Serotonin (5-hydroxytryptamine, 5-HT)1 is one of the best known examples of a neurotransmitter that mediates a wide variety of physiological effects, including peripheral and central actions, through the binding to multiple receptor subtypes (1). The major sites of 5-HT synthesis and storage are located in the periphery, in gut enterochromaffin cells and blood platelets, respectively. The large diversity of 5-HT functions is paralleled by the pharmacological complexity of 5-HT receptors. At least four classes of 5-HT receptors have been distinguished pharmacologically, reflecting the second messenger system to which the receptor is coupled. The family including 5-HT1 and 5-HT5 subtypes of receptors interacts negatively with adenylyl cyclase, the 5-HT2 subfamily of receptors is coupled to the activation of the phospholipase C-␤, the 5-HT3 receptor is a ligand-gated ion channel, and the family, including 5-HT4, 5-HT6, and 5-HT7 subtypes of receptors, activates adenylyl cyclase (2).5-HT2 receptors mediate many of the central and peripheral physiological functions of 5-HT. Cardiovascular effects include contraction of blood vessels and shape change in platelets; central nervous system effects include neuronal sensitization to tactile stimuli and mediation of hallucinogenic effects of lysergic acid diethylamide and related phenylisopropylamine hallucinogens. The most characterized 5-HT2 receptor subtypes are the 5-HT2A (formerly 5-HT2) and the 5-HT2C (formerly 5-HT1C) both of which stimulate phospholipase C-␤. Many investigators have observed that some peripheral 5-HT2-like effects of 5-HT are mediated by "atypical" receptors (3). In the mouse, we cloned a new member (5-HT2B) of the 5-HT2 family which is mainly expressed in the cardiovascular system, gut, and developing brain (4). This mouse 5-HT2B receptor shares the highest degree of homology with the other 5-HT2B receptors cloned from the rat fundus (5, 6) and, more recently, from human libraries (7-9) (for review, see Ref. 10) and from Drosophila (11).5-HT, detected early in embryonic development (12), participates in craniofacial (13) and cardiovascular morphogenesis (14, 15) by unknown molecular mechanisms. We have investigated the growth factor properties mediated by the 5-HT2B receptor since (i) both Drosophila 5-HT2 and mouse 5-HT2B receptors are expressed during embryogenesis (11, 16), (ii) the mitogenic activity of 5-HT has been linked mainly to 5-HT2 receptor-dependent stimulation of phospholipase C-␤/protein kinase C; when expressed at high density in NIH3T3 fibroblasts, both 5-HT2C and 5-HT2A have mitogenic effects induced by 5- HT (17,18). In mammalian cells, the ability to activate the mitogen-activated protein (MAP) kinase cascade is a feature common to many extracellular stimuli, including growth factors, hormones, and neurotransmitters, leading to transcription factor phosphorylation and to cell division (19). The signaling pathways that activate the MAP kinase cascade use receptor tyrosine kinase or non-receptor tyrosine kinases. Other stimuli act...

Roflumilast is a new phosphodiesterase 4 (PDE4) inhibitor developed by Byk Gulden Pharmaceuticals for the treatment of chronic obstructive pulmonary disease and asthma. A placebo-controlled, randomized, double-blind, two-period crossover study was performed to investigate the safety and efficacy of roflumilast in 16 patients with exercise-induced asthma. The patients received placebo or roflumilast (500 microg/day) for 28 days, each according to the randomly determined treatment sequences roflumilast/placebo and placebo/roflumilast. In both study periods, exercise challenge was performed 1 hour after dosing on days 1, 14, and 28. FEV1 was measured before exercise challenge, immediately after the end of exercise challenge, and then at 1, 3, 5, 7, 9, and 12 minutes after the end of challenge. Blood samples for the determination of lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) in whole blood ex vivo as a surrogate marker for the inhibition of inflammatory cell activation were taken predose on days 1 and 28. Serial safety measurements were performed during both study periods. Analysis of variance for the crossover design showed a significant superiority of roflumilast over placebo on day 28. The mean percentage fall of FEV1 after exercise was reduced by 41% as compared to placebo (p = 0.021). An improvement of lung function during roflumilast treatment was also observed on days 1 and 14. The median TNF-alpha level decreased by 21% (p = 0.009) during roflumilast treatment but remained essentially constant under placebo. It is concluded that roflumilast is effective in the treatment of exercise-induced asthma. This result was accompanied by a significant reduction of TNF-alpha levels ex vivo. Treatment with roflumilast was safe and well tolerated.

The human serotonin 5-HT2B receptor, isolated from a human liver cDNA library, was transfected in COS-I cells. Its pharmacological profile shows divergence with serotonin 5-HT2B receptors of other species. In particular, although strong correlation is observed between the human and the rat 5-HT2B receptor pharmacology, the correlation is almost as significant for the mouse 5-HT2B and the human 5-HT1D receptor agonists. The major sites of expression of its mRNA are in the human liver and kidney, with detectable expression in lung and heart. Therefore, this human 5-HT2B receptor could account for functions attributed to the peripheral 5-HTI D/5-HT2-1ike receptors, especially in the cardiovascular system. Thus, its detailed original pharmacology is of prime importance for therapeutic drug development.

The pharmacokinetics of linezolid are altered in patients with major thermal injuries, mainly as a result of increased non-renal clearance. These changes are of sufficient magnitude that linezolid concentrations may be sub-therapeutic in some patients and we suggest that the dosage interval may need to be decreased in this patient population.

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Résumé -La constitution de collections d'échantillons biologiques humains à des fins scientifiques constitue un enjeu majeur en France et en Europe. Dans ce contexte, ces dernières années ont été marquées par la volonté de mettre en place un meilleur encadrement réglementaire. La complexité de celui-ci nécessite cependant quelques éclaircissements. En effet, il convient de préciser la définition de ce qui relève des collections ou des activités de collection biologique, de simplifier les procédures réglementaires de déclaration auprès des Comités de Protection des Personnes (CPP) et du Ministère de l'Enseignement Supérieur et de la Recherche, de discuter de la mise en place d'une méthodologie de référence CNIL (Commission Nationale Informatique et Libertés) dédiée aux modalités particulières de traitement des données associées aux collections biologiques. Il apparait d'autre part indispensable de préciser les modalités d'habilitation et de pérennisation des Centres de Ressources Biologiques, structures dédiées aux activités de collection biologique. Il convient aussi de clarifier le rôle des CPP, notamment dans l'appréciation des modalités d'information et de consentement des sujets au cours de situations particulières comme les collections sur mineurs, les collections avec examen des caractéristiques génétiques ou encore les modalités d'utilisation de collections anciennes. Enfin, en dehors des aspects scientifiques et de santé publique, les collections biologiques d'échantillons humains sont l'objet d'enjeux économiques importants. Dans ce contexte, il est nécessaire d'adapter les procédures permettant par exemple le dépôt de brevets, notamment lorsque plusieurs partenaires publics et/ou privés sont associés. Les prochaines échéances législatives avec la modification du Code de Santé Publique au travers de la loi Jardé et de la révision de la loi de bioéthique permettront peut être de faire valoir ces nécessaires évolutions.Les collections d'échantillons biologiques issus du corps humain constituent un enjeu fondamental, notamment comme support de nombreuses recherches et in fine de progrès diagnostiques et thérapeutiques. Ces dernières années ont été marquées par la volonté d'un meilleur encadrement réglementaire des activités relatives au prélèvement, à la conservation et à l'utilisation des échantillons biologiques issus du corps humain, mais la complexité de la législation française actuelle mérite quelques clarifiPour la liste des participants, voir en fin d'article.cations voire certaines modifications. À l'occasion de cette table ronde, nous nous sommes ainsi penchés sur plusieurs points relatifs aux collections avec le souci d'une vision pragmatique et la volonté de proposer des aménagements à la fois concrets et consensuels. Nos discussions et propositions ont principalement concerné la définition des activités de collection et les processus de déclaration ou d'autorisation qui y sont attachés, le problème de la mise en place de structures pérennes de conservation (Centres de Ressources Biologiques -C...

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