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Annexin A5 (AnxA5) is a protein with high affinity for phosphatidyl serine, a phospholipid exposed on the cell surface during apoptosis. This phenomenon has been used for determination of cell death after myocardial infarction. To evaluate the potential of (99m)Tc-AnxA5 for in vivo scintigraphy of apoptotic cells, the pharmacokinetics and imaging properties of two radiopharmaceuticals, (99m)Tc-(n-1-imino-4-mercaptobutyl)-AnxA5 (I-AnxA5) and (99m)Tc-(4,5-bis(thioacetamido)pentanoyl)-AnxA5 (B-AnxA5), were studied. I-AnxA5 was administered intravenously to seven patients and one healthy volunteer, and B-AnxA5 was administered to 12 patients. All patients in the pharmacokinetic study had myocardial disease. Additionally, imaging was performed in a patient with acute myocardial infarction, as well as in three patients with different malignancies. The plasma concentration, excretion and biodistribution of (99m)Tc-AnxA5 were measured, as well as levels of AnxA5 antigen. The kinetic data of both radiopharmaceuticals in plasma fitted a two-compartment model. Both preparations had similar half-lives, but a different distribution over the two compartments. Plasma levels of AnxA5 antigen showed a broad variation. Both radiopharmaceuticals accumulated in the kidney, liver and gut. B-AnxA5 was excreted significantly faster than I-AnxA5. Both compounds can be used for imaging of the head/neck region, the thorax and the extremities. B-AnxA5 has a faster clearance and a lower radiation dose. Imaging of apoptosis in the abdomen will be difficult with both radiopharmaceuticals, and especially with B-AnxA5 because of its faster appearance in the gut. [ABSTRACT FROM AUTHOR]

Background: 6-[18F]Fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) is a frequently used radiopharmaceutical for detecting neuroendocrine and brain tumors and for the differential diagnosis of Parkinson’s disease. To meet the demand for FDOPA, a high-yield GMP-compliant production method is required. Therefore, this study aimed to improve the FDOPA production and quality control procedures to enable distribution of the radiopharmaceutical over distances.FDOPA was prepared by electrophilic fluorination of the trimethylstannyl precursor with [18F]F2, produced from [18O]2 via the double-shoot approach, leading to FDOPA with higher specific activity as compared to FDOPA which was synthesized, using [18F]F2 produced from 20Ne, leading to FDOPA with a lower specific activity. The quality control of the product was performed using a validated UPLC system and compared with quality control with a conventional HPLC system. Impurities were identified using UPLC-MS.Results: The [18O]2 double-shoot radionuclide production method yielded significantly more [18F]F2 with less carrier F2 than the conventional method starting from 20Ne. After adjustment of radiolabeling parameters substantially higher amounts of FDOPA with higher specific activity could be obtained. Quality control by UPLC was much faster and detected more side-products than HPLC. UPLC-MS showed that the most important side-product was FDOPA-quinone, rather than 6-hydroxydopa as suggested by the European Pharmacopoeia.Conclusion: The production and quality control of FDOPA were significantly improved by introducing the [18O]2 double-shoot radionuclide production method, and product analysis by UPLC, respectively. As a result, FDOPA is now routinely available for clinical practice and for distribution over distances. [ABSTRACT FROM AUTHOR]

Background: In-vivo visualisation and quantification of the extent and time-frame of cell death after acute myocardial infarction would be of great interest. We studied in-vivo cell death in the hearts of patients with an acute myocardial infarction using imaging with technetium-99m-labelled annexin-V-a protein that binds to cells undergoing apoptosis.Methods: Seven patients with an acute myocardial infarction and one control were studied. All patients were treated by percutaneous transluminal coronary angioplasty (six primary and one rescue), resulting in thrombolysis in myocardial infarction (TIMI) III flow of the infarct-related artery. 2 h after reperfusion, 1 mg annexin-V labelled with 584 MBq Tc-99m was injected intravenously. Early (mean 3.4 h) and late (mean 20.5 h) single-photon-emission computed tomographic (SPECT) images of the heart were obtained. Routine myocardial resting-perfusion imaging was also done to verify infarct localisation.Findings: In six of the seven patients, increased uptake of Tc-99m-labelled annexin-V was seen in the infarct area of the heart on early and late SPECT images. No increased uptake was seen in the heart outside the infarct area. All patients with increased Tc-99m-labelled annexin-V uptake in the infarct area showed a matching perfusion defect. In a control individual, no increased uptake in the heart was seen.Interpretation: Increased uptake of Tc-99m-labelled annexin-V is present in the infarct area of patients with an acute myocardial infarction, suggesting that programmed cell death occurs in that area. The annexin-V imaging protocol might allow us to study the dynamics of reperfusion-induced cell death in the area at risk and may help to assess interventions that inhibit cell death in patients with an acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Background and Aims: Sodium [ 18 F]fluoride (Na [ 18 F]F) positron emission tomography imaging allows detailed visualization of early arterial micro-calcifications. This study aims to investigate atherosclerosis manifested by micro-calcification, macro-calcification, and aortic stiffness in patients with type 2 diabetes mellitus (T2DM) with and without albuminuria and severely decreased kidney function., Methods: A cohort was stratified in four groups (N = 10 per group), based on KDIGO categories (G1-5 A1-3). G1-2A1 non-diabetic controls (median [IQR] estimated glomerular filtration rate (eGFR) in mL/min/1.73 m 2 91 [81-104]), G1-2A1 with T2DM (eGFR 87 [84-93], and albumin-creatinin-ratio (ACR) in mg/mmol 0.35 [0.25-0.75]), G1-2A3 with T2DM (eGFR 85 [60-103], and ACR 74 [62-122], and G4A3 with T2DM (eGFR 19 [13-27] and ACR 131 [59-304])., Results: Na [ 18 F]F femoral artery grading score differed significantly in the groups with the highest Na [ 18 F]F activity in A3 groups with T2DM (G1-2A3 with T2DM 228 [100-446] and G4A3 with T2DM 198 [113-578]) from the lowest groups of the G1-2A1 with T2DM (33 [0-93]) and in G1-2A1 non-diabetic controls (75 [0-200], p = 0.001). Aortic Na [ 18 F]F activity and femoral artery computed tomography (CT)-assessed macro-calcification was increased in G4A3 with T2DM compared with G1-2A1 with T2DM (47.5 [33.8-73.8] vs. 17.5 [8.8-27.5] (p = 0.006) and 291 [170-511] vs. 12.2 [1.41-44.3] mg (p = 0.032), respectively). Carotid-femoral pulse wave velocity (PWV)-assessed aortic stiffness was significantly higher in both A3 groups with T2DM compared with G1-2A1 with T2DM (11.15 and 12.35 vs. 8.86 m/s, respectively (p = 0.009))., Conclusions: This study indicates that the presence of severely increased albuminuria in patients with T2DM is cross-sectionally associated with subclinical arterial disease in terms of micro-calcification and aortic stiffness. Additional decrease in kidney function was associated with advanced macro-calcifications., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Abdominal aortic aneurysm (AAA) is a major cause of death in developed countries. The AAA diameter is still the only validated prognostic measure for rupture, and therapeutic interventions are initiated accordingly. This still leads to unnecessary interventions in some cases or unidentified impending ruptures. Vascular calcification has been validated abundantly as a risk factor in the cardiovascular field and may strengthen the rupture risk assessment of the AAA. With this study we aim to assess the correlation between AAA calcification and rupture risk in a retrospective unmatched case-control population., Methods: A database of 334 AAA patients was evaluated. Three groups were formed: elective (eAAA; n = 233), ruptured (rAAA; n = 73) and symptomatic non-ruptured (sAAA; n = 28) AAA patients. The Abdominal Aortic Calcification-8 score (AAC-8) was used to measure the severity of vascular calcification., Results: The AAA diameter (61 ± 12 mm vs. 74 ± 21 mm; p < .001) and AAC-8 score (3.4 ± 2 points vs. 4.9 ± 2.3 points; p < .001) of the eAAA and the combined rAAA and sAAA groups, respectively, were significantly different after univariate analysis. Multivariate analysis showed that larger AAA diameter (odds ratio [OR]: 1.048/mm increase; 95% confidence interval [CI]: 1.042-1.082; p < .001) and a higher AAC-8 score (OR: 1.34/point increase; 95% CI: 1.19-1.53; p < .001) were significantly associated with development into a sAAA or rAAA. Peripheral artery disease was significantly correlated to eventual elective treatment (OR: 0.39; 95% CI: .15-1; p = .049)., Conclusion: This study suggests a trend of an increased degree of calcification in symptomatic or even ruptured AAA patients compared with elective AAA patients., (Copyright © 2013 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved.)

Background: Primary endocardial tumours are rare, but may impose a difficult clinical problem. The definite diagnosis regarding the nature of the tumour is often made after surgery. This is due to the fact that current non-invasive imaging techniques are unable to inform us about the nature of the tumour. In addition, invasive techniques can not be used to obtain biological information of the tumour in these cases, because they carry a high risk of embolic complications., Objective: To assess the possibility of a novel modality of imaging, molecular imaging, in the diagnosis of primary intracardiac tumours., Methods: We evaluated two patients with a primary cardiac tumour. Prior to therapy, we infused human recombinant annexin-V Tc99-m and thallium 201. We used a dual isotope single photon emission computed tomography technique. This allowed us to obtain information about the relation between the anatomical position of the left ventricle and the uptake of the labelled annexin-V within the thoracic cavity., Results: The patient with a malignant primary cardiac tumour showed uptake of labelled annexin-V within the area of the tumour. After surgery, the malignant nature was confirmed by histological analysis. The patient with a benignant intracardiac tumour showed no uptake of annexin-V within the area of the tumour., Conclusion: This novel imaging technique, molecular imaging, may be of help to differentiate non-invasively between a malignant and benignant primary intracardiac tumour.

The purpose of this study was to determine the biodistribution and the associated radiation dose of technetium-99m 4,5-bis(thioacetamido)pentanoyl-annexin-V (99mTc-Apomate), a tracer proposed for the study of apoptosis. Eight patients (including two females) with normal kidney and liver functions were included in the study. An activity of 580 +/- 90 MBq of 99mTc-Apomate was injected intravenously, immediately followed by a dynamic study of 30 frames of 1 min each. At about 1 h, 4 h and 20 h p.i., whole-body scans were acquired. All activity distributions were measured using a dual-head gamma camera. Before injection of activity, a transmission scan with a cobalt-57 flood source had been performed to determine patient attenuation. Blood samples were taken every 10 min during the first hour after injection, and at about 4 and 20 h. Urine and faeces were collected during the first 20 h. Organ uptake was estimated after correction for body background activity, attenuation and scatter. Residence times were calculated from the dynamic and whole-body studies and used as input in the Mirdose 3.1 program to obtain organ doses and effective dose. It was found that radioactivity strongly accumulated in the kidneys and the liver [at 70 min p.i., 28% +/- 8% and 20% +/- 4% of the injected dose (ID), respectively]. Uptake in the target tissues (lymphomas or heart) was negligible from a dosimetric point of view. Extrapolating data from the first 20 h, one finds that approximately 73% of the ID will be excreted in the urine, and 27% in the faeces. The biological half-life of the activity in the total body was 16 +/- 7 h. Some organ doses +/- standard deviation (SD) in microGy/MBq were: kidneys 63 +/- 22, urinary bladder 20 +/- 6, spleen 15 +/- 3, liver 13 +/- 3, upper large intestine 12 +/- 6, lower large intestine 8 +/- 4, testes 6 +/- 2 and red bone marrow 4 +/- 0.7. The effective dose was 7.6 +/- 0.5 microSv/MBq, corresponding to a total effective dose of 4.6 +/- 0.3 mSv for a nominal injected activity of 600 MBq. In conclusion, 99mTc-Apomate has a high uptake in the kidneys and liver--in fact a factor of 1.3-1.6 higher than that found for the previously studied 99mTc-(n-1-imino-4-mercaptobutyl)-annexin-V. The biological half-life is shorter, however, but still long compared with the physical half-life of 99mTc. The faster appearance of activity in the intestines may preclude imaging of apoptosis in the abdomen. The effective dose is within the lower range of values reported for typical 99mTc compounds.

Unlabelled: Annexin V labeled with 99mTc is evaluated as a potential in vivo marker for tissue with increased apoptosis. Promising results in patients have been obtained with 99mTc-(n-1-imino-4-mercaptobutyl)-annexin V (99mTc-i-AnxV). Because information on biodistribution and radiation burden is desired for the application of any radiopharmaceutical, a dosimetric study of 99mTc-i-AnxV was undertaken., Methods: Eight persons with normal kidney and liver functions were included in this study: six patients with myocardial infarction, one with Crohn's disease, and one healthy volunteer. Approximately 600 MBq 99mTc-i-AnxV were injected intravenously immediately before a dynamic study with a dual-head gamma camera in conjugate view mode. In the next 24 h, two to four whole-body scans were acquired. Patient thickness was determined from a transmission scan with a 57Co flood source. Organ uptake was estimated after correction for background, attenuation, and scatter, using a depth-independent buildup factor and an organ-size-dependent attenuation correction. Residence times were calculated from the dynamic and whole-body studies and used as input for the MIRDOSE 3.1 program to obtain organ-absorbed doses and effective dose., Results: Activity strongly accumulated in the kidneys (21% +/- 6% of the injected dose at 4 h postinjection) and the liver (12.8% +/- 2.2%). Uptake in the target tissues (myocardium or colon) was limited and negligible from a dosimetric point of view. The biologic half-life of activity registered over the total body was 62 +/- 13 h. Of the excreted activity, approximately 75% went to the urine and 25% to the feces. The absorbed dose for the more strongly exposed organs was (in microGy/MBq): kidneys, 93 +/- 24; spleen, 22 +/- 6; liver, 17 +/- 2; testes, 15 +/- 3; thyroid, 10 +/- 6; urinary bladder wall, 7.5 +/- 2.6; and red bone marrow, 5.5 +/- 0.8. The effective dose was 9.7 +/- 1.0 microSv/MBq, corresponding to a total effective dose of 5.8 +/- 0.6 mSv for a nominally injected activity of 600 MBq., Conclusion: 99mTc-i-AnxV strongly accumulates in the kidneys and to a lesser degree in the liver. The associated effective dose per MBq is in the midrange of values found for routine 99mTc-labeled compounds. From a dosimetric point of view 99mTc-i-AnxV is therefore well suited for the study of apoptosis in patients.

Therapy with 5-fluorouracil (5-FU) as a single agent has only limited success in palliative treatment of cancer of the large bowel. In the current study, the effect of quercetin on the action of 5-FU in the human colorectal cancer cell lines COLO 320 DM and COLO 205 was evaluated using the MTT and clonogenic assays. Both assays were used in order to discriminate between cell growth inhibition and actual cell kill. As single agents as well as in combination, considerably higher concentrations of 5-FU and quercetin were required in the clonogenic assay to obtain detectable effects than in the MTT assay. In the MTT assay, but not in the clonogenic assay, a synergistic interaction between quercetin and 5-FU was found for COLO 320 DM cells. Our results therefore indicate that this interaction between quercetin and 5-FU mainly takes place at the level of growth inhibition. It is concluded that the cytostatic action of a combination of quercetin and 5-FU in COLO 320 DM cells is superior to that of the single agents., (Copyright © 1994 Gustav Fischer Verlag, Stuttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.)