Interaction of technetium 99m-labeled teboroxime with red blood cells reduces the compound’s extraction and increases apparent cardiac washout

Background

^99mTc-labeled teboroxime shows high myocardial extraction in both in vivo animal and in vitro cell culture and isolated heart studies. Whereas in vivo studies show rapid myocardial clearance of teboroxime, in vitro cell culture and isolated heart studies show slower washout comparable to that of²⁰¹Tl. Binding of teboroxime to blood components may contribute to these conflicting results.

Methods and Results

We measured teboroxime extraction in the isolated blood-perfused rabbit heart after injection in saline solution, brief incubation in red blood cell perfusate, or 4-hour incubation with human red blood cells. Teboroxime in saline solution showed high extraction (E_max=0.89±0.02; E_net=0.69±0.02), whereas brief incubation in perfusate (E_max=0.60±0.06; E_net=0.48±0.05) or prolonged incubation with human red blood cells (E_max=0.43±0.09; E_ne=0.38±0.07) resulted in reduced extraction. Teboroxime clearance was similar for all groups and was slower than²⁰¹Tl clearance. Analysis of total residual cardiac teboroxime (comparable to external imaging) showed that teboroxime clearance was biexponential. Reduced extraction of teboroxime in red blood cells resulted in an increased size of the rapidly clearing (unextracted) fraction, giving the appearance of rapid myocardial washout.

Conclusions

Teboroxime has a high myocardial extraction. Binding to blood components reduces teboroxime extraction and increases the rate of cardiac teboroxime clearance.     

Pharmacokinetics and pharmacodynamics of prolonged oral etoposide in women with metastatic breast cancer

The pharmacokinetics and pharmacodynamics of prolonged oral etoposide chemotherapy were investigated in 15 women with metastatic breast cancer who received oral etoposide 100 mg as a single daily dose for up to 15 days. There was considerable interpatient variability in the day 1 pharmacokinetic parameters: area under the plasma concentration time curve (AUC) (0–24 h) 1.95±0.87 mg/ml per min (mean ± SD), apparent oral clearance 60.9±21.7 ml/min per 1.73 m², peak plasma concentration 5.6±2.5 g/ml, time to peak concentration 73±35 min and half-life 220±83 min. However, intrapatient variability in systemic exposure to etoposide was much less with repeated doses. The intrapatient coefficient of variation (CV) of AUC for day 8 relative to day 1 was 20% and for day 15 relative to day 1 was 15%, compared to the day 1 interpatient CV of 45%. Neutropenia was the principal toxicity. Day 1 pharmacokinetic parameters were related to the percentage decrease in absolute neutrophil count using the sigmoidal E_max equation. A good fit was found between day 1 AUC and neutrophil toxicity (R ²=0.77). All patients who had a day 1 AUC>2.0 mg/ml per min had WHO grade III or IV neutropenia. The predictive performance of the models for neutrophil toxicity was better for AUC (percentage mean predictive error 5%, percentage root mean square error 18.1%) than apparent oral clearance, peak plasma concentration, or daily dose (mg/m²). A limited sampling strategy was developed to predict AUC using a linear regression model incorporating a patient effect. Data sets were divided into training and test sets. The AUC could be estimated using a model utilizing plasma etoposide concentration at only two time points, 4 h and 6 h after oral dosing (R ²=98.9%). The equation AUC_pr=–0.376+0.631×C_4h+0.336×C_6h was validated on the test set with a relative mean predictive error of –0.88% and relative root mean square error of 6.4%. These results suggest monitoring of AUC to predict subsequent myelosuppression as a strategy for future trials with oral etoposide.Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Locked Bag 1, A'Beckett St, Melbourne 3000, Australia     

Nuclear industry family study:methods and description of a United Kingdom study linking occupational information held by employers to reproduction and child health

OBJECTION: To describe the methods used in the nuclear industry family study for which a comprehensive database has been assembled that links employment in the nuclear industry and dosimetry records to information on employees'' reproductive health and the health of their children. To discuss the response rates and characteristics of the study population. METHODS: Occupational cohort design leading to a retrospective cohort study of reproductive outcomes reported by 46 396 current and former employees of both sexes in the nuclear industry. Employees of nuclear establishments in the United Kingdom operated by the Atomic Energy Authority, the Atomic Weapons Establishment, and British Nuclear Fuels were surveyed with postal questionnaires ot collect information on pregnancies, children,and periods of infertility. Information on employment and monitoring for ionising radiation was supplied by the employing nuclear authority and was linked to pregnancies and periods of infertility with unique personal identification numbers. RESULTS: The design and completion of this study resulted in high quality data on a representative population of the Atomic Energy Authority, Atomic Weapons Establishment, and British Nuclear Fuels workforces. The response to the survey was extremely good (82% for male workers and 88% for female workers, excluding undelivered questionnaires), and a unique relational database has been created which will enable infertility, pregnancy, and child health outcomes to be examined with respect to the employment and radiation monitoring characteristics of parents. CONCLUSION: This is the first United Kingdom study to link detailed reproductive history data to occupational information held by employers. The methods developed for the study were found to be feasible and successful. The design can be adapted for other investigations of reproductive hazards to men and women in the workplace and is currently in use to survey over 100 000 armed forces personnel in an investigation of reproductive outcome among veterans of the Gulf war.       

Women's occupation and cancer: preliminary analysis of cancer registrations in England and Wales, 1971-1990.

BACKGROUND: In recent years increasing attention has been paid to examining the relation between women's health and their own occupation. The findings presented here relate to an analysis of 381,915 cancers in women registered in England and Wales over the 20-year period 1971-1990. METHODS: To explore the value of the data for epidemiological research, five sites (pleura, bladder, stomach, lung, and breast) and two occupations (agriculture and textile) were selected. Associations between cancer and occupation were evaluated using age and social class adjusted proportional registration ratios (PRRs) and 95% confidence intervals (CI). RESULTS: Pleural cancer risk was increased in a range of occupations with a potential for asbestos exposure (e.g., PRR 608, 95% CI 381-921 for craft and other production process workers), and the well-established link between bladder cancer and employment in the rubber industry was confirmed (PRR 303, 95% CI 188-464). Associations between "dusty" occupations and stomach cancer were noted (e.g., PRR 198, 95% CI 126-298 for ceramic decorators and finishers), and possible links with lung cancer and smoke in the work environment were highlighted (e.g., PRR 167, 95% CI 147-189 for publicans). As a group, agricultural workers were found to be at increased risk of non-Hodgkin's lymphoma (PRR 164, 95% CI 126-211), and textile workers at increased risk of pleural cancer (PRR 145, 95% CI 111-185). No evidence for an occupational aetiology for breast cancer was found within these data. CONCLUSIONS: Occupational information collected at cancer registration in the United Kingdom can be reliably used to identify groups that may be at increased risk of disease.     

Regional dissemination and control of epidemic methicillin-resistant Staphylococcus aureus. Manitoba Chapter of CHICA-Canada.

A methicillin-resistant Staphylococcus aureus (MRSA) strain introduced into the largest tertiary-care teaching hospital in Manitoba in 1993 led to a sustained outbreak with secondary outbreaks at one community hospital, two large long-term-care facilities, and nosocomial transmission at a second teaching hospital. Control measures were consistent at each institution and were coordinated on a province-wide basis. MRSA is not currently endemic in any facility in the province.     

Outcome of Silicone Ring Vertical Gastroplasty in Patients Aged 50 Years and Older

Background: The authors studied the results of silicone ring vertical gastroplasty (SRVG) in patients aged 50 years and older. Methods: The early and late postoperative results in 28 patients aged 50 years or older undergoing SRVG were reviewed retrospectively. The results were compared to those of 370 patients younger than 50 years operated during the same period. Results: There was no postoperative mortality among patients aged 50 years and older. There was a significantly higher incidence of pulmonary embolus and wound infection among patients aged 50 years and older (p < 0.05). The weight loss did not differ significantly between the two studied age groups. Conclusion: SRVG may be performed on patients aged 50 years or older with acceptable complication rate and favourable postoperative results.     

In vivo CT measurement of blood-brain transfer constant of iopamidol in human brain tumors

Summary We have developed an in vivo method of measuring the blood-brain transfer constant (K) of iopamidol and the cerebral plasma volume (V_p) in brain tumors using a clinical X-ray CT scanner. In patient studies, Isovue 300 (iopamidol) was injected at a dosage of 1 ml/kg patient body weight. Serial CT scans of the tumor site and arterial blood samples from a radial artery were taken up to 48 min after injection. The leakage of iopamidol into the brain through the blood-brain barrier was modelled as an exchange process between two compartments, the intravascular plasma space and the tissue interstitial space. Using this model and the concentration measurements in blood plasma and tissue, quantitative estimates of K and V_p in brain tumors were obtained. In addition, distribution of the estimated values of K and V_p in tumors were displayed as false colour functional images overlaid on the conventional CT scan.In a study of twelve patients with anaplastic astrocytoma (n = 3), glioblastoma multiforme (n = 4) or metastases (n = 5) the mean K and VP values in tumor were found to be 0.0273 ± 0.0060 ml/min/g and 0.068 ± 0.11 ml/g respectively. These values were significantly higher than those in grey or white matter in the contralateral normal hemisphere (p < 0.05). The functional images showed variations in K and V_p within the tumor which were difficult to perceive in the original contrast enhanced CT scans.