Slow Washout Research Articles

Effect of coronary blood flow on thallium-201 uptake and washout.

Myocardial uptake and washout of thallium-201 (201TI) were studied in an experimental dog model in which regional blood flow to the posterior wall was varied by transient 2-minute occlusion of the circumflex coronary artery to produce transient ischemia and reactive hyperemia. Thallium-201 myocardial activity in a region of interest was determined continuously after i.v. administration by a gamma camera and computer program. Activity in the posterior wall was compared with that in the anterior wall in the same dog and the posterior wall of control dogs. Thallium-201 uptake was directly related to blood flow. With reactive hyperemia, there was a rapid and absolute increase in uptake followed by rapid washout; with ischemia, there was slow and decreased uptake followed by a slow washout. The calculated myocardial activity during washout in both ischemic and hyperemic areas approached values in control dogs long after blood flow had returned to baseline levels. Significant differences in washout slopes were found between the three groups of dogs (-0.156%/min in control dogs, -0.244%/min after reactive hyperemia, and -0.076%/min after transient ischemia, with half-washout times of 5.3 hours, 3.4 hours and 11.0 hours, respectively). These data suggest that both the initial decrease in activity in the ischemic area and the initial excess in the hyperemic area are corrected by different washout rates of ischemic and hyperemic cells during redistribution.

Pattern of diffuse slow washout of thallium-201 from the myocardium: Its clinical and angiographic correlates

Pattern of diffuse slow washout of thallium-201 from the myocardium: Its clinical and angiographic correlates

Detection and quantitation of myocardial infarction in vivo using transmission computed tomography.

In vivo studies were performed on 28 dogs to evaluate the usefulness of transmission computed tomography (CT) in the detection and quantitation of experimentally induced myocardial infarction. Intravenously administered contrast material was required to define the internal structure of the heart and to differentiate normal from infarcted tissue. Transmural infarcts with homogeneous central regions were visualized as areas of diminished contrast enhancement compared with the normal myocardium. All transmural infarcts of at least 24 hours' duration showed a surrounding border zone of patchy necrosis that was variable in size and had high CT numbers due to slow washout of the contrast material from this region. Infarct area determined from the images for individual slices correlated well (r = 0.976) with that calculated using pathology. The technique is very sensitive and can detect infarction within a papillary muscle. Nontransmural or patchy infarcts show up as areas of diffuse contrast enhancement without a central core of diminished enhancement. The distribution of the contrast material is similar to that of technetium-99m pyrophosphate in the border zone of the infarct in infusion studies, but in bolus studies it behaves more like thallium-201.

A FLUORINATED GLUCOSE ANALOG, 2-FLUORO-2-DEOXY-D-GLUCOSE (F-18)

Rapid uptake of F-18 FDG was observed in a variety of transplanted and spontaneous tumors in animals. The tumor uptake reached a peak by 30 min and remained relatively constant up to 60 min, with a very slow wash-out of F-18 activity from the tumor thereafter. Tumor-to-normal tissue and tumor-to-blood ratios ranged from 2.10-9.15 and 2.61-17.82, respectively, depending on the type of tumor. A scintiscan of a seminoma in a dog showed very high uptake in the viable part and lack of uptake in the necrotic mass. Toxicological studies in mice using 1000 times human tracer dose (HTD) per wk for 3 wk and in dogs using 50 times HTD per wk for 3 wk did not show any evidence of acute or chronic toxicity.

Facilitation by ‘low sodium-urea’ medium of the washout of dopamine β-hydroxylase released by potassium ions from the perfused rabbit heart

Rabbit hearts were perfused for 2 or 30 min at a constant flow with high K-low Na solution (equimolar substitution of 132 mM NaCl of Tyrode's solution by KCl). The perfusates were collected in 5 min periods and assayed for noradrenaline and dopamine β-hydroxylase activity. High K-low Na solution perfused for 30 min caused a pronounced noradrenaline output with the peak at 0–5 min which subsequently declined exponentially with time. In contrast, the dopamine β-hy-droxylase output rose slowly to its maximum at 15–20 min. If high K-low Na solution was administered for 2 min it failed to produce a peak in the output of dopamine β-hydroxylase. The lack of coincidence of noradrenaline and dopamine β-hydroxylase outputs might have been due to either a slow washout of the enzyme or to a larger ratio of dopamine β-hydroxylase to noradrenaline at 15 than at 5 min. Methacholine (320 μM) or calcium deprivation which preferentially blocked the initial noradrenaline overflow greatly reduced the total output of dopamine β-hydroxylase and abolished the dopamine β-hydroxylase peak at 15–20 min. In the following experiments low Na-urea solution (substitution of 132 mM NaCl of Tyrode's solution by 242 mM urea) was employed to accelerate the washout of dopamine β-hydroxylase. Perfusion of the hearts with high K-low Na for 2 min, followed by low Na-urea solution, evoked a dopamine β-hydroxylase peak already at 5–10 min. The total output of dopamine β-hydroxylase was larger than the combined outputs to be expected of high K-low Na and low Na-urea solutions. The total noradrenaline output was approximately the sum of that during high K-low Na and low Na-urea perfusion. It is concluded that the maximum rate of dopamine β-hydroxylase release evoked by high K-low Na medium occurs at the same time as the initial large noradrenaline overflow that is calcium-dependent and subject to presynaptic muscarinic inhibition. However, there is a delay in the washout of the large compared with the small molecule. Thus, low Na-urea solution can be used as a tool to accelerate the washout of dopamine β-hydroxylase from the perfused rabbit heart.

Immunological studies in cystic fibrosis.

Fibroblast activation protein (FAP), which promotes tumor growth and progression, is overexpressed in cancer-associated fibroblasts of many human epithelial cancers. Owing to its low expression in normal organs, FAP is an excellent target for theranostics. In this study, we used radionuclides with relatively long half-lives, ⁶⁴Cu (half-life = 12.7 h) and ²²⁵Ac (half-life = 10 days), to label FAP inhibitors (FAPI) in mice with human pancreatic cancer xenografts. <b>Methods:</b> Male nude mice (body weight = 22.5 ± 1.2 g) were subcutaneously injected with human pancreatic cancer cells (PANC-1, <i>n</i> = 12; MIA PaCa-2, <i>n</i> = 8). Tumor xenograft mice were investigated after the intravenous injection of ⁶⁴Cu-FAPI-04 (7.21 ± 0.46 MBq) by dynamic and delayed PET scans (2.5 h post injection). Static scans 1 h after the injection of ⁶⁸Ga-FAPI-04 (3.6 ± 1.4 MBq) were also acquired for comparisons using the same cohort of mice (<i>n</i> = 8). Immunohistochemical staining was performed to confirm FAP expression in tumor xenografts using an FAP-alpha antibody. For radioligand therapy, ²²⁵Ac-FAPI-04 (34 kBq) was injected into PANC-1 xenograft mice (<i>n</i> = 6). Tumor size was monitored and compared to that of control mice (<i>n</i> = 6). <b>Results:</b> Dynamic imaging of ⁶⁴Cu-FAPI-04 showed rapid clearance through the kidneys and slow washout from tumors. Delayed PET imaging of ⁶⁴Cu-FAPI-04 showed mild uptake in tumors and relatively high uptake in the liver and intestine. Accumulation levels in the tumor or normal organs were significantly higher for ⁶⁴Cu-FAPI-04 than ⁶⁸Ga-FAPI-04, except in the heart, and excretion in the urine was higher for ⁶⁸Ga-FAPI-04 than ⁶⁴Cu-FAPI-04. Immunohistochemical staining revealed abundant FAP expression in the stroma of xenografts. ²²⁵Ac-FAPI-04 injection showed significant tumor growth suppression in the PANC-1 xenograft mice compared to the control mice, without a significant change in body weight. <b>Conclusion:</b> This proof of concept study showed that ⁶⁴Cu-FAPI-04 and ²²⁵Ac-FAPI-04 could be used in theranostics for the treatment of FAP-expressing pancreatic cancer. Alpha therapy targeting FAP in the cancer stroma is effective and will contribute to the development of a new treatment strategy.

Effects of nicotine on distribution and release of 14C-norepinephrine and 14C-dopamine in rat brain striatum and hypothalamus slices

The effects of nicotine on the uptake and cellular distribution of 14C-norepinephrine ( 14C-NE)and 14C-dopamine ( 14C-DA) were examined in slices prepared from rat brain striatum and hypothalamus. Nicotine inhibited the uptake of both 14C-labelled norepinephrine and dopamine only in hypothalamus slices. Under similar incubation conditions, washout experiments with striatum and hypothalamus slices indicated that nicotine decreased the amount of 14C-NE and 14C-DA present in the slow washout component of the hypothalamus but did not alter 14C-labelled contents in the striatum. Addition of 0.62 mM nicotine produced a sustained increase in 14C-NE efflux from brain slices; the presence of desipramine or the absence of either sodium or calcium ions in the washout solution did not alter this nicotine-induced increase. These findings support the hypothesis that the nicotine-induced release of norepinephrine in the hypothalamus occurs by a specific and direct action at cellular amine binding sites or stores.

Colchicine-binding protein and the secretion of thyroid hormone.

The role of microtubules in the thyrotropin- or adenosine 3',5' cyclic monophosphate (cyclic AMP)-stimulated accumulation of cytoplasmic colloid droplets and secretion of iodine from the mouse thyroid gland has been investigated by means of different classes of agents that affect the stability of microtubules. The onset of inhibition of secretion by colchicine, the uptake of colchicine-(3)H by thyroid lobes, and the binding of colchicine-(3)H to thyroidal soluble protein are shown to have similar time courses Colloid droplet accumulation is also inhibited and does not readily resume upon removal of colchicine from the medium. This appears to be due to the slow washout of the drug (t((1/2)) approximately hr). Thyroids contain a soluble colchicine-binding protein that resembles microtubule proteins of other tissues with respect to apparent K(m) for colchicine, pH optimum, and stability characteristics Colchicine analogues inhibit iodine secretion and colchicine binding in a parallel manner and as a function of their antimitotic potencies. Microtubule-stabilizing agents such as hexylene glycol and D(2)O also inhibit secretion. Thus, inhibition of thyroid secretion by antimitotic agents appears to be mediated by an effect on microtubules. The inhibitory locus of colchicine inhibition occurs after the generation of cyclic AMP, since stimulation of secretion by this nucleotide is blocked by colchicine, whereas thyroid-stimulating hormone-induced accumulation of cyclic AMP is not affected. Thus, the functioning microtubule appears to play a role in the induction of colloid endocytosis.

Pulmonary angiography in pulmonary embolic disease.

Pulmonary emboli were produced in 15 dogs and studied with serial angiography. The most common angiographic sign in the embolized animal was a filling defect and/or a cut-off, with or without regional delay in arterial flow. Less common findings were regional hypovascularity, slow arterial washout with capillary staining, tapered arteries, and beading of small vessels.Two hundred patients were studied with pulmonary angiography for the possible diagnosis of pulmonary emboli. On the basis of pathologic proof in 28 cases (13 with emboli and 15 without pulmonary emboli), criteria were established for the angiographic diagnosis of pulmonary emboli. The most important finding was a filling defect and/or cut-off, with and without regional delay in arterial flow. In 58 patients with these angiographic findings who survived, a high incidence of the clinical findings of pulmonary emboli was found.Less significant pulmonary angiographic findings noted in the dog were found to be associated with many unrelated cardi...