Serving Science and Society Into the New Millenium (1998) / Chapter Skim
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Part II Biotechnology for a Healthy Citizenry
Part II Biotechnology for a Healthy Citizenry
Pages 31-55
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Part II Biotechnology for a Healthy Citizenry
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I am going to talk about 2 studies that used different PET techniques. The first study used glucose metabolism to discern changes in the energy requirements or work of the brain when normal people performed various tasks.
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A biologic marker can identify a developing disease not only in the earliest symptomatic phases, but long before the disease produces alterations in organ function or loss of regulated function. For example, it is thought that breast cancer begins about 9 yr before we pick it up.
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Fowler, Gene-Jack Wang, S John Galley, and Yu-Shin Din Medical and Chemistry Departments Brookhaven National Laboratory Upton, NY Positron emission tomography (PET)
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Nicotine60 effects when administered intravenously6 it is abused much less frequently than is cocaine.7 One question that arises is whether methylphenidate, the most frequently prescribed psychoactive drug in children in the United States, where it is used for the treatment of attention-deficit disorder,8 is as potentially addictive as cocaine or whether variables other than affinity for DAT influence the reinforcing effects. Of particular interest is whether these 2 drugs differ in their pharmacokinetics, inasmuch as previous studies showed that the shorter the interval between intake and perceived effects of a drug, the greater its reinforcing effects.9 lo To address that issue, we compared the distribution and pharmacokinetics of cocaine and methylphenidate in the human brain by labeling cocainell and methylphenidatel2 with 1lC and then measuring their concentrations in the brain with PET.13 [llC]
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cocaine in basal ganglia and temporal course for self-reported "high" induced by intravenous cocaine (0.6 mg/kg iv)
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Thus, the "high" induced by the intravenous administration of cocaine or of methylphenidate appears to be related to the fast uptake of the drug in the brain but not to its continuous presence there. We postulate that the potential for a drug to induce addiction is due not only to its reinforcing effects but also to its ability to facilitate repeated administration.
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o 0.05 0.1 0.3 0.6 Dose (mg/kg iv) FIGURE 5 Extent of DAT occupancy induced by different doses of intravenous cocaine.
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to measure the rate of synthesis of DA have shown significant reductions in cocaine abusers compared with controls .3i Studies using [~iCideprenyl-D2 and [~iCiclorgyline as radioligands to measure the concentration of MAO A and B have been conducted only in cigarette smokers.32 33 These studies showed that the concentration of MAO A and B was significantly lower in the brains of cigarette smokers than in the brains of nonsmoking subjects (see figure 7 for MAO B)
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for 1 plane at basal ganglia in a healthy subject and in an active cigarette smoker.
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We cannot rule out the possibility that the blunting preceded the drug use in the cocaine addicts, but the findings illustrate how drug history can affect a person's response to a psychoactive drug. FUNCTIONAL MEASUREMENTS Regional brain function can be monitored with PET by measuring energy metabolism or by measuring cerebral blood flow (CBF)
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Metabolic studies have also been done to assess the effects of chronic administration of drugs cocaine, alcohol, and marijuana on the human brain. The studies have shown different regional patterns of brain metabolic abnormalities, depending on the substance abused, and have shown different levels of recovery from the metabolic abnormalities on detoxification.
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New directions in positron emission tomography-Part II. In: Bristol JA, editor.
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Mapping human brain monoamine oxidase A and B with llC-suicide inactivatoirs and positron emission tomography. Science.
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Martin PT, Wolf AP, Volkow ND, Fowler JS. GABAergic inhibition of endogeneous dopamine release measured in viva with 1lC-raclopride and positron emission tomography.
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This index of glucose metabolism can also be corrected for lean body weight (instead of total body weight) and serum glucose content, but these corrections have not been found necessary for evaluating some tumors, such as lung cancer.2 The first clinical applications of FDG PET were in the brain.
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We have recently shown that FDG PETis very accurate in identifying metastases to the adrenal glands, which are common sites for the spread of lung cancer.8 Other studies have shown that management changes occur in 30-40% of patients who undergo whole-body scans.69 The whole-body PET study is replacing multiple-imaging studies for staging malignancies (figure 1~. CT and MRI cannot adequately characterize posttreatment pulmonary abnormalities as persistent tumor, scarring, or necrosis.
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(B) Images through posterior portion of body reveal small lung cancer in right lung and multiple vertebral body metastases.
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et al: Whole-body 18F-fluorodeoxyglucose positron emission tomography in preoperative evaluation of lung cancer. Lancet 1994; 1265-1266.
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Department of Energy Laboratory of Structural Biology and Molecular Medicine Molecular Biology Institute UCLA Center for the Health Sciences Los Angeles, California Michael Phelps has described the principles of positron emission tomography (PET) and demonstrated how this technique can be used to monitor biochemical processes in living subjects.
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The development of dynamic, noninvasive imaging techniques, such as PET, led to the marriage of imaging and biochemistry and allowed researchers and clinicians to study biochemical reactions in living animals and in patients. Current Methods for Imaging Genome Function in Vertebrates Developmental and behavioral biologists interested in imaging the expression of individual endogenous genes are restricted to immunochemical detection of protein products or in situ hybridization of mRNA.
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Our goal is to develop imaging technology to monitor expression of reporter genes repeatedly in living experimental vertebrates and in patients. DEVELOPING PET-BASED IMAGING TECHNIQUES TO EXAMINE REPORTER-GENE EXPRESSION IN LIVING SUBJECTS PET Reporter-Gene-PET Reporter-Probe Systems for Imaging Reporter-Gene Expression in Living Animals We are developing a means to "mark" transplanted cells or DNA delivery systems with PET reporter genes (PRGs)
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We are working on procedures to use HSV tk and i8F-labeled substrates as PRG-PRP combinations to image gene expression in vivo repeatedly and noninvasively. DA D2 Receptor and FESP as a PRG-PRP System We have used the DA D2 receptor as an alternative PRG first, because its normal expression at high concentrations is limited primarily to the brain; second, because a DA D2 receptor reporter gene will not be immunogenic; and third, because the nuclear medicine group the University of California, Los Angeles (UCLA)
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fluoroethyl) spiperone examined with positron emission tomography.
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