6 research outputs found

    Perception de l'information orale et Ă©crite par 50 volontaires sains d'une Ă©tude monocentrique

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    Le but de notre enquĂȘte auprĂšs de 50 volontaires sains d'une Ă©tude monocentrique Ă©tait d'Ă©valuer, Ă  partir d'un questionnaire rempli par les participants, la comprĂ©hension, l'apprĂ©ciation de l'information orale et Ă©crite et du cadre lĂ©gal des essais, ainsi que l'hĂ©sitation Ă  participer en fonction de l'Ăąge, du sexe et de la profession. Une satisfaction globale a Ă©tĂ© recueillie sur la comprĂ©hension et l'information orale mais 42 % des participants ont trouvĂ© le consentement Ă©crit trop long et un quart d'entre eux ne l'ont pas lu entiĂšrement. La connaissance du cadre lĂ©gal (20 %) n'influençait pas la comprĂ©hension ni l'hĂ©sitation. Les hĂ©sitants (26 %) ont plus souvent jugĂ© ce cadre rassurant que les non hĂ©sitants (77 % versus 38 %; p=0,015\rm {p} = 0,015). C'Ă©tait le cas des femmes, des professions mĂ©dicales ou paramĂ©dicales et des plus jeunes (≀ 35 ans). Il serait intĂ©ressant d'Ă©tudier chez les personnes ne donnant pas leur consentement, les raisons du refus et l'impact du cadre lĂ©gal et Ă©thique des Ă©tudes cliniques, pour amĂ©liorer le partenariat des patients dans un contexte de mĂ©decine factuelle

    A phase I trial assessing the safety, pharmacokinetics, cerebrospinal fluid penetrance, and food effect of BTK inhibitor tolebrutinib in healthy volunteers

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    Abstract Tolebrutinib is an oral, brain‐penetrant, covalent Bruton's tyrosine kinase inhibitor in development to treat multiple sclerosis at 60 mg/day with food. A phase I trial was conducted in healthy volunteers to assess the safety and pharmacokinetics of tolebrutinib at oral doses higher than 60 mg with food and during fasting, and to determine cerebrospinal fluid (CSF) exposure after a single dose of 60 or 120 mg with food. The trial included double‐blind, placebo‐controlled single ascending dose (120, 240, and 300 mg; fed and fasted) and multiple ascending dose (120, 180, and 240 mg) arms. Additional open‐label cohorts received a single 60 mg dose with a high‐fat meal and during fasting using a crossover design or a single 60 or 120 mg dose with food and lumbar puncture to obtain CSF. Tolebrutinib was rapidly absorbed and converted to an active metabolite (designated “M2”), both of which had a terminal half‐life of ~5 h. Tolebrutinib and M2 exposures increased following administration with food versus fasting, and plasma levels were generally dose proportional. For up to 4 h (the last measurement timepoint) after a 60 mg dose, CSF concentrations of tolebrutinib exceeded its in vitro cellular potency (half‐maximal inhibitory concentration [IC50]) for microglia, and tolebrutinib and M2 surpassed their biochemical IC50. Tolebrutinib was well‐tolerated, and treatment‐emergent adverse events were generally mild. Concentration‐QTc modeling showed no effects on QT/QTc intervals for any tolebrutinib dose or fed status. In conclusion, tolebrutinib has an acceptable safety profile at supratherapeutic doses and achieved bioactive CSF exposures at the phase III dose

    Safety, pharmacokinetics, and target engagement of a brain penetrant RIPK1 inhibitor, SAR443820 (DNL788), in healthy adult participants

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    Abstract SAR443820 (DNL788) is a selective, orally bioavailable, brain penetrant inhibitor of receptor‐interacting serine/threonine protein kinase 1 (RIPK1). This phase I first‐in‐human healthy participant study (NCT05795907) was comprised of three parts: randomized, double‐blind, placebo‐controlled single ascending dose (SAD; part 1a); 14‐day multiple ascending dose (MAD; part 2) parts that evaluated safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of SAR443820; and a separate open‐label, single‐dose part 1b (PK‐cerebrospinal fluid [CSF]) to assess SAR443820 levels in CSF. SAR443820 was well‐tolerated in healthy participants, and no treatment discontinuation related to an adverse event (AE) occurred. Most common AEs were dizziness and headache. No clinically meaningful changes were noted in laboratory values, vital signs, or electrocardiogram parameters. SAR443820 had a favorable PK profile, with plasma half‐lives (geometric mean) ranged between 5.7–8.0 h and 7.2–8.9 h after single and repeated doses, respectively. There were no major deviations from dose proportionality for maximum concentration and area under the curve across SAR443820 doses. Mean CSF‐to‐unbound plasma concentration ratio ranged from 0.8 to 1.3 over time (assessed up to 10 h postdose), indicating high brain penetrance. High levels of inhibition of activated RIPK1, as measured by decrease in pS166‐RIPK1, were achieved in both SAD and MAD parts, with a maximum median inhibition from baseline close to 90% at predose (Ctrough) after multiple dosing in MAD, reflecting a marked RIPK1 target engagement at the peripheral level. These results support further development of SAR443820 in phase II trials in amyotrophic lateral sclerosis (NCT05237284) and multiple sclerosis (NCT05630547)

    Peripheral pain mechanisms in osteoarthritis

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    There is a well-established historical observation that structural joint damage by plain X-ray correlates poorly with symptomatic disease in osteoarthritis (OA). This is often attributed to the inability to visualise soft-tissue pathology within the joint and the recognition of heterogeneous patient factors that drive central pain sensitisation. A major issue is the relative paucity of mechanistic studies in which molecular pathogenesis of pain is interrogated in relation to tissue pathology. Nonetheless, in recent years, three broad approaches have been deployed to attempt to address this: correlative clinical studies of peripheral and central pain outcomes using magnetic resonance imaging, where soft-tissue processes can be visualised; molecular studies on tissue from patients with OA; and careful molecular interrogation of preclinical models of OA across the disease time course. Studies have taken advantage of established clinical molecular targets such as nerve growth factor. Not only is the regulation of nerve growth factor within the joint being used to explore the relationship between tissue pathology and the origins of pain in OA, but it also provides a core model on which other molecules present within the joint can modulate the pain response. In this narrative review, how molecular and pathological tissue change relates to joint pain in OA will be discussed. Finally, a model for how tissue damage may lead to pain over the disease course will be proposed
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