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FundaÃÃo de Amparo à Pesquisa do Estado do Cearà / Amburana cearensis is a medicinal plant from Northeast Brazil popularly known as âcumaruâ. Its stem bark has an odor characteristic of the presence of coumarin, being used in alternative medicine for the treatment of bronchitis and asthma. The present study investigated the toxicity, as well as the anti-inflammatory, antioxidant and smooth muscle relaxant activities of isokaempferide (IKPF, 3-metylflavonol) and amburoside A (AMB, phenolic glucoside), bioactive constituents of the plant. The intraperitoneal administration (ip) of IKPF or AMB, in single doses (50-200 mg/kg), showed low toxicity in mice. In primary hepatocyte cultures, only IKPF (100 ug/ml) reduced significantly the cellular viability, as assessed by the MTT test. ICPF and AMB (12.5- 50 mg/kg, ip) presented anti-inflammatory activities, observed initially by inhibitions of the carrageenan (Cg), prostraglandin E2 (PGE2), dextran (Dx), histamine or serotonin-induced paw edemas. Besides, IKPF and AMB (12.5 â 50 mg/kg) produced 39 and 50% reductions, respectively, of neutrophil migration as assessed by histopathological/morphometric analyses of the Cg-induced paw edema. The increase of vascular permeability induced by Dx in mice was also significantly inhibited by IKPF or AMB. Mice pretreatments (oral or ip) with IKPF or AMB (25 and 50 mg/kg) reduced peritoneal Cg or fMLP-induced leucocytes and neutrophil migrations. Also, IKPF and AMB partially prevented fMlP-induced neutrophil degranulation in human blood, as determined by the decrease in 66 and 52% of activities of the enzymes myeloperoxidase and elastase, respectively. The two compounds were not cytotoxic for neutrophil, as assessed by the MTT test. AMB showed hepatoprotective and antioxidant actions in the model of CCl4-induced liver toxicity in rats, as determined by the liver enzymes activity (AST and ALT), catalase, lipoperoxidation (TBARS assay), reduced glutathione, and histological analysis. In the isolated guinea pig trachea, IKPF (10-1000 Âg/ml) and AMB (10- 3000 Âg/ml) produced a concentration-dependent relaxation of the muscle precontracted by carbacol or KCl. The epithelium removal improved IKPF-induced relaxation, but did not alter the AMB effect. IKPF-induced relaxation was inhibited in 41% by L-NAME; 31 and 50% by ODQ (3 and 33 uM); 31% by propranolol and 37% by capsaicin. In the trachea pre-contracted by KCl (40 mM), the pre-incubation with glibenclamide or iberiotoxin, inhibited the IKPF-induced relaxation by 39% and 38%, respectively. On the other hand, 4-aminopyridine did not significantly influence the effect of IKPF. However, in the muscle pre-contracted with 120mM KCl the relaxant effect of IKPF was significantly reduced and not affected by glibenclamide. In conclusion, results showed that IKPF and AMB present anti-inflammatory, muscular relaxant and/or antioxidant activities, justifying the traditional use of Amburana cearensis in the treatment of respiratory tract diseases that present inflammation, oxidative stress, and bronchoconstriction as pathophysiological characteristics. / Amburana cearensis (Fabaceae) à uma Ãrvore da caatinga nordestina, mais conhecida popularmente como cumaru. Suas cascas (caule) possuem um cheiro caracterÃstico pela presenÃa de cumarina, e sÃo principalmente utilizadas no tratamento da bronquite, tosse e asma. O presente estudo procurou investigar os efeitos tÃxicos e as atividades antiinflamatÃria, antioxidante e relaxante muscular do isocampferÃdio (ICPF, 3-metilflavonol) e/ou do amburosÃdio A (AMB, glucosÃdio fenÃlico) isolados das cascas do caule de A. cearensis. A administraÃÃo intraperitoneal (i.p.) do ICPF ou do AMB em dose Ãnica (50 â 200 mg/kg) mostrou baixa toxicidade em camundongos. Na cultura primÃria de hepatÃcitos apenas o ICPF (100 Âg/ml) reduziu significativamente a viabilidade celular, determinada pelo teste do MTT. O ICPF e o AMB (12,5 â 50 mg/kg, i.p.) apresentaram atividade antiinflamatÃria, observada inicialmente pela inibiÃÃo do edema de pata induzido por carragenina-Cg, prostaglandina E2, dextrano-Dx, histamina ou serotonina e pela reduÃÃo em 39 e 50% respectivamente do infiltrado de neutrÃfilos verificada pela anÃlise histopatolÃgica/morfomÃtrica do edema induzido por Cg. O aumento da permeabilidade vascular induzido pelo Dx em camundongos, foi tambÃm significativamente inibido pelo ICPF ou AMB. O prÃ-tratamento (oral ou i.p.) dos animais com ICPF ou AMB (25 e 50mg/kg) causaram reduÃÃes tanto na migraÃÃo de leucÃcitos quanto neutrÃfilos induzida por Cg ou fMLP no peritÃnio de camundongos. O ICPF e o AMB preveniram parcialmente a degranulaÃÃo de neutrÃfilos humano induzida pelo fMLP, determinada pela reduÃÃo das atividades das enzimas mieloperoxidase e elastase em atà 66 e 52% respectivamente. Os compostos fenÃlicos em estudo nÃo foram citotÃxicos para neutrÃfilos (teste do MTT). O AMB mostrou uma aÃÃo hepatoprotetora/antioxidante no modelo de hepatotoxicidade induzida pelo CCl4 em ratos, determinada pelas enzimas hepÃticas (ALT e AST) e pela catalase, alÃm de TBARS, glutationa reduzida e anÃlise histopatolÃgica. Na traquÃia isolada de cobaia o ICPF (10 â 1000 ÂM) e o AMB (10 â 3000 ÂM) relaxaram de maneira concentraÃÃo-dependente o mÃsculo prÃ-contraÃdo pelo CCh ou KCl. A remoÃÃo do epitÃlio traqueal favoreceu o efeito relaxante do ICPF, mas nÃo modificou o efeito do AMB. O relaxamento induzido pelo ICPF foi inibido em 41% pelo L-NAME; 31 e 50% pelo ODQ (3 e 33 ÂM); 31 % pelo propranolol e 37 % pela capsaicina. Na traquÃia prÃ-contraida pelo KCl (40 mM) a glibenclamida (GLB) ou iberiotoxina reduziram o efeito relaxante do ICPF, enquanto no mÃsculo prÃ-contraÃdo pelo KCL 120mM o efeito do ICPF foi reduzido e nÃo foi afetado pela GLB. Portanto, os resultados apresentados mostram que o ICPF e o AMB possuem atividades antiinflamatÃria, relaxante muscular e antioxidante, o que justifica pelo menos em parte o uso tradicional de A. cearensis no tratamento de doenÃas respiratÃrias onde as caracterÃsticas fisiopatolÃgicas incluem inflamaÃÃo, estresse oxidativo e broncoconstriÃÃo.

Abstract The introduction of physiologically and therapeutically effective drugs in anaesthetic treatment has meant a significant change. Their discovery has thus contributed to a minimisation of their negative effects on a living organism. As a result, anaesthesiology has become more controllable and safer. These new drugs translate into more comfort for the patient in the course of anaesthesiology as well as his or her rapid recovery resulting in a shorter period of hospitalisation. The research of new physiologically and therapeutically effective substances is a pre-requisition of a potential higher standard of medical care. Older substances, e.g. Alkuronium and Gallamin, which, due to their undesirable effects, have come out of use, have lost their significance. Nowadays, these substances have been generally replaced by substances with an intermedial effect, e.g. Rokuronium and Cisatrakurium, which, compared with Alkuronium and Gallamin, show a minimum of undesirable effects. One of the foremost objectives of the current pharmaceutical research is to find a replacement of Sukcinylcholin, which, in spite of its known side effects, has had a non-substitutable position in urgent intubation. As a result, its use is limited to out-patient application and a certain selection of patient categories. Let us hope that we shall see a replacement of Sukcinylcholin being introduced in treatment in the near future. This would mean a final solution of problems arising from its side effects limiting its scope of application.

Les canaux potassiques sensibles à l’ATP (KATP) jouent un rôle primordial dans plusieurs processus cellulaires. La modulation de ces canaux par des molécules activatrices constituerait des applications pharmacologiques et médicinales très intéressantes. À cet effet nous avons conçu et synthétisé de nouvelles molécules hybrides cromakalim-diazoxide et diazoxide-amine/aminoacide. Nous avons également, évalué l’activité myorelaxante de ces composés sur l’aorte de rates. Les résultats obtenus ne montrent pas un effet myorelaxant significatif. Des études sur d’autres tissus, notamment les cellules β pancréatiques et le muscle utérin, sont envisagées afin d’explorer une éventuelle sélectivité tissulaire. Par ailleurs, les interactions protéine-protéine jouent un rôle fondamental dans presque tous les processus cellulaires. Elles sont fortement impliquées dans la formation de la structure dimérique de la protéase du VIH-1 et l’agrégation du peptide β amyloïde impliquée dans la maladie d’Alzheimer. L’inhibition de ces interactions serait donc d’un avantage thérapeutique pour le traitement du SIDA et de la maladie d’Alzheimer. Nous avons conçu et synthétisé d’une part, des pinces moléculaires à base de motifs carbonylhydrazides et oligohydrazides (Azatide), et d’autre part, des molécules pentapeptidiques avec un peudoaminoacide central alcoolfluoré. Enfin, nous avons testé la capacité des pinces moléculaires à perturber le feuillet β terminal de la PR du VIH-1 afin d'inhiber sa dimérisation et donc son activité. Nous avons réalisé de même une étude de relation structure-activité et d’après l’ensemble des résultats obtenus, il semblerait que la flexibilité est délétère pour l’activité inhibitrice. Nous avons également évalué la capacité des nouvelles molécules peptidomimétiques alcool fluorées à accélérer ou inhiber l’agrégation du peptide Aβ1-42 dans le but de diminuer la présence de petits oligomères neurotoxiques. Les résultats obtenus sont très prometteurs, nous avons réussi à développer d’une part un pentapeptide capable d’inhiber totalement l’agrégation de Aβ1-42, et d’autre part des pseudopentapeptides capables d’accélérer son agrégation. Nous avons aussi démontré l’influence de l’atome de fluor sur la structuration d’un pentapeptide. Des études par RMN et DC sont en cours. / ATP-sensitive potassium channels (KATP) play an important role in many cellular processes. The modulation of these channels by activating molecules may constitute very interesting pharmacological and medicinal applications. For this purpose, we have designed and synthesized new hybrid molecules cromakalim-diazoxide and diazoxide-amine/aminoacid. We also evaluated the relaxant activity of these compounds on aorta of rats. The obtained results do not show a significant relaxant effect. Studies on other tissues, including pancreatic  cells and uterine muscle, are envisaged to explore the potency of these compounds and their possible tissue selectivity.Otherwise, Protein-protein interactions play a fundamental role in almost all cellular processes. They are strongly involved in the formation of the dimeric structure of HIV-1 protease and β amyloid peptide aggregation involved in Alzheimer's disease. Inhibition of these interactions would be a therapeutic advantage for the treatment of AIDS and Alzheimer's disease. We designed and synthesized on one hand, molecular tongs based on carbonylhydrazide oligohydrazid (Azatide) fragments and in the other hand, pentapeptide molecules with a central fluorinated and hydroxylated aminoacid. Finally, we tested the ability of molecular tongs to disrupt the terminal β sheet of the HIV-1 PR to inhibit its dimerization and thus its activity. We have also conducted a structure-activity relationship study and According to the results it seems that flexibility is detrimental to the inhibitory activity. We evaluated as well the ability of new fluorinated and hydroxylated peptidomimetics to accelerate or inhibit the aggregation of Aβ1-42 peptide in order to reduce the presence of small toxic oligomers. The results are very promising that we succeeded in developing a pentapeptide able to completely inhibit the aggregation of Aβ1-42, and in the other hand pseudopentapeptides able to accelerate its aggregation. We also demonstrated the influence of fluorine on the structure of a pentapeptides. Studies by NMR and DC are in progress.