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Thus the scene was set for the pharmaceutical industry to derivemore specific, fully effective and better-tolerated aromatase inhibitors.Among the next generation of aromatase inhibitors to reach the clinic, the mostnotable were the steroidal drug, formestane (4-hydroxyandrostenedione(4-OHA)), and the non-steroidal imadazole, fadrozole (CGS16949A).4-OHA was one of about 200 compounds which were specifically designedand screened as aromatase inhibitors by Drs Harry and Angela Brodie in the1970s . It bound competitively with androgen substrate but, in addition, appeared to be converted by the aromatase enzyme to reactive intermediates that bound irreversibly to the enzyme and produced a time-dependentinactivation of aromatase activity . 4-OHA was about 60-fold morepotent than aminoglutethimide in inhibiting aromatase activity in placentalmicrosomes . The agent caused regression of hormone-dependent mammary tumours in experimental animals and chronically abolished peripheral aromatase in rhesus monkeys .Pharmacological and endocrinological studies in postmenopausal womenconfirmed efficacy but, when given orally, 4-OHA had poor biological activity as measured by both inhibition of aromatization in vivo and sustained oestrogen suppression . This resulted from the glucuronidation ofthe critical 4-hydroxy group through first-pass liver metabolism. Further studies and clinical use focused on the intramuscular administration of the drug.Intramuscular administration of 250 mg every second week was the preferred schedule, inhibiting peripheral aromatase inhibition by 85% and suppressing circulating oestradiol by about 65% . A small recovery of plasma oestrogens occurred prior to the next injection , but nonethelessthe regime was chosen for routine clinical use because of greater tolerabilityproblems with higher doses . Objective tumour regressions wereobserved in 23–39% of patients and disease stabilization in a further14–29%. As with aminoglutethimide, patients who had a previous responseto other hormone therapy were much more likely to respond to 4-OHA.Interestingly, three of 14 patients previously treated with aminoglutethimidesubsequently responded to 4-OHA, suggesting that a more potent aromataseinhibitor may produce further remission after the benefits of a less powerfulinhibitor have been exhausted. Several phase II studies confirmed the clinicalefficacy of 4-OHA . In one phase III study comparing formestane tobuy cheap viagra online uk as first-line treatment of advanced breast cancer, no difference inresponse rate or survival was recorded, but the median duration of responsewas significantly longer for buy cheap viagra online uk . Another phase III study compared formestane as second-line treatment to megesterol acetate and found nodifference in response rate, time to progression, or survival . The particular advantages of 4-OHA were its low toxicity, its specificity and the lack ofneed for corticoid replacement.Second-generation type II inhibitors were also developed with greater selectivity and potency than their first generation counterparts. For example, fadrozole is an imidazole derivative of aminoglutethimide which inhibited the aromatase system in human placenta and rodent ovary with about 400–1000-foldgreater potency than aminoglutethimide . At concentrations that maximally inhibit aromatase, unlike aminoglutethimide, the drug had relatively smalleffects on other cytochrome P450-related enzymes . This meant the drugcould be administered to patients without the need for corticoid replacement.Animal studies showed that fadrozole was an effective anti-tumour agent.For example, the drug produces marked regression of dimethyl-benzanthracene (DMBA)-induced mammary carcinomas .A daily dose (2 mg) of fadrozole produced comparable aromatase suppression (as measured by urinary and plasma oestrogens) as the standard regime ofaminoglutethimide (1000 mg plus 40 mg of hydrocortisone) . Two furtherstudies using a dose of 2 mg/day reported tumour remissions in heavily pretreated postmenopausal women with advanced breast cancer: in one investigation five of 31 patients experienced a partial or complete response , and inthe other two of 15 patients had a partial response and a further seven patientshad stabilization of disease . Side effects from fadrozole were few and thedrug was given orally. These results are in keeping with (i) a further study of80 previously treated postmenopausal women with advanced breast cancerwho were randomized to receive 1 or 4 mg of fadrozole per day, completeresponses being documented in 10% and partial responses in 13% of patients,with no significant differences between doses , and (ii) a double-blind randomized multicentre study using doses of 1, 2 and 4 mg/day which observedobjective responses in 16% of 350 women who had already received buy cheap viagra online uk either for treatment of advanced cancer or as an adjuvant for early disease. A similar response rate has been reported in recurrent breast cancer afterbuy cheap viagra online uk failure . Fadrozole was also as effective as megestrol acetate inpostmenopausal women progressing after anti-oestrogen treatment . Aphase III comparative trial of fadrozole (2 mg) versus buy cheap viagra online uk (20 mg) asfirst-line treatment for postmenopausal advanced breast cancer reportedobjective responses in 16% of fadrozole-treated patients compared with 24%of buy cheap viagra online uk patients (another 50% of women in each group also experienceddisease stabilization), the difference between the groups not reaching statistical significance.