Introduction

Pimecrolimus is a topical calcineurin inhibitor used in the treatment of mild-moderate atopic dermatitis who are not candidates for other types of therapy due to previous lack of response or other reasons. Pimecrolimus is an immunomodulating agent that was first marketed by Novartis under the trade name Elidel. It is now promoted in Canada by Galderma since early 2007. It is currently available as a topic cream used in the treatment of atopic dermatitis (eczema). Pimecrolimus is currently the most advanced ascomycin macrolactam under development,that is a colourless, solid compound 2 with a molecular weight of 810.48 daltons. Its Chemical Formula C₄₃H₆₈ClNO₁₁.[1]

Indication

Pimecrolimus is used for treatment of mild to moderate atopic dermatitis.(Figure 1) In other words, it could treat a skin condition called atopic dermatitis in patients with a healthy immune system that are unable to use other medications.

Pharmacodynamics

Interest in pimecrolimus has been intensive because of its signi?cant anti-inflammatory activity and immunomodulatory capabilities and its low systemic immunosuppressive potential.

Pimecrolimus is a chemical that is used to treat atopic dermatitis (eczema). Atopic dermatitis is a skin condition characterized by redness, itching, scaling and inflammation of the skin. The cause of atopic dermatitis is not known; however, scientists believe that it may be due to activation of the immune system by various environmental or emotional triggers. Scientists do not know exactly how pimecrolimus reduces the manifestations of atopic dermatitis, but pimecrolimus reduces the action of T-cells and mast cells which are part of the immune system and contribute to responses of the immune system. Pimecrolimus prevents the activation of T-cells by blocking the effects of chemicals (cytokines) released by the body that stimulate T-cells. Pimecrolimus also reduces the ability of mast cells to release chemicals that promote inflammation.[1]

Mechanism of action

Mechanism of action The mechanism of action of pimecrolimus is the blockage of T cell activation. Ascomycin macrolactams are immunophilin ligands that bind to a speci?c cytosolic receptor. Pimecrolimus binds to immunophilin macrophilin-12, also known as FK506 binding protein, and FKBP-12. Tacrolimus (FK506) and rapamycin also bind to macrophilin-12.[2] Like tacrolimus and cyclosporin A,[3] the mechanism of action of pimecrolimus involves its binding to macrophilin-12. The pimecrolimusmacrophilin complex then binds to the cytosolic enzyme calcineurin phosphatase.[4] Calcineurin is a Ca ²⁺ /calmodulindependent protein phosphatase that regulates the translocation of cytosolic components of nuclear factors, which in turn regulate the promoter activities of several mediators during mRNA transcription. By inhibiting the action of calcineurin, the pimecrolimus-macrophilin complex prevents the dephosphorylation of the cytoplasmic component of the nuclear factor of activated T cells (NF-AT). NF-AT regulates the mRNA transcription of a number of in?ammatory cytokines; therefore, pimecrolimus blocks this transcription, especially Th1 (IL-2, IFN- γ ) and Th2 (IL-4, IL-10) type cytokines. Other cytokines, including IL-5, IL-10 and TFN α , are decreased in production by pimecrolimus in a dose-dependent manner.[4] 

Pimecrolimus also targets mast cells which play an important role to anti-inflammatory activities.[5] Pimecrolimus inhibits not only the transcription and synthesis of cytokines from mast cells, but also the release of preformed mediators serotonin and β -hexosaminidase by the inhibition of Fc ∈-RI-mediated degranulation and secretion.[2] It is important to note that all the inhibition processes occur only when pimecrolimus is bound to macrophilin-12.[2] It is of interest that, during a study of murine mast cell line CPII, it was found that pimecrolimus did not inhibit the transcription of a reporter gene which was under the control of the human TFN α promoter in the murine dendritic cell line, and had no effect on IL-8 release from keratinocytes,fibroblasts and endothelial cells. This is an indication of the speci?city of the pharmacologic activity of pimecrolimus.

The first study of the gene expression analysis of blood cells was performed on seven patients with psoriasis, who had been treated with oral pimecrolimus 30 mg twice daily. [6] Blood samples were taken from the patients prior to treatment and after 13 or 14 days of treatment. Gene chips were used for gene expression analysis and 7129 genes were surveyed. Kehren et al .[6] found a genomic profile of pimecrolimus of approximately 100 genes. As well, it was demonstrated that pimecrolimus treatment caused a strong down-regulation of the expression of mRNA for genes associated with the macrolactam target pathway and inflammation. However, no changes were found in the mRNA for genes which generally reflect drug related side effects, like those associated with apoptosis, stress induction and enzymatic induction. Therefore, Kehren et al .[6] concluded that the genomic analysis of blood cells from psoriatic patients treated with pimecrolimus supports the specific anti-inflammatory nature of the therapy.[7]

Absorption and Metabolism

Because of the low systemic absorption of pimecrolimus following topical application the calculation of standard pharmacokinetic measures such as AUC, Cmax, half-life, etc. cannot be reliably done. 

No drug metabolism was observed in human skin in vitro. Oral administration yielded metabolites produced from O-demethylation and oxygenation reactions.[1]

Conclusion

Pimecrolimus has enormous potential as a topical treatment for inflammatory skin disease. It is highly efficient in blocking T cell activation and inhibiting the synthesis of inflammatory cytokines. Pimecrolimus is effective in dermatoses such as atopic dermatitis and allergic contact dermatitis, and is indicated in the United States for the short-term and intermittent long-term therapy of mild to moderate atopic dermatitis in non-immunocompromised patients aged 2 years and older where alternative conventional therapies are deemed inadvisable because of potential risks, or for patients who are not adequately responsive to, or are intolerant of conventional therapies.

References

[1] Grassberger M, Baumruker T, Enz A, et al. A novel anti-inflammatory drug, SDZ ASM 981, for the treatment of skin diseases: in vitro pharmacology. Br J Dermatol. 1999;141(2):264-273.

[2] Grassberger M, Baumruker T, Enz A et al. A novel antiinflammatory drug, SDZ ASM 981, for the treatment of skin disease: in vitro pharmacology. Br J Dermatol 1999; 141: 263-273.

[3] Luger T. Treatment of immune-mediated skin diseases: Future perspectives. Eur J Dermatol 2001; 11: 343-347.

[4] Mrowietz U. Ascomycin macrolactams. J Cutan Med Surg 2001; 5: 22-25.

[5] Paul C, Ho VC. Ascomycins in Dermatology. Semin Cutan Med Surg 1998; 17: 256-259.

[6] Kehren J, Cordier A, Ebelin M-E et al. Genomic analysis of blood cells from psoriatic patients following treatment with oral pimecrolimus (SDZ ASM 981). The 10th Congress of the European Academy of Dermatology and Venereology (EADV) 2001; [Abstract].

[7] Gupta AK, Chow M. Pimecrolimus: a review. J Eur Acad Dermatol Venereol. 2003;17(5):493-503.