A Clinical Evaluation of Four Hypnotic Agents,Using a Latin-Square Design

A double-blind study with a Latin-square design was undertaken on 25 elderly patients, using a placebo and four hypnotic drugs: ethchlorvynol 500 mg., glutethimide 500 mg., chloral hydrate 500 mg., and secobarbital sodium 100 mg. The trial lasted for five weeks. The drugs were all effective compared with the placebo, differences in sleeping time being statistically significant. Differences between these four drugs were not statistically significant. Sleep was induced soonest by secobarbital and ethchlorvynol. Ethchlorvynol and glutethimide had a relatively somewhat longer period of activity than the others. Glutethimide produced most side effects, especially morning drowsiness. Ethchlorvynol and chloral hydrate produced relatively few cases of drowsiness.     

The effect of previous administration of adrenaline or isoprenaline on the activity of several hypnotics in mice]

Previous administration of adrenaline (0.5 mg/kg i.p.) and isoprenaline (10 mg/kg i.p.) enhances activity of several hypnotic drugs (pentobarbital, barbital, chloral hydrate) in mice but is without effect upon hypnotic activity of ethanol. This potentialisation is blocked by previous administration of pindolol, but not by phentolamine. Administration of SKF 525 A demonstrates that metabolism of pentobarbital is modified by this enzymatic inhibitor, which is not the case for other hypnotics.     

Clinical and Statistical Evaluation of Six Hypnotic Agents

Six hypnotic drugs and a placebo were coded and administered at random, one dose at 8 p.m., to 20 patients in a Toronto hospital. A special evaluation scale was used, studying average duration of sleep, time of onset of sleep, quality of sleep and side effects. Secobarbital sodium and methyprylon were statistically significantly more effective than the placebo. The other drugs, glutethimide and three quinozolinone derivatives, were not statistically different from the placebo in their effects. The placebo effect itself was studied. A particular feature of this report is the detailed statistical treatment of the data collected.     

A Clinical Trial of Four Hypnotic Drugs

A clinical trial of four hypnotic drugs was carried out: Ro 4-5360, 10 mg. (Mogadon), methyprylon, 200 mg. (Noludar), Ro 4-5360, 5 mg. (Mogadon), secobarbital sodium, 100 mg. (Seconal), and a placebo. The study was on the usual double-blind basis, and all observations were made by a full-time nurse. Capsules were given at 10 p.m. for five successive nights, with two nights free from medication or observation. There were five such periods. The nurse carried out her observations right through the night, determining whether the patients were awake or asleep. Each of these drugs was statistically significantly different from the placebo, in terms of length of sleep. Differences between the individual drugs were not significant. The length of action of the various drugs appeared to be similar, with a somewhat longer period of activity for the Mogadon in both dosages. The major side effect was some drowsiness: this was more marked with Mogadon 10 mg. With the hypnotics, the patients had, on the average, about one hour more sleep than on the placebo.     

Chloral hydrate mediated inhibition of cell division and of protein synthesis

Summary Chloral hydrate (along with other anaesthetics and hypnotics) is an inhibitor of cell division. We have shown that chloral hydrate is also an inhibitor of protein synthesis. This inhibition is unlikely to be a result either of the disruption of cell division or of interference with the function of microtubules. The ability of chloral hydrate to inhibit cell division may result from its ability to inhibit protein synthesis.This research was supported by USPHS grant No GMO6965.     

Differential effects of chloral hydrate- and ketamine/xylazine-induced anesthesia by the s.c. route

The proper use of anesthetics in animal experimentation has been intensively studied. In this study we compared the use of chloral hydrate (500 mg kg(-1)) and ketamine (167 mg kg(-1)) combined with xylazine (33 mg kg(-1)) by the s.c. route in male Wistar rats. Chloral hydrate and ketamine/xylazine produced a depth of anesthesia and analgesia sufficient for surgical procedures. The decrease of systolic and diastolic blood pressure was of a higher magnitude in rats anesthetized with chloral hydrate than with ketamine/xylazine. The initial microvascular diameter and blood flow velocity did not differ between both agents. On the other hand, ketamine/xylazine reduced the heart rate more intensively than chloral hydrate. Both anesthetics promoted an increase in arterial pCO(2) and a decrease in pH levels compared to unanesthetized animals. The blood glucose levels were of a higher magnitude in rats after ketamine/xylazine anesthesia than after chloral hydrate. In mesenteric arterioles studied in vivo, ketamine/xylazine anesthesia reduced the constrictive effect of noradrenaline and the dilator effect of bradykinin. However, both anesthetics did not modify the vasodilator effect promoted by acetylcholine. Based on our data, we concluded that both anesthetics alter metabolic and hemodynamic parameters, however the use of chloral hydrate in studies of microvascular reactivity in vivo is more appropriate since ketamine/xylazine reduces the responses to vasoactive agents and increases blood glucose levels.     

1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline-induced apoptosis in the human neuroblastoma cell line SK-N-SH

Trichloroethylene, a common industrial solvent and a metabolic precursor of chloral hydrate, occurs widely in the environment. Chloral hydrate, which is also used as a hypnotic, has been found to condense spontaneously with tryptamine, in vivo, to give rise to a highly unpolar 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) that has a structural analogy to the dopaminergic neurotoxin N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Earlier studies have revealed the relative permeability of the molecule through the blood-brain barrier and its ability to induce Parkinson-like symptoms in rats. In this study, we report that TaClo induces an apoptotic pathway in the human neuroblastoma cell line, SK-N-SH, involving the translocation of mitochondrial cytochrome c to the cytosol and activation of caspase 3. TaClo-induced apoptosis shows considerable differences from that mediated by other Parkinson-inducing agents such as MPTP, rotenone and manganese. Although it is not clear if the clinically administered dosage of chloral hydrate or the relatively high environmental levels of trichloroethylene could lead to an onset of Parkinson's disease, the spontaneous in vivo formation of TaClo and its pro-apoptotic properties, as shown in this report, should be considered.     

不同时间段睡眠剥夺配合改良式水合氯醛保留灌肠法在婴幼儿肺功能检查中的效果分析

摘要 目的：探讨不同时间段睡眠剥夺配合改良式水合氯醛保留灌肠法在婴幼儿肺功能检查中的镇静效果。方法：前瞻性选取2018年2月~2020年8月本院收治并需行肺功能检查的婴幼儿临床资料,纳入194例婴幼儿作为研究对象,根据随机数字表法简单随机分为四组。对照组（n=48）不进行睡眠剥夺,短时段组（n=48）行短时段睡眠剥夺,中时段组（n=49）行中时段睡眠剥夺,长时段组（n=49）行长时段睡眠剥夺。对比四组婴幼儿的入睡时间、镇静效果及不良反应。结果：四组婴幼儿入睡时间的组间差异具有统计学意义（P＜0.05）。与对照组相比,联合睡眠剥夺干预的三组婴幼儿在10 min内进入睡眠的例数明显增多;随着睡眠剥夺时间增加,睡眠剥夺的三组婴幼儿超过30 min才进入睡眠的例数明显少于对照组。四组婴幼儿镇静效果的组间比较差异具有统计学意义（P＜0.05）;与对照组相比,联合睡眠剥夺干预的三组婴幼儿镇静效果明显升高,镇静总有效率均高于对照组（P＜0.05）。在实验期间,四组婴幼儿均出现不同类型的不良反应,各类型不良反应发生率及总发生率的组间比较,差异均无统计学意义（P>0.05）,但长时段组出现情绪烦躁的比例略高。结论：睡眠剥夺配合改良式水合氯醛灌肠法对婴幼儿具有良好的镇静效果,但长时段睡眠剥夺可能会使其情绪烦躁,需在检查完成后悉心安抚婴幼儿情绪。     

Evaluating the effectiveness of a process medical audit in a teaching general hospital.

Medical auditing has moved beyond the traditional chart review to the process audit, which identifies deficiencies in care and suggests remedies. In 1981 the audit committee of the Department of Psychiatry at Toronto General Hospital audited the use of hypnotic drugs in the inpatient unit. The audit produced two recommendations: that nursing staff record sleep graphs for inpatients more often, and that an educational program be instituted to change the physicians'' patterns of prescribing hypnotics. In 1983 the audit was repeated to test the effectiveness of the 1981 auditing process. The 1981 recommendation produced the desired improvement in recording of sleep graphs. However, the medical staff failed to change their patterns of prescribing hypnotics: oxazepam remained the preferred hypnotic. For the process audit to be effective in improving patient care those using it must ensure that the methods reflect the nature and structure of the professional group they are trying to influence.     

Identification of the dopaminergic neurotoxin 1-trichloromethyl-1,2, 3,4-tetrahydro-beta-carboline in human blood after intake of the hypnotic chloral hydrate.

1-Trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo), a potent toxin toward dopaminergic neurons, readily originates in vitro from the biogenic amine tryptamine and the unnatural aldehyde chloral. For this reason, this heterocycle has been postulated to be formed endogenously in humans after administration of the hypnotic chloral hydrate or after exposure to the industrial solvent trichloroethylene by a spontaneous chemical ring closure reaction. In this paper, we report on the first identification of TaClo in blood samples of patients treated orally with chloral hydrate. Using a specific and sensitive gas chromatographic screening procedure based upon electron-capture and mass-selective detection, TaClo was determined after conversion to its volatile trifluoroacetyl derivative. The identity of TaClo in humans was clearly demonstrated by GC-MS analysis in selected-ion-monitoring mode, by the characteristic chlorine isotopic pattern of the molecular ion.     

The effect of desflurane on ameliorating cerebral infarction in rats subjected to focal cerebral ischemia-reperfusion injury

To obtain more information on the cerebral ischemia and reperfusion injury under desflurane anesthesia, we compared the infarct volume and lactate dehydrogenase (LDH) activity in rats subjected to focal cerebral ischemia during different concentration of desflurane anesthesia. Male Long-Evans rats weighing 270-350 g were anesthetized with desflurane in air at 1.0, 1.25 or 1.5 MAC whereas rats in the control group received intraperitoneal chloral hydrate (400 mg/kg) anesthesia. Cerebral infarction was induced by microsurgical procedures with ligation of the right middle cerebral artery (MCA) and clipping of the bilateral common carotid arteries (CCA) for 60 minutes. The rats were sacrificed 24 hours later, serial brain slices of 2mm thickness were taken and stained for the measurement of the infarct area. Cellular damage was evaluated by measuring the LDH level in the plasma. Desflurane (1.0, 1.25 or 1.5 MAC by inhalation) and chloral hydrate (400 mg/kg; ip.) did not produce any changes in pH, blood gases, heart rate or mean arterial blood pressure. In the rats subjected to focal cerebral ischemia, the volume of infarction was significantly less in the desflurane groups in all three different concentrations than in the chloral hydrate group. The changes of LDH activity in plasma also correlated with the result of the infarct volume. Our study suggests that desflurane may offer a neuroprotective effect such as decreased infarct volume after focal cerebral ischemia.     

The Effects of Apomorphine upon Local Cerebral Glucose Utilization in Conscious Rats and in Rats Anesthetized with Chloral Hydrate

The effects of the dopaminergic agonist apomorphine (1 mg . kg-1 i.v.) upon local cerebral glucose utilization in 43 anatomically discrete regions of the CNS were examined in conscious, lightly restrained rats and in rats anesthetized with chloral hydrate by means of the quantitative autoradiographic [14C]2-deoxyglucose technique. In animals anesthetized with chloral hydrate, glucose utilization was reduced throughout all regions of the CNS from the levels observed in conscious animals, although the magnitude of the reductions in glucose use displayed considerable regional heterogeneity. With chloral hydrate anesthesia, the proportionately most marked reductions in glucose use (by 40-60% from conscious levels) were noted in primary auditory nuclei, thalmaic relay nuclei, and neocortex, and the least pronounced reductions in glucose use (by 15-25% from conscious levels) were observed in limbic areas, some motor relay nuclei, and white matter. In conscious, lightly restrained rats, the administration of apomorphine (1 mg . kg-1) effected significant increased in glucose utilization in 15 regions of the CNS (e.g., subthalamic nucleus, ventral thalamic nucleus, rostral neocortex, substantia nigra, pars reticulata), and significant reductions in glucose utilization in two regions of the CNS (lateral habenular nucleus and anterior cingulate cortex). In rats anesthetized with chloral hydrate, the effects of apomorphine upon local glucose utilization were less widespread and less marked than in conscious animals. In only two of the regions (the globus pallidus and septal nucleus), which displayed increased glucose use following apomorphine in conscious rats, were significant increases in local glucose utilization observed with this agent in chloral hydrate-anesthetized rats. In the pars compacta of the substantia nigra, in which apomorphine increased glucose utilization in conscious animals, significant reductions in glucose utilization were observed following apomorphine in rats anesthetized with chloral hydrate. The profound effects of chloral hydrate anesthesia upon local cerebral glucose use, and the modification by this anesthetic regime of the local metabolic responses to apomorphine, emphasize the difficulties which exists in the extrapolation of data from anesthetized animals to the conditions which prevail in the conscious animal.     

Comparative Study to Determine the Optimal Melatonin Dosage form for the Alleviation of Jet Lag

To compare the impact of various dosage forms of melatonin and placebo on jet lag symptoms, 320 volunteers who had flights over 6 to 8 time zones were recruited for a double-blind, randomized, placebo-controlled study. The volunteers received either melatonin 0.5-mg fast-release (FR) formulation, melatonin 5-mg FR formulation, melatonin 2-mg controlled-release (CR) formulation, or placebo. The study medication was taken once daily at bedtime during 4 days after an eastward flight. The volunteers completed the Profile of Mood States (POMS), sleep log, and symptoms questionnaires once daily and the Karolinska Sleepiness Scale (KSS) three times daily prior to departure and during the 4 days of medication intake postflight. A total of 234 (73.1%) participants were compliant and completed the study. The FR melatonin formulations were more effective than the slow-release formulation. The 5-mg FR formulation significantly improved the self-rated sleep quality (p <. 05), shortened sleep latency (p <. 05), and reduced fatigue and daytime sleepiness (p <. 05) after intercontinental flight. The lower physiological dose of 0.5 mg was almost as effective as the pharmacological dose of 5.0 mg. Only the hypnotic properties of melatonin, sleep quality and sleep latency, were significantly greater with the 5.0-mg dose. (Chronobiology International, 15(6), 655-666, 1998)     

Breath Pentane as a Potential Biomarker for Survival in Hepatic Ischemia and Reperfusion Injury��A Pilot Study

Background

Exhaled pentane, which is produced as a consequence of reactive oxygen species-mediated lipid peroxidation, is a marker of oxidative stress. Propofol is widely used as a hypnotic agent in intensive care units and the operating room. Moreover, this agent has been reported to inhibit lipid peroxidation by directly scavenging reactive oxygen species. In this study, using a porcine liver ischemia-reperfusion injury model, we have evaluated the hypothesis that high concentrations of breath pentane are related to adverse outcome and that propofol could reduce breath pentane and improve liver injury and outcome in swine in this situation.

Methodology/Principal Findings

Twenty male swine were assigned to two groups: propofol (n = 10) and chloral hydrate groups (n = 10). Hepatic ischemia was induced by occluding the portal inflow vessels. Ischemia lasted for 30 min, followed by reperfusion for 360 min. Exhaled and blood pentane concentrations in the chloral hydrate group markedly increased 1 min after reperfusion and then decreased to baseline. Breath and blood pentane concentrations in the propofol group increased 1 min after reperfusion but were significantly lower than in the chloral hydrate group. A negative correlation was found between breath pentane levels and survival in the chloral hydrate group. The median overall survival was 251 min after reperfusion (range 150–360 min) in the chloral hydrate group. All of the swine were alive in the propofol group.

Conclusions

Monitoring of exhaled pentane may be useful for evaluating the severity of hepatic ischemia-reperfusion injury and aid in predicting the outcome; propofol may improve the outcome in this situation.     

Improved hypnotic treatment using chlormethiazole and temazepam.

The effects of a single 384 mg oral dose of chlormethiazole were compared with those of 20 mg of temazepam and placebo in healthy old and young women (mean ages 72.9 and 24.7 years respectively). Both drugs were effective hypnotics and had no detectable pharmacological action the next morning. Even four hours after administration performance of a simple psychomotor test was not impaired and sway (measured by an ataxiameter) was not increased in either age group. Pharmacokinetic studies showed that chlormethiazole was rapidly absorbed, distributed, and eliminated by both groups, so that minimal plasma concentrations existed 11 hours after administration. Temazepam, however, was less quickly absorbed and distributed, especially in the young group, and substantial amounts remained in the plasma 11 hours after administration. No unwanted effects occurred after temazepam, but 17 of the 20 subjects suffered from nasal irritation after taking chlormethiazole. Thus hangover effects may be avoided in elderly subjects after they have taken hypnotic drugs, and temazepam and chlormethiazole allow sleep to be interrupted safely.     

Treatment of insomnia in demented nursing home patients: a review

Insomnia and fragmentation are features of the sleep of these patients. In order to list the factors disturbing the sleep of demented nursing home patients and the interventions improving their sleep quality, the literature was reviewed. A Medline search over the period 1966-2000 was performed. This resulted in 22 research articles. Admission to a nursing home is associated with sleep disturbances caused by patient problems (e.g. pain), care routines (e.g. nightly nursing round) and environment (e.g. noise). There are indications that the use of hypnotics in nursing home patients is not always effective and increases the risk of falls. There are several ways to reduce hypnotic consumption in nursing homes. Non-pharmacological interventions to decrease sleep disturbances caused by environmental factors have a favourable although weak effect on sleep itself. By reducing nightly noise, sleep quality does not necessarily improve. Light therapy seems to be the most effective non-pharmacological method to strengthen the circadian sleep/wake rhythm. The struggle against insomnia without using medication perhaps requires a two tracks management: detection and elimination of disturbing environmental factors and implementation of an adequate method to strengthen the circadian sleep/wake rhythm.     

Ion-exchange chromatography in the presence of the non-ionic dissociating agent chloral hydrate. Application to a membrane protein, bovine heart cytochrome c oxidase.

In previous work we have shown that aq. 100% (w/v) chloral hydrate (2,2,2-trichloroethane-1,1-diol) is a potent non-ionic protein dissociating agent. We have employed it in systems of polyacrylamide-gel electrophoresis and have demonstrated the presence of 15 components in a preparation of bovine heart cytochrome c oxidase [Griffin & Landon (1981) Biochem. J. 197, 333-344]. Here we describe the use of solutions containing aq. 100% (w/v) chloral hydrate in the ion-exchange column chromatographic separation on CM-cellulose of the alpha- and beta-chains of human haemoglobin, which we have employed as a model protein of known structure. We also describe the use of similar procedures in order to fractionate the polypeptide components of bovine heart cytochrome c oxidase. An effective separation has been obtained and we suggest that chloral hydrate-containing solutions could have general application in the ion-exchange-chromatographic analysis of membrane proteins, a procedure that has had restricted use owing to the inadequacy of non-ionic dissociating agents available previously.     

Additional components of bovine heart cytochrome c oxidase demonstrated by high-resolution polyacrylamide-gel electrophoresis in the presence of chloral hydrate.

We have shown that aq. 100% (w/v) chloral hydrate (2,2,2-trichloroethane-1,1-diol) dissociates bovine heart cytochrome c oxidase. We have developed new procedures of polyacrylamide-gel electrophoresis in the presence of chloral hydrate that permit variation in the pH of the separation, and, by using these procedures, we have observed 15 components in preparations of the enzyme. This number contrasts with the eight bands that were seen on electrophoresis in the presence of SDS (sodium dodecyl sulphate) and urea. We have isolated material from these eight bands and have characterized each by electrophoresis in the presence of chloral hydrate. Twelve of the fifteen components that were seen by electrophoresis in chloral hydrate were identified as constituents of the eight bands seen by electrophoresis in the presence of SDS and urea. Two-dimensional electrophoretic separations confirmed these identifications ans showed that the other three components which were resolved as discrete bands by electrophoresis in the presence of chloral hydrate appeared to be diffusely present in the electrophoretic separations performed in the presence of SDS and urea, which suggested anomalous behaviour in that detergent. Trypsin treatment of cytochrome c oxidase caused total loss, as observed by electrophoretic separations in the presence of chloral hydrate, of a number of components. The trypsin-sensitive components included all of those that behaved anomalously in the presence of SDS and urea. Chloral hydrate is a potent non-ionic dissociating agent for cytochrome c oxidase and its use in polyacrylamide-gel electrophoresis, with variation in the pH of the gel, permits charge-dependent separations that should have general application in the analysis of membrane proteins.     

Comparative Clinical Study of Two Hypnotic Drugs

The comparative sleep-inducing and sleep-sustaining effects of glutethimide, 0.5 g., and ethchlorvynol, 0.5 g., were studied in 20 patients hospitalized for a considerable time (average: 21 years; minimum nine years and maximum 32 years) and not receiving psychotropic agents. Assessment of sleep and para-sleep parameters (pre-sleep tension; frequency of awakening at night; post-sleep activity) revealed that patients fell asleep faster (P>.001) and slept for a longer time with ethchlorvynol than with glutethimide.