Hindmarch I, Johnson S, Meadows R, Kirkpatrick T, Shamsi Z
HPRU Medical Research Centre, University of Surrey, Guildford, UK.
Curr Med Res Opin. 2001;17(4):241-55. doi: 10.1185/0300799019117011.
To compare the central and peripheral H1 inhibitory effects of acute and sub-chronic doses of levocetirizine (L-CTZ), cetirizine (CTZ), loratadine (LOR) and promethazine (PRM) versus placebo, using a battery of psychomotor and cognitive tests together with measures of the weal and flare reaction. PRM was included in the study as a positive internal control to validate the sensitivity of the psychometric test battery to the CNS effects of the various treatments.
Twenty healthy volunteers (18-50 years) received L-CTZ 5mg, CTZ 10 mg, LOR 10 mg, PRM 30 mg and placebo once daily for four days in a five-way, double-blind, crossover study. For each treatment condition, subjects were assessed using a psychometric test system and a pinprick weal and flare response to 100 mg/ml histamine solution at baseline and at 1, 2, 3 ,4, 6, 8, 10 and 122 hours post-dose on days 1 and 4. The psychometrics comprised critical flicker fusion (CFF), choice reaction time (CRT), a continuous tracking task (CTT) and subjective rating scales for sedation (LARS). On days 2 and 3, subjects took their medication at pre-designated times while out of the unit.
The verum (PRM) established the sensitivity of the test battery: a significant overall reduction in CFF thresholds on both days 1 and 4 (p < 0.05); an overall significant increase (impairment) in recognition, motor and total reaction times on day 1 (p < 0.05); a significant impairment of both the tracking accuracy and reaction time aspects of the CTT task on day 1 (p < 0.005) and significantly higher ratings of subjective sedation on day 1 (p < 0.05). L-CTZ, CTZ and LOR were not distinguishable from placebo in any of the objective and subjective tests at any time point on either day 1 or day 4. With regards to the peripheral inhibitory effects, L-CTZ inhibited both the weal and flare reaction, with maximum inhibition (almost 100%) occurring within two hours of drug ingestion. CTZ also showed evidence of potent peripheral inhibition of histamine, whereas PRM, and especially LOR, showed only a weak weal and flare reaction which had completely attenuated at day 4.
In a study where the psychometric assessments were shown to be sensitive to impairment, L-CTZ 5 mg was found following both initial and repeated doses, but also to be demonstrably free from disruptive and sedative effects on objective measures of psychomotor and cognitive function. Similarly, CTZ showed evidence of pronounced antihistaminic activity and significantly reduced weal and flare scores after both acute and repeated doses, again without evidence of cognitive or psychomotor impairment. LOR also was non-sedative but the antihistaminic reaction was demonstrably weak.
通过一系列心理运动和认知测试以及风团和潮红反应测量，比较左旋西替利嗪（L-CTZ）、西替利嗪（CTZ）、氯雷他定（LOR）和异丙嗪（PRM）急性和亚慢性剂量与安慰剂相比的中枢和外周H1抑制作用。将PRM纳入研究作为阳性内部对照，以验证心理测量测试组对各种治疗的中枢神经系统效应的敏感性。
在一项五组、双盲、交叉研究中，20名健康志愿者（18 - 50岁）每天服用一次L-CTZ 5mg、CTZ 10mg、LOR 10mg、PRM 30mg和安慰剂，持续四天。对于每种治疗条件，在基线以及第1天和第4天给药后1、2、3、4、6、8、10和122小时，使用心理测量测试系统和对100mg/ml组胺溶液的针刺风团和潮红反应对受试者进行评估。心理测量包括临界闪烁融合（CFF）、选择反应时间（CRT）、连续跟踪任务（CTT）和镇静主观评分量表（LARS）。在第2天和第3天，受试者在离开单位时在预先指定的时间服药。
阳性对照药（PRM）证实了测试组的敏感性：第1天和第4天CFF阈值总体显著降低（p < 0.05）；第1天识别、运动和总反应时间总体显著增加（受损）（p < 0.05）；第1天CTT任务的跟踪准确性和反应时间方面均有显著受损（p < 0.005），且第1天主观镇静评分显著更高（p < 0.05）。在第1天或第4天的任何时间点，L-CTZ、CTZ和LOR在任何客观和主观测试中均与安慰剂无差异。关于外周抑制作用，L-CTZ抑制风团和潮红反应，在服药后两小时内出现最大抑制（几乎100%）。CTZ也显示出对组胺有强大的外周抑制作用，而PRM，尤其是LOR，仅显示出微弱的风团和潮红反应，在第4天时已完全减弱。
在一项显示心理测量评估对损伤敏感的研究中，发现初始剂量和重复剂量的L-CTZ 5mg对心理运动和认知功能的客观测量均无明显的干扰和镇静作用。同样，CTZ显示出明显的抗组胺活性，急性和重复给药后风团和潮红评分显著降低，同样没有认知或心理运动损伤的证据。LOR也无镇静作用，但抗组胺反应明显较弱。
