Thalidomide

Pomalidomide is an IMiD(®) immunomodulatory agent, which has shown clinically significant benefits in relapsed and/or refractory multiple myeloma (rrMM) patients when combined with dexamethasone, regardless of refractory status to lenalidomide or bortezomib. (Schey et al, ; San Miguel et al, 2013; Richardson et al, 2014; Scott, ) In this work, we present preclinical data showing that the combination of pomalidomide with dexamethasone (PomDex) demonstrates potent anti-proliferative and pro-apoptotic activity in both lenalidomide-sensitive and lenalidomide-resistant MM cell lines. PomDex also synergistically inhibited tumour growth compared with single-agent treatment in xenografts of lenalidomide-resistant H929 R10-1 cells. Typical hallmarks of IMiD compound activity, including IKZF3 (Aiolos) degradation, and the downregulation of interferon regulatory factor (IRF) 4 and MYC, seen in lenalidomide-sensitive H929 MM cell lines, were also observed in PomDex-treated lenalidomide-resistan...

a ; Felix Contreras, MD b ; M. Casado, MD">. OphSource, Home Journal Collection OphSource Shop Events. Journal Home, ... Francisco A. Rubio, MD, Pedro Herranz, MD, Goretti Robayna, MD, Jose M. Peña, MDa, Felix Contreras, MDb, M. Casado, MD.

Given the generally poor outcome of advanced B cell chronic lymphocytic leukemia, experimental approaches are warranted, especially for younger patients in whom classical treatments have failed. We therefore conducted a prospective single-center study, using polychemotherapy (ESHAP) to prepare patients for hematopoietic stem cell collection and autologous stem cell transplantation as consolidation therapy. Twenty patients entered the study. An adequate response

In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C 2 H 2 zinc finger transcription factors, including SALL4, a member of the spalt-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in SALL4 result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.

Malaria remains a major cause of morbidity and mortality in vast areas of the world, mainly due to the severe forms of Plasmodium falciparum infection. The exacerbated immune response, with increased production of TNF and reactive nitrogen and oxygen intermediates, plays a role in the complex pathogenesis of the disease. It is recognised that thalidomide decreases TNF production and may modulate several functions of the immune system. This work evaluated the influence of thalidomide on macrophage functions, and its ability to protect against severe disease. Plasmodium berghei ANKA-infected mice were (n = 11) or were not (n = 10) intra-gastric treated with thalidomide (150 mg/kg per day), and two other control groups not infected with the parasite were (n = 8) or were not (n = 10) treated with the drug, and macrophage production of hydrogen peroxide and nitric oxide, and phagocytosis were assessed on the eighth day post-infection. Thalidomide increased the survival time of infected mice, in parallel with a 26.5% increase of the mean of macrophage phagocytic index, and augmented in 13% the mean of the production of hydrogen peroxide and in 45% the mean of nitric oxide production by macrophages related to the non-treated P. berghei-infected mice. Our data indicate that thalidomide improves the outcome of P. berghei ANKA-infected CBA mice and suggest that this drug could represent a new alternative to be associated to antimalarial drugs to decrease the morbidity and mortality of severe malaria in non-pregnant individuals.

Psoriasis is a chronic inflammatory skin disease characterized by dysregulation of the immune system and release of pro-inflammatory mediators. Drugs available for psoriasis show some limits as tolerability and route of administration. Apremilast , Otezla®, is an oral small molecule recently approved for the treatment of patients with moderate-to-severe plaque psoriasis. Compared to biologics that target a single cytokine, apremilast, degrading phosphodiesterase 4 (PDE4), interferes with cyclic anti-microbial peptides, which is involved in the transduction of intracellular signals, controlling the balance of pro-inflammatory and anti-inflammatory signals. This review reported the latest data available from Phase I, II and III trials on apremilast for the treatment of plaque psoriasis. A focus on the clinical management of apremilast, safety and clinical efficacy based on two pivotal clinical trials (ESTEEM 1 and ESTEEM 2) currently ongoing was described. A systematic search was cond...