Apremilast: A Novel Drug for Treatment of Psoriasis and Psoriatic Arthritis.

OBJECTIVE: To review the pharmacology, efficacy, and safety of apremilast and determine its role relative to other agents in the treatment of psoriasis and psoriatic arthritis. DATA SOURCES: A PubMed search (1946 to December 2015) using the terms apremilast and CC-10004 was conducted to identify relevant articles. STUDY SELECTION AND DATA EXTRACTION: In vitro or in vivo evaluations of apremilast published in the English language were eligible for inclusion. Controlled clinical trials that involved psoriasis or psoriatic arthritis were selected for review. DATA SYNTHESIS: Four trials were identified on the treatment of psoriasis. In those that involved doses of 30 mg twice daily, a significantly greater percentage of patients receiving apremilast (28.8% to 40.9%) compared with placebo (5.3% to 5.8%) achieved at least 75% improvement from baseline in Psoriasis Area and Severity Index score at 16 weeks. Two trials were identified on the treatment of psoriatic arthritis. In the one that involved a dose of 30 mg twice daily, a significantly greater percentage of patients receiving apremilast (38.1%) compared with placebo (19.0%) achieved the American College of Rheumatology criteria for 20% improvement at 16 weeks. In all trials, the drug had an acceptable safety profile, with the most common adverse effects of diarrhea, nausea, and headache. CONCLUSIONS: Apremilast has a novel mechanism of action and is safe and effective for the management of psoriasis and psoriatic arthritis. At this time, apremilast should be reserved for patients unable to take disease-modifying antirheumatic drugs.

The role of Misshapen NCK-related kinase (MINK), a novel Ste20 family kinase, in the IRES-mediated protein translation of human enterovirus 71.

Human Enterovirus 71 (EV71) commonly causes Hand, Foot and Mouth Disease in young children, and occasional occurrences of neurological complications can be fatal. In this study, a high-throughput cell-based screening on the serine/threonine kinase siRNA library was performed to identify potential antiviral agents against EV71 replication. Among the hits, Misshapen/NIKs-related kinase (MINK) was selected for detailed analysis due to its strong inhibitory profile and novelty. In the investigation of the stage at which MINK is involved in EV71 replication, virus RNA transfection in MINK siRNA-treated cells continued to cause virus inhibition despite bypassing the normal entry pathway, suggesting its involvement at the post-entry stage. We have also shown that viral RNA and protein expression level was significantly reduced upon MINK silencing, suggesting its involvement in viral protein synthesis which feeds into viral RNA replication process. Through proteomic analysis and infection inhibition assay, we found that the activation of MINK was triggered by early replication events, instead of the binding and entry of the virus. Proteomic analysis on the activation profile of p38 Mitogen-activated Protein Kinase (MAPK) indicated that the phosphorylation of p38 MAPK was stimulated by EV71 infection upon MINK activation. Luciferase reporter assay further revealed that the translation efficiency of the EV71 internal ribosomal entry site (IRES) was reduced after blocking the MINK/p38 MAPK pathway. Further investigation on the effect of MINK silencing on heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) localisation demonstrated that cytoplasmic relocalisation of hnRNP A1 upon EV71 infection may be facilitated via the MINK/p38 MAPK pathway which then positively regulates the translation of viral RNA transcripts. These novel findings hence suggest that MINK plays a functional role in the IRES-mediated translation of EV71 viral RNA and may provide a potential target for the development of specific antiviral strategies against EV71 infection.