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1. The approximate oral LD50 for several barbiturates in the cat were as follows: seconal, 50 mg. per Kg.; pentobarbital, 100; the barbiturate of sigmodal, 110; pernoston, 135; phenobarbital, 175. Attention is called to the extreme individual variation which limits the precision of the LD50 values. 2. The courses of action after oral administration of the approximate LD50 dose in the cat are substantially similar for seconal, pentobarbital, the barbiturate of sigmodal, and pernoston, namely, onset of ataxia in about 5 minutes, maximum narcosis in about 30 minutes, duration of the full effects for about 18 hours, and disappearance of ataxia in 2 to 3 days. The onset in the case of phenobarbital is somewhat slower, and the time for disappearance of ataxia is about 3 times as long. 3. The duration of action of the barbiturate of sigmodal in the dog is somewhat shorter than in the cat. 4. Large doses of secondary amyl-beta-bromallyl barbituric acid (barbiturate of sigmodal) produce an irreversible damage of the central nervous system resulting in motor, postural and reflex abnormalities in about 8 per cent of cats, but not in dogs. 5. Large doses of secondary butyl-beta-bromallyl barbituric acid (pernoston) also possess this action on the central nervous system to some degree in cats. 6. This action on the central nervous system of the cat was not observed with several other compounds free of the bromallyl group, namely, seconal, pentobarbital, and phenobarbital. 7. In view of the species differences, the large doses of the barbiturate which were used to produce these central nervous system effects, and the absence of reports of such effects from their therapeutic use, these observations in the cat may not be applicable to the use of these barbiturates in humans, at least in the range of hypnotic doses.

Male rats were given vitamin A acetate orally either daily in a dose of 0, 0.83 or 10.0 mg/kg or every third day at three times this dose, 2 wk before and continuing after daily administration of 50 or 75 mg hexachlorophene (HCP)/kg. At certain levels and regimens, vitamin A offered partial protection against HCP toxicity, in that it retarded the rate at which deaths occurred but not the eventual outcome. The highest level of vitamin A (30 mg/kg) given every third day for 2 wk did not alter significantly the single-dose LD 50 of HCP. Vitamin A deficiency produced by omission of the vitamin from the diet considerably increased the toxicity of HCP after daily dosing at various levels. Cerebrospinal-fluid pressure in vitamin A-deficient control rats was 88 mm saline compared with 251 mm in HCP-treated normal rats. These quantitative differences suggest that these two factors exert independent and possibly additive effects rather than that vitamin A plays a primary role in the genesis of HCP neurotoxicity. Results do indicate, however, that the nutritional status of the animal affects its susceptibility to toxic halogenated hydrocarbons.

Minoxidil, a vasodilating antihypertensive drug, was given orally in doses of 0.5, 1.0, or 3.0 mg/kg to adult Beagle dogs on 2 consecutive days. Within 2 hr of administration, each of these doses produced hypotension and a marked tachycardia which persisted for as long as 24 hr after the second dose of minoxidil. Necropsies performed 24 hr after the second dose revealed focal, superficial areas of epicardial or endocardial hemorrhage in dogs given each of the three dose levels. Hemorrhage was associated with a mild inflammatory reaction and was not limited to the right atrium. Focal arteritis, characterized by extravasation of blood and by focal accumulation of erythrocytes and fibrin-like material in the walls of small coronary arteries, occurred in three hearts from the 3-mg/kg dose group. Myocardial necrosis was noted in one of eight dogs given the minimal pharmacologic dose of 0.5 mg/kg, and in five of eight dogs in each of the groups given 1 or 3 mg/kg. Necrosis was most frequent in the left ventricular papillary muscles, particularly the posterior one. An ischemic origin of the necrosis is suggested by the localization of the lesions and by the pharmacologic effects of minoxidil.

Cats trained in 4-6 weeks to obtain a reward (food pellet) were made 'neurotic' by a randomly occurring air blast at the reward box. Previous studies have shown that d-amphetamine facilitates development of 'neurotic' (conflict-induced) behavior. Caffeine, another stimulant, was examined to determine how it affects positive reinforcement behavior, induction of 'neurosis' and its interaction with depressants. Caffeine, given orally, induced stereotyped behavior, facilitated development of the 'neurotic' behavior and disrupted the feeding cycle. Chlorpromazine, pentobarbital, diazepam, prazepam and fluazepam delayed the onset of the caffeine-facilitated conflict behavior. Phenobarbital antagonized the caffeine effect. Studies of conflict-induced behavior in the cat appear to be useful for the investigation of drug interactions and for the detection of side effects of drugs that are not ordinarily considered to have effects on the central nervous system.

Cats given HCP (20 mg/kg) orally each day developed hindlimb paralysis and greatly elevated CSFP (174 mm saline; 19 mm in controls) in 3 to 5 days. "Status spongiosis" was seen in white matter only in sections of brain and cord. There was no dilation of cerebral ventricles, or damage to their ependymal linings or to the arachnoid villi. The neurological picture excluded any but a terminal effect upon cranial nerve function. There appeared to be no damage to neurons, and recovery of survivors was complete within 6 weeks after cessation of HCP administration. Elevated CSFP in paralyzed anesthetized cats was quickly lowered by an average of 256 mm by slow iv administration of 30% urea (2 g/kg in 10% invert sugar). Unanesthetized cats similarly paralyzed were able to stand and walk for up to 4 hr after this treatment. Neither acetazolamide nor prednisolone alone had any effect, nor did coadministration with urea enhance the effect of urea. The HCP lesion does not appear to be inflammatory in origin, nor does it seem to involve ventricular obstruction or overproduction of cerebrospinal fluid. The reappearance of paralysis about 4 hr after osmotic diuresis, which corresponds with the elimination of urea, suggests that prolonged iv infusion with urea or a similar osmotically active substance may have significant clinical value in the management of HCP poisoning.

Fourteen unanesthetized dogs were infused with nitroprusside for 30 min (10 or 100 μg/kg/min), 3 hr (25 μg/kg/min), or 6 hr (12.5 or 25.0 μg/kg/min) on two consecutive days. Two animals died following the high-dose 6-hr infusion. Minimal left papillary muscle necrosis was detected in one of the four hearts taken from the dogs infused with 12.5 μg/kg/min for 6 hr. In four anesthetized dogs the 12.5- and 25.0-μg/kg/min doses depressed blood pressure by an average of 20–27% and 45–48%, respectively. Both doses increased heart rate approximately 20%. The effect of 60-min nitroprusside infusion of 3.5–28.0 μg/kg/min on a variety of cardiovascular functions was assessed in 10 dogs. The most consistently observed changes were a dose-related decrease in blood pressure (19–50%) and an increase in coronary blood flow (30–300%). In spite of the hypotensive response, only minor changes in heart rate, cardiac output, and ventricular force of contraction occurred. The results indicate that the secondary cardiovascular actions of nitroprusside are not as prominent as with other vasodilators. Consequently nitroprusside appears to possess less acute cardiotoxic potential than other agents such as minoxidil, diazoxide, or hydralazine.

Long-term (including gestational and lactational) restriction of protein (8% of diet) significantly lowered the absolute and relative consumption of 6% ethanol (EtOH) in a two-bottle, free-choice (H 2 O vs EtOH) situation during a 76-day test period. This difference in response between rats fed the low protein diet and those fed an isocaloric normal protein (24%) diet became non-significant in two subsequent 100-day test periods. Statistical analysis of observations on individual performance indicated that regularity, cyclicity, and duration of drinking in each animal was random over all three time intervals for both groups. The early, significantly lower EtOH consumption by the protein-restricted group may be due to a paucity of EtOH-metabolizing enzymes in brain and liver, thereby prolonging the CNS effects of lower doses of EtOH consumed. The disappearance of this difference in subsequent test periods may reflect either a behavioral or metabolic adaptation in the developing protein-deficient rat.

The amount of ouabain necessary to produce ventricular fibrillation (VF) was significantly decreased by 2-hour pretreatment with 50, 100 or 200 mg/kg tolbutamide in anesthetized rabbits. The two higher doses also decreased the dose of ouabain needed to produce ventricular ectopic (VE) beats. Only the 200 mg/kg dose decreased blood glucose. In unanesthetized rabbits, 30-min pretreatment with tolbutamide (200 mg/kg i.v.) significantly decreased the doses of ouabain that produced VE beats and VF. A similar effect was noted when the same dose (200 mg/kg) was given subcutaneously 30 min, 2 or 4 h before ouabain. In these experiments blood glucose decreased after 1 h. Pretreatment for 30 min with subcutaneous administration of 50, 100 or 200 mg/kg tolbutamide significantly reduced the doses of ouabain needed to produce VE beats and VF. Blood glucose was unaltered by any tolbutamide dose after 30 min. Insulin (1 unit) decreased blood glucose but did not alter the amount of ouabain that produced VE beats and VF. The mechanism for enhancement of ouabain cardiotoxicity by tolbutamide appears to be independent of alterations in blood glucose and may be related to some direct myocardial effect.

The antioxidants butylated hydroxytoluene (BHT) and ethoxyquin protected rats against intoxication and mortality normally produced by hexachlorophene (HCP, 100 mg/kg). BHT also prevented the elevation of cerebrospinal fluid pressure, a central nervous system effect of HCP poisoning. In addition, both phenobarbital and SKF-525A protected against HCP poisoning, with the barbiturate also offering significant protection against triethyltin. l -Ascorbic acid, vitamin E, N,N -diphenyl- p -phenylenediamine and reduced and oxidized glutathione over a range of doses were ineffective in preventing HCP lethality. The protective effect of phenobarbital against HCP and triethyltin intoxication further supports existing evidence of a common or similar mechanism of toxic action for these two structurally dissimilar compounds.

Rats, hamsters, rabbits, and mice, species which are born functionally immature, have brain amine levels at birth which are lower than those of adults. The reason for the inability of these newborns to respond with a convulsive seizure to lethal doses of paralytic shellfish poison may be that their central nervous systems are less sensitive to anoxia than those of older animals. This lesser sensitivity to oxygen lack and the minimal oxygen requirement result in a longer survival time. In contrast, the newborn guinea pig and chick, which are born functionally mature, respond with convulsions to a lethal dose of paralytic shellfish poison and survive for only a short time. The brain amine levels of the newborn guinea pig are similar to those of the adults. In the newly hatched chick the norepinephrine levels are high, whereas the levels of 5-hydroxytryptamine are low compared to those of adults.

Summary Age of the animal modifies the toxicity of paralytic shellfish poison administered orally to rats. This influence is of less importance when the toxin is administered intraperitoneally. Weanlings and young adults receiving lethal doses of the toxin exhibit an anoxic type of convulsion before death, whereas newborns die without exhibiting a convulsive seizure. However, newborn rats exhibit seizures when treated with strychnine or pentylenetetrazole. Although paralytic shellfish poison given orally is more toxic to newborn and weanling animals, these rats are able to survive a significantly longer period of time than the young adults. When changes in the electrocardiogram are followed in the three groups of rats receiving a lethal dose of toxin orally, bradycardia is found to occur more rapidly and to a greater degree in the newborns than in the older animals. Auricular conduction defects are also more prominent in newborns. Ventricular conduction time is not significantly altered in any age group. Partial to complete A-V dissociation occurs prior to death in all groups.

Animals pretreated with appropriate doses of anticholinesterase agents develop auricular flutter and fibrillation following injection of acetylcholine or vagal stimulation. Depression of normal sinoauricular nodal function facilitates induction of fibrillation. During fibrillation, additional injections of acetylcholine, or vagal stimulation, increase the rate of fibrillation. Atropine in small doses reverts the fibrillation to normal sinus rhythm.

Rockets and other guided missi les require fuels which deliver extremely large a m o u n t s of energy to small c o m bustion chambers in short periods of t ime. This requires combustible materials of h igh energy and reactivity coupled with powerful oxidizers. In m a n y instances these fuels and oxidizers and their decomposit ion products are poisonous, and condit ions at tending their use m a y present hazards to personnel. Thus i t becomes important for persons concerned wi th these materials to be educated in the nature of the hazards, how to prevent injury, and how to administer first aid if exposure occurs. The following report was prepared by a member of the research staff of the Army Chemical Corps Medical Laboratories, which conduct toxicological investigations in this field for the Armed Forces. It deals w i th the following propellants: (a) Fuels: ammonia , anil ine, alcohols (ethyl, furfuryl, methyl ) , hydrazine, and JP-4. (b) Oxidizers: hydrogen peroxide, l iquid oxygen, and red fuming nitric acid.

Barbital and other barbituric acid derivatives are usually detected by recrystallization (Bachem1), and only few chemical tests for their identity have been described. Most of these tests are obviously crude and unsatisfactory, or at least not specific. One cannot test for the presence of barbital with Millon's reagent, Deniges' reagent, phenylhydrazine and sodium nitroprusside, or sulphuric acid and naphthol (Parri2). The murexide test of Handorf3 is likewise not sufficiently specific. Parri,2 Zwikker,4 and Bodendorf5 used cobaltous salts for the detection of barbiturates, but proved neither the specificity of their tests, nor did they attempt to make them sensitive beyond 1 part in 2000.We devised the following test for the determination of barbiturates. We acidulate the unknown solution with hydrochloric acid, and shake with 10 volumes of chloroform in a separatory funnel. Six cc. of the chloroform extract are divided into 3 equal parts, A, B, and C. To A we add 0.05 cc. of a 1% solution of cobalt acet...

Conclusions(1) The admixture of theophylline with salyrgan reduces the toxicity of the latter as the result of some reaction between the two compounds inasmuch as aging is required before the changed toxicity is demonstrable. (2) This influence of theophylline did not apply to mercurin. (3) In terms of mercury, non-ionizable organic mercurials are not necessarily less toxic than mercuric chloride.

We described1 a colorimetric test for barbiturates and the rate of excretion of barbital determined by this test. We here report on (a) urinary elimination, (b) fate in the blood, (c) presence in organs of barbiturates, and (d) on the clinical application of this test.The progress in these studies was made possible by the colorimetric test and by improved methods of extraction of barbiturates, consisting of shaking urine (alkalinized), oxalated whole blood, plasma or spinal fluid with equal volumes of 10% copper sulphate solution, filtering, acidulating the filtrate with dilute sulphuric acid and shaking the filtrate with 10 volumes of chloroform. The chloroform extract may be concentrated on water bath. Ground organs, before they are shaken with copper sulphate must be liquefied, either by 3% HCl and pepsin, or by mixing thoroughly with 5% KOH. Heating must be excluded in these procedures. The acid-pepsin treated organs must be alkalinized before shaking with copper sulphate.Results. (a) Urinary Excretio...

Recent studies in humans suggest that oral hypoglycemic agents such as tolbutamide (TBA), while lowering blood glucose concentrations, may increase the risk of cardiac death in diabetic patients. The possibility that TBA might adversely influence the cardiotoxicity of isoproterenol (ISO) was studied in adult Long-Evans rats of both sexes. TBA was given po at 500 mg/kg for 30 days; control rats were given vehicle only. On each of Days 29 and 30, ISO was injected sc at doses of 0, 1.0, or 5.0 mg/kg for females and 0, 0.01, and 0.05 mg/kg for males. Surviving rats were sacrificed 24 hr after the last ISO dose, and cardiac lesions were scored histologically for incidence and severity. Mortality after ISO challenge was higher in control groups than in the TBA-treated groups. Body weights were unchanged but absolute heart weights were significantly lower in TBA-treated males after ISO challenge compared with those of control males, and heart-to-body weight ratios were lower in TBA-treated males and females given the high ISO doses. Plasma glucose was lower in TBA-treated rats, but was not affected by ISO in either control or TBA-treated rats. ISO-induced cardiac lesions were similar in both control and TBA-treated rats when related to sex and ISO dose. These data indicate that TBA protects against ISO lethality but does not appear to affect ISO-induced cardiac lesions.

There have been sporadic reports of adverse effects of lindane (γ-hexachlorocyclohexane) in children treated for scabies. These effects usually consisted of tremors, convulsions, anorexia, and possible stunting of growth. Weanling rabbits (6 weeks old; 1.0 kg) given a single topical application of 1% lindane at a dose reportedly used in infants (60 mg/kg) exhibited severe anorexia and convulsions; death occurred in some cases. The effects were more pronounced in weanlings in which the skin was inflamed or not completely intact. In contrast, young adult rabbits (2–3 kg) given the same dose showed only some anorexia and possibly mild excitement. Concentrations of lindane in whole blood of weanlings at the time of convulsion (approximately 24 hr after dosing) ranged from 0.7 to 2.5 μg/ml. These findings suggest a rather pronounced sensitivity of weanlings to lindane in comparison to adults.

The effect of ethanol (EtOH) on permeability of the blood-brain barrier (BBB) to parenteral catecholamines was investigated in neonate chicks. Animals simulataneously administered EtOH, 2 g/kg, and norepinephrine (NE), 5 mg/kg, or epinephrine (E), 5 mg/kg, entered a roosting state which was more pronounced than that observed after either amine alone. Roosting chicks were killed 2 min after NE + EtOH and 10 min after E + EtOH for whole brain amine analysis. NE + EtOH treatment resulted in a 220% increase in whole brain NE over controls receiving this amine alone, whereas E + EtOH produced a 29% increase in brain E. EtOH alone did not alter endogenous levels of either amine in brain. Results indicate that EtOH, a solvent whose solubility characteristics allow it to penetrate easily both aqueous and lipoid membrane components, facilitates entry of E and NE into the brain of the neonate chick across an imperfect BBB present at hatching.

SummaryThe phosphate esters sarin and tabun, potent anticholinesterase compounds, exert profound effects on the respiration, circulation, central nervous system and gastrointestinal tract of experimental animals.

Adult human male subjects exposed for 2-minute periods to isopropyl methylphosphono-fluoridate (Sarin) vapor in concentrations of approximately 2 mg per cubic meter of air, producing only a moderate miosis with no other significant obvious sign of anticholinesterase action, exhibit a significant elevation of absolute visual threshold in the dark-adapted eye. It was found that instillation of Sarin in aqueous solution into the conjunctival sac does not elevate the threshold despite considerable miosis, and protecting both eyes from direct contact with Sarin vapor sufficient to prevent miosis does not prevent the action upon the absolute visual threshold; also in a subject in which miosis was similarly prevented in one eye alone, the visual threshold was elevated in both eyes. It is concluded that Sarin brings about its effect upon the visual threshold through an extraocular action, probably in the central nervous system. Submitted on April 24, 1957

The work of Carson and Campbell(l), which reported the fungistatic action of 3 antihistaminics, prompted an investigation concerning which the following is a preliminary report. In addition to testing fungistasis by several antihistaminics, we were also interested in determining whether the compounds are fungicidal as well. Lastly, it was considered of fundamental biochemical interest to determine whether the antifungal action of antihistaminics is based on interference with utilization of histamine (or a compound or compounds of similar structure) by the fungus.The compounds studied were as follows: Benadryl. (Diphenhydramine HC1) Parke-Davis : Thephorin, (Phenindamine Tartrate) Hoffmann-La Roche; Thenylene, (Methapy-riline HC1) Abbott; Neo-Antergan, (Pyran-isamine Maleate) Merck; Pyribenzamine, (Tripelenamine EC1) Ciba, and Diatrine, (Metaphenilene HCI) Wm. R. Warner. The test culture employed was Trichophyton mentagrophytes (Emmons No. 640).

dl -DOPA given iv to mice promptly induces an aggressive central excitation, i.e., a biting response, furnishing the basis for a method for “screening” for psychoactive action in drugs. Twenty-two compounds were effective in suppressing the biting response. The 10 most active drugs, according to the ED50 values (mg/kg, ip), are: trifluoperazine, 0.15; reserpine, 0.18; haloperidol, 0.9; chlorpromazine, 2.4; diazepam, 2.5; morphine, 5.2; bretylium, 5.6; oxazepam, 8.8; imipramine, 11.5; and chlordiazepoxide, 13. Iproniazid and tranylcypromine potentiated the biting response induced by dl -DOPA. Seven compounds have high therapeutic indices ( LD 50 ED 50 ) by this method: trifluoperazine, 1233; reserpine, 389; diazepam, 150; oxazepam, 104.5; morphine, 53.9; chlorpromazine, 49; and haloperidol, 47.

Serious injury by concentrated nitric acids is not infrequent, accounting for a significant number of the cases of disability and death from hazardous chemicals. Toxicologically, the two major forms may be regarded as identical, since they are both extremely corrosive and since both emit dangerous fumes. Red fuming nitric acid contains dissolved oxides of nitrogen ("nitrous fumes"), which are toxic; decomposition of the acid on contact with oxidizable material liberates more oxides of nitrogen. White fuming nitric acid, though containing little dissolved oxides of nitrogen, decomposes on contact with oxidizable material just as red fuming nitric acid and also liberates oxides of nitrogen. The growing utilization of red fuming nitric acid (RFNA) by industry and by the armed services makes timely a brief restatement of its hazards, how they should be avoided, and what to do in case of exposure. Illustrative case histories are given. The concentrated nitric acids are