Systematic Review with Meta-Analysis: Efficacy and Safety of Lusutrombopag for Severe Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Invasive Procedures.

INTRODUCTION: Lusutrombopag is an oral thrombopoietin receptor agonist (TPO-RA). Clinical trials have shown lusutrombopag's efficacy in reducing need for preoperative platelet transfusion in patients with chronic liver disease (CLD) and severe thrombocytopenia. This analysis assessed efficacy and safety of lusutrombopag in patients with severe thrombocytopenia and CLD undergoing planned invasive procedures. METHODS: An electronic database search (through 1 December 2020) identified three randomised, placebo-controlled, double-blind clinical trials comparing lusutrombopag with placebo in patients with CLD and platelet count below 50 × 109/L scheduled to undergo a procedure with a perioperative bleeding risk. A random-effects meta-analysis examined treatment effect, with Cochrane Collaboration's tool assessing risk of bias. RESULTS: The meta-analysis included 343 (lusutrombopag 3 mg, n = 173; placebo, n = 170) patients. More patients met the criteria for treatment response (platelet count at least 50 × 109/L and increase of at least 20 × 109/L from baseline anytime during the study) with lusutrombopag versus placebo (risk ratio [RR] 6.39; 95% confidence interval [CI] 3.69, 11.07; p < 0.0001). The primary efficacy outcome, proportion of patients requiring no platelet transfusion and no rescue therapy for bleeding for at least 7 days post procedure, was achieved by more patients treated with lusutrombopag versus placebo (RR 3.42; 95% CI 1.86, 6.26; p = 0.0001). The risk of any bleeding event was significantly lower with lusutrombopag compared to placebo (RR 0.55; 95% CI 0.32, 0.95; p = 0.03); conversely, thrombosis event rates were similar between lusutrombopag and placebo (RR 0.79; 95% CI 0.19, 3.24; p = 0.74). CONCLUSION: This meta-analysis showed that treatment of severe thrombocytopenia with lusutrombopag in patients with CLD prior to a planned invasive procedure was efficacious and safe in increasing platelet counts, avoiding the need for platelet transfusions, and reducing risk of bleeding, thereby enhancing the certainty of evidence supporting the efficacy and safety of lusutrombopag.

Organic UV filters mixture exposure and childhood adiposity: A prospective follow-up study in China.

BACKGROUND: UV filters are emerging contaminants with endocrine disrupting effects, but little is known about their health effects, especially for children. OBJECTIVE: To assess the association between multiple organic UV filters exposure and adiposity measures and by gender in peripubertal children. METHODS: This prospective follow-up study included 327 children aged 7-15 years old. Urinary organic UV filters including benzophenone derivatives (BP-2, BP-3), octyl dimethyl para-aminobenzoic acid (OD-PABA), ethylhexyl methoxycinnamate (EHMC) and its metabolite (4-MCA and 4'-MAP) were quantified. Six adiposity biometrics including height, weight, waist and hip circumferences, and triceps and subscapular skinfold thickness were measured with 1.5-year duration. The Bayesian kernel machine regression method was used to estimate the associations of UV filters mixture with adiposity measurements, and longitudinal analyses were then considered to further evaluate the associations between individual UV filters and trajectories of growth development using linear mixed models or generalized linear mixed models. RESULTS: Exposure to mixture of UV filters was negatively associated with most adiposity measurements, with a reduction of 1.399 kg/m2 (95% CI: -2.246 to -0.551 kg/m2) in BMI, 0.674 (95% CI: -1.045 to -0.304) in BMI z-score, 0.033 BF% (95% CI: -0.053 to -0.013), and 2.301 mm (95% CI: -3.823 to -0.78) in subscapular skinfold thickness at baseline, comparing the 75th percentile to the 25th level of UV filters mixture exposure. Consistent associations were found at follow-up. Both baseline and follow-up results suggested that EHMC was identified as the most important contributor to lower adiposity measurements, which was also confirmed by linear mixed models in longitudinal analyses. No significant effects were found in girls. CONCLUSION: This study found that childhood organic UV filters exposure was negatively associated with adiposity measures in peripubertal boys, but not girls.

Lusutrombopag has slightly stronger effects on patients with mild thrombocytopenia compared with those with severe thrombocytopenia: A multicenter propensity score matching study.

BACKGROUND: Lusutrombopag effectively increases platelet count in patients with severe thrombocytopenia. However, no multicenter studies analyzing the effects of Lusutrombopag on patients with mild thrombocytopenia (platelet count > 50 000/µL) have been performed. In this study, we aimed to clarify the efficacy of Lusutrombopag on these patients by unifying background factors by propensity score matching. METHODS: A total of 139 patients with thrombocytopenia were enrolled, and matched for age, sex, etiology, disease, treatment, liver function, renal function, peripheral blood count, and spleen index. The primary endpoint was to compare the increase in platelet count from baseline between the high-platelet group (>50 000/µL) and the low-platelet group (<50 000/µL) after Lusutrombopag treatment, using propensity score matching. The secondary endpoint was to clarify platelet transfusion avoidance rate and adverse events, moreover, to identify independent predictors associated with the increase in platelet count. RESULTS: The mean increase in platelet count was 67 000/µL vs 48 000/µL in all patients (high- vs low-platelet group, P = .024), and 64 000/µL vs 48 000/µL (P = .12) after propensity score matching. The increase in platelet count and the platelet transfusion avoidance rate tended to be higher in the high-platelet group. There was no significant difference between adverse events. Predictors associated with an increase in platelet count were sex, estimated glomerular filtration rate, and spleen index by multivariate analysis. CONCLUSION: Lusutrombopag has a little stronger effect in patients with mild thrombocytopenia than those with severe thrombocytopenia and showed a more substantial effect in patients with impaired renal function and small spleen.

Anti-seizure medications for Lennox-Gastaut syndrome.

BACKGROUND: Lennox-Gastaut syndrome (LGS) is an age-specific epilepsy syndrome characterised by multiple seizure types, including drop seizures. LGS has a characteristic electroencephalogram, an onset before age eight years and an association with drug resistance. This is an updated version of the Cochrane Review published in 2013. OBJECTIVES: To assess the efficacy and tolerability of anti-seizure medications (ASMs) for LGS. SEARCH METHODS: We searched the Cochrane Register of Studies (CRS Web) and MEDLINE (Ovid, 1946 to 28 February 2020) on 2 March 2020. CRS Web includes randomised controlled trials (RCTs) or quasi-RCTs from the Cochrane Central Register of Controlled Trials (CENTRAL); the Specialised Registers of Cochrane Review Groups, including Cochrane Epilepsy; PubMed; Embase; ClinicalTrials.gov; and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). We imposed no language restrictions. We contacted pharmaceutical companies and colleagues in the field to seek any unpublished or ongoing studies. SELECTION CRITERIA: We considered RCTs, including cross-over trials, of ASMs for LGS in children and adults. We included studies of ASMs used as either monotherapy or as an add-on (adjunctive) therapy. We excluded studies comparing different doses of the same ASM. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures, including independent, dual assessment for risk of bias and application of the GRADE approach to rate the evidence certainty for outcomes. MAIN RESULTS: We found no trials of ASM monotherapy. The review included 11 trials (1277 participants; approximately 11 weeks to 112 weeks follow-up after randomisation) using add-on ASMs for LGS in children, adolescents and adults. Two studies compared add-on cannabidiol (two doses) with add-on placebo in children and adolescents only. Neither study reported overall seizure cessation or reduction. We found high-certainty evidence that 72 more people per 1000 (confidence interval (CI) 4 more to 351 more) had adverse events (AE) leading to study discontinuation with add-on cannabidiol, compared to add-on placebo (two studies; 396 participants; risk ratio (RR) 4.90, 95% CI 1.21 to 19.87). One study compared add-on cinromide with add-on placebo in children and adolescents only. We found very low-certainty evidence that 35 more people per 1000 (CI 123 fewer to 434 more) had 50% or greater average reduction of overall seizures with add-on cinromide compared to add-on placebo (one study; 56 participants; RR 1.15, 95% CI 0.47 to 2.86). This study did not report participants with AE leading to study discontinuation. One study compared add-on clobazam (three doses) with add-on placebo. This study did not report overall seizure cessation or reduction. We found high-certainty evidence that 106 more people per 1000 (CI 0 more to 538 more) had AE leading to study discontinuation with add-on clobazam compared to add-on placebo (one study; 238 participants; RR 4.12, 95% CI 1.01 to 16.87). One study compared add-on felbamate with add-on placebo. No cases of seizure cessation occurred in either regimen during the treatment phase (one study; 73 participants; low-certainty evidence). There was low-certainty evidence that 53 more people per 1000 (CI 19 fewer to 716 more) with add-on felbamate were seizure-free during an EEG recording at the end of the treatment phase, compared to add-on placebo (RR 2.92, 95% CI 0.32 to 26.77). The study did not report overall seizure reduction. We found low-certainty evidence that one fewer person per 1000 (CI 26 fewer to 388 more) with add-on felbamate had AE leading to study discontinuation compared to add-on placebo (one study, 73 participants; RR 0.97, 95% CI 0.06 to 14.97). Two studies compared add-on lamotrigine with add-on placebo. Neither study reported overall seizure cessation. We found high-certainty evidence that 176 more people per 1000 (CI 30 more to 434 more) had ≥ 50% average seizure reduction with add-on lamotrigine compared to add-on placebo (one study; 167 participants; RR 2.12, 95% CI 1.19 to 3.76). We found low-certainty evidence that 40 fewer people per 1000 (CI 68 fewer to 64 more) had AE leading to study-discontinuation with add-on lamotrigine compared to add-on placebo (one study; 169 participants; RR 0.49, 95% CI 0.13 to 1.82). Two studies compared add-on rufinamide with add-on placebo. Neither study reported seizure cessation. We found high-certainty evidence that 202 more people per 1000 (CI 34 to 567 more) had ≥ 50% average seizure reduction (one study; 138 participants; RR 2.84, 95% CI 1.31 to 6.18). We found low-certainty evidence that 105 more people per 1000 (CI 17 fewer to 967 more) had AE leading to study discontinuation with add-on rufinamide compared to add-on placebo (one study; 59 participants; RR 4.14, 95% CI 0.49 to 34.86). One study compared add-on rufinamide with another add-on ASM. This study did not report overall seizure cessation or reduction. We found low-certainty evidence that three fewer people per 1000 (CI 75 fewer to 715 more) had AE leading to study discontinuation with add-on rufinamide compared to another add-on ASM (one study; 37 participants; RR 0.96, 95% CI 0.10 to 9.57). One study compared add-on topiramate with add-on placebo. This study did not report overall seizure cessation. We found low-certainty evidence for ≥ 75% average seizure reduction with add-on topiramate (one study; 98 participants; Peto odds ratio (Peto OR) 8.22, 99% CI 0.60 to 112.62) and little or no difference to AE leading to study discontinuation compared to add-on placebo; no participants experienced AE leading to study discontinuation (one study; 98 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: RCTs of monotherapy and head-to-head comparison of add-on ASMs are currently lacking. However, we found high-certainty evidence for overall seizure reduction with add-on lamotrigine and rufinamide, with low-certainty evidence for AE leading to study discontinuation compared with add-on placebo or another add-on ASM. The evidence for other add-on ASMs for overall seizure cessation or reduction was low to very low with high- to low-certainty evidence for AE leading to study discontinuation. Future research should consider outcome reporting of overall seizure reduction (applying automated seizure detection devices), impact on development, cognition and behaviour; future research should also investigate age-specific efficacy of ASMs and target underlying aetiologies.

Safety and efficacy of Melissa officinalis extract containing rosmarinic acid in the prevention of Alzheimer's disease progression.

We conducted a randomized placebo-controlled double-blind 24-week trial using Melissa officinalis (M. officinalis) extract richly containing rosmarinic acid (RA) on patients with mild dementia due to Alzheimer's disease (AD) with the aim to examine the safety and tolerability (primary endpoint) of RA (500 mg daily) and its clinical effects and disease-related biomarker changes (secondary endpoints). Patients (n = 23) diagnosed with mild dementia due to probable AD were randomized to either the placebo or M. officinalis extract group. No differences in vital signs or physical and neurologic examination results were detected between the M. officinalis and placebo groups. No serious adverse events occurred. There were no significant differences in cognitive measures; however, the mean Neuropsychiatric Inventory Questionnaire (NPI-Q) score improved by 0.5 points in the M. officinalis group and worsened by 0.7 points in the placebo group between the baseline and 24-week visit, indicating a significant difference (P = 0.012). No significant differences were apparent in disease-related biomarkers between the groups. M. officinalis extract containing 500 mg of RA taken daily was safe and well-tolerated by patients with mild dementia due to AD. Our results suggest that RA may help prevent the worsening of AD-related neuropsychiatric symptoms.Trial registration: The registration number for this clinical trial is UMIN000007734 (16/04/2012).

Avatrombopag and lusutrombopag for thrombocytopenia in people with chronic liver disease needing an elective procedure: a systematic review and cost-effectiveness analysis.

BACKGROUND: There have been no licensed treatment options in the UK for treating thrombocytopenia in people with chronic liver disease requiring surgery. Established management largely involves platelet transfusion prior to the procedure or as rescue therapy for bleeding due to the procedure. OBJECTIVES: To assess the clinical effectiveness and cost-effectiveness of two thrombopoietin receptor agonists, avatrombopag (Doptelet®; Dova Pharmaceuticals, Durham, NC, USA) and lusutrombopag (Mulpleta®; Shionogi Inc., London, UK), in addition to established clinical management compared with established clinical management (no thrombopoietin receptor agonist) in the licensed populations. DESIGN: Systematic review and cost-effectiveness analysis. SETTING: Secondary care. PARTICIPANTS: Severe thrombocytopenia (platelet count of < 50,000/µl) in people with chronic liver disease requiring surgery. INTERVENTIONS: Lusutrombopag 3 mg and avatrombopag (60 mg if the baseline platelet count is < 40,000/µl and 40 mg if it is 40,000-< 50,000/µl). MAIN OUTCOME MEASURES: Risk of platelet transfusion and rescue therapy or risk of rescue therapy only. REVIEW METHODS: Systematic review including meta-analysis. English-language and non-English-language articles were obtained from several databases including MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials, all searched from inception to 29 May 2019. ECONOMIC EVALUATION: Model-based cost-effectiveness analysis. RESULTS: From a comprehensive search retrieving 11,305 records, six studies were included. Analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy or rescue therapy only, and mostly with a statistically significant difference (i.e. 95% confidence intervals not overlapping the point of no difference). However, only avatrombopag seemed to be superior to no thrombopoietin receptor agonist in reducing the risk of rescue therapy, although far fewer patients in the lusutrombopag trials than in the avatrombopag trials received rescue therapy. When assessing the cost-effectiveness of lusutrombopag and avatrombopag, it was found that, despite the success of these in avoiding platelet transfusions prior to surgery, the additional long-term gain in quality-adjusted life-years was very small. No thrombopoietin receptor agonist was clearly cheaper than both lusutrombopag and avatrombopag, as the cost savings from avoiding platelet transfusions were more than offset by the drug cost. The probabilistic sensitivity analysis showed that, for all thresholds below £100,000, no thrombopoietin receptor agonist had 100% probability of being cost-effective. LIMITATIONS: Some of the rescue therapy data for lusutrombopag were not available. There were inconsistencies in the avatrombopag data. From the cost-effectiveness point of view, there were several additional important gaps in the evidence required, including the lack of a price for avatrombopag. CONCLUSIONS: Avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy, but they were not cost-effective given the lack of benefit and increase in cost. FUTURE WORK: A head-to-head trial is warranted. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019125311. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 51. See the NIHR Journals Library website for further project information.

Thrombocytopenia, which is a reduction in platelet numbers in the blood, is a common complication of chronic liver disease. It increases the risk of bleeding during procedures including liver biopsy and transplantation. It can delay or prevent procedures, leading to illness and death. Established treatment largely involves platelet transfusion before the procedure or as rescue therapy for bleeding. This report aims to systematically review the clinical effectiveness and estimate the cost-effectiveness of the first two recently licensed treatments, thrombopoietin receptor agonists avatrombopag (Doptelet^®; Dova Pharmaceuticals, Durham, NC, USA) (60 mg if platelet count is < 40,000/µl and 40 mg if platelet count is 40,000­< 50,000/µl) and lusutrombopag (Mulpleta^®; Shionogi Inc., London, UK) (3 mg if platelet count is < 50,000/µl), compared with established treatment. From a comprehensive search, six studies were included. Clinical effectiveness analysis showed that avatrombopag and lusutrombopag were superior to no thrombopoietin receptor agonist in avoiding both platelet transfusion and rescue therapy. Only avatrombopag seemed superior to no thrombopoietin receptor agonist in reducing rescue therapy alone. Cost-effectiveness analysis found that lusutrombopag and avatrombopag were more expensive than no thrombopoietin receptor agonist over a lifetime, as the savings from avoiding platelet transfusions were exceeded by the drug cost, and without long-term health benefits. The probabilistic sensitivity analysis, which examined the effect of uncertainty, showed that no thrombopoietin receptor agonist had 100% probability of being cost-effective. Uncertainty about the price of avatrombopag and the content and costs of platelet transfusions and the potential under-reporting of use to estimate platelet transfusion-specific mortality had the greatest impact on results. If the price of avatrombopag was (confidential information has been removed) below the price of lusutrombopag, avatrombopag would become cost saving in the 40,000­< 50,000/µl subgroup. However, although in some scenarios avatrombopag costs could decrease in the 40,000­< 50,000/µl subgroup to around 10% more than the cost of no thrombopoietin receptor agonist, there would be negligible health benefits and the incremental cost-effectiveness ratios would remain very high, meaning that lusutrombopag and avatrombopag would still not be considered cost-effective.

A Randomized, Open-label, Presurgical, Window-of-Opportunity Study Comparing the Pharmacodynamic Effects of the Novel Oral SERD AZD9496 with Fulvestrant in Patients with Newly Diagnosed ER+ HER2- Primary Breast Cancer.

PURPOSE: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2- primary breast cancer awaiting curative intent surgery. PATIENTS AND METHODS: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5-14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety. RESULTS: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (-33.3%) and Ki-67 levels (-39.9%) from baseline, but was also not superior to fulvestrant (PR: -68.7%, P = 0.97; Ki-67: -75.4%, P = 0.98). No new safety findings were identified. CONCLUSIONS: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

Interkingdom Genetic Mix-and-Match To Produce Novel Sunscreens.

Sunscreen-containing skincare products protect the skin from damage caused by sun exposure. However, many of them contain oxybenzone and/or octinoxate, which have been reported to be toxic to juvenile coral and to cause coral bleaching. Thus, there is a growing need for new sunscreen compounds that are less harmful to the environment. Here, we report an engineered biosynthetic pathway employing genes from a vertebrate and two Gram-(+) bacteria that forms novel sunscreen compounds with hybrid structures of gadusol and mycosporine-like amino acids, both of which are found in marine environments. These compounds, named gadusporines, have unique UV absorbance at 340 nm, expanding the range of mycosporine- and gadusol-based sunscreen products. The synthesis of gadusporines in Streptomyces coelicolor establishes a platform for the design and production of novel sunscreens.

Two-generation exposure to 2-ethylhexyl 4-methoxycinnamate (EHMC) in Japanese medaka (Oryzias latipes) and its reproduction and endocrine related effects.

2-Ethylhexyl 4-methoxycinnamate (EHMC) is one of the most widely used UV-filters, and hence has been frequently detected in water environment. EHMC has been reported to induce short-term reproductive toxicity in fish, and thyroid disrupting effects in other animal studies. However, limited information is available for its long-term effects on fecundity, and thyroid disrupting effects in fish. In the present study, effects of EHMC on fecundity, measured as number of eggs, were evaluated in Japanese medaka (Oryzias latipes), and its underlying mechanisms on sex and thyroid hormone disruption were explored. For this purpose, a five-month long (154 d) exposure to F0 generation was conducted on fertilized eggs (<24 h post-fertilization (hpf)), with nominal concentration of 0, 0.05, 0.158, 0.5, 1.58, or 5 mg/L EHMC, followed by a 3-8-d exposure of F1 generation. After >3 months exposure, significant decreases in reproductive performances were observed at all test concentrations as low as 0.05 mg/L. Reproduction effects were not accompanied with sex hormone changes, but up-regulation of vitellogenin gene was observed. Thyroid hormones were decreased by EHMC exposure in F1 fish at -38 day post-fertilization (dpf). In addition, down-regulation of type II iodothyronine deiodinase (dio2) and up-regulation of thyrotropin releasing hormone (trh) were observed in both F0 and F1 juvenile fish, suggesting thyroid disruption potential of EHMC. Our observation suggests that EHMC at the levels one to two orders of magnitude higher than those detected in ambient water may affect reproduction and thyroid hormonal balance of fish.

A randomized controlled trial of lusutrombopag in Japanese patients with chronic liver disease undergoing radiofrequency ablation.

BACKGROUND: Thrombocytopenia represents an obstacle for invasive procedures in chronic liver disease (CLD) patients. We aimed to estimate the appropriate dose and evaluate the efficacy and safety of lusutrombopag for the treatment of thrombocytopenia before percutaneous liver radiofrequency ablation (RFA) for primary hepatic cancer in patients with CLD. METHODS: In this multicenter, randomized, double-blind, placebo-controlled study conducted in Japan, 61 CLD patients with platelet count < 50 × 103/µL at screening were randomized to placebo or lusutrombopag 2, 3, or 4 mg once daily for 7 days, followed by a 28-day post-treatment assessment period. The primary efficacy endpoint was the proportion of patients who did not require platelet transfusion before RFA. The pre-specified key secondary efficacy endpoint was the proportion of responders. Adverse events (AEs) and thrombosis-related AEs were evaluated. RESULTS: The proportion of patients who did not require platelet transfusion before RFA and that of responders were significantly higher (p < 0.01) in the 2-mg (80.0, 66.7%), 3-mg (81.3, 68.8%), and 4-mg groups (93.3, 80.0%) compared with the placebo group (20.0, 6.7%) and showed a dose-dependent effect. The incidence of AEs was 97.8 and 100% in the lusutrombopag (all groups) and placebo groups, respectively; no dose-related increase was observed. Four patients experienced thrombosis-related events (one each in the placebo and 2-mg groups, and two in the 4-mg group). A total of 16 (18%) adverse drug reactions occurred in the safety analysis set. CONCLUSIONS: Lusutrombopag 3 mg once daily for 7 days was effective without raising concerns about excessive increases in platelet count. CLINICAL TRIAL REGISTRATION: The study is registered at JapicCTI-121944.

Update About the Effects of the Sunscreen Ingredients Oxybenzone and Octinoxate on Humans and the Environment.

As skin cancer prevalence continues to rise, the importance of sun protection, including sunscreen use, has become accepted in the public. Sunscreens are divided into two main categories based on the type of their active ingredient, organic and inorganic ultraviolet (UV) filters. It has been shown that inorganic filters are more effective at blocking forms of UV light, both UVA and UVB, as compared with organic filters because organic sunscreens absorb and convert radiation whereas inorganic sunscreens reflect radiation. The use of the two most common organic filters, oxybenzone and octinoxate, has recently been restricted in Hawaii due to their harmful effect on the coral reefs. Here, we discuss recent studies about these specific filters related to the adverse health risks they pose for humans and other organisms, as well as environmental repercussions.

Involvement of an autotoxic compound in asparagus decline.

Asparagus (Asparagus officinalis L.) is a widely cultivated perennial veritable and can be harvested more than ten years. However, the crop quality and yield decline after a few year's cultivation, which is called "asparagus decline". Even though those asparagus plants were replaced with new young asparagus plants, the productivity and quality of the crop remain relatively low, which is known as a "asparagus replant problem". One of the possible reasons for "asparagus decline" and "asparagus replant problem" is thought to be autotoxicity of asparagus. However, the compounds involved in the autotoxicity is not clear. The objective of this study was therefore to determine the potential role of autotoxicity in the "asparagus decline" and "asparagus replant problem". An aqueous methanol extract of 10-year-asparagus-cultivated soils inhibited the growth of asparagus seedlings and other two test plants with concentration dependent manner. The result confirmed that the asparagus soils have autotoxic activity. The extract was then purified by several chromatographies with monitoring the inhibitory activity and a potent growth inhibitory substance causing the autotoxic effect was isolated. The chemical structures of the compound was determined by spectral data to be trans-cinnamic acid. trans-Cinnamic acid inhibited the growth of asparagus seedlings at concentrations greater than 10 µM. The concentrations required for 50% growth inhibition of asparagus (IC50) were 24.1-41.6 µM. trans-Cinnamic acid accumulated 174 µM in the 10-year-asparagus-cultivated soils, which may be enough levels to cause the growth inhibition on asparagus considering its IC50 value. Therefore, trans-cinnamic acid may contribute to the autotoxic effect of asparagus soils, and may be in part responsible for "asparagus decline" and "asparagus replant problem".

A First-in-Human Study of the New Oral Selective Estrogen Receptor Degrader AZD9496 for ER+/HER2- Advanced Breast Cancer.

Purpose: AZD9496 is an oral nonsteroidal, small-molecule inhibitor of estrogen receptor alpha (ERα) and a potent and selective antagonist and degrader of ERα. This first-in-human phase I study determined the safety and tolerability of ascending doses of oral AZD9496 in women with estrogen receptor (ER)+/HER2- advanced breast cancer, characterized its pharmacokinetic (PK) profile, and made preliminary assessment of antitumor activity.Patients and Methods: Forty-five patients received AZD9496 [20 mg once daily (QD) to 600 mg twice daily (BID)] in a dose-escalation, dose-expansion "rolling 6" design. Safety, tolerability, and PK activity in each cohort were reviewed before escalating to the next dose. PK was determined by mass spectrometry. Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Objective tumor response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.Results: Most common causally related AEs were diarrhea (35.6%), fatigue (31.1%), and nausea (22.2%), and seven patients had grade ≥3 AEs. Three patients experienced a dose-limiting toxicity: one each at 150 mg BID (abnormal hepatic function), 400 mg BID (diarrhea and elevated liver function tests), and 600 mg BID (diarrhea), and all were reversible. The maximum tolerated dose was not reached. Partial response was confirmed in one patient, who also had decreased tumor marker Ca15.3. Four patients had stable disease at 12 months' follow-up.Conclusions: AZD9496 is well tolerated with an acceptable safety profile, showing evidence of prolonged disease stabilization in heavily pretreated patients with ER+/HER2- advanced breast cancer. Clin Cancer Res; 24(15); 3510-8. ©2018 AACRSee related commentary by Jordan, p. 3480.

Constituents of Mediterranean Spices Counteracting Vascular Smooth Muscle Cell Proliferation: Identification and Characterization of Rosmarinic Acid Methyl Ester as a Novel Inhibitor.

SCOPE: Aberrant vascular smooth muscle cell (VSMC) proliferation is involved in atherosclerotic plaque formation and restenosis. Mediterranean spices have been reported to confer cardioprotection, but their direct influence on VSMCs has largely not been investigated. This study aims at examining rosmarinic acid (RA) and 11 related constituents for inhibition of VSMC proliferation in vitro, and at characterizing the most promising compound for their mode of action and influence on neointima formation in vivo. METHODS AND RESULTS: RA, rosmarinic acid methyl ester (RAME), and caffeic acid methyl ester inhibit VSMC proliferation in a resazurin conversion assay with IC50 s of 5.79, 3.12, and 6.78 µm, respectively. RAME significantly reduced neointima formation in vivo in a mouse femoral artery cuff model. Accordingly, RAME leads to an accumulation of VSMCs in the G0 /G1 cell-cycle phase, as indicated by blunted retinoblastoma protein phosphorylation upon mitogen stimulation and inhibition of cyclin-dependent kinase 2 in vitro. CONCLUSION: RAME represses PDGF-induced VSMC proliferation in vitro and reduces neointima formation in vivo. These results recommend RAME as an interesting compound with VSMC-inhibiting potential. Future metabolism and pharmacokinetics studies might help to further evaluate the potential relevance of RAME and other spice-derived polyphenolics for vasoprotection.

UV-selective face cream (Acne RA-1,2) in acne patients: clinical study of its effects on epidermal barrier function, sebum production, tolerability and therapy adherence.

BACKGROUND: General skin care recommendations such as the use of moisturizers and products with adequate photoprotection are important components of management for acne patients to complement the medical regimen. This study aimed to evaluate the real-life clinical effects of a novel UV-selective face cream (Acne RA-1,2, Meda Pharma, Solna, Sweden) on acne, epidermal barrier function, sebum production, adherence and tolerability when used together with pharmacological acne treatment. METHODS: Forty patients receiving pharmacological acne treatment applied Acne RA-1,2 once-daily for three months. Investigator's Global Assessment of acne, trans-epidermal water loss, sebum production and tolerability were assessed at one and three months. RESULTS: After 3 months, there was a 38% significant clinical improvement in mean Investigator Global Assessment score (3.4 to 2.1), a 29% significant reduction in trans-epidermal water loss (13.2 to 9.4 g/h/m2), and a 17% significant decrease in sebum production vs. baseline (234.6 to 195.6 µg/cm2; all P<0.01). One hundred percent of patients reported complete adherence to pharmacological therapy over the summer of the study vs. 52.5% in the previous summer. About 87.5% of patients considered their acne improved over the summer of the study, vs. 55.0% in the previous summer. Pruritus, erythema, dryness and total tolerability symptom scores were significantly reduced after 3 months vs. baseline (P<0.05). CONCLUSIONS: Acne RA-1,2 is a useful daily adjunct to pharmacological therapy as it helps to mitigate the irritation these therapies cause, increasing adherence to therapy, and leading to a clinical improvement in acne and epidermal barrier function and a decrease in sebum production.

Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-Willi syndrome: A randomized, double-blind, placebo-controlled trial.

AIMS: There are no treatments for the extreme hyperphagia and obesity in Prader-Willi syndrome (PWS). The bestPWS clinical trial assessed the efficacy, safety and tolerability of the methionine aminopeptidase 2 (MetAP2) inhibitor, beloranib. MATERIALS AND METHODS: Participants with PWS (12-65 years old) were randomly assigned (1:1:1) to biweekly placebo, 1.8 mg beloranib or 2.4 mg beloranib injection for 26 weeks at 15 US sites. Co-primary endpoints were the changes in hyperphagia [measured by Hyperphagia Questionnaire for Clinical Trials (HQ-CT); possible score 0-36] and weight by intention-to-treat. ClinicalTrials.gov registration: NCT02179151. RESULTS: One-hundred and seven participants were included in the intention-to-treat analysis: placebo (n = 34); 1.8 mg beloranib (n = 36); or 2.4 mg beloranib (n = 37). Improvement (reduction) in HQ-CT total score was greater in the 1.8 mg (mean difference -6.3, 95% CI -9.6 to -3.0; P = .0003) and 2.4 mg beloranib groups (-7.0, 95% CI -10.5 to -3.6; P = .0001) vs placebo. Compared with placebo, weight change was greater with 1.8 mg (mean difference - 8.2%, 95% CI -10.8 to -5.6; P < .0001) and 2.4 mg beloranib (-9.5%, 95% CI -12.1 to -6.8; P < .0001). Injection site bruising was the most frequent adverse event with beloranib. Dosing was stopped early due to an imbalance in venous thrombotic events in beloranib-treated participants (2 fatal events of pulmonary embolism and 2 events of deep vein thrombosis) compared with placebo. CONCLUSIONS: MetAP2 inhibition with beloranib produced statistically significant and clinically meaningful improvements in hyperphagia-related behaviours and weight loss in participants with PWS. Although investigation of beloranib has ceased, inhibition of MetAP2 is a novel mechanism for treating hyperphagia and obesity.

A randomized, placebo-controlled trial of beloranib for the treatment of hypothalamic injury-associated obesity.

AIMS: Hypothalamic injury-associated obesity (HIAO) results from damage to the hypothalamus that often occurs with surgical removal/radiation therapy of tumours in the hypothalamic region, such as craniopharyngioma. There is currently no rigorously studied pharmaceutical treatment for the intractable weight gain and cardiometabolic consequences that occur in patients with HIAO. We aimed to assess efficacy, safety and tolerability of beloranib treatment for 4 to 8 weeks in patients with HIAO. MATERIALS AND METHODS: This Phase 2a, double-blind, placebo-controlled study included 14 patients with HIAO, randomized to receive beloranib 1.8 mg or placebo subcutaneously twice weekly for 4 weeks with an optional 4-week open-label extension in which all patients received beloranib. The primary endpoint was change in weight from baseline to Week 4. RESULTS: Participants were 64% female, with a mean (SD) age of 32 (9) years, BMI of 43 (7) kg/m2 and weight of 126 (22) kg. Compared with placebo (N = 4), beloranib 1.8 mg (N = 8) resulted in a mean (95% CI) difference in weight of -3.2 (-5.4, -0.9) kg after 4 weeks. Weight loss continued through the 8 weeks in patients randomized to beloranib (mean -6.2 [-8.2, -4.1] kg). Beloranib treatment was associated with improvements in high-sensitivity CRP. Adverse events were mild to moderate. No patients who received beloranib discontinued treatment. CONCLUSION: Beloranib treatment resulted in progressive weight loss in patients with HIAO that was comparable to that observed with beloranib in patients with exogenous obesity. These findings indicate a novel mechanism for treating obesity in patients with HIAO.