Protection with butylated hydroxytoluene and other compounds against intoxication and mortality caused by hexachlorophene.

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.

Antagonism of caffeine-facilitated conflict-induced behavior by depressants in cats.

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.

Tolbutamide enhancement of ouabain cardiotoxicity in rabbits.

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.

Effect of hexachlorophene intoxication on learning in rats.

Neurotoxicity in the form of hindlimb paralysis is known to be associated with brain lesions characterized by vacuolation of the white matter following hexachlorophene (HCP) intoxication; these paralytic and histopathological effects are reversible with time after discontinuance of HCP exposure. The rates of acquiring a bar-pressing escape and avoidance behavior were measured in female rats after recovery from paralysis following daily oral dosing with HCP (25 mg/kg). Learning deficits were seen as a delay in reaching a 90% escape performance level, as an increase in the number of sessions required to reach a 50% avoidance criterion, as an increase in training time needed to transfer from escape to avoidance responding, and by an increase in the number of sessions needed to reach a maximum level of avoidance behavior over a 35-session period. Peak responding eventually reached a level comparable to controls only after prolonged periods. Brain lesions seen 2-3 months after HCP intoxiciation correlated with the lag in learning ability but not with the maximum avoidance acquisition before sacrifice. These results indicate a long-lasting behavioral deficiency following neurotoxicity which is slowly reversible.

Observations on hexachlorophene-induced paralysis in the cat and its antagonism by hypertonic urea.

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.