Potency assessment of topical corticoids in the vasoconstrictor assay and on tuberculin-induced inflammation.
The topical anti-inflammatory activity of potent and very potent corticoids was studied in normal and inflamed skin using the vasoconstriction assay and tuberculin-induced inflammation in four double-blind intraindividual comparison trials. Instrumental techniques in addition to visual scores and several time points were applied to get better insight into the reliability of the models and the sensitivity of the different variables. Beta-methasone-17-valerate and two concentrations of prednicarbate were used as potent corticoids, clobetasol-17-propionate, betamethasone-17,21-dipropionate and different biopharmaceutical forms of desoximetasone (DOM) as very potent corticoids. Visual scores, the reactive skin hyperemia after arterial occlusion and skin colorimetry were used to quantify vasoconstriction; erythema scores, surface area of infiltration and changes in skin colorimetry, skin blood flow and skin temperature for the tuberculin reaction. The time courses of blanching (n = 20) and of the tuberculin reaction (n = 10) were described by orthogonal polynomials and the coefficients were statistically analyzed by nonparametric tests, the discriminative variables in tuberculin inflammation in addition by the parametric multiple analysis of variance. Important differences in the release rates of corticoids demand several assessment times and not just one as often used. The potency ranking may otherwise be misleading. In general, ointments released corticoids slowlier than the cream which in turn liberated slowlier than the gels. The DOM gel declined rapidly after an apparent peak at 5.5 h in terms of its blanching effect, but was nevertheless comparable after once-daily application to other very potent corticoids in its activity against delayed-type inflammation. Such differences may explain discrepancies found for some corticoid preparations between their blanching response and clinical efficacy. The more potent a corticoid the more the erythema is reduced, the less pronounced the cell infiltration and the more delayed the peak seems from 24 to 48 h in the tuberculin reaction. The inflammatory response is diminished in the following manner: very potent greater than potent corticoids; erythema greater than infiltration. Visual scores were the most reliable parameters in normal and inflamed skin and they correlated well with skin colorimetry which shows greater variability. Reactive hyperemia after arterial occlusion gave poor results in terms of ranking in the vasoconstriction assay as did resting skin blood flow in inflamed skin. Changes in the temperature of inflamed skin are sensitive enough to discriminate the active drugs from the controls, but have a somewhat different time course, reflecting perhaps a higher impact of the amount of mediator release in the early phase relative to the cell invasion in the later phase.
Schalla
W
W
Cutaneous Studies International (CSI), Freiburg, FRG.
Schorning
S
S
D000287:Administration, Topical; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003116:Color; D004311:Double-Blind Method; D005938:Glucocorticoids; D006801:Humans; D006940:Hyperemia / Q000139:chemically induced; D014677:Pharmaceutical Vehicles; D012039:Regional Blood Flow / Q000187:drug effects; D012867:Skin / Q000098:blood supply; D012881:Skin Temperature / Q000187:drug effects; D014374:Tuberculin Test / Q000592:standards; D014661:Vasoconstriction / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D005938:Glucocorticoids; D014677:Pharmaceutical Vehicles