A Novel Selective PKR Inhibitor Restores Cognitive Deficits and Neurodegeneration in Alzheimer Disease Experimental Models.

In Alzheimer disease (AD), the double-strand RNA-dependent kinase protein kinase R (PKR )/EIF2AK2 is activated in brain with increased phosphorylation of its substrate eukaryotic initiation factor 2 (eIF2). AD risk-promoting factors, such as ApoE4 allele or the accumulation of neurotoxic amyloid- oligomers (AOs), have been associated with activation of PKR-dependent signaling. Here, we report the discovery of a novel potent and selective PKR inhibitor (SAR439883) and demonstrate its neuroprotective pharmacological activity in AD experimental models.

A phase I open-label study investigating the disposition of [14C]-cabazitaxel in patients with advanced solid tumors.

Cabazitaxel is a semisynthetic taxane approved for the treatment of patients with hormone-refractory metastatic prostate cancer (now known as metastatic castration-resistant prostate cancer) treated previously with a docetaxel-containing treatment regimen. The human plasma pharmacokinetics of cabazitaxel have been described previously, but detailed analyses of the metabolism and excretion pathways of cabazitaxel have not yet been published. Metabolite profiling, quantification, and identification as well as excretion analyses were carried out on samples from patients with advanced solid tumors who received an intravenous infusion of 25 mg/m [C]-cabazitaxel (50 μCi, 1.