Tacrolimus

Last updated

Tacrolimus
Tacrolimus2DCSD.svg
Tacrolimus-1YAT-ball-and-stick-model.png
Clinical data
Trade names Prograf, Advagraf, Protopic, others
Other namesFK-506, fujimycin
AHFS/Drugs.com Monograph
MedlinePlus a601117
License data
Pregnancy
category
Routes of
administration 		Topical, by mouth, intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 24% (5–67%), less after eating food rich in fat
Protein binding ≥98.8%
Metabolism Liver CYP3A4, CYP3A5
Elimination half-life 11.3 h for transplant patients (range 3.5–40.6 h)
Excretion Mostly fecal
Identifiers
  • (−)-(3S,4R,5S,8R,9E,12S,14S,15R,16S,18R,26aS)-8-allyl-5,6,8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-3-{(E)-2-[(1R,3R,4R)-4-hydroxy-3-methylcyclohexyl]-1-methylvinyl}-14,16-dimethoxy-4,10,12,18-tetramethyl-15,19-epoxy-3H-pyrido[2,1-c] [1,4]oxaazacyclotricosane-1,7,20,21(4H,23H)-tetrone
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.155.367 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C44H69NO12
Molar mass 804.031 g·mol−1
3D model (JSmol)
  • O(C)[C@@H]1[C@@]2(O[C@](O)([C@H](C)C1)C(=O)C(=O)N3[C@](C(=O)O[C@H](\C(=C\[C@H]4C[C@@H](OC)[C@H](O)CC4)\C)[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(\C)/C[C@H](C)C[C@@H]2OC)(CCCC3)[H])[H]
  • InChI=1S/C44H69NO12/c1-10-13-31-19-25(2)18-26(3)20-37(54-8)40-38(55-9)22-28(5)44(52,57-40)41(49)42(50)45-17-12-11-14-32(45)43(51)56-39(29(6)34(47)24-35(31)48)27(4)21-30-15-16-33(46)36(23-30)53-7/h10,19,21,26,28-34,36-40,46-47,52H,1,11-18,20,22-24H2,2-9H3/b25-19+,27-21+/t26-,28+,29+,30-,31+,32-,33+,34-,36+,37-,38-,39+,40+,44+/m0/s1 Yes check.svgY
  • Key:QJJXYPPXXYFBGM-LFZNUXCKSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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. [7] [8]

Contents

Tacrolimus inhibits calcineurin, which is involved in the production of interleukin-2, a molecule that promotes the development and proliferation of T cells, as part of the body's learned (or adaptive) immune response.

Chemically, it is a macrolide lactone [9] that was first discovered in 1987, from the fermentation broth of a Japanese soil sample that contained the bacterium Streptomyces tsukubensis . It is on the World Health Organization's List of Essential Medicines. [10] In 2021, it was the 296th most commonly prescribed medication in the United States, with more than 500,000 prescriptions. [11] [12]

Medical uses

Organ transplantation

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. [13] Clinical outcome is better with tacrolimus than with ciclosporin during the first year of liver transplantation. [14] [15] Long-term outcome has not been improved to the same extent. Tacrolimus is normally prescribed as part of a post-transplant cocktail including steroids, mycophenolate, and IL-2 receptor inhibitors such as basiliximab. Dosages are titrated to target blood levels at specific times after medication administration. [16]

Skin

Tacrolimus 0.1% Ointment Protopic.JPG
Tacrolimus 0.1% Ointment

As an ointment, tacrolimus is used in the treatment of dermatitis (eczema), in particular atopic dermatitis, if topical corticosteroids and moisturisers fail in helping. [17] [18] It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that, unlike steroids, it does not cause skin thinning (atrophy), or other steroid related side effects. [19] [18]

It is applied on the active lesions until they heal off, but may also be used continuously in low doses (twice a week), and applied to the thinner skin over the face and eyelids.[ citation needed ] Clinical trials of up to one year have been conducted. Recently it has also been used to treat segmental vitiligo in children, especially in areas on the face. [20]

Eyes

Tacrolimus solution, as drops, is sometimes prescribed by veterinarians for keratoconjunctivitis, and other dry eye maladies, in the eyes of domestic cats, dogs, and horses. [21] It has been studied for use in human eyes. [22] [23]

Contraindications and precautions

Contraindications and precautions include: [24]

Topical use

Side effects

By mouth or intravenous use

Side effects can be severe and include infection, cardiac damage, hypertension, blurred vision, liver and kidney problems (tacrolimus nephrotoxicity), [26] hyperkalemia, hypomagnesemia, hyperglycemia, diabetes mellitus, itching, lung damage (sirolimus also causes lung damage), [27] and various neuropsychiatric problems such as loss of appetite, insomnia, posterior reversible encephalopathy syndrome, confusion, weakness, depression, vivid nightmares, cramps, neuropathy, seizures, tremors, and catatonia. [28]

In addition, it may potentially increase the severity of existing fungal or infectious conditions such as herpes zoster or polyoma viral infections. [24]

Carcinogenesis and mutagenesis

In people receiving immunosuppressants to reduce transplant graft rejection, an increased risk of malignancy (cancer) is a recognised complication. [24] The most common cancers are non-Hodgkin's lymphoma [29] and skin cancers. The risk appears to be related to the intensity and duration of treatment.

Topical use

The most common adverse events associated with the use of topical tacrolimus ointments, especially if used over a wide area, include a burning or itching sensation on the initial applications, with increased sensitivity to sunlight and heat on the affected areas.[ citation needed ] Less common are flu-like symptoms, headache, cough, and burning eyes. [30]

Cancer risks

Tacrolimus and a related drug for eczema (pimecrolimus) were suspected of carrying a cancer risk, though the matter is still a subject of controversy. The FDA issued a health warning in March 2005 for the drug, based on animal models and a small number of patients. Until further human studies yield more conclusive results, the FDA recommends that users be advised of the potential risks. However, current practice by UK dermatologists is not to consider this a significant real concern and they are increasingly recommending the use of these new drugs. [31] A 2023 systematic review and meta-analysis published in The Lancet Child & Adolescent Health concluded with moderate-certainty evidence that the two drugs were not associated with any increased risk of cancer. [32]

Interactions

Also like cyclosporin, it has a wide range of interactions. Tacrolimus is primarily metabolised by the cytochrome P450 system of liver enzymes, and there are many substances that interact with this system and induce or inhibit the system's metabolic activity. [24]

Interactions include that with grapefruit which increases tacrolimus plasma concentrations. As infections are a major cause of morbidity and mortality in the post-transplant patient, the most commonly[ citation needed ] reported interactions include interactions with anti-microbial drugs. Macrolide antibiotics including erythromycin and clarithromycin, as well as several of the newer classes of antifungals, especially of the azole class (fluconazole, voriconazole), increase tacrolimus levels by competing for cytochrome enzymes. [24]

Pharmacology

Mechanism of action

FKBP12, the target protein of tacrolimus PDB 1fkk EBI.jpg
FKBP12, the target protein of tacrolimus

Tacrolimus is a macrolide calcineurin inhibitor. In T cells, activation of the T cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. Calcineurin then dephosphorylates the transcription factor nuclear factor of activated T cells (NF-AT), 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. [33]

In detail, tacrolimus reduces peptidylprolyl isomerase activity by binding to the immunophilin FKBP12 (FK506 binding protein), creating a new complex. This FKBP12–FK506 complex interacts with and inhibits calcineurin, thus inhibiting both T lymphocyte signal transduction and IL-2 transcription. [34] Although this activity is similar to that of cyclosporin, the incidence of acute rejection is reduced by tacrolimus use over cyclosporin use. [13] 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. [35]

Pharmacokinetics

Oral tacrolimus is slowly absorbed in the gastrointestinal tract, with a total bioavailability of 20 to 25% (but with variations from 5 to 67%) and highest blood plasma concentrations (Cmax) reached after one to three hours. Taking the drug together with a meal, especially one rich in fat, slows down resorption and reduces bioavailability. In the blood, tacrolimus is mainly bound to erythrocytes; only 5% are found in the plasma, of which more than 98.8% are bound to plasma proteins. [24] [36]

The substance is metabolized in the liver, mainly via CYP3A, and in the intestinal wall. All metabolites found in the circulation are inactive. Biological half-life varies widely and seems to be higher for healthy persons (43 hours on average) than for patients with liver transplants (12 hours) or kidney transplants (16 hours), due to differences in clearance. Tacrolimus is predominantly eliminated via the faeces in form of its metabolites. [24] [36]

When applied locally on eczema, tacrolimus has little to no bioavailability. [24]

Pharmacogenetics

The predominant enzyme responsible for metabolism of tacrolimus is CYP3A5. Genetic variations within CYP3A5 that result in changes to the activity of the CYP3A5 protein can affect concentrations of tacrolimus within the body. In particular, individuals who are homozygous for the G allele at the single nucleotide polymorphism (SNP) rs776746 (also known as CYP3A5 *3/*3) have a non-functional CYP3A5 protein. The frequency of the G allele varies worldwide, from 4% in some African populations to 80–90% in Caucasian populations. [37] Across a large number of studies, individuals homozygous for the G allele have been shown to have higher concentrations of tacrolimus and require lower doses of the drug, as compared to individuals who are not homozygous for the G allele. Achieving target concentrations of tacrolimus is important – if levels are too low, then there is a risk of transplant rejection, if levels are too high, there is a risk of drug toxicities. There is evidence to suggest that dosing patients based on rs776746 genotype can result in faster and more frequent achievement of target tacrolimus levels. However, there is a lack of consistent evidence as to whether dosing based on rs776746 genotype results in improved clinical outcomes (such as a decreased risk for transplant rejection or drug toxicities), likely because patients taking tacrolimus are subject to therapeutic drug monitoring. [38] [39] [40] [41]

Studies have shown that genetic polymorphisms of genes other than CYP3A5, such as NR1I2 [42] [43] (encoding PXR), also significantly influence the pharmacokinetics of tacrolimus.

History

Tacrolimus was discovered in 1987; it was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975. [44] It is produced by a soil bacterium, Streptomyces tsukubensis. [45] The name tacrolimus is derived from "Tsukuba macrolide immunosuppressant". [46]

The early development (investigational new drug phase) of tacrolimus, called at the time by the development code FK-506, happened in the next several years. A firsthand account of that process is given in Thomas Starzl's 1992 memoir. [47]

Tacrolimus was first approved by the US Food and Drug Administration (FDA) in 1994, [48] [49] for use in liver transplantation; the indications were extended to include kidney transplants. [50] Generic versions of tacrolimus were approved in the US in 2017. [51]

Tacrolimus was approved for medical use in the European Union in 2002, for the treatment of moderate to severe atopic dermatitis. [52] In 2007, the indications were expanded to include the prophylaxis of transplant rejection in adult kidney or liver allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults. [53] In 2009, the indications were expanded to include the prophylaxis of transplant rejection in adult and paediatric, kidney, liver or heart allograft recipients and the treatment of allograft rejection resistant to treatment with other immunosuppressive medicinal products in adults and children. [54]

Available forms

A branded version of the drug is owned by Astellas Pharma, and is sold under the brand name Prograf, given twice daily. A number of other manufacturers hold marketing authorisation for alternative brands of the twice-daily formulation. [55]

Once-daily formulations with marketing authorisation include Advagraf (Astellas Pharma) and Envarsus (marketed as Envarsus XR in US by Veloxis Pharmaceuticals and marketed in Europe by Chiesi). [55] These formulations are intended to reduce pharmacokinetic variation in blood levels and facilitate compliance with dosing.[ citation needed ]

The topical formulation is marketed by LEO Pharma under the name Protopic. [55]

Biosynthesis

Tacrolimus biosynthesis part 1.tif Tacrolimus biosynthesis part 2.tif Tacrolimus biosynthesis part 3..tif

The biosynthesis of tacrolimus is hybrid synthesis of both type 1 polyketide synthases (PKS 1) and nonribosomal peptide syntheses (NRPS). The research shows the hybrid synthesis consists of ten modules of type 1 polyketide synthase and one module of nonribosomal peptide synthase. The synthetic enzymes for tacrolimus are found in 19 gene clusters named fkb. The 19 genes are fkbQ, fkbN, fkbM, fkbD, fkbA, fkbP, fkbO, fkbB, fkbC, fkbL, fkbK, fkbJ, fkbI, fkbH, fkbG, allD, allR, allK and allA. [56]

There are several possible ways of biosynthesis of tacrolimus. The fundamental units for biosynthesis are following: one molecule of 4,5-dihydroxycyclohex-1-enecarboxylic acid (DHCHC) as a starter unit, four molecules of malonyl-CoA, five molecules of methylmalonyl-CoA, one molecule of allylmalonyl-CoA as elongation units. However, two molecules of malonyl-CoA are able to be replaced by two molecules of methoxymalonyl CoA. Once two malonyl-CoA molecules are replaced, post-synthase tailoring steps are no longer required where two methoxymalonyl CoA molecules are substituted. The biosynthesis of methoxymalonyl CoA to Acyl Carrier protein is proceeded by five enzymes (fkbG, fkbH, fkbI, fkbJ, and fkbK). Allylmalonyl-CoA is also able to be replaced by propionylmalonyl-CoA. [56]

The starter unit, DHCHC from the chorismic acid is formed by fkbO enzyme and loaded onto CoA-ligase domain (CoL). Then, it proceeds to NADPH dependent reduction(ER). Three enzymes, fkbA,B,C enforce processes from the loading module to the module 10, the last step of PKS 1. fkbB enzyme is responsible of allylmalonyl-CoA synthesis or possibly propionylmalonyl-CoA at C21, which it is an unusual step of general PKS 1. As mentioned, if two methoxymalonyl CoA molecules are substituted for two malonyl-CoA molecules, they will take place in module 7 and 8 (C13 and C15), and fkbA enzyme will enforce this process. After the last step (module 10) of PKS 1, one molecule of L-pipecolic acid formed from L-lysine and catalyzed through fkbL enzyme synthesizes with the molecule from the module 10. The process of L-pipecolic acid synthesis is NRPS enforced by fkbP enzyme. After synthesizing the entire subunits, the molecule is cyclized. After the cyclization, the pre-tacrolimus molecule goes through the post-synthase tailoring steps such as oxidation and S-adenosyl methionine. Particularly fkbM enzyme is responsible of alcohol methylation targeting the alcohol of DHCHC starter unit (Carbon number 31 depicted in brown), and fkbD enzyme is responsible of C9 (depicted in green). After these tailoring steps, the tacrolimus molecule becomes biologically active. [56] [57] [58]

Research

Lupus nephritis

Tacrolimus has been shown to reduce the risk of serious infections while also increasing remission of kidney function in lupus nephritis. [59] [60]

Ulcerative colitis

Tacrolimus has been used to suppress the inflammation associated with ulcerative colitis (UC), a form of inflammatory bowel disease. Although almost exclusively used in trial cases only, tacrolimus has shown to be significantly effective in the suppression of flares of UC. [61] A 2022 updated Cochrane systematic review found that tacrolimus may be superior to placebo in achieving remission and improvement in UC. [62]

Related Research Articles

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

Ciclosporin, also spelled cyclosporine and cyclosporin, is a calcineurin inhibitor, used as an immunosuppressant medication. It is taken orally or intravenously for rheumatoid arthritis, psoriasis, Crohn's disease, nephrotic syndrome, eczema, and in organ transplants to prevent rejection. It is also used as eye drops for keratoconjunctivitis sicca.

<span class="mw-page-title-main">Immunosuppressive drug</span> Drug that inhibits activity of immune system

Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent the activity of the immune system.

<span class="mw-page-title-main">Azathioprine</span> Immunosuppressive medication

Azathioprine, sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used for the treatment of rheumatoid arthritis, granulomatosis with polyangiitis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus; and in kidney transplants to prevent rejection. It is listed by the International Agency for Research on Cancer as a group 1 human carcinogen. It is taken by mouth or injected into a vein.

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

Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumour (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mammalian target of rapamycin (mTOR) kinase inhibitor that reduces the sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity.

<span class="mw-page-title-main">Transplant rejection</span> Rejection of transplanted tissue by the recipients immune system

Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient and by use of immunosuppressant drugs after transplant.

<span class="mw-page-title-main">Mycophenolic acid</span> Immunosuppressant medication

Mycophenolic acid is an immunosuppressant medication used to prevent rejection following organ transplantation and to treat autoimmune conditions such as Crohn's disease and lupus. Specifically it is used following kidney, heart, and liver transplantation. It can be given by mouth or by injection into a vein. It comes as mycophenolate sodium and mycophenolate mofetil.

<span class="mw-page-title-main">Graft-versus-host disease</span> Medical condition

Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.

<span class="mw-page-title-main">Ritonavir</span> Antiretroviral medication

Ritonavir, sold under the brand name Norvir, is an antiretroviral medication used along with other medications to treat HIV/AIDS. This combination treatment is known as highly active antiretroviral therapy (HAART). Ritonavir is a protease inhibitor, though it now mainly serves to boost the potency of other protease inhibitors. It may also be used in combination with other medications to treat hepatitis C and COVID-19. It is taken by mouth.

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

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

<span class="mw-page-title-main">Calcineurin</span> Class of enzymes

Calcineurin (CaN) is a calcium and calmodulin dependent serine/threonine protein phosphatase. It activates the T cells of the immune system and can be blocked by drugs. Calcineurin activates nuclear factor of activated T cell cytoplasmic (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of the T cell response. Calcineurin is the target of a class of drugs called calcineurin inhibitors, which include ciclosporin, voclosporin, pimecrolimus and tacrolimus.

<span class="mw-page-title-main">Cidofovir</span> Antiviral drug

Cidofovir, brand name Vistide, is a topical or injectable antiviral medication primarily used as a treatment for cytomegalovirus (CMV) retinitis in people with AIDS.

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

Leflunomide, sold under the brand name Arava among others, is an immunosuppressive disease-modifying antirheumatic drug (DMARD), used in active moderate-to-severe rheumatoid arthritis and psoriatic arthritis. It is a pyrimidine synthesis inhibitor that works by inhibiting dihydroorotate dehydrogenase.

<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.

In molecular biology, immunophilins are endogenous cytosolic peptidyl-prolyl isomerases (PPI) that catalyze the interconversion between the cis and trans isomers of peptide bonds containing the amino acid proline (Pro). They are chaperone molecules that generally assist in the proper folding of diverse "client" proteins. Immunophilins are traditionally classified into two families that differ in sequence and biochemical characteristics. These two families are: "cyclosporin-binding cyclophilins (CyPs)" and "FK506-binding proteins (FKBPs)". In 2005, a group of dual-family immunophilins (DFI) has been discovered, mostly in unicellular organisms; these DFIs are natural chimera of CyP and FKBPs, fused in either order.

<span class="mw-page-title-main">Islet cell transplantation</span> Transference of pancreatic islets

Islet transplantation is the transplantation of isolated islets from a donor pancreas into another person. It is a treatment for type 1 diabetes. Once transplanted, the islets begin to produce insulin, actively regulating the level of glucose in the blood.

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

The FKBPs, or FK506 binding proteins, constitute a family of proteins that have prolyl isomerase activity and are related to the cyclophilins in function, though not in amino acid sequence. FKBPs have been identified in many eukaryotes, ranging from yeast to humans, and function as protein folding chaperones for proteins containing proline residues. Along with cyclophilin, FKBPs belong to the immunophilin family.

Ciclosporin is a cyclic polypeptide that has been used widely as an orally-available immunosuppressant. It was originally used to prevent transplant rejection of solid organs but has also found use as an orally administered agent to treat psoriasis, rheumatoid arthritis, dry eye and other auto-immune related conditions. A variety of pre-clinical and clinical studies have been and are investigating its use to treat lung-related disorders via inhalation.

<span class="mw-page-title-main">Ruxolitinib</span> Medication

Ruxolitinib, sold under the brand name Jakafi among others, is a medication used for the treatment of intermediate or high-risk myelofibrosis, a type of myeloproliferative neoplasm that affects the bone marrow; polycythemia vera, when there has been an inadequate response to or intolerance of hydroxyurea; and steroid-refractory acute graft-versus-host disease. Ruxolitinib is a Janus kinase inhibitor. It was developed and marketed by Incyte Corp in the US under the brand name Jakafi, and by Novartis elsewhere in the world, under the brand name Jakavi.

<span class="mw-page-title-main">Voclosporin</span> Medication

Voclosporin, sold under the brand name Lupkynis, is a calcineurin inhibitor used as an immunosuppressant medication for the treatment of lupus nephritis. It is an analog of ciclosporin that has enhanced action against calcineurin and greater metabolic stability.

Drug-induced gingival enlargement (DIGE), also referred to as drug-induced gingival hyperplasia (DIGH) or drug-induced gingival overgrowth (DIGO), is a side effect of many systemic medications for which the Gingervae are not the target receptor. It is normally resultant of medications including immunoregulators, calcium channel blockers and anticonvulsants. When allowed to progress assisted by routinely poor oral hygiene, DIGE can lead to pain and disfigurement, however there are great variations in its presentation and severity dependent on the case. It is suggested that enlargement is aided by genetic predispositions, tending to occur more frequently in the papillae of the anterior Gingivae in younger age groups.

References

  1. ↑ "Tacrolimus Use During Pregnancy". Drugs.com. 3 October 2019. Retrieved 29 April 2020.
  2. ↑ "Drug and medical device highlights 2019: Helping you maintain and improve your health". Health Canada . 18 November 2020. Retrieved 28 March 2024.
  3. ↑ "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 October 2023.
  4. ↑ "Prograf- tacrolimus capsule, gelatin coated Prograf- tacrolimus injection, solution Prograf- tacrolimus granule, for suspension". DailyMed. Retrieved 16 July 2021.
  5. ↑ "Advagraf EPAR". European Medicines Agency. 17 September 2018. Retrieved 16 July 2021.
  6. ↑ "Protopic EPAR". European Medicines Agency. 17 September 2018. Retrieved 16 July 2021.
  7. ↑ Berdoulay A, English RV, Nadelstein B (2005). "Effect of topical 0.02% tacrolimus aqueous suspension on tear production in dogs with keratoconjunctivitis sicca". Veterinary Ophthalmology. 8 (4): 225–232. doi: 10.1111/j.1463-5224.2005.00390.x . PMID   16008701.
  8. ↑ "Tacrolimus for Dogs and Cats".
  9. ↑ Baldo A, Cafiero M, Di Caterino P, Di Costanzo L (January 2009). "Tacrolimus ointment in the management of atopic dermatitis". Clinical, Cosmetic and Investigational Dermatology. 2: 1–7. doi: 10.2147/ccid.s3378 . PMC   3047924 . PMID   21436963.
  10. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  11. ↑ "The Top 300 of 2021". ClinCalc. Archived from the original on 15 January 2024. Retrieved 14 January 2024.
  12. ↑ "Tacrolimus - Drug Usage Statistics". ClinCalc. Retrieved 14 January 2024.
  13. 1 2 McCauley J (19 May 2004). "Long-Term Graft Survival In Kidney Transplant Recipients". Slide Set Series on Analyses of Immunosuppressive Therapies. Medscape . Retrieved 6 June 2006.
  14. ↑ Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL (October 2006). McAlister V (ed.). "Cyclosporin versus tacrolimus for liver transplanted patients". The Cochrane Database of Systematic Reviews. 2006 (4): CD005161. doi:10.1002/14651858.CD005161.pub2. PMC   8865611 . PMID   17054241.
  15. ↑ O'Grady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A (October 2002). "Tacrolimus versus microemulsified ciclosporin in liver transplantation: the TMC randomised controlled trial". Lancet. 360 (9340): 1119–1125. doi:10.1016/S0140-6736(02)11196-2. PMID   12387959. S2CID   10417106.
  16. ↑ Lee MN, Butani L (June 2007). "Improved pharmacokinetic monitoring of tacrolimus exposure after pediatric renal transplantation". Pediatric Transplantation. 11 (4): 388–393. doi: 10.1111/j.1399-3046.2006.00618.x . PMID   17493218. S2CID   23530214.
  17. ↑ 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.
  18. 1 2 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.
  19. 1 2 Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Protopic.
  20. ↑ Silverberg NB, Lin P, Travis L, Farley-Li J, Mancini AJ, Wagner AM, et al. (November 2004). "Tacrolimus ointment promotes repigmentation of vitiligo in children: a review of 57 cases". Journal of the American Academy of Dermatology. 51 (5): 760–766. doi:10.1016/j.jaad.2004.05.036. PMID   15523355.
  21. ↑ "Tacrolimus, Ophthalmic" (PDF). Plumbs Veterinary Medication Guides. 2017. Archived from the original (PDF) on 18 December 2022. Retrieved 5 August 2022.
  22. ↑ Naves FE, Sakassegawa E (10 May 2013). "Treatment of Dry Eye Using 0.03% Tacrolimus Eye Drops". U.S. National Library of Medicine. Retrieved 5 August 2022.
  23. ↑ Yazu H, Fukagawa K, Shimizu E, Sato Y, Fujishima H (February 2021). "Long-term outcomes of 0.1% tacrolimus eye drops in eyes with severe allergic conjunctival diseases". Allergy, Asthma, and Clinical Immunology. 17 (1): 11. doi: 10.1186/s13223-021-00513-w . PMC   7852099 . PMID   33522964.
  24. 1 2 3 4 5 6 7 8 Haberfeld, H, ed. (2015). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Prograf.
  25. ↑ Fukatsu S, Fukudo M, Masuda S, Yano I, Katsura T, Ogura Y, et al. (April 2006). "Delayed effect of grapefruit juice on pharmacokinetics and pharmacodynamics of tacrolimus in a living-donor liver transplant recipient". Drug Metabolism and Pharmacokinetics. 21 (2): 122–125. doi:10.2133/dmpk.21.122. PMID   16702731.
  26. ↑ Naesens M, Kuypers DR, Sarwal M (February 2009). "Calcineurin inhibitor nephrotoxicity". Clinical Journal of the American Society of Nephrology. 4 (2): 481–508. doi: 10.2215/CJN.04800908 . PMID   19218475.
  27. ↑ Miwa Y, Isozaki T, Wakabayashi K, Odai T, Matsunawa M, Yajima N, et al. (2008). "Tacrolimus-induced lung injury in a rheumatoid arthritis patient with interstitial pneumonitis". Modern Rheumatology. 18 (2): 208–211. doi:10.1007/s10165-008-0034-3. PMID   18306979. S2CID   39537409.
  28. ↑ O'Donnell MM, Williams JP, Weinrieb R, Denysenko L (2007). "Catatonic mutism after liver transplant rapidly reversed with lorazepam". General Hospital Psychiatry. 29 (3): 280–281. doi:10.1016/j.genhosppsych.2007.01.004. PMID   17484951.
  29. ↑ "Key Statistics for Non-Hodgkin Lymphoma". www.cancer.org. Retrieved 19 February 2020.
  30. ↑ Hanifin JM, Paller AS, Eichenfield L, Clark RA, Korman N, Weinstein G, et al. (August 2005). "Efficacy and safety of tacrolimus ointment treatment for up to 4 years in patients with atopic dermatitis". Journal of the American Academy of Dermatology. 53 (2 Suppl 2): S186–S194. doi:10.1016/j.jaad.2005.04.062. PMID   16021174.
  31. ↑ Cox NH, Smith CH (December 2002). "Advice to dermatologists re topical tacrolimus" (PDF). Therapy Guidelines Committee. British Association of Dermatologists. Archived from the original (PDF) on 13 December 2013.
  32. ↑ 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.
  33. ↑ Ganong WF (8 March 2005). Review of medical physiology (22nd ed.). Lange medical books. p. 530. ISBN   978-0-07-144040-0.
  34. ↑ Liu J, Farmer JD, Lane WS, Friedman J, Weissman I, Schreiber SL (August 1991). "Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes". Cell. 66 (4): 807–815. doi:10.1016/0092-8674(91)90124-H. PMID   1715244. S2CID   22094672.
  35. ↑ Abou-Jaoude MM, Najm R, Shaheen J, Nawfal N, Abboud S, Alhabash M, et al. (September 2005). "Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients". Transplantation Proceedings. 37 (7): 3025–3028. doi:10.1016/j.transproceed.2005.08.040. PMID   16213293.
  36. 1 2 Dinnendahl, V, Fricke, U, eds. (2003). Arzneistoff-Profile (in German). Vol. 9 (18 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN   978-3-7741-9846-3.
  37. ↑ Bains RK. "Molecular diversity and population structure at the CYP3A5 gene in Africa" (PDF). University College London. Retrieved 13 June 2016.
  38. ↑ Staatz CE, Tett SE (2004). "Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation". Clinical Pharmacokinetics. 43 (10): 623–653. doi:10.2165/00003088-200443100-00001. PMID   15244495. S2CID   33877550.
  39. ↑ Staatz CE, Goodman LK, Tett SE (March 2010). "Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I". Clinical Pharmacokinetics. 49 (3): 141–175. doi:10.2165/11317350-000000000-00000. PMID   20170205. S2CID   28346861.
  40. ↑ Staatz CE, Goodman LK, Tett SE (April 2010). "Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part II". Clinical Pharmacokinetics. 49 (4): 207–221. doi:10.2165/11317550-000000000-00000. PMID   20214406. S2CID   27047235.
  41. ↑ Barbarino JM, Staatz CE, Venkataramanan R, Klein TE, Altman RB (October 2013). "PharmGKB summary: cyclosporine and tacrolimus pathways". Pharmacogenetics and Genomics. 23 (10): 563–585. doi:10.1097/fpc.0b013e328364db84. PMC   4119065 . PMID   23922006.
  42. ↑ Benkali K, Prémaud A, Picard N, Rérolle JP, Toupance O, Hoizey G, et al. (1 January 2009). "Tacrolimus population pharmacokinetic-pharmacogenetic analysis and Bayesian estimation in renal transplant recipients". Clinical Pharmacokinetics. 48 (12): 805–816. doi:10.2165/11318080-000000000-00000. PMID   19902988. S2CID   19900291.
  43. ↑ Choi Y, Jiang F, An H, Park HJ, Choi JH, Lee H (January 2017). "A pharmacogenomic study on the pharmacokinetics of tacrolimus in healthy subjects using the DMETTM Plus platform". The Pharmacogenomics Journal. 17 (1): 105–106. doi: 10.1038/tpj.2016.85 . PMID   27958377.
  44. ↑ Kino T, Hatanaka H, Hashimoto M, Nishiyama M, Goto T, Okuhara M, et al. (September 1987). "FK-506, a novel immunosuppressant isolated from a Streptomyces. I. Fermentation, isolation, and physico-chemical and biological characteristics". The Journal of Antibiotics. 40 (9): 1249–1255. doi: 10.7164/antibiotics.40.1249 . PMID   2445721.
  45. ↑ Pritchard DI (May 2005). "Sourcing a chemical succession for cyclosporin from parasites and human pathogens". Drug Discovery Today. 10 (10): 688–691. doi:10.1016/S1359-6446(05)03395-7. PMID   15896681. Supports source organism, but not team information
  46. ↑ Ponner, B, Cvach, B (Fujisawa Pharmaceutical Co.): Protopic Update 2005
  47. ↑ Starzl TE (1992). "Chapter 25: The drug with no name". The Puzzle People: Memoirs Of A Transplant Surgeon. University of Pittsburgh Press. pp. 288–308. doi:10.2307/j.ctt9qh63b. ISBN   978-0-8229-3714-2.
  48. ↑ "Prograf: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
  49. ↑ "Prograf: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
  50. ↑ Tacrolimus (Systemic) Monograph . Accessed 16 December 2021.
  51. ↑ "Tacrolimus: FDA-Approved Drugs". U.S. Food and Drug Administration (FDA). Retrieved 29 April 2020.
  52. ↑ "Protopic EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  53. ↑ "Advagraf EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 April 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  54. ↑ "Modigraf EPAR". European Medicines Agency (EMA). 17 September 2018. Retrieved 29 April 2020.
  55. 1 2 3 Joint Formulary Committee. "British National Formulary (online)". London: BMJ Group and Pharmaceutical Press. Retrieved 24 September 2015.
  56. 1 2 3 Ordóñez-Robles M, Santos-Beneit F, Martín JF (May 2018). "Unraveling Nutritional Regulation of Tacrolimus Biosynthesis in Streptomyces tsukubaensis through omic Approaches". Antibiotics. 7 (2): 39. doi: 10.3390/antibiotics7020039 . PMC   6022917 . PMID   29724001.
  57. ↑ Chen D, Zhang L, Pang B, Chen J, Xu Z, Abe I, et al. (May 2013). "FK506 maturation involves a cytochrome p450 protein-catalyzed four-electron C-9 oxidation in parallel with a C-31 O-methylation". Journal of Bacteriology. 195 (9): 1931–1939. doi:10.1128/JB.00033-13. PMC   3624582 . PMID   23435975.
  58. ↑ Mo S, Ban YH, Park JW, Yoo YJ, Yoon YJ (December 2009). "Enhanced FK506 production in Streptomyces clavuligerus CKD1119 by engineering the supply of methylmalonyl-CoA precursor". Journal of Industrial Microbiology & Biotechnology. 36 (12): 1473–1482. doi: 10.1007/s10295-009-0635-7 . PMID   19756799. S2CID   32967249.
  59. ↑ Singh JA, Hossain A, Kotb A, Wells G (September 2016). "Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis". BMC Medicine. 14 (1): 137. doi: 10.1186/s12916-016-0673-8 . PMC   5022202 . PMID   27623861.
  60. ↑ Singh JA, Hossain A, Kotb A, Wells GA (September 2016). "Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis". Systematic Reviews. 5 (1): 155. doi: 10.1186/s13643-016-0328-z . PMC   5020478 . PMID   27619512.
  61. ↑ Baumgart DC, Pintoffl JP, Sturm A, Wiedenmann B, Dignass AU (May 2006). "Tacrolimus is safe and effective in patients with severe steroid-refractory or steroid-dependent inflammatory bowel disease--a long-term follow-up". The American Journal of Gastroenterology. 101 (5): 1048–1056. doi:10.1111/j.1572-0241.2006.00524.x. PMID   16573777. S2CID   10233231.
  62. ↑ Gordon M, Sinopoulou V, Akobeng AK, Pana M, Gasiea R, Moran GW (April 2022). "Tacrolimus (FK506) for induction of remission in corticosteroid-refractory ulcerative colitis". The Cochrane Database of Systematic Reviews. 2022 (4): CD007216. doi:10.1002/14651858.CD007216.pub2. PMC   8987360 . PMID   35388476.

Further reading

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.