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At least 487 records · Page 27Linked to original sources
PubMed2006

Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel.

OBJECTIVE: Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. METHODS AND RESULTS: The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation (P=0.025) and better responsiveness (P=0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose (P=0.025), increased platelet inhibition (P=0.006), and a more optimal drug response (P=0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. CONCLUSIONS: The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.

Adenine↗
PubMed2005

Individual QT-R-R relationship: average stability over time does not rule out an individual residual variability: implication for the assessment of drug effect on the QT interval.

BACKGROUND: Universal QT correction formulae have been shown to under or overcorrect the QT interval duration. Individual QT-R-R modeling has been proposed as a preferable solution for heart rate correction of QT intervals. However, the QT-R-R relationship stability over time needs to be evaluated. METHODS: The present report is part of randomized, double-dummy, and placebo-controlled 4-way crossover phase 1 study (48 healthy volunteers). Each randomized period included a run-in placebo day followed the day after by drug administration, with moxifloxacin as a positive control for QT interval measurement. Digital Holter ECG data were analyzed using the "bin" approach. For each period, individual QT-R-R relationship were calculated using two different models (linear and parabolic log-log models). RESULTS: The mean intrasubject variability for the alpha coefficient of the linear modeling (SDintra = 0.011 +/- 0.005) reached 28.6 +/- 10.2%. When the parabolic model was considered, the SDintra was 0.026 +/- 0.009 for the alpha coefficient. The QT-R-R relationship variability was in part related to long-term RR changes (R2 = 30%, P < 0.05). However, no significant time effect (ANOVA) was evidenced for QT-R-R coefficients. Moxifloxacin significantly increased the alpha coefficient of the QT-R-R relationship from 0.07 +/- 0.018 to 0.085 +/- 0.019, P < 0.05 (linear model). CONCLUSIONS: The individual QT-R-R relationship shows a residual variability in part related to long-term autonomic changes. In addition, the QT-R-R relationship might be modulated by the drug tested. As a consequence, pretherapy QT-R-R relationship obtained in a given patient cannot be used as a fingerprint throughout a drug trial.

Aza Compounds↗
PubMed2006

Topoisomerase II beta expression level correlates with doxorubicin-induced apoptosis in peripheral blood cells.

Anthracyclines are widely used in oncology. Both the response and side-effects of anthracyclines are individually variable, but determinants or predictive markers of this variability are not available. We investigated the variability in the expression of the anthracycline targets topoisomerases II (topo II) alpha and beta and its significance for the apoptotic response following exposure to the anthracycline doxorubicin. Only topo II beta protein expression was detected in peripheral blood cells. Usually considered a constitutively expressed protein, topo II beta varied 3-, 18-, and 16-fold on the mRNA, protein and activity levels, respectively, among the volunteers tested. In addition, the expression of topo II beta was modified by several mitogens, suggesting a role in the regulation of cell cycle. Strikingly, topo II beta activity correlated statistically significantly with the apoptotic response in peripheral blood leukocytes exposed to 1 microM doxorubicin. A longitudinal study in a subset of study subjects demonstrated that 30% of the topo II expression variability may be inherited. However, resequencing of the TOP2B gene in 48 unrelated individuals revealed only 8 gene variants, none of them with obvious effects on the expression or protein sequence of topo II beta. Taken together, the apoptotic response to doxorubicin in peripheral blood cells may be mediated by topo II beta. The expression level of topo II beta is intra- and inter-individually variable, and may in part determine the apoptotic response to doxorubicin and other anthracyclines.

Antibiotics, Antineoplastic↗
PubMed1979

Physiological aspects of the effects of sound on man and animals.

A review of some short-term and long-term physiological effects of sound on non-auditory body functions is given. It is pointed out that the short-term effects depend closely on the acoustic properties of the sound. Habituation is rapid for steady signals but slow for interrupted ones. Irrelevant, meaningless sound, presented to rats over their life-time in such a way as to simulate an industrial acoustic environment, did not affect blood pressure, life-span or morbidity incidence. As far as the injurious effect of sound on the inner ear is concerned, it was shown that spontaneously hypertensive rats were considerably more susceptible to such impairment than were normotensive ones. Hence sound does not produce hypertension, but susceptibility to ear injury may be greater in hypertensive individuals. The protential role which individual variability in physiological properties of the sound conduction system might play for the observed individual variability in noise-induced hearing loss is also discussed.

Animals↗
PubMed1995

Replication and extended analysis of behavior state, environmental events, and related variables among individuals with profound disabilities.

Knowledge from previous studies pertaining to state behavior of individuals with profound and multiple disabilities and its relation to other environmental and physiological variables was replicated and extended. Behavior state and environmental data were collected over a 5-hour period for most of 66 students with profound disabilities from 21 educational settings. Results showed general consistency in state patterns and profile groupings with previous investigations, a strong relation between different state profiles and measures of development, and consistency of state patterns across CA levels. Transitional probabilities and z scores were used to confirm changes in state behavior of half of the subjects following primarily adult interactions. Results were discussed in relation to theoretical implications and intervention recommendations.

Activities of Daily Living↗
PubMed1987

Plasma concentrations of thiothixene and clinical response in treatment-resistant schizophrenics.

Plasma concentrations of thiothixene were measured during treatment of 42 treatment-resistant schizophrenic patients. Inter-individual variability was marked even when patients were treated with the same dose or dose regimen. Intra-individual variability was less but still considerable. A highly significant correlation was found between dose and plasma concentration, but this relationship was unpredictable for individual patients. A median plasma concentration of 12 to 15 ng/ml might be expected with daily doses of 60 mg. No definite range of therapeutic plasma concentrations could be determined. Patients who attained moderate degrees of improvement did so at a median dose of 26 ng/ml, which is within the range of therapeutic plasma concentrations previously reported for thiothixene in similar patients.

Adult↗
PubMed1993

Description of time- and frequency- domain-based measures of heart rate variability in individuals taking antiarrhythmics, beta blockers, calcium channel blockers, and/or antihypertensive drugs after sudden cardiac arrest.

Concomitant drug therapies after sudden cardiac arrest and their potential effect of altering heart rate variability (HRV) represent confounding factors in interpreting the outcome of nonpharmacologic therapies on HRV. The purpose of this study is to describe a broad spectrum of time-domain and frequency-domain measurements of HRV in 50 individuals after sudden cardiac arrest. Some of the individuals were taking antiarrhythmics (n = 9), beta blockers (n = 13), calcium channel blockers (n = 10), nitrates (n = 8), cardiac glycosides (n = 10), and/or antihypertensives (n = 12). Heart rate variability was measured using a Holter recorder for 24 hours and the SpaceLabs FT2000 Monitoring System (Redmond, WA). In those individuals taking antiarrhythmic drugs, the power density within the low-frequency range (.016-.04 Hz) was significantly decreased (P = .001) compared to those not taking antiarrhythmics (n = 41). However, 78% of the people taking antiarrhythmics also had congestive heart failure (New York Heart Association functional classes II and III), which also decreased HRV. Those individuals taking beta blockers tended to have slower heart rates (P < .01). The association between beta blocker use and HRV was positive, but not statistically significant except for the increased power density in the low-frequency range (P < .05). In general, the relationships between HRV and drug therapy--calcium channel blockers, antihypertensives, cardiac glycosides, or nitrates--were not statistically significant.

Adrenergic beta-Antagonists↗
PubMed1999

Population estimation of valproic acid clearance in adult patients using routine clinical pharmacokinetic data.

The aim of the present study was to estimate valproic acid (VPA) clearance values for adult patients with epilepsy, using serum concentrations gathered during their routine clinical care. Retrospective steady state serum concentrations data (n=534) collected from 208 adult patients receiving VPA were studied. Data were analysed according to a one-compartment model using the NONMEM program. The influence of VPA daily dose (Dose), gender, age, total body weight (TBW), and comedication with carbamazepine (CBZ), phenytoin (PHT) and phenobarbital (PB) were investigated. The results of the population pharmacokinetics analysis were validated in a group of 30 epileptic patients. The final regression model for VPA clearance (Cl) was: $¿rm Cl¿left (¿rm L/h ¿right )=0¿rm. 004¿times TBW¿times Dose ¿0.304¿¿rm ¿times 1.363¿,¿rm CBZ¿times 1. 541¿,¿rm PHT¿times 1.397¿,¿rm PB.$ The inter-individual variability in VPA clearance, described by a proportional error model, had a variation coefficient (CV) of 23.4% and the residual variability, described using an additive model, was 11.4 mg/L. These results show that VPA clearance increased linearly with TBW, but increases nonlinearly with increasing VPA daily dose. Concomitant administration of CBZ, PHT and PB led to a significant increase in VPA clearance. The model predictions in the validation group were found to have satisfactory precision and bias. In conclusion, inter-individual variability in VPA clearance can be partly explained by TBW, daily dose and bitherapy with CBZ, DPH or PB. Inclusion of these factors allows this variability to be reduced by 37.23% which may be very useful for clinicians when establishing the initial VPA dosage regimen. However, the magnitude of inter-individual plus residual variabilities, remaining in the final model, render these dosage predictions imprecise and justify the need for VPA serum level monitoring in order to individualize dosage regimens more accurately.

Adolescent↗
PubMedDate not supplied

Variability and discontinuity of the pathognomonic systemic effects caused by Walker 256 tumor progression in rats.

Cancer pathognomonic systemic effects (PSE) have high individual variability. For this reason present data were collected daily and synchronized considering four main points: inoculation day, onset of PSE, aggravation and death. The subclinical period free of PSE ranged between 15.7 +/- 2.2 days, the clinical period was less variable, 8.9 +/- 0.5 days, divided in a moderate and a grave phase of nearly the same length. PSE involved disturbances of fundamental homeostatic regulations: appetite, sodium, water, immune, etc. PSE triggering correlated highly with survival (r2 = 0.95, P < 0.01), but poorly with primary tumor growth, and it was anticipated by metastases from 20.5 +/- 2.6 to 10.6 +/- 1.1 days (P < 0.01). After multifocal simultaneous inoculations, PSE triggering was anticipated to 4.2 +/- 0.2 days (marked reduction of individual variability), in the presence of small total-tumor masses, absence of macroscopic metastases, and without changes in the following clinical period features. PSE triggering seems to be a major prognostic indicator probably related to multifocal tumor growth.

Animals↗
PubMed2006

Shift work and inter-individual differences in sleep and sleepiness.

Inter-individual differences in tolerance for shift work have been studied primarily in terms of external factors affecting alertness on the job or the ability to rest and sleep while at home. However, there is increasing evidence that neurobiological factors play a role as well, particularly the major processes involved in the regulation of sleep and wakefulness. These include a sleep homeostatic process seeking to balance wakefulness and sleep and a circadian process seeking to promote wakefulness during the day and sleep during the night. Shift work is associated with a temporal misalignment of these two endogenous processes. During nightwork, this misalignment makes it difficult to stay awake during the nightshift and sleep during the day. However, inter-individual variability in the processes involved in sleep/wake regulation is substantial. Recent studies have demonstrated the existence of inter-individual differences in vulnerability to cognitive deficits from sleep loss. Moreover, these inter-individual differences were shown to constitute a trait. Interestingly, self-evaluations of sleepiness did not correspond well with the trait inter-individual variability in objective levels of performance impairment during sleep deprivation. Perhaps because of this discrepancy, in operational settings, the inter-individual differences in vulnerability to sleep loss do not appear to be limited due to self-selection mechanisms. Indeed, even among a highly select group of active-duty jet fighter pilots flying a series of simulated night missions, systematic inter-individual differences in performance impairment from sleep loss were still observed. There are significant personal and economic consequences to human error and accidents caused by performance deficits due to sleep loss. It is important, therefore, to study the inter-individual differences in the regulation of sleep and wakefulness in the work environment so that cognitive impairment during shift work may be better anticipated and prevented.

Aviation↗
PubMed2001

Human variability in glucuronidation in relation to uncertainty factors for risk assessment.

The appropriateness of the default uncertainty factor for human variability in kinetics has been investigated for glucuronidation using an extensive database of substrates metabolised primarily by this pathway. Inter-individual variability was quantified for 15 compounds from published pharmacokinetic studies (after oral and intravenous dosing) in healthy adults and other subgroups using parameters relating to chronic exposure (metabolic and total clearances, area under the plasma concentration time-curve (AUC)) and acute exposure (C(max)). Low inter-individual variability (about 30-35%) was found for all parameters (clearance corrected or not corrected for body weight, metabolic clearance, oral AUC and C(max)) after either iv or oral administration to healthy adults. The overall variability of 31% for glucuronidation in healthy adults supported the validity of the default kinetic uncertainty factor of 3.16 for this group, because it would cover more than 99% of individuals. Comparisons between potentially sensitive subgroups and healthy adults using differences in means and variability indicated that neonates showed the greatest impairment of glucuronidation, and that the 3.16 kinetic default factor applied to the mean data for adults would be inadequate for this subpopulation. The in vivo data have been used to derive pathway-related default factors for compounds eliminated largely via glucuronidation.

Administration, Oral↗
PubMedDate not supplied

[The variability of the scabies mite Sarcoptes scabiei de Geer (Acariformes, Sarcoptidae) in relation to the epidemiology of scabies. 4. The variability of the mite population on a patient and its focal variability].

The authors analyze the individual variability of the agent of scabies in populations on individual patients and in foci of the disease. They define an elementary micropopulation and a focal population notions. A total of 763 females, collected from the hands of 100 patients with scabies were examined. The findings evidence that the degree of the chetoid covering joining in the mite females, assessed in grades, may be regarded as an indicator of the population status in the pathologic process. Grades II and III females predominate in the mite population on the patients during the initial period of the disease (up to a month), whereas in the course of a full-bloom process (over a month) Grades I and 0 females prevail. The attendant exo- and endogenous factors shift the grade composition of the females towards the higher grades whatever the length of the disease. A great variety of the females in focal populations evidences reinfection and continuity of the process.

Animals↗
PubMed1992

Evaluating suspected co-proxamol overdose.

In three instances of suicidal poisoning by co-proxamol (paracetamol and dextropropoxyphene) blood samples were obtained from 11 sites together with eight tissue samples, bile, urine, gastric contents and duodenal contents. Site-dependent differences in blood propoxyphene concentration varied between the three cases but concentrations were consistently lowest in peripheral blood and highest in central sites: 3.9-5.5 (pulmonary vein) mg/l; 4.6-25 (pulmonary vein) mg/l; 3.2-40 (aorta) mg/l. There was a less than twofold variation in corresponding blood paracetamol concentrations. Reference data on fatal propoxyphene blood concentrations do not specify the blood sampling site and can be misleading. The intra-individual variability of propoxyphene concentrations in blood in these three cases underscores this problem. Tissue concentrations of propoxyphene showed considerable inter-individual variability in degree and pattern. Tissue concentrations of paracetamol showed a less than twofold intra-individual variation. Body drug loads were calculated by two methods: from organ weights and tissue concentrations; from published volume of distribution data (Vd). For paracetamol the body drug load is underestimated by the organ weight calculation but the Vd calculation approximates the suspected dose based on anamnestic information. For propoxyphene the body drug load is seriously underestimated by the organ weight calculation and overestimated up to 2.5 times by the Vd calculation. Since the two drugs have a fixed ratio in co-proxamol then the dose of propoxyphene (the effective lethal agent) can be inferred from the paracetamol dose calculated by Vd. This approach may be applicable to cases of overdose with other compounded drug preparations.

Acetaminophen↗
PubMed1999

Categorizing asthma severity.

The National Asthma Education and Prevention Program (NAEPP) Expert Panel II recommended a stepped care pharmacotherapy approach to asthma treatment based on an objective assessment of asthma severity using daytime symptoms, nocturnal symptoms, and physiologic lung function. The worst grade of the individual variables determines overall asthma severity. With this approach, patterns of asthma severity categorization might vary among individual variables; one variable might have a predominant effect on overall categorization. During the run-in, pretreatment phase of five controlled clinical trials, data from 744 inhaled steroid nonusers and 685 inhaled steroid users on asthma control were collected and asthma severity categorized. In inhaled steroid nonusers nocturnal symptoms classified the majority of patients as severe, persistent, but wheeze classified 27.3% of patients as mild, intermittent and 25.7% as mild, persistent. If the worst grade from the four asthma symptoms was used for severity grading, most patients were categorized as severe, persistent. beta-Agonist use and FEV(1) classified most as moderate, persistent. There was poor correlation between variables in severity categorization. Severity grading for European patients was similar to that for U.S. patients. Applying the Expert Panel II recommended method for asthma severity categorization to a large data set illustrates that a single variable, nocturnal symptoms, determined to a large extent overall categorization. Development of a validated method for asthma severity categorization is essential for using a stepped care approach to asthma pharmacotherapy.

Administration, Inhalation↗
PubMed2001

Risk perception and experience: hazard personality profiles and individual differences.

The dominance of the "psychometric" paradigm and the consequent emphasis on personality profiles of hazards has resulted in little attention being given to individual variability in risk judgments. This study examines how far differences in experience of risk activities can explain individual variability in risk assessments. A questionnaire study (n = 172) was used to explore the relationships between experience and risk perceptions in relation to 16 risk activities. It was expected that these relationships would differ for voluntary and involuntary activities. Measures of experience included assessments of "impact" and "outcome" valence as well as "frequency." These three aspects of experience each related to risk assessment but their relationship depended on whether the risk experiences were voluntary or not. The results indicate the importance of developing more fine-grained ways of indexing risk experience.

Adolescent↗
PubMed1987

Estimation of whole body bone resorption rate: a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis.

In 37 female patients with primary osteoporosis, urinary hydroxyproline excretion, determined in 18 24-h consecutive complete urine collections was compared with two radioisotopic measurements of bone resorption rate measured simultaneously using 85Sr. A somewhat better fit was obtained when the kinetically determined bone resorption rate was corrected for long-term exchange processes within bone. Regression analysis showed that the intercept of the regression of hydroxyproline excretion on resorption rate, corrected or uncorrected for exchange, was significantly higher than zero at about 100 mumol/day. This is consistent with a substantial fraction of urinary hydroxyproline arising from non-bony sources. Fifteen paired studies were analysed and the results suggested that intra-individual variability in these relationships (when studies were separated by a year or more) were similar to inter-individual variability. We calculated the precision with which an estimate of bone resorption could be determined based on the calculated regressions. As a means of non-invasive quantitation of whole body bone resorption rate, the excretion rate of hydroxyproline, measured over 5 days, for example, appeared competitive with isotopic methods making no correction for exchange and relatively little worse than our exchange corrected method.

Aged↗
PubMed1987

Variation of dark focus of accommodation with laser speckle exposure duration.

Dark focus of accommodation (DFA) was measured in 10 subjects using a computer-aided He-Ne Badal laser optometer having high temporal and amplitude resolution. Accommodative responses were tracked during 5 min sessions for 10 speckle exposure durations ranging from 100 to 1000 ms. DFA-speckle exposure functions fell into four distinct groups. This identifies the laser speckle exposure time as a possible contaminant in measures of DFA made by laser optometers if individual variability across exposure times is ignored. Group averaging of accommodative responses for laser exposure times obfuscates the reported individual variability.

Accommodation, Ocular↗