Persistent Behaviour and Electroencephalographic Changes after Single Doses of Nitrazepam and Amylobarbitone Sodium

In a double-blind cross-over trial the effects of nitrazepam (5 and 10 mg.), amylobarbitone sodium (100 and 200 mg.), and placebo were compared in normal healthy young people. Though they reported a good night''s sleep and adjudged themselves to be alert after all four drug treatments, behavioural tests showed their performance to be significantly impaired 13 hours after treatment with nitrazepam or amylobarbitone, and E.E.G. records showed more drowsiness and light sleep 18 hours after treatment with nitrazepam than with amylobarbitone or placebo. E.E.G. fast activity was more plentiful after drugs in either dosage than with placebo.     

The effect of long-term nitrazepam administration on sleep cycles in rats]

Single and chronic administration of a low dose of nitrazepam (1 mg/kg) had no effect on sleep cycles in rats. A single injection of a high dose (10 mg/kg) of nitrazepam resulted in prolongation of the total duration of synchronized sleep with a corresponding shortening of desynchronized (paradoxical) sleep. The number of sleep cycles was reduced. Chronic injections of nitrazepam (for 7-14 days) in a dose of 10 mg/kg evoked a gradual prolongation of the duration of paradoxical sleep and an increase in number of sleep cycles. After discontinuance of a long-term administration of nitrazepam (1 mg/kg or 10 mg/kg) prolongation of desynchronized sleep and an increase in the number of sleep cycles were more pronounced in comparison with the last day of chronic administration of the drug.     

Benzodiazepine hypnotics remain effective for 24 weeks.

Ninety-seven poor sleepers aged 40-68 years took capsules nightly for 32 weeks and made daily subjective ratings. The benzodiazepine hypnotics lormetazepam 2 mg and nitrazepam 5 mg appeared still to improve sleep after 24 weeks of intake when compared with continuous placebo intake. The sustained effectiveness was most evident in a significant shortening of the time taken to fall asleep in patients receiving lormetazepam. After weeks, sleep latency and the quality of sleep were significantly worse than baseline values. The impairment was maximal on the second night after withdrawal of lormetazepam and on the fourth night after withdrawal of nitrazepam. It is concluded that benzodiazepines remain effective for at least 24 weeks but that a period of disturbed sleep may be expected after withdrawal.     

Hypnotic accumulation and hangover in elderly inpatients: a controlled double-blind study of temazepam and nitrazepam.

The hypnotic and residual sedative effects of the first and seventh of seven regular night-time doses of nitrazepam 5 mg, temazepam 20 mg, and placebo were studied in 58 elderly inpatients. Plasma temazepam and nitrazepam concentrations rose by about 50% and 113% respectively between the mornings of day 1 and day 7. Patients reported sleeping well more often after the first dose of either hypnotic (p less than 0.05), but there was no difference after the seventh dose. Reaction time was unchanged on the morning after the first dose but was significantly prolonged after the seventh dose of both hypnotics (p less than 0.01). The time taken to eliminate the letter E from a page of prose tended to be prolonged after the first dose of both drugs (temazepam v placebo, p less than 0.05; nitrazepam v placebo, not significant) and was further prolonged on the morning after the seventh dose of nitrazepam (nitrazepam v placebo, p less than 0.05). Thus plasma accumulation of the drug was associated with a deterioration in daytime performance. This change in performance did not correlate with age, cerebral blood flow, or plasma concentration, but patients of low intelligence tended to be more severely affected.     

Radioimmunoassay for nitrazepam in plasma.

A radioimmunoassay (RIA) has been developed for the determination of therapeutic levels of the widely used hypnotic and anticonvulsant agent nitrazepam directly in 10 μl samples of plasma. The antiserum to nitrazepam, which was obtained following immunization of rabbits with an albumin conjugate of 3-hemisuccinyloxy-nitrazepam, does not cross-react with its major metabolites 7-amino-nitrazepam and 7-acetylamino-nitrazepam. The specificity of the RIA has been validated by comparison with a high-pressure liquid chromatographic procedure in the determination of intact nitrazepam in plasma following oral administration of 5 and 10 mg of the drug to man. The RIA intra- and inter-assay coefficients of variation did not exceed 7 and 9.5%, respectively. The RIA has a limit of sensitivity of 4 ng/ml using 10 μl of plasma and is ideally suited for routine clinical monitoring of nitrazepam in epileptic patients who are not receiving other benzodiazepines and for detailed pharmacokinetic and bioavailability studies in pediatric or geriatric patients from whom relatively small blood specimens are available.     

Changes in Human Drug Metabolism after Long-term Exposure to Hypnotics

The influence of the newer, non-barbiturate hypnotics Mandrax (diphenhydramine-methaqualone) and nitrazepam on drug-metabolizing capacity was assessed and compared with the effect of amylobarbitone, a known inducer of drug-metabolizing enzymes. Plasma antipyrine and phenylbutazone half-lives and urinary output of 6β-hydroxycortisol were used as indices. Volunteer subjects were exposed to therapeutic amounts of these agents and, in the case of Mandrax and barbiturates, further studies were carried out in dependent patients.Mandrax but not nitrazepam increased the rate of drug metabolism, presumably by enzyme induction. The degree of induction was comparable with that produced by hypnotic doses of amylobarbitone. The Mandrax-dependent and barbiturate-dependent patients were the fastest metabolizers studied. It is concluded that drug interactions resulting from interference with drug metabolism are as likely to occur with Mandrax as with barbiturates. On the other hand, it is unlikely that such drug interactions would occur with nitrazepam.     

Effect of neurotropic substances on sleep disorders caused by electrical stimulation of the hypothalamus in cats

The total period of sleep decreased as a result of the REM-sleep deficite following rage reaction induced in cats by the electrical stimulation of the hypothalamus. Haloperidol (1, 2, 3 mg/kg), diazepam (0.5, 1 mg/kg), nitrazepam (1, 6 mg/kg), glutetymide (10, 30, 60 mg/kg), pentobarbital (5, 15, 30 mg/kg) failed to eliminate sleep disturbances induced by rage reaction; lithium hydroxybutyrate (100, 150 mg/kg), dimedrol (1.5, 6 mg/kg) and imipramine increased the total sleep time on account of the slow wave phase; sodium hydroxybutyrate (100 mg/kg) normalized the electrophysiological pattern of sleep, decreasing the REM-sleep latency and the number of waking cats, and increasing the total REM-sleep time and the number of REM-sleep episodes.     

Increased sensitivity to nitrazepam in old age.

The effects of a single 10 mg oral dose of nitrazepam were compared with those of a placebo in healthy young and old people. Both the young and the elderly slept better on three successive nights after nitrazepam but they felt less awake at 12 and 36 hours (P less than 0-01). Elderly people made significantly more mistakes in a psychomotor test than did the young, despite similar plasma concentrations of nitrazepam and half lives in the two groups. This difference in response to psychomotor testing is probably explained by an increased sensitivity of the ageing brain to the action of nitrazepam.     

清咽滴丸药物冰块治疗甲状腺术后咽痛的疗效及对临床症状和睡眠质量的影响

摘要 目的：探讨清咽滴丸药物冰块治疗甲状腺术后咽痛的疗效,分析其对相关临床症状和睡眠质量的影响。方法：回顾性分析2019年4月至2021年8月期间广东省中医院甲状腺诊治中心收治的甲状腺术后咽痛患者240例的临床资料,根据不同的治疗方法分成三组,每组80例。对照组为药物组,给予清咽滴丸含服;实验I组为冰块组,给予25%高糖冰块含漱;实验II组为药冰组,给予自制清咽滴丸药物冰块含漱。观察比较三组患者治疗48 h后的临床疗效,治疗前和治疗48 h后的中医证候积分、深睡眠质量评分以及治疗前、治疗8 h、24 h和48 h后的视觉模拟评分法（VAS）评分。结果：实验II组治疗48 h后总有效率显著高于实验I组和对照组（P＜0.05）。三组患者治疗48 h后的中医证候积分和深睡眠质量评分均显著低于治疗前（P＜0.05）,三组患者治疗8 h、24 h、48 h后的VAS评分均显著低于治疗前（P＜0.05）,且实验II组治疗48 h后的中医证候积分和深睡眠质量评分均显著低于实验I组与对照组（P＜0.05）,实验II组治疗8 h、24 h、48 h后的VAS评分均显著低于实验I组与对照组（P＜0.05）。结论：清咽滴丸药物冰块治疗可有效缓解甲状腺术后咽痛及相关临床症状,改善患者睡眠质量,具有良好的临床应用价值。     

The Spread of Sleep Loss Influences Drug Use in Adolescent Social Networks

Troubled sleep is a commonly cited consequence of adolescent drug use, but it has rarely been studied as a cause. Nor have there been any studies of the extent to which sleep behavior can spread in social networks from person to person to person. Here we map the social networks of 8,349 adolescents in order to study how sleep behavior spreads, how drug use behavior spreads, and how a friend''s sleep behavior influences one''s own drug use. We find clusters of poor sleep behavior and drug use that extend up to four degrees of separation (to one''s friends'' friends'' friends'' friends) in the social network. Prospective regression models show that being central in the network negatively influences future sleep outcomes, but not vice versa. Moreover, if a friend sleeps ≤7 hours, it increases the likelihood a person sleeps ≤7 hours by 11%. If a friend uses marijuana, it increases the likelihood of marijuana use by 110%. Finally, the likelihood that an individual uses drugs increases by 19% when a friend sleeps ≤7 hours, and a mediation analysis shows that 20% of this effect results from the spread of sleep behavior from one person to another. This is the first study to suggest that the spread of one behavior in social networks influences the spread of another. The results indicate that interventions should focus on healthy sleep to prevent drug use and targeting specific individuals may improve outcomes across the entire social network.     

重复经颅磁刺激联合阿普唑仑治疗失眠症伴焦虑患者的效果分析

摘要 目的：研究重复经颅磁刺激以及阿普唑仑联用治疗失眠症伴焦虑患者的效果。方法：选择2015年1月～2019年12月我院神经内科收治的81例失眠症伴焦虑患者,将其随机分为两组。对照组每晚在睡前30 min服用阿普唑仑0.8 mg,观察组联用重复经颅磁刺激。比较两组的临床疗效,治疗前后焦虑评分、生活质量和睡眠质量评分的变化。结果：治疗后,观察组的有效率为95.00 %,明显高于对照组(73.17 %,P<0.05);两组焦虑评分均较治疗前明显降低(P<0.05),心理领域、社会领域、环境领域和生理领域评分均较治疗前明显升高(P<0.05),且观察组的焦虑评分和心理领域、社会领域、环境领域、生理领域评分明显优于对照组(P<0.05);两组的睡眠持续性、主观睡眠质量、睡眠障碍、日间功能、睡眠潜伏期、安眠药物和入睡时间评分均较治疗前明显升高(P<0.05),且观察组以上指标均明显高于对照组(P<0.05)。结论：重复经颅磁刺激以及阿普唑仑联用治疗失眠症伴焦虑患者的效果明显优于单用阿普唑仑治疗,其能有效减轻其焦虑程度,提高患者生活质量及睡眠质量。     

Effect of sleep restriction on orthostatic cardiovascular control in humans.

We hypothesized that sleep restriction (4 consecutive nights, 4 h sleep/night) attenuates orthostatic tolerance. The effect of sleep restriction on cardiovascular responses to simulated orthostasis, arterial baroreflex gain, and heart rate variability was evaluated in 10 healthy volunteers. Arterial baroreflex gain was determined from heart rate responses to nitroprusside-phenylephrine injections, and orthostatic tolerance was tested via lower body negative pressure (LBNP). A Finapres device measured finger arterial pressure. No difference in baroreflex function, heart rate variability, or LBNP tolerance was observed with sleep restriction (P > 0.3). Systolic pressure was greater at -60 mmHg LBNP after sleep restriction than before sleep restriction (110 +/- 6 and 124 +/- 3 mmHg before and after sleep restriction, respectively, P = 0.038), whereas heart rate decreased (108 +/- 8 and 99 +/- 8 beats/min before and after sleep restriction, respectively, P = 0.028). These data demonstrate that sleep restriction produces subtle changes in cardiovascular responses to simulated orthostasis, but these changes do not compromise orthostatic tolerance.     

Effect of tranquilizers of the 1,4-benzodiazepine series on the xanthine oxidase activity of the rat brain

Experiments in vivo and in vitro on 90 rats were made to study the influence of 1,4-benzodiazepine tranquilizers (phenazepam, nitrazepam and diazepam) on cerebral xanthine oxidase activity. Phenazepam, nitrazepam and diazepam in the dose of 5 mg per 200 g bw were shown to reduce xanthine oxidase activity by 80.4%, 64.3% and 55.8%, respectively 2 h after intraperitoneal injection. 6 h after the injection of benzodiazepines the enzyme activity grows, but control values are achieved only after nitrazepam injection. In vitro experiments revealed direct influence of the tranquilizers on xanthine oxidase. Phenazepam inhibits xanthine oxidase activity in concentration as long as 10(-10) M (to 36.6%), and practically completely in 10(-6) M concentration. Nitrazepam and diazepam inhibit xanthine oxidase activity within concentration range between 10(-8) M (to 51.5% and 33.2%, respectively), and 10(-4) M (practically completely). The inhibition of xanthine oxidase activity is shown to be caused by the competition between hypoxanthine, the reaction substrate, and tranquilizer, to bind with the active site of the enzyme.     

The Sleep,Subjective Fatigue,and Sustained Attention of Commercial Airline Pilots during an International Pattern

International commercial airline pilots may experience heightened fatigue due to irregular sleep schedules, long duty days, night flying, and multiple time zone changes. Importantly, current commercial airline flight and duty time regulations are based on work/rest factors and not sleep/wake factors. Consequently, the primary aim of the current study was to investigate pilots' amount of sleep, subjective fatigue, and sustained attention before and after international flights. A secondary aim was to determine whether prior sleep and/or duty history predicted pilots' subjective fatigue and sustained attention during the international flights. Nineteen pilots (ten captains, nine first officers; mean age: 47.42±7.52 years) participated. Pilots wore wrist activity monitors and completed sleep and duty diaries during a return pattern from Australia to Europe via Asia. The pattern included four flights: Australia‐Asia, Asia‐Europe, Europe‐Asia, and Asia‐Australia. Before and after each flight, pilots completed a 5 min PalmPilot‐based psychomotor vigilance task (PVT) and self‐rated their level of fatigue using the Samn‐Perelli Fatigue Checklist. Separate repeated‐measures ANOVAs were used to determine the impact of stage of flight and flight sector on the pilots' sleep in the prior 24 h, self‐rated fatigue, and PVT mean response speed. Linear mixed model regression analyses were conducted to examine the impact of sleep in the prior 24 h, prior wake, duty length, and flight sector on pilots' self‐rated fatigue and sustained attention before and after the international flights. A significant main effect of stage of flight was found for sleep in the prior 24 h, self‐rated fatigue, and mean response speed (all p<0.05). In addition, a significant main effect of flight sector on self‐rated fatigue was found (p<.01). The interaction between flight sector and stage of flight was significant for sleep in the prior 24 h and self‐rated fatigue (both p<.05). Linear mixed model analyses indicated that sleep in the prior 24 h was a significant predictor of self‐rated fatigue and mean response speed after the international flight sectors. Flight sector was also a significant predictor of self‐rated fatigue. These findings highlight the importance of sleep and fatigue countermeasures during international patterns. Furthermore, in order to minimize the risk of fatigue, the sleep obtained by pilots should be taken into account in the development of flight and duty time regulations.     

A型肉毒毒素耳后注射治疗帕金森病合并神经性耳鸣患者的疗效探讨

摘要 目的：探讨A型肉毒毒素耳后注射治疗帕金森病合并神经性耳鸣患者的疗效。方法：收集2016年3月至2021年6月苏州大学附属第二医院耳鼻喉科或神经内科门诊就诊或住院的帕金森病患者,追问病史,发现部分患者有单侧或双侧耳鸣症状,并进行电测听+声导抗检查回报,其中有73 %患者有神经性听力下降,根据治疗方法将其分为A型肉毒毒素耳后注射组（实验组,22例）和地塞米松耳后注射组（对照组,22例）,A型肉毒毒素注射组予以100U A型肉毒毒素耳垂后方自上而下3个点注射,地塞米松注射组予以5 mg地塞米松耳垂后方自上而下3个点注射,对比两组鸣残疾评估量表（THI）评分、耳鸣评价量表（TEQ）评分、治疗总有效率、汉密尔顿焦虑量表（HAMA）和汉密尔顿抑郁量表（HAMD）评分、匹兹堡睡眠质量指数（PSQI）评分。结果：两组治疗前THI和TEQ评分比较无差异（P>0.05）,两组治疗后THI和TEQ评分均有所降低,且实验组均低于对照组（P<0.05）;实验组治疗后1周、治疗后4周、治疗后14周治疗总有效率为63.64 %、81.82 %、90.91 %,对照组治疗总有效率分别为63.64 %、63.64 %、72.73 %,两组治疗总有效率比较无差异（P>0.05）,但实验组略高于对照组;两组治疗前HAMA、HAMD评分比较无差异（P>0.05）,两组治疗后14周HAMA、HAMD评分均有多下降,且实验组均低于对照组（P<0.05）;两组治疗前入睡时间、睡眠时间、睡眠质量、睡眠效率、睡眠障碍、日间功能障碍、安眠药物评分以及总分比较无差异（P>0.05）,两组治疗后14周上述各项评分均有所降低,且实验组均低于对照组（P<0.05）。结论：A型肉毒毒素耳后注射治疗帕金森病合并神经性耳鸣患者,可改善耳鸣症状,提高临床治疗效果,缓解焦虑抑郁情绪,改善睡眠质量,值得临床不断深入研究。     

Chronic Fenfluramine Administration: Some Cerebral Effects

Human cerebral function was monitored electrophysiologically during sleep over a period of months before, during, and after the intake of fenfluramine, 40-120 mg/day. Effects included dose-related reduction of paradoxical sleep, increase of intra-sleep restlessness, and changes in E.E.G. slow-wave sleep. It is hypothesized that weight loss may be associated with increase of the last. Grinding of teeth (bruxism) also was noted.Long-term studies make it possible to demonstrate changing central effects with time, including tolerance phenomena. Withdrawal abnormalities are related to the time taken for the drug to be eliminated—in the present case reaching a maximum four days after withdrawal.     

Effect of Nitrazepam in Chronic Obstructive Bronchitis

The effect of nitrazepam on ventilatory capacity and arterial blood gas tensions was studied in a double-blind controlled crossover trial in six patients with chronic obstructive bronchitis in ventilatory failure (raised Paco₂). Nitrazepam produced a fall in ventilatory capacity and worsening of the ventilatory failure. In the sixth patient, while on the active drug, the Pao₂ fell from 48 to 35 mm Hg while the Paco₂ tension rose from 59·5 to 68 mm Hg. It is suggested that nitrazepam is contraindicated in patients with severe chronic obstructive bronchitis.     

Evaluation of single-dose hypnotic treatment before elective operation.

A prospective randomised double-blind controlled trial was carried out to evaluate the place of a single dose of triazolam, flurazepam, and placebo on the evening before an elective operation in 96 patients. Features of sleep were recorded by patients and nurses on questionnaires. Onset of sleep was delayed and duration of sleep reduced in two-thirds of patients allocated placebo compared with their normal sleep pattern. Two-thirds of these patients also complained of waking more than twice during the night. Both hypnotics significantly improved the duration and time of onset of sleep and reduced the frequency of wakening when compared with the placebo. Patients who took triazolam, however, fell asleep faster and woke less often than those who took flurazepam. Furthermore, triazolam appeared to have advantages over flurazepam before surgery. Thus giving a single dose of a hypnotic on the night before an elective operation improves the patient''s sleep, and greater benefit was derived from triazolam than flurazepam.