-
The Journal of Prevention of... 2024In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated.
OBJECTIVES
To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB.
DESIGN
Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed.
SETTING
22 clinical sites in the US and 2 in the Netherlands.
PARTICIPANTS
Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT).
INTERVENTION
Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks.
MEASUREMENTS
6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT).
RESULTS
Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively.
CONCLUSION
In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.
Topics: Humans; Lewy Body Disease; Aged; Female; Male; Double-Blind Method; Magnetic Resonance Imaging; Biomarkers; Aged, 80 and over; Neuropsychological Tests; Benzylamines; Fluorocarbons; Indoles
PubMed: 38706271
DOI: 10.14283/jpad.2024.36 -
The Journal of Clinical Investigation May 2024The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac...
The myosin inhibitor mavacamten has transformed the management of obstructive hypertrophic cardiomyopathy (HCM) by targeting myosin ATPase activity to mitigate cardiac hypercontractility. This therapeutic mechanism has proven effective for patients with HCM independent of having a primary gene mutation in myosin. In this issue of the JCI, Buvoli et al. report that muscle hypercontractility is a mechanism of pathogenesis underlying muscle dysfunction in Laing distal myopathy, a disorder characterized by mutations altering the rod domain of β myosin heavy chain. The authors performed detailed physiological, molecular, and biomechanical analyses and demonstrated that myosin ATPase inhibition can correct a large extent of muscle abnormalities. The findings offer a therapeutic avenue for Laing distal myopathy and potentially other myopathies. This Commentary underscores the importance of reevaluating myosin activity's role across myopathies in general for the potential development of targeted myosin inhibitors to treat skeletal muscle disorders.
Topics: Humans; Muscle, Skeletal; Cardiomyopathy, Hypertrophic; Myosin Heavy Chains; Distal Myopathies; Animals; Mutation; Myosins; Benzylamines; Uracil
PubMed: 38690729
DOI: 10.1172/JCI179958 -
International Journal of Molecular... Apr 2024Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to...
Alpha 7 Nicotinic Acetylcholine Receptor Agonist PHA 568487 Reduces Acute Inflammation but Does Not Affect Cardiac Function or Myocardial Infarct Size in the Permanent Occlusion Model.
Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematologic parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h or at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.
Topics: Animals; Myocardial Infarction; alpha7 Nicotinic Acetylcholine Receptor; Mice; Disease Models, Animal; Inflammation; Male; Cytokines; Nicotinic Agonists; Pyridines; Mice, Inbred C57BL; Quinuclidines; Benzylamines; Benzylidene Compounds
PubMed: 38674000
DOI: 10.3390/ijms25084414 -
ACS Biomaterials Science & Engineering May 2024The laminar flow profiles in microfluidic systems coupled to rapid diffusion at flow streamlines have been widely utilized to create well-controlled chemical gradients...
The laminar flow profiles in microfluidic systems coupled to rapid diffusion at flow streamlines have been widely utilized to create well-controlled chemical gradients in cell cultures for spatially directing cell migration. However, within hydrogel-based closed microfluidic systems of limited depth (≤0.1 mm), the biomechanical cues for the cell culture are dominated by cell interactions with channel surfaces rather than with the hydrogel microenvironment. Also, leaching of poly(dimethylsiloxane) (PDMS) constituents in closed systems and the adsorption of small molecules to PDMS alter chemotactic profiles. To address these limitations, we present the patterning and integration of a PDMS-free open fluidic system, wherein the cell-laden hydrogel directly adjoins longitudinal channels that are designed to create chemotactic gradients across the 3D culture width, while maintaining uniformity across its ∼1 mm depth to enhance cell-biomaterial interactions. This hydrogel-based open fluidic system is assessed for its ability to direct migration of U87 glioma cells using a hybrid hydrogel that includes hyaluronic acid (HA) to mimic the brain tumor microenvironment and gelatin methacrylate (GelMA) to offer the adhesion motifs for promoting cell migration. Chemotactic gradients to induce cell migration across the hydrogel width are assessed using the chemokine CXCL12, and its inhibition by AMD3100 is validated. This open-top hydrogel-based fluidic system to deliver chemoattractant cues over square-centimeter-scale areas and millimeter-scale depths can potentially serve as a robust screening platform to assess emerging glioma models and chemotherapeutic agents to eradicate them.
Topics: Humans; Glioma; Cell Movement; Hydrogels; Chemotaxis; Cell Line, Tumor; Cell Culture Techniques, Three Dimensional; Tumor Microenvironment; Chemokine CXCL12; Cyclams; Cell Culture Techniques; Hyaluronic Acid; Gelatin; Benzylamines; Brain Neoplasms
PubMed: 38652035
DOI: 10.1021/acsbiomaterials.4c00041 -
PloS One 2024Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left... (Meta-Analysis)
Meta-Analysis
Evaluating the efficacy and safety of mavacamten in hypertrophic cardiomyopathy: A systematic review and meta-analysis focusing on qualitative assessment, biomarkers, and cardiac imaging.
BACKGROUND
Hypertrophic Cardiomyopathy (HCM) is a complex cardiac condition characterized by hypercontractility of cardiac muscle leading to a dynamic obstruction of left ventricular outlet tract (LVOT). Mavacamten, a first-in-class cardiac myosin inhibitor, is increasingly being studied in randomized controlled trials. In this meta-analysis, we aimed to analyse the efficacy and safety profile of Mavacamten compared to placebo in patients of HCM.
METHOD
We carried out a comprehensive search in PubMed, Cochrane, and clinicaltrials.gov to analyze the efficacy and safety of mavacamten compared to placebo from 2010 to 2023. To calculate pooled odds ratio (OR) or risk ratio (RR) at 95% confidence interval (CI), the Mantel-Haenszel formula with random effect was used and Generic Inverse Variance method assessed pooled mean difference value at a 95% CI. RevMan was used for analysis. P<0.05 was considered significant.
RESULTS
We analyzed five phase 3 RCTs including 609 patients to compare mavacamten with a placebo. New York Heart Association (NYHA) grade improvement and KCCQ score showed the odds ratio as 4.94 and 7.93 with p<0.00001 at random effect, respectively. Cardiac imaging which included LAVI, LVOT at rest, LVOT post valsalva, LVOT post-exercise, and reduction in LVEF showed the pooled mean differences for change as -5.29, -49.72, -57.45, -36.11, and -3.00 respectively. Changes in LVEDV and LVMI were not statistically significant. The pooled mean difference for change in NT-proBNP and Cardiac troponin-I showed 0.20 and 0.57 with p<0.00001. The efficacy was evaluated in 1) A composite score, which was defined as either 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction, or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening and 2) changes in pVO2, which was not statistically significant. Similarly, any treatment-associated emergent adverse effects (TEAE), treatment-associated serious adverse effects (TSAE), and cardiac-related adverse effects were not statistically significant.
CONCLUSION
Mavacamten influences diverse facets of HCM comprehensively. Notably, our study delved into the drug's impact on the heart's structural and functional aspects, providing insights that complement prior findings. Further large-scale trials are needed to evaluate the safety profile of Mavacamten.
Topics: Humans; Cardiomyopathy, Hypertrophic; Heart; Benzylamines; Biomarkers; Uracil
PubMed: 38635724
DOI: 10.1371/journal.pone.0301704 -
Neurologia May 2024The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin... (Observational Study)
Observational Study
BACKGROUND AND PURPOSE
The aim of this study was to assess the possible pharmacological interactions between safinamide and antidepressants, and in particular the appearance of serotonin syndrome with data from real life.
METHODS
We conducted a retrospective observational study of patients with Parkinson's disease from our Movement Disorders Unit, who were under treatment with any antidepressant drug and safinamide. Specifically, symptoms suggestive of serotonin syndrome were screened for. Also, we collected time of simultaneous use, doses of levodopa and other antiparkinsonian drugs.
RESULTS
Clinical records were reviewed for the study period of September 2018 to September 2019. Seventy-eight PD patients who were treated with safinamide of which 25 (32.05%) had a concomitant treatment with an antidepressant drug, being sertraline and escitalopram the most frequent. Mean age was 80 years±8.43 and H&Y stage was 3 [2-4]. Mean dose of levodopa used was 703.75mg±233.15. Median duration of concomitant treatment with safinamide and antidepressant drug was 6 months (IQR 20.5), and over eighteen months in 5 cases. No case of serotonin syndrome was recorded, neither was any of its typical manifestations combined or in isolation.
CONCLUSIONS
Our real clinical practice study suggests that concomitant use of safinamide with antidepressant drugs in PD patients seemed to be safe and well tolerated, even in the long term. However, caution is warranted, individualizing treatment regimens and monitoring the potential appearance of adverse effects.
Topics: Aged, 80 and over; Humans; Alanine; Antidepressive Agents; Benzylamines; Levodopa; Parkinson Disease; Serotonin Syndrome; Aged; Drug Interactions
PubMed: 38616061
DOI: 10.1016/j.nrleng.2021.08.005 -
Molecules (Basel, Switzerland) Apr 2024This study reports on a metal-free Covalent Triazine Framework (CTF) incorporating bithiophene structural units (TP-CTF) with a semicrystalline structure as an efficient...
This study reports on a metal-free Covalent Triazine Framework (CTF) incorporating bithiophene structural units (TP-CTF) with a semicrystalline structure as an efficient heterogeneous photocatalyst under visible light irradiation. The physico-chemical properties and composition of this material was confirmed via different characterization solid-state techniques, such as XRD, TGA, CO adsorption and FT-IR, NMR and UV-Vis spectroscopies. The compound was synthesized through a solvothermal process and was explored as a heterogeneous photocatalyst for the oxidative coupling of amines to imines under visible light irradiation. TP-CTF demonstrated outstanding photocatalytic activity, with high conversion rates and selectivity. Importantly, the material exhibited exceptional stability and recyclability, making it a strong candidate for sustainable and efficient imine synthesis. The low bandgap of TP-CTF enabled the efficient absorption of visible light, which is a notable advantage for visible-light-driven photocatalysis.
PubMed: 38611916
DOI: 10.3390/molecules29071637 -
Journal of the American Heart... Apr 2024The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract... (Clinical Trial)
Clinical Trial
BACKGROUND
The phase 2 PIONEER-HCM (Phase 2 Open-label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer-term treatment are less well described. We report interim results from the PIONEER-OLE (PIONEER Open-Label Extension) study, the longest-term study of mavacamten in patients with symptomatic obstructive HCM.
METHODS AND RESULTS
Patients who previously completed PIONEER-HCM (n=20) were eligible to enroll in PIONEER-OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire-Overall Summary Score, and serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received β-blockers concomitantly. Treatment-emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, -50 [55] mm Hg; Valsalva, -70 [41] mm Hg), and serum NT-proBNP levels (median [interquartile range] change from baseline: -498 [-2184 to -76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire-Overall Summary Score (mean [SD] change from baseline: +17 [16]).
CONCLUSIONS
This long-term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03496168.
Topics: Humans; Benzylamines; Cardiomyopathy, Hypertrophic; Pilot Projects; Stroke Volume; Uracil; Ventricular Function, Left
PubMed: 38591260
DOI: 10.1161/JAHA.123.030607 -
Scientific Reports Apr 2024Ornamental foliage plants that have a dense appearance are highly valued. One way to achieve this is by using plant growth regulators as a tool for plant growth...
Ornamental foliage plants that have a dense appearance are highly valued. One way to achieve this is by using plant growth regulators as a tool for plant growth management. In a greenhouse with a mist irrigation system, a study was conducted on dwarf schefflera, an ornamental foliage plant, which was exposed to foliar application of gibberellic acid and benzyladenine hormones. The hormones were sprayed on dwarf schefflera leaves at 0, 100, and 200 mg/l concentrations, at 15-day intervals in three stages. The experiment was conducted as a factorial based on a completely randomized design, with four replicates. The combination of gibberellic acid and benzyladenine at 200 mg/l concentration had a significant effect on leaf number, leaf area, and plant height. The treatment also resulted in the highest content of photosynthetic pigments. Furthermore, the highest soluble carbohydrate to reducing sugars ratio was observed in treatments of 100 and 200 mg/l benzyladenine, and 200 mg/l gibberellic acid + benzyladenine. Stepwise regression analysis showed that root volume was the first variable to enter the model, explaining 44% of variations. The next variable was root fresh weight, and the two-variable model explained 63% of variations in leaf number. The greatest positive effect on leaf number was related to root fresh weight (0.43), which had a positive correlation with leaf number (0.47). The results showed that 200 mg/l concentration of gibberellic acid and benzyladenine significantly improved morphological growth, chlorophyll and carotenoid synthesis, and reducing sugar and soluble carbohydrate contents in dwarf schefflera.
Topics: Gibberellins; Benzylamines; Plants; Carbohydrates; Hormones; Plant Leaves
PubMed: 38570571
DOI: 10.1038/s41598-024-57985-0 -
Chimia Mar 2024Catalytic conversions in fine-chemical and pharmaceutical production are increasingly performed in trickle-bed rectors. Optimisation of these processes is usually based...
Catalytic conversions in fine-chemical and pharmaceutical production are increasingly performed in trickle-bed rectors. Optimisation of these processes is usually based on end of pipe measurement made at specific residence times. This process is both time-consuming and the data sometimes challenging to interpret. In the present work, operando nuclear magnetic resonance (NMR) techniques both at the scale of the whole bed (global) and spatially resolved within the bed (local) are used to gain new insights into the catalytic conversion process under reaction conditions. Spatially resolved spectroscopic and diffusion-T2-relaxation (D-T2) methods interrogate local differences in chemical conversion and selectivity, and mass transport (molecular self-diffusion) respectively, thereby providing valuable information for process simulation models. This capability is demonstrated using the continuous flow three phase (gas-liquid-solid) hydrogenation of benzonitrile over a fixed bed of 0.5 wt% Pd/Al2O3 catalyst pellets yielding toluene and benzylamine. Global 1H spectroscopic and D-T2 were used to monitor chemical conversion and the approach to steady state; these were subsequently followed by spatially resolved 1H spectra and spatially resolved D-T2 correlations to examine the local differences in axial conversion and selectivity of the catalyst bed packing. At steady-state a global conversion of 63% was achieved with 65% and 25% selectivity to benzylamine and toluene respectively. Heterogeneities in the local (axial) conversion and selectivity differed by 31% along the total catalyst bed length. These techniques should be applicable to many three-phase heterogeneous catalytic systems provided that the T2 relaxation time of the reactants and products is not prohibitively small.
PubMed: 38547014
DOI: 10.2533/chimia.2024.129