Anastrozole

Anastrozole (INN) marketed under the trade name Arimidex by AstraZeneca, is a drug used to treat breast cancer after surgery and for metastases in both pre and post-menopausal women. Anastrozole is an aromatase inhibitor, which means that it interrupts a critical step in the body's synthesis of estrogen. Some breast cancer cells require estrogen to grow, and eliminating estrogen suppresses their growth. Annual sales approx $2.2bn. The first patent for Arimidex expired in June 2010. Although this patent was originally set to expire in December 2009, the manufacturer was given an extension for performing much needed pediatric studies.^[1]

Clinical trials

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both for five years, followed by five years of follow-up.^[2] After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group.^{[citation needed]} The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.^{[citation needed]} Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimidex.^[3]

[edit]Mechanism of action

Anastrozole inhibits the enzyme aromatase, which is responsible for converting androgens to estrogens in peripheral tissues.^[4] Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition. Elevated levels of estrogens may increase the severity of breast cancer, as sex hormones can cause hyperplasia anddifferentiation at estrogen receptor sites.^{[citation needed]}

[edit]Side effects

Bone weakness has been associated with anastrozole. Women who switched to anastrozole after two years on tamoxifen reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).^[3] Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, osteonecrosis of the jaws. Since statins have a bone strengthening effect,^[5] combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks^[6] without jaw osteonecrosis.^[7] In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or about the equivalent of 10 mg Fosamax daily.^[8]

[edit]Usage in men

While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men.^{[citation needed]} Excess estradiol in men can cause benign prostatic hyperplasia, gynecomastia, and symptoms of hypogonadism.^{[citation needed]} Some athletes andbody builders will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; in particular, gynecomastia and water retention.^{[citation needed]} Study data currently suggest that dosages of 0.5 mg to 1 mg a day reduce serum estradiol by about 50% in men, which differs from the typical reduction in postmenopausal women.^{[citation needed]} However the reduction may be different for men with grossly elevated estradiol (clinical data are currently lacking).^{[citation needed]}

[edit]Usage in children

This drug is frequently used in the treatment of children with growth disorder to stop or slow the onset of puberty and in the treatment of moderate-to-severe pubertal gynecomastia.^{[citation needed]} The cause of the growth disorder is through hormones which may trigger the early onset of puberty.^{[citation needed]} At the onset of puberty the bone growth plates begin to close.^{[citation needed]} This can occur in children as young as 5 years old, so for children severely behind in growth, the opportunity for increased growth is diminished.^{[citation needed]} Arimidex is shown to slow or stop this processes.^{[citation needed]}

[edit]Chemistry

Arimidex (anastrozole) 1 mg tablets (AU)

The synthesis begins with nucleophilic substitution of two benzylic bromides in α,α'-dibromomesitylene (prepared by radical bromination of mesitylene, not shown on the scheme) with cyanide by treatment with potassium cyanide under phase transfer conditions, affording the dinitrile.^{[citation needed]} Exhaustive methylation withmethyl iodide and sodium hydride leads to the replacement of the more acidic side chain hydrogen atoms by methyl groups.^{[citation needed]} Treatment with bromine in the presence of benzoyl peroxide leads to the formation of the corresponding benzyl bromide.^{[citation needed]} Reaction of that product with 1,2,4-triazole in the presence of a base completes the synthesis of the aromatase inhibitor