The pharmacological properties of KP-136, an inhibitor of type I allergy, were studied in rat paw models. In four allergic responses, three of the immediate type and one delayed type, KP-136 (p.o.) produced potent inhibitions on the mast cell-mediated type I allergy (ID30 : 1.0 mg/kg) and the neutrophil-infiltrated passive Arthus reaction (ID30 : 1.6 mg/kg). In addition, KP-136 (10 mg/kg, 50 mg/kg, p.o.) inhibited the injury of bone tissues in rat adjuvant arthritis, confirming that it was effective on the allergic inflammation with tissue injury. Although KP-136 was a weak inhibitor of carrageenin-induced paw edema, prostaglandin synthesis and complement-mediated hemolysis, the compound inhibited the release of lysosomal enzymes such as lysozyme and β-glucronidase in the passive Arthus reaction, suggesting the blockage of inflammatory mediator release for its mode of action.

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The electroencephalographic (EEG) effects of buspirone and its major metabolite, 1-(2-pyrimidinyl) piperazine (1-PP), were investigated in rabbits with chronic electrode implants, and the effects were compared with those of diazepam. Intravenous administration of buspirone at 0.1 to 1.0 mg/kg evoked an increase in the arousal EEG pattern period (low amplitude fast waves) in the cortical EEG and synchronization of the hippocampal theta waves with decreased voltages, whereas both 1-PP (0.5 to 2.0 mg/kg, i.v.) and diazepam (1.0 and 2.0 mg/kg) evoked an increase in the drowsy EEG pattern periods : high voltage slow waves and spindle bursts in the cortical EEG and desynchronization of the hippocampal theta waves. Buspirone at higher doses caused behavioral excitation in rabbits, whereas both 1-PP and diazepam produced sedation. Buspirone did not affect EEG arousal responses to both auditory stimulation (2, 000 Hz, monotone) and electrical stimulation (100 Hz, 0.1 msec, 3-6 V) of the midbrain reticular formation or the posterior hypothalamus. However, 1-PP tended to inhibit the EEG arousal response to auditory stimulation but not brain stimulation, and diazepam markedly suppressed the responses induced by both stimulations. The recruiting response induced by centromedian thalamic stimulation at a low frequency (7 Hz, 0.1 msec, 4-8 V) was not affected by buspirone, 1-PP and diazepam. Neither buspirone nor 1-PP had an effect on the photic driving response to a flash light (2 Hz) in the occipital cortex of the rabbit, whereas the response was suppressed by diazepam. Both buspirone and 1-PP enhanced the duration of afterdischarges induced by electrical stimulation (50 Hz, 0.5 msec, 4-15 V) of the dorsal hippocampus, whereas diazepam markedly inhibited the afterdischarges. These results suggest that the EEG effect of buspirone is quite different to those of 1-PP and diazepam in qualitative aspects. It is also suggested that buspirone, unlike diazepam, is an effective anxiolytic drug without a sedative effect.

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Tissue distribution of red blood cells (RBC) that were treated with X-ray contrast media was investigated in rats. The contrast medium mixed with an equivolume of ⁵¹Crlabelled RBC was administered to the internal carotid artery in a dose of 200μl/rat; and the radioactivity in the brain, lung and spleen were determined. The contrast medium mixed with an equivolume of blood was administered to the right atrium in a dose of 4 ml/kg, and the hemoglobin content in the lung and changes in pulmonary and circulatory functions were determined. In the ionic contrast medium (meglumine diatrizoate) -treated group, the radioactivity in the brain remained 30 to 50 times higher compared with the nonionic contrast medium (iopamidol) -and saline-treated group until 15 min after infusion. The radioactivity in the spleen increased and the radioactivity and hemoglobin content in the lung decreased time-dependently in the diatrizoate-treated group, whereas iopamidoland saline-treated groups exhibited constantly low values during the experimental period. Changes in the airway pressure, pulmonary arterial pressure, systemic blood pressure and heart rate were similar after intra-atrial administration of diatrizoate mixed with blood and diatrizoate mixed with saline. These results suggest that the ionic contrast medium affects the RBC and causes a microcirculatory disturbance in the brain.

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Intraperitoneal injection of indomethacin (5, 10 and 20 mg/kg) caused acute gastric mucosal lesions in the conscious restrained rat and also hypersecretion of gastric acid. Cimetidine, an H₂-receptor antagonist, was found to prevent gastric mucosal bleeding and acid secretion induced by indomethacin. Elcatonin at higher doses than 2.5 U/kg (0.5 μg/kg) was effective for protecting the gastric mucosa against indomethacin irritation, and it inhibited acid output in response to this ulcerogen. The acid inhibitory effect of elcatonin might be implicated in its cytoprotective action.

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We studied the effects of OKY-046 on type I allergic reactions. OKY-046 (100 mg/kg) given orally suppressed antigen-induced bronchoconstriction and TXB₂ generation in broncho alveolar lavage fluid in rats passively sensitized with anti-DNP-As monoclonal IgE. At the dose of 30 mg/kg given intraduodenally, it also inhibited antigen-induced bronchoconstriction in guinea pigs passively sensitized with anti DNP-As serum and actively sensitized with ovalbumin. However, aspirin (30 mg/kg) didn't suppressed them significantly. Azelastine (10 mg/kg) inhibited bronchoconstriction in passively sensitized rats and actively sensitized guinea pigs. In 48 hour homologous PCA reactions of rats and mice, oral administration of OKY-046 (300 mg/kg) and tranilast (100 mg/kg) suppressed the extravasated dye in the skin. OKY-046 decreased histamine release from passively sensitized rat peritoneal exudate cells. There was no effect of OKY-046 on SRS-A and leukotriene release from actively sensitized guinea pig lungs and passively sensitized rats. In conclusion, we think that OKY-046 should be an useful asthmatic drug or anti-allergic drug by oral administration.

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We studied the effects of OKY-046 on types II, III and IV allergic reactions, as classified by Coombs and Gell. In Type II, OKY-046 at 30-100 mg/kg intraduodenally (i.d.) and at 1-30 mg/kg intravenously (i.v.) inhibited the bronchoconstriction in a dose-dependent manner after Forssman antigen injection. Aspirin (3 mg/kg, i.v.) also suppressed it. OKY-046 (30-100 mg/kg, i.d.) suppressed the increase of TXB₂ level in the plasma in a dosedependent manner. However, there was no effect of OKY-046 and aspirin on the decrease in complement activity (CH₅₀), platelets and leukocytes. Additionally, OKY-046 (300 mg/ kg, p.o.) prolonged the survival time following Forssman antigen injection. However, the immune hemolysis reaction was not prevented by OKY-046 (10^-6-10^-3M). FUT-175 protected against the Forssman shock at 1 mg/kg, i.v. and the in vitro immune hemolysis reaction at 10^-5M. In Type III, OKY-046 (300 mg/kg, p.o.) significantly suppressed the direct passive Arthus reaction and immune complex nephritis in rats. There was no effect of OKY-046 on the delayed-type hypersensitive response to picryl chloride in mice. We think that OKY-046 should be a beneficial drug for the treatment of types II and III allergic reactions.

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