Incidence of Cereblon in Intensive Care Patients

Classical immunomodulatory drugs (IMiDs) like thalidomide and its second- and third-generation analogues lenalidomide, pomalidomide, avadomide (CC-122), and iberdomide (CC-220) have constantly emerged to new therapeutic areas. Originally developed as a sedative and banned in 1961 for its teratogenic effects when used during pregnancy, thalidomide and a number of newly developed analogues are approved for the treatment of multiple myeloma (MM),4 erythema nodosum5 and myelodysplastic syndrome (MDS) Thalidomide was used as a treatment for morning sickness from 1957 until 1961 but was withdrawn from the market after it was discovered that it caused birth defects. Because of their pleiotropic and especially anti-angiogenic properties, IMiDs have further been reported effective in many off-label indications as for Hodgkin's lymphoma, light chain-associated (AL) amyloidosis, and acute myeloid leukemia (AML). The drug thalidomide binds to cereblon and changes which substrates can be degraded by it, which leads to an antiproliferative effect on myeloma cells and possibly the teratogenic effect on fetal development. The idea that cereblon modulation is responsible for the teratogenic activity of thalidomide in the chick and zebrafish was cast into doubt due to a 2013 report that pomalidomide (a more potent thalidomide analog) does not cause teratogenic effects in these same model systems even though it binds with cereblon more strongly than thalidomide. Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex. Several key findings suggest diverse roles of CRBN, including its regulation of the large-conductance calcium- and voltage-activated potassium (BKCa) channels, regulation of thalidomide-binding proteins, and mediation of lenalidomide treatment in multiple myeloma. Recent studies also indicate that CRBN is involved in energy metabolism and negatively regulates AMP-activated protein kinase signaling. Recent studies also indicate that CRBN is involved i