[The clinical pharmacist, an essential element in the new gradation of care for ambulatory patients]. / Le pharmacien clinicien, un maillon indispensable dans la nouvelle gradation de prise en charge des patients ambulatoires.

OBJECTIVE: Pharmaceutical presence in oncology allows the clinical pharmacist to integrate tripartite consultations for primary prescription of oral anticancer drugs. The aim of the study is to describe the deployment of the clinical pharmacy activity in 2 oncology departments since its implementation in 2019, to assess the financial gain of the pharmaceutical interventions through the new gradation of outpatient management published on September 10, 2020, and finally to assess their satisfaction following the deployment of this pathway. METHOD: A retrospective study was conducted to collect pricing data for oral therapy interviews in patients between January 2019 and December 2022. To complement this, a satisfaction survey was conducted by the oral therapy pharmaceutical team between 01/01/2022 and 12/31/2022 among patients undergoing treatment. RESULTS: 579 patients received a targeted pharmaceutical interview as part of the oral therapy patient pathway. The average invoiced amount of a pharmaceutical consultation carried out as part of a tripartite first prescription was 355.44 euros. The 579 patients who benefited from a targeted pharmaceutical interview generated a revenue of 87,545 euros for the hospital. In terms of evaluating patient satisfaction, 163 usable responses were received out of 267 patients questioned, representing a response rate of 61%, with an overall score of 9.1/10. CONCLUSION: Pending the introduction of a specific remuneration for clinical pharmacy activities, the valuation of tripartite consultations is a lever for financing clinical pharmacy activities in hospitals.

Understanding medicinal taste and odour formation in drinking waters.

The formation of bromophenols during chlorination of phenol- and bromide-containing waters can be critical for taste and odour problems in drinking waters. The work performed has confirmed that flavour threshold concentrations of some bromophenols are in the ng/L range. In addition, under typical drinking water conditions, kinetic experiments and model simulations performed have shown that (1) bromination is the predominant reaction pathway, (2) bromophenol reaction kinetics are rapid leading to taste-and-odour episodes that last for short periods of 10-20 min, (3) increasing phenol concentration and pH tends to increase taste and odour intensity, (4) increasing chlorine or bromide concentrations tends to shorten the duration of the taste-and-odour episode.

A differential role of the platelet ADP receptors P2Y1 and P2Y12 in Rac activation.

The dynamics of the actin cytoskeleton, largely controlled by the Rho family of small GTPases (Rho, Rac and Cdc42), is critical for the regulation of platelet responses such as shape change, adhesion, spreading and aggregation. Here, we investigated the role of adenosine diphosphate (ADP), a major co-activator of platelets, on the activation of Rac. ADP rapidly activated Rac in a dose-dependent manner and independently of GPIIb/IIIa and phosphoinositide 3-kinase. ADP alone, used as a primary agonist, activated Rac and its effector PAK via its P2Y1 receptor, through a G(q)-dependent pathway and independently of P2Y12. The P2Y12 receptor appeared unable to activate the GTPase per se as also observed for the adenosine triphosphate receptor P2X1. Conversely, secreted ADP strongly potentiated Rac activation induced by FcgammaRIIa clustering or TRAP via its P2Y12 receptor, the target of antithrombotic thienopyridines. Stimulation of the alpha(2A)-adrenergic receptor/G(z) pathway by epinephrine was able to replace the P2Y12/G(i)-mediated pathway to amplify Rac activation by FcgammaRIIa or by the thrombin receptor PAR-1. This co-activation appeared necessary to reach a full stimulation of Rac as well as PAK activation and actin polymerization and was blocked by a G-protein betagamma subunits scavenger peptide.

Gi-dependent and -independent mechanisms downstream of the P2Y12 ADP-receptor.

The P2Y12 ADP receptor is one of the major regulators of platelet activation and the target of antithrombotic thienopyridines (ticlopidine and clopidogrel). It has been recently cloned but the signaling pathways triggered by this receptor are still poorly documented. Here, we show that stimulation of the human P2Y12 receptor stably expressed in Chinese hamster ovary cells activates two major intracellular signaling mechanisms leading either to cell proliferation or to actin cytoskeleton reorganization. Both effects were blocked by the active metabolite of clopidogrel, a specific antagonist of P2Y12. The P2Y12-mediated stimulation of proliferation required the pertussis toxin-sensitive activation of PI3-kinase/Akt upstream of MAP-kinases. A partial contribution of a transactivation mechanism, through the tyrosine kinase receptor platelet-derived growth factor (PDGF)-R-beta, was also observed. Conversely, the P2Y12-mediated reorganization of the actin cytoskeleton was Gi-independent, requiring activation of RhoA and Rho-kinase. Our results provide new insights into the molecular basis of P2Y12-mediated intracellular signaling. These data may prove to be useful for a better understanding of the physiological role of P2Y12, particularly in platelets and glial cells which express this important therapeutic target.

Characterisation of Rac activation in thrombin- and collagen-stimulated human blood platelets.

In this study, we characterised the mechanisms of Rac GTPase activation in human platelets stimulated by two physiological agonists, either thrombin, acting through membrane receptors coupled to heterotrimeric G-proteins, or collagen which is known to mobilise a tyrosine kinase-dependent pathway. Both agonists induced a rapid activation of Rac that was not significantly affected by the inhibition of integrin alpha(IIb)beta(3) engagement. Using pharmacological inhibitors, we found that phospholipase C activation and calcium mobilisation were essential for platelet Rac activation by either thrombin or collagen whereas protein kinase C inhibition was without effect. In contrast to Rac, Cdc42 activation was independent of phospholipase C activation, indicating that the two GTPases are differently regulated. We also found that phosphoinositide 3-kinase was not required for Rac activation in response to thrombin but was involved in its activation by collagen.