Skin pharmacology : the official journal of the Skin Pharmacology Society最新文献

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.

The antipsoriatic effects of two topical antipsoriatic agents, betamethasone valerate (Betnovate) and calcipotriol (Daivonex), and a pure nanocolloid gel were assessed in 10 patients with chronic plaque-type psoriasis in a modified psoriasis plaque test. Three noninvasive bioengineering methods were applied to measure antipsoriatic effects: chromametry for objective evaluation of erythema; visiometry, a method for profilometry, and 20-MHz skin ultrasound for the measurement of skin thickness as a parameter of inflammatory infiltration and psoriatic hyperproliferation of the epidermis. Regarding inflammation parameters such as skin thickness (infiltration) and erythema (dilatation of vessels and hyperperfusion), the steroid preparation Betnovate proved to be significantly most effective in our study. Daivonex showed significant decreases in the skin roughness parameters, underlining its antiproliferative effect. The nanocolloid carrier was significantly effective in thickness reduction, this effect being most probably due to occlusion. 20-MHz ultrasound, chromametry and visiometry proved to provide multiparameter assessment of treated and untreated psoriatic skin and can be recommended as objective and reproducible measurements for further studies.

Skin surface stripping with adhesive tape has been used to study the barrier function of the stratum corneum. Usually, the amount of stratum corneum removed by stripping is not linearly proportional to the number of strips removed. The generally accepted quantitative method to determine the amount of stratum corneum material on a tape strip is weighing. This method however has certain drawbacks, it is time consuming and laborious because tape strips have to be weighed twice and sometimes it cannot be used to determine concentration profiles in the skin of active substances in topically applied vehicles. In this paper, the accuracy and reliability of an alternative method to determine the amount of stratum corneum removed by tape stripping of the skin was investigated and compared to weighing. It is based on the spectrophotometric examination of the tape. The light absorption by the proteins on the tape is correlated to the weight of the stratum corneum material. This method was found to be easier and faster than weighing, but it was less reliable because the light scattering of the stratum corneum on the tape largely overshadowed the absorption of the proteins. The light scattering showed a linear increase with an increasing amount of material on the tape, but with a large variability, resulting in calibration curves with correlations of 0.8400. However, direct spectroscopic analysis of stratum corneum tape strips has some distinct advantages even if it cannot be used for the exact quantification of stratum corneum proteins. With direct spectroscopic measurements, a tape strip can be laterally examined to inspect its homogeneity. Direct spectroscopic measurements on tape strips might also be employed to investigate the lateral and in-depth distribution of strongly light-absorbing substances in the stratum corneum.

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.

A new method for an objective assessment of the gloss of human skin is presented. The reflectometric measuring set-up complies with DIN 67530. The principle of this new method is based on a contactless determination of the skin's reflection of light from a tungsten filament lamp, recorded at an angle of 60 degrees by a silicon photocell. In a comparative study with 30 test persons it was discovered that the forehead, with 2.70 standardised reflectometer units (RU; SD +/- 0.59 RU), displayed a significantly higher gloss than the lower arm (1.99 RU, SD 0.28 RU, p < 0.0001). In an investigation into the influence of four different cream bases on the skin gloss it could be determined that the value depends on the percentage of grease, the water concentration and the consistency of the respective base. The method presented permits a fast, contactless, randomly repeatable objective assessment of skin gloss. Since the acceptance of cosmetics and pharmaceutical products depends not least on their skin gloss effect, this method can provide valuable information when estimating the success of old and new products.

It has been previously reported that minoxidil inhibits the activity of lysyl hydroxylase (LH), an enzyme which catalyzes the formation of hydroxylysine, which is necessary for proper maturation of collagen at the transcriptional and enzymatic levels. Using the reverse transcriptase-polymerase chain reaction, we confirmed that this inhibition occurred at least at the transcriptional level. Furthermore, we took advantage of this sensitive and rapid method to perform a quantitative structure activity relation study using several compounds structurally related to minoxidil. We found that when the C6 of the pyrimidinyl moiety was substituted, it had to be by a tertiary nitrogen, i.e. an N-piperidin ring for the inhibition of LH mRNA synthesis to be observed. Surprisingly, however, we found that 2,4-diamino-pyrimidin-3-oxide, a new compound lacking an organic moiety para to the nitroxide oxygen, also retained a high inhibitory effect on LH mRNA expression, comparable to that of minoxidil. We thus conclude that the presence of a substituent para to the nitroxide oxygen is dispensable for inhibition of LH mRNA to be observed in vitro. This brings new insights into the design of therapeutic agents useful in any condition where an overproduction of mature collagen is unwanted, i.e. accelerated wound healing, keloids and localized scleroderma.

Skin mast cells and basophilic leukocytes are known as key elements of acute and subacute IgE-mediated immune responses of the skin. The present paper investigated pharmacological aspects of signal transduction pathways of both cell types using activators and inhibitors of protein kinase C (PKC). The nonselective inhibitor K252a suppressed Fc epsilon RI-mediated histamine release from basophils and skin mast cells dose-dependently with IC50 values of 0.01 and 0.28 mumol/l. However, preincubation of both cell populations with kinase inhibitors showing in vitro selectivity for PKC (Ro 31-7549, calphostin C, GF 109203X) revealed a distinct modulation of cell response: IgE-mediated mediator release was inhibited only in skin mast cells, whereas in experiments with basophils a concentration-dependent potentiation of exocytosis was observed. Further evidence for heterogenous biochemical signals following activation of both cell types derived from studies with the phorbol ester TPA. With respect to acute and late-phase IgE-mediated skin reactions, we suggest that distinct signal transduction mechanisms at the level of PKC (isozymes) in basophils and skin mast cells might reflect their functional heterogeneity.

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.

Repeated open application of clobetasol 17-propionate cream and ointment to normal skin over a period of 6 weeks induced an increase in skin surface roughness as assessed by profilometry (p < 0.05), while 6 weeks' application of triamcinolone acetonide cream and ointment did not. The increase in skin roughness with clobetasol 17-propionate cream turned out to be greater than with ointment containing identical amounts of clobetasol 17-propionate (p < 0.05). A clear-cut correlation between increase of skin surface roughness and skin thickness as assessed by high-frequency ultrasound could be demonstrated only with clobetasol 17-propionate cream and ointment.

Soybean lecithin microemulsion gels offer promising features for the possible use as matrices in transdermal therapeutic systems. In order to assess the skin irritancy potential of the gel, acute and cumulative irriation tests were performed in human subjects in vivo using as comparison an unilamellar soybean lecithin liposome preparation and the solvent isopropyl palmitate (IPP). Acute irritation was tested in 151 volunteers in a 48-hour patch test, whereas cumulative irritation was assessed in a 21-day human repeated insult patch test in 20 volunteers. In the acute irritation test, discrete irritation (erythema only) developed with the gel in 2 subjects (1.3%), with the liposomes in 3 subjects (2.0%), and with IPP in 2 subjects (1.3%). For the assessment of cumulative irritation, the IT50 (irritation time of 50% of the test population) was calculated. IT50 was 13 days for the gel, 14 days for the liposomes and 17 days for IPP. This study shows a very low acute and a low cumulative irritancy potential for the soybean lecithin microemulsion gel making it a candidate matrix for transdermal therapeutic systems also under toxicological aspects.