bromochloroacetic-acid and Dermatitis--Irritant

New therapeutic approaches have to be considered in the treatment of irritant contact dermatitis (ICD). Recently, phosphodiesterase 4 (PDE-4) inhibitors have been introduced as nonsteroidal, antiinflammatory agents. These agents inhibit the secretion of the cytokines thought to be involved in the pathogenesis of ICD. We investigated the effect of a new selective PDE-4 inhibitor (cipamfylline) in human models using single and repeated exposures to an irritant in a blind, randomized pilot study with healthy volunteers. We compared the effect of cipamfylline ointment with a strong corticosteroid (betamethasone-17-valerate) and with a placebo ointment.. Ten volunteers were patch tested at four investigation sites with sodium dodecyl sulphate (1%) for 24 h. In a model that simulates chronic damage, 11 volunteers were patch tested with sodium dodecyl sulphate (0.2%) for 4 h daily for four consecutive days. The investigation sites were treated once a day with the above-mentioned agents. One site was left untreated. We used erythema scoring, measurements of transepidermal water loss (TEWL) and several immunohistochemical markers for epidermal proliferation and differentiation.. Repeated application revealed that betamethasone-17-valerate caused a statistically significant reduction in erythema and TEWL compared to cipamfylline and placebo. We also observed a significant suppression of proliferating cells and cytokeratin 16 expression at sites treated with betamethasone compared to the other sites. In the model for acute ICD, no significant differences were seen between the investigated sites.. Our results show that betamethasone-17-valerate may modulate the response in ICD. In this human model of ICD we could not confirm the efficacy of cipamfylline. Clinical studies are needed before the effect of PDE-4 inhibitors in ICD can be refuted with certainty.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adult; Aged; Betamethasone Valerate; Cell Division; Cyclic Nucleotide Phosphodiesterases, Type 4; Dermatitis, Irritant; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Erythema; Female; Glucocorticoids; Humans; Keratins; Male; Middle Aged; Pilot Projects; Sodium Dodecyl Sulfate; Surface-Active Agents; Water Loss, Insensible; Xanthines

Hydrocolloid (HCD) dressings enhance the efficacy of topical corticosteroids.. We wanted to evaluate the effect of calcipotriol ointment under an HCD dressing in the treatment of psoriatic plaques.. In 9 psoriatic patients, we cleared one plaque using this approach and took biopsies at start, clearance and relapse. Clinical and immunohistochemical validation was assessed.. After an average treatment of 3.6 weeks, each lesion had cleared (apart from some residual erythema). The average remission period was 8 weeks. During this treatment, the number of cycling epidermal cells (Ki-67-positive nuclei) and the expression of keratin 14 and keratin 16 had decreased substantially. In biopsies taken from the skin immediately adjacent to the relapsing lesion, these markers remained reduced which indicated the prolonged effect of calcipotriol on epidermal differentiation.. It is speculated that combination therapy of calcipotriol with treatments with a different mode of action such as photo(chemo)therapy, corticosteroids and cyclosporine might be worthwhile.

Topics: Adult; Aged; Antigens, Nuclear; Apoptosis; Calcitriol; Colloids; Dermatitis, Irritant; Dermatologic Agents; ErbB Receptors; Female; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Keratin-14; Keratins; Ki-67 Antigen; Male; Middle Aged; Nuclear Proteins; Occlusive Dressings; Ointments; Patient Dropouts; Psoriasis; Skin; Treatment Outcome

Genetically engineered mouse models with altered oncogene or tumor suppressor gene activity have been utilized recently for carcinogen identification. The v-rasHa transgenic Tg.AC mouse, with its enhanced susceptibility to skin tumorigenesis, is thought to be well suited for examining the carcinogenicity of topically applied agents. Tg.AC mice were used to examine the carcinogenicity of SEPA 0009, a rationally designed organic molecule designed to enhance drug penetration through the skin. Fifty mg SEPA 0009/kg body weight, 1500 mg SEPA 0009/kg body weight, or the vehicle alone was applied daily to the skin of Tg.AC mice. Nontransgenic FVB/N mice were also treated with the vehicle alone or 1500 mg SEPA 0009. Daily application of a high-dose of SEPA 0009 caused severe and chronic irritation by 1 week that was maintained throughout the experiment. The irritation was accompanied by increased proliferation, increased apoptosis, and expression of the wound-associated keratin 6. High-dose SEPA 0009 induced squamous papillomas in Tg.AC, but not in nontransgenic mice, by 6 weeks. In mice treated with the high dose SEPA 0009, transgene expression was detected in papillomas at week 9, well after the onset of skin irritation and hyperplasia. In contrast, low-dose SEPA 0009 was not irritating to the skin and did not induce papillomas. Thus, SEPA 0009-induced tumorigenesis was associated with chronic and severe irritation. We propose that SEPA 0009-induced tumorigenesis in Tg.AC mice proceeds through an indirect mechanism that is secondary to cutaneous irritation.

Topics: Animals; Carcinogenicity Tests; Carcinogens; Cell Death; Cell Proliferation; Dermatitis, Irritant; Dioxolanes; Dose-Response Relationship, Drug; Epidermis; Female; Gene Expression; Genes, ras; Hyperplasia; Keratin-6; Keratinocytes; Keratins; Mice; Mice, Transgenic; Papilloma; Precancerous Conditions; Skin; Skin Neoplasms; Tetradecanoylphorbol Acetate; Time Factors

The aims of this study were to utilize quantitative immunocytochemical techniques to determine the densities of keratin 16 (K16) and keratin 17 (K17) expressed by keratinocytes during the course of acute patch test reactions to sodium lauryl sulfate (SLS), and to relate these to the proliferative state of the epidermis, as assessed by Ki-67 immunolabelling. Significantly increased numbers of dividing keratinocytes were present in 48h and 96h reactions, concurrent with high levels of expression of K16 and more moderate expression of K17. Statistical analysis indicated a good correlation between K16 expression and the density of Ki-67+ keratinocytes present in the epidermis (r=0.843). This was not the case for K17 (r=0.396). The results demonstrate that both K16 and K17 expression are features of acute irritant contact dermatitis reactions, but suggest that the factors which influence and control their expression differ.

Topics: Adult; Cell Count; Cell Division; Data Interpretation, Statistical; Dermatitis, Irritant; Humans; Immunohistochemistry; Keratinocytes; Keratins; Male; Middle Aged; Patch Tests; Sodium Dodecyl Sulfate; Surface-Active Agents

We have previously reported 18 cases of an ichthyosiform contact dermatitis caused by antiseptic solutions containing 3% cetrimide and 0.3% chlorhexidine. The reaction was traced to cetrimide, a mixture of quaternary ammonium compounds that are widely used as disinfectants and detergents. Quaternary ammonium compounds are known irritants. To elucidate the pathogenesis of the abnormal keratinization caused by cetrimide, electron microscopy was performed on biopsied lesions from five patients and on specimens from rabbits in which a mild reaction had been induced by closed patch with Savlon, cetrimide, and chlorhexidine. The patients' samples revealed hyperkeratosis with striking vesiculation of lamellar bodies in the granular cells and upper spinous cells, premature secretion of lamellar bodies, and abundant remnants of lamellar bodies and retention of desmosomes between the corneocytes. Similar lamellar bodies changes were induced in rabbit skin after 48 hours of closed patch with Savlon 1:30 and cetrimide 0.1%, but not with chlorhexidine 3%-further indication that cetrimide was the cause of the dermatitis. We conclude that the abnormal keratinization can be attributed, at least in part, to dysfunction of lamellar bodies resulting from the direct effects of cetrimide on the lipids and enzymes of lamellar bodies. Vesiculation with dysfunction of lamellar bodies may be an important pathogenetic mechanism in irritant dermatitis caused by quaternary ammonium compounds.

Topics: Animals; Anti-Infective Agents, Local; Anti-Inflammatory Agents, Non-Steroidal; Blister; Cetrimonium; Cetrimonium Compounds; Chlorhexidine; Cytoplasmic Granules; Dermatitis, Contact; Dermatitis, Irritant; Desmosomes; Drug Combinations; Epidermis; Humans; Ichthyosis; Keratinocytes; Keratins; Keratosis; Lipid Metabolism; Microscopy, Electron; Organelles; Patch Tests; Rabbits; Skin

Although the induction of acute irritant dermatitis by detergents has been studied extensively in recent years, our understanding of the cell biological events in the repair phase, and its relevance for the development of chronic irritant dermatitis is limited. Here we studied the reaction pattern of human skin to short-term application of sodium dodecyl sulphate (SDS) in a model that induced a minimal acute inflammatory reaction (absence of polymorphonuclear leucocytes, PMN) and did not have cytopathic effects on the epidermal keratinocytes as determined by histological investigation. All parameters were measured up to 14 days after exposure to SDS. Application of SDS caused disturbances of barrier function as measured by transepidermal water loss and had vascular effects as judged by erythema. Several cell biological markers for epidermal growth and differentiation were examined by immunohistochemistry. A rapid and strong induction of the cornified envelope precursor protein involucrin was seen in the stratum spinosum, with a peak at 24 h. Within 24 h a strong upregulation of epidermal fatty acid binding protein (E-FABP) was noted, with a peak at 7 days after injury. Cellular proliferation in the basal layer was increased fivefold as assessed by nuclear staining for the Ki-67 antigen, showing a peak at 48 h. Surprisingly, no significant induction of cytokeratin 16 and SKALP/elafin expression, two markers associated with epidermal hyper-proliferation and inflammation, was seen. These findings suggest that the cellular changes following exposure to detergent are distinct from those seen in other forms of skin injury. We would speculate that the epidermal response to detergent exposure is primarily directed at restoration of barrier function.

Topics: Adult; Biomarkers; Carrier Proteins; Cell Differentiation; Cell Division; Dermatitis, Irritant; Detergents; Epidermis; Erythema; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Female; Humans; Keratinocytes; Keratins; Ki-67 Antigen; Male; Models, Biological; Myelin P2 Protein; Neoplasm Proteins; Protein Precursors; Proteinase Inhibitory Proteins, Secretory; Proteins; Sodium Dodecyl Sulfate; Time Factors; Tumor Suppressor Proteins

Allergic and irritant contact dermatitis are similar clinically, histologically and on immunohistochemistry. In the present investigation, we assessed whether study of the recruitment of cycling epidermal cells, and the expression of keratin 16 and involucrin, are of use in differentiating between the response to contact allergens and the response to the irritant detergent sodium lauryl sulphate. Both allergic and irritant challenges induced epidermal proliferation, and the expression of keratin 16 and involucrin, but the dynamics were different. Two and 3 days after challenge, a highly significant difference between the allergic and irritant reactions was observed with respect to involucrin expression assessed by MON-150 staining.

Topics: Adult; Aged; Cell Differentiation; Cell Division; Dermatitis, Allergic Contact; Dermatitis, Irritant; Epidermis; Female; Humans; Immunohistochemistry; Keratins; Male; Middle Aged; Protein Precursors; Time Factors