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TacrolimusTacrolimus belongs to a group of drugs called macrolide lactones or calcineurin inhibitors. It has similar immunosuppressant activity to ciclosporin and is given orally or by injection to prevent organ transplantation rejection. Tacrolimus is available as capsules and concentrated injection. The trade name in New Zealand is Prograf. Clinical trials have shown tacrolimus (given orally or applied topically) is often an effective treatment for inflammatory skin diseases such as atopic dermatitis and psoriasis. The topical form of tacrolimus called Protopic is now available in many countries but not yet in New Zealand (January 2004). How does tacrolimus work?Tacrolimus works on the immune system and directly on skin cells. Its mechanism of action is similar to pimecrolimus (Elidel) cream. It binds to a receptor within the cell called the FK binding proteins. This resulting drug-protein complex inhibits calcineurin (a calcium-dependent phosphatase transmitting chemical) that in turn reduces the activity of T-lymphocytes in the immune system. As a consequence, T-cells fail to release their cytokines (these are the chemicals that cause inflammation, redness and itching). In addition, tacrolimus may also have direct effects on skin cells (keratinocytes). It appears to reduce the number of IL-8 cytokine receptors on the keratinocyte, hence reducing inflammation. What is tacrolimus used for?Tacrolimus ointment is mainly indicated for the treatment of moderate to severe atopic dermatitis in adults and children who are: responding poorly to conventional therapy (emollients, topical and oral steroids, antibiotics, phototherapy) and/or suffering side effects from conventional therapy. Children should only be treated with tacrolimus ointment 0.03%. A stronger ointment (0.1%) is also available for adults. Studies have shown that treatment with topical tacrolimus show benefits after about one week and maximum improvement at about 3 months. There is no cure for atopic dermatitis, but tacrolimus provides a steroid-free treatment for controlling the symptoms. It frequently relieves the itch and inflammation caused by atopic dermatitis. Topical tacrolimus may also be useful for lichen planus, discoid lupus and many other inflammatory skin diseases.

How to use tacrolimusTacrolimus ointment is a prescription medicine and should be used only as directed by your doctor. Initial treatment will be for a short period to assess the response. If it is effective it may be continued long-term (6-12 months) if required. A thin layer of ointment should be rubbed in gently and completely onto the affected area(s) twice daily. Once the inflamed skin has returned to normal, the ointment may be discontinued. To prevent frequent recurrences, it may be helpful to apply it to previously affected areas two or three times weekly. Side effectsMost patients tolerate tacrolimus ointment well. The most common side effect that can be experienced around the site of application is a feeling of warmth or a sensation of burning. This is usually mild to moderate in severity and goes away within a few days after starting treatment. However, if this reaction persists for more than one week you should see your doctor. Other less common side effects include headache, cough, fever, flu-like symptoms, muscle aches, infection of the hair follicle (folliculitis) and acne. Unlike topical corticosteroids, topical tacrolimus has not been shown to cause skin thinning, hence it is suitable for application to areas of skin that are thin such as the face, neck and flexures. There are concerns however that topical tacrolimus may aggravate herpes simplex and other viral infections. Long term use of oral tacrolimus, like other immune suppressive agents, is known to increase the risk of skin cancer. Related informationReferences: Bedford C. Tacrolimus Russell JJ. Topical Tacrolimus: A New Therapy for Atopic Dermatitis. Am Fam Physician 2002;66:1899-902 On DermNet NZ: Pimecrolimus Atopic dermatitis Other websites: Consumer medicine information Medsafe Medicine data sheets Medsafe Drugs, Herbs and Supplements MedlinePlus Books about skin diseases:See the DermNet NZ bookstore Author: Vanessa Ngan, staff writer DermNet does not provide an on-line consultation service. TacrolimusFrom Wikipedia, the free encyclopediaThis articleneeds additional citations for verification.Please helpimprove this articlebyadding citations to reliable sources. Unsourced material may bechallengedandremoved.(December 2009)

Tacrolimus

Systematic (IUPAC) name

3S-[3R*[E(1S*,3S*,4S*)],4S*,5R*,8S*,9E,12R*,14R*,15S*,16R*,18S*,19S*,26aR*-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5, 19-dihydroxy-3-[2-(4-hydroxy-3-methoxycyclohexyl)-1-methylethenyl]-14,16-dimethoxy-4,10,12,18-tetramethyl-8-(2-propenyl)-15,19-epoxy-3H-pyrido[2,1-c] [1,4] oxaazacyclotricosine-1,7,20,21(4H,23H)-tetrone, monohydrate

Clinical data

Pregnancy cat.C

Legal statusPrescription only

RoutesTopical, oral,iv

Pharmacokinetic data

Bioavailability20%, less after eating food rich in fat

Protein binding75-99%

MetabolismHepaticCYP3A4

Half-life11.3 h (range 3.5-40.6 h)

ExcretionMostly faecal

Identifiers

CAS number104987-11-3

ATC codeD11AH01L04AD02

PubChemCID 6473866

DrugBankDB00864

ChemSpider4976056

UNIIY5L2157C4J

ChEMBLCHEMBL269732

Chemical data

FormulaC44H69NO12

Mol. mass804.018 g/mol

SMILES[show]

InChI[show]

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Tacrolimus(alsoFK-506orfujimycin, trade namesPrograf,Advagraf,Protopic) is animmunosuppressivedrugthat is mainly used afterallogeneicorgan transplantto reduce the activity of the patient'simmune systemand so lower the risk of organrejection. It is also used in a topical preparation in the treatment ofatopic dermatitis(eczema), severe refractoryuveitisafterbone marrowtransplants, exacerbations ofminimal change disease, and the skin conditionvitiligo.It is a 23-memberedmacrolidelactonediscovered in 1984 from the fermentation broth of aJapanesesoilsample that contained thebacteriaStreptomyces tsukubaensis. It reducesinterleukin-2(IL-2) production byT-cells.Contents[hide] 1History 2Availability 3Mechanism of action 4Indications 4.1Immunosuppression following transplantation 4.1.1Interactions 4.2Ulcerative colitis 4.3Dermatological use 5Side effects 5.1From oral and intravenous administration 5.1.1Carcinogenesis and mutagenesis 5.2From topical use 5.2.1Cancer risks 6Contraindications and precautions 7Use as a biological research tool 8References 9External linksHistory[edit]Tacrolimus was discovered in 1984; it was among the first macrolide immunosuppressants discovered, preceded by the discovery ofrapamycin(sirolimus) onRapa Nui(Easter Island) in 1975.[1]It is produced by a type of soil bacterium,Streptomyces tsukubaensis.[2]The name tacrolimus is derived from 'Tsukubamacrolide immunosuppressant'.[3]Tacrolimus was first approved by theFood and Drug Administration(FDA) in 1994 for use inliver transplantation; this has been extended to include kidney, heart, small bowel, pancreas, lung, trachea, skin, cornea, bone marrow, and limb transplants.Availability[edit]The branded version of the drug is owned byAstellas Pharma, and is sold under the trade namesPrografgiven twice daily,Advagraf, a sustained release formulation allowing once daily dosing, andProtopic(Eczemusin Pakistan by Brookes Pharma), the topical formulation.[4]Advagraf is available in 0.5, 1, 3 and 5mg capsules, the ointment is concentrations of 0.1% and 0.03%.A second once-daily formulation of tacrolimus is in Phase 3 clinical trials in the U.S. and Europe. This formulation also has a smoother pharmacokinetic profile that reduces the peak-to-trough range in blood levels compared to twice-daily tacrolimus.[5]Data from the first Phase 3 trial in stable kidney transplant patients showed that this once-daily formulation was non-inferior in efficacy and safety compared to twice-daily tacrolimus.[6]A second Phase 3 trial in de novo patients is ongoing.[7]Mechanism of action[edit]Tacrolimus is chemically known as amacrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activatecalcineurin. Calcineurin then dephosphorylates the transcription factor NF-AT (nuclear factor of activated T-cells), which moves to the nucleus of the T-cell and increases the activity of genes coding for IL-2 and related cytokines. Tacrolimus prevents the dephosphorylation of NF-AT.[8]In detail, Tacrolimus reduces peptidyl-prolyl isomerase activity by binding to the immunophilinFKBP12(FK506 binding protein) creating a new complex. This FKBP12-FK506 complex interacts with and inhibitscalcineurinthus inhibiting both T-lymphocytesignal transduction and IL-2 transcription.[9]Although this activity is similar tociclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over ciclosporin.[10]Although short-term immunosuppression concerning patient and graft survival is found to be similar between the two drugs, tacrolimus results in a more favorable lipid profile, and this may have important long-term implications given the prognostic influence of rejection on graft survival.[11]Indications[edit]Immunosuppression following transplantation[edit]It has similar immunosuppressive properties to ciclosporin, but is much more potent. Immunosuppression with tacrolimus was associated with a significantly lower rate of acute rejection compared with ciclosporin-based immunosuppression (30.7% vs 46.4%) in one study.[10]Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation.[12][13]Long term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of