Background:Ecstasy (3,4-methylenedioxymethamphetamine (MDMA)) has a relatively low harm and low dependence liability but is scheduled on List I of the Dutch Opium Act (‘hard drugs’). Concerns surrounding increasing MDMA-related criminality coupled with the possibly inappropriate scheduling of MDMA initiated a debate to revise the current Dutch ecstasy policy.Methods:An interdisciplinary group of 18 experts on health, social harms and drug criminality and law enforcement reformulated the science-based Dutch MDMA policy using multi-decision multi-criterion decision analysis (MD-MCDA). The experts collectively formulated policy instruments and rated their effects on 25 outcome criteria, including health, criminality, law enforcement and financial issues, thematically grouped in six clusters.Results:The experts scored the effect of 22 policy instruments, each with between two and seven different mutually exclusive options, on 25 outcome criteria. The optimal policy model was defined by the set of 22 policy instrument options which gave the highest overall score on the 25 outcome criteria. Implementation of the optimal policy model, including regulated MDMA sales, decreases health harms, MDMA-related organised crime and environmental damage, as well as increases state revenues and quality of MDMA products and user information. This model was slightly modified to increase its political feasibility. Sensitivity analyses showed that the outcomes of the current MD-MCDA are robust and independent of variability in weight values.Conclusion:The present results provide a feasible and realistic set of policy instrument options to revise the legislation towards a rational MDMA policy that is likely to reduce both adverse (public) health risks and MDMA-related criminal burden.
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Hyperhomocysteinemia is a risk factor for cardiovascular disease, neurological disorders, and bone abnormalities. The key enzyme in homocysteine metabolism, cystathionine-β-synthase (CBS) is recognized as a target for new homocysteine-lowering therapies including enzyme replacement and gene therapy. Currently, there are no pharmacotherapies available that enhance CBS activity through its allosteric mechanism. The only known allosteric activator of CBS is S-adenosyl-L-methionine (SAM), which is available as a food supplement, but its effectiveness is limited by low membrane permeability and universal involvement in methylation reactions as a substrate. The discovery of CBS activators in high-throughput screening is challenging due to a lack of dedicated assays. Available HTS-compatible activity assays for CBS rely on measuring the product hydrogen sulfide or methanethiol where the signal increases with increased CBS activity. In the case of fluorescence-based assays, it is challenging to discern activators from autofluorescent compounds. In this study, we introduce a homocysteine consumption assay for isolated human CBS (HconCBS) based on the absorbance of Ellman's reagent. This assay leverages a decrease in signal upon CBS activation, with performance parameters exceeding the requirements for high-throughput screening. In a commercial library of 3010 compounds, the HconCBS assay identified 10 hit compounds as more active than SAM, whereas a fluorescence-based assay using 7-azido-4-methylcoumarin (AzMC) identified 141 hits. HconCBS identified 101 compounds with autoabsorbance which did not include hit compounds, while the fluorescence-based assay identified 383 autofluorescent compounds which included all hit compounds. While 4 out of 10 HconCBS hits were confirmed when purchased from a new source, the compounds affected homocysteine rather than CBS. Nevertheless, HconCBS consistently detected the CBS activator seleno-adenosyl-L-methionine (SeAM) added to 4 library plates and re-discovered the same library hits in 3 out of 4 re-screened plates. Taken together, HconCBS was designed to enable the discovery of allosteric CBS activators with greater reliability than fluorescence-based methods. Despite identifying some compounds that acted on homocysteine rather than CBS, the assay consistently identified the CBS activators SAM and SeAM and demonstrated reproducibility across two screening rounds. These findings establish HconCBS as a valuable tool for identifying potential therapeutic candidates for hyperhomocysteinemia, addressing a key gap in the development of CBS-targeted pharmacotherapies.
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ObjectiveThis systematic review aims to reevaluate the role of minerals on muscle mass, muscle strength, physical performance, and the prevalence of sarcopenia in community-dwelling and institutionalized older adults.DesignSystematic review.Setting and ParticipantsIn March 2022, a systematic search was performed in PubMed, Scopus, and Web of Sciences using predefined search terms. Original studies on dietary mineral intake or mineral serum blood concentrations on muscle mass, muscle strength, and physical performance or the prevalence of sarcopenia in older adults (average age ≥65 years) were included.MethodsEligibility screening and data extraction was performed by 2 independent reviewers. Quality assessment was performed with the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies. Risk of bias was evaluated using the Risk Of Bias In Non-randomized Studies-of Exposure (ROBINS-E) tool.ResultsFrom the 15,622 identified articles, a total of 45 studies were included in the review, mainly being cross-sectional and observational studies. Moderate quality of evidence showed that selenium (n = 8) and magnesium (n = 7) were significantly associated with muscle mass, strength, and physical performance as well as the prevalence of sarcopenia. For calcium and zinc, no association could be found. For potassium, iron, sodium, and phosphorus, the association with sarcopenic outcomes remains unclear as not enough studies could be included or were nonconclusive (low quality of evidence).Conclusions and ImplicationsThis systematic review shows a potential role for selenium and magnesium on the prevention and treatment of sarcopenia in older adults. More randomized controlled trials are warranted to determine the impact of minerals on sarcopenia in older adults.
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