To determine estrogen action in PG metabolism in rat uterus, effect of the hormone on the uptake and interconversion of PGF and E was studied using ³H-PGF_α and ³H-PGE₂. The following results were obtained: Uptake of ³H-PGF_α and ³H-PGE₂ was increased at 6 hours after estrogen injection. The conversion into PGF and PGE group from ³H-PGE₂ and ³H-PGF_2α, respectively, was observed in rat uterus, but the hormone action on the interconversion of PG was apparently different between PGF_2α and PGE₂. The conversion of ³H-PGF_2α into PGE group was increased with the lapse of time after estrogen injection. However, estrogen action on the conversion of ³H-PGE₂ into PGF group was not so remarkable as that of ³H-PGF_2α. Effects of indomethacin in vivo and in vitro on the metabolism of PGF_2α. increased by estrogen were also examined. Estrogen action on the uptake of PGF group was inhibited by indomethacin injection, but the conversion into PGE was not influenced by this compound.

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Male and female rats (60 ?? 80 g) of Wistar strain were randomly divided into two groups and were given milk and cereal diets, respectively. Each group was further divided into two groups; one was given the diet containing 100ppm of arsenic trioxide and the other a diet containing “arsenic compound” (100ppm as arsenic trioxide). Each group included five rats of both sexes. A 6-month feeding of the test diet was followed by. provision of a normal diet. The accumulated arsenic was excreted almost 100% from the brain and 20 ?? 30% from organs such as kidney, liver, spleen and lung. The arsenic level persisted in tissues in animals on the cereal diet, as compared with those fed the milk diet. There was no significant difference in the accumulation and excretion of arsenic between the groups given arsenic trioxide or “arsenic compound”.

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Kanechlor-500 (KC-500, a polychlorinated biphenyl mixture containing 55% chlorine) was administered to rats at a dose level of 1, 10 and 100 mg/kg, twice a week for 15 weeks. At 15 weeks, the rats were sacrificed to determine toxicological effects and to analyze polychlorinated biphenyl (PCB) residues in tissues. In other groups, rats were sacrificed 15 weeks after discontinuation of the treatment. During the administration period, the enhancing effect of liver microsomal drug-metabolizing enzymes by KC-500 was more evident than the hematological and serum biochemical alterations. Histopathology of the liver included degeneration of liver cells, single cell necrosis, and lipofuscin accumulation in cytoplasma, and such was dose dependent. After cessation of the KC-500 treatment, several parameters reverted toward control values particularly in animals given lower doses. The order of the PCB levels in tissues analyzed by gas-chromatography was adipose tissue >> liver >> kidney> blood. Following a recovery period of 15 weeks the residue levels in adipose tissue and liver were 40 ?? 60% and 50 ?? 60% of those observed after 15 weeks treatment period to KC-500, respectively. Furthermore, storage levels of PCB in adipose tissue decreased more rapidly following discontinuation of administration of the low dose levels as compared to those given the highest dose. From the findings in the gas-chromatographic analyses, it is likely that some of the components are metabolized more rapidly than others when the activity of liver microsomal drug-metabolizing enzymes is enhanced by KC-500 itself.

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TAI-284, a new non-steroidal acidic analgesic and anti-inflammatory agent was investiagted and the interactions with biopolymers were compared with those of indomethacin (IMC) and ibuprofen (IT). TAI-284 inhibited the heat denaturation of bovine serum albumin at pH 5.3, similar to that seen with IMC and weaker than that seen with phenylbutazone. TAI-284 prevented the rat erythrocyte from heat-induced hemolysis and was twice as potent as IMC. TAI-284 produced alterations in platelet function as characterized by loss of secondary aggregation in response to ADP and inhibition of aggregation by collagen. Both these effects were one fifth as potent as those seen with IMC. In rats, platelet aggregation induced by collagen and secondary ADP aggregation was reduced in a dose-dependent manner by a single oral administration of TAI-284. The inhibitory activity was approximately one fourth that of IMC or twice that of IP in the former and in the latter one fifth that of IMC or similar as that of IP. These results suggest that the essential feature of TAI-284 is its potent membrane stabilizing action which is considered to be an necessary mechanism in the action of anti-inflammatory drugs. It is considered that TAI-284 may be less active than IMC in inhibiting prostaglandin biosynthesis in platelets.

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Effects of drugs that modify tryptaminergic or catecholaminergic mechanisms were determined in mice regarding the analgesic action of difenamizole and morphine. Analgesia was assessed by the writhing movements induced by acetic acid in mice. The following monoamine-related drugs were given at doses which hardly influence the writhing: 5-hydroxytryptophan (5-HTP), 5-hydroxytryptamine (5-HT), p-chlorophenylalanine (p-CPA), 5, 6-dihydroxytryptamine (5, 6-DHT), L-DOPA, dopamine (DA), norepinephrine (NE), methamphetamine, α-methyl-p-tyrosine (α-MT), 6-hydroxydopamine (6-OHDA), diethyldithiocarbamate (DDC), phenoxybenzamine and reserpine. 5-HTP (25 mg/kg, p.o.) and 5, 6-DHT (25 μg/mouse, i.e.) significantly antagonized the analgesic action of difenamizole, but other 5-HT-related drugs did not significantly influence the action of this analgesic. The analgesic action of difenamizole was also antagonized by DA (2.5 and 5.0 μg/mouse, i.c.) but was significantly potentiated by 6-OHDA (50 and 100 μg/mouse, i.c.), phenoxybenzamine (5 and 10 mg/kg, s.c.) and reserpine (1.5 and 2 mg/kg, i.p.). NE (2.5 and 5.0 μg/mouse, i.e.) and DDC (50 mg/kg, s.c.) did not influence the effect of difenamizole. 5-HTP (50 mg/kg), 5-HT (1.0 pg/mouse, i.e.) and NE (2.5 and 5.0 μg/mouse, i.e.) significantly potentiated the analgesic action of morphine, but 5, 6-DHT (25 μg/mouse, i.c.) and 6-OHDA (50 μg/mouse, i.c.) significantly antagonized the effect of this narcotic. The effect of this drug was not significantly modified by pretreatment with other monoamine-related drugs. These results suggest that the analgesic action of difenamizole may be related to DA, but the effect of morphine may be mediated by 5-HT and NE. The biogenic amines may play a different role depending on the type of analgesic.

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To obtain better arterio grafts, we prepared three samples from adventitia of swine carotid arteries, and their antigenicity was studied with immunological procedures. Sample I was prepared from swine carotid arteries by eliminating the extraneous fat and connective tissues. Sample II was prepared from Sample I by treatment with chymotrypsin, and Sample III was prepared from Sample II by treatment with 3% glutaraldehyde for 14 days. From the three samples, the water soluble protein fractions were extracted, and abbreviated as E-I, E-II and E-III, respectively. Immunopharmacological tests in guinea pigs and rabbits including active and passive anaphylaxis, passive cutaneous anaphylaxis, Schultz-Dale test and Arthus's phenomenon among these extracts revealed cross reactions between E-I and E-II. Also, precipitin test and Ouchterlony's method, precipitation was observed between E-I and E-II, and it was suggested that there might be at least a common antigen between E-I and E-II. The rabbits which had been implanted subcutaneously at the back with the minced Sample I evoked severe reactions and died after intravenous injection of E-I at the 3rd or 5th month after implantation. No reaction was observed between Sample III and E-III in the same experiment. From the above results, it was suggested that the antigenicity of swine carotid arteries could be eliminated by the treatment with chymotrypsin and glutaraldehyde.

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In isolated rabbit left atria driven electrically at a frequency of 30/min, the contraction was abolished by increasing external K⁺ concentrations from 5.4 to 22 mM. Addition of isoproterenol (10^-6M) restored the atrial contraction and the magnitude of contractions increased by raising external concentrations of Ca⁺⁺ to 4.4 and 6.6. mM. Hexobendine attenuated the magnitude of contractions restored by isoproterenol and excess Ca⁺⁺ in a dose-dependent manner, as did prenylamine and verapamil. Hexobendine did not significantly influence the membrane depolarization induced by excess K⁺ and there was no evidence of a beta-adrenergic blocking action. In helical strips of rabbit aortae exposed to Ca⁺⁺ -free media and depolarized by excess K⁺, the addition of Ca⁺⁺ caused a marked contraction. Hexobendine, prenylamine and verapamil caused a dose-related attenuation of the Ca⁺⁺-induced contraction. Relative potencies of the inhibition by hexobendine, prenylamine and verapamil were 1:16.5:100. Inhibitory effects of these drugs were partially antagonized by excess Ca⁺⁺. Greater attenuation of the contractile response to 25 mM K⁺ than the response to 2 × 10^-6M noradrenaline was observed in preparations treated with hexobendine. It may be concluded that interference with the influx of Ca⁺⁺ across cell membrane in atrial muscles and aortic smooth muscles participates in the inhibition of contractility by hexobendine.

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Electroencephalographic (EEG) effects of flurazepam were investigated in unanesthetized, unrestrained rabbits with chronic electrode implants and compared with those of diazepam. Flurazepam, at doses of 0.5 ?? 5 mg/kg i.v., induced a drowsy EEG pattern, i.e. high voltage slow waves in the cortex and amygdaloid complex and desynchronization of the hippocampal theta waves. In addition, low voltage fast waves were superimposed, especially on the cortical EEG. Flurazepam suppressed the EEG arousal responses induced not only by auditory stimulation but also by electrical stimulation of the mesencephalic reticular formation, posterior hypothalamus and centromedian thalamus. The EEG arousal response induced by i.v. injection of physostigmine was suppressed by flurazepam. Flurazepam depressed the photic driving response and the augmenting response. The recruiting response was slightly enhanced by flurazepam. The limbic afterdischarges elicited by either hippocampal or amygdaloid stimulation were suppressed by flurazepam. Flurazepam caused reductions of pressor responses to stimulation of the posterior hypothalamus and the mesencephalic reticular formation in anaesthetized rabbits. There was little or no effect on pressor responses to the injection of noradrenaline, carotid artery occulusion and asphyxia with flurazepam. In general, these effects of flurazepam were similar to those of diazepam, but the drug induced actions which differed from those of diazepam.

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The effect of capsaicin was studied in gallamine triethiodide immobilized adult cats. Single neurons were recorded from the medial thalamus with a stainless steel microelectrode. Out of 21 neurons recorded in this experiment, 10 were responsive to both nociceptive (pinch) and non-nociceptive (hair bending and/or tapping) stimuli. Six neurons were responsive to only non-nociceptive stimuli and 5 were not responsive to these stimuli. Out of 10 neurons responding to both nociceptive and non-nociceptive stimuli, 9 were responsive to both bradykinin (3 μg) and capsaicin (3 μg). Out of 6 neurons responding to only non-nociceptive sitmuli, 5 were not responsive to either bradykinin and capsaicin. All neurons responding to bradykinin were also responsive to capsaicin. The latency for bradykinin and capsaicin was 7.64±1.12 sec and 0.97±0.07 sec, respectively. The increase in firing frequency produced by capsaicin was depressed by morphine. However, these depressant effects of morphine on single unit activity were antagonized by naloxone.

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The anti-nociceptive dose of difenamizole, morphine, aminopyrine and aspirin was studied for effects on behavior maintained by schedule of positive reinforcement. Male, albino rats were trained to press a lever for food pellets on a fixed-ratio (FR) 10 and 30 schedule of reinforcement or a differential reinforcement of low rates of responding (DRL) schedule. Difenamizole (200 and 400 mg/kg, p.o.) produced a dose-related decrease in the response under FR-10 schedule. The response rate decrease observed under the FR-10 schedule was similar to that resulting from the oral administration of 400 mg/kg of aminopyrine. Response in the FR-30 schedule was not affected by any dose of difenamizole (100 ?? 400 mg/kg, p.o.) and aminopyrine (200 ?? 400 mg/kg, p.o.). In the response maintained by the DRL schedule, the overall response rate and the mean interresponse time were not altered significantly by most doses of difenamizole, aminopyrine and aspirin given, however, food reinforcement was decreased significantly with ingestion of these drugs. Morphine (20 mg/kg, p.o.) shortened the mean interresponse time and increased the response in DRL schedule. These results suggest that the central action of difenamizole is similar to that produced by aminopyrine, but not that produced by morphine.

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