ABSTRACT
Hematocrit (Hct) determines the ability of blood to carry oxygen. While changes in systemic Hct are known to impact stroke or tumor control, changes in local (tissue) Hct (tHct) induced by these diseases have however received little attention. In this study, we evaluate tHct in acute stroke and in glioma models using a new approach to map tHct across the brain, a dual isotope autoradiography, based on injections of 125I-labeled albumin and 99mTc-lalbeled red blood cells in the same animal. For validation purpose, tHct was mapped in the rat brain (i) under physiological conditions, (ii) following erythropoietin injection, and (iii) following hemodilution. Then, tHct was then mapped in stroke (middle cerebral artery occlusion) and tumor models (9LGS and C6). The mean tHct values observed in healthy brains (tHct = 29 ± 1.3%), were modified as expected by erythropoietin (tHct = 36.7 ± 2.6%) and hemodilution (tHct = 24.2 ± 2.4%). Using the proposed method, we observed a local reduction, spatially heterogeneous, in tHct following acute stroke (tHct = 19.5 ± 2.5%) and in both glioma models (9LGS: tHct = 18.5 ± 2.3%, C6: tHct = 16.1 ± 1.2%). This reduction and this heterogeneity in tHct observed in stroke and glioma raises methodological issues in perfusion imaging techniques where tHct is generally overlooked and could impact therapeutic strategies.
Subject(s)
Autoradiography , Brain Mapping/methods , Glioma/physiopathology , Stroke/physiopathology , Animals , Glioma/metabolism , Hematocrit , Male , Rats , Stroke/metabolismABSTRACT
New strategies allowing the transfer of molecules, especially peptides, through the blood-brain barriers are a major pharmacological challenge for the treatment of brain diseases. The present study aims at evaluating in vivo the cerebral bioavailability of carrier systems, based on small and functionalizable 2,5-diketopiperazine (DKP) motifs. We studied 2 different cyclo(Lys-Lys) DKP scaffolds alone and a cyclo(Lys-Gly) DKP carrier bearing as peptide model, the tau protein hexapeptide VQIVYK sequence. The different carrier systems were synthesized and radiolabeled using one of the free domains. The stability, biodistribution, and ability to cross blood-brain barrier were investigated in vivo in mice for 99m Tc-DKP scaffolds, 99m Tc-HVQIVYK peptide alone, and 99m Tc-DKP-VQIVYK. 125 I-labelled bovine serum albumin was used as negative control for brain uptake. Both radiolabeled DKPs scaffolds and 99m Tc-DKP-VQIVYK showed a high stability, while peptide 99m Tc-HVQIVYK alone was quickly degraded in vivo. The presence of 99m Tc-DKPs scaffolds and 99m Tc-DKP-VQIVYK was observed in the ventricular and subarachnoid spaces and to a lower extent in the brain parenchyma up to 45 minutes post-injection in mice. This work highlights the potentiality of DKP scaffolds as vectors to transport peptides into the brain by limiting proteolysis and favoring cerebral bioavailability.
Subject(s)
Blood-Brain Barrier/metabolism , Diketopiperazines/chemical synthesis , Drug Carriers/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/metabolism , Amino Acid Sequence , Animals , Chemistry Techniques, Synthetic , Diketopiperazines/chemistry , Diketopiperazines/pharmacokinetics , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Stability , Mice , Permeability , Technetium/chemistry , Tissue DistributionABSTRACT
PURPOSE: The αvß3 integrin plays an important role in tumour-induced angiogenesis, tumour proliferation, survival and metastasis. The tetrameric RGD-based peptide, regioselectively addressable functionalized template-(cyclo-[RGDfK])4 (RAFT-RGD), specifically targets the αvß3 integrin in vitro and in vivo. The aim of this study was to evaluate the therapeutic potential of RAFT-RGD radiolabelled with ß(-) emitters in a nude mouse model of αvß3 integrin-expressing tumours. METHODS: Biodistribution and SPECT/CT imaging studies were performed after injection of (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD in nude mice subcutaneously xenografted with αvß3 integrin-expressing U-87 MG cells. Experimental targeted radionuclide therapy with (90)Y-RAFT-RGD or (177)Lu-RAFT-RGD and (90)Y-RAFT-RAD or (177)Lu-RAFT-RAD (nonspecific controls) was evaluated by intravenous injection of the radionuclides into mice bearing αvß3 integrin-expressing U-87 MG tumours of different sizes (small or large) or bearing TS/A-pc tumours that do not express αvß3. Tumour volume doubling time was used to evaluate the efficacy of each treatment. RESULTS: Injection of 37 MBq of (90)Y-RAFT-RGD into mice with large αvß3-positive tumours or 37 MBq of (177)Lu-RAFT-RGD into mice with small αvß3-positive tumours caused significant growth delays compared to mice treated with 37 MBq of (90)Y-RAFT-RAD or 37 MBq of (177)Lu-RAFT-RAD or untreated mice. In contrast, injection of 30 MBq of (90)Y-RAFT-RGD had no effect on the growth of αvß3-negative tumours. CONCLUSION: (90)Y-RAFT-RGD and (177)Lu-RAFT-RGD are potent agents targeting αvß3-expressing tumours for internal targeted radiotherapy.
Subject(s)
Integrin alphaVbeta3/metabolism , Lutetium/therapeutic use , Peptides, Cyclic , Radiopharmaceuticals/therapeutic use , Yttrium Radioisotopes/therapeutic use , Animals , Cell Line, Tumor , Humans , Integrin alphaVbeta3/genetics , Lutetium/adverse effects , Lutetium/pharmacokinetics , Mice , Mice, Nude , Neoplasms, Experimental/genetics , Neoplasms, Experimental/radiotherapy , Peptides, Cyclic/adverse effects , Peptides, Cyclic/pharmacokinetics , Radiopharmaceuticals/adverse effects , Radiopharmaceuticals/pharmacokinetics , Tissue Distribution , Xenograft Model Antitumor Assays , Yttrium Radioisotopes/adverse effects , Yttrium Radioisotopes/pharmacokineticsABSTRACT
Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.
Subject(s)
Atherosclerosis/diagnosis , Diagnostic Imaging , Nuclear Medicine , Atherosclerosis/immunology , Diagnostic Imaging/methods , Evaluation Studies as Topic , Humans , Nuclear Medicine/methods , Positron-Emission Tomography/methodsABSTRACT
PURPOSE: Neoplastic meningitis is often the final outcome of disseminated cancer and is rapidly lethal. Its limited treatment relies on systemic or intrathecal chemotherapy with methotrexate (MTX) or thiotepa. When 5-iodo-2'-deoxyuridine labeled with (125)I ((125)IUdR) is incorporated into the DNA of mitotic tumor cells, the Auger electrons emitted during iodine decay are highly cytotoxic. The radiotherapeutic efficacy of (125)IUdR administered intrathecally has also been established in animals bearing spinal cord tumors, and MTX is known to potentiate the response. This approach has not been tested in the clinic. METHODS: A 44-year-old woman, with locally advanced pancreatic cancer, was treated for three years with complete systemic remission, but then relapsed with cytologically proven neoplastic meningitis. The patient was given four successive intrathecal injections of MTX (10 mg) every 12 h and, with the fourth dose, 1850 MBq (125)IUdR, followed by four additional MTX doses. The response was monitored by cytology and CA19.9 (carbohydrate antigen 19.9) levels in the cerebrospinal fluid (CSF) as well as by clinical status of the patient. RESULTS: The follow-up of cytology and CA19.9 levels in the CSF showed dramatic improvement within 26 days followed by a biological relapse on Day +36. There was no evidence of local central nervous system toxicity. Three months later, neoplastic meningitis recurred and meningeal tumor infiltration was observed on magnetic resonance imaging. Six months after MTX-(125)IUdR treatment, the patient died. CONCLUSION: (125)IUdR treatment proved to be feasible without acute neurological toxicity and seemed to have produced a biological response. This attempt provides the basis for designing prospective clinical trials.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Idoxuridine/therapeutic use , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/radiotherapy , Methotrexate/therapeutic use , Radiopharmaceuticals/therapeutic use , Adult , Antibiotics, Antineoplastic/administration & dosage , Antigens, Tumor-Associated, Carbohydrate/cerebrospinal fluid , Brain Neoplasms/drug therapy , Brain Neoplasms/radiotherapy , Brain Neoplasms/secondary , Combined Modality Therapy , Drug Resistance, Neoplasm , Fatal Outcome , Female , Humans , Idoxuridine/administration & dosage , Injections, Spinal , Iodine Radioisotopes , Meningeal Neoplasms/secondary , Methotrexate/administration & dosage , Neoplasm Recurrence, Local , Pancreatic Neoplasms/drug therapy , Pancreatic Neoplasms/pathology , Radiopharmaceuticals/administration & dosageABSTRACT
AIM: To assess the prognostic impact of a therapeutic program based on bioclinical risk-stratification and myocardial-perfusion-imaging (MPI) data on survival and the occurrence of coronary events (CE=death+myocardial infarction) in asymptomatic patients with diabetes. METHOD: Five hundred twenty one consecutive asymptomatic diabetic outpatients were prospectively enrolled and clinically classified as being at either low or high cardiac risk. All high-risk patients (n=245, age 61+/-9 years) underwent MPI and an intensive multifactorial medical therapeutic program, including anti-ischaemic agents in cases of moderate ischemia; a coronary angiography was performed in all high-risk patients with severe ischaemia (n=38), followed by immediate revascularization if necessary (n=21). Low-risk patients (n=276, age 57+/-9 years) underwent medical management of their risk factors. RESULTS: At the 19-month (median) follow-up (range, 12-36 months), both high- and low-risk patients showed similarly low CE rates (2.3% and 1.5% per year, respectively; age- and gender-adjusted log-rank P=NS). None of the patients who underwent myocardial revascularization experienced any CEs, and none of the low-risk patients died during follow-up. The negative predictive value of first-line bioclinical stratification was 0.98 for the occurrence of CEs, and 0.95 when low-risk patients were combined with high-risk patients who had normal MPI findings. CONCLUSIONS: Bioclinical first-line stratification allows identification of diabetic patients who have a good medium-term cardiac prognosis. The CE rate is similar in selected high-risk asymptomatic patients with diabetes using an intensive MPI-guided program that combines medical therapy, coronary angiography in the 16% of cases with severe ischemia and, if appropriate, revascularization.
Subject(s)
Coronary Disease/epidemiology , Diabetic Angiopathies/epidemiology , Myocardial Ischemia/therapy , Aged , Aged, 80 and over , Diabetes Mellitus, Type 1/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Electrocardiography , Female , France/epidemiology , Humans , Hypoglycemic Agents/therapeutic use , Incidence , Male , Middle Aged , Patient Selection , Risk Factors , SurvivorsABSTRACT
BACKGROUND: The prognostic impact of a myocardial ischemia-based therapeutic program in asymptomatic diabetic patients remains controversial. We prospectively assessed the benefit of a stratification algorithm based upon clinical and myocardial perfusion imaging (MPI) data on cardiovascular events in such patients in a non-randomized register. METHOD: 701 consecutive asymptomatic diabetic patients were classified to be at low or intermediate-to-high cardiac risk according to 13 simple boil-clinical parameters. Intermediate-to-high risk patients were scheduled for MPI and underwent either a conventional (Group 1, n=180) or an intensive multifactorial (Group 2, n=245) therapeutic program. Low risk patients (Group 3, n=276) underwent no specific management. RESULTS: At the end of the survey and as a consequence of intensive management, lipid lowering therapy, antiplatelet drugs, and beta-blockers were more often prescribed in Group 2 than in Group 1 (55, 31 and 17% versus 36, 23, and 8% respectively, p<0.01). Planned coronary angiography in case of severe ischemia on MPI and revascularization were more frequent in Group 2 (16.2 and 8.9%) than in Group 1 (8.0 and 2.8% - p<0.01). At 19-month follow-up (96.7% completed), major event rate in Group 2 was significantly lower than in Group 1 (3.9 versus 9.8%, p<0.01) and similar to that of Group 3 (2.2%, NS). CONCLUSION: Easy-to-perform risk stratification is able to select diabetic patients with good medium-term prognosis. In clinically selected higher risk patients, an intensive medical therapy combined with coronary angiography +/- revascularization in case of large ischemia on MPI is effective to improve prognosis.
Subject(s)
Diabetic Angiopathies/diagnosis , Myocardial Ischemia/diagnosis , Aged , Diabetic Angiopathies/epidemiology , Female , France/epidemiology , Heart Diseases/epidemiology , Humans , Male , Middle Aged , Myocardial Ischemia/epidemiology , Prognosis , Registries , Risk FactorsABSTRACT
PURPOSE: VCAM-1 plays a major role in the chronic inflammatory processes present in vulnerable atherosclerotic plaques. The residues 75-84 (B2702-p) and 84-75/75-84 (B2702-rp) of the major histocompatibility complex-1 (MHC-1) molecule B2702 were previously shown to bind specifically to VCAM-1. We hypothesised that radiolabelled B2702-p and B2702-rp might have potential for the molecular imaging of vascular cell adhesion molecule-1 (VCAM-1) expression in atherosclerotic plaques. METHODS: Preliminary biodistribution studies indicated that 125I-B2702-rp was unsuitable for in vivo imaging owing to extremely high lung uptake. 123I- or 99mTc-labelled B2702-p was injected intravenously to Watanabe heritable hyperlipidaemic rabbits (WHHL, n=6) and control animals (n=6). After 180 min, aortas were harvested for ex vivo autoradiographic imaging, gamma-well counting, VCAM-1 immunohistology and Sudan IV lipid staining. RESULTS: Robust VCAM-1 immunostaining was observed in Sudan IV-positive and to a lesser extent in Sudan IV-negative areas of WHHL animals, whereas no expression was detected in control animals. Significant 2.9-fold and 1.9-fold increases in 123I-B2702-p and 99mTc-B2702-p aortic-to-blood ratios, respectively, were observed between WHHL and control animals (p<0.05). Tracer uptake on ex vivo images co-localised with atherosclerotic plaques. Image quantification indicated a graded increase in 123I-B2702-p and 99mTc-B2702-p activities from control to Sudan IV-negative and to Sudan IV-positive areas, consistent with the observed pattern of VCAM-1 expression. Sudan IV-positive to control area tracer activity ratios were 17.0+/-9.0 and 5.9+/-1.8 for 123I-B2702-p and 99mTc-B2702-p, respectively. CONCLUSION: Radiolabelled B2702-p is a potentially useful radiotracer for the molecular imaging of VCAM-1 in atherosclerosis.
Subject(s)
Adjuvants, Immunologic/pharmacology , Atherosclerosis/diagnostic imaging , Atherosclerosis/pathology , Peptide Fragments/pharmacology , Vascular Cell Adhesion Molecule-1/biosynthesis , Animals , Aorta/diagnostic imaging , Aorta/metabolism , Autoradiography/methods , Azo Compounds/pharmacology , Diagnostic Imaging/methods , Disease Models, Animal , Dose-Response Relationship, Drug , Inflammation , Iodine Radioisotopes/therapeutic use , Major Histocompatibility Complex , Rabbits , Radionuclide ImagingABSTRACT
PURPOSE: Incomplete microvascular reperfusion is often observed in patients undergoing thrombolytic therapy or angioplasty for acute myocardial infarction and has important prognostic implications. We compared the myocardial uptake of diffusible ((201)Tl) and deposited ((99m)TcN-NOET) perfusion imaging agents in the setting of experimental infarction. METHODS: Rats were subjected to permanent coronary occlusion (OCC, n=10) or to 45-min occlusion and reperfusion (REP, n=17). Seven days later, the tracers were co-injected and the animals were euthanised 15 min (all ten rats in the OCC group and 12 rats in the REP group) or 120 min (five rats from the REP group, euthanised at this time point to evaluate any redistribution of the tracers: REP-RED group) afterwards. Infarct size determination and (99m)TcN-NOET/(201)Tl ex vivo imaging were performed. Regional flow and tissue oedema were quantified using radioactive microspheres and (99m)Tc-DTPA, respectively. RESULTS: (99m)TcN-NOET and (201)Tl defect magnitudes were similar in OCC animals (0.11+/-0.01 vs 0.13+/-0.01). In REP animals, (201)Tl defect magnitude (0.25+/-0.02) was significantly lower than the magnitude of (99m)TcN-NOET and flow defects (0.14+/-0.03 and 0.17+/-0.01, respectively; p<0.05), despite the lack of (201)Tl redistribution (REP-RED animals). (99m)Tc-DTPA indicated the presence of oedema in the reperfused area. Blood distribution studies showed that, unlike (99m)TcN-NOET, (201)Tl plasma activity was mostly unbound to plasma proteins. CONCLUSION: (99m)TcN-NOET and (201)Tl delineated the non-viable area in chronic non-reperfused and reperfused myocardial infarction. The significantly decreased (201)Tl defect in reperfused infarction was likely due to partial diffusion of the tracer from the plasma into the oedema present in the infarcted area. Deposited perfusion tracers might be better suited than diffusible agents for the assessment of regional flow following reperfusion of myocardial infarction.
Subject(s)
Myocardial Infarction/diagnostic imaging , Myocardial Reperfusion Injury/diagnostic imaging , Organotechnetium Compounds , Thallium Radioisotopes , Thiocarbamates , Ventricular Dysfunction, Left/diagnostic imaging , Animals , Diffusion , Humans , Isotope Labeling/methods , Male , Myocardial Infarction/complications , Myocardial Reperfusion Injury/complications , Perfusion/methods , Radionuclide Imaging , Radiopharmaceuticals , Rats , Rats, Wistar , Ventricular Dysfunction, Left/etiologyABSTRACT
Coronary artery disease is a common and serious condition in diabetes and the prognosis of the diabetic without a history of cardiovascular disease is either the same or nearly as serious as that of a non-diabetic patient with a history of coronary disease. This is particularly true in women. The prognosis is even worse in the presence of silent myocardial ischaemia. Conversely, anti-ischaemic and anti-thrombotic therapy and myocardial revascularisation of most severely affected patients are effective. This justifies the recent recommendations (as those of the working group of the French Society of Cardiology and the ALFEDIAM) for the diagnosis of coronary artery disease in diabetes, even in asymptomatic patients. This is a two stage process: --First, the identification of patients who should be screened for ischaemia, diabetics with a priori an intermediate or high risk of the presence of CAD, with respect to the presence of markers easily identified on initial examination, like the presence of clinical macroangiopathy (femoral, carotid), of renal disease or ECG changes or the presence of several classical risk factors; --The second stage is the demonstration of myocardial ischaemia in patients identified to be at risk. This article reviews the advantages and limits of the tests available: ECG stress test, myocardial perfusion imaging on effort or under dipyridamole, stress echocardiography. Coronary angiography in asymptomatic patients is only recommended in the presence of significant ischaemia or with a poor prognosis (affecting over 20% of the myocardium or several myocardial territories). This should precede a myocardial revascularisation procedure. The prescription of coronary angiography may be more direct in some symptomatic patients.
Subject(s)
Angina, Unstable/diagnosis , Coronary Artery Disease/diagnosis , Diabetic Angiopathies/diagnosis , Myocardial Infarction/diagnosis , Acute Disease , Humans , Myocardial Ischemia/diagnosis , SyndromeABSTRACT
BACKGROUND: Impairment of insulin-stimulated glucose transport is a characteristic of type 2 diabetes. A radioactive glucose analogue has been synthesized: [(125)I]-6-deoxy-6-iodo-D-glucose. Its biological behaviour in vitro is similar to that of 3-O-methyl-D-glucose, the reference tracer of glucose transport. The aim of the present study was to determine the ability of [(125)I]-6-deoxy-6-iodo-D-glucose to evaluate variations in glucose transport in vivo. METHODS: Biodistributions of [(125)I]-6-deoxy-6-iodo-D-glucose were performed with or without exogenous insulin (iv injection of 1.5 IU/kg) in db/+ non-diabetic control mice and in db/db type 2 diabetic mice, exhibiting a severe insulin resistance characterized by a lack of increase in glucose uptake in response to insulin. RESULTS: In db/+ mice, insulin increased [(125)I]-6-deoxy-6-iodo-D-glucose transport by 30% in most insulin-sensitive tissues (heart, diaphragm and skeletal muscle, p < 0.05) and had no effect in other organs. In db/db mice, [(125)I]-6-deoxy-6-iodo-D-glucose transport in these organs was not modified by insulin. CONCLUSION: [(125)I]-6-deoxy-6-iodo-D-glucose is able to trace in vivo an increase in glucose transport with insulin in non-diabetic mice and a defect of glucose transport in type 2 diabetic mice. It is the first time that an iodinated analogue of glucose has shown such promising results after in vivo injection. The use of this tracer to assess glucose transport in vivo in humans via nuclear imaging warrants further investigation.
Subject(s)
Deoxyglucose/analogs & derivatives , Deoxyglucose/pharmacokinetics , Animals , Biological Transport/drug effects , Biological Transport/genetics , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/metabolism , Female , Glucose/metabolism , Heterozygote , Homozygote , Iodine Radioisotopes , Mice , Mice, Inbred C57BL , Radioisotope Dilution Technique , Reference Values , Tissue DistributionSubject(s)
Coronary Disease/diagnostic imaging , Coronary Vessels/diagnostic imaging , Heart/diagnostic imaging , Organotechnetium Compounds/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Thiocarbamates/pharmacokinetics , Animals , Coronary Circulation , Dogs , Hemodynamics , Humans , Microspheres , Rabbits , Radionuclide Imaging , Regional Blood FlowABSTRACT
To investigate the effect of amlodipine on baroreflex sensitivity and sympathetic system activity, 36 patients with essential hypertension were randomized to once-daily, double-blind treatment with amlodipine 5 mg or placebo 5 mg for 60 days. Measurements with a Finapres device allowed calculation of baroreflex sensitivity and blood pressure (BP) variability. Adrenergic activity was assessed via measurements of lymphocyte beta2-adrenoceptors and plasma catecholamine concentrations. Compared with placebo, amlodipine significantly decreased BP, but did not significantly alter baroreflex sensitivity. Spectral analysis of Finapres data showed that, compared with placebo, amlodipine decreased the variability of systolic blood pressure, diastolic blood pressure, and RR interval in the low frequency band. There were no simultaneous changes in adrenergic function, however, suggesting that these effects of amlodipine were not mediated via sympathetic nervous system activation.
Subject(s)
Amlodipine/therapeutic use , Antihypertensive Agents/therapeutic use , Baroreflex/drug effects , Hypertension/drug therapy , Sympathetic Nervous System/drug effects , Adolescent , Adult , Aged , Blood Pressure/drug effects , Catecholamines/blood , Double-Blind Method , Female , Heart Rate/drug effects , Humans , Male , Middle Aged , Receptors, Adrenergic, beta-2/drug effectsABSTRACT
The current trend in innovative cancer therapy is moving towards targeting the genes of interest by means of oligonucleotides developed for therapeutic or diagnostic use. These new approaches are of particular interest in oncology, and it would therefore be extremely useful to characterise all the biological tools currently available in this field. The chemoresistance profiles of four human cancer cell lines were determined by identifying of the operating conditions needed to characterise the presence of hmdr1, mrp and lrp mRNA by gene amplification.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP-Binding Cassette Transporters/genetics , Drug Resistance, Neoplasm , Proto-Oncogene Proteins/genetics , Zebrafish Proteins , Gene Expression Regulation, Neoplastic/drug effects , HL-60 Cells , Humans , K562 Cells , KB Cells , Multidrug Resistance-Associated Proteins , RNA, Messenger/analysis , Wnt ProteinsABSTRACT
Several Tc-99m complexes were synthesized, substituted with a nitroimidazole group, in order to visualize hypoxic tissues. The complexes were tested on rats (isolated hearts) and showed no significant uptake under hypoxic conditions.
Subject(s)
Hypoxia/diagnostic imaging , Nitroimidazoles/chemical synthesis , Technetium Compounds/chemical synthesis , Animals , Heart/diagnostic imaging , Heart/physiopathology , In Vitro Techniques , Ligands , Molecular Structure , Nitroimidazoles/chemistry , Nitroimidazoles/metabolism , Perfusion , Radionuclide Imaging , Rats , Technetium/metabolism , Technetium Compounds/chemistry , Technetium Compounds/metabolismABSTRACT
BACKGROUND: Technetium 99m N-NOET is a new myocardial perfusion imaging agent currently in phase III clinical trials in Europe. In vitro studies on newborn rat cardiomyocytes have shown that calcium inhibitors, such as verapamil or diltiazem, inhibit its cellular uptake by 40%. To determine whether such a specificity exists ex vivo, we studied the effect of verapamil, diltiazem, and nifedipine on the myocardial uptake and retention of Tc-99m N-NOET in isolated perfused rat hearts. METHODS AND RESULTS: After a 15-minute baseline period, rat hearts were perfused with 0.5 micromol/L verapamil (n = 6), 0.75 micromol/L diltiazem (n = 6), or 0.1 micromol/L nifedipine (n = 6) for 10 minutes before the injection of a bolus (40 microCi/250 microL) of the tracer. Control hearts were perfused with either 1.5 mmol/L calcium (same concentration as in the treated groups; n = 7) or 0.75 mmol/L calcium (same contractility as in the treated groups; n = 6). Myocardial activity of Tc-99m N-NOET was monitored for 30 minutes. The functional parameters of the hearts were recorded throughout the experiments. Calcium inhibitors induced a 40% to 55% decrease in maximal first derivative of left ventricular pressure (dP/dt) (0.0001
Subject(s)
Calcium Channel Blockers/pharmacology , Myocardium/metabolism , Organotechnetium Compounds/pharmacokinetics , Radiopharmaceuticals/pharmacokinetics , Thiocarbamates/pharmacokinetics , Animals , Diltiazem/pharmacology , In Vitro Techniques , Nifedipine/pharmacology , Rats , Verapamil/pharmacologyABSTRACT
UNLABELLED: 99mTcN-NOET (bis[N-ethoxy,N-ethyl]dithiocarbamato nitrido technetium (V)) has been proposed for myocardial perfusion imaging. Biodistribution, safety, and dosimetry were studied in 10 healthy volunteers (5 at rest and 5 during exercise). METHODS: Biodistribution was studied by acquiring dynamic images up to 60 min after injection and whole-body images up to 24 h after injection. The MIRDOSE3 analysis program was used for radiation dosimetry calculations. RESULTS: Safety parameters measured to 48 h after injection revealed no clinically significant changes. Cardiac uptake of 99mTcN-NOET was high (2.9%-3%), with biologic half-life of 210-257 min on average. Lung uptake of 99mTcN-NOET was higher (10%-20%) but, on average, biologic half-life was shorter (1-77 min). Clearance from the blood was rapid (5% by 5 min). Radiation dosimetry calculations indicated an effective absorbed dose of 5.11 x 10(-3) mSv/MBq at rest and 5.38 x 10(-3) mSv/MBq after exercise. CONCLUSION: 99mTcN-NOET exhibits high cardiac uptake and an estimated effective absorbed dose comparable with that of the other 99mTc-labeled compounds used in myocardial perfusion imaging.
Subject(s)
Heart/diagnostic imaging , Organotechnetium Compounds , Radiopharmaceuticals , Thiocarbamates , Adult , Female , Half-Life , Humans , Male , Myocardium/metabolism , Organotechnetium Compounds/pharmacokinetics , Radiation Dosage , Radionuclide Imaging , Radiopharmaceuticals/pharmacokinetics , Safety , Thiocarbamates/pharmacokinetics , Tissue DistributionABSTRACT
Coronary artery disease is a common, serious and insidious complication of diabetes. Myocardial ischaemia is often silent. All diabetics do not have the same coronary risk and, therefore, it is important to determine which investigations to perform and which patients. This strategy is justified because it allows identification of these cases which require a medical or an invasive (angioplasty, surgical revascularisation) approach, as these interventions may improve the prognosis. The first stage is clinical (investigation of cardiovascular risk factors). When more than two risk factors are found, further investigations are justified. Exercise stress testing provide reassuring diagnostic and prognostic data when maximal and negative. When sub-maximal, impossible or significantly ischaemic, a second investigation is useful. Holter ECG recording with analysis of ST variation lacks sensitivity and, above all, specificity. The diagnostic value of perfusion myocardial scintigraphy in the diabetic is not as good as that observed in the general population, but its prognostic value remains good. Ischaemia involving over 20% of the myocardium justifies therapeutic investigation. Stress echocardiography has been validated in the diagnosis and prognosis of coronary artery disease and its sensitivity and specificity are probably the same as those of scintigraphy. The authors conclude that the asymptomatic diabetic requires clinical and staged paraclinical investigation to assess prognosis and, depending on the results, the adoption of a beneficial therapeutic strategy.
Subject(s)
Coronary Disease/diagnosis , Diabetes Complications , Diagnostic Techniques, Cardiovascular , Cardiovascular Agents/therapeutic use , Coronary Angiography , Coronary Disease/complications , Coronary Disease/diagnostic imaging , Coronary Disease/therapy , Echocardiography , Electrocardiography, Ambulatory , Exercise Test , Humans , Myocardial Revascularization , Predictive Value of Tests , Radionuclide Imaging , Sensitivity and Specificity , Technetium Tc 99m SestamibiABSTRACT
BACKGROUND: The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. METHODS AND RESULTS: One thousand one hundred thirty-seven patients (857 men, age 55+/-9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72+/-18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload =75 W) (2. 36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and >/=3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. CONCLUSIONS: The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.