The Safety of Dronabinol and Nabilone: A Systematic Review and Meta-Analysis of Clinical Trials

Dronabinol, a natural cannabinoid, and its semi-synthetic derivative, nabilone, are marketed as medicines in several countries. The aim of our work was to systematically evaluate the frequency of adverse events related to dronabinol or nabilone treatment compared to placebo. Scientific databases were searched for placebo-controlled clinical studies of patients receiving either dronabinol or nabilone therapy with placebo control groups. This meta-analysis was reported following the PRISMA guidelines using the PICO format, and it was registered with the PROSPERO register. There were 16 trials included in the meta-analysis. In the nabilone studies, drowsiness was more than 7 times as frequent in patients treated with nabilone than in the placebo group (OR: 7.25; 95% CI: 1.64–31.95), and the risk of dizziness (OR: 21.14; 95% CI: 2.92–152.75) and dry mouth was also higher (OR: 17.23; 95% CI: 4.33–68.55). The frequency of headache was not different in the two groups. In case of dronabinol, the frequency of dry mouth (OR: 5.58; 95% CI: 3.19–9.78), dizziness (OR: 4.60 95% CI: 2.39–8.83) and headache (OR: 2.90; 95% CI: 1.07–7.85) was significantly higher in the dronabinol groups, whereas in case of nausea, drowsiness and fatigue there was no difference. The severity of adverse events was typically mild-to-moderate and transient. In a risk-benefit assessment, these adverse effects are acceptable compared to the achievable benefit. However, considering the diversity of the adverse effects, more studies are needed to provide a more accurate assessment on the side effect profiles of these two compounds.

Composite endpoint for ALS clinical trials based on patient preference: Patient-Ranked Order of Function (PROOF)

BackgroundPatients with amyotrophic lateral sclerosis (ALS) show considerable variation in symptoms. Treatments targeting an overall improvement in symptomatology may not address what the majority of patients consider to be most important. Here, we propose a composite endpoint for ALS clinical trials that weighs the improvement in symptoms compared with what the patient population actually wants.MethodsAn online questionnaire was sent out to a population-based registry in The Netherlands. Patients with ALS were asked to score functional domains with a validated self-reported questionnaire, and rank the order of importance of each domain. This information was used to estimate variability in patient preferences and to develop the Patient-Ranked Order of Function (PROOF) endpoint.ResultsThere was extensive variability in patient preferences among the 433 responders. The majority of the patients (62.1%) preferred to prioritise certain symptoms over others when evaluating treatments. The PROOF endpoint was established by comparing each patient in the treatment arm to each patient in the placebo arm, based on their preferred order of functional domains. PROOF averages all pairwise comparisons, and reflects the probability that a patient receiving treatment has a better outcome on domains that are most important to them, compared with a patient receiving placebo. By means of simulation we illustrate how incorporating patient preference may upgrade or downgrade trial results.ConclusionsThe PROOF endpoint provides a balanced patient-focused analysis of the improvement in function and may help to refine the risk–benefit assessment of new treatments for ALS.

Communicating Food Risk-Benefit Assessments: Edible Insects as Red Meat Replacers

Risk-benefit Assessment (RBA) is an emerging methodology in the area of Food and Nutrition that offers a simultaneous evaluation of both risks and benefits linked to dietary choices. Communication of such research to consumers may present a challenge due to the dual nature of RBA. We present a case study of a communication strategy developed for the NovRBA-project. The NovRBA-project (Novel foods as red meat replacers—an insight using Risk Benefit Assessment methods) performed a risk-benefit assessment to evaluate the overall health impact of substituting red meat (beef) by a novel food (house cricket), considering the microbial, toxicological and nutritional characteristics of the respective dietary choices. A literature review of risk perceptions and acceptance of beef and insects as food formed the basis of the communication strategy for the study's results, drawing on environmental and emotional as well as health-related motivations to consume or avoid either food and considering the sociodemographic characteristics of likely consumers. Challenges and future directions for consumer protection organizations communicating findings of risk-benefit analyses on food safety are discussed.

Quantitative risk-benefit assessment of Portuguese fish and other seafood species consumption scenarios

Portugal has high fish/seafood consumption, which may have both risks and benefits. This study aims to quantify the net health impact of hypothetical scenarios of fish/seafood consumption in the Portuguese population using a risk-benefit assessment methodology. Consumption data from the National Food, Nutrition and Physical Activity Survey 2015-2016 (n=5811) was used to estimate the mean exposure to methylmercury and EPA+DHA in the current and the alternative scenarios considered. Alternative scenarios (alt) were modelled using probabilistic approaches to reflect substitutions from the current consumption in the type of fish/seafood (alt1: excluding predatory fishes; alt2: including only methylmercury low-level fishes) or in the frequency of weekly fish/seafood consumption (alt3 to alt6: 1,3,5 or 7 times a week, replacing fish/seafood meals with meat or others). The overall health impact of these scenarios was quantified using Disability-Adjusted Life Years (DALYs). In the Portuguese population, about 11450 DALYs could be prevented each year if the fish/seafood consumption increased to a daily basis. However, such a scenario would result in 1398 extra DALYs considering the consumption by pregnant women and the respective risk on foetal neurodevelopment. Our findings support a recommendation to increase fish/seafood consumption up to 7 times/week. However, for pregnant women and children, special considerations must be proposed to avoid potential risks on foetal neurodevelopment due to methylmercury exposure.

Essential nutrient element profiles in rice types: a risk–benefit assessment including inorganic arsenic

Rice is consumed by nearly half of the global population and a significant source of energy and nutrients. However, rice consumption can also be a significant pathway of inorganic arsenic (iAs) exposure, thus requiring a risk–benefit assessment. This study assessed nutrient element (NE) densities in fifty-five rice types (white, brown and wild rice) marketed in the UK. Densities of essential NE were used to rank rice types in meeting daily NE targets under different consumption scenarios through a newly developed optimisation approach. Using iAs data from these rice types, we assessed the margin of exposure (MOE) for low (the UK) and high (Bangladesh) rice intake scenarios. Our results showed that brown and wild rice are significantly higher in many NE and significantly contribute to dietary reference value (DRV). Our modelling showed that switching to brown or wild rice could increase the intake of several essential nutrients by up to eight times that of white rice. Using rice consumption data for mid-to-high-consumption countries, we estimate that brown rice could provide 100 % adult DRV for Fe, Mg, Cr, P and Mo, and substantial contributions for Zn, Se and K. Our results show that the amount of rice primarily determines risk from iAs consumed rather than the type of rice. Therefore, switching from white to brown or wild rice could be beneficial, provided iAs concentration in rice is within the recommended limits.

Quality prescribing in early psychosis: key pharmacotherapy principles

Objective: To present a practical, easy-to-implement clinical framework designed to support evidence-based quality prescribing for people with early psychosis. Method: Identification and explanation of key principles relating to evidence-based pharmacotherapy for people with early psychosis. These were derived from the literature, practice guidelines and clinical experience. Results: Key principles include (1) medication choice informed by adverse effects; (2) metabolic monitoring at baseline and at regular intervals; (3) comprehensive and regular medication risk–benefit assessment and psychoeducation; (4) early consideration of long-acting injectable formulations (preferably driven by informed patient choice); (5) identification and treatment of comorbid mood disorders and (6) early consideration of clozapine when treatment refractory criteria are met. Conclusions: Current prescribing practices do not align with the well-established evidence for quality pharmacotherapy in early psychosis. Adopting evidence-based prescribing practices for people with early psychosis will improve outcomes.

Approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines

At present, there are not much data on the clinical use of live recombinant viral vector vaccines. Characteristics of new vaccines should be factored into requirements/recommendations for quality control, preclinical and clinical studies of vaccines in order to enable further risk/benefit assessment. The aim of this study was to analyse current approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines. The paper provides an overview of the licensed live viral vector vaccines and those at various stages of clinical trials. The authors analysed Russian, European, American, and Japanese guidelines related to quality issues, preclinical and clinical studies of live viral vector vaccines. The analysis demonstrated that the regulatory requirements for live recombinant viral vector vaccines include assessment of a detailed rationale for vaccine development, including information on the choice of the vector, the origin of the heterologous antigen gene(s), elements related to the transgene(s) expression, as well as assessment of the genetic and phenotypic stability of the recombinant virus, the risk of reversion to virulence or recombination with wild type strains, the potential for virus genome integration into the host cell chromosome, the pre-existing immunity to the vector, the intensity of the immune response elicited by the vector, and the reusability of the vector. The choice and number of applicable toxicological and pharmacological models will depend on these aspects. The results of the analysis of approaches to quality control, preclinical and clinical studies of live recombinant viral vector vaccines may be used in the development of Russian regulatory guidelines harmonised with the international norms and regulations.

Risk-Benefit Assessment of Cereal-Based Foods Consumed by Portuguese Children Aged 6 to 36 Months—A Case Study under the RiskBenefit4EU Project

Cereal-based foods, including breakfast (BC) and infant cereals (IC), are among the first solid foods introduced to infants. BC and IC are sources of macro and micronutrients that have beneficial effects on health, but can also be sources of harmful chemical and microbiological contaminants and nutrients that may lead to adverse health effects at high consumption levels. This study was performed under the RiskBenefit4EU project with the aim of assessing the health impact associated with consumption of BC and IC by Portuguese children under 35 months. Adverse effects associated with the presence of aflatoxins, Bacillus cereus, sodium and free sugars were assessed against the benefits of fiber intake. We applied a risk–benefit assessment approach, and quantified the health impact of changes in consumption of BC and IC from current to various alternative consumption scenarios. Health impact was assessed in terms of disability-adjusted life years. Results showed that moving from the current consumption scenario to considered alternative scenarios results in a gain of healthy life years. Portuguese children can benefit from exchanging intake of IC to BC, if the BC consumed has an adequate nutritional profile in terms of fiber, sodium and free sugars, with levels of aflatoxins reduced as much as possible.