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PubMed2005

The decline of androgen levels in elderly men and its clinical and therapeutic implications.

Aging in men is accompanied by a progressive, but individually variable decline of serum testosterone production, more than 20% of healthy men over 60 yr of age presenting with serum levels below the range for young men. Albeit the clinical picture of aging in men is reminiscent of that of hypogonadism in young men and decreased testosterone production appears to play a role in part of these clinical changes in at least some elderly men, the clinical relevancy of the age-related decline in sex steroid levels in men has not been unequivocally established. In fact, minimal androgen requirements for elderly men remain poorly defined and are likely to vary between individuals. Consequently, borderline androgen deficiency cannot be reliably diagnosed in the elderly, and strict differentiation between "substitutive" and "pharmacological" androgen administration is not possible. To date, only a few hundred elderly men have received androgen therapy in the setting of a randomized, controlled study, and many of these men were not androgen deficient. Most consistent effects of treatment have been on body composition, but to date there is no evidence-based documentation of clinical benefits of androgen administration to elderly men with normal or moderately low serum testosterone in terms of diminished morbidity or of improved survival or quality of life. Until the long-term risk-benefit ratio for androgen administration to elderly is established in adequately powered trials of longer duration, androgen administration to elderly men should be reserved for the minority of elderly men who have both clear clinical symptoms of hypogonadism and frankly low serum testosterone levels.

Aged↗
PubMed1999

Population pharmacokinetics. A regulatory perspective.

The application of population approaches to drug development is recommended in several US Food and Drug Administration (FDA) guidance documents. Population pharmacokinetic (and pharmacodynamic) techniques enable identification of the sources of inter- and intra-individual variability that impinge upon drug safety and efficacy. This article briefly discusses the 2-stage approach to the estimation of population pharmacokinetic parameters, which requires serial multiple measurements on each participant, and comprehensively reviews the nonlinear mixed-effects modelling approach, which can be applied in situations where extensive sampling is not done on all or any of the participants. Certain preliminary information, such as the compartment model used in describing the pharmacokinetics of the drug, is required for a population pharmacokinetic study. The practical design considerations of the location of sampling times, number of samples/participants and the need to sample an individual more than once should be borne in mind. Simulation may be useful for choosing the study design that will best meet study objectives. The objectives of the population pharmacokinetic study can be secondary to the objectives of the primary clinical study (in which case an add-on population pharmacokinetic protocol may be needed) or primary (when a stand-alone protocol is required). Having protocols for population pharmacokinetic studies is an integral part of 'good pharmacometric practice'. Real-time data assembly and analysis permit an ongoing evaluation of site compliance with the study protocol and provide the opportunity to correct violations of study procedures. Adequate policies and procedures should be in place for study blind maintenance. Real-time data assembly creates the opportunity for detecting and correcting errors in concentration-time data, drug administration history and covariate data. Population pharmacokinetic analyses may be undertaken in 3 interwoven steps: exploratory data analysis, model development and model validation (i.e. predictive performance). Documentation for regulatory purposes should include a complete inventory of key runs in the analyses undertaken (with flow diagrams if possible), accompanied by articulation of objectives, assumptions and hypotheses. Use of diagnostic analyses of goodness of fit as evidence of reliability of results is advised. Finally, the use of stability testing or model validation may be warranted to support label claims. The opinions expressed in this article were revised by incorporating comments from various sources and published by the FDA as 'Guidance for Industry: Population Pharmacokinetics' (see the FDA home page http:/(/)www.fda.gov for further information).

Data Interpretation, Statistical↗
PubMed1978

Transcendental meditation and mirror-tracing skill.

Learning, performance and patterns of inter- and intra-individual variability of 32 experienced Transcendental Meditators were compared to those of 32 non-meditators. The data indicated that certain effects attributed to the practice of Transcendental Meditation (such as increased alertness and maintenance of attention, greater consistency and less anxiety) are not manifested in terms of learning and performance of a novel perceptual-motor skill.

Adult↗
PubMed1990

[Contribution of automatic sphygmomanometers for one-time measurement of blood pressure].

Due to high intra-individual variability of arterial blood pressure, single measurements provide only estimates of true actual values. Two or three recordings made in sequence in one or a few minutes' intervals are recommended in some clinical studies of antihypertensive therapy, with the aim of decreasing the variability. In order to examine the value of repeated measurements made on one occasion, four sequential resting recordings of blood pressure and heart rate made in one minute intervals with the automatic oscillometric Nippon Colin BP-103N sphygmomanometer were evaluated in 66 subjects, using the analysis of variance methods. Means of three recordings showed a significantly lower variability than single measurements (almost by one half), while the difference between three and four readings was not significant. The Page's rank test revealed that the first measurements are not uniformly the highest ones, and therefore the medians of three readings made in sequence are recommended as characteristics of resting blood pressure. An advantage of the oscillometric method is the possibility of measuring mean arterial pressure. The recorded values were significantly higher than those calculated from the systolic and diastolic pressures according to the current formula, being situated between one third and one half of the pulse pressure. The intra-individual coefficient of variation of the recorded mean arterial pressure was comparable with that of systolic and significantly lower than that of diastolic pressure.

Adult↗
PubMed2001

Factors influencing subjective noise sensitivity in an urban population.

This study was designed to define the individual variables influencing subjective noise sensitivity in an urban population and to investigate the distribution of subjective noise sensitivity with regard to noise exposure. A general questionnaire, a ten-graded noise annoyance scale, the Weinstein's Noise Sensitivity Scale, and the Eysenck Personality Questionnaire were applied to a sample of 413 inhabitants of Belgrade. Distribution of noise sensitivity scores was normal and independent of noise exposure. No significant differences in average noise sensitivity scores were observed concerning gender and exposure to low (Leq < 55 dBA), and high level of traffic noise (Leq > 65 dBA). Multiple regression analysis revealed that neuroticism was the best individual predictor for SNS, for both sexes in the noisy area and for women only, in the quiet area (P < 0.001). Age, education level and introversion were not significantly related to noise sensitivity. Positive relation between reported noise annoyance and noise sensitivity was highly significant (P < 0.0001).

Journal Article↗
PubMed1986

The influence of hepatic plasma flow on alfentanil plasma concentration plateaus achieved with an infusion model in humans: measurement of alfentanil hepatic extraction coefficient.

In a group of seven patients undergoing intracranial surgery under neurolept anesthesia, an alfentanil infusion was initiated with a loading dose of 235 micrograms/kg over 5 min, followed by a maintenance infusion rate of 1.8 microgram X kg-1 X min-1 in order to obtain a steady state plasma concentration (Css) of 400 ng/ml-1 according to an infusion model. The mean values of Css (446 +/- 209 ng/ml) were close to the predicted ones. Nevertheless, an important intersubject variability in Css values was observed. A positive linear correlation existed between alfentanil steady state clearance and indocyanine green clearance (r = 0.88) and between alfentanil steady state clearance and cardiac index (r = 0.93). In three patients, a catheter was inserted into an hepatic vein to determine the alfentanil hepatic extraction coefficient. Alfentanil plasma clearance did not differ from alfentanil hepatic clearance and alfentanil hepatic extraction coefficient values ranged from 0.32-0.53. We conclude that alfentanil is a drug with an intermediate hepatic extraction coefficient and that alfentanil plasma clearance depends on hepatic plasma flow, which is thus one of the factors accounting for individual variability in plasma concentration plateaus achieved with an infusion model.

Adult↗
PubMed2006

The spectrum of phenylalanine variations under tetrahydrobiopterin load in subjects affected by phenylalanine hydroxylase deficiency.

A fall in blood phenylalanine (Phe) after tetrahydrobiopterin (BH(4)) administration is a common trait in phenylalanine hydroxylase (PAH, EC 1.14.16.1) deficiency (McKusick 261600). To explore the extent and biological correlates of this phenomenon we studied: (a) the spectrum of BH(4) response in patients with PAH deficiency; (b) the variability of BH(4) response according to the severity of the biochemical phenotype; and (c) the variability of the response to BH(4) in subjects with the same genotype. Fifty PAH-deficient subjects (age 1 month-35 years) were enrolled for the study (5 with mild hyperphenylalaninaemia (MHPHE), 15 with mild phenylketonuria (MPKU) and 30 with classic phenylketonuria (CPKU) and underwent an identical schedule of blood samplings 24 h before and after oral BH(4) challenge (6(R)-BH4, 20 mg/kg per day), leaving Phe intake unchanged. The effect of BH(4) on blood Phe concentration was evaluated according to the percent decrease of Phe during the 24 h following the challenge (criterion a), and as variation exceeding the individual variability of blood Phe (criterion b). The number of BH(4)-responders according to criterion b was 31 (including all the 14 detected by criterion a): 17 out of 30 CPKU (57%), 9 out of 15 MPKU (60%), and all the MHPHE subjects (chi(2) = 3.45, df = 2, p = 0.178). The effect of BH(4) showed a large interindividual variability unrelated to diagnostic classification, basal value of blood Phe, maximum percentage of Phe reduction, Phe intake, and genotype. Some inconsistencies were found in patients with identical genotype. The first responsive case homozygous for the severe R408W mutation was found. Two new mutations, Y387X and G352C, were identified (the former was BH(4)-responsive), and the responsiveness of three already reported mutations (R261Q, D338Y, T92I) was substantiated.

Adolescent↗
PubMed2006

Individual variation in cortisol responses to acute "on-back" restraint in an outbred hamster.

An outbred species of dwarf hamster (Phodopus campbelli) was used to assess between-individual variability in the response to, and recovery from, a one-time stressor of 6 min of physical restraint in a subordinate, on-back, position. Four repeated plasma samples were drawn under home-cage isoflurane anesthesia from 33 males and 38 females 50 min before, and then 10, 60, and 120 min after the stress onset. Plasma cortisol concentrations were higher in females than males, but there was no evidence for a sex difference in response to the stressor. The expected cross-sectional increase ( approximately 50 ng/ml) in response to the stressor, followed by recovery, was seen. However, there was extensive individual variation, ranging from no reaction to continuous decline from the initial to the final sample. Results were expressed in four ways (absolute concentration, relative concentration, and area under the curve relative to ground and relative to the stress-induced increase) and also standardized and subjected to hierarchical cluster analysis. Clusters failed to effectively partition the between-individual variation and did not cluster by sex, age, or housing conditions. The current study cautions against ignoring individual differences and suggests that outbred animal models might be particularly relevant to understanding stress-related pathological conditions.

Aging↗
PubMed2006

Population pharmacokinetic model of fluvoxamine in rats: utility for application in animal behavioral studies.

The limitations of blood sampling in pharmacokinetic (PK)/pharmacodynamic (PD) studies in behavioral animal models could in part be overcome by a mixed effects modeling approach. This analysis characterizes and evaluates the population PK of fluvoxamine in rat plasma using nonlinear mixed effects modeling. The model is assessed for its utility in animal behavioral PK/PD studies. In six studies with a different experimental setup, study site and/or sampling design, rats received an intravenous infusion of 1, 3.7 or 7.3mg/kg fluvoxamine. A population three-compartment PK model adequately described the fluvoxamine plasma concentrations. Body weight was included as a covariate and mean population PK parameters for CL, V(1), V(2), Q(2), V(3) and Q(3) were 25.1 ml/min, 256 ml, 721 ml, 30.3 ml/min, 136 ml and 1.0 ml/min, respectively. Inter-individual variability was identified on CL (39.5%), V(1) (43.5%), V(2) (50.1%) and Q(2) (25.7%). A predictive check and bootstrap analysis confirmed the predictive ability, model stability and precision of the parameter estimates. Body weight was identified as a significant covariate of the inter-compartmental clearance Q(2). The pharmacokinetics was independent of factors such as dose, surgery (for instrumentation) and study site. The utility of the model in animal behavioral studies was demonstrated in a PK/PD analysis of the effects on REM sleep in which a sparse PK sampling design was used. By using the pertinent information from the population PK model, individual PK profiles and the PK/PD correlation could be adequately described.

Animals↗
PubMed1995

New developments in patient-controlled postoperative analgesia.

Patient-controlled analgesia (PCA) is a newer technique for pain management. Patients are allowed to self-administer small analgesic bolus doses into a running intravenous infusion, intramuscularly, subcutaneously or even into the epidural space. Demands are usually controlled by computer-driven infusion pumps, but can also be delivered by disposable devices. Clinical experience demonstrates that individual variability in pain sensitivity and analgesic needs are of utmost importance. In contrast to earlier expectations, opioid consumption is usually higher than with restrictive conventional dosing regimes, but without an increase in serious side effects. Patients' acceptance is generally enthusiastic because of the possibility of self-control. PCA has proved its importance for pain studies, e.g. for algesimetry, to determine predictors of postoperative pain, to describe drug interactions, to evaluate the concept of pre-emptive analgesia or for pharmacokinetic designs. It is concluded that PCA results have been urgently required in order to change the mind of physicians and nursing staff with respect to individual pain management strategies. Once this goal is achieved, PCA concepts should also be used for the improvement of more conventional techniques.

Analgesia, Patient-Controlled↗
PubMed2002

Frontal brain activity predicts individual performance in an associative memory exclusion test.

Event-related brain potentials (ERPs) were recorded from 24 young adults during a recognition test including Old, New, and Recombined pairs composed of two words studied in different pairs. Recombined pairs called for a response of 'new'. Task difficulty was increased by repetition of some words during the study phase; a subject might study tower/pie, puppet/pie, drill/wreath and bee/wreath (pairs with a Common word), and at test, encounter the Common Recombined pair of puppet/wreath (in addition to Unique Recombined pairs composed of two words studied once). Individual accuracy in the Recombined conditions varied widely, but was unrelated to general memory ability as indexed by accuracy on the Old and New pairs. Posterior brain potentials showed graded amplitudes dependent on the oldness of both the individual words and their combinations (Old > Recombined > New, and Common > Unique), but were also unrelated to accuracy in the Recombined conditions. Amplitudes of ERPs recorded over prefrontal scalp accounted for a large proportion of the individual variability in differentiating studied combinations of words from recombinations of studied elements. The experimental design differentiates three possible roles of prefrontal cortex in source or associative memory tests: resolving a conflict between familiarity and a response of 'new', extended memory search, and evaluation of ambiguous memory signals.

Adult↗
PubMed1985

Differences in memory retrieval: a construct validity investigation.

Long-term memory retrieval efficiency was investigated as a potential underlying source of individual and developmental differences in cognitive functioning. Fourth-grade, eighth-grade, and college-aged subjects participated in a task using the Posner letter-matching paradigm. Letter pairs were presented simultaneously under physical-match and name-match instruction conditions. Reaction times were used to estimate parameters of long-term memory retrieval efficiency, basic encoding, decision, and response time, and name and physical output interference. Psychometric tests of verbal and spatial ability were included to assess convergent and discriminant validity of hypothesized relationships between aptitude test performance and basic cognitive processes. Developmental differences were observed in most but not all of the processing variables. Individual difference analyses indicated that less confounded estimates of processing parameters were not systematically related to verbal ability at any age level. Basic encoding and response speed was the most consistent correlate of spatial ability. The results suggest difficulties in previous interpretations of NIPI-verbal ability relationships. The study of cognitive processes in interaction and embedded in meaningful tasks is discussed.

Adolescent↗
PubMed1983

Prolonged variability in plasma protein binding of disopyramide after acute myocardial infarction.

1 Disopyramide plasma binding was determined in vitro in plasma from 20 patients with acute myocardial infarction (aged 35-79 years) and in 20 age and sex matched healthy subjects. Plasma samples were collected on days 1, 5 and 12 after infarction and when the patient returned to the outpatient clinic. 2 In healthy subjects there was a significant negative correlation between disopyramide free fraction and plasma alpha 1-acid glycoprotein (AAG) concentration. A similar correlation was observed in the patients with myocardial infarction, however this correlation was dependent on time elapsed after infarction. Disopyramide free fraction did not correlate with albumin concentration in either group. 3 Mean plasma AAG concentrations were increased by 63% within 5 days after infarction and had returned to initial levels some months later (73.5 +/- 7.8 days). On each of the four sampling days, a two to four fold individual variability in plasma AAG concentrations was observed. 4 Maximum increases in disopyramide plasma binding were shown on days 5 and 12 after infarction. These increases were dependent on both drug and AAG concentrations. Increases in fraction bound were greater at the higher drug concentrations. Within the usual therapeutic plasma range for disopyramide (2 to 5 mg/l), the mean increases in fraction bound, compared to day 1 data, varied from 22 to 45% respectively. 5 Sequential alteration in AAG concentration after infarction indicates that disopyramide plasma binding may not reach a steady state until some months after infarction. Prediction of the time to achieve this steady state would be difficult due to inter- and intra-patient variability in binding.

Adult↗
PubMed1984

Is borderline fasting hyperglycemia a risk factor for cardiovascular death?

The majority of previously reported studies of borderline hyperglycemia as a risk factor for cardiovascular disease are based on post-challenge glucose levels, are limited to men, and show either no significant association or a possible threshold effect. In order to determine whether fasting plasma glucose (FPG) in the normal range (less than 140 mg/dl) predicts mortality, we prospectively studied a geographically defined Southern California community of 3625 nondiabetic men and women aged 40-79, 99.5% of whom were followed for 9 years. Levels of FPG were significantly associated with levels of most heart disease risk factors. After adjusting for these risk factors, FPG, analyzed either as a continuous or categorical variable, was independently and significantly associated with all-cause, cardiovascular and ischemic heart disease mortality in men in proportional hazard models. An excess of all-cause mortality with the highest levels of FPG (130-139 mg/dl) was the only statistically significant association seen in women. The absence of a significant linear association in women may reflect true sex differences or a lack of power owing to the relatively small numbers of deaths in women. The independent linear glucose mortality association in men found here differs from previous studies, and may reflect both the larger number of events and the use of FPG, which has less intra-individual variability and less potential for misclassification bias than post-challenge glucose.

Adult↗
PubMed1997

The impact of complex chromosomal rearrangements on the detection of radiosensitivity in cancer patients.

BACKGROUND AND PURPOSE: Lymphocytes of a small fraction of cancer patients responded to in vitro irradiation with an extreme chromosomal reaction. A large portion of the observed chromosome aberrations were complex chromosomal rearrangements (CCR). The present study is an attempt to define the impact of CCR on the predictive detection of an intrinsic clinical radiosensitivity in cancer patients in more detail. MATERIALS AND METHODS: A three-colour 'FISH-painting' technique (chromosome in situ suppression (CISS) hybridization) was used for the detection of chromosomal rearrangements, induced by in vitro irradiation, in 81 samples of peripheral blood lymphocytes from 66 cancer patients. Thirty-three of those were assigned for radiation therapy, the others having just undergone radiation therapy. Seven healthy individuals served as controls. RESULTS: CCRs are a very rare event in non-irradiated cells. Lymphocytes of patients who had just undergone therapeutic irradiation, however, not only exhibited high basic frequencies of CCR but also responded to in vitro irradiation with a more drastic increase of CCR than did the lymphocytes of non-exposed patients. A high inter-individual variability of the reaction to in vitro irradiation could be generally stated. The lymphocytes of patients with clinical signs of an outstanding radiosensitivity responded with an unusually high frequency of CCR. The total number of CCRs detected by CISS was found to be dependent on the interval from a previous radiation therapy and was slightly influenced by previous cytostatic therapy. Irrespective of these influences, patients with clinically defined radiation hypersensitivity were those with the highest radiosensitivity also in cytogenetic terms (including CCR). CONCLUSION: The successful use of FISH-painting for the detection of CCR, in addition to the general breakage frequency, highlights its suitability in the identification of individual hypersensitivity to ionizing radiation. The time-consuming cytogenetic examination can be considerably reduced by its use.

Chromosome Aberrations↗
PubMed1998

Losing and gaining in old age: changes in personal network size and social support in a four-year longitudinal study.

OBJECTIVES: Previous studies have shown that most older people have a significant number of relationships. However, the question of whether the aging of old people produces losses in their personal networks remains open for discussion. This study models the individual variability of the changes affecting multiple personal network characteristics. METHODS: Personal interviews were conducted with 2,903 older Dutch adults (aged 55-85) in three waves of a four-year longitudinal study. RESULTS: A stable total network size was observed, with an increasing number of close relatives and a decreasing number of friends. Contact frequency decreased in relationships, and the instrumental support received and emotional support given increased. Age moderated the effect of time for some of the network characteristics, and for many of them, effects of regression towards the mean were detected. Furthermore, major variations in the direction and the speed of the changes were detected among individual respondents, and nonlinear trends were observed. DISCUSSION: The widely varying patterns of losses and gains among the respondents squares with the focus on the heterogeneity of developments among aging people. The instability of the network composition might reflect the natural circulation in the membership of networks.

Activities of Daily Living↗
PubMed1998

Reproducibility of tilt table testing in patients with vasovagal syncope and its relation to variations in autonomic nervous system activity.

To assess the variability of head-up tilt table testing, 35 patients with vasovagal syncope, shown by a positive tilt table test, underwent a second test 1 week later. Also, on the day before each test, spectral and time-domain indexes of heart rate variability were derived from Holter recordings to examine the stability of autonomous nervous system activity in these patients. Fifteen healthy volunteers served as a control group and also underwent two tilt table tests with prior Holter monitoring. Twenty-one (60%) of the 35 patients had a second positive test. None of the patients in the control group experienced syncope during either of the tests. The heart rate variability measures in the control group varied slightly from 1 day to the other, in contrast to the syncopal patients, where only low frequency spectral power and the mean of all 5-minute standard deviations of RR intervals showed comparable behavior. The indexes which reflect parasympathetic activity exhibited significant fluctuations in the syncopal patients. These fluctuations were due entirely to the patients who did not reproduce the outcome of the tilt table test, where high parasympathetic tone was associated with the positive test and normal parasympathetic tone with the negative test. In contrast, the patients with two positive tests had high parasympathetic tone during both test periods, with low individual variability. In conclusion, patients with vasovagal syncope show variations in vagal autonomic tone and appear to be more prone to syncope when their parasympathetic tone is elevated.

Analysis of Variance↗
PubMed2003

[Menopause: towards treatment "à la carte" ].

In spite of questioning and doubt arising from WHT study hormone substitution therapy (HST) has proven efficacy on climacteric symptoms and certain short-term and long-term consequences of menopause. Among 1000 women taking HST for ten years, eight supplementary cases of breast cancer and 6 fewer cases of colonic cancer are observed. No cardiovascular protection has been demonstrated. A history of coronary artery disease, vascular disease, stroke or thromboembolism are contraindications for HST. The vascular impact of estradiol administered via an extra-digestive route in women with a low vascular risk cannot be extrapolated from the HERS and WHI trials because these trials were conducted is high-risk women, using specific types of steroids given orally. Tibolone has demonstrated efficacy and in an alternative to HST after more than one year of menopause. The usefulness of phytoestrogens remains to be determined, particularly due to the wide individual variability of their effects on climacteric symptoms and the low level of proof provided by epidemiological or clinical studies conducted to study the prevention of osteoporosis and the risk of breast cancer. Most of the analyses present methodological biases. Currently, the most widely accepted notion is that there is a beneficial effect on cardiovascular risk. To date, SERMs have selective indications and cannot be prescribed for all women: raloxifen is used for the prevention and treatment of menopause-related osteoporosis. The relative risk of venous thromboembolism with SERMs (raloxifen and tamoxifen) is comparable to that observed with HST. HST or any other treatment given for menopause must be an individual decision balancing the benefits against the risks and taking into account the desires of the patient perfectly informed of the currently available evidence. Prescriptions should be part of an overall scheme including nutritional advise and physical exercise aimed at preserving quality of life and preventing age-related effects which largely depend on genetic predisposition and the psycho-affective environment.

Cardiovascular Diseases↗