Project description:This review provides details about three small molecules that were recently approved by the FDA for the treatment of thrombocytopenia. The new treatments include lusutrombopag, avatrombopag, and fostamatinib. The first two drugs are orally active thrombopoietin receptor (TPO-R) agonists which are FDA-approved for the treatment of thrombocytopenia in adult patients with chronic liver disease who are scheduled to undergo a procedure. Fostamatinib is orally active prodrug that, after activation, becomes spleen tyrosine kinase (SYK) inhibitor. Fostamatinib is currently used to treat chronic and refractory immune thrombocytopenia in patients who have had insufficient response to previous treatment. Chemical structures, available dosage forms, recommended dosing, pharmacokinetics, results of toxicity studies in animals, most frequent adverse effects, significant outcomes of the corresponding clinical trials, and their use in specific patient populations are thoroughly described. Described also is a comparative summary of the different aspects of five currently available therapies targeting TPO-R or SYK for the treatment of thrombocytopenia.
Project description:Amyotrophic lateral sclerosis is a devastating neurodegenerative disease caused by loss of motor neurons. Its pathophysiology remains unknown, but progress has been made in understanding its genetic and biochemical basis. Clinical trialists are working to translate basic science successes into human trials with more efficiency, in the hope of finding successful treatments. In the future, new preclinical models, including patient-derived stem cells may augment transgenic animal models as preclinical tools. Biomarker discovery projects aim to identify markers of disease onset and progression for use in clinical trials. New trial designs are reducing study time, improving efficiency and helping to keep pace with the increasing rate of basic and translational discoveries. Ongoing trials with novel designs are paving the way for amyotrophic lateral sclerosis clinical research.
Project description:Background: The novel coronavirus SARS-CoV-2 has severely affected the health and economy of several countries. Multiple studies are in progress to design novel therapeutics against the potential target proteins in SARS-CoV-2, including 3CL protease, an essential protein for virus replication. Materials & methods: In this study we employed deep neural network-based generative and predictive models for de novo design of small molecules capable of inhibiting the 3CL protease. The generative model was optimized using transfer learning and reinforcement learning to focus around the chemical space corresponding to the protease inhibitors. Multiple physicochemical property filters and virtual screening score were used for the final screening. Conclusion: We have identified 33 potential compounds as ideal candidates for further synthesis and testing against SARS-CoV-2.
Project description:We describe and illustrate a workflow for chemical safety assessment that completely avoids animal testing. The workflow, which was developed within the SEURAT-1 initiative, is designed to be applicable to cosmetic ingredients as well as to other types of chemicals, e.g. active ingredients in plant protection products, biocides or pharmaceuticals. The aim of this work was to develop a workflow to assess chemical safety without relying on any animal testing, but instead constructing a hypothesis based on existing data, in silico modelling, biokinetic considerations and then by targeted non-animal testing. For illustrative purposes, we consider a hypothetical new ingredient x as a new component in a body lotion formulation. The workflow is divided into tiers in which points of departure are established through in vitro testing and in silico prediction, as the basis for estimating a safe external dose in a repeated use scenario. The workflow includes a series of possible exit (decision) points, with increasing levels of confidence, based on the sequential application of the Threshold of Toxicological (TTC) approach, read-across, followed by an "ab initio" assessment, in which chemical safety is determined entirely by new in vitro testing and in vitro to in vivo extrapolation by means of mathematical modelling. We believe that this workflow could be applied as a tool to inform targeted and toxicologically relevant in vitro testing, where necessary, and to gain confidence in safety decision making without the need for animal testing.
Project description:There is great need for improved therapy for patients with acute leukemia. The current systems of clinical drug development and delivery of leukemia care are imperfectly adapted to the optimal identification and testing of future regimens. Novel clinical trial design with increased enrolment and appropriate end point selection would facilitate more efficient validation of candidate therapies. Clinical outcomes registries and biological sample storage would allow patient and leukemic factor substratification for the development of the next generation of targeted personalized therapy. We believe that the standard of care for patients in the USA diagnosed with acute leukemia, if treated with curative intent, is referral to a specialized center where an appropriate clinical trial can be offered.
Project description:BackgroundElectronic cigarettes (ECs) are often marketed as a safer alternative to combustible tobacco products. The global EC market has rapidly expanded since their introduction, creating an urgent need for research describing the toxicity and chemical composition of ECs. We conducted an umbrella review to summarize the evidence from existing systematic reviews (SRs).MethodsThe search for SRs was conducted across four electronic databases through 25 January 2022. Methodological quality was assessed using the AMSTAR-2 quality appraisal tool.ResultsTwenty-five SRs were included in our umbrella review. Chemical profiles widely varied across studies included in the reviews, which was mainly attributed to the lack of standardized protocols investigating the constituents, and differences in EC devices and e-liquids tested. Metals were more abundant in some EC aerosols than cigarettes, while carbonyls were typically found at lower levels. There was consistent evidence of in vitro toxicity from EC aerosol and e-liquid exposure. AMSTAR-2 revealed important limitations across reviews.ConclusionsWhile most reviews concluded that ECs were likely less harmful than cigarettes, there was hesitancy to draw clear conclusions due to variable analytical procedures and inconsistent findings among the included studies. Future SRs with improved methodology and reporting are needed to adequately inform tobacco regulatory actions.
Project description:BackgroundIn a stepped wedge design, schools are randomised to a sequence of measurements, with each sequence transitioning to intervention status at a different time. There are several advantages to such designs, including increased statistical power, logistical benefits and the ability to explore change over time. However, stepped wedge designs have not previously been used to evaluate school-based physical activity interventions in children. This paper aimed to explore the feasibility of this design, by identifying school constraints, balancing these with statistical considerations and exploring the power of this chosen design under different scenarios.MethodsWe conducted three interlinked studies, with the results from one informing the next. Study 1 was a qualitative study to identify school constraints that inform the choice of stepped wedge configuration. Study 2 used simulation to choose a configuration that balanced these school constraints and statistical properties. Study 3 explored the statistical power for the chosen design for different school and pupil sample sizes, using an open cohort design (a mixture of new and repeated pupils).ResultsSchool staff considered the proposed data collection feasible, and supported a maximum of 3-4 measurements per year and an implementation period of one school term. Study 2 therefore considered incomplete stepped wedge designs with five steps. Statistically, the best designs had a mix of control and intervention measurements in terms 2-4 and a spread of measurements across the whole study duration. Power depended on a combination of the overall recruitment rate and the retention rate. For 20 schools with an eligible class size of 30 pupils, we would be able to detect a 6 min difference in average weekday moderate-to-vigorous physical activity with 80% power, provided there were > 50% of pupils measured per school at each time. A similarly powered cluster randomised controlled trial would require 42 schools.ConclusionStepped wedge trials are a viable design for evaluating school-based physical activity interventions. Incomplete designs, where not all schools are measured at each point, offer the flexibility to work around practical constraints.
Project description:Translational readthrough-inducing drugs (TRIDs) rescue the functional full-length protein expression in genetic diseases, such as cystic fibrosis, caused by premature termination codons (PTCs). Small molecules have been developed as TRIDs to trick the ribosomal machinery during recognition of the PTC. Herein we report a computational study to identify new TRID scaffolds. A pharmacophore approach was carried out on compounds that showed readthrough activity. The pharmacophore model applied to screen different libraries containing more than 87000 compounds identified four hit-compounds presenting scaffolds with diversity from the oxadiazole lead. These compounds have been synthesized and tested using the Fluc reporter harboring the UGA PTC. Moreover, the cytotoxic effect and the expression of the CFTR protein were evaluated. These compounds, a benzimidazole derivative (NV2899), a benzoxazole derivative (NV2913), a thiazole derivative (NV2909), and a benzene-1,3-disulfonate derivative (NV2907), were shown to be potential new lead compounds as TRIDs, boosting further efforts to address the optimization of the chemical scaffolds.
Project description:The involvement of the right and left hemispheres in mediating language functions has been measured in a variety of ways over the centuries since the relative dominance of the left hemisphere was first known. Functional magnetic resonance imaging (fMRI) presents a useful non-invasive method of assessing lateralisation that is being increasingly used in clinical practice and research. However, the methods used in the fMRI laterality literature currently are highly variable, making systematic comparisons across studies difficult. Here we consider the different methods of quantifying and classifying laterality that have been used in fMRI studies since 2000, with the aim of determining which give the most robust and reliable measurement. Recommendations are made with a view to informing future research to increase standardisation in fMRI laterality protocols. In particular, the findings reinforce the importance of threshold-independent methods for calculating laterality indices, and the benefits of assessing heterogeneity of language laterality across multiple regions of interest and tasks. This systematic review was registered as a protocol on Open Science Framework: https://osf.io/hyvc4/.