Yeast-induced Fever In Rats Research Articles

Further studies on the pharmacological effect of the anti-inflammatory compound, bis[2-(E-2-octenoylamino)ethyl] disulfide.

Further studies on the pharmacological effect of orally administered bis[2-(E-2-octenoyl-amino)ethyl] disulfide (compd. I-3) was examined by using several experimental models in vivo. Compound I-3 showed analgesic activity, inhibiting both acetic acid- and acetylcholine-induced writhings in mice. This compound also showed antipyretic activity against yeast-induced fever in rats, and significantly inhibited arachidonic acid-induced mortality in mice. However, it had no effect on serotonin-induced paw edema formation or platelet activating factor-acether-induced mortality in mice. The effects of compd. I-3 are suggested to be due to inhibition of prostaglandin biosynthesis.

Pharmacological Properties of a New Anti-Inflammatory Compound, α-(3,5-Di-Tert-Butyl-4-Hydroxybenzylidene)-γ-Butyrolactone (KME-4), and Its Inhibitory Effects on Prostaglandin Synthetase and 5-Lipoxygenase

The pharmacological effects of a new anti-inflammatory compound, α-(3,5-di-tert-butyl-4-hydroxybenzylidene)-γ-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, equ potent 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.

Anti-inflammatory/anti-pyretic salicylic acid esters with low gastric ulcerogenic activity

The methyl and some other esters of acetylsalicylic and salicylic acids and their derivatives were found to have much lower gastric ulcerogenic activity (when assayed in the stress-sensitized rat) compared with their corresponding acids. There was little or no loss in therapeutic potencies of these salicylate esters as determined by assessment of anti-inflammatory activity (against the carrageenan-induced oedema) and antipyretic activity (against yeast-induced fever in rats. The methyl ester of acetylsalicylic acid (=AME) was almost devoid of gastric irritancy/ulcerogenicity (as observed with acetylsalicylic acid) when given orally to pigs for 10 days. AME had appreciable anti-inflammatory activity in the adjuvant-arthritis model and at high doses (200 mg/kg t.i.d.) was without the lethal effects seen with acetylsalicylic acid. Moreover, no toxic effects were seen after long-term administration of 100-1000 mg/kg/day AME for 3-4 months. The results provide further evidence for the hypothesis that the carboxylic acid moiety of salicylates is a major factor in the gastric ulcerogenic activity of these drugs. The methyl esters of these salicylates may be considered as models for the development of pro-drugs and in some cases may be therapeutic alternatives to acetylsalicylic acid or salicylate.

Are all aspirins really alike? A comparison of gastric ulcerogenicity with bio-efficacy in rats

Summary o 1. Fifteen aspirin formulations (including 11 commercial types) and various other salicylate preparations were compared primarily for intrinsic gastric ulcerogenicity in cold stressed rats — a sensitive model for determining potential ulcerogenic activity. Several buffered aspirins were notably just as ulcerogenic as aspirin suspensions. 2. High Na + -containing aspirin formulations were the least ulcerogenic of those examined but also exhibited the shortest duration of action as antipyretics when assayed against yeast-induced fever in rats. Incorporation of D-glucose with certain metabolizable bases (citrate, acetate) markedly reduced the ulcerogenic activity of aspirin. 3. Aspirin impurities, benorylate, several non-acetylated salicylates (e.g. diflunisal, diplosal) were compared for anti-inflammatory potency, antipyretic activity and gastric ulcerogenic. These results suggest that for non-analgesic use, salts of salicylic acid, diflunisal and diplosal would seem preferable to aspirin — conferring the same potential benefit (as anti-inflammatory/antipyretic drugs) but with lower gastric ulcerogenicity.

Prostaglandin synthesis inhibited by formamidine pesticides

The formamidine pesticides, chlordimeform and amitraz, were shown to have both antipyretic and anti-inflammatory activity when given intraperitoneally to rats at 5 to 80 mg per kg. They reduced yeast-induced fever in rats with potencies intermediate between those of indomethacin and aspirin, and antagonized the carageenin-induced swelling of the hind paw. In both these actions, chlordimeform was more potent than amitraz. Both formamidines also inhibited the synthesis of prostaglandin E 2 from arachidonic acid by bovine seminal vesicle microsomes. At an arachidonic acid concentration of 0.4 μM, the I 50 values for chlordimeform and amitraz were 34 and 880 μM respectively, compared to 0.4 μM and 790 μM for indomethacin and aspirin. These aspirin-like actions may provide a clue to some of the physiological effects of the formamidines, which represent a new and unsual group of prostaglandin synthetase inhibitors.

鎮痛, 解熱および抗炎症作用におけるAminopyrineとPhenopyrazoneとの配合効果

Combined effect of aminopyrine with phenopyrazone (1, 4-diphenyl-3, 5-pyrazolidinedione) at the weight ratio of 1 : 1 on analgesic, antipyretic and anti-inflammatory activities was examined by oral administration in experimental animals. ED50 values (mg/kg) of aminopyrine, phenopyrazone, and the combination were 117.2 (n=85), more than 640, and 126.2 (n=85), respectively, for suppressing the phenylquinone-induced writhing in mice, 13.6 (n=56), more than 640, and 10.2 (n=56), respectively, for reducing the yeast-induced fever in rats, and 182.3 (n=128), 574.0 (n=47), and 216.4 (n=78), respectively, for inhibiting the carrageenin-induced edema in rats. Their LD50 values in mice were 522.6 (n=110), more than 3200, and 848.5 (n=110) mg/kg, p.o., respectively. Anti-writhing activity of aminopyrine in the mice pretreated with phenopyrazone daily for 5 days was significantly better than that in the mice pretreated with a vehicle 24 hr after the last administration, and the plasma level of phenopyrazone at the time was almost nil. The anti-writhing activity of aminopyrine (60 mg/kg) was significantly potentiated by the addition of 60 mg/kg of phenopyrazone but not with 6 mg/kg. The parallel shift of the dose-response curve for aminopyrine to the left was significant by the addition of a fixed dose (60 mg/kg) of phenopyrazone to each dose of aminopyrine. These results suggest that analgesic and antipyretic activities of aminopyrine were potentiated by the combined use with phenopyrazone at the weight ratio of 1 : 1 without any potentiating effect on acute lethal toxicity, though the anti-inflammatory activity tended to be potentiated, and the synergism between the drugs appeared to be due to the raised sensitivity of the acting site.