ISSN:0302-3427    

DOI:10.1159/000210955

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Percutaneous absorption of the vasodilator methyl nicotinate (MN) was evaluated in human volunteers at three anatomic sites (forehead, forearm and palm) using the technique of laser Doppler flowmetry (LDF). The experiments were designed to test the hypothesis that the kinetics and extent of skin penetration are dependent upon the appendageal density at the site of application. The LDF technique measured the increase in skin blood flow elicited by topically applied MN once the chemical had penetrated to the microvasculature. Significant differences in the measured LDF responses at the three sites were found, and further analysis of the data suggested that MN penetration was greatest through forehead skin, least through the palm and intermediate across the skin of the forearm. A correlation therefore existed between apparent MN absorption and appendageal density.

ISSN:0302-3427    

DOI:10.1159/000210956

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

In previous studies we reported that the permeation of dexamethasone and hydrocortisone across the skin was decreased and penetration into the skin was increased in the presence of Transcutol® (TC) when compared to water as a solvent. The objective of this investigation was to study the effect of TC on the binding of dexamethasone and hydrocortisone to the skin, and on the accumulation and retention in the skin. Adsorption and desorption studies were conducted for dexamethasone and hydrocortisone with full thickness skin (FTS), and epidermis.The amount of dexamethasone and hydrocortisone adsorbed and desorbed with FTS and epidermis was essentially the same. In the presence of TC the amount of dexamethasone and hydrocortisone adsorbed was increased by 100% with both FTS and epidermis, whereas there was no difference in the amount of dexamethasone and hydrocortisone desorbed. A topical delivery system was developed with and without TC and was evaluated in vivo using the rat as an animal model for hydrocortisone accumulation after multiple dosing. The systemic body burden was reduced by 70% and skin retention of hydrocortisone was incresed by 100% in all the layers of the skin. The detection of hydrocortisone accumulation and retention were studied by autoradiography and electron microscopy, and the results support the hydrocortisone depot in the skin due to TC.

ISSN:0302-3427    

DOI:10.1159/000210957

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

For unknown reasons, the epidermal concentrations of retinol and its metabolite 3,4-didehydroretinol become characteristically changed during treatment with certain synthetic retinoids. In the present study we investigated [3H]retinol uptake and conversion to 3,4-[3H]didehydroretinol in cultured human skin exposed to six different retinoids. The tissue accumulation of [3H]retinol increased by 50–130% following addition of 1.3 μM of all-trans-retinoic acid, 13-cis-retinoic acid, or 3,4-didehydroretinoic acid (putative metabolites of retinol), and by 13–55% after addition of acitretin, arotenoid Ro 13-7410, or 4-(N-hydroxyphenyl)retinamide. The formation of 3,4-[3H]didehydroretinol was markedly inhibited (minus 80–90%) by the three putative retinol metabolites, moderately inhibited (minus 60–70%) by the aromatic retinoic acid analogues acitretin and arotinoid, and only slightly inhibited (minus 25%) by 4-(N-hydroxyphenyl)retinamide. Addition of citral and ketoconazole, substances known to interfere with the oxidative metabolism of vitamin A, diminished the formation of 3,4-didehydroretinol by 70 and 95%, respectively, but only marginally affected the retinol values. We conclude that the increase in retinol and marked reduction in 3,4-didehydroretinol concentrations in epidermis especially during treatment with 13-cis-retinoic acid are most likely due to diminished conversion of retinol to 3,4-didehydroretinol, but whether or not this reflects feedback inhibition of retinol metabolism or direct inhibition of a specific enzyme remains to be established. Nonetheless, in vitro analysis of 3,4-didehydroretinol biosynthesis appears to be a sensitive means for screening compounds for their ability to interfere with the cutaneous vitamin A metabolism.

ISSN:0302-3427    

DOI:10.1159/000210958

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

The purpose of these studies was to directly compare the pharmacologic effects of retinoids on cutaneous cells in vitro and in vivo. Previously, it was demonstrated that all-trans-retinoic acid stimulates the proliferation of growth-arrested human keratinocytes and fíbroblasts in culture. In the present studies, all-trans-retinoic acid was compared to three other retinoids – 13-cis-retinoic acid, P-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl-l-propenyl] benzoic acid (TTNPB) and M-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-2-napthalenyl-l-propenyl] benzoic acid (meta-carboxy-TTNPB] – for growth stimulation using a cultured human squamous epithelial cell line (UM-SCC-1) and human dermal fíbroblasts. These four retinoids were also evaluated for their effects on reduction of horn-filled utriculi when topically applied to the skin of rhino mice. All-trans-retinoic acid stimulated proliferation of both fíbroblasts and epithelial cells over concentrations ranging from 0.01 to 1.0 μg/ml. In fíbroblasts, 13-cis-retinoic acid was less potent than all-trans-retinoic acid, whereas, in epithelial cells these two retinoids were equipotent. In contrast, TTNPB was more potent than all-trans-retinoic acid at stimulating the growth of both fíbroblasts and epithelial cells. The analog, meta-carboxy-TTNPB was essentially inactive as a growth stimulator of both cell types. In the rhino mouse utriculus reduction model, the rank order of potency for the retinoids was the same as that for in vitro cell growth stimulation (TTNPB > all-trans-retinoic acid > 13-cis-retinoic acid). Meta-carboxy-TTNPB was inactive at reducing utriculi at a dose of 5,000 times the ED50 of TTNPB. In summary, the results of these studies show that the effects of retinoids on stimulating proliferation of fíbroblasts and epithelial cells correlate with their effects at reducing utriculi in the rhino mouse. Therefore, these in vitro models appear to have good relevance for studying the mechanisms of the pharmacologic effects of retinoi

ISSN:0302-3427    

DOI:10.1159/000210959

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

It is well known that applications of a single dose of 12-O-tetradecanoylphorbol-13-acetate (TPA) to mouse ears induces an acute inflammatory reaction consisting of erythema, edema and polymorphonuclear leukocyte (PMN) infiltration. We report here that multiple topical applications of TPA to mouse ears produce a prolonged inflammatory reaction characterized by increases in ear weight, inflammatory cell infiltration and epidermal hyperplasia. TPA was applied 5 times over 10 days to mouse ears. Epidermal thickness and PMN infiltration (myeloperoxidase content) increased 3- and 160-fold, respectively, by day 3 and remained elevated over control values throughout the test period. Ear weight was elevated from day 1 and remained high. Hydrocortisone 17-valerate and betamethasone dipropionate significantly reduced all three parameters of inflammation. Indomethacin and two other cyclo-oxygenase inhibitors, and an antihistamine had little or no effect on any of the parameters. This chronic skin inflammation model may be more relevant for evaluating anti-inflammatory compounds than the acute TPA model because the test compounds are applied after the inflammatory lesion is established, which mirrors the use of clinical anti-inflammatory drugs. Also this model may be more selective than the acute TPA model for compounds which affect leukotriene production since other pharmacological agents which are active in the acute model are not active in the multiple-application model.

ISSN:0302-3427    

DOI:10.1159/000210960

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

12-Hydroxyeicosatetraenoic acid (12-HETE) is assumed to play an important role in the pathogenesis of inflammatory skin diseases. Recently, high-affinity binding sites for this eicosanoid have been identified on human keratinocytes by our group. Since ciclosporin exerts therapeutic effects in chronic inflammatory dermatoses such as psoriasis or atopic eczema, the influence of the drug on 12(S)-HETE binding to human keratinocytes was studied. No competitive inhibition of 12(S)-HETE binding was observed in ciclosporin concentrations between 10-10 and 10-6M. In contrast, pretreatment of epidermal cells for 24 h resulted in a dose-dependent decrease of specific 12(S)-HETE binding. The analysis of saturation curves showed that the inhibition of 12(S)-HETE binding by ciclosporin was due to the decrease of 12-HETE binding sites, while receptor affinity remained unchanged. In addition, ciclosporin blocked the interferon-γ-induced increase in epidermal 12(S)-HETE binding. These findings suggest that the effects of ciclosporin in cutaneous disorders could be partly mediated via an influence on epidermal 12(S)-HETE binding

ISSN:0302-3427    

DOI:10.1159/000210961

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

Antipsoriatic agents have been shown to decrease skin levels of arachidonic acid and its metabolites including 12-monohydroxy-eicosatetranoic acid (12-HETE), and leukotriene B4 (LTB4). In addition, specific systemic and topical lipoxygenase inhibitors have been reported to be effective in the treatment of psoriasis. The objective of this study was to investigate the effect of a potent oral leukotriene biosynthesis inhibitor (MK886) in patients with chronic plaque psoriasis. Clinical response together with the changes of LTB4 levels in lesional skin biopsy specimens, and urinary leukotriene E4 (LTE4) excretion were evaluated. In addition, markers of inflammation, proliferation and keratinization were studied immunohistochemically. No change in clinical scores or lesional LTB4 levels were observed with a 101/3-day course of MK886. A statistically significant reduction in urinary LTE4 excretion was observed: mean LTE4 70%) in urinary LTE4 excretion was found, and a slight decrease of epidermal PMN accumulation was observed, no correlative changes in clinical scores or LTB4 levels in skin lesion were found with a short course of MK886.

ISSN:0302-3427    

DOI:10.1159/000210962

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

It is believed that xanthines can inhibit cell proliferation by elevating intracellular cAMP. Therefore, these compounds can be useful in hyperprohferative disorders. Our aim was to assess the efficacy of theophylline, caffeine and dyphylline on 3T3 fibroblast proliferation. 3T3 subconfluent cultures were incubated for 3 days with the xanthine derivatives (1 mM-1μM). At 1 and 0.1 mM the three derivatives exhibited marked inhibition of fibroblast proliferation. Theophylline and caffeine were more potent than dyphylline. At a concentration of 1 mM, the three xanthine derivatives also inhibited proliferation of psoriatic dermal fibroblast, albeit to a lower extent. Caffeine was the most active compound followed by theophylline and dyphylline. We conclude that xanthine derivatives are good candidates for use as fibroblast antiproliferative drugs. We also conclude that 3T3 fibroblasts appear to be a valid system for the pharmacological screening of fibroblast antiproliferative drugs

ISSN:0302-3427    

DOI:10.1159/000210963

出版商:S. Karger AG    

年代:1991

数据来源: Karger

摘要:

5-Iodo-2′-deoxyuridine (IUDR) is a potent topical antiviral agent in experimental animals but is less active in man for treating cutaneous viral infections. We have shown here that IUDR is 5 times less active in human keratinocytes infected in vitro with herpes simplex virus type 1 than in guinea pig embryo cells infected in culture. To account, in part, for this difference in activity of IUDR, we measured the capacity of these different cultures to catabolize and thus inactivate the drug. IUDR is catabolized by thymidine phosphorylase; activity of this enzyme was very high in human keratinocytes in vitro but was very low in guinea pig embryo cells. The antiviral activity of IUDR in human keratinocytes, however, was not increased by inhibiting thymidine phosphorylase; inhibiting thymidine phosphorylase apparently increased the availability of thymidine that would compete with IUDR and, indeed, the activity of IUDR in infected cells was reduced by addition of thymidine to the medium. These data indicate that the catabolism of IUDR and related analogs alters antiviral activity in human keratinocyte

ISSN:0302-3427    

DOI:10.1159/000210964

出版商:S. Karger AG    

年代:1991

数据来源: Karger