Effet secondaire (médecine) | EPFL Graph Search

En médecine en général et en pharmacologie en particulier, un effet secondaire ou effet latéral est un effet survenant en plus de l'effet primaire (ou principal) désiré lors de l'application d'un traitement, pour une indication donnée. Un effet secondaire peut être désirable, indésirable, ou neutre selon les cas. Description La définition d'un effet « secondaire » d'un traitement dépend de la définition de son effet « primaire », qui est l'effet recherché. Par exemple, un médicament essayé pour faire baisser la pression artérielle, le minoxidil, s'est avéré délicat d'emploi pour cet usage, mais s'est révélé faire repousser les cheveux. On en a fait une lotion, transformant l'effet secondaire en effet primaire. Qu'un effet secondaire d'un traitement indiqué soit bénéfique, néfaste ou neutre dépend par la suite de son contexte clinique. Par exemple, l'effet antiagrégant plaquettaire de l'aspirine peut être souhaitable ou non lors de sa prescription contre une fièvre. Tou

A computationally designed chimeric antigen receptor provides a small-molecule safety switch for T-cell therapy

Jaume Bonet Martinez, George Coukos, Bruno Emanuel Ferreira De Sousa Correia, Pablo Gainza Cirauqui, Sailan Shui, Sabrina Susan Vollers

The activity of CAR-T cells is reversibly halted with a small-molecule drug. Approaches to increase the activity of chimeric antigen receptor (CAR)-T cells against solid tumors may also increase the risk of toxicity and other side effects. To improve the safety of CAR-T-cell therapy, we computationally designed a chemically disruptable heterodimer (CDH) based on the binding of two human proteins. The CDH self-assembles, can be disrupted by a small-molecule drug and has a high-affinity protein interface with minimal amino acid deviation from wild-type human proteins. We incorporated the CDH into a synthetic heterodimeric CAR, called STOP-CAR, that has an antigen-recognition chain and a CD3 zeta- and CD28-containing endodomain signaling chain. We tested STOP-CAR-T cells specific for two antigens in vitro and in vivo and found similar antitumor activity compared to second-generation (2G) CAR-T cells. Timed administration of the small-molecule drug dynamically inactivated the activity of STOP-CAR-T cells. Our work highlights the potential for structure-based design to add controllable elements to synthetic cellular therapies.

2020

Study of the stability of the 5-aminolevulinic acid tyrosine ester in aqueous solution

Sandrine Gay, Carla Martoccia, Georges Wagnières, Qian Wang, Matthieu Zellweger

Photodynamic therapy based on photoactivable porphyrins (PAPs) can treat various dermatological conditions. The side-effects as well as the non-selective or insufficient accumulation of PAPs in the targeted tissues limit performances. We studied the stability in solution at different temperatures (21 degrees C; 4 degrees C), different pH values (7.5; 2.0), and as a function of time of 5-aminolevulinic acid's Tyrosine-ester, a molecule presenting interesting properties to selectively produce PAPs in blood vessels after topical application. Solutions of this precursor can be kept up to 24 h at refrigerated temperatures and under acidic pH. At room temperature or physiological pH, they must be prepared minutes before their use.

2014

Endosomes: Guardians Against [Ru(Phen)3]2+ Photo-action In Endothelial Cells During In Vivo pO2 Detection?

Veronika Huntosova, Georges Wagnières

Phototoxicity is a side-effect of in vitro and in vivo oxygen partial pressure (pO(2)) detection by luminescence lifetime measurement methods. Dichlorotris(1,10-phenanthroline)-ruthenium(II) hydrate (Ru(Phen)(3)) is a water soluble pO(2) probe associated with low phototoxicity, which we investigated in vivo in the chick's chorioallantoic membrane (CAM) after intravenous or topical administration and in vitro in normal human coronary artery endothelial cells (HCAEC). In vivo, the level of intravenously injected Ru(Phen)(3) decreases within several minutes, whereas the maximum of its biodistribution is observed during the first 2 h after topical application. Both routes are followed by convergence to almost identical "intra/extra-vascular" levels of Ru(Phen)(3). In vitro, we observed that Ru(Phen)(3) enters cells via endocytosis and is then redistributed. None of the studied conditions induced modification of lysosomal or mitochondrial membranes without illumination. No nuclear accumulation was observed. Without illumination Ru(Phen)(3) induces changes in endoplasmic reticulum (ER)-to-Golgi transport. The phototoxic effect of Ru(Phen)(3) leads to more marked ultrastructural changes than administration of Ru(Phen)(3) only (in the dark). These could lead to disruption of Ca2+ homeostasis accompanied by mitochondrial changes or to changes in secretory pathways. In conclusion, we have demonstrated that the intravenous injection of Ru(Phen)(3) into the CAM model mostly leads to extracellular localization of Ru(Phen)(3), while its topical application induces intracellular localization. We have shown in vivo that Ru(Phen)(3) induces minimal photo-damage after illumination with light doses larger by two orders of magnitude than those used for pO(2) measurements. This low phototoxicity is due to the fact that Ru(Phen)(3) enters endothelial cells via endocytosis and is then redistributed towards peroxisomes and other endosomal and secretory vesicles before it is eliminated via exocytosis. Cellular response to Ru(Phen)(3), survival or death, depends on its intracellular concentration and oxidation-reduction properties.

Royal Soc Chemistry2014

Endosomes: Guardians Against [Ru(Phen)3]2+ Photo-action In Endothelial Cells During In Vivo pO2 Detection?

Veronika Huntosova, Georges Wagnières

Royal Soc Chemistry2014