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  Issue 1 (2005)

Topical therapy based on Pimecrolimus

Substantial arguments alluding to high effectiveness and safety

For the first time after 50 years the calcineurin-inhibitors Pimecrolimus and Tacrolimus have established a novel effective principle for the treatment of inflammatory skin diseases. In the course of a symposium on the occasion of 9th Annual Meeting of the GD in Vienna on 14 and 15 March 2005 manifold data as to the effectiveness and safety in particular of Pimecrolimus were presented. Accordingly, there is a multitude of arguments favouring this innovative and effective therapy for which additional fields of indication will yet be generated besides the atopical eczema in the future.

Dr. Frank Kalthoff, Vienna, compared the effects of glucocorticoids and Pimecrolimus on dendritic cells. They are of central importance for the immune system due to the fact that they combine the hereditary with the acquired immunity as antigen-presenting cells. They are significant both for the immune responses and the interposition of tolerance by the immune system.

Dexamethasone and Betamethasone induced a distinct apoptosis of the precursor cells of dendritic cells in a study. A differentiation with the typical surface markers CD1a, CD40 and CD80 by glucocorticoids has been almost completely inhibited at the surviving dendritical cells whereas a hundredfold higher concentration of Pimecrolimus did not noticeably affect the differentiation of the dendritical cells.

Moreover, the glucocorticoids blocked the secretion of the cytokine IL-12 which is responsible for the differentiation of the Th1-cells in contrast to Pimecrolimus. Kalthoff drew the conclusion that Pimecrolimus unlike the glucocorticoids does not influence the function of the dendritical cells but has a selective impact on the T-cells and mastocytes.

Langerhans cells unaffected

Professor Dr. Adelheid Elbe-Bürger, Vienna, analyzed the effects of glucocorticoids and Pimecrolimus on Langerhans cells - antigen-presenting cells of the epidermis and obtained similar results. In mice apoptotic Langerhans cells and keratinocytes have been found after only double application with hydrocortisone or Clobetasole whereas Pimecrolimus did not affect the vitality of these cells. Further investigations showed that the glucorticoids blocked the ripening of the Langerhans cells.

Professor Dr. Adelheid Elbe-

A significant depletion of the Langerhans cells could be determined at patients suffering from atopical dermatitis after treatment with a glucocorticoid, however not after a treatment based on Pimecrolimus. The effects on Langerhans cells seem to be meaningful due to their key function for the autochthonal immune system of the skin.

Effective T-cell activation

Analyses by Dr. Anthony Winiski, Vienna, aimed at the effectiveness in the treatment of inflammatory skin diseases. As significant model for clinical effects the T-cell activation and release of inflammatory cytokines are considered as these are essential factors for the pathogenesis of the atopical eczema, psoriasis and other inflammatory skin diseases.

It has been investigated in mono-nuclear cells from human blood how an anti-CD3-antibody stimulates the production of the cytokines TNF-α, IFN- γ, GMCSF, IL-1β and IL-8. Thereby Pimecrolimus, Tacrolimus, Betamethasone and Dexamethasone revealed about the same effect. Cyclosporin A and hydrocortisone showed a weaker effect.

In the same test system the inhibition on the T-cell proliferation has been determined whereas Tacrolimus evinced the strongest effect, followed by Pimecrolimus, Betamethasone, Dexamethasone, Cyclosporine A and hydrocortisone. The inhibition of the cytokine release has also been investigated in the T-cell clones which are extracted from the skin of patients suffering from atopical dermatitis. In this context, a comparably effective potency by Pimecrolimus and Tacrolimus has been proven.

Moreover, the relatively frequent resistance towards glucocorticoids - typical for chronical diseases - has been simulated in an in-vitro-model. It could be shown that this resistance can be surmounted by the combination of glucocorticoids and calcineuin-inhibitors. Accordingly, a combination therapy could be an option in case the mono-therapies are no longer sufficient.

Strong effects on mast cells
Professor Dr. Torsten Zuberbier, Berlin, tested the effect of Pimecrolimus on the mediator release in human dermal mast cells and peripheral basophilic leucocytes. These cells are significant due to the expression of the IgE-receptor and as histamine-releasing cells for the mediation of allergic reactions. Moreover, mast cells release additional mediators, for example tryptasis and chymasis to which an increasingly pathogenetic significance for many skin diseases is attributed.

Professor Dr. Torsten

The histamine release could be reduced by up to 70 percent dose-dependent in the nano-molecular concentration area by means of pre-treatment with Pimecrolimus. The effect achieved was stronger than the one obtained when applying Cyclosporine A and Dexamethasone. In addition, Pimecrolimus inhibited the release of Tryptasis and TNF-α so that, according to the estimation by Zuberbier, Pimecrolimus is considered to be the most effective inhibitor in the mediator release in human mast cells available at present

Only minor permeation
through the skin

Dr. Andreas Billich, Wien, performed tests at human, swine and rat skin as to the permeation of Pimecrolimus and Tacrolimus in comparison to different glucocorticoids. While the penetration into the skin layers affected is wanted, the permeation through the skin is to be reduced to a minimum in order to avoid systemical effects.

Test results showed that Pimecrolimus permeates at a significant lower degree than Tacrolimus and the glucocorticoids also tested. The supposed cause for the difference between the two calcineurin inhibitors is the lipophilic structure and the stronger linking of Pimecrolimus to the skin proteins.

In-vitro tests at skin pre-treated with glucocorticoids resulted in higher permeation rates than at normal skin, however, the difference between the two calcineurin inhibitors remained. Accordingly, only very low blood levels are expected for the application with Pimecrolimus on damaged skin.

Kinetics and pharmaco-dynamics
Further distinctions between both therapeutically used calcineurin inhibitors were described by university lecturer Dr. Josef G. Meingassner, Vienna. In animal models of the allergenic contact dermatitis, Tacrolimus and Pimecrolimus revealed both at topical and oral intake in the clinical manifest provocation therapy as highly effective.

In this phase, orally administered Pimecrolimus and Tacrolimus were dose-dependent equipotentially effective in the mouse model during the sensitization phase — the primary immune response — has only been inhibited by Tacrolimus. In the rat model Pimecrolimus inhibited the dermatitis but not the associated reaction in the lymph nodes whereas Tacrolimus only showed the reverse effects at low dosage.

According to the assessment by Meingassner, different kinetics and tissue repartition of the active substances could be responsible for these pharmaco-dynamic discrepancies.

Clinical experience

After the various pharmacological aspects, Dr. Matthias Bräutigam, Nuremberg, presented results concerning the clinical effectiveness of Pimecrolimus in the local therapy of the atopical eczema. Pimecrolimus-cream has been analyzed world-wide in clinical studies at 19,000 patients among which were 2,500 infants. Since the market introduction in March 2002 the preparation has been applied at approx. six million patients.

The guiding symptoms of the topical eczema, itching and insomnia respond to the treatment after two respectively three days. The part of the attack-free patients is significantly increased at gentle course of disease, at moderate course the steroid use is reduced. Altogether the quality of life of patients is improved, Bräutigam explained.

Two different treatment strategies are recommended for the application: in relation to the strength of the attack at minor to moderate occurrence Pimecrolimus and at intense occurrence a steroid can be employed. Alternatively, patients can already use Pimecrolimus at first indices of an attack in the way of self-management.

Dr. Matthias Bräutigam

Bräutigam also presented current analyses based on Pimecrolimus cream: thus by means of a newly developed questionnaire a favourable effect on the quality of life for parents of affected children could be proven. Moreover, effectiveness at the severe atopical eczema could equally be proven for which the preparation has to date not been authorized. In contrast to steroids at which a rebound-effect is often observed after the discontinuation, merely a slight increase of the symptoms has been noticed but no rise beyond the initial value after the discontinuation of Pimecrolimus.

Regarding the application safety Bräutigam emphasized the minimal resorption of Pimecrolimus. There is no significantly higher occurrence of systemical infections at children without application of Pimecrolimus than without treatment. Only a slight increase of the rate of viral skin infections has been observed.

Focus on safety
Also according to the estimation of professor Dr. Thomas Luger, Münster, calcineurin-inhibitors allow a safe and effective therapy. Pimecrolimus induces at topical application neither skin atrophies nor a damage of the dermal barrier function. Furthermore, it does not have a photo-carcinogenic effect, no systemical side effects and it does not affect immunization reactions provided that it is not directly applied at the place of the vaccination.

Also for Tacrolimus - following a 12-year experience comprising approximately 25 million patients - excellent effectiveness and positive safety profile can be determined. When applying it topically only minimal blood levels are obtained. In contrast to Pimecrolimus, Tacrolimus evokes more frequently a light burning at the place of treatment which however, disappears after a few days. There are no indications for neither of the two substances as to an increased tumor risk after local application.

Professor Dr. Thomas Luger

Luger thus counters a premonition recently published by the US-American authorization authority FDA according to which the topical application of both substances the development of skin tumours and lymphoma could possibly be enhanced. There is no evidence whatsoever for a warning of the type, according to Luger. In the course of a multitude of clinical studies the application of neither of the two substances is connected with an increased incidence of tumours. A more frequent development of lymphoma has only been observed in animal experiments after systemical administration of extremely high doses of both substances.

The few cases of lymphoma noticed at topical therapy did not evince a causal coherence as neither the clinical nor the histological picture correspond to the one of lymphoma which usually appears at immune-suppressed patients. Further, the incidence of lymphoma at concurrent local application of Pimecrolimus and Tacrolimus is by a multiple below the frequency to be expected in the standard population.

Promising applications
Luger recommends for a successful therapy of the atopical eczema based on Pimecrolimus, to start treatment early and for a sufficient space of time. The treatment should commence as soon as first signs of the eczema have shown and a sole basis therapy by means of care preparations no longer suffices.

Latest tests pursue the question whether the incidence of eczema attacks can be avoided by regular treatments with Pimecrolimus cream in the interval of one or two weeks. Moreover, the use at infants and the application at other skin diseases is investigated, for example at the seborrhoic eczema, psoriasis and different autoimmune-disases. Individual case reports even allude for favourable effects at lymphoma. Possibly an application at other organ systems, for instance at eyes or nose is feasible.
Concluding, further research of calcineurin-inhibitors can be tracked with interest. tmb/jk



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