20,391 research outputs found

    NGX-4010, a capsaicin 8% patch, for the treatment of painful HIV-associated distal sensory polyneuropathy: integrated analysis of two phase III, randomized, controlled trials

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    BACKGROUND HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. METHODS Data from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. RESULTS Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. CONCLUSIONS A single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated. TRIAL REGISTRATION C107 = NCT00064623; C119 = NCT00321672

    Customizing the therapeutic response of signaling networks to promote antitumor responses by drug combinations

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    Drug resistance, de novo and acquired, pervades cellular signaling networks (SNs) from one signaling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anti-cancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where SN sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potential. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of combination therapies, and design methods to determine drug targets for combination regimens. Based on a joint systems analysis of cellular SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyze the targets of drug combinations. Our method explores mechanisms of sensitizing the SN through a combination of two drugs targeting vertical signaling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to customize the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the down-stream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects together with the capability of drug combinations to suppress resistance mechanisms before they become clinically manifest

    The impact of desilication product on bauxite residue flocculation

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    The pre-desilication step within the Bayer Process seeks to transform reactive silica in bauxite into desilication product (DSP) prior to digestion, thereby reducing post-digestion precipitation and scaling. The precipitated DSP is removed with the other residue phases in the primary settling stage. While the proportion of DSP within the residue can be significant, there are surprisingly few open-literature studies that consider the impact of DSP on residue flocculation and settling. Such studies typically involve bauxites of a fixed composition, which limits the scope to vary residue properties while investigating flocculation mechanisms. In this study, DSP has been formed from the reaction of standard kaolin in synthetic Bayer liquor in the presence of iron oxides. Variation of the reaction conditions (temperature, duration, kaolin to iron oxide ratio) has produced a range of synthetic residue slurries that have been characterised in terms of their physical and flocculation properties. Effective comparison of the latter could only be achieved after detailed optimisation of test conditions, which included (i) slurry stability over time, (ii) solids concentration, (iii) temperature and concentration of the dosed flocculant, and (iv) flocculant make-up/shelf life. The detrimental impact of DSP is clearly reflected in lower settling rates, higher supernatant solids and poor consolidation over a range of solid densities and DSP contents of operational interest. Flocculant dosage response curves are also less steep and shifted towards higher demand. A number of flocculants are contrasted in terms of their suitability for high DSP residues, with the practical implications of their application discussed

    Enhanced stability of layered phases in parallel hard-spherocylinders due to the addition of hard spheres

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    There is increasing evidence that entropy can induce microphase separation in binary fluid mixtures interacting through hard particle potentials. One such phase consists of alternating two dimensional liquid-like layers of rods and spheres. We study the transition from a uniform miscible state to this ordered state using computer simulations and compare results to experiments and theory. We conclude that (1) there is stable entropy driven microphase separation in mixtures of parallel rods and spheres, (2) adding spheres smaller then the rod length decreases the total volume fraction needed for the formation of a layered phase, therefore small spheres effectively stabilize the layered phase; the opposite is true for large spheres and (3) the degree of this stabilization increases with increasing rod length.Comment: 11 pages, 9 figures. Submitted to Phys. Rev. E. See related website http://www.elsie.brandeis.ed