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1.
Eur J Pharmacol ; 431(1): 103-10, 2001 Nov 09.
Article in English | MEDLINE | ID: mdl-11716848

ABSTRACT

The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Benzamides/therapeutic use , Colitis/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Chronic Disease , Colitis/chemically induced , Colitis/pathology , Colon/drug effects , Colon/pathology , Disease Models, Animal , Enzyme Inhibitors/therapeutic use , Peroxidase/antagonists & inhibitors , Rats , Rats, Wistar , Sulfasalazine/therapeutic use , Trinitrobenzenesulfonic Acid , Tumor Necrosis Factor-alpha/biosynthesis
2.
Eur J Med Chem ; 36(7-8): 639-49, 2001.
Article in English | MEDLINE | ID: mdl-11600233

ABSTRACT

This paper describes the synthesis of N-pyridinyl(alkyl)phthalimides related to N-phenyl-4,5,6,7-tetrafluorophthalimides known to be inhibitors of tumour necrosis factor-alpha (TNFalpha) production. Pharmacomodulation at the phthalimidic nitrogen led to the selection of two pharmacophoric fragments (2,4-lutidinyl and beta-picolyl), allowing significant inhibition of TNFalpha production (compounds 12 and 17). Variation of the substituents linked to the homocycle of their phthalimide scaffold indicated that high (TNFalpha production) inhibitory potency could be achieved, notably by 5-fluoro, 4- or 5-nitro, 5-amino and especially tetrafluoro substitution. The most active compound, N-(pyridin-3-ylmethyl)-4,5,6,7-tetrafluorophthalimide (32) (84% inhibition at 10 microM), also produced an anti-oedematous effect in the PMA-induced mouse-ear swelling test. Although less active than dexamethasone, it exerted a marked reduction in ear thickness after oral administration (63% vs. 85% for dexamethasone at 0.2 mMkg(-1)) and remained efficient after topical application (46% vs. 96% for the dexamethasone). It also induced potent inhibition in the rat carrageenan foot oedema test with an ID(50) (0.14 microMkg(-1)) comparable with that of N-(2,6-diisopropylphenyl)phthalimide (4) (0.15 microMkg(-1)).


Subject(s)
Anti-Inflammatory Agents/pharmacology , Carrageenan/antagonists & inhibitors , Phthalimides/pharmacology , Pyridines/pharmacology , Tetradecanoylphorbol Acetate/antagonists & inhibitors , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Animals , Anti-Inflammatory Agents/chemical synthesis , Ear Diseases/chemically induced , Edema/chemically induced , Foot Diseases/chemically induced , Male , Mice , Microbial Sensitivity Tests/methods , Phthalimides/chemical synthesis , Phthalimides/chemistry , Pyridines/chemistry , Rats , Rats, Wistar , Schiff Bases , Tumor Necrosis Factor-alpha/biosynthesis
3.
Eur J Med Chem ; 36(6): 545-53, 2001 Jun.
Article in English | MEDLINE | ID: mdl-11525845

ABSTRACT

N-substituted-(indol-3-yl)carboxamides 10-15 and alkanamides 16-18 were prepared starting from the corresponding acids and submitted to screening for evaluation of their anti-inflammatory activity. None of the considered carboxamides exhibited significant inhibitory effect in the carrageenin-induced rat paw oedema after oral administration of 0.1 mM x kg(-1); nevertheless introduction of an alkyl chain, leading to alkanamides 16-18, induced moderate to high activity: 46-95% inhibition. The efficacy of these compounds in the inhibition of topical inflammation was confirmed by measuring reduction of ear thickness in the acute tetradecanoyl phorbol acetate (TPA)-induced mouse ear swelling assay. Preliminary pharmacomodulation brought to the fore that toxic effects induced, at 0.4 mM x kg(-1), by N-(pyridin-4-yl)(indol-3-yl)propanamide (17) could be attenuated or suppressed by 5-fluorination or introduction of a methoxycarbonylborane moiety, leading to 18 and 21.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Indoles/chemical synthesis , Indoles/pharmacology , Inflammation/drug therapy , Pyridines/chemical synthesis , Pyridines/pharmacology , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Carrageenan/pharmacology , Drug Design , Drug Evaluation, Preclinical , Ear, External/drug effects , Ear, External/pathology , Edema/chemically induced , Edema/drug therapy , Edema/pathology , Indoles/administration & dosage , Indoles/therapeutic use , Inflammation/chemically induced , Inflammation/pathology , Magnetic Resonance Spectroscopy , Male , Mice , Pyridines/administration & dosage , Pyridines/therapeutic use , Rats , Spectrophotometry, Infrared , Structure-Activity Relationship , Tetradecanoylphorbol Acetate/pharmacology
4.
J Pharm Pharmacol ; 53(3): 417-23, 2001 Mar.
Article in English | MEDLINE | ID: mdl-11291760

ABSTRACT

The topical anti-inflammatory activity of a series of N-pyridinyl(methyl)1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)-induced mouse ear swelling test, used as a screening test. All the eight carboxamides tested (9-16) exhibited significant inhibitory activity at 0.4 and 0.2 mM kg(-1). The most potent compound, the 6-bromo derivative 12, induced a 73% inhibition at 0.2 mM kg(-1). Pharmacomodulation was carried out by heterocycle opening and molecular simplification leading to pentafluorobenzoylacetamide 17, pentafluorocinnamamides 18 and 19, and pentafluorobenzaldimines 20 and 21. All the five compounds exerted a reduction in swelling (49-63% at 0.2 mM kg(-1)) comparable with ibuprofen (56%). Anti-inflammatory activity of the most efficient compounds was evaluated by carrageenan-induced rat paw oedema inhibition. The pentafluorobenzaldimine 20 showed the highest activity with an inhibition percentage of 85% at 0.2 mM kg(-1).


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyridines/chemical synthesis , Pyridines/pharmacology , Quinolones/chemical synthesis , Quinolones/pharmacology , Animals , Carrageenan , Ear, External/pathology , Edema/chemically induced , Edema/prevention & control , Foot/pathology , Male , Mice , Rats , Rats, Wistar , Tetradecanoylphorbol Acetate
5.
Toxicon ; 39(8): 1231-7, 2001 Aug.
Article in English | MEDLINE | ID: mdl-11306135

ABSTRACT

The effects of lepadiformine, a natural marine alkaloid isolated from the ascidians Clavelina lepadiformis (Müller) and C. moluccensis (Sluiter), were studied in vivo by arterial blood pressure (aBP) recordings and electrocardiograms (ECG) in anaesthetised rats and in situ by peripheral vascular pressure recordings on perfused rabbit ear. Transmembrane resting (RP) and action (AP) potentials were also recorded by intracellular microelectrodes on electrically stimulated left ventricular papillary muscle and spontaneously beating atrium isolated from rat and frog hearts, respectively. Intravenous injection of lepadiformine (6mg/kg) produced marked bradycardia and a lengthening of ECG intervals as well as a transient decrease of aBP, which rapidly returned to normal. The decrease of aBP may have been related to a vasoconstrictor effect observed in the perfused ear experiment. Lepadiformine did not alter RP, but significantly lengthened the repolarising phase of AP in rat papillary muscle and frog atrium. Lepadiformine also mimicked the effect of Ba(2+) (0.2mM) on the rat AP repolarising phase. Moreover, the lengthening of the AP in frog atrium induced by lepadiformine still developed after the delayed outward K(+) current (I(K)) was blocked by tetraethylammonium (10mM). These observations suggest that lepadiformine-induced lengthening of AP duration was not due to a decrease of I(K), but may reasonably be attributed to a reduction of the inward rectifying K(+) current (I(K1)). This blockade of I(K1) could account for the cardiovascular effects of lepadiformine in vivo and in vitro and suggests that lepadiformine has antiarrhythmic properties.


Subject(s)
Alkaloids/pharmacology , Hemodynamics/drug effects , Urochordata/chemistry , Action Potentials/drug effects , Animals , Electrocardiography/drug effects , Heart/drug effects , Heart/physiology , Male , Membrane Potentials/drug effects , Potassium Channels/drug effects , Rabbits , Rats , Rats, Wistar
6.
Phytother Res ; 14(8): 635-7, 2000 Dec.
Article in English | MEDLINE | ID: mdl-11114002

ABSTRACT

In the Ivory coast, Parkia biglobosa (Mimosaceae) is used in traditional medicine as an analgesic drug, especially against dental pain. Of the three extracts obtained from the plant bark, the hexane fraction was studied to determine its analgesic and/or antiinflammatory activities. The results show that this extract possesses a marked analgesic activity when evaluated with the abdominal writhing test in mice, but, like paracetamol, was ineffective with the hot-plate method, a feature suggesting a peripheral mechanism of action. This activity was accompanied by an antiinflammatory effect, somewhat weaker than the analgesic one.


Subject(s)
Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Medicine, African Traditional , Phytotherapy , Plant Extracts/pharmacology , Plants, Medicinal/therapeutic use , Animals , Cote d'Ivoire , Edema/drug therapy , Hot Temperature , Humans , Male , Mice , Pain/drug therapy , Plant Stems/chemistry , Rats , Rats, Wistar , Tetradecanoylphorbol Acetate/administration & dosage , Trees
7.
Arzneimittelforschung ; 47(5): 635-42, 1997 May.
Article in English | MEDLINE | ID: mdl-9205778

ABSTRACT

Derivatives of N-(4,6-pyridin-2-yl)arylcarboxamides resulting from the integration of the amidic function into 4H-1,2,4-triazole, triazol-3(2H)-one and 1H-tetrazole rings were evaluated as potential anti-inflammatory compounds. The level of activity decreased as compared to carboxamides, nevertheless their precursors and notably the corresponding amidrazones exhibited potent activity; amidrazone 21, whose ID50 was 34.4 mg.kg-1 in the rat paw edema test, was selected for further investigation. These heteroarylcarboxamide derivatives could represent an interesting alternative to classical non-steroidal anti-inflammatories in so far as they partly act by inhibition of tumor necrosis factor-alpha production.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemical synthesis , Pyridines/chemical synthesis , Tetrazoles/chemical synthesis , Triazoles/chemical synthesis , Animals , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Carrageenan , Edema/chemically induced , Edema/drug therapy , Lethal Dose 50 , Male , Pyridines/therapeutic use , Pyridines/toxicity , Rats , Rats, Wistar , Tetrazoles/therapeutic use , Tetrazoles/toxicity , Triazoles/therapeutic use , Triazoles/toxicity
8.
Pharmacol Res ; 36(3): 179-85, 1997 Sep.
Article in English | MEDLINE | ID: mdl-9367661

ABSTRACT

Several non-steroidal anti-inflammatory drugs of the N-pyridinyl-benzamide series that produce experimental peripheral and central anti-inflammatory effects possess a dopaminomimetic component and inhibit eicosanoid synthesis without acting directly on the enzymes classically involved in this process. We compared the anti-inflammatory and analgesic activities of one of the most active benzamide derivatives with those of clonidine. Rat paw and brain edemas were inhibited by these two agents, whereas different methods showed that yohimbine counteracted this effect and the analgesia it induced. The involvement of an alpha2-adrenergic and/or serotoninergic components in these activities is considered, without excluding the possibility that the mechanism of action is in part due to inhibition of prostaglandin synthesis.


Subject(s)
Adrenergic alpha-Agonists/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Benzamides/pharmacology , Brain Edema/drug therapy , Clonidine/pharmacology , Inflammation/drug therapy , Pain Threshold/drug effects , Receptors, Adrenergic, alpha-2/drug effects , Animals , Blood Pressure/drug effects , Brain Edema/physiopathology , Inflammation/physiopathology , Male , Pain Threshold/physiology , Rats , Rats, Wistar , Receptors, Adrenergic, alpha-2/physiology
9.
Agents Actions ; 37(3-4): 268-72, 1992 Nov.
Article in English | MEDLINE | ID: mdl-1295375

ABSTRACT

Several experimental brain edema models are currently available for drug evaluation. Brain edemas are essentially vasogenic and/or cytotoxic, and eicosanoids are involved in the development of these edemas. Thus, a new model developed in our laboratory, which was obtained by phospholipase A2 intracerebral injection was used to study the antiinflammatory effect of clonidine. The copper wire edema model was chosen as reference. Edemas were evaluated by determining the swelling and Na+ and K+ tissue concentrations of each hemisphere. Drugs were administered intraperitoneally. Dexamethasone was the only drug to inhibit copper wire-induced edema, whereas indomethacin and clonidine as well as dexamethasone exhibited marked antiedematous activity in our model. The effect of clonidine, which could be inhibited by prior administration of yohimbine, suggests that central alpha 2-adrenergic stimulation is involved in reducing experimental brain edema.


Subject(s)
Brain Edema/drug therapy , Clonidine/therapeutic use , Animals , Blood Pressure/drug effects , Brain/pathology , Brain Edema/chemically induced , Brain Edema/pathology , Copper , Dexamethasone/pharmacology , Indomethacin/pharmacology , Male , Phospholipases A , Phospholipases A2 , Potassium/metabolism , Rats , Rats, Wistar , Sodium/metabolism , Yohimbine/pharmacology
11.
Toxicon ; 26(12): 1129-36, 1988.
Article in English | MEDLINE | ID: mdl-3238698

ABSTRACT

Two cases of human intoxication caused by the lyophilized powder of Lissoclinum bistratum Sluiter, a New Caledonian ascidian, are reported. The symptoms observed were caused by a substance designated bistramide A (C40H68N2O8) of hitherto unknown chemical structure. Preliminary toxicological investigations indicate that bistramide A may effect the central nervous system, leading to paresthesia and loss of muscle tone. A progressive decrease in cardiac rhythm was also observed in animals. Bistramide A (1.4 x 10(-6) M) did not alter the resting potential of frog heart and skeletal muscle but reduced the amplitude and duration of cardiac action potential and prolonged the interval between action potentials. Bistramide A also has a marked cytotoxic effect on cancer cells KB (IC50 = 4.5 x 10(-8) M) and P 388 (IC50 = 2.0 x 10(-8) M) and on normal endothelial cells (IC50 = 2.2 x 10(-8) M). However, it has not been possible to relate the cytotoxic property to the symptoms of intoxication. Bistramide A may originate from the urochordate itself or from symbiotic algae.


Subject(s)
Acetamides , Pyrans , Toxins, Biological/toxicity , Urochordata , Animals , Artemia/drug effects , Electrophysiology , Ethers, Cyclic/isolation & purification , Ethers, Cyclic/toxicity , Lethal Dose 50 , Mice , Rats , Spiro Compounds , Toxins, Biological/analysis , Toxins, Biological/isolation & purification
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