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Whereas fadrozole is a highly potent compound, it has a relatively shorthalf-life, which accounts for its poorer in vivo activity compared with triazoleinhibitors that are cleared more slowly . Doubts have also been raisedabout the specificity of fadrozole since it can also suppress cortisol and aldosterone synthesis , although these effects may not be of clinical significance . At present, this compound is used widely only in Japan.These aromatase inhibitors include anastrozole , letrozole andexemestane (vorozole was withdrawn early in development despite being highly potent and specific ). Both letrozole and anastrozole are triazoleswhich have a flat aromatic ring providing a good fit with the substrate-bindingsite of the enzyme. Additionally, there is a moiety within the ring structure thatcoordinates with the aromatase haem iron and effectively inhibits the hydroxylation reactions necessary for aromatization. The combination of haemgroup-binding and active-site binding provide high potency and greater targetspecificity. Exemestane is an androgen analogue that inactivates aromatase inthe same manner as formestane.Anastrozole, letrozole and exemstane are all substantially more potent thanaminoglutethimide in terms of inhibiting in vitro aromatase activity (Tab. 2).Whereas the drug concentrations required are micromolar for aminoglutethimide, those for letrozole, anastrozole and exemestane are nanomolar.The superior pharmacokinetic profiles of third-generation drugs also meanthey are even more effective in vivo. In this respect, milligram daily doses ofanastrozole, letrozole and exemestane effectively inhibit whole-body aromatization (Tab. 3), and circulating oestrogens may fall below detectable levels. It is thus worth considering each of these drugs in further detail.This triazole is a potent aromatase inhibitor in vivo, with daily doses of 1 and10 mg given to postmenopausal women showing a mean aromatase suppression of 96.7 and 98.1% respectively. Plasma oestrone, oestradiol and oestronesulphate are reduced by at least 80%, with many treated patients having levelsof buy cheap viagra online uk and oestradiol beneath the level of sensitivity of the assays. Thisoccurs without detectable changes in other steroid hormones . Impressiveanti-tumour effects have also been observed in patients with breast cancer butthese are detailed in other chapters.Letrozole potently inhibits peripheral aromatase and suppresses endogenousoestrogens in postmenopausal women. At 0.5 and 2.5 mg/day, letrozoleinhibits peripheral aromatase by >98% . Doses as low as 0.1 mg/day cansuppress circulating levels of oestrone, buy cheap viagra online uk sulphate and oestradiol bymore than 95% within 2 weeks of treatment , these effects being greaterthan those observed after the use of second-generation inhibitors. In a directcomparison between letrozole and the second-generation inhibitor fadrozole,letrozole was more effective, suppressing plasma oestrogen concentrations toundetectable levels (>95% baseline) at all doses investigated (0.1–5 mg/day)while fadrozole (2–4 mg daily) only achieved above 70% suppression .No substantial suppression of cortisol and aldosterone levels is evident even atdoses of 5 mg/day (and in vitro aldosterone production is only inhibited with10 000-fold higher concentrations than those required to inhibit oestrogensynthesis ). Recently results from a randomized cross-over study of letrozole and anastrozole have been published . Treatment with letrozole suppressed levels of in vivo aromatization below the detection limit of the assays(>99.1% inhibition) in all 12 patients. In contrast, anastrozole treatment produced this degree of suppression inhibition in only one of 12 cases. The meaninhibition of aromatization (97.3% for anastrozole versus >99.1% for letrozole) was significantly different (P = 0.0022). This corresponded to a 10-foldlower residual level of aromatization during letrozole treatment compared toanastrozole (0.006 versus 0.059%). It still remains to be determined whetherthese differences in suppression of aromatase translate into differences in clinical benefit.Clinically, letrozole produces tumour remission in postmenopausal womenwith breast cancer resistant to other endocrine treatments and chemotherapyand these are described in other chapters. However, it is important to note thatletrozole had greater efficacy than the first-generation inhibitor aminoglutethimide in terms of time to progression (P = 0.008) and overall survival(P = 0.002; median, 28 versus 20 months) . This last comparison emphasizes the improvement in efficacy that has occurred by virtue of the development of the new non-steroidal aromatase inhibitors and also emphasizes theimprovement in tolerability: adverse events were 29% with letrozole versus46% with aminoglutethimide.Exemestane is an orally active steroidal inhibitor. A dose of 25 mg/day resultsin an inhibition of aromatase in vivo by 98%. Exemestane will reduce oestrogen levels in patients relapsing on the first-generation inhibitor aminoglutethimide .Specific inhibitors of the aromatase system have several advantages over moregeneral endocrine therapies such as surgical ablation of endocrine glands.First, the actions of aromatase inhibitors are not totally irreversible and, shouldtherapy prove ineffective, oestrogen levels usually return to normal on discontinuation of treatment .