Ponesimod is an orally active selective sphingosine-1-phosphate receptor 1 modulator under investigation for the treatment of multiple sclerosis. This was a single-centre, double-blind, randomized, placebo- and positive-controlled parallel-group study investigating the effects of ponesimod on the QTc interval in healthy individuals. A nested cross-over comparison between moxifloxacin and placebo was included in the combined moxifloxacin/placebo treatment group. Subjects in group A received multiple doses of 10-100 mg ponesimod according to an uptitration regimen on days 2-23 and moxifloxacin-matching placebo on days 1 and 24. Subjects in group B received ponesimod-matching placebo on days 2-23 and were randomized to receive either a single dose of 400 mg moxifloxacin or matching placebo on days 1 and 24. The primary end-point was the baseline-adjusted, placebo-corrected effect on the individually corrected QT interval (QTcI) on days 12 (after 5 days of 40 mg ponesimod) and 23 (after 5 days of 100 mg ponesimod). Ponesimod caused a mild QTcI prolongation with a largest effect of 6.9 ms (90% two-sided confidence interval (CI): 2.5-11.3) and 9.1 ms (90% CI: 4.1-14.0) for doses of 40 mg and 100 mg, respectively. A concentration-effect analysis confirmed the QTcI-prolonging effect of ponesimod with a shallow slope of 0.0053 ms per ng/mL. Using the concentration-effect analysis, the QTc prolongation caused by 20 mg ponesimod and the current highest therapeutic dose was predicted to be below the level of clinical concern (i.e. an upper bound of the two-sided 90% CI of ≥10 ms).
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http://dx.doi.org/10.1111/bcpt.12336 | DOI Listing |
Clin Transl Sci
January 2025
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Despite the widespread use of currently available serum phosphate management options, elevated serum phosphate is common in patients with end-stage kidney disease on dialysis. Characteristics of currently available phosphate binders that lead to poor patient experiences such as large drug volume size of required daily medication (e.g.
View Article and Find Full Text PDFJ Appl Physiol (1985)
December 2024
Integrative Laboratory of Applied Physiology & Lifestyle Medicine, Department of Health and Human Physiology, University of Iowa, Iowa City, IA, USA.
We examined the effect of habitual pre-exercise caffeine supplementation on training-induced adaptations to exercising systolic (SBP), diastolic (DBP), pulse pressure (PP), heart rate (HR), and double product (DP). Young women (mean±SD; 24±7 y) were randomized to a caffeine (120 mg) supplement (CAF; n=17) or placebo (PLA; n=16) group, completed 6-weeks of high intensity exercise training on three non-consecutive days per week, and supplemented with CAF or PLA 30-60 minutes before exercise or else upon waking. Before (PRE) and after (POST) the intervention, SBP, DBP, and HR were measured, and PP and DP calculated, at rest and during fixed-power exercise at 50W and 75W.
View Article and Find Full Text PDFCardiol Rev
October 2024
From the School of Medicine, New York Medical College, Valhalla, NY.
The prevalence of individuals with overweight and obesity has increased by 18% since 1990 and it is projected that by 2030, nearly 50% of US adults will have obesity. Lifestyle modifications, such as diet and exercise, typically lead to approximately 3-5% weight loss, whereas 5-15% weight loss is necessary to significantly impact obesity-associated comorbidities and improve overall health outcomes. In addition to lifestyle modifications, pharmacotherapy has been utilized as an adjunctive treatment to increase weight loss and improve health outcomes.
View Article and Find Full Text PDFNeurosurg Rev
December 2024
Trauma Research Center, Shahid Rajaee (Emtiaz) Trauma Hospital, Chamran Blvd, Shiraz, 7194815711, Iran.
Background: Traumatic Brain Injury (TBI) is a leading cause of hospitalization and disability in young and middle-aged adults. This study aims to survey the efficacy of oral modafinil, a low-side-effect central nervous system stimulant, in the enhancement of consciousness recovery in moderate to severe TBI patients in the ICUs of a referral trauma center.
Materials And Methods: All ICU patients meeting inclusion criteria between April 2021 and April 2023 were screened.
Psychopharmacology (Berl)
December 2024
Department of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, P.O. Box 616, Maastricht, 6200 MD, The Netherlands.
Rationale: Despite the growing scientific interest on mitragynine, the primary alkaloid in kratom (Mitragyna Speciosa), there is a lack of clinical trials in humans.
Objectives: This phase 1 study aimed to evaluate mitragynine's safety profile and acute effects on subjective drug experience, neurocognition, and pain tolerance.
Methods: A placebo-controlled, single-blind, within-subjects study was conducted in two parts.
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