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{{Short description|Pharmaceutical drug}}
{{medref|date=August 2016}}
{{Use dmy dates|date=August 2016}} {{Use dmy dates|date=June 2023}}
{{cs1 config |name-list-style=vanc |display-authors=6}}
{{drugbox
{{Infobox drug
| tradename = Rapamune
| Watchedfields = changed
| synonyms = Rapamycin
| verifiedrevid = 732542693
| Verifiedfields = changed
| image = Sirolimus structure.svg
| verifiedrevid = 464392064
| image_class = skin-invert-image
| IUPAC_name = (3''S'',6''R'',7''E'',9''R'',10''R'',12''R'',14''S'',15''E'',17''E'',19''E'',21''S'',23''S'',<br>26''R'',27''R'',34a''S'')-9,10,12,13,14,21,22,23,24,25,26,<br>27,32,33,34,34a-hexadecahydro-9,27-dihydroxy-3-<br>-<br>1-methylethyl]-10,21-dimethoxy-6,8,12,14,20,26-<br>hexamethyl-23,27-epoxy-3''H''-pyrido-<br>oxaazacyclohentriacontine-1,5,11,28,29<br>(4''H'',6''H'',31''H'')-pentone
| image = Sirolimus.svg
| width = 250 | width = 250
| alt =
| image2 = Sirolimus-from-1C9H-3D-sticks.png | image2 = Sirolimus-from-1C9H-3D-sticks.png
| width2 = 250 | width2 = 250
| alt2 =
| caption =

<!-- Clinical data -->
| pronounce =
| tradename = Rapamune, Fyarro, Hyftor
| Drugs.com =
| MedlinePlus =
| licence_EU = yes
| DailyMedID = Sirolimus
| licence_US = Sirolimus
| pregnancy_AU = C
| pregnancy_AU_comment =
| pregnancy_category=
| routes_of_administration = ], ], ]
| class =
| ATCvet =
| ATC_prefix = L04
| ATC_suffix = AH01
| ATC_supplemental = {{ATC|L01|EG04}}, {{ATC|S01|XA23}}, {{ATCvet|C01|EB90}}

<!-- Legal status -->
| legal_AU = <!-- S2, S3, S4, S5, S6, S7, S8, S9 or Unscheduled -->
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Rapamune FDA label">{{cite web |title=Rapamune- sirolimus solution Rapamune- sirolimus tablet, sugar coated |website=DailyMed |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3275b824-3f82-4151-2ab2-0036a9ba0acc |access-date=26 November 2021 |archive-date=27 November 2021 |archive-url=https://web.archive.org/web/20211127050941/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3275b824-3f82-4151-2ab2-0036a9ba0acc |url-status=live }}</ref><ref name="Fyarro FDA label">{{cite web |title=Fyarro- sirolimus injection, powder, lyophilized, for suspension |website=DailyMed |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f9bb784-53e2-46f9-a65d-1c6c2a230eaf |access-date=19 December 2021 |archive-date=19 December 2021 |archive-url=https://web.archive.org/web/20211219212942/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0f9bb784-53e2-46f9-a65d-1c6c2a230eaf |url-status=live }}</ref><ref name="Hyftor FDA label">{{cite web |title=Hyftor- sirolimus gel |website=DailyMed |date=28 January 2021 |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=edb3ea90-5adc-48ec-99f5-ab963e302f18 |access-date=23 March 2022 |archive-date=24 March 2022 |archive-url=https://web.archive.org/web/20220324021200/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=edb3ea90-5adc-48ec-99f5-ab963e302f18 |url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Rapamune EPAR">{{cite web |title=Rapamune EPAR |website=European Medicines Agency |date=17 September 2018 |url=https://www.ema.europa.eu/en/medicines/human/EPAR/rapamune |access-date=26 November 2021 |archive-date=13 August 2021 |archive-url=https://web.archive.org/web/20210813083523/https://www.ema.europa.eu/en/medicines/human/EPAR/rapamune |url-status=live}}</ref><ref name="Hyftor EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals<ref>{{cite journal |vauthors=Buck ML |title=Immunosuppression With Sirolimus After Solid Organ Transplantation in Children |journal=Pediatric Pharmacotherapy |date=2006 |volume=12 |issue=2 |url=https://www.medscape.com/viewarticle/524753_4 |access-date=4 April 2022 |archive-date=18 April 2020 |archive-url=https://web.archive.org/web/20200418102941/https://www.medscape.com/viewarticle/524753_4 |url-status=live}}</ref>
| protein_bound = 92%
| metabolism = ]
| metabolites =
| onset =
| elimination_half-life = 57–63 hours<ref name="Pubchem Rapamycin" />
| duration_of_action =
| excretion = Mostly fecal

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 53123-88-9
| CAS_supplemental =
| PubChem = 5284616
| IUPHAR_ligand =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00877
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10482078 | ChemSpiderID = 10482078
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = W36ZG6FT64 | UNII = W36ZG6FT64
| ChEMBL_Ref = {{ebicite|correct|EBI}} | KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00753
| ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 9168 | ChEBI = 9168
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| smiles = O1CC(C1OC)C(C)4CC(=O)(C)/C=C(\C)(O)(OC)C(=O)(C)C(C)\C=C\C=C\C=C(/C)(OC)C2CC(C)(O)(O2)C(=O)C(=O)N3CCCC3C(=O)O4
| ChEMBL = 413
| NIAID_ChemDB =
| PDB_ligand = RAP
| synonyms = Rapamycin, ABI-009

<!-- Chemical and physical data -->
| IUPAC_name = (1''R'',9''S'',12''S'',15''R'',16''E'',18''R'',19''R'',21''R'',23''S'',24''E'',26''E'',28''E'',<br />30''S'',32''S'',35''R'')-1,18-dihydroxy-12-{(2''R'')-1--2-propanyl}-<br />19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-<br />11,36-dioxa-4-azatricyclohexatria<br />conta-16,24,26,28-tetraene-2,3,10,14,20-pentone
| C=51 |H=79 |N=1 |O=13
| SMILES = O1CC(C1OC)C(C)4CC(=O)(C)/C=C(\C)(O)(OC)C(=O)(C)C(C)\C=C\C=C\C=C(/C)(OC)C2CC(C)(O)(O2)C(=O)C(=O)N3CCCC3C(=O)O4
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17+,35-25+/t30-,32-,33-,34-,36-,37+,38+,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1 | StdInChI = 1S/C51H79NO13/c1-30-16-12-11-13-17-31(2)42(61-8)28-38-21-19-36(7)51(60,65-38)48(57)49(58)52-23-15-14-18-39(52)50(59)64-43(33(4)26-37-20-22-40(53)44(27-37)62-9)29-41(54)32(3)25-35(6)46(56)47(63-10)45(55)34(5)24-30/h11-13,16-17,25,30,32-34,36-40,42-44,46-47,53,56,60H,14-15,18-24,26-29H2,1-10H3/b13-11+,16-12+,31-17+,35-25+/t30-,32-,33-,34-,36-,37+,38+,39+,40-,42+,43+,44-,46-,47+,51-/m1/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = QFJCIRLUMZQUOT-HPLJOQBZSA-N | StdInChIKey = QFJCIRLUMZQUOT-HPLJOQBZSA-N
| density =
| CAS_number_Ref = {{cascite|correct|??}}
| density_notes =
| CAS_number = 53123-88-9
| melting_point =
| ATC_prefix = L04
| melting_high =
| ATC_suffix = AA10
| melting_notes =
| ATC_supplemental = {{ATC|S01|XA23}}
| boiling_point =
| ChEMBL = 413
| boiling_notes =
| PDB_ligand = RAP
| solubility = 0.0026 <ref>{{cite journal |vauthors = Simamora P, Alvarez JM, Yalkowsky SH |title = Solubilization of rapamycin |journal = International Journal of Pharmaceutics |volume = 213 |issue = 1–2 |pages = 25–29 |date = February 2001 |pmid = 11165091 |doi = 10.1016/s0378-5173(00)00617-7 }}</ref>
| PubChem = 5284616
| sol_units =
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| specific_rotation =
| DrugBank = DB00877
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00753
| C=51 | H=79 | N=1 | O=13
| molecular_weight = 914.172 g/mol
| bioavailability = 14% (oral solution), lower with high-fat meals; 18% (tablet), higher with high-fat meals<ref>{{cite journal|last1=Buck|first1=Marcia L.|title=Immunosuppression With Sirolimus After Solid Organ Transplantation in Children|journal=Pediatric Pharmacotherapy|date=2006|volume=12|issue=2|url=http://www.medscape.com/viewarticle/524753_4}}</ref>
| protein_bound = 92%
| metabolism = Hepatic
| elimination_half-life = 57–63 hours<ref name="Pubchem Rapamycin" />
| licence_EU = Rapamune
| licence_US = Sirolimus
| pregnancy_AU = C
| pregnancy_US = C
| legal_US = Rx-only
| routes_of_administration = Oral
| excretion = Mostly faecal
| solubility = 0.0026 <ref>{{cite journal|last1=Simamora|first1=P|last2=Alvarez|first2=JM|last3=Yalkowsky|first3=SH|title=Solubilization of rapamycin|journal=International journal of pharmaceutics|date=1 February 2001|volume=213|issue=1–2|pages=25–9|pmid=11165091|doi=10.1016/s0378-5173(00)00617-7}}</ref>
}} }}


'''Sirolimus''' (]/]), also known as '''rapamycin''', is a ] compound produced by the ] '']'' that is ] to ] ] and to treat ].<ref name="Rapamune Rx info" /><ref name="Vezi">{{cite journal|vauthors=Vézina C, Kudelski A, Sehgal SN | title = Rapamycin (AY-22,989), a new antifungal antibiotic| journal = J. Antibiot.| volume = 28| issue = 10| pages = 721–6| date=October 1975 |doi=10.7164/antibiotics.28.721| pmid = 1102508 |url=http://joi.jlc.jst.go.jp/JST.Journalarchive/antibiotics1968/28.721?lang=en}}</ref> It has ] functions in humans an is especially useful in preventing the rejection of ] transplants. It inhibits activation of ] and ] by reducing the production of ] (IL-2). Sirolimus is also used as a coating for ]s. '''Sirolimus''', also known as '''rapamycin''' and sold under the brand name '''Rapamune''' among others, is a ] compound that is used to coat ]s, prevent ], treat a rare lung disease called ], and treat ] (PEComa).<ref name="Rapamune FDA label" /><ref name="Fyarro FDA label" /><ref name="Vezi">{{cite journal |vauthors = Vézina C, Kudelski A, Sehgal SN |title = Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle |journal = The Journal of Antibiotics |volume = 28 |issue = 10 |pages = 721–726 |date = October 1975 |pmid = 1102508 |doi = 10.7164/antibiotics.28.721 |title-link = doi |doi-access = free }}</ref><ref name="Cypher" /> It has ] functions in humans and is especially useful in preventing the rejection of ] transplants. It is a ] (mTOR) kinase inhibitor<ref name="Fyarro FDA label" /> that reduces the sensitivity of ] and ] to ] (IL-2), inhibiting their activity.<ref name="Mukherjee_2009" />

This compound also has a use in cardiovascular ] technologies to inhibit ].


Sirolimus was isolated for the first time in 1972 by Suren Sehgal and colleagues from samples of ''Streptomyces hygroscopicus'' found on ].<ref>{{cite journal|last1=Seto|first1=Belinda|title=Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer|journal=Clinical and Translational Medicine|date=2012|volume=1|issue=1|pages=29|doi=10.1186/2001-1326-1-29}}</ref><ref name=RapamycinOrigin>{{cite journal | author=Pritchard DI | title=Sourcing a chemical succession for cyclosporin from parasites and human pathogens | journal=Drug Discovery Today | year=2005 | volume=10 | issue = 10 | pages= 688–691 | pmid = 15896681 | doi=10.1016/S1359-6446(05)03395-7}}</ref> The compound was originally named rapamycin after the native name of the island, Rapa Nui.<ref name="Vezi" /> Sirolimus was initially developed as an ] agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ]. It was approved by the US ] in September 1999 and is marketed under the trade name Rapamune by ] (formerly by ]). It is produced by the ] '']'' and was isolated for the first time in 1972, from samples of ''Streptomyces hygroscopicus'' found on ].<ref>{{cite web |vauthors=Qari S, Walters P, Lechtenberg S |date=21 May 2021 |title=The Dirty Drug and the Ice Cream Tub |url=https://www.wnycstudios.org/podcasts/radiolab/articles/dirty-drug-and-ice-cream-tub |access-date=25 July 2021 |website=Radiolab |archive-date=25 July 2021 |archive-url=https://web.archive.org/web/20210725033538/https://www.wnycstudios.org/podcasts/radiolab/articles/dirty-drug-and-ice-cream-tub |url-status=live }}</ref><ref>{{cite journal |vauthors = Seto B |title = Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer |journal = Clinical and Translational Medicine |volume = 1 |issue = 1 |pages = 29 |date = November 2012 |pmid = 23369283 |pmc = 3561035 |doi = 10.1186/2001-1326-1-29 |doi-access = free }}</ref><ref name="RapamycinOrigin">{{cite journal |vauthors = Pritchard DI |title = Sourcing a chemical succession for cyclosporin from parasites and human pathogens |journal = Drug Discovery Today |volume = 10 |issue = 10 |pages = 688–691 |date = May 2005 |pmid = 15896681 |doi = 10.1016/S1359-6446(05)03395-7 }}</ref> The compound was originally named rapamycin after the native name of the island, Rapa Nui.<ref name="Vezi" /> Sirolimus was initially developed as an ] agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and ] properties due to its ]. It was approved by the U.S. ] (FDA) in 1999.<ref>{{cite web |title=Drug Approval Package: Rapamune (Sirolimus)|id=NDA 021083 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm |date=30 March 2001 |publisher=U.S. ] (FDA) |archive-date=1 February 2022 |archive-url=https://web.archive.org/web/20220201061710/https://www.accessdata.fda.gov/drugsatfda_docs/nda/99/21083A.cfm|url-status=live|quote=(From Medical Reviews Part 1) Rapamycin (sirolimus) Oral Solution should be approved for the indication of prophylaxis of organ rejection in patients receiving allogenic renal transplants, to be used concomitantly with cyclosporine and corticosteroids.}}</ref> Hyftor (sirolimus gel) was approved for topical treatment of facial ] in the European Union in May 2023.<ref name="Hyftor EPAR">{{cite web |date=9 June 2023 |title=Hyftor EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/hyftor |access-date=12 June 2023 |website=] (EMA)}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>


==Medical uses== ==Medical uses==
Sirolimus is ] for the ] of ] and for the treatment of ] (LAM).<ref name="Rapamune FDA label" />


Sirolimus (Fyarro), as protein-bound particles, is indicated for the treatment of adults with locally advanced unresectable or metastatic ] ] (PEComa).<ref name="Fyarro FDA label" /><ref>{{cite press release |title=Aadi Bioscience Announces FDA Approval of its First Product Fyarro for Patients with Locally Advanced Unresectable or Metastatic Malignant Perivascular etc Epithelioid Cell Tumor (PEComa) |website=Aadi Bioscience, Inc. |date=2021-11-23 |url=https://ir.aadibio.com/news-releases/news-release-details/aadi-bioscience-announces-fda-approval-its-first-product |access-date=26 November 2021 |archive-date=2021-11-27 |archive-url=https://web.archive.org/web/20211127054332/https://ir.aadibio.com/news-releases/news-release-details/aadi-bioscience-announces-fda-approval-its-first-product |url-status=live }}</ref>
Sirolimus is ] for the ] of ] and for the treatment of ] (LAM).<ref name="Rapamune Rx info" />

In the EU, sirolimus, as Rapamune, is indicated for the prophylaxis of organ rejection in adults at low to moderate immunological risk receiving a renal transplant<ref name="Rapamune EPAR" /> and, as Hyftor, is indicated for the treatment of facial ] associated with ] complex.<ref name="Hyftor EPAR" />


===Prevention of transplant rejection=== ===Prevention of transplant rejection===
{{See also|Organ rejection|Immunosuppression#Deliberately induced}} {{See also|Organ rejection|Immunosuppression#Deliberately induced}}
The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even chronic renal failure; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for ], as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.{{mcn}}


The chief advantage sirolimus has over ]s is its low toxicity toward kidneys. Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even ]; this can be avoided by using sirolimus instead. It is particularly advantageous in patients with kidney transplants for ], as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used. However, on 7 October 2008, the FDA approved safety labeling revisions for sirolimus to warn of the risk for decreased renal function associated with its use.<ref>{{cite book |url=https://books.google.com/books?id=mIyxO5cLEAcC |title=Drug Discovery: Practices, Processes, and Perspectives |vauthors=Li JJ, Corey EJ |date=3 April 2013 |publisher=John Wiley & Sons |isbn=978-1-118-35446-9 |access-date=1 August 2016 |archive-date=19 August 2020|archive-url=https://web.archive.org/web/20200819144751/https://books.google.com/books?id=mIyxO5cLEAcC |url-status=live}}</ref><ref>{{cite book |url=https://books.google.com/books?id=CVloCgAAQBAJ |title=Nanotechnology in Medicine: Emerging Applications |vauthors=Koprowski G |date=7 February 2012 |publisher=Momentum Press |isbn=978-1-60650-250-1 |access-date=1 August 2016 |archive-date=2020-09-30 |archive-url=https://web.archive.org/web/20200930051705/https://books.google.com/books?id=CVloCgAAQBAJ |url-status=live}}</ref> In 2009, the FDA notified healthcare professionals that a clinical trial conducted by Wyeth showed an increased mortality in stable liver transplant patients after switching from a calcineurin inhibitor-based immunosuppressive regimen to sirolimus.<ref>{{cite web |url = https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm |title = Sirolimus (marketed as Rapamune) Safety |date = 11 June 2009 |publisher = U.S. ] (FDA) |access-date = 1 August 2016 |archive-date = 16 September 2016 |archive-url = https://web.archive.org/web/20160916202213/http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm165731.htm |url-status = live }}</ref> A 2019 cohort study of nearly 10,000 lung transplant recipients in the US demonstrated significantly improved long-term survival using sirolimus + tacrolimus instead of mycophenolate mofetil + tacrolimus for immunosuppressive therapy starting at one year after transplant.<ref>{{cite journal |vauthors = Wijesinha M, Hirshon JM, Terrin M, Magder L, Brown C, Stafford K, Iacono A |title = Survival Associated With Sirolimus Plus Tacrolimus Maintenance Without Induction Therapy Compared With Standard Immunosuppression After Lung Transplant |journal = JAMA Network Open |volume = 2 |issue = 8 |pages = e1910297 |date = August 2019 |pmid = 31461151 |pmc = 6716294 |doi = 10.1001/jamanetworkopen.2019.10297 |title-link = doi |doi-access = free }}</ref>
Sirolimus can also be used alone, or in conjunction with calcineurin inhibitors, such as ] and/or ], to provide steroid-free immunosuppression regimens. Impaired wound healing and ] are a possible side effects of sirolimus; therefore, some transplant centres prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.{{mcn}}

Sirolimus can also be used alone, or in conjunction with a ] (such as ]), and/or ], to provide steroid-free immunosuppression regimens. Impaired wound healing and ] are possible side effects of sirolimus; therefore, some transplant centers prefer not to use it immediately after the transplant operation, but instead administer it only after a period of weeks or months. Its optimal role in immunosuppression has not yet been determined, and it remains the subject of a number of ongoing clinical trials.<ref name="Mukherjee_2009">{{cite journal |vauthors = Mukherjee S, Mukherjee U |title = A comprehensive review of immunosuppression used for liver transplantation |journal = Journal of Transplantation |volume = 2009 |pages = 701464 |date = 1 January 2009 |pmid = 20130772 |pmc = 2809333 |doi = 10.1155/2009/701464 |title-link = doi |doi-access = free }}</ref>


===Lymphangioleiomyomatosis=== ===Lymphangioleiomyomatosis===
In May 2015, the FDA approved sirolimus to treat ] (LAM), a rare, progressive lung disease that primarily affects women of childbearing age. This made sirolimus the first drug approved to treat this disease.<ref name="FDA_2015" /> LAM involves lung tissue infiltration with ]-like cells with mutations of the ] gene (]). Loss of TSC2 gene function activates the ] signaling pathway, resulting in the release of lymphangiogenic ]s. Sirolimus blocks this pathway.<ref name="Rapamune FDA label" />
{{expand section|content on this topic from <ref name="Rapamune Rx info" />|date=August 2016}}

The safety and efficacy of sirolimus treatment of LAM were investigated in ]s that compared sirolimus treatment with a ] group in 89 patients for 12 months. The patients were observed for 12 months after the treatment had ended. The most commonly reported side effects of sirolimus treatment of LAM were mouth and lip ulcers, ], abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, ], headache, dizziness, muscle pain and elevated ]. Serious side effects including hypersensitivity and swelling (]) have been observed in ] patients.<ref name="FDA_2015">{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm448523.htm|title=FDA approves Rapamune to treat LAM, a very rare lung disease|vauthors=Pahon E|date=28 May 2015|publisher=U.S. ] (FDA)|access-date=1 August 2016|archive-date=14 August 2016|archive-url=https://web.archive.org/web/20160814072556/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm448523.htm|url-status=live}}</ref>

While sirolimus was considered for treatment of LAM, it received ] designation status because LAM is a rare condition.<ref name="FDA_2015" />

The safety of LAM treatment by sirolimus in people younger than 18 years old has not been tested.<ref name="Rapamune FDA label" />


===Coronary stent coating=== ===Coronary stent coating===
{{further|Drug-eluting stent}} {{further|Drug-eluting stent}}
The antiproliferative effect of sirolimus has also been used in conjunction with ]s to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by ], a division of ], under the tradename ].<ref>{{cite web|url=http://www.cypherusa.com/ |title=Cypher Sirolimus-eluting Coronary Stent |accessdate=1 April 2008 |publisher=] }}</ref> However, this kind of stent may also increase the risk of vascular thrombosis.<ref name="Shuchman">{{cite journal | author = Shuchman M | title = Trading restenosis for thrombosis? New questions about drug-eluting stents | journal = ] | volume = 355 | issue = 19 | pages = 1949–52 | year = 2006 | pmid = 17093244 | doi = 10.1056/NEJMp068234}}</ref>


The antiproliferative effect of sirolimus has also been used in conjunction with ]s to prevent restenosis in coronary arteries following balloon angioplasty. The sirolimus is formulated in a polymer coating that affords controlled release through the healing period following coronary intervention. Several large clinical studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures. A sirolimus-eluting coronary stent was marketed by ], a division of ], under the tradename ].<ref name="Cypher">{{cite web |url=http://www.cypherusa.com/ |archive-url=https://web.archive.org/web/20030427143416/http://www.cypherusa.com/ |url-status=dead |archive-date=27 April 2003 |title=Cypher Sirolimus-eluting Coronary Stent |access-date=1 April 2008 |publisher=] }}</ref> However, this kind of stent may also increase the risk of vascular thrombosis.<ref name="Shuchman">{{cite journal |vauthors = Shuchman M |title = Trading restenosis for thrombosis? New questions about drug-eluting stents |journal = The New England Journal of Medicine |volume = 355 |issue = 19 |pages = 1949–1952 |date = November 2006 |pmid = 17093244 |doi = 10.1056/NEJMp068234 }}</ref>
==Contraindications==
Sirolimus is ] in individuals with a known ] to the drug.<ref name="Rapamune Rx info" />


===Vascular malformations===
==Adverse effects==
Sirolimus is used to treat vascular malformations. Treatment with sirolimus can decrease pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels.<ref>{{cite web |title = Venous Malformation: Treatments |url = http://www.childrenshospital.org/conditions-and-treatments/conditions/v/venous-malformation/treatments |work = Boston Children's Hospital |access-date = 22 April 2020 |archive-date = 17 January 2021 |archive-url = https://web.archive.org/web/20210117101459/https://www.childrenshospital.org/conditions-and-treatments/conditions/v/venous-malformation/treatments |url-status = dead }}</ref> Sirolimus is a relatively new medical therapy for the treatment of vascular malformations<ref name="pmid32200879">{{cite journal |vauthors = Dekeuleneer V, Seront E, Van Damme A, Boon LM, Vikkula M |title = Theranostic Advances in Vascular Malformations |journal = The Journal of Investigative Dermatology |volume = 140 |issue = 4 |pages = 756–763 |date = April 2020 |pmid = 32200879 |doi = 10.1016/j.jid.2019.10.001 |title-link = doi |doi-access = free }}</ref> in recent years, sirolimus has emerged as a new medical treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation. Hence, sirolimus is ideal for "proliferative" vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway as an antiproliferative agent.<ref name="pmid31864650">{{cite journal |vauthors = Lee BB |title = Sirolimus in the treatment of vascular anomalies |journal = Journal of Vascular Surgery |volume = 71 |issue = 1 |pages = 328 |date = January 2020 |pmid = 31864650 |doi = 10.1016/j.jvs.2019.08.246 |title-link = doi |doi-access = free }}</ref><ref name="pmid27723921">{{cite journal |vauthors = Triana P, Dore M, Cerezo VN, Cervantes M, Sánchez AV, Ferrero MM, González MD, Lopez-Gutierrez JC |title = Sirolimus in the Treatment of Vascular Anomalies |journal = European Journal of Pediatric Surgery |volume = 27 |issue = 1 |pages = 86–90 |date = February 2017 |pmid = 27723921 |doi = 10.1055/s-0036-1593383 |title-link = doi |doi-access = free }}</ref>


===Angiofibromas===
The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: ], ], abdominal pain, headache, nausea, diarrhea, pain, constipation, ], ], increased ], fever, ], ], ], and ].<ref name="Rapamune Rx info" />
Sirolimus has been used as a topical treatment of ]s with ] complex (TSC). Facial angiofibromas occur in 80% of patients with TSC, and the condition is very disfiguring. A retrospective review of English-language medical publications reporting on topical sirolimus treatment of facial angiofibromas found sixteen separate studies with positive patient outcomes after using the drug. The reports involved a total of 84 patients, and improvement was observed in 94% of subjects, especially if treatment began during the early stages of the disease. Sirolimus treatment was applied in several different formulations (ointment, gel, solution, and cream), ranging from 0.003 to 1% concentrations. Reported adverse effects included one case of perioral dermatitis, one case of cephalea, and four cases of irritation.<ref>{{cite journal |vauthors = Balestri R, Neri I, Patrizi A, Angileri L, Ricci L, Magnano M |title = Analysis of current data on the use of topical rapamycin in the treatment of facial angiofibromas in tuberous sclerosis complex |journal = Journal of the European Academy of Dermatology and Venereology |volume = 29 |issue = 1 |pages = 14–20 |date = January 2015 |pmid = 25174683 |doi = 10.1111/jdv.12665 |s2cid = 9967001 }}</ref>

In April 2022, sirolimus was approved by the FDA for treating angiofibromas.<ref name="FDAnews 2022">{{cite web |title=FDA Approves Nobelpharma's Topical Treatment for Facial Angiofibroma |website=FDAnews |date=7 April 2022 |url=https://www.fdanews.com/articles/207319-fda-approves-nobelpharmas-topical-treatment-for-facial-angiofibroma |access-date=24 May 2022 |archive-date=1 June 2022 |archive-url=https://web.archive.org/web/20220601085706/https://www.fdanews.com/articles/207319-fda-approves-nobelpharmas-topical-treatment-for-facial-angiofibroma |url-status=live }}</ref>

==Adverse effects==
The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis in individuals with kidney transplants include: ], ], abdominal pain, headache, nausea, diarrhea, pain, constipation, ], ], increased ], fever, ], ], ], and ].<ref name="Rapamune FDA label" />


The most common adverse reactions (≥20% occurrence, leading to a 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, ], ], acne, ], dizziness, and ].<ref name="Rapamune Rx info" /> The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, ], ], acne, ], dizziness, and ].<ref name="Rapamune FDA label" />


The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:<ref name="Rapamune Rx info" /> The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:<ref name="Rapamune FDA label" />
{| class="wikitable" {| class="wikitable"
! System ! System
! Adverse effects ! Adverse effects
|- |-
| Body as a Whole || ], ], ] infection, ] infection | Body as a whole || ], ], ] infection, ] infection
|- |-
|Cardiovascular || ] (] and ]), ] |] || ] (] and ]), ]
|- |-
|Digestive || ] |] || ]
|- |-
|Hematologic/Lymphatic || ]/] (TTP/HUS), ] |]/] || ]/] (TTP/HUS), ]
|- |-
|Metabolic || Abnormal healing, increased ] (LDH), ], ] |Metabolic || Abnormal healing, increased ] (LDH), ], ]
|- |-
|Musculoskeletal || Bone ] |] || Bone ]
|- |-
|Respiratory || ], ] |] || ], ]
|- |-
|Skin || ], ], ] |Skin || ], ], ]
|- |-
|Urogenital || ], ]s, menstrual disorders (] and ]) |] || ], ]s, menstrual disorders (] and ])
|} |}


===Diabetes-like symptoms=== ===Diabetes-like symptoms===
While sirolimus inhibition of ] appears to mediate the drug's benefits, it also inhibits ], which results in diabetes-like symptoms. This includes decreased glucose tolerance and insensitivity to insulin.<ref>{{cite journal | pmid = 22461615 | doi=10.1126/science.1215135 | volume=335 | issue=6076 | title=Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity |date=March 2012 | journal=Science | pages=1638–43 | author=Lamming DW, Ye L, Katajisto P | pmc = 3324089| bibcode=2012Sci...335.1638L | last2=Ye | last3=Katajisto | last4=Goncalves | last5=Saitoh | last6=Stevens | last7=Davis | last8=Salmon | last9=Richardson | last10=Ahima | last11=Guertin | last12=Sabatini | last13=Baur |display-authors=etal}}</ref> Sirolimus treatment may additionally increase the risk of type 2 diabetes.<ref>{{Cite journal|title = Sirolimus is associated with new-onset diabetes in kidney transplant recipients|url = http://www.ncbi.nlm.nih.gov/pubmed/?term=18385422|journal = Journal of the American Society of Nephrology: JASN|date = 1 July 2008|issn = 1533-3450|pmc = 2440303|pmid = 18385422|pages = 1411–1418|volume = 19|issue = 7|doi = 10.1681/ASN.2007111202|first = Olwyn|last = Johnston|first2 = Caren L.|last2 = Rose|first3 = Angela C.|last3 = Webster|first4 = John S.|last4 = Gill}}</ref> In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or ] such as ] or ].<ref>{{Cite journal|title = Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system|url = http://www.ncbi.nlm.nih.gov/pubmed/?term=26463117|journal = Aging Cell|date = 13 October 2015|issn = 1474-9726|pmid = 26463117|doi = 10.1111/acel.12405|first = Sebastian I.|last = Arriola Apelo|first2 = Joshua C.|last2 = Neuman|first3 = Emma L.|last3 = Baar|first4 = Faizan A.|last4 = Syed|first5 = Nicole E.|last5 = Cummings|first6 = Harpreet K.|last6 = Brar|first7 = Cassidy P.|last7 = Pumper|first8 = Michelle E.|last8 = Kimple|first9 = Dudley W.|last9 = Lamming}}</ref> While sirolimus inhibition of ] appears to mediate the drug's benefits, it also inhibits ], which results in diabetes-like symptoms.<ref name="Rapamycin-induced insulin resistanc">{{cite journal | vauthors = Lamming DW, Ye L, Katajisto P, Goncalves MD, Saitoh M, Stevens DM, Davis JG, Salmon AB, Richardson A, Ahima RS, Guertin DA, Sabatini DM, Baur JA | title = Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity | journal = Science | volume = 335 | issue = 6076 | pages = 1638–1643 | date = March 2012 | pmid = 22461615 | pmc = 3324089 | doi = 10.1126/science.1215135 | bibcode = 2012Sci...335.1638L }}</ref> This includes decreased glucose tolerance and insensitivity to insulin.<ref name="Rapamycin-induced insulin resistanc"/> Sirolimus treatment may additionally increase the risk of type 2 diabetes.<ref>{{cite journal | vauthors = Johnston O, Rose CL, Webster AC, Gill JS | title = Sirolimus is associated with new-onset diabetes in kidney transplant recipients | journal = Journal of the American Society of Nephrology | volume = 19 | issue = 7 | pages = 1411–1418 | date = July 2008 | pmid = 18385422 | pmc = 2440303 | doi = 10.1681/ASN.2007111202 }}</ref> In mouse studies, these symptoms can be avoided through the use of alternate dosing regimens or ] such as ] or ].<ref>{{cite journal | vauthors = Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW | title = Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system | journal = Aging Cell | volume = 15 | issue = 1 | pages = 28–38 | date = February 2016 | pmid = 26463117 | pmc = 4717280 | doi = 10.1111/acel.12405 }}</ref>


===Lung toxicity=== ===Lung toxicity===
Lung toxicity is a serious complication associated with sirolimus therapy,<ref name="ReferenceA">{{cite journal |vauthors=Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M |title=Patterns of pulmonary complications associated with sirolimus |journal=Respiration |volume=73 |issue=3 |pages=367–74 |year=2006 |pmid=16127266 |doi=10.1159/000087945 }}</ref><ref>{{cite journal |vauthors=Morelon E, Stern M, Israël-Biet D, etal |title=Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients |journal=Transplantation |volume=72 |issue=5 |pages=787–90 |date=September 2001 |pmid=11571438 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0041-1337&volume=72&issue=5&spage=787 |doi=10.1097/00007890-200109150-00008}}</ref><ref>{{cite journal |vauthors=Filippone EJ, Carson JM, Beckford RA, etal |title=Sirolimus-induced pneumonitis complicated by pentamidine-induced phospholipidosis in a renal transplant recipient: a case report |journal=Transplant. Proc. |volume=43 |issue=7 |pages=2792–7 |date=September 2011 |pmid=21911165 |doi=10.1016/j.transproceed.2011.06.060 |url=http://linkinghub.elsevier.com/retrieve/pii/S0041-1345(11)00913-4}}</ref><ref>{{cite journal |vauthors=Pham PT, Pham PC, Danovitch GM, etal |title=Sirolimus-associated pulmonary toxicity |journal=Transplantation |volume=77 |issue=8 |pages=1215–20 |date=April 2004 |pmid=15114088 |url=http://meta.wkhealth.com/pt/pt-core/template-journal/lwwgateway/media/landingpage.htm?issn=0041-1337&volume=77&issue=8&spage=1215 |doi=10.1097/01.TP.0000118413.92211.B6}}</ref><ref>{{cite journal |vauthors=Mingos MA, Kane GC |title=Sirolimus-induced interstitial pneumonitis in a renal transplant patient |journal=Respir Care |volume=50 |issue=12 |pages=1659–61 |date=December 2005 |pmid=16318648 |url=http://www.rcjournal.com/contents/12.05/12.05.1659.pdf}}</ref><ref>{{cite journal |vauthors=Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M, Austin EH |title=Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review |journal=J. Heart Lung Transplant. |volume=26 |issue=3 |pages=296–8 |date=March 2007 |pmid=17346635 |doi=10.1016/j.healun.2006.12.004 |url=http://linkinghub.elsevier.com/retrieve/pii/S1053-2498(06)01477-X}} Lung toxicity is a serious complication associated with sirolimus therapy,<ref name="ReferenceA">{{cite journal | vauthors = Chhajed PN, Dickenmann M, Bubendorf L, Mayr M, Steiger J, Tamm M | title = Patterns of pulmonary complications associated with sirolimus | journal = Respiration; International Review of Thoracic Diseases | volume = 73 | issue = 3 | pages = 367–374 | year = 2006 | pmid = 16127266 | doi = 10.1159/000087945 | s2cid = 24408680 }}</ref><ref>{{cite journal | vauthors = Morelon E, Stern M, Israël-Biet D, Correas JM, Danel C, Mamzer-Bruneel MF, Peraldi MN, Kreis H | title = Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients | journal = Transplantation | volume = 72 | issue = 5 | pages = 787–790 | date = September 2001 | pmid = 11571438 | doi = 10.1097/00007890-200109150-00008 | s2cid = 12116798 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Filippone EJ, Carson JM, Beckford RA, Jaffe BC, Newman E, Awsare BK, Doria C, Farber JL | title = Sirolimus-induced pneumonitis complicated by pentamidine-induced phospholipidosis in a renal transplant recipient: a case report | journal = Transplantation Proceedings | volume = 43 | issue = 7 | pages = 2792–2797 | date = September 2011 | pmid = 21911165 | doi = 10.1016/j.transproceed.2011.06.060 | url = https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1087&context=medfp | access-date = 24 September 2019 | url-status = live | archive-url = https://web.archive.org/web/20200807064741/https://jdc.jefferson.edu/cgi/viewcontent.cgi?article=1087&context=medfp | archive-date = 7 August 2020 }}</ref><ref>{{cite journal | vauthors = Pham PT, Pham PC, Danovitch GM, Ross DJ, Gritsch HA, Kendrick EA, Singer J, Shah T, Wilkinson AH | title = Sirolimus-associated pulmonary toxicity | journal = Transplantation | volume = 77 | issue = 8 | pages = 1215–1220 | date = April 2004 | pmid = 15114088 | doi = 10.1097/01.TP.0000118413.92211.B6 | s2cid = 24496443 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mingos MA, Kane GC | title = Sirolimus-induced interstitial pneumonitis in a renal transplant patient | journal = Respiratory Care | volume = 50 | issue = 12 | pages = 1659–1661 | date = December 2005 | pmid = 16318648 | url = http://rc.rcjournal.com/content/respcare/50/12/1659.full.pdf | access-date = 4 April 2022 | url-status = live | archive-url = https://web.archive.org/web/20220605002101/https://rc.rcjournal.com/content/respcare/50/12/1659.full.pdf | archive-date = 5 June 2022 }}</ref><ref>{{cite journal | vauthors = Das BB, Shoemaker L, Subramanian S, Johnsrude C, Recto M, Austin EH | title = Acute sirolimus pulmonary toxicity in an infant heart transplant recipient: case report and literature review | journal = The Journal of Heart and Lung Transplantation | volume = 26 | issue = 3 | pages = 296–298 | date = March 2007 | pmid = 17346635 | doi = 10.1016/j.healun.2006.12.004 }}</ref><ref>{{cite journal | vauthors = Delgado JF, Torres J, José Ruiz-Cano M, Sánchez V, Escribano P, Borruel S, María Cortina J, de la Calzada CS | title = Sirolimus-associated interstitial pneumonitis in 3 heart transplant recipients | journal = The Journal of Heart and Lung Transplantation | volume = 25 | issue = 9 | pages = 1171–1174 | date = September 2006 | pmid = 16962483 | doi = 10.1016/j.healun.2006.05.013 }}</ref>{{Excessive citations inline|date=December 2022}} especially in the case of lung transplants.<ref>{{cite journal | vauthors = McWilliams TJ, Levvey BJ, Russell PA, Milne DG, Snell GI | title = Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation | journal = The Journal of Heart and Lung Transplantation | volume = 22 | issue = 2 | pages = 210–213 | date = February 2003 | pmid = 12581772 | doi = 10.1016/S1053-2498(02)00564-8 }}</ref> The mechanism of the ] caused by sirolimus and other macrolide ] inhibitors is unclear, and may have nothing to do with the ] pathway.<ref>{{cite journal | vauthors = Aparicio G, Calvo MB, Medina V, Fernández O, Jiménez P, Lema M, Figueroa A, Antón Aparicio LM | title = Comprehensive lung injury pathology induced by mTOR inhibitors | journal = Clinical & Translational Oncology | volume = 11 | issue = 8 | pages = 499–510 | date = August 2009 | pmid = 19661024 | doi = 10.1007/s12094-009-0394-y | hdl-access = free | s2cid = 39914334 | hdl = 2183/19864 }}</ref><ref>{{cite journal | vauthors = Paris A, Goupil F, Kernaonet E, Foulet-Rogé A, Molinier O, Gagnadoux F, Lebas FX | title = | language = fr | journal = Revue des Maladies Respiratoires | volume = 29 | issue = 1 | pages = 64–69 | date = January 2012 | pmid = 22240222 | doi = 10.1016/j.rmr.2010.03.026 }}</ref><ref>{{cite journal | vauthors = Maroto JP, Hudes G, Dutcher JP, Logan TF, White CS, Krygowski M, Cincotta M, Shapiro M, Duran I, Berkenblit A | title = Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus | journal = Journal of Clinical Oncology | volume = 29 | issue = 13 | pages = 1750–1756 | date = May 2011 | pmid = 21444868 | doi = 10.1200/JCO.2010.29.2235 | title-link = doi | doi-access = free }}</ref> The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.<ref name="ReferenceA"/><ref>{{cite journal | vauthors = Errasti P, Izquierdo D, Martín P, Errasti M, Slon F, Romero A, Lavilla FJ | title = Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience | journal = Transplantation Proceedings | volume = 42 | issue = 8 | pages = 3053–3054 | date = October 2010 | pmid = 20970608 | doi = 10.1016/j.transproceed.2010.07.066 }}</ref>
</ref><ref>{{cite journal |vauthors=Delgado JF, Torres J, José Ruiz-Cano M, etal |title=Sirolimus-associated interstitial pneumonitis in 3 heart transplant recipients |journal=J. Heart Lung Transplant. |volume=25 |issue=9 |pages=1171–4 |date=September 2006 |pmid=16962483 |doi=10.1016/j.healun.2006.05.013 |url=http://linkinghub.elsevier.com/retrieve/pii/S1053-2498(06)00411-6}}</ref> especially in the case of lung transplants.<ref>{{cite journal |vauthors=McWilliams TJ, Levvey BJ, Russell PA, Milne DG, Snell GI |title=Interstitial pneumonitis associated with sirolimus: a dilemma for lung transplantation |journal=J. Heart Lung Transplant. |volume=22 |issue=2 |pages=210–3 |date=February 2003 |pmid=12581772 |url=http://linkinghub.elsevier.com/retrieve/pii/S1053249802005648 |doi=10.1016/S1053-2498(02)00564-8}}</ref> The mechanism of the ] caused by sirolimus and other macrolide ] inhibitors is unclear, and may have nothing to do with the ] pathway.<ref>{{cite journal |vauthors=Aparicio G, Calvo MB, Medina V, etal |title=Comprehensive lung injury pathology induced by mTOR inhibitors |journal=Clin Transl Oncol |volume=11 |issue=8 |pages=499–510 |date=August 2009 |pmid=19661024 |doi=10.1007/s12094-009-0394-y }}</ref><ref>{{cite journal |vauthors=Paris A, Goupil F, Kernaonet E, etal |title= |language=French |journal=Rev Mal Respir |volume=29 |issue=1 |pages=64–9 |date=January 2012 |pmid=22240222 |doi=10.1016/j.rmr.2010.03.026 |url=http://www.masson.fr/masson/S0761-8425(10)00421-3}}</ref><ref>{{cite journal |vauthors=Maroto JP, Hudes G, Dutcher JP, etal |title=Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus |journal=J. Clin. Oncol. |volume=29 |issue=13 |pages=1750–6 |date=May 2011 |pmid=21444868 |doi=10.1200/JCO.2010.29.2235 |url=http://www.jco.org/cgi/pmidlookup?view=long&pmid=21444868}}</ref> The interstitial pneumonitis is not dose-dependent, but is more common in patients with underlying lung disease.<ref name="ReferenceA"/><ref>{{cite journal |vauthors=Errasti P, Izquierdo D, Martín P, etal |title=Pneumonitis associated with mammalian target of rapamycin inhibitors in renal transplant recipients: a single-center experience |journal=Transplant. Proc. |volume=42 |issue=8 |pages=3053–4 |date=October 2010 |pmid=20970608 |doi=10.1016/j.transproceed.2010.07.066 |url=http://linkinghub.elsevier.com/retrieve/pii/S0041-1345(10)01111-5}}</ref>


===Lowered effectiveness of immune system=== ===Lowered effectiveness of immune system===
There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.<ref name="Rapamune Rx info" /><ref name=DailyMed>http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3275b824-3f82-4151-2ab2-0036a9ba0acc</ref> There have been warnings about the use of sirolimus in transplants, where it may increase mortality due to an increased risk of infections.<ref name="Rapamune FDA label" />


===Cancer risk=== ===Cancer risk===
Sirolimus may increase an individual's risk for contracting ]s from exposure to sunlight or UV radiation, and risk of developing ].<ref name="Rapamune FDA label" /> In studies, the skin cancer risk under sirolimus was lower than under other immunosuppressants such as ] and ]s, and lower than under ].<ref name="Rapamune FDA label" /><ref>{{cite journal | vauthors = Euvrard S, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra AL, Hofbauer GF, Pouteil-Noble C, Campistol JM, Kanitakis J, Roux AS, Decullier E, Dantal J | title = Sirolimus and secondary skin-cancer prevention in kidney transplantation | journal = The New England Journal of Medicine | volume = 367 | issue = 4 | pages = 329–339 | date = July 2012 | pmid = 22830463 | doi = 10.1056/NEJMoa1204166 | hdl-access = free | title-link = doi | doi-access = free | hdl = 2445/178597 }}</ref>
According to ] prescribing information, sirolimus may increase an individual's risk for contracting ]s from exposure to sunlight or UV radiation, and risk of developing ].<ref name="Rapamune Rx info">{{cite web|title=Rapamune Prescribing Information|url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/021083s058,021110s075lbl.pdf|website=United States Food and Drug Administration|publisher=Wyeth Pharmaceuticals, Inc.|accessdate=28 May 2016|date=May 2015}}</ref>


===Impaired wound healing=== ===Impaired wound healing===
Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a high ] (i.e., a BMI of ≥30&nbsp;kg/m<sup>2</sup>).<ref name="Rapamune Rx info" /> Individuals taking sirolimus are at increased risk of experiencing impaired or delayed wound healing, particularly if they have a ] in excess of 30&nbsp;kg/m<sup>2</sup> (classified as obese).<ref name="Rapamune FDA label" />


==Interactions== == Interactions ==
Sirolimus is metabolized by the ] ] and is a substrate of the ] (P-gp) ]; hence, inhibitors of either protein may increase sirolimus concentrations in ], whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.<ref name="Rapamune FDA label" />
{{expand section|interactions listed in <ref name="Rapamune Rx info" />|date=August 2016}}


==Pharmacology== ==Pharmacology==
{{medref|section|date=August 2016}}

===Pharmacodynamics=== ===Pharmacodynamics===
{{See also|mTOR inhibitors}} {{See also|mTOR inhibitors}}
Unlike the similarly named ], sirolimus is not a ], but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on ], and thereby blocks activation of ] and ]s. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting ].<ref name="Mukherjee_2009" />
{{Unreferenced section|date=August 2016}}
Unlike the similarly named ], sirolimus is not a ], but it has a similar suppressive effect on the immune system. Sirolimus inhibits IL-2 and other cytokines receptor-dependent signal transduction mechanisms, via action on ], and thereby blocks activation of ] and ]s. Tacrolimus and cyclosporine inhibit the secretion of IL-2, by inhibiting ].


The mode of action of sirolimus is to bind the ]ic protein ] (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the ] (mechanistic (formerly mammalian) Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1). The mode of action of sirolimus is to bind the ]ic protein ] (FKBP12) in a manner similar to tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the ] (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus) pathway by directly binding to mTOR Complex 1 (mTORC1).<ref name="Mukherjee_2009" />


mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of '']'' that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2. mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR. However, mTOR is now the widely accepted name, since Tor was first discovered via genetic and molecular studies of sirolimus-resistant mutants of '']'' that identified FKBP12, Tor1, and Tor2 as the targets of sirolimus and provided robust support that the FKBP12-sirolimus complex binds to and inhibits Tor1 and Tor2.<ref name="Heitman_1991">{{cite journal | vauthors = Heitman J, Movva NR, Hall MN | title = Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast | journal = Science | volume = 253 | issue = 5022 | pages = 905–909 | date = August 1991 | pmid = 1715094 | doi = 10.1126/science.1715094 | s2cid = 9937225 | bibcode = 1991Sci...253..905H }}</ref><ref name="Mukherjee_2009" />


===Pharmacokinetics=== ===Pharmacokinetics===


Sirolimus is metabolized by the ] ] and is a substrate of the ] (P-gp) ].<ref name="Rapamune FDA label" /> It has linear pharmacokinetics.<ref name="pharmacokinetics1">{{cite journal | vauthors = Ferron GM, Mishina EV, Zimmerman JJ, Jusko WJ | title = Population pharmacokinetics of sirolimus in kidney transplant patients | journal = Clinical Pharmacology and Therapeutics | volume = 61 | issue = 4 | pages = 416–428 | date = April 1997 | pmid = 9129559 | doi = 10.1016/S0009-9236(97)90192-2 }}</ref> In studies on N=6 and N=36 subjects, peak concentration was obtained in 1.3&nbsp;hours +/r- 0.5&nbsp;hours and the terminal elimination was slow, with a ] around 60&nbsp;hours +/- 10&nbsp;hours.<ref name="pmid16418694">{{cite journal | vauthors = Leung LY, Lim HK, Abell MW, Zimmerman JJ | title = Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose | journal = Therapeutic Drug Monitoring | volume = 28 | issue = 1 | pages = 51–61 | date = February 2006 | pmid = 16418694 | doi = 10.1097/01.ftd.0000179838.33020.34 }}</ref><ref name="pharmacokinetics1"/> Sirolimus was not found to effect the concentration of ], which is also metabolized primarily by the ] enzyme.<ref name="pharmacokinetics1"/>
The absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition. This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its ] (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.<ref>{{cite journal |vauthors=McAlister VC, Mahalati K, Peltekian KM, Fraser A, MacDonald AS |title=A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration.|journal=Ther Drug Monit. |volume=24 |issue=3 |pages=346–50 |date=June 2002 |pmid=12021624 |url=http://journals.lww.com/drug-monitoring/Abstract/2002/06000/A_Clinical_Pharmacokinetic_Study_of_Tacrolimus_and.4.aspx |doi=10.1097/00007691-200206000-00004}}</ref>{{npsn}}


The bioavailabiliy of sirolimus is low, and the absorption of sirolimus into the blood stream from the intestine varies widely between patients, with some patients having up to eight times more exposure than others for the same dose. Drug levels are, therefore, taken to make sure patients get the right dose for their condition.<ref name="Mukherjee_2009" />{{npsn|date=June 2024}} This is determined by taking a blood sample before the next dose, which gives the trough level. However, good correlation is noted between trough concentration levels and drug exposure, known as area under the concentration-time curve, for both sirolimus (SRL) and tacrolimus (TAC) (SRL: r2 = 0.83; TAC: r2 = 0.82), so only one level need be taken to know its ] (PK) profile. PK profiles of SRL and of TAC are unaltered by simultaneous administration. Dose-corrected drug exposure of TAC correlates with SRL (r2 = 0.8), so patients have similar bioavailability of both.<ref>{{cite journal | vauthors = McAlister VC, Mahalati K, Peltekian KM, Fraser A, MacDonald AS | title = A clinical pharmacokinetic study of tacrolimus and sirolimus combination immunosuppression comparing simultaneous to separated administration | journal = Therapeutic Drug Monitoring | volume = 24 | issue = 3 | pages = 346–350 | date = June 2002 | pmid = 12021624 | doi = 10.1097/00007691-200206000-00004 | s2cid = 34950948 }}</ref>{{npsn|date=August 2016}}
==Physical and chemical properties==

==Chemistry==
{{expand section|content on this topic from <ref name="Pubchem Rapamycin" />|date=August 2016}} {{expand section|content on this topic from <ref name="Pubchem Rapamycin" />|date=August 2016}}
Sirolimus is a ] and ] ].<ref name="Pubchem Rapamycin">{{cite web|title=Rapamycin|url=https://pubchem.ncbi.nlm.nih.gov/compound/5284616|website=PubChem Compound|publisher=National Center for Biotechnology Information|accessdate=1 August 2016}}</ref> Sirolimus is a ] and ] ].<ref name="Pubchem Rapamycin">{{cite web|title=Rapamycin|url=https://pubchem.ncbi.nlm.nih.gov/compound/5284616|website=PubChem Compound|publisher=National Center for Biotechnology Information|access-date=1 August 2016|archive-date=16 August 2016|archive-url=https://web.archive.org/web/20160816153302/https://pubchem.ncbi.nlm.nih.gov/compound/5284616|url-status=live}}</ref>


===Biosynthesis=== ===Biosynthesis===
The ] of the rapamycin core is accomplished by a type I ] (PKS) in conjunction with a ] (NRPS). The domains responsible for the ] of the linear ] of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the ] of the linear polyketide are in RapC.<ref name=Rapamycin_domains_and_primary_genes>{{cite journal The ] of the rapamycin core is accomplished by a type I ] (PKS) in conjunction with a ] (NRPS). The domains responsible for the ] of the linear ] of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the ] of the linear polyketide are in RapC.<ref name=Rapamycin_domains_and_primary_genes>{{cite journal | vauthors = Schwecke T, Aparicio JF, Molnár I, König A, Khaw LE, Haydock SF, Oliynyk M, Caffrey P, Cortés J, Lester JB | title = The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 17 | pages = 7839–7843 | date = August 1995 | pmid = 7644502 | pmc = 41241 | doi = 10.1073/pnas.92.17.7839 | title-link = doi | doi-access = free | bibcode = 1995PNAS...92.7839S }}</ref> Then, the linear ] is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.<ref name=prerapamycin>{{cite journal | vauthors = Gregory MA, Gaisser S, Lill RE, Hong H, Sheridan RM, Wilkinson B, Petkovic H, Weston AJ, Carletti I, Lee HL, Staunton J, Leadlay PF | title = Isolation and characterization of pre-rapamycin, the first macrocyclic intermediate in the biosynthesis of the immunosuppressant rapamycin by S. hygroscopicus | journal = Angewandte Chemie | volume = 43 | issue = 19 | pages = 2551–2553 | date = May 2004 | pmid = 15127450 | doi = 10.1002/anie.200453764 }}</ref>
<div class="skin-invert-image">{{Wide image|Domain organization of PKS of rapamycin and biosynthetic intermediates.svg|1320px|Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates}}
| author = Schwecke T, Aparicio JF, Molnár I
{{multiple image
| title = The biosynthetic gene cluster for the polyketide immunosuppressant rapamycin
| align = right
| journal = Proc. Natl. Acad. Sci. U.S.A.
| image1 = Prerapamycin skeletal.svg
| volume = 92
| issue = 17 | width1 = 250
| pages = 7839–43 | alt1 =
| caption1 = Figure 2: Prerapamycin, unbound product of ] and ]
| date=August 1995
| image2 = Prerapamycin to rapamycin.svg
| pmid = 7644502
| pmc = 41241 | width2 = 350
| alt2 =
| doi = 10.1073/pnas.92.17.7839
| caption2 = Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin
| bibcode = 1995PNAS...92.7839S
| last2 = Aparicio | footer =
}}</div>
| last3 = Molnar
]
| last4 = Konig
The core ], prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a ] monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.<ref name=Rapamycin_genes>{{cite journal | vauthors = Gregory MA, Hong H, Lill RE, Gaisser S, Petkovic H, Low L, Sheehan LS, Carletti I, Ready SJ, Ward MJ, Kaja AL, Weston AJ, Challis IR, Leadlay PF, Martin CJ, Wilkinson B, Sheridan RM | title = Rapamycin biosynthesis: Elucidation of gene product function | journal = Organic & Biomolecular Chemistry | volume = 4 | issue = 19 | pages = 3565–3568 | date = October 2006 | pmid = 16990929 | doi = 10.1039/b608813a }}</ref>
| last5 = Khaw
| last6 = Haycock
| last7 = Oliynyk
| last8 = Caffrey
| last9 = Cortes
| last10 = Lester
| last11 = Bohm
| last12 = Staunton
| last13 = Leadlay
|display-authors=etal}}</ref> Then, the linear ] is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.<ref name=prerapamycin>{{cite journal
|vauthors=Gregory MA, Gaisser S, Lill RE, etal | title = Isolation and characterization of pre-rapamycin, the first macrocyclic intermediate in the biosynthesis of the immunosuppressant rapamycin by S. hygroscopicus
| journal = Angew. Chem. Int. Ed. Engl.
| volume = 43
| issue = 19
| pages = 2551–3
| date=May 2004
| pmid = 15127450
| doi = 10.1002/anie.200453764
}}</ref>
{{Wide image|Domain organization of PKS of rapamycin and biosynthetic intermediates.svg|1320px|Figure 1: Domain organization of PKS of rapamycin and biosynthetic intermediates}}
{{Double image|right|Prerapamycin skeletal.svg|250|Prerapamycin to rapamycin.svg|350|Figure 2: Prerapamycin, unbound product of ] and ]|Figure 3: Sequence of "tailoring" steps, which convert unbound prerapamycin into rapamycin}}


The biosynthetic ] responsible for rapamycin synthesis have been identified. As expected, three extremely large ] (ORF's) designated as ''rapA'', ''rapB'', and ''rapC'' encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.<ref name=Rapamycin_domains_and_primary_genes /> The ] ''rapL'' has been established to code for a ]-dependent ] cycloamidase, which converts L-] to L-] (figure 4) for incorporation at the end of the polyketide.<ref name=rapamycin_report>{{cite journal | vauthors = Graziani EI | title = Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs | journal = Natural Product Reports | volume = 26 | issue = 5 | pages = 602–609 | date = May 2009 | pmid = 19387497 | doi = 10.1039/b804602f }}</ref><ref>{{cite journal | vauthors = Gatto GJ, Boyne MT, Kelleher NL, Walsh CT | title = Biosynthesis of pipecolic acid by RapL, a lysine cyclodeaminase encoded in the rapamycin gene cluster | journal = Journal of the American Chemical Society | volume = 128 | issue = 11 | pages = 3838–3847 | date = March 2006 | pmid = 16536560 | doi = 10.1021/ja0587603 }}</ref> The ] ''rapP'', which is embedded between the PKS genes and translationally coupled to ''rapC'', encodes for an additional ], an NPRS responsible for incorporating L-pipecolic acid, ] and cyclization of prerapamycin. In addition, genes ''rapI'', ''rapJ'', ''rapM'', ''rapN'', ''rapO'', and ''rapQ'' have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, ''rapG'' and ''rapH'' have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.<ref name=rapG_rapH>{{cite journal | vauthors = Aparicio JF, Molnár I, Schwecke T, König A, Haydock SF, Khaw LE, Staunton J, Leadlay PF | title = Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase | journal = Gene | volume = 169 | issue = 1 | pages = 9–16 | date = February 1996 | pmid = 8635756 | doi = 10.1016/0378-1119(95)00800-4 }}</ref>
The core ], prerapamycin (figure 2), is then modified (figure 3) by an additional five enzymes, which lead to the final product, rapamycin. First, the core macrocycle is modified by RapI, SAM-dependent O-methyltransferase (MTase), which O-methylates at C39. Next, a carbonyl is installed at C9 by RapJ, a ] monooxygenases (P-450). Then, RapM, another MTase, O-methylates at C16. Finally, RapN, another P-450, installs a hydroxyl at C27 immediately followed by O-methylation by Rap Q, a distinct MTase, at C27 to yield rapamycin.<ref name=Rapamycin_genes>{{cite journal
Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the ].<ref name=Rapamycin_domains_and_primary_genes /> Note that the ] ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of ]s with ] or methylmalonyl substrates, which are attached to an ] (ACP) and extend the polyketide by two carbons each. After each successive ], the growing polyketide is further modified according to enzymatic domains that are present to ] and ] it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS ] through ]s by MTases and ]s by P-450s to yield rapamycin.
|vauthors=Gregory MA, Hong H, Lill RE, etal | title = Rapamycin biosynthesis: Elucidation of gene product function
| journal = Org. Biomol. Chem.
| volume = 4
| issue = 19
| pages = 3565–8
| date=October 2006
| pmid = 16990929
| doi = 10.1039/b608813a
}}</ref>
{{Clear}}
]
The biosynthetic ] responsible for rapamycin synthesis have been identified. As expected, three extremely large ] (ORF's) designated as ''rapA'', ''rapB'', and ''rapC'' encode for three extremely large and complex multienzymes, RapA, RapB, and RapC, respectively.<ref name=Rapamycin_domains_and_primary_genes /> The ] ''rapL'' has been established to code for a ]-dependent ] cycloamidase, which converts L-] to L-] (figure 4) for incorporation at the end of the polyketide.<ref name=rapamycin_report>{{cite journal
| author = Graziani EI
| title = Recent advances in the chemistry, biosynthesis and pharmacology of rapamycin analogs
| journal = Nat Prod Rep
| volume = 26
| issue = 5
| pages = 602–9
| date=May 2009
| pmid = 19387497
| doi = 10.1039/b804602f
}}</ref><ref>{{cite journal |title= Biosynthesis of Pipecolic Acid by RapL, a Lysine Cyclodeaminase Encoded in the Rapamycin Gene Cluster |journal= J. Am. Chem. Soc. |year= 2006 |volume= 128 |issue= 11 |pages= 3838–47 |doi= 10.1021/ja0587603 |pmid= 16536560 |author1=Gatto, G. J., Jr. |author2=Boyne, M. T., II |author3=Kelleher,N. L. |author4=Walsh, C. T. }}</ref> The ] ''rapP'', which is embedded between the PKS genes and translationally coupled to ''rapC'', encodes for an additional ], an NPRS responsible for incorporating L-pipecolic acid, ] and cyclization of prerapamycin. In addition, genes ''rapI'', ''rapJ'', ''rapM'', ''rapN'', ''rapO'', and ''rapQ'' have been identified as coding for tailoring enzymes that modify the macrocyclic core to give rapamycin (figure 3). Finally, ''rapG'' and ''rapH'' have been identified to code for enzymes that have a positive regulatory role in the preparation of rapamycin through the control of rapamycin PKS gene expression.<ref name=rapG_rapH>{{cite journal
|vauthors=Aparicio JF, Molnár I, Schwecke T, etal | title = Organization of the biosynthetic gene cluster for rapamycin in Streptomyces hygroscopicus: analysis of the enzymatic domains in the modular polyketide synthase
| journal = Gene
| volume = 169
| issue = 1
| pages = 9–16
| date=February 1996
| pmid = 8635756
| doi = 10.1016/0378-1119(95)00800-4
}}</ref>
Biosynthesis of this 31-membered macrocycle begins as the loading domain is primed with the starter unit, 4,5-dihydroxocyclohex-1-ene-carboxylic acid, which is derived from the shikimate pathway.<ref name=Rapamycin_domains_and_primary_genes /> Note that the ] ring of the starting unit is reduced during the transfer to module 1. The starting unit is then modified by a series of ]s with ] or methylmalonyl substrates, which are attached to an ] (ACP) and extend the polyketide by two carbons each. After each successive ], the growing polyketide is further modified according to enzymatic domains that are present to ] and ] it, thereby introducing the diversity of functionalities observed in rapamycin (figure 1). Once the linear polyketide is complete, L-pipecolic acid, which is synthesized by a lysine cycloamidase from an L-lysine, is added to the terminal end of the polyketide by an NRPS. Then, the NSPS cyclizes the polyketide, giving prerapamycin, the first enzyme-free product. The macrocyclic core is then customized by a series of post-PKS ] through ]s by MTases and ]s by P-450s to yield rapamycin.


==Research== ==Research==
{{medref|section|date=August 2016}}
]]] ]]]


===Cancer=== ===Cancer===
The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting<ref>{{cite journal|pmid=22379028|year=2012|last1=Li|first1=Q|last2=Rao|first2=R|last3=Vazzana|first3=J|last4=Goedegebuure|first4=P|last5=Odunsi|first5=K|last6=Gillanders|first6=W|last7=Shrikant|first7=PA|title=Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity|volume=188|issue=7|pages=3080–7|doi=10.4049/jimmunol.1103365|pmc=3311730|journal=Journal of immunology (Baltimore, Md. : 1950)}}</ref> or otherwise promote tumor regression in clinical trials.<ref>{{cite journal|pmid=17041628|year=2006|last1=Easton|first1=JB|last2=Houghton|first2=PJ|title=MTOR and cancer therapy|volume=25|issue=48|pages=6436–46|doi=10.1038/sj.onc.1209886|journal=Oncogene}}</ref> Sirolimus seems to lower the cancer risk in some transplant patients.<ref name=Law2005>{{cite journal |author=Law BK |title=Rapamycin: an anti-cancer immunosuppressant? |journal=Crit. Rev. Oncol. Hematol. |volume=56 |issue=1 |pages=47–60 |date=October 2005 |pmid=16039868 |doi=10.1016/j.critrevonc.2004.09.009 |url=http://linkinghub.elsevier.com/retrieve/pii/S1040-8428(05)00085-5}}</ref> The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting<ref>{{cite journal | vauthors = Li Q, Rao R, Vazzana J, Goedegebuure P, Odunsi K, Gillanders W, Shrikant PA | title = Regulating mammalian target of rapamycin to tune vaccination-induced CD8(+) T cell responses for tumor immunity | journal = Journal of Immunology | volume = 188 | issue = 7 | pages = 3080–3087 | date = April 2012 | pmid = 22379028 | pmc = 3311730 | doi = 10.4049/jimmunol.1103365 }}</ref> or otherwise promote tumor regression in clinical trials.<ref>{{cite journal | vauthors = Easton JB, Houghton PJ | title = mTOR and cancer therapy | journal = Oncogene | volume = 25 | issue = 48 | pages = 6436–6446 | date = October 2006 | pmid = 17041628 | doi = 10.1038/sj.onc.1209886 | title-link = doi | s2cid = 19250234 | doi-access = }}</ref> Sirolimus seems to lower the cancer risk in some transplant patients.<ref name=Law2005>{{cite journal | vauthors = Law BK | title = Rapamycin: an anti-cancer immunosuppressant? | journal = Critical Reviews in Oncology/Hematology | volume = 56 | issue = 1 | pages = 47–60 | date = October 2005 | pmid = 16039868 | doi = 10.1016/j.critrevonc.2004.09.009 }}</ref>


Sirolimus was shown to inhibit the progression of dermal ] in patients with renal transplants. Other ]s, such as ] (CCI-779) or ] (RAD001), are being tested for use in cancers such as ] and ]. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.<ref></ref> Sirolimus was shown to inhibit the progression of dermal ] in patients with renal transplants.<ref>{{cite journal | vauthors = <!-- no authors listed -->|date= May 2005 |title=A new role for sirolimus: regression of Kaposi's sarcoma in kidney-transplant recipients |journal=Nature Clinical Practice Urology |language=en |volume=2 |issue=5 |pages=211 |doi=10.1038/ncponc0156x |s2cid= 198175394 |issn=1743-4289|doi-access=free }}</ref> Other ]s, such as ] (CCI-779) or ] (RAD001), are being tested for use in cancers such as ] and ]. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.<ref>{{cite web | vauthors = Bankhead C | date = 17 February 2013 | url = http://www.medpagetoday.com/MeetingCoverage/MGUCS/37404 | title = Fatal AEs Higher with mTOR Drugs in Cancer | work = Med Page Today | access-date = 19 February 2013 | archive-date = 28 February 2021 | archive-url = https://web.archive.org/web/20210228220120/https://www.medpagetoday.com/meetingcoverage/mgucs/37404 | url-status = live }}</ref>


A ] of ] and sirolimus has been shown to drive ]-positive lymphomas into ] in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the ] effects of ] drugs, such as ] or ]. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. ]-positive lymphomas were completely resistant to the therapy; ]-expressing lymphomas are not sensitive to sirolimus.<ref>{{cite journal A ] of ] and sirolimus has been shown to drive ]-positive lymphomas into ] in mice. Akt signalling promotes cell survival in Akt-positive lymphomas and acts to prevent the ] effects of ] drugs, such as ] or ]. Sirolimus blocks Akt signalling and the cells lose their resistance to the chemotherapy. ]-positive lymphomas were completely resistant to the therapy; ]-expressing lymphomas are not sensitive to sirolimus.<ref>{{cite journal | vauthors = Sun SY, Rosenberg LM, Wang X, Zhou Z, Yue P, Fu H, Khuri FR | title = Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition | journal = Cancer Research | volume = 65 | issue = 16 | pages = 7052–7058 | date = August 2005 | pmid = 16103051 | doi = 10.1158/0008-5472.CAN-05-0917 | title-link = doi | doi-access = }}</ref><ref name="Chan">{{cite journal | vauthors = Chan S | title = Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer | journal = British Journal of Cancer | volume = 91 | issue = 8 | pages = 1420–1424 | date = October 2004 | pmid = 15365568 | pmc = 2409926 | doi = 10.1038/sj.bjc.6602162 }}</ref><ref name="ScienceDaily">{{cite journal | vauthors = Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S, Cordon-Cardo C, Pelletier J, Lowe SW | title = Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy | journal = Nature | volume = 428 | issue = 6980 | pages = 332–337 | date = March 2004 | pmid = 15029198 | doi = 10.1038/nature02369 | s2cid = 4426215 | bibcode = 2004Natur.428..332W | author-link7 = Carlos Cordon-Cardo }}</ref><ref>{{cite web | title=Combination therapy drives cancer into remission | website=Cold Spring Harbor Laboratory | date=17 March 2004 | url=https://www.cshl.edu/combination-therapy-drives-cancer-into-remission/ | access-date=23 March 2022 | archive-date=1 June 2022 | archive-url=https://web.archive.org/web/20220601214952/https://www.cshl.edu/combination-therapy-drives-cancer-into-remission/ | url-status=live }}</ref><ref name="SignalingGateway">{{cite journal | vauthors = Novak K | date = May 2004 | title = Therapeutics: Means to an end | journal = Nature Reviews Cancer | volume = 4 | page = 332 | doi = 10.1038/nrc1349 | issue = 5 | s2cid = 45906785 | doi-access = free }}</ref>
|vauthors=Sun SY, Rosenberg LM, Wang X, etal | title = Activation of Akt and eIF4E survival pathways by rapamycin-mediated mammalian target of rapamycin inhibition
| journal = Cancer Res.
| volume = 65
| issue = 16
| pages = 7052–8
| date=August 2005
| pmid = 16103051
| doi = 10.1158/0008-5472.CAN-05-0917
| url = http://cancerres.aacrjournals.org/cgi/content/full/65/16/7052
}}</ref><ref name="Chan">{{cite journal | author = Chan S | title = Targeting the mammalian target of rapamycin (mTOR): a new approach to treating cancer | journal = Br J Cancer | volume = 91 | issue = 8 | pages = 1420–4 | year = 2004 | pmid = 15365568 | doi = 10.1038/sj.bjc.6602162 | pmc = 2409926}}</ref><ref name="ScienceDaily">{{cite journal
| author = Wendel HG, De Stanchina E, Fridman JS
| title = Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy
| journal = Nature
| volume = 428
| issue = 6980
| pages = 332–7
| date=March 2004
| pmid = 15029198
| doi = 10.1038/nature02369
| laysummary = http://www.sciencedaily.com/releases/2004/03/040318073757.htm
| laysource = ScienceDaily
| laydate = 18 March 2004
| bibcode = 2004Natur.428..332W
| last2 = Stanchina
| last3 = Fridman
| last4 = Malina
| last5 = Ray
| last6 = Kogan
| last7 = Cordon-Cardo
| authorlink7=Carlos Cordon-Cardo
| last8 = Pelletier
| last9 = Lowe

|display-authors=etal}}</ref><ref name="SignalingGateway">{{cite journal
| last = Novak
| first = Kristine
| date=May 2004
| title = Therapeutics: Means to an end
| journal = Nature Reviews Cancer
| volume = 4
| page = 332
| doi = 10.1038/nrc1349
| url = http://www.signaling-gateway.org/update/updates/200405/nrc1349.html
| issue=5
}}
</ref>


===Tuberous sclerosis complex=== ===Tuberous sclerosis complex===
Sirolimus also shows promise in treating ] (TSC), a congenital disorder that leaves sufferers prone to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and ] in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and ] (Novartis's RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.<ref>{{cite web Sirolimus also shows promise in treating ] (TSC), a congenital disorder that predisposes those afflicted to benign tumor growth in the brain, heart, kidneys, skin, and other organs. After several studies conclusively linked mTOR inhibitors to remission in TSC tumors, specifically subependymal giant-cell astrocytomas in children and ] in adults, many US doctors began prescribing sirolimus (Wyeth's Rapamune) and ] (Novartis's RAD001) to TSC patients off-label. Numerous clinical trials using both rapamycin analogs, involving both children and adults with TSC, are underway in the United States.<ref>{{cite journal | vauthors = Li M, Zhou Y, Chen C, Yang T, Zhou S, Chen S, Wu Y, Cui Y | title = Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis | journal = Orphanet Journal of Rare Diseases | volume = 14 | issue = 1 | pages = 39 | date = February 2019 | pmid = 30760308 | pmc = 6373010 | doi = 10.1186/s13023-019-1012-x | doi-access = free }}</ref>
| author = Tuberous Sclerosis Alliance
| date=October 2009
| title = Current Clinical Trials
| accessdate = 14 October 2009
| url = http://www.tsalliance.org/pages.aspx?content=370
}}
</ref>

Most studies thus far have noted that tumors often regrew when treatment stopped. Theories that claim the drug ameliorates TSC symptoms such as facial angiofibromas and autism are a matter of current research in animal models.{{mcn|date=May 2016}}


===Effects on longevity=== ===Effects on longevity===
], specifically mTORC1, was first shown to be important in aging in 2003, in a study on worms; sirolimus was shown to inhibit and slow aging in worms, yeast, and flies, and then to improve the condition of ]s of various diseases of aging.<ref>{{cite web|vauthors=Lawton G|date=|title=What is rapamycin?|url=https://www.newscientist.com/definition/rapamycin/|access-date=25 July 2021|website=New Scientist|language=en-US|archive-date=25 July 2021|archive-url=https://web.archive.org/web/20210725034527/https://www.newscientist.com/definition/rapamycin/|url-status=live}}</ref><ref name=Apelo2016rev>{{cite journal | vauthors = Arriola Apelo SI, Lamming DW | title = Rapamycin: An InhibiTOR of Aging Emerges From the Soil of Easter Island | journal = The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences | volume = 71 | issue = 7 | pages = 841–849 | date = July 2016 | pmid = 27208895 | pmc = 4906330 | doi = 10.1093/gerona/glw090 | quote = A diverse and severe set of negative side effects likely preclude the wide-scale use of rapamycin and its analogs as a prolongevity agent. }}</ref> Sirolimus was first shown to extend lifespan in wild-type mice in a study published by NIH investigators in 2009; the studies have been replicated in mice of many different genetic backgrounds.<ref name=Apelo2016rev/> A study published in 2020 found late-life sirolimus dosing schedules enhanced mouse lifespan in a sex-specific manner: limited rapamycin exposure enhanced male but not female lifespan, providing evidence for sex differences in sirolimus response.<ref name="pmid33145977">{{cite journal | vauthors = Strong R, Miller RA, Bogue M, Fernandez E, Javors MA, Libert S, Marinez PA, Murphy MP, Musi N, Nelson JF, Petrascheck M, Reifsnyder P, Richardson A, Salmon AB, Macchiarini F, Harrison DE | title = Rapamycin-mediated mouse lifespan extension: Late-life dosage regimes with sex-specific effects | journal = Aging Cell | volume = 19 | issue = 11 | pages = e13269 | date = November 2020 | pmid = 33145977 | pmc = 7681050 | doi = 10.1111/acel.13269 }}</ref><ref>{{cite web | title=Late-Life Rapamycin Regimens Extend Mouse Lifespan in a Sex-Specific Manner | website=Nicotinamide Mononucleotide (NMN) | date=11 November 2020 | url=https://www.nmn.com/news/late-life-rapamycin-regimens-extend-mouse-lifespan-sex-specific-manner | access-date=23 March 2022 | archive-date=28 February 2021 | archive-url=https://web.archive.org/web/20210228013745/https://www.nmn.com/news/late-life-rapamycin-regimens-extend-mouse-lifespan-sex-specific-manner | url-status=live }}</ref> The results are further supported by the finding that genetically modified mice with impaired mTORC1 signalling live longer.<ref name=Apelo2016rev/>
Rapamycin was first shown to extend lifespan in eukaryotes in 2006.{{mcn}} Powers ''et al.'' showed a dose-responsive effect of rapamycin on lifespan extension in yeast cells.<ref name="pmid16418483">{{cite journal | vauthors = Powers RW, Kaeberlein M, Caldwell SD, Kennedy BK, Fields S | title = Extension of chronological life span in yeast by decreased TOR pathway signaling | journal = Genes Dev. | volume = 20 | issue = 2 | pages = 174–84 | year = 2006 | pmid = 16418483 | pmc = 1356109 | doi = 10.1101/gad.1381406 | url = }}</ref>{{npsn}} Building on this and other work, in a 2009 study, the lifespans of ] fed rapamycin were increased between 28 and 38% from the beginning of treatment, or 9 to 14% in total increased maximum lifespan. Of particular note, the treatment began in mice aged 20 months, the equivalent of 60 human years.<ref name="pmid19587680">{{cite journal | vauthors = Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA | title = Rapamycin fed late in life extends lifespan in genetically heterogeneous mice | journal = Nature | volume = 460 | issue = 7253 | pages = 392–5 | year = 2009 | pmid = 19587680 | pmc = 2786175 | doi = 10.1038/nature08221 | laysummary = http://www.timesonline.co.uk/tol/life_and_style/health/article6669805.ece | laysource = The Times | laydate = 8 July 2009}}</ref>{{npsn}} Rapamycin has subsequently been shown to extend mouse lifespan in several separate experiments,<ref name="Miller2010">{{cite journal |vauthors=Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R | title = Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice | journal = J. Gerontol. A Biol. Sci. Med. Sci. | volume = 66 | issue = 2 | pages = 191–201 |date=February 2011 | pmid = 20974732 | pmc = 3021372 | doi = 10.1093/gerona/glq178 }}</ref><ref name=Ingram&Roth2011>{{cite journal |url=https://www.ncbi.nlm.nih.gov/pubmed/21167272 |vauthors=Ingram DK, Roth GS |title=Glycolytic inhibition as a strategy for developing calorie restriction mimetics|journal=Experimental Gerontology|date=February–March 2011|volume=46|issue=2–3|pages=148–54|doi=10.1016/j.exger.2010.12.001|pmid=21167272 | type = review}}</ref> and is now being tested for this purpose in nonhuman primates (the ] monkey),<ref name=Tardif2015>{{cite journal|last1=Tardif|first1=S|last2=Ross|first2=C|last3=Bergman|first3=P|last4=Fernandez|first4=E|last5=Javors|first5=M|last6=Salmon|first6=A|last7=Spross|first7=J|last8=Strong|first8=R|last9=Richardson|first9=A|title=Testing Efficacy of Administration of the Antiaging Drug Rapamycin in a Nonhuman Primate, the Common Marmoset|journal=J Gerontol A Biol Sci Med Sci|date=19 July 2014 |doi=10.1093/gerona/glu101|pmid=25038772|volume=70|pages=577–588}}</ref> and with an ongoing attempt to organize a study in dogs.<ref name=CheckHeyden2014>{{cite journal|last1=Check Hayden|first1=Erika|title=Pet dogs set to test anti-ageing drug|journal=Nature|date=30 October 2014|volume=514|issue=7524|page=546|doi=10.1038/514546a|pmid=25355339|url=http://www.nature.com/news/pet-dogs-set-to-test-anti-ageing-drug-1.16237|accessdate=2 April 2015}}</ref> The Dog Aging Project is funded by pet owners.<ref name="NYT51616">{{cite news|author1=Amy Harmon|title=Dogs Test Drug Aimed at Humans’ Biggest Killer: Age|url=http://www.nytimes.com/2016/05/17/us/aging-research-disease-dogs.html|accessdate=18 May 2016|work=The New York Times|date=16 May 2016}}</ref>


Sirolimus has potential for widespread use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health. In 2014, researchers at Novartis showed that a related compound, ], increased elderly patients' immune response on an intermittent dose.<ref>{{cite journal | vauthors = Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S, Glass DJ, Klickstein LB | title = mTOR inhibition improves immune function in the elderly | journal = Science Translational Medicine | volume = 6 | issue = 268 | pages = 268ra179 | date = December 2014 | pmid = 25540326 | doi = 10.1126/scitranslmed.3009892 | s2cid = 206685475 }}</ref> This led to many in the anti-aging community self-experimenting with the compound.<ref>{{cite news |vauthors=Janin A |title=Can a Kidney Transplant Drug Keep You From Aging? |url=https://www.wsj.com/articles/rapamycin-anti-aging-drug-longevity-a27575f4 |access-date=9 May 2023 |newspaper=Wall Street Journal |date=May 2023 |language=en-US |archive-date=8 May 2023 |archive-url=https://web.archive.org/web/20230508203232/https://www.wsj.com/articles/rapamycin-anti-aging-drug-longevity-a27575f4 |url-status=live }}</ref> However, because of the different biochemical properties of sirolimus, the dosing is potentially very different from that of everolimus. Ultimately, due to known side-effects of sirolimus, as well as inadequate evidence for optimal dosing, it was concluded in 2016 that more research was required before sirolimus could be widely prescribed for this purpose.<ref name="Apelo2016rev" /><ref>{{cite journal | vauthors = Johnson SC, Rabinovitch PS, Kaeberlein M | title = mTOR is a key modulator of ageing and age-related disease | journal = Nature | volume = 493 | issue = 7432 | pages = 338–345 | date = January 2013 | pmid = 23325216 | pmc = 3687363 | doi = 10.1038/nature11861 | bibcode = 2013Natur.493..338J }}</ref> Two human studies on the effects of sirolimus (rapamycin) on longevity did not show statistically significant benefits. However, due to limitations in the studies, further research is needed to fully assess its potential in humans.<ref>Smith, Dana. "Anti-Aging Enthusiasts Are Taking a Pill to Extend Their Lives. Will It Work?" The New York Times, 24 Sept. 2024. https://www.nytimes.com/2024/09/24/well/live/rapamycin-aging-longevity-benefits-risks.html</ref>
Because rapamycin at high doses can suppress the immune system, people taking rapamycin for transplant or cancer therapy are more susceptible to dangerous infections.<ref name="Rapamune Rx info" /> Yet paradoxically, rapamycin was shown to enhance the ability of aging mice to mount an immune response to a vaccine against ].{{mcn}} A similar immunological "rejuvenating" effect was later documented in elderly humans administered a rapamycin analog prior to ] ]), further fueling optimism for the potential of mTOR as a target for anti-aging drugs for humans.{{mcn}} It is not known whether rapamycin will have similar lifespan-lengthening effects in humans, and the authors of one study caution that the drug should not be used by the general population for this purpose.<ref>{{cite journal| author = Jocelyn Rice| date = 8 July 2009 | title = First Drug Shown to Extend Life Span in Mammals| journal = Technology Review| pages = 1–2| accessdate = 9 July 2009| url = http://www.technologyreview.com/biomedicine/22974/page1/| publisher = Massachusetts Institute of Technology}}</ref>{{ums}}


It is hypothesized that some dietary regimes, like ] and ] restriction, cause lifespan extension by decreasing mTOR activity.{{mcn}} It is believed that this is achieved by limiting the essential amino acid ], a potent activator of mTOR.{{mcn|date=October 2014}} The administration of ] into the rat brain has been shown to decrease food intake and body weight via activation of the mTOR pathway.<ref>{{cite journal | vauthors = Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ | title = Hypothalamic mTOR signaling regulates food intake | journal = ] | volume = 312 | issue = 5775 | pages = 927–930 | year = 2006 | pmid = 16690869 | doi = 10.1126/science.1124147 }}</ref>{{npsn}} Sirolimus has complex effects on the immune system—while ] goes up and ] decreases, which suggests an immunostimulatory response, ] and ] are decreased, which suggests an immunosuppressive response. The duration of the inhibition and the exact extent to which mTORC1 and mTORC2 are inhibited play a role, but were not yet well understood according to a 2015 paper.<ref>{{cite journal | vauthors = Weichhart T, Hengstschläger M, Linke M | title = Regulation of innate immune cell function by mTOR | journal = Nature Reviews. Immunology | volume = 15 | issue = 10 | pages = 599–614 | date = October 2015 | pmid = 26403194 | pmc = 6095456 | doi = 10.1038/nri3901 }}</ref>


===Topical administration===
According to the ],<ref name="kriete2010">{{cite journal | vauthors = Kriete A, Bosl WJ, Booker G | title = Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses | journal = PLoS Computational Biology | volume = 6 | issue = 6 | pages = e1000820 | date = June 2010 | pmid = 20585546 | pmc = 2887462 | doi = 10.1371/journal.pcbi.1000820 }}</ref> ] cause damage of ] proteins and decrease of ATP production. Subsequently, via ATP sensitive ], the mTOR pathway is inhibited and ATP consuming protein synthesis is downregulated, since mTORC1 initiates a phosphorylation cascade activating the ].<ref>{{Cite journal|last=Magnuson|first=Brian|last2=Ekim|first2=Bilgen|last3=Fingar|first3=Diane C.|date=1 January 2012|title=Regulation and function of ribosomal protein S6 kinase (S6K) within mTOR signalling networks|url=https://www.ncbi.nlm.nih.gov/pubmed/22168436|journal=The Biochemical Journal|volume=441|issue=1|pages=1–21|doi=10.1042/BJ20110892|issn=1470-8728|pmid=22168436}}</ref> Hence, the proportion of damaged proteins is enhanced. Moreover, disruption of mTORC1 directly inhibits ].<ref name="schieke2006">{{cite journal | vauthors = Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS, Finkel T | title = The Mammalian Target of Rapamycin (mTOR) Pathway Regulates Mitochondrial Oxygen Consumption and Oxidative Capacity | journal = J. Biol. Chem. | volume = 281 | issue = 37 | pages = 27643–27652 | year = 2006 | pmid = 16847060 | doi = 10.1074/jbc.M603536200 }}</ref> These positive feedbacks on the aging process are counteracted by protective mechanisms: Decreased mTOR activity (among other factors) upregulates ]<ref name="schieke2006" /> and removal of dysfunctional cellular components via ].<ref name="kriete2010" />
When applied as a topical preparation, researchers showed that rapamycin can regenerate collagen and reverse clinical signs of aging in elderly patients.<ref>{{cite journal | vauthors = Chung CL, Lawrence I, Hoffman M, Elgindi D, Nadhan K, Potnis M, Jin A, Sershon C, Binnebose R, Lorenzini A, Sell C | title = Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial | journal = GeroScience | volume = 41 | issue = 6 | pages = 861–869 | date = December 2019 | pmid = 31761958 | pmc = 6925069 | doi = 10.1007/s11357-019-00113-y }}</ref> The concentrations are far lower than those used to treat angiofibromas.{{cn|date=November 2024}}


===SARS-CoV-2===
===Tuberous sclerosis in mice, with possible relevance to autism===
Rapamycin has been proposed as a treatment for ] insofar as its ] effects could prevent or reduce the ] seen in very serious cases of COVID-19.<ref name="pmid33031791">{{cite journal | vauthors = Husain A, Byrareddy SN | title = Rapamycin as a potential repurpose drug candidate for the treatment of COVID-19 | journal = Chemico-Biological Interactions | volume = 331 | pages = 109282 | date = November 2020 | pmid = 33031791 | pmc = 7536130 | doi = 10.1016/j.cbi.2020.109282 | bibcode = 2020CBI...33109282H }}</ref> Moreover, inhibition of ] by rapamycin could reduce ].<ref name="pmid33031791" />
In a study of sirolimus as a treatment for tuberous sclerosis, researchers observed improvements in TSC symptoms which overlap with ]. The researchers discovered that sirolimus regulates one of the same proteins the TSC gene does, but in different parts of the body. They decided to treat mice three to six months old (adulthood in mice lifespans); this increased the TSC mice's intellect to about that of normal mice in as little as three days.<ref>{{cite journal
|vauthors=Ehninger D, Han S, Shilyansky C, etal | title = Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis
| journal = Nat. Med.
| volume = 14
| issue = 8
| pages = 843–8
| doi=10.1038/nm1788
| pmid=18568033
| pmc=2664098}}</ref>


===Alzheimer's in mice=== ===Atherosclerosis===
Rapamycin can accelerate degradation of ] in ], thereby lowering the risk of atherosclerosis.<ref name="pmid30666207">{{cite journal | vauthors = Liu Y, Yang F, Zou S, Qu L | title = Rapamycin: A Bacteria-Derived Immunosuppressant That Has Anti-atherosclerotic Effects and Its Clinical Application | journal = Frontiers in Pharmacology | volume = 9 | pages = 1520 | date = 2019 | pmid = 30666207 | pmc = 6330346 | doi = 10.3389/fphar.2018.01520 | title-link = doi | doi-access = free }}</ref> Oxidized LDL cholesterol is a major contributor to atherosclerosis.<ref name="pmid15383655">{{cite journal | vauthors = Stocker R, Keaney JF | title = Role of oxidative modifications in atherosclerosis | journal = Physiological Reviews | volume = 84 | issue = 4 | pages = 1381–1478 | date = October 2004 | pmid = 15383655 | doi = 10.1152/physrev.00047.2003 | title-link = doi | doi-access = }}</ref>
Sirolimus reduced brain lesions and prevented the decline of performance in the water maze in mice with a mouse model of Alzheimer's.<ref></ref> Recent studies have observed a protective effect against Alzheimer's Disease in preventing cognitive deficits and reducing amyloid-β levels in mouse models.
<ref>{{cite journal |vauthors=Spilman P, Podlutskaya N, Hart MJ, etal |title=Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease |journal=PLoS ONE |volume=5 |issue=4 |pages=e9979 |year=2010 |pmid=20376313 |pmc=2848616 |doi=10.1371/journal.pone.0009979 |editor1-last=Ferrari |editor1-first=Pier Francesco}}</ref>


===Lupus===
===Muscular dystrophy in mice===
As of 2016, studies in cells, animals, and humans have suggested that mTOR activation as process underlying ] and that inhibiting mTOR with rapamycin may be a disease-modifying treatment.<ref name=Oaks2016rev>{{cite journal | vauthors = Oaks Z, Winans T, Huang N, Banki K, Perl A | title = Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years | journal = Current Rheumatology Reports | volume = 18 | issue = 12 | pages = 73 | date = December 2016 | pmid = 27812954 | pmc = 5314949 | doi = 10.1007/s11926-016-0622-8 }}</ref> As of 2016 rapamycin had been tested in small clinical trials in people with lupus.<ref name=Oaks2016rev/>
Researchers at Washington University School of Medicine in St. Louis observed that ] coated in sirolimus increases grip strength by 30% and significantly increases cardiac function in mice. The nanoparticle consists of a core of perfluorocarbon and are 200&nbsp;nm in diameter. The nanoparticle accumulates in areas of inflammation, in this case the muscles where it releases a small dose of sirolimus. This suppresses the immune system and promotes ].<ref>{{cite web|url=http://news.wustl.edu/news/Pages/26497.aspx |title=Nanoparticles treat muscular dystrophy in mice &#124; Newsroom &#124; Washington University in St. Louis |publisher=News.wustl.edu |accessdate=7 April 2014}}</ref>


===Lymphatic malformation (LM)===
===Systemic lupus erythematosus in mice and humans===
], lymphangioma or cystic hygroma, is an abnormal growth of lymphatic vessels that usually affects children around the head and neck area and more rarely involving the tongue causing macroglossia. LM is caused by a PIK3CA mutation during lymphangiogenesis early in gestational cell formation causing the malformation of lymphatic tissue. Treatment often consists of removal of the affected tissue via excision, laser ablation or sclerotherapy, but the rate of recurrence can be high and surgery can have complications. Sirolimus has shown evidence of being an effective treatment in alleviating symptoms and reducing the size of the malformation by way of altering the mTOR pathway in lymphangiogenesis. Although an off label use of the drug, Sirolimus has been shown to be an effective treatment for both microcystic and macrocystic LM. More research is however needed to develop and create targeted, effective treatment therapies for LM.<ref>{{cite journal | vauthors = Wiegand S, Dietz A, Wichmann G | title = Efficacy of sirolimus in children with lymphatic malformations of the head and neck | journal = European Archives of Oto-Rhino-Laryngology | volume = 279 | issue = 8 | pages = 3801–3810 | date = August 2022 | pmid = 35526176 | pmc = 9249683 | doi = 10.1007/s00405-022-07378-8 }}</ref>
Sirolimus improves disease activity and dependence on prednisone in ] (SLE) patients resistant or intolerant to immunosuppressant medications. Sirolimus acts through blocking the activation of its molecular target, the mechanistic target of rapamycin complex 1 (mTORC1). The activation of mTORC1, which is associated with suppression of mTORC2, results in the expansion of proinflammatory CD4-CD8- double-negative (DN) T lymphocytes. These DN T cells produce inflammatory cytokines, interleukin-4 (IL-4) and interleukin-17, and they exhibit predisposition to proinflammatory cell death through necrosis. Increased IL-4 production is responsible for activation of autoantibody-producing B lymphocytes in SLE.<ref>{{Cite journal
| pmid = 16947529
| year = 2006
| author1 = Fernandez
| first1 = D
| title = Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus
| journal = Arthritis & Rheumatism
| volume = 54
| issue = 9
| pages = 2983–8
| last2 = Bonilla
| first2 = E
| last3 = Mirza
| first3 = N
| last4 = Niland
| first4 = B
| last5 = Perl
| first5 = A
| doi = 10.1002/art.22085
| pmc=4034146
}}</ref><ref>{{Cite journal
| pmid = 19201859
| year = 2009
| author1 = Fernandez
| first1 = D. R.
| title = Activation of mammalian target of rapamycin controls the loss of TCRzeta in lupus T cells through HRES-1/Rab4-regulated lysosomal degradation
| journal = The Journal of Immunology
| volume = 182
| issue = 4
| pages = 2063–73
| last2 = Telarico
| first2 = T
| last3 = Bonilla
| first3 = E
| last4 = Li
| first4 = Q
| last5 = Banerjee
| first5 = S
| last6 = Middleton
| first6 = F. A.
| last7 = Phillips
| first7 = P. E.
| last8 = Crow
| first8 = M. K.
| last9 = Oess
| first9 = S
| last10 = Muller-Esterl
| first10 = W
| last11 = Perl
| first11 = A
| doi = 10.4049/jimmunol.0803600
| pmc = 2676112
}}</ref><ref>{{Cite journal
| pmid = 20350481
| year = 2010
| author1 = Fernandez
| first1 = D
| title = MTOR signaling: A central pathway to pathogenesis in systemic lupus erythematosus?
| journal = Discovery medicine
| volume = 9
| issue = 46
| pages = 173–8
| last2 = Perl
| first2 = A
| pmc = 3131182
}}</ref><ref>{{Cite journal
| pmid = 23913957
| year = 2013
| author1 = Lai
| first1 = Z. W.
| title = Mechanistic target of rapamycin activation triggers IL-4 production and necrotic death of double-negative T cells in patients with systemic lupus erythematosus
| journal = The Journal of Immunology
| volume = 191
| issue = 5
| pages = 2236–46
| last2 = Borsuk
| first2 = R
| last3 = Shadakshari
| first3 = A
| last4 = Yu
| first4 = J
| last5 = Dawood
| first5 = M
| last6 = Garcia
| first6 = R
| last7 = Francis
| first7 = L
| last8 = Tily
| first8 = H
| last9 = Bartos
| first9 = A
| last10 = Faraone
| first10 = S. V.
| last11 = Phillips
| first11 = P
| last12 = Perl
| first12 = A
| doi = 10.4049/jimmunol.1301005
| pmc = 3777662
}}</ref><ref>{{Cite journal
| pmid = 24683191
| year = 2014
| author1 = Kato
| first1 = H
| title = Mechanistic Target of Rapamycin Complex 1 Expands Th17 and IL-4+ CD4-CD8- Double-Negative T Cells and Contracts Regulatory T Cells in Systemic Lupus Erythematosus
| journal = The Journal of Immunology
| volume = 192
| issue = 9
| pages = 4134–44
| last2 = Perl
| first2 = A
| doi = 10.4049/jimmunol.1301859
| pmc = 3995867
}}</ref> Sirolimus also blocks disease in lupus-prone mice by reversing the activation of mTORC1.<ref>{{Cite journal
| pmid = 23897774
| year = 2013
| author1 = Caza
| first1 = T. N.
| title = HRES-1/Rab4-mediated depletion of Drp1 impairs mitochondrial homeostasis and represents a target for treatment in SLE
| journal = Annals of the Rheumatic Diseases
| last2 = Fernandez
| first2 = D. R.
| last3 = Talaber
| first3 = G
| last4 = Oaks
| first4 = Z
| last5 = Haas
| first5 = M
| last6 = Madaio
| first6 = M. P.
| last7 = Lai
| first7 = Z. W.
| last8 = Miklossy
| first8 = G
| last9 = Singh
| first9 = R. R.
| last10 = Chudakov
| first10 = D. M.
| last11 = Malorni
| first11 = W
| last12 = Middleton
| first12 = F
| last13 = Banki
| first13 = K
| last14 = Perl
| first14 = A
| doi = 10.1136/annrheumdis-2013-203794
| volume=73
| pages=1888–1897
}}</ref> Prospective clinical trial in SLE patients with sirolimus is ongoing.


===Graft-versus-host disease===
===Other afflictions===
Due to its immunosuppressant activity, Rapamycin has been assessed as prophylaxis or treatment agent of ] (GVHD), a complication of ]. While contrasted results were obtained in clinical trials,<ref>{{cite journal | vauthors = Lutz M, Mielke S | title = New perspectives on the use of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation and graft-versus-host disease | journal = British Journal of Clinical Pharmacology | volume = 82 | issue = 5 | pages = 1171–1179 | date = November 2016 | pmid = 27245261 | pmc = 5061796 | doi = 10.1111/bcp.13022 | title-link = doi | doi-access = free }}</ref> pre-clinical studies have shown that Rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells.<ref>{{cite journal | vauthors = Blazar BR, Taylor PA, Panoskaltsis-Mortari A, Vallera DA | title = Rapamycin inhibits the generation of graft-versus-host disease- and graft-versus-leukemia-causing T cells by interfering with the production of Th1 or Th1 cytotoxic cytokines | journal = Journal of Immunology | volume = 160 | issue = 11 | pages = 5355–5365 | date = June 1998 | pmid = 9605135 | doi = 10.4049/jimmunol.160.11.5355 | s2cid = 31313976 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Ehx G, Ritacco C, Hannon M, Dubois S, Delens L, Willems E, Servais S, Drion P, Beguin Y, Baron F | title = Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis | journal = American Journal of Transplantation | volume = 21 | issue = 8 | pages = 2662–2674 | date = August 2021 | pmid = 33512760 | doi = 10.1111/ajt.16505 | s2cid = 231766741 | doi-access = free | hdl = 2268/256132 | hdl-access = free }}</ref>
Studies ''in vitro'' in mice and in humans suggest sirolimus inhibits ] replication through different mechanisms, including downregulation of the coreceptor ]<ref>{{cite journal
|vauthors=Donia M, McCubrey JA, Bendtzen K, Nicoletti F | title = Potential use of rapamycin in HIV infection
| journal = Br J Clin Pharmacol
| volume = 70
| issue = 6
| pages = 784–93
| date=December 2010
| pmid = 21175433
| doi = 10.1111/j.1365-2125.2010.03735.x
| pmc = 3014061
}}</ref> and the induction of ].<ref name="pmid21454634">{{cite journal
|vauthors=Campbell GR, Spector SA | title=Hormonally active vitamin D3 (1{alpha},25-dihydroxycholecalciferol) triggers autophagy in human macrophages that inhibits HIV-1 infection
| journal=J Biol Chem
| date=March 2011
| pmid=21454634
| doi=10.1074/jbc.M110.206110
| volume=286
| issue=21
| pages=18890–902
}}</ref>

In addition, sirolimus is currently being assessed as a therapeutic option for ] (ADPKD). Case reports indicate sirolimus can reduce kidney volume and delay the loss of renal function in patients with ADPKD.<ref name="peces">{{cite journal
|vauthors=Peces R, Peces C, Pérez-Dueñas V, etal | date = 16 January 2009 | title = Rapamycin reduces kidney volume and delays the loss of renal function in a patient with autosomal-dominant polycystic kidney disease
| journal = NDT Plus
| volume = 2
| issue = 2
| pages = 133–5
| publisher = Oxford Journals
| issn = 1753-0792
| doi = 10.1093/ndtplus/sfn210
}}
</ref>

Sirolimus has also been used in preliminary research to combat ], a rare disorder that causes individuals to age at an exceedingly rapid pace, leading to an extremely compromised cell-damage repair capacity and typically resulting in death in the early teenage years due to causes which are generally associated with old age such as ] or ].<ref>''CNN.com'' , 1 July 2011</ref>


===Applications in biology research=== ===Applications in biology research===
Rapamycin is used in biology research as an agent for ].<ref>{{cite journal|authors=Rivera, VM; Clackson, T; Natesan, S; Pollock, R; Amara, JF; Keenan, T; Magari, SR; Phillips, T; Courage, NL; Cerasoli F, Jr; Holt, DA; Gilman, M|title=A humanized system for pharmacologic control of gene expression|journal=Nature Medicine|date=September 1996 |volume=2|issue=9|pages=1028–32|pmid=8782462|doi=10.1038/nm0996-1028}}</ref> In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions. Rapamycin is used in biology research as an agent for ].<ref>{{cite journal | vauthors = Rivera VM, Clackson T, Natesan S, Pollock R, Amara JF, Keenan T, Magari SR, Phillips T, Courage NL, Cerasoli F, Holt DA, Gilman M | title = A humanized system for pharmacologic control of gene expression | journal = Nature Medicine | volume = 2 | issue = 9 | pages = 1028–1032 | date = September 1996 | pmid = 8782462 | doi = 10.1038/nm0996-1028 | s2cid = 30469863 }}</ref> In this application, rapamycin is added to cells expressing two fusion constructs, one of which contains the rapamycin-binding FRB domain from mTOR and the other of which contains an FKBP domain. Each fusion protein also contains additional domains that are brought into proximity when rapamycin induces binding of FRB and FKBP. In this way, rapamycin can be used to control and study protein localization and interactions.{{cn|date=November 2024}}

== Veterinary uses ==
A number of ] ] are participating in a long-term ] examining the effect of rapamycin on the ] of ]s.<ref>{{multiref2|1={{cite web | title=Study to assess healthy aging in dogs: the Dog Aging Project and Test of Rapamycin in Aging Dogs (TRIAD study) | website=University of Georgia College of Veterinary Medicine | date=29 July 2022 | url=https://vet.uga.edu/clinical-trial/study-to-assess-healthy-aging-in-dogs-the-dog-aging-project-and-test-of-rapamycin-in-aging-dogs-triad-study/ | access-date=23 February 2023 | archive-date=23 February 2023 | archive-url=https://web.archive.org/web/20230223234710/https://vet.uga.edu/clinical-trial/study-to-assess-healthy-aging-in-dogs-the-dog-aging-project-and-test-of-rapamycin-in-aging-dogs-triad-study/ | url-status=live }}
|2={{cite web | title=Dog Aging Project TRIAD Study | website=Washington State University Veterinary Teaching Hospital | date=28 March 2022 | url=https://hospital.vetmed.wsu.edu/2022/03/28/dog-aging-project-triad-study/ | access-date=23 February 2023 | archive-date=23 February 2023 | archive-url=https://web.archive.org/web/20230223234732/https://hospital.vetmed.wsu.edu/2022/03/28/dog-aging-project-triad-study/ | url-status=live }}
|3={{cite web | title=Dog aging project - TRIAD (Test of Rapamycin in Aging Dogs) | website=Iowa State University College of Veterinary Medicine | url=https://vetmed.iastate.edu/vmc/clinical-trials/dog-aging-project-triad-test-rapamycin-aging-dogs | access-date=23 February 2023 | archive-date=23 February 2023 | archive-url=https://web.archive.org/web/20230223234717/https://vetmed.iastate.edu/vmc/clinical-trials/dog-aging-project-triad-test-rapamycin-aging-dogs | url-status=live }}}}</ref>


== References == == References ==
{{reflist|2}} {{reflist}}

== Further reading ==
{{refbegin}}
* {{cite journal | vauthors = Benjamin D, Colombi M, Moroni C, Hall MN | title = Rapamycin passes the torch: a new generation of mTOR inhibitors | journal = Nature Reviews. Drug Discovery | volume = 10 | issue = 11 | pages = 868–880 | date = October 2011 | pmid = 22037041 | doi = 10.1038/nrd3531 | s2cid = 1227277 }}
* {{cite journal | vauthors = Freixo C, Ferreira V, Martins J, Almeida R, Caldeira D, Rosa M, Costa J, Ferreira J | title = Efficacy and safety of sirolimus in the treatment of vascular anomalies: A systematic review | journal = Journal of Vascular Surgery | volume = 71 | issue = 1 | pages = 318–327 | date = January 2020 | pmid = 31676179 | doi = 10.1016/j.jvs.2019.06.217 | s2cid = 207831199 | doi-access = free }}
* {{cite journal | vauthors = Geeurickx M, Labarque V | title = A narrative review of the role of sirolimus in the treatment of congenital vascular malformations | journal = Journal of Vascular Surgery. Venous and Lymphatic Disorders | volume = 9 | issue = 5 | pages = 1321–1333 | date = September 2021 | pmid = 33737259 | doi = 10.1016/j.jvsv.2021.03.001 }}
{{refend}}


== External links == == External links ==
{{Commons category}} {{Commons category}}
* {{ClinicalTrialsGov|NCT02494570|A Phase 2 Study of ABI-009 in Patients With Advanced Malignant PEComa (AMPECT)}}
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