Background Propionibacterium acnes is a major contributing factor to the inflammatory component of acne. The interaction of P. acnes with keratinocytes leads to an innate immune response via activation of toll-like receptors (TLR2, TLR4) resulting in the production and secretion of pro-inflammatory mediators. SIG1273, an isoprenylcysteine small molecule modulates inflammatory signaling pathways and kills P. acnes. SIG1273 represents a novel cosmetic functional ingredient that provides relief from blemishes in acne prone skin. Objective To assess the keratinocyte response and microbial growth of SIG1273 in vitro and evaluate the tolerability of SIG1273 gel applied topically in acne prone subjects. Methods For in vitro studies, human keratinocytes were exposed in culture to live P. acnes and peptidoglycan (PGN) to induce IL-8 production. P. acnes were cultured to determine minimal inhibitory concentration and minimal bactericidal concentration values. A total of 30 subjects were randomized in a double-blind controlled trial receiving 3% SIG1273 gel or vehicle for 6 weeks. Evaluation included inflammatory lesions, noninflammatory lesions, microcomedones, Sebutape scores, and P. acnes counts. Results In vitro studies demonstrate SIG1273 inhibits P. acnes-induced IL-8 production and inhibits P. acnes growth. SIG1273 gel was well tolerated with no signs of stinging, redness, or itching. Furthermore, improvement in some aspects of acne was observed in subjects applying SIG1273 gel, including inflammatory lesions, microcomedone counts and Sebutape scores. Facial scrubs taken to measure P. acnes colony-forming units showed those applying SIG1273 gel had 1.0 Log 10 colony reduction over the length of the study, a statistically significantly improvement when compared with vehicle. No significant effects above vehicle were observed for noninflammatory lesions. Conclusions SIG1273 represents a novel cosmetic functional ingredient that provides a safe dual modulating benefit to individuals with acne prone skin by reducing P. acnes counts and reducing inflammation.

Background: Retinoids are photoreactive molecules found in skin and retinal tissue. The use of retinoids in pharmacologic doses, applied topically, raises the potential of phototoxicities. Recent review articles and current US drug labeling indicate that tretinoin is a phototoxin. In developing a new formulation of topical all‐trans‐retinoic acid (tretinoin), formal testing of dermal photoreactions was therefore undertaken.Methods: Four prospective, randomized, and controlled trials were carried out in healthy volunteers at two independent research facilities. Two trials examined phototoxicity following 24 h of drug exposure under occlusion (combined n=51), and two examined photoallergenicity following a 3‐week, six dose induction phase (combined n=72) followed by challenge.Results: No phototoxic or photoallergic reactions occurred with tretinoin 0.05% in a new gel formulation.Conclusion: The findings in these studies are consistent with previous studies of tretinoin in various formulations, and support the conclusion that tretinoin appears to be neither phototoxic nor photoallergenic in vivo.

Removal of necrotic tissue is essential for wound-bed preparation for the treatment of chronic wounds. Enzymatic debridement appears to be most useful in the removal of eschar when surgical techniques cannot be utilized. The purpose of this study is to determine the efficacy of papain–urea chlorophyllin ointment compared to moist wound care using an infected, acute, porcine full thickness wound model. Twenty full thickness wounds were created on the dorsum of domestic pigs. Following hemostasis, the wounds were contaminated with wound-isolated bacteria then treated with test articles and dressed with moisture-retentive dressing. All the wounds were evaluated 1, 4, 8, 11, 14,18, and 21 days postsurgery for epithelialization and biopsies were obtained for microscopic evaluation. The results showed no adverse effect in reepithelialization in acute wounds when using papain–urea chlorophyllin "ointment compared to moist wound care, TEWL measurements also showed no adverse affects from the treatment. Microscopic examination reveals an increase in the number of keratinocytes present in the epidermis of the treated pigs as well as an increase in the depth of rete pegs. New blood vessel formation was increased at all examined time points in the papain–urea chlorophyllin ointment treated pigs, which was verified with CD31 and von Willebrand Factor staining. VEGF was increased after 1 week in the wound fluid from treated wounds compared to moist control. While the reepithelialization rate does not appear to be inhibited by papain–urea-chlorophyllin combination in acute wounds, the healing appears to be more complete based on the number of keratinocytes present in the epidermis and the extensive rete peg formation. The wounds also appear to have enhanced vascularization which is vital in supplying nutrients to the newly healed wound.

Tight junctions are composed of claudins, occludins, junctional adhesion molecules and plaque proteins. Claudin 2 protein forms a cation-selective channel which confers increased permeability in renal epithelial cells and in the intestine where its expression is restricted to the leaky epithelium. Immunohistochemical staining revealed claudin 2 staining in the granular layer of adult epidermis. Analysis of Western blots revealed bands corresponding to the molecular weight of claudin 2 in Madin-Darby canine kidney II cells, human kidney, adult skin and neonatal keratinocytes. Reverse transcriptase polymerase chain reaction on mRNA and cDNA sequence analysis found a 99% sequence homology between our cDNA and human claudin 2 (NIH BLAST sequence). Further, we show that all-trans-retinoic acid increases the expression of claudin 2 in keratinocytes in a dose-dependent manner. The discovery of claudin 2 transcript and protein in the skin could be of importance in epidermal differentiation, barrier function and pathological conditions.

An alternative approach to retinoid therapy is to inhibit the cytochrome P450 (CYP)-mediated catabolism of endogenous all-trans retinoic acid in the skin by applying retinoic acid metabolism blocking agents such as talarozole (R115866).To study the effects of topical talarozole on retinoid biomarkers in normal skin in a randomized phase I trial.Gels containing talarozole (0.35% or 0.07%) and vehicle were applied once daily for 9 days on either buttock of 16 healthy volunteers. Epidermal shave biopsies (for mRNA analysis) and punch biopsies (for histology and immunofluorescence analysis) were collected from the treatment areas. Genes encoding the following were studied by quantitative real-time polymerase chain reaction: cellular retinoic acid binding protein 2 (CRABP2), cytokeratins (KRT2 and KRT4), CYP26A1, CYP26B1, CYP26C1 and CYP2S1, two enzymes in the retinol metabolism (retinal dehydrogenase-2 and retinol acyltransferase) and two proinflammatory cytokines [interleukin (IL)-1 alpha and tumour necrosis factor-alpha].Talarozole treatment increased the mRNA expression of CRABP2, KRT4, CYP26A1 and CYP26B1 dose dependently, and decreased the expression of KRT2 and IL-1 alpha compared with vehicle-treated skin. No mRNA change in retinol-metabolizing enzymes was obtained. There was no induction of epidermal thickness or overt skin inflammation in talarozole-treated skin. Immunofluorescence analysis confirmed an upregulation of KRT4 protein, but no upregulation of CYP26A1 and CYP26B1 expression was detected.Talarozole influences the biomarker pattern consistently with increased retinoic acid stimulation. The low irritancy of talarozole at the two examined dosages is a possible advantage over topical retinoids.

One of the well-known enzymatic debriders is a papain–urea-chlorophyllin ointment. The purpose of this study was to determine the efficacy of this ointment compared with single variable Papain-urea, Copper chlorophyllin, or Urea base ointment and moist wound care in porcine full thickness wounds. Twenty full thickness wounds were made on the dorsum of domestic pigs. Following hemostasis, the wounds were contaminated with wound-isolated bacteria, treated with test articles, and dressed with moisture-retentive dressing. All the wounds were evaluated 1, 4, 8, 11, 14, 18, and 21 days postsurgery visually and biopsies were obtained for microscopy. The results showed no impairment in the rate of epithelialization of the papain–urea-chlorophyllin treatment, nor with single variable actives compared with moist wound care. Microscopic examination revealed an increase in the number of keratinocytes present in the epidermis of the papain–urea-chlorophyllin and papain-treated wounds, and an increase in the depth of rete pegs. Blood vessel formation was increased in the papain–urea-chlorophyllin, papain, and Copper chlorophyllin groups compared to the moist control tissue as seen with CD31 and von Willebrand Factor staining, and was most evident in the papain–urea-chlorophyllin-treated tissues. VEGF was increased after 1 week in the wounds treated with papain–urea-chlorophyllin and papain compared to vehicle, indicating a possible mechanism for neovascularization. The increase was not seen in the Copper chlorophyllin group, indicating the possibility of another mechanism for blood vessel formation in this group. The healing appears to be most complete in the papain–urea-chlorophyllin group based on epidermal morphology and enhanced vascularization, which is vital in supplying nutrients to the newly healed wound.

The purpose of this study was to examine the dermal and epidermal alterations associated with wound healing in wounds treated with papain urea copper chlorophyllin (PUC), papain-urea, copper chlorophyllin, or urea base ointment and compare these with moist wound care using a porcine full-thickness infected wound model. All the wounds were evaluated postsurgery for erythema, transepidermal water loss, microscopic morphology, and changes in protein expression. Examination of stained paraffin sections revealed an increase in the number of keratinocytes present in the epidermis of the PUC and papain-treated pigs, relative to moist control. This increase in keratinocyte number corresponded to an increase in the movement of the keratinocytes into the underlying dermis in the form of rete pegs. In the dermis, there appeared to be an increase in blood vessel formation, collagen I deposition, and mature collagen in the papain and PUC treated tissues. The quality of healing appears to be enhanced based on the number of keratinocytes present in the epidermis, the extensive rete peg formation, the increase in vasculature, and the increase in collagen birefringence.

Many topical corticosteroids currently on the market contain a halogen substitution at the C6, C9, or the side-chain C21 position of the corticosteroid skeleton. These modifications have enhanced the efficacy of corticosteroids as compared to hydrocortisone as topical anti-inflammatory agents, but have often increased side effects such as skin atrophy, adrenal suppression, and telangiectasia. These side effects have been attributed to the presence of halogens in the corticosteroid molecule and have raised concerns regarding the safety of all halogenated corticosteroids. In this review, we assert that it is the position and nature of the halogen atom(s) in the corticosteroid molecule that determine potency/toxicity, rather than their mere presence. A greater understanding of the role of halogenation in determining corticosteroid potency and side effects will clarify why all halogenated steroids are not the same.

Multivesicular emulsion systems are a new patented technology for topical delivery of pharmaceutical and over-the-counter actives. This novel technology involves the creation of a 2-phase, oil-in-water emulsion system that produces concentric multilamellar spheres of oil and water. Active ingredients can be released from their respective layers upon application to the skin. In addition to a controlled-release of active agents, the multivesicular emulsion base improves the biophysical properties of the skin by reducing transepidermal water loss and enhancing skin hydration. This technology has been applied to 6% salicylic acid formulations that in clinical experience show efficacy with high tolerance in several hyperkeratotic disorders. Subjects' self-assessment was clearly indicative of the excellent cosmetic elegance of the multivesicular emulsion system.

A variety of different, experimentally induced human skin inflammatory stimuli including UV‐A (Barr et al., 1982a; Gilchrest et al., 1982), UV‐B (Black et al., 1978, 1980; Hensby et al., 1980; Black, Hensby & Greaves, 1982), UV‐C (Camp et al., 1978), infra‐red (Hensby et al., 1982), trafuril (Plummer et al., 1977) and anthralin (Barr et al., 1982b) cause marked and prolonged elevations of the recoverable levels of arachidonic acid and its cyclo‐oxygenase products. The known pharmacology of many prostanoids (products of the prostaglandin cyclo‐oxy‐genase system) including vasodilatation and synergism with other inflammatory mediators (Hensby, Kingston & Greaves, 1976; Camp, 1982) would suggest a role for prostanoids in various human skin diseases, particularly those associated with an inflammatory component. We now report the preliminary results that we have obtained for the recoverable levels of four prostanoids, namely PGE2, PGD2, PGF2x, and 6‐oxo‐PGF1x in four human skin disorders, viz. psoriasis, tuberculin delayed hypersensitivity, vitiligo and scleroderma.