Administration Of Chloral Hydrate Research Articles

Sodium-dependent high affinity choline uptake: a regulatory step in the synthesis of acetylcholine.

Abstract—The sodium‐dependent high affinity choline uptake into synaptosomes from rat brain has been studied after in vivo treatments which would alter the activity of cholinergic neurons. We utilized a number of treatments to reduce the activity of cholinergc neurons in the brain. Administration of pentobarbital (65 mg/kg), chloral hydrate (40 mg/kg) and γbutyrelactone (750 mg/kg) caused a 50‐80% reduction in sodium‐dependent high affinity choline uptake in several brain regions (30 min). This depression was not found 24 h after injection. Interruption of the cholinergic septal‐hippocampal or habenuleinterpeduncular tracts by lesions (10 min‐1 h) also caused a similar, large reduction in sodium‐dependent high affinity choline uptake in the hippocampus and the interpeduncular nucleus respectively.We reversed the inactivity after pentobarbital administration by direct electrical stimulation of the cholinergic septal‐hippocampal tract. Stimulation (40 Hz) for 10‐15 min completely reversed the depression in sodium‐dependent high affinity choline uptake. Stimulation at lower frequencies or for shorter times caused a partial reversal.Administration of pentylenetetrazol (75 mg/kg), a convulsant, was utilized to increase the activity of central cholinergic neurons. After drug administration, we found a large (60%) increase in sodium‐de‐pendent high affinity choline uptake. This increase was not found in the hippocampus when cholinergic afferents were interrupted by septal lesion prior to drug administration.We also examined the uptake after administration of cholinergic drugs. Oxotremorine (0.75 mg/kg), a muscarinic agonist which reduces acetylcholine release and turnover, caused a reduction in uptake. On the other hand, administration of scopolamine (5 mg/kg), a cholinergic antagonist which increases acetylcholine turnover, caused an increase in sodium‐dependent high affinity choline uptake. Addition of any drug utilized, drectly to uptake samples, did not alter uptake.We examined the conversion of [3H]choline to [3H]acetylcholine in hippocampal synaptosomes after septal lesion, pentylenetetrazol administration and in untreated controls. In all cases, 60‐70% of the total sodium‐dependent tritium content was present as [3H]acetylcholine. Evidence was presented that homoexchange is not or is less involved in choline uptake than in GABA uptake.A kinetic analysis of sodium‐dependent high affinity choline uptake was performed after all treatments. We found changes in Vmax, after all treatments, which were consistently in the same direction as the alterations in activity. The proposal is made that the sodium‐dependent high affinity choline uptake is coupled to cholinergic activity in such a way as to regulate the entry of choline for the maintenance of acetylcholine synthesis. The findings also lead us to propose that sodium‐dependent high affinity choline uptake in vitro be utilized as a rapid, relative measure of the activity of cholinergic nerve terminals in vivo.

Influence of anaesthetics on basal, perphenazine-induced and thyrotrophin releasing hormone-induced prolactin secretion in ovariectomized, oestrogen-treated rats.

Plasma levels of prolactin were determined, by radioimmunoassay, in ovariectomized, oestrogen-treated rats after administration of ether, sodium pentobarbitone, urethane, chloral hydrate or ketamine. These anaesthetics, when administered alone, induced sustained increases in the plasma level of prolactin (continuous ether inhalation), no change in prolactin secretion (urethane), or depressions in the level of prolactin (sodium pentobarbitone, chloral hydrate and ketamine). These same anaesthetics when given before perphenazine failed to alter the stimulatory effect of this phenothiazide on prolactin secretion. Sodium pentobarbitone did not alter the normal increase in prolactin concentration after intra-arterial administration of synthetic thyrotrophin releasing hormone (TRH). These results indicated that anaesthetics do not affect the response of either the central nervous system or the anterior pituitary to perphenazine or TRH although they affect prolactin secretion when administered alone. The site of action of anaesthetics must, therefore, be different from that of perphenazine or perphenazine must be capable of overcoming their influence by direct action on the pituitary.

Effect of paraoxon on the hypnotic action of chloral hydrate

Paraoxon decreased induction time (IT) and increased the duration of the loss-of-righting-reflex time (LORRT) of chloral hydrate (CH) and trichloroethanol (TCE) in mice. Atropine sulfate, but not the peripherally acting agents atropine methylnitrate and pralidoxime, prevented these effects of paraoxon on the activity of CH, suggesting that such effects may be mediated through a central cholinergic mechanism. Mice treated with paraoxon showed higher concentrations of CH and lower concentrations of TCE in brain and plasma 15 min after CH. However, paraoxon treatment of animals did not affect the rate of metabolism of CH by homogenates of their livers. Paraoxon treatment increased the permeability of the blood brain barrier to TCE at 5 min, but not at 30 min, after the administration of CH. The increased brain permeability to TCE may partially explain the shortened IT of CH in animals. Decreased brain concentrations of CH and TCE at both the loss and return of the righting reflex indicated that paraoxon increased the sensitivity of the brain to the depressant action of these hypnotics. Paraoxon, known to cause hypoxia, also caused hypothermia. The paraoxon-induced hypothermia, but not the effects on IT and LORRT, was prevented at 36°C ambient temperature. A single dose of sodium nitrite produced effects similar to those of paraoxon on the hypnotic activity of CH and TCE. It is suggested that a decreased rate of metabolism and an increased sensitivity of the central nervous system due to hypoxia is the primary mechanism by which paraoxon shortens the IT and prolongs the LORRT of CH and TCE.

Failure of diphenylhydantoin to prevent alcohol withdrawal convulsions in mice

Alcohol withdrawal reactions were induced in mice using an established technique. Mice, administered 1.0 mmole/kg pyrazole daily were exposed for 3 days to 10 mg/l ethanol vapor and withdrawal was brought about by discontinuation of the exposure. Diphenylhydantoin administered in doses of 12, 20 or 50 mg/kg by either of two routes (i.p. or p.o.), failed to have any discernable effect on the withdrawal. A 100 mg/kg dose of diphenylhydantoin increased seizure scores. Chloral hydrate administration in doses of 175, 244 or 350 mg/kg, on the other hand, lowered seizure scores in a manner which was dose related and prompt. These findings suggest that the clinical use of diphenylhydantoin for control of the seizures seen in alcohol withdrawal should be re-evaluated. The seizure scores of mice not exposed to ethanol but administered 1.0 mmole/kg pyrazole daily for 3 days were negligible and well within values obtained with naive control mice not exposed to any pharmacological agent.

The effects of long term administration of psychotropic drugs on human sleep: I. Methodology and the effects of placebo

These six papers present the effects on human sleep of long-term administration of reserpine (0.50 mg/day), amitriptyline (50 mg/day), chlorpromazine (50 mg/day), chloral hydrate (500 mg/day), and chlordiazepoxide (50 mg/day). This initial paper describes in detail the methodology of the entire study which involves six 60-day drug periods for each subject completing the protocol-one period on each of the five drugs and one period on placebo, in a balanced design. Measures of laboratory sleep, home sleep, and mood were obtained throughout the study. Comparisons between the long placebo-only period of this study and the more usual “baseline” period-laboratory nights 4-6-revealed a significantly higher total desynchronized sleep time (D-time) and D-time per cent in the placebo period. Other variables were not significantly different. Some clear changes over time within the long placebo period are also described.

Metabolism of pyrrolizidine alkaloids in the ovine rumen. IV. Effects of chloral hydrate and halogenated methanes on rumen methanogenesis and alkaloid metabolism in fistulated sheep

Five halogenated methane analogues (bromoform, chloroform, iodoform, carbon tetrabromide, and carbon tetrachloride) have been shown to inhibit methane formation in the sheep's rumen as well as in rumen fluid in vitvo. On a molar basis the methane analogues were 100-200 times as effective as chloral hydrate in vitro, but in the rumen this difference was reduced by a factor of 10 with four of the compounds and to parity with chloral hydrate in the case of carbon tetrachloride. When rumen methanogenesis was inhibited by administration of chloral hydrate, bromoform, or iodoform, the time taken for metabolism of 2 g of Heliotropium europaeum alkaloids was reduced to 25-40% of that taken in animals not so treated. These results support the conclusion that inhibition of methanogenesis may be a useful protective measure for sheep ingesting plants which contain hepatotoxic pyrrolizidine alkaloids.

Drug Interactions with Warfarin: Studies with Dichloralphenazone, Chloral Hydrate and Phenazone (Antipyrine)

1. Administration of dichloralphenazone, a complex of chloral hydrate and phenazone (antipyrine) caused a fall in steady-state plasma warfarin concentration and loss of anticoagulant control in five subjects. 2. This effect of dichloralphenazone is due to stimulation of the drug-oxidizing enzymes of the liver endoplasmic reticulum by antipyrine, the non-hypnotic part of the complex. Administration of antipyrine caused a fall in steady-state plasma warfarin concentration in five subjects, a shortening of the plasma warfarin half-life, with increased urinary excretion of the metabolites of 14C-labelled warfarin in two subjects and increased urinary excretion of 6β-hydroxycortisol which is formed in the liver endoplasmic reticulum. 3. Administration of chloral hydrate, the hypnotic part of dichloralphenazone, caused no change in anticoagulant control but a fall in steady-state plasma warfarin concentration in five subjects. This is due to the accumulation of trichloroacetic acid which displaces warfarin from plasma protein binding sites. 4. Individual differences in the extent of enzyme induction have been shown to be related to the subjects' rates of drug oxidation. 5. In the rat administration of dichloralphenazone and antipyrine, but not chloral hydrate, caused shortening of pentobarbitone sleeping time and of the plasma [14C]pentobarbitone half-life, shortening of the zoxazolamine paralysis time and increase in the maximal velocity of N-demethylation of ethylmorphine.

Enhanced Mortality of Selected Central Nervous System Depressants in Hypoexcretory Mice

The mortality of nine central nervous system depressant drugs was compared in normal and hypoexcretory mice. Anuria was produced in mice by penile ligation; cholestasis was produced by bile duct ligation. The intraperitoneal administration of prochlorperazine, trifluoperazine, perphenazine, meprobamate, and chloral hydrate produced significantly elevated mortality rates in anuric mice whereas promazine, perphenazine, and meprobamate showed elevated mortality rates in cholestatic mice. The mortality of chlorpromazine and phenobarbital was not altered in hypoexcretory mice.

The salivary secretion and clearance in the horse of chloral hydrate and its metabolites

The salivary secretion of chloral hydrate and its metabolites in the horse have been studied. The concentration of chloral hydrate and trichlorethanol in saliva approximated to that in the plasma, but saliva levels of trichloracetic acid were much lower than plasma levels. Chloral hydrate and trichlorethanol were quickly absorbed after oral administration. About 60 per cent of the dose of chloral hydrate was excreted in the urine as the glucuronide of trichlorethanol ; traces of free trichlorethanol and trichloracetie acid were also detected. After chloral hydrate administration the main plasma constituents were trichlorethanol, trichloracetic acid, and chloral hydrate. Trichloracetic acid persisted longest in the plasma. Chloral hydrate could only be detected in the plasma for four or five hours after its administration whereas the other two metabolites persisted for much longer. Methods for the determination of trichlorethanol and chloral hydrate by gas-liquid chromatography using electron capture have been described. Trichloracetic acid was measured using the Fujiwara reaction. 6

A Method of Anesthetizing the Chicken with Diethyl Ether

A review of literature pertaining to general anesthesia for chickens indicates a divergence of thought on the safety and effectiveness of various methods. Lee (5) and Schwarte (6) consider ether unsatisfactory and even dangerous for use on chickens, and favor oral or intravenous administration of chloral hydrate. Frank (3) indicates that the safety of ether anesthesia depends on the simultaneous administration of a proper proportion of air. Jones (4) maintains that ether has a relatively wide safety margin. Arnall (1) asserts that ether is a potent yet safe anesthetic. He also states that birds, possibly because of their high body temperatures, are able to effect an extremely rapid absorption, detoxication and elimination of drugs. He also points out that toxic quantities of volatile and gaseous anesthetics may be absorbed in a few seconds. The present work was done to develop a safe, effective method of anesthetizing mature chickens with the proper proportions of diethyl ether and air.

Maternal blood and cerebrospinal fluid estimation following the administration of chloral hydrate during the puerperium

Twenty-five unselected puerperal patients were included in this study. The cerebrospinal fluid was obtained by lumbar puncture on the third postpartum day; blood was also obtained from the patient at the same time. The medication was administered in rectal suppositories, 1.2 Gm. Specimens were taken at intervals from 30 minutes following administration of the suppository to 10 hours and 30 minutes.The amounts of chloral hydrate and trichloroacetic acid in the cerebrospinal fluid were small. Urochloralic acid passes into the cerebrospinal fluid in substantial quantities. Exceptionally large quantities of urochloralic acid were demonstrated in Patients 3 and 6. These patients were suffering from severe pre-eclampsia with evidence of liver damage.The concentration of trichloroethanol in the cerebrospinal fluid is variable, but in general is less than that of either chloral hydrate or trichloroacetic acid.

ABSORPTION OF DEXTROSE FROM THE COLON

The ease with which fluids can be introduced through the rectum into the colon has resulted in the widespread use of this method for the administration of a variety of substances. There is undoubtedly a paucity of evidence from carefully controlled experiments on the ability of the colonic mucous membrane to absorb protein, fat or carbohydrate. It is well known that the rectal administration of ether results in general anesthesia. More recently the success with which narcosis may be produced by the rectal administration of sodium amytal and avertin proves that fairly complicated molecules may be absorbed by the mucosa of the large bowel. The sedative effect produced by the colonic administration of chloral hydrate or sodium bromide is a well established clinical phenomenon. The bromide ion, when administered rectally in sufficient amounts, can be recovered from the urine, the sweat and the lacrimal secretions. Recently, Cohn,1in this

Cases with Mental Symptoms following the Administration of Chloral Hydrate

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Cases with Mental Symptoms following the Administration of Chloral Hydrate

Case I.—Mrs. A., ót. 55, married. Admitted into the Infirmary 14th April, 1875, suffering from aortic valvular disease, with sequelae. Ordered iron, digitalis, and gin, generous diet, and an unstinted supply of fresh milk. On account of the sleeplessness and restlessness, on the 30th April, there was prescribed for her 15 grs. of choral hydrate, to be taken at bedtime. A week afterwards this was doubled. About the middle of May she was observed to be getting decidedly “strange;” the mental aberration gradually increased, and towards the end of the month culminated in subacute mania, with hallucinations and illusions of sight. No improvement took place in the physical symptoms.