Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer.
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The goals of this clinical trial involving postmenopausal women with metastatic breast cancer were to: (a) examine the effects of letrozole on tamoxifen (TAM) pharmacokinetics; (b) examine estrogen suppression in patients receiving TAM plus letrozole; and (c) evaluate tolerability, toxicity, objective response, and time to progression for the combination. Postmenopausal women with measurable or evaluable metastatic breast cancer received TAM (20 mg daily) for 6 weeks, and then letrozole (2.5 mg daily) was added. To examine for any effect of letrozole on the levels of TAM and two metabolites [N-desmethyl-TAM and 4-hydroxy-TAM], serum samples were obtained at 6, 12, 18, and 24 weeks. To examine for aromatase inhibition, serum samples were obtained before treatment and at 6, 12, 18, and 24 weeks for estradiol, estrone (E1) E1 sulfate, and sex hormone-binding globulin. A total of 34 patients were entered on this trial, and 23 patients were still on study at week 24, 18 of whom had blood samples available at both week 6 and week 24. The 95% confidence interval for the mean difference between levels at week 24 and levels at week 6 was -34 to 15 ng/ml for TAM, -35 to 45 ng/ml for N-desmethyl-TAM, and -1 to 2 for 4-hydroxy-TAM. For estradiol, a significant decrease (median, 88.5%; range, 73.7-95.2%) was identified after 6 weeks of letrozole, which was maintained for an additional 12 weeks. Similar significant reductions were identified for E1. E1 sulfate levels increased after 6 weeks of TAM alone but then decreased significantly after the addition of letrozole. Sex hormone-binding globulin levels were significantly elevated after 6 weeks of TAM alone and remained elevated after the addition of letrozole. Six of the 34 patients (17.6%) achieved an objective response (95% confidence interval, 6.8-34.5%), with a median time to disease progression of 7.6 months. There was no indication of a systematic decrease in TAM, N-desmethyl-TAM, or 4-hydroxy-TAM after the additional of letrozole. Estrogen suppression induced by letrozole was substantial despite the concomitant administration of TAM. The antitumor effect of TAM plus letrozole was less than expected. (+info)
Effect of physician specialty on outcomes in diabetic ketoacidosis.
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OBJECTIVE: More than 100,000 people are hospitalized annually in the U.S. with diabetic ketoacidosis (DKA). Outcome differences have not been examined for these patients based on whether their primary care provider is a generalist or a diabetes specialist. The objective of this study was to investigate hospital charges and hospital length of stay (LOS) for patients with DKA according to the specialty of their primary care provider. RESEARCH DESIGN AND METHODS: We investigated all patients with a primary diagnosis of DKA during a 3.5-year period (n = 260) in a large urban teaching hospital. Hospital charges and LOS were studied regarding the specialty of the primary care provider. Demographic factors, severity of illness, laboratory data, and readmission rates were compared. RESULTS: Patients cared for by generalists and endocrinologists had a similar case mix and severity of DKA. The age-adjusted mean LOS for patients of generalists was 4.9 days (95% CI 4.5-5.4), and the mean LOS for patients of endocrinologists was 3.3 days (2.6-4.2) (P < 0.0043). Mean hospital charges differed (P < 0.0001) with an age- and sex-adjusted mean for patients of endocrinologists of $5,463 ($4,179-7,141) and a mean for patients of generalists of $10,109 ($9,151-11,166). The additional charges incurred by generalists were due in part to patients undergoing more procedures. No differences in diabetes-related complications occurred during admission, but the endocrinologist-treated group had a lower readmission rate for DKA during the study period than the generalist-treated group (2 vs. 6%, respectively) (P = 0.03). CONCLUSIONS: Endocrinologists provide more cost-effective care than generalists do when serving as primary care providers for patients hospitalized with DKA. (+info)
Comparisons among old and new provocative tests of GH secretion in 178 normal adults.
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Classical provocative stimuli of GH secretion such as insulin-induced hypoglycaemia, arginine, clonidine, glucagon and levodopa have been widely used in clinical practice for approximately 30 years. On the other hand, in the last 10 years new potent stimuli of GH secretion have been proposed, but an extensive comparison with the classical ones has rarely been performed, at least in adults. In order to compare the GH-releasing activity of old and new provocative stimuli of GH secretion, and to define the normative values of the GH response, in 178 normal adults (95 males, 83 females; age range: 20-50 years, all within +/-15% of their ideal body weight), we studied the GH response to: insulin-induced hypoglycaemia (ITT, 0.1IU/kg i.v.), arginine (ARG, 0.5g/kg i.v.), clonidine (CLO, 300 microg/kg p.o.), glucagon (GLU, 1mg i.m.), pyridostigmine (PD, 120mg p.o.), galanin (GAL, 80pmol/kg per min), GH-releasing hormone (GHRH, 1 microg/kg i.v.), GHRH+ARG, GHRH+PD, hexarelin, a GH-releasing protein (HEX, 2 microg/kg i.v.) and GHRH+HEX (0.25 microg/kg i.v.). The mean (+/-s.e.m.) peak GH response to ITT (21.8+/-2.8, range: 3.0-84.0 microg/l) was similar to those to ARG (18.0+/-1.6, range: 2.9-39.5 microg/l) or GLU (20. 5+/-2.2, range: 10.6-36.9 microg/l) which, in turn, were higher (P<0. 001) than those to CLO (8.2+/-1.6, range: 0.3-21.5 microg/l), PD (9. 6+/-1.1, range: 2.2-33.0 microg/l) and GAL (9.3+/-1.1, range: 3.9-18. 3 microg/l). The GH response to GHRH (19.1+/-1.5, range: 2.7-55.0 microg/l) was similar to those after ITT, ARG or GLU but clearly lower than those after GHRH+ARG (65.9+/-5.5, range: 13.8-171.0 microg/l) and GHRH+PD (50.2+/-4.6, range: 17.7-134.5 microg/l) which, in turn, were similar. The GH response to HEX (55.3+/-5.5, range: 13.9-163.5 microg/l) was similar to those after GHRH+ARG and GHRH+PD but lower (P<0.001) than that after GHRH+HEX (86.0+/-4.3, range: 49. 0-125.0 microg/l) which was the most potent stimulus of GH secretion. In this adult population the third centile limits of peak GH response to various stimuli were the following: ITT: 5.3; ARG: 2.9; CLO: 1.5; GLU: 7.6; PD: 2.2; GAL: 4.0; GHRH: 5.0; GHRH+ARG: 17.8; GHRH+PD: 17.9; HEX: 21.6; GHRH+HEX: 57.1. These results confirm that, among classical provocative tests of GH secretion, ITT followed by ARG and GLU are the most potent ones and possess clear limits of normality. GHRH+ARG or PD and HEX are strong stimuli of GH secretion which, however, is maximally stimulated by a combination of GHRH and a low dose of HEX. It is recommended that each test is used with appropriate cut-off limits. (+info)
Trends in diagnostic and therapeutic criteria in Graves' disease in the last 10 years.
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A questionnaire describing a typical clinical case of Graves' disease and 10 variations on it was mailed to 70 Spanish units of endocrinology with the aim of assessing the new diagnostic and therapeutic trends for hyperthyroidism caused by Graves' disease in Spain and to compare the results obtained from previous studies carried out in Europe and Spain 10 years previously. Responses indicated that thyrotrophin (98%) and free thyroxine (88%) were the most used tests in the in vitro diagnosis of Graves' disease with a significant decrease in the use of total thyroxine, total triiodothyronine, and thyroglobulin in comparison with the surveys conducted 10 years previously in Europe and Spain. The presence of antibodies against the thyrotrophin receptor was the most frequently used immune marker in the diagnosis (78%) and the new use of antithyroperoxidase antibodies (36%) in diagnosis is noteworthy. Antithyroid drugs remain the treatment of choice (98%). Surgery was used mainly for large size goitres (33%) and radioiodine for recurrences after medical (61%) or surgical (80%) treatment. In conclusion, the responses obtained from this questionnaire provide insight into current specialist diagnostic and therapeutic practices with respect to Graves' disease and which could be of value to non-specialist units of endocrinology. (+info)
Meeting American Diabetes Association guidelines in endocrinologist practice.
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OBJECTIVE: To determine whether American Diabetes Association (ADA) guidelines can be met in the context of routine endocrinology practice. RESEARCH DESIGN AND METHODS: Charts were reviewed for a group of patients who were examined in 1998, followed for > or = 1 year, and had two or more visits during that year. Process measures and metabolic outcomes were studied for patients with type 2 diabetes, and glycemic control was assessed for patients with type 1 diabetes. RESULTS: A total of 121 patients with type 2 diabetes had a mean age of 63 years, a mean BMI of 31 kg/m2, and a mean duration of diabetes of 12 years. Many had comorbidities or complications: 80% had hypertension, 64% had hyperlipidemia, 78% had neuropathy, 22% had retinopathy, and 21% had albuminuria. Management of type 2 diabetic patients was complex: 38% used oral hypoglycemic agents alone (54% of these were using two or more agents), 31% used oral hypoglycemic agents and insulin, and 26% used insulin alone; 42% of patients taking insulin therapy injected insulin three or more times per day. Within 12 months, 74% of patients had dilated eye examinations, 70% had lipid profiles, and 55% had urine albumin screening. Of the patients, 87% had a foot examination at their last visit. Blood pressure levels averaged 133/72 mmHg, cholesterol levels averaged 4.63 mmol/l, triglyceride levels averaged 1.99 mmol/l, HDL cholesterol levels averaged 1.24 mmol/l, and LDL cholesterol levels averaged 2.61 mmol/l. Random blood glucose levels averaged 8.0 mmol/l, and HbAlc levels averaged 6.9 +/- 0.1%. A total of 87% of patients had HbAlc levels < or = 8.0%. A total of 30 patients with type 1 diabetes had mean age of 44 years, a mean BMI of 26 kg/m2, and a mean duration of diabetes of 20 years. All type 1 diabetic patients used insulin and averaged 3.4 injections a day; their average HbAlc level was 7.1 +/- 0.2%, and 80% had HbAlc levels < or = 8.0%. CONCLUSIONS: Although endocrinologists must manage patients with multifaceted problems, complex treatment regimens yield glycemic control levels comparable with the Diabetes Control and Complications Trial and allow ADA guidelines to be met in a routine practice setting. (+info)
Accurate measurement of endogenous insulin secretion does not require separate assessment of C-peptide kinetics.
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The implication of beta-cell failure as an early defect in type 2 diabetes exacerbates the need for accurate but facile assessment of islet cell secretory rate, particularly in large group studies in which individual assessment of C-peptide kinetics is impractical. This study was designed to examine whether it is possible to obtain accurate secretory rates from the extended combined model, which provides insulin and C-peptide kinetics from plasma measurements of the two peptides. Equimolar intraportal infusions of insulin and C-peptide that are designed to simulate insulin secretion rates during both oral and intravenous glucose tolerance tests were used to generate plasma insulin and C-peptide data in conscious dogs that were examined under clamped glucose conditions. The plasma peptide kinetics were analyzed using the extended combined model to generate estimates of prehepatic insulin secretion that were then compared with the known intraportal infusion rates. The extended combined model was able to reproduce the known intraportal infusion profiles. The model-predicted rates were similar to those calculated with methods that require separate assessment of C-peptide kinetics. Simulation results supported lesser clearance of insulin during rapid changes of portal insulin (as measured by an intravenous glucose tolerance test) versus slow changes in portal insulin (as measured by an oral glucose tolerance test). The extended combined model accurately calculates prehepatic insulin appearance. It may be possible to apply this approach to large studies of beta-cell function designed to identify changes in islet function in subjects at risk for diabetes. Such an approach could strengthen epidemiological and genetic studies of the pathogenesis of diabetes. (+info)
Intracrinology: role of the family of 17 beta-hydroxysteroid dehydrogenases in human physiology and disease.
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In women and men, an important proportion of estrogens and androgens are synthesized locally at their site of action in peripheral target tissues. This new field of endocrinology has been called intracrinology. In postmenopausal women, 100% of active sex steroids are synthesized in peripheral target tissues from inactive steroid precursors while, in adult men, approximately 50% of androgens are made locally in intracrine target tissues. The last and key step in the formation of all estrogens and androgens is catalyzed by members of the family of 17beta-hydroxysteroid dehydrogenases (17 beta-HSDs) while different 17 beta-HSDs inactivate these steroids in the same cell where synthesis takes place. To date, seven human 17 beta-HSDs have been cloned, sequenced and characterized. The 17 beta-HSDs provide each cell with the means of precisely controlling the intracellular concentration of each sex steroid according to local needs. (+info)
Efficient evaluation of thyroid nodules by primary care providers and thyroid specialists.
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OBJECTIVE: To determine whether primary care providers and thyroid specialists at Gundersen Lutheran Medical Center are evaluating thyroid nodules efficiently by following recently published clinical guidelines. STUDY DESIGN: One-year retrospective chart review. PATIENTS AND METHODS: We reviewed patient records from 1996 and tabulated the use of fine-needle aspiration cytology, radionuclide scanning, and thyroid ultrasonography by 49 primary care physicians evaluating 81 thyroid nodules and by 5 thyroid specialists evaluating 29 thyroid nodules. The results were compared with our previous findings and those recently reported by others. RESULTS: Fine-needle aspiration cytology was widely used by both groups of Gundersen Lutheran healthcare providers. Primary care physicians used imaging studies modestly and generated $106 per patient in unnecessary costs. Thyroid specialists occasionally used radionuclide scanning but did not use thyroid ultrasonography; they generated $41 per patient in unnecessary costs. Overall, the introduction of fine-needle aspiration cytology at our institution has reduced the use of radionuclide scanning from 90% to 12% and the use of thyroid ultrasonography from 30% to 10%. We also found that the frequency of surgery in patients with thyroid nodules fell substantially, yet detection of thyroid cancer in the operative specimens increased from 16% to 43% while the cost of removing a thyroid carcinoma decreased from $64,000 to $25,000. CONCLUSIONS: Fine-needle aspiration cytology, adopted as the initial test for diagnosing thyroid nodules by most of our healthcare providers, has reduced the use of imaging studies far below the frequency reported by others and has substantially decreased the cost of thyroid nodule management. (+info)