A Phase IIb Randomized, Double-Blind, Placebo-Controlled, Group-Sequential, Multicenter, Dose Finding Study of the Safety and Efficacy of SUN N4057 (Piclozotan)Administered for 72 Hours by Continuous Intravenous Infusion in Subjects with Acute Ischemic Stroke and Measurable Penumbra on MRI.
A Phase IIb Randomized, Double-blind, Placebo-Controlled, Group-Sequential, Multicenter, Dose Finding Study of the Safety and Efficacy of SUN N4057 (Piclozotan) Administered for 72 Hours by Continuous Intravenous Infusion in Subjects With Acute Ischemic Stroke and Measurable Penumbra on MRI
This research study is designed to evaluate the safety, tolerability, and efficacy of SUN N4057 (piclozotan) in subjects with acute ischemic stroke within 9 hours of the onset of symptoms.
Serotonin 1A receptor agonists have attracted much interest recently as potential therapeutic agents for levodopa-induced motor complications, such as dyskinesia and motor fluctuations. The effects of piclozotan (SUN N4057) on a rat model of advanced Parkinson's disease were investigated. Parkinsonian rats, unilaterally 6-hydroxydopamine-lesioned rats, were administered levodopa for 8 to 9 weeks. Based on the results of rotational behavior and forelimb hyperkinesia in Week 5, the rats were allocated to three treatment groups (saline and two dosing rates of piclozotan set at 0.018 and 0.036 mg/kg/h). Piclozotan was administered via continuous subcutaneous infusion using an osmotic pump for 3 to 4 weeks. At Week 7 of repeated levodopa dosing, the effects of piclozotan on levodopa-induced behavior were evaluated. In addition, extracellular levels of levodopa-derived dopamine in the striatum were measured using microdialysis in Weeks 8 to 9 after completion of the respective behavioral studies. Chronic treatment with levodopa-induced forelimb hyperkinesia and shortened the duration of rotational behavior. Piclozotan (0.018 and 0.036 mg/kg/h, plasma concentrations 5.3±0.7 and 14.3±2.9 ng/ml) reduced levodopa-induced forelimb hyperkinesia by 55% and 69%, respectively, at 1h relative to the control. Piclozotan (0.036 mg/kg/h) significantly lengthened the duration of rotational behavior by 26% versus the control and attenuated the increase in striatal levodopa-derived extracellular dopamine levels. These findings suggest that piclozotan, a serotonin 1A agonist, can improve motor complications in patients with advanced Parkinson's disease.
A new series of 1,4-benzoxazepine derivatives was designed, synthesized, and evaluated for binding to 5-HT1A receptor and cerebral anti-ischemic effect. A lot of compounds exhibited nanomolar affinity for 5-HT1A receptor with good selectivity over both dopamine D2 and alpha1-adrenergic receptors. Among these compounds, 3-chloro-4-[4-[4-(2-pyridinyl)-1,2,3,6-tetrahydropyridin-1-yl]butyl]-1, 4-benzoxazepin-5(4H)-one (50: SUN N4057 (Piclozotan) as 2HCl salt) showed remarkable neuroprotective activity in a transient middle cerebral artery occlusion (t-MCAO) model.
Other Neuroprotective Therapies on Trial in Acute Stroke
3区 · 医学
作者: Ferro, Jose M. ; Davalos, Antoni
New neuroprotective agents on trial may potentially offer benefit to stroke patients without the associated hemorrhagic risk of thrombolytic therapy. Clinical investigation of these drugs has been designed to obtain the highest probability of success, or concentrates on the salvageable ischemic brain and use infarct growth on MRI as a surrogate end-point. Nine substances in 10 trials are currently being tested in three therapeutical strategies in patients with acute ischemic stroke. These strategies focus on: (1) the optimal management of serum glucose with the infusion of glucose, insulin and potassium to induce and maintain euglycemia; (2) the modulation of the inflammatory response with recombinant human interferon-beta(1a), and (3) interfering with the ischemic cascade using magnesium, albumin, the metal iron chelator DP-b99, the AMPA receptor antagonist zonampanel, the serotonin agonists repinotan and piclozotan, the free radical scavenger cerovive, and the membrane modulator citicoline. Future directions should develop neuroprotective compounds that are safe and well tolerated, are effective in a broad range of patients and can be used with or without rt-PA.