Effects of alminoprofen (AP), a non-steroidal anti-inflammatory agent, were investigated using several experimental gouty models. AP (3-30 mg/kg, p.o.) dose-dependently inhibited urate crystal-induced rat paw edema. AP (3-30 mg/kg, p.o.) inhibited the accumulation of exudate and decreased the total counts of leukocytes and the amount of PGE2 in a dose-dependent manner in sodium urate crystal-induced pleuritic rats. AP (0.3-10 mg/kg, p.o.) showed a dose-related analgesic activity on the pain response in sodium urate crystal-induced arthritic rats. AP (10(-5)-10(-3)M) inhibited the sodium urate crystal-induced beta-glucuronidase release from guinea pig neutrophils at more than 10(-4) M. AP (10(-5)-10(-3)M) did not inhibit the sodium urate crystal-induced production of O2- from guinea-pig neutrophils. AP (10(-6)-10(-4) M) inhibited dose-dependently the chemotaxis of leukocytes induced by chemotactic factors from guinea pig neutrophils stimulated with sodium urate crystals. AP (10(-6)-10(-4) M) inhibited the sodium urate crystal-induced production of PGE2 from rat peritoneal leukocytes in a dose-related manner. These results suggest that AP has a potent anti-inflammatory and analgesic activity in sodium urate crystal-induced inflammations, and these effects are exerted through its combined inhibitions of PGE2 synthesis, leukocyte chemotaxis and lysosomal enzyme release.

The anti-pyretic activity of alminoprofen (AP), a non-steroidal anti-inflammatory agent, and its mode of action were investigated in conscious febrile rabbits. A fever was evoked by i.v. injection of lipopolysaccharide (LPS), intracisternal (i.c.) injection of leukocytic pyrogen (LP) or i.c. injection of arachidonic acid (AA). The amount of PGE2 or AP in the cerebrospinal fluid (CSF) after i.v. LPS was estimated using an RIA or HPLC method. AP (3-30 mg/kg, p.o.) dose-dependently inhibited the LPS (0.5 micrograms/kg, i.v.)-induced fever; AP, ibuprofen, indomethacin and pranoprofen had ED50 values of 9.64, 26.45, 4.41 and 11.91 mg/kg, p.o., respectively. PGE2 in the CSF was markedly increased during the elevation of body temperature after i.v. LPS (0.5 microgram/kg). AP (30 mg/kg, p.o.) markedly inhibited the increase in PGE2 that was observed in the CSF during fever developed in response to i.v. LPS (0.5 micrograms/kg). The AP concentration in the CSF 2 hr after AP (30 mg/kg, p.o.) was 2.86 x 10(-6) (1.15-4.57 x 10(-6) M, a concentration too low to inhibit PG synthesis. A dose-dependent fever was observed after i.c. LP (1-8 unit) or AA (10-100 micrograms). AP (30 mg/kg, p.o.) shifted the dose-response curves for the i.c. LP-induced fever to the right, but did not have any effect on the i.c. AA-induced fever. These results suggest that AP has a relatively potent anti-pyretic activity, and its mechanism of action involves competition with LP at a site in the CNS, but does not involve an inhibition of cyclooxygenase at a central site, which has been considered as an anti-pyretic mechanism of nonsteroidal anti-inflammatory drugs.

The writhing reaction in mice induced by kaolin, a factor XII activator, was studied. An intraperitoneal injection of kaolin clearly induced a writhing reaction in a dose-dependent fashion, and the reaction disappeared about 10-15 min later. The writhing reaction reached a peak at 5-10 min after the injection of kaolin (0.5 ml/mouse, i.p.; 5 mg/ml saline). A simultaneous intraperitoneal injection of soybean trypsin inhibitor (SBTI, 2.5 mg/mouse) almost completely suppressed the writhing reaction caused by kaolin (2.5 mg/mouse) for the first 10 min. The kaolin-induced writhing reaction was markedly potentiated by a simultaneous intraperitoneal injection of captopril (50 micrograms/mouse). At 60 min after kaolin injection during the disappearance of the writhing reaction, the reaction reappeared when captopril was injected, but reactions observed at this later stage were completely blocked by SBTI. Indomethacin, ibuprofen and alminoprofen inhibited the writhing reaction dose-dependently. Kaolin thus induces a clear and reproducible writing reaction, which might be mainly dependent on the action of bradykinin via activation of factor XII, and should prove to be a simple and convenient model of bradykinin-induced pain for the assessment of analgesic actions.

The anti-allergic effects of EB-382, a non-steroidal antiinflammatory agent, were examined on the experimental animal models of allergic reactions. EB-382 showed no inhibition against the heterologous passive cutaneous anaphylaxis reaction in guinea-pigs (type I). EB-382 suppressed significantly the active Arthus reaction in rabbits at doses of 3 and 10 mg/kg, p.o. and the reversed passive Arthus reaction in guinea-pigs at a dose of 3 mg/kg, p.o. (type III), respectively. EB-382 showed no inhibition on the complement fixation reaction of sheep erythrocytes in vitro (type II) and the tuberculin-induced delayed type allergic reaction in guinea-pigs (type IV). It is suggested that EB-382 is a new type of non-steroidal antiinflammatory agent with a precedent pharmacological action, since it shows an inhibitory effect on the experimental model of type III of allergic reaction.

This study was conducted to clarify the antiinflammatory profile of EB-382, comparing it with those of ibuprofen and other antiinflammatory agents. EB-382 had a more potent inhibition on the acetic acid-induced intensive mouse intraperitoneal vascular permeability and carrageenin-induced rat hind paw edema, but a less potent inhibition on the ultraviolet-induced guinea-pig erythema and the prostaglandin biosynthesis in vitro than ibuprofen. The inhibition by EB-382 was equipotent to that of indomethacin on carrageenin-induced rat pleurisy and the zymosan air pouch, and it demonstrated a strong inhibition on the kallikrein and zymosan-induced intensive guinea-pig skin vascular permeability. EB-382 had a more effective activity on paper disk-induced granuloma and adjuvant arthritis, and it had a less potent action on the gastric mucosal membrane than ibuprofen. EB-382 had a weak action on histamine-induced rat back skin vascular permeability and heat-induced protein denaturation and hemolysis in vitro, as also shown by other test agents. The above results indicate that EB-382 will be useful as an antiinflammatory agent with a new pharmacological effectiveness besides possessing properties common to other acidic non-steroidal antiinflammatory agents in clinical studies.

The analgesic and antipyretic effects of EB-382 as a new non-steroidal antiinflammatory agent were examined in mice and rats. EB-382 had an equipotent inhibition to ibuprofen on the writhing syndrome caused by acetic acid, phenylquinone and acetylcholine in mice, but phenylbutazone was less potent in these experiments. EB-382 had a much more potent inhibition on the pain by the Randall-Selitto method and silver nitrate-induced arthritic pain in rats than ibuprofen and phenylbutazone. EB-382 had no analgesic effect on the pain of non-treated foot by the Randall-Selitto method in rats and by the hot-plate method in mice. EB-382 had a much more potent inhibition on the yeast-induced chronic inflammatory and adjuvant arthritic pains in rats than ibuprofen and phenylbutazone. The antipyretic activity of EB-382 was almost equipotent to that of ibuprofen in rats. EB-382 had no effect on the normal body temperature in rats, which was different from aminopyrine. The above results suggest that EB-382 will be a useful analgesic agent with an antipyretic antiinflammatory activity in clinical studies.

The safety and efficacy of a conjugate of pyridoxalated hemoglobin and polyethylene glycol (pyridoxalated PEG hemoglobin) were evaluated after administration to rats. The LD50 (lethal dose for 50% survival of group) of pyridoxalated polyethylene glycol (PEG) hemoglobin was greater than 200 ml/kg. Any pro- or anticoagulation activity was not demonstrated in in vitro coagulation tests. One day after 70% exchange-transfusion with pyridoxalated PEG hemoglobin, slight elevations of the serum glutamic-oxaloacetic transaminase, serum glutamic-pyruvic transaminase, and blood urea nitrogen values, which were 101.7 +/- 22.6 IU/L, 33.3 +/- 7.2 IU/L, and 23.1 +/- 1.4 mg/dl, respectively, were observed. However, these values were in the normal range after 3 days. With greater than 90% exchange-transfusion, all rats exchange-transfused with pyridoxalated PEG hemoglobin survived for greater than 2 weeks in contrast to the death of all the rats exchange-transfused with stroma-free hemoglobin or albumin.

Thymoxamine and its metabolites, deacetyl-thymoxamine (DAM) and deacetyl-demethyl-thymoxamine(Met-X), have competitive α-adrenergic blocking action.

The influence of adrenergic agents, epinephrine and clonidine, on plasma immunoreactive insulin and plasma glucose concentrations was studied in mice. Subcutaneous injection of epinephrine in fasted mice did not alter the plasma glucose concentration (PG), while plasma immunoreactive insulin concentration (IRI) tended to increase gradually. Intravenous injection of glucose markedly increased IRI. Glucose-induced IRI increase was inhibited by a subcutaneous injection of epinephrine in spite of high elevation of PG. This inhibition of glucose-induced IRI increase by epinephrine was reversed after treatment with an alpha-adrenergic blocking agent, phentolamine. Propranolol, an beta-adrenergic blocking agent suppressed IRI to a greater extent as compared with IRI induced by simultaneous injection of glucose and epinephrine. These results indicate that beta-adrenoceptor stimulating action accelerates the insulin release induced by glucose while alpha-adrenoceptor stimulating action inhibits it. Subcutaneous injection of clonidine in fasted mice slightly decreased IRI and increased PG. The response of PG to clonidine was dose-dependent. Glucose-induced IRI increase was inhibited by an intravenous injection of clonidine, and PG was elevated under the same conditions. The inhibition of glucose-induced IRI increase by clonidine was reversed when phentolamine was given, and under these conditions, PG showed no change. Propranolol treatment did not result in a recovery of the inhibition of glucose-induced IRI increase by clonidine. When compared with the results of epinephrine treatment, it may be concluded that clonidine shows alpha-adrenoceptor stimulating action in the secretion of insulin from beta-cells of the endocrine pancreas.

Intracellular localization of histamine receptors in small intestinal smooth muscle of the cat was studied by investigating distribution of marker enzymes in the receptor rich fraction. Distribution of membrane markers coincided with that of the radiochemically labeled receptor fraction. Membrane fraction was further purified and it was concluded that the histamine receptor rich fraction is mainly composed of cell membrane. The chemical composition of the fraction lent support to this conclusion.

The cardiovascular effects resulting from intracisternal (i.e.) injections of sympathomimetic amines were studied in a-chloralose-urethanized rats. Norepinephrine (0.5-5 μg i.e.) caused a typical rise in blood pressure with no significant change in heart rate and a fall in blood pressure with a bradycardia, which were completely blocked after treatment with phentolamine (10-50 μg i.e.). l-isoproterenol (0.05-0.5 μg i.e.) and trimetoquinol (0.5-3 μg i.e.), a L-sympathomimetic agent, usually caused a fall in blood pressure with a tachycardia, which was reduced after treatment with propranolol (10-50 μg i.e.), but trimetoquinol was inclined to cause a rise in blood pressure with a tachycardia. Epinephrine (5 μg i.e.) showed both centrally mediated α- and β-sympathomimetic effects. Tyramine (0.5-1 mg i.e.) caused mixed blood pressure responses presumably due to a release of norepinephrine and epinephrine, and these responses were partially blocked after treatment with phentolamine (100 μg i.e.) or propranolol (50 μg i.e.). These observations suggest that both α- and β-sensitive adrenergic zones may exist on the vasomotor center of the pons and medulla in rats, and both norepinephrine and epinephrine might centrally play a physiological role as the neurotransmitters controlling blood pressure in rats.