Methyl alcohol poisoning III. Ocular toxicity.

The ocular toxicity of methyl alcohol has been investigated in six rhesus monkeys. All the animals developed fundus changes within 43 to 171 hours after its ingestion. The only fundus lesion seen was optic disc edema and associated changes, usually of a marked degree. Fluorescein fundus angiography confirmed the findings. The retinal and choroidal circulations, including the retinal capillary bed, were normal. Ophthalmoscopically and angiographically, optic disc edema in methyl alcohol poisoning was indistinguishable from that seen in raised intracranial pressure, except that no increased intracranial pressure was observed. It is postulated that optic disc edema in methyl alcohol poisoning is due to an axoplasmic flow stasis.

Methyl alcohol poisoning. II. Development of a model for ocular toxicity in methyl alcohol poisoning using the rhesus monkey.

Rhesus monkeys were intoxicated with methyl alcohol, using an initial dose of 2 gm/kg and subsequent doses were administered in order to maintain an attenuated and prolonged state of intoxication. Arterial blood samples were drawn for methyl alcohol, formate, PO2, PCO2, and pH, which were monitored periodically throughout the course of the experiment. With the use of these procedures monkeys developed metabolic acidosis with the accumulation of formic acid in the blood and a corresponding decrease in blood bicarbonate. These animals served as models, which allowed for ocular evaluation for early signs related to methyl alcohol poisoning. A mechanism to explain toxicity is proposed and discussed.

Methyl alcohol poisoning. IV. Alterations of the morphological findings of the retina and optic nerve.

The ocular morphological findings of three methyl alcohol-intoxicated rhesus monkeys with optic disc swelling was investigated with light and electron microscopy in conjunction with intravascular horse radish peroxidase. Alterations observed in the optic nerve head were confined to the axons and consisted of swelling and clustering of the mitochondria, disruption of the neurotubules, the formation of vesicles, and enlargement of the axon segments in the prelaminar region. Swelling of the oligodendroglial cytoplasm in contact with the axons and of the astrocytes was seen in the retrolaminar optic nerve and the intraorbital optic nerve. Alterations were not observed in the retina. It is hypothesized that the alterations in the axons are the result of disrupted axoplasmic flow. Possible mechanisms relating methyl alcohol intoxication to disruption of axoplasmic flow are discussed.

A comparative study of the effect of some steroid hormones on the response of rats to other drugs.

The effect of a series of steroid hormones on the pentetrazol convulsing action, hexobarbital narcotic action and hepatic drug metabolizing enzyme activities was determined in rats. All steroid compounds used antagonized the pentetrazol effect: the most potent was cortisone and the least potent testosterone. Glucocorticoids and androgens shortened the hexobarbital sleeping time and increased the hepatic drug metabolizing enzyme activity. Estradiol exhibited the opposite effect, whereas progesterone and desoxycorticosterone did not affect these two parameters.

Effect of hashish smoke on some blood and serum parameters in rabbits.

Exposure of rabbits to hashish smoke every other day for a period of one month resulted in a marked increase in blood ammonia. This increase is not probably due to any hepatic damage since there was no concomitant increase in the number of serum enzymes known to be elevated during hepatic damage. It might be related to the inhibitory effect of hashish on incorporation of amino acids into proteins resulting in an increased availability of amino acids to the catabolic pathways coupled with an increase in the glutamate dehydrogenase activity. These factors could also account for the increased blood urea concentrations in these animals.

Effect of hashish on brain gamma aminobutyric acid system, blood fibrinolytic activity and glucose and some serum enzymes in the rat.

Adult male rats were exposed to Hashish smoke for 15 min. Certain biochemical parameters were determined. This treatment did not change the brain glutamic acid level, whereas it significantly decreased brain gamma aminobutyric acid level. There was a significant increase in the activity of the brain enzyme forming gamma aminobutyric acid, namely glutamate decarboxylase, as well as in that enzyme metabolizing gamma aminobutyric acid, namely aminobutyrate aminotransferase. However, the increase was much more marked in the case of aminobutyrate aminotransferase, a finding that might explain the decrease observed in brain gamma aminobutyric acid upon exposure to Hashish. Blood glucose and fibrinolytic activity were significantly increased. It was concluded that these changes might be due to an adrenaline releasing effect of Hashish smoke inhalation. Serum lactate dehydrogenase and serum glutamate oxalacetate transaminase activities were significantly increased, whereas serum glutamate pyruvate transaminase activity was unaffected. From these data it was suggested that the source of leakage of these enzyme activities into the blood is probably the skeletal muscles rather than the liver.

Steroidal derivatives. Part 1: some novel steroidal thiosemicarbazones. Their synthesis, anticancer and endocrinological activities.

The synthesis of several novel thiosemicarbazone derivatives of steroids, including estrogens and androgens, is described. Evaluation of the products in P 388 Lymphocytic Leukemia indicated no anticancer activity. The endocrinological screening showed that estrogenicity is slightly reduced but not abolished in the thiosemicarbazones derived from estrone-3-methyl ether (compounds 1, 2 and 4). The androgenic activity of the thiosemicarbazones derived from testosterone (compounds 7--9) was more pronounced than that of testosterone. Among the same thiosemicarbazone derivatives 7--9, only o-tolyl derivative 8 exhibited anabolic activity.

The role of formate and S-adenosylmethionine in the reversal of nitrous oxide inhibition of formate oxidation in the rat.

Studies have been performed in rats in order to test whether methionine reverses the inhibition of formate oxidation produced by nitrous oxide by virtue of the conversion of methionine to formate. At a dose of methionine (100 mg/kg, 671 mumol/kg) that completely reverses the nitrous oxide inhibition of formate oxidation no significant conversion of the methyl group, carboxyl, or backbone of methionine to formate was apparent. No increases in hepatic formate levels were seen after the administration of 671 mumol/kg methionine or ethionine, and formate treatment did not alter the rate of 14CO2 formed after methionine was administered labeled in the methyl, carboxyl, or backbone position. The reversal of nitrous oxide inhibition of formate oxidation was found to correlate temporally with either S-adenosylmethionine levels after methionine administration or S-adenosylethionine levels following ethionine treatment. After methionine or ethionine administration, elevated hepatic steady state levels of tetrahydrofolate were observed and were coincident with elevated S-adenosylmethionine or S-adenosylethionine. Since formate oxidation rates are dependent on the hepatic tetrahydrofolate level, the mechanism of methionine reversal of nitrous oxide inhibition appears to be related to effects of hepatic S-adenosylmethionine which are important in maintaining and regulating tetrahydrofolate, rather than formate generation from methionine.

Effect of nitrous oxide and methionine treatments on hepatic S-adenosylmethionine and methylation reactions in the rat.

Nitrous oxide administration to experimental animals leads to significant alterations in the hepatic folate pathway. This pathway is closely linked to the metabolism of methionine and S-adenosylmethionine (AdoMet), two compounds that play a central role in biologically important methylation reactions. This study was carried out to assess whether nitrous oxide administration to animals can affect the metabolism of AdoMet and the AdoMet-dependent methylation reactions. Exposure of rats to a mixture of nitrous oxide and oxygen (50:50) for 2 hr reduced hepatic AdoMet levels. However, when methionine was administered to these rats, hepatic AdoMet rapidly increased to levels that were significantly higher than those observed in air-exposed animals. Concomitant with this increase, there was a significant and marked increase in the rate of methylation of phospholipids and carboxymethylation of proteins. Thus, nitrous oxide, in addition to its inhibitory effect on 5-methyltetrahydrofolate:homocysteine methyltransferase (methionine synthase, EC 2.1.1.13) activity, possesses another effect. It increases the rate of conversion of exogenously administered methionine into AdoMet with a subsequent increase in the rate of methylation of key cellular constituents.