Neuroprotective Effects of Modafinil on MPTP Mouse Model of Parkinson′s Disease

Aim To observe the neuroprotective effects of modafinil on the Parkinson'sdisease ( PD ) model induced by 1-methyl-4-phenyl-1, 2,3, 6-tetrahydropyridine (MPTP ). Methods Themodel of PD was induced by intraperitoneal injection of MPTP into C57BL/6J mice for 4 d. Modafinil(ip, 50 or 100 mg·kg^(-1)·d^(-1)) was administered following MPTP for 4 d and for another 10 dconsecatirely. The effects of modafinil on the locomotor activity, and the incubation, maintenanceperiod and grade of the tremor, the duration of the climbing rod of mouse, and the distribution ofpositive cells of ty-rosine hydroxylase (TH) and Nissl bodies in the striatum and substantia nigra(SN) were observed. The contents of dopam-ine (DA) , noradrenaline (NA) and 5-hydroxytryptamine(5-HT) in the striatum were determined. Results Modafinil (50 and 100 mg·kg^(-1)) significantlyprevented the locomotor, the tremor and climbing rod defect behavior in a dose-dependent manner (P <0.05 and P < 0.01, n = 10), prevented the decrease in the number of TH-positive cells and Nisslbodies (P<0.05, n=10), and reduced the decrease of DA, NA, and 5-HT in the striatum (P < 0.05, n =10) induced by MPTP. Conclusion Modafinil improves the behavioral deficits and prevents themonoaminergic neuron lesion in seriously impaired MPTP mouse model.

新型精神兴奋药Modafinil的合成

本品以二苯基甲醇等为主要原料,通过缩合、氯化、氨解、氧化制得一种新型精神兴奋药。

精神兴奋药Modafinil

合成本品的合成方法有两种: 1.二苯基甲醇(Ⅰ)与氯乙酸(Ⅱ)在硫脲(Ⅲ)存在下在浓氢溴酸中于95°缩合而得2-(二苯甲基硫)乙酸(Ⅳ),Ⅳ与氯化亚砜在苯中回流转变成酸性氯化物(Ⅴ),Ⅴ在水-二氯甲烷中与NH_4OH反应生成2-(二苯甲基硫)乙酰胺(Ⅵ),最后Ⅵ经Hv2O_2氧化成本品。 2.化合物Ⅳ也可用H_2O_2氧化成2-(二苯甲基亚磺酰)乙酸(Ⅶ),Ⅶ经硫酸二甲酯和NaHCO_3甲基化,生成相应的甲酯(Ⅷ),最后在无水甲醇中用氨处理而获得本品。

The Effects of Modafinil in People with a Diagnosis of Schizophrenia

This review seeks to describe the use and effects of the drug modafinil. Specifically, it presents the research of the impact of modafinil for people with diagnosis and experience of schizophrenia. Recent reviews have shown that modafinil can positively impact on cognitive function in people with a diagnosis of schizophrenia. There is emerging evidence for the positive impact of modafinil on negative symptoms, functioning, quality of life, wellbeing, and body mass index (BMI) for people with schizophrenia. Compared to other central nerve stimulant (CNS) drugs, modafinil has a low risk of dependency and few negative side effects;but there are risks of triggering positive symptoms in schizophrenia. A well designed and sufficiently large randomised control trial is required to test the potential of the impact of modafinil in the lives of people with a diagnosis of schizophrenia. Future research should report participant’s perspective of the value of modafinil connected to what concerns them and what they want to achieve in their lives.

Ventricular Tachycardia during Treatment with Modafinil for Narcolepsy: A Case Report

Pharmacological treatment of narcolepsy is complex. We reported a case of recurrent episodes of polymorphic ventricular tachycardia attributed to the use of modafinil, a recently approved wake-promoting agent for narcolepsy and shift work sleep disorder. Modafinil is also approved as adjunctive treatment of obstructive sleep apnea/hypopnea syndrome. While the exact mechanism of action for modafinil is not known, central dopamine receptors seem to play an essential role. Adverse influences on the electrocardiogram (ECG) or drug-related cardiac arrhythmias are rarely reported, but are considered as clinically important.

Hypersexuality after Modafinil Treatment： A Case Report

Modafinil is employed for the treatment of narcolepsy and other sleep disorders like idiopathic hypersornnia. Modafinil is involved in the modulation of orexin, a hypothalamic neuropeptide that regulates wakefulness. It also indicated that the drug interferes with the activity of additional neurotransmitters like hypocretin, histamine, gamma-aminobutyricacid, glutamate and norepinephrine. Modafinil can also block the dopamine transporter by increasing brain dopamine levels. Common side effects of modafinil include headache, nausea, nervousness, anxiety and trouble sleeping. Other side effects are affective lability, hyposexuality, personality change, aggression, abnormal dreams, irritability, suicidal ideas, mania, hypomania and psychotic exacerbation. In this case report, we present a 45 year old woman with idiopathic hypersomnia which is characterized primarily excessive day time sleepiness. Before modafinil treatment ESS （Epworth Sleepiness Scale） score of patient was 13. Treatment with Modafmil 200 mg daily within two weeks produced a subjective improvement in her daytime sleepiness （ESS score after treatment is 4）. But one week after the start of modafmil treatment, her sexual desire increased. Before this treatment, her sexual intercourse frequency was 1-2 times per week and after this treatment she wanted coitus every day. She has continual thoughts about sexuality. She didn＇t have any additional medication use or medical condition that increase sexual desire. Modafinil dose was decreased 100 mg/daythen to 50 mg/day. Her ESS score was 7 and daytime sleepiness had no effect on her life. After decreasing modafinil treatment her sexual desire returned to normal. Hypersexuality has not been reported as a side effect of modafinil yet. The pathophysiological mechanism of modafinil induced hypersexuality is not clear. In conclusion, clinicians should be aware of this rare significant side effect of modafinil and should maintain treatment with the lowest possible dose.

Influence of sex on the pharmacokinetics of modafinil in healthy Chinese volunteers

The purpose of this study was to determine the pharmacokinetic characteristics of modafinil and its metabolite modafinil acid in healthy subjects including Chinese Mongolian, Korean and Uyghur, and assess the influence of sex on the pharmacokinetic profiles of modafinil in Chinese subjects. Fifteen healthy Chinese male subjects and fifteen female subjects received 200 mg of modafinil, and the plasma samples were collected at the designed time points. The plasma modafinil concentration was determined by HPLC-UV method. Pharmacokinetic parameters were calculated by DAS software. The pharmacokinetics of modafinil for all of the subjects were in accordance with the two-compartment open model. The mean pharmacokinetic parameters for males and females are as follows： Cmax （4.39±0.53） and （5.86±1.23） μg/mL, AUC0 -∞（65.36±13.93） and （71.74±16.48） μg.h/mL, t1/2β （15.19±3.05） and （14.48±3.95） h for modafinil; Cmax （2.68±0.52） and （3.56±0.57） μg/mL, AUC0 -∞ （29.99±6.05） and （34.53±6.41） μg.h/mL, t1/2β （6.46±1.31） and （5.35±1.46） h for modafinil acid, respectively. Statistical analysis of the pharmacokinetics ofmodafinil and modafmil acid in male and female groups shows that sex has a significant impact on the metabolism of modafinil and modafinil acid. More attention should be paid on the dosage to male or female patients.

莫达非尼不良事件风险信号的数据挖掘和分析

目的对莫达非尼药品不良事件的发生状况和一般规律进行数据挖掘和分析,为莫达非尼的临床安全用药提供参考。方法从美国食品药品监督管理局药品不良事件报告系统(FAERS)调取2004年1月1日至2023年9月30日莫达非尼不良事件报告,采用报告比值比法(ROR)、比例报告比法(PRR)及英国药品和保健标准法挖掘数据,对患者的基本信息、风险信号等进行回顾性分析。结果共获得莫达非尼不良事件报告1933份(女性51.22%,男性35.02%),年龄以18~64岁为主,报告中以美国占比最高(73.10%),报告者主要为消费者(56.18%)。报告共涉及1163个信号,发生频次较高的是药物无效(381例)、疲劳(163例)、嗜睡(147例);检出阳性信号193个,其中报告数大于10例且与不良反应相关的阳性信号共43个,主要为精神病类(21个)和各类神经系统疾病(13个),信号强度排名前三位的是猝倒症(ROR=107.90,PRR=107.61)、嗜眠症(ROR=87.47,PRR=87.24)、睡眠过度(ROR=9.99,PRR=9.95),其中实施自杀行为、戒断综合征、自发流产等12项不良反应在说明书中未提及。结论FAERS有助于提高医务者对莫达非尼临床应用风险信号的认识;在莫达非尼的临床应用过程中,应重点关注药物滥用、自杀倾向、猝倒症、皮疹和心脏疾病等不良反应的发生。

Identification of adrafinil and its main metabolite modafinil in human hair.Self-administration study and interpretation of an authentic case

For several years,the misuse of stimulant substances is increasingly observed both in the field of sport,to improve the functions of the body and therefore to be more performant,and also by non-athletes to make life more tolerable on a daily basis.Adrafinil,2-((diphenylmethyl)sulfinyl)-N-hydroxyacetamide,is a drug designed for the treatment of narcolepsy by promoting an awakened state,and to treat alertness and neurological symptoms in the elderly.It is primarily metabolized in vivo to an active form,i.e.modafinil,2-((diphenylmethyl)sulfinyl)acetamide.The World Anti-Doping Agency(WADA)banned these two drugs in sports in 2004.The authors report an authentic case involving adrafinil and modafinil.The laboratory was requested to test for adrafinil in a hair strand collected from a woman found in posses-sion of vials of adrafinil and suspected of trafficking.A specific method was developed by liquid chromatography tandem mass spectrometry(LC-MS/MS).Unlike modafinil(varying from 6.8 to 13.9ng/mg),adrafinil was not identified in the strand.The interpretation of the results was difficult because this is the first case describing human hair analysis.In order to be able to interpret the results,a self-administration study was conducted after an oral administration to a volunteer(200 mg)whose beard hair was collected 10days after adminis-tration.The analysis of this specimen highlighted the presence of adrafinil at 0.8ng/mg and modafinil at 0.5 ng/mg.These results demonstrate the dual identification of both compounds after a single consumption,even after administration of a low dose.According to these results,the analysis of the hair strand from the authentic case does not match with a con-sumption of adrafinil,in accordance with abuse of modafinil alone.Intelligence considered that this was a trafficking case of adrafinil,with no self-consumption.

Effects of modafinil on vestibular function during 24 hour sleep deprivation

The aim of this research was to investigate the effects of modafinil,a new wake-promoting agent,on vestibular function during 24 h sleep deprivation(SD)so as to provide experimental evidence for the rational use of this drug among air crew.Eight young,healthy male volunteers were exposed to two 24 h periods of continuous wakefulness during the crossover experiment.Initially,200 mg dose of modafinil was given,and one week later,a matching placebo was administered.The SD time started from 08:00 of the first day to 08:00 of the second day.Drugs were given at 0:00 on the second day.Vestibular function was tested at 21:00 on the first day and 1,3,5,7 h after drug administration.The accuracy of saccade tracking and gains in visual-vestibular optokinetic reflex(VVOR)and optokinetic nystagmus(OKN)in the placebo group decreased during 24 h SD,especially at 01:00–05:00 on the second day,while OKN gains in the modafinil group increased significantly.There were no significant differences in the other vestibular functional indices between the modafinil group and placebo group.The 24 h SD can influence vestibular function to a certain degree,but modafinil may improve OKN.

Thermodynamic Resolution of Pharmaceutical Precursor Modafinil Acid on the Basis of Chiral-at-Metal Strategy

Chiral-at-metal strategy was developed to resolve the essential sulfoxide pharmaceutical intermediates R-modafinil acid and its ana-logues with high yields and ee values.The efficient resolution process was achieved based on the diastereoselective discrimination caused by hydrogen bond and intramolecular π-π interaction between chiral-at-metal center and the coordinated chiral sulfoxide ligands.Moreover,the chiral Ir(lll)receptor can be reused with complete retention of their configurations and without the loss of reaction activity and enantioselectivity.This work provides a new access to synthesize R-modafinil acid as well as its analogues and develops the application of chiral-at-metal strategy in chiral resolution.

莫达非尼对阻塞性睡眠呼吸暂停低通气综合征患者白天嗜睡及认知功能改善的临床研究

目的:观察评价莫达非尼(modafinil)对重度OSAHS患者白天嗜睡及认知功能的改善。方法:选取2022年1月至2022年12月甘肃省人民医院就诊并经多导睡眠监测(PSG)初次确诊且未经治疗的重度阻塞性睡眠呼吸暂停低通气综合征(OSAHS)患者98例作为研究对象,随机分为单纯持续气道正压通气(CPAP)组、莫达非尼组、CPAP+莫达非尼组。收集患者的一般临床资料,并采用白天小睡试验对患者白天嗜睡的情况进行评估,采用简易智力状态检查量表(MMSE)进行认知功能评分,比较3组患者的白天嗜睡及认知功能的改善差异,并进行相关因素分析。结果:1)3组的性别、年龄、体质量指数比较,差异均无统计学意义(均P>0.05);2)治疗前,PSG、白天多次小睡及认知量表的评估显示,重度OSAHS合并程度一致的嗜睡及一致的轻度认知障碍,治疗后3组患者的白天嗜睡及认知障碍均有改善,CPAP+莫达非尼对重度OSAHS的白天嗜睡及认知功能改善更明显,并缩短治疗时间。结论:莫达非尼可改善重度OSAHS患者的白天嗜睡及认知功能,联用CPAP治疗可缩短治疗时间,值得临床推广应用。

单次口服莫达芬尼片在中国健康志愿者的药代动力学

目的研究单次口服莫达芬尼片的药代动力学。方法选择9名健康成年男性受试者分别单次口服100,200,300mg 3个剂量的莫达芬尼片后,用HPLC法测定血中原形药莫达芬尼及代谢产物莫达芬尼酸浓度,用3P97软件进行数据处理,计算药代动力学参数。结果原形药莫达芬尼的药-时曲线符合二房室模型,其主要药代动力学参数的Cmax、AUC0-∞、AUC0-t随剂量加大而增加;t1/2b、tmax、b、CL与给药剂量无关。莫达芬尼片原形药经肾排泄较少,48h经肾累积排泄率分别为(4.44±4.28)%,(3.35±2.20)%和(2.86±1.39)%。主要代谢产物莫达芬尼酸药-时曲线符合二房室模型,48h莫达芬尼酸经肾累积排泄率分别为(33.51±18.90)%,(32.36±19.92)%和(22.88±6.89)%。结论莫达芬尼在100～300mg内,呈线性动力学特征而无饱和性,其消除过程是经肝脏代谢,代谢产物为莫达芬尼酸,代谢产物主要经肾排泄。

莫达芬尼对48h睡眠剥夺时视听运动反应和疲劳感的影响

目的观察 48h睡眠剥夺 (sleepdeprivation ,SD)条件下正常人服用新型促醒剂莫达芬尼改善视听反应能力和疲劳感的效果。方法 6名健康男性青年志愿者 ,在 2次SD实验 (间隔 2周 )中交叉服用莫达芬尼和安慰剂 ,SD时间从第 1天 7∶0 0至第 3天 7∶0 0 ,于第 2天 0∶0 0、1 6∶0 0和第 3天 0∶0 0分别服用莫达芬尼 2 0 0mg或安慰剂 ,采用随机双盲给药 ,并在第 1天 2 1∶0 0及每次服药后 1h、3h、5h、7h各完成 1次测试 ,内容包括 :1 )声、光刺激运动反应时 ;2 )注意分配 ;3)临界闪光融合频率 (criticalflickerfusionfre quency ,CFF) ;4) .斯坦福嗜睡量表 (stanfordsleepinessscale ,SSS) ;5 )自认疲劳分级表 (ratingofper ceivedexertion ,RPE)。结果与安慰剂组比较 ,第 2、3次服用莫达芬尼后CFF值较安慰剂组明显升高 ,斯坦福量嗜睡表、RPE表分值较安慰剂组明显下降 ;声、光刺激运动反应时与注意分配无明显变化。

高效液相色谱法测定人血浆中莫达非尼及莫达非尼酸的浓度

目的:建立高效液相色谱法同时测定人血浆中莫达非尼及莫达非尼酸的浓度,以适合于大样本的血浆样品测定需要。方法:采用600 μL甲醇沉淀200μL血浆样品蛋白,高速离心后取上清液20 μL进样分析。分析柱:Diamonsil C_(18)柱(200 mm×4.6 mm,5μm),流动相:0.02 mol·L^(-1)磷酸二氢钾缓冲液(用磷酸调 pH=2.6)-甲醇-乙腈(60:20:20),紫外检测波长:220nm,流速:1.0 mL·min(-1),柱温:室温,以卡马西平作内标,按内标法定量。结果:血浆中莫达非尼和莫达非尼酸的线性范围均为0.1～10.0μg·mL^(-1),回归方程分别为:Y=0.252X+0.0094(r=0.9999)和 Y=0.2102X+0.0084(r=0.9991),最低定量限为0.1μg·mL^(-1)。莫达非尼、莫达非尼酸及内标卡马西平的保留时间分别为14.81,19.86,23.09 min,日内和日间 RSD 均小于11.0%,提取回收率和方法回收率分别在86.9%～95.8%,86.9%～96.8%和88.4%～94.7%,88.3%～99.8%之内。结论:本法具有快速、简便、灵敏、准确等优点,适用于人血浆中莫达非尼,莫达非尼酸浓度测定及药动学研究。

服用莫达非尼对48h睡眠剥夺条件下模拟飞行操作能力的影响

目的观察48h睡眠剥夺（sleep deprivation，SD）条件下正常人服用莫达非尼改善模拟器飞行操作能力的效果。方法以6名健康男性青年志愿者为对象，在间隔2周的两次48hSD（从第1天8：00至第3天8：00）实验中交叉服用莫达非尼和安慰剂（于实验第2天0：00、16：00和第3天0：00服用，每次200mg），于第1天21：00及每次服药后1h、3h、5h、7h进行J7-E模拟器飞行操作测试。结果安慰剂组的模拟器飞行成绩随SD时间延长逐渐下降，在第3天1：00—7：00的飞行成绩明显降低：操作错误随着SD延长而增加，在第3天1：00—7：00的出错次数增多，并且左上转弯和着陆阶段的操纵错误较多。与安慰剂组相比，莫达非尼组的飞行成绩在第3次服药后明显提高。莫达非尼组48h SD总的操作错误数较安慰剂组降低了19％，第3天1：00—7：00的错误数较安慰剂组降低了40％。结论服用莫达非尼明显改善48hSD条件下的模拟飞行操作能力，在SD复合生物节律的影响时药效更明显。

高效液相色谱法测定莫达非尼及其胶囊剂含量

目的:测定莫达非尼原料药及其胶囊剂的含量。方法:采用高效液相色谱法。色谱柱为Phenomenex ODS(150mm×4.6mm,5μm),柱温30℃,流动相为甲醇-50mmoL·L^(-1)甲酸(50:50,pH=2.5),流速1.0mL·min^(-1),UV检测波长225nm。结果:莫达非尼浓度在1.0～20μg·mL^(-1)范围标准曲线线性良好,最低检测浓度0.5μg·L^(-1),日内RSD为1.8％(n=5),日间RSD为2.0％(n=5),加样回收率98.0％～99.6％(n=3)。结论:本法简便快速,准确可靠,可用于莫达非尼及其胶囊剂含量测定等相关研究。

莫达非尼的研究进展

莫达非尼是一种新型精神兴奋剂，治疗发作性睡眠症及自发性睡眠过度。莫达非尼具有一定的抗震颤麻痹和神经保护作用，可能为帕金森病和呼吸麻痹病提供一种更好的治疗方法。综述近几年来莫达非尼的研究进展，着重阐述其可能的作用机制。

新型提神醒脑药物莫达非尼的合成

以二苯甲基氯和巯基乙酸乙酯为起始原料，经醚化，氨解，氧化三步反应得到新型提神醒脑药物莫达非尼（１），总收率：４１％．实验结果表明：该方法具有合成路线短、反应条件温和、产物易纯化、收率高等优点，完全适合工业化生产．