Raloxifene

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Raloxifene
Raloxifene Chemical Structure V.1.svg
Systematic (IUPAC) name
[6-hydroxy-2-(4-hydroxyphenyl)- benzothiophen-3-yl]- [4-[2-(1-piperidyl)ethoxy]phenyl] -methanone
Clinical data
Trade names Evista
AHFS/Drugs.com monograph
MedlinePlus a698007
Licence data EMA:Link, US FDA:link
Pregnancy cat.
Legal status
  • Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability 2%
Protein binding 95%
Metabolism Gut glucuronidation[1]
CYP system not involved
Half-life 27.7 hours
Excretion Fecal
Identifiers
CAS number 84449-90-1 YesY
ATC code G03XC01
PubChem CID 5035
IUPHAR ligand 2820
DrugBank DB00481
ChemSpider 4859 YesY
UNII YX9162EO3I YesY
ChEBI CHEBI:8772 YesY
ChEMBL CHEMBL81 YesY
PDB ligand ID RAL (PDBe, RCSB PDB)
Chemical data
Formula C28H27NO4S 
Mol. mass 473.584 g/mol
 YesY (what is this?)  (verify)

Raloxifene (marketed as Evista by Eli Lilly and Company) is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women.

In 2006, the National Cancer Institute announced that raloxifene was as effective as tamoxifen in reducing the incidence of breast cancer in postmenopausal women at increased risk. A major adverse effect of tamoxifen is uterine cancer; raloxifene caused fewer cases of uterine cancer. Tamoxifen increased the risk of cataracts, but raloxifene did not. Both groups had more blood clots in veins and the lungs, but that side effect was more common with tamoxifen than raloxifene.[2][3][4] On September 14, 2007, the U.S. Food and Drug Administration announced approval of raloxifene for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.[5]

An editorial in Lancet Oncology criticized the way that information about the drug was released.[6]

Description[edit]

Raloxifene hydrochloride (HCl) has the empirical formula C28H27NO4S•HCl, which corresponds to a molecular weight of 510.05 g/mol. Raloxifene HCl is an off-white to pale-yellow solid that is slightly soluble in water.

SERMs mimic estrogen in some tissues and have anti-estrogen activity in others. Other SERMs, such as Pfizer's lasofoxifene and Wyeth's bazedoxifene are in the later development phases.

Indication[edit]

Raloxifene is indicated for the treatment and prevention of osteoporosis in postmenopausal women. It is also used for reduction of risk and treatment of invasive breast cancer, and it also reduces breast density.[7] For either osteoporosis treatment or prevention, supplemental calcium and/or vitamin D should be added to the diet if daily intake is inadequate.

Contradications and precautions[edit]

Raloxifene is contraindicated in lactating women or women who are or may become pregnant, in women with active or past history of venous thromboembolic events, including deep vein thrombosis, pulmonary embolism, and retinal vein thrombosis and in women known to be hypersensitive to raloxifene.

Adverse reactions[edit]

Common adverse events considered to be drug-related were hot flashes and leg cramps.[citation needed]

Raloxifene may infrequently cause serious blood clots to form in the legs, lungs, or eyes. Other reactions experienced include leg swelling/pain, trouble breathing, chest pain, vision changes. Raloxifene is a teratogenic drug, i.e., can cause developmental abnormalities such as birth defects.

In a 2006 study published in New England Journal of Medicine, raloxifene produced significantly more strokes and blood clots than the placebo.[8]

A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen and raloxifene, used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.[9]

As cancer drug[edit]

Bottle of Raloxifene

Raloxifene reduces the risk of hormone-positive breast cancer and vertebral fractures "without a shadow of a doubt," but its effects on cardiovascular disease remain less certain, according to the results of the "Raloxifene for Use of the Heart" (RUTH) study published in the July 13, 2006 issue of the New England Journal of Medicine by Dr. Elizabeth Barrett-Connor (University of California at San Diego) and colleagues.[10]

In the trial, in women with coronary heart disease (CHD) or multiple risk factors for CHD, raloxifene had no significant effect on the primary end point, coronary events, but it did significantly increase the risk of venous thromboembolism (VTE). And although the drug had no effect on stroke, there was a seemingly paradoxical significant increase in death from stroke.[11]

On September 14, 2007, Steven K. Galson, the director of the United States Food and Drug Administration's Center for Drug Evaluation and Research announced authorization of the sale of raloxifene to prevent invasive breast cancer in post-menopausal women.[12]

Chemical synthesis[edit]

Raloxifene syn.png

Jones, Charles D.; Jevnikar, Mary G.; Pike, Andrew J.; Peters, Mary K.; Black, Larry J.; Thompson, Allen R.; Falcone, Julie F.; Clemens, James A. (1984). "Antiestrogens. 2. Structure-activity studies in a series of 3-aroyl-2-arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone hydrochloride (LY 156758), a remarkably effective estrogen antagonist with only minimal intrinsic estrogenicity". Journal of Medicinal Chemistry 27 (8): 1057–66. doi:10.1021/jm00374a021. PMID 6431104. 

References[edit]

  1. ^ Jeong, Eun Ju; Liu, Yong; Lin, Huimin; Hu, Ming (2005-03-15). "Species- and Disposition Model-Dependent Metabolism of Raloxifene in Gut and Liver: Role of UGT1A10". Drug Metabolism and Disposition ( ASPET) 33 (6): 785–794. doi:10.1124/dmd.104.001883. PMID 15769887. Retrieved 2010-10-20. 
  2. ^ Study of Tamoxifen and Raloxifene (STAR) Trial Cancer.gov
  3. ^ Results of the Study of Tamoxifen and Raloxifene (STAR) Released: Osteoporosis Drug Raloxifene Shown to be as Effective as Tamoxifen in Preventing Invasive Breast Cancer (Press Release) 06/21/2006
  4. ^ Vogel, Victor; Joseph Constantino, Lawrence Wickerman et al. (2006-06-21). "Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes". The Journal of the American Medical Association 295 (23): 2727–2741. doi:10.1001/jama.295.23.joc60074. PMID 16754727. 
  5. ^ "FDA Approves New Uses for Evista" (Press release). U.S. Food and Drug Administration. 2007-09-14. Retrieved 2007-09-15. 
  6. ^ Thelancetoncology, (2006). "A STARring role for raloxifene?". Lancet Oncol 7 (6): 443. doi:10.1016/S1470-2045(06)70701-X. PMID 16750489. 
  7. ^ Jeon-Hor, Chen et al (September 15, 2003). "Reduction of Breast Density Following Tamoxifen Treatment Evaluated by 3-D MRI: Preliminary Study". Magn Reson Imaging. doi:10.1016/j.mri.2010.07.009. Retrieved March 30, 2013. 
  8. ^ 355:125-137 July 13, 2006, Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women Elizabeth Barrett-Connor, Lori Mosca, Peter Collins, et al. for the Raloxifene Use for The Heart (RUTH) Trial Investigators [Free full text]
  9. ^ OncoGenetics.Org (September 2009). "Medications Effective in Reducing Risk of Breast Cancer But Increase Risk of Adverse Effects". OncoGenetics.Org. Retrieved 2009-09-14. [dead link]
  10. ^ Lisa Nainggolan (July 12, 2006). A balancing act: The pro and cons of raloxefene. 
  11. ^ Barrett-Connor E, Mosca L, Collins P, et al. (2006-07-13). "Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women". New England Journal of Medicine 355 (2): 125–137. doi:10.1056/NEJMoa062462. PMID 16837676. 
  12. ^ AFP.google.com, US approves Lilly's Evista for breast cancer prevention

External links[edit]