Search PubMed⌕ Search

Biomedical subjects

H Lundqvist

Publications and source records attributed to H Lundqvist.

At least 37 records · Page 2Linked to original sources
PubMed1999

Positron emission tomography and radioimmunotargeting--general aspects.

To optimize radioimmunotherapy, in vivo information on individual patients, such as radionuclide uptake, kinetics, metabolic patterns and optimal administration methods, is important. An overriding problem is to determine accurately the absorbed dose in the target organ as well as critical organs. Positron Emission Tomography (PET) is a superior technique to quantify regional kinetics in vivo with a spatial resolution better than 1 cm3 and a temporal resolution better than 10 s. However, target molecules often have distribution times of several hours to days. Conventional PET nuclides are not applicable and alternative positron-emitting nuclides with matching half-lives and with suitable labelling properties are thus necessary. Over many years we have systematically developed convenient production methods and labelling techniques of suitable positron nuclides, such as 110In(T(1/2) = 1.15 h), 86Y(T(1/2) = 14 h), 76Br(T(1/2) = 16 h) and 124I(T(1/2) = 4 days). 'Dose planning' can be done, for example, with 86Y- or 124I-labelled ligands before therapy, and 90Y- and 131I-labelled analogues and double-labelling, e.g. with a 86Y/90Y-labelled ligand, can be used to determine the true radioactivity integral from a pure beta-emitting nuclide. The usefulness of these techniques was demonstrated in animal and patient studies by halogen-labelled MAbs and EGF-dextran conjugates and peptides chelated with metal ions.

Bromine Radioisotopes↗
PubMed1999

Positron emission tomography and radioimmunotargeting--aspects of quantification and dosimetry.

Positron emission tomography (PET) is a medical imaging tool with high resolution and good quantitative properties, which makes it suitable for in vivo quantification of radioimmunotargeting agents. Most radionuclides used in radioimmunotherapy have positron-emitting analogues, which can be used for PET imaging, and this opens the possibility of performing dosimetry with PET. These isotopes, however, often emit gamma radiation and high-energy positrons in their decay, influencing the imaging properties of PET. Spatial resolution, reconstructed background and line source recovery for a number of non-pure positron emitters were investigated and compared with the imaging properties of 18F. PET imaging properties did not degrade severely for these non-pure positron emitters, but caution has to be applied when doing quantitative measurements. To assess the possibility of conducting PET studies during therapy, by combining, for example, a small amount of 124I with 131I, the influence of the presence of large amounts of gamma radiation on PET count rate characteristics was studied. The results of these studies were related to the necessary amounts of radioactivity needed for treatment of post-operative remains of glioma. The results indicate that the count rate capabilities of 2D PET permit PET studies for dose evaluation during radioimmunotherapy.

Dose-Response Relationship, Radiation↗
PubMed1999

Gamma camera imaging of platinum in tumours and tissues of patients after administration of 191Pt-cisplatin.

The aim of this study was to visualize non-invasively the uptake of platinum in tumours and tissues after treatment with cisplatin. 191Pt-cisplatin was synthesized from 191PtCl4 with rigorous pharmaceutical quality control. The uptake of platinum by both tumorous and healthy tissues was studied by gamma camera imaging in 14 patients, 5 of whom showed a clear uptake of platinum in regions corresponding to known tumour sites. Maximum concentrations of platinum in the tumours were on average 4.9+/-1.0 microg/g, when normalized to an administered amount of 180 mg cisplatin. In all the patients, the liver was the organ that showed the highest uptake. Platinum uptake was also seen in the spleen, gall bladder, gastrointestinal tract, bladder, kidneys, ureter, neck and mediastinum and urogenital region. By using in-house production of 191Pt-cisplatin, it was possible to monitor the uptake of platinum in tumorous tissues and healthy organs.

Adult↗
PubMed1999

Kinetics of 76Br-labeled anti-CEA antibodies in pigs; aspects of dosimetry and PET imaging properties.

A monoclonal antibody labeled with the positron-emitting radionuclide 76Br (T(1/2) 16.2 h) has previously been shown useful for positron emission tomography (PET) imaging of experimental tumors. Our aim in the present study was to investigate the effects of the complex decay scheme of this radionuclide on normal organ dosimetry and PET image quality. Three mini-pigs were injected intravenously with 46-75 MBq of the 76Br-labeled anti-CEA antibody 38S1, and the whole-body kinetics followed by PET imaging for 19 h. From PET data, absorbed doses in human organs were estimated using the MIRDOSE 3.0 software. The highest 76Br concentrations were found in lungs, after a correction for the air volume in this organ. The lungs received the highest absorbed dose (mGy/MBq, mean+/-maximum error), 0.84+/-0.16, followed by liver, 0.74+/-0.28, and small intestine, 0.55+/-0.05, while the effective dose equivalent was 0.41+/-0.03 mSv/MBq. The PET imaging properties of 76Br in a two-dimensional 2D PET camera, including central area resolution and scattering effects, were investigated in phantoms and compared to those of 18F. In a 0.97 g/cm3 material, approximating soft tissue density, the FMHW ("full width at half-maximum") value of the point spread function was 7.7+/-0.2 mm for 76Br and 6.0+/-0.1 mm for 18F. In conclusion, radioimmuno PET using 76Br-labeled antibodies resulted in a fairly even distribution of the radiation dose, where the highest absorbed organ doses were only about two to three times higher than the mean absorbed body dose. The high energy beta+ spectrum in the 76Br decay had only minor effects on the resolution, but may decrease the quantification accuracy, especially in organs with a lower density such as a lung.

Animals↗
PubMed1998

Long-term tacrine treatment in three mild Alzheimer patients: effects on nicotinic receptors, cerebral blood flow, glucose metabolism, EEG, and cognitive abilities.

The effect of long-term treatment with tacrine (tetrahydroaminoacridine) was studied in three Alzheimer patients (aged 57, 64, and 68 years) with mild dementia. All three patients had a Mini-Mental State Examination score of 24/30 and carried at least one apolipoprotein E (ApoE) epsilon4 allele. Tacrine was given in doses between 80 and to 160 mg daily for 13-31 months. A lower tacrine concentration was observed generally in cerebrospinal fluid (CSF) compared with plasma. The acetylcholinesterase activity in CSF tended to be increased following longer periods of tacrine treatment, whereas the butyrylcholinesterase activity was decreased. The three patients repeatedly underwent positron emission tomography investigation of cerebral blood flow, nicotinic receptors, cerebral glucose metabolism, and electroencephalogram (EEG) and cognitive tests. Positive influences on these parameters were observed following both short-term and long-term treatment with tacrine. Improvement of nicotinic receptors (measured as 11C-nicotine binding), cerebral blood flow, EEG, and some cognitive tests (trail making test, block design test) occurred earlier after initiation of tacrine treatment compared with the glucose metabolism, which was increased after several months of tacrine treatment. An improvement in attention (trail making test) was observed following tacrine as sign for frontal lobe activation (EEG). The functional effects of tacrine in Alzheimer patients appeared to be related to both dose and length of cholinesterase inhibitor treatment.

Aged↗
PubMed1998

(S)-(-)-[11C]nicotine binding assessed by PET: a dual tracer model evaluated in the rhesus monkey brain.

A dual tracer model, consisting of the administration of 15O-water and (S)-(-)-[11C]nicotine in close succession, is suggested to assess nicotine binding in the brain. Regional cerebral blood flow (rCBF) determined by 15O-water was used to flow compensate two nicotine model parameters, k1 and k2, obtained in a two-compartment kinetic model. In the present study, this dual tracer approach was evaluated in the rhesus monkey by altering the rCBF or by administering (S)-(-)-[11C]nicotine at either high or low specific radioactivity. The model parameter, k2' = k2/rCBF, was found to be independent of rCBF in different regions of interest in the monkey brain. The parameter, k2', increased significantly when (S)-(-)-[11C]nicotine was given at low specific radioactivity, indicating lower nicotine binding in the brain. Thus, this observation implies an influence on specific receptor binding on the corrected efflux rate constant. This dual tracer model may be useful in evaluating nicotine binding changes in the human brain and the effect of drug treatment in neurodegenerative disorders such as Alzheimer disease.

Animals↗
PubMed1998

Conjugate chemistry, iodination and cellular binding of mEGF-dextran-tyrosine: preclinical tests in preparation for clinical trials.

A conjugate with specific binding to the epidermal growth factor receptor, EGFR, and of interest for clinical tests was prepared using mouse epidermal growth factor, mEGF, and dextran. The mEGF was first coupled to dextran by reductive amination in which the free amino group on the N-terminal of mEGF was reacted with the aldehyde group on the reductive end of the dextran chain. The end-end coupled intermediate was further activated by the cyanopyridinium agent CDAP and tyrosines introduced to the dextran part of the conjugate. The mEGF-dextran-tyrosine conjugate was, with high efficiency, iodinated with the chloramine-T method. Approximately 25-35% of the radioactivity could be removed from the conjugate after exposure to protease K while 65-75% of the radioactivity could be removed after exposure to dextranase. Thus, the largest amount of the iodine was on the dextran part of the conjugate. The iodinated mEGF-dextran-tyrosine had EGFR specific binding since the binding to an EGFR rich human glioma cell line could be displaced by an excess of non-radioactive mEGF. The conjugate was to a large extent internalized in these cells and the administrated radioactivity was thereby retained inside the cells for at least up to 50 h.

Animals↗
PubMed1997

Intraoperative gamma detection reveals abdominal endocrine tumors more efficiently than somatostatin receptor scintigraphy.

BACKGROUND: [(111)In]-diethylenetriamine pentaacetic acid (DTPA)-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), combined with single photon emission computed tomography (SPECT), has limited possibilities to detect small abdominal endocrine tumors. This study explores the efficacy of OctreoScan and a newly developed handheld gamma detector probe (H-probe2) for the localization of neuroendocrine abdominal tumors. METHODS: Twenty-one patients with endocrine pancreatic or midgut carcinoid tumors were given 100-200 megabecquerels (MBq) [(111)In]-DTPA-D-[Phe1]-octreotide and underwent preoperative SPECT examination, after which time surgery was undertaken within 24-48 hours. Intraoperatively the radioactivity of tumors and normal tissues was measured with the H-probe2 connected to a portable personal computer. Resected intestinal specimens of ten patients with carcinoid tumors were examined by gamma camera ex vivo. Biopsies of all tumors subsequently were investigated in a wellcounter and by routine histopathology. RESULTS: Disregarding liver metastases, a total of 34 of 60 abdominal tumors were detected by SPECT; however, SPECT failed to visualize any tumor < 9 mm. The shielding of the manual probe allowed intraoperative examination despite the substantial radiation energy of (111)In. The H-probe2 detected 91% of the tumors investigated, and these included all those > 5 mm. In the wellcounter the H-probe2-detected tumors exhibited 4.7-157.7 times higher radionuclide uptake than the surrounding normal tissues. The gamma camera analysis detected 68% of tumors in the resected specimens. CONCLUSIONS: The intraoperative H-probe2 examination provided substantial improvement in the detection of small endocrine lesions accumulating [(111)In]-DTPA-D-[Phe1]-octreotide and all lesions with a size > 5 mm in greatest dimension could be identified.

Adult↗
PubMed1997

A gamma detector probe with ex vivo detection of carcinoid tumors superior to intraoperative palpation.

BACKGROUND: Despite the generally successful scintigraphic detection of endocrine tumors with [(111)In]-DTPA-D-[Phe1]-octreotide (OctreoScan, Mallinckrodt Medical, Petten, The Netherlands), its intraoperative application awaits the development of suitable gamma detectors. This study describes a novel probe (H-probe2) and its ex vivo efficacy for the detection of midgut carcinoid tumors. METHODS: The probe measures 180 mm x 24 mm, and contains a bismuth germinate crystal connected to a photomultiplicator tube, a lead shield, and a tantalum collimator with an angled, 3-mm wide opening. It was characterized in a test bench utilizing solublilized (111)In and 99mTc, and 8 fresh operative specimens containing 26 histologically verified midgut carcinoid tumors (2-40 mm) from patients exposed to OctreoScan. Measurements were made at 2.5-mm intervals over the entire specimens and presented three dimensionally. RESULTS: The test bench analysis supported efficient shielding, and a total collimation of 27 degrees for (111)In and 20 degrees for 99mTc. In addition to 18 palpable tumors, 4 of 6 surgically occult tumors (2-3 mm in dimension) could be discovered with H-probe2. Small tumors in close apposition to a large tumor could not be separated. Wellcounter examination showed that tumors detected with the H-probe2 exhibited 1.7-84.1 times higher radionuclide uptake than the surrounding normal tissue. CONCLUSION: Ex vivo analysis of H-probe2 supported detection of tumors inaccessible to surgical palpation, but its clinical efficiency awaits intraoperative evaluation.

Carcinoid Tumor↗
PubMed1997

Translocation of annexin XI to neutrophil subcellular organelles.

In an earlier study, annexin XI was found to be present in the cytosol of neutrophil granulocytes (Blood (1996) 87, 4817). The protein was isolated by calcium-dependent translocation to specific granules and was found to be a 42-kDa truncated form of annexin XI. Using human autoantibodies directed against annexin XI we have now reinvestigated the ability of full size annexin XI to translocate to different neutrophil organelles isolated by subcellular fractionation. The autoantisera used recognised a protein of 55-kDa in neutrophil cytosol and comparison with a whole cell lysate indicated that the larger portion of the cellular content of this protein is localised to the cytosol. Azurophil granules, specific granules and secretory vesicles/plasma membrane were isolated by subcellular fractionation on Percoll gradients, mixed respectively with neutrophil cytosol and the calcium concentration was raised. Immunoblotting showed that annexin XI translocated to specific granules and secretory vesicles/plasma membrane at 100 micromol/l calcium. When raising the concentration of calcium to 1 mmol/l, annexin XI translocated to the azurophil granules as well. Periphagosomal translocation of annexin XI occurred during phagocytosis of yeast particles, implying that this protein plays a role in the events associated with the phagocytic process.

Annexins↗
PubMed1997

Methodological aspects for in vitro characterization of receptor binding using 11C-labeled receptor ligands: a detailed study with the benzodiazepine receptor antagonist [11C]Ro 15-1788.

As a complement to in vivo studies with positron emission tomography (PET), it is desirable to perform in vitro characterization of newly developed 11C tracers. In this report we describe the technique for determination of receptor-ligand kinetics utilizing ligands labeled with the short-lived radionuclide 11C. The limitations and advantages are discussed. The benzodiazepine antagonist [11C]Ro 15-1788 was used as a model substance, and the use of storage phosphor plates for quantification of radioactivity was validated. Storage phosphor plates showed an excellent linear range (approximately 10[3]) and acceptable resolution (approximately 0.5 mm). Receptor-ligand kinetics, including depletion, association and dissociation, saturation and displacement were evaluated with good results through the use of short-lived radiotracers and storage phosphor plates.

Animals↗
PubMed1997

Pharmacokinetics and experimental PET imaging of a bromine-76-labeled monoclonal anti-CEA antibody.

UNLABELLED: Bromine-76 is potentially useful as a radiolabel for monoclonal antibodies (MAbs) in PET imaging. The purpose of the present study was to evaluate the 76Br-labeled anticarcinoembryonic antigen (-CEA) MAb 38S1 as a tumor imaging agent in an experimental tumor model and to study the pharmacokinetics of 76Br-38S1 in comparison with 125I-38S1. METHODS: Nude rats carrying human colon carcinoma xenografts were co-injected with directly labeled 76Br-38S1 and 125I-38S1. Biodistribution of labeled 38S1 was monitored for 4 days after administration, in the case of 76Br activity, including PET imaging. In addition, catabolism of radiolabeled MAbs was analyzed by gel filtration chromatography of blood plasma and homogenized tissues. RESULTS: Tumor sites could be readily identified by PET imaging from 46 hr after administration of 76Br-38S1 and onwards. The concentration of 76Br activity in tumors, blood and most normal tissues was higher than the corresponding 125I concentration at all time points. This was mainly due to catabolism of radiolabeled MAb, resulting in free radiohalides, of which 76Br- was retained in contrast to the rapidly excreted 125I- ion. CONCLUSION: Bromine-76-labeled anti-CEA MAbs may be applied for experimental tumor imaging with PET.

Adenocarcinoma↗
PubMed1997

Comparative PET imaging of experimental tumors with bromine-76-labeled antibodies, fluorine-18-fluorodeoxyglucose and carbon-11-methionine.

UNLABELLED: The potential of a 76Br-labeled anti-carcinoembryonic antigen monoclonal antibody (MAb), 38S1, as tumor-imaging agent for PET was investigated in a comparative experimental study with [18F]fluorodeoxyglucose ([18F]FDG) and L-[methyl-11C]methionine ([11C]Met). METHODS: The three radiotracers were administered to nude rats carrying subcutaneous xenografts or liver metastases from a human colonic carcinoma. Tracer biodistribution was evaluated by PET imaging and radioactivity measurement of dissected tissues and also by whole-body autoradiography for subcutaneous xenografts. RESULTS: For PET imaging of subcutaneous tumors, 76Br-38S1 proved superior to the other radiotracers. Tumor-to-tissue ratios were, except for the tumor-to-blood ratio, generally higher for 76Br-labeled MAb than for [18F]FDG and [11C]Met. Liver metastases were imaged with PET using both 76Br-38S1 and [18F]FDG, and the metastases-to-liver ratios of dissected samples were not significantly different for the two radiotracers. CONCLUSION: The tumor-imaging capacity of 76Br-labeled MAb 38S1 was superior to [18F]FDG and [11C]Met in the subcutaneous tumor model, whereas 76Br-38S1 and [18F]FDG were equally successful for the identification of liver metastases.

Animals↗
PubMed1996

A simple chemiluminescence assay for the determination of reactive oxygen species produced by human neutrophils.

We show that phagocyte production of reactive oxygen species can be measured using a microtitre plate based chemiluminescence blotting technique. The production of reactive oxygen species is determined by their ability to catalyze the oxidation of luminol or isoluminol, resulting in light emission which is recorded on a photographic film. The method permits the determination of NADPH oxidase activity from as few as 9000 cells. It could be used to detect NADPH oxidase defects in neutrophils (e.g. from patients suffering from chronic granulomatous disease), and to screen pharmaceuticals with scavenging activity for reactive oxygen species.

Humans↗
PubMed1996

Serotonin-2 and dopamine-1 binding components of clozapine in frontal cortex and striatum in the human brain visualized by positron emission tomography.

The specific binding of N-methyl-11C-clozapine in the human brain was studied in five healthy volunteers with positron emission tomography (PET). Four of the volunteers were reexamined after treatment with the dopamine D1 and D2 receptor antagonist flupenthixol, and all five volunteers were reexamined after pretreatment with the serotonin2 receptor antagonist ritanserin. The examinations after flupenthixol and ritanserin treatment were performed on different occasions. In the flupenthixol part of the study, two of the subjects were given an oral dose of 1 mg flupenthixol 2-3 h before the posttreatment study with PET. The other two subjects received 0.5 mg orally three times during the 24 h preceding the posttreatment PET study, with the last dose being administered < or = 4 h before the scan. All five ritanserin-treated subjects followed the same dosing regimen. During the 5 days preceding the posttreatment PET study, they were given a 10-mg tablet of ritanserin in the evening. The last dose was administered 2-1/2 hours before the study. Both flupenthixol and ritanserin pretreatment were associated with decreased binding of N-methyl-11C-clozapine in dorsolateral and medial frontal cortical regions. These results support previous findings that clozapine has affinity for both dopamine D1 and serotonin 5-HT2 receptors in the human frontal cortex. No consistent change of binding was observed in striatal regions following flupenthixol or ritanserin pretreatment. The clinical aspects of this feature are discussed, both with respect to efficacy and side effects.

Adult↗
PubMed1996

Phorbol myristate acetate-induced NADPH oxidase activity in human neutrophils: only half the story has been told.

The paradigm for activation of the neutrophil NADPH oxidase with the protein kinase C activator phorbol myristate acetate (PMA) states that the oxidase assembles the plasma membrane and that the metabolites generated are released extracellularly. This paradigm is challenged by the results presented. Most of the PMA-induced oxidase activity measured as chemiluminescence and dichlorofluorescein fluorescence was insensitive to scavengers of superoxide anion and hydrogen peroxide. This indicates that oxidase activity also takes place in a cellular compartment that the scavengers cannot reach. From the results obtained with granule-deficient HL-60 cells and cord blood neutrophils, we suggest that the scavenger-insensitive part of the NADPH oxidase activity in normal neutrophils resides in an intracellular compartment identical to or originating from granules. Our results also indicate that specific and azurophil granules have to be in very close contact to allow the generated oxygen metabolites to reach and react with myeloperoxidase.

Adult↗
PubMed1996

Okadaic acid inhibits the signal responsible for activation of the NADPH-oxidase in neutrophils stimulated with serum-opsonized yeast.

The effects of the phosphatase inhibitor okadaic acid (OA) on human neutrophil phagocytic activity were investigated. The chemiluminescence response was found to be greatly reduced in OA-treated neutrophils during phagocytosis of serum opsonized yeast particles in comparison to control cells. However, the OA-treated neutrophils phagocytosed yeast particles to the same extent as control cells and the engulfment of the prey was accompanied by phagolysosomal formation in both OA-treated and nontreated cells. We thus found that the OA effect was selective in the sense that it inhibits the NADPH-oxidase activity in neutrophils phagocytosing yeast particles but not uptake of the prey or phagolysosomal formation. Based on the fact that the NADPH-oxidase activity induced by the chemoattractant formyl-methionyl-leucyl-phenylalanine was not reduced but elevated in OA-treated neutrophils, we conclude that the state of phosphorylation has no direct effect on the oxidase, but is of importance for the NADPH-oxidase activating signal(s) generated during phagocytosis of the yeast particles.

Animals↗