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PubMed1998

Drug-metabolism research challenges in the new millennium: individual variability in drug therapy and drug safety.

One of the most challenging research areas in pharmacology in the new millennium is to understand why individuals respond differently to drug therapy and to what extent that individual variability in disposition is responsible for the observed differences in therapeutic efficacy and adverse reactions. To answer these complex questions, drug-metabolism research will rely on multidisciplinary approaches more than ever to investigate the many components involved in drug metabolism and disposition. Major research challenges include the following: (1) the genetic variation of drug targets (receptors, enzymes, etc.), drug transporters (multispecific organic anion transporter, P-glycoprotein, alpha-1-acid glycoprotein, etc.), and drug-metabolizing enzymes (cytochrome P450s and other enzymes); (2) the structure and function of all genetic variants of drug receptors, transporters, and metabolizing enzymes; (3) the induction, repression, and inhibition of all components involved in drug disposition; (4) the development of noninvasive in vivo methods to determine the physiological significance of various components in the handling of specific therapeutic agents in humans; (5) the mechanism of idiosyncratic adverse drug reactions; and (6) the pharmacokinetic and pharmacodynamic relationships to explain the individual differences in therapeutic efficacy and drug safety. Thus successful drug-metabolism research in the new millennium must integrate receptor biology, enzymology, recombinant DNA technology, biochemical toxicology, and drug disposition into study design and conduct balanced in vitro and in vivo experiments to allow a full understanding of the mechanisms of individual variability in drug therapy and drug safety.

Animals↗

PubMed2005

Towards a molecular code for individuality in the absence of MHC: screening for individually variable genes in the urochordate Ciona intestinalis.

Urochordates possess several well described allorecognitions systems, the molecular nature of those is not yet understood. A prerequisite for any self-/nonself discimination system is the presence of a group of highly variable molecules, which should vary between individuals. Using suppression subtractive hybridisation (SSH) we surveyed Ciona intestinalis for individually variable genes. Our search so far identified two genes, ciS7 and ciMETA2, which both display an unexpected high degree of intra- and interindividual variability, code for secreted proteins, and contain multiple domains suitable for protein-protein interactions. The possible role of these molecules in allorecognition is discussed.

Amino Acid Sequence↗

PubMed1994

Inter-individual variability of human hepatic glutathione S-transferase isozymes assessed by inhibitory capacity.

Glutathione S-transferases (GSTs) are important as drug metabolizing enzymes mainly in the detoxication process. To assess individual differences in susceptibility to different chemicals, it would be useful to know the activity of specific GST isozymes in individuals. In order to study individual variability, typical substrates specific for the three major classes of GSTs were used not only as substrates but also as inhibitors using 17 organ-donor livers. Out of 17, 4 livers were low in the mu-form isozyme, judging from the depressed GST activity for trans-4-phenyl-3-buten-2-one (tPBO), a mu-class substrate. The range of tPBO activity exhibited more than 20-fold variation, while less than 2-fold variation was observed in the activities for 1-chloro-2,4-dinitrobenzene (CDNB), a non-specific substrate for alpha-, mu-, and pi-class GSTs. In addition to the conventional approach to assessing individual variability, well known substrates for GSTs, cumene hydroperoxide (CHP, alpha-class), tPBO (mu) and ethacrynic acid (EA, pi) were used as inhibitors against CDNB-GSH conjugation. CHP inhibited the CDNB-GSH conjugation in mu-depressed livers more potently than in the non-depressed livers, probably because CHP is a specific inhibitor for alpha-class GST. Inhibition by CHP may therefore be used to detect livers which are low in mu-form. The inhibition by tPBO was found to be weak and the variability was small (CV of 9% in 17 livers). EA potently inhibited GST activity with its inhibition constant (Ki) 2,000-fold lower than that of CHP. The small individual variation in inhibition by EA (CV of 6%) supported that EA is a universal but potent inhibitor against major GSTs contained in human liver.

Benzene Derivatives↗

PubMed1990

Haemoglobin adducts formed by aromatic amines in smokers: sources of inter-individual variability.

In a previous study we found that aromatic amines, particularly 4-aminobiphenyl, formed haemoglobin adducts at higher concentrations in the blood of smokers compared to non-smokers. We re-analyse here data on haemoglobin adducts of 14 aromatic amines in order to ascertain if the inter-individual variability left unexplained by tobacco smoking could be attributed to differences in individual metabolic patterns. For this purpose we computed residuals from analysis of variance in order to adjust for individual smoking habits (type and amount of tobacco). Residuals were correlated within two clearly distinct groups: one formed by binuclear compounds (4-aminobiphenyl, 3-aminobiphenyl and 2-naphthylamine) and the other formed by all other (i.e. mononuclear) compounds. Within each group, highly statistically significant correlation coefficients were found, whereas compounds belonging to one group were not correlated to compounds in the other group. These results can be interpreted as a suggestion that two different metabolic pathways exist, one for binuclear and one for mononuclear arylamines, and that inter-individual differences in such pathways can explain part of inter-individual variability in adduct levels. This interpretation is consistent with recent animal experiments suggesting that there are different enzyme systems for the two classes of compounds.

2-Naphthylamine↗

PubMed2000

Intra- and inter-individual variability in human sperm concentration, motility and vitality assessment during a workshop involving ten laboratories.

The aim of the present study was to assess variability in the evaluation of human sperm concentration, motility and vitality. Technicians and biologists from 10 teams involved in multicentre studies on semen quality attended the same laboratory, each team using its own methods and equipment to analyse the same semen samples. Inter-individual variability was assessed from 17 fresh semen samples of varying quality. Intra-individual variability was assessed from pools of frozen samples for sperm concentration and motility and stained smears for vitality with three blind evaluations by sample and smear. The mean inter-individual coefficients of variation were 22.9, 21.8 and 17.5% for sperm concentration, motility and vitality respectively. There was no statistical difference among participants for sperm concentration assessment, but significant differences for both motility and vitality (both P: < 0.05). The mean intra-individual coefficients of variation were 15.8, 26.2 and 13.1% for sperm concentration, motility and vitality respectively, with marked differences between expert and novice participants: concentration 9.8% versus 28.0%; motility 22.8% versus 33.0%; and vitality 10.0% versus 19.3%. The present data confirm the need for external quality control schemes for diagnostic purposes, and indicate their utmost importance in multicentre studies on semen quality.

Cell Survival↗

PubMed2006

Premorbid intra-individual variability in intellectual performance and risk for schizophrenia: a population-based study.

BACKGROUND: Some, but not most, schizophrenia patients have below-average intelligence years before they manifest psychosis. However, it is not clear if those whose intelligence falls within-normal-range nevertheless have cognitive abnormalities. We examined the association between intra-individual variability in intellectual performance and risk for schizophrenia in individuals with normal IQ. METHODS: 555,326 adolescents, mandatory assessed by the Israeli Draft Board were followed up over 8 to 17 years for psychiatric hospitalization by means of the Israeli National Psychiatric Hospitalization Case Registry. Data were available on 4 intelligence sub-tests, and on behavioral and psychosocial variables. Variability was computed from the variance of the four intelligence tests' standardized scores. RESULTS: There was a significant monotonic association between increased intra-individual variability in intellectual performance and risk of schizophrenia in individuals with within-normal-range IQ. Individuals with the highest variability were 3.8 times more likely to have schizophrenia [95%CI: 2.32-6.08; p < 0.0001] compared with individuals with the lowest variability. This association held after controlling for the effects of potential confounders. CONCLUSIONS: Despite within-normal-range premorbid IQ, apparently healthy adolescents who will later on manifest schizophrenia, nevertheless have cognitive abnormalities such as increased variability across intellectual tasks, possibly related to frontal lobe abnormalities.

Adolescent↗

PubMed2001

Correlation analyses as a step to identify foods that are sources of inter-individual variability in nutrients; their use for the development of food based dietary guidelines.

Food Based Dietary Guidelines (FBDG), in order to be attainable, should take into account the cultural context of the population for which they are developed. They need to focus on foods that actually determine the intake of nutrients for which desirable changes have been identified. Inter-individual variability of nutrient intakes--a measure of the heterogeneity of intakes--is determined by the variability in the consumption of its food sources among the population. The foods that determine a high proportion of inter-individual variability in nutrient intake can be identified on the basis of data banks that describe food and nutrient intakes in the population. The experience accumulated to design Food Frequency Questionnaire through selection of key foods suggests that high quantitative contributors to a specific nutrient may not be important determinants of its intake. On the other hand, the Pearson correlation between the intake of each food source and the total nutrient intake allows quantification of the percentage of variability explained by each item and takes into account the possibility of correlations between different food sources. Once a key food is identified, several strategies are available to modify its intake in the population: through changes in the percentage of consumers/in the mean portion size/in the frequency of intake. The anticipated level of change can be predicted according to the strategy adopted.

Databases, Factual↗

PubMed2005

[The inter-individual variability of the response to clopidogrel].

Clopidogrel is an anti-platelet aggregation drug with proven efficacy in the prevention of atherothrombotic complications. However, according to studies, between 5 and 20% of patients have further thrombotic episodes despite treatment with clopidogrel. The principal ex vivo evaluation methods of clopidogrel's efficacy are platelet aggregometry, and using flow cytometry to measure platelet activation and the quantatitive analysis of VASP phosphorylation. VASP analysis is the most selective method for clopidogrel's effect. These tests show great inter-individual variability in the response to treatment. This variability is such that about a third of treated patients show an "insufficient" response to clopidogrel. The exact causes of this variability have not yet been clearly identified. They could correspond with observer error, inter-individual variability in intestinal absorption or hepatic metabolism, or polymorphism of clopidogrel's target, the P2Y12 receptor. Accordingly it may be necessary to adapt the dose of clopidogrel or to use an alternative treatment. Failure to respond to clopidogrel would be a risk factor for atherothrombotic complications, but this association has yet to be demonstrated.

Cell Adhesion Molecules↗

PubMed2005

[Intra-individual variability of the platelet anti-aggregation effect of aspirin in coronary patients].

UNLABELLED: Several studies have reported a biochemical resistance to aspirin in 5 to 10% of coronary patients. However, the stability of the platelet anti-aggregation effect with aspirin over time remains poorly understood. OBJECTIVE: To study the intra-individual variability at 6 months of the anti-platelet action of aspirin in coronary patients. METHOD: Prospective study including 40 consecutive patients with acute coronary syndrome and taking regular aspirin (250 mg a day). The biochemical impact of aspirin was determined by measuring the time to occlusion (TO) on a collagen/epinephrine cartridge with PFA-100. The determination of the TO was performed 2 months (TO1) and then 8 months (TO2) after starting aspirin. In our population, a resistance to aspirin was defined as a TO < or =125 sec. RESULTS: The median value for TO was generally stable over the two periods, at 158 sec for TO1 and 179 sec for TO2 (p = 0.29). Among the 9 initially resistant patients (22.5%), 4 became sensitive to aspirin without changing the dosage, while only one of the 31 initially sensitive patients became biochemically resistant. CONCLUSION: the existence of a medium term intra-individual variability in the antiplatelet response to aspirin in coronary patients underlines the importance of biochemical surveillance in these high vascular risk patients.

Acute Disease↗

PubMed1995

Inter-individual and intra-individual variability of ethanol concentration-time profiles: comparison of ethanol ingestion before or after an evening meal.

1. The magnitude of the variability of ethanol absorption is an important factor for studies that seek to determine the significance of potential interactions between ethanol and drugs. The aim of this study was to determine the extent of inter- and intra-individual variability of ethanol concentration-time profiles in fasted and fed subjects. 2. Twenty-four healthy male subjects were randomized to receive ethanol 0.3 g kg-1 before an evening meal on two study days and ethanol 0.3 g kg-1 after an evening meal on two study days. Plasma ethanol concentrations were measured at intervals from 0-240 min. 3. There were significant differences in the mean area under the ethanol concentration-time curve (AUC), the mean peak ethanol concentration (Cmax), the mean ethanol elimination slope and the time to peak ethanol concentration between the fed and fasted subjects. There were no significant differences between the first and second study days for either fed or fasting subjects for all parameters. 4. There was no statistically significant difference in inter- or intra-subject variance between fed and fasted studies although the coefficients of variation (standard deviation expressed as a percentage of the mean) for the differences between the first and second study day were higher for fed studies. 5. The large inter- and intra-individual variability of alcohol absorption for both fasted and fed subjects must be considered in the design of alcohol-drug interaction studies.

Adult↗

PubMed2000

Assay of prick test inoculum volume. II. Average values and individual variability.

INTRODUCTION: The amount of reagent introduced into the skin by a prick test is critical in studies on the reproducibility and standardization of the method. OBJECTIVE: The purpose of the present study was to measure the average volume and the individual variability of the inoculum performed with a prick test standardized technique. METHODS: Two hundred forty prick tests--16 inoculations per subject--were performed on the volar sides of arms of 15 healthy volunteers. The tests were performed by a skilled tester whose technical performance complied with the criteria of good reproducibility described in international guidelines. A 1-mm tip standard device and a 50% glycerosaline solution labeled with Tc99m were used for the test. The inoculum size was calculated using a direct assay method based on the gamma camera. RESULTS: The average volume of the prick test inoculum was equal to 0.016 microliters, with a remarkable dispersion of the values around the mean (median, 15906: range, 418 to 82253 picoliters). Further, we observed great variability from one subject to another and great variability in the same subject from one skin site to another. A statistical analysis of the data shows that this variability depends on the individual characteristics of the subjects examined. A skilled tester using a standardized technique is not responsible for significant variability. CONCLUSIONS: Even when performed by a skilled operator and with standardized techniques, the prick test shows great limits of reproducibility, at least as far as the size of the inoculum volume is concerned. The variability of the inoculum depends, in a statistically significant way, on the subject's individual characteristics and therefore can be reduced only within certain limits by the standardization and perfectibility of the technique.

Allergens↗

PubMed1984

[Individual variability in the proliferative potential of human diploid fibroblasts in vitro].

The rate of individual variability of proliferative potential determined by the percentage of colonies containing 16 and more cells (the cloning efficiency) was studied 16 embryonic and 15 postnatal strains of human diploid fibroblasts. It is highly probable that these differences are hereditary in nature and determined by the genotype of the given cell line. This conclusion is based on the fact that the cloning efficiency is a criterion marking each individual cell line and is well reproducible in a series of experiments.

Cell Division↗

PubMed1991

Individual variability in tail tendon fiber break time in three age cohorts of different strains of mice.

Individual variability in mouse tail tendon fiber denaturation in urea was investigated. Differences in break time between fibers within tendons and between tendon groups were examined. Mean break times for each strain increased with age with the shorter-lived DBA/2 mice exhibiting higher break times within age cohorts than the C57BL/6 animals. Fibers from the two ventral tendon groups had consistently higher break times than those from the two dorsal groups, implying differential rates of collagen maturation between these two areas within the tail. Histological examination revealed conspicuous morphological dorsal/ventral differences in tendon number, proximity to a major blood vessel, and the amount of surrounding muscle tissue. These findings have methodological and experimental design implications for the use of tail tendon break time (TTBT) as a biomarker of aging. Furthermore, they suggest possible physiological mechanisms for differential rates of collagen aging.

Aging↗

PubMed1983

Intra-individual variability in divergent thinking in response to audio, visual, and tactile stimuli.

This study explored intra-individual variability in divergent thinking (fluency, flexibility, and originality) in response to audio, visual, and tactile stimuli. Forty-four participants responded to three divergent thinking tasks. The divergent thinking assessors were structurally similar (i.e. duration of task, amount of stimuli presented, time allowed for responding), but differed in that one was based on auditory stimuli, a second used visual stimuli, and the third required participants to respond to tactile stimuli. A within-subjects repeated measures research design was used; task treatment order was counterbalanced across subjects. A principal components factor analysis with oblique rotation distinguished three divergent thinking factors defined by sensory modality response preferences. Within-individual differences in level of originality appeared as a function of the kind of stimuli which served to evoke divergent thinking. Results are discussed in the light of the need for discriminating the dimensionality of creativity as a construct.

Acoustic Stimulation↗

PubMed2006

Intra-individual variability of penetrating keratoplasty outcome after excimer laser versus motorized corneal trephination.

PURPOSE: To assess the intra-individual variability of outcomes after penetrating keratoplasty by comparing mechanical and nonmechanical corneal trephination. METHODS: Fifteen patients (30 eyes, 16 with keratoconus and 14 with Fuchs' dystrophy; median age at penetrating keratoplasty 56.3/53.5 years) were assessed whose trephination was performed using a motor trephine in one eye and the 193-nm excimer laser (MEL 60, Carl Zeiss-Meditec) in the other eye by one experienced surgeon. Subjective refractometry, standard keratometry, and corneal topography were used to assess best spectacle-corrected visual acuity (BSCVA); spherical equivalent refraction; keratometric and topographic central corneal power; refractive, keratometric, and topographic astigmatism; surface regularity index; surface asymmetry index; and potential visual acuity preoperatively, before first suture removal (at 1 year), and at last available follow-up after final suture removal but before additional surgery (1.3 and 1.9 years, respectively). RESULTS: Before first suture removal BSCVA was significantly higher (0.7 vs 0.5; P=.008) after excimer laser trephination. At the end of follow-up, refractive/ keratometric/topographic astigmatism (2.20/2.10/2.40 diopters [D] vs 5.00/6.00/7.10 D) and surface regularity index (0.8 vs 1.1) were significantly lower (P=.02, P=.005, P=.01, and P=.03, respectively) and potential visual acuity was significantly higher (0.9/0.6; P=.02) after excimer laser trephination. CONCLUSIONS: During long-term follow-up, all-sutures-out postkeratoplasty astigmatism and surface regularity are superior in the eye where nonmechanical excimer laser was applied in contrast to the fellow eye with motor trephination in the same individual.

Adult↗

PubMed1986

[Individual variability and inheritance of the number and size of the nucleolar organizer regions in chromosomes of domestic swine].

Individual variability of the number and size of silver-staining nucleolar organiser regions (NOR) was studied in 76 pigs of Semirechenskaya, Big White and Duroc breeds. The variability of the NOR number is exclusively caused by the presence of the 8NOR- allele (the chromosomes of the 8th homologous pair lacking the silver-staining NOR). Concentration of the 8NOR- allele is about 0.7 in the average for all three breeds. All 7 offsprings from the homozygous parents male 8NOR- /8NOR- and female 8NOR+/8NOR+ were heterozygotes 8NOR- /8NOR+. These data, together with good agreement between found and expected (according to the Hardy-Weinberg law) frequencies of homo- and heterozygotes suggest the codominant character of the NOR number inheritance. This allows using the NOR analysis to control the parentage announced. The study of inheritance of the size of NOR did not prove unequivocally its codominant character.

Alleles↗

PubMed1986

Patterns of juvenile criminal activity as a function of demographic, family, and individual variables.

Patterns of juvenile criminal activity were investigated with respect to differences in a range of demographic, family, and individual variables. Subjects were 89 juveniles who were referred to a county juvenile services center (70 males, 19 females; 78 Caucasians, 10 Blacks, 1 Oriental; mean age = 15.7). Discriminant function analyses were used to assess the discriminating power of the variables across crime categories (felony vs. misdemeanor), crime subcategories (person vs. property), number of prior referrals (none vs. one or more), and grade level (junior vs. senior high). All groups could be discriminated effectively on the basis of Wilks' lambda and associated chi-square tests of statistical significance.

Adolescent↗

PubMed2000

[Individual variability in the structure and topography of the celiac plexus and its clinical significance].

Using anatomical and histological methods individual variability of structure and topography of coeliac plexus 94 preparations of adults of both sexes were studied. In 32% coeliac plexus was presented as a multitude of small ganglia connected by a network of nerve fibres remote from visceral branches of aorta. In 38% the plexus was composed of middle sized ganglia concentrated into groups at the level of coeliac trunk from the left and at the level of the source of superior mesenteric artery without contacts wit lig.arcuatum from right, histologically ganglia had lobular structure with low amount of connective tissue (29%-50%). In 30% it was comprised of 2-4 large conglomerates of ganglia attached to lig.arcuatum from the bottom forming a dense circle around the vessel, decline in neuron relative number was discovered histologically. Single neurons surrounded by rough fibrous tissue were observed instead of lobules (42-94%). Correlation between structure and topography of the plexus and skeletotopy of coeliac trunk, aorta and lig.arcuatum were established which can be used to reveal "risk" groups involving neuroganglionic component in extravasal compression of coeliac trunk.

Adult↗