Photoactivation of corticosteroids in UVB-exposed skin.

The photodegradation of flumethasone (FM) and fluocinolone acetonide (FC) was studied in solution and in the pig skin. Both glucocorticosteroids applied to the pig skin were unstable under UVB light. The photoproducts formed in the skin were the lumi-, photolumi- and andro-derivatives for FM, the same found in vitro. Instead, FC hydroperoxide formed in solution was not found in the skin: the reactivity and oxidative ability of this photoproduct towards biological substrates (lipids, proteins) seems the reason of the lack of its detection in the ex vivo model. In fact, it demonstrated to quickly oxidize amino acids and peptides, and to react with BSA both in the dark and under irradiation. Moreover, the presence in the irradiated pig skin of the FC andro-derivative, which usually forms in H-donating environment, seems consistent with the mechanism of Norrish I fragmentation followed by H-abstraction, likely from the surrounding biological substrates. These findings indicate that photoreactivity of these compounds may take place in the skin of patients exposing themselves to sunlight and is a warning about possible skin damage as a result of that. Furthermore, photolability of these drugs in the skin might cause loss of their therapeutic activity.

Confirmation of synthetic glucocorticoids with liquid chromatography/mass spectrometry: organization and results of an international interlaboratory comparison test.

Within the framework of a European Union (EU) research project entitled "Food Safety Screening: Synthetic Glucocorticoids (QLK1-1999-00122)," an international interlaboratory ring test was organized to compare and evaluate different liquid chromatography/mass spectrometry (LC/MS) confirmatory methods that are applied in European monitoring programs for detecting the use of synthetic glucocorticoids. Liver and urine samples of bovines treated with synthetic glucocorticoids were collected and sent to the participants of the study for analysis. Participants received 3 liver and 3 urine samples and were free to use either their own LC/MS method or an LC/MS-based method developed during the EU research project. The residue concentrations in the samples were calculated as the mean of the concentrations reported by each laboratory. The mean dexamethasone concentration of liver sample L1 was calculated as 2.27 microg/kg [relative standard deviation (RSD) 43%, n = 9], which exceeds the maximum residue level (MRL) of 2 microg/kg. Three of the 9 laboratories (33%) reported concentration levels less than 2 microg/kg, resulting in obviously false compliant results. The overall mean concentration of flumethasone in liver sample L2 was calculated as 3.27 microg/kg (RSD 33%, n = 8). Applying a comparable limit for flumethasone of 2 microg/kg, 8 of the 9 laboratories would have obtained a correct noncompliant result. As for the blank liver sample, 1 participant found a false noncompliant result. The urine sample U1 contained prednisolone residues at a mean concentration of 1.58 microg/kg (RSD 43%, n = 9). Four out of 9 results were less than a theoretical minimum required performance level (MRPL) of 2 microg/kg. The calculated concentration of dexamethasone in urine sample U3 was 5.21 microg/kg (RSD 62%, n = 9). One of the 9 results was lower than 2 microg/kg. Urine sample U2 was correctly reported as blank by all participants.

Advantages of the scanning ion microscopy for mapping halogen corticoids in normal and transformed cells in culture.

The intra-cellular distribution of eight halogen glucocorticoids was investigated by ion microscopy in two cellular varieties of cultured non-cancer cells (fibroblast 3T3) and cancer cells (human breast tumor cells MCF-7). Two types of ion microscopy helped to determine this distribution, a direct imaging ion microscope (SMI 300) with low spatial resolution, and a scanning ion microscope (IMS4F), featuring high resolution, serving to obtain maps representing the intra-cellular distribution of the fluorine elements and drugs present in these monolayer cultured cells. The fluorine images representative of the drugs containing fluorine showed that these drugs are essentially concentrated in the cell nuclei. In these nuclei, the distribution of these drugs is different from that of heterochromatin and of the nucleolus.

[Studies on percutaneous absorption of flumetasone pivalate and salicylic acid from a corticoid combination for topical use (author's transl)]. / Untersuchungen über die perkutane Resorption von Flumetasonpivalat und Salicylsäure aus einem Kortikoid-Kombinationsexternum.

The combination of 0.02% flumetasone pivalate and 1% salicylic acid in a water-alcohol solution (Locasalen) is a novel therapeutic for topical treatment of the hairy scalp and also for the cosmetically acceptable treatment of other skin areas, that is, exposed skin. An investigation was carried out in 6 patients with psoriasis capitis and 6 control subjects in order to determine whether the use of Locasalen Tincture on the hairy scalp leads to percutaneous absorption of the corticosteroid and the salicylic acid. In the patients with psoriasis a few slight transient changes in biochemical-endocrinological parameters were observed, but not in the control subjects. However, these changes remained within the normal, non-pathological range so that they are of no clinical consequence. Percutaneous absorption of salicylic acid was not observed in either patient group.

The administration of flumethasone, by three different routes, its measurement in the plasma and some effects on wool growth in Merino wethers.

Flumethasone was given to Merino wethers weighing 30-50 kg at rates of 0.62-1.35 mg/kg(0.75) by intravenous (experiments 1 and 2), intraruminal (experiment 4) and subcutaneous (experiment 5) routes over 8 days. In experiment 3, 1.2 mg flumethasone/kg(0.75) was given intravenously over 4, 5 or 6 days. The plasma concentration profiles showed concentrations in the order: intravenous greater than subcutaneous greater than intraruminal. Plasma concentration patterns usually were highest during the first 48 h of infusion followed by relatively stable values. This last feature was not evident in experiments when the rate of hormone infusion was increased. Estimates of the metabolic clearance rates for flumethasone in experiments 1, 2 and 5 were 200-700 ml/min during the equilibrium concentration periods. The effects of flumethasone on some aspects of wool growth revealed interactions between the routes of administration, the period of dosage and the rate of wool growth in the recipients. In experiments 1 and 2 intravenous infusion of 1.20-1.33 mg flumethasone/kg(0.75) caused the shedding of all wool fibres about 30 days after treatment. Some effects of dosing sheep with flumethasone at a time when wool growth was decreasing were also observed in experiment 2. Flumethasone given at a rate of 1.2 mg/kg(0.75) over 4, 5 or 6 days caused the shedding of only some wool fibres which were firmly retained on the sheep by the continuous fibres. Intraruminal and subcutaneous infusions of 0.62-1.35 mg flumethasone/kg(0.75) had similar results to the last in the majority of animals although in a few cases no discontinuity of wool fibres was observed. Recovery in wool growth was observed after treatment. Animals regained their pretreatment wool growth in experiments 1, 4 and 5 by 60 days after treatment and probably equalled at that time wool growth in controls. Recovery was retarded in some individuals in experiment 2 and in some groups in experiment 3. In experiment 1, 21 days wool growth was estimated to have been lost. Some aspects of complete versus partial shedding of wool fibres are discussed particularly with reference to wool harvesting. Some similarities in the appearance of fleeces of steroid-treated sheep and naturally shedding animals are also discussed. In some experiments, particularly when the infusion rate of flumethasone was increased (experiment 3), the sheep showed temporary but significant feed refusals during, but more commonly after, treatment. Speculative discussion as to the metabolic causes of this response is included.