Cutaneous polyarteritis nodosa successfully treated with topical diflucortolone valerate: a case report & review of the literature.

Cutaneous Polyarteritis Nodosa (cPAN) was first described in 1931. cPAN is considered a rare disease, its true incidence is unknown. The age of onset is diverse. Most studies have shown no significant gender predominance. cPAN presents with distinct skin findings, such as a maculopapular rash, subcutaneous nodules, livedoid vasculitis, panniculitis, ischemic finger lesions, or erythematous patchy rash. Etiology is unclear. It is still believed to be an immune complex-mediated disease, although a possible mechanism recently proposed relates a familial form of the disease to impaired activity of Adenosine Deaminase 2. cPAN may reflect an underlying disease, infection or medical treatment. There is no consensus as to initial treatment, dosage and length of treatment. Patients with constitutional symptoms, visceral involvement, a more severe course of the disease, or high acute phase reactants, were treated mainly with systemic corticosteroids and/or cytotoxic agents for varying durations. However, persistence of cutaneous lesions has been documented. We describe a 14 year old male suffering from persistent cPAN, with no constitutional symptoms or involvement of internal organs. The patient was treated with a local corticosteroid-based ointment during exacerbations, until complete remission. Although reported in only one study, treatment with topical corticosteroid compound may result in significant improvement or complete regression of skin lesions in cPAN patients.

Effect of a topical steroid on gene expressions for chemokines in mice with contact hypersensitivity.

Effects of a topical corticosteroid drug, diflucortolone valerate, on the mRNA expressions for four CC- and four CXC-chemokines, which have been reported to be associated with recruitment of different kinds of proinflammatory and inflammatory cells, were investigated by RT-PCR in mice with 2,4,6-trinitrochlorobenzene (TNCB)-induced contact hypersensitivity (CHS) response. All of the eight gene expressions were clearly up-regulated in the lesion site of the CHS response up to 24 h post-challenge of TNCB at which ear swelling response reached a peak, so that heavy infiltration of inflammatory cells consisting mainly of mononuclear cells and neutrophils was likely induced by these chemokines. Topical treatment with diflucortolone valerate suppressed completely the infiltrates as well as the ear swelling response. In addition, the up-regulation of gene expressions for these eight chemokines were suppressed by the treatment, indicating that the corticosteroid drug attenuates the expression of chemokine genes essential for orientating nonspecific skin response to hapten-specific CHS response through the recruitment of inflammatory cells from the circulation into the tissue site.

Dorsal skin reactions of hairless dogs to topical treatment with corticosteroids.

Dorsal skin reactions to continuous topical treatment with different types of corticosteroids were histologically investigated in hairless descendants of Mexican hairless dogs. The preparations tested were prednisolone (ST-1; weak), fluocinolone acetonide (ST-2; moderate), diflucortolone valrerate (ST-3; strong), and mometasone furoate (ST-4; very strong). Grossly, the sites treated with ST-3 and ST-4 showed moderate inflammatory reactions. After completion of the corticosteroid treatment, both sites were less pigmented and had a thin texture. The severity of histologic changes in the skin was dependent on the efficacy of the corticosteroids. The epidermis was prominently thinned from 1 wk after treatment with the corticosteroids, resulting in a flat dermis-epidermis junction. By the end of the corticosteroid treatment, these lesions became progressively more severe. At 2 wk after completion of topical treatment, the epidermal thickness in the sites treated with ST-1 and ST-2 began to return to normal values, whereas the epidermis of the skin treated with ST-3 and ST-4 became thinner. At 3-4 wk after topical treatment with ST-3 and ST-4, the dermis showed hyalinization of collagen bundles. These dermatologic findings in hairless dogs are in accordance with steroid-induced skin atrophy of human beings. These results suggest that the skin of hairless dogs responds sensitively to topical corticosteroids and that these animals are a useful model for investigating the efficacy and adverse effects of cutaneous topical corticosteroids.

6 alpha-Fluoro- and 6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione: synthesis and evaluation of activity and kinetics of their C-22 epimers.

It is generally accepted that the anti-inflammatory effect of glucocorticosteroids cannot be separated from their adverse effects at the receptor level. However, modification of the pharmacokinetics through structural alterations could provide steroids with a better therapeutic index than those currently used. Thus, new 16 alpha,17 alpha-acetals between butyraldehyde and 6 alpha-fluoro- or 6 alpha,9 alpha-difluoro-16 alpha-hydroxycortisol were synthesized and studied. Acetalization of the corresponding 16 alpha,17 alpha-diols or transacetalization of their 16 alpha,17 alpha-acetonides in dioxane produced mixtures of C-22 epimers, which were resolved by preparative chromatography. Alternatively, an efficient method was used to produce the 22R-epimer stereoselectively through performing the acetalization and transacetalization in a hydrocarbon with an inert material present. The C-22 configuration of (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione was unambiguously established by single crystal X-ray diffraction. The present compounds, especially the 22R-epimer just mentioned, bind to the rat thymus glucocorticoid receptor with high potency. The C-22 epimers of the 6 alpha,9 alpha-difluoro derivatives showed a 10-fold higher biotransformation rate than the budesonide 22R-epimer when incubated with human liver S9 subcellular fraction. The high receptor affinity in combination with the high biotransformation rate indicates that (22R)-6 alpha,9 alpha-difluoro-11 beta,21-dihydroxy-16 alpha,17 alpha-propylmethylenedioxypregn-4-ene-3,20-dione may be an improved 16 alpha,17 alpha-acetal glucocorticosteroid for therapy of inflammatory diseases, in which the mucous membranes are involved, such as those in the intestinal tract as well in the respiratory tract.

Local anti-inflammatory activity and systemic side effects of NM-135, a new prodrug glucocorticoid, in an experimental inflammatory rat model.

The local anti-inflammatory activity and systemic side effects of NM-135 (6alpha,9-difluoro-11beta-hydroxy-16alpha-methyl-21[[2 ,3,4,6-tetrakis-O-(4-methylbenzoyl)-beta-D-glucopyranosyl]oxy]-pregna-1, 4-diene-3,20-dione) in croton oil-induced granuloma pouches and ear edema in rats were studied. The local anti-inflammatory activity of NM-135 was stronger than that of betamethasone 17-valerate (BV). As to systemic side effects, BV and diflucortolon valerate (DFV) caused thymolysis at the doses required for the anti-inflammatory activity. In contrast, no clear systemic side effect was observed in rats administered NM-135 at the dose producing the anti-inflammatory activity. These results suggest that NM-135 is a drug exhibiting a high degree of dissociation between the local anti-inflammatory activity and systemic side effects.

Topical glucocorticosteroids modulate the expression of CRABP I and II in human skin differently.

Epidermal cells express two retinotic acid-binding proteins (CRABP I and II). Because CRABP II protein is strongly induced by topical retinoic acid, the respective roles of the two proteins in the pharmacological activity and toxicity of topical retinoids deserve particular attention. Since topical steroids diminish the irritation induced by retinoic acid (RA), whereas retinoic acid may counteract the atrophogenic effects of steroids, the possible interplay of both compounds in the expression of CRABP I and II appeared worth studying. We have analyzed the effects of topical application of triamcinolone acetonide (TA) on the retinoic acid-induced altered expression of CRABP I and II in normal human skin, at the protein and mRNA levels. We found that CRABP II protein and mRNA were strongly increased upon retinoic acid application: this induction was significantly inhibited by concomitant application of triamcinolone acetonide; a more potent steroid, difluocortolone valerate, was also found to diminish normal endogenous expression of CRABP II. In contrast, CRABP I protein was decreased by topical retinoic acid, and the down modulating effect of retinoic acid was counteracted by triamcinolone acetonide.

Diflucortolone valerate. Asian experience.

More than 10 years ago, diflucortolone valerate (Nerisone, Nerisona) was introduced in Germany and soon after in Asian countries in a concentration of 0.1% in cream, ointment and fatty ointment bases. 897 patients were included in the first Southeast Asian multicentre trial with these 3 formulations, and good efficacy and tolerability combined with a rapid onset of effect were shown. These results were confirmed later in Indonesia in an extended follow-up trial which included 1295 patients. A combination of 0.1% diflucortolone valerate with 1.0% chlorquinaldol was introduced after a multicentre Southeast Asian trial involving 8668 patients with inflammatory or allergic skin conditions for which a supplementary anti-infective treatment, for prophylaxis or therapy, was considered to be indicated. Excellent results were obtained in terms of efficacy, tolerability and cosmetic properties. A randomised double-blind trial comparing this preparation with a so-called 'shotgun' combination containing 0.05% betamethasone 17-valerate, 0.1% gentamicin, 1.0% tolnaftate and 1.0% clioquinol in 288 patients in the Philippines resulted in a better efficacy for the diflucortolone preparation in the 80 patients with bacterially or mycotically infected skin diseases. A 0.3% concentration of diflucortolone valerate was developed and introduced as a high potency topical corticosteroid. A trial in the Philippines which involved 143 patients with mostly severe chronic recurrent and resistant corticosteroid-responsive skin disease confirmed a pronounced clinical efficacy with a low incidence of side effects. For the treatment of inflammatory or eczematised dermatomycosis. 0.1% diflucortolone was combined with 1.0% isoconazole nitrate (Travocort). In a randomised double-blind study of 294 patients in Thailand, this preparation was compared with a plain 1.0% clotrimazole formulation. The results were significantly better for the diflucortolone plus isoconazole nitrate combination in terms of remission of symptoms, and after 1 week the mycological cure rates were also better, as shown in potassium hydroxide and culture investigations. It is concluded, therefore, that diflucortolone valerate in the available galenic bases and in effective combinations with other agents has been proven in extensive clinical trials to be a valuable therapeutic tool in dermatological practice.

Diflucortolone valerate (Nerisona): a comparative vasoconstriction test in artificially induced hyperemia of the skin.

In 20 healthy volunteers of both sexes the vasoconstrictive activity of diflucortolone valerate in two of its commercially available formulations (water-in-oil emulsion and pure fat base) was compared with that of four other substances: fluocinonide; betamethasone-17,21-dipropionate; hydrocortisone-17-butyrate; and clobetasol-17-propionate in corresponding galenical formulations. The visual assessment of vasoconstrictive activity after 10 hours revealed a statistically significant superiority of diflucortolone valerate in its fat base over the corresponding galenical formulations of fluocinonide, clobetasol-17-propionate, and hydrocortisone-17-butyrate. Diflucortolone valerate in a water-in-oil emulsion was statistically better after eight hours than the cream formulations of fluocinonide; clobetasol-17-propionate, and betamethasone-17,21-dipropionate.

[Antimicrobial activity of the broad spectrum antimycotic isoconazole nitrate in humans (author's transl)]. / Antimikrobielle Wirksamkeit des Breitspektrum-Antimykotikums Isoconazolnitrat im Humanversuch.

A comparative study (occlusion test according to Marples and Kligman) was conducted in 100 test subjects with several formulations of isoconazole nitrate. The following results were obtained: 1. There are no differences in efficacy between the free base, isoconazole, and the nitrate. 2. Increasing the active substance concentration of isoconazole nitrate above 1% produced a noticeable increase in its effect so that 2% and 4% preparations are appropriate for particular uses. 3. 1% isoconazole nitrate (Travogen cream, Gyno-Travogen cream) is more effective than a commercial cream containing 1% clotrimazole. 4. The addition of a corticosteroid (diflucortolone-21-valerate 0.1%, Travocort cream) does not influence the action of isoconazole nitrate.