RESUMO
The lyophilized formulation of melphalan has several limitations based on its marginal solubility, limited stability after reconstitution, and the requirement to reconstitute it in propylene glycol (PG). PG-free melphalan (Evomela; Spectrum Pharmaceuticals, Irvine CA) overcomes these limitations by using the solubilizing agent Captisol (Ligand Pharmaceuticals, Inc., LaJolla CA) to improve the stability of the reconstituted melphalan and avoid the potential toxicities of PG. This phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the carmustine, etoposide, and cytarabine (BEAM) regimen for adult patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). Carmustine, etoposide, and cytarabine were given at standard doses on day -6 through day -3. PG-free melphalan, 140 mg/m2, was infused over 30 minutes on day -2. The primary endpoint was toxicity. Fifty patients (33 NHL/17 HL) completed BEAM with PG-free melphalan and stem cell infusion. The most common grades 3 to 4 nonhematologic toxicities were neutropenic fever (68%), infections (36%), and electrolyte abnormalities. Forty-one patients (82%) had oral mucositis, which was mostly grades 1 to 2 (6% grade 3). Moderate or severe gastrointestinal toxicities were uncommon. There were no treatment-related deaths. Forty-nine patients (98%) had neutrophil and platelet engraftment at a median of 10 and 19 days, respectively. At response assessment at 60 to 100 days after autologous stem cell transplantation, 42 patients (82%) were in complete remission, 2 in partial remission, and 6 had progressive disease. Progression-free survival at 1 year was 70%. These results demonstrate that PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing autologous stem cell transplantation. It has a safety profile that compares favorably with standard lyophilized melphalan, and the engraftment rate and response rates were consistent with expectations.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Agonistas Mieloablativos/administração & dosagem , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Idoso , Carmustina/administração & dosagem , Citarabina/administração & dosagem , Etoposídeo/administração & dosagem , Feminino , Sobrevivência de Enxerto , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Linfoma/complicações , Linfoma/mortalidade , Masculino , Melfalan/administração & dosagem , Melfalan/toxicidade , Análise de Sobrevida , Condicionamento Pré-Transplante/efeitos adversos , Transplante Autólogo , Resultado do Tratamento , Adulto JovemRESUMO
Combination of the structure-based design and solid-phase parallel synthesis provided an integrated approach to rapidly develop the structure-activity relationship of benzopyran COX-2 inhibitors. Binding free energies predicted by free energy perturbation theory yielded good agreement with experimental results. New potent and selective lead compounds with improved metabolic properties were identified.
Assuntos
Benzopiranos/química , Inibidores de Ciclo-Oxigenase 2/química , Ciclo-Oxigenase 2/química , Microssomos/metabolismo , Animais , Benzopiranos/síntese química , Benzopiranos/farmacologia , Química Farmacêutica , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/síntese química , Inibidores de Ciclo-Oxigenase 2/farmacologia , Humanos , Ligação Proteica , Ratos , Relação Estrutura-Atividade , TermodinâmicaRESUMO
Interactions between the bone marrow microenvironment and MDS tumor clones play a role in pathogenesis and response to treatment. We hypothesized G-CSF and plerixafor may enhance sensitivity to azacitidine in MDS. Twenty-eight patients with MDS were treated with plerixafor, G-CSF and azacitidine with a standard 3 + 3 design. Subjects received G-CSF 10 mcg/kg D1-D8, plerixafor D4-D8, and azacitidine 75 mg/m2 D4-D8, but the trial was amended to reduce G-CSF dose to 5 mcg/kg for 5 days after 2 patients had significant leukocytosis. Plerixafor was dose escalated to 560 mcg/kg/day without dose limiting toxicity. Two complete responses and 6 marrow responses were seen for an overall response rate (ORR) of 36% in evaluable patients, and ORR of 53% in patients receiving the triplet. Evidence of mobilization correlated with a higher ORR, 60% vs. 17%. Plerixafor, G-CSF and azacitidine appears tolerable when given over 5 days and has encouraging response rates.KEY POINTSPlerixafor and G-CSF can be safely combined with azacitidine for 5 days in patients with MDS.The overall response rate of 53% for evaluable patients with this regimen is higher than expected and more responses were seen in patients with blast mobilization.
Assuntos
Compostos Heterocíclicos , Síndromes Mielodisplásicas , Azacitidina/efeitos adversos , Benzilaminas , Ciclamos , Fator Estimulador de Colônias de Granulócitos , Mobilização de Células-Tronco Hematopoéticas , Compostos Heterocíclicos/efeitos adversos , Humanos , Síndromes Mielodisplásicas/tratamento farmacológicoRESUMO
A series of N-aryl isonipecotamide alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13.
Assuntos
Ácidos Hidroxâmicos/química , Inibidores de Metaloproteinases de Matriz , Administração Oral , Amidas , Animais , Ácidos Hidroxâmicos/síntese química , Ácidos Hidroxâmicos/farmacologia , Concentração Inibidora 50 , Ratos , Bibliotecas de Moléculas Pequenas , Solubilidade , Especificidade por Substrato , SulfonasRESUMO
A series of phenyl piperidine alpha-sulfone hydroxamate derivatives has been prepared utilizing a combination of solution-phase and resin-bound library technologies to afford compounds that are potent and highly selective for MMP-13, are dual-sparing of MMP-1 and MMP-14 (MT1-MMP) and exhibit oral bioavailability in rats.
Assuntos
Inibidores de Metaloproteinases de Matriz , Administração Oral , Animais , Disponibilidade Biológica , Ácidos Hidroxâmicos/administração & dosagem , Metaloproteinase 1 da Matriz/efeitos dos fármacos , Metaloproteinase 14 da Matriz/efeitos dos fármacos , Piperidinas , Ratos , Bibliotecas de Moléculas Pequenas , Solubilidade , Especificidade por Substrato , SulfonasRESUMO
Potent, highly selective and orally-bioavailable MMP-13 inhibitors have been identified based upon a (pyridin-4-yl)-2H-tetrazole scaffold. Co-crystal structure analysis revealed that the inhibitors bind at the S(1)(') active site pocket and are not ligands for the catalytic zinc atom. Compound 29b demonstrated reduction of cartilage degradation biomarker (TIINE) levels associated with cartilage protection in a preclinical rat osteoarthritis model.
Assuntos
Inibidores de Metaloproteinases de Matriz , Osteoartrite/tratamento farmacológico , Ácidos Picolínicos/química , Inibidores de Proteases/química , Tetrazóis/química , Administração Oral , Animais , Sítios de Ligação , Cartilagem/efeitos dos fármacos , Cartilagem/metabolismo , Domínio Catalítico , Cristalografia por Raios X , Modelos Animais de Doenças , Descoberta de Drogas , Metaloproteinase 13 da Matriz/metabolismo , Ácidos Picolínicos/síntese química , Ácidos Picolínicos/farmacologia , Inibidores de Proteases/síntese química , Inibidores de Proteases/farmacologia , Ratos , Tetrazóis/síntese química , Tetrazóis/farmacologia , Zinco/químicaRESUMO
Donor lymphocyte infusion (DLI) without prophylactic immunosuppression has been used for relapsed AML after allogeneic stem cell transplant (allo-SCT). However DLI is associated with an increased incidence of acute Graft vs. Host Disease (aGVHD). In mice, administration of azacitidine (AzaC) on days 4, 6, 8, and 10 post DLI increases regulatory T cell (Treg) numbers and prevents GVHD without hindering Graft vs. Leukemia (GVL). Based on these findings, we conducted a phase 1 study of AzaC post DLI for AML relapse post allo-SCT. AzaC was administered on days 4, 6, 8 and 10 post-DLI. Dose escalation was done using a 3+3 design with three AzaC dose levels: 30mg/m(2) (level -1), 45mg/m(2) (level 1) and 75mg/m(2) (level 2). Three patients were treated in the 45mg/m(2) dose level and 5 patients were treated in the 75mg/m(2) dose level; no DLTs or grade 3-5 treatment related toxicities were observed. After a median follow-up of 5.2 months, no patients developed grade III-IV aGVHD and no patients died of aGVHD. Six out of 8 patients in the treatment group responded to treatment including two cytogenetic complete remissions, one hematologic complete remission, and three complete remissions with incomplete count recovery. In conclusion, administration of AzaC early post DLI is well tolerated and can potentially prevent GVHD after DLI. Further studies are required to evaluate the effect of azacitidine early post DLI on GVHD and GVL.
Assuntos
Azacitidina/administração & dosagem , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos , Adulto , Idoso , Esquema de Medicação , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Efeito Enxerto vs Leucemia , Humanos , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/mortalidade , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Recidiva , Indução de Remissão/métodos , Terapia de Salvação/métodos , Transplante de Células-Tronco/efeitos adversos , Transplante Homólogo , Resultado do TratamentoRESUMO
Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by bone marrow failure which frequently progress to acute myeloid leukemia. Patients who fail to respond to, or progress on first-line DNA hypomethylating agents (HMA) have a poor prognosis. Conventionally dosed lenalidomide has activity in 5q-MDS. In other subtypes, it may reduce RBC transfusion requirements but does not result in cytogenetic responses. We previously reported that high-dose lenalidomide induction (50 mg/day) results in complete remissions in a high fraction of patients. We, therefore, conducted a Phase 2 trial of the same regimen in MDS refractory to HMA. Marrow complete remissions were seen in 33% of patients and hematological improvement in 8% of patients. Significant infections complicated more than 50% of cases. Future trials to explore alternative dosing schedules of high-dose lenalidomide to increase efficacy while decreasing toxicity are warranted.
Assuntos
Fatores Imunológicos/administração & dosagem , Síndromes Mielodisplásicas/tratamento farmacológico , Talidomida/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Metilação de DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Fatores Imunológicos/efeitos adversos , Lenalidomida , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Indução de Remissão , Retratamento , Talidomida/administração & dosagem , Talidomida/efeitos adversos , Resultado do TratamentoRESUMO
Matrix metalloproteinase-13 (MMP-13) is a zinc-dependent protease responsible for the cleavage of type II collagen, the major structural protein of articular cartilage. Degradation of this cartilage matrix leads to the development of osteoarthritis. We previously have described highly potent and selective carboxylic acid containing MMP-13 inhibitors; however, nephrotoxicity in preclinical toxicology species precluded development. The accumulation of compound in the kidneys mediated by human organic anion transporter 3 (hOAT3) was hypothesized as a contributing factor for the finding. Herein we report our efforts to optimize the MMP-13 potency and pharmacokinetic properties of non-carboxylic acid leads resulting in the identification of compound 43a lacking the previously observed preclinical toxicology at comparable exposures.
Assuntos
Metaloproteinase 13 da Matriz/efeitos dos fármacos , Inibidores de Metaloproteinases de Matriz/síntese química , Inibidores de Metaloproteinases de Matriz/farmacologia , Osteoartrite/tratamento farmacológico , Pirimidinas/síntese química , Pirimidinas/farmacologia , Tetrazóis/síntese química , Tetrazóis/farmacologia , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/patologia , Colagenases/efeitos dos fármacos , Cães , Desenho de Fármacos , Humanos , Rim/metabolismo , Macaca fascicularis , Masculino , Inibidores de Metaloproteinases de Matriz/toxicidade , Modelos Moleculares , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-AtividadeRESUMO
Elevated plasma levels of low-density lipoprotein (LDL) cholesterol are a major risk factor for atherosclerosis leading to coronary artery disease (CAD), which remains the main cause of mortality in Western society. We believe that by preventing the reabsorption of bile acids, a minimally absorbed apical sodium-codependent bile acid transporter (ASBT) inhibitor would lower the serum cholesterol without the potential systemic side effects of an absorbed drug. A series of novel benzothiepines (3R,3R'-2,3,4,5-tetrahydro-5-aryl-1-benzothiepin-4-ol 1,1-dioxides) were synthesized and tested for their ability to inhibit the apical sodium dependent bile acid transport (ASBT)-mediated uptake of [(14)C]taurocholate (TC) in H14 cells. A 3R,4R,5R/3S,4S,5S racemate was found to have greater potency than the other three possible racemates. Addition of electron-donating groups such as a dimethylamino substituent at the 7 position greatly enhanced potency, and incorporation of a long-chain quaternary ammonium substituent on the 5-phenyl ring was useful in minimizing systemic exposure of this locally active ASBT inhibitor while also increasing water solubility and maintaining potency. The reported results describe the synthesis and SAR development of this benzothiepine class of ASBT inhibitors resulting in an 6000-fold improvement in ASBT inhibition with desired minimal systemic exposure of this locally acting drug candidate.
Assuntos
Anticolesterolemiantes/síntese química , Benzotiepinas/síntese química , Ácidos e Sais Biliares/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacologia , Benzotiepinas/química , Benzotiepinas/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cricetinae , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Mesocricetus , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Ácido Taurocólico/metabolismoRESUMO
In the preceding paper several compounds were reported as potent apical sodium-codependent bile acid transporter (ASBT) inhibitors. Since the primary site for active bile acid reabsorption is via ASBT, which is localized on the luminal surface of the distal ileum, we reasoned that a nonsystemic inhibitor would be desirable to minimize or eliminate potential systemic side effects of an absorbed drug. To ensure bioequivalency and product stability, it was also essential that we identify a nonhygroscopic inhibitor in its most stable crystalline form. A series of benzothiepines were prepared to refine the structure-activity relationship of the substituted phenyl ring at the 5-position of benzothiepine ring and to identify potent, crystalline, nonhygroscopic, and efficacious ASBT inhibitors with low systemic exposure.
Assuntos
Anticolesterolemiantes/síntese química , Benzotiepinas/síntese química , Ácidos e Sais Biliares/metabolismo , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Absorção , Animais , Anticolesterolemiantes/química , Anticolesterolemiantes/farmacocinética , Benzotiepinas/química , Benzotiepinas/farmacocinética , Linhagem Celular , Cricetinae , Cristalização , Humanos , Umidade , Masculino , Mesocricetus , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Ácido Taurocólico/metabolismo , Difração de Raios XRESUMO
In acute lymphoblastic leukemia (ALL) the bone marrow microenvironment provides growth and survival signals that may confer resistance to chemotherapy. Granulocyte colony-stimulating factor (G-CSF) potently inhibits lymphopoiesis by targeting stromal cells that comprise the lymphoid niche in the bone marrow. To determine whether lymphoid niche disruption by G-CSF sensitizes ALL cells to chemotherapy, we conducted a pilot study of G-CSF in combination with chemotherapy in patients with relapsed or refractory ALL. Thirteen patients were treated on study; three patients achieved a complete remission (CR/CRi) for an overall response rate of 23%. In the healthy volunteers, G-CSF treatment disrupted the lymphoid niche, as evidenced by reduced expression of CXCL12, interleukin-7, and osteocalcin. However, in most patients with relapsed/refractory ALL expression of these genes was markedly suppressed at baseline. Thus, although G-CSF treatment was associated with ALL cell mobilization into the blood, and increased apoptosis of bone marrow resident ALL cells, alterations in the bone marrow microenvironment were modest and highly variable. These data suggest that disruption of lymphoid niches by G-CSF to sensitize ALL cells to chemotherapy may be best accomplished in the consolidation where the bone marrow microenvironment is more likely to be normal.
Assuntos
Medula Óssea/patologia , Células-Tronco Neoplásicas/patologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nicho de Células-Tronco , Microambiente Tumoral , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Fator Ativador de Células B/biossíntese , Fator Ativador de Células B/genética , Quimiocina CXCL12/biossíntese , Quimiocina CXCL12/genética , Resistencia a Medicamentos Antineoplásicos/fisiologia , Etoposídeo/administração & dosagem , Feminino , Filgrastim/administração & dosagem , Filgrastim/farmacologia , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Humanos , Ifosfamida/administração & dosagem , Interleucina-7/biossíntese , Interleucina-7/genética , Masculino , Mesna/administração & dosagem , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Osteocalcina/biossíntese , Osteocalcina/genética , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Recidiva , Indução de Remissão , Terapia de Salvação , Nicho de Células-Tronco/efeitos dos fármacos , Microambiente Tumoral/efeitos dos fármacos , Adulto JovemAssuntos
Antineoplásicos/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Oligopeptídeos/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Inibidores de Proteassoma/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Humanos , Oligopeptídeos/administração & dosagem , Oligopeptídeos/efeitos adversos , Inibidores de Proteassoma/administração & dosagem , Inibidores de Proteassoma/efeitos adversos , Recidiva , Retratamento , Resultado do TratamentoRESUMO
A series of 5-aryl-3,3-dibutyl-7-(dimethylamino)-1,2-benzothiazepin-4-ol 1,1-dioxides were prepared and were found to inhibit the apical sodium co-dependent bile acid transporter (ASBT) for the potential treatment for hyperlipidemia. Several 1,2-benzothiazepines exhibited low nanomolar in vitro activity. The synthesis and initial in vitro potency data is presented for this novel class of compounds.