Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023380 (lethargy)
 5,697 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aromatase inhibitor, 'pyridoglutethimide' (PyG), has been shown previously to suppress serum oestrogen levels in postmenopausal breast cancer patients and to achieve clinical responses at a dose of 500 mg twice daily (b.d.). This report gives the results of a detailed pharmacokinetic and endocrine study of PyG in ten patients. Four doses were tested at intervals of 2 weeks in the following order: 200 mg b.d., 400 mg b.d., 800 mg b.d., 1200 mg b.d. Concentration-time profiles of serum levels of PyG were curvilinear in all patients probably reflecting a saturation of metabolic enzymes. During repeat-dosing metabolism was enhanced approximately 2-fold. Plasma levels of oestradiol were significantly suppressed by the lowest dose of PyG. Although higher doses appeared to achieve greater suppression this was not statistically significant in this small group of patients. There were no significant effects at any dose on the serum levels of cortisol, aldosterone, luteinising hormone, follicle stimulating hormone, prolactin, sex hormone binding globulin or thyroid stimulating hormone. There was a dose-related increase in 17 alpha-hydroxyprogesterone levels and a dose-related decrease in levels of dehydroepiandrosterone sulphate (DHAS). The androgens DHA, testosterone and androstenedione also were significantly suppressed with at least one of the doses of PyG. Synacthen tests did not support these changes being a result of inhibition of 17,20 lyase. It is possible that they are due to enhanced clearance of DHAS. Two patients experienced no toxicity throughout the study, whilst a total of four patients were withdrawn because of side-effects: one at 400 mg b.d., two at 800 mg b.d., and one at 1200 mg b.d. The most frequent side-effects were nausea and lethargy. One patient showed an objective response to treatment.
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PMID:Endocrine, pharmacokinetic and clinical studies of the aromatase inhibitor 3-ethyl-3-(4-pyridyl)piperidine-2,6-dione ('pyridoglutethimide') in postmenopausal breast cancer patients. 193 11

4-Hydroxyandrostenedione (4-OHA), a potent new aromatase inhibitor, was given i.m. (500-1000 mg) to 58 patients with advanced postmenopausal breast cancer. Of 52 assessable patients 14 responded (27%), in 10 (19%) the disease stabilized, and in 28 (54%) the disease progressed. Sterile abscesses occurred at the injection site in 6 patients and painful lumps were found in a further 3 patients. Two patients developed allergic-type reactions and 4 developed lethargy, suspected to be treatment induced. Plasma estradiol levels were suppressed from a mean of 7.2 +/- 0.8 (SE) pg/ml before treatment to 2.6 +/- 0.2, 2.7 +/- 0.2, and 2.8 +/- 0.3 pg/ml after 1, 2, and greater than 4 months, respectively, of treatment and remained suppressed in patients whose disease relapsed. No significant fall in estrone levels was seen. Similarly, dehydroepiandrosterone sulfate, sex hormone binding globulin, and gonadotrophin levels were unaltered after 6 months of treatment. Plasma 4-OHA levels were measured in a radioimmunoassay for androstenedione after chromatographic separation of 4-OHA from androstenedione. Drug concentrations ranged from 0.7 to 23.2 (7.8 +/- 1.1) ng/ml after 2 months on treatment. 4-OHA is an effective drug in the management of postmenopausal patients with breast cancer and does not produce notable systemic side effects.
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PMID:Treatment of advanced postmenopausal breast cancer with an aromatase inhibitor, 4-hydroxyandrostenedione: phase II report. 294 41

Recent treatment strategies have been directed toward blockade of estrogen action or inhibition of estrogen biosynthesis as a means of inducing regression of hormone-dependent breast cancer. The major source of estrogen in postmenopausal women is the peripheral conversion of androstenedione to estrone through the enzyme aromatase. It is known that aromatase activity increases proportionately with degree of obesity in women. To test the importance of this modulatory factor, we correlated body weight with estrogen excretion in our population of patients with breast cancer and found significant relationships. In situ production of estradiol from plasma precursors within breast cancer tissue may provide another source of estrogen. Major enzymes mediating estrogen biosynthesis were found to be present in tumor biopsy specimens. Aromatase activity was found to be present in 48/61 human tumors, sulfatase in 35/35, and 17 beta -hydroxysteroid dehydrogenase in 41/41. One inhibitor of aromatase, aminoglutethimide, has been extensively studied in patients with breast cancer. The additional effects of this drug on cholesterol side-chain cleavage and on 11-hydroxylase activity require coadministration of replacement glucocorticoid in treatment regimens. In pilot trials, 37% of patients experienced objective tumor regression with a combination of 1000 mg aminoglutethimide and 40 mg hydrocortisone daily. In randomized clinical trials with this regimen, aromatase inhibition with aminoglutethimide produced tumor regression with similar frequency as did surgical hypophysectomy, surgical adrenalectomy, or tamoxifen administration. The side effects of aminoglutethimide, including lethargy, skin rash, and ataxia complicate its use even though these problems are generally transient. Regimens of low-dose aminoglutethimide are being developed to reduce these side effects. Low-dose aminoglutethimide appears to block aromatase effectively and to have limited side effects, and is undergoing extensive clinical trial. A more specific aromatase inhibitor, 4-hydroxyandrostenedione, is now also being tested clinically, whereas MDL 18962, another new selective inhibitor, is undergoing study in animals.
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PMID:Inhibition of aromatase as treatment of breast carcinoma in postmenopausal women. 354 61

4-Hydroxyandrost-4-ene-3,17-dione (formestane) is a selective aromatase inhibitor. It is indicated for postmenopausal patients with advanced breast cancer. The aim of the present study was to investigate the effect of 4-hydroxyandrost-4-ene-3,17-dione on the bile secretion and metabolism of 4-(14)C-cholesterol to bile acid. The experiments were carried out in the ovariectomized and sham-operated female Wistar rats. Formestane (20 mg/kg, i.m., daily) was administered to animals for 2 weeks. Twenty four hours after the last drug administration, rats were anesthetized with ethyl urethane. 4-(14)C-cholesterol (740 kBq/kg, s.a. 2.28 GBq/mmol) was infused for 1 min by catheter inserted into the jugular vein. Bile samples were assayed for total 14C radioactivity 14C-bile acids were determined in bile (after thin-layer chromatographic separation) by the use of isotopic technique with liquid scintillator. Previous studies showed that systemic adverse effects occurred in about 12% of patients following intramuscular drug administration. Many of them such as hot flushes, vaginal spotting and emotional lability were related to the mechanism of action of formestane i.e. estrogen suppression. Lethargy, rash, nausea, dizziness, indigestion, ataxia, cramps and facial swelling have also been reported. The results of the present study have shown that formestane administered to the female ovariectomized rats decreased the bile secretion and diminished conversion of 4-(14)C-cholesterol to trihydroxy bile acids. The decreased synthesis of trihydroxy bile acids and increased concentrations of cholesterol and litocholic acid in bile may be associated with increased risk of gallstone formation.
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PMID:Effect of 4-hydroxyandrost-4-ene-3,17-dione (formestane) on the bile secretion and metabolism of 4-(14)C-cholesterol to bile acids. 1638 15