The challenges of clinical trials in fragile X syndrome

RATIONALE: Advances in understanding the underlying mechanisms of conditions such as fragile X syndrome (FXS) and autism spectrum disorders have revealed heterogeneous populations. Recent trials of novel FXS therapies have highlighted several challenges including subpopulations with possibly differential therapeutic responses, the lack of specific outcome measures capturing the full range of improvements of patients with FXS, and a lack of biomarkers that can track whether a specific mechanism is responsive to a new drug and whether the response correlates with clinical improvement. OBJECTIVES: We review the phenotypic heterogeneity of FXS and the implications for clinical research in FXS and other neurodevelopmental disorders. RESULTS: Residual levels of fragile X mental retardation protein (FMRP) expression explain in part the heterogeneity in the FXS phenotype; studies indicate a correlation with both cognitive and behavioral deficits. However, this does not fully explain the extent of phenotypic variance observed or the variability of drug response. Post hoc analyses of studies involving the selective mGluR5 antagonist mavoglurant and the GABAB agonist arbaclofen have uncovered significant therapeutic responses following patient stratification according to FMR1 promoter methylation patterns or baseline severity of social withdrawal, respectively. Future studies designed to quantify disease modification will need to develop new strategies to track changes effectively over time and in multiple symptom domains. CONCLUSION: Appropriate selection of patients and outcome measures is central to optimizing future clinical investigations of these complex disorders

RNA Oligomerisation without Added Catalyst from 2 ',3 '-Cyclic Nucleotides by Drying at Air-Water Interfaces

For the emergence of life, the abiotic synthesis of RNA from its monomers is a central step. We found that in alkaline, drying conditions in bulk and at heated air-water interfaces, 2 ',3 '-cyclic nucleotides oligomerised without additional catalyst, forming up to 10-mers within a day. The oligomerisation proceeded at a pH range of 7-12, at temperatures between 40-80 degrees C and was marginally enhanced by K+ ions. Among the canonical ribonucleotides, cGMP oligomerised most efficiently. Quantification was performed using HPLC coupled to ESI-TOF by fitting the isotope distribution to the mass spectra. Our study suggests a oligomerisation mechanism where cGMP aids the incorporation of the relatively unreactive nucleotides C, A and U. The 2 ',3 '-cyclic ribonucleotides are byproducts of prebiotic phosphorylation, nucleotide syntheses and RNA hydrolysis, indicating direct recycling pathways. The simple reaction condition offers a plausible entry point for RNA to the evolution of life on early Earth

Stimulation programs for pediatric drug research – do children really benefit?

Most drugs that are currently prescribed in pediatrics have not been tested in children. Pediatric drug studies are stimulated in the USA by the pediatric exclusivity provision under the Food and Drug Administration Modernization Act (FDAMA) that grants patent extensions when pediatric labeling is provided. We investigated the effectiveness of these programs in stimulating drug research in children, thereby increasing the evidence for safe and effective drug use in the pediatric population. All drugs granted pediatric exclusivity under the FDAMA were analyzed by studying the relevant summaries of medical and clinical pharmacology reviews of the pediatric studies or, if these were unavailable, the labeling information as provided by the manufacturer. A systematic search of the literature was performed to identify drug utilization patterns in children. From July 1998 to August 2006, 135 drug entities were granted pediatric exclusivity. Most frequent drug groups were anti-depressants and mood stabilizers, ACE inhibitors, lipid-lowering preparations, HIV antivirals, and non-steroidal anti-inflammatory and anti-rheumatic drugs. The distribution of the different drugs closely matched the distribution of these drugs over the adult market, and not the drug utilization by children

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Aims  To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results  In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). Conclusions  Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable

Developing argumentation skills in mathematics through computer-supported collaborative learning: the role of transactivity

Collaboration scripts and heuristic worked examples are effective means to scaffold university freshmen’s mathematical argumentation skills. Yet, which collaborative learning processes are responsible for these effects has remained unclear. Learners presumably will gain the most out of collaboration if the collaborators refer to each other’s contributions in a dialectic way (dialectic transactivity). Learners also may refer to each other’s contributions in a dialogic way (dialogic transactivity). Alternatively, learners may not refer to each other’s contributions at all, but still construct knowledge (constructive activities). This article investigates the extent to which constructive activities, dialogic transactivity, and dialectic transactivity generated by either the learner or the learning partner can explain the positive effects of collaboration scripts and heuristic worked examples on the learners’ disposition to use argumentation skills. We conducted a 2 × 2 experiment with the factors collaboration script and heuristic worked examples with N = 101 math teacher students. Results showed that the learners’ engagement in self-generated dialectic transactivity (i.e., responding to the learning partner’s contribution in an argumentative way by critiquing and/or integrating their learning partner’s contributions) mediated the effects of both scaffolds on their disposition to use argumentation skills, whereas partner-generated dialectic transactivity or any other measured collaborative learning activity did not. To support the disposition to use argumentation skills in mathematics, learning environments should thus be designed in a way to help learners display dialectic transactivity. Future research should investigate how learners might better benefit from the dialectic transactivity generated by their learning partners

Treatment of depressive disorders in primary care - protocol of a multiple treatment systematic review of randomized controlled trials

Background: Several systematic reviews have summarized the evidence for specific treatments of primary care patients suffering from depression. However, it is not possible to answer the question how the available treatment options compare with each other as review methods differ. We aim to systematically review and compare the available evidence for the effectiveness of pharmacological, psychological, and combined treatments for patients with depressive disorders in primary care. Methods/Design: To be included, studies have to be randomized trials comparing antidepressant medication (tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), hypericum extracts, other agents) and/or psychological therapies (e.g. interpersonal psychotherapy, cognitive therapy, behavioural therapy, short dynamically-oriented psychotherapy) with another active therapy, placebo or sham intervention, routine care or no treatment in primary care patients in the acute phase of a depressive episode. Main outcome measure is response after completion of acute phase treatment. Eligible studies will be identified from available systematic reviews, from searches in electronic databases (Medline, Embase and Central), trial registers, and citation tracking. Two reviewers will independently extract study data and assess the risk of bias using the Cochrane Collaboration's corresponding tool. Meta-analyses (random effects model, inverse variance weighting) will be performed for direct comparisons of single interventions and for groups of similar interventions (e.g. SSRIs vs. tricyclics) and defined time-windows (up to 3 months and above). If possible, a global analysis of the relative effectiveness of treatments will be estimated from all available direct and indirect evidence that is present in a network of treatments and comparisons. Discussion: Practitioners do not only want to know whether there is evidence that a specific treatment is more effective than placebo, but also how the treatment options compare to each other. Therefore, we believe that a multiple treatment systematic review of primary-care based randomized controlled trials on the most important therapies against depression is timely