bluuebunny/crossref_metadata_2025_split huggingface dataset:
Steady‐State Pharmacokinetics of Citalopram in Young and Elderly Subjects
Authors: Gutierrez Marcelo , Abramowitz Wattanaporn 
Published: June 2004

Study Objectives. To compare the steady‐state pharmacokinetics of citalopram after multiple‐dose administration in elderly and young subjects, and to correlate pharmacokinetic measurements with tolerability.Design. Single‐blind, multiple‐dose, dose‐escalating, randomized, placebo‐controlled trial.Setting. The Orlando Clinical Research Center, Orlando, Florida.Subjects. Twenty‐four healthy elderly and eight healthy young men and women.Interventions. Subjects randomized to citalopram received 10 mg once/day for the first week, 20 mg once/day for the second week, and 40 mg once/day for the remaining 3 weeks.Measurements and Main Results. Blood samples were collected weekly to determine steady‐state pharmacokinetics of citalopram and its primary metabolites. During dose escalation, samples were collected just before dose increase. After the final dose, blood samples were collected periodically over 480 hours to characterize the terminal elimination phase. In elderly subjects, maximum concentration, time associated with the maximum concentration, area under the concentration versus time curve from 0–24 hours, half‐life, and volume of distribution were all slightly increased; oral clearance was slightly decreased. However, only half‐life was statistically different between the groups, 30% longer in the elderly. In addition, the frequency and severity of adverse events were comparable between the two age groups and did not appear to be dose related.Conclusions. The pharmacokinetics and tolerability of citalopram in elderly subjects are similar to those observed in younger subjects. The slight differences observed in the elderly likely reflect declining liver and kidney function.
Effects of Steady‐State Bupropion on the Pharmacokinetics of Lamotrigine in Healthy Subjects
Authors: Odishaw Joi , Chen Chao 
Published: June 2004

Study Objective. To evaluate the effect of steady‐state bupropion SR sustained‐release (BUP) on the pharmacokinetics of a single 100‐mg dose of lamotrigine (LTG).Design. Randomized, open‐label, two‐way crossover study.Setting. Clinical Studies Ltd., Fort Lauderdale, Florida.Patients. Twelve healthy subjects.Intervention. Treatment A: LTG 100 mg with steady‐state BUP 150 mg twice/day; treatment B: LTG 100 mg.Measurements and Main Results. The pharmacokinetics of LTG were determined by noncompartmental methods using plasma and urine concentrations. Geometric least squares mean ratios and 90% confidence intervals were calculated for treatment comparison. Safety assessments included clinical laboratory tests, vital signs, and adverse events monitoring. Pharmacokinetic parameters of LTG were not significantly different between treatments. Five subjects experienced seven mild, potentially drug‐related adverse events (insomnia [2]; nausea, headache, facial pain, fatigue, and depression [1 each]) that resolved spontaneously.Conclusion. Steady‐state BUP caused no clinically relevant changes in the pharmacokinetics of a single dose of LTG.
Evaluation of the Influence of Diabetes Mellitus on Antipyrine Metabolism and CYP1A2 and CYP2D6 Activity
Authors: Matzke Gary R. , Frye Reginald F. , Early John J. , Straka Robert J. , Carson Stanley W. 
Published: June 2004

Study Objective. To evaluate the metabolism of antipyrine, a general metabolic probe, caffeine, a probe for cytochrome P450 (CYP) 1A2 and N‐acetyltransferase activity, and dextromethorphan, a specific probe for CYP2D6 activity in patients with type 1 or 2 diabetes mellitus.Design. Prospective, controlled study.Setting. Research facility.Patients. Fifteen patients with type 1 and 16 with type 2 diabetes, and 16 healthy controls.Intervention. Each subject simultaneously received antipyrine 10 mg/kg, caffeine 100 mg, and dextromethorphan 30 mg.Measurements and Main Results. The pharmacokinetics of antipyrine and its primary metabolites were determined from saliva and urine samples. Type 1 diabetes had marked effects on antipyrine metabolism whereas type 2 disease did not alter the metabolism of any of the probe drugs. The apparent oral clearance of antipyrine was increased 72% in patients with type 1 disease compared with controls (p=0.0001). In addition, formation clearances of 4‐hydroxyantipyrine and 3‐hydroxymethylantipyrine were increased by 74% and 137% in those patients relative to controls. The caffeine metabolic index (paraxanthine/caffeine) was increased 34% (p=0.11), and N‐acetylation and CYP2D6 phenotype were not altered.Conclusion. The metabolism of antipyrine is increased in patients with type 1 diabetes. Based on in vitro reports of antipyrine metabolism and current caffeine metabolic index data, the predominant effect of type 1 diabetes appears to be an increase in CYP1A2 activity. Assessment of the effect of the disease on other specific CYP metabolic pathways is warranted.
Quantification of Human H1 Histamine Receptor mRNA from Peripheral Blood
Authors: Rosebraugh Curtis J. , Yasuda Robert P. , Yasuda Sally Usdin 
Published: June 2004

Study Objective. To develop a reverse transcription (RT)‐polymerase chain reaction (PCR) technique to detect and quantify human histamine1 (H1) receptor mRNA in peripheral blood.Methods. Primer pairs were based on the human H1 receptor nucleotide sequence. A competitive reference standard (CRS) was developed that used the same primers as wild‐type mRNA but contained a 92‐bp deletion. RT‐PCR was performed with 5 μg of total RNA obtained from venous blood of six subjects that was added to known concentrations of CRS RNA. Linear regression comparing wild‐type with CRS product was used to quantify wild‐type mRNA.Measurements and Main Results. Three subjects had detectable H1 mRNA, with a range of 31–435 pg. In three subjects PCR product was not detected, although the presence of RNA was confirmed. Redesigned primer pairs showed mRNA to H1 receptor in two of the remaining subjects, but it was undetectable in the third.Conclusion. RT‐PCR can be used to detect and quantify human H1 receptor mRNA from peripheral blood.
The Pharmacokinetics and Pharmacodynamics of Argatroban: Effects of Age, Gender, and Hepatic or Renal Dysfunction
Authors: Swan Suzanne K. , Hursting Marcie J. 
Published: June 2004

Study Objective. To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.Design. Prospective, open‐label study (studies 1 and 3); prospective, open‐label, parallel‐group study (study 2).Settings. Two research centers and an inpatient clinic.Subjects. Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.Intervention. Study 1, argatroban 125‐μg/kg bolus followed by 4‐hour continuous infusion of 2.5 μg/kg/minute; study 2, 4‐hour infusion of 2.5 μg/kg/minute (1.25 μg/kg/minute in one patient with hepatic impairment); study 3, 5‐μg/kg/minute continuous infusion over 4 hours.Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two‐compartment model with first‐order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady‐state volume of distribution, and half‐life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half‐life of argatroban were increased approximately 2‐to 3‐fold; clearance was one‐fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.
Gender Differences in Labetalol Kinetics: Importance of Determining Stereoisomer Kinetics for Racemic Drugs
Authors: Johnson Julie A. , Akers Wendell S. , Herring Vanessa L. , Wolfe Michael S. , Sullivan Jay M. 
Published: June 2004

Study Objective. To evaluate the impact of gender on labetalol kinetics.Design. Part of a randomized, crossover study.Setting. Academic medical center.Patients. Nineteen hypertensive patients (14 men, 5 women; 6 blacks, 13 whites).Interventions. Participants had labetalol dosages titrated to a specific antihypertensive response, then underwent ambulatory blood pressure monitoring (ABPM) and a pharmacokinetic study. Labetalol plasma concentrations were measured by high‐performance liquid chromatography (HPLC) and labetalol stereoisomer ratios were determined in a single plasma sample by chiral HPLC, both with fluorescence detection.Measurements and Main Results. Labetalol concentrations were 80% higher in women (area under the concentration‐time curve [AUC]/dose•1000: 6.79 ± 2.11 in women vs 3.82 ± 1.37 hr/L in men, p<0.05), yet both genders had a similar antihypertensive response by 24‐hour ABPM. Dose‐corrected AUC (AUC/dose•1000) for labetalol's stereoisomers in women and men, respectively, were S,R‐labetalol 7.55 ± 1.47 and 4.83 ± 1.54 hr/L (p<0.05), S,S‐labetalol 8.23 ± 2.93 and 4.65 ± 1.78 hr/L (p<0.05), R,S‐labetalol 6.99 ± 3.30 and 4.25 ± 2.35 hr/L (p= 0.11), and R,R‐labetalol 3.91 ± 2.57 and 3.55 ± 3.08 hr/L (NS).Conclusion. The higher labetalol concentration in women than in men was explained largely by differences in inactive and α1‐blocking stereoisomers. However, concentrations were similar between genders for the (β‐blocking stereoisomer (R,R‐labetalol), possibly explaining the similarity in antihypertensive response to the drug. This study highlights the importance of determining stereoisomer kinetics for agents administered as racemates, particularly when relating concentrations to pharmacologic response.
Determinants of Ceftriaxone Clearance by Continuous Venovenous Hemofiltration and Hemodialysis
Authors: Matzke Gary R. , Frye Reginald F. , Joy Melanie S. , Palevsky Paul M. 
Published: June 2004

Study Objective. To guide individual ceftriaxone dosages in patients receiving continuous renal replacement therapy.Design. Prospective, outpatient study.Setting. University‐affiliated general clinical research center.Patients. Eight patients receiving hemodialysis.Intervention. We performed controlled clearance studies with three hemofilters: an acrylonitrile copolymer 0.6 m2 (AN69), polymethylmethacrylate 2.1 m2 (PMMA), and polysulfone 0.65 m2 (PS).Measurements and Main Results. Subjects received ceftriaxone 1000 mg intravenously before the start of a clearance study. The concentration of ceftriaxone in multiple plasma and dialysate‐ultrafiltrate samples was determined by high‐performance liquid chromatography. The diffusional clearances (Cldiffusion) and sieving coefficients (SC) of ceftriaxone, urea, and creatinine were compared by a mixed‐model repeated‐measures analysis of variance with filter and blood, dialysate inflow, or ultrafiltration rate as the main effect and patient as a random effect. The fraction of ceftriaxone bound to plasma proteins was 43 ± 15% (range 13–92%). Concentration dependence was evident in all three groups. The fraction unbound to plasma proteins (fup) at the time that SCs were determined was significantly lower in the PS group (0.16 ± 0.07) than the AN69 group (0.30 ± 0.17, p<0.01), but similar to that in the PMMA group (0.27 ± 0.12). Despite the higher fup, the SC of unbound ceftriaxone with the AN69 filter (0.48 ± 0.13) was significantly lower than values for the PMMA (0.86 ± 0.33) and PS (0.82 ± 0.22) groups (p<0.05). Continuous venovenous hemofiltration clearance of urea and unbound ceftriaxone increased significantly only for the PMMA (p= 0.006) and PS (p= 0.015) filters when the ultrafiltration rate was increased. Significant linear relationships (p<0.0001) were observed between Cldiffusion of unbound ceftriaxone and clearance of urea for all three filters: AN69 slope = 0.57, PMMA slope = 0.90, and PS slope = 1.02. The slope of this relationship for the AN69 filter was significantly lower than for the other two filters.
Caffeine Citrate for the Treatment of Apnea of Prematurity: A Double‐Blind, Placebo‐Controlled Study
Authors: Erenberg Allen , Leff Richard D. , Haack Dennis G. , Mosdell Kristen W. , Hicks Gregory M. , Wynne Beverley A. ,   Caffeine Citrate Study Group
Published: June 2004

Study Objective. To evaluate the efficacy and safety of caffeine citrate for treatment of apnea of prematurity.Design. Multicenter, parallel, randomized, double‐blind, placebo‐controlled trial with open‐label rescue.Setting. Nine neonatal intensive care units.Patients. Eighty‐five infants, 28–32 weeks postconception and 24 hours or more after birth who had six or more apnea episodes within 24 hours.Intervention. Caffeine citrate 10 mg/kg (as caffeine base) administered intravenously, followed by 2.5 mg/kg/day orally or intravenously, or placebo, for up to 10 days. Infants failing double‐blind therapy could receive open‐label rescue.Measurements and Main Results. Success was defined as 50% or greater reduction in apnea episodes and elimination of apnea. Caffeine citrate was significantly more effective than placebo in reducing apnea episodes by at least 50% in 6 days (p<0.05), and approached statistical significance (p<0.10) in 3 days. It was significantly better than placebo in eliminating apnea in 5 days (p<0.05), and approached significance (p<0.10) in 2 days. The number of infants with an aggregate of 7–10 days of at least a 50% reduction in apnea events or elimination of apnea was significantly higher in the caffeine citrate than in the placebo group. Adverse events did not differ significantly between groups. No correlations were found between success and mean daily plasma concentrations or baseline characteristics. Volume of distribution and clearance increased with weight, supporting weight‐adjusted dosing of caffeine citrate.Conclusion. Caffeine citrate 10 mg/kg caffeine base (equivalent to 20 mg/kg caffeine citrate) intravenously followed by 2.5 mg/kg/day caffeine base (equivalent to 5 mg/kg/day caffeine citrate) either intravenously or orally for 10 days is safe and effective for treating apnea of prematurity in infants 28–32 weeks postconception.
Vancomycin Assay Performance in Patients with End‐Stage Renal Disease Receiving Hemodialysis
Authors: Kingery Joanna R. , Sowinski Kevin M. , Kraus Michael A. , Klaunig James E. , Mueller Bruce A. 
Published: June 2004

Study Objective. To compare the performance of polyclonal fluorescence polarization immunoassay (pFPIA) with that of enzyme‐multiplied immunoassay technique (EMIT) in patients receiving vancomycin and hemodialysis.Setting. Outpatient hemodialysis center.Patients. Seven subjects with end‐stage renal disease treated with hemodialysis 3 times/week with a cellulose triacetate hemodialyzer.Intervention. Subjects received vancomycin 1000 mg intradialytically during the first study session and 750 mg every other hemodialysis session thereafter for 4 weeks.Measurements and Main Results. Blood samples were obtained throughout the study, and vancomycin serum concentrations were determined by pFPIA and EMIT. The mean ± SD difference (estimate of bias) between assays was −1.10 ± 1.35 mg/L. The limits of agreement (mean difference ± 1.96 • SD) between them were −3.80–1.60 mg/L.Conclusion. Our data suggest that the manufacturer's changes in the vancomycin pFPIA eliminated overestimation of drug concentrations in patients undergoing high‐permeability hemodialysis.
A Prospective Evaluation of Empiric versus Protocol‐Based Sedation and Analgesia
Authors: MacLaren Robert , Plamondon Johanna M. , Ramsay Kirk B. , Rocker Graeme M. , Patrick Ward D. , Hall Richard I. 
Published: June 2004

Study Objective. To compare empiric and protocol‐based therapies of sedation and analgesia in terms of pharmacologic cost, effects on mechanical ventilation and intensive care unit (ICU) stay, and quality of sedation and analgesia.Design. Prospective study.Setting. A 24‐bed medical‐surgical‐neurologic ICU.Patients. Seventy‐two patients evaluated during empiric therapy and 86 during protocol‐based therapy.Intervention. Assessment of data collected for 4 months before and 5 months after an evidence‐based sedation and analgesia protocol was implemented.Measurements and Main Results. Protocol adherence rate was 83.7%. The hourly cost (Canadian dollars) of sedation was less with protocol‐based therapy ($5.68 ± 4.27 vs $7.69 ± 5.29, p<0.01) likely due to increased lorazepam use. Pharmacologic cost savings may be negated since sedation duration tended to be longer (122.7 ± 142.8 vs 88.0 ± 94.8 hrs, p<0.1) and extubation may have been delayed (61.6 ± 97.4 vs 39.1 ± 54.7 hrs, p= 0.13) with protocol use. Duration of ICU stay after sedation was discontinued was not significantly different before and after protocol implementation. With the protocol, however, the percentage of modified Ramsay sedation scores representing discomfort decreased from 22.4 to 11% (p<0.001) and the percentage at a score of 4 increased from 17.2% to 29.6% (p<0.01). The percentage of modified visual analog measurements representing pain decreased from 9.6 to 5.9% (p<0.05) with the protocol. When data were stratified according to duration of sedation, the benefits and delayed extubation associated with protocol‐based therapy were limited to patients requiring long‐term sedation.Conclusion. Compliance with this protocol reduced drug costs and enhanced the quality of sedation and analgesia for patients requiring long‐term sedation. Protocol‐based therapy with lorazepam may have delayed extubation but did not delay ICU discharge.
Age and Gender Effects on the Pharmacokinetics of Gatifloxacin
Authors: LaCreta Frank P. , Kollia Georgia D. , Duncan Glenn , Behr Douglas , Grasela Dennis M. 
Published: June 2004

Study Objective. To compare the pharmacokinetics and safety of gatifloxacin in elderly (≥ 65 yrs) and young (18–45 yrs) men and women.Design. Open‐label, parallel‐group, single‐dose study.Setting. GFI Pharmaceutical Services Inc., Evansville, Indiana, USA.Subjects. Forty‐eight healthy subjects in four groups of 12 each.Interventions. Subjects received single oral doses of gatifloxacin 400 mg. Serial blood and urine samples were collected for 96 hours after dosing to determine drug concentrations.Measurements and Main Results. Age and gender had moderate effects on the pharmacokinetics of gatifloxacin. Elderly women had a 21% higher geometric mean peak plasma concentration (Cmax) and a 32% higher area under the plasma concentration‐time curve (AUC0–∞) than young women. Adjustment for creatinine clearance had only a slight effect on Cmax but reduced the estimated effect of age on AUC0–∞ in women from a 32% increase to a 15% increase. Gender effects on pharmacokinetic values were noted among elderly subjects only. Geometric means for Cmax and AUC0–∞ were 21% and 33% higher, respectively, for elderly women and elderly men. Adjustment for body weight reduced these differences to 11% and 20%, respectively.Conclusion. The effects of age on gatifloxacin pharmacokinetic values were largely attributed to declining renal function, whereas those of gender were largely attributed to differences in body weight. These modest age‐ and gender‐related differences do not warrant dosage adjustment.
Nalmefene to Prevent Epidural Narcotic Side Effects in Pediatric Patients: A Pharmacokinetic and Safety Study
Authors: Rosen David A. , Morris John L. , Rosen Kathleen R. , Nelson Elizabeth R. , Steelman Robert J. , Gustafson Robert A. , Wilhelm Jeffrey A. , Chang Cheng T. , Thackara Jeffrey W. , Frye Reginald F. 
Published: June 2004

Study Objective. To determine the pharmacokinetics and preliminary efficacy of nalmefene in children in preventing epidural‐induced narcotic side effects.Design. Double‐blind, placebo‐controlled study.Setting. University‐affiliated children's hospital.Patients. Thirty‐four children (aged 2–12 yrs) undergoing cardiothoracic surgery with epidural anesthesia.Interventions. Patients were randomized to receive intravenous bolus nalmefene 1 μg/kg or placebo.Measurements and Main Results. Six blood samples (one before nalmefene administration and five from 13 randomly designated time points) from each patient were assayed to determine plasma nalmefene concentrations. Patients were assessed for pain, nausea, vomiting, and urinary retention for 24 hours after administration. Concentration‐time data were analyzed by a limited sampling strategy with adult pharmacokinetic parameters used as Bayesian priors. A two‐compartment, first‐order model was fitted to the data using ADAPT II. Pharmacokinetic parameter estimates in these patients were similar to values reported in adults. The initial disposition half‐life (t1/2α) was 0.36 ± 0.11 hour, the terminal elimination half‐life (t1/2β) 8.7 ± 2.3 hours, clearance 0.729 ± 0.172 L/kg/hr, and steady‐state volume of distribution 7.21 ± 2.49 L/kg. Ability to prevent epidural narcotic‐induced side effects could not be documented at the 1‐μg/kg dose. No statistically significant differences were noted between study and placebo groups with regard to pain, nausea, vomiting, or urinary retention.Conclusion. Nalmefene has similar pharmacokinetics in children as in adults. It was administered safely to these patients and did not produce unmanageable pain.
Tachycardia‐Induced Heart Failure Does Not Alter Myocardial P‐glycoprotein Expression
Authors: Sims J. Jason , Neudeck Brien L. , Loeb Jennifer M. , Wiegert Nicholas A. 
Published: June 2004

Study Objective. To determine the effects of tachycardia‐induced heart failure on myocardial P‐glycoprotein (P‐gp) expression.Design. Nonblinded, parallel, sham‐controlled, animal model study.Setting. University laboratory.Animals. Thirty mongrel dogs.Intervention. Heart failure was induced by rapid ventricular pacing over 4 weeks; sham procedures were performed for the control group.Measurements and Main Results. Myocardial biopsies were taken from the left ventricular lateral wall and prepared for P‐gp quantification by laser‐induced fluorescence. The relative amount of P‐gp messenger RNA (mRNA) was assessed by reverse transcriptase polymerase chain reaction. Rapid ventricular pacing produced heart failure and reduced the area ejection fraction from 48% ± 6% to 21% ± 6% (p<0.05 vs baseline). However, heart failure did not alter the quantity of myocardial P‐gp (0.20 ± 0.02 μg/ml for the control group vs 0.23 ± 0.02 μg/ml for the intervention group, p=0.4). Furthermore, heart failure did not alter P‐gp expression significantly.Conclusion. Myocardial P‐gp does not change in response to tachycardia‐induced heart failure. Thus, there is a low likelihood for P‐gp–related drug resistance during a syndrome similar to tachycardia‐induced heart failure.