Alpha emitter radium-223 and survival in metastatic prostate cancer.

BACKGROUND: Radium-223 dichloride (radium-223), an alpha emitter, selectively targets bone metastases with alpha particles. We assessed the efficacy and safety of radium-223 as compared with placebo, in addition to the best standard of care, in men with castration-resistant prostate cancer and bone metastases. METHODS: In our phase 3, randomized, double-blind, placebo-controlled study, we randomly assigned 921 patients who had received, were not eligible to receive, or declined docetaxel, in a 2:1 ratio, to receive six injections of radium-223 (at a dose of 50 kBq per kilogram of body weight intravenously) or matching placebo; one injection was administered every 4 weeks. In addition, all patients received the best standard of care. The primary end point was overall survival. The main secondary efficacy end points included time to the first symptomatic skeletal event and various biochemical end points. A prespecified interim analysis, conducted when 314 deaths had occurred, assessed the effect of radium-223 versus placebo on survival. An updated analysis, when 528 deaths had occurred, was performed before crossover from placebo to radium-223. RESULTS: At the interim analysis, which involved 809 patients, radium-223, as compared with placebo, significantly improved overall survival (median, 14.0 months vs. 11.2 months; hazard ratio, 0.70; 95% confidence interval [CI], 0.55 to 0.88; two-sided P=0.002). The updated analysis involving 921 patients confirmed the radium-223 survival benefit (median, 14.9 months vs. 11.3 months; hazard ratio, 0.70; 95% CI, 0.58 to 0.83; P<0.001). Assessments of all main secondary efficacy end points also showed a benefit of radium-233 as compared with placebo. Radium-223 was associated with low myelosuppression rates and fewer adverse events. CONCLUSIONS: In this study, which was terminated for efficacy at the prespecified interim analysis, radium-223 improved overall survival. (Funded by Algeta and Bayer HealthCare Pharmaceuticals; ALSYMPCA ClinicalTrials.gov number, NCT00699751.).

Uranium series isotopes in the Avon Valley, Nova Scotia.

An U-series isotopic study was carried out in the waters of the Avon Valley, Nova Scotia. The fresh and acidic recharge waters flow rapidly through the watershed composed of a granitic highland and a sedimentary, largely carbonate, lowland plain, before draining to the sea. There is no significant anthropogenic pollution; but, naturally elevated U levels can be encountered within the bedrock. Nonetheless, the U concentrations of the surface and groundwater are low (generally within the range of several hundredths to several tenths of a microg l(-1)), except in the proximity to weathering of U mineralization. The dissolved U in the surface waters appears to be stabilized by organic rather than inorganic complexes. Both the groundwaters and surface waters have similar (234)U/(238)U activity ratios that rarely deviate from secular equilibrium by more than 20% throughout the watershed. The magnitude of the (234)U/(238)U activity ratio is not determined by lithology but rather by the weathering mechanism, the high rate of flushing, and the leaching of local U mineralization. Dissolved Ra is consistently absent. The dissolved Rn concentrations, though variable, are measurable even in surface waters. This may be due to a continual degassing from the U-enriched bedrock or release from local sites of U mineralization underlying the surface water sources.

Pharmacokinetics and metabolism of formestane in breast cancer patients.

Formestane (Lentaron(R), 4-hydroxyandrostenedione) is a steroidal aromatase inhibitor used for treatment of advanced breast cancer. Clinically, it is administered as a depot form once fortnightly by intramuscular (i.m.) injection. To investigate the pharmacokinetics, bioavailability and metabolism of the drug, seven patients received single 250 mg i.m. doses of commercial formestane on Days 0, 21, 35, 49 and 63 of this trial. On Day 63, three of the patients received an additional single intravenous (i.v.) pulse dose of 1 mg of 14C-labelled formestane. The plasma kinetics after i.m. dosing confirmed a sustained release of formestane from the site of injection. Within 24-48 h of the first dose, the circulating drug reached a C(max) of 48.0+/-20.9 nmol/l (mean+/-S.D.; N=7). At the end of the dosing interval, after 14 days, the plasma concentration was still at 2.3+/-1.8 nmol/l. The kinetic variables did not significantly change during prolonged treatment. Intramuscular doses appear to be fully bioavailable. Following i.v. injection of 14C-formestane, the unchanged drug disappeared rapidly from plasma, the terminal elimination half-life being 18+/-2 min (N=3). Plasma clearance, CL was 4.2+/-1.3 l/(h kg) and the terminal distribution volume V(z) was 1.8+/-0.5 l/kg. The drug is mainly eliminated by metabolism, renal excretion of metabolites accounting for 95% of dose. The excretory balance of 14C-compounds in urine and faeces totals up to 98.9+/-0.8% of the i.v. dose after 168 h. The 14C-compounds in plasma and urine were separated by HPLC, and three major metabolites were submitted to structural analysis by MS, NMR and UV spectroscopy. One of the metabolites is the direct 4-O-glucuronide of formestane. The other two represent 3-O-sulfates of the exocons 3beta,4beta-dihydroxy-5alpha-androstane-17-one and 3alpha,4beta-dihydroxy-5alpha-androstane-17-one, their ratio being 7:3. These exocons are formed by stereoselective 3-keto reduction, accompanied by reduction of the 4,5-enol function. The exocons do not inhibit human placental aromatase activity in vitro.

Influence of aromatase inhibitors on plasma total homocysteine in postmenopausal breast cancer patients.

In this study, we evaluated the effect of estrogen suppression with three aromatase inhibitors, aminoglutethimide (n = 30), formestane (n = 12), and exemestane (n = 10), and the progestin megestrol acetate (n = 21) on plasma total homocysteine (tHcy) in patients suffering from advanced breast cancer. Treatment with 1 g/day aminoglutethimide for 2 and 3-5 months increased plasma tHcy by a mean value of 24.5% [95% confidence interval, 10.5-40.4%] at 2 months and 35.8% (95% confidence interval, 18.2-55.9%) at 3-5 months, corresponding to increases in the mean plasma tHcy of 1.90 and 3.67 micromol/L, respectively. In contrast, none of the other treatment options influenced plasma tHcy concentrations. The finding that aminoglutethimide, but none of the other aromatase inhibitors or megestrol acetate, influenced plasma tHcy suggests that this effect is achieved by mechanisms not related to suppression of plasma estrogens or to the glucocorticoids administered in concert.

Influence of treatment with aminoglutethimide on plasma and red-blood-cell glutathione status in breast cancer patients.

PURPOSE: Elevated cellular glutathione has been associated with resistance to cancer chemotherapy. Treatment with the aromatase inhibitor aminoglutethimide increases the concentration of gamma-glutamyl transpeptidase (gamma-GT) in breast cancer patients. This enzyme catalyzes the first step in the degradation of extracellular glutathione, and the products formed may act as precursors for intracellular glutathione synthesis. METHODS: Plasma and red-blood-cell glutathione levels were determined in 26 patients suffering from advanced breast cancer before and during treatment with aminoglutethimide (n = 16) or the steroidal aromatase inhibitors exemestane or formestane (n = 10) and in 5 cancer patients receiving dexamethasone. RESULTS: Pretreatment values for gamma-GT in the total patient group (n = 31) correlated negatively with the level of reduced (P < 0.0001), oxidized (P < 0.025), and total glutathione (P < 0.005) in plasma. Plasma gamma-GT levels increased by a mean value of 249% during treatment with aminoglutethimide. The concentration of reduced and oxidized glutathione in plasma decreased to 42.7% (P < 0.0005) and 80.6% (P < 0.005) of their pretreatment levels, respectively. This fall in reduced plasma glutathione correlated negatively with the increase in gamma-GT (P < 0.001). The ratio of oxidized to reduced glutathione increased by 88.9% (P < 0.005), and this increase correlated positively with the increase in gamma-GT (P < 0.005). Treatment with the steroidal aromatase inhibitors (exemestane and formestane) or dexamethasone did not influence the plasma thiol status. CONCLUSIONS: We conclude that aminoglutethimide influences plasma glutathione disposition by mechanisms not related to estrogen suppression or due to glucocorticoids given in concert.

Endocrine and clinical effects of exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmenopausal breast cancer patients: a phase I study.

Clinical and endocrinological effects of exemestane (6-methylenandrosta-1,4-diene-3,17-dione; PNU 155971) were evaluated in an open Phase I study. Thirteen postmenopausal women suffering from advanced breast cancer received exemestane in escalating doses over a 12-week period. Starting on 5 mg once daily (o.d.), exemestane was subsequently escalated at 2-week intervals to 10, 25, 50, 100, and 200 mg o.d. Each patient subsequently continued treatment on the highest tolerated dose until time of progression. One patient terminated treatment after 6 days due to diarrhea that was probably not related to drug therapy, although a relationship could not be excluded. Apart from this, no serious side effects were seen during the dose escalation period. Exemestane (10 mg o.d.) caused maximal suppression of plasma estradiol (E2) and estrone (E1) to a mean of 14.6 and 5.8% of pretreatment levels, respectively, whereas 25 mg of exemestane o.d. suppressed estrone sulfate (E1S) to 8.9% of pretreatment levels. No fall in adrenal steroid levels was recorded. Exemestane (5 mg o.d.) suppressed urinary E2 and E1 to a mean of 11.9 and 12.2% of pretreatment levels, respectively. Administering exemestane at doses of 50-200 mg o.d. caused no further suppression of urinary E1, whereas urinary E2 fell to 6-7% of pretreatment levels. Median time to progression was 63 weeks. We conclude that exemestane is a well-tolerated aromatase inhibitor that effectively suppresses plasma and urinary estrogens in postmenopausal patients with breast cancer.

Plasma estrogen suppression with aromatase inhibitors evaluated by a novel, sensitive assay for estrone sulphate.

Aromatase inhibition is a well-defined treatment option for postmenopausal breast cancer. Although several aromatase inhibitors such as aminoglutethimide, formestane and fadrozole have been found to inhibit in vivo aromatization by >85%, previous studies reported plasma estrogen levels to be sustained at approximately 20-50% of their control level during treatment with these drugs. The discrepancy could be due to lack of sensitivity or non-specific crossreactions in the radioimmunoassay (RIA) methods. Mean plasma levels of estrone (E1) and estradiol (E2) in postmenopausal women are approximately 80 and 20 pmol/l, respectively; on the contrary, mean plasma levels of the estrogen conjugate estrone sulphate (E1S) are approximately 4-500 pmol/l. Most RIA methods for plasma E2 and E1 measurements have sensitivity limits in the range of 2-3 and 7-10 pmol/l, respectively; accordingly, the suppression of plasma estrogens by more than 80-90% will produce hormone values below the sensitivity limit of the method in many patients. Recently, we developed a new method to determine plasma E1S. This assay has a sensitivity limit of 2.7 pmol/l. In theory, this method may allow the determination of plasma E1S levels suppressed to less than 2% of control values in the majority of patients. Using this method, we found different aromatase inhibitors such as formestane, aminoglutethimide, formestane and aminoglutethimide administered in concert or anastrozole to suppress plasma E1S levels down to 24, 13, 7 and 4%, respectively. The suppression of plasma E1S evaluated with this method thus approaches the percentage aromatase inhibition measured with tracer studies.

Treatment with formestane alone and in combination with aminoglutethimide in heavily pretreated breast cancer patients: clinical and endocrine effects.

We studied the clinical and endocrine effects of the aromatase inhibitor formestane (4-hydroxyandrostenedione, 4-OHA) in heavily pretreated breast cancer patients (median number of previous endocrine treatments 2, range 1-4). Of 30 patients eligible for response evaluation, 3 patients (10%) showed a partial response while 11 patients (36.7%) experienced stable disease over a time period of at least 6 months. Plasma levels of oestrone, oestradiol and oestrone sulphate were found suppressed to a mean of 33.9, 35.6 and 24.2% of control values. 4 of 6 patients experienced a further substantial reduction in plasma oestrone sulphate to < 5% of pretreatment values when aminoglutethimide (AG) was added after relapse on 4-OHA monotherapy. Our findings suggest that these aromatase inhibitors may suppress plasma oestrogen levels by a percentage approaching the percentage inhibition of in vivo aromatisation measured by tracer techniques.

Influence of plasma estrogen levels on the length of the disease-free interval in postmenopausal women with breast cancer.

The influence of plasma estrogen levels on disease-free interval (time from primary treatment to first relapse, DFI) in breast cancer patients is not known. Any relation between plasma estrogens and the outcome in breast cancer patients may have implications considering use of hormone replacement therapy (HRT) in patients treated for breast cancer. We measured plasma estradiol (E2), estrone (E1), and estrone sulfate (E1S) in 92 postmenopausal women with breast cancer relapse and correlated plasma estrogen levels to the length of their disease-free interval (DFI1) and the length of the DFI in the subgroup of patients in whom this extended a time period of more than 2 years (DFI2). The length of DFI2 correlated negatively to plasma level of E1S (p < 0.025) and E2 (p < 0.05) and to the E2/E1 and E1S/E1 ratios (p < 0.05), while the length of DFI1 correlated negatively to plasma level of E1S (p < 0.025) and the E1S/E1 ratio (p < 0.005). We also analyzed for possible correlations between DFIs and plasma estrogen levels in subgroups based on tumor stage at diagnosis and previous therapy. In general, these subgroup analyses revealed negative correlations of statistical significance or borderline significance between the DFI1 and DFI2 and E2 and the E2/E1 ratio and non-significant negative correlations between plasma levels of E1S and DFI1 and DFI2. In particular, strong negative correlations between plasma estrogen levels and the length of DFI1 and DFI2 were found among patients responding to first line endocrine treatment for relapse and among patients with primar stage III tumors. Our findings suggest plasma E2 and E1S to stimulate the growth of micrometastases in patients treated for breast cancer.

Influence of tamoxifen on sex hormones, gonadotrophins and sex hormone binding globulin in postmenopausal breast cancer patients.

Estrone sulphate (E1S) may be an important estrogen source in breast cancers, particularly in postmenopausal women. Recent studies have shown that tamoxifen inhibits the uptake and metabolism of E1S to estradiol (E2) in cell cultures. To evaluate a possible influence of tamoxifen on E1S disposition in vivo, we measured plasma levels of E1S together with unconjugated estrogens (E1 and E2), androgens (T, A, DHEA and DHEAS), SHBG, FSH and LH in 32 postmenopausal breast cancer patients before and during tamoxifen treatment. In a subgroup of 10 patients, we measured 24 h urinary excretion of estrogen metabolites to evaluate the influence of tamoxifen treatment on estrogen metabolism and total estrogen production. Tamoxifen increased plasma levels of E1S (mean increase of 18.1%, P < 0.05) and the ratio of E1S/E1 (mean increase of 25.7%, P < 0.01) and E1S/E2 (mean increase of 34.7%, P < 0.0005). No significant change in plasma E1 was seen, but plasma E2 was reduced (mean reduction of 12.1%, P < 0.005). The fall in plasma E2 was probably secondary to a fall in plasma T (mean reduction of 11.9%, P < 0.05) due to a reduced ovarian excretion of this androgen. The mechanisms may be a reduced gonadotrophin stimulation of the ovary, as plasma FSH and LH fell by mean values of 45.5 and 48.1%, respectively (P < 0.0001 for both). The increase in plasma E1S was accompanied by a reduced ratio of 2OHE1/E1 in urine (mean reduction of 38.2%, P < 0.025) indicating reduced 2-hydroxylation. Possible mechanisms for these alterations are discussed.

Relations between sex hormones, sex hormone binding globulin, insulin-like growth factor-I and insulin-like growth factor binding protein-1 in post-menopausal breast cancer patients.

OBJECTIVE: Oestrogens, androgens and anti-endocrine drugs such as tamoxifen and aminoglutethimide influence plasma insulin-like growth factor-I (IGF-I). IGF-I, in turn, has been found to stimulate the peripheral aromatase in vitro. The aim of this study was to examine relations between sex hormones, IGF-I and insulin-like growth factor binding protein-1 (IGFBP-1) in post-menopausal women with breast cancer. DESIGN: To measure plasma sex steroids, sex hormone binding globulin (SHBG), IGF-I, IGFBP-1, insulin and urinary oestrogen metabolites in post-menopausal women with breast cancer not receiving any endocrine therapy. PATIENTS: Thirty-two patients had fasting blood samples obtained between 0800 and 1000 h. A sub-group of 10 patients had 24-hour urine oestrogen metabolites determined. MEASUREMENTS: Plasma steroids and proteins were measured by radioimmunoassays. Urinary oestrogens were measured by GC-MS. RESULTS: SHBG correlated negatively with plasma androstenedione (P < 0.001), insulin (P < 0.001), IGF-I, height and plasma oestrone sulphate (P < 0.025 for all), but positively with plasma IGFBP-1 (P < 0.025). IGFBP-1 correlated negatively with IGF-I (P < 0.001) and the testosterone/SHBG ratio (P < 0.05). Neither IGF-I nor IGFBP-1 correlated with any of the plasma or urinary sex hormones or with the oestrone/androstenedione and oestradiol/testosterone ratios. Multivariate analysis revealed plasma SHBG to correlate positively with IGFBP-1 (P = 0.029) and negatively with insulin (P = 0.031). Plasma IGFBP-1 correlated negatively with IGF-I (P < 0.0001) but not with insulin. CONCLUSION: Our results do not suggest any influence of plasma sex steroids in physiological concentrations on IGF-I or IGFBP-1 in post-menopausal breast cancer patients, nor do they indicate IGF-I at physiological concentrations influences the ratios between plasma oestrogens and their androgen precursors.

Plasma changes in breast cancer patients during endocrine therapy--lipid measurements and nuclear magnetic resonance (NMR) spectroscopy.

Side-effects following long-term endocrine therapy might have clinical implications. The aim of this study was to study potential methods to detect effects on plasma induced by hormonal therapies. The composite methylene (chemical shift between 1.2-1.4 ppm) and methyl (0.8-0.9 ppm) aliphatic peaks of the 1H magnetic resonance spectrum (500 MHz) were analysed in consecutive plasma samples of 23 cancer patients drawn before and during treatment with hormonally acting drugs. The aliphatic peaks were analyzed for line width at half-height and then averaged. In addition, 13C magnetic resonance spectroscopy (125 MHz) analyses were done in selected patients. The blood samples were analyzed for triglyceride, cholesterol, apolipoprotein A1 (apo A1), and apolipoprotein B (apo B) levels. The methylene line width increased significantly after 9 weeks of tamoxifen (41.4 vs. 37.6 Hz). A trend of differences was observed in the saturated part of the 13C magnetic resonance spectrum. A significant decrease in total cholesterol (mean decrease, 13%), increases in apo A1 (9%) and in the ratio of apo A1 to apo B (28%), but unchanged total triglycerides were found, indicating a decrease in LDL and increase in HDL lipoproteins in these patients following tamoxifen therapy. During dose escalation with the aromatase inhibitor exemestane, the methylene line width seemed to decrease (31.9 vs 38.8 Hz, at 12 weeks and baseline, respectively). Significant decreases in total (13%) and HDL (32%) cholesterol, apo A1 (25%), and total triglyceride (16%) levels were found during the same interval. The apo A1/apo B ratio decreased by 25%. For patients on dexamethasone, the proton aliphatic line widths increased one day after the initiation of therapy. The changes in line shape observed during dexamethasone therapy indicated lower levels of triglyceride-rich relative to triglyceride-poor lipoproteins, consistent with results from the lipid analyses. In conclusion, nuclear magnetic resonance spectroscopy might have potential to detect effects on plasma induced by endocrine therapy. The lipid analyses in these patients were in support of the changes in lipid profile as evaluated by nuclear magnetic resonance spectroscopy.

Plasma and urinary oestrogens in breast cancer patients on treatment with 4-hydroxyandrostenedione.

Plasma and urinary oestrogens were measured in nine breast cancer patients (eight postmenopausal women and one man) before and during treatment with the aromatase inhibitor 4-hydroxyandrostenedione. Urinary oestrogens were measured by using a highly specific GC-MS method. Plasma levels of oestrone, oestradiol and oestrone sulphate were suppressed by 66.6% (+/- 3.6%), 57.7% (+/- 5.1%) and 51.8% (+/- 6.4%) respectively (P < 0.005 for all). Twenty-four hour urinary excretion of total oestrogens, oestradiol, oestriol, 2-hydroxyoestrone, 16 alpha-hydroxyoestrone and the minor metabolites 16 beta- and 15 alpha-hydroxyoestrone were all suppressed by mean values ranging from 60% to 82%, (oestradiol: P < 0.025, otherwise P < 0.005). There were no significant changes in the ratios between the different plasma oestrogens. The finding of sustained plasma and urinary oestrogens at 20-40% compared to their control levels indirectly support a hypothesis of alternative oestrogen sources in postmenopausal breast cancer patients on treatment with 4-hydroxyandrostenedione.

Aromatase inhibitors in malignant diseases of aging.

Aromatase inhibition is an established endocrine treatment modality in postmenopausal breast cancer and is currently considered as an interesting experimental treatment approach in other malignant conditions such as endometrial carcinomas and prostatic cancer. While the 'classic' aromatase inhibitor aminoglutethimide causes many adverse effects that makes it unfit for use in elderly patients, several novel aromatase inhibitors with minimal adverse effects are currently being investigated. These drugs may provide important new tools in the endocrine treatment of malignant diseases in aging patients.

Influence of tamoxifen, aminoglutethimide and goserelin on human plasma IGF-I levels in breast cancer patients.

Plasma insulin-like growth factor-I (IGF-I) was measured in breast cancer patients before and during treatment with tamoxifen, goserelin or aminoglutethimide. 24 out of 27 postmenopausal women treated with tamoxifen 20 or 30 mg daily experienced a decrease in plasma IGF-I levels (mean levels before treatment 14.8 nM, during treatment 10.2 nM, P less than 0.001). In 8 out of 12 premenopausal breast cancer patients there was a reduction in plasma IGF-I during treatment with goserelin (mean levels before treatment 23.3 nM, during treatment 19.4 nM, P = 0.052). Contrary, 15 out of 17 postmenopausal women treated with the aromatase inhibitor aminoglutethimide had an increase in plasma IGF-I level (mean level before treatment 17.0 nM, during treatment 21.1 nM, P less than 0.01). These preliminary results indicate that different forms of endocrine treatment of breast cancer may influence plasma IGF-I levels in different directions.

Influence of aminoglutethimide on plasma oestrogen levels in breast cancer patients on 4-hydroxyandrostenedione treatment.

The clinical and biochemical effects of combined treatment with the two aromatase inhibitors aminoglutethimide and 4-hydroxyandrostenedione were evaluated in 10 patients suffering from advanced breast cancer. All patients had become resistant to treatment with one of the drugs before having combined treatment. Seven patients progressing on 4-hydroxyandrostenedione who had aminoglutethimide added to their treatment and achieved a further suppression of plasma oestradiol by a mean of 40.0% (p < 0.05). Plasma oestrone was suppressed by a mean of 40.6% (p < 0.025) and plasma oestrone sulphate was suppressed by a mean of 63.6% (p < 0.025). Two of the patients, neither of whom had responded to 4-hydroxyandrostenedione alone, experienced objective tumour regression when aminoglutethimide was given in concert. Three patients progressing on aminoglutethimide who had 4-hydroxyandrostenedione added showed no further suppression of their plasma oestrogen levels, and no tumour regression was observed. These findings suggest a dose-response relationship between plasma oestrogen suppression at low postmenopausal levels and objective tumour response in breast cancer.

Response to sodium lactate infusion in alcoholics with panic attacks.

The authors studied the response to sodium lactate infusion of 12 alcoholics with a history of panic attacks, 10 alcoholics without a history of panic attacks, and 16 nonalcoholic patients with panic disorder. The rate of lactate-induced panic was significantly higher in alcoholics with panic attacks than in alcoholics without panic attacks. Alcoholics with panic attacks were similar to nonalcoholic patients with panic disorder in their response to lactate. These findings support the specificity of lactate-induced panic for panic states and suggest that panic attacks in alcoholics resemble those in nonalcoholics. Lactate infusion may prove useful in the diagnosis of panic disorder in alcoholics.

Effects of aminoglutethimide on plasma estrone sulfate not caused by aromatase inhibition.

Plasma levels of estrone and estrone sulfate were measured in 16 postmenopausal women with advanced breast cancer before and during chronic aminoglutethimide therapy. Aminoglutethimide caused a significant reduction in plasma estrone (mean 36%, P less than 0.025) and estrone sulfate (mean 65%, P less than 0.001). The estrone/estrone sulfate ratio was increased by a mean of 84% (P less than 0.0025). These results suggest that aminoglutethimide influences plasma estrone sulfate by mechanisms unrelated to aromatase inhibition. The findings in this study are consistent with previous results suggesting that aminoglutethimide treatment enhances the rate of estrone sulfate metabolism. This biochemical effect of aminoglutethimide treatment could be a contributory factor to the drugs mechanism of action.

Prevalence, onset, and clinical recognition of panic states in hospitalized male alcoholics.

Alcoholism has been associated with a high prevalence of anxiety and phobic disorders. The authors ascertained the current prevalence of panic disorder and the lifetime prevalence of infrequent panic attacks in 154 male alcoholics in an inpatient alcohol treatment program. Thirteen percent (N = 20) gave a lifetime history of panic attacks and 45% (N = 9) of these had current panic disorder. Panic attacks preceded or coincided with the onset of problem drinking in 50% (N = 9) of the 18 patients with both diagnoses. Only two patients with histories of panic had been previously diagnosed, and none had been treated. Clinical implications of these findings are discussed.

Alterations in the production rate and the metabolism of oestrone and oestrone sulphate in breast cancer patients treated with aminoglutethimide.

Plasma level, plasma clearance, production rate and interconversions of oestrone and oestrone sulphate were measured in six breast cancer patients receiving aminoglutethimide therapy. Three additional patients had the production rate of oestrone sulphate investigated. Plasma oestrone and oestrone sulphate levels were reduced by a mean of 46% (P less than 0.05) and 71% (P less than 0.005) respectively. These alterations were due to a combined action of aminoglutethimide inhibiting oestrogen production but also increasing oestrogen metabolism. While oestrone and oestrone sulphate production rate was reduced by a mean of 31% (P less than 0.05) and 41% (P less than 0.005) respectively, the plasma clearance rate of oestrone was found to be increased by a mean of 30% (P less than 0.05), and the plasma clearance rate of oestrone sulphate was increased by a mean of 112% during aminoglutethimide treatment. The fraction of oestrone sulphate converted into plasma oestrone was reduced by 52% (P less than 0.05), the transfer of circulating oestrone into sulphate was non-significantly reduced by a mean of 16%. The findings in this investigation show that aminoglutethimide treatment influences oestrogen disposition by mechanisms unrelated to aromatase inhibition. The possibility that such effects might be partly responsible for the mechanism of action of aminoglutethimide in advanced breast cancer should be considered.