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991.
Synthesis and positron emission tomography studies of carbon-11-labeled imatinib (Gleevec) 总被引:2,自引:0,他引:2
Kil KE Ding YS Lin KS Alexoff D Kim SW Shea C Xu Y Muench L Fowler JS 《Nuclear medicine and biology》2007,34(2):153-163
INTRODUCTION: Imatinib mesylate (Gleevec) is a well known drug for treating chronic myeloid leukemia and gastrointestinal stromal tumors. Its active ingredient, imatinib ([4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)-2-pyrimidinyl]amino]phenyl]benzamide), blocks the activity of several tyrosine kinases. Here we labeled imatinib with carbon-11 as a tool for determining the drug distribution and pharmacokinetics of imatinib, and we carried out positron emission tomography (PET) studies in baboons. METHODS: [N-(11)C-methyl]imatinib was synthesized from [(11)C]methyl iodide and norimatinib was synthesized by the demethylation of imatinib (isolated from Gleevec tablets) according to a patent procedure [Collins JM, Klecker RW Jr, Anderson LW. Imaging of drug accumulation as a guide to antitumor therapy. US Patent 20030198594A1, 2003]. Norimatinib was also synthesized from the corresponding amine and acid. PET studies were carried out in three baboons to measure pharmacokinetics in the brain and peripheral organs and to determine the effect of a therapeutic dose of imatinib. Log D and plasma protein binding were also measured. RESULTS: [N-(11)C-methyl]imatinib uptake in the brain is negligible (consistent with P-glycoprotein-mediated efflux); it peaks and clears rapidly from the heart, lungs and spleen. Peak uptake and clearance occur more slowly in the liver and kidneys, followed by accumulation in the gallbladder and urinary bladder. Pretreatment with imatinib did not change uptake in the heart, lungs, kidneys and spleen, and increased uptake in the liver and gallbladder. CONCLUSIONS: [N-(11)C-methyl]imatinib has potential for assessing the regional distribution and kinetics of imatinib in the human body to determine whether the drug targets tumors and to identify other organs to which the drug or its labeled metabolites distribute. Paired with tracers such as 2'deoxy-2'-[(18)F]fluoro-D-glucose ((18)FDG) and 3'deoxy-3'-[(18)F]fluorothymidine ((18)FLT), [N-(11)C-methyl]imatinib may be a useful radiotracer for planning chemotherapy, for monitoring response to treatment and for assessing the role of drug pharmacokinetics in drug resistance. 相似文献
992.
Kim SW Ding YS Alexoff D Patel V Logan J Lin KS Shea C Muench L Xu Y Carter P King P Constanzo JR Ciaccio JA Fowler JS 《Nuclear medicine and biology》2007,34(5):541-551
INTRODUCTION: (3E)-3-[(2,4-dimethoxyphenyl)methylene]-3,4,5,6-tetrahydro-2,3'-bipyridine (GTS-21), a partial alpha7 nicotinic acetylcholine receptor agonist drug, has recently been shown to improve cognition in schizophrenia and Alzheimer's disease. One of its two major demethylated metabolites, 4-OH-GTS-21, has been suggested to contribute to its therapeutic effects. METHODS: We labeled GTS-21 in two different positions with carbon-11 ([2-methoxy-(11)C]GTS-21 and [4-(11)C]GTS-21) along with two corresponding demethylated metabolites ([2-methoxy-(11)C]4-OH-GTS-21 and [4-methoxy-(11)C]2-OH-GTS-21) for pharmacokinetic studies in baboons and mice with positron emission tomography (PET). RESULTS: Both [2-(11)C]GTS-21 and [4-methoxy-(11)C]GTS-21 showed similar initial high rapid uptake in baboon brain, peaking from 1 to 3.5 min (0.027-0.038%ID/cc) followed by rapid clearance (t(1/2)<15 min), resulting in low brain retention by 30 min. However, after 30 min, [2-methoxy-(11)C]GTS-21 continued to clear while [4-methoxy-(11)C]GTS-21 plateaued, suggesting the entry of a labeled metabolite into the brain. Comparison of the pharmacokinetics of the two labeled metabolites confirmed expected higher brain uptake and retention of [4-methoxy-(11)C]2-OH-GTS-21 (the labeled metabolite of [4-methoxy-(11)C]GTS-21) relative to [2-methoxy-(11)C]4-OH-GTS-21 (the labeled metabolite of [2-methoxy-(11)C]GTS-21), which had negligible brain uptake. Ex vivo studies in mice showed that GTS-21 is the major chemical form in the mouse brain. Whole-body dynamic PET imaging in baboon and mouse showed that the major route of excretion of C-11 is through the gallbladder. CONCLUSIONS: The major findings are as follows: (a) extremely rapid uptake and clearance of [2-methoxy-(11)C]GTS-21 from the brain, which may need to be considered in developing optimal dosing of GTS-21 for patients, and (b) significant brain uptake of 2-OH-GTS-21, suggesting that it might contribute to the therapeutic effects of GTS-21. This study illustrates the value of comparing different label positions and labeled metabolites to gain insight on the behavior of a central nervous system drug and its metabolites in the brain, providing an important perspective on drug pharmacokinetics. 相似文献
993.
Quantification of rodent cerebral blood flow (CBF) in normal and high flow states using pulsed arterial spin labeling magnetic resonance imaging 总被引:1,自引:0,他引:1
PURPOSE: To implement a pulsed arterial spin labeling (ASL) technique in rats that accounts for cerebral blood flow (CBF) quantification errors due to arterial transit times (dt)-the time that tagged blood takes to reach the imaging slice-and outflow of the tag. MATERIALS AND METHODS: Wistar rats were subjected to air or 5% CO(2), and flow-sensitive alternating inversion-recovery (FAIR) perfusion images were acquired. For CBF calculation, we applied the double-subtraction strategy (Buxton et al., Magn Reson Med 1998;40:383-396), in which data collected at two inversion times (TIs) are combined. RESULTS: The ASL signal fell off more rapidly than expected from TI = one second onward, due to outflow effects. Inversion times for CBF calculation were therefore chosen to be larger than the longest transit times, but short enough to avoid systematic errors caused by outflow of tagged blood. Using our method, we observed a marked regional variability in CBF and dt, and a region dependent response to hypercapnia. CONCLUSION: Even when flow is accelerated, CBF can be accurately determined using pulsed ASL, as long as dt and outflow of the tag are accounted for. 相似文献
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997.
Bastin ME Clayden JD Pattie A Gerrish IF Wardlaw JM Deary IJ 《Neurobiology of aging》2009,30(1):125-136
Regions of diffuse periventricular white matter hyperintensities (PVWMH) are a common finding on T(2)-weighted MRI scans of older subjects, but their aetiology remains unclear. The aim of this study was to characterize differences in water diffusion and magnetization transfer MRI parameters between macroscopically normal-appearing white matter (NAWM) and PVWMH in a cohort of normal older subjects. Forty-two non-demented 83-year olds underwent structural, diffusion tensor and magnetization transfer MRI. Mean diffusivity (), fractional anisotropy (FA), axial (lambda(ax)) and radial (lambda(rad)) diffusivity, and magnetization transfer ratio (MTR) were measured in both NAWM and PVWMH in frontal and parieto-occipital white matter, and centrum semiovale. For all three regions, PVWMH had greater , lambda(ax) and lambda(rad) than NAWM, while FA and MTR were significantly reduced compared with normal tissue (p<0.01). For PVWMH, MTR was significantly correlated (Spearman's rho in the range -0.93 to 0.70; p<0.01) with , FA, lambda(ax) and lambda(rad) in all three regions. Conversely, for NAWM, the only significant correlation between MTR and a water diffusion parameter was for lambda(rad) in parieto-occipital white matter (rho=-0.40; p<0.05), with all other correlations close to the rho=0 level. These data indicate that in normal white matter, characterized by structurally coherent cell membranes, the degree of water molecule diffusion and myelination are held within relatively tight limits. However, within PVWMH, MTR correlates strongly with water diffusion parameters probably because of the pathologically associated neuronal loss, demyelination and gliosis. 相似文献
998.
Activated PKR protein regulates downstream anti-viral effects, including inhibition of translation. Thus, many viruses encode proteins to inhibit PKR. Here, we provide evidence that the vaccinia virus K1 protein, a host-range protein, possesses this function. First, the expression of the wild-type K1 protein was necessary to inhibit virus-induced eIF2α phosphorylation, an indirect measure of PKR activation, in RK13 and HeLa cells. Second, virus-induced eIF2α phosphorylation no longer occurred in PKR-deficient HeLa cells, suggesting PKR was responsible for vaccinia virus-induced eIF2α modification. Third, in normal HeLa cells, K1 protein expression also prevented virus-mediated PKR phosphorylation (activation). Residues in the C-terminal portion of the ANK2 region of K1 were identified as necessary for this inhibitory phenotype. Interestingly, mutant viruses that failed to inhibit PKR activation, such as S2C#2, also did not replicate in HeLa cells, suggesting that K1's inhibition of PKR was required for a productive infection. In support of this theory, when PKR was absent from HeLa cells, there was a modest restoration of viral protein synthesis during S2C#2 infection. However, the increased protein synthesis was insufficient for a productive infection. 相似文献
999.
David J. Waine David Honeybourne E. Grace Smith Joanna L. Whitehouse Chris G. Dowson 《Journal of clinical microbiology》2009,47(11):3444-3448
Multilocus sequence typing (MLST) is a genetic typing tool designed to provide information about the relatedness of isolates at the core genome level. The utility of MLST in regard to cystic fibrosis (CF)-related infection with Pseudomonas aeruginosa is unknown. The molecular clock speed of the MLST genes was studied using 219 colonies isolated longitudinally from 49 patients with CF. A cross-sectional study examining 27 to 46 colonies per sputum sample for samples from 16 patients was also undertaken. The molecular clock speed was estimated to be 2.05 × 10−5 (upper 95% confidence limit) or 4.75 × 10−6 (50% confidence limit) point mutations per nucleotide per year. In the cross-sectional study, 50% of patients were infected with more than one sequence type. There was evidence of point mutations, recombination events, and coinfection with epidemic and unique strains. A clonal complex that was highly genetically distinct from the rest of the P. aeruginosa population was identified. The MLST scheme uses genes with an appropriate clock speed and provides useful information about the genetic variation of P. aeruginosa within and between patients with CF.Multilocus sequence typing (MLST) is a typing tool based on the DNA sequences of several housekeeping genes. Housekeeping genes are chosen because they are assumed to be under low selection pressure and therefore to have a low molecular clock speed, i.e., to undergo mutations at a low rate. This allows MLST to provide data about the core evolutionary genome of a bacterium which allow deductions about population structure and the relatedness of different strains. Where populations are rapidly diversifying by recombination, as may occur in a clinical outbreak, MLST is able to identify closely related isolates (22) which may have undergone changes in one or two loci. MLST has recently been used to estimate the molecular clock speed of the housekeeping genes in cystic fibrosis (CF)-related Burkholderia cepacia complex infection and to identify presumed recombination events in infected patients (24). We hypothesized that the clock speed of the housekeeping genes of the Pseudomonas aeruginosa MLST scheme in patients with CF would be of the same order and that point mutations and recombination events would be identified. These hypotheses were tested by examining sequential isolates from chronically infected patients with CF (clock speed study) and by examining multiple isolates from single sputum samples (cross-sectional study). 相似文献
1000.
Polanowska K Seniów J Paprot E Leśniak M Członkowska A 《Neuropsychological rehabilitation》2009,19(3):364-382
The aim of this randomised, double-blind study was to investigate the therapeutic effectiveness of left-hand electrical stimulation for patients with post-stroke left visuo-spatial neglect. This approach was hypothesised to enhance activation of the right hemisphere attention system and to improve visual exploration of extrapersonal space. Participants (n = 40) in the study were in a relatively early stage of recovery from their first right hemisphere stroke, and were randomly assigned to the experimental (E) or control (C) group. Group E received conventional visual scanning training combined with electrostimulation of the left hand, while Group C received scanning training with sham stimulation. Their visuo-spatial neglect was assessed twice, prior to the rehabilitation programme and on its completion, using cancellation tests and a letter-reading task. The effect of electrostimulation on hemineglect was assessed following a single administration and after a month-long rehabilitation programme. Although the immediate effect of stimulation was poor, after a month-long rehabilitation period we found significantly greater improvement in Group E patients than in Group C patients. Interestingly, the presence of hemisensory loss did not weaken the observed effect. Therefore, we claim that contralesional hand stimulation combined with visual scanning was a more effective treatment for hemineglect rehabilitation than scanning training alone. 相似文献