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PURPOSE: Edaravone is a neuroprotective agent approved as an intravenous treatment for amyotrophic lateral sclerosis (ALS). The intravenous administration of edaravone places a burden on patients and there is a clinical need for oral agents for the treatment of ALS. This report aimed to assess the pharmacokinetics and safety of an edaravone oral suspension in patients with ALS after oral and percutaneous endoscopic gastrostomy (PEG) tube administration. METHODS: Two single-dose, open-label phase 1 clinical studies were conducted. Edaravone oral suspension (105 mg of edaravone in 5 mL aqueous suspension) was administered orally and via PEG tube to 9 and 6 Japanese patients with ALS, respectively. Plasma and urinary pharmacokinetics of unchanged edaravone and its metabolites (sulfate and glucuronide conjugates) were determined. Safety was also evaluated. FINDINGS: After reaching maximum plasma concentration, the mean plasma concentration-time of unchanged edaravone showed a triphasic elimination. Mean plasma concentration-time profiles of the metabolites were higher than those of unchanged edaravone. The mean urinary excretion ratios were higher for the glucuronide conjugate than for either unchanged edaravone or the sulfate conjugate. In patients administered edaravone orally, a single adverse event occurred (blood urine present), which was mild and improved without medical intervention. No adverse drug reactions or serious adverse events were reported. In patients administered edaravone via PEG tube, 5 treatment-emergent adverse events were reported in 3 patients; none were related to the study drug. No adverse drug reactions were reported. IMPLICATIONS: In patients with ALS, a single dose of edaravone oral suspension was well absorbed and mainly eliminated in urine as the glucuronide conjugate. No safety concerns emerged. Pharmacokinetics were similar to those previously reported in healthy participants following oral administration. This indicates that effective drug concentrations were achieved and edaravone can be successfully administered both orally and via a PEG tube in patients with ALS. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT04176224 (oral administration) and NCT04254913 (PEG tube administration), www. CLINICALTRIALS: gov.
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Esclerose Lateral Amiotrófica , Fármacos Neuroprotetores , Humanos , Esclerose Lateral Amiotrófica/tratamento farmacológico , Edaravone/farmacocinética , Glucuronídeos/uso terapêutico , Fármacos Neuroprotetores/farmacocinética , Sulfatos/uso terapêuticoRESUMO
INTRODUCTION/AIMS: An intravenous (IV) formulation of edaravone has been shown to slow the rate of physical functional decline in amyotrophic lateral sclerosis (ALS). An oral suspension formulation of edaravone was recently approved by the United States Food and Drug Administration for use in patients with ALS. This study assessed the safety and tolerability of oral edaravone. METHODS: This global, open-label, phase 3 study evaluated the long-term safety and tolerability of oral edaravone in adults with ALS who had a baseline forced vital capacity ≥70% of predicted and disease duration ≤3 y. The primary safety analysis was assessed at weeks 24 and 48. Patients received a 105-mg dose of oral edaravone in treatment cycles replicating the dosing of IV edaravone. RESULTS: The study enrolled 185 patients (64.3% male; mean age, 59.9 y; mean disease duration, 1.56 y). The most common treatment-emergent adverse events (TEAEs) at week 48 were fall (22.2%), muscular weakness (21.1%) and constipation (17.8%). Serious TEAEs were reported by 25.9% of patients; the most common were worsening ALS symptoms, dysphagia, dyspnea, and respiratory failure. Twelve TEAEs leading to death were reported. Forty-six (24.9%) patients reported TEAEs that were considered related to study drug; the most common were fatigue, dizziness, headache, and constipation. Sixteen (8.6%) patients discontinued study drug due to TEAEs. No serious TEAEs were related to study drug. DISCUSSION: This study indicated that oral edaravone was well tolerated during 48 wk of treatment, with no new safety concerns identified.
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Esclerose Lateral Amiotrófica , Edaravone , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Administração Oral , Esclerose Lateral Amiotrófica/tratamento farmacológico , Constipação Intestinal , Edaravone/administração & dosagem , Edaravone/efeitos adversosRESUMO
Intravenous edaravone is used to treat patients with amyotrophic lateral sclerosis. This randomized, open-label, two-way crossover, single-dose phase 1 study compared the relative bioavailability of a newly developed edaravone oral suspension when administered orally and via a nasogastric tube (NGT) as a model of percutaneous endoscopic gastrostomy tube administration in healthy adult subjects. Thirty-six subjects were randomly assigned to one of two groups, with 18 per group. Blood was collected pre- and post-dose for pharmacokinetic assessments; safety was evaluated. Plasma concentration-time profiles of unchanged edaravone were similar between administration routes. Comparative bioavailability analysis revealed that geometric least squares mean ratios (NGT/oral) for maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity of unchanged edaravone were 1.052 and 0.981, respectively. No serious adverse events or adverse drug reactions were reported. These results suggest that oral edaravone suspension can be administered directly to the stomach without dose adjustment via feeding tubes; both oral and NGT administration are well tolerated.
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Intubação Gastrointestinal , Humanos , Adulto , Edaravone/efeitos adversos , Disponibilidade Biológica , Administração OralRESUMO
PURPOSE: The safety and efficacy of intravenous edaravone, a neuroprotectant used for the treatment of amyotrophic lateral sclerosis (ALS), have been shown in clinical trials. An oral suspension of edaravone has been developed, but the food effect on its pharmacokinetic profile has not been evaluated. This study aimed to assess the food effect on the pharmacokinetic profile of edaravone after oral administration and to investigate dosing regimens and administration instructions with different meal intake and timing. METHODS: Data from 3 Phase I clinical studies were used to evaluate the effect of food on the pharmacokinetic profiles of a single dose of edaravone oral suspension. In all 3 studies, participants received a single dose of edaravone with various meal conditions. Healthy Japanese adult male participants (Studies 1, 2, and 3) or female participants (Study 3) aged 20 to 45 years at the time of informed consent were included. FINDINGS: In Study 1, 6 participants were enrolled and 5 completed the study. Nine and 16 participants were treated in Studies 2 and 3, respectively, and all completed the study. The Cmax and AUC0-∞ of edaravone were lower when administered 30 minutes after a high-fat meal compared with those in a fasted condition (Study 1). Lower plasma edaravone concentrations (approximately within the first hour) and subsequent lower Cmax and AUC0-∞ were observed after administration of edaravone 4 hours after a high-fat meal (Study 2) or 2 hours after a low-fat meal (Study 3). The Cmax and AUC0-∞ of oral edaravone were generally similar and not affected when administered 8 hours after a high-fat meal, 4 hours after a low-fat meal, or 2 hours after a light meal relative to the fasted condition. Administration of edaravone 1 hour before a high-fat meal resulted in no effect on Cmax or AUC0-∞ relative to the fasted condition. Administration of edaravone in the fed or fasted conditions resulted in a similar urine pharmacokinetic profile. IMPLICATIONS: Oral administration of edaravone with a meal decreased the plasma concentration of edaravone. Oral administration of edaravone 8 hours after a high-fat meal, 4 hours after a low-fat meal, 2 hours after a light meal, and 1 hour before a high-fat meal showed no effect of food on the PK profile of unchanged edaravone compared with that observed under a fasted condition. CLINICALTRIALS: gov identifiers: NCT04481750, NCT04481789, and NCT05342597.
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Jejum , Interações Alimento-Droga , Adulto , Feminino , Humanos , Masculino , Administração Oral , Área Sob a Curva , Disponibilidade Biológica , Estudos Cross-Over , Edaravone , Voluntários SaudáveisRESUMO
The neuroprotective agent edaravone is an intravenous treatment for amyotrophic lateral sclerosis. As intravenous administration burdens patients, orally administered treatments are needed. This phase 1, open-label, single-dose crossover study in 42 healthy adults evaluated bioequivalence of a 105-mg edaravone oral suspension and intravenous edaravone (60 mg/60 min). The evaluation was whether the 90% confidence intervals (CIs) for the ratio of the maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity of unchanged edaravone were between the bioequivalence limit of 0.80 and 1.25. Metabolic profiles and elimination pathways were also compared between the 2 routes. Geometric mean ratios and 90%CIs of area under the plasma concentration-time curve from time 0 to the last quantifiable time point and to infinity for unchanged edaravone satisfied bioequivalence limits. The geometric mean ratio and its lower limit of 90%CI of Cmax of the 105-mg oral suspension compared with 60-mg intravenous formulations for unchanged edaravone fell within bioequivalence limits. Both formulations showed triphasic plasma concentration-time profiles of unchanged edaravone after reaching Cmax . Plasma concentrations of edaravone inactive metabolites after oral administration were higher than with intravenous administration. Edaravone in both routes underwent urinary excretion, mainly as the glucuronide conjugate and, to a lesser extent, as the sulfate conjugate. Urinary excretion of unchanged edaravone was low, and urinary relative composition ratios of unchanged edaravone and metabolites were similar for both formulations. These findings showed equivalent exposure of the 105-mg oral suspension of edaravone to the 60-mg intravenous formulation, supporting further investigation of the oral suspension for treating amyotrophic lateral sclerosis.
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Composição de Medicamentos/métodos , Edaravone/administração & dosagem , Edaravone/metabolismo , Sequestradores de Radicais Livres/administração & dosagem , Sequestradores de Radicais Livres/metabolismo , Administração Oral , Adolescente , Adulto , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Suspensões , Equivalência Terapêutica , Adulto JovemRESUMO
Edaravone is a low-molecular-weight antioxidant drug targeting peroxyl radicals among many types of reactive oxygen species. Because of its amphiphilicity, it scavenges both lipid- and water-soluble peroxyl radicals by donating an electron to the radical. Thus, it inhibits the oxidation of lipids by scavenging chain-initiating water-soluble peroxyl radicals and chain-carrying lipid peroxyl radicals. In 2001, it was approved in Japan as a drug to treat acute-phase cerebral infarction, and then in 2015 it was approved for amyotrophic lateral sclerosis (ALS). In 2017, the U.S. Food and Drug Administration also approved edaravone for treatment of patients with ALS. Its mechanism of action was inferred to be scavenging of peroxynitrite. In this review, we focus on the radical-scavenging characteristics of edaravone in comparison with some other antioxidants that have been studied in clinical trials, and we summarize its pharmacological action and clinical efficacy in patients with acute cerebral infarction and ALS.
RESUMO
BACKGROUND: There is an increasing clinical research focus on neuroprotective agents in amyotrophic lateral sclerosis (ALS). However, it is unclear how generalisable clinical study trial results are between different countries and regions. OBJECTIVE: To assess similarities and differences in clinical practice and treatment guidelines for ALS, and also to compare the demographics and rate of progression of disease in patients with ALS enrolled in clinical trials in Japan, the US, and Europe. METHODS: We performed a review of clinical studies published since 2000 to compare the demographics and characteristics of patients with ALS. Progression of ALS disease was assessed in patients receiving placebo. The changes per month in ALSFRS-R score were calculated and compared between the studies. RESULTS: Overall, diagnostic criteria, recognition of ALS symptoms, comorbidities, use of riluzole, and nutritional, and respiratory support were similar. Regarding demographics and characteristics, there were no clear differences in the incidence of sporadic ALS (range 91-98%), bulbar onset (range 11-41%), and median time from onset to diagnosis (range 9-14 months) among the populations despite the difference in race between regions. However, use of tracheostomy-based invasive respiratory support was higher in Japan (29-38%) than in the US (4%) and Europe (1-31%). Rate of progression of disease was similar between the US and Europe study populations (range -0.89 to -1.60 points/month), and the Japanese study populations (range -1.03 to -1.21 points/month). CONCLUSION: There is evidence to support the generalisability of data from the Japanese ALS trial experience to the US and Europe populations in early to mid-stage of ALS.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Demografia/normas , Progressão da Doença , Guias de Prática Clínica como Assunto/normas , Esclerose Lateral Amiotrófica/tratamento farmacológico , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/normas , Demografia/métodos , Europa (Continente)/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Fármacos Neuroprotetores/uso terapêutico , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: The treatment strategy for diffuse large B-cell lymphoma (DLBCL) in elderly patients is problematic. Although several researchers have reported the effectiveness of comprehensive geriatric assessment (CGA) and the futility of curative treatment in 'unfit' patients with DLBCL, these propositions are not firmly established. PATIENTS AND METHODS: We conducted a retrospective analysis using a database. Patients with DLBCL were eligible if ⧠60 yr old. CGA stratification was performed using medical records. RESULTS: One hundred and 35 patients were identified. Anthracycline-based chemotherapy with curative intent was performed in 115 (85%) patients. According to CGA, 82 (61%) patients were classified as 'fit'. Their 1-yr overall survival (OS) was significantly better than that of 'unfit' patients [91.3% vs. 53.8%, P < 0.001]. Patients classified as 'unfit' treated with curative intent had a significantly better 1-yr OS when compared with those receiving palliative measures [66.1% vs. 19.0%, P < 0.001]. CONCLUSIONS: CGA is an effective tool for predicting outcomes in older patients with DLBCL. The patients treated with curative intent had significantly better outcomes compared with those receiving palliation, irrespective of CGA stratification. Curative treatment should be considered even for 'unfit' patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Avaliação Geriátrica , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Seleção de Pacientes , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
A 77-year-old man was diagnosed with cold agglutinin disease in 2004. He had been treated with prednisolone with stabilization of hemoglobin in the 6- to 8-g/dl range. However, his hemolytic anemia worsened, and computed tomography showed systemic lymphadenopathy in May 2012. A pathological diagnosis of small lymphocytic lymphoma was made based on an inguinal lymph node biopsy. Treatment was started with rituximab. However, there was no response to 6 doses of rituximab monotherapy. He next received 6 courses of bendamustine in combination with rituximab. This resulted in stabilization of hemoglobin and independence from transfusion support. To the best of our knowledge, this is only the second case report describing bendamustine plus rituximab treatment for non-Hodgkin lymphoma complicated by cold agglutinin disease. Our results in this case suggest bendamustine to potentially be a useful therapeutic option in patients with cold agglutinin disease.
Assuntos
Anemia Hemolítica Autoimune/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Compostos de Mostarda Nitrogenada/uso terapêutico , Idoso , Anticorpos Monoclonais Murinos/administração & dosagem , Cloridrato de Bendamustina , Humanos , Masculino , Compostos de Mostarda Nitrogenada/administração & dosagem , Rituximab , Resultado do TratamentoRESUMO
Transverse myelitis is an inflammatory disorder of the spinal cord that results in motor, sensory, and autonomic dysfunction. Herein, we describe a 40-year-old Japanese female who developed acute transverse myelitis (ATM) after an unrelated bone marrow transplantation for Philadelphia-positive acute lymphoblastic leukemia in molecular complete remission. Approximately 90 days after transplantation, she suffered from paresthesias, sphincter dysfunction, and lower extremity weakness. Spinal cord magnetic resonance imaging scan demonstrated findings consistent with ATM. The symptoms were resolved with the administration of steroids, followed by intravenous immunoglobulin therapy for a few sequelae. To the best of our knowledge, the presentation of ATM after hematopoietic stem cell transplantation is relatively rare. As the functional prognosis of ATM depends on prompt diagnosis and treatment, we consider that ATM should be included in the differential diagnosis of post-transplant myelopathies.
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Transplante de Medula Óssea/efeitos adversos , Mielite Transversa/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/cirurgia , Doença Aguda , Adulto , Feminino , Humanos , Transplante HomólogoRESUMO
A desiccation-tolerant cyanobacterium, Nostoc commune, shows unique responses to dehydration. These responses are: (i) loss of PSII activity in parallel with the loss of photosynthesis; (ii) loss of PSI activity; and (iii) dissipation of light energy absorbed by pigment-protein complexes. In this study, the deactivation of PSII is shown to be important in avoiding photoinhibition when the Calvin-Benson cycle is repressed by dehydration. Furthermore, our evidence suggests that dissipation of light energy absorbed by PSII blocks photoinhibition under strong light in dehydrated states.
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Dessecação , Nostoc commune/metabolismo , Nostoc commune/efeitos da radiação , Água/metabolismo , Fotossíntese/fisiologia , Fotossíntese/efeitos da radiação , Complexo de Proteína do Fotossistema I/metabolismo , Complexo de Proteína do Fotossistema II/metabolismo , TemperaturaRESUMO
Virulence mechanism of infection with Mycobacterium tuberculosis is currently focused to be clarified in the context of cell surface lipid molecule. Comparing two mycobacterial glycolipids, we observed toxicity and prominent granulomatogenic activity of trehalose 6,6'-dimycolate (TDM) injection in mice, evident by delayed body weight gain and histological observations, whereas 2,3,6,6'-tetraacyl trehalose 2'-sulfate (SL) was non-toxic and non-granulomatogenic. Likewise, TDM but not SL caused temporarily, but marked increase of lung indices, indicative of massive granuloma formation. Interestingly, co-administration of TDM and SL prevented these symptoms distinctively and SL inhibited TDM-induced release of tumor necrosis factor alpha (TNF-alpha) in a dose-dependent manner. Histological findings and organ index changes also showed marked inhibition of TDM induced granuloma formation by co-administration of SL. Simultaneous injection of SL together with TDM was highly effective for this protection, as neither injection 1h before nor after TDM injection showed highly inhibitory. In parallel studies on a cellular level, TDM elicited strong TNF-alpha release from alveolar but not from peritoneal macrophages in vitro. This effect was blocked when alveolar macrophages were incubated in wells simultaneously coated with TDM and SL, indicating that SL suppresses TDM-induced TNF-alpha release from macrophages. Our results suggest a novel mechanism by which SL could contribute to virulence at early stage of mycobacterial infection or stimulation with the glycolipids by counteracting the immunopotentiating effect of TDM.
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Fatores Corda/antagonistas & inibidores , Fatores Corda/toxicidade , Glicolipídeos/toxicidade , Granuloma/induzido quimicamente , Mycobacterium tuberculosis/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Fatores Corda/metabolismo , Glicolipídeos/metabolismo , Granuloma/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos ICR , Especificidade da Espécie , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fatores de VirulênciaRESUMO
A case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is reported. A 27-year-old man presented with fever and abdominal swelling. His laboratory examination revealed pancytopenia and liver dysfunction. The diagnosis of SPTCL was made by biopsy based on thickened subcutaneous tissue. In addition, bone marrow specimen showed a hemophagocytosis syndrome (HPS). Methylprednisolone pulse therapy was initiated followed by prednisolone (60 mg/day) and cyclosporin A (150 mg/day). He responded to the treatment and remained asymptomatic for at least for 6 months. Our results suggest that a trial of cyclosporin A is warranted in patients with SPTCL complicated by HPS.
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Antineoplásicos Hormonais/administração & dosagem , Ciclosporina/administração & dosagem , Imunossupressores/administração & dosagem , Linfoma de Células T/tratamento farmacológico , Paniculite/tratamento farmacológico , Prednisolona/administração & dosagem , Adulto , Quimioterapia Combinada , Humanos , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Linfoma de Células T/complicações , Linfoma de Células T/patologia , Masculino , Paniculite/complicações , Paniculite/patologia , Indução de RemissãoRESUMO
To evaluate the results of high-dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with diffuse B-cell aggressive non-Hodgkin's lymphoma(NHL). Between 1991 and 2004, 25 patients who did not achieve complete remission and 26 in complete remission from conventional chemotherapy received HDC-ASCT. Of 25 patients with refractory NHL,14 were chemotherapy-sensitive before HDT-ASCT and 11 were chemotherapy-resistant. CR was achieved after HDC-ASCT in 50% of 14 chemotherapy sensitive patients and in none of 11 chemotherapy-resistant patients. The 5-year probability of event-free survival for chemotherapy-sensitive and chemotherapy-resistant patients was 51.3% and 20.8%, respectively (p<0.05, log-rank test). Moreover, the 5-year probability of event-free survival for patients in the low-risk group with International Prognostic Index (IPI) and in the high-risk group with IPI was 75.0% and 16.3%, respectively (p<0.05, log-rank test). HDT-ASCT should be considered for patients with refractory aggressive NHL who are chemotherapy-sensitive rather than chemotherapy-resistant. Twenty-six patients in complete remission received consolidation therapy with HDT-ASCT. The 5-year probability of disease-free survival for patients in the low-risk group and in the high-risk group was 68.8% and 60.0%,respectively (p = 0.9 6). HDT-ASCT should be considered for patients at high risk who achieve complete remission after induction treatment. In future, HDT-ASCT combined with rituximab as induction therapy or as consolidation therapy is needed for patients with aggressive NHL in the high-risk group.
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Transplante de Células-Tronco Hematopoéticas , Linfoma de Células B/terapia , Linfoma Difuso de Grandes Células B/terapia , Transplante Autólogo , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/administração & dosagem , Terapia Combinada , Ciclofosfamida/administração & dosagem , Citarabina/administração & dosagem , Intervalo Livre de Doença , Esquema de Medicação , Etoposídeo/administração & dosagem , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Compostos de Nitrosoureia/administração & dosagem , Indução de Remissão , Resultado do TratamentoRESUMO
We experienced the VNCOP-B (etoposide, mitoxantrone, cyclophosphamide, vincristine, predonisolone, bleomycin) combination regimen for the treatment of elderly patients with aggressive non-Hodgkin lymphoma (NHL) in a multicenter study by 6 collaborative institutions. Patients were previously untreated > or = 60 years of age and received prophylactic G-CSF. Twenty patients entered this trial, and all of them were evaluated for feasibility, toxicity, and efficacy. The complete remission rate was 75.0%, with a 100% overall response rate; overall survival (OS) rate at 3 years was 79.1% (median follow up 761.5 days), with a 60.7% progression-free 3-year survival (PFS) rate (median follow-up 600.0 days). Our trial was promising and well-tolerated. According to IPI, high/high-intermediate risk was associated with significantly worse OS and PFS than low/low-intermediate risk (2-year OS: 51.8% versus 100.0%, p=0.0118; 2-year PFS: 33.3% versus 80.0%, p=0.0125). Grade 3/4 infections occurred in 3 patients, but no patients experienced it with predonisolone reduced.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma não Hodgkin/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bleomicina/administração & dosagem , Bleomicina/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Esquema de Medicação , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Estudos de Viabilidade , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Linfoma não Hodgkin/mortalidade , Masculino , Pessoa de Meia-Idade , Mitoxantrona/administração & dosagem , Mitoxantrona/efeitos adversos , Neutropenia/induzido quimicamente , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Indução de Remissão , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Changes in photosynthetic activities under hypertonic conditions were studied in a terrestrial, highly desiccation-tolerant cyanobacterium, Nostoc commune, and in some desiccation-sensitive cyanobacteria. The amounts of water sustained in the colony matrix outside the N. commune cells and the cellular solute concentration were estimated by measuring the water potential, and the solute concentration was supposed to correspond to around 0.22 M sorbitol. Incubation of the colonies in 0.8 M sorbitol solution inhibited the energy transfer from the phycobilisome (PBS) anchor to PSII core complexes. At higher sorbitol concentrations, light energy absorbed by PSI, PSII, and PBS was dissipated to heat. PSI and cyclic electron flow around PSI was also deactivated by hypertonic treatment. Fv/Fm and (Fm'-F)/Fm' values started to decrease at 0.6 and 0.3 M sorbitol and reached zero at 1.0 and 0.8 M, respectively. Decreases in these two fluorescence parameters corresponded to the decreases in PSII fluorescence (F695) and photosynthetic CO2 fixation, respectively. The intensity of delayed light emission started to decrease at 1.0 M sorbitol and became negligible at 4.0 M. Comparing these changes in N. commune with those in desiccation-sensitive species, we found that N. commune cells actively deactivates photosynthetic systems on sensing water loss.
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Cianobactérias/metabolismo , Desidratação/metabolismo , Fotossíntese/fisiologia , Equilíbrio Hidroeletrolítico/fisiologia , Dióxido de Carbono/metabolismo , Cianobactérias/efeitos dos fármacos , Cianobactérias/genética , Transporte de Elétrons/efeitos dos fármacos , Transporte de Elétrons/genética , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Soluções Hipertônicas/farmacologia , Luz , Pressão Osmótica/efeitos dos fármacos , Oxirredução/efeitos dos fármacos , Fotossíntese/efeitos dos fármacos , Equilíbrio Hidroeletrolítico/efeitos dos fármacosRESUMO
The Wilms tumor gene, WT1, is overexpressed not only in leukemias and myelodysplastic syndrome (MDS) but also in various types of solid tumors, including lung and breast cancer, and the WT1 protein is a tumor antigen for these malignancies. In clinical trials of WT1 peptide-based cancer immunotherapy, patients with overt leukemia from MDS or MDS with myelofibrosis were injected intradermally with 0.3 mg of an HLA-A*2402-restricted, 9-mer WT1 peptide emulsified with Montanide ISA51 adjuvant. Only a single dose of WT1 vaccination resulted in an increase in WT1-specific cytotoxic T-lymphocytes, which was followed by a rapid reduction in leukemic blast cells. Severe leukopenia and local erythema at the injection sites of WT1 peptide were observed as adverse effects. These results have provided us with the first clinical evidence suggesting that WT1 peptide-based immunotherapy is an attractive treatment for patients with leukemias or MDS.
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Antígenos de Neoplasias/administração & dosagem , Imunoterapia/métodos , Leucemia/terapia , Síndromes Mielodisplásicas/patologia , Proteínas WT1/imunologia , Idoso , Antígenos de Neoplasias/uso terapêutico , Feminino , Antígenos HLA-A/administração & dosagem , Antígenos HLA-A/uso terapêutico , Humanos , Leucemia/etiologia , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/imunologia , Fragmentos de Peptídeos/uso terapêutico , Mielofibrose Primária/patologia , Resultado do Tratamento , VacinaçãoRESUMO
We report four cases with spinal non-Hodgkin's lymphoma (3 male and 1 female, 33 to 58 years old). On administration, back pain progressing to paraplegia was observed in all cases. Sphincter dysfunction was observed in two cases. Magnetic resonance imaging (MRI) studies were most useful for the clinical diagnosis of spinal lymphoma. Diffuse large B cell lymphoma was revealed from immunohistochemical studies of bone biopsies. The patients' clinical stagings were IV in three and I E in one case. One case treated by surgery followed by chemotherapy (CMT) and radiation therapy (RT) resulted in progressive disease. RT followed by CMT was given in the other cases. Two cases showed a partial response and one died from progressive disease. In all cases, either surgical or radiation therapy was helpful for the amelioration of the patients' progressive paraplegia and sphincter dysfunction.
Assuntos
Linfoma não Hodgkin/diagnóstico , Neoplasias da Coluna Vertebral/diagnóstico , Adulto , Terapia Combinada , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Linfoma não Hodgkin/patologia , Linfoma não Hodgkin/terapia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neoplasias da Coluna Vertebral/patologia , Neoplasias da Coluna Vertebral/terapia , Resultado do TratamentoRESUMO
Recovery processes of photosynthetic systems during rewetting were studied in detail in a terrestrial, highly drought-tolerant cyanobacterium, Nostoc commune. With absorption of water, the weight of N. commune colony increased in three phases with half-increase times of about 1 min, 2 h and 9 h. Fluorescence intensities of phycobiliproteins and photosystem (PS) I complexes were recovered almost completely within 1 min, suggesting that their functional forms were restored very quickly. Energy transfer from allophycocyanin to the core-membrane linker peptide (L(CM)) was recovered within 1 min, but not that from L(CM) to PSII. PSI activity and cyclic electron flow around PSI recovered within 2 min, while the PSII activity recovered in two phases after a time lag of about 5 min, with half times of about 20 min and 2 h. Photosynthetic CO(2) fixation was restored almost in parallel with the first recovery phase of the PSII reaction center activity. Although the amount of absorbed water became more than 20 times the initial dry weight of the N. commune colony in the presence of sufficient water, about twice the initial dry weight was enough for recovery and maintenance of the PSII activity.