三七总皂苷对CYP450的影响及药物相互作用预测

目的：研究三七总皂苷（血塞通）对肝微粒体CYP450酶不同亚型的影响，进一步了解其在肝脏的代谢特点并据此对该药与其他药物相互作用的安全性进行预测，为临床合理应用提供依据。方法：检测肝药酶CYP1A2和CYP3A4的专属探针药物咖啡因、氨苯砜的原型浓度，采用原型药物减少初始速率测定法考察其体外代谢变化情况，从而评价三七总皂苷对CYPIA2、CYP3A4的诱导或抑制作用。结果：三七总皂苷对肝药酶CYPIA2有诱导作用，而对CYP3A4无影响。结论：三七总皂苷对CYP450。不同亚型酶的影响不同。在临床应用时，尤其是与CYPIA2代谢有关的药物合用时，应充分考虑到这种影响，以避免潜在的毒性或不良反应。     

细胞色素P450—3A4相关的药物相互作用

目的：综述与细胞色素P4503A4相关的药物相互作用。方法：检索Medline和中国药学文摘。结果：发现多种由CYP3A4催化代谢的药物之间可以竞争药物代谢酶,引起药物相互作用,CYP3A4的抑制剂和诱导剂均可以抑制或诱导CYP3A4催化代谢的药物代谢。导致有益或不良的药物相互作用。结论：CYP3A4催化代谢的药物联合使用,特别是CYP3A4抑制剂与底物联合使用时,可能因为抑制了药物的代谢而导致严重的药物不良反应。     

CYP3A酶内源性标志物的研究进展

CYP3A酶主要分布于人体肝脏和小肠,广泛参与各种药物代谢。该酶在介导药物代谢的同时也会受底物影响,其活性被诱导或抑制,从而影响其他经由CYP3A酶代谢的药物体内过程。目前可以通过体外探针药物和内源性生物标志物评价CYP3A酶活性,前者需要口服探针药物,后者只需检测内源性标志物如4β-羟基胆固醇和6β-羟基氢化可的松。文献报道,研究CYP3A酶活性除了有助于阐明不同个体的药物代谢差异,还可以提示药物相互作用情况下合用药物的剂量调整,预测药物疗效和毒性反应,为个体化用药提供理论指导,评估新药潜在的药物相互作用,降低新药上市风险。笔者对上述2种常用的内源性标志物的相关研究和临床应用进行综述。     

P450酶介导的EGFR-TKIs药物与其他药物的相互作用

目的探讨细胞色素P450酶介导的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)与其他药物的相互作用。方法查阅文献,统计国家药品监督管理局批准用于治疗晚期非小细胞肺癌的7个EGFR-TKIs与P450酶相关的药物相互作用。结果 7个EGFR-TKIs中,阿法替尼的代谢不经过P450酶途径,也并非CYP酶系的诱导剂或抑制剂;其余EGFR-TKIs主要经CYP3A4酶、CYP2D6酶及CYP1A2酶代谢,并可明显抑制CYP2D6酶、CYP3A4酶、CYP2C8/9酶的活性,药物相互作用较多。结论 EGFR-TKIs类药物中,除阿法替尼与P450酶底物发生相互作用的概率较低外,其余药物对P450酶均可产生明显的抑制作用,临床医师应结合患者病情合理选用该类药物,避免不合理合用。     

海藻–昆布药对对大鼠肝微粒体代谢酶的影响及肝毒性研究

目的发现不同剂量海藻–昆布药对提取物对大鼠肝微粒体代谢酶的诱导或抑制作用,预测服用海藻–昆布药对时可能出现的药物–药物相互作用及肝脏毒性。方法雌雄各半SD大鼠18只,被随机分为海藻–昆布药对低、高剂量组和对照组,低、高剂量组大鼠分别ig给予海藻–昆布药对提取物10.8、86.4 g/(kg·d),连续经口给药15 d后麻醉处死,取肝组织制备肝微粒体及HE染色石蜡切片。通过肝微粒体体外孵育方法测定3种肝脏CYP450同工酶特异性底物非那西丁(CYP1A2)、氯唑沙宗(CYP2E1)及咪达唑仑(CYP3A4)的降解和代谢产物生成量来评价肝药酶的诱导或抑制作用,并以光镜下的组织病理切片检查来考察其肝毒性。结果低剂量组大鼠无显著诱导或抑制3种CYP450代谢酶亚型1A2、2E1和3A4现象,肝组织出现了肝窦扩张、轻度水肿等适应性改变,高剂量组能显著诱导CYP3A4亚型,但也不能显著的诱导或抑制肝微粒体代谢酶CYP1A2、CYP2E1亚型,肝组织出现了脂肪变、点状坏死等可逆性损伤。结论海藻–昆布药对具有诱导肝微粒体代谢酶CYP3A4的作用和轻微的肝细胞毒性,高剂量经口给药能引起有临床意义的CYP450酶的诱导现象和肝脏损伤并可能导致不期望的药物–药物相互作用。     

综合性医院门诊处方中常见CYP3A4抑制剂和诱导剂的代谢性相互作用调查

代谢性相互作用是指两种或两种以上药物在同时或前后序贯用药时,在代谢环节发生的相互作用[1]。根据对药物代谢酶的作用结果,可以分为酶抑制作用和酶诱导作用。肝脏的细胞色素P450系统(CYP)在药物的代谢中起着重要作用,其中CYP3A4占肝脏CYP总量的30%,含量最高,而且有50%的药物在氧化代谢中需要CYP3A4的     

银杏叶提取物对细胞色素P450影响的研究进展

银杏叶提取物(Ginkgo biloba extract,GBE)是目前使用最为广泛的中草药之一。GBE与其他药物合用是否产生药物相互作用得到关注。GBE与其他药物合用,可能通过影响肝药酶的活性发生药物相互作用,其中GBE对肝药酶的诱导或抑制作用的研究较为深入。本综述回顾了近年来报道的关于GBE对细胞色素P450 CYP3A4、CYP2C9、CYP1A2、CYP2C19的影响。     

海藻-昆布药对对大鼠肝微粒体代谢酶的影响及肝毒性研究

目的 发现不同剂量海藻-昆布药对提取物对大鼠肝微粒体代谢酶的诱导或抑制作用, 预测服用海藻-昆布药对时可能出现的药物-药物相互作用及肝脏毒性。方法 雌雄各半SD大鼠18只, 被随机分为海藻-昆布药对低、高剂量组和对照组, 低、高剂量组大鼠分别ig给予海藻-昆布药对提取物10.8、86.4 g/(kg·d), 连续经口给药15 d后麻醉处死, 取肝组织制备肝微粒体及HE染色石蜡切片。通过肝微粒体体外孵育方法测定3种肝脏CYP450同工酶特异性底物非那西丁(CYP1A2)、氯唑沙宗(CYP2E1)及咪达唑仑(CYP3A4)的降解和代谢产物生成量来评价肝药酶的诱导或抑制作用, 并以光镜下的组织病理切片检查来考察其肝毒性。结果 低剂量组大鼠无显著诱导或抑制3种CYP450代谢酶亚型1A2、2E1和3A4现象, 肝组织出现了肝窦扩张、轻度水肿等适应性改变, 高剂量组能显著诱导CYP3A4亚型, 但也不能显著的诱导或抑制肝微粒体代谢酶CYP1A2、CYP2E1亚型, 肝组织出现了脂肪变、点状坏死等可逆性损伤。结论 海藻-昆布药对具有诱导肝微粒体代谢酶CYP3A4的作用和轻微的肝细胞毒性, 高剂量经口给药能引起有临床意义的CYP450酶的诱导现象和肝脏损伤并可能导致不期望的药物-药物相互作用。     

西沙必利与其他药物的相互作用

目的　了解促胃肠动力药西沙必利与其他药物合用时的相互作用。方法　通过对近期文献的阅读、分析和归纳,加以综述。结果　西沙必利由细胞色素P-450 (CYP) 3A4代谢,有较强的首过效应,所以许多CYP3A4底物或(和)抑制剂都能抑制西沙必利的代谢,使其血药浓度升高,从而可能引起心脏QT间期延长、心律失常,甚至导致扭转型室速(TdP)。药效学研究表明,西沙必利与可以引起QT间期延长的药物合用后,也可能增加心脏的毒性反应。结论　西沙必利应避免与CYP3A4抑制剂、CYP3A4底物及易引起QT间期延长的药物合用。如果必需合用,应密切观察合用后的情况,并进行心电监护或血药浓度的监测,以保证临床用药的安全有效     

贯叶金丝桃对健康受试者体内茶碱药动学的影响

贯叶金丝桃由于能诱导细胞色素 P450(CYP)3A4和 P-糖蛋白(P-gp)而改变某些与之合用药物的药动学参数。考虑到茶碱代谢主要受 CYP1A2和部分受 CYP2E1与CYP3A4调控,作者采用随机、公开标签和交     

Clinical pharmacokinetic profile of modafinil

Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. After single or multiple oral doses, modafinil is readily absorbed, reaching maximum plasma concentrations at 2-4 hours after administration and pharmacokinetic steady state within 2-4 days. Its pharmacokinetics are dose-independent between 200 and 600 mg/day. The elimination half-life is approximately 12-15 hours, which is largely reflective of the pharmacokinetics of the longer-lived l-enantiomer. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil. In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.     

Polymorphisms of ADORA2A modulate psychomotor vigilance and the effects of caffeine on neurobehavioural performance and sleep EEG after sleep deprivation

BACKGROUND AND PURPOSE

Prolonged wakefulness impairs sustained vigilant attention, measured with the psychomotor vigilance task (PVT), and induces a compensatory increase in sleep intensity in recovery sleep, quantified by slow-wave activity (SWA) in the sleep electroencephalogram (EEG). These effects of sleep deprivation are counteracted by the adenosine receptor antagonist caffeine, implying involvement of the adenosine neuromodulator/receptor system. To examine a role for adenosine A_2A receptors, we investigated whether variation of the A_2A receptor gene (ADORA2A) modified effects of caffeine on PVT and SWA after sleep deprivation.

EXPERIMENTAL APPROACH

A haplotype analysis of eight single-nucleotide polymorphisms of ADORA2A was performed in 82 volunteers. In 45 young men carrying five different allele combinations, we investigated the effects of prolonged waking and 2 × 200 mg caffeine or 2 × 100 mg modafinil on psychomotor vigilance, sleepiness, and the waking and sleep EEG.

KEY RESULTS

Throughout extended wakefulness, the carriers of haplotype HT4 performed faster on the PVT than carriers of non-HT4 haplotype alleles. In haplotype HT4, caffeine failed to counteract the waking-induced impairment of PVT performance and the rebound of SWA in recovery sleep. However, caffeine was effective in non-HT4 allele carriers, and modafinil reduced the consequences of prolonged waking, independently of ADORA2A haplotype.

CONCLUSIONS AND IMPLICATIONS

Common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in rested and sleep-deprived state. It also modulates individual responses to caffeine after sleep deprivation. These findings demonstrate a role for adenosine A_2A receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.     

The 5-min pupillary alertness test is sensitive to modafinil: a placebo controlled study in patients with sleep apnea

Rationale The extent of pupillary miosis during 5 min in darkness is a simple, recently introduced alertness test which may become useful in the clinical assessment of normal and pathological sleepiness. Objectives In this study, we further validated this test by testing its sensitivity to the effects of modafinil, a non-stimulant, alertness-promoting drug. Methods Twelve unmedicated patients recently diagnosed with obstructive sleep apnea (OSA) after polysomnography, received placebo or modafinil (200 mg), according to a double-blind, cross-over design. The patients’ resting pupil diameter (RPD) was sampled over 5 min in darkness before (10:00 a.m.) and after treatment (2:00 p.m.), and their light reflexes were elicited and recorded in darkness with an infrared video pupillometer. Results We found a circadian miosis at 2:00 p.m. in the placebo treatment condition, which was reversed by modafinil. This effect correlated with modafinil-induced increase in subjective alertness, and it was greater in the most severely affected patients in terms of lowest oxygen saturation, independently of body mass index, age, or apneic episodes during sleep. Modafinil reduced the light reflex amplitude, suggesting an increase in the inhibitory input at the pupilloconstrictor Edinger-Westphal nucleus. Conclusions These effects of modafinil are best explained via an activation of the hypoxia-sensitive nucleus locus coeruleus. The 5-min pupillary alertness test has promising predictive validity, and it holds promise as a fast and sensitive method for the objective assessment of excessive daytime sleepiness, monitoring of disease progression, and response to treatment.     

Pharmacokinetic evaluation of armodafinil for the treatment of bipolar depression

Introduction: Bipolar disorder is a psychiatric illness with recurring episodes of mania and depression. Armodafinil , the R-enantiomer of modafinil, approved for treating excessive sleepiness associated with narcolepsy, obstructive sleep apnea and shift work disorder, is possibly effective as an adjunctive treatment for bipolar depression. Areas covered: This review covers the pharmacokinetics of armodafinil, with an emphasis on its use in bipolar depression. Its clinical efficacy in the treatment of bipolar depression is evaluated, along with current data regarding its safety and tolerability. Expert opinion: One placebo-controlled trial is available, in which armodafinil was efficacious as an adjunctive treatment in bipolar depression. Armodafinil shows a linear pharmacokinetic profile over a broad dose range of 50 - 400 mg (maximal plasma concentration and area under concentration-time curve). Compared with modafinil, an equivalent dose of armodafinil attains higher blood concentrations 4 - 6 h post-dose. The possibility of drug interactions is generally low, although interactions have been shown with some drugs used in bipolar disorder, through mild CYP3A4-induction and CYP2C19-inhibition. Armodafinil is well tolerated and presents a possible new treatment option for bipolar depression. However, further investigation is still needed in order to confirm its efficacy and to clarify its role in the treatment of bipolar depression.     

REM期睡眠剥夺和恢复及莫达非尼干预后大鼠海马突触可塑性变化

目的：探讨不同程度快动眼睡眠（REM）期睡眠剥夺和恢复及中枢性兴奋药莫达非尼干预后大鼠海马突触可塑性变化,观察莫达非尼对其的影响作用。方法：成年雄性SD大鼠随机分为对照组和睡眠剥夺组,对照组有空白对照（cage control,CC）和环境对照（tank control,TC）,睡眠剥夺组分非用药组（non-drug group,NDG）和用药组（drug group,DC）,每组分睡眠剥夺1d（SD 1d）、3d（SD 3d）、5d （SD 5d）,剥夺5d后恢复6h（SD 5 d/RS 6h）、12h（SD 5d/RS 12h）共5小组,每小组6只大鼠,采用改良多平台睡眠剥夺法（MMPM）进行REM期睡眠剥夺,运用免疫组织化学和电镜的方法分析大鼠海马CA3区突触素（synapsinⅠ）的表达,观察突触可塑性变化。结果：免疫组化结果显示,CC组和TC组间无显著差异（P＞0．05）；在SD 1 d、SD 3 d、SD 5 d、SD 5 d/RS 6 h、SD 5 d/RS 12h各时间点用药组突触素阳性表达均高于非用药组（P＜0．05）；非用药组和用药组SD1d、SD 3 d、SD 5d、SD 5 d/RS 6h各时间点比CC组均有减少（P＜0．05）,而用药组中的SD 5d/RS 12h组与CC组无显著差异（P＞0．05）。电镜下观察显示,非用药SD 1d组的突触联系、突触前膜囊泡数量均较CC组减少,但用药SD 1 d组较非用药SD 1d组增加。结论：REM期睡眠剥夺能够引起大鼠海马突触素表达减少,影响大鼠海马突触可塑性,而莫达非尼可以显著改善睡眠剥夺后突触素的表达减少,调节大鼠海马突触可塑性。     

Modafinil : a review of its use in excessive sleepiness associated with obstructive sleep apnoea/hypopnoea syndrome and shift work sleep disorder

Modafinil (Provigil is a wake-promoting agent that is pharmacologically distinct from CNS stimulants, such as amfetamine, dexamfetamine and methylphenidate. Modafinil is approved for use in the US and certain European countries for use in patients with excessive sleepiness associated with narcolepsy, obstructive sleep apnoea/hypopnoea syndrome (OSA/HS) or shift work sleep disorder (SWSD).Oral modafinil promotes wakefulness in patients with OSA/HS and SWSD. It is an effective adjunctive therapy in patients with residual excessive sleepiness associated with OSA/HS who are receiving nasal continuous positive airway pressure (nCPAP) therapy. In SWSD, the drug improves night-time wakefulness without disrupting daytime sleep. Modafinil is generally well tolerated in patients with OSA/HS or SWSD and has a low abuse potential. Thus, modafinil is a valuable new treatment option for use in patients with excessive sleepiness associated with OSA/HS (as an adjunct to nCPAP) or SWSD.     

Approved and investigational uses of modafinil : an evidence-based review

Modafinil is a wake-promoting agent that is pharmacologically different from other stimulants. It has been investigated in healthy volunteers, and in individuals with clinical disorders associated with excessive sleepiness, fatigue, impaired cognition and other symptoms. This review examines the use of modafinil in clinical practice based on the results of randomized, double-blind, placebo-controlled clinical trials available in the English language in the MEDLINE database. In sleep-deprived individuals, modafinil improves mood, fatigue, sleepiness and cognition to a similar extent as caffeine but has a longer duration of action. Evidence for improved cognition in non-sleep-deprived healthy volunteers is controversial.Modafinil improves excessive sleepiness and illness severity in all three disorders for which it has been approved by the US FDA, i.e. narcolepsy, shift-work sleep disorder and obstructive sleep apnoea with residual excessive sleepiness despite optimal use of continuous positive airway pressure (CPAP). However, its effects on safety on the job and on morbidities associated with these disorders have not been ascertained. Continued use of CPAP in obstructive sleep apnoea is essential. Modafinil does not benefit cataplexy.In very small, short-term trials, modafinil improved excessive sleepiness in patients with myotonic dystrophy. It was efficacious in fairly large studies of attention deficit hyperactivity disorder (ADHD) in children and adolescents, and was as efficacious as methylphenidate in a small trial, but has not been approved by the FDA, in part because of its serious dermatological toxicity. In a trial of 21 non-concurrent subjects, with 2-week treatment periods, modafinil was as effective as dexamfetamine in adult ADHD. Modafinil was helpful for depressive symptoms in bipolar disorder in a trial that excluded patients with stimulant-induced mania. A single dose of modafinil may hasten recovery from general anaesthesia after day surgery. A single dose of modafinil improved the ability of emergency room physicians to attend didactic lectures after a night shift, but did not improve their ability to drive home and caused sleep disturbances subsequently.Modafinil had a substantial placebo effect on outcomes such as fatigue, excessive sleepiness and depression in patients with traumatic brain injury, major depressive disorder, schizophrenia, post-polio fatigue and multiple sclerosis; however, it did not provide any benefit greater than placebo.Trials of modafinil for excessive sleepiness in Parkinson's disease, cocaine addiction and cognition in chronic fatigue syndrome provided inconsistent results; all studies had extremely small sample sizes. Modafinil cannot be recommended for these conditions until definitive data become available.Modafinil induces and inhibits several cytochrome P450 isoenzymes and has the potential for interacting with drugs from all classes. The modafinil dose should be reduced in the elderly and in patients with hepatic disease. Caution is needed in patients with severe renal insufficiency because of substantial increases in levels of modafinil acid. Common adverse events with modafinil include insomnia, headache, nausea, nervousness and hypertension. Decreased appetite, weight loss and serious dermatological have been reported with greater frequency in children and adolescents, probably due to the higher doses (based on bodyweight) used. Modafinil may have some abuse/addictive potential although no cases have been reported to date.     

Armodafinil for excessive daytime sleepiness

Armodafinil is the (R)-enantiomer of the wakepromoting compound modafinil (racemic), with a considerably longer half-life of 10-15 hours. Armodafinil (developed by Cephalon, Frazer, PA, USA) was approved in June 2007 for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea syndrome and shift work disorder, and the indications are the same as those for modafinil. Like modafinil, the mechanisms of action of armodafinil are not fully characterized and are under debate. Clinical trials in these sleep disorders demonstrated an enhanced efficacy for wake promotion (wake sustained for a longer time period using doses lower than those of modafinil). The safety profile is consistent with that of modafinil, and armodafinil is well tolerated by the patients. Like modafinil, armodafinil is classified as a non-narcotic Schedule IV compound. Many patients with excessive sleepiness may prefer the longer duration of effect and may have better compliance (with low doses) with armodafinil. The commercial challenge to armodafinil may come from generic modafinil, which may become available in 2012, as well as from classical amphetamine and amphetamine-like compounds (for the treatment of narcolepsy).     

In vitro inhibition and induction of human hepatic cytochrome P450 enzymes by modafinil.

The ability of modafinil to affect human hepatic cytochrome P450 (CYP) activities was examined in vitro. The potential for inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, CYP3A4/5, and CYP4A9/11 by modafinil (5-250 microM) was evaluated with pooled human liver microsomes. Modafinil exhibited minimal capacity to inhibit any CYP enzyme, except CYP2C19. Modafinil inhibited the 4'-hydroxylation of S-mephenytoin, a marker substrate for CYP2C19, reversibly and competitively with a K(i) value of 39 microM, which approximates the steady-state C(max) value of modafinil in human plasma at a dosage of 400 mg/day. No irreversible inhibition of any CYP enzyme was observed, and there was no evidence of metabolism-dependent inhibition. The potential for induction of CYP activity was evaluated by exposing primary cultures of human hepatocytes to modafinil (10-300 microM). Microsomes were then prepared and assayed for CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 activities. The mean activities of microsomal CYP1A2, CYP2B6, and CYP3A4/5 from modafinil-treated hepatocytes were higher (up to 2-fold) than those in the solvent-treated controls but were less than those produced by reference inducers of these enzymes. At high concentrations of modafinil (>/=100 microM), the mean activity of CYP2C9 was decreased (up to 60%) relative to that in the solvent controls. Overall, modafinil was shown to have effects on human hepatic CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4/5 activities in vitro. Although effects obtained in vitro are not always predictive of effects in vivo, such results provide a rational basis for understanding drug-drug interactions that are observed clinically and for planning subsequent investigations.     

Effect of a novel histamine subtype-3 receptor inverse agonist and modafinil on EEG power spectra during sleep deprivation and recovery sleep in male volunteers

Rationale

Histamine and dopamine contribute to the maintenance of wakefulness.

Objective

This study aims to conduct an exploratory analysis of the effects of 10 and 50?mg of MK-0249, a novel histamine subtype-3 receptor inverse agonist, and 200?mg of modafinil, a presumed dopaminergic compound, on EEG power spectra during sleep deprivation and subsequent recovery sleep.

Methods

A total of 25 healthy men were recruited to a double-blind, placebo-controlled cross-over design. EEG power spectra, an electrophysiological marker of changes in sleepiness and vigilance, were obtained at the beginning of wake maintenance tests at two-hourly intervals throughout a night and day of sleep deprivation, which is an established model of excessive sleepiness.

Results

After placebo, sleep deprivation was associated with enhancements in delta and theta and reductions in alpha and beta activity. Following dosing at 02:00 h, MK-0249 and modafinil reduced delta and theta activity and enhanced alpha and beta activity, compared to placebo. During recovery sleep initiated at 21:00?h, latency to sleep onset and number of awakenings were not different from placebo for any of the active treatments. Wake after sleep onset and stage 1% was increased and total sleep time, SWS% and REM% were reduced after both doses of MK-0249. Compared to placebo, MK-0249, the 50-mg dose in particular, reduced activity in some delta and theta/alpha frequencies and enhanced beta activity during NREM sleep and REM sleep. After modafinil, no changes were observed for power spectra during sleep.

Conclusion

Both MK-0249 and modafinil exert effects on the EEG which are consistent with wake promotion.