Dextran Oedema Research Articles

Study of anti-inflammatory and antinociceptive properties of new derivatives of condensed 3-aminothieno[2,3-b]pyridines and 1,4-dihydropyridines

Background. α-сyanothioacetamide derivatives are promising targets for the search for effective and safe antinociceptive agents with antipyretic and antiexudative activity. The aim. To conduct in vivo experimental study of anti-inflammatory and analgesic effects of new thienopyridines and 1,4-dihydropyridines derivatives. Materials and methods. The synthesized cyanothioacetamide derivatives were subjected to virtual bioscreening using Swiss Target Prediction online service. 140 laboratory rats were randomly distributed into intact and control (dextran edema) groups, reference groups (acetylsalicylic acid and nimesulide) and ten experimental groups for the investigated derivatives of thieno[2,3-b]pyridine and 1,4-dihydropyridine. The anti-inflammatory activity of the compounds at a dose of 5 mg/kg was evaluated by modeling acute dextran edema of rat paw. Determination of analgesic activity was carried out in the hotplate analgesic assay on 130 rats in comparison with sodium metamizole. Results. 1,4-dihydropyridines AZ331 and AZ420, as well as thienopyridine derivative AZ023 were determined to have strong anti-inflammatory activity (2.5 times more effective than nimesulide and 2.2 times more effective than acetylsalicylic acid). Compounds AZ023, AZ331 and AZ383 showed pronounced analgesic activity. The time of stay on the heated plate for rats of experimental groups that were fed with AZ331 and AZ383 for prophylactic purpose was respectively 9.56 and 9.93 times more than the same index in the reference group. The animals receiving AZ023 were characterized by an increase in the latent reaction time up to 241.2 seconds, which is 14.53 times higher than that in the rats received sodium metamizole. Conclusion. New thienopyridine and 1,4-dihydropyridine derivatives with high antiinflammatory and analgesic activity were synthesized and studied; they were recognized as promising targets for further preclinical studies.

Senna still causes laxation in rats maintained on a diet deficient in essential fatty acids.

The laxative effect of senna has been investigated in normal and essential fatty acid deficient (EFAD) rats. Oral administration of senna pod extract (7-5-90 mg kg-1) produced a dose-dependent increase in the number of soft faeces excreted by normal rats. Senna 30 mg kg-1 also reversed net absorption of water and increased the prostaglandin (PG) production in the colonic lumen of normal rats by about four times. Oral administration of senna pod extract to rats, maintained on a fat-free diet for 30-90 days, produced diarrhoea and reversed net absorption of water as in normal rats. However, a fat-free diet reduced the PG production drastically in the colonic lumen both in senna-free rats and in senna-treated rats. In EFAD rats carrageenan oedema, but not dextran oedema, was also drastically reduced. Since PG mediation is not present in EFAD rats we conclude that the PG are not essential for laxation induced by senna and that water secretion and PG production in the rat intestinal lumen are unrelated.

Anti-inflammatory and Analgesic Activities of the Crude Extracts from Stem Bark of Bauhinia Guianensis

Methylene chloride, ethyl acetate and methanolic extracts from the stem bark of Bauhinia guianensis (Leguminosae, Caesalpinoideae) were obtained. These extracts were evaluated for antiinflammatory activity which was conducted using carrageenin, dextran and histamine-induced paw edema in rats. The extracts of B. guianensis were also assessed for analgesic activity which was conducted using the writhing test in mouse. The different animal groups were treated with these extracts (100 mg/kg i.p. and p.o, IC 50) 30 min prior to the application of stimuli. The methanolic extract demonstrated significant inhibition in the carrageenin-induced edema model. In the dextran-induced edema model, all three extracts inhibited the inflammatory process significantly, with the methanolic extract being the most active. The ethyl acetate extract was the only one shown to be effective in the histamine-induced edema model. Finally, all extracts inhibited effectively the algogenic process in the writhing test induced by acetic acid.

Copper(II) Dihydroxybenzoates; Synthesis and Properties

Compounds of composition Cu(2,5-DHB)2 . 4 H2O (DHB, dihydroxybenoate anion) and Cu(2,Y-DHB)2 . 8 H2O (Y = 4 or 6) were prepared as potential antiinflamatory gents with a view of pharmacological screening. The room-temperature magnetic moments allow to classify all compounds into the group of magnetically diluted copper(II) complexes. According the EPR and electronic spectra, the degree of tetragonal distortion increases passing from Cu(2,6-DHB)2 . 8 H2O (III) through Cu(2,4-DHB)2 . 8 H2O (I) to Cu(2,5-DHB)2 . 4 H2O (II. The complexes differ also in the cooperative ordering in their structures. All tested compounds exhibit higher antiinflamatory activities (on dextran edema) than free carboxylic acids. However, their effects were accompanied with relatively high toxicity. Remarkable results were also achieved on evaluating the antipyretic activity.

Effects of prolactin on rat paw oedema induced by different irritants.

Evidence suggests that prolactin (PRL) may have a role in immune function, but no data exist on the possible interference between PRL and inflammatory processes, in spite of the known correlation between inflammatory and immune reactions. In the present study the activity of prolactin on rat paw oedema was investigated. Repeated administrations of ovine PRL or a hyperprolactinaemia induced by pituitary gland graft provoked an evident increase of the inflammatory response induced by carrageenan. This effect was also present when adrenalectomised animals were used. Indomethacin completely suppressed the pro-inflammatory effect of ovine PRL; bromocriptine reduced the paw oedema, but when both bromocriptine and PRL were administered the two opposite effects seem to annual each other. Also phospholipase A2-induced paw oedema was potentiated by PRL pretreatment and inhibited by bromocriptine, whereas in dextran or serotonin-induced paw oedema both PRL and bromocriptine were ineffective. A possible involvement of prostaglandins and/or of phospholipase A2 in the pro-oedemigenic activity of PRL is suggested.

Inhibition of rat paw oedema and pleurisy by the extract fromMandevilla velutina

This study reports the oral anti-inflammatory profile of the crude extract (CE) of Mandevilla velutina, a plant which has been previously demonstrated to selectively antagonize bradykinin response of the isolated tissues on rat paw oedema and pleurisy caused by different phlogistic agents. The CE (50 to 200 mg/kg), given 60 min before, inhibited in a dose-dependent manner bradykinin (BK) and cellulose sulphate-induced paw oedema, maximal inhibition of 59% and 65%, respectively. In the same range dose the CE also significantly antagonized pleural exudate and cell infiltration caused by these substances, maximal inhibition of 34% and 46%, respectively. In addition, the CE (100 and 200 mg/kg) also inhibited paw oedema induced by serotonin, PAF-acether and zymosan, maximal inhibition of 55%, 38% and 46%, respectively, but enhanced histamine oedema. However, the CE revealed only partial or no inhibition in pleural exudate caused by these agents. The CE (100 and 200 mg/kg) also inhibited in a dose and time-dependent manner carrageenan-induced paw oedema with a maximal inhibition of 44%, but only partially affected carrageenan-induced pleural exudate. The CE also partially inhibited dextran oedema, but even at a higher dose (400 mg/kg) it failed to interfere with Bothrops Jaracaca-induced paw oedema. The CE inhibited BK and to a lesser extent cellulose sulphate-induced cell migration, but failed to interfere with the differential leukocyte migration in the pleural cavity. These findings provide evidence that the CE from M. velutina, besides antagonizing kinin action, exhibit an oral anti-oedematogenic activity against a variety of phologistic agents, but it was more effective in inhibiting those models where kinins are more involved.

Vasocortin-like proteins indiced by glucocorticoids in vascular tissue

Rat and bovine aorta rings incubated with 10 −5 M dexamethasone release proteins which inhibit rat dextran oedema. These proteins seem to be related to vasocortin, derived from the peritoneal fluid of dexamethasone-treated rats, and may contribute to the control that glucocorticoids exert on vascular tonus and permeability.

Vasocortin: a novel glucocorticoid-induced anti-inflammatory protein.

The preliminary characterization of ;vasocortin' a novel glucocorticoid-induced anti-inflammatory protein, is described. Vasocortin is released into the rat peritoneal cavity following systemic dexamethasone administration, has an apparent mol. wt. of 100 kD and inhibits rat dextran oedema. Vasocortin is distinct from lipocortin and is likely to be associated with the anti-inflammatory effect of glucocorticoids.

Anti-inflammatory, analgesic properties and antipyretic action of 3-aminoindazole derivatives

We reported an interesting anti-inflammatory effect of one of 3-aminoindazole derivatives in the proceeding paper. We wish to report the anti-inflammatory, analgesic and antipyretic effect of 3-aminoindazole derivatives. Several new derivatives of 3-aminoindazole were synthesized. They were examined for their anti-inflammatory effect by the method of anti-inflammatory assays by using carrageenin edema, dextran edema, serotonin edema, histamine edema and bradykinin edema. The analgesic effect in mice was examined by using the acetic acid writhing test and the antipyretic effect in rats was examined with yeast. 3-(3-Morpholinopropylamino) indazole which is a representative compound was found to possess three times more effective anti-inflammatory property with the carrageenin edema than the reference drug, tiaramide and the same analgesic property as tiaramide. 3-(3-Morpholinopropylamino) indazole is thought to possess different mechanism of acidic non-steroidal anti-inflammatory drugs such as indomethacin and mefenamic acid because this compound inhibited the hind paw edema induced with histamine, serotonin, bradykinin and dextran. It was found that this compound at 50mg/kg, p.o. was as effective in its antipyretic action as indomethacin at 10mg/kg, p.o. Among other 15 new derivatives, 3-[3-(2, 6-dimethylpiperidino) propylamino] indazole was also found to possess a similar degrees of anti-inflammatory, analgesic and antipyretic effect as 3-(3-morpholinopropylamino) indazole.

Glucocorticoid-induced low molecular mass anti-inflammatory factors which do not inhibit phospholipase A 2

The peritoneal lavage fluid of dexamethasone (DXM)-pretreated rats was filtered through an Amicon YM-10 membrane (cutsize 10 kD). The retentate inhibited dextran oedema. Its 40 kD fraction (lipocortin) obtained by molecular sieving on Sephadex (SG)-75, suppressed carrageenin-induced foot swelling and phospholipase A 2 (PLA 2) activity, but it had no effect on the dextran response. The Amicon filtrate was chromatographed on SG-25 gel and yielded 6 and 2 kD fractions suppressing dextran and serotonin (5-HT) oedema but not carrageenin inflammation and PLA 2 activity. These fractions may be active fragments of vasocortin, a glucocorticoid-induced mediator regulating vascular permeability.

Pharmacology of an extract of salai guggal ex-Boswellia serrata, a new non-steroidal anti-inflammatory agent.

Pharmacological evaluation of alcoholic extract of salai guggal (AESG) has been carried out in experimental animals. AESG displayed marked anti-inflammatory activity in carrageenan induced oedema in rats and mice and dextran oedema in rats. It was equally effective in adrenalectomised rats. In formaldehyde and adjuvant arthritis, AESG produced prominent anti-arthritic activity but no significant effect was observed in cotton pellet-induced granuloma test. It inhibited inflammation induced increase in serum transaminase levels and leucocyte counts but lacked any analgesic or anti-pyretic effects. The gestation period or parturition time in pregnant rats or onset time of castor oil-induced diarrhoea was unaffected by AESG and no significant effect was seen on cardiovascular, respiratory and central nervous system functions. No ulcerogenic effects were found in the rat stomach. The oral and intraperitoneal LD50 was greater than 2 g/Kg in mice and rats.

Insulin-induced factors derived from lymph node cells influence anaphylactoid reaction in the rat.

The effect of supernatants of isolated lymph node cells exposed to insulin has been studied on the anaphylactoid reaction induced by dextran in the rat paw. Native supernatants derived from rat lymphocytes were shown to increase dextran response only from April to October, while in the intermediate period no potentiation was obtained. The supernatants were filtered through sephadex G-25, G-50, and G-100 gels. Pro-inflammatory activity was recovered in the void volume of sephadex G-25 or G-50 columns, while it ran with bovine serum albumin marker suggesting an approximate mol. wt. of 70-kilodalton. Potentiation was detectable in adrenalectomized rats from November through April. A fraction of the eluate recovered from sephadex G-25 gels in the range of 1- to 6-kilodalton was found to suppress dextran edema. Supernatants of calf lymph node cells with insulin were fractionated on DEAE-sephadex A-50 and yielded two distinct fractions, one with pro-inflammatory and the other with anti-inflammatory effect. These results suggest that insulin affects anaphylactoid reaction via the release of some lymphocyte mediators.

Endogenous inhibitor of prostaglandin biosynthesis in inflammation.

Rat serum exhibits a concentration-related inhibition of PG biosynthesis by rat peritoneal leucocytes phagocytosing killed bacteria. The serum inhibitory potency is increased by inducing carrageenan foot oedema in animals whereas it is not altered by dextran oedema. The increase of the inhibitory activity of serum from carrageenan-treated rats develops in a time-dependent way reaching its maximum at 24 h. Since the increased inhibitory activity does not occur following indomethacin administration we suggest that PG formation at the inflammatory site may stimulate the ability of serum to inhibit PG biosynthesis.

Pharmacological studies on bamboo grass. IV. Toxicological and pharmacological effects of the extract (FIII) obtained from Sasa albomarginata Makino et Shibata (author's transl)

F I (precipitate), F II (sugar fraction, mol. wt.>10000) and F III (sugar fraction, mol. wt. 5000-10000) were obtained by further purification of a water-soluble fraction (crude Folin) extracted from Sasa albomarginata MAKINO et SHIBATA (Bambusaceae). Acute toxicity and pharmacological effects were examined mainly with F III in small animals. F III showed no apparent toxic effect in mice. It effected a significant decrease of rat dextran edema by topical administration. However, oral administration effected a decrease in the early and an increase in the later stage of rat dextran edema. Antagonistic effect was also observed against contraction induced by serotonin and nicotine in the isolated guinea-pig ileum. The therapeutic effect on rat stress ulcer was in the potency order of F III>F II>F I. F II and F III had no antibacterial effect. No remarkable effects were observed in surface anesthesia of guinea-pig carrageenin edema and urinary excretion of rats treated with F III. Furthermore, F II showed a slight antitumor effect against S180A in mice.

Anti-inflammatory properties of griseofulvin.

Anti-inflammatory activity of griseofulvin has been investigated in comparison with indomethacin and flufenamic acid. In vitro, griseofulvin has been proved the most effective of these agents in suppressing the contractions of smooth muscle preparations induced by a variety of proposed mediators of inflammation, i.e. histamine, 5-hydroxy-tryptamine, bradykinin and prostaglandin E2. In vivo, griseofulvin was unable to modify dextran oedema but suppressed carrageenin oedema, although its activity was poor when compared to that exhibited by indomethacin and flufenamic acid. When tested in rat pleurisy induced by dextran or homologous serum griseofulvin was able to prevent polymorph migration into the pleural space while mononuclears remained virtually unaffected. In contrast indomethacin and flufenamic acid mainly suppressed mononuclear migration while polymorphs resulted only slightly affected. Similar results have been exhibited by the drugs when tested on mononuclear turnover in pleural cavities from normal rats. Results are discussed in the light of the clinically established ability of griseofulvin to prevent cutaneous inflammatory reactions as well as of its effectiveness in the treatment of several polyarthritic syndromes.

Pharmacological studies on the Chinese crude drug "Shôma". I. Acute toxicity and anti-inflammatory action of Cimicifuga rhizoma, Cimicifuga dahurica Maxim. (author's transl)

Pharmacological effect of isoferuric acid and crude extracts CD-2-to-6, obtained from the chinese crude drug "Shoma" (the rhizome of Cimicifuga dahurica MAXIM.), was examined in mice and rats. Isoferuric acid showed a significant hypothermic, anti-pyretic, analgesic, and anti-edematous effect. CD4 strongly reduced writhing responses and carrageenin edema. CD6 showed significant hypothermic and anti-pyretic effects. It also showed a marked reduction of writhing responses. However, CD6 did not show any inhibition of carrageenin edema or analgesic effect using the tail pressure test. Only a slight reduction of writhing responses and dextran edema was found in CD5. CD2 showed a tendency of preventing lactic acid-induced anal ulcer, and a slight inhibition of carrageenin edema. The significance of these pharmacological results was discussed.

Sephadexentzündung bei der Ratte

Question: A single s. c. injection of Dextran is very suitable in producing an inflammatory response in t-he rat. The Dextran edema has become a standard method. It seems not unlikeley that Sephadex, the Dextran gel widely used in the gelchromatography may have a similar effeet. Sephadex, because of its physicochemical properties, would offer some advantages in the studies of inflammatory reactions. But first of all the following questions have to be answered: 1. Does one single s. c. injection of Sephadex produce an inflammation at all and what are the characteristics on the microscopical level? 2. Does it make any difference if Sephadex of different types are injected? Material and methods: Male and female Wistar rats (100-250 g) in groups of 5 animals each. Diet: Rat pellets “Tagger” and tap water ad libitum. Sephadex (Pharmacia Fine Chemicals) of the types G-25 m, G-50 m, G-100 and G-200 were soaked in 0.9% saline for the prescribed time and afterwards preserved until the Sephadex gel had settled on the bottom of the vessel. 1 ml of this Sephadex gel slurry each were subcutaneously injected to the shaved dorsal skin of the rats (right below). At different intervals (3, 6, 24 and 72 hours; 6, 14, 20 and 28 days) the Sephadex depot and the surrounding tissue were exstirpated and examined histologically. During all the procedures the animals were subjected to ether anesthesia. From the tissue samples frozen sections (Kryocut, — 30 °C) were prepared and stained with hematoxylin and eosin or after van Gieson. Moreover, several preparations were stained after Pappenheim and Weigart (fibrin) or with PAS and toluidine blue. For recording of probable differences in the effect of the particular Sephadex types always 2 values were determined histometrically. The number of exudate cells emigrated between the Sephadex beads within the area of an ocular-net (edge length 1.66 mm) were counted at 500-fold magnification. Furthermore, the number of eosinophils was determined by the technique. However, because of poor occurrence the eosinophils were counted in 10 fields of view. Tests with Sephadex G-10 were omitted as preliminary tests had shown that it is not suitable for s. c. injeetions because of its gritty consistency (due to poor soaking properties). Results: One singles. c. injection of Sephadex in the rat induces an acute inflammation. The exudative phase marked by a massive leucocytic infiltration (espeeially PMN leucocytes) is followed by the appearance of mononuclear leucocytes and fibroblasts after the 2nd day. The inflammation declines within approximately 3 weeks. Thereafter the Sephadex depot is encapsulated by a fibrous tissue. A chronie inflammation was never observed. ln the microscopical aspect of the inflammation produced by the different types of Sephadex were detectable. The Sephadex lying in the tissue does not change its original shape, it is insoluble and is not disintegrated. The size of the particles prevents the transport into the blood or lymph vessels. Thus the Sephadex beads remain in the place of injection, a circumstance which might facilitate the investigations of some local reacting during the inflammation. Zusammenfassung Das aus der Gelchromatographie bekannte Dextrangel Sephaclex erzeugt bei subkutaner Injektion bei der Ratte eine heftige akute Entzündung. Der Charakter dieser Entzündung ist nach den hier angewandten histologischen Kriterien unabhängig vom Vernetzungsgrad der verwendeten Geltypen. Der Prozeß nimmt den regulären Verlauf einer akuten Entzändung, die nach etwa 3 Wochen ihr Ende findet. Nachdem die entzündungsauslösende Substanz weder abgebant noch abtransportiert wird, steht in toto ein gut lokalisiertes Entzündungsmodell zur Verfügung.

Effects of adrenergic agents, theophylline and other drugs on dextran edema and histamine release in rats

Pretreatment of rats with various catecholamines, theophylline and dibutyryl cyclic AMP decreased the reaction to dextran and reduced the associated release of histamine into the plasma. Protection by the catecholamines was inhibited by the β-blocker, propranolol. Some of these protective drugs owed their effectiveness in large part to the production of hyperglycemia. However, it appeared likely that they also acted directly on the mast cells to prevent the release of histamine and other vasoactive factors, as previously observed in vitro. Phenoxybenzamine, nicotinamide and ethanol also afforded protection not explainable by effects on blood sugar.

Sensitization by insulin of the anaphylactoid inflammation in rats.

The possible mode of action of insulin, in terms of its sensitizing effect on dextran-induced anaphylactoid reaction was studied. In normal rats, the sensitizing effect was inhibited by actinomycin D and cycloheximide 1 h after the administration of the drugs. 24 h after actinomycin D or cycloheximide, the inflammatory response was considerably reduced. The inhibition could not be reversed by insulin. In contrast, insulin restored the decreased susceptibility of diabetic animals to dextran. This effect was not influenced by actinomycin D and cycloheximide. None of the drugs used influenced the blood-sugar-lowering activity of insulin. Cyclophosphamide, parallel to the profound lymphopenia produced, prevented the sensitizing effect of the hormone. Viable lymphoid cells prepared from young normal rats completely restored the suppressed insulin response. Liver cells had no such an effect. Lymph node cells incubated in the presence of insulin released a factor(s), capable of increasing dextran edema, to the incubation medium. Pretreatment with actinomycin D and cycloheximide of the lymphocyte-donor rats interfered with the ability of insulin to produce the pro-inflammatory factor(s). The possible significance of the findings is discussed.

Effect of external lymph drainage and of coumarin treatment on dextran edema.

A significant protective effect is afforded against dextran oedema by external thoracic duct cannulation; the protective effect of coumarin is even more pronounced. The theoretical background of these phenomena is discussed.