A comparative study of three hypnotics: methyprylon,glutethimide and chloral hydrate

A controlled study designed to evaluate the hypnotic potentiality of methyprylon (300 mg.), glutethimide (500 mg.) and chloral hydrate (1000 mg.) was carried out on 50 in-patients experiencing long-standing insomina. The patients ranged in age from 21 to 60 years, the sexes were equally represented and the clinical diagnoses were psychoneurosis, reactive depression, or anxiety reaction. An interesting feature of the experimental design allowed for the exclusion of placebo reactors before the initiation of the main trials. No difference in effectiveness of maintaining sleep could be established among the three hypnotic agents, indicating that at the usual levels of statistical significance, all three agents were equally effective as hypnotics. However, a significant trend (P = .05) was found for methyprylon (Noludar) to be the most effective and chloral hydrate to be the least effective of the three drugs in maintaining sleep. Methyprylon was found statistically (P = .05) to be the fastest sleep-inducing agent, whereas glutethimide (Doriden) proved to be the slowest of the three hypnotics with respect to sleep induction time.     

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.     

K–STIMULATED ACETYLCHOLINE RELEASE: INHIBITION BY SEVERAL BARBITURATES AND CHLORAL HYDRATE BUT NOT BY ETHANOL, CHLORDIAZEPOXIDE OR 11-OH-Δ9-TETRAHYDROCANNABINOL

Abstract— Thiamylal, methohexital, secobarbital, amobarbital, pentobarbital, phenobarbital and barbital, and also chloral hydrate inhibited K-stimuiated acetylcholine (ACh) release from rat midbrain slices in a dose related manner. The concentrations required for 50% inhibition were related to the lipid partition coefficient. None of the barbiturates nor chloral hydrate inhibited unstimulated ACh release. Ethanol, chlordiazepoxide and 11-OH-Δ⁹-tetrahydrocannabinol were without effect on both unstimulated and stimulated ACh release. The results are discussed in terms of other effects of these drugs on the cholinergic system.     

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.     

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.     

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.     

Effect of anesthetics on efficiency of remote ischemic preconditioning

Remote ischemic preconditioning of hind limbs (RIPC) is an effective method for preventing brain injury resulting from ischemia. However, in numerous studies RIPC has been used on the background of administered anesthetics, which also could exhibit neuroprotective properties. Therefore, investigation of the signaling pathways triggered by RIPC and the effect of anesthetics is important. In this study, we explored the effect of anesthetics (chloral hydrate and Zoletil) on the ability of RIPC to protect the brain from injury caused by ischemia and reperfusion. We found that RIPC without anesthesia resulted in statistically significant decrease in neurological deficit 24 h after ischemia, but did not affect the volume of brain injury. Administration of chloral hydrate or Zoletil one day prior to brain ischemia produced a preconditioning effect by their own, decreasing the degree of neurological deficit and lowering the volume of infarct with the use of Zoletil. The protective effects observed after RIPC with chloral hydrate or Zoletil were similar to those observed when only the respective anesthetic was used. RIPC was accompanied by significant increase in the level of brain proteins associated with the induction of ischemic tolerance such as pGSK-3β, BDNF, and HSP70. However, Zoletil did not affect the level of these proteins 24 h after injection, and chloral hydrate caused increase of only pGSK-3β. We conclude that RIPC, chloral hydrate, and Zoletil produce a significant neuroprotective effect, but the simultaneous use of anesthetics with RIPC does not enhance the degree of neuroprotection.     

Influence of different anaesthetics on pro-inflammatory cytokine expression in rat spleen

We examined the effect of five anaesthetic drugs commonly used in laboratory animal research (tribromoethanol, ketamine/xylazine, chloral hydrate, pentobarbital, and urethane) on the expression of four pro-inflammatory cytokines. The anaesthetic agents were applied at dosages normally used for deep surgical anaesthesia. Semiquantitative image analysis of interleukin (IL)-1beta, IL-2, IL-6, and tumour necrosis factor alpha (TNFalpha) mRNA expression in the spleen of male Wistar rats 4 h after application of the anaesthetic drugs showed that these had moderate immunomodulatory effects. Ketamine/xylazine, chloral hydrate, and pentobarbital enhanced the basal expression of IL-1beta and IL-6 mRNA in rat spleen, while urethane reduced splenic IL-1beta mRNA expression. Tribromoethanol, ketamine/xylazine, and urethane reduced the basal TNFalpha mRNA levels, whereas TNFalpha mRNA expression was unaffected by chloral hydrate and by pentobarbital. The data demonstrate that these anaesthetics have slight, but significant, effects on the basal immune status of rats.     

Caffeine and theophylline counteract diazepam effects in man

A total of 237 healthy subjects were studied in four placebo-controlled double-blind trials with parallel treatment groups. The subjects ingested a capsule (diazepam or placebo) and decaffeinated coffee with or without added caffeine or theophylline. Diazepam (10 and 20 mg) impaired dose dependently cognitive skills as measured by digit symbol substitution and letter cancellation, the balance of extraocular muscles, flicker fusion, and tapping speed. With diazepam 10 mg statistically significant effects were seen on digit symbols and exophoria only. Theophylline (10 mg/kg) increased tapping speed and heart rate, whereas other objective measurements were negative for the effects of theophylline or caffeine (250 and 500 mg) alone. Subjectively they reduced calmness, and caffeine also increased alertness. Caffeine 250 mg counteracted diazepam induced (10 mg) impairment of cognitive skills and relaxation of extraocular muscles whereas caffeine 500 mg counteracted the same effects of diazepam 20 mg, respectively. Theophylline antagonized diazepam-induced impairment in digit symbol substitution and tapping speed tests. Subjectively, caffeine and theophylline counteracted diazepam induced drowsiness and mental slowness. The results suggest, therefore, that the ample use of methylxanthines compensates various side-effects of benzodiazepines in man. It may also increase the need of sedation and thus the consumption of benzodiazepines.     

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.     

Differential Effects of Chloral Hydrate and Pentobarbital Sodium on a Cocaine Level and Its Catecholamine Response in the Medial Prefrontal Cortex: A Comparison with Conscious Rats

Abstract: Adult male Sprague-Dawley rats anesthetized with chloral hydrate and pentobarbital sodium were used as two different treatment groups. Conscious rats were used as a control group. By using baseline (precocaine) concentration as 100%, after cocaine administration (3.0 mg/kg i.v.), the maximal dopamine (DA) increase occurring at the first microdialysis collection period (20 min) in the medial prefrontal cortex was 299 ± 46% for the chloral hydrate group, 168 ± 12% for the pentobarbital sodium group, and 325 ± 23% for the conscious group. At the same time, norepinephrine (NA) increases reached a maximum and were 162 ± 20%, 100 ± 5%, and 141 ± 17%, respectively. The maximal changes of DA and NA in the chloral hydrate group and in the control group were both significantly higher than that in the pentobarbital sodium group. Meanwhile, the cocaine concentration was higher over a 100-min period of time in the chloral hydrate group when compared with the pentobarbital group and the control group. The peak cocaine concentration in dialysate occurred in the same time slot of maximal DA and NA responses, which were 0.65 ± 0.08, 0.30 ± 0.02, and 0.41 ± 0.05 µ M , respectively. Anesthetics suppress the pharmacologic response of neurons, which may explain the difference in catecholamine response between the pentobarbital sodium and the conscious groups. Conversely, because there was no significant difference in DA and NA response between the chloral hydrate group and the conscious group, it may possibly be due to the balancing effect between the higher existing cocaine concentration and the anesthetic suppression on pharmacological response of neurons in the chloral hydrate group. The effect of guide cannula implantation on the cocaine-induced catecholamine response was also evaluated.     

Fate of 2,2,2-trichloroacetaldehyde (chloral hydrate) produced during trichloroethylene oxidation by methanotrophs.

Four different methanotrophs expressing soluble methane monooxygenase produced 2,2,2-trichloroacetaldehyde, or chloral hydrate, a controlled substance, during the oxidation of trichloroethylene. Chloral hydrate concentrations decreased in these cultures between 1 h and 24 h of incubation. Chloral hydrate was shown to be biologically transformed to trichloroethanol and trichloroacetic acid by Methylosinus trichosporium OB3b. At elevated pH and temperature, chloral hydrate readily decomposed and chloroform and formic acid were detected as products.     

Effect of maintaining frog sartorius muscles in a number of chloral hydrate solutions on their resistance to the harmful action of this substance]

A study was made of the effect of maintenance of m. sartorius of the grass frog in several concentrations of chloral hydrate (0.0025 M, 0.005 M, 0.008 M, 0.01 M, and 0.02 M) on their resistance to 0.08 M concentration of this substance. The increase in resistance of muscles was observed after the maintenance in all the several concentrations of the agent except one (0.02 M). The increase in resistance was maximal after a 5 minute maintenance in any concentration. The optimal dose of the effect was a 5 minute maintenance in 0.005 M chloral hydrate solution. In this case the increase in resistance to 0.08 chloral hydrate was the highest (about 23%). The study of the effect of optimal doses on the resistance of muscle tissue to 0.12 M solution fluoride, 3.48 M ethyl alcohol and to 36 derees showed a statistically significant increase in resistance from 22.7 to 39.4%.     

Fate of 2,2,2-trichloroacetaldehyde (chloral hydrate) produced during trichloroethylene oxidation by methanotrophs.

Four different methanotrophs expressing soluble methane monooxygenase produced 2,2,2-trichloroacetaldehyde, or chloral hydrate, a controlled substance, during the oxidation of trichloroethylene. Chloral hydrate concentrations decreased in these cultures between 1 h and 24 h of incubation. Chloral hydrate was shown to be biologically transformed to trichloroethanol and trichloroacetic acid by Methylosinus trichosporium OB3b. At elevated pH and temperature, chloral hydrate readily decomposed and chloroform and formic acid were detected as products.     

Staining Paraffin Sections with Protargol 5. Chloral Hydrate Mixtures, with and Without Formamide, for Fixing Peripheral Nerves

A series of experiments was directed toward finding a means of improving fixation of mammalian glandular tissue and peripheral nerves with chloral hydrate. Specimens from cat, dog, rat, guinea pig, and man were fixed in solutions of 5-15% chloral hydrate in ethyl, methyl, and propyl alcohols, both pure and diluted with varying amounts of water. Modifiers were added, including acids, alkalies, alkaloids, amines, formamide, pyridine, piperidine, and formalin. The sectioned material was stained by the 2-hour method (AgNO₃-protargol) described previously (Davenport et al., 1939). The acidification of alcoholic chloral hydrate mixtures was deleterious to fixation but alkalinization was not. Among the modifiers, formamide was the one which showed definite improvement of fixation. A 10% solution of formamide alone in 50% ethyl alcohol gave good fixation and staining of peripheral nerve trunks, but addition of 5-7% chloral hydrate to this mixture improved staining. Treatment with 1% ammoniated alcohol after fixation and before embedding was of no value in section staining. Block stains were not tried.     

Effect of Chloral Hydrate on Methane and Propionic Acid in the Rumen

Methane production from pyruvate by mixed rumen bacteria in vitro was nearly totally inhibited by chloral hydrate (0.1 mumole/ml of incubation fluid). This effect was accompanied by an accumulation of gaseous hydrogen and an increase in propionic acid production. Infusion of chloral hydrate (4 g/day) into the rumen of a sheep produced the same effects. Evidence is presented for a direct toxic effect of chloral hydrate upon methane bacteria. Results are discussed in terms of fermentation balances.     

Effects of hypnotic drugs on memory

An original design and new task procedures were used to evaluate the effects of morning recall of flunitrazepam 2 mg and secobarbital 100 mg taken at bedtime the previous night. Both flunitrazepam and secobarbital produced anterograde amnesia on the morning following the first drug night; with flunitrazepam, this effect was still evident on the third drug night, but did not appear to be related to plasma drug concentrations. These results suggest that when patients ingest certain benzodiazepine hypnotics before or at bedtime, there may be a decrement in memory retrieval of information acquired before sleep onset or during nocturnal awakenings. Further studies are needed to determine whether the anterograde amnesia produced by benzodiazepine drugs is an aspect of state-dependent learning.     

Trial of atenolol and chlorthalidone for hypertension in black South Africans.

Twenty-four black patients (Zulus) with hypertension participated in a double-blind, placebo-controlled cross-over trial of the efficacy of a beta-blocking agent (atenolol) 100 mg once daily as compared with chlorthalidone 25 mg once daily. The two drugs were also given combined at these doses and the effects compared with those of the drugs given alone. Atenolol as sole treatment had no appreciable effect on blood pressure as compared with placebo. Chlorthalidone produced a small decrease, but this was not statistically significant. Combining the two drugs, however, produced a significant reduction in blood pressure (mean lying blood pressure p < 0.001; mean standing blood pressure p < 0.0002). These findings suggest that beta-blockers should not be regarded as baseline treatment of hypertension in blacks.     

Influence of O(3)/O(2)-pneumoperitoneum as an oxidative stressor on duration of anaesthesia, loss of different reflexes and cytokine mRNA expression

We analysed the effect of intraperitoneal insufflated ozonized oxygen on the anaesthetic strength generated by tribromoethanol, ketamine/xylazine, chloral hydrate, pentobarbital, and urethane in male Wistar rats. High dosages of anaesthetic drugs normally used for deep surgical anaesthesia were injected. The ozonized oxygen gas mixture was given five times daily on five consecutive days at 0.8 mg ozone/kg body weight before anaesthesia. The reflexes were measured 15, 30, 60, 90, 120, 180, and 240 min after injection of the anaesthetic drug. The sleeping time and the loss and regain of six different reflexes on noxious and non-aversive stimuli were recorded during the 4 h of observation. O(3)/O(2)-pneumoperitoneum (O(3)/O(2)-PP) reduced the sleeping time induced by tribromoethanol and ketamine/xylazine and increased it for chloral hydrate and pentobarbital. In accordance to the changes in the duration of anaesthesia, the O(3)/O(2)-PP induced significant changes in the loss of different reflexes. Additionally, the modulatory effect of the anaesthetic drugs on splenic cytokine mRNA expression was further influenced by O(3)/O(2)-PP. Thus, the influence of an oxidative stressor on anaesthetic potency and on the resting immune system has to be taken into account for experimental designs in which surgical anaesthesia is necessary for small laboratory animals.     

一种简易小鼠尾部皮肤移植教学实验改良方法的建立

目的 为本校生物工程系实验动物学课程小鼠尾部皮肤移植实验课提供一种合适的操作方法.方法 分别用0.7%、1%、1.5%戊巴比妥钠和10%水合氯醛对小鼠进行麻醉试验,选出合适的麻醉方法;再进行小鼠尾部皮肤移植,对比玻璃套管法和创可贴法2种包扎方法的效果,以选出合适的手术方法.结果 0.7%和1%戊巴比妥钠麻醉持续时间过短,1.5%戊巴比妥钠和10%水合氯醛能维持足够手术操作所需的时间,但1.5%戊巴比妥钠易导致动物死亡,故采用10%水合氯醛麻醉小鼠较合适;玻璃套管法包扎的效果较创可贴法为好且更简便.结论 10%水合氯醛麻醉结合玻璃套管法包扎进行小鼠尾部皮肤移植是一种有效、简便、经济的小鼠尾部皮肤移植手术实验方法;此方法技术失败率低,适合学生实验课采用.