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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
Identifiers
CAS number	159351-69-6
ATC code	L01XE10 L04AA18
PubChem	6442177
DrugBank	DB01590
Chemical data
Formula	C53H83NO14
Mol. mass	958.224 g/mol
Synonyms	42-O-(2-hydroxyethyl)rapamycin
Pharmacokinetic data
Half life	~30 hours[1]
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	D(US)
Legal status	℞ Prescription only
Routes	Oral
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Everolimus (RAD-001) (marketed by Novartis under the tradenames Certican (transplantation) and Afinitor (oncology)) is a derivative of Rapamycin (sirolimus) (the structure can be written as 42-O-(2-hydroxyethyl)rapamycin), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. Much research has also been conducted on Everolimus and other mTOR inhibitors for use in a number of cancers.

The FDA has approved everolimus for the treatment of advanced kidney cancer on March 30, 2009.^[2]

[edit] 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.

[edit] 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.^[3]

[edit] Laboratory tests and Monitoring

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

[edit] 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, which is approved for sale and available in Europe. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently an investigational device in the United States and 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.

[edit] References

1. ^ 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. 
2. ^ Novartis (2009-03-30). "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib". Press release. http://www.novartis.com/newsroom/media-releases/en/2009/1301801.shtml. Retrieved April 6, 2009. 
3. ^ 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. 

• 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. 

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