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Glucocorticoid inhibition of zymosan-induced arachidonic acid release by rat alveolar macrophages.

Peters-Golden M, Bathon J, Flores R, Hirata F, Newcombe DS.

The phospholipase-dependent liberation of arachidonic acid (AA) from membrane phospholipids has been proposed as the rate-limiting step in the synthesis of bioactive AA metabolites, which play an important role in the expression of inflammatory and immune reactions. We have examined the effects of steroids in vitro on the release of AA by rat alveolar macrophages exposed to zymosan. Fluocinolone (1 microM) significantly inhibited the zymosan-induced release of radiolabeled AA from phosphatidylcholine as well as the production of radiolabeled prostaglandin E2. (PGE2). Dose-response curves gave the following rank order of potency: fluocinolone greater than dexamethasone greater than hydrocortisone. The maximal degree of inhibition of radiolabeled AA release observed was approximately 70%. Inhibition was not observed after 3 h of glucocorticoid pretreatment, but maximal inhibition was achieved after 10 h of pretreatment. Pretreatment with gonadal sex hormones (1 microM) did not inhibit AA release. Concurrent incubation of macrophages with hydrocortisone and excess concentrations of the partial glucocorticoid agonist, progesterone, blunted the degree of inhibition observed with hydrocortisone alone. These data are consistent with a receptor-mediated process. The time course suggests a response dependent on new protein synthesis, and the increased concentration of the phospholipase-inhibitory protein, lipomodulin, in steroid-treated cultures is putative evidence of new protein synthesis.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6437305&dopt=Abstract fluocinolone Synalar



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Glucocorticoids inhibit the coordinated translation of alpha- and beta-globin mRNAs in Friend erythroleukemia cells.

Papaconstantinou J, Stewart JA, Rabek JP, McClintock PR, Wong EY.

The dimethylsulfoxide (Me2SO)-mediated induction of hemoglobin synthesis in Friend erythroleukemia cells is inhibited by the glucocorticoids hydrocortisone, dexamethasone, and fluocinolone acetonide; hydrocortisone, at concentrations of 10(-5) to 10(-8) M inhibits by 90-30% and fluocinolone acetonide at concentrations of 10(-8) to 10(-11) M shows a greater than 90% inhibition. At these concentrations the hormones have no effect on cell growth or viability. In this study it has been shown that there is a group of proteins, including the alpha- and beta-globins, whose regulation is associated with the induction of Friend erythroleukemia cell differentiation, and that the expression of some of these, in addition to alpha- and beta-globin, is affected by glucocorticoids. The levels of alpha- and beta-globin mRNAs are very close to fully induced levels and preclude transcription as a major site for glucocorticoid control. In addition, it has been shown that glucocorticoids inhibit the translation of alpha- and beta-globin mRNAs, that the level of this inhibition is concentration dependent, and that the translation of beta-globin mRNA is slightly more sensitive to inhibition than the translation of alpha-globin mRNA. It is concluded that, although the translation of alpha- and beta-globin mRNA is a major site of inhibition by glucocorticoids, there is a detectable amount of alpha- and beta-globin synthesized. Thus, part of this mechanism may involve a differential sensitivity of alpha- and beta-globin mRNA translation which results in unequal amounts of globin synthesis and an overall more potent inhibition of hemoglobin formation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6582803&dopt=Abstract fluocinolone Synalar



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The effect of fluocinolone acetonide and 12-O-tetradecanoyl-phorbol-13-acetate on the binding and biological activity of epidermal growth factor in rat fibroblasts.

Lockyer JM, Bowden GT, Magun BE.

Synthetic glucocorticoids such as fluocinolone acetonide (FA) have been shown to be potent inhibitors of phorbol ester-mediated tumor promotion. When Rat-1 cells were incubated with FA the cells showed an increased capacity to bind [125I]-epidermal growth factor (EGF) to surface receptors. A partial reversal of the ability of the phorbol ester tumor promoter 12-O-tetradecanoyl-phorbol-13-acetate to reduce EGF binding to the class of high affinity receptors occurred following pre-exposure of cells to FA. The increased binding of EGF induced by FA resulted in a faster rate of degradation of EGF from the culture medium and reversed the inhibition of degradation caused by TPA. When EGF was present at low concentrations (less than or equal to 1 ng/ml), at which level FA was effective in increasing EGF degradation, FA-treated cells displayed a decreased induction of ornithine decarboxylase (ODC) activity and DNA synthesis. At higher EGF concentrations, the same level of ODC activity and DNA synthesis occurred in the presence or absence of FA, although some differences in the rates of induction were noted. These results support the hypothesis that the hyperplasia-inhibiting ability of glucocorticoid antipromoters may act by modulating EGF levels in the extracellular environment. However, our data also indicate that these antipromoters may act through other cellular mechanisms as well.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6602667&dopt=Abstract fluocinolone Synalar



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Inhibition of wound healing by topical steroids.

Marks JG Jr, Cano C, Leitzel K, Lipton A.

A new animal model was used to study the effect of topical agents on wound healing. A weak- (hydrocortisone cream 1%) and medium-strength (fluocinolone acetonide ointment 0.025%) steroid and their vehicles were applied to full-thickness skin wounds placed on the backs of female Syrian hamsters. Wound healing was significantly retarded by both steroids when compared to their vehicles. Fluocinolone had a greater inhibitory effect than hydrocortisone.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=6619384&dopt=Abstract fluocinolone Synalar



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Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery device.

Jaffe GJ, Yang CH, Guo H, Denny JP, Lima C, Ashton P.

Department of Ophthalmology, Duke University, Durham, North Carolina. Control Delivery Systems, Watertown, Massachusetts, USA. jaffe001 mc.duke.edu

PURPOSE: To determine the safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained drug delivery device. METHODS: Nonbiodegradable drug delivery devices containing 2 or 15 mg of a synthetic corticosteroid, fluocinolone acetonide, were constructed. The long-term in vitro release rates of these devices were determined in protein-free buffer or buffer containing 50% plasma protein. Fifteen-milligram devices were also implanted into the vitreous cavities of rabbit eyes. Intravitreal drug levels, the amount of drug remaining in explanted devices, and the release rate of explanted devices were determined over a 1-year time period. Drug toxicity was assessed over this same time period by slit lamp examination, indirect ophthalmoscopy, electroretinography, and histologic examination. RESULTS: The drug release rates for the 2-mg device, 1.9 +/- 0.25 microg/d, and for the 15-mg device, 2.2 +/- 0.6 microg/d, remained linear over the 6-month and 45-day testing period, respectively. The release rate increased by approximately 20% when devices were transferred from protein-free buffer to buffer that contained protein (P: < 0.0001). Vitreous levels remained fairly constant (0.10-0.21 microg/ml) over a 1-year period. No drug was present in the aqueous humor during this time period. Based on the device release rates, the predicted life span of the 2- and 15-mg devices are 2.7 and 18.6 years, respectively. There was no evidence of drug toxicity by clinical examination, electroretinography, or histologic examination. CONCLUSIONS: It is feasible to construct a nontoxic fluocinolone acetonide drug delivery device that reproducibly releases fluocinolone acetonide in a linear manner over an extended period. These devices show great promise in the treatment of ocular diseases such as uveitis, which are often managed with chronic corticosteroid therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11006254&dopt=Abstract fluocinolone Synalar