James M. Fujimoto

The effect of certain inhibtors in producing shortening of hexobarbital action

Abstract Agents that initially prolong the duration of hexobarbital action (phase A) by decreasing its rate of biotransformation seem to have a subsequent shortening effect (phase B) on hexobarbital action. By inferences based on studies using ethionine and methionine, the phase B effects of SKF 525-A, EPB, nikethamide, and iproniazid appeal to involve adaptive increases in activity of the enzyme system of the liver that metabolizes hexobarbital. PIH was one agent tested that did not produce the diphasic effect. It produced the phase A effect, but under the present conditions the phase B effect was not present. The phase B effect of PIH may be masked by a central component; however, no direct time relationship between the central anticonvulsant activity and effect on hexobarbital action was found.

Studies on the antidiuretic action of mophine in the rat

Abstract Morphine sulfate (MS) given s.c. or i.v. produces a dose-response related decrease in urine flow in the alcohol-anesthetized-diuresing rat with a bladder fistula. The antidiuretic effect is not seen if the hydrating infusion contains mannitol instead of glucose-saline. These results are compatible with the proposal that the acute antidiuretic effect of morphine is mediated by the release of ADH from the neurohypophysis. Tolerance to the antidiuretic effect of MS rapidly develops in rats treated on an increasing schedule of MS. After 5 days of MS treatment, tolerance to the antidiuretic effect of MS given i.v. or s.c. is nearly complete and the initial response to MS becomes diuretic. At the same time renal sensitivity to Pitressin is unchanged. The development of tolerance to the antidiuretic effect of MS, seen after one or more doses, may be due to a morphine induced blockade of ADH release.

ENHANCED SULFOBROMOPHTHALEIN DISAPPEARANCE IN MICE PRETREATED WITH VARIOUS DRUGS.

Abstract Pretreatment of mice with certain drugs caused changes in liver function subsequently measured by concentrations of sulfobromophthalein in plasma. Drugs such as phenobarbital, nikethamide, urethan, and β-phenylisopropylhydrazine produced significantly elevated concentration of sulfobromophthalein in plasma soon after pretreatment. Findings of greatest interest were the enhanced disappearance of sulfobromophthalein from plasma with many of the above agents as well as with SKF 525A, N-methyl-3-piperidyl-NN-diphcnylcarbamate, and tolbutamide. Countercurrent analyses of acetone extracts of plasma indicated the enhanced disappearance of the parent compound, sulfobromophthalein. Countercurrent analyses of liver extracts indicated a hepatic mechanism which appears to follow an adaptive type of response.

Effect of carbon tetrachloride on distribution of sulfobromophthalein in plasma and liver of mice

Countercurrent analyses of sulfobromophthalein (BSP) and its metabolite in plasma and liver were performed in control and CCl4-treated mice, altering in turn the time of sampling, time of CCl4 treatment, and dose of BSP. First, where the sampling times for analyses were 7, 10, 15, and 30 minutes in mice given CCl4 24 hours earlier, retention of BSP was greatest at the earlier times and decreased toward 30 minutes. In the corresponding liver samples, lower concentrations of BSP were found than in the control livers at 10 and 15 minutes, with the maximal difference occurring at 15 minutes. The metabolite concentrations followed that of the parent compound. It appeared that processes such as uptake and storage of BSP by the liver were affected more than processes such as conjugation and excretion. Second, where the time of CCl4 treatment was changed and the sampling time kept at 15 minutes, a temporal dissociation was obtained between the maximal effect of CCl4 in producing retention of BSP in the plasma and effect on the liver. Changes in the BSP concentration within the liver did not directly reflect the alteration seen in the plasma concentrations. Third, where the dose of BSP was reduced from 100 to 65 mg/kg in the CCl4-treated group, the BSP concentrations in the plasma were the same as in controls. Now the liver BSP concentrations in the CCl4 group were lower than in controls at sampling times. These temporal analyses indicated that the several processes of uptake, storage, conjugation, and excretion were differentially affected by CCl4.

Urethan induced acceleration of hexobarbital metabolism.

Summary Urethan pretreatment shortens hexobarbital sleeping time and lowers hexo-barbital body levels in mice. These results suggest that urethan increases rate of biotransformation of hexobarbital in mice.

Sodium and Potassium Excretion in Rats Treated Chronically with Morphine.

Summary Tolerance has been shown to develop to the antidiuretic effect of morphine upon chronic administration. Urinary excretion of sodium and potassium increased initially but returned to control values as treatment was continued for 14 days. No changes in muscle or plasma concentrations of these ions were seen.

The diuretic effect of morphine in the chicken

Abstract The unilateral infusion of morphine 0.35 mg/kg/min into the renal portal circulation of the chicken produces a bilateral increase in urine volume, sodium and potassium excretion. The urine excretion is increased five-fold while sodium and potassium excretion are doubled. The peak diuresis occurs 5 to 15 min after the cessation of morphine infusion. Although the responses are bilateral, the infusion of C14-morphine indicates that the renal portal system is functional and that morphine is handled mainly by the infused kidney. The systemic infusion of morphine via the wing vein also produces the same results as renal portal administration. A second dose of morphine produces a diuretic effect which is much less than seen after the first dose. Rehydration of the chicken prior to the second dose of morphine does not alter this effect. Nalorphine given together with morphine completely blocks the morphine-induced diuresis, while nalorphine alone does not alter the urine flow. The delay in effect and bilateral nature of the response suggests that morphine may act through a hormonal mechanism to produce a diuresis, rather than by a direct action on the kidney tubules.

The development of tolerance to the antidiuretic effect of morphine in the mouse.

Abstract Mice treated for 8 days on a schedule of increasing doses of morphine develop tolerance more rapidly to the analgesic than to the antidiuretic effect. A schedule of treatment consisting of morphine 30 mg/kg b.i.d., the dosage being increased 30 mg/kg/day, produced a decrease in the antidiuretic effect when tested with morphine 30 mg/kg. The response declined 25% after 2 days, 40% after 3 days, and 46% after 4 days of treatment. Antidiuretic tolerance occurred concomitantly with an increase in sodium but not potassium excretion. Morphine treatment resulted in an immediate decrease of about 50% in daily food and water consumption accompanied by a decrease in body weight, while daily urine excretion was increased. The development of tolerance to morphine antidiuresis did not appear to be due to a depletion of pituitary vasopressin or a change in renal sensitivity to Pitressin.

The antidiuretic effect of narcotic analgesics in the mouse

Abstract Morphine sulfate in doses from 2–60 mg/kg, sc, produced a doseresponse related antidiuresis in water-loaded mice. Morphine, methadone, levorphanol, and fentanyl produced antidiuresis and ranked in that order (least to most potent) when compared as the free bases. Nalorphine hydrochloride at 1 and 5 mg/kg, sc, partially antagonized and at 10, 20, or 30 mg/kg, completely antagonized the antidiuretic effect of morphine sulfate 30 mg/kg, sc. The mouse antidiuretic procedure is shown to be a simple, reproducible method for the assessment of the antidiuretic effect of narcotic analgesics.

Effect of Carbon Tetrachloride on Thioridazine Action and Metabolism.

Summary CCI4 treatment was found to increase both lethal and hypothermic potency of thioridazine. The dose of CCI4 employed produced liver damage but no kidney damage. A method is described for determining thioridazine in tissues. Whole body concentrations of this phenothiazine were found to be significantly higher in mice treated with CCI4.