anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.
ABSTRACT The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.
SourceAvailable from: Andrei I Khlebnikov[Show abstract] [Hide abstract]
ABSTRACT: c-Jun N-terminal kinases (JNKs) participate in many physiological and pathological processes, including inflammatory diseases. Recently, we synthesized the sodium salt of 11H[1,2-b]quinoxalin-11-one oxime ( IQ-1S: ) and demonstrated that it is a high-affinity JNK inhibitor and inhibited murine delayed-type hypersensitivity. Here we show that IQ-1S: is highly specific for JNK and that its neutral form is the most abundant species at physiological pH. Molecular docking of the IQ-1S: syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of co-crystallized JNK inhibitor SP600125. Evaluation of the therapeutic potential of IQ-1S: showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin (IL)-1β in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S: either prior to or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S: -treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared to those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S: treatment. In contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one ( IQ-18: ) had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S: treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S: increased the number of Foxp3(+)CD4(+)CD25(+) regulatory T cells in lymph nodes. Thus, the IQ-1S: can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis. The American Society for Pharmacology and Experimental Therapeutics.Journal of Pharmacology and Experimental Therapeutics 03/2015; DOI:10.1124/jpet.114.220251 · 3.86 Impact Factor
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ABSTRACT: Carrot (Daucus carota L.) is of importance in the molecular farming field as it constitutes the first plant species approved to produce biopharmaceuticals for human use. In this review, features that make carrot an advantageous species in the molecular farming field are analyzed and a description of the developments achieved with this crop thus far is presented. A guide for genetic transformation procedures is also included. The state of the art comprises ten vaccine prototypes against Measles virus, Hepatitis B virus, Human immunodeficiency virus, Yersinia pestis, Chlamydia trachomatis, Mycobacterium tuberculosis, enterotoxigenic Escherichia coli, Corynebacterium diphtheria/Clostridium tetani/Bordetella pertussis, and Helicobacter pylori; as well as the case of the glucocerebrosidase, an enzyme used for replacement therapy, and other therapeutics. Perspectives for these developments are envisioned and innovations are proposed such as the use of transplastomic technologies-, hairy roots-, and viral expression-based systems to improve yields and develop new products derived from this advantageous plant species.Molecular Biotechnology 01/2015; 57(3). DOI:10.1007/s12033-014-9837-y · 2.28 Impact Factor