An L-type calcium channel agonist, bay K8644, extends the window of intervention against ischemic neuronal injury.

Our previous data indicate that the inhibition of L-type calcium channels (LTCCs) might be the cause of post-ischemic neuronal injury and that the activation of LTCCs can give rise to neuroprotection. In the present study, we aimed to profile the intervention window of Bay K8644, an LTCC agonist, and determine the involved mechanisms. The four vessel occlusion and oxygen-glucose deprivation models were employed to mimic ischemia/reperfusion damage in vivo and in vitro. Neuronal injury was analyzed using Nissl and Fluoro-Jade B staining in vivo and Hoechst 33342 and propidium iodide staining in vitro. The behavioral effects were tested using the Morris water maze. The phosphorylation of P38, Jun N-terminal kinase, and extracellular-regulated kinase (ERK) was detected by Western blotting. Our results show that Bay K8644 administered as late as 24 h after reperfusion prevented CA1 neuronal death and ameliorated the deficiencies in spatial learning performance induced by global ischemia. In oxygen-glucose deprivation (OGD), Bay K8644 delivered from 1 to 12 h after re-oxygenation reduced neuronal death. The decrease in p-ERK1/2 that was observed at 1 h after OGD was reversed by Bay K8644, and the effect of Bay K8644 was blocked by treatment with U0126 and MEK kinase dead transfection. Moreover, similar to Bay K8644, FPL 64176, another potent LTCC agonist, extends the window of intervention against neuronal injury in an in vitro model of ischemia. In conclusion, our data suggest that opening LTCCs may be a practicable approach for stroke therapy.

Hospital admissions for drug-induced liver injury: clinical features, therapy, and outcomes.

We investigated clinical features, therapy, and outcomes of patients hospitalized for drug-induced liver injury (DILI). DILI resolution was defined as liver biochemistry values back to normal or lower than CIOMS laboratory criteria; Chronicity was defined as persistent biochemical abnormality for >6 months after drugs' withdrawal. Three-hundred cases were reviewed retrospectively; mean age 51 (13-86) years, and 204 (68 %) were females. It included 267 (89 %) hepatocellular injury, 16 (5.3 %) cholestatic injury, and 17 (5.7 %) mixed injury cases. In hepatocellular injury group, 197 (73.8 %) patients with TBIL < 10× ULN included 142 (72.1 %) females and 70 (26.2 %) patients with TBIL ≥ 10× ULN included 39 (55.7 %) females (P = 0.012). Of 70 patients (TBIL ≥ 10× ULN), 20 were treated with steroid step-down therapy (79 ± 26 days) and others with non-steroid therapy. The steroid therapy group showed higher DILI resolution rate (P = 0.029) and shorter recovery time (P = 0.012). Notably, 274/300 (91.3 %) patients resolved, 18/300 (6 %) developed chronic liver injury, 7/300 (2.3 %) died, and one patient received liver transplantation. In death group, TBIL, ALB, PT, and PTA revealed more severe abnormality than in recovery group. In 121/300 (40.3 %) patients, use of herbal medicines was the leading cause of liver injury, followed by antibiotics, cardiovascular drugs, and endocrine drugs. We concluded that step-down steroid therapy for DILI improved curative effect, shortened disease course, and was safe.