Pimecrolimus
Encyclopedia
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 compound in Canada since early 2007) under the trade name Elidel.
macrolactam
derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12(also referred to as FKBP-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 cell
s.
, 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.
Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells. It has lower permeation through the skin than topical steroids or topical tacrolimus
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. It has been proven to be effective in various inflammatory
skin diseases, e.g., seborrheic dermatitis, cutaneous lupus erythematosus, oral lichen planus
, vitiligo
, and psoriasis
. Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.
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.
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. Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy. 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.
Dermatologists' and Allergists' professional societies, the American Academy of Dermatology
http://www.medicalnewstoday.com/articles/21091.php, 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."http://www.aaaai.org/members/resources/calcineurin_task_force.pdf.
Immunomodulator
An immunomodulator, also known as an immunotherapy is a substance which has an effect on the immune system.- Immunosuppressants :Inhibits immune response in organ transplantation and autoimmune diseases.- Immunostimulants :...
used in the treatment of atopic dermatitis
Atopic dermatitis
Atopic dermatitis is an inflammatory, chronically relapsing, non-contagious and pruritic skin disorder...
(eczema). It is currently available as a topical cream, once marketed by Novartis
Novartis
Novartis International AG is a multinational pharmaceutical company based in Basel, Switzerland, ranking number three in sales among the world-wide industry...
(however Galderma
Galderma
Galderma is a global leading pharmaceutical company specializing in the research, development and marketing of innovative medical solutions in dermatology...
is promoting the compound in Canada since early 2007) under the trade name Elidel.
Pharmacology
Pimecrolimus is an ascomycinAscomycin
Ascomycin, also called Immunomycin, FR-900520, FK520, is an ethyl analog of tacrolimus with strong immunosuppressant properties. It can be used to treat autoimmune diseases and skin diseases, and can help prevent rejection after an organ transplant....
macrolactam
Lactam
A lactam is a cyclic amide. Prefixes indicate how many carbon atoms are present in the ring: β-lactam , γ-lactam , δ-lactam...
derivative. It has been shown in vitro that pimecrolimus binds to macrophilin-12(also referred to as FKBP-12) and inhibits calcineurin
Calcineurin
Calcineurin is a protein phosphatase also known as protein phosphatase 3, PPP3CA, and calcium-dependent serine-threonine phosphatase, and formerly known as protein phosphatase 2B . It activates the T cells of the immune system and can be blocked by drugs...
. 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 cell
Mast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
s.
General characteristics
Pimecrolimus, like tacrolimusTacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
, 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.
Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells. It has lower permeation through the skin than topical steroids or topical tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
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. It has been proven to be effective in various inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
skin diseases, e.g., seborrheic dermatitis, cutaneous lupus erythematosus, oral lichen planus
Oral lichen planus
Mucosal lichen planus, or oral lichen planus , is an inflammatory auto-immune disease that affects oral mucosa, with or without the involvement of the skin and other mucous membranes.- Epidemiology :...
, vitiligo
Vitiligo
Vitiligo is a condition that causes depigmentation of sections of skin. It occurs when melanocytes, the cells responsible for skin pigmentation, die or are unable to function. The cause of vitiligo is unknown, but research suggests that it may arise from autoimmune, genetic, oxidative stress,...
, and psoriasis
Psoriasis
Psoriasis is an autoimmune disease that appears on the skin. It occurs when the immune system mistakes the skin cells as a pathogen, and sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious. However, psoriasis has been linked to an increased risk of...
. Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants.
Side effects
See also: Immunomodulators in the treatment of eczemaIn January 2006, the United States Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) announced that Elidel packaging would be required to carry a black box warning
Black box warning
In the United States, a black box warning is a type of warning that appears on the package insert for prescription drugs that may cause serious adverse effects...
regarding the potential increased risk of lymph node
Lymph node
A lymph node is a small ball or an oval-shaped organ of the immune system, distributed widely throughout the body including the armpit and stomach/gut and linked by lymphatic vessels. Lymph nodes are garrisons of B, T, and other immune cells. Lymph nodes are found all through the body, and act as...
or skin malignancy, as for the similar drug tacrolimus
Tacrolimus
Tacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
. Whereas current practice by UK
United Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of such new drugs.
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
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
or nonmelanoma skin cancer
Skin cancer
Skin neoplasms are skin growths with differing causes and varying degrees of malignancy. The three most common malignant skin cancers are basal cell cancer, squamous cell cancer, and melanoma, each of which is named after the type of skin cell from which it arises...
, and systemic immunosuppression after short-term or intermittent long-term topical application seems an unlikely mechanism. Another recent review of evidence concluded that postmarketing surveillance shows no evidence for this systemic immunosuppression or increased risk for any malignancy. 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.
Dermatologists' and Allergists' professional societies, the American Academy of Dermatology
American Academy of Dermatology
The American Academy of Dermatology is the largest organization of dermatologists in the world. It was founded in 1938 and represents 17,000 dermatologists in the United States, Canada, and around the world. The Academy grants Fellowships and Associate Memberships, as well as Fellowships for...
http://www.medicalnewstoday.com/articles/21091.php, and the American Academy of Allergy, Asthma, and Immunology
American Academy of Allergy, Asthma, and Immunology
The American Academy of Allergy, Asthma & Immunology Founded in 1943, the AAAAI is a professional medical membership organization of nearly 6,500 allergist/immunologists and related professionals around the world with advanced training and experience in allergy, asthma and other immunologic diseases...
, 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."http://www.aaaai.org/members/resources/calcineurin_task_force.pdf.