P1008A new pseudopeptidic elastase inhibitor with protective effects on skinelastic fibers following topical administration

Yann Mahe, PhD, L’Oreal, Clichy, France; Lionel Breton, PhD, L’Oreal, Clichy,France; Maria Dalko, PhD, L’Oreal, Aulnay-sous-Bois, France; Anne Rolland, MD,L’Oreal, Clichy, France

Neutrophil elastases are thought to be central players to the process of intrinsic skinaging and photoaging. Indeed, not only they directly contribute to the directdegradation of elastic fibers under oxidative stress but also, through a complexnetwork of biochemical reactions, their interfere with collagen homeostasis in skinand contribute, to some extent, to exacerbate oxidative stress in skin and itsconsequences in terms of extracellular matrix quality. We used an in vitro modelconsisting of human skin maintained in culture ex vivo and (i) irradiated with asingle low dose of UVA or (ii) treated with human leukocyte elastase (HLE) in theculture medium to induce elastic fibers degradation in vitro. Under these experi-mental elastolysis conditions, since repair system are shut down, as low as one single8 J/cm2 UVA irradiation could totally disrupt the thin oxytalan elastic fibers,perpendicular and physically anchored to the dermoeepithelial junction. In bothexperimental conditions, topical application of the pseudo peptidic HLE inhibitorthat we designed and selected from enzymatic profiling against HLE in vitro wasfound to also totally protect 3D organized elastic fibers against elastolysis ex vivo.This protective activity on elastic fibers following HLE digestion of skin explantsin vitro was further confirmed on human skin biopsies of volunteers following top-ical application of the pseudopeptidic inhibitor in vivo, suggesting a good bio-disponibility and a protective efficacy in skin. Furthermore, in was shown toclinically improve skin elasticity in vivo using a torquemeter assay. This newlydeveloped compound might thus prove being useful to protect either photoaged,aged or stressed skin against matrix degradation such as elastolysis or otherextracellular matrix alterations such as reported in skin wrinkles formation.

100% is sponsored by L’Oreal Life Sciences Research.

P1006Chitosan coated nanocapsules, a promising new topical delivery systemfor the improvement of cyclosporin a skin penetration

Carles Trullas, PhD, ISDIN Skin Research Center, Barcelona, Spain; Ana Vila, PhD,Advancell SL, Santiago de Compostela, Spain; Silvia Suarez, PhD, Advancell SL,Santiago de Compostela, Spain; Ignasi Escamilla, PhD, ISDIN Skin ResearchCenter, Barcelona, Spain

Cyclosporine A (CsA) is an immunosuppressant that is efficacious in severalinflammatory skin disorders. Topical forms of CsA have been tried but they donot seem to be effective, presumably because of insufficient penetration of the skin.Chitosan is a hydrophilic polycation with mucoadhesive, biodegradable, andpenetration enhancement properties. With the solvent displacement technique, itis possible to obtain chitosan nanocapsules loaded with different drugs. The aim ofthis work was to assess by in vitro methods the absorption and distribution throughhuman skin of CsA incorporated at the concentration of 5 mg/ml in two topicalformulations: control trinary delivery system and chitosan-coated nanocapsules.Percutaneous in vitro absorption was studied quantitatively through human skinbiopsies mounted in a Franz diffusion cell. A first study was conducted evaluatingthe percutaneous penetration of radio-labelled 3H-CsA through frozen human skin.The amounts recovered in the full epidermis were very promising, but the nature ofthe skin did not allow separating the horny layer from the epidermis. So a secondstudy was performed, evaluating the percutaneous absorption and the completeskin distribution of radio-labelled 3H-CsA through fresh human skin. In the otherside the moisturizing effect of empty chitosan-coated nanocapsules was evaluated.Results show that the amount of CsA recovered in the viable epidermis and in thehorny layer (stratum corneum) at the end of the diffusion period is statisticallyhigher from the nanocapsules than from the control trinary delivery system. Itappears that the penetration of CsA is more intense when the drug is formulated asnanocapsules than as a trinary delivery system containing a penetration enhancer.This work suggests that the particular accumulation in the living epidermis of CsA,after the application of chitosan-coated nanocapsules can be of high interest indermatology.

100% sponsored by ISDIN Laboratories.

P1007Evaluation of the efficacy and tolerability of eflornithine HCl 13.9% creamin adult Indian women with hirsutism

Vidyagauri Baliga, PhD, Glenmark Pharmaceuticals Ltd, Mumbai, MA, India;D. Saple, MD, G T Hospital, Mumbai, India; Daljeet Kaur, MD, Indus Hospital,Mohali, India; Akhilesh Sharma, MD, Glenmark Pharmaceuticals Ltd, Mumbai,India

Objective: The present study was undertaken to assess the efficacy, safety, andtolerability of eflornithine HCl cream 13.9% in adult Indian women with hirsutism.

Material and methods: A total of 116 adult nonpregnant women (with negativeb-human chorionic gonadotropin test) with excessive, unwanted facial hair (hirsut-ism) meeting the inclusion criteria were enrolled in this prospective, multicenter,randomized, open-label, noncomparative, single group, phase III study afterapproval by the respective Institutional Ethics Committees and obtaining patients’informed consent. Selected patients were instructed to apply twice daily a thin layerof eflornithine HCl cream 13.9% to affected areas of the face and adjacent involvedareas under the chin. The duration of treatment was 12 weeks, followed by a 4-weekno-treatment period. Efficacy was assessed by Physician’s Global Assessment andSubjects Self-assessment Questionnaire (SSAQ). Tolerability and safety was assessedby physical examination, laboratory investigations, and evaluation of adverse events.

Results: One hundred and eleven patients completed the study while 5 patientswere lost to follow-up and considered as drop-outs. At the end of 4 weeks, 31.5 % oftotal cases reported total clearance/marked improvement which was a significant(P\.05) change from baseline. At the end of 12 weeks, 43.2% patients reported totalclearance/marked improvement which was also significant. Even 4 weeks afterdiscontinuation of therapy, 29.8% of the total cases still reported total clearance/marked improvement which indicated that the efficacy was retained even afterdiscontinuation of therapy. At baseline mean SSAQ scores were ranging from 75.62-84.07. After therapy with eflornithine cream, the mean scores declined significantly(P \.05) to 37.04 to 41.10 at the end of 12 weeks. A total 21.6% of the study casesreported adverse events. The most common adverse events were acne (9.5%) andpseudofolliculitis barbae (6.9%) followed by tingling burning, pruritus, rash, andstinging. The severity of the events was mild in all the cases and disappeared withcontinued treatment. No abnormalities in the vital parameters or laboratoryinvestigations were noted at the end of therapy.

Conclusion: Eflornithine HCl topical cream 13.9% applied twice daily is an effective,safe and well tolerated option in the reduction of unwanted facial hair in adult Indianwomen with hirsutism.

Study grant was provided for the study by Glenmark Pharmaceuticals Ltd.

P1009L-ergothioneine reduces UVA340-induced hydrogen peroxide in fibro-blasts more efficiently than idebenone

Kelly Dong, MS, AGI Dermatics, Freeport, NY, United States; Matthew Canning,MS, AGI Dermatics, Freeport, NY, United States; Kenneth Smiles, PhD, AGIDermatics, Freeport, NY, United States; Daniel Yarosh, PhD, AGI Dermatics,Freeport, NY, United States

L-ergothioneine is a well known antioxidant that has been used in several topicalapplications. Recently, idebenone has been added to topical applications for itsantioxidant properties. This study evaluated the ability of idebenone and L-ergothioneine to reduce both hydrogen peroxide when added directly to the mediawithout cells and the UVA340-induced hydrogen peroxide in fibroblasts (NHDF).Media containing 1 mM hydrogen peroxide were treated with 150 �M L-ergothio-neine or idebenone for 2 hours. L-ergothioneine caused a larger reduction inhydrogen peroxide than idebenone as measured with dihydrorhodamine 123. Toexamine the influence of these two antioxidants on UVA340-induced hydrogenperoxide, NHDF were treated with 10 �M idebenone or L-ergothioneine in phenolred-free media 24 hours prior to irradiation with 100 kJ/m2 UVA340. Hydrogenperoxide levels in the media were measured just before irradiation, immediatelyafter irradiation, and 1 hour after irradiation with dihydrorhodamine 123.Immediately after irradiation, hydrogen peroxide increased. L-ergothioneine causeda larger reduction in UVA340 induced hydrogen peroxide than idebenone. Theseresults indicate that L-ergothioneine has a more powerful antioxidant effect thanidebenone.

Commercial support: None identified.

AB86 J AM ACAD DERMATOL FEBRUARY 2007