59 research outputs found
Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials
Get PDFAIMS/HYPOTHESIS: Delayed-release metformin (Metformin DR) was developed to maximise gut-based mechanisms of metformin action by targeting the drug to the ileum. Metformin DR was evaluated in two studies. Study 1 compared the bioavailability and effects on circulating glucose and gut hormones (glucagon-like peptide-1, peptide YY) of Metformin DR dosed twice-daily to twice-daily immediate-release metformin (Metformin IR). Study 2 compared the bioavailability and glycaemic effects of Metformin DR dosages of 1,000Â mg once-daily in the morning, 1,000Â mg once-daily in the evening, and 500Â mg twice-daily.
METHODS: Study 1 was a blinded, randomised, crossover study (three × 5 day treatment periods) of twice-daily 500 mg or 1,000 mg Metformin DR vs twice-daily 1,000 mg Metformin IR in 24 participants with type 2 diabetes conducted at two study sites (Celerion Inc.; Tempe, AZ, and Lincoln, NE, USA). Plasma glucose and gut hormones were assessed over 10.25 h at the start and end of each treatment period; plasma metformin was measured over 11 h at the end of each treatment period. Study 2 was a non-blinded, randomised, crossover study (three × 7 day treatment periods) of 1,000 mg Metformin DR once-daily in the morning, 1,000 mg Metformin DR once-daily in the evening, or 500 mg Metformin DR twice-daily in 26 participants with type 2 diabetes performed at a single study site (Celerion, Tempe, AZ). Plasma glucose was assessed over 24 h at the start and end of each treatment period, and plasma metformin was measured over 30 h at the end of each treatment period. Both studies implemented centrally generated computer-based randomisation using a 1:1:1 allocation ratio.
RESULTS: A total of 24 randomised participants were included in study 1; of these, 19 completed the study and were included in the evaluable population. In the evaluable population, all treatments produced similar significant reductions in fasting glucose (median reduction range, -0.67 to -0.81 mmol/l across treatments) and postprandial glucose (Day 5 to baseline AUC0-t ratio = 0.9 for all three treatments) and increases in gut hormones (Day 5 to baseline AUC0-t ratio range: 1.6-1.9 for GLP-1 and 1.4-1.5 for PYY) despite an almost 60% reduction in systemic metformin exposure for 500 mg Metformin DR compared with Metformin IR. A total of 26 randomised participants were included in study 2: 24 had at least one dose of study medication and at least one post-dose pharmacokinetic/pharmacodynamic assessment and were included in the pharmacokinetic/pharmacodynamic intent-to-treat analysis; and 12 completed all treatment periods and were included in the evaluable population. In the evaluable population, Metformin DR administered once-daily in the morning had 28% (90% CI -16%, -39%) lower bioavailability (least squares mean ratio of metformin AUC0-24) compared with either once-daily in the evening or twice-daily, although the glucose-lowering effects were maintained. In both studies, adverse events were primarily gastrointestinal in nature, and indicated similar or improved tolerability for Metformin DR vs Metformin IR; there were no clinically meaningful differences in vital signs, physical examinations or laboratory values.
CONCLUSIONS/INTERPRETATION: Dissociation of gut hormone release and glucose lowering from plasma metformin exposure provides strong supportive evidence for a distal small intestine-mediated mechanism of action. Directly targeting the ileum with Metformin DR once-daily in the morning may provide maximal metformin efficacy with lower doses and substantially reduce plasma exposure. Metformin DR may minimise the risk of lactic acidosis in those at increased risk from metformin therapy, such as individuals with renal impairment.
TRIAL REGISTRATION: Clinicaltrials.gov NCT01677299, NCT01804842 FUNDING: : This study was funded by Elcelyx Therapeutics Inc
Impact of the COVID-19 pandemic on the implementation of mobile health to improve the uptake of hydroxyurea in patients with sickle cell disease: Mixed methods study
Get PDFBACKGROUND: Hydroxyurea therapy is effective for reducing complications related to sickle cell disease (SCD) and is recommended by National Health Lung and Blood Institute care guidelines. However, hydroxyurea is underutilized, and adherence is suboptimal. We wanted to test a multilevel mobile health (mHealth) intervention to increase hydroxyurea adherence among patients and improve prescribing among providers in a multicenter clinical trial. In the first 2 study sites, participants were exposed to the early phases of the COVID-19 pandemic, which included disruption to their regular SCD care.
OBJECTIVE: We aimed to describe the impact of the COVID-19 pandemic on the implementation of an mHealth behavioral intervention for improving hydroxyurea adherence among patients with SCD.
METHODS: The first 2 sites initiated enrollment 3 months prior to the start of the pandemic (November 2019 to March 2020). During implementation, site A clinics shut down for 2 months and site B clinics shut down for 9 months. We used the reach, effectiveness, adoption, implementation, and maintenance (RE-AIM) framework to evaluate the implementation and effectiveness of the intervention. mHealth implementation was assessed based on patients\u27 daily app use. Adherence to hydroxyurea was calculated as the proportion of days covered (PDC) from prescription records over the first 12 and 24 weeks after implementation. A linear model examined the relationship between app usage and PDC change, adjusting for baseline PDC, lockdown duration, and site. We conducted semistructured interviews with patients, health care providers, administrators, and research staff to identify factors associated with mHealth implementation and effectiveness. We used a mixed methods approach to investigate the convergence of qualitative and quantitative findings.
RESULTS: The percentage of patients accessing the app decreased after March 15, 2020 from 86% (n=55) to 70% (n=45). The overall mean PDC increase from baseline to week 12 was 4.5% (P=.32) and to week 24 was 1.5% (P=.70). The mean PDC change was greater at site A (12 weeks: 20.9%; P=.003; 24 weeks: 16.7%; P=.01) than site B (12 weeks: -8.2%; P=.14; 24 weeks: -10.3%; P=.02). After adjustment, PDC change was 13.8% greater in those with increased app use after March 15, 2020. Interview findings indicated that site B\u27s closure during COVID-19 had a greater impact, but almost all patients reported that the InCharge Health app helped support more consistent medication use.
CONCLUSIONS: We found significant impacts of the early clinic lockdowns, which reduced implementation of the mHealth intervention and led to reduced patient adherence to hydroxyurea. However, disruptions were lower among participants who experienced shorter clinic lockdowns and were associated with higher hydroxyurea adherence. Investigation of added strategies to mitigate the effects of care interruptions during major emergencies (eg, patient coaching and health navigation) may insulate the implementation of interventions to increase medication adherence.
TRIAL REGISTRATION: ClinicalTrials.gov NCT04080167; https://clinicaltrials.gov/ct2/show/NCT04080167.
INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/16319
Advanced Glycation End Product Interventions Reduce Diabetes-Accelerated Atherosclerosis
Get PDFAdvanced glycation end product (AGE) formation may contribute to the progression of atherosclerosis, particularly in diabetes. The present study explored atherosclerosis in streptozotocin-induced diabetic apolipoprotein E–deficient (apoE�/�) mice that were randomized (n � 20) to receive for 20 weeks no treatment, the AGE cross-link breaker ALT-711, or the inhibitor of AGE formation aminoguanidine (AG). A sixfold increase in plaque area with diabetes was attenuated by 30 % with ALT-711 and by 40 % in AG-treated mice. Regional distribution of plaque demonstrated no reduction in plaque area or complexity within the aortic arch with treatment, in contrast to the thoracic and abdominal aortas, where significant attenuation was seen. Diabetes-associated accumulation of AGEs in aorta
Effects of Coleus Forskohlii Supplementation on Body Composition and Hematological Profiles in Mildly Overweight Women
Get PDF<p>Abstract</p> <p>Purpose</p> <p>This study investigated the effects of <it>Coleus Forskohlii </it>(CF) on body composition, and determined the safety and efficacy of supplementation.</p> <p>Methods</p> <p>In a double blind and randomized manner, 23 females supplemented their diet with ForsLean™ (250 mg of 10% CF extract, (n = 7) or a placebo [P] (n = 12) two times per day for 12-wks. Body composition (DEXA), body weight, and psychometric instruments were obtained at 0, 4, 8 & 12 weeks of supplementation. Fasting blood samples and dietary records (4-d) were obtained at 0 and 12-wks. Side effects were recorded on a weekly basis. Data were analyzed by repeated measures ANOVA and are presented as mean changes from baseline for the CF and placebo groups, respectively.</p> <p>Results</p> <p>No significant differences were observed in caloric or macronutrient intake. CF tended to mitigate gains in body mass (-0.7 ± 1.8, 1.0 ± 2.5 kg, p = 0.10) and scanned mass (-0.2 ± 1.3, 1.7 ± 2.9 kg, p = 0.08) with no significant differences in fat mass (-0.2 ± 0.7, 1.1 ± 2.3 kg, p = 0.16), fat free mass (-0.1 ± 1.3, 0.6 ± 1.2 kg, p = 0.21), or body fat (-0.2 ± 1.0, 0.4 ± 1.4%, p = 0.40). Subjects in the CF group tended to report less fatigue (p = 0.07), hunger (p = 0.02), and fullness (p = 0.04). No clinically significant interactions were seen in metabolic markers, blood lipids, muscle and liver enzymes, electrolytes, red cells, white cells, hormones (insulin, TSH, T3, and T4), heart rate, blood pressure, or weekly reports of side effects.</p> <p>Conclusion</p> <p>Results suggest that CF does not appear to promote weight loss but may help mitigate weight gain in overweight females with apparently no clinically significant side effects.</p
Catching Element Formation In The Act
Full text linkGamma-ray astronomy explores the most energetic photons in nature to address
some of the most pressing puzzles in contemporary astrophysics. It encompasses
a wide range of objects and phenomena: stars, supernovae, novae, neutron stars,
stellar-mass black holes, nucleosynthesis, the interstellar medium, cosmic rays
and relativistic-particle acceleration, and the evolution of galaxies. MeV
gamma-rays provide a unique probe of nuclear processes in astronomy, directly
measuring radioactive decay, nuclear de-excitation, and positron annihilation.
The substantial information carried by gamma-ray photons allows us to see
deeper into these objects, the bulk of the power is often emitted at gamma-ray
energies, and radioactivity provides a natural physical clock that adds unique
information. New science will be driven by time-domain population studies at
gamma-ray energies. This science is enabled by next-generation gamma-ray
instruments with one to two orders of magnitude better sensitivity, larger sky
coverage, and faster cadence than all previous gamma-ray instruments. This
transformative capability permits: (a) the accurate identification of the
gamma-ray emitting objects and correlations with observations taken at other
wavelengths and with other messengers; (b) construction of new gamma-ray maps
of the Milky Way and other nearby galaxies where extended regions are
distinguished from point sources; and (c) considerable serendipitous science of
scarce events -- nearby neutron star mergers, for example. Advances in
technology push the performance of new gamma-ray instruments to address a wide
set of astrophysical questions.Comment: 14 pages including 3 figure
Surface-Anchored Monomeric Agonist pMHCs Alone Trigger TCR with High Sensitivity
Get PDFAt the interface between T cell and antigen-presenting cell (APC), peptide antigen presented by MHC (pMHC) binds to the T cell receptor (TCR) and initiates signaling. The mechanism of TCR signal initiation, or triggering, remains unclear. An interesting aspect of this puzzle is that although soluble agonist pMHCs cannot trigger TCR even at high concentrations, the same ligands trigger TCR very efficiently on the surface of APCs. Here, using lipid bilayers or plastic-based artificial APCs with defined components, we identify the critical APC-associated factors that confer agonist pMHCs with such potency. We found that CD4+ T cells are triggered by very low numbers of monomeric agonist pMHCs anchored on fluid lipid bilayers or fixed plastic surfaces, in the absence of any other APC surface molecules. Importantly, on bilayers, plastic surfaces, or real APCs, endogenous pMHCs did not enhance TCR triggering. TCR triggering, however, critically depended upon the adhesiveness of the surface and an intact T cell actin cytoskeleton. Based on these observations, we propose the receptor deformation model of TCR triggering to explain the remarkable sensitivity and specificity of TCR triggering
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