Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes

Aims  To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). Methods and results  In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4–11%). Conclusions  Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable

Stimulation sous-thalamique dans la maladie de Parkinson sévère: Étude de la localisation des contacts effectifs

International audienceThe subthalamic nucleus (STN) is the main target of deep brain stimulation (DBS) treatment for severe idiopathic Parkinson's disease. But there is still no clear information on the location of the effective contacts (used during the chronic phase of stimulation). Our aim was to assess the anatomical structures of the subthalamic area (STA) involved during chronic DBS. Ten patients successfully treated were included. The surgical procedure was based on direct STN targeting (stereotactic MRI based) pondered by the acute effects of intraoperative stimulation. We used a formaldehyde-fixed human specimen to compare by matching MRI images obtained at 1.5 Tesla (performed in clinical stereotactic conditions) and at very high field at 4.7 Tesla. This allowed accurate analysis of the anatomy of the STA and retrospective precision of the location of the center of effective contacts which were located within the STN in 4 patients, at the interface between the STN and the ZI and/or FF in 13, at the interface between ZI and FF in 2 and between the STN and the substantia nigra in one. These results were consistent with the literature, revealing the implication of neighboring structures, especially the zona incerta and Forel's Field, in the clinical benefit.Le noyau sous-thalamique (NST) s’est imposé comme la cible de choix de la stimulation cérébrale profonde (SCP) dans la maladie de Parkinson idiopathique sévère. Toutefois, la position des contacts utilisés lors de la stimulation chronique (contacts effectifs) reste mal connue. Notre but était de préciser, au sein de la région sous-thalamique (RST), la topographie des contacts effectifs. Pour cela, nous avons réalisé en préalable un travail sur spécimen anatomique, par mise en correspondance d’images IRM à 1,5 Tesla (en conditions cliniques) et à très haut champ à 4,7 Tesla, explorant la RST. Nous avons ensuite étudié une série de 10 patients traités par DBS bilatérale avec un bon résultat clinique. L’implantation avait été réalisée en visée directe (repérage direct du STN sur IRM stéréotaxique) pondérée en fonction des effets de la stimulation aiguë per-opératoire. Nous avons revu a posteriori, en s’aidant de l’anatomie IRM très haut champ, la position du centre des contacts effectifs. Si certains contacts étaient placés à l’intérieur du NST (4 fois), la plupart se trouvaient à l’interface de ce dernier et de la zona incerta et/ou des champs de Forel (13 fois), à l’interface zona incerta et champs de Forel (2 fois) et à l’interface NST substance noire (1 fois). Ces résultats sont en accord avec la littérature. L’implication des structures voisines du NST dans le bénéfice clinique, en particulier la zona incerta et le champ de Forel, semble donc probable

Nuclear oxysterol receptors, LXRs, are involved in the maintenance of mouse caput epididymidis structure and functions

International audienc