Discovery of a Novel Inhaled PI3Kδ Inhibitor for the Treatment of Respiratory Diseases.

Oral PI3Kδ inhibitors such as Idelalisib and Duvelisib have shown efficacy as anticancer agents and Idelalisib has been approved for the treatment of three B-cell cancers. However, Idelalisib has a black box warning on its product label regarding the risks of fatal and serious toxicities including hepatic toxicity, severe diarrhea, colitis, pneumonitis, infections, and intestinal perforation. Some of these side effects are mechanism-related and could hinder the development of Idelalisib for less severe conditions.

Discovery of a Potent, Selective, and Orally Available PI3Kδ Inhibitor for the Treatment of Inflammatory Diseases.

The delta isoform of the phosphatidylinositol 3-kinase (PI3Kδ) has been shown to have an essential role in specific immune cell functions and thus represents a potential therapeutic target for autoimmune and inflammatory diseases. Herein, the optimization of a series of pyrrolotriazinones as potent and selective PI3Kδ inhibitors is described. The main challenge of the optimization process was to identify an orally available compound with a good pharmacokinetic profile in preclinical species that predicted a suitable dosing regimen in humans.

[Epidemiological profile and sensitivity pattern of isolates causing invasive fungal infection vs. colonizing isolates in non-neutropenic critically ill patients].

Background: Patients admitted to critical care units can be infected with a large number of fungal isolates that are occasionally responsible for invasive fungal infections (IFI).

Aims: To describe the epidemiological profile and antifungal susceptibility patterns of fungal isolates in our unit, and to identify key risk factors associated with the development of IFI.

Methods: A descriptive cohort and retrospective study with patients admitted to a polyvalent Critical Care Unit of a university hospital was carried out.

[Prognosis value of thrombin activatable fibrinolysis inhibitor concentration and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis].

Objective: To analyze the prognostic value of thrombin activatable fibrinolysis inhibitor (TAFI) and C1040T polymorphism in acute myocardial infarction treated with fibrinolysis. To analyze C1040T polymorphism influence on its plasma level.

Design: An observational, prospective study performed from November 2003 to November 2005 and with a 3 month follow-up.