Anti-inflammatory, analgesic and anti-pyretic activities of a new anti-inflammatory compound, 2-[4-(3-methyl-2-butenyl)phenyl] propionic acid (TA), in experimental animals

Anti-inflammatory, analgesic and anti-pyretic activities of orally administered TA were investigated in experimental animals. Against acetic acid-induced vascular permeability in mice, carrageenin-induced hind paw edema in rats and ultra-violet ray-induced erythema in guinea pigs, TA produced a dose related inhibition at doses of 40-160 mg/kg, 10-40 mg/kg and 10-40 mg/kg, respectively. TA produced no inhibition against histamine-induced vascular permeability even at a dose of 200 mg/kg in rats. Cotton pellet-induced granuloma and adjuvant-induced arthritis in rats were significantly inhibited by repeated administration of TA at a dose of 50 mg/kg/day for 6 days and 25 mg/kg/day for 6 days, respectively. TA showed a dose related analgesic effect at a dose of 50-200 mg/kg in acetic acid writhing, Randall-Selitto and adjuvant arthritic pain methods. A high dose of TA was needed to produce an analgesic effect in the pressure method using mice. TA produced an anti-pyretic effect against the pyrexia induced by yeast in rats. On the other hand, TA showed no effect against normal body temperature in rats. These results suggest that anti-inflammatory, analgesic and anti-pyretic activities of TA are generally a little weaker than those of ibuprofen, and the mode of action of TA is similar to that of a typical acidic non-steroidal anti-inflammatory drug such as ibuprofen, indomethacin or phenylbutazone. The ulcerogenic activity of TA was about 2 and 4 times weaker than that of ibuprofen in rats and mice, respectively. TA showed a protective effect against gastric necrosis induced by HCl.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antiedema effects of basic nonsteroidal anti-inflammatory drugs that are not inhibitors of prostaglandin biosynthesis

Antiedema effects of basic nonsteroidal anti-inflammatory drugs that don't inhibit prostaglandin biosynthesis were investigated with carrageenin-induced hind paw edema in rats. Locally administered mepirizole, tiaramide.HCl and aminopyrine, the basic nonsteroidal anti-inflammatory drugs, didn't show any suppression against the edema formation. In the case of indomethacin, phenylbutazone and ketoprofen, inhibitors of prostaglandin biosynthesis, they inhibited the edema formation. Inhibitory effects of orally and subcutaneously administered basic nonsteroidal anti-inflammatory drugs such as tiaramide.HCl and benzydamine on the edema formation were more potent in fasted rats than in nonfasted rats. In the case of acidic nonsteroidal anti-inflammatory drugs such as indomethacin and ibuprofen, their inhibitory activities were almost the same in both the fasted rats and nonfasted rats. These results suggest that the site of action of the basic nonsteroidal anti-inflammatory drugs such as tiaramide.HCl and mepirizole is not the inflamed site, and certain systemic effects may contribute to the anti-edema effects.     

Pharmacological studies of 4-ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (M73101). (2). Anti-inflammatory activity (author's transl)]

The anti-inflammatory activity and the mode of action of M73101, a new non-steroid analgesic anti-inflammatory agent, were investigated in experimental animals and compared with those of reference drugs. M73101 inhibited the increase in vascular permeability induced by acetic acid and its activity was more potent than that of phenylbutazone. M73101 showed a marked inhibitory effect against rat paw edema induced by various phlogistic agents (carrageenin, dextran, histamine, serotonin and bradykinin) and the activities were equal to or more potent than those of aminopyrine, mepirizole and tiaramide HCl. M73101 also inhibited the edema induced by mustard, scalding and anti-rat rabbit serum in rats. In addition, the anti-edematous effect of M73101 on carrageenin-induced rat paw edema was not influenced by spinalectomy or adrenalectomy, indicating that the anti-inflammatory action of M73101 was not mediated by the central nervous system and the adrenals. Local and oral administration of M73101 inhibited significantly the leucocyte migration into the fluid of CMC pouch in rats and the activity was more potent than phenylbutazone, suggesting that the anti-inflammatory effect of M73101 was due to the direct action at the inflamed site. On the other hand, M73101 did not show any marked activities on the experimental chronic inflammatory models. From these results, it is suggested that M73101 may be useful for clinical application as a basic analgesic, anti-inflammatory drug with remarkable anti-inflammatory activity in acute and subacute cases. The mechanism of the anti-inflammatory action of M73101 probably involves inhibition of an increase in vascular permeability and leucocyte migration.     

Mechanism of anti-inflammatory action of 2-(2-fluoro-4-biphenylyl) propionic acid (flurbiprofen)]

Anti-inflammatory mechanism of 2-(2-fluoro-4-biphenylyl) propionic acid (Flurbiprofen, FP-70) was studied by various analysis in comparison with other drugs. It was found in the test of rat edema induced by various phlogists that carrageenin and yeast-induced edemas were markedly inhibited by FP-70, whereas dextran, formalin, serotonin and bradykinin-induced edemas were scarcely inhibited by FP-70. The action of FP-70 was similar to that of soy bean trypsin inhibitor. However, FP-70 showed no effects on kinin synthetase and kininase. FP-70 showed a marked inhibition on prostaglandin synthesis. The inhibitory effect of FP-70 was 10.1, 96.5 and 2280.6 times as large as indomethacin, ibuprofen and acetylsalicylic acid, respectively. FP-70 did not inhibit the permeability of dye induced by prostaglandin E2 in the rat skin. FP-70 inhibited the acid phosphatase and beta-glucuronidase activities of isolated lysosome of rat liver and also suppressed the release of acid phosphatase from the lysosome. These effects were similar to those of indomethacin. On the other hand, FP-70 suppressed markedly the heat-induced hemolysis of dog erythrocytes. The effect was similar to that of indomethacin and was 10 times stronger than those of ibuprofen, ibufenac and phenylbutazone. Activation of rat liver mitochondrial ATPase by FP-70 at a concentration of 10 muM was 74.7%, while indomethacin showed 37.8% activation at the same concentration. FP-70 as well as ibuprofen and phenylbutazone uncoupled the oxidative phosphorylation in rat liver mitochondria. From the above and previously reported results, it is suggested that the potent anti-inflammatory action of FP-70 is the result of the following effects; inhibition on the protein and leucocyte migration, inhibition on the prostaglandin synthesis, stabilization of the cell membrane and activation of ATPase.     

Pharmacological studies of d1-2-[3-(2'-chlorophenoxy)phenyl]propionic acid. (2) Sites and mechanisms of analgesic and antipyretic effects

Effects of d1-2-[3-(2'-chlorophenoxy)phenyl]propionic acid (CPP) on the nociceptive response induced by injection of bradykinin (BK) into rabbit femoral artery were studied. When drugs were administered intravenously, the analgesic activity of morphine was 2 to 10 times more potent than that of CPP; but when it was injected into the femoral artery, CPP was approximately 5 times more potent than morphine. Intraventricular injection of a small dose of 10 micrograms/head morphine produced a prominent analgesic activity, while even a large dose of 500 micrograms/head CPP had little effect. Prostaglandin E1 (PGE1) alone in a dose range of 0.1 to 1 microgram i.a. produced no nociceptive response, but an intra-arterial pre-injection of PGE1 enhanced BK-induced nociceptive response. Morphine suppressed the BK-response pretreated with PGE1, but CPP as well as indomethacin had little effect. These results suggest that CPP suppresses BK-induced nociceptive response at the periphery, probably at the paravascular "pain receptor", and the analgesic effect of CPP may be due to inhibition of endogenous PG synthesis. On the other hand, CPP in a dose range of 2.5 to 20 mg/kg, i.v. produced antipyretic effects on the fever induced by typhoid vaccine. Intraventricular injection of 500 micrograms/head CPP produced a slight antipyretic effect. CPP had no effect on PGE1 -induced fever. These results suggest that CPP produces the antipyretic effect acting on the central nervous system, probably due to inhibition of endogenous PG synthesis.     

Effect of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen) on experimental allergic reactions

The effects of (+/-)-2-[p-(2-thenoyl)phenyl] propionic acid (suprofen), a new anti-inflammatory agent, on experimental allergic reaction and antibody formation were examined. The action was compared with those of ketoprofen, ibuprofen, indomethacin, tranilast, chlorpheniramine, prednisolone and/or cyclophosphamide. Suprofen inhibited homologous PCA in rats, immunological histamine release from rat peritoneal mast cells and guinea pig lung tissues, Forssman cutaneous vasculitis (FCV) and the Arthus reaction in guinea pigs. The potency for inhibition of the PCA reaction was similar to that of ketoprofen and more potent than ibuprofen and trailast. As for the release of anaphylactic mediators, suprofen was less potent than tranilast in terms of histamine release, but not the release of the slow reacting substance of anaphylaxis (SRS-A). Suprofen inhibited FCA more potently than other nonsteroidal anti-inflammatory drugs (NSAID). The inhibition of the Arthus reaction by suprofen was similar to those of other NSAID and prednisolone. Suprofen hardly affected delayed hypersensitivity in guinea pigs and antibody (IgM or IgE) formation in mice or rats.     

Pharmacological studies of dl-2[3-(2'-chlorophenoxy)phenyl]propionic acid. I. Analgesic and antipyretic effects

Analgesic and antipyretic effects of dl-2[3-(2'-chlorophenoxy)phenyl] propionic acid (CPP) were studied in mice, rats and guinea-pigs. CPP produced a dose dependent inhibition of acetic acid-induced writhing syndrome. Its ED50 values 1 and 3 hr after oral administration were 47 and 31 mg/kg, respectively. CPP had a potent analgesic effect on bradykinin-induced nociceptive response in rats, and its ED50 value was 15 mg/kg 2 hr after oral administration. The analgesic activity of CPP in these experiments was less potent than that of indomethacin, but it was approximately equivalent to ibuprofen and 10 to 20 times as potent as aspirin. CPP had no analgesic effect on both the tail pinch and hot plate tests in mice, while CPP potentiated the analgesic effect of codeine on these tests. CPP had no effect on the nociceptive response induced by intradermal injection of bradykinin and/or EDTA in guinea-pigs. On the other hand, when CPP was given orally in a dose range of 1.25 to 5 mg/kg, it produced an antipyretic effect on yeast-induced fever in rats. The antipyretic activity of CPP was equivalent to ibuprofen and 10 to 15 times as potent as aspirin.     

Pharmacological properties of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolacto ne (KME-4), and its inhibitory effects on prostaglandin synthetase and 5-lipoxygenase

The pharmacological effects of a new anti-inflammatory compound, alpha-(3,5-di-tert-butyl-4-hydroxybenzylidene)-gamma-butyrolactone (KME-4), and its inhibitory effects on arachidonate prostaglandin synthetase and 5-lipoxygenase activities were examined. KME-4 showed anti-inflammatory activity. It was less active than indomethacin, but more active than naproxen and ibuprofen in carrageenin-induced paw edema in rats; and it was less active than indomethacin, equipotent as naproxen, but more active than ibuprofen in granuloma formation in rats. The ulcerogenic activity of KME-4 was weaker than indomethacin and naproxen, but stronger than ibuprofen in starved rats. The ratio of UD50 stomach to ED30 carrageenin edema or to ED25 granuloma for KME-4 showed higher values than those of the reference drugs. KME-4 showed antipyretic activity in yeast-induced fever in rats. It also inhibited platelet aggregation induced by arachidonic acid and protected rabbits from arachidonic acid-induced death. Furthermore, KME-4 was found to be equipotent in inhibiting both prostaglandin synthetase and 5-lipoxygenase activities of rat basophilic leukemia cells, unlike indomethacin, naproxen and ibuprofen. It also inhibited the prostaglandin synthetase activity of bovine seminal vesicle. The present findings indicate that KME-4 may be a new type of anti-inflammatory drug with dual prostaglandin synthetase and 5-lipoxygenase inhibition.     

Amide derivatives of [6-(5-methyl-3-phenylpyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acids as potential analgesic and anti-inflammatory compounds

In this study, amide derivatives of [6-(5-methyl-3-phenyl-pyrazole-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were synthesized and tested for their in vivo analgesic and anti-inflammatory activity by using the p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a, 6d, 6e, 6g, 6h and 6m were more potent than that of aspirin as an analgesic and indomethacin as an anti-inflammatory drug, respectively. The other derivatives generally resulted in comparable activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro human whole blood assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and other mechanisms might be involved.     

Anti-inflammatory action of 2-(2-fluoro-4-biphenylyl) propionic acid (flubiprofen]

2-(2-fluoro-4-biphenylyl) propionic acid (flurbipofen, FP-70), a newly synthesized anti-inflammatory agent, was examined for its effects and then compared with the actions of other standard drugs. Inhibition of capillary permeability in mice: the activity of FP-70 was 7.8 times as potent as ibuprofen (IP), 61 times that of acetylsalicylic acid (AS), 5.7 times that of indomethacin (IM) and 25 times that of phenylbutazone (PB). Inhibition of carrageenin-induced edema in rat paw: the activity of FP-70 was 52 times as potent as IP, 250 times that of potent as AS, 14 times that of potent as IM and 110 times that of potent as PB. Inhibition of heat-induced coagulation of BSA: the activity of FP-70 showed the marked effects much the same as IP. In adrenalectomized rat, FP-70 was also effective. Inhibition of the ultra-violet erythema in guinea-pigs, the activity of FP-70 was 26 times as potent as IP, 790 times that of AS, 25 times that of IM and 68 times that of PB. Regarding the inhibition of CMC induced pouch in rats, the potency of FP-70 was to the same degree as that of predonisolone. In adjuvant induced arthritis in rats, FP-70 reduced and cured inflammatory syndromes and activity was the same or more effective than that of IM. From these results, FP-70 appears to be a most potent nonsteroidal anti-inflammatory agent.     

Studies on the anti-inflammatory effects of<Emphasis Type="Italic">clerodendron trichotomum</Emphasis> thunberg leaves

Clerodendron trichotomum Thunberg Leaves (CTL) have been used for centuries in Chinese folk medicine for their anti-inflammatory properties. We have studied the anti-inflammatory effects of CTL extracts in rats, mice and in Raw 264.7 cells. 1 mg/kg solutions of the 30% and 60% methanol extracts of CTL were used and a 1 mg/kg of indomethacin was used as a positive anti-inflammatory standard; these were then administrated to rats. Carrageenan was injected subcutaneously to induce hind paw edema in rats. The result of carrageenan-induced rat paw oedema showed that a 1 mg/kg of the 30%, and 60% methanol fraction of CTL and 1 mg/kg of indomethacin inhibited the hind paw edema by 19.5%, 23.0%, and 20.5% respectively. The effect of CTL on inflammation in mice by a capillary permeability assay was examined by detecting Evans blue leakage from capillaries after the intraperitoneal injection of acetic acid, a potent inflammatory stimulus. The 60% methanol fraction of CTL inhibited Evans blue dye leakage by 47.0%, which was 10% higher than that of the inhibition of 1 mg/kg of indomethacin. Also, the 60% methanol fraction of CTL suppressed the prostaglandin E2 (PGE2) generation in RAW 264.7 macrophage cells after treatment with lipopolysaccharide (LPS) by as much as the inhibition of 1 mg/kg of indomethacin and this led to the synthesis of PGE2 by COX-2 induction. The inhibition of the carrageenan-induced rat paw oedema, vascular permeability and the PGE2 generation demonstrates that the 60% methanol fraction of CTL contains a potent anti-inflammatory activity.     

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.     

合成鱼腥草素的抗炎作用及其机制

目的进一步研究合成鱼腥草素的抗炎作用及其机制。方法正常大鼠及去肾上腺大鼠足肿胀的测定;大鼠胸膜炎模型炎症渗出和白细胞游走的测定;大鼠巴豆油气囊肿测定;大鼠肾上腺重量和维生素C含量的测定;炎症渗出物中PGE含量的测定;SRS-A致豚鼠离体回肠收缩测定。结果合成鱼腥草素（HOU）ig对角叉菜胶致正常大鼠及去肾上腺大鼠足肿胀、大鼠白细胞游走和巴豆油所致向芽组织增生都有显著抑制作用;明显降低炎症渗出物中PGE含量;体外给药可以拮抗SRS-A（LTC4、LTD4、LTE4三者混和物）所致豚鼠离体回肠收缩，其IC50为6×10-6mol·L-1;对肾上腺重量及肾上腺中维生素C的含量无明显影响。结论HOU对炎症3种不同时相都有不同程度的抑制作用，其抗炎作用不依赖于垂体-肾上腺皮质系统，而和抑制炎症介质PGE、SRS-A有关。     

Synthesis of amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl] acetic acid and their analgesic and anti-inflammatory properties

A series of structurally different amide derivatives of [6-(3,5-dimethylpyrazol-1-yl)-3(2H)-pyridazinone-2-yl]acetic acid were prepared and tested for their analgesic and anti-inflammatory activity in vivo by using p-benzoquinone-induced writhing test and carrageenan-induced hind paw edema model, respectively. The analgesic and anti-inflammatory activity of the compounds 6a and 6b were equipotent, and 6m was more potent than acetyl salicylic acid (CAS 50-78-2) as an analgesic and indometacin (CAS 53-86-1) as an anti-inflammatory drug, respectively. The other amide derivatives and parent carboxylic acid molecule generally resulted in lower activity to reference compounds. Inhibitor activity of the active compounds on cyclooxygenase isoforms was also investigated by using in vitro COX inhibitor screening assay and found that these derivatives did not exert their analgesic and anti-inflammatory activities through COX inhibition and that other mechanisms might be involved.     

Pharmacological properties of a new non-steroidal anti-inflammatory drug: flunoxaprofen

The anti-inflammatory, analgesic and antipyretic activities of S-(+)-2(4-fluorophenyl)-alpha-methyl-5 benzoxazole acetic acid (flunoxaprofen: Flu), a new non-steroidal anti-inflammatory drug, were compared with those of indomethacin and other non-steroidal anti-inflammatory drugs (NSAIDs) in experimental animals. Flu showed strong inhibitory activity on acute and subacute inflammation tests in rats, such as carrageenin hind paw oedema (oral: 6-25 mg/kg; rectal: 50-100 mg/kg); pellet-induced granuloma formation (5-20 mg/kg/day) and adjuvant-induced arthritis (10 mg/kg/day). Its potency was comparable with that of indomethacin (I) and higher than that of acetyl salicylic acid (ASA), ibuprofen (IBU) or phenylbutazone (P). The analgesic activity of Flu, evaluated by the hot plate method and tail pinching in mice, was slightly lower than that of I but higher than that of ASA and IBU. In pyretic rabbits Flu showed an antipyretic activity higher than that of ASA and IBU. The ability of Flu to affect platelet aggregation, mucopolysaccharide synthesis by fibroblasts and the proteolytic action of trypsin was also investigated.     

国产酮基布洛芬的药效学研究

<正> 酮基布洛芬(Ketoprofen, KP)是一种芳香丙酸类非甾体抗炎药。我们用国产的酮基布洛芬和其他一些非甾体抗炎药进行动物试验,认为酮基布洛芬的安全性较大且疗效较好,现报告于后。 一、材料和方法 1、药品:酮基布洛芬系西南合成药厂提供,系标准纯品;消炎痛(ID)由重庆     

Effects of 12-sulfodehydroabietic acid monosodium salt (TA-2711), a new anti-ulcer agent, on gastric mucosal lesions induced by necrotizing agents and gastric mucosal defensive factors in rats

Effects of TA-2711 on gastric mucosal lesions induced by various necrotizing agents and several defensive factors of gastric mucosa were investigated in rats. Oral administration of TA-2711 at 12.5 to 200 mg/kg prevented the formation of gastric mucosal lesions induced by 99.5% ethanol, 0.6 N HCl, 0.2 N NaOH and boiling water with ED50 values of 24, 58, 16 and 101 mg/kg, respectively. Oral TA-2711 at 100 mg/kg increased the gastric mucosal prostaglandin E2 (PGE2) level without any change in transmucosal potential difference. A sustained decrease in gastric mucosal blood flow produced by intragastric administration of 99.5% ethanol was inhibited by oral TA-2711 (50, 100 mg/kg) and 16,16-dimethyl PGE2 (10 micrograms/kg). The effect of TA-2711 on ethanol-induced decrease in blood flow was suppressed by indomethacin (10 mg/kg, s.c.). Oral TA-2711 (25-100 mg/kg) dose-dependently increased the amount of mucus adherent to the gastric mucosa. In addition, gastric HCO3- secretion was increased by intragastric TA-2711 at 2.5 and 5.0 mg/ml. These results suggest that TA-2711 enhances gastric mucosal resistance by increasing mucus and HCO3- secretion and by maintaining mucosal blood flow, and protects the gastric mucosa against various irritants. The effects of TA-2711 appear to be mediated by mucosal prostaglandins such as PGE2.     

Pharmacological studies on (4S)-1-methyl-3-[(2S)-2-[N-((1S)-1-ethoxycarbonyl-3-phenylpropyl)amino] propionyl]-2-oxo-imidazolidine-4-carboxylic acid hydrochloride (TA-6366), a new ACE inhibitor: I. ACE inhibitory and anti-hypertensive activities

TA-6366 and its active metabolite 6366A inhibited swine renal angiotensin converting enzyme (ACE) activity with IC50s of 9900 and 2.6 nM, respectively. TA-6366 (0.05-0.5 mg/kg, p.o.) inhibited the angiotensin I (AT-I)-induced pressor response in rats. 6366A augmented bradykinin (BK)-induced contraction of guinea pig ileum more potently than captopril. However, when the augmentation on BK-induced hypotension in rats was used as an indicator, TA-6366 was less active than captopril. TA-6366 increased plasma renin activity and plasma AT-I concentration. Oral administration of TA-6366 lowered the blood pressure in two-kidney one-clip renal hypertensive rats at 0.5 to 2 mg/kg and in spontaneously hypertensive rats (SHRs) at 2 to 10 mg/kg. The antihypertensive effect of TA-6366 was approximately 5 times more potent than that of captopril and almost as potent as that of enalapril. In SHRs, the antihypertensive action of TA-6366 was intensified in potency when administered repeatedly. The duration of action was longer than those of captopril and enalapril. However, TA-6366 had no substantial effect on the blood pressure in DOCA/saline hypertensive rats. These results indicate that TA-6366 is a potent and long lasting antihypertensive agent and that its antihypertensive action is attributable to the inhibition of ACE.     

Inhibitory effect of 2-(2-fluoro-4-biphenylyl)propionic acid (Flurbiprofen) on prostaglandin synthesis]

Inhibitory effects of 2-(2-fluoro-4-biphenylyl) propionic acid (Flurbiprofen, FP-70) on prostaglandin (PG) synthesis and PG activity were investigated both in vivo and in vitro. FP-70 at 0.64 micronM showed 50% inhibitory effect on PG synthesis from arachidonic acid in cell-free homogenate of guinea pig lung. PGE2 and PGF2alpha in the sample of lung homogenate incubated with arachidonic acid were separated by thin-layer chromatography in solvent AI system. FP-70 inhibited strongly both synthesis of PGE2 and PGF2alpha at 3 micron, but inhibited more extensively the synthesis of PGE2 than that of PGF2alpha at 0.3 micronM. FP-70 at 1 mg/kg, p.o. inhibited mostly arachidonic acid potentiation of carrageenin-induced edema in the rat paw, but did not inhibit PGE2 potentiation of carrageenin-induced edema. FP-70 also did not inhibit the contraction of rat stomach strip induced by PGE2. From the above and previously5) reported results, FP-70 proved to inhibit PG synthesis but not PG activity. It is suggested that the potent anti-inflammatory action of FP-70 is the result of inhibition of PG synthesis.     

The modes of anti-inflammatory and analgesic actions of aspirin and salicylic acid

The modes of anti-inflammatory and analgesic actions of aspirin and salicylic acid were investigated using some experimental animal models. Anti-inflammatory potencies of aspirin were almost equal to those of sodium salicylate in the carrageenin hind paw edema, the cotton pellet granuloma and the adjuvant arthritis tests in rats. On the other hand, in the ultra-violet ray erythema and the arachidonic acid erythema tests in guinea pigs, aspirin was more potent than sodium salicylate. Aspirin and sodium salicylate exhibited almost the same inhibitions of the rat hind paw edema induced by a mixture of carrageenin and prostaglandin E1. These results suggest that inhibition of cyclo-oxygenase by aspirin does not play any important roles for the prevention of the vascular permeability increment and the granulation in the inflamed tissue. Aspirin may exert its antiinflammatory activity mainly as salicylic acid which is not an inhibitor of prostaglandins biosynthesis in vitro. Aspirin showed about 5 times more potent analgesic action than sodium salicylate in the lameness test using adjuvant arthritic rats. Analgesic potency of aspirin was decreased to the level of sodium salicylate by injection of prostaglandin E2 into the inflamed rat paw in the adjuvant-induced lameness test. On the other hand, analgesic potency of sodium salicylate was not decreased by the same treatment. It is concluded that aspirin has two analgesic effects on the inflammatory pain, one is inhibition of prostaglandins biosynthesis by acetylation of cyclo-oxygenase and the other is an action due to salicylic acid, but the action of salicylic acid was not totally explained by the inhibition of prostaglandins synthetase.