It has been well documented that fever could be mediated with endogenous pyrogen released from reticuloendothelial system(RES) by administration of bacterial endotoxin(LPS) intravenously to rabbits. On the contrary, reserpine which has various pharmacological activities by depleting catecholamines decreases the normal body temperature as well as endotoxin induced fever. In this paper, we focussed our attention on the effect of reserpine on the production of endogenous pyrogen with relation to the antipyretic effect in endotoxin fever and obtained the following results: Endogenous pyrogen could be detected by intravenous administration of LPS(0.5 μg/kg) during the fever. However, endogenous pyrogen was undetectable with intracisternal administration of LPS(0.01 μg/body) which provoked long-lasting fever. Reserpine (1 mg/kg, i.v.) decreased both body temperature induced by intracisternal administration of LPS(0.01 μg/body) or intravenous administration of LPS(0.5 μg/kg), however the degree was more extensive in cases of LPS-induced fever. Pretreatment of rabbits with reserpine (1 mg/kg, i.v.) suppressed the fever induced by an intravenous administration of LPS (0.5 μg/kg), but did not suppress the release of endogenous pyrogen. These data suggest that endogenous pyrogen may not be an important factor in the pathogenesis of endotoxin fever.

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Effects of diazepam and baclofen on the anemic decerebrate rigidity in rats were studied by using the drugs that modify GABAergic mechanisms or deplete catecholamine. Rigid forelimb tension in anemic decerebrate rats took the form of tonically sustained tension (tonic component), while the phasic tension (phasic component) was induced by mechanical stimulation of hindlimbs. Diazepam exerted a marked dose-dependent inhibition of the phasic component, whereas baclofen produced a similar effect on both tonic and phasic components. In rats pretreated with semicarbazide, the inhibitory effect of diazepam on phasic component was reduced, and the effect of semicarbazide was antagonized by pyridoxine. The effect of diazepam was slightly enhanced by pretreatment with aminooxyacetic acid, and antagonized by picrotoxin. In contrast to diazepam, the depressant actions of baclofen on both components were not affected by semicarbazide, aminooxyacetic acid or picrotoxin. Catecholamine depletion produced by a-methyltyrosine or disulfiram significantly reduced the effect of baclofen on the phasic component. It thus appears that GABA is involved in the effect of diazepam on the phasic component, and noradrenaline is involved in the same effect of baclofen in anemic decerebrate rats.

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Antitumor activity and lethality of cyclophosphamide alone and in combination with several drugs were investigated in male ddY mice. The antitumor activity was estimated by weighing the solid tumor on the 15th day after Ehrlich ascites cell inoculation. Pentobarbital induced sleeping time for monitoring the activity of hepatic drug-metabolizing enzymes was defined as the time between the loss and the recovery of the righting reflex. Consecutive administration of pentobarbital shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. On the contrary, a single administration of SKF 525A or cycloheximide prolonged the pentobarbital sleeping time significantly and decreased the antitumor activity after cyclophosphamide. Consecutive administration of aminopyrine, or chlorpromazine shortened the pentobarbital sleeping time and increased the antitumor activity after cyclophosphamide. These results indicate that aminopyrine and chlorpromazine may increase the levels of the hepatic drug-metabolizing components and may activate cyclophosphamide by conversion to an active form. Effect of a consecutive administration of morphine on the pentobarbital sleeping time and the antitumor activity was uncertain in individual cases. On the other hand, aminopyrine, chlorpromazine, or morphine in consecutive administration increased the lethality of cyclophosphamide.

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Preventive and therapeutic effects of tiopronin (2-mercaptopropionylglycine) and glutathione on ethionine induced liver damage were studied. Administration of 1 g/kg ethionine resulted in significant differences in the degree of liver damage, and such was dependent on the feeding conditions of the animals. The present experiment was performed under the conditions where the most serious liver damage was observed. In the experiment on the preventive effects, serum GOT and GPT were markedly elevated by ethionine, but such elevation could be suppressed by administering tiopronin or glutathione 10 min before ethionine administration. Liver nonprotein thiol (NPSH) content decreased by 40-60% of the normal level 16 hr after ethionine administration, but increased by 30-45% 24 hr later. Administration of tiopronin suppressed the initial fall of liver NPSH content caused by ethionine, but this tendency was not observed in the glutathione treatment. Both liver cholesterol and triglyceride increased in the ethionine treated rats, and triglycerides in particular decreased with administration of tiopronin or glutathione. In the experiment on the therapeutic effects, the maximal values of serum GOT and GPT brought by ethionine were suppressed by the thiol compounds given 16 hr after ethionine administration, but liver NPSH content and liver lipids were not influenced. Thus, tiopronin and glutathione are considered to have preventive and therapeutic effects on liver damage induced by ethionine.

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In our previous papers, tiopronin (2-mercaptopropionylglycine) and glutathione were reported to suppress the liver damage induced by ethionine. In the present study, we evaluated such suppressive effect from the aspect of drug metabolizing activity. Aniline hydroxylating enzyme activity and aminopyrine N-demethylating enzyme activity of the liver microsome of rats 24 hr after administration of 1 g/kg ethionine were decreased to 53.2% and 61.7% respectively as compared with those of the normal rats. Administration of tiopronin or glutathione to the ethionine treated rats suppressed the decrease of both enzyme activities induced by ethionine. Ethionine did not influence NADH-cytochrome c reductase (fp₁) but brought about increase of the activity of NADPH-cytochrome c reductase (fp₂) and decrease of the cytochrome P-450 content. These thiol compounds did not influence fp₁ and fp₂ but tended to suppress the cytochrome P-450 content decreased by administration of ethionine. In particular, tiopronin suppressed the content significantly. Disappearance of aminopyrine, hexobarbital and pentobarbital from the blood was markedly delayed by ethionine administration. It was revealed, however, that such delay was recovered by tiopronin or glutathione. The sleeping time induced by hexobarbital and pentobarbital was also prolonged by ethionine, but this tended to be shortened by tiopronin or glutathione.

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The mechanism of liver enlargement and anti-fatty liver effect of NKK-105 in the rat were investigated by the mesurement of drug-metabolizing enzyme activities and morphological changes in liver tissue detected using electron microscopy. A single administration of NKK-105(250, 500, 1000 mg/kg, p.o.) induced an apparent increase in liver weight. The elevation of aminopyrine demethylase activity and slight increase in microsomal cytochrome b₅ and cytochrome P-450 content were seen with the administration of NKK-105. NKK-105 inhibited lipid peroxide formation in mitochondrial and microsomal fractions. Total lipid content of liver decreased at 12 hr after the administration of NKK-105. Lipid peroxide formation in mitochondrial and microsomal fractions was markedly inhibited by the addition of NKK-105(1×10^-3M), in vitro. Disarrangement of rough endoplasmic reticulum and increase in smooth endoplasmic reticulum were observed by the administration of NKK-105. The decrease in drug-metabolizing enzymes caused by CCl₄ or ethionine was protected in the combination with NKK-105. NKK-105 markedly inhibited the elevation of lipid peroxide formation caused by CCl₄ or ethionine. Similar effects on lipid peroxide formation were also obtained in vitro. These results suggest that the enlargement induced by NKK-105 indicates a functional not a toxic response. The inhibition of lipid peroxide formation in mitochondrial and microsomal fractions may thus play an important role in the mechanism of anti-fatty liver effect of NKK 105 on the CCl₄ or ethionine-induced fatty liver.

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Using the modified model of Masugi's nephritis in rats, the antinephritic effects of sodium chondroitin sulfate (CS) and other drugs were evaluated by determining the biochemical parameters in urine, serum and renal cortex as well as light microscopic observation in kidneys by preventive and curative tests. In the preventive test where drug treatment was initiated at the same time as the injection of anti-kidney serum, CS (200 mg/kg p.o.) was effective in reducing serum triglyceride level, but was ineffective against other parameters. In the curative test where drug treatment was given from the 10th day after the induction of nephritis, CS (200 mg/kg p.o.) resulted in reductions of urinary excretions of protein and enzymes such as alkaline phosphatase and N-acetyl-β-glucosaminidase, the inhibition of urinary fibrinolytic activity and reduction in levels of serum cholesterol and triglyceride. Moreover, histological examination indicated a significant reduction of the index of glomerular lesions by the treatment of this drug. Of other drugs, dexamethasone (0.1 mg/kg p.o.) was effective in both tests, while warfarin potassium (0.05 or 0.1 mg/kg p.o.) exerted a beneficial effect only in the preventive test. From these results, the effectiveness of CS in the curative test is probably due to promotion of healing of damaged tissue in the kidneys.

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Behavioral and EEG effects of water soluble fraction extracted from Zingiber mioga RoscoE (Z. mioga) were investigated in mice, rats and rabbits. Z. mioga was dissolved in isotonic saline and given i.p. into mice and rats, and i.v. into rabbits, respectively. Z. mioga at doses of 50 ?? 400 mg/kg produced a marked reduction in locomotor activity of mice in the open-field test. The peak time of reduction was 30 min after the injection. In mice, Z. mioga at the same doses lowered significantly the rectal temperature and prolonged the sleeping time induced by thiopental-Na (40 mg/kg, i.v.). Z. mioga at a dose of 400 mg/kg had no anticonvulsant effects and it produced a slight muscle relaxation in mice. Z. mioga at doses of 50 ?? 200 mg/kg induced a significant inhibition of the active conditioned avoidance response of the rat in a shuttle box without affecting the unconditioned escape response. In the step-down method, however, the passive conditioned avoidance response was rarely affected by Z. mioga, but the response was suppressed by chlorpromazine. In rabbits with chronically implanted electrodes, Z. mioga at doses of 20 ?? 30 mg/kg induced a drowsy pattern of spontaneous EEG, i.e. high voltage slow waves in the neocortex and amygdala, and desynchronization in the case of hippocampal theta waves. The EEG arousal response to the external auditory stimulation was inhibited by the same doses of Z. mioga, whereas it failed to suppress the arousal response to either the midbrain reticular or posterior hypothalamic stimulation, as with chlorpromazine. Neither the recruiting response nor the photic driving response were affected by Z. mioga. On the other hand, the limbic after-discharges to the hippocampal or amygdaloid stimulation were enhanced by Z. mioga as well as chlorpromazin, but they were inhibited by diazepam. The EEG effects of Z. mioga were qualitatively similar to chlorpromazine, but not to diazepam. These results indicate the similarty of behavioral and EEG effects of Z. mioga to those seen with neuroleptics such as chlorpromazine.

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In male Wistar rats, 1α-HCC and 1α, 25-DHCC induced diuretic effects in doses of 2.5 and 25μg/kg p.o., while no such effects of 1α-HCC were seen with a dose of 0.25 μg/kg p.o. Effect of 1α-HCC appeared later than that of 1α, 25-DHCC, but at 24 hr, the difference disappeared. Similar results were obtained with urinary concentrations of calcium (increase) and phosphorus (decrease). Glomerular filtration rate (GFR) and tubular reabsorption of phosphate (TRP) were remarkably elevated by 1α, 25-DHCC, and effects of 1α-HCC were rather weak and apparently not dose dependent. In light of these results and the finding that there was no difference between the effects of 1α-HCC and 1α, 25-DHCC on serum calcium and phosphorus at 24 hr, the mechanism of action of these sterols on the renal function seems to differ. In male Beagle dogs, 0.25 μg/kg/day p.o. of 1α-HCC or 1α, 25-DHCC induced a severe hypercalcemia and GFR was decreased in the 1α, 25-DHCC treated group. A gradual recovery occurred with cessation of the administration. Thus decrease in GFR was considered to be due to calcification of the kidney.

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The effect of M73101, a new non-steroidal analgesic anti-inflammatory agent, on liver microsomal drug-metabolizing enzymes was investigated. Rats were treated orally with M73101 (100, 200, 500 mg/kg), phenylbutazone (PZ, 200 mg/kg), aminopyrine (AM, 100 mg/kg) or phenobarbital sodium (PB, 100 mg/kg) once daily for 2 weeks and then were observed for 2 weeks during which treatment was not given. On treatment with M73101, PZ, AM and PB, the liver enlarged but was restored to normal 1 week after the last administration. The rate of increase in the case of M73101 was lower than that seen with the reference compounds. M73101 markedly increased the content of microsomal protein, cytochrome P-450 or b₅ and NADPH cytochrome C reductase, aniline hydroxylase and AM demethylase activity, but these increments returned to the normal level 1 week after the last administration. The serum concentration of M73101 after repeated administration (200 mg/kg; p.o.) for 1 week was lower than that after a single administration. Furthermore, M73101 increased Vmax for both aniline hydroxylase and AM demethylase, whereas it increased Km only for aniline hydroxylase. M73101 did not enhance the lipid peroxidation. Our observations suggest that the enlargement of rat liver seen with M73101 was due to the induction of drug-metabolizing enzymes and that this agent can probably be classified as a phenobarbital-type inducer.

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