Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme

Objective: To investigate safety and tolerability of nalmefene for reduction of alcohol consumption in alcohol-dependent patients.

Methods: Pooled data from three randomized, placebo-controlled studies (two 6-month; one 12-month) of 18 mg nalmefene (as-needed use) in alcohol-dependent patients looking at the total population (placebo n = 824, nalmefene n = 1123) and patients with high/very high drinking risk levels at screening and randomization (target population: placebo n = 374, nalmefene n = 450).

Results: In the study, 62.7% of patients on placebo and 74.7% on nalmefene in the total population had treatment-emergent adverse events (TEAEs). Fourty-seven (5.9%) on placebo and 149 (13.0%) on nalmefene dropped out due to TEAEs. Thirty-five (4.4%) on placebo and 57 (5.0%) on nalmefene had serious adverse events. Tolerability and safety were similar in the target population and total population. Most frequent TEAEs were transient, mainly occurring at treatment initiation. There was no difference in tolerability and safety if nalmefene was taken daily or intermittently; no signal of increased risk of suicide-related behavior with nalmefene. The higher incidence of psychiatric events in the nalmefene group was mainly due to the TEAE of confusional state.

Conclusions: Although there was a higher incidence of TEAEs and TEAEs leading to dropout, nalmefene was well-tolerated and no major safety issues were identified.     

(R)-2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

相似文献   

Genetic variations of the ABCC2 gene in the Chinese, Malay, and Indian populations of Singapore

MRP2 is a drug transporter that is responsible for the gastrointestinal absorption and biliary excretion of a wide variety of endogenous and xenobiotic compounds, including many clinically used drugs. This study aims to identify genetic variations of ABCC2 gene in three distinct ethnic groups of the Singaporean population (n = 288). The coding region of the gene encoding the transporter protein was screened for genetic variations in the study population by denaturing high-performance liquid chromatography and DNA sequencing. Twenty-two genetic variations of ABCC2, including 8 novel ones, were found: 1 in the 5' untranslated region, 10 in the coding exons (8 nonsynonymous and 2 synonymous variations), and 11 in the introns. Three novel nonsynonymous variations: 2686G > A (Glu896Lys), 4240C > T (His1414Tyr) and 4568A > C (Gln1523Pro) were detected in single heterozygous Malay, Chinese, and Indian subjects, respectively. Among the novel nonsynonymous variations, 4240C > T and 4568A > C were predicted to be functionally significant. These data would provide fundamental and useful information for pharmacogenetic studies on drugs that are substrates of MRP2 in Asians.     

Effects of a selection of histone deacetylase inhibitors on mast cell activation and airway and colonic smooth muscle contraction

Studies of histone deacetylase (HDAC) inhibitors, novel anticancer drugs, in models of autoimmune diseases, asthma, and inflammatory bowel disease suggest that HDAC inhibitors may also have useful anti-inflammatory effects. Accordingly, in vitro studies relevant to asthma and inflammatory bowel disease were conducted using a selection of HDAC inhibitors: suberoylanilide hydroxamic acid (SAHA, Vorinostat), and a related branched hydroxamic acid, diamide (1), MGCD0103 and two short chain fatty acid derivatives: sodium butyrate (of use in inflammatory bowel disease) and sodium valproate. The ability of those HDAC inhibitors to modulate antigen- or agonist-induced contraction of isolated guinea pig tracheal rings and colon, agonist-induced contraction of rat colon, and histamine release from rat peritoneal mast cells was examined. Pre-incubation (up to 6 h) with 10-40 microM of SAHA, diamide (1), or MGCD0103 caused significant inhibition of the antigen-induced contraction of sensitised guinea pig tracheal rings as well as inhibition of the contraction induced by histamine, 5-hydroxytryptamine and carbachol (G-protein coupled receptor agonists), while sodium butyrate (1 mM) and sodium valproate (100 microM) were weak inhibitors. Contraction of tracheal rings by sodium fluoride (NaF, a non-selective G-protein activator), KCl and a peroxyl radical generator was blocked by MGCD0103. Additionally, MGCD0103 significantly inhibited antigen-induced histamine release from IgE antibody-sensitised rat peritoneal mast cells, and NaF-induced histamine release, as well as inhibiting NaF-induced colon contraction. Those various effects appear to involve modulation of cell signaling, probably involving G-protein coupled pathways, and further support the development of HDAC inhibitors as anti-inflammatory agents.     

Deep learning for survival outcomes

Deep learning is a class of machine learning algorithms that are popular for building risk prediction models. When observations are censored, the outcomes are only partially observed and standard deep learning algorithms cannot be directly applied. We develop a new class of deep learning algorithms for outcomes that are potentially censored. To account for censoring, the unobservable loss function used in the absence of censoring is replaced by a censoring unbiased transformation. The resulting class of algorithms can be used to estimate both survival probabilities and restricted mean survival. We show how the deep learning algorithms can be implemented by adapting software for uncensored data by using a form of response transformation. We provide comparisons of the proposed deep learning algorithms to existing risk prediction algorithms for predicting survival probabilities and restricted mean survival through both simulated datasets and analysis of data from breast cancer patients.     

Managing the pain of labour: factors associated with the use of labour pain management for pregnant Australian women

Background

Despite high rates of women''s use of intrapartum pain management techniques, little is known about the factors that influence such use.

Objective

Examine the determinants associated with women''s use of labour pain management.

Design

Cross‐sectional survey of a substudy of women from the ‘young’ cohort of the Australian Longitudinal Study of Women''s Health (ALSWH).

Setting and participants

Women aged 31–35 years who identified as being pregnant or recently given birth in the 2009 ALSWH survey (n = 2445) were recruited for the substudy. The substudy survey was completed by 1835 women (RR = 79.2%).

Main variables studied

Determinants examined included pregnancy health and maternity care [including complementary and alternative medicine (CAM)] for their most recent pregnancy and any previous pregnancies. Participants'' attitudes and beliefs related to both CAM and maternity care were also included in the analysis.

Main outcome measures

The outcome measures examined were the use of both pharmacological and non‐pharmacological pain management techniques (NPMT).

Results

Differences were seen in the effects of demographics, health service utilization, health status, use of CAM, and attitudes and beliefs upon use of intrapartum pain management techniques across all categories. The only variable that was identified as a determinant for use of all types of pain management techniques was a previous caesarean section (CS).

Discussion and conclusions

The effect of key determinants on women''s use of pain management techniques differs significantly, and, other than CS, no one determinant is clearly influential in the use of all pain management options.     

Development of a fragile X syndrome (FXS) knowledge scale: towards a modified multidimensional measure of informed choice for FXS population carrier screening

Background

Genetic carrier screening is increasingly possible for many conditions, but it is important to ensure decisions are informed. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to evaluate informed choice in prenatal screening for Down syndrome, measuring knowledge, attitudes and uptake. To apply the MMIC in other screening settings, the knowledge scale must be modified.

Objective

To develop and validate a modified MMIC knowledge scale for use with women undergoing carrier screening for fragile X syndrome (FXS).

Setting and participants

Responses to MMIC items were collected through questionnaires as part of a FXS carrier screening pilot study in a preconception setting in Melbourne, Australia.

Design

Ten knowledge scale items were developed using a modified Delphi technique. Cronbach''s alpha and factor analysis were used to validate the new FXS knowledge scale. We summarized the knowledge, attitudes and informed choice status based on the modified MMIC.

Results

Two hundred and eighty‐five women were recruited, 241 eligible questionnaires were complete for analysis. The FXS knowledge scale items measured one salient construct and were internally consistent (alpha = 0.70). 71% (172/241) of participants were classified as having good knowledge, 70% (169/241) had positive attitudes and 27% (65/241) made an informed choice to accept or decline screening.

Discussion and conclusions

We present the development of a knowledge scale as part of a MMIC to evaluate informed choice in population carrier screening for FXS. This can be used as a template by other researchers to develop knowledge scales for other conditions for use in the MMIC.     

Legal Action Against Health Claims on Foods and Beverages Marketed to Youth

The prevalence of obesity among US children raises numerous health concerns. One pathway to reduce childhood obesity is by decreasing energy intake through the ingestion of fewer calories. Yet, food and beverage manufacturers often promote energy-dense items for children via varied health claims.Deceptive health claims are prohibited, and may be addressed through litigation or governmental regulatory efforts. While the amount of legal action against these potentially deceptive claims has increased, no comprehensive assessment has been conducted.This article, which analyzes litigation and governmental regulatory activities, considers key factors that may influence decisions to take legal action against potentially deceptive health claims on foods and beverages, including scientific support, forum selection, selection of plaintiffs, and potential public health impact.During the last 3 decades, the prevalence of obesity among US children has increased.1 Today, one third of youths are overweight or obese, and 17% are obese.2 Childhood obesity raises numerous health concerns, including greater likelihood of cardiovascular disease risk factors, presence of pre-diabetic indicators, and psychosocial issues.3–5 Obese children are more likely to become overweight or obese adults, with attendant risks for cardiovascular disease, metabolic challenges, and certain cancers.6–9Decreasing energy intake through the ingestion of fewer calories represents one pathway to reduce childhood obesity.10 Yet, companies that advertise foods and beverages often promote energy-dense items for children (i.e., items high in sugar, fat, or calories, such as sugar-sweetened beverages or certain breakfast cereals).11,12 This may be particularly confusing for parents seeking nutritious choices for their children, since some companies use health-related claims to promote energy-dense products (e.g., “good source of vitamin C”).13By law, however, “deceptive” claims are prohibited.14 A deceptive claim is one that: (1) is likely to mislead consumers when viewed by those acting reasonably under the circumstances; and (2) contains a message directly tied to a consumer’s purchasing decision.15 Federal regulatory authority for health claims is shared by the US Food and Drug Administration (FDA), for food labeling, and the Federal Trade Commission (FTC), for food advertising.16 In addition, state attorneys general, other state-level regulators, and private individuals may take legal action against potentially deceptive health claims.17Although federal agencies such as the FDA and FTC may use varied administrative tools to address allegedly deceptive health claims on foods and beverages, litigation brought by federal or state governments or private individuals may also encourage food and beverage manufacturers to limit their risk. This litigation often relies on federal or state consumer protection or false advertising laws, which require that consumers receive product information that is truthful and not misleading. In response to threatened litigation, or to avoid future litigation, manufacturers may voluntarily remove deceptive health claims from their products.18,19Although several analyses have examined specific claims that received regulatory attention,20,21 no comprehensive assessment of these actions has been conducted. We conducted a comprehensive review of federal, state, and private litigation and governmental regulatory activities regarding potentially deceptive health claims on foods and beverages marketed to children. We identify trends in these legal actions and discuss lessons learned for policymakers, practitioners, and other stakeholders seeking to limit the untruthful or misleading marketing of foods and beverages to children.     

Chemical Safety for Sustainability (CSS): Human in vivo biomonitoring data for complementing results from in vitro toxicology—A commentary

The U.S. Environmental Protection Agency (EPA) has instituted the Chemical Safety for Sustainability (CSS) research program for assessing the health and environmental impact of manufactured chemicals. This is a broad program wherein one of the tasks is to develop high throughput screening (HTS) methods and follow-up confirmation for toxicity at realistic environmental exposure levels. The main tools under this task are in vitro toxicity testing, in silico molecular modeling, and in vivo (systemic) measurements documentation. The in vivo research component is intended to support and corroborate in vitro chemical toxicity prioritization with observations of systemic perturbations and statistical parameters derived from intact (living) organisms. Based on EPA's Biomonitoring Framework for human health research, such observations are intended to link environmental exposures to a cascade of biomarker chemicals to help identify and clarify adverse outcome pathways within the context of systems biology. This commentary discusses the issues regarding interpretation of in vitro changes from HTS as an adverse result, an adaptive (non-adverse) response, or a random/irrelevant occurrence. A second goal is to inform in vitro strategies as to relevant dosing (potency) levels at the cellular level that reflect realistic systemic exposures. Although we recognize the high value of in vivo animal toxicity testing, herein we focus on observational (minimally invasive) human biomonitoring methods and propose complementary in vivo testing that could help guide the design of high-throughput analyses and the ultimate interpretation of their outcomes.