Home About us Contact
|
Home About us Contact | ||
|
|
||
Interindividual Variability (interindividual + variability)
Kinds of Interindividual Variability Selected AbstractsMeasuring natural abundance of 13C in respired CO2: variability and implications for non-invasive dietary analysisFUNCTIONAL ECOLOGY, Issue 6 2001S. E. PERKINS Summary 1,Three experiments were performed, using laboratory mice (Mus musculus) as a model species, to evaluate the potential of using measurements of carbon isotope ratios in expired CO2 for tracing diets. 2,Breath 13C signatures of mice fed a constant diet (,21·4, ± 0·35) reflected their diet, but were depleted by on average ,5·7,. Body mass, sex and age were independent and significant factors correlated with the variability of 13C enrichment in respired CO2. 3,Breath 13C signatures from starved mice (7 h) were lower than unstarved mice by 2·0,. Subsequently when starved mice were fed a small meal of a new diet, breath 13C signatures approached those of the new diets within 15 min, returning to preingestion levels after 105 min. 4,After a permanent diet switch 13C values of breath were not asymptotic within 6 days, possibly because of use of fat reserves during the daytime carrying an isotopic memory of the previous diet. Hence, individual breath 13C signatures may vary according to nutritive state and previous dietary history. 5,Interindividual variability was measured at 3·3,. The implications are that large samples of individuals will be required to distinguish between diets of different populations where the isotopic difference between their diets was small , for example, that expected between herbivorous and carnivorous diets. However, breath would be suitable for distinguishing between dietary intakes of individuals for food types that are isotopically more distinct , such as between C3 and C4 plants. [source] Dynamic contrast-enhanced MRI using Gd-DTPA: Interindividual variability of the arterial input function and consequences for the assessment of kinetics in tumors ,MAGNETIC RESONANCE IN MEDICINE, Issue 6 2001Ruediger E. Port Abstract Gd-DTPA kinetics in arterial blood was investigated by dynamic MRI in 47 patients with malignant and benign mammary tumors. Signal enhancement was monitored for 10 min after the beginning of a 1-min infusion of 0.1 mmol/kg Gd-DTPA. Kinetics in blood was biexponential with median half-lives of 21 sec and 11.1 min, respectively. Peak signal enhancement and the area under the signal enhancement,time curve varied 2.5- and 3.7-fold between patients. The shortest mean residence time in one of up to three tumor compartments, MRT*, was estimated using either the individual (reference) or a mean population (surrogate) arterial input function (AIF). MRT* (reference estimate) was 1.0 (0,1.5), 1.9 (1.5,2.3), and 2.5 (2.3,2.8) min in carcinomas, fibroadenomas, and mastopathies, respectively (median and interquartile distance). Surrogate estimates were unbiased but differed from the reference estimates 1.5-fold or more in 23% of cases. AIFs should be monitored individually if accurate estimates of individual MRT* are desired. Magn Reson Med 45:1030,1038, 2001. © 2001 Wiley-Liss, Inc. [source] Variability of limb muscle size in young menAMERICAN JOURNAL OF HUMAN BIOLOGY, Issue 1 2010Taku Wakahara The purpose of this study was to determine the interindividual variability of the upper and lower limb muscle size in young men. Subjects were 655 Japanese men aged 18,39 years. They were sedentary and mildly to highly active individuals, including college athletes of various sports. Muscle thicknesses at each of the anterior and posterior portions of the upper arm, thigh, and lower leg were measured using B-mode ultrasonography. Interindividual variability of muscle thickness was evaluated by coefficients of variation (CVs). The CVs of muscle thicknesses were found to be in the order of upper arm posterior (17.7%), thigh anterior (14.8%), thigh posterior (12.6%), upper arm anterior (12.2%), lower leg anterior (9.8%), and lower leg posterior (9.4%). The CVs were significantly different between each pair of measurement sites except for those of upper arm anterior-thigh posterior and lower leg anterior-posterior. These differences remain significant even when the muscle thicknesses were normalized to the segment length. The observed differences in the size variability can be interpreted as muscle-related differences in hypertrophic responsiveness to resistance training. The muscle-dependent size variability may be related to the differences in the fiber-type composition and/or muscle usage in daily life among examined muscle groups. Am. J. Hum. Biol. 2010. © 2009 Wiley-Liss, Inc. [source] Interindividual variability in the concentration,effect relationship of antilymphocyte globulins,a possible influence of Fc,RIIIa genetic polymorphismBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 1 2008David Ternant WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT ,,There is interindividual variability in the antilymphocyte globulin (ALG) effect, but there is no pharmacokinetic,pharmacodynamic study of this subject. ,,In addition, a time dependence of the pharmacokinetics of some therapeutic antibodies has been described. ,,ALGs may partly act by antibody-dependent cellular cytotoxicity (ADCC), but their mechanism of action in humans is not known. WHAT THIS STUDY ADDS ,,Horse ALG pharmacokinetics can be described using a two-compartment model with time-dependent central volume of distribution. ,,After an initial concentration-independent lymphocyte depletion, the concentration,effect relationship can be described using a physiological indirect response model. ,,The genetic polymorphism of Fc,RIIIa at position 158 may influence the ALG concentration,effect relationship and these polyclonal antibodies may therefore act by ADCC. AIMS Polyclonal antilymphocyte globulins (ALGs) are currently used in transplantation, but the sources of interindividual variability of their effect are poorly understood. No pharmacokinetic,pharmacodynamic (PK,PD) study of ALG is available. Moreover, the genetic polymorphism of Fc,RIIIa, a receptor for the Fc portion of immunoglobulins involved in antibody-dependent cellular cytotoxicity (ADCC), may influence their concentration,effect relationship. METHODS Fourteen kidney transplant patients treated by horse ALG were included in a prospective, noncomparative study. A population two-compartment PK model including a time dependence of the central volume of distribution was developed. Total lymphocyte count was used as biomarker of effect. Concentration,effect data were described using a physiological indirect response model, combining concentration-dependent and -independent inhibitions of lymphocyte input into the circulation. In addition, six kidney transplant patients in whom ALG concentrations were not available were included retrospectively. All patients were genotyped for FCGR3A. RESULTS Both the PK and the PK,PD model described the data satisfactorily and showed high interindividual variability. Asymptotic T1/2 -, and T1/2 -,-values were 1.3 and 25 days, respectively. The concentration of ALG leading to a 50% inhibition of lymphocyte input (IC50) was lower in FCGR3A- V carriers than in FCGR3A- F/F patients (383 ± 199 vs. 593 ± 209 mg l,1, P = 0.008). CONCLUSIONS This is the first description of the ALG effect on lymphocyte count using PK,PD modelling. Our results show that part of the variability in their concentration,effect relationship may be explained by Fc,RIIIa genetic polymorphism and therefore that horse ALG may deplete lymphocytes by ADCC. [source] Variability in non-nucleoside reverse transcriptase and protease inhibitor concentrations among HIV-infected adults in routine clinical practiceBRITISH JOURNAL OF CLINICAL PHARMACOLOGY, Issue 5 2006José Moltó What is already known about this subject ,,The concentration of protease and non-nucleoside reverse transcriptase inhibtors in plasma has been related to both efficacy and toxicity. ,,Most antiretroviral concentration data come from selected populations of patients undergoing therapeutic drug monitoring programmes, which may overestimate interindividual variability. What this study adds ,,Our study has demonstrated the large interindividual variability in antiretroviral drug concentrations in an unselected population of patients during routine clinical practice. ,,These results may provide interesting information to clinicians for the management of antiretroviral therapy in HIV-infected patients. Aims The objective of this study was to assess interindividual variability in trough concentrations of plasma of non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) among HIV-infected adults in a routine outpatient setting. Methods One hundred and seventeen patients who attended our clinic for routine blood tests, and who were receiving antiretroviral therapy which included NNRTI or PI were studied. Patients were not informed that drug concentrations were going to be measured until blood sampling. The times of the last antiretroviral dose and of blood sampling were recorded. Drug concentrations were considered optimal if they were above the proposed minimum effective value. In addition, efavirenz, nevirapine and atazanavir concentrations were considered potentially toxic if they were >,4.0 mg l,1, >,6.0 mg l,1 and >,0.85 mg l,1, respectively. Results Overall, interindividual variability of NNRTI and PI concentrations in plasma was approximately 50%, and only 68.4% of the patients had drug concentrations within the proposed therapeutic range. Poor adherence explained only 35% of subtherapeutic drug concentrations. Conclusion Interindividual variability in trough concentrations of NNRTI and PI among HIV-infected adults is large in routine clinical practice, with drug concentrations being outside the therapeutic window in a significant proportion of patients. These findings provide further evidence that therapeutic drug monitoring may be useful to guide antiretroviral therapy in clinical practice. [source] Development of motor speed and associated movements from 5 to 18 yearsDEVELOPMENTAL MEDICINE & CHILD NEUROLOGY, Issue 3 2010THEO GASSER PHD Aim, To study the development of motor speed and associated movements in participants aged 5 to 18 years for age, sex, and laterality. Method, Ten motor tasks of the Zurich Neuromotor Assessment (repetitive and alternating movements of hands and feet, repetitive and sequential finger movements, the pegboard, static and dynamic balance, diadochokinesis) were administered to 593 right-handed participants (286 males, 307 females). Results, A strong improvement with age was observed in motor speed from age 5 to 10, followed by a levelling-off between 12 and 18 years. Simple tasks and the pegboard matured early and complex tasks later. Simple tasks showed no associated movements beyond early childhood; in complex tasks associated movements persisted until early adulthood. The two sexes differed only marginally in speed, but markedly in associated movements. A significant laterality (p<0.001) in speed was found for all tasks except for static balance; the pegboard was most lateralized, and sequential finger movements least. Associated movements were lateralized only for a few complex tasks. We also noted a substantial interindividual variability. Interpretation, Motor speed and associated movements improve strongly in childhood, weakly in adolescence, and are both of developmental relevance. Because they correlate weakly, they provide complementary information. [source] Early recognition of newborn goat kids by their mother: II.DEVELOPMENTAL PSYCHOBIOLOGY, Issue 4 2003Auditory recognition, evidence of an individual acoustic signature in the neonate Abstract The vocal recognition of newborn kids by their mother at 2 days postpartum and the possible existence of interindividual differences in the voice structure of newborn kids were investigated in two separate studies. The ability of goats to discriminate between the bleats of their own versus an alien kid was tested at 2 days postpartum in mothers being prevented access to visual and olfactory cues from the young. Goats spent significantly more time on the side of the enclosure from which their own kid was bleating, looked in its direction for longer, and responded more frequently to the bleats of their own than to those of the alien kid (p,<,0.05). In the second study, the sonograms of 13 kids, studied from Days 1 to 5, showed significant interindividual differences for the five variables taken into account and on each of the 5 days (duration of bleat, fundamental frequency, peak frequency, and numbers of segments and of harmonics). The potential for individual coding ranged between 1.1 and 4.1, indicating that for some variables variations between individuals were greater than intraindividual variations. Furthermore, when considering the five parameters together, the discriminating scores showed an average of 95% in the 78 combinations of any 2 kids for any given day. Finally, some significant intraindividual differences also were found between days, suggesting ontogenic changes in the characteristics of the kid's voice in early life. Therefore, mother goats are likely to recognize the vocalizations of their 48-hr-old kids, as they show sufficient interindividual variability to allow the existence of individual vocal signatures, even though some of the characteristics of the bleats change rapidly over time. © 2003 Wiley Periodicals, Inc. Dev Psychobiol 43: 311,320, 2003. [source] Fungal rDNA signatures in coronary atherosclerotic plaquesENVIRONMENTAL MICROBIOLOGY, Issue 12 2007Stephan J. Ott Summary Bacterial DNA has been found in coronary plaques and it has therefore been concluded that bacteria may play a role as trigger factors in the chronic inflammatory process underlying coronary atherosclerosis. However, the microbial spectrum is complex and it is not known whether microorganisms other than bacteria are involved in coronary disease. Fungal 18S rDNA signatures were systematically investigated in atherosclerotic tissue obtained through catheter-based atherectomy of 38 patients and controls (unaffected coronary arteries) using clone libraries, denaturating gradient gel analysis (DGGE), in situ hybridization and fluorescence in situ hybridization (FISH). Fungal DNA was found in 35 of 38 (92.11%) coronary heart disease patients by either polymerase chain reaction (PCR) with universal primers or in situ hybridization analysis (n = 5), but not in any control sample. In a clone library with more than 350 sequenced clones from pooled patient DNA, an overall richness of 19 different fungal phylotypes could be observed. Fungal profiles of coronary heart disease patients obtained by DGGE analysis showed a median richness of fungal species of 5 (range from 2 to 9) with a high interindividual variability (mean similarity 18.83%). For the first time, the presence of fungal components in atherosclerotic plaques has been demonstrated. Coronary atheromatous plaques harbour diverse and variable fungal communities suggesting a polymicrobial contribution to the chronic inflammatory aetiology. [source] Hormesis: Why it is important to toxicology and toxicologists,ENVIRONMENTAL TOXICOLOGY & CHEMISTRY, Issue 7 2008Edward J. Calabrese Abstract This article provides a comprehensive review of hormesis, a dose-response concept that is characterized by a low-dose stimulation and a high-dose inhibition. The article traces the historical foundations of hormesis, its quantitative features and mechanistic foundations, and its risk assessment implications. The article indicates that the hormetic dose response is the most fundamental dose response, significantly outcompeting other leading dose-response models in large-scale, head-to-head evaluations. The hormetic dose response is highly generalizable, being independent of biological model, endpoint measured, chemical class, and interindividual variability. Hormesis also provides a framework for the study and assessment of chemical mixtures, incorporating the concept of additivity and synergism. Because the hormetic biphasic dose response represents a general pattern of biological responsiveness, it is expected that it will become progressively more significant within toxicological evaluation and risk assessment practices as well as have numerous biomedical applications. [source] Variable expression of CYP and Pgp genes in the human small intestineEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 6 2003M. Lindell Abstract Background ,The small intestine is receiving increased attention for its importance in drug metabolism. However, knowledge of the intervariability and regulation of the enzymes involved, cytochrome P450 and P-Glycoproteins (CYP and Pgp), is poor when compared with the corresponding hepatic enzymes. Methods ,The expression of eight different CYP genes and the Pgp were determined by reverse transcription polymerase chain reaction (RT-PCR) in 51 human duodenum biopsies. And the variability and correlation of expression was analyzed. Results ,Extensive interindividual variability was found in the expression of most of the genes. Only CYP2C9, CYP3A4 and Pgp were found in all samples. CYP1A2, CYP2A6 and CYP2E1 exhibited the highest interindividual variability. No strong correlation of expression existed between the genes. But a highly significant correlation was found between CYP2D6/1A2, 2D6/2E1, 1A2/2E1 and 2B6/2C9. Acetylsalicylic acid and omeprazole significantly increased the expression of CYPs 2A6, 2E1 and 3A4, respectively. Conclusions ,Extensive interindividual variability is characteristic for the expression of drug-metabolizing CYP and Pgp genes in human duodenum, and external factors such as drugs may further increase the variability. It is possible that the large interindividual variability may lead to variable bioavailability of orally used drugs and hence complicate optimal drug therapy, especially for drugs with a small therapeutic window. Elucidation of factors contributing to clinically important variances warrants further investigation. [source] Expression of melanoma-associated antigens in melanoma cell culturesEXPERIMENTAL DERMATOLOGY, Issue 7 2005Mirjana Urosevic Abstract:, The efficiency of melanoma immunotherapy appears to depend on both melanoma- and immune system-specific factors. Melanoma-specific factors include melanoma-associated antigen (MAA) expression as well as HLA class I molecule expression. We investigated the expression of five MAA , Melan-A/MART-1, tyrosinase, gp100, MAGE-1 and MAGE-3 , by means of FACS analysis in 50 melanoma cell cultures and compared them to the cultures of human foreskin-derived melanocytes and melanoma cell line UKRV-Mel2. Melan-A, tyrosinase and gp100 expression was frequently reduced in melanoma cell cultures, compared to that in foreskin melanocytes, whereas MAGE-1 and MAGE-3 expression showed variable degree of upregulation, compared to that in foreskin melanocytes. The expression of all tested MAA demonstrated high interindividual variability. We further show that cell cultures derived from the same tissue sample are oligoclonal in nature, by demonstrating the presence of up to three cell populations bearing distinct MAA profile. Analysing samples derived from the same patient but each at a different time point, we show that MAA expression profile changes over time either in positive (increase) or in negative (decrease) direction. Finally, we demonstrate that brain metastasis-derived cell cultures significantly overexpress Melan-A and MAGE-3, compared to primary tumours and other metastatic sites (P -value range: 0.05,0.001). Elucidation of the MAA expression patterns and the kinetics within the same patient as well as during the course of the disease may help improve current and develop new immunotherapeutic strategies. [source] Extension of variance components approach to incorporate temporal trends and longitudinal pedigree data analysisGENETIC EPIDEMIOLOGY, Issue 3 2002Mariza de Andrade Abstract Here we present a method that permits one to evaluate genetic effects and to detect genetic linkages by using serial observations of quantitative traits in pedigrees. We developed a statistical method that incorporates longitudinal family data and genetic marker information into an estimating equations framework. With this approach, we can study changes in components over time that measure polygenic and major genetic variances as well as shared and individual-specific environmental effects. Our method provides a measure of heritability from analysis of longitudinal data. Results using longitudinal family data from the Center for Preventive Medicine (Nancy, France) are presented. The results of our analysis show that the apolipoprotein E locus has no effect on interindividual variability in systolic blood pressure. We found that the longitudinal measure of heritability of systolic blood pressure is 0.32. Genet. Epidemiol. 22:221,232, 2002. © 2002 Wiley-Liss, Inc. [source] Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver,HEPATOLOGY, Issue 4 2009Anne T. Nies An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide single-nucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113- and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P , 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P = 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin. (HEPATOLOGY 2009.) [source] Clinical application of measurement of hippocampal atrophy in degenerative dementiasHIPPOCAMPUS, Issue 6 2009Josephine Barnes Abstract Hippocampal atrophy is a characteristic and early feature of Alzheimer's disease. Volumetry of the hippocampus using T1-weighted magnetic resonance imaging (MRI) has been used not only to assess hippocampal involvement in different neurodegenerative diseases as a potential diagnostic biomarker, but also to understand the natural history of diseases, and to track changes in volume over time. Assessing change in structure circumvents issues surrounding interindividual variability and allows assessment of disease progression. Disease-modifying effects of putative therapies are important to assess in clinical trials and are difficult using clinical scales. As a result, there is increasing use of serial MRI in trials to detect potential slowing of atrophy rates as an outcome measure. Automated and yet reliable methods of quantifying such change in the hippocampus would therefore be very valuable. Algorithms capable of measuring such changes automatically have been developed and may be applicable to predict decline to a diagnosis of dementia in the future. This article details the progress in using MRI to understand hippocampal changes in the degenerative dementias and also describes attempts to automate hippocampal segmentation in these diseases. © 2009 Wiley-Liss, Inc. [source] Pharmacokinetics after an intravenous single dose of the opioid ketobemidone in childrenACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 4 2010S. LUNDEBERG Background: Ketobemidone is often used as an alternative to morphine in children in the Scandinavian countries. The aim of this clinical trial was to explore the pharmacokinetics of ketobemidone in children because these properties have not been reported previously. Methods: Thirty children, newborn to 10 years, scheduled for elective surgery were included in the trial. Ketobemidone hydrochloride was administered as a single intravenous bolus dose and ketobemidone and norketobemidone concentrations were measured by LC-MS over 8 h. Pharmacokinetic parameters were determined using compartmental methods. Results: Six children were excluded from pharmacokinetic analysis because of incomplete blood sampling. The values of ketobemidone clearance (l/h/kg) given as median (range) were 0.84 (0.29,3.0) in Group A (0,90 days), 0.89 (0.55,1.35) in Group B (1,2.5 years) and 0.74 (0.50,0.99) in Group C (7,10 years). The corresponding values for apparent volume of distribution (l/kg) were 4.4 (3.7,6.9) (Group A), 2.6 (2.0,5.6) (Group B) and 3.9 (2.7,5.0 (Group C), and for elimination half-life (h) 3.0 (1.4,8.9) (Group A), 2.0 (1.2,4.7) (Group B) and 3.7 (2.4,6.9) (Group C), respectively. In the two neonates the elimination half-life was almost 9 h. The metabolite norketobemidone did not reach levels above the limit of quantification (0.07 ng/ml) in any of the patients. Conclusion: The pharmacokinetic parameters of ketobemidone in children older than 1 month appear to be similar to those in adults. Because of the large interindividual variability of the pharmacokinetics in neonates, further studies especially in this age group are warranted. [source] Ontogeny of human hepatic cytochromes P450JOURNAL OF BIOCHEMICAL AND MOLECULAR TOXICOLOGY, Issue 4 2007Ronald N. Hines Abstract Significant changes in drug-metabolizing enzyme (DME) expression occur during ontogeny. Such changes can have a profound effect on therapeutic efficacy in the fetus and child, as well as the risk for adverse drug reactions. To gain a better understanding of DME ontogeny, enzyme contents for six key cytochromes P450 were measured in 240 human liver samples representing ages from 8 weeks gestation to 18 years. Where possible, both quantitative western blotting and activity assays with probe substrates were performed. Although oversimplified, the DME can be grouped into one of three categories. As typified by CYP3A7, some enzymes are expressed at their highest level during the first trimester and either remain at high concentrations or decrease during gestation and are silenced or expressed at low levels within 1,2 years after birth. These data cause one to query whether these enzymes have an important endogenous function. Representatives of a second group, CYP3A5 and CYP2C19, are expressed at relatively constant levels throughout gestation. Postnatal increases in CYP2C19 are observed within the first year, but not for CYP3A5. CYP2C9, 2E1, and 3A4 are more typical of a third group of enzymes that are not expressed or are expressed at low levels in the fetus with the onset of expression generally in either the second or third trimester. Substantial increases in expression are observed within the first 1,2 years after birth; however, considerable interindividual variability is observed in the immediate postnatal (1,6 months) onset or increase in expression of these enzymes, often resulting in a window of hypervariability. © 2007 Wiley Periodicals, Inc. J Biochem Mol Toxicol 21:169,175, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20179 [source] Comparison of genetic polymorphisms of the NAT2 gene between Korean and four other ethnic groupsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 6 2009T. S. Kang MS Summary Background and objective:,N -acetyltransferase 2 (NAT2) is responsible for the acetylation of numerous drugs and in the transformation of aromatic and heterocyclinc amines into carcinogenic intermediates. Polymorphism of NAT2 may contribute to interindividual variability in such acetylation. The aim of this study was to determine the allele frequencies of polymorphisms of the NAT2 gene, analyse linkage disequilibrium (LD) block and haplotypes in Koreans and compare them with those of other ethnic groups. Methods:, We analysed genetic polymorphisms in all functional promoter and exons of the NAT2 gene by direct sequencing of genomic DNA from 192 healthy Korean subjects. The LD and haplotype blocks of these subjects were constructed from genotype data using an expectation,maximization algorithm. We compared these allele frequencies, LD block and haplotype structure with those of other ethnic groups registered on the International HapMap database. Results and discussion:, We identified 33 polymorphisms including six novel single nucleotide polymorphisms, ,10778T>C, ,10777A>G, ,10351A>G, ,10199C>T and ,10104G>T in promoter and 578C>T in exon2 (T193M) in the Korean subjects tested. All allele frequencies reported in the Koreans were similar to those of Asians except for one allele (rs4345600, ,9306A>G), whereas African and European groups had different frequencies in exon2. The haplotype structure and LD block among the five groups also revealed significant differences. Conclusion:, Ethnic differences in the NAT2 genotype frequencies may be one of the important factors explaining variability in cancer incidence and drug toxicity. Our observations could be useful in assessing the susceptibility of different populations to cancer and contribute to better predictions of the pharmacokinetics and pharmacodynamics of drugs that are metabolized by NAT2, in different populations. [source] Population pharmacokinetics of cefepime in neonates with severe nosocomial infectionsJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 3 2008V. Lima-Rogel MD Summary Objective:, To define the pharmacokinetic behaviour of cefepime in neonates with severe nosocomial infections using a mixed effects model. Patients and methods:, Thirty-one newborn infants were included in the study; 10 additional infants participated in the validation of the pharmacokinetic model. Cefepime CL and V were determined using an open monocompartmental model with first-order elimination. The influence of demographic and clinical characteristics on the model was evaluated. The non-linear mixed effect model (nonmem) program was used to determine the pharmacokinetic population model. Results:, The mean corrected gestational age for infants participating in the construction and validation of the model were 35 and 33 weeks, respectively. Factors included in the final pharmacokinetic model were body surface area (BSA) and calculated CLCR. The final population model was CL (L/h) = 0·457 BSA (m2) + 0·243 CLCR (L/h) and V(L) = 4·12 BSA (m2). This model explains 33·3% of the interindividual variability for CL and 12·8% for V. This model was validated in ten neonates with nosocomial infections by assessing the predictive capacity of plasma cefepime concentrations using a priori and Bayesian strategies. Conclusions:, The predictive performance of this population model for cefepime plasma concentrations was adequate for clinical purposes and can be used for individualizing cefepime therapy in newborn infants with severe infections. Cefepime plasma concentrations can be predicted based on BSA and calculated CLCR. Cefepime therapy using a 250 mg/m2 dose administered every 12 h is adequate to achieve plasma concentrations greater than 8 ,g/mL during more than 60% of the dosing interval and is expected to be effective in the treatment of bloodstream infections caused by most gram negative organisms in newborn infants. A dose of 550 mg/m2 would be required for the treatment of infections caused by Pseudomonas sp. [source] Nonparametric population modeling of valproate pharmacokinetics in epileptic patients using routine serum monitoring data: implications for dosageJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2004I. B. Bondareva Summary Therapeutic drug monitoring (TDM) of valproate (VAL) is important in the optimization of its therapy. The aim of the present work was to evaluate the ability of TDM using model-based, goal-oriented Bayesian adaptive control for help in planning, monitoring, and adjusting individualized VAL dosing regimens. USC*PACK software and routine TDM data were used to estimate population and individual pharmacokinetics of two commercially available VAL formulations in epileptic adult and pediatric patients on chronic VAL monotherapy. The population parameter values found were in agreement with values reported earlier. A statistically significant (P < 0.001) difference in median values of the absorption rate constant was found between enteric-coated and sustained-release VAL formulations. In our patients (aged 0·25,53 years), VAL clearance declined with age until adult values were reached at about age 10. Because of the large interindividual variability in PK behavior, the median population parameter values gave poor predictions of the observed VAL serum concentrations. In contrast, the Bayesian individualized models gave good predictions for all subjects in all populations. The Bayesian posterior individualized PK models were based on the population models described here and where most patients had two (a peak and a trough) measured serum concentrations. Repeated consultations and adjusted dosage regimens with some patients allowed us to evaluate any possible influence of dose-dependent VAL clearance on the precision of total VAL concentration predictions based on TDM data and the proposed population models. These nonparametric expectation maximization (NPEM) population models thus provide a useful tool for planning an initial dosage regimen of VAL to achieve desired target peak and trough serum concentration goals, coupled with TDM soon thereafter, as a peak,trough pair of serum concentrations, and Bayesian fitting to individualize the PK model for each patient. The nonparametric PK parameter distributions in these NPEM population models also permit their use by the new method of ,multiple model' dosage design, which allows the target goals to be achieved specifically with maximum precision. Software for both types of Bayesian adaptive control is now available to employ these population models in clinical practice. [source] Interindividual variation of serum haloperidol concentrations in Japanese patients , clinical considerations on steady-state serum level,dose ratiosJOURNAL OF CLINICAL PHARMACY & THERAPEUTICS, Issue 2 2003E. Yukawa Summary Objective:, Marked interpatient variability in haloperidol (HAL) level,dose (L/D) ratios makes it difficult to use the administered dose for predicting serum concentrations. Objective:, To investigate the effect of dose, age, total body weight and co-medication on steady-state HAL L/D ratios. Method:, Retrospective analysis of dose and HAL blood level data from 168 patients. Results:, The HAL L/D ratio decreased curvilinearly with increasing daily dose of HAL. The patients treated with concomitant antiparkinsonian drugs showed a mean HAL L/D ratio that was 24·9% higher than those without antiparkinsonian drugs. The patients treated with concomitant antiepileptic drugs showed a mean HAL L/D ratio that was 27·2% lower than those without antiepileptic drugs. The mean HAL L/D ratio of patients treated with concomitant CYP2D6 substrates was not significantly different from those without CYP2D6 substrates. Conclusion:, There is a wide interindividual variability in blood levels of HAL in patients given the same dose. Routine monitoring of HAL serum level is useful, especially in patients who require associated antiepileptic and/or antiparkinsonian medication. [source] Extremely prolonged neuromuscular blockade after rocuronium: a case reportACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2009A. C. MORALES MARTÍN It is known that the duration of rocuronium action can be prolonged in elderly patients and that such action shows important interindividual variability. We report a case of prolonged neuromuscular block lasting 11 h, in a woman subjected to kidney transplantation. The possible causes of such prolonged action, inherent to the drug, or related to external factors, are commented. [source] Extrapolating in vitro metabolic interactions to isolated perfused liver: Predictions of metabolic interactions between R -bufuralol, bunitrolol, and debrisoquineJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2010Sami Haddad Abstract Drug,drug interactions (DDIs) are a great concern to the selection of new drug candidates. While in vitro screening assays for DDI are a routine procedure in preclinical research, their interpretation and relevance for the in vivo situation still represent a major challenge. The objective of the present study was to develop a novel mechanistic modeling approach to quantitatively predict DDI solely based upon in vitro data. The overall strategy consisted of developing a model of the liver with physiological details on three subcompartments: the sinusoidal space, the space of Disse, and the cellular matrix. The substrate and inhibitor concentrations available to the metabolizing enzyme were modeled with respect to time and were used to relate the in vitro inhibition constant (Ki) to the in vivo situation. The development of the liver model was supported by experimental studies in a stepwise fashion: (i) characterizing the interactions between the three selected drugs (R -bufuralol (BUF), bunitrolol (BUN), and debrisoquine (DBQ)) in microsomal incubations, (ii) modeling DDI based on binary mixtures model for all the possible pairs of interactions (BUF,BUN, BUF,DBQ, BUN,DBQ) describing a mutual competitive inhibition between the compounds, (iii) incorporating in the binary mixtures model the related constants determined in vitro for the inhibition, metabolism, transport, and partition coefficients of each compound, and (iv) validating the overall liver model for the prediction of the perfusate kinetics of each drug determined in isolated perfused rat liver (IPRL) for the single and paired compounds. Results from microsomal coincubations showed that competitive inhibition was the mechanism of interactions between all three compounds, as expected since those compounds are all substrates of rat CYP2D2. For each drug, the Ki values estimated were similar to their Km values for CYP2D2 indicative of a competition for the same substrate-binding site. Comparison of the performance between the novel liver physiologically based pharmacokinetic (PBPK) model and published empirical models in simulating the perfusate concentration,time profile was based on the area under the curve (AUC) and the shape of the curve of the perfusate time course. The present liver PBPK model was able to quantitatively predict the metabolic interactions determined during the perfusions of mixtures of BUF,DBQ and BUN,DBQ. However, a lower degree of accuracy was obtained for the mixtures of BUF,BUN, potentially due to some interindividual variability in the relative proportion of CYP2D1 and CYP2D2 isoenzymes, both involved in BUF metabolism. Overall, in this metabolic interaction prediction exercise, the PBPK model clearly showed to be the best predictor of perfusate kinetics compared to more empirical models. The present study demonstrated the potential of the mechanistic liver model to enable predictions of metabolic DDI under in vivo condition solely from in vitro information. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4406,4426, 2010 [source] Allosteric kinetics of human carboxylesterase 1: Species differences and interindividual variability,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 12 2008Shiori Takahashi Abstract Esterified drugs such as imidapril, derapril, and oxybutynin hydrolyzed by carboxylesterase 1 (CES1) are extensively used in clinical practice. The kinetics using the CES1 substrates have not fully clarified, especially concerning species and tissue differences. In the present study, we performed the kinetic analyses in humans and rats in order to clarify these differences. The imidaprilat formation from imidapril exhibited sigmoidal kinetics in human liver microsomes (HLM) and cytosol (HLC) but Michaelis-Menten kinetics in rat liver microsomes and cytosol. The 2-cyclohexyl-2-phenylglycolic acid (CPGA) formation from oxybutynin were not detected in enzyme sources from rats, although HLM showed high activity. The kinetics were clarified to be different among species, tissues, and preparations. In individual HLM and HLC, there was large interindividual variability in imidaprilat (31- and 24-fold) and CPGA formations (15- and 9-fold). Imidaprilat formations exhibited Michaelis-Menten kinetics in HLM and HLC with high activity but sigmoidal kinetics in those with low activity. CPGA formations showed sigmoidal kinetics in high activity HLM but Michaelis-Menten kinetics in HLM with low activity. We revealed that the kinetics were different between individuals. These results could be useful for understanding interindividual variability and for the development of oral prodrugs. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 97:5434,5445, 2008 [source] Tacrolimus is a class II low-solubility high-permeability drug: The effect of P-glycoprotein efflux on regional permeability of tacrolimus in ratsJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2002Shigeki Tamura Abstract The objective of this study is to investigate the role of P-glycoprotein (P-gp), a membrane efflux pump associated with multidrug resistance (MDR) and a known substrate for tacrolimus, in determining the regional intestinal permeability of tacrolimus in rats. Thus, isolated segments of rat jejunum, ileum, or colon were perfused with tacrolimus solutions containing polyethoxylated hydrogenated castor oil 60 surfactant, and with or without verapamil, a P-gp substrate used to reverse the MDR phenotype. The results indicated that the intrinsic permeability of tacrolimus in the jejunum, calculated on the basis of the concentration of non-micellized free tacrolimus, was quite high (,,1.4,×,10,4 cm/s). The apparent permeability (Papp) in the jejunum was unaffected by the presence of verapamil; however, the Papp in the ileum and the colon increased significantly in the presence of verapamil and were similar to the values observed in the jejunum. The results suggest that systemic absorption of tacrolimus from the gastrointestinal tract could be significantly affected by P-gp efflux mechanisms. It is also possible that differences in P-gp function at various intestinal sites in a subject or at a given intestinal site in various subjects could lead to large intra- and interindividual variability in bioavailability of tacrolimus following oral administration. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:719,729, 2002 [source] Methodological and statistical issues in pharmacogenomicsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 2 2010Bas J. M. Peters Abstract Pharmacogenomics strives to explain the interindividual variability in response to drugs due to genetic variation. Although technological advances have provided us with relatively easy and cheap methods for genotyping, promises about personalised medicine have not yet met our high expectations. Successful results that have been achieved within the field of pharmacogenomics so far are, to name a few, HLA-B*5701 screening to avoid hypersensitivity to the antiretroviral abacavir, thiopurine S-methyltransferase (TPMT) genotyping to avoid thiopurine toxicity, and CYP2C9 and VKORC1 genotyping for better dosing of the anticoagulant warfarin. However, few pharmacogenetic examples have made it into clinical practice in the treatment of complex diseases. Unfortunately, lack of reproducibility of results from observational studies involving many genes and diseases seems to be a common pattern in pharmacogenomic studies. In this article we address some of the methodological and statistical issues within study design, gene and single nucleotide polymorphism (SNP) selection and data analysis that should be considered in future pharmacogenomic research. First, we discuss some of the issues related to the design of epidemiological studies, specific to pharmacogenomic research. Second, we describe some of the pros and cons of a candidate gene approach (including gene and SNP selection) and a genome-wide scan approach. Finally, conventional as well as several innovative approaches to the analysis of large pharmacogenomic datasets are proposed that deal with the issues of multiple testing and systems biology in different ways. [source] Heritability of diurnal type: a nationwide study of 8753 adult twin pairsJOURNAL OF SLEEP RESEARCH, Issue 2 2007MARKKU KOSKENVUO Summary Twin studies suggest a genetic component in diurnal types. In 1981, a questionnaire sent to the Older Finnish Twin Cohort yielded responses from 2836 adult monozygotic (MZ) and 5917 like-sexed dizygotic (DZ) twin pairs with four category self-report on diurnal type. We used structural equation modelling to estimate genetic and environmental components of variance in morningness and eveningness. The model fitting was best when the morningness and the eveningness were analysed together. The ADE-model (including additive genetic, dominant genetic and non-shared environmental effects) fitted best to the data. ADE-models for men and women separately did not differ in a statistically significant manner from the combined model, and similarly ADE-models for young and old age groups separately did not differ either. The estimate for overall genetic effect (broad sense heritability) was 49.7% (95% confidence interval 46.4,52.8), with the remainder accounted for by environmental factors not shared by siblings. The variance component estimates for the underlying liability to diurnal type were 11.7% (95% CI 0,23.7) for additive genetic factors, 38.0% (24.7,51.3) for genetic factors due to dominance. Genetic effects thus account for about one-half of the interindividual variability in diurnal type in adults. [source] The pharmacokinetics of idraparinux, a long-acting indirect factor Xa inhibitor: population pharmacokinetic analysis from Phase III clinical trialsJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2009C. VEYRAT-FOLLET Summary.,Background: Idraparinux, a long-acting synthetic pentasaccharide, is a specific antithrombin-dependent inhibitor of activated factor X that has been investigated in the treatment and prevention of thromboembolic events. Objectives: To characterize the population pharmacokinetic profile of idraparinux in patients enrolled in van Gogh and Amadeus Phase III clinical trials. Patients and methods: Idraparinux was administered once-weekly subcutaneously at a dose of 2.5 mg, or 2.5 mg (first dose) and then 1.5 mg for patients with severe renal insufficiency (creatinine clearance <30 mL min,1). A population pharmacokinetic model was developed using data from 704 patients with acute deep-vein thrombosis or pulmonary embolism, 1310 patients suffering from atrial fibrillation, and 40 healthy subjects. Potential covariates analyzed included demographics (age, sex, weight and ethnicity), and serum creatinine and creatinine clearance determinations. Results: A three-compartment model best described idraparinux pharmacokinetics, with interindividual variability on clearance, central volume of distribution, and absorption rate constant; residual variability was low. Typical clearance, central volume of distribution, absorption rate constant and volume of distribution at steady-state were 0.0255 L h,1, 3.36 L, 1.37 h and 30.8 L, respectively. Peak concentration was reached at 2.5 h. The terminal half-life was 66.3 days and time to steady-state was 35 weeks. At steady-state, exposures were similar for patients without and with severe renal impairment receiving adjusted-dose. Creatinine clearance was the most important covariate affecting idraparinux clearance. The particular characteristics of idraparinux , rapid onset of action and long-acting anticoagulant effect , offer interesting clinical perspectives currently under investigation with idrabiotaparinux, the reversible biotinylated form of idraparinux. [source] The Residual Platelet Aggregation after Deployment of Intracoronary Stent (PREDICT) scoreJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 1 2008T. GEISLER Summary.,Background:,Recent studies suggest a high interindividual variability of response to clopidogrel associated with adverse cardiovascular outcome. Different clinical factors are considered to influence a persistent residual platelet aggregation (RPA) despite conventional antiplatelet therapy. Objectives:,To investigate clinical factors that affect RPA after 600-mg clopidogrel loading in a large unselected cohort of patients with symptomatic CAD. Methods:,The study population included a consecutive cohort of 1092 patients treated with coronary stenting for stable angina and acute coronary syndromes (ACS). Residual platelet activity was assessed by ADP (20 ,mol L,1)-induced platelet aggregation , 6 h after LD. Eleven clinical factors were included in the primary analysis. Results:,In multivariate regression analysis increased RPA was significantly influenced by ACS, reduced LV-function, diabetes mellitus, renal failure (creatinine > 1.5 mg dL,1), and age > 65 years. In a factor-weighed model the risk for high RPA increased with higher score levels (OR for patients with a score of 1,3, 1.21, 95% CI 0.7,2.1; score 4,6, OR 2.0, 95% CI 1.17,3.5; P = 0.01; score 7,9, OR 3.3, 95% CI 1.8,6.0). During a 30-day follow-up the incidence of major adverse events was higher in patients with RPA in the upper tertile (4.8% vs. 2.5% in the 2nd and 1.5% in the 1st tertile; P < 0.05). Conclusions:,The PREDICT score provides a good tool to estimate residual platelet activity after clopidogrel LD by easily available patient details. Additionally, we demonstrate its association with short-term outcome. Thus, patients with a high score may benefit from intensified antiplatelet therapy by improved platelet inhibition and risk reduction for thromboischemic events. [source] Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndromeJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 4 2003H. Aubert Summary., Increased plasma thrombin-activatable fibrinolysis inhibitor (TAFI) levels were recently shown to be a part of the insulin resistance syndrome. We investigated the relationship between plasma TAFI antigen levels and insulin resistance markers and compared these results with those obtained for PAI-1 and fibrinogen which are known to be closely related to insulin resistance syndrome and fat mass, respectively. Eighty-nine obese females had 1.3-, 1.2-, and 3-fold higher circulating TAFI, fibrinogen and PAI-1, respectively, compared with 64 lean females. Univariate analysis showed that the significance level for association between TAFI or fibrinogen concentrations and insulin resistance markers was lower than the significance level for association between PAI-1 and insulin resistance markers. Nevertheless, TAFI, fibrinogen, and PAI-1 plasma levels were significantly associated to each other. In linear stepwise ascendant analysis, insulin resistance markers accounted for 50% of the interindividual variability of plasma PAI-1 and only for 10% of plasma TAFI and 13% of fibrinogen variability. The contribution of insulin resistance markers to plasma TAFI antigen levels variability disappeared when PAI-1 or fibrinogen was entered in the statistical model. TAFI mRNA was detected in the liver but not in adipose tissue and endothelial cells. No TAFI mRNA was detected in normal or atherosclerotic vessels either. These results suggest that elevated TAFI antigen levels found in obese subjects are not independently associated with the metabolic markers of the insulin resistance syndrome. Increased plasma TAFI antigen levels in obesity might reflect a specific pathway of regulation at the liver level. [source] Cyclosporine exposure and calcineurin phosphatase activity in living-donor liver transplant patients: Twice daily vs. once daily dosingLIVER TRANSPLANTATION, Issue 2 2006Masahide Fukudo We have compared the pharmacokinetics and pharmacodynamics of cyclosporine between once- and twice-daily dosing regimens in de novo patients of living-donor liver transplantation (LDLT). A total of 14 patients were enrolled in this study, who had received cyclosporine microemulsion (Neoral) twice a day (BID, n = 5) or once daily in the morning (QD, n = 9) after transplantation. On postoperative day (POD) 6, the QD regimen significantly increased cyclosporine exposure; the blood concentration at 2 hours postdose (C2) and area under the concentration-time curve (AUC) for 4 hours (AUC0,4), compared with the BID regimen. Moreover, the area under the calcineurin (CaN) activity in peripheral blood mononuclear cells time-curve (AUA) for 12 hours (AUA0,12) and 24 hours (AUA0,24) were decreased by approximately 42 and 25% with the QD regimen relative to the BID regimen, respectively. The C2 level was significantly correlated with the AUC0,4 (r2 = 0.95), which was negatively related to the AUA0,12 with a large interindividual variability (r2 = 0.59). However, a significant correlation was found between the AUA0,12 or AUA0,24 and CaN activity at trough time points. According to a maximum inhibitory effect attributable to the drug (Emax) model, the mean estimates of Emax and the Cb value that gives a half-maximal effect (EC50) for CaN inhibition were not significantly different between the 2 groups, respectively. These findings suggest that a once daily morning administration of cyclosporine may improve oral absorption and help to provide an effective CaN inhibition early after LDLT. Furthermore, CaN activity at trough time points would be a single surrogate predictor for the overall CaN activity throughout dosing intervals following cyclosporine administration. Liver Transpl 12:292,300, 2006. © 2006 AASLD. [source] | ||||||||||||||||||||||||||||||||||