[Equipment for modification of nuclear medicine lung diagnosis as triggered SPECT--presentation, phantom studies and clinical value].
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Humans↗
Biomedical subjects
J Kropp
Publications and source records attributed to J Kropp.
Effects of configuration on the myocardial uptake of radioiodinated 3(R)-BMIPP and 3(S)-BMIPP in rats.
UNLABELLED: Radioiodinated 3(R)-(+)- and 3(S)-(-)-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) were prepared and evaluated in rats to investigate the effects of absolute configuration of the 3(beta)-methyl group on myocardial uptake and release kinetics. METHODS: The 3(R)-(+)-BMIPP analog was synthesized by initial acylation of a thiophene template with the acid chloride of ethyl 3(R)-methylglutarate. 3(S)-(-)-BMIPP was obtained by separation from the mixture of diastereomeric amides prepared from reaction of the acid chloride of racemic BMIPP with the S-(-)-alpha-methylbenzylamine. The amide of synthetic 3(R)-BMIPP prepared from S-(-)-alpha-methylbenzylamine was identical to the chromatographically more polar isomer. Free acids were obtained by acid hydrolysis of the amides, fully characterized and then converted to the radioiodinated BMIPP isomers. RESULTS: Biodistribution studies in rats with the dual-labeled [(131)I]-3(S)-BMIPP/[(125)I]-3(R)-BMIPP mixture demonstrated greater myocardial uptake of 3(R)-BMIPP compared with the 3(S)-BMIPP isomer [60 min: 3(R)-BMIPP = 4.37 %ID/g; 3(S)-BMIPP = 3.44; p < 0.05; 180 min, 2.31 and 1.78 %ID/G, respectively, p < 0.01], although both isomers had similar myocardial washout curves (5-180 min). Percent ID/g values for other tissues which were examined (blood, lungs, thyroid) were similar. CONCLUSION: Higher myocardial uptake of the 3(R)-BMIPP isomer observed in these animal studies may suggest differences in carrier-mediated myocyte uptake of the two isomers. These studies suggest that [(123)I]-3(R)-BMIPP is a candidate for clinical evaluation and may show greater myocardial uptake than the 3(S)-BMIPP isomer and may thus require reduced injected dose.
Animals↗
Both total chain length and position of dimethyl-branching effect the myocardial uptake and retention of radioiodinated analogues of 15-(p-iodophenyl)-3,3-dimethylpentadecanoic acid (DMIPP).
Introduction of geminal dimethyl-branching into the 3-position of 15-(p-iodophenyl) pentadecanoic acid (IPPA) significantly delays myocardial clearance in rats and dogs following intravenous administration. Several new analogues of DMIPP have been synthesized and evaluated in fasted rats. The effects of both the position of dimethyl-branching and the total chain-length of 3, 3-dimethyl analogues on heart uptake and clearance kinetics have been studied. In the first series of compounds, two methyl groups were introduced into the 3-, 4-, 6-, or 9- position. Tissue distribution studies of the 15-(p-[I-125] iodophenyl)-analogues demonstrated that the position of dimethyl-branching is an important factor affecting both myocardial specificity and retention. The [I-125] labeled 3,3- and 4,4-DMIPP analogues showed higher myocardial uptake and faster blood clearance than the 6,6- and 9,9-DMIPP analogues [heart, % dose/gm heart: blood), 30 min: 3,3-DMIPP = 5.06 (12:1); 4,4-DMIPP = 8.03 (16.7: 1); 6,6-DMIPP = 2.26 (3.1:1); 9,9-DMIPP = 3.06 (2.77)]. In the second series, the effects of total fatty acid chain length were evaluated with 3,3-dimethyl-substituted analogues with C11, C12, C13, C14, C15, and C19 chain lengths. The C14 and C15 chain length analogues showed the best properties [global heart: blood ratios): 30 min: C11, 0.70 (0.82); C12, 1.25 (0.68); C13, 0.47 (0.90); C14, 1.63 (3.54); C15, 5.06 (12); C19. 1.29 (0.82). These detailed studies have demonstrated that both total chain length and the position of geminal dimethyl-branching are important structural parameters which affect myocardial specificity and retention of omega-(p-iodophenyl)-substituted fatty acid analogues and that 3,3-DMIPP and 4,4-DMIPP are the best candidates with optimal properties for further study.
Animals↗
Pharmacokinetics of radioiodinated fatty acid myocardial imaging agents in animal models and human studies.
Since the oxidation of long chain fatty acids is the major pathway for energy production for the normoxic myocardium, the use of radiolabeled fatty acids for myocardial imaging continues to be a major area of both basic and clinical research. This paper focuses on a discussion of the kinetics of myocardial uptake of radioiodinated fatty acids, including planar and SPECT imaging of various iodine-123-labeled analogues, and data from animal and isolated heart studies, and where possible, comparison with results of clinical studies. Key examples include iodoalkyl-substituted straight chain fatty acids such as 17-IHDA (17-iodoheptadecanoic acid). These analogues are rapidly metabolized in the myocardium, resulting in release of free radioiodide, and can only be practically used for planar imaging. Terminal iodophenyl-substituted fatty acids illustrate a successful approach of stabilizing radioiodine to overcome the release of free iodide encountered with the straight-chain analogues. These analogues, exemplified by p-IPPA [15-(p-iodophenyl)pentadecanoic acid], are widely used in clinical practice. Although washout can be delayed by increase in the arterial lactate levels by mild exercise, SPECT imaging must still be carefully timed. In contrast to these examples, the ortho iodide-substituted IPPA isomer (ortho- instead of para-phenyl substitution of radioiodide) is a unique example which shows rapid myocardial washout in laboratory animals but nearly irreversible retention in humans. Introduction of methyl-branching is a major important approach which has been successfully used to alter tracer kinetics of radioiodinated fatty acids by increasing myocardial retention. A key example in this class of compounds is 3-(R,S)-BMIPP [15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid], an analogue of p-IPPA in which methyl-branching has been introduced into the beta-position of the carbon chain. Although tracer washout is significantly delayed with this structural perturbation, a large number of clinical studies have shown that slow myocardial washout is still observed. Detailed biochemical studies with radioiodinated 3-BMIPP have demonstrated that initial alpha-oxidation produces a metabolite that can then be catabolized by alpha-oxidation. An unexpected and important observation with the (123I]-3-(R,S)-BMIPP agent has been the mis-match between perfusion tracer distribution and the regional BMIPP distribution which has been widely observed in jeopardized, but viable myocardial regions. Another example in the methyl-branched series is DMIPP [15-(p-iodophenyl)- 3,3-dimethylpentadecanoic acid], which has very prolonged myocardial retention and slow washout kinetics although only animal studies have been reported with this agent. Still another more recent approach has been the synthesis and laboratory animal and human evaluation of analogues containing a phenylene bridge in the fatty acid chain. One example is 3-10 [13-(4'-iodophenyl)]-3-(p-phenylene)tridecanoic acid (PHIPA 3-10), which has also proven successful in delaying myocardial tracer washout. This paper focuses on a discussion of the effects of molecular structure on the myocardial uptake and release of these various radioiodinated fatty acid analogues.
Animals↗
Iodine-123-labelled fatty acids for myocardial single-photon emission tomography: current status and future perspectives.
Renewed interest in the clinical use of iodine-123-labelled fatty acids is currently primarily focused on the use of iodine-123-labelled 15-(p-iodophenyl)pentadecanoic acid (IPPA) and "modified" fatty acid analogues such as 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid (BMIPP) which show delayed myocardial clearance, thus permitting single-photon emission tomographic imaging. Interest in the use of BMIPP and similar agents results from the differences which have often been observed in various types of heart disease between regional myocardial uptake patterns of [123I]BMIPP and flow tracer distribution. Although the physiological basis is not completely understood, differences between regional fatty acid and flow tracer distribution may reflect alterations in important parameters of metabolism which can be useful for patient management or therapy planning. These tracers may also represent unique metabolic probes for correlation of energy substrate metabolism with regional myocardial viability. The two agents currently most widely used clinically are 123I-labelled IPPA and BMIPP. While [123I]IPPA is commercially available as a radiopharmaceutical in Europe (Cygne) and Canada (Nordion), multicenter trials are in progress in the United States as a prelude to approval for broad use. [123I]BMIPP was recently introduced as Cardiodine for commercial distribution in Japan (Nihon Medi-Physics, Inc.). [123I]BMIPP is also being used in clinical studies on an institutional approval basis at several institutions in Europe and the United States. In this review, the development of a variety of radioiodinated fatty acids is discussed. The results of clinical trials with [123I]IPPA and [123I]BMIPP are discussed in detail, as are the future prospects for fatty acid imaging.
Animals↗
Cardiac SPECT with iodine-123-labeled fatty acids: evaluation of myocardial viability with BMIPP.
The use of 123I-labeled fatty acids is witnessing a resurgence of interest, primarily because of data from recent clinical protocols comparing regional myocardial uptake of 123I-labeled 15-(p-iodophenyl)-3-(R,S)-methylpentandecanoic acid (BMIPP) with flow tracers. Comparison of mismatches in BMIPP and flow tracer distribution (BMIPP < flow tracer) has demonstrated the usefulness of evaluating myocardial viability with BMIPP. BMIPP was introduced in 1993 as "Cardiodine" as an approved radiopharmaceutical in Japan by Nihon Medi-Physics, Inc. This article reviews the clinical use of BMIPP in the assessment of cardiomyopathy, myocardial infarction, ischemic heart disease and for the evaluation of myocardial viability in comparison with PET tracers. The results of two specific protocols demonstrating the utility of using BMIPP to detect viable myocardium are described in detail. The first study compares BMIPP and sestamibi uptake to wall motion and inotropic reserve after acute myocardial infarction in conjunction with two-dimensional echocardiography and low-dose dobutamine stimulation. The second example describes results of a triple SPECT technique using BMIPP reinjection for the assessment of ischemia.
Cardiomyopathies↗
Evaluation of pancreatic lipase activity by simple urine analysis after oral administration of a new iodine-131-labeled triglyceride.
A new iodine-131-labeled triglyceride analogue called "MIPAG" [1,2-dipalmitoyl-3-[(15-p-iodophenyl) pentadecan-1-oyl]rac-glycerol] has been prepared in which 15-(p-iodophenyl)pentadecanoic acid (IPPA) is attached to position-3. MIPAG has been developed for the evaluation of pancreatic exocrine function by simple urine analysis and has been evaluated in rats and humans. After oral administration, IPPA is released from the triglyceride by the action of pancreatic lipases followed by intestinal absorption and the principal IPPA metabolite (p-iodobenzoic acid, IBA) is primarily excreted in the urine. Excretion in the urine and feces was evaluated in rats, as well as the biodistribution in various organs over 21 days. Twenty patients without pancreatic disease (normals) and four patients without pancreatic insufficiency were also investigated. Following oral administration of 30 microCi of MIPAG, urine was collected for two successive 24-h periods. Blood samples were drawn and thin-layer chromatographic (TLC) analysis was performed on the serum lipid extracts. Urine from normals contained 44.9% +/- 7.7% and 61.8% +/- 8.4% of the administered activity after 24 and 48 h, respectively. The patients with pancreatic insufficiency excreted 13.1 +/- 5.6% and 18.9% +/- 6.2%, respectively, which was significantly decreased (P < 0.001) compared with normals. The TLC profiles showed an increasing proportion of IBA with time. Urine analysis after oral administration of MIPAG thus appears to be an attractive new techniques for the evaluation of pancreatic lipase activity by a simple urine analysis.
Animals↗
[Intra- and extrahepatic shunts in liver cirrhosis--evaluation by means of combined invasive nuclear medicine methods].
The use of combined invasive nuclear medicine procedures allows the estimation of intra- and extrahepatic shunt volumes in patients with liver cirrhosis. The investigations were carried out after transhepatic portography and injection of 99mTc-MAA into the peripheral portal vein (hilum of the spleen) as well as into the central portal vein (hilum of the liver). A subtraction technique allowed the evaluation of shunt volumes (percentage). In 32 out of 36 patients an extra-hepatic shunt volume of 29.2% (0%-84%) and an intra-hepatic shunt volume of 23.6% (0%-81%) was found. This technique may contribute to improving the results of shunt surgery.
Humans↗
Myocardial scintigraphy with iodine-123 phenylpentadecanoic acid and thallium-201 in patients with coronary artery disease: a comparative dual-isotope study.
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Coronary Disease↗
Inhalation scintigraphy with an ultrafine aerosol in infants with functional bronchial stenoses.
Evaporation of Tc-99m pertechnetate at about 2500 degrees C on a carbon surface generates an ultrafine aerosol of Tc-99m-labeled carbon clusters (Technegas). The small particle size of about 100 nm enables the aerosol to behave similarly to a gas in its ability to penetrate. After inhalation, the radioactive particles adhere to the walls of the respiratory bronchioles and alveoli, or to the greater bronchial tubes if the airflow is not laminar. The high concentration of radioactivity in the argon carrier gas makes it possible to perform inhalation scintigraphy after only a few breaths. The authors investigated 24 infants with multiple events of bronchitis, most of whom had pneumonia. Seventeen patients had inhalation scintigraphy and bronchoscopy. Of these, 11 had scans diagnostic of bronchial stenosis and 6 had normal scans. Except for two pathologic scans, all scintigraphic findings matched well with the results of bronchoscopy. Seven patients had scintigraphy only, of which four were normal. Inhalation scintigraphy with Technegas is a reliable, nonhazardous procedure to preselect young patients for directed bronchoscopy.
Aerosols↗
Tc-99m labeled monoclonal antibodies against granulocytes (BW 250/183) in the detection of appendicitis.
Scintigraphy with Tc-99m labeled antigranulocyte antibodies (BW 250/183 MoABs) was performed in 32 patients with suspected appendicitis. Abdominal imaging (planar/SPECT) was performed 2 hours after injection of the tracer. All patients also had surgery and a histologic examination of the resected tissue. Of the patients, 17 suffered from "acute appendicitis" and 12 had right positive scans (sensitivity = 70.6%). In 15 patients, acute appendicitis could have been ruled out, and in 11 of these cases the scan was true negative (specificity = 73.3%). The overall accuracy was 71.8% (23/32 cases). The use of Tc-99m antigranulocyte MoABs may overcome the problems associated with the Tc-99m HMPAO granulocyte and In-111 oxine approaches, which include nonspecific intestinal activity or the lack of timeliness. The use of Tc-99m labeled antigranulocyte antibodies is suitable as an emergency procedure and may play a role in the management of patients with suspected appendicitis.
Adolescent↗
Site-specific/stable radioiodination of 1,2-Pal-3-IPPA: an agent for the potential clinical evaluation of pancreatic insufficiency by urine analysis.
To measure pancreatic lipase activity, we synthesized a triglyceride containing a radioiodinated fatty acid. The urinary excretion of radioactivity was measured in five rats following administration of the agent by feeding tube. We attached 15-phenylpentadecanoic acid (PPA) to position-3 of 1,2-dipalmitoyl-rac-glycerol (1,2-Pal) to form 1,2-Pal-3-PPA. The 1,2-Pal-3-IPPA (expected lipase substrate) was prepared by the thallation-iodide displacement method. In a dual-label study, the 125I-1,2-Pal-3-IPPA triglyceride was administered with the 131I-IPPA free acid to rats (n = 5) by oral gavage. Urine and feces were collected daily and the tissue distribution of both tracers was evaluated over a five-day period. A significant portion of the administered activity was excreted in 24 hr in the urine (125I, 30.31% + 4.32%; 131I, 35.0% + 7.29%), which cochromatographed with hippuric acid by thin layer chromatography. Release of the acidic components from the conjugated excretory products by acid hydrolysis of the urine provided the radioactive acidic metabolites. Analysis of the Folch extracts of fat samples demonstrated that the radioactive components cochromatographed in the triglyceride region. This agent appears useful for the evaluation of various gastrointestinal diseases.
Animals↗
Incorporation of radioiodinated IPPA and BMIPP fatty acid analogues into complex lipids from isolated rat hearts.
Heart lipids were extracted by the Folch technique from Langendorff-perfused rat hearts after administration of 15-(p-[131I]iodophenyl)pentadecanoic acid and 15-(p-[125I]iodophenyl)-3-R,S-methylpentadecanoic acid. Techniques utilizing successive high performance liquid chromatographic (HPLC) analyses have been developed for the evaluation of the uptake of the tracers into neutral lipids and phospholipids of the rat hearts. Phospholipids were separated on a SiO2 column eluted with a gradient of acetonitrile/water (97.5/2.5) and acetonitrile/water (85/15) followed by separation of the neutral lipids on a C-18 reversed phase column with a gradient consisting of acetonitrile and 2-propanol/hexane (60/40) containing 1 N H2SO4 (5 microL/100 mL). Both tracers show the incorporation into the expected major lipid classes.
Animals↗
Effects of head-down tilt and saline loading on body weight, fluid, and electrolyte homeostasis in man.
We studied the effects of head-down tilt bedrest (HDT) on body weight, fluid and sodium homeostasis. A fluid load session with rapid intravenous infusion of 22 ml/kg body weight (BW) isotonic saline was performed before, during and after HDT. During the pre- and post HDT periods the test subjects were given a diet containing 2600 kcal/day. The energy intake was reduced to 2000 kcal/day during HDT. Water intake was kept constant at 40 ml/kg BW, sodium intake was 2.2 mmol/kg BW and protein intake was 1.4 g/kg BW, while the daily fat and carbohydrate intake was reduced during the HDT period. As expected plasma volume and BW changed rapidly in the beginning of HDT and during early recovery. A total body water loss of 0.6 l was observed within the second day after tilting. Plasma volume was reduced by 16% during HDT-bedrest. The time course of the body fluid loss paralleled a decrease in body sodium that then remained fairly constant during the HDT-bedrest period (except for the interference caused by the fluid loading on day S06). A restoration of body fluid and body sodium content occurred early in the recovery period. Fluid loading caused a negative fluid balance of 0.6-0.9 l over a 48 hr period following infusion regardless of the phase of the HDT study. These results demonstrate that under our strictly controlled conditions 1) HDT alters body fluid and sodium balances, 2) a standard fluid loading causes a net negative 3-day fluid balance during all phases of the study.
Adult↗
Technetium-99m-labeled anti-granulocyte antibodies in suspected bone infections.
The introduction of 99mTc-labeled anti-granulocyte antibodies seemed to provide advantages in comparison with formerly used in vitro methods to label autologous white blood cells for inflammation imaging. For this reason, we have undertaken a study to evaluate the clinical significance of this method. Thirty unselected patients with suspected bone infections were studied prospectively using the monoclonal 99mTc-labeled anti-granulocyte antibody. Twenty patients were referred with suspected infections of the peripheral bones (Group I), as well as 10 patients with suspected infections of the spine (Group II). Planar whole-body scans were performed 4 hr and 20 to 24 hr after administration of 500 MBq of the labeled antibody. Scans were considered positive for a bacterial (septic) infection when a focally increased antibody accumulation occurred. All scans were evaluated in blinded fashion by two experienced readers. Of the 20 studies from Group I patients, four false-positive scintigraphic findings were observed, and one false-negative, resulting in a specificity of only 64% and a sensitivity of 89%. In Group II (10 studies), five scans were true-negative, and five false-negative. For both groups, the specificity of the scintigraphic method was quite low (75%), and the sensitivity was also relatively low (57%). The results of this study demonstrate that in an unselected patient population in whom the diagnosis is not known, scintigraphy with 99mTc-anti-granulocyte antibodies is not a reliable method for detecting septic inflammatory lesions: In addition, use of this method excludes septic lesions with only a moderate likelihood (83% negative predictive value).
Adolescent↗
Dependence of blood volume changes on oral sodium uptake.
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Adult↗
[Scintigraphy with 123I-labelled fatty acids in coronary heart disease].
Forty-two patients (6 women, 36 men; mean age 55 [39-69] years), with one-, two- or three-vessel disease on coronary angiography, were studied using single-photon emission computer tomography with 15-p-123I-iodophenyl-pentadecanoic acid (IPPA), in order to evaluate this new method of demonstrating abnormalities of myocardial perfusion. The reference range for fatty acid turnover was determined in eleven controls (4 women, 7 men; mean age 41 [20-51] years) with no coronary stenosis. 185 MBq (5 mCi) of IPPA was administered intravenously during submaximal stress on a bicycle ergometer. Comparison between different regions of the tomograms revealed changes in fatty acid utilization typical of ischaemia. The sensitivity, specificity and predictive value of a positive result compared with coronary angiography were 95%, 89% and 93%, respectively, for the area supplied by the anterior interventricular artery, 92%, 91% and 93% for the circumflex branch and 89%, 91% and 90% for the right coronary artery. In 25 out of 31 patients (81%) with myocardial infarction, IPPA scintigraphy infarct localization agreed with the clinical findings. In two cases with unremarkable scintigrams left ventriculography showed hypokinesia, while in four cases neither method demonstrated any abnormality. There was one false-positive scintigram. IPPA scintigraphy has greater sensitivity and specificity than conventional nuclear medicine techniques in the demonstration of coronary heart disease.
Adult↗
Single photon emission tomography imaging of myocardial oxidative metabolism with 15-(p-[123I]iodophenyl) pentadecanoic acid in patients with coronary artery disease and aorto-coronary bypass graft surgery.
A total of 29 patients with coronary artery disease (CAD) were investigated with 15-(p-[123I] iodophenyl)pentadecanoic acid (123I-IPPA) and sequential single photon emission tomography (SPET). Of these, 19 were studied after aorto-coronary bypass graft surgery. Some 13 patients without evidence of CAD served as a control group. Two SPET studies (early and late) were carried out within 45 min after intravenous administration of 200 MBq 123I-IPPA at peak sub-maximal exercise. Semi-quantification of uptake (related to perfusion) and turnover (linked to metabolism) was obtained by segmental comparison of oblique slices. Taking coronary arteriography as the "gold standard", 123I-IPPA scintigraphy had the following figures of merit for sensitivity and specificity in the diagnosis of CAD: for the left anterior descending artery territory 93% and 95%, for the left circumflex artery region 96% and 92%, and for the right coronary artery territory 77% and 92%, respectively. In all, 90% of the reperfused myocardial segments showed an improvement of uptake. Of these, 61% exhibited increased turnover after revascularization and 39% had pathologic turnover and thus a dissociation of improvement of perfusion and oxidative metabolism after surgery.
Adult↗