Effect of a non-steroidal anti-inflammatory agent, tolmetin sodium on exudative inflammation in experimental animals (author's transl)

Effect of tolmetin sodium(Tol) on acute and subacute exudative inflammation was tested in experimental animals. Tol had a potent inhibitory activity (ED50 = 0.75 mg/kg, p.o.) on the increased vascular permeability induced by acetic acid in mice, and the potency was about 0.4 times that of indomethacin (Ind), and 6-93 times that of ibuprofen (Ibu), phenylbutazone(Phe) and aspirin(Asp). The inhibitory activity of Tol(ED50 = 18.2 mg/kg, p.o.) on UV-induced erythema in guinea pigs was about 0.3 times that of Ind. A recovery of the hind paw edema of rats, produced by a mixture of kaolin and carrageenin, was promoted by oral administration of Tol(2.5 approximately 20 mg/kg x 5/2 days). Tol(80 mg/kg/day, p.o.) showed a significant activity in inhibiting the exudation caused by croton oil in rats, and the activity was about 0.025 times that of Ind and greater than that of Ibu, Phe and Asp. Tol(100-800 microgram/ml) inhibited in a dose-dependent manner the phytohemagglutinin-induced blast transformation of cultured lymphocytes from rat thymus, as did salicylic acid. In vitro, Tol showed a potent activity similar to that of Ibu and Phe in preventing the denaturation of bovine serum albumin and the lysis of rat erythrocytes. From these results, it is suggested that Tol has a particularly potent inhibitory activity on acute exudative inflammation, and the mode of action may be attributed to a mechanism similar to that seen with other acidic non-steroidal anti-inflammatory drugs.     

Pharmacological studies on carprofen, a new non-steroidal anti-inflammatory drug, in animals (author's transl)]

The pharmacological profile of carprofen as a new non-steroidal anti-inflammatory drug has been established in various experimental inflammation models in animals. This compound possesses marked effects on prevention of adjuvant arthritis, cotton-pellet granuloma formation and hyperalgesic edema (scalding) and the extent is similar to that observed with indomethacin and piroxicam. The anti-inflammatory potency of carprofen is markedly stronger than those seen in cases of phenylbutazone, mefenamic acid, ibufenac and acetylsalicylic acid, almost equal to that of diclofenac and slightly lower than that of indomethacin in the following parameters: carrageenin-edema, granuloma-pouch, UV-erythema, and bradykinin and histamine-induced capillary permeability. As is the case with other non-steroidal anti-inflammatory drugs, carprofen has no inhibitory effect on lethal anaphylactic shock, passive cutaneous anaphylaxis and hyperuricemia. Carprofen induces ulcerogenicity and fecal occult bleeding to a extent markedly less than those seen with indomethacin and piroxicam. These investigations on anti-inflammatory drugs indicate a probable dissimilarity to the extent of anti-inflammatory effects and induction of gastrointestinal disturbances. Repeated administration of carprofen has no effect on spontaneous excretion of corticosterone and aldosterone into adrenal vein of rats.     

Anti-inflammatory activity of a non-steroidal anti-inflammatory agent, oxaprozin, in experimental models

Anti-inflammatory activity and mode of action of oxaprozin, a new non-steroidal anti-inflammatory agent, were investigated in experimental animal models and in vitro tests. Anti-inflammatory potency of oxaprozin was almost equal to that of aspirin in acetic acid vascular permeability, carrageenin hind paw edema, cotton pellet granuloma and adjuvant arthritis tests in rats. On the other hand, in mice, oxaprozin was more potent than aspirin, ibuprofen and phenylbutazone, and it was as potent as sulindac and fenbufen in acetic acid vascular permeability and carrageenin hind paw edema tests. In adrenalectomized rats, the anti-edema activity of oxaprozin in the carrageenin hind paw edema test was the same as that in intact rats. Oxaprozin inhibited erythema formation induced by ultra-violet rays in guinea pigs. The inhibitory potency of oxaprozin against prostaglandin E2 biosynthesis in vitro was equal to that of ibuprofen. Oxaprozin showed a concentration-dependent inhibition of heat-induced denaturation of bovine serum albumin and lysis of rabbit erythrocytes in vitro. However, oxaprozin did not inhibit rat hind paw edemas induced by dextran, formalin and serotonin. It was suggested from these results that the mode of action of oxaprozin is similar to those of other acidic non-steroidal anti-inflammatory drugs. Ulcerogenicity of oxaprozin was weaker than those of phenylbutazone and aspirin in rats. Species differences in the metabolic rate of oxaprozin were shown. The blood concentration of oxaprozin in rats is extremely low because the metabolic rate of oxaprozin is rapid in rats. Therefore, in rats, oxaprozin exhibited a weak anti-inflammatory effect. However, in mice, oxaprozin had a low metabolic rate, and the effect of oxaprozin was as potent as sulindac and fenbufen. The elimination half-life of oxaprozin is extended, 49 to 69 hr, in humans. It was suggested from these findings that oxaprozin is a potent and long acting anti-inflammatory drug in clinical use.     

Inhibition of prostaglandin synthetase by tolmetin (Tolectin,McN-2559), a new non-steroidal anti-inflammatory agent

Tolmetin [1-methyl-5-p-tolouylpyrrole-2-acetic acid (McN-2559, Tolectin)] and several of its analogs were shown to be potent inhibitors of the synthesis of prostaglandin E₂ from arachidonic acid by bovine seminal vesicle prostaglandin synthetase in vitro. Kinetic studies indicated that tolmetin, like indomethacin and aspirin, inhibited the synthetase competitively with respect to substrate. Unlike most non-steroidal anti-inflammatory agents, however, tolmetin was a competitive reversible inhibitor, and did not promote a time-dependent inactivation of the prostaglandin synthetase. Tolmetin and these other 1-methyl-pyrrole acetic acids represent a new structural class of anti-inflammatory agents which inhibit prostaglandin synthetase.     

Site of analgesic action of a non-steroidal, anti-inflammatory drug, tolmetin sodium, in rats.

1 The site of the analgesic action of tolmetin sodium was investigated by use of the acetic acid writhing test in rats. 2 Tolmetin sodium was administered to the rat between 15 and 60 min after intraperitoneal injection of 1 ml of a 1% acetic acid aqueous solution. Number of writhing was counted for 20 min beginning from 60 min after acetic acid injection. 3 When the rat was given tolmetin sodium 5 mg/kg orally, a relatively large quantity of tolmetin was found in the peritoneal exudate and there was a rough correlation between anti-writhing activity and the exudate tolmetin content. 4 Anti-writhing ED50 of tolmetin sodium was 1.42 (0.82-2.91) and 92.0 (57.0-140) microgram/kg when given intraperitoneally and intravenously, respectively, and the potency ratio of intraperitoneal to intravenous tolmetin sodium was 40.0 (18.5-80.2). This potency ratio for salicylic acid and morphine hydrochloride was 19.4 and 1.0, respectively. 5 When equipotent doses ( 5 microgram/kg i.p.; 200 microgram/kg i.v.) of tolmetin sodium were administered to the rat, the plasma tolmetin level after the intraperitoneal administration was less than one-fortieth that after the intravenous administration during the counting time of 20 min, while both the peritoneal exudate contents of tolmetin were nearly equal. 6 From these results, it is concluded that the site of anti-writhing action of tolmetin sodium is in the peritoneum and that tolmetin sodium produces its anti-writhing action mainly by a peripheral mechanism in the rat.     

Analgesic efficacy of non-steroidal anti-inflammatory drugs in experimental pain in humans

1. The aim of this study was to establish a simple and reliable experimental pain model that could distinguish the analgesic effects of non-steroidal anti-inflammatory drug (NSAID) treatment from placebo in human volunteers. 2. The reproducibility and reliability over time of subject pain ratings was compared using cutaneous electrical stimuli applied to either the thenar eminence or the ear lobe at varying intensities and modes. Subjects were asked to respond firstly, when the stimulus became clearly sharp and painful ('first pain') and secondly, when the sensation became deep and burning and no further increase in stimulus intensity could be tolerated ('second pain'). 3. Constant voltage stimuli were found to be more reproducible than constant current stimuli. Both phasic (intermittent) and tonic (continuous) stimulation modalities produced 'first' and 'second pain' sensations. The latter sensation was more reproducible, and was perceived as a burning pain which is akin to clinical pain. 4. Analgesics from the NSAID class were found to attenuate reliably only 'second pain' sensations. The analgesic effects of ibuprofen (ibuprofen vs placebo: 0.12 +/- 0.09 vs 0.02 +/- 0.07 volt h(-1), P = 0.03; 95% confidence interval for differences (CI): 0.03-0.18) and diflunisal (diflunisal vs placebo: 0.29 +/- 0.40 vs 0.005 +/- 0.27 volt h(-1), P = 0.0001; CI: 0.168-0.407), respectively, could be distinguished from placebo.     

新型非甾体抗炎药洛索洛芬钠的研究进展

洛索洛芬钠（LoxoprofenSodium）系由日本三共株式会社研发,1986年7月在日本上市,商品名“乐松”,是第一个丙酸类前体型非甾体抗炎药（NSAIDs）,口服后在体内代谢成trans—OH型药物,抑制前列腺素的生物合成。其镇痛效果比酮洛芬、吲哚美辛、萘普生强10—20倍,起效迅速且具强效、均衡的镇痛、抗炎、解热作用;使用更安全,前体药物消化道不良反应发生率低,可长期服用,副作用小;应用范围广,用于类风湿性关节炎、骨性关节炎、腰痛、肩周炎、颈肩腕综合征以及手术、拔牙后的疼痛,急性上呼吸道炎症等病症。     

Effects of a new psychotropic agent, CS-430, on the central nervous system of experimental animals (author's transl)]

In rats and rabbits with chronically implanted electrodes CS-430(10-bromo-2, 3, 7, 11b-tetrahydro--11b-(2-fluorophenyl)-oxazolo(3, 2d) [1, 4]benzodiazepine-6(5H)-one) (3 mg/kg, .o.) decreased the slightly awake period and increased the slow-wave sleep period. The onset time of sleep was significantly shortened. In the rat pre-treated with p-chlorophenylalaine (500 mg/kg, p.o.), the awake period was remarkable increased and the slow wave sleep period was considerably decreased at 48 hours after the pre-treatment. In these rats CS-430 given in the same dose decreased significantly the awake peiod and the onset time of sleep and increased the slow wave sleep period. CS-430 raised the threshold of the arousal response with stimulation of the posterior hypothalamus, but not of the mesencephalic reticular formation. These effects of CS-430 were almost as potent as those of nitrazepam (NZP). CS-430 reduced duration of after-discharges following stimulation of the hippocampus, depressed the decerebrate rigidity and inhibited activity of lumbar gamma-motoneurons in anesthetized cats. CS-430 (10 mg/kg, p.o.) inhibited the evoked responses recorded from the proreus gyrus following stimulation of either the baso-magnocellularis of the amygdaloid nuclear or the ventral hippocampus, although such did not inhibit the responses between the olfactory bulb and the pyriform cortex, the thalamus and the sensory-motor cortex. Thus CS-430 has a sleep-inducing effect in animals of almost the same potency as is seen with NZP, and site(s) of the action in the limbic system appear to be specific.     

Analgesic,antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals

Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19-isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl-derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker’s yeast-induced fever model, 3 and 5 significantly reduced rats’ rectal temperature (p < 0.05). In a carrageenan-induced inflammation model, 1, 3 and 5 significantly reduced rats’ paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity.     

Effect of non-steroidal anti-inflammatory drugs on plasma protein binding of corticosterones (author's transl)]

A series of non-steroid antiinflammatory drugs (NSAD) as well as substances with different spectra of pharmacological action were investigated with regard to the influence on binding of corticosterone to plasma protein in rats after repeated oral administration. At pharmacologically active doses, NSAD cause a time and dose dependent increase in rat plasma of the corticosterone fraction which can be ultra-filtrated. The effect on corticosterone binding to plasma protein largely parallels the antiinflammatory efficacy of the NSAD. This does not occur by a mere displacement of corticosterone from the plasma protein binding, but is apparently the consequence of a qualitative and/or quantitative change of the binding proteins. Organic acids, cytostatic or other drugs which strongly bind to plasma protein do not show any corresponding influence on the corticosterone binding to plasma protein under comparable conditions. The increase of the fraction of corticosterone which can be ultra-filtrated effected by the NSAD accelerates the excretion of corticosterone into the bile of rats. The phenomenon of decrease in binding of corticosteroids to plasma protein is discussed with respect to its importance for the mode of action of the NSAD.     

The analgesic and antipyretic effects of a non-steroidal antiinflammatory agent, EB-382, in experimental animals

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.     

Pharmacological properties of droxicam, a new non-steroidal anti-inflammatory agent

Droxicam showed high antiinflammatory activity in carrageenin-induced edema in rat. At doses of 0.25 and 0.5 mg/kg, droxicam was as active as piroxicam and more active than phenylbutazone given at 2.5 and 5 mg/kg. Against nystatin-induced edema, droxicam (ED50, p.o., 5, 6, 7, 8 h: 7.5, 12.9, 4.8, 8.4 mg/kg) was 4-11 times more active than phenylbutazone and more than 12 times more active than isoxicam. In cotton pellet-induced granuloma in rats, title compound was as active as suprofen. In U.V. light-induced erythema in guinea pigs, droxicam (ED50, p.o., 1, 2, 3, 4 h: 0.51, 0.94, 1.56, 4.88 mg/kg) was 5-9 times more active than phenylbutazone. At doses of 0.1, 0.33 and 1.0 mg/kg/day, droxicam, similar to piroxicam, showed good antiarthritic activity in rats injected with Mycobacterium butyricum against primary and secondary lesions. Droxicam demonstrated strong analgesic activity in protecting against writhings: induced by phenylbenzoquinone in mice: ED50: droxicam = 5.3, phenylbutazone = 61.5, acetylsalicylic acid = 90.7, dipyrone = 83.6, isoxicam = 88.3 mg/kg, p.o.; induced by acetylcholine bromide in mice: ED50: droxicam = 1.1, phenylbutazone = 32.1, acetylsalicylic acid = 32.2, isoxicam = 32.7 mg/kg, p.o.; induced by acetic acid in rat: ED50: droxicam = 0.94, acetylsalicylic acid = 8.72, isoxicam = 4.70 mg/kg, p.o. Antipyretic activity of title compound was demonstrated in rats with pyresis induced by brewer's yeast, being 4-13 times more active than dipyrone. In pyresis induced by Salmonella typhi, droxicam was more active than acetylsalicylic acid and 4-aminoantipyrine at all times and doses. In a study of protection against diarrhea induced by castor oil in rats, droxicam and piroxicam showed equal activity (ED50 = 0.081 and 0.079 mg/kg, p.o., respectively) and were 3.9 and 15.6 times more active than isoxicam and phenylbutazone, respectively. Droxicam significantly inhibited peritoneal capillary permeability in mice at a dose of 5 mg/kg, p.o., while isoxicam and phenylbutazone required 100 and 200 mg/kg, p.o., respectively. Droxicam did not exhibit uricosuric activity in rats. It did not show cardiovascular or respiratory effects in anesthetized cats, nor modify their response to administration of acetylcholine, norepinephrine and histamine. In the Irwin's test, droxicam did not alter rat behavior (80 mg/kg, i.p.) nor that of mice (160 mg/kg, p.o.). Induction of gastrointestinal injuries in rats by droxicam was 10 times less than by piroxicam (UD50: droxicam, 57 mg/kg, p.o.; piroxicam, 5.6 mg/kg, p.o.). The potentiation of gastric injuries induced by stress through cold in rats was also studied.(ABSTRACT TRUNCATED AT 400 WORDS)