX, MFLX and LVFX against Bifidobacterium species were 2, 0.5 and 4 microg/mL, respectively. MIC90 s of GRNX, MFLX and LVFX against Bifidobacterium species were 8, 2 and 8 microg/mL, respectively. MIC ranges of C. difficile for GRNX, MFLX and LVFX were 0.5 - > 64, 1-64, and 0.125-32 microg/mL, respectively. MIC50s of GRNX, MFLX and LVFX against C. difficile were 2, 2 and 0.5 microg/mL, respectively. MIC90 s of GRNX, MFLX and LVFX against C. difficile were 64, 16 and 8 microg/mL, respectively. LVFX would preserve Bifidobacterium species, and also would be bactericidal for C. difficile, which might lead to the low rate of gastrointestinal disorder in LVFX. GRNX would preserve Bifidobacterium species, however, might be lead to CDC in some cases, since antimicrobial activity for C. difficile has been weak compared with LVFX. Since MFLX would be bactericidal for Bifidobacterium species and antibacterial activity of MFLX for C. difficile would be weak compared with LVFX, we have to pay attention to antibiotics associated diarrhea in MFLX treatment.


Assuntos
Antibacterianos/farmacologia , Bifidobacterium/efeitos dos fármacos , Clostridioides difficile/efeitos dos fármacos , Quinolonas/farmacologia , Administração Oral , Antibacterianos/efeitos adversos , Bifidobacterium/isolamento & purificação , Clostridioides difficile/isolamento & purificação , Farmacorresistência Bacteriana , Enterocolite Pseudomembranosa/microbiologia , Humanos , Intestinos/microbiologia
19.
Cancer Sci ; 101(1): 188-95, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19843072

RESUMO

This phase I, open-label study investigated the Toll-like receptor 9 agonist, PF-3512676, in combination with carboplatin and paclitaxel in Japanese patients with advanced, non-small-cell lung cancer (NSCLC). Patients (n = 12) with treatment-naive stage IIIB or IV NSCLC received single-agent PF-3512676 subcutaneously once during the first 7 days (monotherapy phase) in three escalating dose levels (0.1, 0.2, and 0.4 mg/kg) followed by a combination phase during which patients received 0.1 or 0.2 mg/kg PF-3512676 subcutaneously on days 8 and 15 of each 3-week cycle of carboplatin (area under the curve, 6 mg x min/mL) and paclitaxel (200 mg/m(2)). Safety and pharmacokinetics of PF-3512676 were assessed during monotherapy and combination therapy phases. PF-3512676 was tolerable as monotherapy or in combination with chemotherapy in patients with NSCLC. Most common treatment-related, non-hematologic adverse events (AEs) throughout the study were injection-site reactions (n = 12, 100%) and flu-like symptoms (n = 11, 91.7%) that were each grade 1 or 2 in all but one patient. All patients experienced neutropenia and leukopenia (>or=grade 3 in 11 [91.7%] and seven [58.3%] patients, respectively). One patient in dose level 2 had a dose-limiting toxicity: grade 3 rash and grade 3 increase in gamma-glutamyltransferase during combination therapy. Mean PF-3512676 half-life ranged from 4.8 to 21.6 h (longer with higher doses). Four (33%) patients had objective responses (one complete response, three partial responses), and seven (58%) patients achieved stable disease. PF-3512676 as monotherapy and in combination with chemotherapy had an acceptable safety profile in Japanese patients with treatment-naive NSCLC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oligodesoxirribonucleotídeos/administração & dosagem , Receptor Toll-Like 9/antagonistas & inibidores , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligodesoxirribonucleotídeos/efeitos adversos , Oligodesoxirribonucleotídeos/farmacocinética , Paclitaxel/administração & dosagem
20.
Jpn J Antibiot ; 62(5): 415-34, 2009 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-20055119

RESUMO

We investigated antifungal susceptibility of 96 Candida species strains (37 strains of Candida albicans, 30 of Candida glabrata, 16 of Candida tropicalis and 13 of Candida parapsilosis) isolated from patients with invasive fungal peritonitis. Antifungal activity showed micafungin (MCFG), voriconazole (VRCZ)>itraconazole (ITCZ)>fluconazole (FLCZ). Judged by clinical breakpoints of Clinical and Laboratory Standards Institute (CLSI), FLCZ-resistant C. albicans, ITCZ-resistant C. albicans and VRCZ-resistant C. albicans were detected in the frequency of 5.4% (2/37), 21.6% (8/37) and 5.4% (2/37), respectively. We also retrospectively investigated the association of both antifungal susceptibility judged by CLSI breakpoints and clinical efficacy in 16 patients with invasive fungal peritonitis treated by injectable ITCZ. Clinical success and failure were obtained in cases of ITCZ MIC < or = 1 microg/mL and > or = 4 microg/ml, respectively. We conclude that we should re-consider CLSI breakpoints on ITCZ.


Assuntos
Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Candida/efeitos dos fármacos , Candida/isolamento & purificação , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Itraconazol/uso terapêutico , Peritonite/tratamento farmacológico , Peritonite/microbiologia , Idoso , Candida/classificação , Farmacorresistência Fúngica , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos
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