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In vitro and ex vivo binding to uterine progestin receptors of the rat as a tool to assay progestational activity of glucocorticoids.

Luzzani F, Gallico L, Glasser A.

The competition of some widely employed glucocorticoids with the binding of [3H]-promegestone, a highly potent synthetic progestagen, to uterine cytosol progestin receptors of the immature rat has been studied both in in vitro and ex vivo experiments. The relative binding affinities (RBA's) to progesterone were determined in vitro: fluocinolone acetonide greater than triamcinolone acetonide greater than betamethasone 17-valerate greater than prednisolone, betamethasone, triamcinolone and cortisol. After pretreating rats in vivo with progesterone or chlormadinone acetate (subcutaneously), a dose-dependent decrease in in vitro binding of [3H]-promegestone to uterine cytosol was evident. Similar decreases were obtained after pretreatment with some of the other glucocorticoids tested. Potency ratios to progesterone, arbitrarily set at 1.0, were: fluocinolone acetonide 86.7, triamcinolone acetonide 5.6, betamethasone valerate 4.1, chlormadinone acetate 2.6. Prednisolone, betamethasone, triamcinolone and cortisol were inactive. Both the in vitro and the ex vivo results clearly indicate that glucocorticoids interact with the uterine cytosol progestin receptor system, depending on their chemical structures; this interaction may account for some of their unwanted side-effects in the endocrine system. Moreover, this experimental system may prove to be a useful tool for evaluation of the progestational activities of glucocorticoids and other steroids, using the rat as an animal model.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7121132&dopt=Abstract fluocinolone Synalar



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Pharmacokinetics of the fluocinolone/5-fluorouracil codrug in the gas-filled eye.

Perkins SL, Gallemore RP, Yang CH, Guo H, Ashton P, Jaffe GJ.

Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina 27710, USA.

PURPOSE: To determine the effect of intraocular gas tamponade on drug levels achieved with the intravitreal sustained-release fluocinolone (FL)/5-fluorouracil (5-FU) codrug pellet. METHODS: After insertion of a 10-mg codrug pellet into the right eyes of 43 New Zealand white rabbits, perfluoropropane (0.4 mL of 100% C3F8) or a control sham was then injected into the midvitreous cavity. On postoperative days 2, 4, 7, 21, and 42, aqueous samples were collected, the rabbits were killed, and the right eyes were enucleated. The vitreous and remaining codrug pellet were then isolated. Pellet and intravitreal drug levels were determined by high-pressure liquid chromatography. RESULTS: No measurable drug levels were detected in any of the aqueous samples. Maximal gas expansion occurred by day 4 and partial resorption was observed by days 14 to 21. Vitreous FL and 5-FU levels during C3F8 expansion (day 2) were statistically significantly higher in the gas-filled eyes. On postoperative days 4, 7, 21, and 42, there were no statistically significant differences between FL and 5-FU drug levels in eyes containing C3F8 as compared with control eyes. Pellet codrug, FL, and 5-FU levels over time were similar in gas-filled and control eyes. CONCLUSIONS: Intraocular gas tamponade does not significantly affect the sustained intravitreal drug levels achieved with the FL/5-FU codrug. If clinically efficacious, the FL/5-FU codrug formulation does not need to be altered to treat proliferative vitreoretinopathy in the presence of intraocular gas.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11039427&dopt=Abstract fluocinolone Synalar



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Tumor promoters induce the synthesis of a secreted glycoprotein in mouse skin and cultured primary mouse epidermal cells.

Gottesman MM, Yuspa SH.

The effect of tumor promoters and anti-promoters on the synthesis and secretion of a 35,000 mol wt transformation-dependent secreted glycoprotein (MEP) by primary mouse epidermal cells has been investigated. MEP is synthesized and secreted at low levels by cultured epidermal basal cells. The phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) induces a 3-fold increase in the synthesis of MEP as determined by quantitative immunoprecipitation from pulse-labeled cell extracts. This increase is maximal 6 h after treatment and parallels an increase in secretion of MEP measured by appearance of radiolabeled protein in the medium or by radioimmunoassay of culture supernatants. An increase in MEP synthesis is also observed in the skin of mice exposed to TPA. The phorbol ester antagonists retinoic acid, lidocaine and fluocinolone acetonide were examined to determine their effect on the synthesis and secretion of MEP. Of these agents, only fluocinolone acetonide affects MEP levels by suppressing the basal level of MEP synthesis but not its relative induction by TPA. These data suggest that the modifying effects of these three agents on tumor promotion are not mediated via an alteration in MEP synthesis per se is not sufficient for promotion.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7296764&dopt=Abstract fluocinolone Synalar



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Effect of anti-inflammatory agents on ricin-induced macrophage toxicity.

Naseem SM, Pace JG.

Toxinology Division, United States Army Medical Research, Fort Detrick, Frederick, MD 21702-5011.

The toxicity of ricin in susceptible cells is well characterized biochemically, but the pathophysiological implications of its toxicity and the immune response to ricin challenge in the lung are unknown. Incubating macrophage cell line with ricin (1 pM-10 nM) for 4 hours markedly inhibited 3H-leucine incorporation (acid insoluble) into protein (> 95%, at 1 nM) without affecting the acid-soluble radioactivity. In spite of increased uptake of total thymidine (141 +/- 13.5%) and total uridine (135 +/- 17.2%), DNA synthesis in ricin-treated cells was progressively inhibited although RNA synthesis was not affected. Fluocinolone (an anti-inflammatory glucocorticoid) pretreatment increased the ricin-induced inhibition of protein synthesis. The synergistic effect of fluocinolone on ricin-induced protein synthesis inhibition was due to an increased binding (167%, p < 0.01) and internalization (134 +/- 12%, p < 0.025) of ricin. Partial protection from ricin-induced inhibition of protein synthesis by indomethacin (nonsteroidal, anti-inflammatory agent) was due to decreased binding and internalization of ricin. These results show that macrophages are sensitive to ricin and that pharmacologically active drugs may regulate ricin's toxicity, perhaps by controlling synthesis and release of certain mediators of fast death.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7505334&dopt=Abstract fluocinolone Synalar



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Lack of effect of retinoic acid and fluocinolone acetonide on mirex tumor promotion indicates a novel mirex mechanism.

Kim TW, Smart RC.

Department of Toxicology, North Carolina State University, Raleigh 27695-7633, USA.

Mirex, a halogenated hydrocarbon, is a potent skin tumor promoter in 7,12-dimethylbenz[a]anthracene (DMBA)-initiated mouse skin. In the present study retinoic acid (RA) and fluocinolone acetonide (FA), classical inhibitors of phorbol ester- and non-phorbol ester-type skin tumor promoters, were examined for their ability to inhibit mirex tumor promotion. Female CD-1 mice were initiated with 200 nmol DMBA and promoted with equipotent promoting doses of either 5 nmol 12-O-tetradecanoylphorbol-13-acetate (TPA) or 200 nmol mirex twice weekly for 25 weeks and RA (2(1 or 5 nmol), FA (0.5 or 2 nmol) or acetone were applied 30 min prior to each TPA or mirex dose. TPA-promoted papilloma formation was strongly inhibited by > 70% with both doses of RA and by > 90% with both doses of FA. In contrast, mirex-promoted papilloma formation was not inhibited by either dose of RA or 0.5 nmol FA and 2 nmol FA weakly inhibited mirex-promoted papillomas by only 32%. TPA- and mirex-promoted papillomas that were refractory to RA and FA demonstrated the same incidence of Ha-ras mutation as TPA- or mirex-promoted papillomas without RA and FA treatment, further indicating that the inhibitory activity of RA and FA is promoter-dependent and not solely dependent on mutant Ha-ras. FA (2 nmol) treatment completely abolished TPA-induced epidermal hyperplasia and proliferating cell nuclear antigen (PCNA) S phase-positive cells, however, FA had no inhibitory effect on the weak proliferative response induced by mirex. Collectively, these results indicate that the promotional activity of mirex, as well as its weak proliferative response, result from a distinct promoter mechanism and/or that mirex promotes a unique population of epidermal cells that are insensitive to FA and RA and cannot be distinguished by their mutant Ha-ras genotype.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7554075&dopt=Abstract fluocinolone Synalar