A5083100447- Muscle Physiology and Disorders
- Neuropeptides and Animal Physiology
- Cannabis and Cannabinoid Research
- Pharmacological Receptor Mechanisms and Effects
- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Neuroscience and Neuropharmacology Research
- Pain Mechanisms and Treatments
- Muscle activation and electromyography studies
- Children's Physical and Motor Development
- Neurogenetic and Muscular Disorders Research
- Inflammatory mediators and NSAID effects
- Crystallization and Solubility Studies
- Eicosanoids and Hypertension Pharmacology
- Prosthetics and Rehabilitation Robotics
- X-ray Diffraction in Crystallography
- HIV-related health complications and treatments
- Psychedelics and Drug Studies
- Health Systems, Economic Evaluations, Quality of Life
- Cardiomyopathy and Myosin Studies
- Neuroendocrine regulation and behavior
- Diet and metabolism studies
- Cerebral Palsy and Movement Disorders
- Pharmacology and Obesity Treatment
- Pharmacogenetics and Drug Metabolism
Cambridge Collaborative (United States)
2018-2024
Analysis Group (United States)
2017-2023
University College London
2023
Sherwood Forest Hospitals NHS Foundation Trust
2023
Royal College of Obstetricians and Gynaecologists
2023
Great Ormond Street Hospital
2023
Kings Mill Hospital
2014-2021
Children's National
2020
University of Florida
2020
Agostino Gemelli University Polyclinic
2020
The profile of action beta-funaltrexamine (beta-FNA), the fumaramate methyl ester derivative naltrexone, on antinociceptive tests in vivo was investigated. Beta-FNA demonstrated actions that were short duration and appeared to be mediated by kappa receptor interaction. In contrast, antagonist beta-FNA remarkably long selective toward nu agonist interactions. This is consistent with vitro. long-lasting antagonism mu-mediated effects may great value elucidation multiple opioid function.
Pravadoline (1) is an (aminoalkyl)indole analgesic agent which inhibitor of cyclooxygenase and, in contrast to other NSAIDs, inhibits neuronally stimulated contractions mouse vas deferens (MVD) preparations (IC50 = 0.45 microM). A number conformationally restrained heterocyclic analogues pravadoline were synthesized the morpholinoethyl side chain was tethered indole nucleus. Restraining morpholine diminished ability these inhibit prostaglandin synthesis vitro. In contrast, inhibitory...
Six novel aminoalkylindole analogs, related structurally to the dual cyclooxygenase inhibitor and nonopioid analgesic pravadoline, were evaluated in mouse determine whether their pharmacological profile of activity was similar that exhibited by delta 9-tetrahydrocannabinol (delta 9-THC). Analog I (C2-H; C3-methoxy-benzoyl) reduced locomotion, but had no other effects (hypothermia, antinociception or ring-immobility) up 21 mumol/kg. Analogs II III (C3-naphthoyl; C2-H C2-methyl, respectively)...
The antinociceptive properties of morphine (mu), ethylketazocine (kappa), nalorphine [D-Ala2, D-Leu5]enkephalin (delta) and Met5]enkephalinamide (mu, delta) were assessed using the radiant heat tail-flick acetic acid-induced writhing assays in mice. apparent pA2 values for interaction naloxone with same regardless nociceptive stimulus employed or route administration morphine. interactions test differed significantly from that naloxone. Nalorphine did not produce a consistent effect on test....
A binding assay for WIN 55212-2, an aminoalkylindole (AAI) with antinociceptive activity in rodents, is described. [3H]WIN 55212-2 bound to rat cerebellar membranes a Kd of 2 nM and maximum 1.2 pmol/mg protein. Specific this filtration was greater than 90%, saturable, reversible, stereospecific, pH sensitive heat labile. Binding decreased by Na+, K+, Li+ nonhydrolyzable analogs GTP increased Mg++ Ca++. The density specific sites varied throughout the central nervous system highest found...
In previous studies it was shown that the structurally dissimilar compounds delta 9-THC, CP 55,940 and WIN 55,212 produced more or less same pharmacological effects interacted with cannabinoid receptor. However, their potencies vary across a number of assays, suggesting single mechanism may not account for all actions. To further explore possible differences among these cannabinoids, cross-tolerance were conducted. Specifically, ability to produce hypoactivity, hypothermia, antinociception...
OVERVIEW:Companies continuously seek to innovate more quickly and effectively both within often beyond their core markets product lines. This has resulted in the practice of "open innovation" wherein firms recognize that all components an innovation do not need come from within, they can accelerate own efforts or perhaps even broaden scope these by acquiring some required technology externally. Research across multiple business segments identified a number practices have adopted identify...
Aminoalkylindoles (AAIs) are antinociceptive agents which act through two distinct mechanisms: inhibition of cyclooxygenase and a novel mechanism retained by AAI analogs do not inhibit cyclooxygenase. This latter is reflected neuronally mediated contractions in several smooth muscle bioassays. The present studies explored the potential receptor interactions AAIs preparations rat brain membranes. Experiments an electrically stimulated mouse vas deferens preparation (MVD) demonstrated that...
Functional variability among boys with Duchenne muscular dystrophy (DMD) is well recognised and complicates interpretation of clinical studies. We hypothesised that DMD could be clustered into groups sharing similar trajectories ambulatory function over time, as measured by the North Star Ambulatory Assessment (NSAA) total score. also explored associations other variables such age, functional abilities, genotype. Using NorthStar Clinical Network database, 395 patients >1 NSAA assessment were...
High variability in patients' changes 6 minute walk distance (6MWD) over time has complicated clinical trials of treatment efficacy Duchenne muscular dystrophy (DMD). We assessed whether boys with DMD could be grouped into classes that shared similar ambulatory function trajectories as measured by 6MWD. Ambulatory aged 5 years or older genetically confirmed who were enrolled a natural history study at 11 care centers throughout Italy included. For each boy, standardized assessments 6MWD...
Both opioids and cannabinoids bind to G-protein-coupled receptors inhibit adenylyl cyclase in neurons. These reactions were assayed brain membranes, where maximal inhibitory activity occurred the following regions: mu-opioid inhibition rat thalamus, delta-opioid striatum, kappa-opioid guinea pig cerebellum, cannabinoid cerebellum. The of by both opioid agonists was typical G-protein-linked receptors: they required GTP, not supported non-hydrolyzable GTP analogs, abolished (in primary...
Using external controls based on real-world or natural history data (RWD/NHD) for drug evaluations in Duchenne muscular dystrophy (DMD) is appealing given the challenges of enrolling placebo-controlled trials, especially multi-year trials. Comparisons to controls, however, face risks bias due differences outcomes between trial and RWD/NHD settings. To assess this empirically, we conducted a multi-institution study comparing mean 48-week changes North Star Ambulatory Assessment (NSAA) total...
Evaluations of treatment efficacy in Duchenne muscular dystrophy (DMD), a rare genetic disease that results progressive muscle wasting, require an understanding the 'meaningfulness' changes functional measures. We estimated minimal detectable change (MDC) for selected motor function measures ambulatory DMD, i.e., degree measured needed to be confident true underlying has occurred rather than transient variation or measurement error. MDC estimates were compared across multiple data sources,...
We report the synthesis and in vitro biological activity of nonpeptide bradykinin receptor antagonist WIN 64338, [[4-[[2-[[bis(cyclohexylamino)methylene]amino]-3-(2- naphthyl)-1-oxopropyl]amino]phenyl]methyl]tributylphosphonium chloride monohydrochloride. 64338 inhibits [3H]-bradykinin binding to B2 on human IMR-90 cells with a inhibition constant (Ki) 64 +/- 8 nM demonstrates competitive bradykinin-stimulated 45Ca2+ efflux from (pA2 = 7.1). The bradykinin-mediated guinea pig ileum...
Objective The purpose of this study was to conduct a proof-of-concept evaluate remote recruitment and assessment individuals (“virtual research visits”) with Parkinson's disease who have pursued direct-to-consumer genetic testing. Methods Participants in 23andMe’s “Parkinson’s Research Community” were contacted by 23andMe. Fifty willing participants living 23 states underwent remote, standardized including cognitive motor tests neurologist via video conferencing then completed survey....
To investigate the role of brain H2-receptors in opioid antinociceptive mechanisms, effects several antagonists histamine were determined on morphine (MOR)-induced antinociception, opioid-mediated footshock-induced antinociception (FSIA) and other opiate rats. Zolantidine dimaleate (ZOL), first brain-penetrating H2 antagonist (0.03-1.6 mumol/kg s.c.) caused a dose-related inhibition MOR both tail-flick hot-plate tests, with no effect base-line responding. ZOL also inhibited FISA similar...
<h3>Objective</h3> To evaluate the suitability of real-world data (RWD) and natural history (NHD) for use as external controls in drug evaluations ambulatory Duchenne muscular dystrophy (DMD). <h3>Methods</h3> The consistency changes 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms sources NHD/RWD. Six reporting 48-week Δ6MWD were identified via literature review represented 4 sets inclusion/exclusion criteria (n = 383 patients total). Five RWD/NHD...
The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought identify prognostic factors for changes 4SC, assess their consistency across data sources, the extent which scores could be useful DMD clinical trial design analysis. Data from patients with placebo arm of a phase 3 (Tadalafil trial) two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] Cincinnati Children's Hospital Medical...