Disease relevance of Cytadren

• Surprising activity of flutamide withdrawal, when combined with aminoglutethimide, in treatment of "hormone-refractory" prostate cancer [1].
• Aminoglutethimide, alveolar damage, and hemorrhage [2].
• Aminoglutethimide and cholestasis [3].
• Cholestatic jaundice and aminoglutethimide [4].
• A further 12 patients (23%) had stable disease during aminoglutethimide therapy, while a total of 9 patients with bone metastases reported marked relief of pain without objective evidence of response [5].

Psychiatry related information on Cytadren

• Side effects for aminoglutethimide (including lethargy, rash, and depression) were more common than for tamoxifen, and 7% of aminoglutethimide-treated patients had to discontinue treatment because of these compared with 0% on tamoxifen [6].
• Two patients with obsessive compulsive disorder associated with depression showed striking improvement on aminoglutethimide combined with a serotonin re-uptake inhibitor [7].
• It was previously observed that the corticosteroid synthesis inhibitor, aminoglutethimide (AG), markedly facilitates lateral hypothalamide (AG), markedly facilitates lateral hypothalamic self-stimulation (LHSS) in food-restricted rats [8].
• We conclude that serum aminoglutethimide concentrations are useful in evaluating patient compliance [9].
• Single doses of aminoglutethimide induced a dose-dependent depression of spontaneous locomotor activity, rotarod performance, righting reflex and body temperature and a dose-related antileptazol activity [10].

High impact information on Cytadren

• We randomized 96 postmenopausal women with metastatic breast carcinoma to receive surgical adrenalectomy or medical therapy with an adrenal inhibitor, aminoglutethimide (AG), plus replacement hydrocortisone [11].
• Low-dose aminoglutethimide and aromatase inhibition [12].
• The clinical and endocrine effects of low-dose aminoglutethimide without hydrocortisone in patients with advanced breast cancer were investigated [13].
• Adding FeSO4 to C6 cells increased the synthesis of both P and D. Even in the presence of aminoglutethimide, an inhibitor of P450scc, FeSO4 increased the synthesis of both steroids, indicating that the Fe2+-sensitive process does not involve P450scc [14].
• In the present work, we show that mitochondria of C6-2B cells convert (22R)-22-hydroxycholesterol to pregnenolone by a mechanism blocked by aminoglutethimide [15].

Chemical compound and disease context of Cytadren

• A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer [11].
• 222 patients with disseminated breast cancer have been randomised to receive either a combination of hormone therapies using tamoxifen, aminoglutethimide with hydrocortisone, and danazol (TAD), or tamoxifen alone [16].
• Adequacy of estrogen suppression with aminoglutethimide and hydrocortisone as treatment of human breast cancer: correlation of hormonal data with clinical responses [17].
• PATIENTS AND METHODS: Three sequential phase II trials were performed in patients with refractory epithelial ovarian carcinoma, using high-dose megestrol acetate (800 mg/d for 30 days, then 400 mg/d), high-dose tamoxifen (80 mg/d for 30 days, then 40 mg/d), and aminoglutethimide (1 g/d plus tapering doses of hydrocortisone) [18].
• Phase II study of suramin plus aminoglutethimide in two cohorts of patients with androgen-independent prostate cancer: simultaneous antiandrogen withdrawal and prior antiandrogen withdrawal [19].

Biological context of Cytadren

• We found no effect of tamoxifen on aminoglutethimide pharmacokinetics or acetylation [20].
• The steady state kinetics of tamoxifen were determined when administered alone (phase A) and after coadministration of aminoglutethimide for 6 weeks (phase B) [20].
• Further investigation showed that the inactivity of AG in the rat was due to extensive acetylation of this compound [21].
• The aminoglutethimide data suggest that the ACTH effect on blood pressure is due to a steroid, and the metyrapone studies suggest that the steroid may be an 11-desoxysteroid [22].
• In the main, antisteroidal therapies do not have many side-effects and those that do, e.g. aminoglutethimide, are the focus of increased efforts in drug design to produce increased drug specificity [23].

Anatomical context of Cytadren

• When corticotropin was administered in vivo in the presence of aminoglutethimide, an inhibitor of steroidogenesis, there was a parallel movement of SCP with cholesterol to the inner mitochondrial membrane [24].
• Methylprednisolone treatment approximately doubled ileal brush border Na+/H+ exchange, whereas aminoglutethimide led to a 50% decrease in Na+/H+ exchange [25].
• Aminoglutethimide (AG) is a potent inhibitor of aromatization in placental microsomes and in peripheral tissues in postmenopausal women [26].
• Aminoglutethimide was originally introduced as an inhibitor of steroidogenesis in the adrenal cortex [27].
• Aminoglutethimide augments follicle-stimulating hormone-induced aromatase activity in cultured porcine granulosa cells [28].

Associations of Cytadren with other chemical compounds

• Rat adrenal mitochondria accumulated cholesterol during ether stress in vivo when side-chain cleavage was inhibited by aminoglutethimide (control = 14.6 vs. aminoglutethimide = 26.5 micrograms of cholesterol per mg of protein) [29].
• Furthermore, 1 mM aminoglutethimide, which completely blocks FSH-stimulated progesterone biosynthesis, does not decrease the induction of LH receptors by FSH [30].
• After a median follow-up of 5.3 years, the 5-year disease-free survival in the aminoglutethimide plus tamoxifen group was 83.6% versus 83.7% in the monotherapy group (P =.89) [31].
• In comparison with other aromatase inhibitors, the compounds reduced ovarian estrogen secretion in the rat to the same extent as aminoglutethimide, whereas Teslac was without effect [32].
• Effects of aromatase inhibitors, aminoglutethimide, and 4-hydroxyandrostenedione on cyclic rats and rats with 7,12-dimethylbenz(a)anthracene-induced mammary tumors [33].

Gene context of Cytadren

• In Y1 cells transfected with MVDP antisense cDNA, forskolin-induced toxicity was abolished by aminoglutethimide [34].
• Effects of treatment with megestrol acetate, aminoglutethimide, or formestane on insulin-like growth factor (IGF) I and II, IGF-binding proteins (IGFBPs), and IGFBP-3 protease status in patients with advanced breast cancer [35].
• Aminoglutethimide inhibited aromatase activity of benign and malignant ovarian tumors, uterine myoma, choriocarcinoma cells and purified human placental P-450arom in a similar manner [36].
• The adrenostatic compound aminoglutethimide (AG), a potent inhibitor of the P450 side chain cleavage enzyme, is used in the treatment of ACTH-dependent or adrenal Cushing's syndrome [37].
• Aminoglutethimide suppresses adrenocorticotropin receptor expression in the NCI-h295 adrenocortical tumor cell line [37].

Analytical, diagnostic and therapeutic context of Cytadren

• For optimal results, particularly in terms of quality of life, aminoglutethimide should generally be used prior to chemotherapy [5].
• Although no differences in disease-free survival between the two groups have emerged so far, a significant trend favors aminoglutethimide in overall survival (P =.005) and breast cancer-specific survival (P =.06) [38].
• Pharmacokinetic studies revealed that aminoglutethimide alters its own metabolic clearance rate as well as that of dexamethasone, a synthetic glucocorticoid [39].
• The medical adrenalectomy regimen of aminoglutethimide plus glucocorticoid offers a suitable alternative to surgical adrenalectomy or hypophysectomy in the management of postmenopausal patients with metastatic breast carcinoma [40].
• CONCLUSION: Hypothyroidism should be included in the differential diagnosis of lethargy in elderly patients who are receiving aminoglutethimide for prostate cancer [41].

References