Calcineurin inhibitors

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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Synonym(s)

Calcineurin antagonists; Calcineurin inhibitors; Topical calcineurin inhibitors

Definition
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Group of immunosuppressive drugs that bind complexly to specific mediators ( Ciclosporin A to cyclophilin, Tacrolimus to the protein FKBP12). These complexes in turn bind to calcineurin and thus prevent the activation of transcription factors (NFAT, NFKB), which leads to a reduced synthesis of interleukin-2 in the T-helper cells.

The cell cycle remains in the G0 phase without transition to the G1 phase of the cell cycle; T-cell activation is thus inhibited.

S.a.o. Tacrolimus (protopic), Pimecrolimus (Elidel), Ciclosporin A (immunosporin).

Furthermore, calcineurin inhibitors bind to the capsaicin receptor and thus trigger a neurogenic inflammation. On the one hand, this explains the initial burning sensation of the therapy, on the other hand it explains its antipruritic effect.

General definition
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  • Besides the known indications for Ciclosporin A (systemic: autoimmune diseases and diseases with disturbed keratinization), Tacrolimus (systemic: autoimmune diseases, psoriasis vulgaris), Pimecrolimus and Tacrolimus (topical: atopical eczema), the use of calcineurin inhibitors for the topical therapy of psoriasis vulgaris is also discussed in the literature. Basically, all mentioned drugs are attributed an antipsoriatic potency.
  • Ciclosporin, topical: The topical application of Ciclosporin, however, is insufficient due to the galenic preparation. Ciclosporin is characterized by lipophilicity, high molecular weight and a ring structure which impairs the penetration through the skin.
  • Tacrolimus is currently approved in a 0.1% or 0.03% lipophilic ointment for the topical treatment of the atopical eczema. The previous applications in the form of a 0.3% ointment for the therapy of psoriasis did not reveal any effectiveness so far. Up to now, an effectiveness has only been observed for the inverse psoriasis (apply Tacrolimus ointment 0.1% twice a day).
  • Pimecrolimus: Similar experiences are available for Pimecrolimus; under occlusive application, clinical effects are shown with the application of a 0,1% lipophilic cream. Successes with the psoriasis inversa as well as in childhood are described in individual cases. In summary, the individual galenical systems have to be optimally further developed for efficient topical applications. The assessment of the antipsoriatic potency in controlled studies remains to be awaited.

Undesirable effects
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see below the individual preparations

Preparations
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Tacrolimus (Protopic®)

Pimecrolimus (Elidel®)

Ciclosporin A (Immunosporin®)

Note(s)
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  • In childhood most topical calcineurin inhibitors represent an off-label use.
  • The safety of the topical calcineurin inhibitors and thus their application was questioned in 2006 by a "black box warning" of the FDA. A restrained prescription of calcineurin inhibitors was especially recommended for children due to a possible increased risk of skin cancer and lymphoma. A systematic analysis of the study situation of different However, a systematic analysis of the study situation of various authors could not prove an increased incidence of lymphoma or skin cancer compared to the normal population.
  • Also leading European dermatologists or the American Academy of Dermatology (AAD) consider the fears to be no longer justified.
  • For Pimecrolimus (10mg/g cream - 2x daily) could be obtained satisfactory to good results in 2439 children (PETITE study) from 3 months on. The application was carried out 2 x daily at first signs of itching or eczema. Pimecrolimus neither influenced the growth of the children nor were there any infections observed.
  • An algorithm worked out by an international expert group recommends the short-term (3-4 days) application of mild topical glucocorticoids (class I according to Niedner), afterwards the combination with local calcineurin inhibitors and further on the monotherapy with calcineurin inhibitors according to the requirements in case of acute symptoms of a light to medium severe atopical eczema.

Literature
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  1. Huang C et al (2014) Pimecrolimus cream 1% in the management of atopic dermatitis in pediatric patients: a meta-analysis. PLoS One doi: 10.1371/journal.pone.0093095
  2. Lee SJ et al (2014) Functional interpretation of metabolomics data as a new method for predicting long-term side effects: treatment of atopic dermatitis in infants. Sci Rep. doi: 10.1038/srep07408

  3. Luger T et al (2013) Recommendations for pimecrolimus 1% cream in the treatment of mild-to-moderate atopic dermatitis: from medical needs to a new treatment algorithm. Eur J Dermatol 23:758-66

  4. Salgo R (2011) Difficult decision in childhood dermatotherapy: Topical calcineurin inhibitors in children: Often off label, very carefully or not at all? Abstract CD 46th DDG meeting: AKS17/04.

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Last updated on: 29.10.2020