The effects of deferoxamine mesylate on gallium-67 distribution in normal and abscess-bearing animals: concise communication.

Deferoxamine mesylate (DFO), given to rabbits 20 min after gallium-67 citrate, induces prompt and rapid urinary excretion of Ga-67 activity with concommitant decrease in blood and muscle activity. When DFO is given after 2 hr or later, the effect is smaller (15% decrease in blood activity compared with 50%). In abscess-bearing rats the same effect was observed: DFO accelerated the Ga-67 blood clearance by increasing urinary excretion. Tissue-distribution studies and direct counting of abscesses showed that DFO lowers Ga-67 activity in all organs as well as in the abscess if given 2 or 4 hr after Ga-67 citrate, but the abscess-to-blood ratio increases. At 24 hr after Ga-67 citrate, DFO administration causes an improvement in the ratios of abscess-to-blood and abscess-to-normal tissue. Thus, DFO could be used to decrease the radiation burden from Ga-67 citrate after imaging has been performed, and also to increase the target-to-nontarget ratio.

Imaging of cocaine-induced global and regional myocardial ischemia.

Severe and often fatal cardiac complications have been reported in cocaine users with narrowed coronary arteries caused by atherosclerosis as well as in young adults with normal coronaries. We have found that in normal dogs cocaine induces severe temporary hypoperfusion of the left ventricle as indicated by a significantly lower 201Tl concentration compared to the baseline state. The most significant decrease in uptake occurred 5 min after injection and was more pronounced in the septal and apical segments. Following intravenous administration of cocaine, instead of gradual disappearance of 201Tl from the left ventricle, there was continuous increase in 201Tl concentration in the left ventricle. These imaging experiments indicate that the deleterious effects of cocaine on the heart are probably due to spasm of the coronaries and decreased myocardial perfusion. Since spasm of the large subpericardial vessels does not seem to explain the magnitude of the increased coronary resistance and decreased coronary flow after cocaine as described in the literature, it is suggested that microvascular spasm of smaller vessels plays a major role in the temporary decrease in perfusion. The data may also suggest that severe temporary myocardial ischemia is probably the initiating factor for the cardiac complications induced by cocaine.

Possible enhancement of 67Ga-citrate imaging by iron dextran.

The whole-body retention of 67Ga-citrate was studied in intact and in abscess-bearing rabbits. The abscess-to-muscle ratio was obtained using a data processor. Administration of iron dextran lowers the whole-body retention in both the intact and abscess-bearing animals. The optimum time for administering the iron dextran was 24 hr after the 67Ga-citrate injection. At this time, the abscess-to-muscle ratio was highest and the cathode-ray screen images showed lowered back-ground activity and much better definition of the lesion.

Analysis of liver scanning in a general hospital.

The specificity and sensitivity of liver scanning in a general referral population of 125 patients was studied. All patients had a liver biopsy prior to the scan or not more than 10 days later. The results of this study were compared with one earlier and one ongoing study in the same laboratory. The differences in accuracy are mostly attributable to the difference in the populations studied. It is apparent that the multiple-view scintillation camera technique is not superior to the rectilinear two-view scans for studying the liver.

Role of iron-binding proteins and enhanced capillary permeability on the accumulation of gallium-67.

We studied the role of the iron-binding proteins transferrin and lactoferrin and of increased capillary permeability on the accumulation of gallium-67 in rabbits. Intramuscular injection of histamine caused accumulation of gallium-67 (injected i.v. as citrate), and of Tc-99m DTPA, at the i.m. injection site. Normal saline and albumin did not. Intramuscular injection of transferrin or lactoferrin similarly caused Ga-67 uptake. No accumulation of Tc-99m DTPA was observed at the site of transferrin injection but there was a slight accumulation at the site of lactoferrin injection. Prior saturation of transferrin or lactoferrin with ferric ion abolished their effect on Ga-67 accumulation. Gallium-67, pre-bound to transferrin vitro, did not accumulate at the site of histamine or transferrin injection, but there was a slight accumulation at the lactoferrin site. Our results suggest that either increased capillary permeability or iron-binding progeins can cause local uptake of Ga-67. Since these factors are present at sites of inflammation, they may contribute to the accumulation of gallium in inflammatory lesions.

Detection of cardiomyopathy in an animal model using quantitative autoradiography.

A fatty acid analog (15-p-iodophenyl)-3,3 dimethyl-pentadecanoic acid (DMIPP) was studied in cardiomyopathic (CM) and normal age-matched Syrian hamsters. Dual tracer quantitative wholebody autoradiography (QARG) with DMIPP and 2-[14C(U)]-2-deoxy-2-fluoro-D-glucose (FDG) or with FDG and 201Tl enabled comparison of the uptake of a fatty acid and a glucose analog with the blood flow. These comparisons were carried out at the onset and mid-stage of the disease before congestive failure developed. Groups of CM and normal animals were treated with verapamil from the age of 26 days, before the onset of the disease for 41 days. In CM hearts, areas of decreased DMIPP uptake were seen. These areas were much larger than the decrease in uptake of FDG or 201Tl. In early CM only minimal changes in FDG or 201Tl uptake were observed as compared to controls. Treatment of CM-prone animals with verapamil prevented any changes in DMIPP, FDG, or 201Tl uptake. DMIPP seems to be a more sensitive indicator of early cardiomyopathic changes as compared to 201Tl or FDG. The trial of DMIPP and SPECT in the diagnosis of human disease, as well as for monitoring the effects of drugs which may prevent it seems to be warranted.

Cortex perfusion index: a sensitive detector of acute rejection crisis in transplanted kidneys.

Damage to the renal cortical microcirculation, an early event in the course of acute rejection crisis (ARC), usually precedes measurable functional derangements in the transplanted kidney. Direct assessment of cortical blood flow by radionuclide renography may provide a sensitive and reliable index to the diagnosis of ARC, with particular regard to the differential diagnosis of ARC and ATN. Computer generated time-activity curves of global, cortical, and medullary renal blood flow were analyzed in 67 instances (35 patients) of renal allograft dysfunction and correlated with needle biopsy of these kidneys. No increase in cortex perfusion index (CPI), i.e., decrease in cortical perfusion, was found when the patients were suffering from ureteral obstruction or drug and viral nephropathy (mean perfusion index (PI) increase (8%). In contrast, a marked increase in CPI of 193% was noted in ARC. Global and medullary PI increased only 116%. As a result, global and medullary PI were capable of diagnosing ARC in only 73% and 55% of the cases, respectively, whereby cortex PI correctly diagnosed ARC in 94% of the cases. Selective analysis of cortical perfusion may thus enhance the accuracy of [99mTc]DTPA scans (radionuclide renograph) for the early detection of ARC and in differentiating ARC from nonimmunological causes of kidney allograft dysfunction.

Regional left ventricular filling: does it reflect diastolic abnormalities in contiguous areas of myocardium?

To test the hypothesis that regional left ventricular filling reflects diastolic changes in contiguous areas of myocardium, we performed radionuclide ventriculograms on normal subjects, patients with left anterior descending coronary artery disease, and patients with anteroseptal myocardial infarctions. We reasoned that because diastolic properties of the anteroseptal myocardium should be different in the three groups of patients, regional filling in the anteroseptal area of the left ventricle should also be different, if regional filling does, indeed, reflect diastolic changes in the adjacent myocardium. While anteroseptal regional filling in the normal subjects was different than regional filling in the two patient groups, the degree of filling abnormality was similar in patients with and without myocardial infarctions. Our results suggest that regional left ventricular filling is not exclusively determined by diastolic changes in contiguous areas of myocardium.

Radioimmunoimaging of experimental thrombi in dogs using technetium-99m-labeled monoclonal antibody fragments reactive with human platelets.

Monoclonal antibody 50H.19, which reacts with human platelets, was converted to fragments, pretinned, and made into kits for subsequent radiolabeling with 99mTc. The antibody, which cross-reacts with dog platelets, was used to evaluate in vitro binding to blood clots and in vivo in experimental thrombi in dogs. After radiolabeling, 97.4 +/- 6.4% of the 99mTc was antibody-associated. The preparations retained immunoreactivity, as determined by: binding studies using whole blood and determining the ratio of cell-to-plasma radioactivity (ratios of 57.6-61.2) and binding of the antibody to clots (clot/serum ratios were 57.2-74.6%). Approximately 50% of the radioactivity was cleared from the blood in 3-6 min and 18-24% was excreted in urine within 3 hr. Experimental thrombi in dogs could be visualized consistently within 2-3 hr postinjection in peripheral veins and arteries, pulmonary arteries, and the right ventricle. In addition, damage to blood vessel intima without visible thrombi could also be detected. This method has the following advantages: short and simple pre-imaging preparation, and rapid visualization of thrombi with no need for blood-pool subtraction or delayed imaging.

Acute response to elastase in sheep lungs measured with Ga-67.

The early inflammatory changes in sheep's lungs were studied with Ga-67 citrate, injected i.v. immediately following intrabronchial instillation of different doses of elastase into the right diaphragmatic lobes of 15 sheep. The elastase-induced lesions in the first five sheep (two received 4,000 units; three got 6,000) were imaged up to seven times in an 8-day period to measure the temporal changes in the lesion and to select the appropriate imaging time; the other ten sheep (800-8,000 units) were imaged once at 52 hr. Localization of Ga-67, as seen on the posterior and right lateral projections, was confined to a well-circumscribed region in the right lung field. The lesion could be detected as early as 4 hr after elastase instillation. It decreased to 60% of its initial area at 4 hr, while the total Ga-67 activity in the sheep remained constant after 52-75 hr. Gallium-67 uptake in the lesion correlated positively with the dose of elastase (r = 0.88, p less than 0.001) and with the reduction in perfusion, as determined 4 wk after the elastase instillation (r = 0.66, p less than 0.05). Early Ga-67 uptake in inflammatory lung lesions could therefore be used as a reliable predictor of the size of the acute elastase-induced inflammatory reaction, as well as of the sequelae involving the regional vascular supply 4 wk later.

Quantitative autoradiography with radiopharmaceuticals, Part 2: Applications in radiopharmaceutical research: concise communication.

We describe the application of macroautoradiography, a relatively simple, quantifiable method for the evaluation of positron-emitting and gamma-emitting radiopharmaceuticals. We have investigated the response properties of two types of film to positron (F-18) and negatron (C-14) emitters. Variations in the response of film to increasing film-to-source distance are described, along with the effects of different intensifying screens and mounting tape. Digitization of whole-body autoradiograms (WBARG) in small animals was performed by using a videodensitometry system (videocamera interfaced to a computer). Quantitation was derived from analysis of a series of step-wedge standards that covered the range of radioactivities in the sample. By using a close-up lens on the videocamera, a 2- by 2-cm field is digitized as a 128 X 128 array, each pixel representing 156 X 156 micron. The effect of chlorpromazine (CPZ) on glucose metabolism in mice was studied by giving C-14 2DG followed by CPZ and F-18 FDG in the same animal. Muscle activity decreased and brown-fat activity increased. The high spatial resolution of this technique enables quantification in structures as small as the basal ganglia in mice. The use of dual-nuclide ARG permits each animal to be its own control, which greatly increases the utility of this method.

Ruthenium-97 DTPA: a new radiopharmaceutical for cisternography.

Ruthenium-97 DTPA (diethylenetriamine penta-acetic acid) was evaluated for its possible use as a cerebrospinal fluid imaging agent. Ru-97 has favorable physical properties that are highly suitable for imaging: decay by electron capture; gamma energy = 216 keV, 85%; T 1/2 = 2.9 days. Dogs were injected with 0.4 mCi Ru-97 DTPA or In-111 DTPA into the cisterna magna. The movement of the agents was monitored with a camera interfaced to a computer, or with a dual-probe system placed over the head and urinary bladder. In addition, blood and urine samples were collected at fixed intervals for 6 hr. High-quality images were obtained up to 48 hr after injection. The results show that the kinetics and excretion of Ru-97 DTPA are similar to those of In-111 DTPA. Radiation dose for identical activities is twice as high for In-111, in part because of greater abundance of the low-energy electron emission of In-111.

A fluorinated glucose analog, 2-fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection.

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.

Quantitative autoradiographic measurement of cocaine-induced regional myocardial metabolic changes in hypertensive rats.

A rat model of hypertensive cardiomyopathy was studied to evaluate the acute effects of cocaine on the myocardium. Using autoradiographic microimaging techniques, myocardial perfusion (201Tl) and energy substrate utilization (glucose: [14C]2-fluoro-2-deoxy-D-glucose-[14C]2DG and fatty acid (15-[p-iodophenyl])-3-R,S-methyl pentadecanoic acid-[131I]BMIPP) were studied in Dahl strain salt-sensitive normotensive and hypertensive rats with and without intravenous cocaine. The right ventricle, septum, endocardium and epicardium of the left ventricle were analyzed. Increased perfusion (18%) was seen in the myocardium of the hypertensive rats as compared to the normotensive rats. There was higher [14C]2DG (254%) and lower fatty acid (13.2%) uptake in the hypertensive rats, indicative of a shift from aerobic to anaerobic substrate utilization. In cocaine-treated normotensive rats, a generalized decrease in myocardial perfusion (30%) and increased glucose metabolism (89%) was seen. In cocaine-treated hypertensive rats, the increased myocardial perfusion (16%) was heterogeneous and was more pronounced in septum and epicardium. The endocardium and epicardium in the hypertensive rats showed an overall increase (23%) in glucose utilization after cocaine which was not as dramatic as was seen in the normotensive heart and a slight increase in fatty acid utilization. These results are consistent with prior observations that under pressure overload the myocardium responds non-uniformly. It may well be that the hypertensive cardiomyopathic heart is unable to respond to the challenge of cocaine by further increasing glucose utilization. These data obtained in an animal model of hypertension seem to indicate that hypertension may increase the risk of cardiac complications related to cocaine.

Abscess scintigraphy with 99mTc-human immunoglobulin (IgG) using a one-step labeling method.

It was shown earlier that non-specific human gamma globulin (IgG) labeled with 111In can be used as an agent for abscess localization. We describe experimental results with 99mTc-IgG in animals bearing abscesses and tumors using a one-step labeling method with 99mTc. We studied this compound in several animal models: mice bearing turpentine abscesses and subcutaneously transplanted sarcomas, in rats with turpentine or E. coli abscesses and intracerebrally implanted gliomas and in rabbits with E. coli or turpentine abscesses. Blood clearance was studied in dogs. It was found that the absolute concentration of 111In-IgG in abscess and tumor was higher than that of 99mTc-IgG. However, the abscess-to-tumor ratio was higher for 99mTc-IgG. The 99mTc-IgG images were of high quality and abscesses could be detected as early as 30 min post-injection (p.i.). It appears that 99mTc-IgG has many potential advantages over 111In-IgG because of better physical properties of 99mTc, simpler preparation, lower cost and greater availability and the possibility of using higher 99mTc doses.

Spatial and temporal distribution of cocaine and effects of pharmacological interventions: wholebody autoradiographic microimaging studies.

Whole body timed distribution of pharmacological doses of 14C-cocaine was studied in rats using quantitative autoradiographic microimaging. Rapid, intense uptake was seen in the brain, spinal cord, adrenals and nuchal brown fat pad. Clearance of cocaine was fastest from the cerebellum. Cortex activity reached soft tissue activity within 20 min. Uptake in the heart and adrenals was very intense following the same time course as in the brain. Kidney activity increased gradually at the same time as in the liver, probably representing specific binding as well as an excretory pathway of cocaine. Desipramine decreased uptake in the heart and adrenals and a piperazine derivative (GBR 12909) caused decreased uptake in the brain, heart and adrenals. Scopolamine, pentobarbital and cold cocaine caused decreased uptake in all organs and increased uptake (excretion) in the liver. Thus, cocaine appears to bind in the brain to the dopamine transporter and to a lesser extent to transporters for norepinephrine and serotonin. In the heart cocaine binds to norepinephrine, serotonin and dopamine. The targeting of cocaine to specific organs and the time sequence correspond to the pharmacological effects of cocaine.

Enhanced external counterpulsation as an adjunct to revascularization in unstable angina.

Enhanced external counterpulsation (EECP) is an effective noninvasive treatment for chronic stable angina. Despite intensive risk factor modification, a patient required two surgical coronary revascularizations and seven multivessel angioplasties over a 26-month period, demonstrating recurrent unstable angina and persistent thallium perfusion defects despite revascularization. Post EECP, angina was relieved, thallium defects were resolved and the patient has remained asymptomatic for 36 months.

Visualization of caput medusa in a patient with hepatoma.

A 70-year-old man presented with a history of alcohol abuse and three prior episodes of bleeding from esophageal varices. On physical examination, he had ascites and a bruit over the right lobe of the liver. A diagnosis of hepatoma was established by needle biopsy. Radionuclide studies demonstrated a photon-deficient region in the liver by Tc-99m sulfur colloid, which picked up Ga-67 citrate. Angiography with Tc-99m labeled RBCs demonstrated an arterioportal fistula and a caput medusa.

Increased pulmonary technetium-99m DTPA accumulation in a patient with Goodpasture's syndrome.

Goodpasture's syndrome is characterized by the triad of glomerulonephritis, intra-alveolar pulmonary hemorrhage, and presence of antiglomerular basement membrane antibodies. It has been shown earlier that intra-alveolar hemorrhage can be detected with radioisotopic techniques. A patient with Goodpasture's syndrome showing increased pulmonary accumulation of Tc-99m DTPA with no evidence of pulmonary hemorrhage is presented.

Asymmetric gallbladder contraction following cholecystokinin hepatobiliary imaging.

Three patients are presented with abnormal hepatobiliary images. A slow infusion of the terminal octapeptide of cholecystokinin caused asymmetric contraction in all three. Two of the patients displayed a bilobate appearance of the gallbladder. In one of the patients, there were typical changes associated with adenomyomatosis by other imaging modalities. The third patient showed good contraction of the fundus of the gallbladder but not of the proximal segment. In two of the patients, the global ejection fraction was considered to be normal. The asymmetrical contraction under the stimulus of cholecystokinin may be an important indicator of biliary dysfunction despite a normal ejection fraction.