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Medicine and Science in Sports and... Oct 2023Our purpose was to examine the effects of 2 yr of creatine monohydrate supplementation and exercise on bone health in postmenopausal women. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Our purpose was to examine the effects of 2 yr of creatine monohydrate supplementation and exercise on bone health in postmenopausal women.
METHODS
Two hundred and thirty-seven postmenopausal women (mean age, 59 yr) were randomized to receive creatine (0.14 g·kg -1 ·d -1 ) or placebo during a resistance training (3 d·wk -1 ) and walking (6 d·wk -1 ) program for 2 yr. Our primary outcome was the femoral neck bone mineral density (BMD), with lumbar spine BMD and proximal femur geometric properties as the secondary outcomes.
RESULTS
Compared with placebo, creatine supplementation had no effect on BMD of the femoral neck (creatine: 0.725 ± 0.110 to 0.712 ± 0.100 g·cm -2 ; placebo: 0.721 ± 0.102 to 0.706 ± 0.097 g·cm -2 ), total hip (creatine: 0.879 ± 0.118 to 0.872 ± 0.114 g·cm -2 ; placebo: 0.881 ± 0.111 to 0.873 ± 0.109 g·cm -2 ), or lumbar spine (creatine: 0.932 ± 0.133 to 0.925 ± 0.131 g·cm -2 ; placebo: 0.923 ± 0.145 to 0.915 ± 0.143 g·cm -2 ). Creatine significantly maintained section modulus (1.35 ± 0.29 to 1.34 ± 0.26 vs 1.34 ± 0.25 to 1.28 ± 0.23 cm 3 (placebo), P = 0.0011), predictive of bone bending strength, and buckling ratio (10.8 ± 2.6 to 11.1 ± 2.2 vs 11.0 ± 2.6 to 11.6 ± 2.7 (placebo), P = 0.011), predictive of reduced cortical bending under compressive loads, at the narrow part of the femoral neck. Creatine reduced walking time over 80 m (48.6 ± 5.6 to 47.1 ± 5.4 vs 48.3 ± 4.5 to 48.2 ± 4.9 s (placebo), P = 0.0008) but had no effect on muscular strength (i.e., one-repetition maximum) during bench press (32.1 ± 12.7 to 42.6 ± 14.1 vs 30.6 ± 10.9 to 41.4 ± 14 kg (placebo)) and hack squat (57.6 ± 21.6 to 84.4 ± 28.1 vs 56.6 ± 24.0 to 82.7 ± 25.0 kg (placebo)). In the subanalysis of valid completers, creatine increased lean tissue mass compared with placebo (40.8 ± 5.7 to 43.1 ± 5.9 vs 40.4 ± 5.3 to 42.0 ± 5.2 kg (placebo), P = 0.046).
CONCLUSIONS
Two years of creatine supplementation and exercise in postmenopausal women had no effect on BMD; yet, it improved some bone geometric properties at the proximal femur.
Topics: Female; Humans; Middle Aged; Bone Density; Creatine; Postmenopause; Osteoporosis, Postmenopausal; Femur Neck; Dietary Supplements; Double-Blind Method
PubMed: 37144634
DOI: 10.1249/MSS.0000000000003202 -
ACR Open Rheumatology Jul 2023To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype.
OBJECTIVE
To evaluate mepolizumab's efficacy in eosinophilic granulomatosis with polyangiitis (EGPA) with and without a vasculitic phenotype.
METHODS
The MIRRA study (NCT02020889/GSK ID: 115921) included adults with relapsing/refractory EGPA and 4 or more weeks of stable oral glucocorticoids (OG). Patients received mepolizumab (300 mg subcutaneously every 4 weeks) or placebo, plus standard of care for 52 weeks. This post hoc analysis assessed EGPA vasculitic phenotype using antineutrophil cytoplasmic antibody (ANCA) history, baseline Birmingham Vasculitis Activity Score (BVAS), and Vasculitis Damage Index (VDI) score. Coprimary endpoints included accrued remission over 52 weeks and proportion in remission at Week 36 and Week 48. Remission was defined as a BVAS equal to 0 and an OG dose of 4 or more mg/day of a prednisone equivalent. Types of relapses (vasculitis, asthma, and sino-nasal) and EGPA vasculitic characteristics (by study remission status) were also assessed.
RESULTS
A total of 136 patients were included (n = 68, mepolizumab and placebo). Irrespective of history of ANCA positivity status, baseline BVAS, or baseline VDI, the accrued remission duration and the proportion of patients in remission at Weeks 36 and 48 were greater with mepolizumab compared with placebo. With mepolizumab, remission at both Week 36 and Week 48 was achieved by 54% of patients with and 27% of patients without a history of ANCA positivity compared with 0% and 4%, respectively (placebo); 45% of patients with a BVAS of 0 and 22% of patients with BVAS of greater than 0 compared with 5% and 2%, respectively (placebo); and 29% of patients with a VDI score of less than 5 and 37% of patients with a VDI score of 5 or more compared with 6% and 0%, respectively (placebo). Mepolizumab reduced all types of relapses as compared with placebo. Baseline vasculitic characteristics (neuropathy, glomerulonephritis, alveolar hemorrhage, palpable purpura, and ANCA positivity) were generally similar among patients with and without remission.
CONCLUSION
Mepolizumab is associated with clinical benefits for patients with and without a vasculitic EGPA phenotype.
PubMed: 37312233
DOI: 10.1002/acr2.11571 -
Diabetes, Obesity & Metabolism Oct 2023To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R)... (Randomized Controlled Trial)
Randomized Controlled Trial
Tolerability, safety and pharmacodynamics of oral, small-molecule glucagon-like peptide-1 receptor agonist danuglipron for type 2 diabetes: A 12-week, randomized, placebo-controlled, Phase 2 study comparing different dose-escalation schemes.
AIM
To evaluate the tolerability, safety and pharmacodynamics of different dose-escalation schemes of the oral small-molecule glucagon-like peptide-1 receptor (GLP-1R) agonist danuglipron.
MATERIALS AND METHODS
This Phase 2a, double-blind, placebo-controlled, parallel-group study randomly assigned adults with type 2 diabetes (T2D) treated with metformin to placebo or danuglipron (low [5-mg] or high [10-mg] starting dose, with 1- or 2-week dose-escalation steps, to target doses of 80, 120 or 200 mg twice daily [BID]) and adults with obesity without diabetes to placebo or danuglipron 200 mg BID.
RESULTS
Participants with T2D (n = 123, mean glycated haemoglobin [HbA1c] 8.19%) or obesity without diabetes (n = 28, mean body mass index 37.3 kg/m ) were randomly assigned and treated. Discontinuation from study medication occurred in 27.3% to 72.7% of participants across danuglipron groups versus 16.7% to 18.8% for placebo, most often due to adverse events. Nausea (20.0%-47.6% of participants across danuglipron groups vs. 12.5% for placebo) and vomiting (18.2%-40.9% danuglipron vs. 12.5% placebo, respectively) were most commonly reported in participants with T2D. Gastrointestinal adverse events were generally related to danuglipron target dose and were not substantially affected by starting dose. In participants with T2D, least squares mean changes from baseline in HbA1c (-1.04% to -1.57% across danuglipron groups vs. -0.32% for placebo), fasting plasma glucose (-23.34 mg/dL to -53.94 mg/dL danuglipron vs. -13.09 mg/dL placebo) and body weight (-1.93 to -5.38 kg danuglipron vs. -0.42 kg placebo) at Week 12 were generally statistically significant for danuglipron compared with placebo (P < 0.05).
CONCLUSIONS
Danuglipron resulted in statistically significant reductions in HbA1c, FPG and body weight over 12 weeks, in the setting of higher discontinuation rates and incidence of gastrointestinal adverse events with higher target doses.
CLINICALTRIALS
gov identifier: NCT04617275.
Topics: Adult; Humans; Diabetes Mellitus, Type 2; Glucagon-Like Peptide-1 Receptor; Glycated Hemoglobin; Hypoglycemic Agents; Body Weight; Obesity; Double-Blind Method; Treatment Outcome; Blood Glucose
PubMed: 37311722
DOI: 10.1111/dom.15168 -
The New England Journal of Medicine Feb 2024The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
The CD40-CD40L costimulatory pathway regulates adaptive and innate immune responses and has been implicated in the pathogenesis of multiple sclerosis. Frexalimab is a second-generation anti-CD40L monoclonal antibody being evaluated for the treatment of multiple sclerosis.
METHODS
In this phase 2, double-blind, randomized trial, we assigned, in a 4:4:1:1 ratio, participants with relapsing multiple sclerosis to receive 1200 mg of frexalimab administered intravenously every 4 weeks (with an 1800-mg loading dose), 300 mg of frexalimab administered subcutaneously every 2 weeks (with a 600-mg loading dose), or the matching placebos for each active treatment. The primary end point was the number of new gadolinium-enhancing T1-weighted lesions seen on magnetic resonance imaging at week 12 relative to week 8. Secondary end points included the number of new or enlarging T2-weighted lesions at week 12 relative to week 8, the total number of gadolinium-enhancing T1-weighted lesions at week 12, and safety. After 12 weeks, all the participants could receive open-label frexalimab.
RESULTS
Of 166 participants screened, 129 were assigned to a trial group; 125 participants (97%) completed the 12-week double-blind period. The mean age of the participants was 36.6 years, 66% were women, and 30% had gadolinium-enhancing lesions at baseline. At week 12, the adjusted mean number of new gadolinium-enhancing T1-weighted lesions was 0.2 (95% confidence interval [CI], 0.1 to 0.4) in the group that received 1200 mg of frexalimab intravenously and 0.3 (95% CI, 0.1 to 0.6) in the group that received 300 mg of frexalimab subcutaneously, as compared with 1.4 (95% CI, 0.6 to 3.0) in the pooled placebo group. The rate ratios as compared with placebo were 0.11 (95% CI, 0.03 to 0.38) in the 1200-mg group and 0.21 (95% CI, 0.08 to 0.56) in the 300-mg group. Results for the secondary imaging end points were generally in the same direction as those for the primary analysis. The most common adverse events were coronavirus disease 2019 and headaches.
CONCLUSIONS
In a phase 2 trial involving participants with multiple sclerosis, inhibition of CD40L with frexalimab had an effect that generally favored a greater reduction in the number of new gadolinium-enhancing T1-weighted lesions at week 12 as compared with placebo. Larger and longer trials are needed to determine the long-term efficacy and safety of frexalimab in persons with multiple sclerosis. (Funded by Sanofi; ClinicalTrials.gov number, NCT04879628.).
Topics: Adult; Female; Humans; Male; CD40 Ligand; Double-Blind Method; Gadolinium; Magnetic Resonance Imaging; Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Antibodies, Monoclonal; CD40 Antigens; Administration, Intravenous; Injections, Subcutaneous
PubMed: 38354138
DOI: 10.1056/NEJMoa2309439 -
Advanced Drug Delivery Reviews Feb 2024The advent of numerous treatment modalities with desirable therapeutic efficacy has been made possible by the fast development of nanomedicine and materdicine, among... (Review)
Review
The advent of numerous treatment modalities with desirable therapeutic efficacy has been made possible by the fast development of nanomedicine and materdicine, among which the ultrasound (US)-triggered sonocatalytic process as minimal or non-invasive method has been frequently employed for diagnostic and therapeutic purposes. In comparison to phototherapeutic approaches with inherent penetration depth limitations, sonocatalytic therapy shatters the depth limit of photoactivation and offers numerous remarkable prospects and advantages, including mitigated side effects and appropriate tissue-penetration depth. Nevertheless, the optimization of sonosensitizers and therapies remains a significant issue in terms of precision, intelligence and efficiency. In light of the fact that nanomedicine and materdicine can effectively enhance the theranostic efficiency, we herein aim to furnish a cutting-edge review on the latest progress and development of nanomedicine/materdicine-enabled sonocatalytic therapy. The design methodologies and biological features of nanomedicine/materdicine-based sonosensitizers are initially introduced to reveal the underlying relationship between composition/structure, sonocatalytic function and biological effect, in accompany with a thorough discussion of nanomedicine/materdicine-enabled synergistic therapy. Ultimately, the facing challenges and future perspectives of this intriguing sonocatalytic therapy are highlighted and outlined to promote technological advancements and clinical translation in efficient disease treatment.
Topics: Humans; Nanomedicine; Ultrasonography; Ultrasonic Therapy; Precision Medicine; Neoplasms; Theranostic Nanomedicine
PubMed: 38110153
DOI: 10.1016/j.addr.2023.115160 -
Journal of Nanobiotechnology May 2024Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via... (Review)
Review
Different from most of the conventional platforms with dissatisfactory theranostic capabilities, supramolecular nanotheranostic systems have unparalleled advantages via the artful combination of supramolecular chemistry and nanotechnology. Benefiting from the tunable stimuli-responsiveness and compatible hierarchical organization, host-guest interactions have developed into the most popular mainstay for constructing supramolecular nanoplatforms. Characterized by the strong and diverse complexation property, cucurbit[8]uril (CB[8]) shows great potential as important building blocks for supramolecular theranostic systems. In this review, we summarize the recent progress of CB[8]-based supramolecular theranostics regarding the design, manufacture and theranostic mechanism. Meanwhile, the current limitations and corresponding reasonable solutions as well as the potential future development are also discussed.
Topics: Theranostic Nanomedicine; Bridged-Ring Compounds; Imidazoles; Humans; Animals; Nanoparticles; Heterocyclic Compounds, 2-Ring; Macrocyclic Compounds; Imidazolidines
PubMed: 38725031
DOI: 10.1186/s12951-024-02349-z -
Journal of Materials Chemistry. B Jul 2023Cancer is a mortal disease that can invade other parts of the body and cause severe complications. Despite their continuous progress, conventional cancer therapies... (Review)
Review
Cancer is a mortal disease that can invade other parts of the body and cause severe complications. Despite their continuous progress, conventional cancer therapies including surgery, chemotherapy, and radiation therapy have their inherent limitations. To improve the precision of cancer treatment, maximize the therapeutic effect and minimize mortality, synergistic therapies combining imaging guiding technologies, phototherapy, and other therapies have emerged due to the mutually strengthening therapeutic efficacy. However, traditional organic phototherapeutic agents are limited since their aggregation in aqueous media usually affects both their luminescence behavior and therapeutic effect. In contrast, aggregate-induced emission luminogens (AIEgens) provide an ideal solution to develop phototherapy with bright fluorescence and a significant treatment effect in the aggregate state. Combining AIE-based phototherapy and conventional therapies benefits from synergistic effects and extends the potential of developing accurate cancer therapy. AIE-based synergistic therapy has been popularly discussed with such unexplored potential in recent years. This review will introduce the most recent progress of AIE-based synergistic cancer therapy.
Topics: Humans; Luminescence; Fluorescence; Theranostic Nanomedicine; Neoplasms; Phototherapy
PubMed: 37272910
DOI: 10.1039/d3tb00219e -
Nature Reviews. Rheumatology Oct 2023Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without... (Review)
Review
Osteoarthritis (OA) is the most common form of arthritis worldwide, affecting ~500 million people, yet there are no effective treatments to halt its progression. Without any structure-modifying agents, management of OA focuses on ameliorating pain and improving function. Treatment approaches typically have modest efficacy, and many patients have contraindications to recommended pharmacological treatments. Drug development for OA is hindered by the gradual and progressive nature of the disease and the targeting of established disease in clinical trials. Additionally, new medications for OA cannot receive regulatory approval without demonstrating improvements in both structure (pathological features of OA) and symptoms (reduced pain and/or improved function). In clinical trials, people with OA show high 'placebo responses', which hamper the ability to identify new effective treatments. Placebo responses refer to the individual variability in response to placebos given in the context of clinical trials and other settings. Placebo effects refer specifically to short-lasting improvements in symptoms that occur because of physiological changes. To mitigate the effects of the placebo phenomenon, we must first understand what it is, how it manifests, how to identify placebo responders in OA trials and how these insights can be used to improve clinical trials in OA. Leveraging placebo responses and effects in clinical practice might provide additional avenues to augment symptom management of OA.
Topics: Humans; Osteoarthritis, Knee; Placebo Effect; Pain; Treatment Outcome; Drug Development
PubMed: 37697077
DOI: 10.1038/s41584-023-01021-4 -
Chemical Reviews Mar 2024The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an... (Review)
Review
The ability to gain spatiotemporal information, and in some cases achieve spatiotemporal control, in the context of drug delivery makes theranostic fluorescent probes an attractive and intensely investigated research topic. This interest is reflected in the steep rise in publications on the topic that have appeared over the past decade. Theranostic fluorescent probes, in their various incarnations, generally comprise a fluorophore linked to a masked drug, in which the drug is released as the result of certain stimuli, with both intrinsic and extrinsic stimuli being reported. This release is then signaled by the emergence of a fluorescent signal. Importantly, the use of appropriate fluorophores has enabled not only this emerging fluorescence as a spatiotemporal marker for drug delivery but also has provided modalities useful in photodynamic, photothermal, and sonodynamic therapeutic applications. In this review we highlight recent work on theranostic fluorescent probes with a particular focus on probes that are activated in tumor microenvironments. We also summarize efforts to develop probes for other applications, such as neurodegenerative diseases and antibacterials. This review celebrates the diversity of designs reported to date, from discrete small-molecule systems to nanomaterials. Our aim is to provide insights into the potential clinical impact of this still-emerging research direction.
Topics: Fluorescent Dyes; Precision Medicine; Cell Line, Tumor; Drug Delivery Systems; Fluorescence; Theranostic Nanomedicine
PubMed: 38422393
DOI: 10.1021/acs.chemrev.3c00778