bluuebunny/crossref_metadata_2025 huggingface dataset:
The Pharmacokinetics and Pharmacodynamics of Zoledronic Acid in Cancer Patients with Varying Degrees of Renal Function
Authors: Skerjanec Andrej , Berenson James , Hsu ChyiHung , Major Pierre , Miller Wilson H. , Ravera Christina , Schran Horst , Seaman John , Waldmeier Felix
Published: April 2003

An open‐label pharmacokinetic and pharmacodynamic study of zoledronic acid (Zometaθ) was performed in 19 cancer patients with bone metastases and known, varying levels of renal function. Patients were stratified according to creatinine clearance (CLcr) into different groups of normal (CLcr > 80 mL/min), mildly (CLcr = 50–80 mL/min), or moderately/severely impaired (CLcr = 10–50 mL/min) renal function. Three intravenous infusions of 4 mg zoledronic acid were administered at 1‐month intervals between doses. Plasma concentrations and amounts excreted in urine were determined in all subjects, and 4 patients were administered 14C‐labeled zoledronic acid to assess excretion and distribution of drug in whole blood. In general, the drug was well tolerated by the patients. Mean area under the plasma concentration versus time curve and mean concentration immediately after cessation of drug infusion were lower, and mean amounts excreted in urine over 24 hours from start of infusion were higher in normal subjects than in those with impaired renal function (36% vs. 28% of excreted dose), although the differences were not significant. Furthermore, with repeated doses, there was no evidence of drug accumulation in plasma or changes in drug exposure in any of the groups, nor was there any evidence of changes in renal function status. Serum levels of markers of bone resorption (serum C‐telopeptide and N‐telopeptide) were noticeably reduced after each dose of zoledronic acid across all three renal groups. It was concluded that in patients with mildly to moderately reduced renal function, dosage adjustment of zoledronic acid is likely not necessary.
Pharmacokinetics of Nateglinide in Renally Impaired Diabetic Patients
Authors: Devineni Damayanthi , Walter Yulia H. , Smith Harold T. , Lee James S. , Prasad Pratapa , McLeod James F.
Published: April 2003

Treatment of hyperglycemia in patients with diabetes mellitus and renal insufficiency is complicated by altered pharmacokinetics of hypoglycemic agents. This study evaluated the pharmacokinetic profile and safety of nateglinide, an amino acid derivative that improves early phase insulin secretion and reduces mealtime glucose excursions. This open‐label, single‐dose, two‐center study included patients (mean age = 57 ± 10 years) with type 1 or 2 diabetes with impaired renal function (IRF) (n = 10) or with renal failure undergoing hemodialysis (n = 10). Both groups were compared with age‐, sex‐, height‐, and weight‐matched healthy controls (n = 20). All participants received a single 120‐mg dose of nateglinide immediately before breakfast. Pharmacokinetic and safety evaluations were undertaken up to 48 hours postdose. All 40 subjects completed the study. Plasma nateglinide concentrations increased rapidly in patients undergoing dialysis and matched healthy subjects (tmax = 0.95 vs. 0.78 h, respectively) and was comparable with patients with IRF and matched healthy subjects (tmax = 0.80 vs. 0.65 h, respectively). There were no statistically significant differences for Cmax or AUC0‐t between the groups. Nateglinide was eliminated rapidly in all groups (t1/2 = 1.9–2.8 h). There was no correlation between the level of renal function and systemic exposure. There was a low extent of renal excretion of nateglinide in healthy subjects (11%) and diabetic patients with IRF (3%). Nateglinide was well tolerated. These data suggest that nateglinide is suitable for use in diabetic patients with IRF or with renal failure undergoing dialysis. Given the comparable absorption and elimination profiles of nateglinide in renally impaired and healthy subjects, no dose adjustment appears necessary in the renally impaired.
Pharmacokinetic and Safety Assessments of Concurrent Administration of Risperidone and Donepezil
Authors: Zhao Qinying , Xie Charles , Pesco‐Koplowitz Luana , Jia Xinwei , Parier Jean‐Loup
Published: April 2003

Treatment of Alzheimer's disease sometimes uses combinations of drugs because dementia is frequently associated with behavioral symptoms. Risperidone and donepezil are both metabolized through cytochrome P450 2D6 and 3A4, raising the possibility of drug interactions with combination therapy. The objective of this study was to determine whether significant drug interactions occur with concomitant administration of donepezil and risperidone. In an open‐label, three‐way crossover study, 24 healthy men were randomly assigned to receive 0.5 mg of risperidone twice daily, 5 mg of donepezil once daily, or both drugs for 14 consecutive days, followed by a 21‐day washout period. The treatment ratios of AUC and associated 90% confidence intervals (CIs) for risperidone active moiety, defined as risperidone plus 9‐hydroxyrisperidone (ratio = 110.2%; 90% CI = 103.7–117.2), and for donepezil (ratio = 97.1%; 90% CI = 90.0–103.6) were within the 80% to 125% of bioequivalence range. The treatment ratios of Cmax and associated 90% CIs for risperidone active moiety (ratio = 114.6%; 90% CI = 107.0–122.8) and for donepezil (ratio = 96.1%; 90% CI = 90.0–102.6) were also within the bioequivalence range. Therefore, no significant pharmacokinetic differences occurred in either risperidone active moiety or donepezil when given alone or in combination. Adverse events (predominantly headache, nervousness, and somnolence) were minor and comparable for all treatment groups. The results indicate that no clinically meaningful drug interactions occurred between risperidone 1 mg daily and donepezil 5 mg daily at steady state, and therefore no dosage adjustment is required when both drugs are combined with the dosage regimen studied. Additional investigations are warranted to determine the potential for interactions in elderly patients with dementia who may eliminate risperidone and donepezil more slowly and thus be more vulnerable to clinical drug interactions than the young healthy subjects examined in this study.
Pharmacokinetics of Rosiglitazone in Patients with Varying Degrees of Renal Insufficiency
Authors: Chapelsky Martha C. , Thompson‐Culkin Kathleen , Miller Ann K. , Sack Marshall , Blum Robert , Freed Martin I.
Published: April 2003

This study investigated the effect of varying degrees of renal insufficiency on the pharmacokinetics of rosiglitazone. Subjects were stratified by estimated creatinine clearance: normal (> 80 mL/min; n = 12), mild renal insufficiency (60–80 mL/min; n = 15), moderate renal insufficiency (30–59 mL/min; n = 18), and severe renal insufficiency not requiring dialysis (≤ 29 mL/min; n = 12). Plasma rosiglitazone concentrations and protein binding were determined after a single oral 8‐mg dose of rosiglitazone. Total and unbound pharmacokinetic parameters were generated using noncompartmental methods. AUC, Cmax, and t1/2 data were analyzed separately by ANOVA to provide point estimates and corresponding 95% confidence intervals. The pharmacokinetics of rosiglitazone was not markedly affected by mild, moderate, or severe renal insufficiency. Slight increases (approximately 10%–20%) in mean unbound AUC0‐∞ values were observed for each insufficiency group compared to the normal group but were not considered to be clinically relevant. Patients with severe insufficiency exhibited a 38% increase in mean fraction unbound, leading to an increase in total clearance, which resulted in a 19% to 24% lower mean total AUC0‐∞ and Cmax values relative to the normal group. The rates of mild or moderate adverse events were similar for all groups; there were no severe adverse events. Impaired renal function does not markedly alter the pharmacokinetics of total or unbound rosiglitazone following a single dose of rosiglitazone. Therefore, the starting dose of rosiglitazone does not need to be adjusted in patients with renal impairment. Subsequent dose adjustments should be based on individual patient response.
Multiple‐Dose Escalation, Safety, and Tolerability Study of Wood Creosote, the Principal Active Ingredient of Seirogan, an Herbal Antidiarrheal Medication, in Healthy Subjects
Authors: Kuge Tomoo , Shibata Takashi , Willett Michael S.
Published: April 2003

Seirogan, an herbal medicine containing wood creosote (CAS 8021‐39‐4), a mixture of simple phenolic compounds, has been marketed for the past century in Asia for the treatment of acute diarrhea and associated symptoms, such as abdominal discomfort and cramping. The present study was designed to assess the safety and tolerability of an anticipated acute antidiarrheal dosing regimen. Sixty healthy males were randomized into five groups of 12 subjects each (9 wood creosote; 3 placebo) to receive 45‐, 90‐, 135‐, 180‐, and 225‐mg tablets every 2 hours for five doses. Serial sitting and standing vital signs, ECG rhythm strips, and continuous telemetry monitoring were obtained predose and for 24 hours after the first dose. Clinical laboratory tests and 12‐lead resting ECGs were obtained predose and 24 hours postdose. Of the subjects, 27% (12/45) receiving wood creosote and 27% (4/15) receiving placebo reported adverse events. The most common adverse events were altered taste and somnolence, reported more often with 180‐ and 225‐mg doses. Wood creosote had no clinically significant effects on vital signs, ECG intervals or interpretations, or clinical laboratory tests. No clinically significant or serious dysrhythmias were reported on continuous telemetry monitoring. It was concluded that oral doses of wood creosote 45 to 225 mg every 2 hours for up to five doses were safe and well tolerated in 45 healthy subjects. Wood creosote doses ranging from 45 to 135 mg per dose, which are commonly administered antidiarrheal doses in Asia, were associated with minimal side effects.
Pharmacokinetic Strategies in Deciphering Atypical Drug Absorption Profiles
Authors: Zhou Honghui
Published: April 2003

Drug absorption is a very complex process that manifests itself through potential interaction with a host of physicochemical and physiological variables. Some factors that may affect the absorption processes include presystemic metabolism/efflux, the “absorption window” along the gastrointestinal tract, disease states, demographics (gender, age, ethnicity), and biopharmaceutical classification of solid dosage forms. Despite the complexity of the absorption processes, the analysis of the absorption kinetic data is mostly empirical, and the assumption of first‐order absorption is axiomatic. Nevertheless, we often encounter irregular drug absorption profiles (such as double‐peak, absorption window—type absorption profiles, etc.) that cannot be satisfactorily described by a simple first‐order absorption process. The selection of an inappropriate absorption model would result in the misspecification of the pharmacokinetic model and subsequent erroneous prediction of the dosing regimen. This article presents several pharmacokinetic strategies in analyzing typical and atypical absorption profiles. The atypical absorption profiles discussed in this article include parallel first‐order absorption, mixed zero‐order and first‐order absorption, Weibull‐type absorption, absorption window with or without Michaelis‐Menton absorption, time‐dependent absorption, and inverse Gaussian density absorption. In any event, intravenous drug concentration‐time data are generally needed to avoid the ambiguousness in the absorption analyses.
Single‐Dose Pharmacokinetics and Pharmacodynamics of RWJ 67657, a Specific p38 Mitogen‐Activated Protein Kinase Inhibitor: A First‐in‐Human Study
Authors: Parasrampuria Dolly A. , de Boer Peter , Desai‐Krieger Daksha , Chow Andrew T. , Jones C. Richard
Published: April 2003

The objective of this study was to investigate the pharmacokinetics and ex vivo pharmacodynamics of increasing doses of RWJ 67657, along with the effect of food at one dose level in a first‐in‐human (FIH) study. This was a placebo‐controlled, double‐blind, randomized trial in healthy male subjects. Subjects received increasing doses of RWJ 67657 or placebo as a single oral dose (0.25–30 mg/kg) under fasting conditions. The effect of food was investigated for the 10‐mg/kg dose. Plasma concentrations of RWJ 67657 were measured over a period of 48 hours using a validated LC‐MS/MS method. To evaluate the pharmacodynamics of RWJ 67657, inhibition of cytokine production was monitored from ex vivo—stimulated polymorphonuclear blood cells (PBMCs). Pharmacokinetic/pharmacodynamic modeling was used to characterize the inhibitory activity of RWJ 67657. RWJ 67657 was rapidly absorbed (mean tmax = 0.6–2.5 h). The pharmacokinetics of RWJ 67657 appear to be nonlinear with respect to single‐dose administration of the investigative formulation. Coadministration of food did not have a significant effect on half‐life or time to peak concentration (tmax) but decreased the exposure. Mean Cmax values in the presence of food were almost 50% lower than during fasting (542 vs. 1283 ng/mL), and the AUC decreased from 2832 to 1904 ng•h/mL with food. RWJ 67657 inhibited TNF‐a, IL‐8, and IL‐6 in a concentration‐dependent manner with mean IC50 values of 0.18 μM, 0.04 μM, and 0.43 μM, respectively. At 20 mg/kg, the median inhibition was greater than 85%. There were no significant adverse effects associated with single doses of this drug. This study demonstrates that RWJ 67657 has acceptable safety and pharmacokinetics to warrant further investigation in a repeat‐dose setting. In addition, the early determination of effect on biomarkers suggests potential efficacy in diseases mediated by proinflammatory and inflammatory cytokines.
Population Pharmacokinetics and Pharmacodynamics of Ciclesonide
Authors: Rohatagi S. , Arya V. , Zech K. , Nave R. , Hochhaus G. , Jensen B. K. , Barrett J. S.
Published: April 2003

Ciclesonide is a novel glucocorticoid that is converted into ciclesonide—active principle (CIC‐AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC‐AP using nonlinear mixed‐effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD) parameters, and investigate the effects of CIC‐AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400–3600 μg) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC‐AP population PK analysis. Various models examined inter‐ and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% coefficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC‐AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC‐AP can be described using mixed‐effect modeling. The estimated EC50 is similar to mean Cmax from an 800–μg dose, further suggesting CIC‐AP has little effect on cortisol suppression.
Reproducibility of Dorsal Hand Vein Responses to Phenylephrine and Prostaglandin F2α Using the Dorsal Hand Vein Compliance Method
Authors: Schindler C. , Grossmann M. , Dobrev D. , Francke K. , Ravens U. , Kirch W.
Published: April 2003

Assessment of drug‐induced venodilation by the dorsal hand vein compliance method requires stable constriction of the vein. This study was designed to investigate intra‐ and intersubject reproducibility of the venous preconstriction technique in response to phenylephrine and prostaglandin F2α and to determine the influence of basal vein size. Twelve healthy male nonsmokers participated in a prospective crossover study. Inter‐ and intrasubject variability was tested in response to phenylephrine and PGF2α on different study days in the same hand vein. The dose of the respective constrictor causing approximately 80% constriction of the vein (ED80) was determined and infused for another 100 minutes. Actual vein size was measured every 5 minutes. Coefficient of variation and regression analyses were performed to analyze influence of vessel size on ED80 of the respective constrictor. Adjusted constriction levels were stable and well reproducible in all subjects. The intersubject coefficient of variation of ED80 ranged from 0.9% to 6.7% for phenylephrine and from 0.9% to 6.9% for PGF2α. Whereas responses to phenylephrine were independent of basal vein diameter, there was a positive correlation between ED80 of PGF2α and basal vein size. Thus, the hand vein compliance method is a suitable method to study dilatory responses in phenylephrine‐ or PGF2α‐constricted veins with considerable interindividual but small intraindividual variability. However, in such studies, phenylephrine appears to be a more reliable tool than PGF2α.
A Model of Pharmacology Education: The Experience of Istanbul Medical Faculty
Authors: Eroğlu Lütfiye , Uresin Yagiz
Published: April 2003

This article describes the pharmacology education program that has been applied since 1990 at the Istanbul Medical Faculty. In Turkey, medical education lasts 6 years after 11 years of general training. Each year, approximately 350 students join the Istanbul Medical Faculty. The education is mainly in conventional form: basic sciences and elementary clinical information are given mostly as didactic lectures accompanying practical courses for small groups, with each group consisting of about 50 students during the first 3 years. In the subsequent 2 years, students have several clinical clerkships, and the last year is an internship. Pharmacology, the bridge between basic and clinical sciences, has a special place in the medical training. Accordingly, the courses were expanded to 3, 4, and 5 years, the sum of all courses being approximately 140 hours. Pharmacology education took place along with basic sciences in the first years but with clinical sciences in the later years and is based on active learning methods.
Pharmacokinetics of Pregabalin in Subjects with Various Degrees of Renal Function
Authors: Randinitis Edward J. , Posvar Edward L. , Alvey Christine W. , Sedman Allen J. , Cook Jack A. , Bockbrader Howard N.
Published: April 2003

The objectives of this study were to determine the single‐dose pharmacokinetics of pregabalin in subjects with various degrees of renal function, determine the relationship between pregabalin clearance and estimated creatinine clearance (CLcr), and measure the effect of hemodialysis on plasma levels of pregabalin. Results form the basis of recommended pregabalin dosing regimens in patients with decreased renal function. Thirty‐eight subjects were enrolled to ensure a wide range of renal function (CLcr < 30 mL/min, n = 8; 30–50, n = 5; 50–80, n = 7; and > 80, n = 6). Also enrolled were 12 subjects with renal impairment requiring hemodialysis. Each subject received 50 mg of pregabalin as two 25‐mg capsules in this open‐label, parallel‐group study. Pregabalin concentrations were measured using previously validated liquid chromatographic methods. Pregabalin pharmacokinetic parameters were evaluated by established noncompartmental methods. Pregabalin was rapidly absorbed in all subjects. Total and renal pregabalin clearance were proportional (56% and 58%, respectively) to CLcr. As a result, area under the plasma concentration‐time profile (AUC) and terminal elimination half‐life (t1/2) values increased with decreasing renal function. Pregabalin dosage adjustment should be considered for patients with CLcr < 60 mL/min. A 50% reduction in pregabalin daily dose is recommended for patients with CLcr between 30 and 60 mL/min compared to those with CLcr > 60 mL/min. Daily doses should be further reduced by approximately 50% for each additional 50% decrease in CLcr. Pregabalin was highly cleared by hemodialysis. Supplemental pregabalin doses may be required for patients on chronic hemodialysis treatment after each hemodialysis treatment to maintain steady‐state plasma pregabalin concentrations within desired ranges.
Randomized, Double‐Blind, Placebo‐Controlled Comparison of the Analgesic Efficacy of Oxycodone 10 mg/Acetaminophen 325 mg versus Controlled‐Release Oxycodone 20 mg in Postsurgical Pain
Authors: Gammaitoni Arnold R. , Galer Bradley S. , Bulloch Scott , Lacouture Peter , Caruso Frank , Ma Tina , Schlagheck Thomas
Published: April 2003

This randomized, controlled trial compared the analgesic efficacy and safety of the new oxycodone 10‐mg/acetaminophen 325‐mg formulation (Percocet®) for the treatment of acute pain following oral surgery with double the dose of oxycodone alone (controlled‐release [CR] oxycodone 20 mg [OxyContin®]). A total of 150 male and female patients with ≥ 2 full or partial bone‐impacted mandibular molars, at least moderate persistent pain, and moderate trauma received a single dose of combination agent, CR oxycodone, or placebo following oral surgery and rated pain intensity and pain relief over the next 6 hours. The intent‐to‐treat population comprised 141 patients (55 on combination agent, 56 on oxycodone, and 30 on placebo). Combination agent and CR oxycodone were significantly superior to placebo for all efficacy measures. Combination agent was statistically superior to CR oxycodone in four of five outcome measures of pain intensity and pain relief (PPID, PPAR, SPID, and SPRID). It also provided a faster onset and 24% reduction in the number of patients reporting treatment‐related adverse events compared with twice the dose of opioid alone. This new formulation offers the combination of two analgesic drugs with complementary mechanisms of action, which results in enhanced analgesia, an “opioid‐sparing” effect, and an improved side effect and safety profile.
Pharmacokinetic/Pharmacodynamic Modeling of Luteinizing Hormone (LH) Suppression and LH Surge Delay by Cetrorelix after Single and Multiple Doses in Healthy Premenopausal Women
Authors: Nagaraja Nelamangala V. , Pechstein Birgit , Erb Katharina , Klipping Christine , Hermann Robert , Locher Mathias , Derendorf Hartmut
Published: April 2003

Cetrorelix (CET) is a potent luteinizing hormone—releasing hormone (LH‐RH) antagonist and is used to prevent premature ovulation in IVF (in vitro fertilization) procedures. The objective of the present study was to develop a pharmacokinetic/pharmacodynamic (PK/PD) model for the LH suppression and LH surge delay after single doses (SD) and multiple doses (MD) of CET in healthy premenopausal women without ovarian stimulation. CET was given by subcutaneous route (SD, 0.25, 0.5, or 1 mg) on cycle day 3 and as similar multiple once‐a‐day doses from cycle day 3 to day 16 in two consecutive menstrual cycles. The concentration‐time data of CET and LH were used for PK/PD modeling. A two‐compartment model described the PK of CET with median terminal half‐life estimates of 9.2 and 54.5 hours after SD and MD, respectively. An indirect‐response Emax model was used to describe the LH suppression and the LH surge delay. LH suppression was linked to plasma concentrations of CET, while the delay in the LH surge was linked to the PK of CET through a hypothetical effect compartment. Since the SD regimen on day 3 did not cause significant delay, these values were used as controls in the analysis of surge delay in MD data. The IC50 (for suppression) estimate was 0.73 ng/ml for SD, and EC50 (surge delay) was 1.42 ng/ml for MD. The PK/PD model adequately described the LH suppression and the surge delay.
Pharmacokinetics of an Immediate‐Release Oral Formulation of Fampridine (4‐Aminopyridine) in Normal Subjects and Patients with Spinal Cord Injury
Authors: Hayes K. C. , Katz M. A. , Devane J. G. , Hsieh J. T. C. , Wolfe D. L. , Potter P. J. , Blight A. R.
Published: April 2003

Plasma concentration profiles of the K+ channel‐blocking compound Fampridine were obtained from (1) control subjects (n = 6) following oral administration of doses of 10, 15, 20, and 25 mg and (2) patients with spinal cord injury (SCI) (n = 11) following a single oral dose of 10 mg of an immediate‐release formulation. Plasma concentrations were determined using a reversed‐phase ion‐pair high‐performance liquid chromatography (HPLC) assay with ultraviolet light detection employing liquid extraction. The drug was rapidly absorbed with a tmax ∼1 hour for both groups; tmax was independent of dose. Cmax and AUC0‐∞ were linearly related to dose, and t1/2 was 3 to 4 hours for both groups. There were no obvious differences in the (10‐mg) plasma concentration profiles between control subjects and SCI patients. The drug was well tolerated, with only mild and transient side effects of light‐headedness, dysesthesias, and dizziness.
Tegaserod Pharmacokinetics Are Similar in Patients with Severe Renal Insufficiency and in Healthy Subjects
Authors: Swan Suzanne K. , Zhou Honghui , Horowitz Ann , Alladina Latifa , Hubert Martine , Appel‐Dingemanse Silke , Osborne Stuart , Lambrecht Larry , McLeod James F.
Published: April 2003

Tegaserod (HTF 919), a selective 5‐HT4 receptor partial agonist with promotile activity throughout the gastrointestinal tract, is in development for the treatment of irritable bowel syndrome. In an open‐label, parallel‐group study, the pharmacokinetics of a single 12‐mg oral dose of tegaserod in patients with severe renal insufficiency requiring hemodialysis were compared with data obtained from healthy subjects matched for age, weight, height, and gender (n = 10, both). The pharmacokinetics of tegaserod were similar in both groups (AUC(0h‐tz), ng • h/ml: 14.6 ± 8.5 vs. 14.3 ± 7.1; Cmax, ng/ml: 4.6 ± 2.3 vs. 5.1 ± 2.2; tmax, h: 1.0, for both). Tegaserod had similar tolerability in renally impaired patients and healthy volunteers, with adverse events largely related to the gastrointestinal pharmacological actions of the drug. Therefore, no dose adjustment of tegaserod is necessary for patients with renal insufficiency.
Short‐Term Exposure to Low‐Dose Ritonavir Impairs Clearance and Enhances Adverse Effects of Trazodone
Authors: Greenblatt David J. , von Moltke Lisa L. , Harmatz Jerold S. , Fogelman Steven M. , Chen Gengsheng , Graf Jennifer A. , Mertzanis Polyxane , Byron Susan , Culm Kerry E. , Granda Brian W. , Daily Johanna P. , Shader Richard I.
Published: April 2003

Antiretroviral agents may participate in drug interactions that influence the efficacy and toxicity of other antiretrovirals, as well as pharmacologic treatments of coincident or complicating diseases. The viral protease inhibitor, ritonavir, may cause drug interactions by inhibiting the activity of cytochrome P450‐3A (CYP3A) isoforms. In a single‐dose, blinded, four‐way crossover study, 10 healthy volunteer subjects received 50 mg of trazodone hydrochloride or matching placebo concurrent with low‐dose ritonavir (four doses of 200 mg each) or with placebo. Compared to the control condition, ritonavir significantly reduced apparent oral clearance of trazodone (155 ± 23 vs. 75 ± 12 ml/min, p < 0.001), prolonged elimination half‐life (6.7 ± 0.7 vs. 14.9 ± 3.9 h, p < 0.05), and increased peak plasma concentrations (842 ± 64 vs. 1125 ± 111 ng/ml, p < 0.05) (mean ± SE). Coadministration of trazodone with ritonavir increased sedation, fatigue, and performance impairment compared to trazodone plus placebo; differences reached significance only for the digit‐symbol substitution test. Three subjects experienced nausea, dizziness, or hypotension when trazodone was given with ritonavir; 1 of these subjects also experienced syncope. Thus short‐term low‐dose administration of ritonavir impairs oral clearance of trazodone and increases the occurrence of adverse reactions. The findings are consistent with impairment of CYP3A‐mediated trazodone metabolism by ritonavir.
Effects of Orlistat, a Lipase Inhibitor, on the Pharmacokinetics of Three Highly Lipophilic Drugs (Amiodarone, Fluoxetine, and Simvastatin) in Healthy Volunteers
Authors: Zhi Jianguo , Moore Rema , Kanitra Linda , Mulligan Thomas E.
Published: April 2003

To investigate the effect of orlistat on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin), the authors performed double‐blind, placebo‐controlled, randomized two‐period crossover (for fluoxetine and simvastatin) or parallel (for amiodarone) studies in healthy volunteers ages 18 to 65 years of a body mass index between 18 and 30 kg/m2. During treatment with orlistat or matching placebo for 5 to 13 ⅓ days, a single oral dose of highly lipophilic drug was administered, followed by obtaining serial blood samples for measuring plasma (for fluoxetine and simvastatin) or serum (for amiodarone) concentrations of the lipophilic drug and its active metabolite. Treatments were compared for the pharmacokinetic parameters AUC0‐∞, Cmax, tmax, and t1/2 of highly lipophilic drugs and active metabolites. Analysis of variance was performed to assess the significance of the sequence effect and provide the variance estimate for the 90% confidence intervals. Subjects were also evaluated for adverse events, vital signs, and clinical and laboratory safety. The absorption of amiodarone (and active metabolite) was significantly reduced by approximately one‐quarter using parameters of Cmax and AUC, while no inhibition of absorption was observed for fluoxetine and simvastatin as well as their active metabolites. There were no clinically significant differences in t1/2 and tmax for all three drugs tested. Due to expected gastrointestinal adverse events known to occur with orlistat, there was a higher incidence of adverse events under regimen B (highly lipophilic drugs and orlistat) than under regimen A (highly lipophilic drugs and placebo). Other adverse events were sporadic and unremarkable. There were no clinically relevant changes in vital signs or laboratory values. In conclusion, except for amiodarone, there was no effect of orlistat on the pharmacokinetics of highly lipophilic drugs when these drugs were taken concomitantly with orlistat.
Biomarkers in Drug Discovery and Development: From Target Identification through Drug Marketing
Authors: Colburn Wayne A.
Published: April 2003

Biomarkers of disease play an important role in medicine and have begun to assume a greater role in drug discovery and development. The challenge for biomarkers is to allow earlier, more robust drug safety and efficacy measurements. Their role in drug development will continue to grow for the foreseeable future. For biomarkers to assume their rightful role, greater understanding of the mechanism of disease progression and therapeutic intervention is needed. In addition, greater understanding of the requirements for biomarker selection and validation, biomarker assay method validation and application, and clinical endpoint validation and application is needed. Biomarkers need to be taken into account while the therapeutic target is still being identified and the concept is being formulated. Biomarkers need to be incorporated into a continuous cycle that takes what is learned from the discovery and development of one series of biomarkers and translates it into the next series of biomarkers. Optimum biomarker development and application will require a team approach because of the multifaceted nature of biomarker selection, validation, and application, using such techniques as pharmacoepidemiology, pharmacogenetics, pharmacogenomics, and functional proteomics; bioanalytical method development and validation; disease process and therapeutic intervention assessments; and pharmacokinetic/pharmacodynamic modeling and simulation to improve and refine drug development. The potential for biomarkers in medicine and drug development will be limited by the least effective component of the processes. The team approach will minimize the potential for the least effective component to be fatal to the rest of the process. As scientific/regulatory foundations for biomarkers in medicine and drug development begin to be established, successes and applications will need to be effectively communicated with all of the stakeholders, including not only internal and external drug developers and regulators but also the medical community, to ensure that biomarkers are totally integrated into drug discovery and development as well as the practice of medicine.
I Can Hear You, but Can I See You?
Authors: Bolls Paul D.
Published: April 2003

This study tested the proposition that high-imagery radio advertisements engage visual cognitive resources. Participants in a within-subjects experiment were exposed to 60-second radio advertisements previously coded as either high- or low-imagery ads. During half of the ads, participants were also presented a series of pictures unrelated to the content of the ads. Dual-task interference between the cognitive tasks of listening to the radio advertisements and viewing the unrelated pictures was found in recognition data for high-imagery ads but not low-imagery ads. This pattern of results indicates listening to high-imagery radio ads competes with visual tasks for cognitive resources. Therefore, it appears listening to high-imagery radio advertisements engages visual cognitive resources despite the fact these advertisements are auditory messages. Implications for theories of communication-evoked mental imagery are discussed.
The “Trap” Effect of Television and Its Competitors
Authors: Schoenbach Klaus , Lauf Edmund
Published: April 2003

The “trap” effect is the alleged ability of television (a) to disseminate political information to those who are not interested in politics and (b) to influence them more strongly than other channels of political information, such as newspapers, can. These ideas are tested in 12 European countries for the campaign of the European election in 1999: Was television really more powerful than newspapers among the many citizens who did not care about that election? The authors' analyses show that the trap power of television was far from being impressive. Also, seemingly favorable national conditions for a trap effect of television, such as more TV news coverage on the European elections and fewer TV channels to evade that coverage, did not help. Instead, personal conversations better persuaded the uninterested to turn out and vote than television (and newspapers) did.
Knowledge, Reservations, or Promise?
Authors: Nisbet Matthew C. , Scheufele Dietram A. , Shanahan James , Moy Patricia , Brossard Dominique , Lewenstein Bruce V.
Published: April 2003

This study introduces a media effects model specific to public perceptions of science and technology. Analysis of the National Science Board's Science and Engineering Indicators Survey provides evidence that different media—newspapers, general television, science television, and science magazines—do affect perceptions differently. These media effects are direct but also indirect, as mediated through effects on science knowledge. Although newspaper reading, science television viewing, and science magazine reading all promote positive perceptions of science, given the relative size of its audience, the impact of general television viewing remains the most compelling finding. The negative images of science on television appear to cultivate scientific reservations, whereas television's portrayal of science as sometimes omnipotent, and offering hope for the future, appears to also promote a competing schema related to the promise of science. Television's direct effect on reservations is reinforced through the medium's negative relationship with science knowledge.
Base-Rate Bingo
Authors: Berger Charles R.
Published: April 2003

Alternative explanations for the thrice-replicated interaction between the presence andabsence of population data andsex on apprehension andvictimization risk were examined. Consistent with three previous experiments, men first exposed to population increase data were less apprehensive after reading a news story containing frequency depictions of increasing threat than were men not first exposed to population data. Women's apprehension levels were unaffected by exposure to population data. However, this interaction was reversedwhen a thought-listing task was interpolatedbetween the threatening story and the apprehension judgments. Although men showed significantly higher statistical skill levels than did women and individuals with higher levels of statistical skill reportedless apprehension, statistical skill did not account for the observedinteraction between sex andexposure to population data. Analyses of cognitive responses suggested that although both women and men heed relevant base-rate data, these data prompt men and women to alter the production of different cognitive responses. Sex differences in reportedapprehension as a function of exposure to base-rate data appear to be mediated by different cognitive responses to base-rate data.
The Effects of Increased Cognitive Involvement on College Students' Interpretations of Magazine Advertisements for Alcohol
Authors: WeintraubAustin Erica , Miller Amber Coral-Reaume , Silva John , Guerra Petra , Geisler Neva , Gamboa Luxelvira , Phakakayai Orlalak , Kuechle Bryant
Published: April 2003

An experiment with 520 college students tested whether heightened awareness of cognitive processes during media exposure would affect the message interpretation process by enhancing skepticism, with the enhanced skepticism influencing both affective and cognitive aspects of decision making. Skepticism has affective andlogical components, which can be representedby trust (more affective) andperceivedrealism (more logical), andskepticism's effects on affective and logical decision making are manifested somewhat differently. The results of this study suggest that a minimal intervention that activates skepticism can have both direct and indirect effects on the message interpretation process that can improve the quality of decision making.
Agenda Setting and the “New” News
Authors: Althaus Scott L. , Tewksbury David
Published: April 2003

This study examines whether readers of the paper and online versions of a national newspaper acquire different perceptions of the importance of political issues. Using data from a weeklong experiment in which subjects either readthe print version of the New York Times , the online version of that paper, or received no special exposure, this study finds evidence that people exposed to the Times for 5 days adjusted their agendas in response to that exposure and that print readers modified their agendas differently than did online readers.
Captured by the World Wide Web
Authors: Lang Annie , Borse Jennifer , Wise Kevin , David Prabu
Published: April 2003

This article uses a limited-capacity information-processing perspective to investigate which structural features of computers elicit orienting responses in attentive computer users. The results of three experiments test the ability of plain text, boxed text, warnings, nonanimated banner advertisements, and animated banner advertisements to elicit cardiac-orienting responses in attentive computer users. A second question asks if user or computer control of stimulus presentation alters orienting behavior. A final hypothesis predicts stimuli that elicit orienting will be better recognized than those that do not. Results show that plain text, boxed text, and nonanimated banner advertisements do not elicit cardiac orienting. However, warnings and animated banner advertisements do elicit orienting. In general, stimuli that elicit orienting are recognized better than those that do not. Control over stimulus onset has little or no effect on orienting behavior.
Gender as a Variable in Interpretation of Alcohol-Related Messages
Authors: Andsager Julie L. , Austin Erica Weintraub , Pinkleton Bruce E.
Published: April 2003

Research suggests that adolescents employ logic and emotion in processing media messages. Gender schema theory argues that gender roles are internalized by adolescence; gender should thus affect information processing. This study exposed 578 ninth and twelfth graders to eight alcohol-related messages. Boys found individualistic messages in alcohol advertising more persuasive and memorable, and girls were more persuaded by collectivist messages in public-service announcements. The findings suggest that gender should be incorporated in models attempting to understand how adolescents analyze messages.
Body Image, Race, and Fashion Models
Authors: David Prabu , Morrison Glenda , Johnson Melissa A. , Ross Felecia
Published: April 2003

The perceived effects of advertising on body-image factors were tested in both Black and White college-age women. After seeing magazine ads that portrayed either Black fashion models or White fashion models, respondents rated perceived effects of these ads on body-image factors. The effects were rated on self, on other Black women on campus, and other White women on campus. When projecting perceived effects on others—of the same race or a different race—both Blacks and Whites indicated that media effects would be maximal when the race of the model matched the race of the respondent. However, when rating perceived effects on self, whereas Blacks identified strongly with Black models, there was no significant difference in the way Whites identified with fashion models of either race. The results are examined within the framework of social distance and social identification.
Of Dark Clouds and Silver Linings: Effects of Exposure to Issue Versus Candidate Advertising on Persuasion , Information Retention, and Issue Salience
Authors: Groenendyk Eric W. , Valentino Nicholas A.
Published: April 2003

In this study, we examine the impact of sponsorship cues in issue versus candidate advertising on perceived credibility, persuasion, information retention, and priming of message-relevant issues. Theories of persuasion and attitude change suggest that citizens should react differently to the same message when source cues are varied. In an experiment, adult participants saw either an actual ad sponsored by the Sierra Club, an edited version in which Al Gore was depicted as the sponsor, or no ad at all. Although participants were slightly less able to correctly identify the sponsor of the issue ad, the ad was seen as more credible and persuasive than the candidate-sponsored version. Though both were negative in tone, the issue ad did not depress participatory intentions as much as the candidate ad. Participants also retained more information from the issue appeal. Finally, the issue ad was a more powerful prime for message-relevant performance criteria in evaluations of the target, George W. Bush. The implications of these findings for the ongoing debate on campaign-finance reform are discussed.
Person-Effects and Heuristic-Systematic Processing
Authors: Neuwirth Kurt , Frederick Edward , Mayo Charles
Published: April 2003

The study explores the relationship between heuristic and systematic processing and first-, second-, and third-person effects. Controversy surrounding a referendum over the Confederate battle emblem appearing on the Mississippi state flag served as a backdrop for a survey of residents (N = 520) concerning the perceptions of the media's influence on self and others. Results suggest that accuracy-motivated heuristic and systematic processing shows a limited relationship to third- and first-person effects while at the same time demonstrating a robust relationship with transpersonal (second-person) effects. The study revealed that inferred attention of others to the flag issue accounted for additional variance beyond inferred exposure. In addition, systematic processing and second-person effects emerged as significant predictors of indicators of civic participation, discussion and voting, and media censorship. Implications of using the heuristic-systematic model in areas such as political campaigns, social capital and trust, agenda-setting, framing, and the spiral of silence are discussed.
Testing Alternative Explanations for Exposure Effects in Media Campaigns
Authors: Slater Michael D. , Kelly Kathleen J.
Published: April 2003

This study examines longitudinal evidence for the impact of exposure to an in-school media campaign on adolescent substance use attitudes and behaviors, using data from four middle schools in two school districts. Amount of exposure to the campaign directly impacted perceptions that marijuana use was inconsistent with personal aspirations and intentions to use marijuana and appeared to reduce maturational decay in those attitudes. Path analyses suggested effects on behavior change, consistent with the theory of reasoned action, were via effects on intention and exposure effects on intention were via effects on aspirations. Reverse causation was tested and rejected, as were possible moderation models that might also qualify exposure effects. Analyses of a foil recognition measure using a treatment and control population suggested that response set artifacts were nominal in size and that response bias was slight and could be statistically controlled.
When the Frame Paints the Picture
Authors: Lannutti Pamela J. , Monahan Jennifer L.
Published: April 2003

Alcohol myopia theory and relational framing theory were used to explain how alcohol consumption affects perceptions of sexual scenarios. In a within-subjects design, participants (N = 51) evaluated scenarios that emphasized consensual cues only and scenarios with consensual and nonconsensual sexual behaviors (mixed cues). Participants read both scenario types at three blood alcohol levels (.00, .04, and .08 g/dl). Participants viewed affiliation judgments as significantly more relevant than dominance judgements when evaluating the consensual scenarios, regardless of their level of alcohol consumption. For the mixed cues scenarios, participants did not view either dimension as more relevant when sober; when drinking, they viewed dominance judgments as more relevant. As alcohol consumption increased, women were more likely to report that they would act like the female in both scenario types, whereas men were more likely to act like the male in the consensual scenario only.
Perceived Characteristics, Perceived Needs, and Perceived Popularity
Authors: Zhu Jonathan J. H. , He Zhou
Published: April 2003

The Internet has arrived in China, the most populous nation in the world, at a rapid rate. To account for the adoption and use of the Internet by Chinese audiences, the current study develops a theoretical framework that centers on three key independent variables in the diffusion process: perceptions (i.e., perceived characteristics of the Internet or PCI), motivations (perceived need for the Internet or PNI), and social context (perceived popularity of the Internet or PPI). In addition, adoption is conceptualized as involving four categories that are mutually exclusive at a given time but interchangeable over time. This classification enables investigation of discontinuance. The current study also examines reinvention by integrating use into diffusion process. Data from a probability survey of 2,500 residents in Beijing and Guangzhou in 2000 largely support the hypotheses of the model. The study illustrates the importance and benefits of a theory-driven approach to new media research.
Imagery Effects on the Selective Reading of Internet Newsmagazines
Authors: Knobloch Silvia , Hastall Matthias , Zillmann Dolf , Callison Coy
Published: April 2003

An Internet newsmagazine was created, involving all features of online interactivity. The text of all available reports was held constant. The imagery of a subset of articles was manipulated, however. The manipulated articles were presented either without images, with text-related innocuous images, or with text-related threatening images in both their headline displays and their text bodies. During a fixed period of time, readers were free to sample articles and to read as much of them as they pleased. Unbeknownst to them, their selective exposure behavior was automatically recorded. It was observed that the incorporation of threatening images fostered more frequent selection of the associated articles and markedly increased reading times of the corresponding texts. The incorporation of innocuous images had similar but more moderate effects. Retrospective accounts of reading were consistent with the recorded exposure behavior.