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|Half-life||46.8 h |
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Anastrozole (INN) (marketed under the trade name Arimidex by AstraZeneca) is a non-steroidal aromatase-inhibiting drug approved for treatment of breast cancer after surgery, as well as for metastasis in both pre and post-menopausal women. The severity of breast cancer can be increased by estrogen, as sex hormones cause hyperplasia, and differentiation at estrogen receptor sites. Anastrozole works by inhibiting the synthesis of estrogen. The patent on Arimidex by AstraZeneca expired June 2010.
It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.
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. After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group. The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer, which is estrogen receptor (ER) positive. Another study found that the risk of recurrence was reduced 40%, but was associated with an increased risk of bone fractures. The study concluded that ER positive patients benefited from switching from tamoxifen to anastrozole in patients who have completed 2 years' adjuvant tamoxifen. A more recent trial found that anastrozole significantly reduced the incidence of breast cancer in postmenopausal women relative to placebo, and while there were side effects related to estrogen deprivation observed, the researchers concluded that this was probably not related to the treatment. Lead author Jack Cuzick was quoted by the BBC as saying, "This class of drugs is more effective than previous drugs such as tamoxifen and crucially, it has fewer side effects," adding that he thought there was now enough evidence to support offering the drug.
Mechanism of action
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%). Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors. The level of circulating estradiol is likely causal here and not the anastrozole itself, and so the dose will determine likelihood of osteoporosis (estradiol inhibits osteoclasts, which resorb bone).
Usage in men
Anastrozole has been tested for reducing estrogens, including estradiol, in men. Excess estradiol in men can cause benign prostatic hyperplasia, gynecomastia, and symptoms of hypogonadism. It can also contribute to increased risk of stroke, heart attack, chronic inflammation, prostate enlargement and prostate cancer. Some athletes and body builders use anastrozole as part of their steroid cycle to reduce and prevent symptoms of excess estrogen--gynecomastia, emotional lability and water retention. Study data suggests dosages of 0.5 mg to 1 mg a day reduce serum estradiol approx. 50% in men, which differs in postmenopausal women.
Usage in children
Anastrozole may be used off-label in children with precocious puberty, or children with pubertal gynecomastia. Following the onset of puberty, the epiphyseal plate begins to close due to an increased amount of estrogen production escaping local metabolism and spreading to the circulatory system. It is shown to help slow this process, and increase adult height prediction in adolescent males treated with protein-based peptide hormones for the treatment of growth hormone deficiency.
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. The resulting bis-nitrile in DMF was then deprotonated with sodium hydride in the presence of excess methyl iodide to give the bis-dimethylated product. Subsequently, a Wohl–Ziegler reaction was carried out using N-bromosuccinimide (NBS), and a catalytic amount of benzoyl peroxide (BPO) as the radical initiator. Finally, an SN2 displacement with sodium triazole afforded anastrozole as a white solid.
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