Graphical human insulin time-activity profiles using standardized definitions.

The purpose of this study was to (1) develop consistent definitions to report time-activity profiles of insulin formulations, (2) determine human insulin time-activity profiles based on all available pharmacokinetic studies of biosynthetic human insulin rDNA(E. coli) (Humulin), and (3) create graphs that accurately and usefully represent human insulin time-activity profiles (TAPs). Standard definitions of onset, peak, duration, and time of 50% maximal activity were developed for human insulin. Results from all pharmacokinetic and pharmacodynamic studies available on human insulin from searches of both published literature and unpublished work were analyzed by these standard methods. Data obtained using these definitions were used to construct diagrams of the time-activity relationships for each formulation. Sixty-three insulin tests utilizing a variety of methodologies and data analysis techniques were located. Time-activity curves generated by application of standardized definitions varied depending on methodology, and on whether glucose, insulin and/or glucose infusion rates were used as the measure of insulin activity. A method of standard analysis is required for evaluating insulin pharmacokinetic studies due to the wide variation in design of these studies. Graphic representation of ranges obtained by standard analysis of onset, peak, duration, and 50% maximal activity increase the information transmitted when compared to currently used tables of time-activity data. The time of 50% maximal activity during increasing and decreasing phases may be a better marker of clinically significant activity than the classically defined parameters of onset and duration.

Update on the MEN 2A c804 RET mutation: is prophylactic thyroidectomy indicated?

BACKGROUND: Mutations of the RET proto-oncogene co-segregate with multiple endocrine neoplasia type 2A. A rare sequence abnormality at codon 804 (c804) has been reported in 6 kindreds and linked to mild C-cell disease, which raises the question of the appropriateness of thyroidectomy in childhood. The purpose of this study was to (1) report the clinical correlates of 5 additional c804 kindreds, and (2) clarify therapeutic options in children. METHODS: Thirty-eight members from five c804 kindreds underwent genetic analysis. Biochemical, operative, and pathology reports were reviewed. RESULTS: Twenty-three gene carriers were identified, of whom 14 had thyroidectomy. Medullary thyroid carcinoma was found in 7 patients (aged 5-56 years), C-cell hyperplasia in 6 patients (aged 13-40 years), and normal histology in a single patient (aged 27 years). One patient with medullary thyroid carcinoma died of metastases (aged 12 years). Nine of the 23 gene carriers delayed operation, 4 of whom had calcitonin testing. Three of the 4 patients had abnormal calcitonin levels and a single patient was negative (aged 40 years). Of the remaining 9 patients, 2 await thyroidectomy, and 3 have refused evaluation. CONCLUSIONS: Penetrance of the c804 mutation is highly variable. Medullary thyroid carcinoma associated with this genotype has aggressive potential. Prophylactic thyroidectomy in childhood is a viable approach.