Evaluating the effects of sugammadex on coagulation in humans: reversed translational research to unravel off-target pharmacology

Sugammadex (Bridion®, laboratory code Org 25969) encapsulates neuromuscular blocking agents rocuronium and vecuronium and reverses their pharmacological effect in the post-operative setting. During the development trajectory of this first selective relaxant binding agent, it was found that sugammadex has an effect on standard coagulation laboratory coagulation assays. However, this off-target effect was not further evaluated in clinical studies. This raised safety concerns by the European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) during their review of the application for marketing authorization for sugammadex.This thesis is comprised of a variety of in vitro, ex vivo and in vivo (clinical) pharmacology studies to provide more insight into the off-target effect of sugammadex on coagulation. The research involved the search for a mechanism, but also the clinical consequences on both primary and secondary hemostasis in clinical studies that included healthy volunteers. This evaluation was indispensable to overcome the bleeding safety concerns raised by both the EMA and the FDA.LUMC / Geneeskund

A randomized single and multiple ascending dose study in healthy volunteers of LTI-291, a centrally penetrant glucocerebrosidase activator

Aims A mutation in the GBA1 gene is the most common genetic risk factor for developing Parkinson's disease. GBA1 encodes the lysosomal enzyme glucosylceramidase beta (glucocerebrosidase, GCase) and mutations decrease enzyme activity. LTI-291 is an allosteric modulator of GCase, enhancing its activity. These first-in-human studies evaluated the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple ascending doses of LTI-291 in healthy volunteers.Methods In the single ascending dose (SAD) study, 40 healthy volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Single doses of 3, 10, 30 and 90 mg LTI-291 were investigated. In the multiple ascending dose (MAD) study, 40 healthy middle-aged or elderly volunteers were randomly assigned to LTI-291 (n = 8 per dose level) or placebo (n = 2 per dose level). Fourteen consecutive daily doses of 3, 10, 30 and 60 mg LTI-291 or placebo were administered. In both the SAD and MAD studies, glycosphingolipid levels were measured and a test battery of neurocognitive tasks was performed.Results LTI-291 was generally well tolerated and no deaths or treatment-related SAEs occurred and no subject withdrew from a study due to AEs. C-max, AUC(0-24) and AUC(0-inf) increased in a dose proportional manner. The median half-life was 28.0 hours after multiple dosing. No dose-dependent glycosphingolipid changes occurred. No neurocognitive adverse effects were detected.Conclusions These first-in-human studies demonstrated that LTI-291 was well tolerated when given orally once daily for 14 consecutive days. This supports the continued clinical development and the exploration of LTI-291 effects in a GBA1-mutated Parkinson population.Perioperative Medicine: Efficacy, Safety and Outcome (Anesthesiology/Intensive Care

Remodeling of the myocardium in early trabeculation and cardiac valve formation; a role for TGF beta 2

Cardiolog

Pharmacological interactions between brivaracetam and ethanol in healthy males

Stress-related psychiatric disorders across the life spa

Regional differences in WT-1 and Tcf21 expression during ventricular development: implications for myocardial compaction

Cardiolog

Safety and Immunogenicity of Intradermal Fractional Dose Administration of the mRNA-1273 Vaccine: A Proof-of-Concept Study

Clinical epidemiolog

Effective Treatment of Refractory CMV Reactivation After Allogeneic Stem Cell Transplantation With In Vitro-generated CMV pp65-specific CD8(+) T-cell Lines

Transplantation and immunomodulatio