Pimecrolimus

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Pimecrolimus
Pimecrolimus.svg
Pimecrolimus ball-and-stick.png
Clinical data
Trade names Elidel
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU:B3
Routes of
administration 		topical
Drug class immunosuppressant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability low systemic absorption
Protein binding 74%–87%
Metabolism Hepatic CYP3A
Identifiers
  • (3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,19R,26aS)-3-{(E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl}-8-ethyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c][1,4]oxaazacyclotricosin-1,7,20,21(4H,23H)-tetrone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.124.895 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C43H68ClNO11
Molar mass 810.46 g·mol−1
3D model (JSmol)
  • Cl[C@@H]1CC[C@H](C[C@H]1OC)\C=C(/C)[C@H]2OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@]3(O)O[C@H]([C@H](C[C@@H](C)CC(\C)=C\[C@@H](CC)C(=O)C[C@H](O)[C@H]2C)OC)[C@@H](OC)C[C@H]3C
  • InChI=1S/C43H68ClNO11/c1-10-30-18-24(2)17-25(3)19-36(53-8)39-37(54-9)21-27(5)43(51,56-39)40(48)41(49)45-16-12-11-13-32(45)42(50)55-38(28(6)33(46)23-34(30)47)26(4)20-29-14-15-31(44)35(22-29)52-7/h18,20,25,27-33,35-39,46,51H,10-17,19,21-23H2,1-9H3/b24-18+,26-20+/t25-,27+,28+,29-,30+,31+,32-,33-,35+,36-,37-,38+,39+,43+/m0/s1 Yes check.svgY
  • Key:KASDHRXLYQOAKZ-ZPSXYTITSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Pimecrolimus is an immunosuppressant drug of the calcineurin inhibitor class used in the treatment of atopic dermatitis (eczema).

Contents

It is available as a topical cream. It was developed and formerly marketed by Novartis under the trade name Elidel.

Medical uses

It has been proven to be effective in various inflammatory skin diseases, e.g., seborrheic dermatitis, [2] cutaneous lupus erythematosus, [3] oral lichen planus, [4] vitiligo, [5] and psoriasis. [6] [7] Tacrolimus and pimecrolimus are both calcineurin inhibitors and function as immunosuppressants. [8]

Atopic dermatitis

If topical corticosteroids and moisturisers fail in the treatment of atopic dermatitis, short-term treatment with topical calcineurin inhibitors such as tacrolimus or pimecrolimus may be tried. Both tacrolimus and pimecrolimus are effective and safe to use in AD. [9] [10]

Side effects

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 cancer, 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]

A 2023 systematic review and meta-analysis published in The Lancet Child & Adolescent Health further concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer. [14] However, strong debates and controversies continue regarding the exact indications of immunomodulators and their duration of use in the absence of active controlled trials. [15] Dermatologists' and allergists' professional societies, the American Academy of Dermatology, [16] 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." [17]

Pharmacology

Pimecrolimus is an ascomycin macrolactam derivative. It has been shown in vitro that pimecrolimus binds to FKBP1A and also inhibits calcineurin.[ citation needed ] 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.[ citation needed ]

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. [18] Pimecrolimus has a similar mode of action to that of tacrolimus but is more selective, with no effect on dendritic (Langerhans) cells. [19] It has lower permeation through the skin than topical steroids or topical tacrolimus [20] 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. [21]

Development and Production

Pimecrolimus was developed by Novartis. Its development number was ascomycin derivative ASM 981. [22]

The NDA was filed December 15, 2000. It received US FDA approval on December 13, 2001. [23] At its US approval, it was one of the first new eczema treatments introduced since the topical corticosteroids of the 1950s. [24] It is available as a topical cream, once marketed by . Since early 2007, Galderma has been promoting the compound in Canada. The trade name is Elidel.

Related Research Articles

<span class="mw-page-title-main">Dermatitis</span> Inflammatory disease of the skin

Dermatitis is inflammation of the skin, typically characterized by itchiness, redness and a rash. In cases of short duration, there may be small blisters, while in long-term cases the skin may become thickened. The area of skin involved can vary from small to covering the entire body. Dermatitis is often called eczema, and the difference between those terms is not standardized.

<span class="mw-page-title-main">Tacrolimus</span> Immunosuppressive drug

Tacrolimus, sold under the brand name Prograf among others, is an immunosuppressive drug. After allogenic organ transplant, the risk of organ rejection is moderate. To lower the risk of organ rejection, tacrolimus is given. The drug can also be sold as a topical medication in the treatment of T-cell-mediated diseases such as eczema and psoriasis. For example, it is prescribed for severe refractory uveitis after a bone marrow transplant, exacerbations of minimal change disease, Kimura's disease, and vitiligo. It can be used to treat dry eye syndrome in cats and dogs.

Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and urticaria caused by plants such as poison ivy or stinging nettle. It can also be caused by chronic kidney disease and related conditions.

<span class="mw-page-title-main">Dyshidrosis</span> Human disease

Dyshidrosis is a type of dermatitis that is characterized by itchy blisters on the palms of the hands and bottoms of the feet. Blisters are generally one to two millimeters in size and heal over three weeks. However, they often recur. Redness is not usually present. Repeated attacks may result in fissures and skin thickening.

<span class="mw-page-title-main">Desonide</span> Chemical compound

Desonide (INN) is a low-potency topical corticosteroid anti-inflammatory that has been available since the 1970s. It is primarily used to treat atopic dermatitis (eczema), seborrheic dermatitis, contact dermatitis and psoriasis in both adults and children. It has a fairly good safety profile and is available as a cream, ointment, lotion, and as a foam under the tradename Verdeso Foam. Other trade names for creams, lotions, and ointments include Tridesilon, DesOwen, Desonate. It is a group VI corticosteroid under US classification, the second least potent group.

<span class="mw-page-title-main">Cradle cap</span> Human medical condition

Cradle cap causes crusty or oily scaly patches on a baby's scalp. The condition is not painful or itchy, but it can cause thick white or yellow scales that are not easy to remove. Cradle cap most commonly begins sometime in the first three months but can occur in later years. Similar symptoms in older children are more likely to be dandruff than cradle cap. The rash is often prominent around the ear, the eyebrows or the eyelids. It may appear in other locations as well, where it is called infantile seborrhoeic dermatitis. Cradle cap is just a special—and more benign—case of this condition. The exact cause of cradle cap is not known. Cradle cap is not spread from person to person (contagious). It is also not caused by poor hygiene. It is not an allergy, and it is not dangerous. Cradle cap often lasts a few months. In some children, the condition can last until age 2 or 3.

<span class="mw-page-title-main">Atopic dermatitis</span> Long-term form of skin inflammation

Atopic dermatitis (AD), also known as atopic eczema, is a long-term type of inflammation of the skin (dermatitis). It results in itchy, red, swollen, and cracked skin. Clear fluid may come from the affected areas, which can thicken over time. AD may also simply be called eczema, a term that generally refers to a larger group of skin conditions.

<span class="mw-page-title-main">Betamethasone valerate</span> Chemical compound

Betamethasone valerate is a synthetic glucocorticoid ester. It is the 17-valerate ester of betamethasone. Betamethasone valerate is often used to treat mild eczema with good efficacy and lower incidence of steroid induced adverse effects due to its lower potency compared to other glucocorticoids. Betamethasone-17-valerate is available in cream, ointment, lotion, and foam preparations for topical use.

<span class="mw-page-title-main">Alclometasone</span> Chemical compound

Alclometasone is a synthetic corticosteroid for topical dermatologic use, possessing anti-inflammatory, antipruritic, and vasoconstrictive properties.

<span class="mw-page-title-main">Ascomycin</span> Chemical compound

Ascomycin, also called Immunomycin, FR-900520, FK520, is an ethyl analog of tacrolimus (FK506) with strong immunosuppressant properties. It has been researched for the treatment of autoimmune diseases and skin diseases, and to prevent rejection after an organ transplant.

<span class="mw-page-title-main">Clocortolone</span> Pharmaceutical drug

Clocortolone (Cloderm) is a topical steroid. It is used in the form of an ester, clocortolone pivalate, and applied as a cream. It is used for the treatment of dermatitis and is considered a medium-strength corticosteroid. It is unusual among steroids in that it contains a chlorine atom and a fluorine atom.

<span class="mw-page-title-main">Amcinonide</span> Chemical compound

Amcinonide is a topical glucocorticoid used to treat itching, redness and swelling associated with several dermatologic conditions such as atopic dermatitis and allergic contact dermatitis. Amcinonide can also be classified as a multi-functional small molecule corticosteroid, which has been approved by the FDA and is currently marketed as an ointment, lotion, or cream. It acts as both a transcription factor for responses to glucocorticoids and modulator for other transcription factors while also regulating phospholipase A2 activity.

<span class="mw-page-title-main">Balanitis circinata</span> Medical condition

Balanitis circinata is a skin condition comprising a serpiginous ring-shaped dermatitis of the glans penis. While circinate balanitis is one of the most common cutaneous manifestations of reactive arthritis, it can also occur independently. Topical corticosteroid therapy is the most commonly used treatment, and topical calcineurin inhibitors have also been used successfully.

In medicine, a finger tip unit (FTU) is defined as the amount of ointment, cream or other semi-solid dosage form expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin-crease to the tip of the index finger of an adult. The "distal skin-crease" is the skin crease over the joint nearest the end of the finger. One FTU is enough to treat an area of skin twice the size of the flat of an adult's hand with the fingers together, i.e. a "handprint". Two FTUs are approximately equivalent to 1 g of topical steroid.

<span class="mw-page-title-main">Ear eczema</span> Medical condition

Auricular eczema is an eczema of the ear that may involve the helix, postauricular fold, and external auditory canal, with the most frequently affected site being the external canal, where it is often a manifestation of seborrheic dermatitis or allergic contact dermatitis. This is an neuroallergic inflammation of skin with evident itch.

<span class="mw-page-title-main">Hand eczema</span> Skin condition

Hand eczema presents on the palms and soles, and may sometimes be difficult or impossible to differentiate from atopic dermatitis, allergic contact dermatitis, and psoriasis, which also commonly involve the hands. Even a biopsy of all these conditions may not result in a definitive diagnosis, as all three conditions may demonstrate spongiosis and crusting on the hands.

The Quality of Life Index for Atopic Dermatitis (QoLIAD) is a disease specific patient reported outcome which measures the impact that atopic dermatitis (AD) has on a given patient's quality of life.

<span class="mw-page-title-main">Topical steroid withdrawal</span> Medical condition

Topical steroid withdrawal, also known as red burning skin and steroid dermatitis, has been reported in people who apply topical steroids for 2 weeks or longer and then discontinue use. Symptoms affect the skin and include redness, a burning sensation, and itchiness, which may then be followed by peeling.

Childhood granulomatous periorificial dermatitis (CGPD), is a rare benign granulomatous skin disease of unknown cause. The disorder was first described in 1970 by Gianotti in a case series of five children. CGPD is more common in boys than girls.

<span class="mw-page-title-main">Topical glucocorticoids</span>

Topical glucocorticoids are the topical forms of glucocorticoids. Topical glucocorticoids are used in the treatment of many skin conditions. They provide anti-inflammatory, antimitotic, and immune-system suppressing actions through various mechanisms.

References

  1. ↑ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA . Retrieved 22 Oct 2023.
  2. ↑ Firooz A, Solhpour A, Gorouhi F, Daneshpazhooh M, Balighi K, Farsinejad K, et al. (August 2006). "Pimecrolimus cream, 1%, vs hydrocortisone acetate cream, 1%, in the treatment of facial seborrheic dermatitis: a randomized, investigator-blind, clinical trial". Archives of Dermatology. 142 (8): 1066–1067. doi:10.1001/archderm.142.8.1066. PMID   16924062.
  3. ↑ Kreuter A, Gambichler T, Breuckmann F, Pawlak FM, Stücker M, Bader A, et al. (September 2004). "Pimecrolimus 1% cream for cutaneous lupus erythematosus". Journal of the American Academy of Dermatology. 51 (3): 407–410. doi:10.1016/j.jaad.2004.01.044. PMID   15337984.
  4. ↑ Gorouhi F, Solhpour A, Beitollahi JM, Afshar S, Davari P, Hashemi P, et al. (November 2007). "Randomized trial of pimecrolimus cream versus triamcinolone acetonide paste in the treatment of oral lichen planus". Journal of the American Academy of Dermatology. 57 (5): 806–813. doi:10.1016/j.jaad.2007.06.022. PMID   17658663.
  5. ↑ Boone B, Ongenae K, Van Geel N, Vernijns S, De Keyser S, Naeyaert JM (2007). "Topical pimecrolimus in the treatment of vitiligo". European Journal of Dermatology. 17 (1): 55–61. doi:10.1684/ejd.2007.0093 (inactive 31 January 2024). PMID   17324829.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  6. ↑ Kreuter A, Sommer A, Hyun J, Bräutigam M, Brockmeyer NH, Altmeyer P, Gambichler T (September 2006). "1% pimecrolimus, 0.005% calcipotriol, and 0.1% betamethasone in the treatment of intertriginous psoriasis: a double-blind, randomized controlled study". Archives of Dermatology. 142 (9): 1138–1143. doi: 10.1001/archderm.142.9.1138 . PMID   16983001.
  7. ↑ Jacobi A, Braeutigam M, Mahler V, Schultz E, Hertl M (2008). "Pimecrolimus 1% cream in the treatment of facial psoriasis: a 16-week open-label study". Dermatology. 216 (2): 133–136. doi:10.1159/000111510. PMID   18216475. S2CID   35741213.
  8. ↑ Scheinfeld N (July 2004). "The use of topical tacrolimus and pimecrolimus to treat psoriasis: a review". Dermatology Online Journal. 10 (1): 3. doi:10.5070/D35ZK7V6CS. PMID   15347485.
  9. ↑ Cury Martins J, Martins C, Aoki V, Gois AF, Ishii HA, da Silva EM (July 2015). "Topical tacrolimus for atopic dermatitis". The Cochrane Database of Systematic Reviews. 2015 (7): CD009864. doi:10.1002/14651858.CD009864.pub2. PMC   6461158 . PMID   26132597.
  10. ↑ Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID   36370744. S2CID   253470127.
  11. ↑ Cox NH, Smith CH (December 2002). "Advice to dermatologists re topical tacrolimus". Therapy Guidelines Committee. British Association of Dermatologists. Archived from the original (DOC) on 2006-05-25.
  12. ↑ Berger TG, Duvic M, Van Voorhees AS, VanBeek MJ, Frieden IJ (May 2006). "The use of topical calcineurin inhibitors in dermatology: safety concerns. Report of the American Academy of Dermatology Association Task Force". Journal of the American Academy of Dermatology. 54 (5): 818–823. doi:10.1016/j.jaad.2006.01.054. PMID   16635663.
  13. ↑ Spergel JM, Leung DY (July 2006). "Safety of topical calcineurin inhibitors in atopic dermatitis: evaluation of the evidence". Current Allergy and Asthma Reports. 6 (4): 270–274. doi:10.1007/s11882-006-0059-7. PMID   16822378. S2CID   40761750.
  14. ↑ Devasenapathy N, Chu A, Wong M, Srivastava A, Ceccacci R, Lin C, et al. (January 2023). "Cancer risk with topical calcineurin inhibitors, pimecrolimus and tacrolimus, for atopic dermatitis: a systematic review and meta-analysis". The Lancet. Child & Adolescent Health. 7 (1): 13–25. doi:10.1016/S2352-4642(22)00283-8. PMID   36370744. S2CID   253470127.
  15. ↑ Stern RS (September 2006). "Topical calcineurin inhibitors labeling: putting the "box" in perspective". Archives of Dermatology. 142 (9): 1233–1235. doi:10.1001/archderm.142.9.1233. PMID   16983018.
  16. ↑ "Statement Regarding FDA Decision On Two Eczema Medications By American Academy Of Dermatology". Archived from the original on 2008-04-07. Retrieved 2007-09-24.
  17. ↑ Fonacier L, Spergel J, Charlesworth EN, Weldon D, Beltrani V, Bernhisel-Broadbent J, et al. (June 2005). "Report of the Topical Calcineurin Inhibitor Task Force of the American College of Allergy, Asthma and Immunology and the American Academy of Allergy, Asthma and Immunology". The Journal of Allergy and Clinical Immunology. 115 (6): 1249–1253. doi:10.1016/j.jaci.2005.04.006. PMID   15940142.
  18. ↑ Allen BR, Lakhanpaul M, Morris A, Lateo S, Davies T, Scott G, et al. (November 2003). "Systemic exposure, tolerability, and efficacy of pimecrolimus cream 1% in atopic dermatitis patients". Archives of Disease in Childhood. 88 (11): 969–973. doi:10.1136/adc.88.11.969. PMC   1719352 . PMID   14612358.
  19. ↑ Meingassner JG, Kowalsky E, Schwendinger H, Elbe-Bürger A, Stütz A (October 2003). "Pimecrolimus does not affect Langerhans cells in murine epidermis". The British Journal of Dermatology. 149 (4): 853–857. doi:10.1046/j.1365-2133.2003.05559.x. PMID   14616380. S2CID   26517363.
  20. ↑ Billich A, Aschauer H, Aszódi A, Stuetz A (January 2004). "Percutaneous absorption of drugs used in atopic eczema: pimecrolimus permeates less through skin than corticosteroids and tacrolimus". International Journal of Pharmaceutics. 269 (1): 29–35. doi:10.1016/j.ijpharm.2003.07.013. PMID   14698574.
  21. ↑ Murrell DF, Calvieri S, Ortonne JP, Ho VC, Weise-Riccardi S, Barbier N, Paul CF (November 2007). "A randomized controlled trial of pimecrolimus cream 1% in adolescents and adults with head and neck atopic dermatitis and intolerant of, or dependent on, topical corticosteroids". The British Journal of Dermatology. 157 (5): 954–959. doi:10.1111/j.1365-2133.2007.08192.x. PMID   17935515. S2CID   34706897.
  22. ↑ Eichenfield, L, Lucky, A, Boguniewicz, M (April 2002). "Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents". Journal of the American Academy of Dermatology. 46 (4): 495–504. doi:10.1067/mjd.2002.122187. PMID   11907497.
  23. ↑ "Application No.: 21-302 Elidel (Pimecrolimus) Cream". US DHHS. Retrieved 11 April 2024.
  24. ↑ "US SEC FORM 20-F NOVARTIS AG filed January 31, 2007" (PDF). www.novartis.com. NOVARTIS Inc. 31 January 2007. Retrieved 11 April 2024.
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