Synthèse par SRN et évaluation de l'activité amoebicide de nouveaux dérivés quinoléiniques

Des dérivés quinoléiniques porteurs de chaînes carbonées, soufrées ou phosphorées, ainsi que des furoquinoléines sont obtenus à partir du Clioquinol (Vioforme) par des réactions de substitution nucléophile radicalaires en chaîne (S_RN¹) inédites dans cette famille d'hétérocycles. Une évaluation de leur activité in vitro est effectuée sur des cultures d'Entamoeba histolytica et de Trichomonas vaginalis.     

Quelques dérivés de l'amino-11 vinburnine à propriétés protectrices cérébrales

Quelques dérivés de l'amino-11 vinburnine (amides, aminoamides, urée, carbamates) sont préparés. Leurs propriétés protectrices contre l'œdème cérébral provoqué chez le rat par le triéthylétain sont évaluées.     

Étude de la cytotoxicitéin vitro de dérivés du carbazole III. 3-Amino et 3-nitro-1,4-diméthyl-9H-carbazoles diversement substitués en position 6

La synthèse d'une série de 3-nitro et 3-amino-1,4-diméthyl-9H-carbazoles diversement substitués en positions 6 et 8 est décrite. Leur activité cytotoxique, évaluée in vitro au moyen de la culture clonogénique de la leucémie L1210, dépend fortement de la nature et de la position des substituants. Le plus cytotoxique d'entre eux, le dérivé 3-amino 6-hydroxy, présente une cytotoxicité comparable à celle de l'acétate de N2-méthyl-9-hydroxy ellipticinium (NMHE). Ces résultats et ceux présentés dans les deux publications précédentes, permettent une discussion détaillée des relations structure-activité dans la série du 9H-carbazole et du 1,4-diméthyl 9H-carbazole et suggèrent, pour les dérivés du 3-amino 1,4-diméthyl 9H-carbazole, un mécanisme d'action proche de celui des dérivés de l'ellipticine.     

Synthèse et étude préliminaire de l'activité psychotrope d'alkylamino et iminopyrrolo[1,2-a]indoles

La synthèse de nouveaux pyrrolo[1,2-a]indoles est décrite. Le test d'habituation révèle in vivo pour certains dérivés une activité psychostimulante non amphétaminique.     

Les espèces réactives de l’azote : bénéfiques ou délétères ?Reactive nitrogen species: deleterious or not?

NO^• exerts many effect on the organism, either beneficial or detrimental. Beneficial ones are mainly mediated by NO^• itself (through activation of guanylyl cyclase—the cGMP-dependent pathway—or through S-nitrosylation) in a specific microenvironment, generated at low concentrations by endothelial or neuronal NO-synthases in a regulated manner. By contrast, prolonged and high-ouput inducible NOS-derived NO^• may exert both oxidative and nitrosative stress, respectively through peroxynitrite-mediated oxidation, nitration and oxidative nitrosylation and through dinitrogen trioxide-mediated nitrosation. Integration of all determinants of the net effect of NO^• is complex and is the topic of intensive research for potential adapted, selective and titrated treatment.     

Place et impact des régimes chez les personnes très âgées

Successful ageing promotion is a major goal of care in geriatrician patients, even in old age. Cardiovascular prevention strategy, diabetes care or kidney protection involve dietary management. However, mortality and morbidity risk factors are modified in the oldest old, and on the other hand, dietary restrictions could impair health status of the older. Studies devoted to the oldest old are scarce. In most situations, exercise training promotion seems to better address the prevention goals than do diets.     

Aspects médicaux, éthiques et déontologiques de la grève de la faim en milieu carcéral

Background: A hunger strike is a common form of protest in prison and is a potential cause of many types of problems, both for facility administrators and health care staff. Issues of conflict of rights and obligations involved, and how to treat people who are subject, have created major controversies. Objectives: To identify and review published studies that discuss the medical, ethical and legal considerations of managing a hunger strike in a prison setting from a physician''s perspective. Methods: A database search using "Medline" "Ovid" and "Science Direct was conducted to identify relevant publications. We included case series, guidelines and, review articles. Results: The physician must clearly inform the striker of the risks and provide clinical assessment and regular monitoring of the concerned. The role of the psychiatrist is to detect an initial mental pathology underlying or secondary to fasting and assess the capacity of the striker''s judgment. Thus, the clinician is faced with two paradoxical obligations: to assist and respect the striker''s will. In addition, medical intervention is possible if the prognosis is life-threatening even without the patient''s consent. Conclusion: The current practice of non-consensual attitude among hunger-striking seeking in detention needs a closer inquiry. Medical practitioners should be aware of their ethical and legal responsibilities, and that they should act independently of government or institutional interests.     

Synthesis and structure-activity relationships of N-6 substituted analogues of 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of Wee1 and Chk1 checkpoint kinases

A series of N-6 substituted 9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were prepared from N-substituted (5-methoxyphenyl)ethenylindoles. The target compounds were tested for their ability to inhibit the G2/M cell cycle checkpoint kinases, Wee1 and Chk1. Analogues with neutral or cationic N-6 side chains were potent dual inhibitors. Acidic side chains provided potent (average IC(50) 0.057 microM) and selective (average ratio 223-fold) Wee1 inhibition. Co-crystal structures of inhibitors bound to Wee1 show that the pyrrolo[3,4-c]carbazole scaffold binds in the ATP-binding site, with N-6 substituents involved in H-bonding to conserved water molecules. HT-29 cells treated with doxorubicin and then target compounds demonstrate an active Cdc2/cyclin B complex, inhibition of the doxorubicin-induced phosphorylation of tyrosine 15 of Cdc2 and abrogation of the G2 checkpoint.