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Dermatotherapy
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-
Bürger |
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
Zuberbier |
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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