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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.

Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13·4%]) and ramipril (1150 [13·5%]; hazard ratio [HR] 1·00, 95% CI 0·92–1·09), but was increased with combination therapy (1233 [14.5%]; HR 1·09, 1·01–1·18, p=0·037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2·21%]) and ramipril (174 [2·03%]; HR 1·09, 0·89–1·34) and more frequent with combination therapy (212 [2·49%]: HR 1·24, 1·01–1·51, p=0·038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (−2·82 [SD 17·2] mL/min/1·73 m 2 vs −4·12 [17·4], p<0·0001) or combination therapy (−6·11 [17·9], p<0·0001). The increase in urinary albumin excretion was less with telmisartan (p=0·004) or with combination therapy (p=0·001) than with ramipril. In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes. Boehringer-Ingelheim.

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 . . .

Studies have challenged the appropriateness of accepted blood pressure targets. We hypothesised that different levels of low blood pressure are associated with benefit for some, but harm for other outcomes. In this analysis, we assessed the previously reported outcome data from high-risk patients aged 55 years or older with a history of cardiovascular disease, 70% of whom had hypertension, from the ONTARGET and TRANSCEND trials investigating ramipril, telmisartan, and their combination, with a median follow-up of 56 months. Detailed descriptions of randomisation and intervention have already been reported. We analysed the associations between mean blood pressure achieved on treatment; prerandomisation baseline blood pressure; or time-updated blood pressure (last on treatment value before an event) on the composite outcome of cardiovascular death, myocardial infarction, stroke, and hospital admission for heart failure; the components of the composite outcome; and all-cause death. Analysis was done by Cox regression analysis, ANOVA, and χ2. These trials were registered with ClinicalTrials.gov, number NCT00153101. Recruitment for ONTARGET took place between Dec 1, 2001, and July 31, 2008. TRANSCEND took place between Nov 1, 2001, and May 30, 2004. 30 937 patients were recruited from 733 centres in 40 countries and followed up for a median of 56 months. In ONTARGET, 25 127 patients known to be tolerant to angiotensin-converting-enzyme (ACE)-inhibitors were randomly assigned after a run-in period to oral ramipril 10 mg/day (n=8407), telmisartan 80 mg/day (n=8386), or the combination of both (n=8334). In TRANSCEND, 5810 patients who were intolerant to ACE-inhibitors were randomly assigned to oral telmisartan 80 mg/day (n=2903) or placebo (n=2907). Baseline systolic blood pressure (SBP) 140 mm Hg or higher was associated with greater incidence of all outcomes compared with 120 mm Hg to less than 140 mm Hg. By contrast, a baseline diastolic blood pressure (DBP) less than 70 mm Hg was associated with the highest risk for most outcomes compared with all DBP categories 70 mm Hg or more. In 4052 patients with SBP less than 120 mm Hg on treatment, the risk of the composite cardiovascular outcome (adjusted hazard ratio [HR] 1·14, 95% CI 1·03–1·26), cardiovascular death (1·29, 1·12–1·49), and all deaths (1·28, 1·15–1·42) were increased compared with those in whom SBP was 120–140 mm Hg during treatment (HR 1 for all outcomes, n=16099). No harm or benefit was observed for myocardial infarction, stroke, or hospital admission for heart failure. Mean achieved SBP more accurately predicted outcomes than baseline or time-updated SBP, and was associated with the lowest risk at approximately 130 mm Hg, and at 110–120 mm Hg risk increased for the combined outcome, cardiovascular death, and all-cause death except stroke. A mean DBP less than 70 mm Hg (n=5352) during treatment was associated with greater risk of the composite primary outcome (HR 1·31, 95% CI 1·20–1·42), myocardial infarction (1·55, 1·33–1·80), hospital admission for heart failure (1·59, 1·36–1·86) and all-cause death (1·16, 1·06–1·28) than a DBP 70–80 mm Hg (14 305). A pretreatment and mean on-treatment DBP of about 75 mm Hg was associated with the lowest risk. Mean achieved SBP less than 120 mm Hg during treatment was associated with increased risk of cardiovascular outcomes except for myocardial infarction and stroke. Similar patterns were observed for DBP less than 70 mm Hg, plus increased risk for myocardial infarction and hospital admission for heart failure. Very low blood pressure achieved on treatment was associated with increased risks of several cardiovascular disease events. These data suggest that the lowest blood pressure possible is not necessarily the optimal target for high-risk patients, although it is not possible to rule out some effect of reverse causality. Boehringer Ingelheim.

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.

In a multicenter trial, 20,332 patients who had recently had an ischemic stroke were randomly assigned to receive either telmisartan or placebo. All patients also received medications for blood-pressure control at the investigators' discretion. At a mean follow-up of 2.5 years, there was no significant difference between the two study groups in the rates of recurrent stroke or major cardiovascular events. Patients who had recently had an ischemic stroke were randomly assigned to receive either telmisartan or placebo. At a mean follow-up of 2.5 years, there was no significant difference between the study groups in the rates of recurrent stroke or major cardiovascular events. Stroke is the second most frequent cause of death in the world and is responsible for about 5 million deaths each year. 1 An additional 15 million persons have nonfatal strokes, with about a third having disabling consequences. Elevated blood pressure is the strongest risk factor for stroke, and lowering of blood pressure, especially in patients with substantially elevated levels (e.g., systolic pressure, >160 mm Hg), reduces the risk of stroke. 2 After a stroke, lowering blood pressure with a combination of an angiotensin-converting–enzyme (ACE) inhibitor and a diuretic reduced rates of recurrent stroke in the Perindopril Protection against Recurrent Stroke Study . . .

Synthetic retinoid compounds can kill both growing and persister MRSA cells by disrupting the membrane lipid bilayer, and are effective in a mouse model of chronic MRSA infection. Drugs to beat persistence Bacterial persisters are a subpopulation of cells that can survive lethal antibiotics and other stresses. They are a major challenge for antimicrobial therapy as they cannot be killed by traditional therapeutic agents. Eleftherios Mylonakis and colleagues have developed retinoid compounds that can kill both growing and persister MRSA cells by disrupting the membrane. They develop one of these compounds with an improved cytotoxicity profile, and show that it is effective in treating a mouse model of chronic MRSA infection. Further development of these antibiotics is required to improve safety margins to move the antibiotics closer to being viable clinical candidates. A challenge in the treatment of Staphylococcus aureus infections is the high prevalence of methicillin-resistant S. aureus (MRSA) strains and the formation of non-growing, dormant ‘persister’ subpopulations that exhibit high levels of tolerance to antibiotics 1 , 2 , 3 and have a role in chronic or recurrent infections 4 , 5 . As conventional antibiotics are not effective in the treatment of infections caused by such bacteria, novel antibacterial therapeutics are urgently required. Here we used a Caenorhabditis elegans –MRSA infection screen 6 to identify two synthetic retinoids, CD437 and CD1530, which kill both growing and persister MRSA cells by disrupting lipid bilayers. CD437 and CD1530 exhibit high killing rates, synergism with gentamicin, and a low probability of resistance selection. All-atom molecular dynamics simulations demonstrated that the ability of retinoids to penetrate and embed in lipid bilayers correlates with their bactericidal ability. An analogue of CD437 was found to retain anti-persister activity and show an improved cytotoxicity profile. Both CD437 and this analogue, alone or in combination with gentamicin, exhibit considerable efficacy in a mouse model of chronic MRSA infection. With further development and optimization, synthetic retinoids have the potential to become a new class of antimicrobials for the treatment of Gram-positive bacterial infections that are currently difficult to cure.

This large trial compared the angiotensin-receptor blocker telmisartan, the angiotensin-converting–enzyme inhibitor ramipril, and combination therapy with both drugs in patients with vascular disease or high-risk diabetes. Outcomes were the same with telmisartan and ramipril, and there were more adverse events with combination therapy. This trial compared the angiotensin-receptor blocker telmisartan, the angiotensin-converting–enzyme inhibitor ramipril, and combination therapy in patients with vascular disease or high-risk diabetes. Outcomes were the same with telmisartan and ramipril, and there were more adverse events with combination therapy. Randomized, controlled trials involving about 150,000 patients have convincingly demonstrated that angiotensin-converting–enzyme (ACE) inhibitors reduce rates of death, myocardial infarction, stroke, and heart failure among patients with heart failure, 1 left ventricular dysfunction, 2 – 4 previous vascular disease alone, 5 – 7 or high-risk diabetes. 8 ACE inhibitors do not block the production of all angiotensin II, so direct receptor blockade might be more effective. ACE inhibitors reduce bradykinin degradation, which enhances vasodilatation, but increase the rates of angioedema and cough. In patients with heart failure, angiotensin II levels may increase and symptoms worsen, despite the use of ACE inhibitors. 9 The use of an angiotensin-receptor . . .

Abstract Background Current anti-dementia drugs cannot benefit mild cognitive impairment (MCI). Sodium benzoate (a D-amino acid oxidase [DAO] inhibitor) has been found to improve the cognitive function of patients with early-phase Alzheimer’s disease (mild Alzheimer’s disease or MCI). However, its effect on brain function remains unknown. This study aimed to evaluate the influence of benzoate on functional magnetic resonance imaging in patients with amnestic MCI. Methods This was a 24-week, randomized, double-blind, placebo-controlled trial that enrolled 21 patients with amnestic MCI and allocated them randomly to either of 2 treatment groups: (1) benzoate group (250–1500 mg/d), or (2) placebo group. We assessed the patients’ working memory, verbal learning and memory, and resting-state functional magnetic resonance imaging and regional homogeneity (ReHo) maps at baseline and endpoint. Results Resting-state ReHo decreased in right orbitofrontal cortex after benzoate treatment but did not change after placebo. Moreover, after benzoate treatment, the change in working memory was positively correlated with the change in ReHo in right precentral gyrus and right middle occipital gyrus; and the change in verbal learning and memory was positively correlated with the change in ReHo in left precuneus. In contrast, after placebo treatment, the change in working memory or in verbal learning and memory was not correlated with the change in ReHo in any brain region. Conclusion The current study is the first to our knowledge to demonstrate that a DAO inhibitor, sodium benzoate herein, can alter brain activity as well as cognitive functions in individuals with MCI. The preliminary finding lends supports for DAO inhibition as a novel approach for early dementing processes.

In this trial involving patients with cirrhosis and thrombocytopenia, treatment with eltrombopag before invasive procedures reduced the need for platelet transfusions. More thrombotic events of the portal venous system were observed with eltrombopag than with placebo. Thrombocytopenia is frequently observed in patients with chronic liver disease, with studies suggesting that it occurs in up to 76% of patients with cirrhosis. 1 – 3 The degree of thrombocytopenia is proportional to the severity of the liver disease. 4 , 5 Thrombocytopenia increases the risk of bleeding during and after invasive procedures and may result in the cancellation or postponement of elective procedures. 6 Platelet transfusions are commonly used to reduce the risk of bleeding during a procedure, but their short duration of efficacy and the risk of transfusion reactions limit their use. 7 , 8 Furthermore, the development of antiplatelet antibodies (alloimmunization) can cause . . .