Pharmacological effects of methylone and MDMA in humans.

Methylone is one of the most common synthetic cathinones popularized as a substitute for 3,4-methylenedioxymethamphetamine (MDMA, midomafetamine) owing to its similar effects among users. Both psychostimulants exhibit similar chemistry (i.e., methylone is a ß-keto analog of MDMA) and mechanisms of action. Currently, the pharmacology of methylone remains scarcely explored in humans. Herein, we aimed to evaluate the acute pharmacological effects of methylone and its abuse potential in humans when compared with that of MDMA following oral administration under controlled conditions. Seventeen participants of both sexes (14 males, 3 females) with a previous history of psychostimulant use completed a randomized, double-blind, placebo-controlled, crossover clinical trial. Participants received a single oral dose of 200 mg of methylone, 100 mg of MDMA, and a placebo. The variables included physiological effects (blood pressure, heart rate, oral temperature, pupil diameter), subjective effects using visual analog scales (VAS), the short form of the Addiction Research Center Inventory (ARCI), the Evaluation of Subjective Effects of Substances with Abuse Potential questionnaire (VESSPA-SSE), and the Sensitivity to Drug Reinforcement Questionnaire (SDRQ), and psychomotor performance (Maddox wing, psychomotor vigilance task). We observed that methylone could significantly increase blood pressure and heart rate and induce pleasurable effects, such as stimulation, euphoria, wellbeing, enhanced empathy, and altered perception. Methylone exhibited an effect profile similar to MDMA, with a faster overall onset and earlier disappearance of subjective effects. These results suggest that abuse potential of methylone is comparable to that of MDMA in humans. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05488171; Identifier: NCT05488171.

Interaction of Energy Drinks with Prescription Medication and Drugs of Abuse.

In recent years, the consumption of energy drinks (EDs) has become increasingly popular, especially among adolescents. Caffeine, a psychostimulant, is the main compound of EDs which also contain other substances with pharmacological effects. This review aims to compile current evidence concerning the potential interactions between EDs, medicines, and drugs of abuse as they are frequently consumed in combination. The substances involved are mainly substrates, inductors or inhibitors of CYP1A2, psychostimulants, alcohol and other depressant drugs. Furthermore, intoxications reported with EDs and other substances have also been screened to describe acute toxicity. The results of our review show that the consumption of both EDs alone and in combination is not as safe as previously thought. Health professionals and consumers need to be aware of the potential interactions of these drinks as well as the absence of long-term safety data.

Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration.

INTRODUCTION: Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach. METHODS AND ANALYSIS: Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo. ETHICS AND DISSEMINATION: Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations. TRIAL REGISTRATION NUMBERS: NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.

Pilot, double-blind, randomized, placebo-controlled clinical trial of the supplement food Nyaditum resae® in adults with or without latent TB infection: Safety and immunogenicity.

BACKGROUND: Nyaditum resae® (NR) is a galenic preparation of heat-killed Mycobacterium manresensis, a new species of the fortuitum complex, that is found in drinkable water, and that has demonstrated to protect against the development of active TB in a murine experimental model that develop human-like lesions. METHODS: Double-blind, randomized, placebo-controlled Clinical Trial (51 volunteers included). Two different doses of NR and a placebo were tested, the randomization was stratified by Latent Tuberculosis Infection (LTBI)-positive (n = 21) and LTBI-negative subjects (n = 30). Each subject received 14 drinkable daily doses for 2 weeks. RESULTS: All patients completed the study. The 46.3% of the overall reported adverse events (AE) were considered related to the investigational treatment. None of them were severe (94% were mild and 6% moderate). No statistical differences were found when comparing the median number of AE between the placebo group and both treatment groups. The most common AE reported were gastrointestinal events, most frequently mild abdominal pain and increase in stool frequency. Regarding the immunogenic response, both LTBI-negative and LTBI-positive volunteers treated with NR experienced a global increase on the Treg response, showed both in the population of CD25+CD39-, mainly effector Treg cells, or CD25+CD39+ memory PPD-specific Treg cells. CONCLUSION: This clinical trial demonstrates an excellent tolerability profile of NR linked to a significant increase in the population of specific effector and memory Tregs in the groups treated with NR in both LTBI-positive and negative subjects. NR shows a promising profile to be used to reduce the risk of active TB.

Quality assessment of peripheral artery disease clinical guidelines.

BACKGROUND: Clinical practice guidelines (CPGs) provide recommendations to assist health professionals and patients in the process of making decisions for specific clinical conditions to improve the quality of the patient care. However, there are concerns about the quality of some CPGs. The aim of this study was to review the quality of CPGs in pharmacologic management of peripheral artery disease (PAD). METHODS: A systematic review of CPGs for the pharmacologic treatment of PAD was performed. CPGs published between 2003 and January 2015 in English, Spanish, or French were retrieved using PubMed, Cochrane, and TRIP databases; guideline developer organization Web sites, and European and American scientific societies related to PAD Web sites. One reviewer performed the search and guideline selection, which was validated by a second reviewer. Three appraisers independently assessed the quality of CPGs using the Appraisal of Guidelines, REsearch and Evaluation II (AGREE II) instrument. RESULTS: A total of seven CPGs, published between 2006 and 2012, were included. All except one were written in English. Average AGREE II guidelines scores varied from 45% to 72%. There was considerable variation in the quality of the CPGs across the AGREE II domain scores (ranging from 4% to 85%). The highest scored domains were 'clarity of presentation' and 'editorial independence' and the lowest scored domain was 'applicability.' The reviewers consider that six CPGs could be recommended with modifications for use and one without modification. CONCLUSIONS: There is great variability in the quality of the CPGs on pharmacologic treatment in PAD. All of the assessed guidelines could be recommended; however, there is considerable scope to improve their quality by highlighting aspects of applicability, the involvement of the stakeholder, as well as the rigor of development.