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Issue March 2001

Dermatotherapeutics on the horizon

This macrolide also known as rapamycin is a metabolic substrate of the fungus streptomyces hygroscopicus. Discovered already twenty years ago by the Ayerst Research Laboratories in the course of an antibiotic-screening, yet despite its effectiveness against yeast fungi, it has not been applied in indications for years. This has only changed when Tacrolimus, very similar in structure, has been discovered a few years later for the treatment of transplant rejection and recently also for the treatment of the atopical dermatitis.

Applying Sirolimus in the transplant medicine means making use of the suppression of the T-lymphocytes by macrolides. As a result these lymphocytes prevent the attacking of the donor tissue. The indication extension has been initiated by the realization that a hyperactivity of T-cells comes equally about in case of the atopical dermatitis in the scope of allergic reactions. The immunosuppressive effect could be proven for Sirolimus by means of a reduced incorporation of radioactively marked phosphorus in yeast- RNA - and - DNA - cords. Similar expectations are now focused on Sirolimus as it is the case with Tacrolimus as far as effectivity and good tolerability are concerned including the field of application for the atopical dermatitis.

The effective mechanism of Tacrolimus and Sirolimus could be clarified in the last years. It distinguishes from the one of the glucocorticoids which makes it likely to suspect that during the application far less side effects could appear. The target resembles to that of a third very current and effective immunosuppressant, the cyclic oligopeptide ciclosporin which however has several side effects. Both Sirolimus as well as Tacrolimus are sufficiently lipophile in order to permeate without carrier intermediary into the cytoplasm of their target cell. Here, they compete for the same cytosol receptor. This goal structure belongs to the group of the so-called macrophilines (thus the "macrolide-liking" receptors) and is designated as Sirolimus-Tacrolimus binding protein. Only as complex, both macrolides are in a position to immigrate into the nucleus.

Under the heading " Dermatotherapeutika am Horizont (Dermatherapeutics on the Horizon)" we will present in irregular succession the pharmacological profile of substances which could be introduced in the Dermatotherapy one day. The macrolide Sirolimus leads off arousing expectations due to its immunosuppressive properties concerning the application for atopical dermatitis and other allergic skin diseases. The comments about Sirolimus have been drawn up by the pharmacist Bettina Sauer, doctorand of professor Dr. Monika Schäfer-Korting at the department pharmacy of the Freie Universität (Free University) Berlin.

Thus Tacrolimus inhibits the calcium-dependent serine-threonine kinase Calcineurin which normally activates transcription factors of the Interleukin-(IL)-synthesis. The Tacrolimus-induced IL-2 shortage inhibits the proliferation and activation of T-lymphocytes. Cell cycle analyses showed that Tacrolimus ultimately prevents the transition of the T-lymphocytes from the G0-phase, i.e. the inactive resting form to the protein synthesizing form and as consequence in the end the mitose-ready G1-phase.

The Sirolimus-macrophiline-complex instead does not bind to Calcineurin but to a different, recently discovered new target namely the mTOR (mammalian Target of Rapamycin). This equally concerns a serine-threonine-kinase the inhibition of which also correlates with the reduction of the T-lymphocyte activity. In the cell cycle the transition from the G1 to S-phase is blocked by Sirolimus, i.e. from the protein-biosynthesis to the DNA-replication. Although the cell cycle is then interrupted at various positions, a promising T-cell inactivation in relation to allergic skin diseases remains as result of both pharmaca. Furthermore, both macrolides normalize enhanced IgE-speculi as they are the case for the atopical dermatitis.

The expectations relating to Sirolimus increase due to the fact that Tacrolimus has shown a good tolerability equally at a widespread local application. However, clinical studies with Sirolimus are still pending confirming that for the topical application in fact only the attenuation of an exuberant immune reaction emerges as hoped for, but not a harmful suppression of the endogenous phylaxis. In addition, the blood level determinations for the exclusion of systemical side effects are necessary.

If clinical studies are successful, the interest relating to both pharmaca will probably further increase and go beyond the indication as explained above. Because of the effective mechanism of Sirolimus and Tacrolimus, an applicability for alopecia areata, lupus erythematodes and lichen ruber is hoped for.

Abraham et al., Immunopharmacology of Rapamycin, Annu. Rev. Immunol. 14, 483-510 (1996) Brattstrom et al., Pharmacokinetics and safety of single oral doses of Sirolimus in healthy male volunteers, Ther. Drug Monit. 22 (5), 537-544 (2000)
Ingle et al., Sirolimus: Continuing the evolution of transplant immunosuppression, Annl. Pharmacother 34, 1044-1055 (2000)


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