Does insulin release kinins in rats?

Rat uterus maintained in situ was used as a bioassay of kinins possibly released in vivo by hyperglycaemia or insulin. Intravenous injections of bradykinin induced contractions of rat uterus which were suppressed by HOE 140, a bradykinin B2 receptor antagonist. Des-Arg9-bradykinin, a kinin B1 receptor agonist, did not elicit any response. After propranolol, the effects of bradykinin were enhanced and dose-dependent. This potentiation did not appear in adrenalectomized rats. Captopril, an angiotensin-converting enzyme (ACE) inhibitor, largely increased the effects of bradykinin. In animals pretreated with propranolol, captopril and atosiban, an oxytocin antagonist, intravenous infusion of glucose induced hyperglycaemia and after a delay increased the uterine contractile activity. This contractile effect of glucose was abolished by HOE 140. Infusion of insulin with glucose induced contractions of the uterus. These responses did not appear or were suppressed by HOE 140 or by soya bean trypsin inhibitor (SBTI), a plasma kallikrein inhibitor. These results are direct evidence that insulin induces a release of kinins.

Design, synthesis, and pharmacological evaluation of pyridinic analogues of nimesulide as cyclooxygenase-2 selective inhibitors.

In this study, we report the synthesis and pharmacological evaluation of original pyridinic sulfonamides related to nimesulide, a cyclooxygenase-2 (COX-2) preferential inhibitor widely used as an anti-inflammatory agent. These original pyridinic derivatives were synthesized in three steps starting from the condensation of 3-bromo-4-nitropyridine N-oxide with appropriately substituted phenols, thiophenols, or anilines followed by a reduction of the nitro moiety into the corresponding aminopyridine, which was finally condensed with alkane- or trifluoromethanesulfonyl chloride to obtain the corresponding sulfonamides. The pK(a) determinations demonstrated that the major ionic form present in solution at physiological pH depends on the nature of the sulfonamide moiety subsituent. Indeed, alkanesulfonamides were mainly present as zwitterionic molecules while trifluoromethanesulfonamides, more acidic derivatives, were mainly present as anionic molecules. The in vitro pharmacological evaluation of the synthesized compounds against COX-1 and COX-2 was performed in a human whole blood model. Results obtained demonstrated that most of alkanesulfonamide derivatives displayed a COX-2 preferential inhibition with selectivity ratio values (IC(50)(COX-1)/IC(50)(COX-2)) up to 7.92 (celecoxib displaying a ratio value of 7.46 in the same test). On the other hand, trifluoromethanesulfonamide derivatives displayed weaker selectivity ratios although they exhibited IC(50) values against COX-2 up to 0.09 microM (celecoxib IC(50) against COX-2: 0.35 microM). Finally, in vivo evaluation of selected compounds showed that they exhibited anti-inflammatory properties similar to that of nimesulide when tested in a carrageenan-induced rat paw oedema model.

New pyridobenzodiazepine derivatives: modifications of the basic side chain differentially modulate binding to dopamine (D(4.2), D(2L)) and serotonin (5-HT(2A)) receptors.

A series of new pyridobenzodiazepines with variation of the basic side chain were synthesized and evaluated for their binding to D(4.2), D(2L), and 5-HT(2A) receptors in comparison with clozapine, haloperidol, and two parent compounds previously described, 8-chloro-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (8) and 8-methyl-6-(4-methyl-1-piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (9). In the piperazine series, replacing the N-methyl group by a N-phenyl moiety (15-17, 30-32) provided a dramatic decrease of affinity for all receptors (K(i) > 1000 nM). A N-cyclohexyl group (20, 35) restored some affinity. Compounds with a N-benzyl (18, 33) or N-phenethyl side chain (19, 34) had significant affinities at D(4.2) and 5-HT(2A) receptors. Homologation of the piperazine nucleus (29, 44) led to a significant decrease of the affinity at all receptors investigated. In the 4-aminopiperidine series, N-methyl derivatives (21, 36) possessed less affinity in comparison with the N-methylpiperazine analogues (8, 9) while the N-benzyl congeners (22, 37) showed similar affinities. The rigidification of piperidine nucleus as obtained in azabicyclo[3.2.1]octane derivatives (23, 38) involved a slight reduction of the affinity at D(4.2) and 5-HT(2A) receptors while the affinity at D(2L) receptors was dramatically increased. The introduction of N-substituted aminoalkylamines to replace N-methylpiperazine generally led to a significant decrease in the affinity for D(4.2) receptors but some of these molecules (24, 25, 41) presented a significant 5-HT(2A) binding affinity. The presence of a more flexible side chain induced an increased conformational freedom. Consequently, the preferential position of the distal nitrogen or its basicity in piperazine derivatives was greatly modified. 19 with a high D(4.2) and 5-HT(2A) affinity (K(i) = 40 and 103 nM, respectively) did not induce cataleptic phenomenon in the paw test in rats but significantly reduced the immobility time in Porsolt's test in mice suggesting antidepressant properties.

Spectral and crystallographic study of pyridinic analogues of nimesulide: determination of the active form of methanesulfonamides as COX-2 selective inhibitors.

Compound 7, N-(3-phenoxy-4-pyridinyl)trifluoromethanesulfonamide, showed in vitro (whole blood assay) a strong inhibitory activity on the two cyclooxygenase (COX) enzymes (IC(50)(COX-1) = 2.2 microM and IC(50)(COX-2) = 0.4 microM), being more active but less COX-2-selective than nimesulide. Physicochemical studies and structural analyses indicated that the anionic sulfonamidate species seemed to be the active form of methanesulfonamides, which optimally interacted with the COX enzymes' active sites.

Biocompatibility of thermosensitive chitosan-based hydrogels: an in vivo experimental approach to injectable biomaterials.

Chitosan, an amino-polysaccharide obtained from the alkaline deacetylation of chitin, presents an interest as a drug vehicle. Indeed, chitosan solutions containing glycerol-2-phosphate (beta-GP) undergo sol-gel transition at a temperature close to 37 degrees C, which make them suitable for the parenteral administration of drugs. However, before using these chitosan derivatives for biomedical applications, it is important to evaluate their biocompatibility, and particularly to test their inflammatory effects. When injected in the hindpaw of the rat, we have shown that: (i) four chitosan/beta-GP solutions tested triggered a non-specific response, with solutions prepared with chitosans of higher deacetylation degrees yielding a lesser inflammatory reaction and (ii) systemic pretreatment of animals with icatibant, apafant and diphenhydramine did not significantly diminish this response; dexamethasone practically abolished it for all solutions and ketanserine only slightly decreased it in one preparation at two different times. In conclusion, it appears that a higher degree of deacetylation of the chitin chain is desirable for superior biocompatibility.

Minimal effects of JL 13, a pyridobenzoxazepine derivative with an antipsychotic potential, on circulating prolactin levels in male rats.

Antipsychotic therapy is frequently associated with several side effects such as hyperprolactinemia. The influence of a putative antipsychotic JL 13 on prolactin release was assessed after intraperitoneal injection in gentled male rats in comparison with clozapine and haloperidol. A total of 30 or 150 min after administration, whole blood was collected for preparing serum samples. Prolactin was quantified by radioimmunoassay method. At 30 min, JL 13 like clozapine, increased prolactin concentration only at the higher dose (30 mg/kg) while haloperidol at both tested doses induced a dramatic increase of prolactin concentration. At 150 min after injection, only haloperidol (0.3 mg/kg) significantly increased serum prolactin level. This minimal effect on prolactinemia reinforces the similarity of clozapine and JL 13 regarding the atypical antipsychotic profile.

Effects of prodelphinidins isolated from Ribes nigrum on chondrocyte metabolism and COX activity.

Articular diseases, such as osteoarthritis, is the clinical expression of the loss of cartilage function. COX inhibitors are widely used in the treatment of such pathologies for their beneficial effects on inflammation but often produce a negative activity on cartilage synthesis. In this study, we determined the effect of different prodelphinidins, the major compounds isolated from Ribes nigrum leaves, on the proteoglycans (PGs), type II collagen (coll. II) and prostaglandin E(2) (PGE(2)) production by differentiated human chondrocytes cultivated in long term (12 days) and in clusters as well as their inhibition potential on COX-1 and COX-2 in vitro. Gallocatechin trimer (GC-GC-GC) showed the higher stimulation of PGs and coll. II production (1 microg ml(-1)) and the synthesis of PGE(2) was significantly reduced by gallocatechin dimer (GC-GC), gallocatechin-epigallocatechin (GC-EGC) and GC-GC-GC at 10 and 100 microg ml(-1). The inhibition of PGE(2) synthesis was confirmed by the in vitro test on purified COX enzymes, showing the selectivity of prodelphinidins on COX-2. However, the prodelphinidins had no effects on COX activity in the whole blood assay. Our studies suggest that the prodelphinidins fractions from R. nigrum may be useful as an additive agent in the prevention of osteoarthritis.

Inhibitory effects of proanthocyanidins from Ribes nigrum leaves on carrageenin acute inflammatory reactions induced in rats.

BACKGROUND: The anti-inflammatory effects of proanthocyanidins (PACs), isolated from blackcurrant (Ribes nigrum L.) leaves, were analysed using carrageenin-induced paw oedema and carrageenin-induced pleurisy in rats. RESULTS: Pretreatment of the animals with PACs (10, 30, 60 and 100 mg/kg, i.p.) reduced paw oedema induced by carrageenin in a dose and time-dependent manner. PACs also inhibited dose-dependently carrageenin-induced pleurisy in rats. They reduced (A) lung injury, (B) pleural exudate formation, (C) polymorphonuclear cell infiltration, (D) pleural exudate levels of TNF-alpha, IL-1beta and CINC-1 but did not affect IL-6 and IL-10 levels. They reduced (E) pleural exudate levels of nitrite/nitrate (NOx). In indomethacin treated rats, the volume of pleural exudate was low, its content in leukocytes and its contents in TNF-alpha, IL-1beta, IL-6 and IL-10 but not in NOx were reduced. These data suggest that the anti-inflammatory properties of PACs are achieved through a different pattern from those of indomethacin. CONCLUSION: These results suggest that the main mechanism of the anti-inflammatory effect of PACs mainly lies in an interference with the migration of the leukocytes. Moreover, PACs inhibited in vivo nitric oxide release.