We investigated antidotal effects of nine drugs against acute fenitrothion poisoning in rats. The antidotal effects were evaluated by a relief from toxic signs, an increased survival ratio and a prolonged surviving time. In the poisoning with approximate LD₅₀ fenitrothion (500 mg/kg), oximes such as 2-PAM (2-pyridine aldoxime methiodide) and TPMM (1-(methyl morphorinium)-3-(4-hydroxyiminomethylpyridinium) propane dibromide), diphenhydramine and parasympatholytics such as atropine, scopolamine and biperiden significantly increased survival ratio and/or prolonged surviving time. These effective drugs did not sufficiently depress the toxic signs, except that the parasympatholytics markedly blocked salivation, miosis and motor ataxia. In contrast, reduced glutathione and central depressants such as diazepam and phenobarbital made the poisoning serious. In the poisoning with 100% lethal dose of fenitrothion (800 mg/kg), the parasympatholytics were more effective then 2-PAM and diphenhydramine, and they elevated the survival ratio up to 20-40%. The best therapy against the severe poisoning with 100% lethal dose of fenitrothion was confirmed to be repeated and combined treatment with atropine and 2-PAM as established in parathion poisoning, resulting in 90% survival ratio and considerable alleviation from the toxic signs.

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The dispositon and metabolism of afloqualone [6-amino-2-fluoromethyl-3-(o-tolyl)-4(3H)-quinazolinone, AFQ] were studied in monkeys and dogs after oral administration of ¹⁴C-AFQ. In both species the blood radioactivity reached a maximum 1 to 2 h after the administration, and decreased with apparent half-lives of 3.2 h in the monkey and 7.2 h in the dog. A total of about 90% of the administered radioactivity was recovered from the urine (monkey, 72.3%; dog, 51.8%) and feces (monkey, 19.4%; dog, 36.7%) within 4 or 5 d.AFQ was extensively metabolized in both species. There were species differences in the composition of the urinary metabolites. In the dog, AFQ was monohydroxylated at the 2-, 2'-, 3'- and principally 4'-position and each metabolite was further conjugated with glucuronic acid. N-Acetylated metabolites were not detected. In the monkey, N-acetylation was the main initial step of metabolism followed by hydroxylation at the acetyl-methyl, 2'- methyl and 2-fluoromethyl groups. Phenolic metabolites such as 3'- and 4'-hydroxylated AFQ were not detected. Both animals excreted sulfur-containing metabolites such as the 2-methylthio, 2-methylsulfinyl and 2-methyhylsulfonyl derivatives of AFQ.

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γ-Hexachlorocycloexane (γ-HCH) was metabolized by dehydrochlorination, dehydrogenation and dechlorination in rat liver microsomes and these initial metabolites of γ-HCH were identified as γ-pentachlorocyclohexene (γ-PCCH), γ-hexachlorocyclohexene (γ-HCCH) and γ-tetrachlorocyclohexene (γ-TCCH) by gas chromatography-mass spectrometry (GC/MS). The dehydrochlorination and dehydrogenation were performed in incubation media containing NADPH and p, p'-tetramethyldiaminodiphenyl methane (TPD, 30 nmol) which is known to inhibit the degradation of initial metabolites formed during an aerobic incubation of γ-HCH with microsomes at 25°C. The dechlorination was found to proceed well under anaerobic conditions. The dehydrogenation was inhibited by SKF 525-A, CO, piperonyl butoxide, N₂ and the absence of NADPH, but not by cyanide. Additionally, pretreatment of rats with phenobarbital (PB), but not with 3-methylcholanthrene (3-MC), induced the dehydrogenation of γ-HCH. These results suggest that cytochrome P-450 is involved in this reaction.The cytochrome b₅ system may not be involved. The dehydrochlorination was inhibited by N₂, CO, piperonyl butoxide, KCN and the absence of NADPH, but not by SKF 525-A. This reaction was enhanced by pretreatment of rats with SKF 525-A, CoCl₂ and piperonyl butoxide. Pretreatment with PB and 3-MC did not show a significant effect on the dehydrochlorination activity. Thus, the results suggest that the dehydrochlorination could be catalyzed by a specific species of cytochrome P-450 and cytochrome b₅ system and/or other microsomal enzyme systems.

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Although the mechanism of antihypertensive action of β-adrenergic blocking drugs (β-blockers) is not known, a theoretical advantage of cardioselective β-blockers over nonselective ones has been proposed in the treatment of hypertension. To study this hypothesis, we examined cardiovascular responses to handling stress in spontaneously hypertensive (SHR) rats after a single (100 mg/kg) and multiple oral treatments (100 mg/kg per day for 17 d) with either atenolol or propranolol. Atenolol and propranolol markedly suppressed the tachycatdia induced by handling stress after acute and chronic administration. Resting mean arterial pressure (MAP) was reduced by acute and chronic atenolol treatment, but not by propranolol.Stress-induced increase in MAP was significantly reduced by chronic treatment with propranolol, whereas no consistent effects were observed with atenolol. Acute treatment with guanethidine (30 mg/kg) markedly reduced the rise in MAP induced stress. These results suggest that suppression of cardiac function by β-blockers does not always attenuate the rise in MAP induced by stress, thus cardioselective β-blockers might not confer any further reduction of the blood pressure increase due to sympatho-adrenal excitation. Inhibition of stress-induced MAP rise by propranolol could be mediated by a modulation of the catecholamine release.

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Two hemagglutinins were separated from extracts of Cytisus multiflorus seeds by successive affinity chromatographies on columns of galactose- and di-N-acetylchitobiose-Sepharose 4B. One was found to be inhibited by di-N-acetylchitobiose or tri-N-acetylchitotriose and shown to possess anti-H(O) activity [Cytisus-type anti-H(O) hemagglutinin designated as Cytisus multiflorus hemagglutinin I]. The other, which was not a blood group-specific hemagglutinin, was inhibited by galactose or lactose (hemagglutinin II). Hemagglutinins I and II were further purified by gel filtration on Sephacryl S-300. These Prepatations were homogeneous as judged by polyactylamide gel electrophoresis and gel filtration. The molecular weights of the purified hemagglutinins I and II were found to be 86000 by sedimentation equilibrium analysis and 80000 by gel filtration. On disc gel electrophoresis in the presence of sodium dodecyl sulfate and dithiothreitol, both hemagglutinins gave a single component of a molecular weight of 42000±2000, suggesting that these hemagglutinins are dimeric proteins of two identical subunits. Hemagglutinins I and II contain 2.7% and 1.5% carbohydrate, respectively, and only very small amounts of cystine and methionine were detected, but they are rich in aspartic acid and serine. Treatment of human O erythrocytes with a purified H-decomposing enzyme (α-L-fucosidase from Bacillus fulminans abolished the agglutinability of the cells with hemagglutinin I. This indicates that the L-fucosyl residue is important even for the H-specificity detected by this di-N-acetylchitobiose-specific hemagglutinin I.

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The relationships between behavioral responses and levels of serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in brain of mice were investigated after intravenous injection of fumitremorgin A (FTA). The latent periods to the onset of tremor, clonic convulsion, tonic convulsion and death induced by FTA are observed in a dose-dependent fashion. However, the dose-dependency is not observed between levels of 5-HT and 5-HIAA and activities of 5-HT metabolizing enzymes in brain of FTA-treated mice. Insignificant participation of serotonergic mechanism in modulation of those behavioral states elicited by FTA is conclusively suggested.

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A 20% phenytoin (PHT) plain mixture with excipients (20%PM) and three PHT products prepared by wet granulation, which are 20% fine granule (20%FG), 99% air-dried fine granule (99%FG-A) and 99% freeze-dried fine granule (99%FG-F), were prepared.The extents of PHT absorption from these products and the Aleviatin Fine Granules[○!R] (97%FG) prepared with microcrystalline PHT powder were compared with those from commercially available PHT powder (Aleviatin[○!R]) and tablet (Hydantol Tablet 25 mg), which are of the Pharmacoposia of Japan grade, in healthy adult volunteers. In single dose study, the extents of PHT absorption from the powder, 20%PM, 20%FG, 99%FG-A, 99%FG and tablet were 89.7, 92.2, 99.0 96.7, 99.1, 99.1, and 99.3%, respectively. The property of almost complete absorption of PHT from the product was shown in the 20%FG, 99%FG-F and 97%FG similar to the tablet. In multiple dose study, the minimum and the average estimated free concentrations of PHT at steady-state for 99%FG-F and 97%FG were nearly equal to those for the tablet, and were higher than those for the powder. In epileptic patients, the plasma PHT concentrations were increased when dosage form was changed from the powder to 99%FG-F. However, the plasma PHT concentrations were scarcely altered when dosage form was changed from the tablet to 99%FG-F. The change in dosage forms from the tablet to 99%FG-F and 97%FG or opposite direction can be done without causing toxicity in epileptic patients, so long as these products are used at the same amounts as PHT.

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BaCl₂ stimulated significantly p-aminohippurate (PAH) accumulation in rat kidney cortical slices. The accumulation, however, was not stimulated by Sr²⁺, Mn²⁺ and Mg²⁺. Pretreatment of the slices with Ba²⁺ also increased PAH accumulation in the slices during incubation without BaCl₂. Kinetical analyses of PAH accumulation showed that the effect of Ba²⁺ was to increase V_max. No evidence for the effect of Ba²⁺ on PAH efflux from the slices was obtained. Thus, evidence indicating that Ba²⁺ stimulated PAH influx to the kidney cell was presented. Water distribution and energy metabolism in the slices were not related to the stimulative effect of Ba²⁺ on PAH accumulation. Ba²⁺ slightly lowered Na²⁺ concentration in the slices. However, in the presence of ouabain, further addition of Ba²⁺ recovered PAH accumulation to a control value in spite of poor Na⁺ gradient as compared with that in control slices. Therefore, it is suggested that stimulation of PAH accumulation by Ba²⁺ was not due to changes in Na⁺ gradient. No stimulation of tetraethylammonium (TEA), an organic base, transport system by Ba²⁺ was observed. These data suggest that Ba²⁺specifically stimulates the organic acid transport system in rat kidney cortical slices by increasing PAH influx to the cells.

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Effects of Chlordiazepoxide, diazepam and oxazepam on the antitumor activity and acute toxicity of cyclophosphamide and the level of its active metabolites in the plasma were investigated in mice. Cyclophosphamide was administered 24 h after the final injection of chlordiazepoxide, diazepam or oxazepam (100 mg/kg/d for 3 d, i.p.). Pretreatment with these drugs increased the acute toxicity of cyclophosphamide (300 or 450 mg/kg, i.p.), whereas drugs had no effect on the antitumor activity of cyclophosphamide (100 mg/kg, i.p.) against Ehrlich solid carcinoma. A high level of active metabolites of cyclophosphamide in the plasma after the administration of cyclophosphamide (300 or 450 mg/kg, i.p.) was observed in chlordiazepocide-, diazepam- or oxazepam-treated mice. On the other hand, chlordiazepoxide, diazepam or oxazepam enhanced significantly the activity of cyclophosphamide oxidase in hepatic microsomes. It is concluded that potentiation of the acute toxicity at a high dose of cyclophosphamide by chlordiazepoxide, diazepam and oxazepam is due to an induction of microsomal drug-metabolizing enzyme which are responsible for the in vivo activation of cyclophosphamide.

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The investigation was undertaken to study the neurological symptoms in rats caused by maintaining high plasma concentration of about 30 nmol/ml or more, of clioquinol. Clioquinol suspension which was prepared using polysorbate 80 was administered intraperitoneally to rats and plasma and tissue concentrations were determined. On administration of clioquinol of 100 and 200 mg/kg, the mean plasma concentrations of clioquinol reached maximum values of 30 and 58 nmol/ml, respectively, after 0.5-1 h and thereafter decreased rapidly. With 400 mg/kg, however, plasma concentration reached maximum value of about 75 nmol/ml and fell slowly. By single and repeated administration of the suspension, clioquiol was distributed in the liver and kidney at a high concentration, and also in the nervous system. In experiments on appearance of neurotoxicity in rats by repeated administration of the suspension, all of 10 rats administered intraperitoneally with 100 mg/kg/d did not develope any neurological symptoms for about 30 d. On the other hand, one of 10 and 7 of 13 rats administered with 200 and 400 mg/kg/d, respectively, developed ataxia in the hind legs or all legs on the 3rd to the 12th day after starting administration. Pathologically, a slight change of the peripheral nerve, central chromatolysis of the anterior horn neuron and severe neuronal degeneration of the Ammon's horn were observed in the rats with ataxia.

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Prostaglandins A₁, A₂ and B₂ (PG A₁, A₂ and B₂) dose-dependently inhibited specific [³H] diazepam binding to rat brain membranes but did not affect specific [³H]Ro 5-4864 binding to kidney membranes. The inhibition of [³H] diazepam binding to brain membranes by benzodiazepine agonists (diazepam and flurazepam) was potentiated by 30 μM GABA, whereas those of prostaglandins were not modified by the same concentration of GABA. These results suggest that PG A₁, A₂ and B₂ specifically interact with central type-benzodiazepine receptors in a manner different from interactions seen with benzodiazepine agonists.

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Effect of experimental acute renal failure (EARF) on the intrinsic renal tubular secretory clearance (CL^SCN_int) of tetraethylammonium bromide (TEA) and N¹-methylnicotinamide (NMN) was examined in rats treated with glycerol, folate, salicylate, uranium and gentamicin. The values of CL^SCN_int was calculated by an equation incorporating the determinants of the renal clearance (CL_r), i.e., renal tubular secretory clearance (CL^SCN_r), glomerular filtration rate (GFR), renal plasma flow (RPF), free fraction of the drug in plasma (f_p) and fraction (F_reabs) of the drug reabsorbed after filtration and secretion in the urine. In the EARF-rats, the values of CL^SCN_intof NMN and TEA were decreased by 0.017-0.575 times and by 0.005-0.737 times as compared to those of the normal rats, respectively. It was suggested that the decreases in CL^SCN_r of both NMN and TEA were due not to the decrease in RPF, but to that in CL^SCN_int.

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Effect of β-cyclodextrin (β-CyD) on the local tissue toxicity of chlorpromazine (CPZ) was investigated following the intramuscular injection to rabbits. From the gross and histological examinations, β-CyD was found to alleviate the muscular tissue damage produced by CPZ on M. vastus lateralis in rabbits. The protective effect of β-CyD may be ascribed to the decrease in affinity of CPZ to the tissue membrane through inclusion complexation. The present data suggest that β-CyD complexation is particularly useful to reduce the local toxicity of phenothiazine neuroleptics without altering the pharmacological efficacy.

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An intracereboventricular injection of d-coclaurine (50μg), a benzyltetrahydro-isoquinoline alkaloid extracted from Magnolia salicifolia, produced a slight increase in 3, 4-dihydroxyphenylacetic acid level and a significant increase in homovanillic acid level in the mouse striatum. Another alkaloid d-reticuline (200 μg) increased only homovaillic acid level. An intracerebroventricular pretreatment with d-colaurine (50 μg) did not antagonize suppressive effect of apomorphine on l-dopa formation produced by γ-butyrolactone (750 mg/kg i.p.) plus armatic amino acid decarboxylase inhibitor, NSD-1015 (100 mg/kg i.p.). These results suggest that d-coclaurine blocks postsynaptic but not presynaptic dopamine receptors in the mouse striatum.

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