1,019 research outputs found

    Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.

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    PurposeDasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit-risk profile of dasatinib 100 mg once daily, exposure-response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).Patients and methodsDasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure-response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).ResultsMajor cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.ConclusionDasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety

    Causal Modifications of Gravity and Their Observational Bounds

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    Since general relativity is the unique theory of massless spin 2 particles at large distances, the most reasonable way to have significant modifications is to introduce one or more light scalars that mediate a new long-range force. Most existing studies of such scalars invoke models that exhibit some kind of "screening" at short distances to hide the force from solar system tests. However, as is well known, such modifications also exhibit superluminality, which can be interpreted as a form of acausality. In this work we explore explicitly subluminal and causal scalar field models. In particular, we study a conformally coupled scalar ϕ\phi, with a small coupling to matter to obey solar system bounds, and a non-canonical kinetic term K(X)K(X) (X=(∂ϕ)2/2X=(\partial\phi)^2/2) that obeys all subluminality constraints and is hyperbolic. We consider K(X)K(X) that is canonical for small XX, but beyond some nonlinear scale enters a new scaling regime of power pp, with 1/2<p<11/2<p<1 (the DBI kinetic term is the limit p=1/2p=1/2 and a canonical scalar is p=1p=1). As opposed to screening (and superluminality), this new force becomes more and more important in the regime of high densities (and subluminality). We then turn to the densest environments to put bounds on this new interaction. We compute constraints from precession in binary systems such as Hulse-Taylor, we compute corrections to neutron star hydrostatic equilibrium, and we compute power in radiation, both tensor mode corrections and the new scalar mode, which can be important during mergers.Comment: 43 pages, 5 figures. V3: Small update

    Imipramine blue sensitively and selectively targets FLT3-ITD positive acute myeloid leukemia cells.

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    Aberrant cytokine signaling initiated from mutant receptor tyrosine kinases (RTKs) provides critical growth and survival signals in high risk acute myeloid leukemia (AML). Inhibitors to FLT3 have already been tested in clinical trials, however, drug resistance limits clinical efficacy. Mutant receptor tyrosine kinases are mislocalized in the endoplasmic reticulum (ER) of AML and play an important role in the non-canonical activation of signal transducer and activator of transcription 5 (STAT5). Here, we have tested a potent new drug called imipramine blue (IB), which is a chimeric molecule with a dual mechanism of action. At 200-300 nM concentrations, IB is a potent inhibitor of STAT5 through liberation of endogenous phosphatase activity following NADPH oxidase (NOX) inhibition. However, at 75-150 nM concentrations, IB was highly effective at killing mutant FLT3-driven AML cells through a similar mechanism as thapsigargin (TG), involving increased cytosolic calcium. IB also potently inhibited survival of primary human FLT3/ITD+ AML cells compared to FLT3/ITDneg cells and spared normal umbilical cord blood cells. Therefore, IB functions through a mechanism involving vulnerability to dysregulated calcium metabolism and the combination of fusing a lipophilic amine to a NOX inhibiting dye shows promise for further pre-clinical development for targeting high risk AML

    Rational Design, Synthesis and Biological Evaluation of Pyrimidine-4,6-diamine derivatives as Type-II inhibitors of FLT3 Selective Against c-KIT.

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    FMS-like Tyrosine Kinase 3 (FLT3) is a clinically validated target for acute myeloid leukemia (AML). Inhibitors targeting FLT3 have been evaluated in clinical studies and have exhibited potential to treat FLT3-driven AML. A frequent, clinical limitation is FLT3 selectivity, as concomitant inhibition of FLT3 and c-KIT is thought to cause dose-limiting myelosuppression. Through a rational design approach, novel FLT3 inhibitors were synthesized employing a pyridine/pyrimidine warhead. The most potent compound identified from the studies is compound 13a, which exhibited an IC50 value of 13.9 ± 6.5 nM against the FLT3 kinase with high selectivity over c-KIT. Mechanism of action studies suggested that 13a is a Type-II kinase inhibitor, which was also supported through computer aided drug discovery (CADD) efforts. Cell-based assays identified that 13a was potent on a variety of FLT3-driven cell lines with clinical relevance. We report herein the discovery and therapeutic evaluation of 4,6-diamino pyrimidine-based Type-II FLT3 inhibitors, which can serve as a FLT3-selective scaffold for further clinical development

    Incidence, outcomes, and risk factors of pleural effusion in patients receiving dasatinib therapy for Philadelphia chromosome-positive leukemia.

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    Dasatinib, a second-generation BCR-ABL1 tyrosine kinase inhibitor, is approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, both as first-line therapy and after imatinib intolerance or resistance. While generally well tolerated, dasatinib has been associated with a higher risk for pleural effusions. Frequency, risk factors, and outcomes associated with pleural effusion were assessed in two phase 3 trials (DASISION and 034/Dose-optimization) and a pooled population of 11 trials that evaluated patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia treated with dasatinib (including DASISION and 034/Dose-optimization). In this largest assessment of patients across the dasatinib clinical trial program (N=2712), pleural effusion developed in 6-9% of patients at risk annually in DASISION, and in 5-15% of patients at risk annually in 034/Dose-optimization. With a minimum follow up of 5 and 7 years, drug-related pleural effusion occurred in 28% of patients in DASISION and in 33% of patients in 034/Dose-optimization, respectively. A significant risk factor identified for developing pleural effusion by a multivariate analysis was age. We found that overall responses to dasatinib, progression-free survival, and overall survival were similar in patients who developed pleural effusion and in patients who did not. clinicaltrials.gov identifier 00481247; 00123474
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