Centre for Human Drug Research, Zernikedreef 10, Leiden, The Netherlands.
Br J Clin Pharmacol. 2013 Jun;75(6):1455-67. doi: 10.1111/bcp.12015.
To report the first three studies with SCH 900435, a selective glycine-1 re-uptake inhibitor in development for treating schizophrenia, using systematic evaluations of pharmacodynamics to understand the observed effects.
Three double-blind, placebo-controlled studies (single, visual effect and multiple dose) were performed. In the single and multiple dose study SCH 900435 (0.5-30 mg) was given to healthy males and frequent pharmacokinetic and pharmacodynamic measurements were performed. The visual effects study incorporated visual electrophysiological measures of macular, retinal and intracranial visual pathway function.
In the single dose study (highest difference, 95% CI, P) increases in smooth pursuit eye movements (8, 12 mg (-6.09, 10.14, -2.04, 0.013), 30 mg), pupil : iris ratio (20 and 30 mg (-0.065, 0.09, -0.04, <0.0001)), VAS colour perception (30 mg (-9.48, 13.05, -5.91, <0.0001)) and changes in spontaneous reports of visual disturbance were found, while FSH (8 mg (0.42, 0.18, 0.66, 0.0015), 12, 20 mg), LH (8-30 mg (1.35, 0.65, 2.05, 0.0003)) and EEG alpha2 activity decreased (12, 20, 30 mg (0.27, 0.14, 0.41, 0.0002)). A subsequent dedicated visual effects study demonstrated that visual effects were transient without underlying electrophysiological changes. This provided enough safety information for starting a multiple ascending dose study, showing less visual symptoms after twice daily dosing and titration, possibly due to tolerance.
Several central nervous system (CNS) effects and gonadotropic changes resulted from administration of 8 mg and higher, providing evidence for CNS penetration and pharmacological activity of SCH 900435. Antipsychotic activity in patients, specificity of the reported effects for this drug class and possible tolerance to visual symptoms remain to be established.
报告 SCH 900435 的前三项研究结果，SCH 900435 是一种选择性甘氨酸-1 再摄取抑制剂，用于治疗精神分裂症，采用系统的药效学评估来了解观察到的作用。
进行了三项双盲、安慰剂对照研究（单次、视觉效果和多次剂量）。在单次和多次剂量研究中，健康男性给予 SCH 900435（0.5-30mg），并进行频繁的药代动力学和药效学测量。视觉效果研究包括黄斑、视网膜和颅内视觉通路功能的视觉电生理测量。
在单次剂量研究中（最高差异，95%CI，P），发现平滑追踪眼球运动（8、12mg（-6.09、10.14、-2.04，0.013），30mg）、瞳孔：虹膜比（20 和 30mg（-0.065、0.09、-0.04，<0.0001））、VAS 颜色感知（30mg（-9.48、13.05、-5.91，<0.0001））和视觉障碍自发报告的变化，而 FSH（8mg（0.42、0.18、0.66、0.0015）、12、20mg）、LH（8-30mg（1.35、0.65、2.05、0.0003））和 EEGα2 活动减少（12、20、30mg（0.27、0.14、0.41、0.0002））。随后的专门视觉效果研究表明，视觉效果是短暂的，没有潜在的电生理变化。这为开始多次递增剂量研究提供了足够的安全性信息，表明每日两次给药和滴定后视觉症状较少，可能是由于耐受。
8mg 及以上剂量会导致几种中枢神经系统（CNS）效应和促性腺激素变化，这为 SCH 900435 穿透中枢神经系统和发挥药理学活性提供了证据。在患者中的抗精神病活性、所报告的此类药物作用的特异性以及对视觉症状的可能耐受仍有待确定。
