13 technical review-2

Nuclear Medicine must concentrate on its unique strengths
if it is to continue to prove clinically useful and survive into
the new century.

People undertake research in Cancer imaging; chemistry, such as the development of the development and a survey of the literature potentially ‘useful’ new products, but few, avenues for clinical exploitation in years the ability to distinguish true infection radiolabelled white cells. In cancer, the characterised by the clinical application of naturally occurring radioactive salts such individual tailoring of patient therapies.
following the introduction of technetium- possibilities become available, it will be essential to determine ways of identifying 99mTc-pyrophosphate for bone scanning.
those patients who will benefit from such The period up to the early 80’s pursued pharmaceuticals that were taken up by the therapeutic radiopharmaceuticals – such as different mechanisms – colloids for liver lymphoma, radiolabelled octreotide analogs clinical utility. This has stimulated further research into other therapeutic applications and even the use of ‘new’ radionuclides such as the beta-emitter Lu-177 and alpha- imaging is to translate the successes of the bind to receptors in vitro, have been developed, their application in-vivo label white cells in-vivo in whole-blood neuropeptides such as somatostatin analogues thereby removing the need for manipulation specificity for infection rather than sterile of the blood ex-vivo. Perhaps the most widely inflammation, the target to background ratios expression of their receptors on the surface of their use has not yet been pursued in the fragment which binds to the NCA-90 epitope clinic. By contrast, the use of 99mTc labelled millennium and is likely to do so for the on white cells. Although developed with the ciprofloxacin, a fluoroquinolone antibiotic, foreseeable future. The increasing availability has been studied in almost 1,000 patients with of strong competing imaging modalities such circulating white cells which subsequently encouraging results. In fact, ciprofloxacin is migrate to the site of infection, it appears that this is not its real mechanism of action. The antibiotics that have been labelled with the strengths if it is to continue to prove clinically uptake is due in part to ‘non-specific’ aim of infection imaging. More developments extravasation of the labelled antibody at the can be expected in this field as antibiotics, site of infection followed (perhaps) by binding with more specific bacterial interactions and to local white cells in the vicinity. Other more favourable patterns of biodistribution, Nuclear Medicine are (i) the use of very high ligands, such as cytokines and chemotactic are identified. Of particular interest is the use specific activity tracers which permit the peptides, which recognise different markers on different populations of white cells, are infections. Antibiotics specific for fungal or mechanisms in-vivo and (ii) the therapeutic currently being explored and may find wider parasitic infections may be very valuable in application of targeted radionuclides. The the context of adventitious infections in knowledge that non-specific mechanisms can developments in the future will arise from the contribute to imaging of inflammation has led application of these strengths to the solution several research groups to pursue entirely of real clinical problems. Thus the directions non-white cell mediated solutions to this Cancer imaging
of radiopharmaceutical research will tend to problem. Among the most successful has been radiopharmaceuticals in the management of functional assessment of tissues, from targets (HIG) and liposomes. These can be labelled on the outside of cell membranes to those with a variety of radioisotopes, in particular buried deep within the cytoplasm and cell nucleus, from ‘passive’ imaging in the therefore have the potential for use in imaging both the same day and for several days after interventional applications in the operating administration. Clinical trials with these theatre and from the diagnosis of disease to its agents have demonstrated high sensitivity in the detection of inflammation but neither has The reality is that socio-economic issues, achieved widespread use. Perhaps the main as well as clinical realities, mean that Nuclear mainly in the following areas of research: cause for this is that, for a variety of reasons, Medicine is unlikely to play a significant role in either screening or primary diagnosis. But the product, obtained market authorisation and it can play an increasingly important part in made it universally available. Without this radiopharmaceutical, however ‘good’, is likely to remain an item of purely academic Inflammation imaging
The issues in inflammation imaging lie in the sensitivity and high specificity. In recent years it has been recognised that 18FDG can investigation – labelled white cells, and also in source of the inflammation. The important deliver at least the first two of these attributes question is whether or not to continue the use and clinical PET centre development is now inflammation caused by underlying infection of antibiotics. Thus attempts are being made the most rapidly developing application of from that caused by other causes. The widely to develop radiopharmaceuticals that interact Nuclear Medicine in the developed world. At not with the body’s own defence mechanisms able to compete with FDG in this arena is not facilities and carries the risk of needle-stick themselves. Among the current candidates of infection from blood-borne infections such as hepatitis and HIV. Attempts to overcome this problem have included the use of tracers that spectrum of bacteria. Although these have specificity of FDG. Among the most widely process, researchers have labelled a variety of arises when cell surveillance systems detect substrates for cell metabolism including a high levels of DNA damage which, if the cell radiolabelled neuropeptides. Although their number of different nucleotides and amino- was allowed to divide normally, would lead to acids. One of the most widely studied is 18F- a risk of inherited mutations in the genetic specific diseases in which expression of the 3’-deoxy-3’-fluorothymidine (FLT). PET code. One of the effects of apoptosis is a imaging with FLT delineates the major sites refolding of the cell membrane resulting in pharmaceuticals do have the potential to fill of normal cell proliferation, in particular the the exposure on the outside of the cell of this current deficiency in cancer staging. To efficiently image many tumours albeit with surface. These elements can be used as targets peripheral neuroreceptor imaging remains the for radiopharmaceuticals which aim to image family of somatostatin receptors. However, likely to be just one of the forerunners of a the apoptotic process as a measure of tumour because of its success, this application is also response to therapy. The most well developed approach is the use of radiolabelled annexin- administered before and after a cytotoxic drug, would be able to provide a quantitative receptor imaging, but will have broader utility measure of drug response. However, to justify components exposed during the early stages across the field of neuropeptide receptor the clinical use of such tracers, it is important of apoptosis. Annexin-V has been labelled targeting. Examples include the development to validate their mechanism of uptake and with technetium-99m and studied in a number of improved methods for labelling peptides retention and FLT represents a good model with technetium-99m. Thus, the combination for such studies. FLT diffuses across the cell membrane into the cytosol where it is trapped and validated in animal models, in fact some technetium coordination has been shown to kinase1. Thus, the uptake of FLT by a tissue will depend upon the level of TK1 activity acquired in ‘natural’ apoptosis such as, in performance of these tracers for imaging and therein. In order to determine if TK1 activity myocardial infarction. Although uptake of is related to proliferation, Rasey and co- producing the tri-carbonyl, tri-aqua reactive workers (Rasey J.S, Grierson J.R, Wiens L.W, Kolb P.D, Schwarz J.L., paper in Journal of degree of uptake is very varied and the quality Nuclear Medicine, 2002; 43: 1210-7) compared the cellular uptake of FLT with the certainly a number of reasons for this; not characteristics. The horizon will see the number of dividing cells and the TK1 level least that apoptosis is a transient phenomenon application of this new chemistry to a range and found a linear relationship with both unpredictable. However a contributory factor proliferation. However, in a transformed cell substrate for radiopharmaceutical application.
It is a relatively large protein that clears only substrates such as thymidine, situations may cancer are highly toxic and one of the major also arise in which TK1 levels are elevated proteins, diffuses only slowly into tumours.
deficiencies in the current management of independently of proliferation since this patients is our inability to identify whether would provide a survival benefit. Wagner and achieved are therefore sub-optimal. It seems co-workers (Seitz U., Wagner M., Neumaier likely that annexin-V will be a paradigm for a particular combination of drugs. The classical B., Wawra E., Glatting G., Leder G., et al., new generation of radiopharmaceuticals for paper in European Journal of Nuclear only able to provide information some time Medicine Molecular Imaging, 2002; 29: after the patient has received a course of often 1174-81) studied the levels of TK1 (and other debilitating therapy. An investigation which enzyme) activity is a variety of pancreatic primarily to conventional established cancer therapies, radiopharmaceuticals also have a effectiveness of a particular therapy, even varied independently of cell proliferation.
potential use in defining the role of newly after one dose, could be very valuable and Many such studies will be performed over the save not only a lot of money but also a lot of next few years to validate the use of markers angiogenic therapies have little immediate unnecessary toxicity by patients who will not of proliferation before their routine clinical effect on tumour size, and their effectiveness benefit significantly from their treatment.
One of the most valuable measures of drug structural imaging. Tracers, which target response would be its effect on tumour cell proliferation. In order to try and image this markers of drug efficacy in clinical trials of neuroreceptor imaging radiopharmaceutical determinants of effective therapy. We employ must show high stability (in solution, in As well as indicating responses to therapy a variety of different radionuclides with a serum and in-vitro), high in-vitro binding range of different physical decay properties affinity, good in-vitro binding selectivity, help to identify those patients which will acceptable brain uptake and specific receptor benefit from a particular type of therapy. It uptake in-vivo. While the first three has long been known that tumours, which are requirements are achievable, combining these hypoxic, are less responsive to external beam much about the mechanism of action of low- dose targeted radiotherapy. Is it the same as presents a real problem. To date, effective oxygen levels. This has prompted a search for high-dose external beam therapy, i.e.
radiopharmaceuticals — the uptake of which primarily double-stranded DNA cleavage, or is determined by tissue oxygen levels. The most widely explored class of compounds are the nitroimidazoles. These are preferentially parameters. At the same time, it has been reduced and consequently bound in hypoxic argued that irrespective of the underlying The underpinning technology, which links all tissues and, if radiolabelled, can potentially of the clinical applications described in this be used to image the distribution of oxygen studies are in-vivo trials of efficacy either in review, is radiopharmaceutical chemistry. An patients or animal models. For such studies, understanding of the coordination chemistry, organs such as the heart. Nitroimidazoles availability of the radioisotope rather than its mode of decay. In recent years the number of relationships between this chemistry and the behaviour of the radiotracers in biological with technetium-99m. Several of these are in increased with several sources of yttrium-90 environments, is essential if developments in clinical trials although their role, and the and, more recently, lutetium-177 appearing.
radiopharmaceutical design are to continue.
This is likely to lead to a significant increase The ability to manipulate the stability, charge, in the ability of researchers to undertake size and lipophilicity of bifunctional chelates in particular will allow us to generate new degrees of retention in hypoxic or normoxic Neuroreceptor imaging
properties that translate into novel patterns of generation of radiopharmaceuticals beyond semithiocarbazone tracers is reduction of preserve of specialist PET chemists. As a consequence of their work, a large number of shown that varying the substituents on the radioligands with affinity for a variety of reduction potential of the copper core and by developed but the application of these tracers widely used then, either more centres will need to develop access to the technology (a Cancer therapy
Since 2001, Dr. Stephen Mather has been As suggested at the beginning of this review, clinical PET) or analogues of these tracers Professor of Radiopharmacy, St Bartholomew’s and Royal London Hospitals School of Medicine and Dentistry, University of radionuclide therapy and recent years have significant number of iodine-123 labelled London. He is also Head, ICRF Nuclear seen a resurgence of interest in this field. The compounds has now been established and at stimulus for this has been the development of Bartholomew’s Hospital. He is author of more two new indications for targeted therapy – than 100 peer-reviewed publications and expense and limited availability of iodine-123 invited reviews, and more than 150 published conference abstracts and also the editor of technetium-99m labelled receptor ligands is two books. For a full listing of references, neuroendocrine cancer. A major difficulty in still the goal of several research groups but its this area of research is the lack of basic E-mail: [email protected]

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INTRODUCCIÓN*Imperio y canon en William Henry HudsonLeila Gómez University of Colorado, Boulder En 1941, se publica en Argentina la pionera Antología de Guillermo Enrique Hudson con estudios críticos sobre su vida y su obra , con textos de Fernando Pozzo, E. Martínez Estrada, Jorge Casares, Jorge Luis Borges, H. J. Massingham, V. S. Pritchett y Hugo Manning. Fue este uno de los principales

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