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PubMedDate not supplied

Inferring systemic exposure from a pharmacokinetic screen: model-free and model-based approaches.

To infer patterns of average systemic exposure and to estimate individual exposures in phase III clinical trials of a new anxiolytic, two statistical methodologies were applied and compared: non-linear mixed-effect modelling, and a model-free approach based on quartiles of dose-normalized plasma concentrations of the drug. Although the model-based approach provides more quantitative insight about relationships between average exposure and demographic covariates, the model-free approach provides qualitatively similar results about average clearance and quantitatively similar results about individual exposures, and the model-free approach is easy and inexpensive to implement.

Adult↗
PubMed2003

Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter.

BACKGROUND: Despite dramatic declines in children's blood lead concentrations and a lowering of the Centers for Disease Control and Prevention's level of concern to 10 microg per deciliter (0.483 micromol per liter), little is known about children's neurobehavioral functioning at lead concentrations below this level. METHODS: We measured blood lead concentrations in 172 children at 6, 12, 18, 24, 36, 48, and 60 months of age and administered the Stanford-Binet Intelligence Scale at the ages of 3 and 5 years. The relation between IQ and blood lead concentration was estimated with the use of linear and nonlinear mixed models, with adjustment for maternal IQ, quality of the home environment, and other potential confounders. RESULTS: The blood lead concentration was inversely and significantly associated with IQ. In the linear model, each increase of 10 microg per deciliter in the lifetime average blood lead concentration was associated with a 4.6-point decrease in IQ (P=0.004), whereas for the subsample of 101 children whose maximal lead concentrations remained below 10 microg per deciliter, the change in IQ associated with a given change in lead concentration was greater. When estimated in a nonlinear model with the full sample, IQ declined by 7.4 points as lifetime average blood lead concentrations increased from 1 to 10 microg per deciliter. CONCLUSIONS: Blood lead concentrations, even those below 10 microg per deciliter, are inversely associated with children's IQ scores at three and five years of age, and associated declines in IQ are greater at these concentrations than at higher concentrations. These findings suggest that more U.S. children may be adversely affected by environmental lead than previously estimated.

Child, Preschool↗
PubMed2026

Does Timing Matter? Age of First Mobile Phone Acquisition and Psychological Outcomes in Middle and Late Adolescence.

The age at which adolescents acquire their first smartphone has decreased markedly in recent years; however, evidence on its long-term effects on psychosocial adjustment remains limited. This study investigated whether age at first mobile phone acquisition is associated with psychosocial functioning in middle and late adolescence, including social integration and competence, emotion regulation difficulties, disordered eating behaviors and problematic social media use (PSMU). The sample comprised 1179 adolescents aged 15-17 years (53.8% female). Linear regression and generalized additive mixed models were used to examine both linear and nonlinear associations, adjusting for age, gender and school clustering. Earlier smartphone acquisition was linearly but weakly associated with greater emotion regulation difficulties, disordered eating and PSMU, even after adjustment for covariates. In contrast, associations with social integration and competence were nonlinear: acquiring a first smartphone between ages 6 and 10 or after age 13 was associated with lower social integration in adolescence, whereas acquisition between ages 11 and 13 was linked to higher social functioning. These findings suggest that the developmental timing of first smartphone access shows a modest association with subsequent psychosocial functioning during middle and late adolescence. Focusing on the timing of access, alongside other demographic and contextual factors, may contribute to a better understanding of digital influences on adolescent well-being.

Humans↗
PubMed2001

Repeated-measures models to evaluate a hepatitis B vaccination programme.

In 1985-1986, a hepatitis B vaccination programme was conducted in a Belgian institution for the mentally handicapped. A group of 97 residents was followed up for 11 years in order to characterize the long-term persistence of hepatitis B antibodies after vaccination. This paper proposes the use of linear mixed-effects models to account for serial correlation and between-individual heterogeneity in the data, while adjusting the analysis for various individual characteristics and important risk factors in the response to vaccination. We propose several model building strategies and focus on the prediction of future levels of antibodies.

Belgium↗
PubMed2003

Population pharmacokinetics of temozolomide and metabolites in infants and children with primary central nervous system tumors.

PURPOSE: To construct a population pharmacokinetic model for temozolomide (TMZ), a novel imidazo-tetrazine methylating agent and its metabolites MTIC and AIC in infants and children with primary central nervous system tumors. METHODS: We evaluated the pharmacokinetics of TMZ and MTIC in 39 children (20 boys and 19 girls) with 132 pharmacokinetic studies (109 in the training set and 23 in the validation set). The median age was 7.1 years (range 0.7 to 21.9 years). Children received oral TMZ dosages ranging from 145 to 200 mg/m(2) per day for 5 days in each course of therapy. Serial plasma samples were collected after the first and fifth doses of the first and third courses. Approximately eight plasma samples were collected up to 8 h after each dose, and assayed for TMZ, MTIC, and AIC by HPLC with UV detection. A one-compartment model was fitted to the TMZ and metabolite plasma concentrations using maximum likelihood estimation. Covariates, including demographics and biochemical data were tested for their effects on TMZ clearance (CL/F) and MTIC AUC utilizing a two-stage approach via linear mixed-effects modeling. RESULTS: The population mean (inter- and intrapatient variability expressed as %CV) for the pharmacokinetic parameters (based on the training set) were as follows: TMZ CL/F 5.4 l/h (53.4, 17.5), Vc/F 14.0 l (48.5, 39.2), C(max) 9.1 mg/l (20.8, 29.1), and MTIC AUC 1.0 microg/ml.h (13.9, 30.0). Covariate analysis showed that increasing age and body surface area (BSA) were associated with a significant increases in TMZ CL, Vc, and C(max) ( P<0.05), and that increasing age was associated with significant decreases in TMZ and MTIC AUC. Indicators of liver and renal function were not significantly associated with TMZ pharmacokinetics or MTIC AUC. The final model with the significant covariates was validated using the remaining 23 pharmacokinetic studies. CONCLUSIONS: This study extends previous work done in adults, and identified BSA and age as covariates that account for variability in TMZ disposition in infants and children with primary CNS malignancies.

Adolescent↗
PubMedDate not supplied

Mixed-effects regression models for studying the natural history of prostate disease.

Although prostate cancer and benign prostatic hyperplasia are major health problems in U.S. men, little is known about the early stages of the natural history of prostate disease. A molecular biomarker called prostate specific antigen (PSA), together with a unique longitudinal bank of frozen serum, now allows a historic prospective study of changes in PSA levels for decades prior to the diagnosis of prostate disease. Linear mixed-effects regression models were used to test whether rates of change in PSA were different in men with and without prostate disease. In addition, since the prostate cancer cases developed their tumours at different (and unknown) times during their periods of follow-up, a piece-wise non-linear mixed-effects regression model was used to estimate the time when rapid increases in PSA were first observable beyond the background level of PSA change. These methods have a wide range of applications in biomedical research utilizing repeated measures data such as pharmacokinetic studies, crossover trials, growth and development studies, aging studies, and disease detection.

Aged↗
PubMed2001

Comparison of five experimental pain tests to measure analgesic effects of alfentanil.

BACKGROUND: Several experimental pain models have been used to measure opioid effects in humans. The aim of the current study was to compare the qualities of five frequently used experimental pain tests to measure opioid effects. METHODS: The increase of electrical, heat, and pressure pain tolerance and the decrease of ice-water and ischemic pain perception was determined at baseline and at four different plasma concentrations of alfentanil (n = 7) administered as target controlled infusion or placebo (n = 7). A linear mixed-effects modeling (NONMEM) was performed to detect drug, placebo, and time effect as well as interindividual and intraindividual variation of effect. RESULTS: Only the electrical, ice-water, and pressure pain tests are sensitive to assess a concentration-response curve of alfentanil. At a plasma alfentanil concentration of 100 ng/ml, the increase in pain tolerance compared with baseline was 42.0% for electrical pain, 22.2% for pressure pain, and 21.7% for ice-water pain. The slope of the linear concentration-response curve had an interindividual coefficient of variation of 58.3% in electrical pain, 35.6% in pressure pain, and 60.0% in ice-water pain. The residual error including intraindividual variation at an alfentanil concentration of 100 ng/ml was 19.4% for electrical pain, 6.1% for pressure pain, and 13.0% for ice-water pain. Electrical pain was affected by a significant placebo effect, and pressure pain was affected by a significant time effect. CONCLUSION: Electrical, pressure, and ice-water pain, but not ischemic and heat pain, provide significant concentration-response curves in the clinically relevant range of 200 ng/ml alfentanil or lower. The power to detect a clinically relevant shift of the curve is similar in the three tests. The appropriate test(s) for pharmacodynamic studies should be chosen according to the investigated drug(s) and the study design.

Adult↗
PubMed2005

Modelling the progression towards duodenal cancer among patients with familial polyposis on the basis of two different score profiles.

The objective was to design a method that considers, on clinical arguments, the likely existence of patient subgroups with different evolution profiles. The method is applied in familial adenomatous polyposis to predict the proportion of patients that would develop duodenal cancer. A subject-specific linear mixed-effects model was elaborated to explicitly model heterogeneity in regression parameters. The estimates of the parameters were obtained by Bayesian inference using Gibbs sampling. The application concerned two potential polyposis subgroups: stable-state and progressive. Each patient's score was expressed in function of his putative subgroup, the reference subgroup mean score (intercept), the rate of change (slope), and time. The estimated proportion of stable-state patients was 35%. In progressive-state patients, the estimated annual score increase was 0.38 (95% CI: 0.27-0.48). The regression model predicted that the proportion of patients with a score > or = 9 is near 43% at age 60 (36-50%) and 50% at 70 (43-57%). The method indicates the evolution profile of each subject, which facilitates therapeutic decisions. The modelling may be extended to other more complex situations with several subgroups, with different change rates, or with various genetic or therapeutic profiles.

Adenomatous Polyposis Coli↗
PubMed1999

Subject-by-formulation interaction in determinations of individual bioequivalence: bias and prevalence.

PURPOSE: 1. To determine properties of the estimated variance component for the subject-by-formulation interaction (sigma D2) in investigations of individual bioequivalence (IBE), and 2, to evaluate the prevalence of interactions in replicate-design studies published by FDA. METHODS: Four-period crossover studies evaluating IBE were simulated repeatedly. Generally, the true bioequivalence of the two formulations, including sigma D2 = 0, was assumed. sigma D2 was then estimated in a linear mixed-effect model by restricted maximum likelihood (REML). The same method was applied for estimating sigma D2 for the data sets of FDA. RESULTS: 1. sigma D estimated by REML was positively biased. The bias and dispersion of the estimated sigma D increased approximately linearly with the estimated within-subject standard deviation for the reference formulation (sigma WR). Only a small proportion of the estimated sigma D exceeded the estimated sigma WR. 2. Distributions of the estimated sigma D were evaluated. At sigma WR = 0.30, a level of estimated sigma D = 0.15 was exceeded, by random chance, with a probability of about 25%. 3. Importantly, the behaviour of the sigma D2 values estimated from the FDA data sets was similar to that exhibited by the simulated estimates of sigma D2 which were generated under the conditions of true bioequivalence. CONCLUSIONS: 1. sigma D estimated by REML is biased; the bias increases proportionately with the estimated sigma WR. Consequently, exceeding a fixed level of sigma D (e.g., 0.15) does not indicate substantial interaction. 2. The data sets of FDA are compatible with the hypothesis of sigma D2 = 0. Consequently, they do not demonstrate the prevalence of subject-by-formulation interaction. Therefore, it could be sufficient and reasonable to evaluate bioequivalence from 2-period crossover studies.

Computer Simulation↗
PubMed2000

Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males.

Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine, (-)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined. At least six subjects were studied at each dose level, with each subject studied in three of five periods, receiving two different doses of racemic dOTC and one placebo dose. Plasma and urine drug concentrations were measured for 24 to 48 h after each dose. Pharmacokinetic models were fitted to the plasma concentrations of (+)dOTC and (-)dOTC using maximum likelihood and maximum a posteriori Bayesian procedures. Statistical hypothesis testing was by nonparametric analysis of variance (where possible) and, when tests with dose as a covariate were performed, by linear mixed-effects modeling. The mean terminal elimination half-lives for (+)dOTC and (-)dOTC were 15.3 h (coefficient of variation [CV], 28%) and 11.3 h (CV, 43%), respectively (P<0.05). The mean CV for total oral clearance (liter/h/65 kg) was 17.5 (25%) for (+)dOTC and 21.5 (24%) for (-)dOTC; for oral steady-state volume of distribution (liter/65 kg), values were 61.8 (24%) for (+)dOTC and 34.1 (33%) for (-)dOTC (P<0.05). The mean CV for renal clearance (liter/h/65 kg) of (+)dOTC was 10.4 (19%) and for (-)dOTC was 13.6 (20%) (P<0.05). There was no significant effect of dose size on the pharmacokinetics of racemic dOTC. All doses were well tolerated, and no serious adverse events or laboratory abnormalities were observed.

Adolescent↗
PubMed2005

Statistical modelling of formaldehyde occupational exposure levels in French industries, 1986-2003.

Occupational exposure databanks (OEDBs) have been cited as sources of exposure data for exposure surveillance and exposure assessment in epidemiology. In 2003, an extract was made from COLCHIC, the French national OEDB, of all concentrations of formaldehyde. The data were analysed with extended linear mixed-effects models in order to identify influent variables and elaborate a multi-sector picture of formaldehyde exposures. Respectively, 1401 and 1448 personal and area concentrations were available for the analysis. The fixed effects of the personal and area models explained, respectively, 57 and 53% of the total variance. Personal concentrations were related to the sampling duration (short-term higher than TWA levels), decreased with the year of sampling (-9% per year) and were higher when local exhaust ventilation was present. Personal levels taken during planned visits and for occupational illness notification purpose were consistently lower than those taken during ventilation modification programmes or because the hygienist suspected the presence of significant risk or exposure. Area concentrations were related to the sampling duration (short-term higher than TWA levels), and decreased with the year of sampling (-7% per year) and when the measurement sampling flow increased. Significant within-facility (correlation coefficient 0.4-0.5) and within-sampling campaign correlation (correlation coefficient 0.8) was found for both area and personal data. The industry/task classification appeared to have the greatest influence on exposure variability while the sample duration and the sampling flow were significant in some cases. Estimates made from the models for year 2002 showed elevated formaldehyde exposure in the fields of anatomopathological and biological analyses, operation of gluing machinery in the wood industry, operation and monitoring of mixers in the pharmaceutical industry, and garages and warehouses in urban transit authorities.

Air Pollutants, Occupational↗
PubMed2001

Chronic hyperlactatemia in HIV-infected patients taking antiretroviral therapy.

OBJECTIVE: To determine the prevalence, course and risk factors for hyperlactatemia in HIV-infected patients. DESIGN: A prospective, longitudinal study of venous lactate concentrations over an 18-month period in 349 participants of the Western Australian HIV Cohort Study. RESULTS: In 516 patient-years of observation, two patients experienced severe fulminant lactic acidosis (lactate > 5 mmol/l) and hepatic steatosis attributable to nucleoside analogue reverse transcriptase inhibitors (NRTI). A further five patients with lesser elevations of lactate (2.8-4.1 mmol/l) but with symptoms of nausea or abdominal discomfort and evidence of hepatic steatosis had NRTI therapy revised, with relief of symptoms and a fall in lactate levels. Most remaining patients on highly active antiretroviral therapy (HAART) had mild, chronic, asymptomatic hyperlactatemia, with mean lactate level between 1.5 mmol/l and 3.5 mmol/l most commonly. Longitudinal data was analysed in a non-linear mixed effects growth model which indicated that average lactate levels rose after the start of HAART but tended to stabilise at low-grade elevation, with an average 0.23 mmol/l greater long term level in stavudine users compared with zidovudine users (p < 0.01). A multiple linear regression model showed that the association between stavudine and higher lactate level was not confounded by longer duration of total NRTI exposure. Risk of hyperlactatemia was not significantly associated with use of other NRTIs, protease inhibitors, non-nucleoside analogue reverse transcriptase inhibitors or multiple immunological and virological factors in multivariate analyses. CONCLUSIONS: Chronic, compensated, asymptomatic hyperlactatemia is common in patients taking HAART. Decompensated, life-threatening lactic acidosis/hepatic steatosis is rare. Treatment with stavudine appears to be the predominant risk factor for development of chronic hyperlactatemia.

Acidosis, Lactic↗
PubMed2006

Using plasma topotecan pharmacokinetics to estimate topotecan exposure in cerebrospinal fluid of children with medulloblastoma.

The purpose of this study was to estimate ventricular cerebrospinal fluid (vCSF) topotecan lactone (TPT) exposures in pediatric medulloblastoma patients from plasma concentration-time data by using a pharmacokinetic (PK) model. We studied children with high-risk medulloblastoma who received pharmacokinetically guided TPT (target plasma area under the concentration-time curve [AUC], 120-160 ng/ml-h) and obtained serial vCSF samples to assess TPT exposure. Population pharmacokinetic parameters were determined by using linear mixed-effects modeling via the two-stage approach. We simulated TPT vCSF exposure duration at plasma TPT AUC values of 120 to 200 ng/ml-h and determined percentages of studies meeting or exceeding the vCSF exposure duration threshold (EDT) of 1 ng/ml for 8 h. We then used bootstrap methods to estimate variability in vCSF EDT. Eighteen PK studies were conducted in six patients (median age, 4.8 years). In these patients, seven of nine studies attaining target plasma TPT AUC achieved the vCSF EDT. Given a plasma TPT AUC of 120 ng/ml-h, the median percentage of results meeting or exceeding EDT was 78% (95% CI, 61%-100%). One patient (four studies) with tumor blockage of CSF flow, which can alter CSF pharmacokinetics, was removed, and the bootstrap analysis was repeated. In this subset, a median 93% (95% CI, 79%-100%) of studies achieved vCSF EDT. Increasing plasma TPT AUC values resulted in increased ability to achieve vCSF EDT. We demonstrated that a plasma PK model could estimate vCSF TPT concentrations. Further, our results indicate that the TPT vCSF EDT can be achieved in more than 80% of studies targeted to a plasma TPT AUC of 120 ng/ml-h.

Adolescent↗
PubMed2000

Linear mixed-effect multivariate adaptive regression splines applied to nonlinear pharmacokinetics data.

In a frequently performed pharmacokinetics study, different subjects are given different doses of a drug. After each dose is given, drug concentrations are observed according to the same sampling design. The goal of the experiment is to obtain a representation for the pharmacokinetics of the drug, and to determine if drug concentrations observed at different times after a dose are linear in respect to dose. The goal of this paper is to obtain a representation for concentration as a function of time and dose, which (a) makes no assumptions on the underlying pharmacokinetics of the drug; (b) takes into account the repeated measure structure of the data; and (c) detects nonlinearities in respect to dose. To address (a) we use a multivariate adaptive regression splines representation (MARS), which we recast into a linear mixed-effects model, addressing (b). To detect nonlinearity we describe a general algorithm that obtains nested (mixed-effect) MARS representations. In the pharmacokinetics application, the algorithm obtains representations containing time, and time and dose, respectively, with the property that the bases functions of the first representation are a subset of the second. Standard statistical model selection criteria are used to select representations linear or nonlinear in respect to dose. The method can be applied to a variety of pharmacokinetics (and pharmacodynamic) preclinical and phase I-III trials. Examples of applications of the methodology to real and simulated data are reported.

Algorithms↗
PubMed1994

A comparison of normal and nonnormal mixed models for number of lambs born in Norwegian sheep.

A comparison of linear (LM), threshold (TM), and Poisson (PM) mixed models for genetic analysis of number of lambs born (NLB) from 1-yr-old ewes was conducted using 37,718 and 18,633 records of two Norwegian breeds, Dala and Spaelsau, respectively. Models fitted included flock-year as a fixed effect and the random effect of sire. In the Poisson model, the residual variation was assumed to be Poisson, whereas it was normal in LM and multinomial in TM. The models were compared with respect to goodness of fit, predictive ability, and ranking of sires. Goodness of fit and predictive ability were assessed via the mean squared error and the correlation between observed NLB and fitted (predicted) values. Predictive ability was evaluated by estimating effects of sire and flock-year using a random half of the data and then using these estimates to predict records on the other half of the data. The heritability of NLB for Dala was estimated to be .20, .39, and .08 with LM, TM, and PM, respectively. For Spaelsau, corresponding estimates were .12, .26, and .00, respectively. In the PM, problems of low or zero estimates of sire variances were encountered. Hence, an alternative sire variance (PM-L) was approximated from the heritability estimated on the outward scale by REML. All models performed similarly with respect to goodness of fit, predictive ability, and ranking of sires. The TM was very slightly better for both breeds, but the PM and PM-L seemed clearly poorer than TM and LM. An approximate test rejected the hypothesis that the conditional distribution of NLB was Poisson.

Animals↗
PubMed2007

Bacterial flora and risk of infection of the ovine teat duct and mammary gland throughout lactation.

We collected samples of teat duct material and mammary secretion from ewes in three farms (flock A, polyparous n=7; flock B, polyparous n=6, primiparous n=4; flock C, polyparous n=4): 14 samples immediately after lambing (before sucking of lambs), 244 samples during the suckling period and 156 samples during the milking period. Conventional bacteriological techniques were used. The results were modeled using survival analysis, initially by the Kaplan-Meier method and then by the Cox Proportional Hazards method. Then, we calculated the minimum true risk of an "at-risk" teat or mammary gland being infected and analyzed these data with STATA using the GLLAMM program for Generalised Linear Latent and Mixed Models. During the suckling period, bacteria were isolated from 52 (21%) duct material and 19 (8%) secretion samples; respective results for the milking period were 20 (13%) and 9 (6%). There was an increased risk of duct rather than secretion samples being infected (P<0.001). There was a significant difference among flocks in isolating bacteria from duct (P<0.01) or secretion (P<0.001) samples during suckling period, but not during hand-milking period (P>0.4 and 0.1, respectively). There were no differences between isolation of bacteria from duct (P>0.5) or secretion (P>0.7) samples among primiparous and polyparous animals. Most bacterial isolates were staphylococci. Persistent isolation of the same bacterial species from duct material samples obtained from a particular ewe was recorded with five Staphylococcus spp. and two Mannheimia haemolytica isolates. The results indicate that infections of the teat duct can take place easily; however, not all infections result to infection of the mammary gland. The results support experimental evidence that defence mechanisms of the healthy teat are able to limit the infection. Maintenance of healthy teats contributes to effective defence mechanisms, and coupled with minimal infections of the teat duct, would contribute to the prevention of mastitis in ewes.

Animals↗
PubMed2005

Tramadol disposition in the very young: an attempt to assess in vivo cytochrome P-450 2D6 activity.

BACKGROUND: Tramadol is potentially a very useful pain relief medication in neonates and infants. It is primarily metabolized into O-demethyl tramadol (M1) by CYP2D6. Data concerning tramadol disposition and CYP2D6 activity in young infants are not available. METHODS: A population pharmacokinetic analysis of tramadol and M1 time-concentration profiles was undertaken using non-linear mixed-effects models (NONMEM), based on newly collected data on tramadol and M1 time-concentration profiles in neonates and young infants (n=20) and published studies on intravenous tramadol in children and adults. M1 formation served as a surrogate for CYP2D6 activity. RESULTS: Tramadol clearance was described using a two-compartment linear model with zero-order input and first-order elimination. Clearance increased from 25 weeks post-conception age (PCA) (5.52 litre h(-1) [70 kg](-1)) to reach 84% of the mature value by 44 weeks PCA (standardized to a 70 kg adult using allometric '1/4 power' models). The central volume of distribution decreased from 25 weeks PCA (256 litre [70 kg](-1)) to reach 120% of its mature value by 87 weeks PCA. Formation clearance to M1 contributed 43% of tramadol clearance, but had no relationship with PCA. There was a weak non-linear relationship between PCA and M1 metabolite clearance. CONCLUSIONS: Maturational clearance of tramadol is almost complete by 44 weeks PCA. A target concentration of 300 microg litre(-1) is achieved after a bolus of tramadol hydrochloride 1 mg kg(-1) and can be maintained by infusion of tramadol hydrochloride 0.09 mg kg(-1) h(-1) at 25 weeks PCA, 0.14 mg kg(-1) h(-1) at 30 weeks PCA, 0.17 mg kg(-1) h(-1) at 35 weeks PCA, 0.18 mg kg(-1) h(-1) at 40 weeks, 0.19 mg kg(-1) h(-1) at 50 weeks PCA to 1 yr, 0.18 mg kg(-1) h(-1) at 3 yr and 0.12 mg kg(-1) h(-1) in adulthood. CYP2D6 activity was observed as early as 25 weeks PCA, but the impact of CYP2D6 polymorphism on the variability in pharmacokinetics, metabolism and pharmacodynamics of tramadol remains to be established.

Adult↗
PubMed2005

Improvements in antimicrobial prescribing for treatment of upper respiratory tract infections through provider education.

BACKGROUND: Inappropriate use of antimicrobials to treat acute upper respiratory tract infections (URIs), which usually have a viral etiology, contributes to emergence and spread of antimicrobial resistance in Streptococcus pneumoniae and other human bacterial pathogens. OBJECTIVE: To reduce antimicrobial use for management of acute URIs in adult and pediatric patients. DESIGN: Prospective, nonrandomized, controlled trial. SETTING: Four primary care clinics within a staff model HMO in Detroit, Mich. PARTICIPANTS: Twenty-one primary care physicians at clinics where the educational intervention was implemented, and 9 primary care physicians at control clinics where no educational programs were implemented. MEASUREMENTS: Antibiotic prescribing for acute URIs during the baseline and study years among the intervention and control groups. RESULTS: A generalized linear mixed-effects model was used and showed that antimicrobial prescribing among the intervention group physicians decreased 24.6% from the baseline to the postintervention period (P<.0001) for both pediatric and adult medicine physicians. From the baseline to the study period, there was no significant decline in rates of antimicrobial prescribing by the control group of physicians (pediatricians, P=.35; internists, P=.42). The rates of decline in antimicrobial prescribing differed significantly between the intervention and control groups (P<.0003 for pediatricians and P<.01 for Internists). CONCLUSIONS: An interactive, case-based educational program for physicians and their staff proved effective for reducing unwarranted prescribing of antibiotics in the treatment of URIs by primary care physicians in a Medicaid HMO setting.

Anti-Bacterial Agents↗