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Abstract: The treatment of psoriasis has evolved over the years, with the recent focus largely on the use of biologics and anti-interleukin-17 agents. With treatment options expanding, practitioners and patients may find control of psoriasis more convenient and safer to achieve. In this article, we review the literature on emerging medications for...
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... Treatment modalities evaluated and approved for the same are methotrexate, cyclosporine, acitretin, infliximab, itolizumab, erlotinib, Narrow band-Ultraviolet B (NB-UVB) phototherapy and PUVA (Psoralen plus Ultraviolet A) phototherapy etc. either alone or in combination. [5] Methotrexate is an economical and effective antipsoriatic agent. It exerts an anti-mitotic action on psoriatic skin by competitively inhibiting dihydrofolate reductase and hence DNA synthesis. ...
... Some studies have been conducted to look for histological and immunohistochemical changes after giving treatment either in the form of phototherapy or drugs like acitretin, PUVA, [19] calcipotriol, [20] infliximab, [21] anthralin or aloe vera [21] but very few have been done using methotrexate [ Table 4]. [5] In the present study, histomorphology and expression of p53 and Bcl2 before and after methotrexate therapy in psoriatic patients was studied. All the histomorphological parameters were reduced significantly (p<0.05) after methotrexate therapy. ...
Background: Psoriasis is a chronic, relapsing, inflammatory, and hyperproliferative skin disease. The growth of keratinocytes is regulated by a delicate balance between molecules controlling cell survival (such as Bcl2) and cell death (such as p53). The study was conducted to observe the clinical and histopathological effect of Methotrexate on psoriatic lesions. Materials & Methods: The immunohistochemical expression of pro-apoptotic (p53) and anti-apoptotic (Bcl2) proteins was correlated with histomorphological changes (epidermal thickness, munro microabscess, granular layer, lymphocytic infiltrate, blood vessels) in the psoriatic skin. Results: A total of 35 cases of psoriasis were studied. Male predominance was seen and trunk was the initial site of involvement in 40% cases. There was a significant reduction in PASI (Psoriasis Area Severity Index) score, grade 3 cases of psoriasis and mean expression of p53 in all the histomorphological parameters in the subsequent 2 and 6 weeks of methotrexate therapy. The expression of p53 in all parameters and Bcl2 in the lymphocytes is significantly higher (p <0.05) in psoriatic skin as compared to the normal skin (control group). Conclusion: Low dose of methotrexate (0.3-0.5 mg/kg) contribute to reduction in epidermal thickness and thereby remain an effective therapy for psoriasis.
Keywords: Hyperproliferative; Apoptosis; Biopsy; Post treatment
... 1,2 Early treatment with effective agents that target the pathophysiologic pathways of psoriasis and have improved safety profiles is needed for long-term treatment of patients with chronic plaque psoriasis. 3 Apremilast, an oral small-molecule phosphodiesterase 4 (PDE4) inhibitor, works intracellularly to regulate inflammatory mediators, including pathways relevant to the pathogenesis of psoriasis. 4,5 PDE4 inhibition elevates cyclic adenosine monophosphate levels, which downregulates inflammatory responses and upregulates production of anti-inflammatory cytokines. ...
Background:
Apremilast, an oral, small-molecule phosphodiesterase 4 inhibitor, has demonstrated efficacy in patients with moderate-to-severe psoriasis.
Objective:
Evaluate efficacy and safety of apremilast vs. placebo in biologic-naive patients with moderate-to-severe plaque psoriasis and safety of switching from etanercept to apremilast in a phase IIIb, randomized, double-blind, placebo-controlled study (NCT01690299).
Methods:
Two hundred and fifty patients were randomized to placebo (n = 84), apremilast 30 mg BID (n = 83) or etanercept 50 mg QW (n = 83) through Week 16; thereafter, all patients continued or switched to apremilast through Week 104. The primary efficacy endpoint was achievement of PASI-75 at Week 16 with apremilast vs. placebo. Secondary endpoints included achievement of PASI-75 at Week 16 with etanercept vs. placebo and improvements in other clinical endpoints vs. placebo at Week 16. Outcomes were assessed through Week 52. This study was not designed for apremilast vs. etanercept comparisons.
Results:
At Week 16, PASI-75 achievement was greater with apremilast (39.8%) vs. placebo (11.9%; P < 0.0001); 48.2% of patients achieved PASI-75 with etanercept (P < 0.0001 vs. placebo). PASI-75 response was maintained in 47.3% (apremilast/apremilast), 49.4% (etanercept/apremilast) and 47.9% (placebo/apremilast) of patients at Week 52. Most common adverse events (≥5%) with apremilast, including nausea, diarrhoea, upper respiratory tract infection, nasopharyngitis, tension headache and headache, were mild or moderate in severity; diarrhoea and nausea generally resolved in the first month. No new safety or tolerability issues were observed through Week 52 with apremilast.
Conclusion:
Apremilast demonstrated significant efficacy vs. placebo at Week 16 in biologic-naive patients with psoriasis, which was sustained over 52 weeks, and demonstrated safety consistent with the known safety profile of apremilast. Switching from etanercept to apremilast did not result in any new or clinically significant safety findings, and efficacy was maintained with apremilast through Week 52.
Psoriasis is characterized as chronic inflammatory disorder of skin having unregulated hyperproliferation and shedding of plaques. As per first line treatment methotrexate is the most widely used cytotoxic drug for psoriasis. It shows anti-proliferative effect with hDHFR while anti-inflammatory and immunosuppressive action is due to AICART. Serious hepatotoxic effects are recognized with long-term treatment of methotrexate. In this study, in silico technique is used in this work to find Dual-Acting Methotrexate-like molecules with increased efficacy and decreased toxicity. Structure-based virtual screening assisted by a fragment-based method against a library of chemicals that are similar to methotrexate revealing 36 and 27 potential inhibitors of hDHFR and AICART respectively. Further, based on dock score, binding energy, molecular interactions, and ADME/T analysis compound 135565151 was chosen for dynamic stability evaluation. Overall, these findings provided information on possible methotrexate analogues for the treatment of psoriasis that had lower hepatotoxicity.Communicated by Ramaswamy H. Sarma.
Preclinical Research Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term management due to its chronic nature. Available treatment options include topical, systemic or biological therapies, which have long-term limitations associated to toxicity, tolerability and risk for adverse effects requiring its intermittent use and close monitoring. Small molecules modulate proinflammatory cytokines, selectively inhibit signaling pathways and showing potential to treat inflammatory diseases in patients not responding to conventional treatments. Presently, small molecules available are phosphodiesterase 4 inhibitors or Janus kinase inhibitors. Other small molecules under development for psoriasis include fumaric acid esters, amygdalin analogs, protein kinase C inhibitors, mitogen-activated protein kinase inhibitors, spleen protein kinase inhibitors, other tyrosine kinase inhibitors, sphingosine 1-phosphate receptor agonists, and A3 adenosine receptor agonists. These new treatment options represent important advances in the development of specific drugs to respond to the goals of treatment and improve patient quality of life. Drug Dev Res, 2015. © 2015 Wiley Periodicals, Inc.
© 2015 Wiley Periodicals, Inc.
