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Venous leg ulcers (VLUs) are one of the most prevalent types of chronic wounds. The aim of this study was to determine the safety and dose-response efficacy of the human synthetic peptide LL-37 in the treatment of hard-to-heal VLUs. This first-in-man trial included 34 participants with VLUs and comprised a 3-week, open-label, run-in period on placebo, followed by a 4-week randomized double-blind treatment phase with twice weekly applications of LL-37 (0.5, 1.6, or 3.2 mg/mL) or placebo, and a 4-week follow-up. The healing rate constants for 0.5 and 1.6 mg/mL of LL-37 were approximately six- and threefold higher than for placebo (p = 0.003 for 0.5 mg/mL and p = 0.088 for 1.6 mg/mL). Square-root transformed wound area data showed improved healing for the 0.5 and 1.6 mg/mL dose groups compared with pretreatment values (p < 0.001 and p = 0.011, respectively). Consistently, treatment with the two lower doses markedly decreased the mean ulcer area (68% for 0.5 mg/mL and 50% for 1.6 mg/mL groups). No difference in healing was observed between the groups receiving 3.2 mg/mL of LL-37 and placebo. There were no safety concerns regarding local or systemic adverse events. In conclusion, topical treatment with LL-37 for chronic leg ulcers was safe and well tolerated with the marked effect on healing predictors at the two lower doses warranting further investigations.

Since nitric oxide (NO) has been implicated in the pathogenesis of various hyperproliferative and inflammatory diseases, the mRNA expression of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) were investigated in psoriatic skin by reverse transcriptase coupled to the polymerase chain reaction (PCR). The study showed that the mRNA expression of brain nitric oxide synthase (bNOS), one of two isoforms of cNOS, was weak in both psoriatic plaques lesions and uninvolved skin, while mRNA transcripts for the second isoform, endothelial nitric oxide synthase (eNOS), were not detectable using the present method. In contrast, the mRNA expression of iNOS was markedly increased in lesional skin as compared to uninvolved skin. Cultured human keratinocytes exposed to a combination of interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha) for 4 h, showed strong gene expression of iNOS, while in 24 h, the expression had returned to baseline expression. In summary, the study demonstrates that mRNA for the inducible form of NOS is over-expressed in psoriatic lesions. The cause of this may be the local presence of inflammatory cytokines. These findings imply that iNOS may play an important part in local regulation of NO synthesis in psoriasis and other inflammatory dermatoses.

Pro-vitamin A(beta-carotene) and the predominant forms of vitamin A in human skin (retinol and dehydroretinol) were analyzed in hydrolyzed specimens from 4 cadavers and 22 healthy subjects. Beta-carotene was identified in extracts of epidermis by its specific absorption spectrum. Vitamin A was determined by high-pressure liquid chromatography. The concentrations were related to the wet weight or protein content of the sample. The analysis of different skin compartments showed that the concentrations of the 3 constituents were usually related as follows: carotene greater than retinol greater than dehydroretinol. The concentrations were always higher in the epidermis than in the upper dermis. Skin surface lipids contained carotene and retinol but not in amounts sufficient to contribute to the higher epidermal values. Analysis of epidermal autopsies from 5 different skin areas (back, breast, arm, leg and foot) and of epidermal biopsies from the back of the healthy subjects showed that the interindividual differences were larger for carotene and dehydroretinol than for retinol, whereas the intraindividual variations were larger for retinol. The mean (+/- SD) concentrations of carotene, retinol and dehydroretinol in back skin epidermis of healthy subjects were 13 +/- 5, 1.7 +/- 0.4 and 0.4 +/- 0.2 microgram/g protein, respectively. No significant variations with age and sex were found.

This article is partially based on the findings presented at a symposium on Cutaneous Gene Therapy, held in Uppsala, September 2001, and abstracted in Acta Derm Venereol 81: 227–239. Abstract. Khavari PA, Rollman O, Vahlquist A (Stanford University School of Medicine, Stanford, CA, USA; and Department of Medical Sciences, Dermatology, Uppsala University, Uppsala, Sweden). Cutaneous gene transfer for skin and systemic diseases (Review). J Intern Med 2002; 252: 1–10. Recent progress in molecular genetics has illuminated the basis for a wide variety of inherited and acquired diseases. Gene therapy offers an attractive therapeutic approach capitalizing upon these new mechanistic insights. The skin is a uniquely attractive tissue site for development of new genetic therapeutic approaches both for its accessibility as well as for the large number of diseases that are amenable in principle to cutaneous gene transfer. Amongst these opportunities are primary monogenic skin diseases, chronic wounds and systemic disorders characterized by low or absent levels of circulating polypeptides. For cutaneous gene therapy to be effective, however, significant progress is required in a number of domains. Recent advances in vector design, administration, immune modulation, and regulation of gene expression have brought the field much nearer to clinical utility.