The effects of colchicine and its analogs on the carrageenin-induced footpad edema in rats were investigated. The anti-inflammatory effects of colchicine analogs were measured at 3 and 5 hr after the carrageenin injection. Colchicine, 1-demethylcolchicine and 3-demethylcolchicine markedly inhibited the carrageenin edema whereas 2-demethylcolchicine was much less active. Thiocolchicinoids, having a thiomethyl group at C-10 instead of a methoxy group, were considerably less potent. These results suggest that the presence of methoxy groups at C-2 and C-10 in colchicine is necessary to maintain anti-inflammatory activity. Inactivity of deacetylcolchicine indicates that substitution of the amino group at C-7 with electron withdrawing groups is also important. Significant inhibition of carrageenin edema and strong binding to tubulin in vitro were manifested by colchicine, 3-demethylcolchicine, N-butyryldeacetylcolchicine and colchifoline. On the other hand, N-carbethoxydeacetylcolchicine which did bind well to tubulin, did not show much effect on the carrageenin edema. These results suggest that the anti-inflammatory action of colchicinoids may not be regulated through the microtubule system.

Animals↗

PubMed1987

Lack of association and linkage between HLA and familial polyposis coli.

We investigated possible association of and linkage between HLA and familial polyposis coli (FPC). In 182 individuals from 66 pedigrees of FPC and 108 individuals from a normal population, HLA-A, -B, and -C antigens were determined. When the frequencies of HLA antigens in 66 unrelated patients and in normal controls were compared, no association of FPC with HLA was observed. For the linkage analysis, HLA haplotypes of 17 affected sib pairs were investigated by the affected sib pair method. The number of pairs which shared two, one, and no haplotypes identical by descent was not significantly different from the number expected with random occurrence (P greater than 0.95). Finally, seven families were analyzed using Morton's sequential test. A maximum lod score of -0.056 at a recombination fraction of 0.4, and a lod of -3.089 at a recombination fraction of 0.05 were obtained. Therefore, there is neither an association of nor linkage between FPC and HLA.

Adenomatous Polyposis Coli↗

PubMed1987

[Genetic factors involved in carcinogenesis].

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Adenomatous Polyposis Coli↗

PubMed1986

Effects of forskolin and prostaglandin E1 on leukotriene C- and D-induced plasma exudation in the rat skin.

Leukotriene C and D markedly enhanced plasma exudation in rat skin, using [131I]-labeled human serum albumin ([131I]-HSA) to measure vascular permeability. The adenylate cyclase activator forskolin only slightly increased plasma exudation, while markedly potentiating the leukotriene response. Prostaglandin E1 increases plasma exudation in rat skin, but appears to act by a different mechanism than leukotrienes, since the responses to combinations of prostaglandin and leukotrienes are synergistic and the responses to prostaglandins are inhibited by forskolin. The phosphodiesterase inhibitor, isobutylmethylxanthine also potentiated the leukotriene C-induced response. The effects of the various agents on leukotriene responses are similar to effects of these agents on bradykinin and histamine-induced plasma exudation. These results suggest that an increase in the cyclic AMP in the rat skin, elicited by forskolin or prostaglandin potentiates the leukotriene C and D-induced plasma exudation and that leukotriene C and D increase the vascular permeability through the same type of mechanism that pertains for histamine and bradykinin.

Animals↗

PubMed1986

Vascular permeability responses and the role of prostaglandin E2 in an experimental allergic inflammation of air pouch type in rats.

Rats were sensitized with azobenzene arsonate-conjugated acetyl bovine serum albumin. An allergic inflammation was induced in the preformed air pouch in the dorsum of the sensitized rats by injecting the antigen dissolved in a 2% sodium carboxymethyl cellulose solution into the air pouch. Time course changes of vascular permeability, accumulated pouch fluid volume and prostaglandin E2 (PGE2) levels in the pouch fluid were compared in sensitized and non-sensitized rats to characterize the allergic inflammatory reaction. Effects of three cyclo-oxygenase inhibitors (indomethacin, diclofenac sodium and tiaprofenic acid) on vascular permeability and accumulated pouch fluid volume 4 and 24 h after the immunological challenge injection were examined to elucidate a possible role of PGE2 in the inflammatory response. Four h after initiating the allergic reaction, although the level of PGE2 in the pouch fluid reached a high level, the vascular permeability response, measured over the period 3.5-4 h, was not suppressed by treatment with the three cyclo-oxygenase inhibitors and neither was the pouch fluid volume measured over the period 0-4 h. However, vascular permeability and accumulated pouch fluid volume at 24 h were suppressed by the cyclo-oxygenase inhibitors in a dose-dependent manner. These observations suggest that in this model, endogenous PGE2 does not affect oedema formation measured at 4 h. However, oedema formation measured at 24 h may be dependent on PGE2 generation.

Animals↗

PubMed1985

Release of T-kinin and bradykinin in carrageenin induced inflammation in the rat.

Plasma and inflammatory fluid kininogen levels, and blood and inflammatory fluid free kinin levels were determined in rats 24 h after the injection of carrageenin into an air pouch. Plasma T-kininogen levels increased 7-fold. In the inflammatory fluid levels reached 8 micrograms/ml. Blood levels of free kinin showed a 5-fold increase. The kinins were identified on HPLC as T-kinin (Ile-Ser-bradykinin) and bradykinin, 63 and 37%, respectively. These results indicate for the first time that free T-kinin as well as bradykinin is released during an inflammatory response in rat and confirms our previous finding that T-kininogen may be a major acute-phase protein in inflammation.

Animals↗

PubMed1985

Potential occurrence of calcium bilirubinate stone after gastrectomy.

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Adult↗

PubMed1984

Adenosine analogs: potentiation of bradykinin-induced plasma exudation in rat skin and prevention by caffeine and theophylline.

Adenosine and various analogs potentiated plasma exudation elicited by bradykinin in rat skin using 125I-labelled bovine serum albumin (125I-BSA) as a tracer. L-N6-Phenylisopropyladenosine (L-PIA) was much more effective than D-PIA, adenosine, N6-cyclohexyladenosine (CHA) and 2-chloroadenosine, all of which were comparable in activity. Adenosine 5'-cyclopropylcarboxamide was the least effective analog. Caffeine and theophylline had no effect on basal or bradykinin-elicited plasma exudation, while inhibiting plasma exudation elicited by L-PIA, CHA or a combination of bradykinin and L-PIA. 8-Phenyltheophylline was more potent than caffeine or theophylline versus the bradykinin and L-PIA combination. 2',5'-Dideoxyadenosine, a P-site inhibitor of adenylate cyclase, had no effect on plasma exudation elicited by bradykinin, L-PIA or a combination of bradykinin and L-PIA, but did inhibit plasma exudation elicited by prostaglandin E1 (PGE1) or a bradykinin-PGE1-combination. The antihistamine cyproheptadine slightly reduced plasma exudation elicited by a bradykinin-PGE1 combination. The results suggest that adenosine potentiates bradykinin-induced plasma exudation via an adenosine receptor and that histamine may be involved to some extent in the phenomenon.

Adenosine↗

PubMed1984

Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin.

The effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin were investigated using [125I]bovine serum albumin (125I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. On the other hand, 14,15-dihydroforskolin and 1,9-dideoxyforskolin, which are weak or inactive as activators of adenylate cyclase, did not have any significant effect on bradykinin and prostaglandin E1-induced plasma exudations. The phosphodiesterase inhibitors, ZK 62711, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E1-induced response. Papaverine had biphasic effects on the bradykinin-response and slight inhibitory effects on the prostaglandin E1-response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 microgram potentiated the bradykinin-induced plasma exudation, but had no effect at doses of 10 and 100 micrograms. 8-Bromo cyclic AMP at all doses significantly inhibited the prostaglandin E1-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E1 in rat skin derive from activation of cyclic AMP-generating systems.

8-Bromo Cyclic Adenosine Monophosphate↗

PubMed1983

Effect of forskolin on alterations of vascular permeability induced with bradykinin, prostaglandin E1, adenosine, histamine and carrageenin in rats.

The effect of the diterpene forskolin on vascular permeability alone and in combination with bradykinin, prostaglandin E1, adenosine or histamine has been investigated in rats. Vascular permeability in rat skin was measured using [125I]-labelled bovine serum albumin ([125I]BSA) as a tracer. In addition, the effect of forskolin on footpad edema induced by the injection of a mixture of 2% carrageenin was determined. Forskolin caused a marked potentiation of the increase in vascular permeability in rat skin elicited by the intradermal injection of histamine or bradykinin. However, forskolin caused a significant suppression of the prostaglandin E1-induced vascular permeability response and at a low concentration suppressed the response to adenosine. Forskolin greatly potentiated the footpad edema induced with carrageenin in rats. Intravenous administration of the enzyme bromelain, which reduces plasma kininogen levels, inhibited the footpad edema induced with carrageenin or with a mixture of carrageenin and forskolin. Parenteral administration of a prostaglandin synthetase inhibitor, indomethacin, suppressed the footpad edema induced with carrageenin, but did not inhibit the footpad edema induced with a mixture of carrageenin and forskolin. An antihistamine, cyproheptadine, had no effect on carrageenin-induced footpad edema either in the presence or absence of forskolin. These results suggest that both bradykinin and prostaglandins are essential for the development of carrageenin-induced footpad edema and that bradykinin plays an important role in the potentiative effect of forskolin on footpad edema induced with carrageenin in rats.

Adenosine↗

PubMed1982

The predominance of flunisolide in the topical use of anti-inflammatory steroids.

Local and systemic anti-inflammatory effects of topically applied flunisolide on hind footpad edema induced by subplantar injection of 1 microgram of serotonin in mice were evaluated in comparison with those of three related steroids. The order of the potency for local anti-inflammatory effect observed in the foot injected with the steroids was flunisolide, dexamethasone, betamethasone valerate and beclomethasone dipropionate in decreasing order. In contrast, potency for systemic effect of flunisolide observed on the opposite foot was rather weak compared with its strong local effect. When steroids were administered orally, the order of the anti-inflammatory potency as dexamethasone, beclomethasone dipropionate, flunisolide and betamethasone valerate in decreasing order. All of the data demonstrate that flunisolide is highly active in topical use, while systemically it is relatively weak, especially by oral administration. Those characteristics of flunisolide could be attributable to its rapid metabolic inactivation in the liver, which suggests a great advantage of its topical use in the clinical medicine.

Administration, Topical↗

PubMed1981

Suppression by dexamethasone of vascular permeability responses induced with leukotrienes C and D in the rat skin.

The present experiment was designed to investigate whether glucocorticoids counteract proinflammatory action of leukotrienes C and D which were suggested to play an important role as mediators in the inflammatory exudate response. Vascular permeability was measured using 131I-labeled human serum albumin (131I-HSA) as a tracer. The vascular permeability was elevated promptly after intradermal injection of chemically synthesized leukotriene C or D and then rapidly fell down to the control level. A positive dose-response relationship was observed in the dose levels of 0.01-1 microgram of leukotrienes. Dexamethasone at doses of 0.15, 0.5 and 1.5 mg/kg caused dose-dependent suppression of vascular permeability response induced with leukotrienes C and D. The present data indicate that glucocorticoids are capable of exerting direct inhibitory effect against proinflammatory action of leukotrienes C and D produced through phospholipase A2-arachidonate-lipoxygenase pathway.

Animals↗

PubMed1981

Mechanism of anti-inflammatory action of glucocorticoids: re-evaluation of vascular constriction hypothesis.

1 The question whether constriction of local vessels is essential for the anti-inflammatory action of glucocorticoids in carrageenin-induced granulomatous inflammation was studied. 2 The vasodilator prostaglandin E1 injection into the granuloma pouch fluid increased the exudation of plasma protein into the granuloma tissue. 3 Noradrenaline significantly reduced plasma exudation, possibly through alpha-adrenoceptor stimulation. 4 Cortisol and dexamethasone in doses sufficient to inhibit vascular permeability were without effect on the blood content in the granuloma tissue. 5 The results suggest that constriction of local vessels does not play an essential role in the anti-exudative effect of glucocorticoids in chronic proliferation inflammation.

Animals↗

PubMed1980

Comparative study between steroidal and nonsteroidal anti-inflammatory drugs on the mode of their actions on vascular permeability in rat carrageenin-air-pouch inflammation.

In an attempt to clarify mechanisms of anti-inflammatory actions of steroidal and nonsteroidal anti-inflammatory drugs with special reference to the possible role of E type prostaglandins in the inflammatory process, mode of actions of these drugs was investigated by using acute exudative stage and chronic proliferative stage of carrageenin-air-pouch inflammation in rats. This inflammation was induced on the back of rats by subcutaneous injection with air and carrageenin solution. Plasma exudation in the inflammation locus was determined with the aid of radioiodinated serum albumin. In the acute exudative stage of this inflammation, a single oral administration of dexamethasone, indomethacin, phenylbutazone or aspirin all exerted potent anti-exudative effect, while in the chronic proliferative stage, only dexamethasone was effective in inhibiting the exudation of the labeled albumin. Prostaglandin E level in the exudate of the acute stage inflammation was suppressed by either dexamethasone or indomethacin in accordance with the inhibition of the vascular permeability. These results suggest (1) significant role of prostaglandin E in the acute exudative inflammation, (2) similarity between steroidal and nonsteroidal anti-inflammatory drugs in the mechanism of their anti-exudative actions in the acute inflammation, (3) independency of the exudative process in the chronic proliferative inflammation from prostaglandins and (4) role of extra-prostaglandin mechanism(s) for the anti-exudative action of the anti-inflammatory steroids.

Animals↗