The fetal toxicity of potassium nitrate (KNO₃) used widely as a food additive was studied in Wistar rats. The pregnant rats were fed a diet containing 2.5, 0.5 or 0.1 % of KNO₃ from day 7 to 14 of pregnancy. Neither maternal nor fetal toxicity including external malformations were observed at term in any group. After spontaneous delivery, the offspring were reared until 13 weeks after birth. No harmful effects were detected in any group. The female offspring (F₁) of all groups were mated with the male (F₁) of the same group. Good reproductive performances were shown in all groups. The pregnant rats were fed the same diet, which their mothers (F₀) had been fed, from day 7 to 14 of pregnancy. Various types of malformations such as exencephaly, cleft lip and palate, polydactyly and micro or anophthalmia were observed in 6 of 133 fetuses and 7 of 63 newborns from dams treated with 2.5% KNO₃, but no external malformations were observed in other groups. The male offspring (F₂) of the treated groups showed slow growth until 13 weeks after birth. These results suggest that a dose of 2.5% KNO₃ is toxic to the F₂ generation, but not to the F₁ generation.

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Analgesic and antipyretic effects of dl-2{3-(2'-chlorophenoxy)phenyl} propionic acid (CPP) were studied in mice, rats and guinea-pigs. CPP produced a dose dependent inhibition of acetic acid-induced writhing syndrome. Its ED50 values 1 and 3 hr after oral administration were 47 and 31 mg/kg, respectively. CPP had a potent analgesic effect on bradykinin-induced nociceptive response in rats, and its ED50 value was 15 mg/kg 2 hr after oral administration. The analgesic activity of CPP in these experiments was less potent than that of indomethacin, but it was approximately equivalent to ibuprofen and 10 to 20 times as potent as aspirin. CPP had no analgesic effect on both the tail pinch and hot plate tests in mice, while CPP potentiated the analgesic effect of codeine on these tests. CPP had no effect on the nociceptive response induced by intradermal injection of bradykinin and/or EDTA in guinea-pigs. On the other hand, when CPP was given orally in a dose range of 1.25 to 5 mg/kg, it produced an antipyretic effect on yeast-induced fever in rats. The antipyretic activity of CPP was equivalent to ibuprofen and 10 to 15 times as potent as aspirin.

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The inhibitory effect of etafenone hydrochloride (etafenone) on platelet aggregation in rabbit platelet rich plasma and the involvement of the arachidonic acid (AA) cascade in the inhibitory mechanism for etafenone on platelet aggregation were studied. 1) Etafenone exhibited a dose-dependent inhibitory effect on collagen (15 ?? 20 μ/ml)-induced platelet aggregation, and its median inhibitory concentration (IC50) was 1.7 ×10^-5M. 2) In ADP (20 μM)-induced aggregation, etafenone also exhibited a dose-dependent inhibitory effect, but its IC50 was 2.7×10^-4M and was significantly higher than that in the case of collagen. 3) Etafenone inhibited AA (0.3 ?? 0.5mM)-induced platelet aggregation dose-dependently. Its IC50 was 2.8×10^-5M. 4) In thromboxane (TX) A₂-induced aggregation, etafenone exhibited a dose-dependent inhibition, and the IC50 was 3.2×10^-4M. 5) Trapidil which was reported to inhibit platelet aggregation via phosphodiesterase (PDE) inhibition had a similar IC50 on ADP and TXA₂-induced platelet aggregation to that of etafenone, but in collagen and AAinduced aggregation, its IC50 was higher than that of etafenone. 6) Etafenone (3×10^-6 ?? 3×10^-4M) dose-dependently inhibited the production of TXB₂ in PRP induced by collagen. 7) Etafenone scarcely affected TXA₂ synthetase activity in rabbit platelet homogenate. 8) The correlation between the inhibitory effect of etafenone on platelet aggregation and inhibition of AA metabolism activation and PDE inhibition was discussed.

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Antral pH was varied by an intragastric administration of a buffer solution with weak or strong acidity. There is a highly significant correlation between the intragastric pH and serum gastrin level (SG). FM-100 (800 mg/kg, i.d.) decreased SG independently of the intragastric pH, but cimetidine (400 mg/kg, i.d.) did not affect SG beyond the control range. The combination of FM-100 and cimetidine decreased SG significantly as compared with that after cimetidine alone; however, the SG was significantly higher than that after FM-100 alone. These results suggest that FM-100 inhibited gastrin release from the antrum independently of a feedback mechanism due to the intragastric pH, cimetidine increased SG dependently on the feedback mechanism, and FM-100 inhibited the increase in SG after cimetidine in pylorus-ligated rats.

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The serum half-life of PSP(PSP t/2) was determined in normal and nephropathy rats by repeated blood collection under an unanesthetized condition to estimate its usefulness as a renal functional parameter. In normal rats, the serum disappearance curve of PSP (5 mg/kg) could be resolved into two exponential components, and the mean PSP t/2 in the second component was 12 min (n=100). About 71% of the PSP loaded was excreted in urine and 19% in bile. A single subcutaneous injection of HgC12 delayed the serum disappearance of PSP and simultaneously decreased its urinary excretion and increased its biliary excretion. The serum protein binding ratio of PSP became higher when the serum concentration of PSP was decreased, while it became lower when the serum albumin level was decreased. PSP t/2 in rats treated with gentamicin or puromycin amino-nucleoside as well as that in rats given HgCl₂ was increased in correlation with changes in common renal functional parameters such as serum urea nitrogen, serum creatinine, urinary protein and morphologic changes of the kidney. Masugi-type nephritis rats showed no change in PSP t/2. Moreover, PSP t/2 was well correlated with the maximal tubular secretion rate of p-amino-hippuric acid. Since PSP t/2 can be determined periodically on the same animal, it is considered to have effective application as a renal functional test in rats, especially for examining tubular secretion.

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Protective effects of KB-53 on acute liver injury induced by carbon tetrachloride (CCl₄) and l-naphtylisothio-cyanate (ANIT) in mice was investigated by means of histopathological, histochemical and enzymehistochemical examinations. Diffuse centrilobular necrosis, ballooning degeneration of hepatocytes and hemorrhage were markedly observed in the livers of the mice one to three days after a subcutaneous injection of CCl₄. On the other hand, in the livers of KB-53 pretreated mice, forcal necrosis was observed and inflammatory cells had already infiltrated one day after CCl₄-intoxication. Three days later, remarkable development of absorbent granulation tissues with syncytium and hepatocytic mitosis was observed. Furthermore, a number of PAS positive materials such as mucopolysaccharides and mucoproteins were detected in the livers of KB-53 pretreated mice. KB-53 inhibited the disappearance of glucose-6-phosphatase (G-6-Pase) in the liver after CCl₄-intoxication and the rise of alkaline phosphatase (Al-Pase) in the liver after ANIT-intoxication. In addition, KB-53 inhibited the rise of Al-Pase and total bilirubin in the serum of mice after CCl₄ and ANIT-intoxication. All these findings suggest that KB-53 protects liver against the morphological and functional changes, and it potentiates the proliferative and regenerative activity of the liver impaired with CCl₄ and ANIT.

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A study was carried out to investigate the influence of 3 kinds of hepatotoxic agents on the peripheral blood leucocyte population, the splenocyte population and the delayed type hypersensitivity (DTH) in mice. These parameters were not affected by the intraperitoneal injection of D-galactosamine (Gal). The intensity of picryl chloride induced DTH (PC-DTH) in mice was significantly lowered with the administration of carbon tetrachloride (CCl₄) and 1-naphtylisothiocyanate (ANIT) in a dose-dependent manner after the mice were sensitized to picryl chloride (PC) from one to three days after the subcutaneous injection of CCl₄ and ANIT. However the peripheral blood leucocyte population and splenocyte population were not affected by these chemicals. The lowering effect of CCL₄ and ANIT on PC-DTH was somewhat weakened when PC sensitization was performed seven days after the injection of CCl₄ and ANIT. No lowering effect was observed when PC sensitization was performed fourteen days after the injection of CCl₄ and ANIT. The intensity of PPD induced DTH (PPD-DTH) was also lowered by the administration of CCl₄ and ANIT when the sensitization to tubercle bacilli was performed three days after the injection of CCl₄ and ANIT. Cianidanol (KB-53) prevented the decrease of PC-DTH and PPD-DTH in the mice injected with CCl₄ and ANIT in a dose-dependent manner, but did not affect DTH in normal mice. So it seems that KB-53 has an immunostimulating effect on decreased cellular immunity.

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Effects of cianidanol on chronic liver injury induced by prolonged administration of carbon tetrachloride (CCl₄) and on liver regeneration after partial hepatectomy of normal liver and CCl₄ chronically injured liver were investigated by the measurement of plasma and liver biochemical parameters. Cianidanol increased the total plasma protein and ¹⁴C-Leu incorporation into plasma protein, while it reduced the contents of liver cholesterol and triglycerides. In rats with chronically injured liver or regenerating liver after partial hepatectomy of chronically infujed liver, cianidanol improved the retention rate of BSP and the content of liver sugar. In rats with chronically infujed liver, plasma GPT and GOT activities were reduced with the administration of cianidanol. Cianidanol had no effect on the regeneration rate after partial hepatectomy of normal liver, but it increased the regeneration rate after partial hepatectomy of chronically injured liver. These results suggest that cianidanol has the effect of improving the function of liver cells damaged by CCl₄ treatment and of promoting the recovery of cell function to a normal level.

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The effects of eptazocine on spontaneous movements in mice were investigated by using a multi-dimensional behavioral analyzer (Animex II) in comparison with those of pentazocine and morphine. Eptazocine at 20, 40 and 80 mg/kg increased the spontaneous movements in a dose-dependent fashion. On the contrary, the spontaneous movements in mice were significantly decreased by pentazocine in the same dose range. On the other hand, morphine produced biphasic effects: 20 mg/kg morphine inhibited the spontaneous movements, but it potentiated them at doses of 40 and 80 mg/kg. The effects of these three drugs on the spontaneous movements were antagonized by naloxone. The effects of pentazocine and morphine on the spontaneous movements were modified by the successive administration of these drugs, but not by eptazocine administration. The eptazocine-induced hyperactive movements were potentiated by apomorphine and were inhibited by haloperidol, α-methyl-ρ-tyrosine and disulfiram. On the contrary, the inhibitory effects of pentazocine on the spontaneous movements were antagonized by apomorphine. On the other hand, the inhibitory effects of 20 mg/kg morphine on the spontaneous movements were also inhibited by apomorphine and haloperidol. These results suggest that the pharmacological effects of eptazocine on the spontaneous movements in mice are different from those of pentazocine and morphine. The effects of eptazocine may be mediated by opiate receptors and catecholaminergic neurons, but the potency of eptazocine to induce tolerance is less than pentazocine and morphine.

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FUT-175 is a new synthetic protease inhibitor which strongly inhibits complement-mediated hemolysis via the classical and alternative pathways. The present study was undertaken to examine the effects of FUT-175 on antibody formation and host defense in mice since the complement system participates in both immunological responses and host defense against bacterial infection. FUT-175 did not suppress the primary IgM and IgG antibody responses to sheep red blood cells, although FUT 175 was given at 10 to 100 mg/kg/day p.o. for 3 days before or after immunization. On the other hand, the primary anti-DNP IgE antibody response to DNPconjugated ovalbumin was slightly suppressed only by post-administration of FUT-175 in a dose of 100 mg/kg/ day p.o. for 5 days. However, the results of the adoptive transfer experiments indicate that FUT-175 did not affect either T cells or B cells participating in the secondary anti-DNP IgE antibody formation. FUT-175 in a dose of 10^-4M but not at 10^-6 to 10^-5M significantly decreased the proliferation of spleen cells caused by concanavalin A, lipopolysaccharide or the one-way mixed lymphocytes culture reaction using 1000 R-irradiated spleen cells from BDF₁ mice as stimulator cells and those from C57BL/6 mice as responder cells. FUT-175 had an inhibitory rather than an enhancing effect on host defense to infection with Escherichia coli when administered at 10 to 100 mg/kg/day p.o. for 3 days before or after infection. These results strongly suggest that FUT-175 does not affect antibody formation and host defense in mice.

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FUT-175 is a new anti-complemental drug which strongly inhibits complement-mediated allergic reactions in animals. It was reported that FUT-175 does not affect both antibody formation and host defense to bacterial infection in mice. The present study was undertaken to examine the effects of FUT-175 on various immunological reactions in humans. FUT-175 dose-dependently decreased the antigen-induced anaphylactic histamine release from leukocytes of atopic patients. However, i.d. treatment of FUT-175 neither inhibited antigenor compound 48/80-induced immediate type skin reactions in atopic patients nor antigen-induced early, late or delayed type skin reactions in Candida-sensitive patients. FUT-175 also did not inhibit the PPD-mediated delayed type skin reaction in healthy subjects. FUT-175 at a dose of 10^-4M but not at 10^-8 to 10^-5M significantly decreased the proliferation of human atopic peripheral blood lymphocytes (PBL) caused by mite antigen, concanavalin A or pokeweed mitogen. ⁵¹Cr release from human PBL was slightly enhanced by FUT-175 at a dose range of 10^-6 to 10^-4M. FUT-175 did not change the number of SIg receptors or C3 receptors on human B cells. FUT-175 hardly affected the nitroblue tetrazolium reduction test and Escherichia coli-mediated chemotaxis in human neutrophils. These results strongly suggest that FUT-175 does not affect immunological functions and host defense in humans.

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The therapeutic effects of cianidanol on the rat liver cirrhosis induced by CCl₄ were investigated by means of pathological examination. Rats were administered with CCl₄ subcutaneously twice a week for a consecutive 10 weeks. From a macroscopical viewpoint, pailing grayish discoloration, granular hyperplastic nodules and the disappearance of luster on the surface of the liver, and the formation of pseudolobule on the cut surface were observed in the control group. In the histopathological findings, degenerative fatty change and ballooning degeneration of parenchymal liver cells, a formation of pseudolobule caused by septal fibrosis proliferation, an acinar arrangement caused by pericellular fibrosis, and a cholangiollar proliferation were observed. All these abnormalities were diminished by the oral administration of 200 and 400 mg/kg of cianidanol for 7 days. The therapeutic effects of cianidanol were dose-dependent on the liver cirrhosis rats. Consequently, it is suggested that cianidanol has therapeutic effects on liver cirrhosis induced by CCl₄ by relieving hepatocytes disorder, improving regeneration of hepatocytes and the absorption of proliferated fibrotic tissues.

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