RESUMO
Human schistosomiasis is a neglected tropical disease caused by Schistosoma mansoni, S. haematobium, and S. japonicum. Praziquantel (PZQ) is the method of choice for treatment. Due to constant selection pressure, there is an urgent need for new therapies for schistosomiasis. Previous treatment of S. mansoni included the use of oxamniquine (OXA), a drug that is activated by a schistosome sulfotransferase (SULT). Guided by data from X-ray crystallography and Schistosoma killing assays more than 350 OXA derivatives were designed, synthesized, and tested. We were able to identify CIDD-0150610 and CIDD-0150303 as potent derivatives in vitro that kill (100%) of all three Schistosoma species at a final concentration of 71.5 µM. We evaluated the efficacy of the best OXA derivates in an in vivo model after treatment with a single dose of 100 mg/kg by oral gavage. The highest rate of worm burden reduction was achieved by CIDD -150303 (81.8%) against S. mansoni, CIDD-0149830 (80.2%) against S. haematobium and CIDD-066790 (86.7%) against S. japonicum. We have also evaluated the ability of the derivatives to kill immature stages since PZQ does not kill immature schistosomes. CIDD-0150303 demonstrated (100%) killing for all life stages at a final concentration of 143 µM in vitro and effective reduction in worm burden in vivo against S. mansoni. To understand how OXA derivatives fit in the SULT binding pocket, X-ray crystal structures of CIDD-0150303 and CIDD-0150610 demonstrate that the SULT active site will accommodate further modifications to our most active compounds as we fine tune them to increase favorable pharmacokinetic properties. Treatment with a single dose of 100 mg/kg by oral gavage with co-dose of PZQ + CIDD-0150303 reduced the worm burden of PZQ resistant parasites in an animal model by 90.8%. Therefore, we conclude that CIDD-0150303, CIDD-0149830 and CIDD-066790 are novel drugs that overcome some of PZQ limitations, and CIDD-0150303 can be used with PZQ in combination therapy.
Assuntos
Anti-Helmínticos , Esquistossomose mansoni , Esquistossomose , Animais , Humanos , Praziquantel/farmacologia , Praziquantel/química , Oxamniquine/farmacologia , Esquistossomose/tratamento farmacológico , Esquistossomose/parasitologia , Schistosoma mansoni , Terapia Combinada , Doenças Negligenciadas/tratamento farmacológico , Esquistossomose mansoni/tratamento farmacológico , Esquistossomose mansoni/parasitologiaRESUMO
Glioblastoma (GBM) is the most prevalent and aggressive type of adult brain tumors with low 5-year overall survival rates. Epidemiologic data suggest that estrogen may decrease brain tumor growth, and estrogen receptor beta (ERß) has been demonstrated to exert antitumor functions in GBM. The lack of potent, selective, and brain permeable ERß agonist to promote its antitumor action is limiting the therapeutic promise of ERß. In this study, we discovered that Indanone and tetralone-keto or hydroxyl oximes are a new class of ERß agonists. Because of its high activity in ERß reporter assays, specific binding to ERß in polar screen assays, and potent growth inhibitory activity in GBM cells, CIDD-0149897 was discovered as a possible hit by screening a library of compounds. CIDD-0149897 is more selective for ERß than ERα (40-fold). Treatment with CIDD-0149897 markedly reduced GBM cell viability with an IC50 of â¼7 to 15 µmol/L, while having little to no effect on ERß-KO cells and normal human astrocytes. Further, CIDD-0149897 treatment enhanced expression of known ERß target genes and promoted apoptosis in established and patient-derived GSC models. Pharmacokinetic studies confirmed that CIDD-0149897 has systemic exposure, and good bioavailability in the brain. Mice tolerated daily intraperitoneal treatment of CIDD-0149897 (50 mg/kg) with a 7-day repeat dosage with no toxicity. In addition, CIDD-0149897 treatment significantly decreased tumor growth in U251 xenograft model and extended the survival of orthotopic GBM tumor-bearing mice. Collectively, these findings pointed to CIDD-0149897 as a new class of ERß agonist, offering patients with GBM a potential means of improving survival.
Assuntos
Neoplasias Encefálicas , Glioblastoma , Humanos , Camundongos , Animais , Glioblastoma/patologia , Receptor beta de Estrogênio/genética , Linhagem Celular Tumoral , Encéfalo/metabolismo , Estrogênios , Neoplasias Encefálicas/patologiaRESUMO
Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.
Assuntos
Antivirais/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio/fisiologia , Ebolavirus/fisiologia , Doença pelo Vírus Ebola/terapia , Terapia de Alvo Molecular , Internalização do Vírus/efeitos dos fármacos , Animais , Antivirais/uso terapêutico , Células 3T3 BALB , Benzilisoquinolinas/farmacologia , Benzilisoquinolinas/uso terapêutico , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio/genética , Ebolavirus/efeitos dos fármacos , Feminino , Técnicas de Inativação de Genes , Células HeLa , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/virologia , Camundongos , NADP/análogos & derivados , NADP/metabolismo , Interferência de RNA , Transdução de Sinais , Verapamil/farmacologia , Verapamil/uso terapêuticoRESUMO
Patients with acute leukemia develop venous thrombosis (VT) related to central venous catheters (CVCs). Anticoagulation (AC) in these patients who are thrombocytopenic and often coagulopathic is challenging. To evaluate the safety and efficacy of AC in treating CVC-related VT, we retrospectively compared outcomes of patients with acute leukemia who were treated or not with AC during induction chemotherapy and post-discharge. Twenty-one patients with CVC-related VT received AC, 14 did not. VT resolved in 80% of patients in the AC group (similarly with low-dose and high-dose enoxaparin) and 45% in the non-AC group (p = 0.11). Fourteen (67%) patients in the AC group are alive (median survival not reached), compared to four patients (29%) in the non-AC group (median survival 9 months) (p = 0.015) with a hazard ratio (HR) of 0.32 (95% confidence interval: 0.12-0.85) in favor of AC. HR remained < 1 after adjustments for leukemia type and cytogenetics. Bleeding (< grade 4) occurred in five and one patients in the AC vs. non-AC groups, respectively (p = 0.37).
Assuntos
Anticoagulantes/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cateterismo Venoso Central/efeitos adversos , Hemorragia/tratamento farmacológico , Leucemia/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Trombose Venosa/tratamento farmacológico , Doença Aguda , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Seguimentos , Hemorragia/etiologia , Humanos , Leucemia/complicações , Leucemia/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Trombose Venosa/etiologiaRESUMO
The hypomethylating agents azacitidine and decitabine are standard therapy for myelodysplastic syndromes (MDS), and are often used to treat patients with acute myeloid leukemia (AML) unlikely to benefit from cytotoxic chemotherapy. Switching hypomethylating agents after treatment failure is common, but this approach is not well studied. We retrospectively reviewed data on 25 patients with MDS, MDS/myeloproliferative neoplasm (MDS/MPN) or AML who were treated with decitabine after primary or secondary azacitidine failure at the University of Maryland Greenebaum Cancer Center. Five patients with MDS or MDS/MPN achieved stable disease with decitabine, but no patient achieved complete or partial remission or hematologic improvement. Most patients discontinued therapy due to disease progression or death after a median of 2 cycles and median survival was 5.9 months after decitabine initiation. Based on our data, decitabine therapy after azacitidine failure is of little benefit beyond disease stabilization in some patients.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Azacitidina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Decitabina , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Falha de TratamentoRESUMO
FLT3 internal tandem duplication (ITD) mutations are present in acute myeloid leukemia (AML) in 30% of patients with acute myeloid leukemia (AML), most commonly in those with a normal karyotype, and are associated with short relapse-free survival. Both in vitro and in vivo studies of FLT3-ITD cell lines have demonstrated reactive oxygen species-mediated DNA double-strand breaks and associated error-prone DNA repair as a mechanism of genomic instability, and we hypothesized that genomic instability might be manifested by cytogenetic changes at relapse of FLT3-ITD AML. We retrospectively reviewed charts of patients with cytogenetically normal (CN) FLT3-ITD AML treated at the University of Maryland Greenebaum Cancer Center, with attention to metaphase analysis results at relapse. Cytogenetic data were available from first and, when applicable, subsequent relapses for 15 patients diagnosed with CN FLT3-ITD AML. Among 12 patients with documented FLT3-ITD at first and, when applicable, subsequent relapse, 10 had cytogenetic changes, including nine with rare structural abnormalities. The high frequency of rare structural chromosome abnormalities at relapse in our case series supports a role of genomic instability in the genesis of relapse, and suggests that reactive oxygen species-generating and DNA repair pathways might be therapeutic targets in FLT3-ITD AML.
Assuntos
Leucemia Mieloide Aguda/genética , Recidiva Local de Neoplasia/genética , Tirosina Quinase 3 Semelhante a fms/genética , Adulto , Idoso , Aberrações Cromossômicas , Análise Citogenética , Reparo do DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio , Estudos Retrospectivos , Sequências de Repetição em TandemRESUMO
The goal of this research was to identify structurally novel, non-quaternarypyridinium reactivators of GF (cyclosarin)-inhibited hAChE that possess the capacity to mediate in vitro reactivation of GF-inhibited human acetylcholinesterase (hAChE). New compounds were designed, synthesized and assessed in GF-inhibited hAChE assays. Structure activity relationships for AChE binding and reactivation of GF-inhibited hAChE were developed. Lead compounds from two different chemical series, represented by compounds 17 and 38, displayed proficient in vitro reactivation of GF-inhibited hAChE, while also possessing low inhibition of native enzyme.
Assuntos
Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Desenho de Fármacos , Compostos Organofosforados/farmacologia , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Compostos Organofosforados/síntese química , Compostos Organofosforados/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The management of pediatric type I open fractures remains controversial. There has been no consistent protocol established in the literature for the non-operative management of these injuries. METHODS: A protocol was developed at our institution for the non-operative management of pediatric type I open forearm fractures. Each patient was given a dose of intravenous antibiotics at the time of the initial evaluation in the emergency department. The wound was then irrigated and a closed reduction performed in the emergency department. The patient was admitted for three doses of intravenous antibiotics (over approximately a 24-h period) and then discharged home without oral antibiotics. RESULTS: In total, 45 consecutive patients were managed with this protocol at our hospital between 2004 and 2008. The average age was 10 (range 4-17) years. The average number of doses of intravenous antibiotics was 4.06 per patient. Thirty patients (67 %) received cefazolin (Ancef®) as the treating medication and 15 patients received clindamycin (33 %). There were no infections in any of the 45 patients. CONCLUSION: In this study we outline a consistent management protocol for type I open pediatric forearm fractures that has not previously been documented in the literature. Our results corroborate the those reported in the literature that pediatric type I open fractures may be managed safely in a non-operative manner. There were no infections in our prospective series of 45 consecutive type I open pediatric forearm fractures using our protocol. Using a protocol of only four doses of intravenous antibiotics (one in the emergency department and three additional doses during a 24-h hospital admission) is a safe and efficient method for managing routine pediatric type I open fractures non-operatively.
RESUMO
We retrospectively reviewed outcomes in 45 previously untreated patients with acute myeloid leukemia (AML) considered unfit for chemotherapy who were treated with 10-day courses of decitabine 20 mg/m(2) daily outside of a clinical trial, with no cut-offs for organ function or performance status (PS). Nineteen had Eastern Cooperative Group performance status (ECOG PS) ≥ 2, and 39 had ≥ 2 comorbidities. Fourteen patients (31%) achieved complete remission (CR) and five (11%) CR with incomplete count recovery, for an overall response rate of 42%, after a median of 2 (range, 1-4) courses. The only pretreatment characteristic that differed significantly between responders and non-responders was percent marrow blasts (median 42% vs. 65%; p = 0.01). Median overall survival was 9.0 months; it was 19.4 and 2.3 months for responders and non-responders, respectively (p < 0.001). Thus 10-day decitabine therapy has efficacy in patients with AML considered unfit for chemotherapy, and may serve as a backbone for the addition of other novel agents.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Leucemia Mieloide Aguda/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Decitabina , Feminino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
A focused screening strategy identified thienopyrimidine 12 as a cannabinoid receptor type 2 agonist (hCB2) with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a new more polar series of purine CB2 agonists. Examples from this novel scaffold were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1, often having no CB1 agonist activity at the highest concentration measured (>100 µM). Compound 26 is a centrally penetrant molecule which possesses good biopharmaceutical properties, is highly water-soluble, and demonstrates robust oral activity in rodent models of joint pain. In addition, the peripherally restricted molecule 22 also demonstrated significant efficacy in the same analgesic model of rodent inflammatory pain.
Assuntos
Osteoartrite/tratamento farmacológico , Purinas/síntese química , Receptor CB2 de Canabinoide/agonistas , Animais , Cães , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Células HEK293 , Humanos , Masculino , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Ratos Endogâmicos Lew , Relação Estrutura-AtividadeRESUMO
BACKGROUND: The PI3K-Akt pathway is frequently activated in acute leukemias and represents an important therapeutic target. UCN-01 and perifosine are known to inhibit Akt activation. METHODS: The primary objective of this phase I study was to determine the maximum tolerated dose (MTD) of UCN-01 given in combination with perifosine in patients with advanced acute leukemias and myelodysplastic syndrome. Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and efficacy. Perifosine 150 mg every 6 h was given orally on day 1 followed by 100 mg once a day continuously in 28-day cycles. UCN-01 was given intravenously over 3 h on day 4 at three dose levels (DL1=40 mg/m(2); DL2=65 mg/m(2); DL3=90 mg/m(2)). RESULTS: Thirteen patients were treated (DL1, n=6; DL2, n=4; DL3, n=3) according to a traditional "3+3" design. Two patients at the DL3 experienced dose-limiting toxicity including grade 3-4 pericardial effusion, hypotension, hyperglycemia, hyperkalemia, constitutional symptoms and grade 5 pneumonitis. Other frequent toxicities were grade 1-2 nausea, diarrhea, vomiting, fatigue and hyperglycemia. The MTD was determined to be UCN-01 65 mg/m(2) with perifosine 100 mg a day. No appreciable direct Akt inhibition could be demonstrated in patients' mononuclear cells using Western blot, however, reduced phosphorylation of the downstream target ribosomal protein S6 in leukemic blasts was noted by intracellular flow cytometry. No objective responses were observed on this study. CONCLUSION: UCN-01 and perifosine can be safely administered, but this regimen lacked clinical efficacy. This approach may have failed because of insufficient Akt inhibition in vivo.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Leucemia/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Fosforilcolina/administração & dosagem , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Fosforilcolina/farmacocinética , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estaurosporina/administração & dosagem , Estaurosporina/efeitos adversos , Estaurosporina/análogos & derivados , Estaurosporina/farmacocinética , Resultado do Tratamento , Adulto JovemRESUMO
Little is known about disparities in myelodysplastic syndromes (MDS). We performed a retrospective chart review of patients with MDS (n = 252) evaluated at the University of Maryland Greenebaum Cancer Center between 2000 and 2010. The median age at diagnosis was 65 years, which was lower than the median age of 76 years for patients with MDS in the Surveillance, Epidemiology and End Results database. Black males were younger than white males (62 vs. 68 years; p = 0.03) and had longer time to referral (9 vs. 1.5 months; p = 0.03), but black and white females did not differ in age or in time to referral. A difference in World Health Organization subtype classification was noted in black and white patients at diagnosis, but not at referral. There was no difference between all other pretreatment characteristics, treatment and survival by race. Our data suggest barriers to tertiary care referral for older patients and for black males.
Assuntos
Disparidades nos Níveis de Saúde , Síndromes Mielodisplásicas/epidemiologia , Encaminhamento e Consulta , Centros de Atenção Terciária , Adulto , Fatores Etários , Idoso , Baltimore , População Negra , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Análise de Sobrevida , População BrancaRESUMO
A focused screening strategy identified thienopyrimidine 1 as a hCB2 cannabinoid receptor agonist with moderate selectivity over the hCB1 receptor. This initial hit suffered from poor in vitro metabolic stability and high in vivo clearance. Structure-activity relationships describe the optimization and modification to a less lipophilic purine core. Examples from this novel series were found to be highly potent and fully efficacious agonists of the human CB2 receptor with excellent selectivity against CB1. Compound 10 possesses good biopharmaceutical properties, is highly water soluble and demonstrates robust oral activity in rodent models of joint pain.
Assuntos
Furanos/química , Purinas/química , Receptor CB2 de Canabinoide/agonistas , Animais , Avaliação Pré-Clínica de Medicamentos , Furanos/farmacocinética , Furanos/uso terapêutico , Meia-Vida , Humanos , Dor/tratamento farmacológico , Purinas/farmacocinética , Purinas/uso terapêutico , Ratos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptor CB2 de Canabinoide/metabolismo , Relação Estrutura-AtividadeRESUMO
CD4 count ≤200×10(6) cells/L has been identified as a predictor of short survival in HIV-associated acute myeloid leukemia (HIV-AML), but karyotype, which is the best predictor of survival in AML, has not been evaluated in HIV-AML patients. A retrospective cohort of 31 patients was created from 9 local cases and 22 published cases. HIV-AML karyotypes were heterogeneous and were similar in distribution to those in HIV-negative AML. Among intensively treated patients, most achieved complete remission, but succumbed to infectious complications, mostly non-opportunistic, during consolidation therapy. Median survival for intensively-treated patients with CD4 counts ≤200×10(6) cells/L was 8.5 months, compared to 48 months for those with >200×10(6) CD4 cells/L (p=0.03). In contrast, AML karyotype did not predict survival (p=0.43), albeit with small numbers in each karyotype group. Thus, CD4 count is a strong predictor of short survival in HIV-AML patients regardless of karyotype. Studies evaluating innovative strategies for infection prophylaxis and for improving immune reconstitution are needed.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções por HIV/complicações , HIV , Leucemia Mieloide/tratamento farmacológico , Doença Aguda , Adulto , Idoso , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/virologia , Humanos , Cariótipo , Leucemia Mieloide/genética , Leucemia Mieloide/imunologia , Masculino , Pessoa de Meia-Idade , Medição de Risco , Análise de Sobrevida , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Disease presentation and outcomes differ by race in a number of malignancies, but data in adult acute myeloid leukemia (AML) are limited. MATERIALS AND METHODS: We conducted a retrospective analysis of pretreatment characteristics, referral and treatment patterns, and outcomes in 548 AML patients evaluated at the University of Maryland Greenebaum Cancer Center, a tertiary care referral center in Baltimore, MD, from 2000 through 2009. Cases were analyzed for time from diagnosis to referral, age, race, gender, socioeconomic status, antecedent hematologic disorder, cytotoxic or radiation therapy for prior malignancy, karyotype, fms-like tyrosine kinase receptor-3 (FLT3) mutations, intensive chemotherapy, clinical trial participation, hematopoietic stem cell transplantation (HSCT) and overall survival (OS). RESULTS: Black patients (n=105) were younger than white patients (n=396) (54 vs. 61 years, p<0.001), were more commonly female (55% vs. 45%, p<0.001), and had a lower estimated median household income ($42,677 vs. $53,534 per year, p<0.001). Black patients more frequently had complex karyotypes (26% vs. 12%, p=0.002) and less frequently normal karyotypes (27% vs. 42%, p=0.02). FLT3 mutation frequency was similar. Time to referral and proportion of patients receiving intensive chemotherapy did not differ, but both clinical trial participation (43% vs. 54%, p=0.04) and HSCT (17% vs. 35% for patients ≤70 years old, p=0.001) were less frequent in blacks than whites. Nevertheless, OS was similar in all black and white patients (median 15 vs. 14 months, p=0.23), and when stratified by age, gender and karyotype risk classification. CONCLUSION: AML presentation and treatment differed in black and white patients, but OS was similar. Black patients appear to have barriers to clinical trial participation and HSCT, and there may be barriers to tertiary care referral for black males.
Assuntos
Negro ou Afro-Americano/estatística & dados numéricos , Leucemia Mieloide Aguda/etnologia , Leucemia Mieloide Aguda/mortalidade , Padrões de Prática Médica , Encaminhamento e Consulta , População Branca/estatística & dados numéricos , Baltimore , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Cariotipagem , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mutação/genética , Taxa de Mutação , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that inhibit BCR-ABL have had a favorable impact on the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). TKIs are generally well tolerated, but they can induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in patients with acute leukemia. We present three patients with Ph+âALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy who developed subdural hematomas (SDHs). All three were thrombocytopenic and had undergone repeated lumbar punctures for prophylactic intrathecal chemotherapy, but they were not coagulopathic and did not have meningeal leukemia. SDHs occurred in three of a total of 10 adult patients with Ph+âALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy at our institution from 2007 to 2010, but in none of 22 adult patients with Ph-âALL receiving the same therapy without imatinib mesylate (pâ<â0.05). Patients with Ph+âALL receiving imatinib mesylate, and likely also dasatinib, in conjunction with systemic and intrathecal chemotherapy may be at increased risk of SDH, and should be closely monitored for subtle manifestations of this complication.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Hematoma Subdural/etiologia , Piperazinas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Pirimidinas/efeitos adversos , Adulto , Antineoplásicos/administração & dosagem , Benzamidas , Evolução Fatal , Feminino , Hematoma Subdural/diagnóstico , Humanos , Mesilato de Imatinib , Injeções Espinhais/efeitos adversos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Piperazinas/administração & dosagem , Pirimidinas/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Earlier studies have found that children with fractures and PPO insurance have no access problems to orthopaedic care, but children with Medicaid have problems with access to orthopaedic care. METHODS: Fifty randomly selected orthopaedic offices in each of the 2 counties served by a children's hospital were telephoned to seek an appointment for a fictitious 10-year-old boy with a forearm fracture. Each office was called twice, 1 time reporting that the child had PPO insurance and 1 time that he was having Medicaid. In the second arm of the study, data including insurance status were prospectively collected on all patients with fractures seen in the emergency department of children's hospital. RESULTS: Of the 100 offices telephoned, 8 offices gave an appointment within 1 week to the child with Medicaid insurance. Thirty-six of the 100 offices gave an appointment within 1 week to the child with PPO insurance. For the 2210 pediatric fractures seen in the emergency department, the payer mix for patients presenting initially to our facility (1326 patients) was 41% Medicaid, 9% selfpay, and 50% commercial. For the patients presenting to our emergency department after being seen at an outside facility first (884 patients), the payer mix was 47% Medicaid, 13% self-pay, and 40% commercial. The percentages between these two groups were similar but did have a statistically significant difference (P=0.021). CONCLUSIONS: To the best of our knowledge, this is the first study that reports a majority (64/100) of orthopaedic offices in the region would not care for a child with a fracture regardless of insurance status. Consistent with earlier studies, children with Medicaid have less access to care. The similar insurance status of children sent to the emergency department from other facilities compared with those presenting directly suggests that children in this study are sent to a children's hospital for specialized care rather than for economic reasons. LEVEL OF EVIDENCE: Level II.
Assuntos
Fraturas Ósseas/terapia , Acessibilidade aos Serviços de Saúde/economia , Cobertura do Seguro/estatística & dados numéricos , Procedimentos Ortopédicos/economia , Adolescente , Criança , Serviço Hospitalar de Emergência/economia , Serviço Hospitalar de Emergência/estatística & dados numéricos , Fraturas Ósseas/economia , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Hospitais Pediátricos/estatística & dados numéricos , Humanos , Cobertura do Seguro/economia , Seguro Saúde/economia , Seguro Saúde/estatística & dados numéricos , Masculino , Medicaid/economia , Medicaid/estatística & dados numéricos , Procedimentos Ortopédicos/métodos , Organizações de Prestadores Preferenciais/estatística & dados numéricos , Estudos Prospectivos , Estados UnidosRESUMO
Triapine, a potent inhibitor of ribonucleotide reductase, has demonstrated anti-leukemia activity in pre-clinical models. We conducted a Phase I study of Triapine administered as a 2 h infusion for 5 days in 25 adults with advanced leukemias. We established that Triapine at 96 mg/m2 once a day can be given safely on days 1-5 and 15-19 or 1-5 and 8-12 of a 4-week cycle. When administered twice a day on days 1-5 and 8-12, the maximum tolerated dose of Triapine appears to be 64 mg/m2, although the true criteria for DLT were not met by protocol definition. No CR or PR were observed, but 76% of patients had a >50% reduction in white blood cell counts. At all dose levels, the peak plasma concentration of Triapine (2.2-5.5 microM) was above levels required to achieve in vitro/in vivo leukemia growth inhibition. Based on these data, we conclude that Triapine warrants further investigation in hematologic malignancies.
Assuntos
Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Leucemia/tratamento farmacológico , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ribonucleotídeo Redutases/antagonistas & inibidores , Tiossemicarbazonas/administração & dosagem , Tiossemicarbazonas/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Leucemia/sangue , Masculino , Dose Máxima Tolerável , Pessoa de Meia-IdadeRESUMO
MS-275 is a benzamide derivative with potent histone deacetylase (HDAC) inhibitory and antitumor activity in preclinical models. We conducted a phase 1 trial of orally administered MS-275 in 38 adults with advanced acute leukemias. Cohorts of patients were treated with MS-275 initially once weekly x 2, repeated every 4 weeks from 4 to 8 mg/m2, and after 13 patients were treated, once weekly x 4, repeated every 6 weeks from 8 to 10 mg/m2. The maximum-tolerated dose was 8 mg/m2 weekly for 4 weeks every 6 weeks. Dose-limiting toxicities (DLTs) included infections and neurologic toxicity manifesting as unsteady gait and somnolence. Other frequent non-DLTs were fatigue, anorexia, nausea, vomiting, hypoalbuminemia, and hypocalcemia. Treatment with MS-275 induced increase in protein and histone H3/H4 acetylation, p21 expression, and caspase-3 activation in bone marrow mononuclear cells. No responses by classical criteria were seen. Our results show that MS-275 effectively inhibits HDAC in vivo in patients with advanced myeloid leukemias and should be further tested, preferably in patients with less-advanced disease.