The behavioral pharmacological effects of Ca-4-(3, 5-dihydroxy-3-methylpenthylamido) butyrate (mevalonic-GABA, MV-GABA), a new GABA derivative were studied in comparison with those of Ca-hopantenate (HOPA) in mice. MV-GABA had no effect on the general behavior and electric shock-induced fighting behavior. The dosage of MV-GABA which caused locomotor hypoactivity produced an impairment of the rotarod performance. MVGABA inhibited the hyperactivity induced by a dopamine (DA) agonist (methamphetamine) and acetylcholine (ACh) antagonists (scopolamine and atropine) at a dose which did not affect locomotor activity in normal mice. MV-GABA prolonged the pentobarbital-Na-induced sleeping time, and it prolonged the latencies until convulsion and death after administration of strychnine. MV-GABA and HOPA antagonized the electroconvulsive shock-induced amnesia in the passive avoidance response of mice. These results suggest that MV-GABA has effects on the central nervous systems, in particular, ACh and DA neural systems. The actions of MV-GABA were qualitatively similar to those of HOPA except for the effect on the DA neural system.

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Effects of troxipide on several acute gastric lesions in rats were investigated in comparison with those of cetraxate. Troxipide (100, 200, 300 mg/kg) and cetraxate (100, 300, 1, 000 mg/kg), given orally, dose-dependently protected the gastric mucosa from damage due to ethanol. Aspirin and 0.6 N HCl-induced gastric lesions were dose-dependently inhibited by troxipide (200, 300 mg/kg), but only significantly inhibited by cetraxate at high dose (1, 000 mg/kg). Troxipide (100, 200, 300 mg/kg) dose-dependently prevented the formation of gastric lesions induced by water-immersion stress, whereas cetraxate (600, 1, 000 mg/kg) also significantly prevented gastric lesions. That is, protective effects of troxipide were much more potent than those of cetraxate against aspirin-, 0.6 N HCl- and water-immersion stress-induced gastric lesions, whereas both were almost equal against ethanol-induced gastric lesions. In addition, cytoprotective effects of troxipide against ethanol-induced lesions were most remarkable at 10, 30, 60 min after administration (100, 300 mg/kg) and lasted for up to 240 min. These results suggested that troxipide might be useful for the treatment of acute gastric lesions in humans.

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The effects of dietary magnesium (Mg) deficiency on dermal mast cells were studied in young Wistar rats weighing about 50 g. The rats fed with a Mg-deficient diet (0.001% Mg) showed hyperemia on the 3rd or the 4th day after they were fed the diet. The dermal mast cells of the control rats were filled with granules, while the cells of rats fed the Mg-deficient diet for 4 days contained less granules than the controls, but contained extensively dilated rough surfaced endoplasmic reticulum, well-developed Golgi complexes, many mitochondria and ribosomes. These data suggest that hypomagnesemia could induce a release of histamine from dermal mast cells. So, the effect of a low Mg medium on the release of histamine was studied using peritoneal mast cells in vitro. A low Mg medium (0.2 mM Mg) induced much more histamine release than control medium (1 mM Mg) from the peritoneal mast cells obtained from both control and Mg-deficient rats fed with the Mg-deficient diet for 2 days. The peritoneal mast cells obtained on the 8th day of Mgdeficiency released much more histamine than controls in 1 mM Mg medium. These results suggest that hyperemia observed in Mg-deficient rats depends partly on histamine released from dermal mast cells.

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Effect of a non-steroidal anti-inflammatory drug, pranoprofen (PPF), on sodium urate crystal-induced inflammation was investigated in comparison with standard drugs for treating acute gout in experimental animals. PPF inhibited sodium urate crystal-induced paw edema in both rats (1 ?? 10 mg/kg, p.o.) and mice (5 ?? 25 mg/kg, p.o.) in a dose-dependent manner. On rat sodium urate crystal-induced paw edema, PPF was found to be almost equally active as indomethacin (IM) and colchicine. In addition, PPF (2.5 ?? 10 mg/kg, p.o.) inhibited the accumulation of exudate and decreased the leucocyte numbers and the amount of prostaglandin E₂ (PGE₂)-like substance in sodium urate crystal-induced pleurisy in rats dose-dependently, with a potency slightly greater than that of IM. The specific anti-gout agent colchicine (5 mg/kg, p.o.) also suppressed the accumulation of exudate and decreased the leucocyte numbers, without affecting the amount of PGE₂-like substance. Moreover, in mouse peritonitis, PPF (1 ?? 10 mg/kg, p.o.) suppressed the sodium urate crystal-induced increase in vascular permeability in a dose-dependent manner. Furthermore, in experimental models of articular gout, PPF inhibited the pain response (abnormal gait) of sodium urate crystal-induced arthritis in both rats (0.25 and 1 mg/kg, p.o.) and dogs (3 mg/kg, p.o.), with a potency greater than that of IM and phenylbutazone, respectively. These results indicate that as an anti-gout agent, PPF is at least as effective as other standard drugs, so that it should have good clinical potential.

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The mechanism of the inhibitory effect of pranoprofen on sodium urate crystal-induced inflammation was investigated with several inflammatory parameters using leucocytes stimulated with sodium urate crystals in vitro. At 10^-5M, pranoprofen tended to inhibit the production of chemotactic factor in guinea pig polymorphonuclear leucocytes (PMNL) stimulated with sodium urate crystals and at 10^-4M, significantly inhibited it. At 10^-3M and 10^-4M, it potentiated the chemotaxis of guinea pig PMNL. Furthermore, it inhibited the production of superoxide anion (O₂^-) in guinea pig PMNL stimulated with sodium urate crystals, with an IC50 value of 5.0 × 10^-4M, comparable to that of indomethacin. At 10^-3M, it inhibited the release of β-glucuronidase stimulated by sodium urate crystals. From doses as low as 10^-6M, it inhibited dose-dependently the production of PGE₂-like substance by the phagocytosis of sodium urate crystals by rat peritoneal leucocytes, with an IC50 value of 7.5 × 10^-6M. These results suggest that in inhibiting the production of PGE₂ stimulated by sodium urate crystals, pranoprofen shows an inhibitory effect on sodium urate crystal-induced inflammation.

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The effects of Y-8894 on learning and memory were studied using the pole climbing avoidance (PCA) response in intact and experimentally induced amnesic rats. The following results were obtained: 1) A single administration of Y-8894 (2.5 mg/kg, i.p.) to experimentally induced amnesic rats significantly antagonized the decrease in the mean number of PCA responses induced by an electroconvulsive shock (ECS). At a higher dose (10 mg/kg, i.p.), however, this effect was reduced. 2) Repeated administration of Y-8894 (5 mg/kg, i.p.) significantly antagonized the facilitation of the extinction of the PCA response induced by exposure to C0₂. 3) Repeated administration of Y-8894 (2.5 mg/kg, i.p.;) significantly facilitated the learning of the PCA response in intact rats. At a higher dose (5 mg/kg, i.p.), however, this effect was reduced. 4) A single administration of Y-8894 (5 mg/kg, i.p. and 25 mg/kg, p.o.) significantly delayed the extinction of the PCA response in intact rats. These results suggest that Y-8894 has an ameliorative and facilitative effect on learning and memory in experimentally induced amnesic and intact rats.

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We investigated the effects of sodium 5-hydroxydecanoate (5-HD) on experimentally induced ischemic arrhythmia and its mechanisms of action by biochemical and electrophysiological techniques. 5-HD, at the single dose of 200 mg/kg (p.o.) or at the one week multiple doses of 3 to 100 mg/kg (p.o.), suppressed the incidence of ventricular fibrillation induced by coronary ligation in rats. 5-HD at the dose of 3 or 10 mg/kg (i.v.) elevated the ischemically decreased ventricular fibrillation threshold in the coronary ligated dogs. In isolated rat heart, 5-HD suppressed the K⁺ release from ischemic myocardium at the doses of 10^-5 to 10^-3M. 5-HD at the dose of 10^-4M decreased the open state probability of ATP regulated K⁺ channel in isolated myocardial cell of guinea pig. Contents of highenergy-phosphate compounds were markedly decreased in ischemic myocardium of rats, and they were not affected by 5-HD. These results demonstrate the efficacy of 5-HD against experimental ischemic ventricular arrhythmia. Its antiarrhythmic action may be attributed, at least in part, to the suppression of K⁺ release from ischemic myocardium by possibly inhibiting the ATP regulated K⁺ channel.

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