Vesicular systems for delivering conventional small organic molecules and larger macromolecules to and through human skin

The history of using vesicular systems for drug delivery to and through skin started nearly three decades ago with a study utilizing phospholipid liposomes to improve skin deposition and reduce systemic effects of triamcinolone acetonide. Subsequently, many researchers evaluated liposomes with respect to skin delivery, with the majority of them recording localized effects and relatively few studies showing transdermal delivery effects. Shortly after this, Transfersomes were developed with claims about their ability to deliver their payload into and through the skin with efficiencies similar to subcutaneous administration. Since these vesicles are ultradeformable, they were thought to penetrate intact skin deep enough to reach the systemic circulation. Their mechanisms of action remain controversial with diverse processes being reported. Parallel to this development, other classes of vesicles were produced with ethanol being included into the vesicles to provide flexibility (as in ethosomes) and vesicles were constructed from surfactants and cholesterol (as in niosomes). Thee ultradeformable vesicles showed variable efficiency in delivering low molecular weight and macromolecular drugs. This article will critically evaluate vesicular systems for dermal and transdermal delivery of drugs considering both their efficacy and potential mechanisms of action.

Topical delivery of a naproxen-dithranol co-drug: in vitro skin penetration, permeation, and staining

Purpose This work probed the topical delivery and skin-staining properties of a novel co-drug, naproxyl-dithranol (Nap-DTH), which comprises anti-inflammatory (naproxen) and anti-proliferative (dithranol) moieties. Method Freshly excised, full-thickness porcine ear skin was dosed with saturated solutions of the compounds. After 24 h, the skin was recovered and used to prepare comparative depth profiles by the tape-stripping technique and to examine the extent of skin staining. Results Depth profiles showed that Nap-DTH led to a 5-fold increase in drug retention in the skin compared to dithranol. The application of Nap-DTH also demonstrated improved stability, resulting in lower levels of dithranol degradation products in the skin. Furthermore, significantly less naproxen from hydrolysed Nap-DTH permeated into the receptor phase compared to naproxen when applied alone (0.08 ± 0.03 nmol cm-² and 180 ± 60 nmol cm-², respectively). Moreover, the reduced staining of the skin was very apparent for Nap-DTH compared to dithranol. Conclusions Topical delivery of Nap-DTH not only improves the delivery of naproxen and dithranol, but also reduces unwanted effects of the parent moieties, in particular the skin staining, which is a major issue concerning the use of dithranol.

Immunogenetics of drug-induced skin blistering disorders. Part II: Synthesis

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon examining the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events including Stevens-Johnson syndrome and Toxic epidermal necrolysis). New results from an exemplar study on shared precipitating and perpetuating inner causes with other related disease phenotypes including aphtous stomatitis, Behcets, erythema multiforme, Hashimoto's thyroiditis, pemphigus, periodic fevers, Sweet's syndrome and drug-induced multisystem hypersensitivity are presented. A call for a collaborative, wider demographic profiling and deeper immunotyping in suggested future work is made.

Immunogenetics of drug-induced skin blistering disorders. Part I: Perspective

The overall immunopathogenesis relevant to a large series of disorders caused by a drug or its associated hyperimmune condition is discussed based upon the examination of the genetics of severe drug-induced bullous skin problems (sporadic idiosyncratic adverse events, including Stevens-Johnson syndrome and toxic epidermal necrolysis). An overarching pharmacogenetic schema is proposed. Immune cognition and early-effector processes are focused upon and a challenging synthesis around systems evolution is explained by a variety of projective analogies. Etiology, human leukocyte antigen-B, immune stability, clysiregulation, pharmacomimicry, viruses and an aggressive ethnically differentiated 'karmic' response are discussed.

The staphylococcus aureus surface protein IsdA mediates resistance to the innate defenses of human skin

Resistance to human skin innate defenses is crucial for survival and carriage of Staphylococcus aureus, a common cutaneous pathogen and nasal colonizer. Free fatty acids extracted from human skin sebum possess potent antimicrobial activity against S. aureus. The mechanisms by which S. aureus overcomes this host defense during colonization remain unknown. Here, we show that S. aureus IsdA, a surface protein produced in response to the host, decreases bacterial cellular hydrophobicity rendering them resistant to bactericidal human skin fatty acids and peptides. IsdA is required for survival of S. aureus on live human skin. Reciprocally, skin fatty acids prevent the production of virulence determinants and the induction of antibiotic resistance in S. aureus and other Gram-positive pathogens. A purified human skin fatty acid was effective in treating systemic and topical infections of S. aureus suggesting that our natural defense mechanisms can be exploited to combat drug-resistant pathogens.

A seven-year follow-up of men following a benign prostate biopsy

Objectives: To determine the incidence and clinical relevance of newly diagnosed cases of prostate cancer in a group of men who had an elevated PSA and benign prostate biopsy 7 years previously. Patients and Method: Patients under the age of 80 years with an elevated PSA who had had a benign prostate biopsy in the 12 months between March 1, 1994 and February 28, 1995 were studied. One hundred and sixty four patients with a mean age of 66.8 years (range 47-79 years) were identified. The mean PSA for this group was 10.3 ng/ml (range 4.1-81 ng/ml). One hundred and fifty nine of the 164 (97%) hospital records were available for review and all but 21 (12.8%) of the General Practitioners were contacted. Results: Eighteen (11%) of the original 164 patients were subsequently diagnosed with prostate cancer, 2 died from their disease. Conclusions: In a population where the follow-up of patients with a benign biopsy was arranged on clinical grounds alone, 11% of the study group were diagnosed with prostate cancer during a seven-year follow-up. Although some of these cancers appear to be slow growing, most of those diagnosed in the initial follow-up period were deemed to be clinically significant and a small proportion progressed rapidly to metastases. All patients who have an elevated PSA, but benign biopsy, should undergo a period of PSA monitoring until it is clear that their PSA is not rising. We propose an initial intensive monitoring period to avoid missing those with clinically aggressive disease. (C) 2003 Elsevier Science B.V. All rights reserved.

Quantitative thermal imaging analysis of aircraft materials: through skin sensing (Invited Paper)

Thermal non-destructive testing (NDT) is commonly used for assessing aircraft structures. This research work evaluates the potential of pulsed -- transient thermography for locating fixtures beneath aircraft skins in order to facilitate accurate automated assembly operations. Representative aluminium and carbon fibre aircraft skin-fixture assemblies were modelled using thermal modelling software. The assemblies were also experimentally investigated with an integrated pulsed thermographic evaluation system, as well as using a custom built system incorporating a miniature un-cooled camera. Modelling showed that the presence of an air gap between skin and fixture significantly reduced the thermal contrast developed, especially in aluminium. Experimental results show that fixtures can be located to accuracies of 0.5 mm.

The use of gaseous ozone and gas packaging to control populations of Salmonella infantis and Pseudomonas aeruginosa on the skin of chicken portions

Chilled breasts of chicken were inoculated with Salmonella infantis or Pseudomonas aeruginosa and then given one of the following treatments: (i) exposure to gaseous ozone (>2000 ppm for up to 30 min); (ii) storage under 70% CO2:30% N-2; and (iii) exposure to gaseous ozone (>2000 ppm for 15 min) followed by storage under 70% CO2:30% N-2; all storage at 7degreesC. Gaseous ozone reduced the counts of samnonellae by 97(Y,, and pseudomonads by 95%, but indigenous coliforms were unaffected. Under the modified atmosphere, the cell count of S. infantis was reduced by 72% following initial exposure and then stabilised, coliforms grew, but Ps. aeruginosa behaved like S. infantis-initial reduction (58%) followed by stability. Exposure to gaseous ozone followed by gas packaging allowed survival of S. infantis, Ps. aeruginosa and coliforms over 9 days at 7degreesC, but there was no evidence of any sensory deterioration. It is proposed that the latter treatment could, in a modified form perhaps, be used to reduce the contamination of chicken carcasses with salmonellae and improve their shelf-life. (C) 2004 Elsevier Ltd. All rights reserved.

Molecular interactions between the penetration enhancer 1,8-cineole and human skin

Penetration enhancers are chemicals that temporarily and reversibly diminish the barrier function of the outermost layer of skin, the stratum corneum, to facilitate drug delivery to and through the tissue. In the current study, the complex mechanisms by which 1,8-cineole, a potent terpene penetration enhancer, disrupts the stratum corneum barrier is investigated using post-mortem skin samples. In order to validate the use of excised tissue for these and related studies, a fibre optical probe coupled to an FT-Raman spectrometer compared spectroscopic information for human skin recorded from in vivo and in vitro sampling arrangements. Spectra from full-thickness (epidermis and dermis) post-mortem skin samples presented to the spectrometer with minimal sample preparation (cold acetone rinse) were compared with the in vivo system (the forearms of human volunteers). No significant differences in the Raman spectra between the in vivo and in vitro samples were observed, endorsing the use of post-mortem or surgical samples for this investigational work. Treating post-mortem samples with the penetration enhancer revealed some unexpected findings: while evidence for enhancer-induced disruption of the barrier lipid packing in the stratum corneum was detected in some samples, spectra from other samples revealed an increase in lipid order on treatment with the permeation promoter. These findings are consistent with phase-separation of the enhancer within the barrier lipid domains as opposed to homogeneous disruption of the lipid lamellae. Copyright (C) 2006 John Wiley & Sons, Ltd.

Permeation of bioactive constituents from Arnica montana preparations through human skin in-vitro

This study investigated and characterised transdermal permeation of bioactive agents from a topically applied Arnica montana tincture. Permeation experiments conducted over 48 h used polyclimethylsiloxane (silastic) and human epidermal membranes mounted in Franz-type diffusion cells with a methanol-water (50:50 v/v) receptor fluid. A commercially available tincture of A. montana L. derived from dried Spanish flower heads was a donor solution. Further donor solutions prepared from this stock tincture concentrated the tincture constituents 1, 2 and 10 fold and its sesquiterpene lactones 10 fold. Permeants were assayed using a high-performance liquid chromatography method. Five components permeated through silastic membranes providing peaks with relative retention factors to an internal standard (santonin) of 0.28, 1.18, 1.45, 1.98 and 2.76, respectively. No permeant was detected within 12 h of applying the Arnica tincture onto human epidermal membranes. However, after 12 h, the first two of these components were detected. These were,shown by Zimmermann reagent reaction to be sesquiterpene lactones and liquid chromatography/diode array detection/mass spectrometry indicated that these two permeants were 11,13-dihydrohelenalin (DH) analogues (methacrylate and tiglate esters). The same two components were also detected within 3 h of topical application of the 10-fold concentrated tincture and the concentrated sesquiterpene lactone extract.