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PubMed2004

Comparative population pharmacokinetics of lorazepam and midazolam during long-term continuous infusion in critically ill patients.

AIMS: It is well established that there is a wide intra- and interindividual variability in dose requirements for lorazepam and midazolam in intensive care patients. The objective of this study was to compare the population pharmacokinetics of lorazepam and midazolam after long-term continuous infusion in mechanically ventilated critically ill patients. METHODS: Forty-nine critically ill patients randomly received either lorazepam (n = 28) or midazolam (n = 21) by continuous infusion for at least 24 h. Multiple blood samples were obtained for determination of the drug and metabolite concentrations by HPLC. Population pharmacokinetic models were developed using the Non-Linear Mixed Effect Modelling (NONMEM) program. The influence of selected covariates was investigated. The prospective performance of the models was evaluated on the basis of results in separate groups of patients for lorazepam (n = 31) and midazolam (n = 33). RESULTS: The pharmacokinetics of lorazepam were best described by a two-compartment model. Alcohol abuse, positive end expiratory pressure (PEEP) and age were identified as significant covariates. Total body clearance for patients without alcohol abuse was 4.13 - (PEEP - 5) x 0.42 l h-1, and 0.74 l h-1 for patients with alcohol abuse. The volume of distribution was 0.74 l, the steady state volume of distribution was 56 - (age - 58) x 2.1 l and the intercompartmental clearance was 10 l h-1. The proportional residual error was 15% and the median absolute prediction error was 13.6% with a bias of 1.5%. The pharmacokinetics of midazolam were best described by a two-compartment model with alcohol abuse, APACHE score and age as significant covariates. Total body clearance for patients without alcohol abuse was 11.3 - (age - 57) x 0.14 l h-1, and 7.27 - (age -57) x 0.14 l h-1 for patients with alcohol abuse. The volume of distribution was 7.15 l, the steady state volume of distribution was 431 l, and the intercompartmental clearance was 40.8 - (APACHE score - 26) x 2.75 l h-1. The proportional residual error was 31% with an additive residual error of 32 ng ml-1. The median absolute prediction error was 12.9% with a bias of 1.2%. The prospective performance in the lorazepam evaluation group was better with the covariate adjusted model, but in the midazolam evaluation group it was not better than with the simple model. In all models a tendency to overestimate the lower plasma concentrations was observed. CONCLUSIONS: The pharmacokinetics of both lorazepam and midazolam were well described by a two-compartment model. Inclusion of alcohol abuse and age as covariates improved both models. PEEP was identified as an additional covariate for lorazepam, and the APACHE score for midazolam. For both drugs there is a large interindividual variability in their pharmacokinetics when used for long-term sedation in critically ill patients. However, the intra-individual variability is much lower for lorazepam.

Adolescent↗
PubMed2001

Hospital readmission: predicting the risk.

This approach focused on identifying specific variables that predict the likelihood of readmission. It involved clinical, utilization, and demographic variables that are generally available on hospital computer abstract databases. The approach included a process for identifying and comparing individual variables with the highest risk of readmission. It also contained a procedure for assembling risk populations including combinations of variables. The approach demonstrated the potential for using risk analysis to maximize the focus of clinical management on patient outcomes while reducing the amount of resources required for this process.

Adult↗
PubMed1981

Flow-volume curves in healthy non-smokers and in smokers.

Maximum expiratory flow-volume curves were recorded in lung healthy non-smokers and in smokers. Multiple linear regression analysis was performed with regard to sex, age, height and weight. The regressions for maximum expiratory flow at 50% and 25% of vital capacity (MEF50 and MEF25, respectively) on age were significantly different for non-smokers and smokers, in males as well as females, but the large scatter around the regression line resulted in more than 50% of presently studied smokers to fall within 1 SD of the reference values for non-smokers. A skew distribution of MEF25 around the mean was observed at ages above 60 years and so set an upper limit for the linear regression. Above 60 years no linear age dependence was found for MEF25. There was a minor reduction (2%) in the residual standard deviation of the peak expiratory flow (PEF), MEF50 and MEF25 regressions when height was added as an independent variable besides age, while the addition of weight did not reduce the scatter. We conclude that the inter-individual variability in MEF50 and MEF25 is relatively large even when sex and age are accounted for and that there is no further benefit in including height or weight in the regression equations. The discriminating ability of the MEF50 and MEF25 variables is small, indicated by considerable overlapping between non-smokers and smokers.

Adolescent↗
PubMed1982

Food and drug interactions.

A significant contribution could be made to patient care if nutritional biochemists, basic and clinical toxicologists, and pharmacologists in the various fields were to mount the studies needed to understand the nature of food-drug interactions. If only a small fraction of the 120 billion dollars per year spent for food or the 10 billion dollars expended for drugs were allocated for research in this area, advances might be made for the health of the nation. Changes in man's diet produce marked effects on drug metabolism. We know that changing a customary diet to one high in protein and low in carbohydrate increases the rates of metabolism of antipyrine and theophylline, and shifting to an isocaloric diet of low protein-high carbohydrate slows the rates of metabolism of these drugs. Presumably, high-protein-low carbohydrate diets in man resemble the animal studies with high protein diets that show enhanced hepatic drug metabolism. However, numerous studies emphasize the considerable individual variability to changes in human diets; some people have dramatic changes, whereas others exhibit little or no response. Similar individuality has been found in the response to enzyme induction by smoking. Numerous foods and food ingredients affect drug metabolism in human beings and apparently follow the same patterns as found in experimental animal studies with changes in the levels of cytochrome P-450 dependent monooxygenases in the liver and intestine. These changes presumably exert some protective action against environmental carcinogens, cocarcinogens, or promoters. Dietary modifications are brought about by use of weight-reducing diets, vegetarian diets, hospitalization, or post-operative regimens. These diets are often continued for long periods of time and it is likely they result in changes in the metabolism by the body of subsequently administered drugs or exposure to environmental chemicals. Methods are needed to measure inter-individual and inter-group differences in metabolism of foreign compounds in order to accurately assess dietary influences on drug metabolism and vice versa. Epidemiologic studies of rigorously selected human populations, coupled with the newer sensitive chemical analytical methods, will provide the necessary data base for these investigations.

Animals↗
PubMedDate not supplied

Occult intraosseous fracture: magnetic resonance appearance versus age of injury.

Twenty-two cases of occult intraosseous fracture in the region of the knee are presented. Occult intraosseous fractures have been incidentally detected in the magnetic resonance (MR) evaluation of the knee in the setting of a recent physical injury and normal radiographic studies. There is no unique mechanism of injury, but occult intraosseous fracture presumably results from direct impaction or axial overloading. MR shows speckled or band-like areas of low signal in the intramedullary space of the epiphyses, and occasionally, the adjacent metaphyses. In most cases, T2-weighted images show high signal in corresponding regions of variable size. The relative extent of high signal findings is shown to vary significantly with the age of injury. Individual variability within groups, however, precludes the actual prediction of lesion age on the basis of the MR appearance. Our observations provide indirect evidence that the findings on T2-weighted images resolve earlier than the corresponding findings on T1-weighted proton density images. The primary differential diagnosis in cases of occult intraosseous fracture is stress fracture. The diagnosis of occult intraosseous fracture may be important in explaining persistent pain after injury in otherwise normal knees.

Adolescent↗
PubMed2006

The evaluation of a novel conductometric device for the diagnosis of cystic fibrosis.

BACKGROUND: We evaluated the diagnostic discrimination of a new micro-flow cell device (Nanoduct) which measures sweat conductivity in situ at a regional referral centre for cystic fibrosis (CF). METHODS: The device was evaluated in comparison to the measurement of sweat chloride with the established quantitative pilocarpine iontophoresis test (QPIT) and extended in a number of patients to conductivity measurements in liquid sweat collected with the Macroduct system. Sweat testing was conducted simultaneously on patients referred for diagnostic sweat testing, on patients known to have CF and on adult volunteers. The intra-individual variability, the failure rate and diagnostic accuracy were determined. RESULTS: A total of 110 tests were performed on 100 individuals, 36 of whom had classical CF and six of whom had non-classical CF. The Nanoduct system produced a false negative result in one quarter of the patients with classical CF. Moreover, conductivity was negatively biased compared with chloride in this group. Repeat testing of the false negatives using a new batch of sensors and/or measuring conductivity in liquid sweat collected with the Macroduct device gave accurate diagnostic discrimination indicating that the original sensors were faulty. Photographic examination confirmed that a batch of sensors were defective. CONCLUSIONS: Our experience suggests that the prototype microflow cell conductometric device cannot be used for the diagnosis of CF due to the high false negative rate. As a consequence of this study, the manufacturers have implemented a pre-testing system to quality control the sensors prior to issue.

Adolescent↗
PubMed1995

[Contribution of computers to pharmacokinetics, Bayesian approach and population pharmacokinetics].

A major objective for pharmacokineticians is to help practicians to define drug administration protocols. Protocols are generally designed for all the patients but inter individual variability would need monitoring for each patient. Computers are widely used to determine pharmacokinetic parameters and to try to individualize drug administration. Severals examples are summarily described: terminal half-life determination by regression; model fitting to experimental data; Bayesian statistics for individual dose adaptation; population pharmacokinetic methods for parameter evaluation. These methods do not replace the pharmacokinetician thought but could make possible drug administration taking into account individual characteristics.

Antineoplastic Agents↗
PubMed1996

Pharmacokinetic and pharmacodynamic drug interactions with polypharmacotherapy of treatment-resistant affective and obsessive-compulsive disorders.

The concomitant use of multiple therapeutic agents in the treatment of resistant affective and obsessive-compulsive disorders increases the likelihood of a patient experiencing a drug-drug interaction at either the pharmacokinetic or pharmacodynamic level. Recent developments in molecular biology and pharmacogenetics have allowed the identification of which psychotropic agents are substrates, inducers, or inhibitors of specific hepatic cytochrome P450 isozymes. This increases the predictability of which drug combinations may lead to kinetic interactions. However the individual variability in kinetic disposition and pharmacodynamic response still limits the predictability of a drug-drug interaction in an individual patient treated with polytherapy.

Antidepressive Agents↗
PubMed2000

How do types of employment relate to health indicators? Findings from the second European survey on working conditions.

STUDY OBJECTIVE: To investigate the associations of various types of employment with six self reported health indicators, taking into account the part played by demographic variables, individual working conditions and four ecological indicators at the country level. DESIGN: Cross sectional survey (structured interview) of a sample of the active population of 15 European countries aged 15 years or over. Main independent variables were nine types of employment categorised as follows: small employers, full and part time permanent employees, full and part time fixed term employees, full and part time sole traders and full and part time temporary contracts. Main outcome measures were three self reported health related outcomes (job satisfaction, health related absenteeism, and stress) and three self reported health problems (overall fatigue, backache, and muscular pains). Logistic regression and multilevel models were used in the analyses. SETTING: 15 countries of the European Union. PARTICIPANTS: 15 146 employed persons aged 15 or over. MAIN RESULTS: Precarious employment was consistently and positively associated with job dissatisfaction but negatively associated with absenteeism and stress (as compared with full time permanent workers). Fatigue, backache and muscular pains also tended to be positively associated with precarious employment, particularly with full time precarious employment. Small employers reported high percentages of stress and fatigue, but absenteeism was relatively low. Sole traders generally reported high percentages of all outcomes, except for absenteeism, which was low. For each type of employment (except temporary contracts), full time workers tended to report worse health outcomes than part time workers. Patterns were generally consistent across countries. Associations persisted after adjustment for individual level working conditions and were not modified by country level variables. CONCLUSIONS: This study is the first to examine the relations between various types of employment and six health related indicators for all 15 member states of the European Union. Suggestive patterns worthy of further exploration have been found. Standardised definitions of types of underemployment and health related outcomes, more potent epidemiological designs and the inclusion of socioeconomic information (for example, social security systems, incapacity benefit schemes) at the regional level are proposed for inclusion in further research.

Adolescent↗
PubMed2001

Adolescent drug use in Mexico and among Mexican American adolescents in the United States: environmental influences and individual characteristics.

The authors compared high school students in Baja California Norte (BCN), Mexico (n = 775), with Mexican American students in Los Angeles (LA), California (n = 516). The students' use of cigarettes, alcohol, marijuana, cocaine, inhalants, and other illicit drugs were compared, because these vary by gender, country, and their age of first drug use and are influenced by demographic variables, individual characteristics, and environmental influences. More BCN students than LA students had used alcohol, but more LA than BCN students had used illicit drugs and initiated drug use earlier. When demographic variables were influential, they were most powerful and increased the risk for drug use more than environmental factors or individual characteristics. Environmental factors were most influential for boys' drug use, whereas environmental and demographic variables were most influential for girls' drug use.

Adolescent↗
PubMed1988

A longitudinal study of urinary creatinine and creatinine clearance in normal subjects. Race, sex, and age differences.

The purpose of this study was to examine the variability of 24-hour urinary and serum creatinine levels and creatinine clearance in normal subjects and to develop nomograms for assessing the adequacy of 24-hour urine collections. The data were from a longitudinal research program examining biochemical, hormonal, and hemodynamic parameters in normal subjects. Bloods and 24-hour urine specimens were collected at yearly intervals from 144 people over 9 years, and from an additional 110 over 4 years. The subjects were originally distributed equally by sex, race (black, white), blood pressure (three groups within the normal range), and age (three groups). Men had 33% higher urine creatinines per weight than females (P less than 0.001). Because they only had 8% higher creatinine clearance per weight they also exhibited 21% higher serum creatinine. Blacks had 5% higher urine creatinine per weight than whites, perhaps reflecting greater muscle mass, but their serum creatinines were not different from those of whites, reflecting a 5% higher creatinine clearance by weight than whites (P less than 0.01). Interestingly, older black men (age greater than 60 years) had 12% lower urine creatinine/weight than younger black men (P less than 0.001). They also had 13% lower creatinine clearance by weight, resulting in no net difference in serum creatinine. The intraindividual variability in urine creatinine excretion averaged 15% and did not differ between blacks and whites and men and women. The within individual variability in serum creatinine and creatinine clearance averaged 14 and 20%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1988

Prediction of neuroleptic on-drug response in schizophrenic in-patients by EEG.

The subjects were 34 acutely ill in-patients who met the RDC criteria of schizophrenic psychosis, and 4 EEGs were recorded from each patient before, 2 h and 24 h after oral intake of a single dose of 150 mg perazine, and on the 28th day of the neuroleptic treatment period. As a criterion of clinical response a decrease of at least 66% in the schizophrenia-specific sum score of the Brief Psychiatric Rating Scale on day 28 relative to the baseline value was decided upon. The EEGs were assessed using a newly developed procedure which takes into consideration 4 derivations simultaneously. As we tried to search out EEG variables with predictive value the statistical data analysis underlying our findings should largely by regarded as exploratory. Independent of day, responders (R) showed a tendency towards more low voltage desynchronized epochs (non-A stage) than non-responders (NR). Thus, R exhibited a higher degree of dynamic variability or a broader range of control of the spontaneous vigilance fluctuation (dynamic lability) than NR (dynamic rigidity). Furthermore, R and NR differed with respect to their time-dependent changes of non-A epoch frequencies before medication. While R showed a monotonous increase which is typical for normals, NR did not. Because of considerable inter-individual variability these group differences could not be used for individual prediction of the therapy response. By means of a qualitative data analysis R could be distinguished from NR with regard to various test dose-induced changes of the topographical distribution of absolute alpha power. All the group differentiating variables showed a time course of the same kind: R showed a prompt and ample deflection and the same recovery of baseline; NR, in contrast, showed no significant deflections at all. These findings are in line with the results concerning the dynamics of vigilance and certain claims of earlier authors according to which EEG changeability should be decisive for therapeutic outcome.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed2006

Electrophysiological and information processing variability predicts memory decrements associated with normal age-related cognitive decline and Alzheimer's disease (AD).

Recent theoretical models of cognitive aging have implicated increased intra-individual variability as a critical marker of decline. The current study examined electrophysiological and information processing variability and memory performance in normal younger and older controls, and older adults with Alzheimer's disease (AD). It was hypothesized that higher levels of variability would be indicative of age-related and disease-related memory deficits. Results indicated both implicit and explicit memory deficits associated with AD. Consistent with previous research, behavioral speed and variability emerged as sensitive to age- and disease-related change. Amplitude variability of P3 event-related potentials was a unique component of electrophysiological activity and accounted for significant variance in reaction time (RT) mean and RT standard deviation, which in turn accounted for significant variance in memory function. Results are discussed in light of theoretical and applied issues in the field of cognitive aging.

Adult↗
PubMed2006

Cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder.

A growing body of literature has examined the cognitive effects of immediate-release methylphenidate in children with attention-deficit/hyperactivity disorder (ADHD). However, a clear understanding of the types and magnitude of such effects are difficult to discern from such a large and varied collection of published reports. This review evaluated a total of 40 relevant placebo-controlled studies published since Rapport and Kelly's [1993. Psychostimulant effects on learning and cognitive function. In: Matson, J.L. (Ed.), Handbook of Hyperactivity in Children. Allyn & Bacon, Boston, pp. 97-136] original review of cognitive effects of methylphenidate in children with ADHD. Of these published studies, 63.5% identified some improvement in cognitive function following methylphenidate treatment. Methylphenidate improved performance on saccadic eye movement, planning/cognitive flexibility, attention/vigilance, and inhibitory control tasks in 83.3%, 71.4%, 70.6%, and 69.7% of studies, respectively. A total 58.3% and 50% of studies that evaluated the effect of methylphenidate on tasks of memory and working memory/divided attention, respectively, noted improvement. Variability of findings across studies may be explained by differential effects of methylphenidate on brain function, intra- and inter-individual variability in medication response, methodological limitations, and problems associated with repeated neuropsychological assessment and metric properties of commonly utilised neuropsychological instruments.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

Predictors of physician frustration in the care of patients with rheumatological complaints.

Recent studies of the doctor-patient relationship have shown that certain patients are perceived as frustrating or difficult by their doctors; however, little is known about the characteristics of these patients that elicit this dissatisfaction. As part of a larger study of rheumatology clinic patients with fibromyalgia or rheumatoid arthritis (N = 68) we used stepwise multiple regression to select the factors most associated with physician frustration while controlling for the effects of other variables. Variable domains included demographics, psychiatric diagnoses, personality factors, functional disability, disease state, and trauma history. These domains as well as individual variables within these domains were systematically evaluated for their unique contribution to the prediction of physician frustration as measured by the Difficult Doctor-Patient Relationship Questionnaire (DDPRQ). Initial bivariate correlates of physician frustration included marital status, current dysthymia and agoraphobia, lifetime panic disorder and obsessive-compulsive disorder, adult rape and physical abuse, somatization disorder, physical and social disability, the presence of fibromyalgia, as well as neuroticism, illness impact, and perceived loss of control. The best multivariable model for estimating frustration magnitude included somatization disorder, perception of lack of control over illness, and a lifetime history of obsessive-compulsive disorder. These factors explained 48% of the variance in DDPRQ score. Physicians in this study were most frustrated with patients who had ongoing preoccupation with multiple medically unexplained physical symptoms as well as the perception of greater impact and lack of control over their illness. These findings suggest that treatment of somatization in patients with chronic symptoms may decrease physician frustration.

Adult↗
PubMed1987

Examination of two issues concerning functional gain measurements.

The test-retest variability of aided sound-field thresholds and the feasibility of using corrected 2-cm3 coupler gain values to predict individual functional gain were examined. Test-retest data were used to generate critical differences (in dB) for statistical significance between two aided sound-field thresholds. To be significantly different at the .05 level, two aided thresholds would have to differ by greater than 15 dB. Functional gain and 2-cm3 coupler gain were compared for 20 subjects using careful measurement procedures. Individual variability in the difference between functional gain and 2-cm3 coupler gain was reduced substantially from previous studies and indicates that corrected coupler gain measurements may have some clinical utility.

Adult↗
PubMed1994

Follicle stimulating hormone (FSH) dynamics of low dose step-up ovulation induction with FSH in patients with polycystic ovary syndrome.

Pharmacodynamics of follicle stimulating hormone (FSH) were studied during low dose step-up gonadotrophin therapy in patients with polycystic ovary syndrome (PCOS). To obtain stable levels of FSH, Metrodin was administered i.v. By making daily determinations, the FSH concentration was slowly increased in steps of approximately 1 IU/l. A total of 16 patients were treated for a maximum of three treatment cycles. Out of 38 treatment cycles, in 26 (68%) a single dominant follicle developed. The overall ovulation rate was 78%. FSH concentrations were evaluated with regard to intra- and interindividual variability of the FSH threshold and with regard to the relationship between FSH concentrations, FSH dose and treatment outcome. The high variability of the FSH threshold, ranging from 5.7 to 12 IU/l, appeared to be mainly a function of inter-individual variability. Higher FSH concentrations were associated with multifollicular growth as opposed to monofollicular growth, whereas the increases in concentration from a substimulating to a stimulating level were not. Multifollicular growth might thus be associated with a higher elevation of FSH concentration above the threshold. Different patterns of FSH concentration in the course of the growth phase of the dominant follicle in mono- compared to multifollicular cycles suggested a difference in the effect of endogenous FSH on the plasma concentration. Endogenous feedback on FSH release may therefore still play a role during treatment with exogenous FSH.

Adult↗
PubMed2006

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

BACKGROUND: Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first-line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O-desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N-desmethylvenlafaxine (NDV). OBJECTIVES: The aim of this study was to assess whether the O-demethylation phenotype of V has an impact on the pharmacokinetics and clinical outcome. METHOD: In 100 patients treated with V, serum concentrations of V, ODV and NDV and the ratios of concentrations ODV/V as a measure of O-demethylation were determined. Individuals exhibiting abnormally high or low metabolic ratios of ODV/V were selected for genotyping. Clinical effects were monitored by the Clinical Global Impressions Scale and side effects by the UKU (Udvalg for Kliniske Undersogelser Side Effect Rating Scale) rating scale. RESULTS: There was wide inter-individual variability in ODV/V ratios. The median ratio ODV/V was 1.8 and the 10th and 90th percentiles 0.3 and 5.2, respectively. Individuals with ODV/V ratios below 0.3 were all identified as poor metabolizers (PM), with the genotypes *6/*4 (n = 1), *5/*4 (n = 2) or *6/*6 (n = 1). Individuals with ratios above 5.2 were all ultra rapid metabolizers (UM, n = 6) due to gene duplications. Five individuals with intermediate metabolic activity (ODV/V, 1.1 +/- 0.8) were heterozygotes with the CYP2D6*4 genotype, and one patient with an intermediate metabolic ratio of 4.8 had the genotype *4/2x*1. Clinical outcome measurements revealed that patients with ODV/V ratios below 0.3 had more side effects (P < 0.005) and reduced serum concentrations of sodium (P < 0.05) in comparison with other patients. Gastrointestinal side effects, notably nausea, vomiting and diarrhoea were the most common. Differences in therapeutic efficacy were not significant between the different phenotypes. CONCLUSION: The O-demethylation phenotype of V depends strongly on the CYP2D6 genotype. A PM phenotype of CYP2D6 increases the risk of side effects.

Adolescent↗