tetomilast and Inflammatory-Bowel-Diseases

In the last decades, the better understanding of inflammatory bowel diseases (IBD) pathogenesis has contributed to the identification of new therapeutic targets that can be modulated to induce and maintain disease remission. Monoclonal antibodies against tumor necrosis factor, interleukin (IL)-12/IL-23p40, and the integrin α4β7 and inhibitors of Janus kinase molecules are valid compounds to limit the function of molecules implicated in the control of IBD-related inflammation. However, not all patients respond to treatment with such drugs, some of them lose response over time and others develop serious side effects, such as infections or malignancies, which lead to the discontinuation of the therapy. Thus, an intensive research is ongoing with the goal to identify new targets and develop novel therapeutic options. In this context, restoration of TGF-β activity and inhibition of phosphodiesterase 4 (PD4) represent two relevant strategies. TGF-β is an immunesuppressive cytokine, whose activity is severely impaired in IBD due to the abundance of the intracellular inhibitor Smad7. Knockdown of Smad7 with a specific antisense oligonucleotide restores TGF-β signalling and dampens effector immune responses in pre-clinical studies and initial clinical trials in Crohn's disease patients, even though a recent phase 3 trial was discontinued due to an apparent inefficacy. PD4 inhibition determines the increase of intracellular levels of cyclic adenosine monophosphate, a mechanism that decreases pro-inflammatory cytokine production. A recent phase 2 study has shown that oral administration of PD4 associates with clinical benefit in patients with ulcerative colitis. In this article, we review the rationale and the available data relative to the use of these two agents in IBD.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Humans; Inflammatory Bowel Diseases; Oligonucleotides; Phosphodiesterase 4 Inhibitors; Thalidomide; Thiazoles; Transforming Growth Factor beta

cAMP-specific phosphodiesterase type 4 (PDE4) is one of the hot targets for treatment of inflammatory diseases. PDE4 inhibitors can suppress inflammation by increasing the concentration of cAMP in inflammatory cells. The efficacy and safety evaluations of several PDE4 inhibitors are currently carried on in clinical trials, for example GSK256066 in asthma, roflumilast and GSK256066 in chronic obstructive pulmonary disease, tetomilast in inflammatory bowel disease, and apremilast in dermatitis and arthritis etc. This article reviews the recent progress on PDE4-targeted therapy for inflammatory diseases.

Topics: Aminopyridines; Aminoquinolines; Arthritis; Asthma; Benzamides; Cyclopropanes; Dermatitis; Humans; Inflammation; Inflammatory Bowel Diseases; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Sulfones; Thalidomide; Thiazoles

Tetomilast is a novel thiazole phosphodiesterase-4 (PDE-4) inhibitor, which may prove useful in both the treatment of inflammatory bowel disease (IBD) and chronic obstructive pulmonary disease (COPD). Here, the authors review the pharmacology of the drug, and offer critical review of the available data for use of tetomilast in the treatment of IBD.. Peer-reviewed publications, including Phase I and II clinical trials, all other formats included.. Tetomilast may be beneficial in IBD. Small differences in molecules and in recombinant proteins can translate into substantial differences in clinical effects and toxicity in IBD. This is a reasonable approach when exploring new options like tetomilast.

Topics: Animals; Anti-Inflammatory Agents; Humans; Inflammatory Bowel Diseases; Phosphodiesterase 4 Inhibitors; Thiazoles

Topics: Azepines; Cholinergic Agents; Colitis, Ulcerative; Crohn Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Isoquinolines; Pyridazines; Tacrolimus; Thiazoles