Topical Ciclosporin for Psoriasis: In vitro Skin Penetration and Clinical Study

Hermann, Richard C.; Taylor, Robert W.; Ellis, Charles N.; Williams, N A; Weiner, Norman; Flynn, Gordon L.; Annesley, Thomas M.; Voorhees, John J.

doi:10.1159/000210782

Cited by 50 publications

(27 citation statements)

References 8 publications

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“…Indeed, penetration studies using excised human skin confirmed the poor penetration properties of topical CyA when it was dissolved in standard solvents [21]. It was then investigated whether the penetration properties of CyA could be increased by the addition of specific ingredients, using rat skin in Franz-type diffusion chambers [22].…”

Section: Discovery Of Topical Calcineurin Inhibitors For the Treatmenmentioning

confidence: 99%

Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

Stuetz

Baumann

Grassberger

et al. 2006

Int Arch Allergy Immunol

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Using a newly developed model of allergic contact dermatitis in pigs, calcineurin inhibitors of the tacrolimus and ascomycin type were shown to have a highly anti-inflammatory action after topical application. These findings provided the first pharmacological evidence of the efficacy of this novel class of topical agents in the treatment of inflammatory skin diseases, and, thus, their potential to become the first alternative to corticosteroids in more than 40 years. As a result of a large research program into ascomycins, pimecrolimus (Elidel®, SDZ ASM 981) was selected for development due to its favorable pharmacology and safety profile, alongside tacrolimus (Protopic®, FK 506). In vitro, pimecrolimus inhibits the transcription and release of pro-inflammatory cytokines in T cells. Similar to the corticosteroids, betamethasone-17-valerate and dexamethasone, pimecrolimus is effective at nanomolar concentrations. Targeting mainly T cells, pimecrolimus has, however, a more specific mode of action. Moreover, in contrast to corticosteroids, pimecrolimus has no effect on Langerhans’ cells, the professional antigen- presenting dendritic cells of the skin that are crucial for local immunosurveillance. When applied topically, pimecrolimus exerts a high and selective anti-inflammatory activity in the skin, shows minimal percutaneous absorption, and has a low potential to affect systemic immunoreactions. Pimecrolimus cream 1% has proven to be well tolerated, safe, and highly effective in clinical studies in patients with atopic dermatitis.

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Section: Discovery Of Topical Calcineurin Inhibitors For the Treatmenmentioning

confidence: 99%

Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

Stuetz

Baumann

Grassberger

et al. 2006

Int Arch Allergy Immunol

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“…The changes seen in DNFB-ACD sites 8 hours after elicitation of the hypersensitivity reaction consisted of a mild hyperplastic epidermis with spongiosis and inflammatory cells in the lower layers. In the uppermost portion of the dermis, vasodilatation, perivascular edema, and cellular infiltration were present, overall scored at 17.0 (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29). Subsequently, these changes increased and reached maximal intensity 24-48 hours after challenge (scores 31.5 and 33.0 [27][28][29][30][31][32][33][34][35][36], respectively).…”

Section: Histopathologymentioning

confidence: 99%

“…3,29,31,38,43 For example, topical cy-closporine A is highly active in rodent ACD but inactive in domestic pigs and humans because permeability of rodent skin is higher than in humans or swine. 25,37,51 For previously mentioned reasons domestic pigs or minipigs are increasingly used for preclinical studies in investigative dermatology, which in turn has resulted in increased availability of new investigative tools such as monoclonal antibodies to cell surface markers or cytokines. 17,24,34,40,46,49,55,59,61 In addition, the possible use of genetically altered pigs as organ donors for humans created tremendous interest in swine immunology as an investigative tool.…”

mentioning

confidence: 99%

Morphologic and Immunohistochemical Features of Experimentally Induced Allergic Contact Dermatitis in Göttingen Minipigs

Vana

Meingassner

2000

Vet Pathol

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Abstract. Many preclinical studies in investigative dermatology are performed preferably in pigs because pig skin is more similar to human skin than is rodent skin. A frequently used model is allergic contact dermatitis (ACD); however, this T-cell-mediated skin condition so far is not well characterized in pigs. The present study is aimed at the evaluation of morphologic and immunohistochemical features of experimentally induced acute ACD in Göttingen minipigs using 2,4-dinitrofluorobenzene (DNFB) as a hapten. Eight minipigs were sensitized with 10% DNFB and challenged 2 weeks later at different sites with 1% DNFB. In addition to clinical examinations, cutaneous blood flow was quantified by laser Doppler velocimetry (Periflux PF3). These examinations were performed before challenge and 8, 24, 48, and 72 hours after challenge. Skin biopsies were taken at the same time points, fixed, sectioned, and stained with Giemsa for histologic evaluation, or with mouse anti-swine monoclonal antibodies (CD1, CD2, CD4, CD5, CD8, CD25, CD45, MHCII) and with one mouse anti-human monoclonal antibody (CD62E) cross-reacting with swine for immunohistochemical evaluation. Positively stained cells were counted per square millimeter of epidermis and dermis by using a video image analyzing system (Videoplan Kontron). Erythema and cutaneous blood flow peaked at 24 hours. The major epidermal changes most pronounced at 48 hours were acanthosis, spongiosis, intracellular edema, exocytosis, and abscesses mainly containing neutrophils and mononuclear cells (MNC). Perivascular infiltrates of MNC as well as neutrophils and eosinophils were the most significant dermal changes, with peak levels at 24-48 hours. In biopsies taken before challenge, CD1ϩ dendritic cells were found in similar numbers and locations as MHCII ϩ cells in the epidermis. In the epidermis the maximum CD1 ϩ cell decrease occurred at 24 hours whereas in the dermis the maximum increase in CD1 ϩ stained cells was seen at 72 hours. The dermal infiltrate (CD2 ϩ , CD5 ϩ , CD25 ϩ , and CD45 ϩ ) was most dense at 48 hours. Between 8 and 48 hours more CD4 ϩ were present than CD8 ϩ cells, whereas at 72 hours CD4 ϩ and CD8 ϩ cells were similar in numbers. These findings closely resemble changes in human ACD. Therefore, DNFB-induced ACD in Göttingen minipigs is considered to be an appropriate animal model to study immunopathologic mechanisms and pharmacologic intervention.Key words: Allergic contact dermatitis; 2,4-dinitrofluorobenzene; Göttingen minipig; histopathology; immunohistochemistry; skin inflammation; swine.Preclinical research in biomedical science uses laboratory animals to profile new compounds for possible uses as drugs. Therefore, laboratory animals serve either as models for the assessment of pharmacodynamic effects or, in advanced stages of drug development, for the identification of untoward effects (toxicities) of drug candidates. Therefore, the results obtained from animal pharmacology or animal toxicology studies should be reliably predictive for the situation in hum...

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“…The concentration-time profile should be determined by the release rate of capsaicin from the lipogel vehicle [63]. The development of a reservoir of lipophilic substances in the stratum corneum depends on layer thickness and the composition of the acceptor layer.…”

Section: Discussionmentioning

confidence: 99%

Cutaneous Drug Delivery of Capsaicin after in vitro Administration of the 8% Capsaicin Dermal Patch System

Wohlrab

Neubert²,

Heskamp³

et al. 2014

Skin Pharmacol Physiol

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Objective: Epicutaneous application of capsaicin causes a long-lasting analgesic effect by binding to the membrane transient receptor potential vanilloid 1 (TRPV1) on mechanoheat-sensitive C and Aδ fibres, changing axonal integrity and inhibiting neurogenic inflammatory processes. To date, no information is available regarding the cutaneous drug delivery of capsaicin following patch application. Methods: Using a Franz diffusion cell, the cutaneous concentration-time profiles 30, 60 and 90 min after application of a patch containing 8% capsaicin (640 µg/cm²) on ex vivo thin (mamma) and thick (plantar) human skin were investigated at 32°C, and additionally at 42°C for thin skin and 10°C for thick skin. An HPLC-MS method was used for the analytic detection of capsaicin. Results: The results show that already after a 30-min application of the 8% capsaicin patch, an equilibrium reservoir can be found in the stratum corneum in both thick and thin skin. Under physiological temperature conditions, a sufficient bioavailability of capsaicin in the cutaneous target compartments can be found. Raising the temperature to 42°C has no relevant impact on the concentration-time profile, while reducing the temperature to 10°C leads to a significantly lower bioavailability. Conclusion: After 30 min of application, a sufficient cutaneous bioavailability of capsaicin is reached in thick as well as thin skin. Whether shorter application times may suffice to achieve therapeutic effectiveness requires further investigation. © 2014 S. Karger AG, Basel

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Topical Ciclosporin for Psoriasis: In vitro Skin Penetration and Clinical Study

Cited by 50 publications

References 8 publications

Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

Discovery of Topical Calcineurin Inhibitors and Pharmacological Profile of Pimecrolimus

Morphologic and Immunohistochemical Features of Experimentally Induced Allergic Contact Dermatitis in Göttingen Minipigs

Cutaneous Drug Delivery of Capsaicin after in vitro Administration of the 8% Capsaicin Dermal Patch System

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