Inaxaplin for Proteinuric Kidney Disease in Persons with Two APOL1 Variants.

BACKGROUND: Persons with toxic gain-of-function variants in the gene encoding apolipoprotein L1 (APOL1) are at greater risk for the development of rapidly progressive, proteinuric nephropathy. Despite the known genetic cause, therapies targeting proteinuric kidney disease in persons with two APOL1 variants (G1 or G2) are lacking. METHODS: We used tetracycline-inducible APOL1 human embryonic kidney (HEK293) cells to assess the ability of a small-molecule compound, inaxaplin, to inhibit APOL1 channel function. An APOL1 G2-homologous transgenic mouse model of proteinuric kidney disease was used to assess inaxaplin treatment for proteinuria. We then conducted a single-group, open-label, phase 2a clinical study in which inaxaplin was administered to participants who had two APOL1 variants, biopsy-proven focal segmental glomerulosclerosis, and proteinuria (urinary protein-to-creatinine ratio of ≥0.7 to <10 [with protein and creatinine both measured in grams] and an estimated glomerular filtration rate of ≥27 ml per minute per 1.73 m2 of body-surface area). Participants received inaxaplin daily for 13 weeks (15 mg for 2 weeks and 45 mg for 11 weeks) along with standard care. The primary outcome was the percent change from the baseline urinary protein-to-creatinine ratio at week 13 in participants who had at least 80% adherence to inaxaplin therapy. Safety was also assessed. RESULTS: In preclinical studies, inaxaplin selectively inhibited APOL1 channel function in vitro and reduced proteinuria in the mouse model. Sixteen participants were enrolled in the phase 2a study. Among the 13 participants who were treated with inaxaplin and met the adherence threshold, the mean change from the baseline urinary protein-to-creatinine ratio at week 13 was -47.6% (95% confidence interval, -60.0 to -31.3). In an analysis that included all the participants regardless of adherence to inaxaplin therapy, reductions similar to those in the primary analysis were observed in all but 1 participant. Adverse events were mild or moderate in severity; none led to study discontinuation. CONCLUSIONS: Targeted inhibition of APOL1 channel function with inaxaplin reduced proteinuria in participants with two APOL1 variants and focal segmental glomerulosclerosis. (Funded by Vertex Pharmaceuticals; VX19-147-101 ClinicalTrials.gov number, NCT04340362.).

Different reactor configurations for enhancement of CO2 methanation.

Greenhouse gas emissions are a massive concern for scientists to minimize the effect of global warming in the environment. In this study, packed bed, coated wall, and membrane reactors were investigated using three novel nickel catalysts for the methanation of CO2. CFD modelling methodologies were implemented to develop 2D models. The validity of the model was investigated in a previous study where experimental and simulated results in a packed bed reactor were in a good agreement. It was observed that the coated wall reactor had poorer performance compared to the packed bed, approximately 30% difference between the results, as the residence time of the former was lower. In addition, two membrane configurations were proposed, including a membrane packed bed and membrane coated wall reactor. Additional studies were performed in the coated wall reactor revealing that lower flow rates lead to higher conversion values. As for the bed thickness the optimum layer was found to be 1 mm. In both membrane reactor configurations, the effect of the thickness of M1 membrane, which indicates the membrane for the removal of H2O, didn't show difference while the reduction of the thickness of M2 membrane, which indicates the membrane for the removal of CO2, H2 and H2O, showed better results in terms of conversion.

Computational Studies on Microreactors for the Decomposition of Formic Acid for Hydrogen Production Using Heterogeneous Catalysts.

Sustainable alternatives to conventional fuels have emerged recently, focusing on a hydrogen-based economy. The idea of using hydrogen (H2) as an energy carrier is very promising due to its zero-emission properties. The present study investigates the formic acid (FA) decomposition for H2 generation using a commercial 5 wt.% Pd/C catalyst. Three different 2D microreactor configurations (packed bed, single membrane, and double membrane) were studied using computational fluid dynamics (CFD). Parameters such as temperature, porosity, concentration, and flow rate of reactant were investigated. The packed bed configuration resulted in high conversions, but due to catalyst poisoning by carbon monoxide (CO), the catalytic activity decreased with time. For the single and double membrane microreactors, the same trends were observed, but the double membrane microreactor showed superior performance compared with the other configurations. Conversions higher than 80% were achieved, and even though deactivation decreased the conversion after 1 h of reaction, the selective removal of CO from the system with the use of membranes lead to an increase in the conversion afterwards. These results prove that the incorporation of membranes in the system for the separation of CO is improving the efficiency of the microreactor.

Exact matrix treatment of the statistical mechanics of adsorption of large aromatic molecules on graphene.

Experimental studies of adsorption from solution of the large aromatic molecules 1,2-dihydroxybenzene (catechol) and phenyl hydroquinone on graphene nanoplatelets show that at low coverage adsorption is followed by a transition which occurs from adsorbed molecules in flat to more vertically oriented states. Catechol adsorption isotherms exhibit 2 plateaus while phenyl hydroquinone shows 3 plateaus indicating 2 and 3 active conformers respectively participating in the adsorption process. Modelling such adsorption isotherms presents a challenge. Here, an exact matrix treatment of the statistical mechanics of a one-dimensional model of adsorption of catechol and dihydroquinone on graphene nanoplatelets is presented. The theoretical adsorption isotherms successfully reproduce all the features of both the catechol and dihydroquinone experimental adsorption isotherms. As suggested by the experimentalists, our theoretical model demonstrates that adsorbed phenyl hydroquinone molecules adopt a flat orientation at low concentrations and an edge orientation at higher coverage before eventually adopting a vertical configuration. Both catechol and phenyl hydroquinone can be described by our interconvertible monomer-dimer-trimer model. The theoretical adsorption isotherms obtained show several plateaus reflecting the types of conformer on the graphene surface.

Plastic Solid Waste (PSW) in the Context of Life Cycle Assessment (LCA) and Sustainable Management.

Over the past few decades, life cycle assessment (LCA) has been established as a critical tool for the evaluation of the environmental burdens of chemical processes and materials cycles. The increasing amount of plastic solid waste (PSW) in landfills has raised serious concern worldwide for the most effective treatment. Thermochemical post-treatment processes, such as pyrolysis, seem to be the most appropriate method to treat this type of waste in an effective manner. This is because such processes lead to the production of useful chemicals, or hydrocarbon oil of high calorific value (i.e. bio-oil in the case of pyrolysis). LCA appears to be the most appropriate tool for the process design from an environmental context. However, addressed limitations including initial assumptions, functional unit and system boundaries, as well as lack of regional database and exclusion of socio-economic aspects, may hinder the final decision. This review aims to address the benefits of pyrolysis as a method for PSW treatment and raise the limitations and gaps of conducted research via an environmental standpoint.

A review of the valorization and management of industrial spent catalyst waste in the context of sustainable practice: The case of the State of Kuwait in parallel to European industry.

Industrial solid waste management encompasses a vital part of developed and developing countries strategies alike. It manages waste generated from vital industries and governs the hazardous waste generated as a major component of integrated waste management strategies. This article reviews the practices that govern the management approaches utilized in the developed world for industrial spent catalysts. It critically assesses the current situation of waste management within the developing world region focusing on the industrial waste component, in a novel attempt to crucially develop a strategy for a way forward based on best practices and future directions with major European industries. The review also draws parallels with European countries to compare their practices with those of the State of Kuwait, which rely solely on landfilling for the management of its industrial waste. Spent catalysts recovery methods are discussed at length covering conventional methods of valuable metals and chemicals recovery (e.g., hydrometallurgical, solid-liquid and liquid-liquid extraction) as well as biological recovery methods. A major gap exists within regulations that govern the practice of managing industrial waste in Kuwait, where it is essential to start regulating industries that generate spent catalysts in-view of encouraging the establishment of valorization industries for metal and chemical recovery. This will also create a sustainable practice within state borders, and can reduce the environmental impact of landfilling such waste in Kuwait.

Statistical mechanics of binary mixture adsorption in metal-organic frameworks in the osmotic ensemble.

Although crucial for designing separation processes little is known experimentally about multi-component adsorption isotherms in comparison with pure single components. Very few binary mixture adsorption isotherms are to be found in the literature and information about isotherms over a wide range of gas-phase composition and mechanical pressures and temperature is lacking. Here, we present a quasi-one-dimensional statistical mechanical model of binary mixture adsorption in metal-organic frameworks (MOFs) treated exactly by a transfer matrix method in the osmotic ensemble. The experimental parameter space may be very complex and investigations into multi-component mixture adsorption may be guided by theoretical insights. The approach successfully models breathing structural transitions induced by adsorption giving a good account of the shape of adsorption isotherms of CO2 and CH4 adsorption in MIL-53(Al). Binary mixture isotherms and co-adsorption-phase diagrams are also calculated and found to give a good description of the experimental trends in these properties and because of the wide model parameter range which reproduces this behaviour suggests that this is generic to MOFs. Finally, a study is made of the influence of mechanical pressure on the shape of CO2 and CH4 adsorption isotherms in MIL-53(Al). Quite modest mechanical pressures can induce significant changes to isotherm shapes in MOFs with implications for binary mixture separation processes.This article is part of the theme issue 'Modern theoretical chemistry'.

BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial.

BACKGROUND: BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. METHODS: In this randomized, double-blind, placebo controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg); sumatriptan 100 mg (active comparator); and placebo. Patients were treated for a single migraine attack. The primary endpoint was pain freedom at two hours post-dose. RESULTS: Of patients who took the study drug, 799 had one post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, P = 0.002), 150 mg (32.9%, P < 0.001), and 300 mg (29.7%, P = 0.002) groups and the sumatriptan group (35%, P < 0.001) had pain freedom at two hours post-dose versus placebo (15.3%). For the secondary endpoint of sustained pain freedom from two to 24 hours post-dose, BMS-927711 doses (25-600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs. CONCLUSIONS: BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

Safety and Tolerability of the APOL1 Inhibitor, Inaxaplin, following Single- and Multiple-Ascending Doses in Healthy Adults.

Introduction: Toxic gain-of-function Apolipoprotein L1 (APOL1) variants contribute to the development of proteinuric nephropathies collectively referred to as APOL1-mediated kidney disease (AMKD). Despite standard-of-care treatments, patients with AMKD experience accelerated progression to end-stage kidney disease. The identification of two APOL1 variants as the genetic cause of AMKD inspired development of inaxaplin, an inhibitor of APOL1 channel activity that reduces proteinuria in patients with AMKD. Methods: We conducted two phase 1 studies evaluating the safety, tolerability, and pharmacokinetics of single-ascending doses (SAD) and multiple-ascending doses (MAD) of inaxaplin in healthy participants. In the SAD cohorts, participants were randomized to receive inaxaplin as a single dose (range, 7.5 mg to 165 mg) or placebo. In the MAD cohorts, participants were randomized to receive multiple doses of inaxaplin (range, 15 to 120 mg daily) or placebo for 14 days. We assessed safety and tolerability based on adverse events (AEs), clinical laboratory values, electrocardiograms (ECGs), and vital signs. Results: A total of 178 participants were randomized in the SAD/MAD cohorts of both studies (mean age: 36.7 years; 94.9% male). The proportion of participants with any AEs was similar in the inaxaplin (24.6%) and placebo (22.7%) groups. All AEs were mild or moderate in severity; there were no serious AEs. Headache was the most common AE: 10.4% and 2.3% in the inaxaplin and placebo groups, respectively. There were no drug-related treatment discontinuations and no clinically relevant trends in laboratory values, ECGs, or vital signs. Discussion/Conclusion: Inaxaplin is safe and well tolerated at single doses up to 165 mg and multiple doses up to 120 mg daily for 14 days. These results are consistent with the favorable safety profile of inaxaplin in a completed phase 2a proof-of-concept study. Together, these findings support continued evaluation of inaxaplin in an ongoing phase 2/3 pivotal trial as a potential precision medicine for patients with AMKD.

Recent progress on sonochemical production for the synthesis of efficient photocatalysts and the impact of reactor design.

Sonochemical-assisted synthesis has flourished recently for the design of photocatalysts. The main power used is ultrasound that allows the nanomaterials shape and size modification and control. This review highlights the effect in formation mechanism by ultrasound application and the most common photocatalysts that were prepared via sonochemical techniques. Moreover, the challenge for the suitable reactor design for the synthesis of materials or for their photocatalytic evaluation is discussed since the most prominent reactor systems, batch, and continuous flow, has both advantages and drawbacks. This work summarises the significance of sonochemical synthesis for photocatalytic materials as a green technology that needs to be further investigated for the preparation of new materials and the scale up of developed reactor systems to meet industrial needs.

Formic Acid Decomposition Using Palladium-Zinc Preformed Colloidal Nanoparticles Supported on Carbon Nanofibre in Batch and Continuous Flow Reactors: Experimental and Computational Fluid Dynamics Modelling Studies.

The need to replace conventional fuels with renewable sources is a great challenge for the science community. H2 is a promising alternative due to its high energy density and availability. H2 generation from formic acid (FA) decomposition occurred in a batch and a packed-bed flow reactor, in mild conditions, using a 2% Pd6Zn4/HHT (high heated treated) catalyst synthesised via the sol-immobilisation method. Experimental and theoretical studies took place, and the results showed that in the batch system, the conversion was enhanced with increasing reaction temperature, while in the continuous flow system, the conversion was found to decrease due to the deactivation of the catalyst resulting from the generation of the poisoning CO. Computational fluid dynamics (CFD) studies were developed to predict the conversion profiles, which demonstrated great validation with the experimental results. The model can accurately predict the decomposition of FA as well as the deactivation that occurs in the continuous flow system. Of significance was the performance of the packed-bed flow reactor, which showed improved FA conversion in comparison to the batch reactor, potentially leading to the utilisation of continuous flow systems for future fuel cell applications for on-site H2 production.

Plastic catalytic pyrolysis to fuels as tertiary polymer recycling method: effect of process conditions.

This paper presents results regarding the effect of various process conditions on the performance of a zeolite catalyst in pyrolysis of high density polyethylene. The results show that polymer catalytic degradation can be operated at relatively low catalyst content reducing the cost of a potential industrial process. As the polymer to catalyst mass ratio increases, the system becomes less active, but high temperatures compensate for this activity loss resulting in high conversion values at usual batch times and even higher yields of liquid products due to less overcracking. The results also show that high flow rate of carrier gas causes evaporation of liquid products falsifying results, as it was obvious from liquid yield results at different reaction times as well as the corresponding boiling point distributions. Furthermore, results are presented regarding temperature effects on liquid selectivity. Similar values resulted from different final reactor temperatures, which are attributed to the batch operation of the experimental equipment. Since polymer and catalyst both undergo the same temperature profile, which is the same up to a specific time independent of the final temperature. Obviously, this common temperature step determines the selectivity to specific products. However, selectivity to specific products is affected by the temperature, as shown in the corresponding boiling point distributions, with higher temperatures showing an increased selectivity to middle boiling point components (C(8)-C(9)) and lower temperatures increased selectivity to heavy components (C(14)-C(18)).

Modelling of packed bed and coated wall microreactors for methanol steam reforming for hydrogen production.

A Computational Fluid Dynamics (CFD) study has been conducted to assess the performance of packed bed and coated wall microreactors for the steam reforming of methanol with a CuO/ZnO/Al2O3 based catalyst (BASF F3-01). The results obtained were compared to experimental data from the literature to assess the validity and robustness of the models, and a good validation has been obtained. The performance of the packed bed and coated wall microreactors is similar at a constant reforming temperature. It was found that methanol conversion is enhanced with increasing temperature, residence time, steam to methanol ratio, and catalyst coating thickness. Furthermore, internal and external mass transfer phenomena were investigated using the models, and it was found that there were no internal and external mass transfer resistances for this reactor configuration. Further studies demonstrated that larger catalyst pellet sizes led to the presence of internal mass transfer resistance, which in turn causes lower methanol conversions. The CFD models have exhibited a sound agreement with the experimental data, hence they can be used to predict the steam reforming of methanol in microreactors.

Predicting the Features of Methane Adsorption in Large Pore Metal-Organic Frameworks for Energy Storage.

Currently, metal-organic frameworks (MOFs) are receiving significant attention as part of an international push to use their special properties in an extensive variety of energy applications. In particular, MOFs have exceptional potential for gas storage especially for methane and hydrogen for automobiles. However, using theoretical approaches to investigate this important problem presents various difficulties. Here we present the outcomes of a basic theoretical investigation into methane adsorption in large pore MOFs with the aim of capturing the unique features of this phenomenon. We have developed a pseudo one-dimensional statistical mechanical theory of adsorption of gas in a MOF with both narrow and large pores, which is solved exactly using a transfer matrix technique in the Osmotic Ensemble (OE). The theory effectively describes the distinctive features of adsorption of gas isotherms in MOFs. The characteristic forms of adsorption isotherms in MOFs reflect changes in structure caused by adsorption of gas and compressive stress. Of extraordinary importance for gas storage for energy applications, we find two regimes of Negative gas adsorption (NGA) where gas pressure causes the MOF to transform from the large pore to the narrow pore structure. These transformations can be induced by mechanical compression and conceivably used in an engine to discharge adsorbed gas from the MOF. The elements which govern NGA in MOFs with large pores are identified. Our study may help guide the difficult program of work for computer simulation studies of gas storage in MOFs with large pores.

Intramuscular aripiprazole in the control of agitation.

OBJECTIVE: To evaluate response to intramuscular (IM) aripiprazole injections using secondary analyses from clinical trials. METHODS: Data from one trial in patients with bipolar I disorder and two trials in patients with schizophrenia were assembled and used for three secondary analyses. Analysis 1 looked at data from "nonsedated" patients (i.e., patients with scores < 8 [deep sleep] or 9 [unarousable] on the Agitation-Calmness Evaluation Scale [ACES]). In analysis 2, patients were subdivided into "higher" and "lower" agitation groups according to a median split on the baseline score for the Positive and Negative Syndrome Scale (PANSS) Excited Component (PEC) (median = 18). Analysis 3 looked at the patients who received a second injection within the 24-hour study period. In each analysis, the mean change from baseline in PEC scores was re-evaluated. RESULTS: Analysis 1 found that nonsedated patients with bipolar I disorder and schizophrenia showed significant decreases in PEC scores following treatment with aripiprazole IM (p < 0.005). Analysis 2 found that aripiprazole IM significantly reduced agitation compared with placebo in patients with bipolar I disorder who had lower baseline agitation (p < 0.01), while patients with bipolar I disorder who had higher baseline agitation showed similarly large PEC decreases with aripiprazole (-9.9) and placebo (-7.9). Patients with schizophrenia showed significant reductions in PEC scores compared with placebo regardless of baseline level of agitation (p < 0.01). Analysis 3 found that a second injection of aripiprazole IM significantly reduced agitation in patients with bipolar I disorder or schizophrenia (p < 0.05); repeated injections were safe and well tolerated. CONCLUSION: Improvements with aripiprazole IM appeared to be specific to core agitation symptoms, as opposed to nonspecific sedation, and to be independent of baseline level of agitation. Furthermore, patients benefited from a repeated aripiprazole injection when clinically warranted. These results address important clinical issues regarding use of aripiprazole IM in treating agitation.

Efficacy and safety of oral aripiprazole compared with haloperidol in patients transitioning from acute treatment with intramuscular formulations.

OBJECTIVE: To report efficacy and safety of transitioning patients receiving intramuscular (IM) formulations of aripiprazole or haloperidol to their respective oral formulations. METHODS: 448 agitated patients with schizophrenia (73%) or schizoaffective disorder (27%) were randomized to receive aripiprazole IM 9.75 mg, haloperidol IM 6.5 mg, or placebo IM within 24 hours. Patients treated with aripiprazole IM or haloperidol IM who completed this 24-hour IM phase were transitioned to the respective blinded oral formulations for 4 days (aripiprazole 10-15 mg/day, n = 153; haloperidol 7.5-10 mg/day, n = 151). Patients treated with placebo IM were transitioned to oral aripiprazole (analysis not included). The primary efficacy measure was mean change in Positive and Negative Syndrome Scale-Excited Component (PEC) score from baseline of oral phase (last value from 24-hour IM phase) to endpoint (study day 5, last observation carried forward). RESULTS: During the oral phase, aripiprazole 15 mg and haloperidol 10 mg were both effective in maintaining responses achieved on all efficacy measures during the 24-hour IM phase. Mean improvements in PEC scores from study day 1 to 5 were -1.37 for aripiprazole and -1.40 for haloperidol (p = NS for aripiprazole versus haloperidol). Oral aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were lower for aripiprazole (1.3%) than haloperidol (8.0%). Nausea and vomiting occurred more frequently in patients receiving aripiprazole (3.9% and 2.6%, respectively) than in those receiving haloperidol (0.7% and 1.3%, respectively). CONCLUSIONS: Acutely agitated patients with schizophrenia or schizoaffective disorder treated with aripiprazole IM or haloperidol IM demonstrated similar effective and safe transition to their respective oral formulations. Initial benefits of reduced agitation and improved clinical status during the IM phase of the study were maintained throughout the oral phase of the study with good tolerability.

Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol.

INTRODUCTION: This double-blind, placebo-controlled study investigated the efficacy and safety of intramuscular (IM) aripiprazole and IM haloperidol for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder. MATERIALS AND METHODS: Four-hundred and forty-eight patients were randomized (2:2:1 ratio) to IM aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo. Patients could receive up to three injections over the first 24 h, with second and third injections administered > or =2 and > or =4 h, respectively, after the first if deemed clinically necessary. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component (PEC) score from baseline to 2 h. RESULTS: Mean improvement in PEC at 2 h was significantly greater for IM aripiprazole (-7.27) vs placebo (-4.78; p<0.001); IM aripiprazole was noninferior to IM haloperidol (-7.75) on PEC. All secondary efficacy measures showed significantly greater improvements at 2 h for IM aripiprazole and IM haloperidol over placebo. Mean number of injections/patient and percentage of patients requiring benzodiazepines were significantly lower for IM aripiprazole vs placebo (p<0.01). IM aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were similar for aripiprazole (1.7%) and placebo (2.3%) and lower than with haloperidol (12.6%). CONCLUSION: These results show that IM aripiprazole is an effective treatment, comparable to IM haloperidol, and well-tolerated for acute agitation in patients with schizophrenia.

Exact matrix treatment of an osmotic ensemble model of adsorption and pressure induced structural transitions in metal organic frameworks.

Here we present an exactly treated quasi-one dimensional statistical mechanical osmotic ensemble model of pressure and adsorption induced breathing structural transformations of metal-organic frameworks (MOFs). The treatment uses a transfer matrix method. The model successfully reproduces the gas and pressure induced structural changes which are observed experimentally in MOFs. The model treatment presented here is a significant step towards analytical statistical mechanical treatments of flexible metal-organic frameworks.

Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial.

PURPOSE: We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib. PATIENTS AND METHODS: Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). RESULTS: At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms. CONCLUSION: These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.

Aripiprazole treatment of irritability associated with autistic disorder and the relationship between prior antipsychotic exposure, adverse events, and weight change.

OBJECTIVE: The purpose of this study was to evaluate the impact of prior antipsychotic exposure (PAE) on safety and tolerability outcomes in pediatric subjects receiving aripiprazole treatment. METHODS: This study was a post-hoc analysis of pooled data from two 8-week, double-blind, randomized, placebo-controlled studies evaluating aripiprazole for the treatment of irritability in pediatric subjects with autistic disorder, aged 6-17 years. Subjects were stratified by PAE; adverse events (AEs), and changes in weight, and metabolic measures were evaluated. For subjects receiving aripiprazole, regardless of PAE, baseline weight, age, gender, and symptom severity were evaluated in a regression model predicting body weight change. RESULTS: Of 316 randomized subjects, 259 (82.0%) were antipsychotic naïve (AN) and 57 (18.0%) had a PAE. Aripiprazole-treated AN subjects were more likely than PAE subjects to report somnolence (11.9% vs. 2.8%), sedation (22.7% vs. 11.1%), or fatigue (17.0% vs. 13.9%). Rates of extrapyramidal disorder and drooling, but not akathisia or tremor, were marginally higher in AN subjects. Overall, 10.8% of aripiprazole-treated AN subjects had at least one AE leading to discontinuation compared with 8.3% of aripiprazole-treated PAE subjects. AN subjects receiving aripiprazole had a larger change in weight from baseline to endpoint compared with those receiving placebo (1.9 vs. 0.7 kg; treatment difference 1.2 kg, 95% CI: 0.5, 1.9) than PAE subjects receiving aripiprazole compared with subjects receiving placebo (0.4 vs. -0.4 kg; treatment difference 0.9 kg, 95% CI: -0.6, 2.4). Regression analysis identified that younger subjects with higher baseline weight z-score were at highest risk for weight gain. There were no significant changes in metabolic measures compared with placebo in either group. CONCLUSIONS: Weight gain was more pronounced in AN subjects and more likely to occur in younger subjects with a higher baseline weight z-score. AN subjects were more likely to experience AEs related to somnolence. However, based on discontinuations rates from AEs, overall tolerability was good for both AN and PAE groups. CLINICAL TRIAL REGISTRATION: Study of aripiprazole in the treatment of children and adolescents with autistic disorder. Registry: www.clinicaltrials.gov . Identifiers: NCT00332241 and NCT00337571.