Preclinical pilot study monitoring topical drug penetration and dermal bioavailability of a peptidase inhibitor from different galenic formulations into pig dermis, using cutaneous microdialysis.

BACKGROUND: Cutaneous microdialysis (CM) is an ex vivo technique that allows study of tissue chemistry, including bioavailability of actual tissue concentration of unbound drug in the interstitial fluid of the body. AIM: To test the penetration and dermal bioavailability of galenic formulations of the small-molecule IP10.C8, a dual-protease inhibitor of the dipeptidyl peptidase and aminopeptidase families. METHODS: Using CM, we tested the penetration and dermal bioavailability of IP10.C8 into the dermis and subcutis of pigs, and determined the tissue concentration of IP10.C8 enzymatically, using an enzyme activity assay (substrate Gly-Pro-pNA) and high performance liquid chromatography. RESULTS: Dermal bioavailability was enhanced by using microemulsion or the addition of the penetration enhancer oleic acid to a hydroxyethylcellulose (HEC) gel formulation. Dermal bioavailability was also enhanced when galenic formulations were prepared with higher pH (7.5 vs. 6.5) or higher drug concentration (5% vs. 1%) in HEC gel. CONCLUSION: It seems possible, using CM for topical skin penetration testing in anaesthetized domestic pigs, to test the bioavailability of newly designed drugs. However, the experimental time is limited due to the anaesthesia, and is dependent on drug recovery. Validation of this technique for routine use is challenging, and more experiments are needed to validate this preclinical set-up.

Pharmacokinetic profile of methotrexate in psoriatic skin via the oral or subcutaneous route using dermal microdialysis showing higher methotrexate bioavailability in psoriasis plaques than in non-lesional skin.

AIMS: The aim of this pilot study was to use microdialysis to evaluate levels of Methotrexate (MTX) directly in psoriatic skin following oral or subcutaneous administration of MTX to elaborate a complete pharmacokinetic profile within the dermal skin. METHODS: Six patients with chronic plaque psoriasis on the arm undergoing treatment with MTX were included in a mono-centre clinical trial. Patients were under treatment with p.o. or s.c. MTX (7.5 and 15 mg) for at least 3 months. Interstitial fluid was collected ex vivo via dermal microdialysis from lesional or non-lesional skin and via intravenous microdialysis as well as blood serum every hour up to 10 h after methotrexate administration every hour. MTX was analysed via liquid chromatography. RESULTS: The area under the curve (AUC) of methotrexate from peripheral blood was up to four times higher than from microdiaylsis, which detection of free unbound MTX. The AUC from dialysates in psoriatic lesional skin was higher than in non-lesional psoriatic skin, and the AUC levels from i.v. microdialysis were non-significantly higher than those from lesional psoriatic skin. Pharmacokinetic profiles were individually quite different and did not primarily depend on the dose or the means (p.o. vs. s.c.) in which it was administered. CONCLUSION: Dermal microdialysis is a valid tool to evaluate levels of methotrexate in the skin of psoriasis patients. Drug levels and bioavailability of methotrexate were higher in lesional than non-lesional psoriatic skin. The individual AUC of MTX was not primarily dependent on the route or dose of administration.

Expression of epidermal stem cell markers in skin and adnexal malignancies.

BACKGROUND: Epidermal stem cells are multipotent cells that maintain the skin epidermis. Potential markers for stem cells have been identified in mammalian skin from mouse experiments; however, it is unclear if stem cells also contribute to tumour formation in human skin. OBJECTIVES: To investigate the expression of potential stem cell markers, such as leucine-rich repeat-containing G protein-coupled receptor (Lgr) 5, Lgr6, leucine-rich repeats and immunoglobulin-like domain protein 1 (Lrig1) and cytokeratin 15 (CK15) in basal cell carcinomas and tumours of the skin appendages. METHODS: We tested 45 human basal cell carcinomas (BCCs), including superficial, nodular, adenoid, infiltrating and sclerosing types, and 38 human tumours of skin appendages, including 13 sebaceous adenomas and carcinomas, 20 eccrine sweat gland tumours and five pilomatricomas, for the expression of hair follicle stem cell markers such as Lgr5, Lrig1, CK15, ß-catenin and SRY (sex determining region Y)-box 9 (SOX9), and compared these findings with those of healthy age-matched human epidermis. RESULTS: We detected the expression of stem cell markers in all tumours tested. Regarding Lgr5, Lrig1, CK15 and SOX9, expression seemed to be lower in more aggressive tumour types, such as in the most advanced parts of infiltrating BCC, in sebaceous carcinoma and late-stage porocarcinoma, compared with less aggressive superficial or nodular BCC or early-stage porocarcinoma and sebaceous gland tumours. In aggressive, sclerosing BCC, Lrig1 and Lgr5 were downregulated but CK15, SOX9 and nuclear ß-catenin were upregulated. CONCLUSIONS: Expression of potential stem cell markers of the epidermis and hair follicles was observed in skin tumours of appendages and BCCs. However, during tumour progression, many of these markers seemed to be downregulated.

Selective regional perfusion of the bilateral external carotid arteries with pegylated liposomal doxorubicin and melphalan to treat metastatic malignant melanoma of the scalp.

We present the case of a 79-year-old patient with extensive metastatic malignant melanoma (MM) of the scalp. Cutaneous MM of the head and neck often presents a therapeutic challenge. Radical surgical procedures and conventional chemotherapy are often unfeasible and contraindicated because of the difficult anatomy, the extent of the tumour process, and systemic toxicity. In our patient, selective intra-arterial perfusion with pegylated liposomal doxorubicin (PLD) and melphalan was performed after catheterization of both bilateral external carotid arteries with an arterial port system. PLD 4.5 mg/m(2) and melphalan (1.35 mg/m(2), followed by 2.7 mg/m(2) after reaching tolerance) were given as short-term infusions at two-weekly intervals into the right and left external carotid arteries, respectively. After eight applications with tolerable side-effects, no MM cells were detected; however, infiltrates of lymphocytes and melanophages were seen. This case suggests that intra-arterial chemotherapy may be a useful treatment for metastatic melanoma of the scalp.

[Networking as an opportunity to profile a clinic? Strategy options after the evaluation of resource allocation]. / Vernetzung als Chance zur Profilierung einer Klinik? Strategieoptionen nach Evaluation der Zuweiser.

BACKGROUND AND OBJECTIVES: Diagnosis-related groups of medical services has recently been introduced for reimbursing hospital services. The aim has been to optimize bed capacity, decrease the duration of inpatient stay and provide good follow-up medical care. This confronts hospitals with the need for closely cooperating with the referring general practitioners or specialists. METHOD: A specially structured questionnaire was sent to all those general practitioners and specialists (n=890) who had referred patients to a university department of dermatology. The response rate was 23%. The completed questionnaires were analysed with respect to criteria judged to be important in determining referral for inpatient care and the quality of medical and related service provisions. RESULTS: Especially important to the referring doctors were optimal competence of patient care, the degree of cooperation and prompt, detailed information after the patients have been discharged. CONCLUSION: This type of analysis can serve to optimize the course of diagnosis/treatment and to utilize fully the available hospital resources. Also considered are various ways in which a hospital department can, by networking with general practitioners and specialists, become a centre for providing optimal services.