Efficacy and safety of Y- 2 sublingual tablet for patients with acute ischaemic stroke: protocol of a phase III randomised double- blind placebo- controlled multicentre trial

Background and purpose Clinical studies have demonstrated that edaravone dexborneol can improve the functional outcomes in patients with acute ischaemic stroke(AIS).The present clinical trial aimed at testing the efficacy and safety of Y-2 sublingual tablet on 90-day functional outcome in patients with AIS.Methods and design This is a randomised,double-blind,placebo-controlled,multicentre,parallel-group trial of Y-2 sublingual tablet on patients with AIS.An estimated 914 patients at age of 18–80 years with AIS within 48 hours after symptom onset from 40 hospitals will be randomly assigned to receive Y-2 sublingual tablet or placebo for 14 days.Patients are at score 6–20 points on National Institutes of Health Stroke Scale(NIHSS)and had a modified Rankin Scale(mRS)≤1 before this stroke,except mechanical thrombectomy and neuroprotective agents treatment.Study outcomes The primary outcome is the proportion of patients with mRS≤1 on day 90 after randomisation.Secondary efficacy outcomes include mRS score on day 90,the proportion of patients with mRS≤2 on day 90;the change of NIHSS score from baseline to day 14 and the proportion of patients with NIHSS score≤1 at the days 14,30 and 90.Discussion This trial will provide valuable evidence for the efficacy and safety of Y-2 sublingual table for improving 90 days the functional outcomes in patients with AIS.Trial registration number NCT04950920.

Preclinical evaluation of ZL006-05,a new antistroke drug with fast-onset antidepressant and anxiolytic effects

Background Poststroke depression and anxiety,independent predictor of poor functional outcomes,are common in the acute phase of stroke.Up to now,there is no fast-onset antidepressive and anxiolytic agents suitable for the management of acute stroke.ZL006-05,a dual-target analgesic we developed,dissociates nitric oxide synthase from postsynaptic density-95 while potentiatesα2-containingγ-aminobutyric acid type A receptor.This study aims to determine whether ZL006-05 can be used as an antistroke agent with fast-onset antidepressant and anxiolytic effects.Methods Photothrombotic stroke and transient middle cerebral artery occlusion were induced in rats and mice.Infarct size was measured by TTC(2,3,5-Triphenyltetrazolium chloride)staining or Nissl staining.Neurological defects were assessed by four-point scale neurological score or modified Neurological Severity Scores.Grid-walking,cylinder and modified adhesive removal tasks were conducted to assess sensorimotor functions.Spatial learning was assessed using Morris water maze task.Depression and anxiety were induced by unpredictable chronic mild stress.Depressive behaviours were assessed by tail suspension,forced swim and sucrose preference tests.Anxiety behaviours were assessed by novelty-suppressed feeding and elevated plus maze tests.Pharmacokinetics,toxicokinetics and long-term toxicity studies were performed in rats.Results Administration of ZL006-05 in the acute phase of stroke attenuated transient and permanent ischaemic injury and ameliorated long-term functional impairments significantly,with a treatment window of 12 hours after ischemia,and reduced plasminogen activato-induced haemorrhagic transformation.ZL006-05 produced fast-onset antidepressant and anxiolytic effects with onset latency of 1 hour in the normal and CMS mice,had antidepressant and anxiolytic effects in stroke mice.ZL006-05 crossed the blood-brain barrier and distributed into the brain rapidly,and had a high safety profile in toxicokinetics and long-term toxicological studies.Conclusion ZL006-05 is a new neuroprotectant with fast-onset antidepressant and anxiolytic effects and has translational properties in terms of efficacy,safety and targeting of clinical issues.