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Metabolic Ratio (metabolic + ratio)
Selected AbstractsCerebral Metabolism is Influenced by Muscle Ischaemia During Exercise in HumansEXPERIMENTAL PHYSIOLOGY, Issue 2 2003Mads K. Dalsgaard Maximal exercise reduces the cerebral metabolic ratio (O2/(glucose + 1/2lactate)) to < 4 from a resting value close to 6, and only part of this decrease is explained by the ,intent' to exercise. This study evaluated whether sensory stimulation of brain by muscle ischaemia would reduce the cerebral metabolic ratio. In 10 healthy human subjects the cerebral arterial-venous differences (a-v differences) for O2, glucose and lactate were assessed before, during and after three bouts of 10 min cycling with equal workload: (1) control exercise at light intensity, (2) exercise that elicited a high rating of perceived exertion due to a 100 mmHg thigh cuff, and (3) exercise followed by 5 min of post-exercise muscle ischaemia that increased blood pressure by , 20%. Control exercise did not significantly affect the a-v differences. However, during the recovery from exercise with thigh cuffs the cerebral metabolic ratio decreased from a resting value of 5.4 ± 0.2 to 4.0 ± 0.4 (mean ±s.e.m.. P < 0.05) as a discrete lactate efflux from the brain at rest shifted to a slight uptake. Also, following post-exercise muscle ischaemia, the cerebral metabolic ratio decreased to 4.5 ± 0.3 (P < 0.05). The results support the hypothesis that during exercise, cerebral metabolism is influenced both by the mental effort to exercise and by sensory input from skeletal muscles. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] Impact of the basal metabolic ratio in predicting early deaths after allogeneic stem cell transplantation,AMERICAN JOURNAL OF HEMATOLOGY, Issue 9 2009Satoshi Nishiwaki First page of article [source] Effects of Angelicae tenuissima radix, Angelicae dahuricae radix and Scutellariae radix Extracts on Cytochrome P450 Activities in Healthy VolunteersBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 4 2009SoJeong Yi A total of 24 healthy male volunteers were assigned to one of three parallel herbal treatment groups, each consisting of eight volunteers. A cocktail of probe drugs for CYP enzymes was orally administered before and after multiple administrations of herbal medicines, three times a day for 13 days. Probe drugs used to measure CYP activities were caffeine (CYP1A2), losartan (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4). The probe drugs and their metabolites were quantified in plasma or urine using HPLC or LC-MS/MS. Changes in each CYP activity was evaluated by metabolic ratio of the probe drug (concentration ratio of metabolite to parent form at reference time point) following the herbal medication period, compared to the baseline values. A. dahuricae radix significantly decreased CYP1A2 activity to 10% of baseline activity (95% CI: 0.05,0.21). S. radix also showed significant changes in CYP2C9 and CYP2E1 activities. Compared to baseline values, the metabolic activities of losartan were decreased to 71% (0.54,0.94). In addition, S. radix showed a 1.42-fold (1.03,1.97) increase in chlorzoxazone metabolic activity. However, CYP activities were not meaningfully influenced by A. tenuissima radix. Changes in certain CYP activities were observed after the administration of S. radix and A. dahuricae radix in healthy volunteers. Therefore, herbal medicines containing S. radix or A. dahuricae radix are candidates for further evaluation of clinically significant CYP-mediated herb-drug interactions in human beings. [source] The CYP2D6 polymorphism in relation to the metabolism of amitriptyline and nortriptyline in the Faroese populationBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008Jónrit Halling WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,The metabolisms of amitriptyline (AT) to (E)-10-hydroxyamitriptyline and of nortripyline (NT) to (E)-10-hydroxynortriptyline are catalysed by CYP2D6. ,,A correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and the AT/(E)-10-hydroxyamitriptyline ratios, respectively, has been observed in patients in treatment with the same dose of AT or NT. ,,The frequency of CYP2D6 poor metabolizers (PMs) is 15% (twofold compared with other Whites) among healthy Faroese. ,,This frequency has not been investigated in Faroese patients in AT treatment and the consequences of the CYP2D6 PM phenotype for dose and plasma concentrations of AT and metabolites are not known in these patients. WHAT THIS STUDY ADDS ,,In patients treated with different daily dosages (5,100 mg) of AT a correlation between the sparteine metabolic ratio and the NT/(E)-10-hydroxynortriptyline and AT/(E)-10-hydroxyamitriptyline ratios was observed. ,,A high proportion (22%) of CYP2D6 PMs in a Faroese patient group medicated with AT was observed. ,,However, similar doses of AT and concentrations of AT and NT were noted in extensive metabolizers and in PMs. AIM To determine the frequency of CYP2D6 poor metabolizers (PMs) in a Faroese patient group medicated with amitriptyline (AT) and to investigate plasma concentrations of AT and metabolites in relation to CYP2D6. METHODS CYP2D6 phenotype and genotype were determined in 23 Faroese patients treated with AT. Plasma concentrations of AT and metabolites were determined by high-performance liquid chromatography and investigated in relation to CYP2D6 activity. RESULTS Of the 23 patients phenotyped and genotyped, five (22%) (95% confidence interval 7.5, 43.7) were CYP2D6 PMs. No difference was found in AT daily dosage between PMs (median 25 mg day,1; range 5,80) and extensive metabolizers (EMs) (median 27.5 mg day,1; range 10,100). The (E)-10-OH-nortriptyline (NT)/dose concentrations were higher in EMs than in PMs and the NT/(E)-10-OH-NT and AT/(E) -10-OH-AT ratios were higher in PMs compared with EMs. The log sparteine metabolic ratio correlated positively with the NT/(E)- 10-OH-NT ratio (rs = 0.821; P < 0.0005) and the AT/(E)- 10-OH-AT ratio (rs = 0.605; P < 0.006). CONCLUSION A high proportion of CYP2D6 PMs was found in a Faroese patient group medicated with AT. However, similar doses of AT and concentrations of AT and NT were noted in EMs and PMs, probably due to varying doses and indications for AT treatment. [source] Pharmacokinetics of sabeluzole and dextromethorphan oxidation capacity in patients with severe hepatic dysfunction and healthy volunteersBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 2 2001G. P. Pageaux Aims, The primary objective of this study was to determine how the pharmacokinetics of sabeluzole, an investigational drug with specific effects on memory and learning abilities, are affected by chronic liver disease. Since sabeluzole is metabolised by CYP2D6, a secondary objective was to study the correlation between CYP2D6 activity (as assessed by the dextromethorphan dextrorphan metabolic ratio) and hepatic dysfunction. Methods, The single-dose pharmacokinetics of sabeluzole (10 mg) was compared in 10 healthy Caucasian subjects and 10 patients with severe hepatic dysfunction. The urinary dextromethorphan/dextrorphan (DMP/DRP) metabolic ratio was determined after intake of 20 mg dextromethorphan (NODEX® capsules). Results, The terminal half-life of sabeluzole was significantly prolonged in subjects with severe hepatic dysfunction vs healthy subjects (respectively 39.3 ± 11.5 h; 17.5 ± 10.2 h (mean ±,s.d.)). The areas under the curve (AUC) were significantly higher in subjects with severe hepatic dysfunction than in healthy volunteers (681 ± 200 ng ml ,1h vs 331 ± 282 ng ml ,1h). There was a significant correlation between the AUC(0,,) and the DMP/DRP metabolic ratio in healthy volunteers and subjects with severe hepatic dysfunction. AUC was greater and elimination of sabeluzole slower in poor metabolizers compared with extensive metabolizers. Conclusions, These results suggest that a) sabeluzole dose should be reduced in patients with severe hepatic dysfunction and b) the AUC of sabeluzole is linked to individual CYP2D6 activity. [source] CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxineJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 5 2006M. E. E. Shams PhD Summary Background:, Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O -desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N -desmethylvenlafaxine (NDV). Objectives:, The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. Method:, In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. Results:, There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1·8 and the 10th and 90th percentiles 0·3 and 5·2, respectively. Individuals with ODV/V ratios below 0·3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5·2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1·1 ± 0·8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4·8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0·3 had more side effects (P < 0·005) and reduced serum concentrations of sodium (P < 0·05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. Conclusion:, The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects. [source] The in-vivo effects of sho-saiko-to, a traditional Chinese herbal medicine, on two cytochrome P450 enzymes (1A2 and 3A) and xanthine oxidase in manJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 11 2003Junji Saruwatari ABSTRACT The Chinese herbal medicine sho-saiko-to is a mixture of seven herbal components (Bupleurum root, Pinellia tuber, Scutellaria root, Jujube fruit, Ginseng root, Glycyrrhiza root and Ginger rhizome) that is widely administered to patients with chronic hepatitis in Japan. We assessed the effects of sho-saiko-to on the activity of cytochrome P450 (CYP) 1A2, CYP3A and xanthine oxidase (XO) in man. Twenty-six healthy subjects were studied to evaluate their baseline activity of CYP1A2 and XO by the respective urinary metabolic ratios of an 8-h urine sample after an oral 150-mg dose of caffeine and of CYP3A by a urinary excretion ratio of 6,-hydroxycortisol (6,-HC) to free cortisol (FC). Thereafter, the subjects received a twice-daily 2.5-g dose of sho-saiko-to for five days, and underwent the caffeine test on day 1 and day 5. The mean activity of CYP1A2 decreased by 16% on both day 1 and day 5 compared with the baseline (P = 0.001). The mean activity of XO also significantly decreased by 25% on day 1 and 20% on day 5 (P < 0.0001) compared with the baseline value. The activity of CYP3A tended to be lower on day 5 than the baseline (P = 0.146). It is concluded that sho-saiko-to reduces CYP1A2 and XO activity in man. [source] Population pharmacokinetic modelling of aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patientsBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 6 2008Jung-Ryul Kim WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT , Almost all reported studies have investigated the pharmacokinetics of aripiprazole in healthy volunteers. , The pharmacokinetics of dehydroaripiprazole have not been identified in a combined model with aripiprazole. WHAT THIS STUDY ADDS , The data on aripiprazole and dehydroaripiprazole in psychiatric patients were modelled jointly using a population approach. , The apparent clearance of aripiprazole in cytochrome P450 (CYP) 2D6 intermediate metabolizers (IM) was approximately 60% of that in CYP2D6 extensive metabolizers (EM) having two functional alleles, but the exposure to dehydroaripiprazole in CYP2D6 IM was similar to that in EM. AIMS The aims of this study were to develop a combined population pharmacokinetic model for both aripiprazole and its active metabolite, dehydroaripiprazole, in psychiatric patients and to identify to what extent the genetic polymorphisms of cytochrome P450 (CYP) enzymes contribute to the variability in pharmacokinetics (PK). METHODS A population pharmacokinetic analysis was performed using NONMEM software based on 141 plasma concentrations at steady state from 80 patients receiving multiple oral doses of aripiprazole (10,30 mg day,1). RESULTS A one-compartment model with first-order kinetics for aripiprazole and dehydroaripiprazole each was developed to describe simultaneously the concentration data. The absorption rate constant was fixed to 1.06 h,1. The typical value of apparent distribution volume of aripiprazole was estimated to be 192 l. Covariate analysis showed that CYP2D6 genetic polymorphisms significantly influenced the apparent clearance of aripiprazole (CL/F), reducing the interindividual variability on CL/F from 37.8% CV (coefficient of variation) to 30.5%. The CL/F in the CYP2D6 IMs was approximately 60% of that in CYP2D6 EMs having two functional alleles. Based on the CYP2D6 genotype, the metabolic ratios were calculated at 0.20,0.34. However, the plasma concentration : dose ratios of dehydroaripiprazole were not different across the CYP2D6 genotype. CONCLUSIONS This population pharmacokinetic model provided an adequate fit to the data for both aripiprazole and dehydroaripiprazole in psychiatric patients. The usefulness of CYP genotyping as an aid to select the starting dose should be further investigated. [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] | ||||||||||