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PubMed2006

Clinical development of anti-tuberculosis drugs.

In the clinical development of new anti-tuberculosis drugs, the most important step is efficient Phase II studies to show whether the drug is likely to be able to shorten treatment and with what other drugs it has the greatest sterilizing activity. The use of non-linear mixed effects modelling applied to serial sputum cfu counts appears to be the most effective technique, but we know little about the optimal design of such novel studies. A paper in the current journal reports on the relative efficiencies of various timing patterns in sampling sputum.

Antitubercular Agents↗
PubMed2003

Evaluation of the American Stop Smoking Intervention Study (ASSIST): a report of outcomes.

BACKGROUND: The National Cancer Institute funded an 8-year, nonrandomized demonstration project for tobacco prevention and control, the American Stop Smoking Intervention Study (ASSIST). To evaluate ASSIST, we compared changes in adult smoking prevalence, per capita cigarette consumption, and tobacco control policies between the 17 ASSIST states and the 33 non-ASSIST states and the District of Columbia. METHODS: The strength of tobacco control index was used to measure state-level program elements directed at tobacco control, and the initial outcomes index (IOI) was used to measure states' tobacco control policy outcomes. Prevalence data were obtained from the Tobacco Use Supplement to the Current Population Survey, and consumption data were obtained from the Tobacco Institute's bimonthly sales figures for cigarette packs moved from wholesale warehouses. Two-stage regression and mixed-effects linear modeling were used to analyze the various outcomes. Statistical analyses for testing individual regression coefficients were one-sided. RESULTS: ASSIST states had a greater decrease in adult smoking prevalence than non-ASSIST states, with an adjusted difference of -0.63% (P =.049). Per capita cigarette consumption was not statistically significantly different between ASSIST and non-ASSIST states. However, an increase in the IOI of a state from the 25th to the 75th percentile was associated with a reduction in per capita cigarette consumption by 0.57 packs per person per month. State IOI was also inversely, albeit not statistically significantly, associated with smoking prevalence (regression coefficient = -0.11;P =.06). CONCLUSIONS: The reduction in adult smoking prevalence associated with ASSIST could have translated into approximately 278 700 fewer smokers nationwide if all states had implemented ASSIST. Investment in building state-level tobacco control capacity and promoting changes in tobacco control policies are effective strategies for reducing tobacco use.

Adolescent↗
PubMed2003

Pharmacokinetics of the low molecular weight heparin enoxaparin during 48 h after bolus administration as an anticoagulant in haemodialysis.

BACKGROUND: The interest of low molecular weight heparins (LMWH) regarding bleeding risk is controversial in renal failure patients. In haemodialysis patients, there are very few data on the pharmacokinetics of LMWH after the end of the session. The aim of the study was to evaluate the duration of anticoagulation after bolus administration of the LMWH enoxaparin at the start of haemodialysis. METHODS: The pharmacokinetics of enoxaparin were studied during the 48 h following a single bolus injection at the start of the dialysis session in 30 chronic haemodialysis patients. Pharmacokinetics were determined using a population approach (Non Linear Mixed Effects Modelling). RESULTS: A single injection of enoxaparin at 60 U IU/kg (4000 +/- 455 IU) led to an anti-Xa activity higher than 1.2 IU/ml during the first 2 h of the session, and between 0.4 and 1.2 IU during the third and fourth hours. After the end of the session, anti-Xa activity remained higher than 0.4 IU/ml up to 10 h after injection, and higher than 0.1 IU/ml up to 24 h. The pharmacokinetic model showed that only weight improved the predicted vs observed anti-Xa activity plot. The model was used to simulate single and multiple dosing with decreased enoxaparin doses. Whatever the procedure, anti-Xa activity remained high (>0.22 +/- 0.99 UI/ml) up to 12 h after the start of the dialysis session. CONCLUSIONS: These results suggest that haemodialysis patients receiving the LMWH enoxaparin during dialysis are at risk of bleeding up to 10 h after the injection.

Adult↗
PubMed2000

Weight gain continues in the 1990s: 10-year trends in weight and overweight from the CARDIA study. Coronary Artery Risk Development in Young Adults.

The prevalence of obesity increased in the United States through the 1980s. The authors examined 10-year aging and secular (time-related) trends in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort for indications of whether these trends are continuing and for ages of peak weight gain in young adults. CARDIA is a population-based, prospective study of 5,115 African-American and White men and women aged 18-30 years at baseline. Body weight and overweight prevalence were measured at five time points from 1985-1986 to 1995-1996. Linear, mixed-model regression was used to partition weight gain into that due to secular trends and that due to aging. Prevalence of overweight (body mass index (BMI) > or = 25.0 kg/m2) increased markedly, and prevalence of severe obesity (BMI > or = 40.0 kg/m2) doubled in all race-sex groups. Each race-sex group experienced significant secular weight gains, ranging from 0.96 kg/year (95% confidence interval: 79, 1.13) in African-American women to 0.55 kg/year (95% confidence interval: 0.41, 0.69) in White women. Significant secular gains were present during each follow-up period. Each race-sex group also experienced significant weight increases related to aging during their early to midtwenties. Secular trends for weight gain are continuing in CARDIA, but the magnitude of weight gain differed among the four race-sex groups.

Adolescent↗
PubMed2005

Surface tension of upper airway mucosal lining liquid in obstructive sleep apnea/hypopnea syndrome.

STUDY OBJECTIVES: The obstructive sleep apnea hypopnea syndrome (OSAHS) is a disorder characterized by repetitive closure and reopening of the upper airway during sleep. Upper airway luminal patency is influenced by the surface tension (gamma) acting within the liquid layer lining the upper airway. The aim of the present study was to examine the gamma of upper airway mucosal lining liquid (UAL) in both healthy subjects and patients with OSAHS before and after sleep. DESIGN: Measurements were performed before (PM) and after (AM) an overnight polysomnographic study. SETTING: Sleep laboratory. PARTICIPANTS: We studied 11 healthy adults (5 men, 6 women) and 15 patients with OSAHS (14 men, 1 woman). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: The gamma of UAL ("pull-off' force technique, pooled PM and AM samples) in patients with OSAHS was increased (59.9 [53.8, 58.8] mN/m; mean [95% confidence interval]) compared with healthy subjects (56.3 [57.7, 62.1] mN/m; linear mixed effects models; P =.05). In both groups there was no significant difference between PM (56.6 [53.7, 59.5] mN/m for healthy subjects, 60.1 [57.9, 62.3] mN/m for the patients with OSAHS) and AM (56.1 [51.8, 60.4] mN/m and 59.6 [57.4, 61.8] mN/m, respectively) samples for gamma of UAL and salivary flow rate (5 minutes unstimulated collection; PM =0.53 [0.22, 0.84] mL/minute for healthy subjects, 0.38 [0.22, 0.54] mL/minute for OSAHS; AM=0.39 [0.23, 0.55] mL/minute and 0.32 [0.2, 0.44] mL/minute). However, the occurrence of nasal breathing during sleep was associated with a fall in gamma of UAL overnight (r2 = 0.15, P < .05). CONCLUSION: Patients with OSAHS have normal salivary flow rate but an increased gamma of UAL. In both healthy subjects and OSAHS patients, nasal breathing during sleep was associated with an overnight fall in the gamma of UAL.

Adult↗
PubMed2003

Laryngoscopic intubation: learning and performance.

BACKGROUND: Many healthcare professionals are trained in direct laryngoscopic tracheal intubation (LEI), which is a potentially lifesaving procedure. This study attempts to determine the number of successful LEI exposures required during training to assure competent performance, with special emphasis on defining competence itself. METHODS: Analyses were based on a longitudinal study of novices under training conditions in the operating room. The progress of 438 LEIs performed by the 20 nonanesthesia trainees was monitored by observation and videotape analysis. Eighteen additional LEIs were performed by experienced anesthesiologists to define the standard. A generalized linear, mixed-modelling approach was used to identify key aspects of effective training and performance. The number of tracheal intubations that the trainees were required to perform before acquiring expertise in LEI was estimated. RESULTS: Subjects performed between 18 and 35 laryngoscopic intubations. However, statistical modeling indicates that a 90% probability of a "good intubation" required 47 attempts. Proper insertion and lifting of the laryngoscope were crucial to "good" or "competent" performance of LEI. Traditional features, such as proper head and neck positions, were found to be less important under the study conditions. CONCLUSIONS: This study determined that traditional LEI teaching for nonanesthesia personnel using manikin alone is inadequate. A reevaluation of current standards in LEI teaching for nonanesthesia is required.

Adult↗
PubMed2001

Transthoracic monitoring of the impedance of the right lung in patients with cardiogenic pulmonary edema.

OBJECTIVE: To evaluate the suitability of the new electrical impedance monitor RS-205 for monitoring of cardiogenic pulmonary edema (CPE). DESIGN: Prospective, controlled study. SETTING: A department of internal medicine in a 1,200-bed university-affiliated, teaching hospital. PATIENTS: Sixty patients, aged 52-80 yrs, 30 without CPE (controls) and 30 with or at high risk for CPE. INTERVENTIONS: Internal thoracic impedance (ITI) was monitored by the RS-205. The RS-205 is approximately three times more sensitive than the Kubicek monitor, and it eliminates the effect of the drift of skin-to-electrode impedance. This is achieved by eliminating skin electrode impedance by a special algorithm, thus allowing measurement of ITI rather than total transthoracic impedance. Measuring ITI, the main component of which is lung impedance, is a noninvasive and safe method. CPE was diagnosed in accordance with well-accepted clinical and roentgenological criteria. MEASUREMENTS AND MAIN RESULTS: The controls' initial ITI was 68.3 +/- 12.38 ohms. During 6 hrs of monitoring, the ITI attained a minimum average value of -1.3 +/- 2.08% and a maximum average value of 4.6 +/- 3.56% relative to baseline. In all patients entering CPE, ITI decreased by 14.4 +/- 5.42% on the average (p <.001) 1 hr before the appearance of clinical symptoms. In patients with evolving CPE, ITI decreased significantly compared with controls (22.25 +/- 9.82%, p <.001). In patients at the peak of pulmonary edema, ITI was 2.1 times lower than in the control group (33.1 +/- 10.90 ohms, p <.001). In the last hour before the resolution of CPE, ITI increased in all patients by 17.7 +/- 19.74% compared with the peak of disease (p <.05). After the resolution of pulmonary edema, ITI increased in all patients by 44.14 +/- 26.90% compared with the peak of disease (p <.001). Importantly, the trend in ITI in all patients changed in accordance with the dynamics of CPE. A mixed general linear model shows that ITI values correlated well with the degree of crepitation, a direct characteristics of CPE. CONCLUSIONS: The RS-205 is suitable for monitoring patients at high risk of CPE development. It enables detection of CPE and the monitoring of patients at all stages of CPE.

Aged↗
PubMedDate not supplied

Acoustic echoplanar scanner noise and pure tone hearing thresholds: the effects of sequence repetition times and acoustic noise rates.

PURPOSE: Our goal was to determine the effects of acoustic echoplanar scanner noise on pure tone hearing thresholds in normal volunteers and to determine the influence of echoplanar sequence repetition time on threshold effects. METHOD: With use of a calibrated audiometer, pure tones ranging from 125 to 8,000 Hz were delivered monaurally to 10 normal-hearing volunteers in a quiet MR scanner suite and in the presence of acoustic scanner noise produced by three separate single shot blipped echoplanar pulse sequences varying only in repetition time (TR = 1,000, 2,000, or 3,000 ms), with all other parameters including the number of slices held constant. The magnitude of noise-induced threshold changes and the slopes of the threshold curves produced by each of the three echoplanar pulse sequences were then analyzed using multiple comparisons and a least significant difference method. The shapes of the threshold curves produced in each background state were best fit using a quadratic effect for frequency in a mixed effects linear model and compared using F test statistics. RESULTS: All of the volunteers demonstrated entirely normal hearing thresholds throughout the full range of tonal frequencies tested (< 25 dB) when no acoustic scanner noise was present in the scanner suite. Pure tone hearing thresholds significantly increased (p < 0.01) in the presence of acoustic scanner noise, with the magnitude of change inversely proportional to the repetition time and therefore the rate of periodic noise production by the echoplanar sequence used. The shape of the threshold curve in the presence of noise produced by the 1,000 ms TR sequence was not equivalent across the frequency spectrum tested but had a quadratic distribution with peak effects at 750-2,000 Hz. As the repetition time was increased and the periodic noise rate decreased, the magnitude of the noise-induced threshold changes significantly lessened (p < 0.01) and the quadratic distributions of the threshold curves changed significantly (p < 0.01), tending toward a more planar configuration. CONCLUSION: Background acoustic echoplanar scanner noise can significantly increase pure tone thresholds in the optimal frequency hearing range (125-8,000 Hz). However, the threshold effects are not equivalent across the frequency spectrum, and the magnitude of threshold changes is dependent on the rate at which periodic acoustic scanner noises are produced for a given sequence repetition time.

Acoustic Stimulation↗
PubMed2001

One-to-one versus group sessions to improve prescription in primary care: a pragmatic randomized controlled trial.

OBJECTIVES: The objective of the study was to evaluate the effectiveness of 2 educational strategies aimed at improving prescribing standards in primary care. METHODS: A pragmatic controlled trial was designed; the study population included general and family practitioners in Galicia (northwestern Spain) divided into 3 study groups: a one-to-one education group (n = 98), a by-group education group (n = 92), and a control group (n = 405). The educational intervention included explicit recommendations for selecting nonsteroidal anti-inflammatory drugs (NSAIDs) for inflammation signs. Some of the subjects were given reminders. Mixed-effect linear models were applied to data analysis. Analyses were done by intention-to-treat. The dependent variable is a rate with a numerator that is the number of prescribed units of the NSAIDs recommended during intervention; the denominator is the total number of prescribed units of the NSAID total. RESULTS: One-to-one education obtained an average prescribing behavior improvement of 6.5% (P < 0.001) in the 9 months after intervention. In the education group, the average improvement was 2.4% (P < 0.05) for the same period. Statistically significant differences were observed between the group intervention and one-to-one groups. The reminder increased significantly the effectiveness of the one-to-one intervention. CONCLUSIONS: A single, short educational session to primary care doctors can improve their prescribing standards during long periods of > or = 9 months. Of the 2 strategies followed in the trial, one-to-one education has shown to be the most effective. Results also show that the effectiveness of these interventions increases when presented together with written material.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Description of blood pressure changes in patients beginning cyclosporin A therapy.

Cyclosporin A (CyA) is the primary immunosuppressive agent for the prophylaxis of rejection episodes in renal, cardiac, liver, and other transplants. Recently, its use in autoimmune diseases has been investigated as well. Although several studies have produced promising results, nephrotoxicity and hypertension can result from CyA treatment, and their development must be understood in order to facilitate patient management. This article describes the diastolic blood pressure (DBP) responses in two populations of patients during three months of CyA therapy. Study A involved psoriasis patients and Study B involved postoperative renal transplant patients. The relationship between blood pressure and systemic CyA exposure and other covariates was evaluated using linear mixed effects modeling. Temporal patterns of blood pressure changes with varying duration of CyA exposure were investigated. In Study A, the psoriasis patients showed transient exposure-related increases in DBP on CyA. These elevations, while statistically significant, were clinically insignificant. In Study B, the renal transplant patients showed no CyA-related rises in DBP. In neither study was there evidence for a difference in effect on DBP between Sandimmune and Neoral, the two formulations of CyA presently approved for marketing by the Food and Drug Administration, after differences in CyA exposure were taken into account.

Adult↗
PubMed2005

Postmenopausal oral estrogen therapy and blood pressure in normotensive and hypertensive subjects: the Estrogen in the Prevention of Atherosclerosis Trial.

OBJECTIVE: To determine if 17beta-estradiol increases blood pressure in postmenopausal women. DESIGN: A total of 222 healthy postmenopausal women were randomly assigned to either 1 mg micronized 17beta-estradiol daily or placebo for 2 years. Blood pressure measurements were obtained every other month and common carotid artery intima-media thickness measured every 6 months. Statistical analyses comparing longitudinal changes in systolic and diastolic blood pressure between treatment groups used a mixed general linear model including interaction terms to evaluate variations by age or estradiol level. RESULTS: Both placebo and estradiol groups showed small declines in systolic and diastolic blood pressure during the trial among the normotensive subjects and subjects on antihypertensive medications. However, the decline did not differ significantly between the groups. Treatment effects on systolic blood pressure differed significantly by the age of the subject (interaction P value = 0.04) with younger women on estradiol showing on average a rise in systolic blood pressure, and older women a decline. The association between serum estradiol level and systolic blood pressure showed a similar modification with age (P = 0.03). Changes in systolic blood pressure in women on estradiol were positively correlated with intima-media thickness progression (P = 0.03). CONCLUSIONS: Overall, 17beta-estradiol did not influence changes in blood pressure in normotensive or hypertensive women. The effect of 17beta-estradiol treatment on systolic blood pressure may be influenced by a woman's age. Estradiol may increase systolic blood pressure in younger postmenopausal women, while having the opposite effect in older postmenopausal women.

Age Factors↗
PubMed2006

Unprotected anal intercourse and substance use among men who have sex with men with recent HIV infection.

OBJECTIVES: To examine within-subjects and combined between- and within-subjects associations between substance use and unprotected anal intercourse (UAI) among men who have sex with men (MSM) with recent HIV infection. METHODS: One hundred ninety-four MSM who were recently infected with HIV completed a computer-assisted questionnaire regarding sexual behaviors and substance use with their last 3 partners. Associations between UAI and substance use were assessed using conditional logistic regression (CLR) to assess associations among the 116 MSM reporting UAI with some but not all partners and generalized linear mixed effects models (GLMMs) to examine a combination of within- and between-subjects associations in the entire sample (N = 194). RESULTS: In multivariate CLR models and GLMMs, UAI was associated with the use of methamphetamine (odds ratio [OR] = 4.9 and OR = 3.5, respectively), marijuana (OR = 4.0 and OR = 2.2, respectively) and erectile dysfunction medications (EDMs) when used with a main partner (OR = 13.8 and OR = 10.1, respectively). CONCLUSIONS: Results indicate that a direct association may exist between specific substances and UAI and provide evidence that the use of methamphetamine and EDMs may contribute to HIV transmission.

Adult↗
PubMed2006

Reproducibility of a scoring system for computed tomography scanning in cystic fibrosis.

INTRODUCTION: Computerized tomography (CT) scanning shows promise as an outcome surrogate for cystic fibrosis (CF) lung disease progression. The scoring system used to convert the CT image to numeric data is an essential determinant of the performance of CT scanning. METHODS: Three radiologists independently scored 16 high-resolution CT scans performed on children in the Wisconsin CF Neonatal Screening Project. The test scans were selected to provide a broad range of disease severity. The scoring system provided subscores for the presence and severity of 5 findings of CF lung disease. The sum of the subscores provided a total score. The CT scans were then read again by each of the radiologists at least 11 months later. Using Mixed Effects Linear Model Analysis, the sources of error (scan-to-scan variation, interrater variance, and intrarater variance) were calculated. RESULTS: For the total score, the scan-to-scan variation was 14.48, interrater variance was 0.28, and intrarater variance was 0.45, with an overall reproducibility of 95%. The square root of scan-to-scan variance, a measure of sensitivity, was 3.81. Evaluation of the subscores showed higher reproducibility for bronchiectasis and hyperinflation (95% and 88%, respectively). The bronchiectasis score was more sensitive than the air-trapping score (1.46 vs. 0.89). DISCUSSION: This system was developed to provide a reproducible method that could be used to evaluate the lobar location, severity, and extent of a broad spectrum of CT features of CF lung disease, especially in children. This study demonstrates that the overall score is both sensitive to variation in the severity of lung disease and reproducible.

Adolescent↗
PubMed1997

A comparison of the infusion pharmacokinetics and pharmacodynamics of cisatracurium, the 1R-cis 1'R-cis isomer of atracurium, with atracurium besylate in healthy patients.

We have compared the pharmacokinetics of cisatracurium with atracurium when given by bolus dose followed by continuous infusion. Twenty healthy patients were anaesthetised with thiopentone, midazolam, fentanyl and 70% nitrous oxide in oxygen. Ten patients (Group C) were randomly allocated to receive cisatracurium 0.1 mg.kg-1 and 10 patients (Group A) were given atracurium 0.5 mg.kg-1. Neuromuscular block was monitored using a mechanomyograph. When the first twitch of the train-of-four had recovered to 5% of control, an infusion of cisatracurium 3 micrograms.kg-1.min-1 was started in Group C and an infusion of atracurium 10 micrograms.kg-1.min-1 was started in Group A. The infusion rates were adjusted to maintain the first twitch of the train-of-four at 5% of control. The times to 90% and maximum depression of the first twitch of the train-of-four were significantly longer after cisatracurium than atracurium (2.2 and 3.4 min compared with 1.3 and 1.8 min, respectively; p < 0.01 in each instance). No significant differences were found in recovery parameters between the two groups. Blood samples were taken at regular intervals following the bolus, during the infusion and for 8 h thereafter. The plasma samples were analysed using high-performance liquid chromatography for cisatracurium and atracurium (using a method which distinguishes between the three geometric isomer groups), laudanosine and monoquaternary alcohol. The results were analysed using the Non-linear Mixed Effects Model program. A two-compartment model was fitted to the data. The different isomer groups of atracurium have different pharmacokinetics, the trans-trans group having the highest clearance (1440 ml.min-1) and the cis-cis group the lowest (499 ml.min-1). The clearance of cisatracurium (425 ml.min-1) is less than that of cis-cis atracurium and its elimination half-life is longer (34.9 min and 21.9 min, respectively). The plasma concentration of laudanosine after cisatracurium was one-fifth of that after atracurium.

Adult↗
PubMed1993

A search for associations between major histocompatibility complex restriction fragment length polymorphism bands and resistance to Haemonchus contortus infection in sheep.

Polymorphic bands were detected within the DQB and DRB regions of the ovine major histocompatibility complex by probing TaqI digested DNA from three large sheep half-sib families derived from a highly resistant ram. All animals were phenotypically assessed for Haemonchus contortus resistance by faecal egg counts and associations with RFLP bands and haplotypes were estimated using mixed model, best linear unbiased prediction statistical methods. Although the highly resistant sire was homozygous at the MHC, no significant associations were found between any band or haplotype and faecal egg count.

Animals↗
PubMed2005

Administration of enoxaparin by continuous infusion in a naturalistic setting: analysis of renal function and safety.

STUDY OBJECTIVE: To describe the clinical use and safety of continuous infusion (CI) enoxaparin in a naturalistic setting and to evaluate the influence of renal function on enoxaparin elimination. DESIGN: Retrospective medical record review. SETTING: 1000-bed tertiary care teaching centre. PATIENTS: Hospitalized patients that received enoxaparin by CI during a 2-year period. INTERVENTIONS: None. MEASUREMENTS: Specific details of dosage and monitoring were collected. Adverse drug reactions (ADR) were recorded. Creatinine clearance (CrCl) was calculated using Cockroft and Gault and Brater equations. A population pharmacokinetic analysis was performed using the non-linear mixed effect model (NONMEM). For patients located in the intensive care unit (ICU) and ward, POSTHOC pharmacokinetic parameter estimates were evaluated using the Wilcoxon rank-sum. Pearson correlation coefficient was calculated to determine the association between renal function and anti-Xa clearance. MAIN RESULTS: Sixty-seven patients received enoxaparin by CI of which 61.2% were in the ward and 38.8% in the ICU. The average initial rate and duration of infusion were 5.2 mg/h and 5.6 days, respectively. The number of anti-Xa concentration measurements averaged five per patient. Nine patients experienced an ADR. The most frequent ADR was gastrointestinal bleeding (n = 4). Among the 67 patients, 48 had available anti-Xa concentrations and were included in the NONMEM model. The anti-Xa CL and volume of distribution for ICU and ward patients averaged 0.64 +/- 0.34 L/h, 10.6 +/- 1.55 L and 1.01 +/- 0.39 L/h, 9.08 +/- 1.17 L, respectively. CrCl was not a significant covariate when included in the NONMEM model, and the association between CrCl and anti-Xa clearance was not significant (R2 = 0.0005; P = 0.8916). CONCLUSIONS: This study is the first to report the use and safety of prolonged CI enoxaparin. Pharmacokinetic parameters of enoxaparin differ in ICU vs. ward patients. Overall, we found the safety of CI to be comparable to subcutaneous administration. Also, we found no effect of renal function on enoxaparin elimination.

Anticoagulants↗
PubMed2005

Population pharmacokinetics of theophylline in very premature Japanese infants with apnoea.

OBJECTIVE: To estimate the population pharmacokinetics of theophylline in very premature infants using the non-linear mixed effects modelling. METHOD: A total of 167 serum concentration measurements obtained from routine theophylline monitoring of 107 very premature Japanese infants were collected. RESULTS: The final pharmacokinetic parameters were CL (mL/h) = [6.98 . body weight (BW) (kg)(2.17) + 0.244 . post-conceptional age (weeks)] . 1.24(oxygen support), Vd (L) = 0.492 . BW (kg) and F = 0.660, respectively. Clearance was increased by 24% for patients receiving oxygen support. The inter-individual variabilities in clearance and apparent volume of distribution were 15.6% and 80.4%, respectively, and the residual variability was 34.2% as a coefficient of variation. CONCLUSION: Application of the findings in this study to patient care may permit selection of an appropriate initial maintenance dosage to achieve target theophylline concentrations, thus enabling the clinician to achieve the desired therapeutic effect in very premature Japanese infants.

Apnea↗
PubMed2004

Daytime variation in performance and tiredness/sleepiness ratings in patients with insomnia, narcolepsy, sleep apnea and normal controls.

Daytime tiredness or sleepiness and deficits in cognitive performance are common complaints in sleep disordered patients. Till now there are few studies comparing patients from different diagnostic groups of sleep disorders in the same experimental protocol. We studied the time course of cognitive functions and subjective alertness in a parallel group design with four groups of patients [narcolepsy, untreated or treated obstructive sleep apnea (OSA), or psychophysiological insomnia] and a control group of subjects without sleep complaints. Each group consisted of 10 subjects, matched for age and gender. After a night with polysomnography, subjects were studied for 10 h from 08:00 hours to 18:00 hours at 20 min intervals under standardized environmental conditions. Four psychological tests were applied, (1) a critical flicker fusion (CFF) test to measure optical fusion threshold (alertness); (2) a paper-and-pencil visual line tracking test (selective attention); (3) a visual analog scale (VAS) for tiredness/sleepiness; and (4) the Tiredness Symptoms Scale (TSS), a 14 items check list. Each test session lasted for 8 min, followed by a 12 min pause. The level and time course of cognitive performance and self-rating data were analysed with hierarchical linear mixed effects models. Cognitive tests showed decrements in alertness and selective attention in untreated patients with insomnia, narcolepsy, and sleep apnea. Narcoleptic patients and untreated OSA had a lower CFF threshold than controls, and for narcoleptic patients the time course differed from that of all other groups. In the visual tracking test the performance of all groups of patients was worse compared with normal controls. Self-rated tiredness/sleepiness was significantly more pronounced in the three groups of untreated patients than in control subjects.

Attention↗