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The thrombopoietin receptor agonist eltrombopag has been shown to be safe, tolerable, and effective for adults with chronic immune thrombocytopenia. We aimed to investigate the safety and efficacy of eltrombopag for children with chronic immune thrombocytopenia. PETIT2 was a two part, randomised, multicentre, placebo-controlled study done at 38 centres in 12 countries (Argentina, Czech Republic, Germany, Hong Kong, Israel, Italy, Russia, Spain, Taiwan, Thailand, UK, and USA). Paediatric patients aged 1–17 years who had chronic immune thrombocytopenia and platelet counts less than 30 × 109 per L were randomly assigned (2:1) to receive eltrombopag or placebo. We stratified patients by age into three cohorts (patients aged 12–17 years, 6–11 years, and 1–5 years) before randomly entering them into a 13 week, double-blind period. Randomisation was done by the GlaxoSmithKline Registration and Medication Ordering System and both patients and study personnel were masked to treatment assignments. Patients who were allocated eltrombopag received tablets (except for those aged 1–5 years who received an oral suspension formulation) once per day for 13 weeks. Starting doses for patients aged 6–17 were based on bodyweight, and ethnic origin and ranged between 50 mg/day and 25 mg/day (starting dose for patients aged 1–5 years was 1·2 mg/kg/day or 0·8 mg/kg/day for east Asian patients). Patients who completed the double-blind period entered a 24 week open-label treatment period in which all patients received eltrombopag at either the starting dose (if they were formerly on placebo) or their established dose. The primary outcome was the proportion of patients achieving platelet counts of at least 50 × 109 per L in the absence of rescue therapy for 6 or more weeks from weeks 5 to 12 of the double-blind period. The intention-to-treat population included in the efficacy assessment consisted of all patients who were randomly assigned to one of the treatment groups, and the safety population included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01520909. Beginning in March 15, 2012, 92 patients were enrolled, and the trial was completed on Jan 2, 2014. 63 patients were assigned to receive eltrombopag and 29 were assigned to receive placebo. In the double-blind period, three patients discontinued treatment because of adverse events: two patients in the eltrombopag group withdrew because of increased liver aminotransferases and one in the placebo group withdrew because of abdominal haemorrhage. 25 (40%) patients who received eltrombopag compared with one (3%) patient who received placebo achieved the primary outcome of platelet counts of at least 50 × 109 per L for 6 of the last 8 weeks of the double-blind period (odds ratio 18·0, 95% CI, 2·3–140·9; p=0·0004). Responses were similar in all cohorts (eltrombopag vs placebo: 39% vs 10% for patients aged 12–17 years, 42% vs 0% for patients aged 6–11 years, and 36% vs 0% for patients aged 1–5 years). Proportionately fewer patients who received eltrombopag (23 [37%] of 63 patients) had WHO grades 1–4 bleeding at the end of the double-blind period than did those who received placebo (16 [55%] of 29 patients); grades 2–4 bleeding were similar (three [5%] patients who received eltrombopag vs two [7%] patients who received placebo). During the 24-week open-label treatment period, 70 [80%] of 87 patients achieved platelet counts of 50 × 109 per L or more at least once. Adverse events that occurred more frequently with eltrombopag than with placebo included nasopharyngitis (11 [17%] patients), rhinitis (10 [16%] patients), upper respiratory tract infection (7 [11%] patients), and cough (7 [11%] patients). Serious adverse events occurred in five (8%) patients who received eltrombopag and four (14%) who received placebo. Safety was consistent between the open-label and double-blind periods. No deaths, malignancies, or thromboses occurred during the trial. Eltrombopag, which produced a sustained platelet response in 40% of patients with chronic immune thrombocytopenia, is a suitable therapeutic option for children with chronic symptomatic immune thrombocytopenia. We identified no new safety concerns and few patients discontinued treatment because of adverse events. GlaxoSmithKline.

Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov, NCT03110562. The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. Of 457 patients screened for eligibility, 402 were randomly allocated—195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group—and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2–19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4–19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73–not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11–10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53–0·93], p=0·0075). The most frequent grade 3–4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32–0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. Karyopharm Therapeutics.

Purpose Cancer cachexia is characterized by decreased body weight (mainly lean body mass [LBM]) and negatively impacts quality of life (QOL) and prognosis. Anamorelin (ONO-7643) is a novel selective ghrelin receptor agonist under development for treating cancer cachexia. Methods In this double-blind, exploratory phase 2 trial, we examined the efficacy and safety of anamorelin in Japanese patients ( n  = 181) with non-small cell lung cancer (NSCLC) and cancer cachexia (≥5 % weight loss within the previous 6 months). The participants were randomized into three groups and were administered 50 or 100 mg anamorelin, or placebo, orally every day for 12 weeks. The co-primary endpoints were the changes from baseline over 12 weeks in LBM and handgrip strength (HGS). Secondary endpoints included body weight, QOL, Karnofsky Performance Scale (KPS), and serum biomarkers. Results The change in LBM over 12 weeks was 0.55 and 1.15 kg in the placebo and 100-mg anamorelin groups, respectively, but the efficacy of anamorelin in HGS was not detected. The changes in body weight were −0.93, 0.54, and 1.77 kg in the placebo, 50-mg anamorelin, and 100-mg anamorelin groups, respectively. Anamorelin (100 mg) significantly improved KPS and QOL-ACD compared with placebo. Administration of anamorelin for 12 weeks was well tolerated. Conclusions This phase 2 study showed that 100 mg anamorelin has promising results in improving lean body mass, performance status, and especially, QOL in patients with cancer cachexia.

Patients with advanced cancer frequently experience anorexia and cachexia, which are associated with reduced food intake, altered body composition, and decreased functionality. We assessed anamorelin, a novel ghrelin-receptor agonist, on cachexia in patients with advanced non-small-cell lung cancer and cachexia. ROMANA 1 and ROMANA 2 were randomised, double-blind, placebo-controlled phase 3 trials done at 93 sites in 19 countries. Patients with inoperable stage III or IV non-small-cell lung cancer and cachexia (defined as ≥5% weight loss within 6 months or body-mass index <20 kg/m2) were randomly assigned 2:1 to anamorelin 100 mg orally once daily or placebo, with a computer-generated randomisation algorithm stratified by geographical region, cancer treatment status, and weight loss over the previous 6 months. Co-primary efficacy endpoints were the median change in lean body mass and handgrip strength over 12 weeks and were measured in all study participants (intention-to-treat population). Both trials are now completed and are registered with ClinicalTrials.gov, numbers NCT01387269 and NCT01387282. From July 8, 2011, to Jan 28, 2014, 484 patients were enrolled in ROMANA 1 (323 to anamorelin, 161 to placebo), and from July 14, 2011, to Oct 31, 2013, 495 patients were enrolled in ROMANA 2 (330 to anamorelin, 165 to placebo). Over 12 weeks, lean body mass increased in patients assigned to anamorelin compared with those assigned to placebo in ROMANA 1 (median increase 0·99 kg [95% CI 0·61 to 1·36] vs −0·47 kg [–1·00 to 0·21], p<0·0001) and ROMANA 2 (0·65 kg [0·38 to 0·91] vs −0·98 kg [–1·49 to −0·41], p<0·0001). We noted no difference in handgrip strength in ROMANA 1 (−1·10 kg [–1·69 to −0·40] vs −1·58 kg [–2·99 to −1·14], p=0·15) or ROMANA 2 (−1·49 kg [–2·06 to −0·58] vs −0·95 kg [–1·56 to 0·04], p=0·65). There were no differences in grade 3–4 treatment-related adverse events between study groups; the most common grade 3–4 adverse event was hyperglycaemia, occurring in one (<1%) of 320 patients given anamorelin in ROMANA 1 and in four (1%) of 330 patients given anamorelin in ROMANA 2. Anamorelin significantly increased lean body mass, but not handgrip, strength in patients with advanced non-small-cell lung cancer. Considering the unmet medical need for safe and effective treatments for cachexia, anamorelin might be a treatment option for patients with cancer anorexia and cachexia. Helsinn Therapeutics.

This trial tested the efficacy of eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, in patients with immune thrombocytopenia who had not had a response to at least one previous treatment for the disorder. At a dose of 50 or 75 mg, the agonist, which had been shown to increase platelet production in normal volunteers, increased platelet counts to a clinically safe level (≥50,000 per cubic millimeter) in most patients. Eltrombopag, a small nonpeptide agonist of the thrombopoietin receptor, increased platelet counts to a clinically safe level (≥5;50,000 per cubic millimeter) in most patients. Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease in which antiplatelet antibodies accelerate the destruction of platelets. In addition, platelet production can be impaired 1 because the antiplatelet antibodies can also damage megakaryocytes. 2 – 4 Although the thrombocytopenia of ITP can be severe, signs of bleeding are usually only minor. Persistently low platelet counts (<20,000 per cubic millimeter), however, are associated with an increased risk of serious bleeding, such as intracranial hemorrhage. 5 , 6 The goal of managing chronic ITP is to maintain platelet counts, with the least possible intervention, at levels that prevent bleeding, thereby reducing treatment-related toxicity. 7 Glucocorticoids and intravenous immunoglobulins . . .

While studies have explored the feasibility of switching between various thrombopoietin receptor agonists in treating immune thrombocytopenia (ITP), data on the switching from eltrombopag to hetrombopag remains scarce. This post-hoc analysis of a phase III hetrombopag trial aimed to assess the outcomes of ITP patients who switched from eltrombopag to hetrombopag. In the original phase III trial, patients initially randomized to the placebo group were switched to eltrombopag. Those who completed this 14-week eltrombopag were eligible to switch to a 24-week hetrombopag. Treatment response, defined as a platelet count of ≥ 50 × 109/L, and safety were evaluated before and after the switch. Sixty-three patients who completed the 14-week eltrombopag and switched to hetrombopag were included in this post-hoc analysis. Response rates before and after the switch were 66.7% and 88.9%, respectively. Among those with pre-switching platelet counts below 30 × 109/L, eight out of 12 patients (66.7%) responded, while eight out of nine patients (88.9%) with pre-switching platelet counts between 30 × 109/L and 50 × 109/L responded post-switching. Treatment-related adverse events were observed in 50.8% of patients during eltrombopag treatment and 38.1% during hetrombopag treatment. No severe adverse events were noted during hetrombopag treatment. Switching from eltrombopag to hetrombopag in ITP management appears to be effective and well-tolerated. Notably, hetrombopag yielded high response rates, even among patients who had previously shown limited response to eltrombopag. However, these observations need to be confirmed in future trials.

Cage like CuFe.sub.2O.sub.4 hollow nanostructure has been synthesized successfully using hard template method under the hydrothermal condition. Cu(NO.sub.3).sub.2·6H.sub.2O, Fe(NO.sub.3).sub.2·9H.sub.2O and glucose were dissolved in water, and the mixture was heated to 180 °C in an autoclave. The removal of carbon was achieved by calcination at 800 °C and finally, the cage like CuFe.sub.2O.sub.4 hollow structure was obtained. This cage like CuFe.sub.2O.sub.4 hollow structure was characterized by FE-SEM, EDS, TEM and XRD. The catalytic performance of this hollow nanostructure was evaluated for the synthesis of bis pyrazol-5-ols. To this end, the one pot condensation reactions of phenylhydrazine, ethyl acetoacetate and different aromatic aldehyde at 80 °C under the solvent free condition were performed. The optimum amount of applied catalyst for this transformation was obtained to be 0.04 mol %. Noteworthy, catalyst was easily recoverable and was reused for 7 times with the remaining of its initial structure as well as its catalytic activity. Graphical Cage like CuFe.sub.2O.sub.4 hollow nanostructure are stably and efficiently attainable for conversion of precursors to 4,4'-(aryl methylene)bis(3-methyl-1H-pyrazol-5-ol)s

Cage like CuFe.sub.2O.sub.4 hollow nanostructure has been synthesized successfully using hard template method under the hydrothermal condition. Cu(NO.sub.3).sub.2·6H.sub.2O, Fe(NO.sub.3).sub.2·9H.sub.2O and glucose were dissolved in water, and the mixture was heated to 180 °C in an autoclave. The removal of carbon was achieved by calcination at 800 °C and finally, the cage like CuFe.sub.2O.sub.4 hollow structure was obtained. This cage like CuFe.sub.2O.sub.4 hollow structure was characterized by FE-SEM, EDS, TEM and XRD. The catalytic performance of this hollow nanostructure was evaluated for the synthesis of bis pyrazol-5-ols. To this end, the one pot condensation reactions of phenylhydrazine, ethyl acetoacetate and different aromatic aldehyde at 80 °C under the solvent free condition were performed. The optimum amount of applied catalyst for this transformation was obtained to be 0.04 mol %. Noteworthy, catalyst was easily recoverable and was reused for 7 times with the remaining of its initial structure as well as its catalytic activity.

Zn‐CO2 batteries (ZCBs) are promising for CO2 conversion and electric energy release. However, the ZCBs couple the electrochemical CO2 reduction (ECO2R) with the oxygen evolution reaction and competitive hydrogen evolution reaction, which normally causes ultrahigh charge voltage and CO2 conversion efficiency attenuation, thereby resulting in ~90% total power consumption. Herein, isolated FeN3 sites encapsulated in hierarchical porous carbon nanoboxes (Fe‐HPCN, derived from the thermal activation process of ferrocene and polydopamine‐coated cubic ZIF‐8) were proposed for hydrazine‐assisted rechargeable ZCBs based on ECO2R (discharging process: CO2 + 2H+ → CO + H2O) and hydrazine oxidation reaction (HzOR, charging process: N2H4 + 4OH− → N2 + 4H2O + 4e−). The isolated FeN3 endows the HzOR with a lower overpotential and boosts the ECO2R with a 96% CO Faraday efficiency (FECO). Benefitting from the bifunctional ECO2R and HzOR catalytic activities, the homemade hydrazine‐assisted rechargeable ZCBs assembled with the Fe‐HPCN air cathode exhibited an ultralow charge voltage (decreasing by ~1.84 V), excellent CO selectivity (FECO close to 100%), and high 89% energy efficiency. In situ infrared spectroscopy confirmed that Fe‐HPCN can generate rate‐determining *N2 and *CO intermediates during HzOR and ECO2R. This paper proposes FeN3 centers for bifunctional ECO2R/HzOR performance and further presents the pioneering achievements of ECO2R and HzOR for hydrazine‐assisted rechargeable ZCBs. Isolated FeN3 centers that anchored porous carbon substrates are reported as an efficient and stable electrocatalyst for catalyzing the reduction of CO2 to CO and hydrazine oxidation systems. The homemade hydrazine‐assisted rechargeable ZCBs assembled with the Fe‐HPCN air cathode exhibited an ultralow charge voltage (decreasing by ∼1.84 V), excellent CO selectivity (FECO close to 100%), and high 89% energy efficiency.

The coupling of energy-saving small molecule conversion reactions and hydrogen evolution reaction (HER) in seawater electrolytes can reduce the energy consumption of seawater electrolysis and mitigate chlorine corrosion issues. However, the fabrication of efficient multifunctional catalysts for this promising technology is of great challenge. Herein, a heterostructured catalyst comprising CoP and Ni 2 P on nickel foam (CoP/Ni 2 P@NF) is reported for hydrazine oxidation (HzOR)-assisted alkaline seawater splitting. The coupling of CoP and Ni 2 P optimizes the electronic structure of the active sites and endows excellent electrocatalytic performance for HzOR and HER. Impressively, the two-electrode HzOR-assisted alkaline seawater splitting (OHzS) cell based on the CoP/Ni 2 P@NF required only 0.108 V to deliver 100 mA·cm −2 , much lower than 1.695 V for alkaline seawater electrolysis cells. Moreover, the OHzS cell exhibits satisfactory stability over 48 h at a high current density of 500 mA·cm −2 . Furthermore, the CoP/Ni 2 P@NF heterostructured catalyst also efficiently catalyzed glucose oxidation, methanol oxidation, and urea oxidation in alkaline seawater electrolytes. This work paves a path for high-performance heterostructured catalyst preparation for energy-saving seawater electrolysis for H 2 production.