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Pimecrolimus
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| Systematic (IUPAC) name | |
| (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS) -3-{(E)-2-[(1R,3R,4S)-4-Chloro-3 |
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| Identifiers | |
| CAS number | |
| ATC code | D11 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C43H68ClNO11 |
| Mol. mass | 810.453 g/mol |
| Pharmacokinetic data | |
| Bioavailability | low systemic absorption |
| Protein binding | 74%–87% |
| Metabolism | Hepatic CYP3A |
| Half life | ? |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
C(US) |
| Legal status | |
| Routes | topical |
Pimecrolimus is an immunomodulating agent used in the treatment of atopic dermatitis (eczema). It is currently available as a topical cream, once marketed by Novartis (however Galderma is promoting the molecule in Canada since early 2007) under the trade name Elidel.
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Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12 and inhibits calcineurin. Thus pimecrolimus inhibits T-cell activation by inhibiting the synthesis and release of cytokines from T-cells. Pimecrolimus also prevents the release of inflammatory cytokines and mediators from mast cells.
Pimecrolimus, like tacrolimus, belongs to the ascomycin class of macrolactam immunosuppressives, acting by the inhibition of T-cell activation by the calcineurin pathway and inhibition of the release of numerous inflammatory cytokines, thereby preventing the cascade of immune and inflammatory signals.[1] Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells.[2] It has lower permeation through the skin than topical steroids or topical tacrolimus[3] although they have not been compared with each other for their permeation ability through mucosa. In addition, in contrast with topical steroids, pimecrolimus does not produce skin atrophy.[4]
Due to its immunosuppressive properties it is also being evaluated as the anti-proliferative agent for drug-eluting stents.
Pimecrolimus 1% cream has been approved by the Food and Drug Administration (FDA) for the treatment of atopic dermatitis. It has been proven to be effective in various inflammatory skin diseases, eg, seborrheic dermatitis,[5] cutaneous lupus erythematosus,[6] oral lichen planus,[7] vitiligo,[8] and psoriasis.[9][10]
See also: Immunomodulators in the treatment of eczema
In January 2006, the United States Food and Drug Administration (FDA) announced that Elidel packaging would be required to carry a black box warning regarding the potential increased risk of lymph node or skin malignancy, as for the similar drug tacrolimus. Whereas current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.[11]
Importantly, although the FDA has approved updated black-box warning for tacrolimus and pimecrolimus, the recent report of the American Academy of Dermatology Association Task Force finds that there is no causal proof that topical immunomodulators cause lymphoma or nonmelanoma skin cancer, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism.[12] Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy.[13] However, there are still some strong debates and controversies regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials.[14] Dermatologists' and Allergists' professional societies, the American Academy of Dermatology[1], and the American Academy of Allergy, Asthma, and Immunology, have protested the inclusion of the black box warning. The AAAAI states "None of the information provided for the cases of lymphoma associated with the use of topical pimecrolimus or tacrolimus in AD indicate or suggest a causal relationship."[2].
Topical corticosteroids can cause different types of systemic and local adverse effects. Systemic adverse events consist of glaucoma (in periorbital application), cataract, iatrogenic Cushing syndrome, retarded growth, and Addison crises, hyperglycemia and diabetes mellitus, osteopathy/osteoporosis, hypertension, peptic ulcer, and hypocalcemia. Local side effects encompass atrophic changes (e.g. skin atrophy, telangiectasia, striae, purpura, stellate pseudoscars, ulceration, and easy bruising), Infections (e.g. masked microbial infections, cutaneous candidiasis, herpes, or demodex aggravation, Kaposi sarcoma reactivation, granuloma gluteale infantum, Steroid acne, perioral dermatitis, allergic contact dermatitis, steroid rosacea, hirsutism, hyperpigmentation, hypopigmentation, photosensitization, psoriasis rebound flare, and epidermal barrier disturbance, hypertrichosis, delayed wound healing and aged-like effect on skin.[15][16] In light of the known side effects of steroids which are used first line for many dermatological conditions, many doctors prefer to use this drug instead. In practice, other doctors use the drug as a second-line remedy only after conventional methods of treatment have failed.
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