摘要:

Cytochromes P-450 (CYPs) are the most versatile and important class of drug-metabolizing enzymes which are induced in mammalian skin in response to xenobiotic exposure. CYPs are the target of special interest in the development of pharmaceuticals for skin diseases because most, if not all, drugs available in the armamentarium of the dermatologist are substrates, inducers or inhibitors of this enzyme family. The functional significance of drug metabolism in the skin and the implication of CYP in skin pathology and therapy is an area for future investigation. A detailed insight into the mechanism of action of various cutaneous CYPs, being capable of modulating the drug bioavailability, will be helpful in the development of better strategies for novel therapy against constantly increasing skin disorders. This brief review puts some of these perspectives together and suggests additional research in the area of CYPs with regard to their expression and modulation in mammalian skin as well as their implication in dermatological disorders and the therapy of skin diseases.

ISSN:1660-5527    

DOI:10.1159/000211420

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

We tested the effect of various imidazole derivatives applied topically, on P-450-dependent enzyme activity of a reconstructed epidermis in conditions simulating clinical use. At nontoxic concentrations (determined by a cytotoxicity test based on the reduction of a tetrazolium salt, MTT, by mitochondrial deshydrogenase) econazole and clotrimazole had a biphasic effect on 7-ethoxycoumarin-O-deethylase (ECOD) activity in the epidermis, with induction at low concentrations and inhibition at high concentrations. Dermatological preparations (emulsions, gels) containing imidazole derivatives, which are nontoxic for the epidermis, decreased ECOD activity by about 40% 18 h after topical application. These results are in keeping with in vivo observations after topical application, and stress the value of the reconstructed epidermis for pharmacotoxicological and mechanistic studies of topical agents used in dermatology.

ISSN:1660-5527    

DOI:10.1159/000211421

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Opioid agents have been shown to protect against tissue damage caused by hypoxia/reperfusion, an event which has a significant reactive-oxygen-species (ROS) involvement. We have investigated the potential anti-inflammatory activity of three opioid agonists, DAMGO, DPDPE and U50488 in rat skin inflammation induced by the ROS hydrogen peroxide. The model involves the intradermal injection of the enzyme glucose oxidase which converts glucose to D-gluconic acid and H2O2 which is locally released. Following injection, a well-delineated inflammatory response develops rapidly, is maximal at 5 h and still measurable after 48 h. Co-administration of the δ or κ opioid agonists DPDPE or U50488 (7.5-60 μg per site) significantly reduced the inflammation, in a dose-dependent manner, for periods of up to 3 h for DPDPE, and up to 5 h with U50488. The μ-opioid agonist DAMGO (7.5-60 μg per site) was ineffective. Co-administration of the opioid antagonist naltrexone (120 μg) partially reversed the anti-inflammatory effects of DPDPE and U50488. We conclude that the δ and κ opioid receptor agonists DPDPE and U50488 are able to inhibit ROS-induced skin inflammation and that this may have clinical implications.

ISSN:1660-5527    

DOI:10.1159/000211422

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Percutaneous absorption and cutaneous bioavailability of zinc and copper from zinc 2-pyrrolidone 5-carboxylate (ZnPC), zinc oxide (ZnO), zinc sulfate (ZnSO4), copper 2-pyrrolidone 5-carboxylate (CuPC) and copper sulfate (CuSO4) were compared using 5 formulations (3 emulsions and 2 ointments) that were applied topically on human skin in vitro. After application for 72 h, percutaneous absorption of zinc from ointments containing ZnO and ZnSO4 was found to be lower than that from a ZnPC-containing emulsion (0.36 and 0.34 versus 1.60% of applied dose). In the case of copper, the flux after a 72-hour treatment period showed that there had been minimal release from CuPC- and CuSO4-containing formulations (approximately 5 ng/cm2/h). All formulations used in this study effected an increase in zinc and copper concentrations in whole skin and epidermis. Bioequivalence of the 5 formulations based on pharmacokinetic results was assessed, and salt and vehicle effects were discussed.

ISSN:1660-5527    

DOI:10.1159/000211423

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Microorganisms play an important role in the pathomechanism of acne vulgaris which is treated with antibiotics, particulary erythromycin (ERY). The main problem in the topical use of ERY lies in achieving sufficient penetration of the drug into sebaceous follicles. Doubly enhanced penetration of an ion pair composed of ERY and octadecansulfonate (OS) in contrast to the commonly used ERY base was observed, using a multilayer membrane model (MMM). The aim of the present study was to evaluate the results obtained on the MMM using excised human skin. The amount of ERY penetrating into sebaceous follicles of freshly excised human skin was measured using [N-methyl-14C]erythromycin. The ex vivo penetration of the ion pair ERY/OS into the sebaceous follicles was observed to be doubly enhanced compared with the penetration of the ERY base. The model was shown to be suitable for predicting in vivo penetration of anti-acne formulations into sebaceous glands.

ISSN:1660-5527    

DOI:10.1159/000211424

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

Clinical and in vitro evidence suggests that the physicochemical properties of the skin influence the process by which drugs are transported through skin. The effects of skin storage, preparation and pretreatment on the permeation and metabolism of (8-methoxypsoralen (8-MOP), as a model penetrant, were studied using the flow-through in vitro cell diffusion system. The metabolites and unchanged drug were estimated by thin-layer chromatography. While the permeability of 8-MOP was similar in fresh (445 cm·• h-1) and azide-treated (449 cm • h-1) skin (p < 0.01), decreased permeability was observed in frozen skin (406 cm·h-1, p < 0.01). A 2.8-fold increase in the cumulative flux of 8-MOP at 24 h through azide-pretreated (2.5 × 10-3 μmol • h-1 • cm-1) versus fresh skin (9.1 × 10-4 μmol·h-1 • cm-1) was observed (p < 0.01). There was a slight increase in the flux of 8-MOP at 24 h when skin was frozen, compared with untreated skin. Increase in the flux of 8-MOP in frozen skin might result from the alteration of the molecular arrangement of the skin components during freezing. In addition to the obvious differences between frozen and fresh skin, these observations discourage the use of frozen skin. There is a moderate relationship between the permeability and flux of 8-MOP through frozen skin. A similar but nonrelated correlation was observed between the permeability and flux of 8-MOP through azide-treated skin samples (r = 0.6). These findings suggest that azide and freezing treatments lower the skin barrier properties to the transport of 8-MOP. Apparently, factors that may affect the inherent permeability of human skin, particularly those related to the handling, storage and pretreatment of skin with solvents and chemicals, can also influence topical drug delivery. The metabolic capacity of frozen skin and fresh skin remained constant during the period of study. These data may be of value in the development of topical methoxypsoralen systems. Further in vitro and in vivo studies are required to ascertain the generalization of this process.

ISSN:1660-5527    

DOI:10.1159/000211425

出版商:S. Karger AG    

年代:1996

数据来源: Karger

摘要:

FK 506 and cyclosporin A (CyA) are two immunosuppressive drugs which are known to be effective in the treatment of psoriasis by inhibiting the activation of T cells. In contrast, their influence on the proliferation of keratinocytes is discussed controversially. The second messenger cyclic adenosine monophosphate (cAMP) has been regarded as a regulator for cell growth and proliferation for 20 years. Hyperproliferation of many cells and particularly of psoriatic keratinocytes was speculated to be due to a decrease in cAMP levels in the psoriatic epidermis, whereas new findings could not confirm these observations. To clarify this discussion we determined the intracellular cAMP content in isoprenaline-stimulated keratinocytes from psoriatics and controls after treatment with CyA or FK 506. Ethanol and the β-blocking drug propranolol served as controls. The basal level of cAMP and the response to isoprenaline in psoriatic keratinocytes did not differ from those of controls. CyA dramatically reduced the cAMP level and FK 506 just slightly diminished it in a dose-dependent manner. Both drugs diminished the cAMP level more effectively in the keratinocytes from lesional psoriatic skin than in keratinocytes from controls. These data provide evidence that CyA influences early signal transduction pathways by depressing the intracellular cAMP in keratinocytes. This supports the view of other groups that CyA and perhaps also FK 506 influence not only immunocompetent cells but also keratinocytes in the treatment of psoriasis. Furthermore, it is doubtful that a low cAMP level is a positive regulator for cell growth and the hyperproliferation of psoriatic keratinocytes.

ISSN:1660-5527    

DOI:10.1159/000211426

出版商:S. Karger AG    

年代:1996

数据来源: Karger