What is already known about this subject • In recent years, it has been suggested that hair follicles represent important shunt routes into the skin for drugs and chemicals [1–3]. • In vitro studies have shown the importance of skin appendages for skin penetration by hydrophilic compounds [4]. Investigation of follicular penetration in vivo has been difficult due to the absence of appropriate analytical methods or suitable animal model systems. • Recently, a new method was described that quantifies follicular penetration in vivo by using selective closure of hair follicles [5]. • Caffeine is frequently used in skin penetration experiments as a model for highly water‐soluble compounds. Occlusion [6] and skin thickness [7] seem to have little influence on the penetration of caffeine. However, percutaneous absorption rates for caffeine exhibit regional skin differences in humans in vivo[1]. What this study adds • The results of the present study demonstrate that a fast drug delivery of caffeine occurs through shunt routes. Therefore, hair follicles are considerable weak spots in our protective sheath against penetration into the body by hydrophilic substances. • We showed that there is a quantitative distinction between follicular penetration and interfollicular diffusion of caffeine in vivo. • These findings are of importance for the development and optimization of topically applied drugs and cosmetics. In addition, such properties must be considered in the development of skin protection measures. Aims The skin and its appendages are our protective shield against the environment and are necessary for the maintenance of homeostasis. Hypotheses concerning the penetration of substances into the skin have assumed diffusion through the lipid domains of the stratum corneum. It is believed that while hair follicles represent a weakness in the shield, they play a subordinate role in the percutaneous penetration processes. Previous investigation of follicular penetration has mostly addressed methodical and technical problems. Our study utilized a selective closure technique of hair follicle orifices in vivo, for the comparison of interfollicular and follicular absorption rates of caffeine in humans. Methods Every single hair follicle within a delimited area of skin was blocked with a microdrop of a special varnish‐wax‐mixture in vivo. Caffeine in solution was topically applied and transcutaneous absorption into the blood was measured by a new surface ionization mass spectrometry (SI/MS) technique, which enabled a clear distinction to be made between interfollicular and follicular penetration of a topically applied substance. Results Caffeine (3.75 ng ml−1) was detected in blood samples, 5 min after topical application, when the follicles remained open. When the follicles were blocked, caffeine was detectable after 20 min (2.45 ng ml−1). Highest values (11.75 ng caffeine ml−1) were found 1 h after application when the follicles were open. Conclusions Our findings demonstrate that hair follicles are considerable weak spot...

The concentration of clobetasol propionate in the stratum corneum after application of three different formulations was determined, quantifying the influence of the formulations on the bioavailability of the drug. The stratum corneum was sampled by tape stripping. The concentrations of clobetasol propionate were determined quantitatively by HPLC. After application of Clobetasol Propionate Cream USP, 0.05%, and Temovate Cream, 0.05%, identical amounts of the drug were found in the stratum corneum, whereas after application of Temovate ε Emollient, 0.05%, the quantity was clearly decreased. From results obtained measuring the drug concentration in the adjacent sites of the skin where the creams had not been applied, it became clear that clobetasol propionate in Temovate ε Emollient, migrated to a large extent in the lateral direction. This explains the lower concentration measured for this formulation in the skin areas where the cream had been applied. In general, a lateral distribution of the applied drug must be taken into account when positioning the application areas on the forearm.

Tobacco smoke is a complex mixture with over 8700 identified constituents. Smoking causes many diseases including lung cancer, cardiovascular disease, and chronic obstructive pulmonary disease. However, the mechanisms of how cigarette smoke impacts disease initiation or progression are not well understood and individual smoke constituents causing these effects are not generally agreed upon. The studies reported here were part of a series of investigations into the contributions of selected smoke constituents to the biological activity of cigarette smoke. In vitro cytotoxicity measured by the neutral red uptake (NRU) assay and in vitro mutagenicity determined in the Ames bacterial mutagenicity assay (BMA) were selected because these assays are known to produce reproducible, quantitative results for cigarette smoke under standardized exposure conditions. In order to determine the contribution of individual cigarette smoke constituents, a fingerprinting method was developed to semi-quantify the mainstream smoke yields. For cytotoxicity, 90% of gas vapor phase (GVP) cytotoxicity of the Kentucky Reference cigarette 1R4F was explained by 3 aldehydes and 40% of the 1R4F particulate phase cytotoxicity by 10 smoke constituents, e.g., hydroquinone. In the microsuspension version of the BMA, 4 aldehydes accounted for approximately 70% of the GVP mutagenicity. Finally, the benefits of performing such studies along with the difficulties in interpretation in the context of smoking are discussed.

The detection and fragmentation behaviour of adducts of the chemotherapeutic cis-diamminedichloroplatinum(II) (cisplatin) with the dinucleosidemonophosphates d(ApG), d(GpG) and d(TpC) as model compounds for DNA adducts in an ion trap with electrospray ionization were studied. Mainly the monofunctional adduct, the bifunctional adduct and the bifunctional adduct with platinum bridging two dinucleosidemonophosphates were detected. In addition, several more complex adducts were seen resulting from reactions among these species. Adduct formation was low in the case of d(TpC). Fragmentation could be controlled strongly by varying the temperature of the transfer capillary; furthermore, tandem mass spectrometric (MS/MS) experiments on both the monofunctional and the bifunctional adducts were performed. For the adducts of d(ApG) and d(GpG) losses of NH(3) and HCl were the most dominant reactions, followed by the losses of one, then another two units of 98 amu from the sugar-phosphate backbone, whereas d(TpC)-Pt predominantly forms the dinucleosidemonophosphate. In the gas phase, the conversion of the monofunctional into the bifunctional adducts through binding to another site in the dinucleotide accompanied by loss of NH(3) or HCl could also be observed. The removal of a ligand from the coordination sphere of the square-planar platinum complexes appeared to be the crucial step for the induction of further fragmentation of the dinucleotide ligand. MS(n) experiments of the bifunctional adducts of d(ApG) and d(GpG) revealed different fragmentation pathways involving the loss of phosphoric acid, metaphosphoric acid, deoxyribose units (intact or dehydrated) and the nucleobases in different orders, leaving characteristic binding site-determining fragments. Fragmentation of these ions was also performed, mainly resulting in fragmentation of the bases. The study confirmed the remarkable stability of the platinum-guanine bond compared with other nucleobases.

The method applied is well-suited to determine the reservoir formation in the stratum corneum for topically applied substances.