Mechanism of uptake and retention of F-18 BMS-747 158-02 in cardiomyocytes: a novel PET myocardial imaging agent

Background BMS-747158-02 is a novel fluorine 18-labeled pyridazinone derivative designed for cardiac imaging. The uptake and retention mechanisms of F-18 BMS-747158-02 in cardiac myocytes were studied in vitro, and the biodistribution of F-18 BMS-747158-02 was studied in vivo in mice. Methods and Results Fluorine 19 BMS-747158-01 inhibited mitochondrial complex I (MC-I) in bovine heart submitochondrial particles with an IC₅₀ of 16.6±3 nmol/L that was comparable to the reference inhibitors of MC-1, rotenone, pyridaben, and deguelin (IC₅₀ of 18.2±6.7 nmol/L, 19.8±2.6 nmol/L, and 23.1±1.5 nmol/L, respectively). F-18 BMS-747158-02 had high uptake in monolayers of neonatal rat cardiomyocytes (10.3%±0.7% of incubated drug at 60 minutes) that was inhibited by 200 nmol/L of rotenone (91%±2%) and deguelin (89%±3%). In contrast, an inactive pyridaben analog, P-0 (IC₅₀ value>4 μmol/L in MC-1 assay), did not inhibit the binding of F-18 BMS-747158-02 in cardiomyocytes. Uptake and washout kinetics for F-18 BMS-747158-02 in rat cardiomyocytes indicated that the time to half-maximal (t_1/2) uptake was very rapid (approximately 35 seconds), and washout t_1/2 for efflux of F-18 BMS-747158-02 was greater than 120 minutes. In vivo biodistribution studies in mice showed that F-18 BMS-747158-02 had substatial myocardial uptake (9.5%±0.5% of injected dose per gram) at 60 minutes and heart-to-lung and heart-to-liver ratios of 14.1±2.5 and 8.3±0.5, respectively. Positron emission tomography imaging in the mouse allowed clear cardiac visualization and demonstrated sustained myocardial uptake through 55 minutes. Conclusions F-18 BMS-747158-02 is a novel positron emission tomography cardiac tracer targeting MC-I in cardiomyocytes with rapid uptake and slow washout. These characteristics allow fast and sustained accumulation in the heart.     

Long-term follow-up and the role of surgery in adolescents with morbid obesity

PURPOSE: Obesity has become a health-care crisis in the United States. Adolescent obesity is now one of the most common childhood disorders, with 4.7 million American adolescents having a body mass index (BMI) greater than the 95th percentile. Most patients do not respond to diet modification or exercise programs and attention is now turning toward surgery as a source of weight loss in adolescents. Few studies have looked at the overall morbidity and mortality of weight loss surgery in this patient population. METHODS: This is a retrospective study of medical charts of 15 bariatric surgical procedures performed on 14 adolescents without known genetic syndromes associated with severe childhood obesity from 1971 to 2001 at the University of Minnesota. Procedures performed on these patients included vertical banded gastroplasty (n = 7), Roux-en-Y gastric bypass (n = 5), and jejunoileal bypass (n = 3). Jejunoileal bypass procedures were performed from 1971 to 1977, after which time this procedure was abandoned. Patient age ranged from 13 to 17 years (mean, 15.7 years). Mean follow-up time was 6 years, with 9 patients available for long-term follow-up. RESULTS: All procedures were performed using an open technique by 1 surgeon. There were no perioperative deaths; complications included 1 case of wound infection, 2 episodes of dumping syndrome that resolved without revision, 1 episode of hypoglycemia, and 1 case of short-term electrolyte imbalance in a patient who underwent jejunoileal bypass. The average BMI dropped from 58.5 +/- 13.7 to 32.1 +/- 9.7 kg/m(2) (P < .01)--a 45% reduction. CONCLUSIONS: Surgery for morbid obesity is safe and results in significant weight loss in adolescents who fail medical therapy.     

Inverting a Laplacian topography map

Summary There are some occasions when it is better to use the Laplacian of the scalp voltages (e.g., for topographic displays and dipole source localization) and other occasions when it is better to use the original voltages (e.g., for comparison to non-Laplacian topography maps). This paper presents a simple algorithm for going between these two representations of the data. The inverse Laplacian involves iterative feedback. An Excel spreadsheet implementation of the algorithm is presented.This research was supported by grant AFOSR 89-0238 from the Air Force Office of Sponsored Research.     

Potential interference of agents on radioiodide thyroid uptake in the euthyroid rat.

The objective of this research was to investigate the merits of controlled studies with euthyroid rats as a means of determining the influence of dose and time after administration of agents that may interfere with radioiodide uptake in the thyroid. METHODS: Potassium iodide (KI), propylthiouracil (PTU), diatrizoate meglumine, and iohexol were selected to represent interfering agents. Two dose levels per agent were investigated. Doses used were 1 and 2 mg/kg of body weight for KI, 3.5 and 7 mg/kg of body weight for PTU, 1 mL/kg (282 mg I/kg) and 2 mL/kg (564 mg I/kg) of body weight for diatrizoate meglumine, and 1 mL/kg (300 mg I/kg) and 2 mL/kg (600 mg I/kg) of body weight for iohexol. The 24-h radioiodide thyroid uptake was determined after (131)I was given at 1, 8, 15, and 22 d after administration of interfering agents. RESULTS: The percentage radioiodide uptake value for the thyroid decreased significantly compared with controls for all agents and both doses on day 1 but returned to control levels by day 22 for all agents and both doses The time to return to normal varied between agents and doses. CONCLUSION: We conclude that the interfering agent, the dose given, and the length of time after administration influence the potential for an agent to affect radioiodide uptake in the thyroid. Further studies with the rat, preferably hyperthyroid, would be beneficial in generating data to reduce confusing contradictory information on the length and severity of interference of agents in radioiodide thyroid studies.     

From the Editor

Sexuality and Disability -