Abstract
The anti-inflammatory effects of the new ster-oidal antedrug, 21-acetyloxy-9α-fluoro-11β-hy-droxyl-3, 20-dioxo-1, 4-pregnadieno-[16α, 17α-d] isoxazoline (FP-ISO-21AC), on nitric oxide (NO) and interleukin 8 (IL-8) production, were inves-tigated together with its parent steroid predni-solone (PRED). PRED is one of the anti-in-flammatory steroids but has systemic side ef-fects which limit the use of it. PRED was modi-fied with ‘antedrug concept’ to create safer drugs that attack problems such as inflamma-tion, then quickly become inactive before they can cause systemic side effect. We had a test about the effect of the modified anti-inflamma-tory steroidal antedrug on anti-inflammatory activity. The present study evaluated their ability to inhibit cytokine-induced NO and IL-8 produc-tion in human alveolar epithelial cells. We also investigated their ability to enhance the expres-sion of inhibitory cytokine receptor, interleukin 22 receptor (IL-22R) in human alveolar epithelial cells. Our results showed that FP-ISO-21AC sh- owed higher ability to inhibit the cytokine - in-duced production of NO than PRED. Exogenous IL-22 was added to the media of both human alveolar epithelial cells (A549) and human lung fibroblast (HLF-1). In the presence of the ex-ogenous inhibitory cytokine IL-22, further re-duction of NO production was observed in A549 cells, which express IL-22R, but not in HLF1, which does not express IL-22R. These data suggested that the steroidal antedrugs en-hanced the expression of IL-22R. FP-ISO- 21AC showed higher potency than PRED to restore the expression of IL-22R. FP-ISO-21AC further reduced NO production to 27% and PRED further reduced NO production to 39%. In con-clusion, a synthesized steroidal antedrug FP- ISO-21AC showed higher anti-inflammatory ef-fects than PRED by inhibiting the expression of pro-inflammatory mediator NO and stimulating the expression of IL-22R.
Highlights
Glucocorticoid is one of the most commonly and effectively used drugs to relieve inflammation [1,2,3,4]
The present study addresses the following fundamental questions: 1) Does structural modification of anti-inflammatory steroidal antedrugs increase the therapeutic index of potent corticosteroids with reducing their systemic side effects? 2) Do these anti-inflammatory steroidal antedrugs enhance or restore the expression of anti-inflammatory proteins? the effect of FP-ISO-21AC, an active synthetic derivative of antiinflammatory steroidal antedrug, was evaluated on reduced production of pro-inflammatory mediators (IL-8 and nitric oxide (NO))
There was no significant difference between FP-ISO-21AC and PRED on inhibitory effect on cytokine-induced interleukin 8 (IL-8) expression, but the FP-ISO-21AC showed higher inhibitory effect on cytokine-induced NO production (Figure 2) and enhanced interleukin 22 receptor (IL-22R) expression (Figure 4A) with less systemic side effects
Summary
Glucocorticoid is one of the most commonly and effectively used drugs to relieve inflammation [1,2,3,4] These drugs display a number of serious systemic side effects such as suppression on pituitary-adrenal axis and on the immune system, aggravation of diabetes, hypertension, retardation of growth in children and osteoporosis. These systemic side effects limit the clinical use of corticosteroids [5,6,7,8,9]. As Lee et al described in previous papers, antedrug is defined as a compound which acts locally on the target tissue and it is rapidly metabolized to an inactive metabolite through enzymatic reaction upon entry into the systemic circulation [10,11,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
