Claude Marchand

The role of metabolism in chloroform hepatotoxicity

Abstract Since there is indirect evidence that a metabolite may be responsible for the hepatotoxicity of CCl 4 , the possibility that chloroform may also act through a similar mechanism was investigated. Pretreatment with stimulators of drug metabolizing enzymes like phenobarbital, 3-methylcholanthrene or 3,4-benzopyrene increased the toxicity of chlorform in rats, as reflected by increased serum glutamic-pyruvic transaminase and a decrease in liver glucose-6-phosphatase activity. This enhancement of the toxicity of CHCl 3 was associated with an increase in 14 CHCl 3 metabolism, as measured by pulmonary excretion of 14 CO 2 . An inhibitor of drug metabolizing enzymes, SKF 525-A, was found to decrease pulmonary excretion of 14 CO 2 . If these observations may be taken as indirect evidence that the hepatotoxic effect of CHCl 3 is due to a metabolite, other data do not seem to support such an hypothesis. No metabolite of CHCl 3 could be detected by gas-liquid chromatography; there was no quantitative correlation between the increase in toxicity and the increase in CHCl 3 metabolism. Finally, SKF 525-A did not decrease CHCl 3 hepatotoxicity. It is concluded that metabolism of CHCl 3 may be involved in the hepatotoxic effect of CHCl 3 , but other factors may also play a role in determining this response.

Protection by 2-diethylaminoethyl-2,2-diphenylvalerate hydrochloride against carbon tetrachloride hepatotoxicity: A possible mechanism of action

Abstract Recently, it was found that pretreatment with SKF 525-A decreases the concentrations of CCl 4 in the liver and other tissues after oral administration of the halogenated hydrocarbon. This was interpreted as a possible explanation for the protective effect of SKF 525-A on the hepatotoxicity of CCl 4 . To test this hypothesis, the relationship between the liver concentration of CCl 4 and its hepatotoxicity has been studied. Rats were given an oral dose of 14 CCl 4 , which produced liver concentrations similar to those found in rats given twice the dose of 14 CCl 4 but pretreated with SKF 525-A. A comparative study of the toxicity of CCl 4 revealed a good correlation between CCl 4 liver concentration and both serum glutamic pyruvic transaminase activity and hepatic triglycerides. There seemed to be no correlation with liver glucose 6-phosphatase activity. It is suggested that the protective effect of SKF 525-A on CCl 4 hepatotoxicity can be explained by a decrease in liver CCl 4 concentration.

The Diuretic and Antidiuretic Effect of Morphine Sulphate in Rats

Summary Administration of morphine sulfate in water-loaded rats exerts an antidiuretic effect that is dose dependent. In animals not waterloaded, the narcotic exerts a diuretic effect at a dose of 3 mg/kg sc but not at 6 and 12 mg/kg. The diuresis is characterized by an increase in urea and calcium excretion. Since, in the past, experiments dealing with the antidiuretic effect of morphine were usually carried out under hydrated conditions, the clinical significance of the effect of the narcotic on urine must be reevaluated, especially under nonwater-loading conditions.

Inhibition of the gastrointestinal absorption of p‐ aminosalicylate (PAS) in rats and humans by diphenhydramine

Injection of diphenhydramine, 25 mg per kilogram, intraperitoneally, decreased the blood concentration of sodium p‐aminosalicylate (PAS), 200 mg per kilogram, administered per os. This effect was observed 10,20,30,45, and 60 minutes after administration of PAS. A dose‐response study (2 to 25 mg per kilogram) revealed that the effect was proportional to the dose of diphenhydramine. The decrease in blood concentration of PAS was associated with a similar decrease in the PAS levels in brain, lung, liver, lipids, muscle, and kidney of animals treated with diphenhydramine. PAS levels in the stomach after diphenhydramine, revealed that more than 20% of the PAS remained in the stomach 45 minutes after oral administration but only 3% remained in the stomach in the control animals. Study of the gastrointestinal peristalsis with 51Cr indicated that, 45 minutes after injection of diphenhydramine, 60% of the radioactive marker was found in the stomach, whereas less than 10% was recovered in the stomach of control rats in which most of 51Cr was located in the first segment of the ileum. Human volunteers treated with diphenhydramine, 50 mg intramuscularly, 10 minutes before ingestion of PAS, 2 gm, had significantly less PAS in the blood 10 minutes after ingestion. These observations indicate the importance of the gastrointestinal tract as a site of drug interaction.

Physician attitudes toward sources of drug information.

What is the attitude of the professional to the type of information he is getting? During the past thirty years many studies have been undertaken to answer the question. Given the monetary implications, one may understand the interest in the subject. Some of the studies have been published, others have remained in the files of drug companies. All too often the quality of the published studies may be questioned. Since parameters to be measured were seldom well defined, it is difficult to compare these studies, and try to explain certain apparent contradictions. To try to dissect and compare all the published studies in this area is an impossible task in the time allowed. With all the reservation that we have made, however, we will try to draw some tentative conclusions. Let us summarize some of the most important factors as reflected by a number of studies done between 1952 and 1971. 1) Detail men: a) The attitude of physicians toward the detail man Most physicians consider him useful, and receive him in their offices. b) The influence of the detail man on the physician As a source of first notice of a new drug: the most important factor. In the decision to use a new drug: much less important.

Plasma magnesium concentration and urinary magnesium excretion in rats treated chronically with morphine

Abstract Since an acute dose of morphine caused changes in magnesium metabolism in rats, and since the ion is believed to be implicated in alcoholism and delirium tremens, tissue and urine magnesium was measured in rats treated chronically with morphine. The hypermagnesemia observed 1 hr after administration of the narcotic was the same at the beginning and at the end of a chronic morphine treatment. However, 8 hr after morphine injection, there was less magnesium in the plasma of morphinized rats; no change was observed in the concentrations of magnesium in muscle and bone. Chronic morphine treatment was associated with an increase in urine output and magnesium excretion. During morphine withdrawal, injection of magnesium had little effect on plasma concentration and urinary excretion of magnesium. These observations may be taken as evidence that magnesium does not play a major role in morphine tolerance and withdrawal phenomena.

The diuretic effects of dihydrocodeinone bitartrate and sodium salicylate in rats

Abstract After the observation that chronic morphine treatment in rats increases the urine output, two other analgesics were investigated for their effect on diuresis. Chronic treatment with sodium salicylate was found to have a mild diuretic effect at relatively small doses, but this could not be attributed to an increase in osmotic load. Dihydrocodeinone caused a more marked increase in urine output, which was qualitatively similar to that described during chronic morphine treatment. No morphological lesions were found in the kidneys of salicylate-treated rats, but deposits of calcium were observed in 40% of the kidneys of rats treated with dihydrocodeinone.

Disposition kinetics of barbital in hamsters with hereditary heart failure

SummaryWithin a few minutes after oral administration of sodium barbital, 100 mg/kg, in hamsters with hereditary heart failure, the concentration of the drug was found to be lower in the plasma, kidney, brain and striated muscle of these animals than in the tissue of control hamsters. This could be explained by delayed intestinal absorption, as evidenced by greater amounts of drug recovered from the intestine of cardiomyopathy animals a few minutes after barbital administration. However, 6–24 hours later, the concentration of the drug in these tissues was higher than in those of control hamsters; also, the elimination rate of the drug from these tissues was found to be slower than in control animals. This slower elimination rate of the drug from the tissue of animals in heart failure was responsible for the greater drug bioavailability in the tissues, as reflected by the area under the curve of drug concentration in the tissue vs. time. Fromin vitro studies of aniline and aminopyrine metabolism by liver microsomal enzymes of hamsters in heart failure, it is concluded that impairment of drug metabolism by the liver may be partially responsible for the slower drug elimination from the body of patients in heart failure.