Muir K W, Grosset D G, Lees K R
University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland.
Clin Neuropharmacol. 1997 Aug;20(4):311-21. doi: 10.1097/00002826-199708000-00003.
Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
离子通道阻断药物盐酸阿替加奈（CNS 1102，Cerestat）对N-甲基-D-天冬氨酸（NMDA）受体的阻断在局灶性脑缺血中具有神经保护作用。健康男性志愿者对高达30微克/千克的短时间静脉输注耐受性良好。我们对20名男性志愿者进行了一项随机、双盲、安慰剂对照研究，以检验一种与治疗用途设想相似的给药方案的安全性、耐受性以及对心血管和精神运动的影响。盐酸阿替加奈在4小时内输注，总剂量为15、32、50或73微克/千克。平均动脉压随剂量组显著升高（协方差分析，p<0.01）。运动反应时间与最大血浆浓度相关（r2 = 0.21，p<0.001）。在总剂量为32微克/千克时出现了周围感觉异常、头晕和欣快感的短暂症状和体征。更高剂量与运动迟缓、知觉障碍和幻觉（1例）有关。清除率为125±55升/小时，分布容积为537±1261。健康男性对4小时内输注高达32微克/千克的盐酸阿替加奈总剂量耐受性良好。盐酸阿替加奈会导致血压升高，并伴有与其他非竞争性NMDA拮抗剂相似的中枢神经系统症状和体征。
