A generic model for 11C labelled radiopharmaceuticals for imaging receptors in the human brain.

A large number of radiopharmaceuticals labelled with 11C (half-time 0.340 h) are being developed for positron emission tomographic studies of different types of receptor in the human brain. For most of these agents, the available biokinetic data are insufficient to construct realistic compound-specific biokinetic models for calculating the internal radiation dose delivered to persons undergoing investigation. A generic model for brain receptor substances that predicts the internal dose with sufficient accuracy for general radiation protection purposes has, therefore, been developed. Biokinetic data for 13 11C-radiopharmaceuticals used clinically for imaging different brain receptors indicate that, despite differences in chemical structure, their uptake and retention in the human brain and other tissues are broadly similar. The proposed model assumes instantaneous deposition of 5% of the injected radioactivity in the brain, with the remaining radioactivity being rapidly and uniformly distributed throughout all other tissues. Elimination from all tissues is assumed to occur with a half-time of 2 h. It is further assumed that 75% of the injected 11C is excreted in the urine, and 25% via the gall bladder, with a half-time of 2 h. This model yields an effective dose of 4.5 x 10(-3) mSv MBq(-1), with doses of 3.2 x 10(-2), 1.7 x 10(-2), 8.7 x 10(-3), 5.2 x 10(-3), and 3.8 x 10(-3) mGy MBq(-1) to the urinary bladder, gall bladder, kidneys, brain and ovaries, respectively. These doses are well within the range of those reported using compound-specific models for the radiopharmaceutals studied.

Biokinetics of iodide in man: refinement of current ICRP dosimetry models.

A compartmental model describing the distribution and retention of radioactive iodide in thyroid and other organs is presented. The model is developed from published ICRP models. It is designed primarily for radiation dosimetry of iodine radionuclides used in nuclear medicine, but may also be useful for occupational radiation protection. In the proposed model, the distribution of iodide to the thyroid is assumed to be more rapid than in earlier models. Uptakes in stomach wall and salivary glands are considered, and the absorbed doses to these organs calculated. The partitioning of iodide between stomach wall and content is also discussed. Recirculation of organic iodine is also taken into account. Age-dependent half-times for iodide in the thyroid, as well as for organically-bound iodine are presented. The proposed model is applicable for dose estimations with different uptakes in the thyroid as well as for the situation when the thyroid is blocked, completely or incompletely.

Biokinetics and radiation doses for carbon-14 urea in adults and children undergoing the Helicobacter pylori breath test.

The long-term biokinetics and dosimetry of carbon-14 were studied in nine adults and eight children undergoing carbon-14 urea breath test for Helicobacter pylori (HP) infection. The elimination of 14C via exhaled air and urine was measured with the liquid scintillation counting technique and with accelerator mass spectrometry. After the subjects had been given 110 kBq 14C-urea (children: 55 kBq) orally, samples of exhaled air were taken up to 180 days after administration and samples of urine were collected up to 40 days. Sixteen of the subjects were found to be HP-negative. In these subjects a total of 91.1%+/-3.9% (mean of adults and children +/- standard error of the mean) of the administered 14C activity was recovered. The majority of the administered activity, 88.3%+/-6.2% in adults and 87.7%+/-5.0% in children, was excreted via the urine within 72 h after administration. A smaller fraction was exhaled. In adults 4.6%+/-0.6% of the activity was exhaled within 20 days and in children 2.6%+/-0.3%. Uncertainties in the biokinetic results are mainly due to assumptions concerning endogenous CO2 production and urinary excretion rate and are estimated to be less than 30%. The absorbed dose to various organs and the effective dose were calculated using the ICRP model for urea and CO2. The urinary bladder received the highest absorbed dose: in adults, 0.15+/-0.01 mGy/MBq and in children of various ages (7-14 years), 0.14-0.36 mGy/MBq. The findings indicate that an investigation with 14C-urea gives an effective dose to adults of 2.1+/-0.1 microSv (for 110 kBq) and to children of 0.9-2.5 microSv (for 55 kBq). From a radiation protection point of view, there is thus no reason for restrictions on even repeated screening investigations with 14C-urea in whole families, including children.

Application of accelerator mass spectrometry (AMS) for high-sensitivity measurements of 14CO2 in long-term studies of fat metabolism.

Long-term measurements of 14C in CO2 expired after ingestion of 14C-labelled triolein were performed using accelerator mass spectrometry (AMS). About 30% of a given amount of 14C-labelled triolein was catabolized rapidly, while the remaining 70% had a very slow turnover. The study shows the potential of the AMS technique for the study of the long-term biokinetics of 14C-labelled pharmaceuticals. The AMS technique allows the administered activity to be reduced by several orders of magnitude without compromising the study. It may also allow studies of rare drug metabolites.

Effective dose from radiopharmaceuticals.

The effective dose, as defined by the International Commission on Radiological Protection (ICRP 1991), provides a possibility of expressing the radiation risk to patients undergoing different radiodiagnostic procedures by means of a single figure. This has been obtained by introducing organ or tissue weighting factors reflecting the radiation sensitivity of the organs. Such weighting factors were first published by the ICRP in publication 26 (1977), and have now been revised in publication 60 (1991). The effective dose for almost all radiopharmaceuticals in clinical use has been recalculated using the new weighting factors from ICRP 60 (1991) and compared with results from former calculations. A slight decrease in the numerical value for the effective dose has been observed, on average 11%. However, this does not correspond to a decrease in the estimated risk from the irradiation, since this has been re-evaluated and found to be higher than earlier believed (NAS 1990; ICRP 1991).

Fate of bone grafts in acetabular roof reconstructions assessed by roentgenography and scintigraphy.

Autogeneic bone grafts--26 femoral heads, four femoral and two iliac bone grafts--were used in 32 total hip arthroplasties, mainly on patients with complete dislocation of the hip, to reconstruct deficiencies of the acetabular roof by a standardized procedure. At the follow-up examination after 24 to 101 months (median, 52 months), roentgenography demonstrated lateral resorption of the graft in 20 of 32 hips, but resorption involved bone support of the socket in only three of the hips. Analysis of serial roentgenograms showed that resorption was not a function of time. Complete incorporation of the grafts was observed in 27 hips; partial incorporation was shown in three. Roentgenographically, two grafts were not incorporated. None of three grafts of a cortical nature was incorporated. Graft uptake of radioactive tracer was found by 99mTc-diphosphonate emission scintigraphy in 16 of 21 hips, but did not correlate with progressive bone resorption, nonunion, or loss of bone structure. High quality serial roentgenograms showing good bone detail provided the best information about the integrity of the acetabular roof reconstructions.

Excretion of radionuclides in human breast milk after the administration of radiopharmaceuticals.

The fraction of injected activity that was excreted through the breast milk of nursing mothers at different times after the injection of various radiopharmaceuticals has been measured in 21 patients. For 99mTc-labeled radiopharmaceuticals the total excreted fraction was 10% for pertechnetate and 1.5-3% for MAA, plasmin, diethylenetriaminepentaacetic acid (DTPA), and methylene diphosphonate (MDP). For [125I]hippuran and [131I]hippuran the corresponding value was 3%. For the above mentioned radiopharmaceuticals the activity concentration in the milk decreased exponentially with an effective half-life of approximately 4 hr. For chromium-51 ethylenediaminetetraacetic acid ([51Cr]EDTA) and [99mTc]RBC, much smaller amounts were excreted in the breast milk. The absorbed dose to various organs of the baby has been calculated. We conclude that when [99mTc]pertechnetate, [99mTc]MAA, [99mTc]plasmin, [125I]hippuran, or [131I]hippuran are used the child should be fed just before the administration of the radionuclide to the mother and the next three milk fractions should not be used. For [99mTc]DTPA and [99mTc]MDP as well as [51Cr]EDTA, only the first fraction should not be used. According to our earlier investigations breast feeding has to be stopped for at least 3 wk after investigations with [125I]fibrinogen.

Glomerular filtration rate, autonomic nerve function, and orthostatic blood pressure in patients with diabetes mellitus.

Glomerular filtration rate (GFR) measured by the 51Cr-EDTA clearance method, autonomic nerve function evaluated by the heart rate reaction to deep breathing (E/I ratio) and to tilting (acceleration and brake indices), and orthostatic blood pressures were followed up after 5-7 yr in 43 patients with Type 1 diabetes. At follow up, 20 patients showed a decrease in GFR greater than expected. In the first study, these patients showed low E/I ratios and brake indices indicating vagal neuropathy, while the acceleration index fell, indicating sympathetic denervation, between the studies. Accordingly, vagal neuropathy preceded decreases in GFR and sympathetic denervation favoured deteriorations in GFR. The present report provides evidence that sympathetic denervation might be behind the development of diabetic kidney complications.

Effective dose equivalent from radiopharmaceuticals.

The concept of "effective dose equivalent", which was introduced by the International Commission on Radiological Protection (ICRP) for occupationally exposed workers, has also created the possibility of expressing by means of a single figure, the radiation risk to patients undergoing different medical radiodiagnostic procedures. In this study, we present the effective dose equivalent for various nuclear-medicine investigations. The figures given are primarily based on a review of data contained in the literature on the mean absorbed dose to various organs. In many cases, however, our own calculations, using biokinetic data derived from the literature, have been used. It was found that for the different radiopharmaceuticals, the effective dose equivalent per activity unit administered extends over an interval of five orders of magnitude, from 0.00015 to 20 mSv/MBq. For the technetium-labelled compounds, the absorbed dose for 90% of the substances lies within the narrower interval between 0.0060 and 0.025 mSv/MBq. With the aid of the figures presented, each nuclear medicine department will be able to estimate the effective dose equivalent and, hence, the risk to patients undergoing different investigations.

Radioactive dextran particles for studying circulation in animals.

Two types of dextran particles, (density 1.12 g X cm-3), ie chelating dextran particles (diameters 15.0 and 52.0 microns) and Sephadex (diameter 49.5 microns) were prepared for use as radioactive microspheres after labelling with 57Co, 58Co or 131I. The labelling efficiency was 96.4% with 57Co or 58Co and 7.8% with 131I. The specific activities were in the range 1 to 60 microCi X mg-1. The dissociation of cobalt label was found to be negligible in vitro, and in vivo 0.4 to 0.7% per h. Most of this activity was rapidly excreted in the urine. 35 days after injection of 15 microns particles they were still entrapped in the lungs and had undergone no microscopic changes and caused no tissue reaction. The findings validate the use of cobalt labelled particles for animal experiments of several hours duration. The dissociation of the iodine label was considerable both in vitro and in vivo limiting the use of the iodine labelled particles to experiments where a single determination of blood flow distribution is sufficient.

Is CEA analysis of value in screening for recurrences after surgery for colorectal carcinoma?

The progress of 139 patients operated upon for cure of colorectal carcinoma, was followed postoperatively with a standardized protocol. A CEA test was performed for comparison with other parameters. Median observation time was four years. When an upper limit for CEA of 7.5 micrograms/1 was allowed, sensitivity was found to be 78 per cent, specificity 91 per cent, and predictive value of an elevated CEA concentration, 83 per cent. In general, CEA measurement traced recurrence six months before clinical diagnosis. In only a few cases was recurrence first heralded by an abnormality in other blood chemistry test results. CEA may thus be used in postoperative screening for recurrence even though most recurrences, when detected, are not curable.

Bone formation of transplanted autologous bone matrix in rabbit evaluated by technetium radionuclide bone imaging.

In adult rabbits a 12 mm piece of the radius was bilaterally resected and subsequently decalcified. One piece was placed in one of the radial defects and the other in a skin tube on the back. The other radial defect served as a control. The bone formation process was evaluated by roentgenographic examination and quantified radionuclide bone imaging by technetium diphosphonate scintigraphy at 3 and 6 months postoperatively. Reliability of the scintigraphy method was assessed by means of testing interexamination variability where the same sample was measured twice and where no significant difference was found. In the defect restituted with decalcified bone matrix there was a significantly (p less than 0.01) higher bone formation rate at 3 months postoperatively, with a mean increase of 47% compared to the control side. In the skin tube the implanted matrix showed mineral formation both at 3 and 6 months postoperatively and increased radionuclide uptake compared to the adjacent tissues. Technitium radionuclide imaging was found to be a suitable method for evaluation of the bone formation in these small defects.

Whole body measurements of sodium turnover in offspring of patients with sustained essential hypertension.

The elimination rate (percent per day) of injected 22Na using a whole body measurement technique was significantly lower (5.8 +/- 1.5) in normotensive or borderline hypertensive offspring of essential hypertensive patients than in 15 age- and sex-matched, normotensive controls (7.3 +/- 1.0). There were no significant differences in exchangeable sodium, whole body potassium or in the urinary excretion of sodium, potassium and creatinine. The basis for the difference in turnover rate during week 1 is probably an alteration in the cellular handling of sodium (i.e. increased intracellular sodium) in the still normotensive offspring of patients with essential hypertension. The long-term (more than 100 days) whole body retention of 22Na was found to be only 0.1% of that injected, which justifies the use of this method on larger population groups.

Abnormal whole-body and cellular (erythrocytes) turnover of 22Na+ in normotensive relatives of probands with established essential hypertension.

1. Whole-body elimination rate of 22Na+ was decreased in normotensive or borderline first-degree relatives of hypertensive probands. 2. Whole-body potassium, exchangeable sodium and urine excretion of sodium, potassium and creatinine were similar in relatives and controls. 3. Erythrocyte net influx of 22Na+ was significantly increased in normotensive relatives. 4. Abnormal whole-body and cellular handling of sodium (22Na+) demonstrated in relatives indicates that this abnormality may have an important role in the development of essential hypertension in man.

Evaluation of the microsphere method for determination of cardiac output and flow distribution in the rat.

The radioactive microsphere technique was applied to determine simultaneous cardiac output and flow distribution in the rat. Left ventricular injections of large numbers of microspheres were given, without significant adverse effects, allowing determination of flow to organs and tissues with low perfusion rates. In order to determine coronary blood flow it was necessary to excise the inner lining of the left ventricle, thus eliminating activity from deposits of microspheres. Cardiac output determination showed less variation with the sampling catheter in the abdominal aorta than in the femoral artery. It is concluded that the microsphere method can be conveniently used for hemodynamic studies in the rat, and that the abdominal aorta is the preferred site for the placement of the reference catheter in the rat.

Catabolic rate of alpha1-antitrypsin of of Pi types S, and MMalton and of asialylated M-protein in man.

1. Human alpha1-antitrypsin was isolated with preserved microheterogeneity from subjects of Pi types M, S and MMalton. The M-protein was partially (20%) and completely desialylated. The proteins were labelled with either 125I or 131I. 2. The disappearance rate of these alpha1-antitrypsins was studied after simultaneous injection of the two types of labelled protein into Pi M subjects. The fractional catabolic rates of S- and MMalton-protein were 0.36 and 0.34 day(-1) respectively compared with 0.28 day(-1) for M-protein. The ratio of extravascular to plasma pools was 1.4 for S- protein and 1.6 for MMalton-protein. The 20% desialylated M-protein showed an increase of about 100% in its fractional catabolic rate. The disappearance rate of completely desialylated alpha1-antitrypsin was extremely rapid. 3. The slightly higher fractional catabolic rate of S- than of M-protein can only partly explain the 40% lower plasma concentration in subjects of Pi type S. Similarly the slight increase in catabolic rate of Pi MMalton- protein is too small to explain why the alpha1-antitrypsin content of the blood in Pi MMalton subjects is only 15% of that normally found. A low hepatic secretion seems to be the major cause of the low alpha1-antitrypsin concentration found in subjects of types Pi S and MMalton, as in Pi type Z.

Studies in pharmacokinetics and tolerance of substances temporarily retained in the liver by microsphere embolization.

Earlier investigation has shown that a temporary arrest of arterial blood flow can be achieved by embolization with degradable microspheres. This study was made to investigate the change in pharmacokinetics, and drug tolerance which takes place when a substance is retained in the liver by a microsphere embolization. 14C-labelled inulin and 5-fluorouracil were studied. The administration of these substances with microspheres led to a delay in their systemic distribution. Furthermore there was an increased tolerance to 5-fluoro-uracil, probably due to a prolonged first pass effect when the substance was temporarily retained in the liver by a microsphere embolization.

Myocardial scintigraphy with 99mTc-pyrophosphate in patients with unstable angina pectoris.

A total of 400 patients, aged 25-82 years, admitted to the Coronary Care Unit due to clinical suspicion of acute myocardial infarction, were examined with 10 mCi 99mTc labelled to pyrophosphate. The examinations were carried out 4-120 hours post onset of symptoms, with a mobile gamma camera. Scintigrams were evaluated with regard to presence, localization and intensity of an uptake. Among 249 patients with a verified acute myocardial infarction, uptake was found in 237. Sixty-two of 85 patients with unstable angina showed a diffuse uptake with low intensity. Scintigraphy could not be used as a prognostic index of which patients would later develop an infarct. However, the scintigraphic pattern was useful as an aid in the differential diagnosis between acute myocardial infarction and unstable angina.

Metrizamide in urography. II. A comparison of 51Cr-EDTA clearance and metrizamide clearance in man.

In nine subjects undergoing urography with metrizamide measurements of total serum clearance of 51Cr-EDTA have been made before, during, and after the urography. During the urography both total serum clearances and renal clearances were determined for 51Cr-EDTA and metrizamide. The present study in man confirms the previous results from investigations in rabbits, that most of the intravenously injected metrizamide is excreted through the kidneys, that tubular reabsorption of metrizamide occurs and suggests that metrizamide might be used with advantage for urography.