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Liquid Exemestane
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Pharmacology and pharmacokinetics of the newer generation aromatase inhibitors.
Buzdar AU.
The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments inpostmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.
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"This also led me to think about the aromasin stuff... aparently anatrozole and letrozole are non-steroidal... where as aromasin is steroidal... they said that there were "androgenic side effects" to use of exemestane (aromasin)... now my question is.. wouldnt this be the AI of choice>? because it also has androgenic sides, while blocking the aromatase enzyme???
Buzdar AU.
The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030.
The newer generation aromatase inhibitors (AIs) as a class show efficacy and tolerability benefits over previously established treatments inpostmenopausal women with advanced breast cancer. At clinically administered doses, the plasma half-lives of anastrozole (1 mg once daily), letrozole (2.5 mg once daily), and exemestane (25 mg once daily) are 41-48 h, 2-4 days, and 27 h, respectively. Time to steady-state plasma levels is 7 days for both anastrozole and exemestane and 60 days for letrozole. Androgenic side effects have only been reported with exemestane. Anastrozole treatment has no impact on plasma lipid levels, whereas both letrozole and exemestane have an unfavorable effect. From indirect comparisons, anastrozole shows the highest degree of selectivity compared with letrozole and exemestane, in terms of a lack of effect on adrenosteroidogenesis. To date, there are no data suggesting any major differences in clinical efficacy between the newer generation AIs anastrozole and letrozole. Based on the observed pharmacological profiles, however, it cannot be assumed that the AIs will display the same tolerability and safety profiles when given for extended periods of time in the adjuvant setting. The effects of anastrozole, letrozole, and exemestane are being investigated in the adjuvant setting, and these data will elucidate the possible long-term consequences of the pharmacological effects reported after short-term exposure.
_____________________________________________
"This also led me to think about the aromasin stuff... aparently anatrozole and letrozole are non-steroidal... where as aromasin is steroidal... they said that there were "androgenic side effects" to use of exemestane (aromasin)... now my question is.. wouldnt this be the AI of choice>? because it also has androgenic sides, while blocking the aromatase enzyme???
Also, another big question is dosage. This will Help:
AROMASIN ORAL
Pharmacology & Chemistry
Exemestane is an irreversible, selective steroidal aromatase inhibitor structurally related to the natural substrate androstenedione.Unlike nonsteroidal (type II) aromatase inhibitors (e.g., aminoglutethimide, letrozole), steroidal inhibitors such as exemestane (type I aromatase inhibitors) act as false substrates and are converted by aromatase to reactive alkylating intermediates that bind covalently to the substrate binding site of the enzyme; this binding to the active site of aromatase is irreversible, resulting in its inactivation (i.e., “suicide” inhibition).As a result of these differences, there appears to be a lack of cross-resistance in susceptible cancers between type I and II inhibitors.Exemestane selectively inhibits the conversion of androgens to estrogens.Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.In postmenopausal women,ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme,is the principal source of estrogens.Exemestane selectively inhibits the synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.In dose-ranging (0.5—800 mg) studies, 25 mg was the minimum dose to exhibit maximum suppression of plasma estrogens.A single 25-mg exemestane dose reduces plasma estrogen (estradiol, estrone,and estrone sulfate) concentrations in postmenopausal women by as much as 85—95% within 2—3 days, with maximal suppression persisting up to at least 4—5 days after dosing.After 4—12 weeks of exemestane therapy (25 mg daily) in postmenopausal women, plasma estrogen concentrations were suppressed by an average of 91—95%,and whole body aromatization was suppressed by 98%.Although an apparently lower suppression (e.g., by 60—70%) of plasma estrogens has been reported in some studies, these studies used a less-specific assay method (i.e., RIA) than the method (i.e., HPLC) used in studies reporting higher levels of suppression.A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with exemestane dosages of 2.5 mg or more daily.Slight, dose-independent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations have been observed even at low dosages as a result of negative feedback on the pituitary gland.At dosages up to 25 mg daily, no clinically important effect on circulating concentrations of testosterone, androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone is observed; however, at dosages of 200 mg or more daily, testosterone and androstenedione concentrations are increased.17-Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may become clinically important at high (e.g., 200 mg daily)exemestane dosages.Exemestane is principally metabolized via oxidation by the cytochrome P-450 (CYP) 3A4 isoenzyme.Serum exemestane concentrations increased by approximately 40% after a high-fat breakfast.Unlike aminoglutethimide, exemestane does not adversely affect plasma total homocysteine concentrations.
AROMASIN ORAL
Pharmacology & Chemistry
Exemestane is an irreversible, selective steroidal aromatase inhibitor structurally related to the natural substrate androstenedione.Unlike nonsteroidal (type II) aromatase inhibitors (e.g., aminoglutethimide, letrozole), steroidal inhibitors such as exemestane (type I aromatase inhibitors) act as false substrates and are converted by aromatase to reactive alkylating intermediates that bind covalently to the substrate binding site of the enzyme; this binding to the active site of aromatase is irreversible, resulting in its inactivation (i.e., “suicide” inhibition).As a result of these differences, there appears to be a lack of cross-resistance in susceptible cancers between type I and II inhibitors.Exemestane selectively inhibits the conversion of androgens to estrogens.Because estrogen acts as a growth factor for hormone-dependent breast cancer cells, reduction of serum and tumor concentrations of estrogen inhibits tumor growth and delays disease progression.In postmenopausal women,ovarian secretion of estrogen declines and conversion of adrenal androgens (mainly androstenedione and testosterone) to estrone and estradiol in peripheral tissues (adipose, muscle, and liver), catalyzed by the aromatase enzyme,is the principal source of estrogens.Exemestane selectively inhibits the synthesis of estrogens and does not affect synthesis of adrenal corticosteroid, aldosterone, or thyroid hormone.In dose-ranging (0.5—800 mg) studies, 25 mg was the minimum dose to exhibit maximum suppression of plasma estrogens.A single 25-mg exemestane dose reduces plasma estrogen (estradiol, estrone,and estrone sulfate) concentrations in postmenopausal women by as much as 85—95% within 2—3 days, with maximal suppression persisting up to at least 4—5 days after dosing.After 4—12 weeks of exemestane therapy (25 mg daily) in postmenopausal women, plasma estrogen concentrations were suppressed by an average of 91—95%,and whole body aromatization was suppressed by 98%.Although an apparently lower suppression (e.g., by 60—70%) of plasma estrogens has been reported in some studies, these studies used a less-specific assay method (i.e., RIA) than the method (i.e., HPLC) used in studies reporting higher levels of suppression.A dose-dependent decrease in sex hormone binding globulin (SHBG) has been observed with exemestane dosages of 2.5 mg or more daily.Slight, dose-independent increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH) concentrations have been observed even at low dosages as a result of negative feedback on the pituitary gland.At dosages up to 25 mg daily, no clinically important effect on circulating concentrations of testosterone, androstenedione, dehydroepiandrostenedione sulfate, or 17-hydroxyprogesterone is observed; however, at dosages of 200 mg or more daily, testosterone and androstenedione concentrations are increased.17-Hydroexemestane, a metabolite, exhibits substantial intrinsic androgenic activity, which may become clinically important at high (e.g., 200 mg daily)exemestane dosages.Exemestane is principally metabolized via oxidation by the cytochrome P-450 (CYP) 3A4 isoenzyme.Serum exemestane concentrations increased by approximately 40% after a high-fat breakfast.Unlike aminoglutethimide, exemestane does not adversely affect plasma total homocysteine concentrations.
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