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Metabolite Ratios (metabolite + ratio)
Selected AbstractsA Short-echo-time Proton Magnetic Resonance Spectroscopic Imaging Study of Temporal Lobe EpilepsyEPILEPSIA, Issue 9 2002Robert J. Simister Summary: ,Purpose: We used short-echo-time proton magnetic resonance spectroscopy imaging (MRSI) to study metabolite concentration variation through the temporal lobe in patients with temporal lobe epilepsy (TLE) with and without abnormal MRI. Methods: MRSI was performed at TE = 30 ms to study 10 control subjects, 10 patients with TLE and unilateral hippocampal sclerosis, and 10 patients with TLE and unremarkable MRI (MRI negative). We measured the concentrations of N -acetyl aspartate +N -acetyl aspartyl-glutamate (NAAt), creatine (Cr), choline (Cho), glutamate + glutamine (Glx), and myoinositol, in the anterior, middle, and posterior medial temporal lobe (MTL), and in the posterior lateral temporal lobe. Segmented volumetric T1 -weighted MRIs gave the tissue composition of each MRSI voxel. Normal ranges were defined as the control mean ± 3 SD. Results: In the hippocampal sclerosis group, seven of 10 had abnormally low NAAt in the ipsilateral anterior MTL. In the MRI-negative group, four of 10 had low NAAt in the middle MTL voxel ipsilateral to seizure onset. Metabolite ratios were less sensitive to abnormality than was the NAAt concentration. Group analysis showed low NAAt, Cr, and Cho in the anterior MTL in hippocampal sclerosis. Glx was elevated in the anterior voxel contralateral to seizure onset in the MRI-negative group. Metabolite concentrations were influenced by voxel position and tissue composition. Conclusions: (a) Low NAAt, Cr, and Cho were features of the anterior sclerotic hippocampus, whereas low NAAt was observed in the MRI-negative group in the middle MTL region. The posterior temporal lobe regions were not associated with significant metabolite abnormality; (b) The two patient groups demonstrated different metabolite profiles across the temporal lobe, with elevated Glx a feature of the MRI-negative group; and (c) Voxel tissue composition and position influenced obtained metabolite concentrations. [source] 1H magnetic resonance spectroscopy in human hydrocephalusJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 3 2003Kees P.J. Braun MD Abstract Purpose To evaluate cerebral metabolism in clinical hydrocephalus with 1H magnetic resonance spectroscopy (MRS). Materials and Methods In 24 children and adults with progressive, arrested, or normal pressure hydrocephalus, long-echo time 1H MR spectra were acquired from periventricular white matter and intraventricular cerebrospinal fluid (CSF). Metabolite ratios, and the presence of lactate, were compared with 38 age-matched controls. Results Metabolite ratios of patients were within the 95% confidence interval (CI) of controls. A small lactate resonance was detected in 20% of control and hydrocephalic subjects. Lactate was consistently visible in CSF spectra, though lactate concentrations were normal. The CSF lactate T2 was long in comparison with the known intracellular metabolite T2 relaxation times. In three neonates with hydrocephalus and spina bifida, 3-hydroxybutyrate was detected in CSF in vivo. Conclusion Within the limits of the present methods, 1H MRS could not detect cerebral metabolic abnormalities in human hydrocephalus and provided no additional diagnostic information. The long T2 of lactate in CSF explains its high visibility. Hence, the detection of lactate in spectra acquired from voxels that contain CSF does not necessarily imply cerebral ischemia. J. Magn. Reson. Imaging 2003;17:291,299. © 2003 Wiley-Liss, Inc. [source] Role of Proton Magnetic Resonance Spectroscopy in Differentiating Oligodendrogliomas from AstrocytomasJOURNAL OF NEUROIMAGING, Issue 1 2010Sanjeev Chawla PhD ABSTRACT BACKGROUND AND PURPOSE Preoperative differentiation of astrocytomas from oligodendrogliomas is clinically important, as oligodendrogliomas are more sensitive to chemotherapy. The purpose of this study was to assess the role of proton magnetic resonance spectroscopy in distinguishing astrocytomas from oligodendrogliomas. METHODS Forty-six patients [astrocytomas (n= 17) and oligodendrogliomas (n= 29)] underwent magnetic resonance imaging and multi voxel proton magnetic resonance spectroscopic imaging before treatment. Peak areas for N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI), glutamate/glutamine (Glx), and lipids + lactate (Lip+Lac) were analyzed from voxels that exhibited hyperintensity on fluid-attenuated inversion recovery images and were normalized to Cr from each voxel. The average metabolite/Cr ratios from these voxels were then compared between astrocytomas and oligodendrogliomas. Receiver-operating curve analyses were used as measures of differentiation accuracy of metabolite ratios. A threshold value for a metabolite ratio was estimated by maximizing the sum of sensitivity and specificity. RESULTS A significant difference in mI/Cr was observed between astrocytomas and oligodendrogliomas (.50 ± .18 vs. 0.66 ± 0.20, P < .05). Using a threshold value of .56 for mI/Cr ratio, it was possible to differentiate oligodendrogliomas from astrocytomas with a sensitivity of 72.4% and specificity of 76.4%. CONCLUSION These results suggest that mI/Cr might aid in distinguishing oligodendrogliomas from astrocytomas. J Neuroimaging 2010;20:3-8. [source] Combined Use of F-18 Fluorocholine Positron Emission Tomography and Magnetic Resonance Spectroscopy for Brain Tumor EvaluationJOURNAL OF NEUROIMAGING, Issue 3 2004Sandi A. Kwee MD ABSTRACT Background. Choline metabolism is often abnormal in malignant brain tumors.Methods. Brain positron emission tomography (PET) imaging with F-18 fluorocholine (FCH) was performed on 2 patients with intracranial lesions suspected to be high-grade malignant gliomas on the basis of magnetic resonance (MR) imaging and multivoxel 1H-MR spectroscopic imaging (MRSI) findings. Standardized uptake value (SUV) measurements on PET were compared with measurements of choline/creatine metabolite ratio on MRSI in corresponding regions. Brain biopsy revealed glioblastoma multiforme (GBM) in one case and demyelinating disease in the other.Results. In the case of GBM, the tumor demonstrated increased FCH uptake on PET. The mean and maximum SUV in areas of the tumor correlated with regional choline/ creatine ratio measurements (r= 0.76,P < .001;r= 0.83,P < .001, respectively). In the case of tumefactive demyelinating lesions, the lesion demonstrated low FCH uptake, which did not correlate with choline/ creatine ratio measurements.Conclusions. Assessments of choline metabolism may aid in evaluating intracranial mass lesions. [source] Transrectal ultrasound-guided biopsy of prostate voxels identified as suspicious of malignancy on three-dimensional 1H MR spectroscopic imaging in patients with abnormal digital rectal examination or raised prostate specific antigen level of 4,10 ng/mlNMR IN BIOMEDICINE, Issue 1 2007Virendra Kumar Abstract Results of the evaluation of transrectal ultrasound (TRUS) guided needle biopsy of voxels identified as suspicious of malignancy on magnetic resonance spectroscopic imaging (MRSI) in a large cohort of men (n,=,83) with abnormal digital rectal examination (DRE) [prostate specific antigen (PSA) 0,4,ng/ml] or PSA less than 10,ng/ml, are reported. Three-dimensional 1H MRSI was carried out at 1.5 T using a pelvic-phased array coil in combination with an endorectal surface coil. Voxels were classified as suspicious of malignancy based on Cit/(Cho,+,Cr) metabolite ratio. TRUS-guided biopsy of suspicious voxels was performed using the z - and x -coordinates obtained from MR images and two to three cores were taken from the suspected site. A systematic sextant biopsy was also carried out. MRSI showed voxels suspicious of malignancy in 44 patients while biopsy revealed cancer in 11 patients (25%). Patients who were negative for malignancy on MRSI were also negative on biopsy. An overall sensitivity of 100%, specificity of 54%, negative predictive value of 100% and accuracy of 60% were obtained. The site of biopsy was confirmed (n,=,20) as a hypo-intense area on repeat MRI while repeat MRSI revealed high choline and low citrate. The overall success rate of MRI-directed TRUS-guided biopsy of 25% was higher compared with a 9% success rate achieved without MR guidance in another group of 120 patients. Our results indicate that TRUS-guided biopsy of suspicious area identified as malignant from MRSI can be performed using the coordinates of the voxel derived from MR images. This increases the detection rate of prostate cancer in men with PSA level <10,ng/ml or abnormal DRE and also demonstrates the potential of MR in routine clinical practice. Copyright © 2006 John Wiley & Sons, Ltd. [source] Relative increase in choline in the occipital cortex in chronic fatigue syndromeACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2002B. K. Puri Puri BK, Counsell SJ, Zaman R, Main J, Collins AG, Hajnal JV, Davey NJ. Relative increase in choline in the occipital cortex in chronic fatigue syndrome. Acta Psychiatr Scand 2002: 106: 224,226. © Blackwell Munksgaard 2002. Objective:,To test the hypothesis that chronic fatigue syndrome (CFS) is associated with altered cerebral metabolites in the frontal and occipital cortices. Method:,Cerebral proton magnetic resonance spectroscopy (1H MRS) was carried out in eight CFS patients and eight age- and sex-matched healthy control subjects. Spectra were obtained from 20 × 20 × 20 mm3 voxels in the dominant motor and occipital cortices using a point-resolved spectroscopy pulse sequence. Results:,The mean ratio of choline (Cho) to creatine (Cr) in the occipital cortex in CFS (0.97) was significantly higher than in the controls (0.76; P=0.008). No other metabolite ratios were significantly different between the two groups in either the frontal or occipital cortex. In addition, there was a loss of the normal spatial variation of Cho in CFS. Conclusion:,Our results suggest that there may be an abnormality of phospholipid metabolism in the brain in CFS. [source] 1H spectroscopic imaging of human brain at 3 Tesla: Comparison of fast three-dimensional magnetic resonance spectroscopic imaging techniquesJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 3 2009Matthew L. Zierhut PhD Abstract Purpose To investigate the signal-to-noise-ratio (SNR) and data quality of time-reduced three-dimensional (3D) proton magnetic resonance spectroscopic imaging (1H MRSI) techniques in the human brain at 3 Tesla. Materials and Methods Techniques that were investigated included ellipsoidal k -space sampling, parallel imaging, and echo-planar spectroscopic imaging (EPSI). The SNR values for N-acetyl aspartate, choline, creatine, and lactate or lipid peaks were compared after correcting for effective spatial resolution and acquisition time in a phantom and in the brains of human volunteers. Other factors considered were linewidths, metabolite ratios, partial volume effects, and subcutaneous lipid contamination. Results In volunteers, the median normalized SNR for parallel imaging data decreased by 34,42%, but could be significantly improved using regularization. The normalized signal to noise loss in flyback EPSI data was 11,18%. The effective spatial resolutions of the traditional, ellipsoidal, sensitivity encoding (SENSE) sampling scheme, and EPSI data were 1.02, 2.43, 1.03, and 1.01 cm3, respectively. As expected, lipid contamination was variable between subjects but was highest for the SENSE data. Patient data obtained using the flyback EPSI method were of excellent quality. Conclusion Data from all 1H 3D-MRSI techniques were qualitatively acceptable, based upon SNR, linewidths, and metabolite ratios. The larger field of view obtained with the EPSI methods showed negligible lipid aliasing with acceptable SNR values in less than 9.5 min without compromising the point-spread function. J. Magn. Reson. Imaging 2009;30:473,480. © 2009 Wiley-Liss, Inc. [source] Proton magnetic resonance spectroscopic imaging to differentiate between nonneoplastic lesions and brain tumors in children,JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 2 2006Roula Hourani MD Abstract Purpose To investigate whether in vivo proton magnetic resonance spectroscopic imaging (MRSI) can differentiate between 1) tumors and nonneoplastic brain lesions, and 2) high- and low-grade tumors in children. Materials and Methods Thirty-two children (20 males and 12 females, mean age = 10 ± 5 years) with primary brain lesions were evaluated retrospectively. Nineteen patients had a neuropathologically confirmed brain tumor, and 13 patients had a benign lesion. Multislice proton MRSI was performed at TE = 280 msec. Ratios of N-acetyl aspartate/choline (NAA/Cho), NAA/creatine (Cr), and Cho/Cr were evaluated in the lesion and the contralateral hemisphere. Normalized lesion peak areas (Chonorm, Crnorm, and NAAnorm) expressed relative to the contralateral hemisphere were also calculated. Discriminant function analysis was used for statistical evaluation. Results Considering all possible combinations of metabolite ratios, the best discriminant function to differentiate between nonneoplastic lesions and brain tumors was found to include only the ratio of Cho/Cr (Wilks' lambda, P = 0.012; 78.1% of original grouped cases correctly classified). The best discriminant function to differentiate between high- and low-grade tumors included the ratios of NAA/Cr and Chonorm (Wilks' lambda, P = 0.001; 89.5% of original grouped cases correctly classified). Cr levels in low-grade tumors were slightly lower than or comparable to control regions and ranged from 53% to 165% of the control values in high-grade tumors. Conclusion Proton MRSI may have a promising role in differentiating pediatric brain lesions, and an important diagnostic value, particularly for inoperable or inaccessible lesions. J. Magn. Reson. Imaging 2006. Published 2005 Wiley-Liss, Inc. [source] A multi-center 1H MRS study of the AIDS dementia complex: Validation and preliminary analysisJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 6 2003Patricia Lani Lee PhD Abstract Purpose To demonstrate the technical feasibility and reliability of a multi-center study characterizing regional levels of the brain metabolite ratios choline (Cho)/creatine (Cr) and myoinositol (MI)/Cr, markers of glial cell activity, and N-acetyl aspartate (NAA)/Cr, a marker of mature neurons, in subjects with AIDS dementia complex (ADC). Materials and Methods Using an automated protocol (GE PROBE-P), short echo time spectra (TE = 35 msec) were obtained at eight sites from uniformly prepared phantoms and from three brain regions (frontal white matter, basal ganglia, and parietal cortex) of normal volunteers and ADC and HIV-negative subjects. Results A random-effects model of the phantom and volunteer data showed no significant inter-site differences. Feasibility of a multi-center study was further validated by detection of significant differences between the metabolite ratios of ADC subjects and HIV-negative controls. ADC subjects exhibited significantly higher Cho/Cr and MI/Cr in the basal ganglia and significantly reduced NAA/Cr and significantly higher MI/Cr in the frontal white matter. These results are consistent with the predominantly subcortical distribution of the pathologic abnormalities associated with ADC. Conclusion This is the first study to ascertain and validate the reliability and reproducibility of a short echo time 1H-MRS acquisition sequence from multiple brain regions in a multi-center setting. It should now be possible to examine the regional effects of HIV infection in the brain in a large number of subjects and to study the metabolic effects of new therapies for the treatment of ADC in a clinical trial setting. J. Magn. Reson. Imaging 2003;17:625,633. © 2003 Wiley-Liss, Inc. [source] Applications of neural network analyses to in vivo 1H magnetic resonance spectroscopy of Parkinson disease patientsJOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 1 2002David Axelson PhD Abstract Purpose To apply neural network analyses to in vivo magnetic resonance spectra of controls and Parkinson disease (PD) patients for the purpose of classification. Materials and Methods Ninety-seven in vivo proton magnetic resonance spectra of the basal ganglia were recorded from 31 patients with (PD) and 14 age-matched healthy volunteers on a 1.5-T imager. The PD patients were grouped as follows: probable PD (N = 15), possible PD (N = 11), and atypical PD (N = 5). Total acquisition times of approximately five minutes were achieved with a TE (echo time) of 135 msec, a TR (repetition time) of 2000 msec, and 128 scan averages. Neural network (back propagation, Kohonen, probabilistic, and radial basis function) and related (generative topographic mapping) data analyses were performed. Results Conventional data analysis showed no statistically significant differences in metabolite ratios based on measuring signal intensities. The trained networks could distinguish control from PD with considerable accuracy (true positive fraction 0.971, true negative fraction 0.933). When four classes were defined, approximately 88% of the predictions were correct. The multivariate analysis indicated metabolic changes in the basal ganglia in PD. Conclusion A variety of neural network and related approaches can be successfully applied to both qualitative visualization and classification of in vivo spectra of PD patients. J. Magn. Reson. Imaging 2002;16:13,20. © 2002 Wiley -Liss, Inc. [source] In vivo quantitative proton MRSI study of brain development from childhood to adolescence,JOURNAL OF MAGNETIC RESONANCE IMAGING, Issue 2 2002Alena Horská PhD Abstract Purpose To quantify regional variations in metabolite levels in the developing brain using quantitative proton MR spectroscopic imaging (MRSI). Materials and Methods Fifteen healthy subjects three to 19 years old were examined by in vivo multislice proton MRSI. Concentrations of N-acetyl aspartate (NAA), total choline (Cho), total creatine (Cr), and peak area ratios were determined in selected frontal and parietal gray and white matter regions, basal ganglia, and thalamus. Results In cortical gray matter regions, the ratio of NAA/Cho increased to a maximum at 10 years and decreased thereafter (P = 0.010). In contrast, in white matter, average ratios NAA/Cho increased linearly with age (P = 0.045). In individual brain regions, age-related changes in NAA/Cho were found in the putamen (P = 0.044). No significant age-related changes in NAA, Cho, Cr, or other metabolite ratios could be determined. Conclusion Consistent with recent studies using other structural and functional neuroimaging techniques, our data suggest that small but significant changes occur in regional cerebral metabolism during childhood and adolescence. Non-linear age related changes of NAA/Cho in frontal and parietal areas, resembling previously reported age related changes in rates of glucose utilization and cortical volumes, may be associated with dendritic and synaptic development and regression. Linear age-related changes of NAA/Cho in white matter are also in agreement with age-related increases in white matter volumes, and may reflect progressive increases in axonal diameter and myelination. J. Magn. Reson. Imaging 2002;15:137,143. Published 2002 Wiley-Liss, Inc. [source] Role of Proton Magnetic Resonance Spectroscopy in Differentiating Oligodendrogliomas from AstrocytomasJOURNAL OF NEUROIMAGING, Issue 1 2010Sanjeev Chawla PhD ABSTRACT BACKGROUND AND PURPOSE Preoperative differentiation of astrocytomas from oligodendrogliomas is clinically important, as oligodendrogliomas are more sensitive to chemotherapy. The purpose of this study was to assess the role of proton magnetic resonance spectroscopy in distinguishing astrocytomas from oligodendrogliomas. METHODS Forty-six patients [astrocytomas (n= 17) and oligodendrogliomas (n= 29)] underwent magnetic resonance imaging and multi voxel proton magnetic resonance spectroscopic imaging before treatment. Peak areas for N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (mI), glutamate/glutamine (Glx), and lipids + lactate (Lip+Lac) were analyzed from voxels that exhibited hyperintensity on fluid-attenuated inversion recovery images and were normalized to Cr from each voxel. The average metabolite/Cr ratios from these voxels were then compared between astrocytomas and oligodendrogliomas. Receiver-operating curve analyses were used as measures of differentiation accuracy of metabolite ratios. A threshold value for a metabolite ratio was estimated by maximizing the sum of sensitivity and specificity. RESULTS A significant difference in mI/Cr was observed between astrocytomas and oligodendrogliomas (.50 ± .18 vs. 0.66 ± 0.20, P < .05). Using a threshold value of .56 for mI/Cr ratio, it was possible to differentiate oligodendrogliomas from astrocytomas with a sensitivity of 72.4% and specificity of 76.4%. CONCLUSION These results suggest that mI/Cr might aid in distinguishing oligodendrogliomas from astrocytomas. J Neuroimaging 2010;20:3-8. [source] Quantitative Lipid Metabolomic Changes in Alcoholic Micropigs With Fatty Liver DiseaseALCOHOLISM, Issue 4 2009Angela M. Zivkovic Background:, Chronic ethanol consumption coupled with folate deficiency leads to rapid liver fat accumulation and progression to alcoholic steatohepatitis (ASH). However, the specific effects of alcohol on key liver lipid metabolic pathways involved in fat accumulation are unknown. It is unclear whether lipid synthesis, lipid export, or a combination of both is contributing to hepatic steatosis in ASH. Methods:, In this study we estimated the flux of fatty acids (FA) through the stearoyl-CoA desaturase (SCD), phosphatidylethanolamine- N -methyltransferase (PEMT), and FA elongation pathways in relation to liver triacylglycerol (TG) content in Yucatan micropigs fed a 40% ethanol folate-deficient diet with or without supplementation with S -adenosyl methionine (SAM) compared with controls. Flux through the SCD and PEMT pathways was used to assess the contribution of lipid synthesis and lipid export respectively on the accumulation of fat in the liver. Liver FA composition within TG, cholesterol ester (CE), phosphatidylethanolamine, and phosphatidylcholine classes was quantified by gas chromatography. Results:, Alcoholic pigs had increased liver TG content relative to controls, accompanied by increased flux through the SCD pathway as indicated by increases in the ratios of 16:1n7 to 16:0 and 18:1n9 to 18:0. Conversely, flux through the elongation and PEMT pathways was suppressed by alcohol, as indicated by multiple metabolite ratios. SAM supplementation attenuated the TG accumulation associated with alcohol. Conclusions:, These data provide an in vivo examination of liver lipid metabolic pathways confirming that both increased de novo lipogenesis (e.g., lipid synthesis) and altered phospholipid metabolism (e.g., lipid export) contribute to the excessive accumulation of lipids in liver affected by ASH. [source] Metabolic differences between primary and recurrent human brain tumors: a 1H NMR spectroscopic investigationNMR IN BIOMEDICINE, Issue 6 2005Fritz-Georg Lehnhardt Abstract High-resolution proton magnetic resonance spectroscopy was performed on tissue specimens from 33 patients with astrocytic tumors (22 astrocytomas, 11 glioblastomas) and 13 patients with meningiomas. For all patients, samples of primary tumors and their first recurrences were examined. Increased anaplasia, with respect to malignant transformation, resulting in a higher malignancy grade, was present in 11 recurrences of 22 astrocytoma patients. Spectroscopic features of tumor types, as determined on samples of the primary occurrences, were in good agreement with previous studies. Compared with the respective primary astrocytomas, characteristic features of glioblastomas were significantly increased concentrations of alanine (Ala) (p,=,0.005), increased metabolite ratios of glycine (Gly)/total creatine (tCr) (p,=,0.0001) and glutamate (Glu)/glutamine (Gln) (p,=,0.004). Meningiomas showed increased Ala (p,=,0.02) and metabolite ratios [Gly, total choline (tCho), Ala] over tCr (p,=,0.001) relative to astrocytomas, and N -acetylaspartate and myo-inositol were absent. Metabolic changes of an evolving tumor were observed in recurrent astrocytomas: owing to their consecutive assessments, more indicators of malignant degeneration were detected in astrocytoma recurrences (e.g. Gly, p,=,0.029; tCho, p,=,0.034; Glu, p,=,0.015; tCho/tCr, p,=,0.001) in contrast to the comparison of primary astrocytomas with primary glioblastomas. The present investigation demonstrated a correlation of the tCho-signal with tumor progression. Significantly elevated concentrations of Ala (p,=,0.037) and Glu (p,=,0.003) and metabolite ratio tCho/tCr (p,=,0.005) were even found in recurrent low-grade astrocytomas with unchanged histopathological grading (n,=,11). This may be related to an early stage of malignant transformation, not yet detectable morphologically, and emphasizes the high sensitivity of 1H NMR spectroscopy in elucidating characteristics of brain tumor metabolism. Copyright © 2005 John Wiley & Sons, Ltd. [source] Multi-variate analysis predicts clinical outcome 30 days after middle cerebral artery infarctionACTA NEUROLOGICA SCANDINAVICA, Issue 1 2000M. Giroud Background and purpose, To evaluate the functional prognostic value of proton magnetic resonance spectroscopy performed within the 5 days of an infarction of the middle cerebral artery territory, compared with previously demonstrated prognostic factors. Methods, Proton magnetic resonance spectroscopy was performed on 77 consecutive non-comatosed patients during the acute stage of middle cerebral artery infarction. The functional status was determined for each patient via the Orgogozo score. Proton magnetic resonance spectroscopic data were acquired in the infarction and in contra-lateral normal tissue and the results were expressed as metabolite ratios. Correlations were evaluated between the Orgogozo score at day 1 and day 30, the age, the sex, the volume of the infarction, and the metabolic ratios. Results, In a monovariate analysis, the decrease of the NAA/choline ratio was correlated with a low Orgogozo score at days 1 and 30 (P<0.05) and with a large infarction (P<0.05). A stepwise analysis showed a significant relationship between the Orgogozo score at day 30 and the Orgogozo score at day 1, the sex, the volume of infarction, and the NAA/Cho ratio within the infarction. Conclusions, Our work demonstrates that a good clinical outcome at day 30 depends on a good initial clinical score at day 1, a small volume of infarction, a small decrease of NAA/Cho, and being of the female gender. [source] Should TPMT genotype and activity be used to monitor 6-mercaptopurine treatment in children with acute lymphoblastic leukaemia?JOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2007M. Fakhoury PharmD PhD Summary Background and objective: The activity of thiopurine S -methyltransferase (TPMT), a key enzyme in the metabolism of purine analogues, displays wide inter-subject variability partly due to a genetic polymorphism. Previous studies have suggested adjusting purine analogues dosing according to TPMT activity but measurements are costly and time-consuming. It is still unclear, especially under treatment, whether the simpler TPMT genotyping reliably predicts enzyme activity. Our aim was to study the possible correlation of TPMT genotype with phenotype. Methods: We determined the genotypic status and TMPT activity, at diagnosis and after 6 months of maintenance therapy, of 118 children with acute lymphoblastic leukaemia (ALL). Results and Discussion: Eighty-nine per cent of the children had a homozygous wild-type genotype (group 1), 11% had one or two mutant allele(s) (group 2). At both time points, TPMT activity (U/mL peripheral red blood cell) was significantly higher in group 1 than in group 2 (P < 0·001) but inter-group levels overlapped considerably. There was considerable heterogeneity in the percentage increase in TPMT activity after therapy, and little correlation between metabolites ratio [6-methylmercaptopurine derivative/6-thioguanine nucleotides (6-TGN)] and TPMT activity at the end of 6 months' maintenance treatment. These results show that TPMT activity cannot be used as an accurate tool for 6-mercaptopurine monitoring. Conclusion: Genotyping at diagnosis identifies patients with a homozygous mutant TPMT and may prevent severe and life-threatening toxicity. ALL treatment monitoring should preferentially be based on repeated determinations of intracellular active metabolites (6-TGN) and methylated metabolites. [source] Rofecoxib is a potent inhibitor of cytochrome P450 1A2: studies with tizanidine and caffeine in healthy subjectsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 3 2006Janne T. Backman Aims Case reports suggest an interaction between rofecoxib and the CYP1A2 substrate tizanidine. Our objectives were to explore the extent and mechanism of this possible interaction and to determine the CYP1A2 inhibitory potency of rofecoxib. Methods In a randomized, double-blind, two-phase cross-over study, nine healthy subjects took 25 mg rofecoxib or placebo daily for 4 days and, on day 4, each ingested 4 mg tizanidine. Plasma concentrations and the urinary excretion of tizanidine, its metabolites (M) and rofecoxib, and pharmacodynamic variables were measured up to 24 h. On day 3, a caffeine test was performed to estimate CYP1A2 activity. Results Rofecoxib increased the area under the plasma concentration,time curve (AUC0,,) of tizanidine by 13.6-fold [95% confidence interval (CI) 8.0, 15.6; P < 0.001), peak plasma concentration (Cmax) by 6.1-fold (4.8, 7.3; P < 0.001) and elimination half-life (t1/2) from 1.6 to 3.0 h (P < 0.001). Consequently, rofecoxib markedly increased the blood pressure-lowering and sedative effects of tizanidine (P < 0.05). Rofecoxib increased several fold the tizanidine/M-3 and tizanidine/M-4 ratios in plasma and urine and the tizanidine/M-5, tizanidine/M-9 and tizanidine/M-10 ratios in urine (P < 0.05). In addition, it increased the plasma caffeine/paraxanthine ratio by 2.4-fold (95% CI 1.4, 3.4; P = 0.008) and this ratio correlated with the tizanidine/metabolite ratios. Finally, the AUC0,25 of rofecoxib correlated with the placebo phase caffeine/paraxanthine ratio (r = 0.80, P = 0.01). Conclusions Rofecoxib is a potent inhibitor of CYP1A2 and it greatly increases the plasma concentrations and adverse effects of tizanidine. The findings suggest that rofecoxib itself is also metabolized by CYP1A2, raising concerns about interactions between rofecoxib and other CYP1A2 substrate and inhibitor drugs. [source] | ||||||||||||||||||||||