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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/01/19 17:57:01」(JST)

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Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

Approvals and indications

Everolimus is approved for various conditions:

Advanced kidney cancer (approved in March 2009)^[2]
Prevention of organ rejection after renal transplant(April 2010)^[3]
Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)^[4]
Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)^[5]
Breast cancer in post-menopausal women with advanced hormone-receptor positive, HER2-negative type cancer, in conjunction with exemestane (July 2012)^[6]

Clinical trials

As of October 2010^[update], Phase III trials are under way in gastric cancer, hepatocellular carcinoma and lymphoma.^[7] The use of everolimus in refractory chronic graft-versus-host disease has been reported in 2012.^[8]

Interim phase III trial results in 2011 showed that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.^[9]

Mechanism

In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.?

Role in heart transplantation

Everolimus may have a role in heart transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.^[10]

Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.

Use in vascular stents

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produces an everolimus-eluting stent called the Xience V. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently in use in the United States and as an investigational device in Japan. It is also available under a private-label version called the PROMUS Everolimus-Eluting Coronary Stent System and it is currently available in most major European and Asia-Pacific markets.

Everolimus
Systematic (IUPAC) name
	dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Licence data	US FDA:link
Pregnancy cat.	D (US)
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Half-life	~30 hours
Identifiers
CAS number	159351-69-6
ATC code	L01XE10 L04AA18
PubChem	CID 6442177
DrugBank	DB01590
ChemSpider	21106307
UNII	9HW64Q8G6G
KEGG	D02714
ChEMBL	CHEMBL1201755
Synonyms	42-O-(2-hydroxyethyl)rapamycin
Chemical data
Formula	C53H83NO14
Mol. mass	958.224 g/mol
	SMILES OCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4;
	InChI InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 ; Key:HKVAMNSJSFKALM-GKUWKFKPSA-N ;
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Discovery and development of mTOR inhibitors

References

^ R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). "The evolving experience using everolimus in clinical transplantation". Elsevier 36 (2): S495–S499. http://www.transplantation-proceedings.org/article/S0041-1345(04)00016-8/abstract.
^ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 2009-03-30. http://www.novartis.com/newsroom/media-releases/en/2009/1301801.shtml. Retrieved April 6, 2009.
^ "Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients" (Press release). Novartis. 2010-04-22. http://www.novartis.com/newsroom/media-releases/en/2010/1406625.shtml. Retrieved April 26, 2010.
^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010. http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/.
^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
^ "US FDA approves Novartis drug Afinitor for breast cancer". 20 Jul 2012. http://www.reuters.com/article/2012/07/20/novartis-afinitor-idUSL2E8IKD8B20120720.
^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
^ Lutz M, Kapp M, Grigoleit GU, Stuhler G, Einsele H, Mielke S (April 2012). "Salvage therapy with everolimus improves quality of life in patients with refractory chronic graft-versus-host disease". Bone Marrow Transplant 47 (S1): S410–S411. http://www.nature.com/bmt/journal/v47/n1s/pdf/bmt201237a.pdf.
^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011. http://www.genengnews.com/gen-news-highlights/positive-trial-data-leads-novartis-to-plan-breast-cancer-filing-for-afinitor-by-year-end/81245384/.
^ Eisen HJ, Tuzcu EM, Dorent R, et al. (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N. Engl. J. Med. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12944570&promo=ONFLNS19.

External links

Sedrani R, Cottens S, Kallen J, Schuler W (August 1998). "Chemical modification of rapamycin: the discovery of SDZ RAD". Transplant. Proc. 30 (5): 2192–4. doi:10.1016/S0041-1345(98)00587-9. PMID 9723437. http://linkinghub.elsevier.com/retrieve/pii/S0041-1345(98)00587-9.

UpToDate Contents

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1. 転移性の胃腸膵管系神経内分泌腫瘍：腫瘍増殖およびホルモン過剰分泌による症状を管理するための全身治療の選択肢 metastatic gastroenteropancreatic neuroendocrine tumors systemic therapy options to control tumor growth and symptoms of hormone hypersecretion
2. 現在開発中の冠動脈ステントの種類 coronary artery stent types in development
3. 肺移植後の免疫抑制の維持 maintenance immunosuppression following lung transplantation
4. 腎血管筋脂肪腫 renal angiomyolipomas
5. 転移性ホルモン受容体陽性乳癌に対する治療アプローチ：内分泌療法 treatment approach to metastatic hormone receptor positive breast cancer endocrine therapy

English Journal

Safety and efficacy of molecularly targeted agents in patients with metastatic kidney cancer with renal dysfunction.

Gupta S, Parsa V, Heilbrun LK, Smith DW, Dickow B, Heath E, Vaishampayan U.SourceaDivisions of Hematology/Oncology bBiostatistics Core, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan, USA.
Anti-cancer drugs.Anticancer Drugs.2011 Sep;22(8):794-800.
Multiple molecularly targeted agents (MTAs) have been approved for the management of metastatic renal cell carcinoma (mRCC). Sunitinib and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) are primarily metabolized in the liver, whereas the metabolism of bevacizumab is unclear. The
PMID 21799472

Everolimus-Eluting Versus Paclitaxel-Eluting Stents for Treatment of Bare Metal Stent Restenosis.

Almalla M, Schroder JW, Pross V, Stegemann E, Marx N, Hoffmann R.SourceDepartment of Cardiology, University Hospital RWTH Aachen, Aachen, Germany.
The American journal of cardiology.Am J Cardiol.2011 Aug 15;108(4):518-522. Epub 2011 May 31.
First-generation drug-eluting stents have been proved to be very effective for the treatment of bare metal stent in-stent restenosis (BMS ISR). The efficacy of second-generation drug-eluting stents in this setting remains less well defined. The present study compared the long-term clinical outcome a
PMID 21624553

Japanese Journal

A case of effective repeated distal protection on acute and subacute phase PCI to occluded sirolimus-eluting stent in SVG

重城健太郎,齊藤克己,鈴木ゆき,天野宏,河合靖,竹内靖夫
Journal of the Japanese Coronary Association, 2013
… After the recovery of systemic conditions by repeated thrombectomy and intracoronary nicorandil administration, everolimus-eluting stent (EES) was directly implanted over SES with distal protection. …
NAID 130002585932

今月の症例エベロリムス溶出性冠動脈ステントによる薬剤性間質性肺炎が疑われた1例

千葉哲矢,石塚豪,尾形剛 [他]
日本内科学会雑誌 101(12), 3522-3524, 2012-12-10
NAID 40019553376

Involvement of autophagy in the pharmacological effects of the mTOR inhibitor everolimus in acute kidney injury.

Nakagawa Shunsaku,Nishihara Kumiko,Inui Ken-Ichi,Masuda Satohiro
European journal of pharmacology 696(1-3), 143-154, 2012-12-05
… Using cells from normal kidney epithelial cell lines, we found that the antiproliferative effects of mTOR inhibitor everolimus accompanied the accumulation of a marker for cellular autophagic activity, the phosphatidylethanolamine-conjugated form of microtubule-associated protein 1 light chain 3 (LC3-II) in cells. … We also showed that the primary autophagy factor UNC-51-like kinase 1 was involved in the antiproliferative effects of everolimus. …
NAID 120004996384