Elidel
Pimecrolimus does not affect Langerhans cells in murine epidermis.

Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Burger A, Stutz A.

Novartis Forschungsinstitut, Brunnerstrasse 59, A-1235 Vienna, Austria. josef.meingassner pharma.novartis.com

BACKGROUND: Langerhans cells (LCs) function as specialized antigen-presenting cells in the epidermis, and therefore play a critical role in cutaneous immunological reactions. Topical treatment with corticosteroids is associated with a decrease in epidermal LC number and antigen-presenting capacity in laboratory animals and humans. OBJECTIVES: To examine whether pimecrolimus, a nonsteroidal inflammatory cytokine inhibitor recently introduced for the topical treatment of atopic dermatitis, differs from corticosteroids in effects on LCs. METHODS: Groups of BALB/c mice were treated twice daily on one to five consecutive days on the inner surface of the right ear with 10 micro L of ethanolic solutions of the test compounds at their clinically used concentrations (1% pimecrolimus, 0.1% betamethasone-17-valerate, 1% hydrocortisone and 0.05% clobetasol propionate) or with the vehicle (controls) alone. At selected time points after the treatment epidermal sheets were prepared and examined histomorphometrically for LCs immunolabelled with antibodies to major histocompatibility complex (MHC) class II and DEC 205, and adenosine diphosphatase staining. RESULTS: No changes in number or morphology of LCs were observed in epidermal sheets of mice treated for 5 days with pimecrolimus. In contrast, an almost complete depletion of LCs was observed in skin samples treated with hydrocortisone, betamethasone or clobetasol. Even a single-day treatment schedule with hydrocortisone, betamethasone or clobetasol caused a significant reduction in MHC class II+ LCs, by 31%, 62% and 87%, respectively. CONCLUSIONS: It is therefore unlikely that topically applied pimecrolimus affects epidermal LCs, in contrast to corticosteroids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14616380&dopt=Abstract pimecrolimus Elidel



Elidel
The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) is a potent inhibitor of mediator release from human dermal mast cells and peripheral blood basophils.

Zuberbier T, Chong SU, Grunow K, Guhl S, Welker P, Grassberger M, Henz BM.

Department of Dermatology and Allergy, Charite, Humboldt University Berlin, Germany.

BACKGROUND: The ascomycin macrolactam pimecrolimus (Elidel, SDZ ASM 981) has recently been developed as a novel and cell-selective inhibitor of inflammatory cytokine secretion; it has fewer adverse effects than currently available drugs. OBJECTIVE: In this study, we investigated the capacity of pimecrolimus to directly inhibit in vitro mediator release from human skin mast cells and basophils. METHODS: Purified cutaneous mast cells or basophil-containing peripheral blood leukocytes were obtained from healthy human donors and preincubated with pimecrolimus (0.1 nmol/L to 1 micromol/L) in the absence or presence of its specific antagonist (rapamycin), cyclosporin A (100 nmol/L to 1 micromol/L), or dexamethasone (1 micromol/L) and then stimulated with anti-IgE or with calcium ionophore A23187 plus phorbol myristate acetate. Cell supernatants were kept for analysis of histamine, tryptase, LTC4, and TNF-alpha. RESULTS: Pimecrolimus caused a strong and dose-dependent inhibition of anti-IgE--induced release of histamine from mast cells and basophils (maximally 73% and 82%, respectively, at 500 nmol/L pimecrolimus) and of mast cell tryptase (maximally 75%) and a less pronounced inhibition of LTC4 (maximally 32%) and of calcium ionophore plus phorbol myristate acetate--induced mast cell TNF-alpha release (90% maximum at 100 nmol/L pimecrolimus). In contrast, inhibition achieved during mast cell histamine release was maximally 60% with cyclosporin A and only 28% with dexamethasone. CONCLUSION: These data demonstrate a marked inhibitory capacity of pimecrolimus on mediator release from human mast cells and basophils with a potency exceeding that of cyclosporin A and dexamethasone. Pimecrolimus might thus be expected to be effective in the treatment of mast cell-- and basophil-dependent diseases.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11496246&dopt=Abstract pimecrolimus Elidel



Elidel
Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus.

Billich A, Aschauer H, Aszodi A, Stuetz A.

Novartis Research Institute Vienna, Brunnerstrasse 59, A-1235 Vienna, Austria. andreas.billich pharma.novartis.com

For treatment of skin diseases with topical drugs, penetration of the agents into the relevant layers of the skin is required. Permeation through the skin should, however, be kept to a minimum, in order to avoid the risk of systemic side effects. Here we compared the in vitro skin penetration and permeation of two novel drugs used in the therapy of atopic eczema (pimecrolimus and tacrolimus) and three representative corticosteroids (betamethasone-17-valerate, clobetasol-17-propionate, and diflucortolon-21-valerate). Drug concentrations of pimecrolimus and corticosteroids in human skin were found to be in the same order of magnitude. Permeation of pimecrolimus through human skin was, however, lower by factors of 70-110 as compared to the steroids. When pimecrolimus was compared with tacrolimus in human, pig, or rat skin, similar concentrations of the two compounds were measured in the skin, whereas permeation of pimecrolimus through skin was consistently lower by factors of 9-10. Lipophilicity was found to be highest for pimecrolimus, its octanol-water distribution coefficient being higher by factors of 8 and 25-450 than that of tacrolimus and the corticosteroids, respectively. The low permeation of pimecrolimus may be explained by its higher lipophilicity (compared to tacrolimus and the corticosteroids) and higher molecular weight (compared to steroids). In conclusion, pimecrolimus appears to have a favourable skin penetration/permeation profile, featuring a low degree of percutaneous absorption.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14698574&dopt=Abstract pimecrolimus Elidel



Elidel
Topical pimecrolimus in the treatment of human allergic contact dermatitis.

Amrol D, Keitel D, Hagaman D, Murray J.

Vanderbilt University, Nashville, Tennessee, USA. damrol gw.mp.sc.edu

BACKGROUND: Contact dermatitis is a common clinical problem, with prevalent sensitizers being cosmetics, metals, medicines, and plants. Plants of the Toxicodendron species cause allergic contact dermatitis (ACD) in 50% to 70% of the population. Pimecrolimus is an ascomycin macrolactam developed for the treatment of inflammatory skin diseases and approved by the US Food and Drug Administration for atopic dermatitis. There are studies supporting the effectiveness of macrolactams when administered before antigen challenge, but there are no studies describing the effectiveness of these drugs in the treatment of established human ACD. OBJECTIVE: To investigate the effect of topical pimecrolimus in the treatment of Toxicodendron-induced ACD once rash is evident. METHODS: Poison ivy tincture was applied to the bilateral anterior forearms of 12 subjects with Finn Chambers (Allerderm Diagnostic Products, Petaluma, CA). After dermatitis was evident, volunteers treated each arm twice daily with either 1% topical pimecrolimus cream or placebo in a blinded fashion. Outcomes measured were a dermatitis grading score and time to rash and itch resolution. RESULTS: The median +/- SEM time for rash resolution was 16.55 +/- 1.59 days in the treatment group and 16.27 +/- 1.82 days in the placebo group (P = 0.601). The median time for itch resolution was 4.73 +/- 1.56 days in the treatment group and 4.91 +/- 1.59 days in the placebo group (P = 0.167). The average dermatitis score was 2.26 +/- 0.17 in the treatment group and 2.32 +/- 0.15 in the placebo group (P = 0.62). CONCLUSIONS: The application of topical pimecrolimus is ineffective in the treatment of ongoing Toxicodendron-induced ACD.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=14700441&dopt=Abstract pimecrolimus Elidel