A novel synthetic vitamin A-like compound (a polyprenoic acid derivative, E-5166) inhibits the release of arachidonic acid stimulated by epidermal growth factor

Little is known about the mechanisms of anti-inflammatory activity of retinoids. A new synthetic vitamin A-like compound (polyprenoic acid derivative, E-5166) has a strong in vitro binding affinity to intracellular binding proteins for acidic retinoids. In order to elucidate the anti-inflammatory activity of E-5166, we studied the effect of E-5166 on the epidermal growth factor (EGF)-stimulated arachidonic acid (AA) release of pig epidermis. E-5166 significantly inhibited the EGF-stimulated AA release and this inhibitory effect of E-5166 required a longer incubation than hydrocortisone did. Furthermore, E-5166 inhibited the EGF-stimulated phosphatidylinositol (PI) turnover of pig epidermis. These results indicate that E-5166 inhibited the EGF-stimulated AA release through the inhibition of the EGF-stimulated PI turnover.     

TOPICAL CORTIOSTKROIDS—AN EXPERIMENTAL EVALUATION OF THE VASOCONSTRICTOR TEST AS AN INDKX OF ANTI-INFLAMMATORY ACTIVITY

SUMMARY. —A tripartite investigation is reported in which the vasoconstrictor properties of triamcinolone, fluocinolone and hydrocortisone ointments were compared with their clinical effectiveness in the treatment of eczema.
Dimethylacetamide (D.M.A.) was chosen as the universal base, after its use had been shown experimentally to be associated with more vasoconstriction than other bases tested In particular, the vasoconstrictor activity of hydrocortisone in D.M.A. approached that of triamcinolone and fluocinolone.
In the clinical trial it was shown that in the concentrations used fluocinolone was slightly more effective than hydrocortisone, but many "equal results" were obtained and this has been attributed to the use of a highly efficient base.
The results of the clinical trial suggest that the vasoconstrictor test is a useful measure of anti-inflammatory activity. It is suggested that more effective use could be made of certain topical steroids by using better bases.     

Squamometry in seborrheic dermatitis

BACKGROUND: Seborrheic dermatitis is a corticosteroid-responsive condition. Topical corticosteroids exhibit distinct activities according to the type and cellular site of action of the hormone and its vehicle. The latter influences not only drug penetration, but also the structure and function of the horny layer. OBJECTIVE: The present study compared the early response of seborrheic dermatitis to two topical corticosteroids using objective quantifications of the stratum corneum alterations. METHOD: Squamometry was used to supplement the clinical assessment of the therapeutic activity of 0.1% hydrocortisone butyrate in an oil-in-water emulsion (Locoid Crelo) and 0.05% betamethasone 17-21 dipropionate lotion (Diprosone lotion). RESULTS: The hydrocortisone butyrate formulation had a faster onset of efficacy as documented by a greater improvement of lesions after a 1-week twice-daily treatment. Clearance or marked improvement was observed in the two treatment groups at completion of the 2-week trial. CONCLUSIONS: As the ranking of the clinical efficacy was not predicted by the intrinsic anti-inflammatory potency of the steroids, it is suggested that the vehicle contributed itself to the global in vivo efficacy. The anti-inflammatory action of hydrocortisone butyrate appears to be synergistically implemented by the emollient effect of the specially designed oil-in-water emulsion.     

Objective assessment of topical corticosteroids and non-steroidal anti-inflammatory drugs in methyl-nicotinate-induced skin inflammation

The aim of this study was to compare the activities of the two main classes of topical anti-inflammatory drugs in methyl-nicotinate-induced skin inflammation, using a new methodology based on laser-Doppler velocimetry. Six topical non-steroidal anti-inflammatory drugs (NSAIDs) (bufexamac, diclofenac, ibuprofen, indomethacin, phenylbutazone and niflumic acid) and three topical corticosteroids (clobetasol propionate, hydrocortisone and hydrocortisone butyrate) were tested. Drugs were commercially available (except indomethacin) and were applied under occlusion for 4 h to the forearms of 16 healthy male volunteers. Thirty minutes after excess drug removal, skin inflammation was induced by a 1-min application of methyl nicotinate (3 mM). This was repeated 44 h later. Each methyl-nicotinate application was followed by continuous skin blood flow recordings over 1 h. Overall, NSAIDs proved more effective than corticosteroids in inhibiting methyl-nicotinate-induced increases in skin blood flow. Diclofenac and indomethacin showed a potent prolonged inhibitory effect. Different types of activity were observed in the corticosteroid group: (a) At 30 min, hydrocortisone and hydrocortisone butyrate moderately inhibited methyl-nicotinate reactions whereas clobetasol propionate produced no detectable effects; (b) at 44 h, clobetasol propionate produced a significant inhibition whereas hydrocortisone butyrate and hydrocortisone exhibited either weak or no inhibitory action at all. These pharmacodynamic discrepancies between the corticosteroids tested could be related to differences in drug affinity to cutaneous receptors and in vasoconstrictive potency.     

Effect of five anti-inflammatory steroids on collagen and glycoaminoglycan synthessis in vitro

The effect of five anti-inflammatory corticosteroids, i. e. hydrocortisone, hydrocortisone 17-butyrate, betamethasone 17-valerate, nicocortonide acetate and nicocortonide, on the synthesis of hyaluronic acid, sulphated glycosaminoglycans and collagen by cultured skin fibroblasts was studied. As inhibitors of all these parameters the steroids could be arranged in order hydrocortisone < hydrocortisone 17-butyrate < betamethasone 17-valerate, nicocortonide acetate and nicocortonide. The corticosteroid concentrations required for inhibition of hyaluronic acid were very low as compared to those required for inhibition of sulphated glycosaminoglycan and collagen synthesis.     

Topical betamethasone 17-valerate is an anticorticosteroid in the rat

In the oxazolone-induced delayed hypersensitivity inflammation in the rat ear, betamethasone 17-valerate, in contrast to other topical corticosteroids, is incapable of suppressing oedema. When given in combination with triamcinolone acetonide, betamethasone 17-valerate competitively anta-gonizes the anti-inflammatory action of the active steroid. When tested in the mouse, betamethasone 17-valerate behaved as an anti-inflammatory agent 15 and 80 times as potent as betamethasone and hydrocortisone respectively. In an in vitro lymphocyte culture system in which preincubation with corticosteroids prevents subsequent phytohaemagglutinin induced DNA synthesis, betamethasone 17-valerate was less active than even hydrocortisone when rat lymph node cells were used, but with human cell preparations it was more potent than either hydrocortisone or betamethasone. Betamethasone 17-valerate behaves uniquely in the rat as an anticorticosteroid; in mouse and in man the compound behaves as a normal corticosteroid.     

Anti-inflammatory activity of antifungal preparations

Background Although steroid/antifungal combination medications are used extensively, they are associated with potential disadvantages. Antifungal preparations possessing inherent anti-inflammatory activity, leading to rapid symptomatic relief while providing mycologic cure, would be very useful. Objective Our purpose was to investigate the anti-inflammatory activity of proprietary antifungal preparations in an in vivo, human experimental model. Methods Using a double-blind, controlled protocol, we assessed the comparative ability of antifungal preparations to suppress the expected delayed erythema response following in vivo human exposure to ultraviolet B (UVB) irradiation generated by a solar stimulator. Results Currently available allylamine preparations and ciclopirox olamine proved to be the most anti-inflammatory, while ketoconazole was intermediate in anti-inflammatory activity under these experimental conditions. These agents were superior to oxiconazole, econazole, and 2.5% hydrocortisone. Conclusions Some antifungal preparations possess inherent anti inflammatory activity, although the exact mechanism remains uncertain.     

The decrease of hyaluronate synthesis by anti-inflammatory steroids in vitro

The effect of anti-inflammatory steroids (prednisolone and derivatives of hydrocortisone, dexamethasone and betamethasone) on the synthesis of hyaluronic acid and sulphated glycosaminoglycans in human skin fibroblast culture was studied. The concentrations of steroids varied between 1 x 10(-10)M and 1 x 10(-6)M. All tested steroids decreased the synthesis of hyaluronic acid to the same final level which was about 40--50% of the controls, but the concentrations required varied between different steroids. The relative inhibitory potencies of the steroids were calculated based on concentrations needed to decrease the synthesis of hyaluronate. When the inhibitory potency of hydrocortisone was calculated as one, the values of the other steroids were: prednisolone 5, hydrocortisone 17- butyrate 20, betamethasone alcohol 30, dexamethasone alcohol 38, betamethasone 17-valerate 350--400, dexamethasone monosodium phosphate and betamethasone disodium phosphate over 400. Hydrocortisone sodium succinate was as potent an inhibitor of hyaluronate synthesis as hydrocortisone alcohol. None of the tested steroids affected the synthesis of sulphated glycosaminoglycans at these concentrations. The changes ovbserved in glycosaminoglycans in the medium were in accordance with the changes in the cell layer. The possible significance of hyaluronate synthesis inhibition by anti-inflammatory steroids is discussed.     

OBSERVATIONS ON THE INTERACTIONS BETWEEN NON-STEROID ANTI-INFLAMMATORY AGENTS AND CORTICOSTEROIDS*

We have shown that corticosteroids and non-steroid anti-inflammatory agents suppress the increase in skin thickness in response to irritants applied to guinea pig skin. The combination of salicylic acid with corticosteroids and acetyl salicylic acid with hydrocortisone results in an antagonistic reduction of their anti-inflammatory activities. Indomethacin, in contrast, acts synergistically with corticosteroids. Sodium salicylate also suppresses DNA synthesis of human skin in vitro and hydrocortisone sodium succinate is able to abolish this suppression. This result, together with the results of trials on human volunteers, suggests that our findings may be relevant to the use of preparations containing combinations of non-steroid and steroid anti-inflammatory drugs in the clinical situation. The antagonism between salicylates on the one hand and indomethacin and steroids on the other, has been demonstrated by our work on the skin of man and the guinea pigs. A similar effect had been previously described in adjuvant induced arthropathy in the rat. These findings should alert clinicians who use anti-inflammatory agents in various combinations, to the possible reduction of clinical effect due to antagonism between salicylates and other anti-inflammatory drugs.     

Assessment of the antiphlogistic effect of naftifin-HCl in the UV-B erythema test

In a placebo-controlled double-blind comparative study conducted in 19 healthy volunteers, naftifin hydrochlorid cream was tested against clotrimazole 1%, clotrimazole 1%+hydrocortisone 1%, and various hydrocortisone preparations (0.5%; 1%; 2.5%) for erythema-suppressive effects. The anti-inflammatory effect of naftifine hydrochloride demonstrated earlier was confirmed in this study. The results prove a potency comparable to that of weak topical glucocorticosteroids.     

Oxidized sterols inhibit the formation of podophyllin-induced metaphase figures in mouse vaginal epithelia

Summary The antimitotic activity of oxidized derivatives of cholesterol was investigated using an assay developed by Van Scott and Bonder. In this assay, a drug that has antimitotic activity and is not a metaphase-blocking agent will inhibit the formation of podophyllin-induced metaphase figures, as counted on histologic specimens. Mouse vaginal epithelia were classified as being estrogen or progesterone predominant on the basis of histologic criteria. Podophyllin-injected mice in the estrogenic phase of the estrus cycle demonstrated high metaphase-figure counts, with an average of 284.86±132.01. In this group, all intravaginally administered compounds, inhibited the formation of metaphase figures, including a propylene-glycol ethanol vehicle (60% suppression); thus, it is concluded that animals in this phase are not a suitable model for assaying antimitotic activity. Mice in the progesterone-predominant phase of the estrus cycle had lower counts of podophyllin-induced metaphase figures, i.e., 142.13±39.29. In this group, 25-OH-cholesterol was the most effective inhibitor (59% suppression), followed by 7-ketocholesterol (48% suppression) and methotrexate (40% suppression). Cholesterol (5% suppression) and vehicle (20% suppression) did not have any significant effects. Progesterone-predominant epithelium was only susceptible to methotrexate and oxidized sterols. This suggests that oxidized sterols may have antimitotic activity.     

A trial of hydrocortisone butyrate in the treatment of rosacea and perioral dermatitis

In a blind trial a non-fluorinated steroid, 0.1% hydrocortisone butyrate, was compared with 1% hydrocortisone alcohol on twenty-eight patients suffering from steroid induced atrophy superimposed on rosacea and perioral dermatitis. The hydrocortisone butyrate did not behave like a fluorinated steroid, in that it did not prevent the beneficial effect of tetracycline nor the disappearance of telangiectasis and atrophy. In twenty-eight patients, hydrocortisone butyrate was superior in fifteen, in six hydrocortisone alcohol, and in seven the results were equal. It is concluded that although hydrocortisone butyrate is as effective as triamcinolone acetonide or fluocinolone in the treatment of psoriasis and eczema, it does not prevent the recovery of steroid atrophy on the face, and thus may not even cause it.     

Measurement of croton oil induced rabbit ear swelling and evaluation of anti-inflammatory agents with a standard low pressure caliper

Background/aims: Carbobenzoxy-phenylalanyl-methionine (CBZ-Phe-Met), a known inhibitor of the chemotactic peptide N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro, has not been evaluated as a topical anti-inflammatory agent in vivo. In order to measure the effect of CBZ-phe-met, one needs a repeat-able, quantitative, easily obtainable standard measurement of the edema formation. In this study, a caliper designed for measuring soft materials was used to evaluate the edema, induced by croton oil on rabbit ears, as well as the effects of CBZ-phe-met.
Methods: The model used in this study was croton-induced inflammation on rabbit ears. A caliper for measuring soft materials (European standard DIN 863 part 3, manufactured by TESA Ltd., Renens, Switzerland) was used to evaluate the edema, which is part of the inflammatory effect. The action of CBZ-phe-met and two other anti-inflammatory agents; hydrocortisone and Na-ibuprofen, were compared.
Results: CBZ-phe-met 1-5% was found to reduce the edema on rabbit ears induced by croton oil by 15 to 93%. 5% CBZ-phe-met was found to be as effective as 5% Na-ibuprofen and 0.1% hydrocortisone.
Conclusion: The caliper for soft materials was found to be suitable for measuring the edema induced by croton-oil, as well as the reducing edema due to anti-inflammatory treatment. It was also found that CBZ-phe-met is a potent topical anti-inflammatory agent in the croton-oil-induced inflammatory model. This may indicate a new approach in the treatment of inflammation.     

The effect of clobetasone butyrate and other topical steriods on skin thickness of the domestic pig

A new glucocorticoid, clobetasone butyrate, has been shown in patients to have good topical anti-inflammatory activity and a minimal effect on hypothalamic-pituitary-adrenal function. Among a group of topically active corticosteroids, compared in a controlled study in the domestic pig, clobetasone butyrate is shown to cause less epidermal thinning than any of the others except only 1% hydrocortisone. This evidence of a lesser atrophogenic effect may indicate further dissociation of unwanted from wanted properties in clobetasone butyrate.     

Patch-testing with serial dilutions of tixocortol pivalate and potential cross-reactive substances

Of patch-tested patients with dermatitis, 4-5% are allergic to corticosteroids. Four groups of corticosteroids are recognized (A-D), where substances from the same group may cross-react. We investigated the potential cross-reactivity pattern and dose-response relationship for several corticosteroids from group A. We also included the corresponding aldehyde to hydrocortisone, as this degradation product has been proposed to be immunogenic. Eleven patients shown to be allergic to tixocortol pivalate were patch-tested with several corticosteroids from group A, as well as with the aldehyde, all in serial dilutions. All 11 reacted to both tixocortol pivalate and hydrocortisone. The dose-response relationship for the corticosteroids tended to be similar to sensitizers lacking anti-inflammatory potential. Patients with simultaneous reactions to many substances had high patch-test reactivity to tixocortol pivalate and hydrocortisone, while patients with few such reactions showed low reactivity (p=0.001 and 0.003, respectively). Several patients reacted to the aldehyde, supporting the theory that it is an intermediate in sensitization.     

Study of the effects of hydrocortisone and hydrocortisone 17-butyrate ointments on plasma ACTH levels and Synacthen responses in children with eczema

This study compares the effects on the hypothalamo-pituitary adrenal (HPA) axis of two dosage schedules of hydrocortisone 17-butyrate and hydrocortisone ointments in 20 children suffering from eczema. Children with moderately extensive eczema received either 30 g of 0.1% hydrocortisone 17-butyrate or 30 g of 1% hydrocortisone ointment weekly for 4 weeks without occlusion. Children with extensive eczema received either 60 g of hydrocortisone 17-butyrate or 60 g of hydrocortisone weekly for 4 weeks. All four groups showed some clinical improvement. Although many of the children appeared to have some impairment of adrenal function prior to entering the trial, no further significant depression of the HPA axis as reflected by the plasma ACTH levels and a 30-min Synacthen test was observed during the trial. On the basis of 4 weeks' treatment, hydrocortisone 17-butyrate did not have a significantly different effect on the HPA axis in children from that of hydrocortisone.     

Efficacy of bufexamac (NFN) cream in skin diseases. A double-blind multicentre trial.

The effect of a new non-steroid anti-inflammatory substance (bufexamac) in a special constituent was compared with that of 0.1% triamcinolone acetonide, 1% hydrocortisone cream, and placebo during a double-blind multicentre trial. The clinical effect of these four creams was studied in 193 patients receiving treatment for the following skin disorders: atopic dermatitis, allergic contact dermatitis, and non-allergic contact dermatitis, as well as dermatitis seborrheica. After 2 and 4 weeks' treatment, when 193 and 157 patients, respectively, were re-examined, the effect of triamcinolone acetonide and hydrocortisone cream was significantly better, than that obtained with bufexamac in the cream basis employed. On the other hand, no statistically significant difference in effect between bufexamac and placebo cream was observed.     

Comparative testing of Kamillosan cream and steroidal (0.25% hydrocortisone, 0.75% fluocortin butyl ester) and non-steroidal (5% bufexamac) dermatologic agents in maintenance therapy of eczematous diseases

We report on 161 patients suffering from inflammatory dermatoses on hands, forearms, and lower legs who had been initially treated with 0.1% difluocortolone valerate. During the maintenance therapy carried out over a period of 3 to 4 weeks, we tested the efficacy of Kamillosan cream vs. 0.25% hydrocortisone, 0.75% fluocortin butyl ester, and 5% bufexamac in a bilateral comparative study. For the indications tested Kamillosan cream showed more or less equieffective therapeutic results as compared to 0.25% hydrocortisone. It is superior, however, to the non-steroidal anti-inflammatory agent 5% bufexamac as well as to 0.75% fluocortin butyl ester, a further glucocorticoid. With regard to neurodermitis, Kamillosan cream not only shows the same therapeutic effect as 0.25% hydrocortisone but is even of marked superiority towards other reference products.     

Does naftifine have anti-inflammatory properties? A double-blind comparative study with 1% clotrimazole/1% hydrocortisone in clinically diagnosed fungal infection of the skin

In a multicentre, double-blind, randomized, parallel group study in general practice, 269 patients with clinically diagnosed fungal infection of the skin were treated with either naftifine (Exoderil®) or 1% clotrimazole plus 1% hydrocortisone (CHC: Canesten HC®) applied twice daily for 4 weeks. Only 115 patients were shown subsequently to have a fungal infection by laboratory tests; the others had inflammatory disease of unknown aetiology. In those with fungal disease, both treatments were equally effective in terms of mycological cure (negative microscopy and culture). Clinical results for all 265 patients showed no clinically identifiable difference between the two preparations in terms of resolution of the disease, indicating that naftifine does have anti-inflammatory activity at least equal to CHC. This study suggests that there is no clinical advantage in treating patients with clinically diagnosed fungal infection of the skin with an antimycotic/corticosteroid combination as opposed to naftifine alone.     

Comparison of the Effect of Human Milk and Topical Hydrocortisone 1% on Diaper Dermatitis

Diaper dermatitis is one of the most common skin problems in infants and children, affecting between 7% and 35% of infants. This randomized clinical trial compared the efficacy of hydrocortisone 1% ointment with that of human breast milk in treating acute diaper dermatitis in infants ages 0 to 24 months. Infants with diaper rash were treated with either hydrocortisone 1% ointment (n = 70) or human breast milk (n = 71) for 7 days. Improvement in the rash from baseline was seen in both treatment groups on days 3 and 7; there was no significant difference in total rash scores on days 3 and 7. Treatment with human breast milk was as effective as hydrocortisone 1% ointment alone. Human breast milk is an effective and safe treatment for diaper dermatitis in infants.