Measurement, model prediction and uncertainty quantification of plasma clearance of cerium citrate in humans.

Double tracer studies in healthy human volunteers with stable isotopes of cerium citrate were performed with the aim of investigating the gastro-intestinal absorption of cerium (Ce), its plasma clearance and urinary excretion. In the present work, results of the clearance of Ce in blood plasma are shown after simultaneous intravenous and oral administration of a Ce tracer. Inductively coupled plasma mass spectrometry was used to determine the tracer concentrations in plasma. The results show that about 80% of the injected Ce citrate cleared from the plasma within the 5 mins post-administration. The data obtained are compared to a revised biokinetic model of Ce, which was initially developed by the International Commission on Radiological Protection (ICRP). The measured plasma clearance of Ce citrate was mostly consistent with that predicted by the ICRP biokinetic model. Furthermore, in an effort to quantify the uncertainty of the model prediction, the laboratory animal data on which the ICRP biokinetic Ce model is based, was analyzed. The measured plasma clearance and its uncertainty was also compared to the plasma clearance uncertainty predicted by the model. It was found that the measured plasma clearance during the first 15 min after administration is in a good agreement with the modelled plasma clearance. In general, the measured clearance falls inside the 95% confidence interval predicted by the biokinetic model.

Biokinetic measurements and modelling of urinary excretion of cerium citrate in humans.

Tracer kinetics in healthy human volunteers was studied applying stable isotopes of cerium citrate to obtain biokinetic human data for the urinary excretion of cerium. These data were then used to compare and validate the biokinetic model for lanthanides (cerium) proposed by Taylor and Leggett (Radiat Prot Dosim 105:193-198, 2003), which is substantially improved and more realistic than the biokinetic model currently recommended by the International Commission on Radiological Protection (ICRP Publication 67, 1993); both models are primarily based on animal data. In the present study, 16 adults were investigated and two cerium tracers were simultaneously administered, both intravenously and/or orally. The cerium concentrations in urine were determined by inductively coupled plasma mass spectrometry. Ingested cerium citrate was poorly absorbed, and its low excretion was similar to the prediction of the biokinetic model of Taylor and Leggett. In contrast, after injection of cerium citrate its urinary excretion was rapidly increased, and the model underestimated the experimental results. These results suggest that urinary excretion of cerium may be dependent on the administered chemical form of cerium (speciation).

Measuring technique for thermal ionisation mass spectrometry of human tracer kinetic study with stable cerium isotopes.

Thermal ionisation mass spectrometry (TIMS) method has been developed for the simultaneous detection of different cerium isotopes in biological samples (i.e., blood and urine) at very low concentrations. The work has been done in the frame of a biokinetic study, where different stable cerium isotopes have been administered orally and intravenously as tracers to the human body. In order to develop an appropriate detection method for the tracers in the biological samples, an optimum sample preparation technique has been set and adapted to the specific requirements of the analysis technique used, i.e., TIMS. For sample evaporation and ionisation, the double tantalum filament technique showed the best results. The ions produced were simultaneously collected on a secondary electron multiplier so that the isotopic ratios of the cerium isotopes in the biological samples could be measured. The technique has been optimised for the determination of cerium down to 1 ng loaded on the evaporation filament corresponding to cerium concentrations of down to 1 ng ml(-1) in the blood or urine samples. It has been shown that the technique is reliable in application and enables studies on cerium metabolism and biokinetics in humans without employing radioactive tracers.

Cerium isotope effects in Ce(III) malate and lactate complex formation studied by long-distance displacement chromatography.

Isotope effects of cerium were observed in malate and lactate complex formations during the long-distance displacement chromatographic processes at 313 K. Heavier isotopes were found fractionated in the frontal edges of the Ce adsorption bands in both the systems, registering a preference of the heavier isotopes for the Ce(III) complexes in the solution phase over the simply hydrated Ce(III) ions in the resin phase. The fractionation coefficients epsilon for the 136Ce/140Ce, 138Ce/140Ce and 142Ce/140Ce isotopic pairs were 7.1 x 10(-6), 5.2 x 10(-6) and -2.1 x 10(-6) for the malate system, and 4.8 x 10(-6), 4.5 x 10(-6) and-2.6 x 10(-6) for the lactate system, respectively. They all show the mass-dependent law if the deviation of epsilon for the 138Ce/140Ce pair was considered merely due to the isobaric interference in Ce isotopic ratio measurements, suggesting the molecular vibration, rather than the nuclear field shift, mainly contributes to the Ce isotope effects in the complex formation systems. The absolute values of epsilon between the two systems are comparable, suggesting no instinct difference in structural properties between Ce malate and lactate complexes involved.

Observation of cerium isotope fractionation in ion-exchange chromatography of Ce(III)-malate complex.

The cerium isotope fractionation between Ce(III)-malate complex in aqueous solution and cerium ions in a cation-exchange resin was conducted by displacement chromatography. The pH and the chemical composition of the eluent were optimized for maintaining the self-sharpening band boundaries and the 21 m chromatographic migration of the Ce band underwent. Graphite slurry was coated on the tantalum filament prior to sample loading for reducing the isobaric interferences in cerium isotopic ratio determination by mass spectrometry. From the experimental results, it was found that the heavier isotope was enriched in the front boundary part of the cerium adsorption band, which meant that the heavier isotope was preferentially fractionated into the Ce3+ malate complex rather than simply hydrated Ce3+ ions. The isotope separation coefficient for the 136Ce/140Ce and 142Ce/140Ce was 5.2 x 10(-5) and -1.9 x 10(-5), respectively, at 298 K.

Blood flow measurements in skin flaps.

For the last 50 years, the empirical approach of set length to width ratios for skin flaps has been held valid. Not until Milton's work in 1971 was this concept challenged. This report represents a method where precise, reproducible, and quantitative measurements of skin blood flow can be made using four radioactive nuclide microspheres and measures the blood flow changes in flaps of differing length to width ratios. Conclusions from our data suggest that the cutaneous blood flow in ventrally based, abdominal skin flaps in dogs is independent of base width as measured immediately after outlining and elevation.

Arteriovenous intestinal communications in shock. Experimental study using tagged microspheres.

Microspheres 25 plus or minus 5 microns in diameter labeled with Ce141 and Sr85 were used to study the influence of oligemic shock on any arteriovenous anastomoses of the small intestine mucosa of dogs and rabbits. We found no open AVA's larger than 20 microns in diameter either before or during oligemic shock.

Uterine prostaglandin E secretion and uterine blood flow in the pregnant rabbit.

Studies were performed in pregnant rabbits to assess the effect of inhibition of prostaglandin synthesis on uterine blood flow. Cardiac output and uteroplacental blood flow (UPBF) were measured using radiolabeled microspheres. Prostaglandin E (PGE) concentration was measured by radioimmunoassay in the uterine vein and peripheral artery of the pregnant nephrectomized rabbit. Either meclofenamate or indomethacin 2 mg/kg were utilized to inhibit prostaglandin synthesis. Systemic arterial pressure increased from 86 mm Hg to 98 mm Hg (P less than0.0001) after prostaglandin inhibition. Cardiac output was unchanged after the inhibition of prostaglandin synthesis, 326 ml/min to 7.8 ml/min. Uterine vein PGE concentration was extremely high, 172.4 ng/ml, with concomitant peripheral arterial PGE 2.1 NG/ML. Intravenous administration of either meclofenamate or indomethacin reduced uterine vein PGE to 23 ng/ml (P less than 0.01) and arterial PGE to 1.0 ng/ml (P less than 0.05). Male and nonpregnant female rabbits had lower arterial PGE, 0.37 ng/ml (P less 0.05). Studies in non-nephrectomized pregnant animals demonstrated that uteroplacental secretion of PGE was greater than five times renal secretion. These studies demonstrate that the rabbit uteroplacental unit is a rich source of PGE and suggest that production of the vasoactive lipid may have a key role in regulating UPBF during pregnancy.

Variable effects of heart rate on phasic and regional left ventricular muscle blood flow in anaesthetized dogs.

Tachycardia to 240 beats/min in anaesthetized dogs increases coronary blood flow while flow in the left ventricular wall remains homogeneous. An arteriovenous fistula causes subendocardial ischaemia at 120 beats/min but pacing to 180 to 210 beats/min increases subendocardial blood flow by increasing diastolic coronary driving pressure per minute.

Influence of perfusion pressure and heart rate on local myocardial flow in the collateralized heart with chronic coronary occlusion.

We studied the influence of controlled changes in perfusion pressure and heart rate on the regional distribution of myocardial flow in normal dogs and in dogs with multiple chronic coronary artery occlusions but without infarctions. Local myocardial blood flow was determined with the tracer microsphere technique. By stepwise altering of systemic blood pressure during maximal vasodilation classical pressure flow relations were obtained. One week after complete chronic occlusion a functionally and anatomically well-defined compartmentation of blood flow was found. The dilatory reserve is clearly compromised not only in the collateral-dependent myocardium but also in the apparently normal myocardium which delivers collateral flow. An "arterio-arterial shunting" mechanism is shown to exist. Several months after coronary occlusion, regional mycoardial flow is still nonhomogeneous. Although the coronary dilatory capacity of the collateralized myocardium is nearly normal, that of the normal myocardium is found to be higher than normal. Vessel growth in both areas is discussed as being responsible for this phenomenon. Right ventricular pacing during maximal vasodilation produces a flow decrease to the endocardial muscle layers in normal dogs, while the epicardial flow is unchanged. One week after complete chronic coronary occlusion pacing during maximal vasocilation reduces the dilatory capacity in the collateralized areas to such an extent that the supplementary increase in myocardial oxygen demand will induce ischemia because of the compromised oxygen supply.

Coronary collateral blood flow in acute myocardial infarction.

The evolution and transmural distribution of coronary collateral blood flow in acute myocardial infarction was determined in 24 trained, unanesthetized dogs by injection of radioactive microspheres into the coronary circulation. Acute coronary artery occlusion resulted in a greater decrease in subendocardial flow than subepicardial flow in both the central and marginal zones of the infarct. Coronary collateral blood flow was distributed primarily to the marginal zone and to the subepicardium of the central zone of the infarct. The greatest increase in collateral flow occured between 12 and 18 hours after coronary artery occlusion. By 24 hours after coronary occlusion, blood flow to all areas of the infarct except the subendocardium of the central zone had returned to near control levels. This dispropotionate distribution of coronary collateral blood flow during the early stages of myocardial ischemic injury helps to explain the apparent lack of protection of the subendocardium by collateral flow.

Changes in regional coronary blood flow with hypertonic mannitol in conscious dogs.

Systemic haemodynamics and regional myocardial blood flow responses to hypertonic mannitol were studied in 10 conscious and 23 anaesthetized dogs. Mannitol infusion significantly increased regional myocardial blood flow in the conscious, intact dogs. Mannitol increased total coronary flow 20% in anasethetized animals compared to 80% in the awake ones. In both groups mannitol exerted a significant positive inotropic effect as evidenced by increases in maximal LV dp/dt and dp/dt/p. These studies have also demonstrated that the intact conscious dog that has not received any sedation has an inner:outer wall left ventricular flow ratio greater than 1-0.

The radioactive microsphere method for the assessment of regional myocardial blood flow after coronary artery occlusion. Inaccuracies due to variations in the diameter distribution of the spheres.

In this study, we have tried to determine the magnitude of the inaccuracy of the radioactive microsphere method - due to variations in the diameter distribution of the spheres - for measuring regional myocardial blood flow after coronary artery occlusion. In 5 mongrel dogs, three types of 15 mum microspheres, labelled with 125I, 141Ce or 85Sr, were injected simultaneously after the descending branch of the left coronary artery had been ligated. Myocardial samples wert taken from the left ventricle and divided into four groups according to the number of spheres per sample. The radioactivity of the various isotopes per gram tissue was expressed as percentage of their activity per milliliter of the reference sample. The diameter distribution of microspheres, labelled with each of the isotopes, was determined light-microscopically in suspensions belonging to three different batches. The relative error, as determined from the difference in relative radioactivity of the various types of microspheres in the tissue samples, was higher than the theoretical error for each of the number of spheres per sample. It is very likely that this discrepancy is caused by the differences in diameter distribution of the various types of microspheres, resulting in non-random error. The smaller spheres tended to go to low flow areas and the larger ones to high flow areas. Because of the non-randomness, the error due to diameter variations in the spheres can be diminished by randomizing the order of injection of the various isotopes. The present study indicates that the relatively high degree of accuracy of the microsphere method for the determination of blood flow to large parts of the myocardium with an unimpeded coronary circulation, as was described in literature, cannot be extrapolated to the determination of regional myocardial blood flow after coronary artery occlusion, when the combination of small tissue samples, variations in the diameter distribution of the spheres and an unevenly distributed myocardial blood flow unfavourably affect the accuracy of the method.

Myocardial blood flow distribution during ischemia-induced coronary vasodilation in the unanesthetized dog.

This study was designed to determine whether coronary vasodilation distal to a flow-limiting coronary artery stenosis could result in redistribution of myocardial blood flow to produce subendocardial underperfusion. Studies were performed in 10 awake dogs chronically prepared with electromagnetic flow-meters and hydraulic occluders on the left circumflex coronary artery. Regional myocardial blood flow was measured using radionuclide-labeled microspheres, 7-10 mum in diameter, injected into the left atrium. A 5(-s) coronary artery occlusion was followed by reactive hyperemia with excess inflow of arterial blood effecting 375+/-20% repayment of the blood flow debt incurred during occlusion. When, after a 5(-s) occlusion, the occluder was only partially released to hold arterial inflow to the preocclusion level for 20 s before complete release, the delayed reactive hyperemia was augmented (mean blood flow repayment = 610+/-45%, P < 0.01). This augmentation of the reactive hyperemia suggested that ischemia was continuing during the interval of coronary vasodilation when coronary inflow was at the preocclusion level. Measurements of regional myocardial blood flow demonstrated that endocardial flow slightly exceeded epicardial flow during control conditions. When arterial inflow was limited to the preocclusion rate during vasodilation after a 5(-s) total coronary artery occlusion, however, flow to the subepicardial myocardium was increased at the expense of underperfusion of the subendocardial myocardium. Thus, in the presence of a flow-limiting proximal coronary artery stenosis, ischemia-induced coronary vasodilation resulted in redistribution of myocardial blood flow with production of subendocardial ischemia in the presence of a net volume of arterial inflow which, if properly distributed, would have been adequate to prevent myocardial ischemia.