Association of adverse cardiovascular events with gabapentin and pregabalin among patients with fibromyalgia

PLoS ONE, Journal Year: 2024, Volume and Issue: 19(7), P. e0307515 - e0307515

Published: July 26, 2024

Objective Fibromyalgia, a chronic pain disorder, impacts approximately 2% of adults in the US. Gabapentin and pregabalin are common treatments to manage fibromyalgia-related pain. Our recent study showed risk adverse cardiovascular events increased diabetic neuropathy patients who were prescribed gabapentin or pregabalin. Here, we investigated whether prescription has similar with fibromyalgia. Methods This retrospective cohort leveraged electronic health records from 64 US healthcare organizations 112 million patients. The population included 105,602 first diagnosed fibromyalgia followed by gabapentin, pregabalin, other FDA-approved drugs for treating 2010 2019. Outcomes deep venous thrombosis (DVT), myocardial infarcts (MI), peripheral vascular disease (PVD), strokes, heart failure, pulmonary embolism (PE). In propensity-score-matched cohorts, 1-year 5-year hazard ratios (HRs) computed their respective 95% confidence intervals (CIs). Additionally, conducted sensitivity analyses on subpopulations without possible indications. Results For follow-up, PVD (HR = 1.46, CI 1.17–1.80), MI 1.31, 1.03–1.66), failure 1.27, 1.10–1.48), DVT 1.80, 1.33–2.44), PE 2.23, 1.62–3.07). Pregabalin 1.49, 1.01–2.20), 2.24, 1.43–3.50). 1.32, 1.11–1.57), 1.35, 1.09–1.68), 1.36, 1.17–1.57). 1.06–1.63) 1.25, 1.03–1.52). Sensitivity trends. Conclusion patients, moderately several events. risk, together benefits reactions, should be considered when prescribing these medications

Language: Английский

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The G Protein-First Mechanism for Activation of the Class B Glucagon-like Peptide 1 Receptor Coupled to N-Terminal Domain-Mediated Conformational Progression

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 12, 2024

Recently, there has been a great deal of excitement about new glucagon-like peptide 1 receptor (GLP-1R) agonists (e.g., semaglutide and tirzepatide) that have received FDA approval for type 2 diabetes obesity. Although effective, these drugs come with side effects limit their use. While research efforts continue to focus intensively on long-lasting, orally administered GLP-1R medications fewer effects, major impediment developing improved is the mechanism by which an agonist activates imitate signaling not known. Here we present validate G protein (GP)-first supported extensive atomistic simulations. We propose preactivated through formation GLP-1R-GP precoupled complex at cell membrane prior ligand binding. Despite transmembrane helix 6 (TM6)-bentout conformation characteristic activated GLP-1R, this remains unactivated until binds elicit signaling. Notably, hypothesis offers unified predictive model activities series full partial agonists, including peptides ExP5, GLP-1(7-36), GLP-1(9-36). Most surprisingly, our simulations reveal N-terminus domain (NTD)-swing/agonist-insertion wherein long extracellular NTD tightly holds C-terminal half progressively shifts N-terminal head facilitate insertion into orthosteric pocket. Our findings provide novel mechanistic insights activation function class B GPCRs should realistic basis structure-based design.

Language: Английский

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A Brain Reward Circuit Inhibited By Next-Generation Weight Loss Drugs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 17, 2024

Abstract Glucagon-like peptide-1 receptor agonists (GLP1RAs) effectively reduce body weight and improve metabolic outcomes, yet established peptide-based therapies require injections complex manufacturing. Small-molecule GLP1RAs promise oral bioavailability scalable manufacturing, but their selective binding to human versus rodent receptors has limited mechanistic studies. The neural circuits through which these emerging therapeutics modulate feeding behavior remain undefined, particularly in comparison GLP1RAs. Here, we developed humanized GLP1R mouse models investigate how small- molecule influence behavior. Integrating genetic manipulations, calcium imaging, profiling, discovered that compounds regulate both homeostatic hedonic parallel circuits. Beyond engaging canonical hypothalamic hindbrain networks control homeostasis, recruit a discrete population of Glp1r-expressing neurons the central amygdala, selectively suppress consumption palatable foods by reducing dopamine release nucleus accumbens. Stimulating amygdalar curtail feeding, whereas targeted deletion this cell specifically diminishes anorectic efficacy for reward-driven intake. These findings reveal dedicated circuit small reward processing, suggesting broad therapeutic potential conditions dysregulated signaling including substance use disorder binge eating.

Language: Английский

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Validation of the Reasons for Quitting Smoking Cannabis Scale Among People with Cannabis Use Disorder

Substance Use & Misuse, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 12

Published: Sept. 9, 2024

The prevalence of cannabis use disorder (CUD) has increased in the last ten years with medicinal and recreational legalization across United States increasing accessibility worldwide. Estimates suggest that 8-18% individuals who meet diagnostic criteria for CUD, leading to significant impairments functioning. However, there are currently no measures assess reasons quitting smoking treatments validation evidence those CUD.

Language: Английский

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The Beneficial Effects of GLP-1 Receptor Agonists Other than Their Anti-Diabetic and Anti-Obesity Properties

Medicina, Journal Year: 2024, Volume and Issue: 61(1), P. 17 - 17

Published: Dec. 26, 2024

As an incretin hormone, Glucagon-like peptide-1 (GLP-1) has obvious effects on blood glucose regulation and weight loss. GLP-1 receptor (GLP-1R) agonists are synthetic products that have similar to but less prone degradation, they widely used in the treatment of type 2 diabetes obesity. In recent years, different beneficial GLP-1R were discovered, such as reducing ischemia-reperfusion injury, improving function various organs, alleviating substance use disorder, affecting tumorigenesis, regulating bone metabolism, changing gut microbiota composition, prolonging graft survival. Therefore, great potential for clinical application diseases. Here, we briefly summarized other than anti-diabetic anti-obesity effects.

Language: Английский

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