bluuebunny/crossref_metadata_2025 huggingface dataset:
Serotonin and Serotonin Antagonism in Cardiovascular and Non‐Cardiovascular Disease
Authors: Frishman William H. , Huberfeld Seymour , Okin Stuart , Wang Yuh‐Huey , Kumar Anil , Shareef Babar
Published: March 2013

Serotonin, or 5‐hydroxytryptamine, is a naturally‐occurring vasoactive substance found primarily in the brain, enterochromaffin tissue, and blood platelets. It has diffuse cardiophysiologic effects. The multiple effects of serotonin on blood vessels can be explained by the existence of 2 serotonergic receptor subtypes (the S1 receptor mediates vasodilation, and the S2 receptor vasoconstriction). Serotonin via the S2 receptor also augments the actions of several other vasoconstricting substances. Serotonin may be responsible for causing, or at least perpetuating, some forms of systemic hypertension through peripheral and central nervous system (CNS) actions. Ketanserin is a highly selective S2‐serotonergic antagonist with additional α‐adrenergic blocking activity, which has been proposed as a therapy for various cardiovascular diseases including hypertension. It has been shown to be more effective than placebo in treating hypertension and comparable in effectiveness to other antihypertensive drugs. Its major side effects relate to the CNS, and prolongation of the electrocardiogram QT interval has been described. Caution must be used when using ketanserin in patients receiving potassium‐ and magnesium‐losing agents, because of the risk of torsades de pointes. Ketanserin has potential utility in the treatment of eclampsia, peripheral vascular disease, carcinoid syndrome, and “shock lung.” The drug is not yet approved for clinical use in the United States.
Excretion of Fluoxetine and Its Metabolite, Norfluoxetine, in Human Breast Milk
Authors: Taddio Anna , Ito Shinya , Koren Gideon
Published: March 2013

A study was conducted to measure breast milk concentrations of fluoxetine and its active metabolite, norfluoxetine, excreted in breast milk in a cohort of nursing women using fluoxetine, and to estimate infant dose from nursing. The study included 10 women nursing 11 infants (median age, 185 days). The mean fluoxetine dose was 0.39 mg/kg/day. Each patient manually collected 3 to 6 milk samples throughout a dosing interval. Concentrations of fluoxetine and norfluoxetine in milk were measured by gas‐liquid chromatography. Mothers reported whether they observed adverse effects in their infants. The average infant doses of fluoxetine and norfluoxetine, as estimated for an exclusively breast‐fed infant ingesting 1000 mL of milk per day, were 0.077 mg (SD = 0.054 mg) and 0.084 mg (SD = 0.043 mg), respectively. The total dose of fluoxetine and norfluoxetine (expressed as fluoxetine equivalents) was 0.165 mg (SD = 0.092 mg), which was equivalent to 10.8% (SD = 2.2%) of the maternal dose, adjusted on a mg/kg basis in a 4‐kg infant. No adverse events were reported by mothers in their infants. Approximately one tenth of the adult therapeutic dose of fluoxetine is excreted in breast milk. Although short‐term adverse effects in the infant from exposure through nursing were not reported in this cohort, future studies that assess the potential long‐term consequences are needed.
Pharmacokinetics of Recombinant Human Granulocyte‐Macrophage Colony‐Stimulating Factor: The Effects of Zidovudine
Authors: Aweeka Francesca T. , Kwong Mae , Mak May , Al‐Uzri Almira , Affrime Mel , Cutler David , Kahn James , Gambertoglio John G.
Published: March 2013

Recombinant human granulocyte‐macrophage colony‐stimulating factor (rHu GM‐CSF) enhances bone marrow production of and stimulates granulocytes, macrophages, and eosinophils. Granulocyte‐macrophage colony‐stimulating factor may be used concomitantly with zidovudine in human immunodeficiency virus (HIV)‐positive patients to minimize zidovudine‐associated neutropenia. This open‐label, randomized, placebocontrolled study was performed to evaluate the pharmacokinetic disposition of rHu GMCSF in HIV‐positive, asymptomatic patients in the absence and presence of concomitant zidovudine administration. Eight participants received rHu GM‐CSF (5 μg/kg subcutaneously) daily for 4 days in combination with placebo or zidovudine (200 mg orally every 8 hours) in a randomized, crossover fashion, with each study period separated by a 3‐day washout phase. Pharmacokinetic blood sampling was performed over 16 hours on days 1 and 4 of both treatment periods, and subsequent analysis of serum was performed using an enzyme‐linked immunosorbent assay. Pharmacokinetic results of rHu GM‐CSF at steady state (days 4 of periods I and II) in the absence (placebo) and presence of zidovudine included apparent total body clearance, half‐life, and apparent volume of distribution, all of which were not significantly altered with concomitant administration of zidovudine. Mean pharmacokinetic results of rHu GM‐CSF after the first dose (days 1 of periods I and II) were similar to steady‐state values; however, total body clearance was significantly increased at steady state compared with the results of the first dose. Concurrent administration of zidovudine does not influence the pharmacokinetic disposition of rHu GM‐CSF after single or multiple doses.
Pharmacodynamic Evaluation of Codeine Using Tooth Pulp Evoked Potentials
Authors: Suri Ajit , Kaltenbach Matthieu L. , Grundy Betty L. , Derendorf Hartmut
Published: March 2013

Pain assessment in human volunteers is difficult, and it often requires a large number of subjects to show analgesic efficacy with statistical significance. Electrical tooth pulp stimulation elicits a painful sensation and produces an electroencephalographic (EEG) signal that can be recorded from the scalp when precisely controlled dental stimuli are delivered. These somatosensory evoked potentials (EP) consist of a series of peaks or waves each characterized by their polarity, latency, and amplitude. They are obtained by processing the EEG signals that occur after tooth pulp stimulation. There is good correlation between subjective pain reports and evoked potential amplitudes (N150‐P250 component). Thus, EP may provide a useful model for the assessment of analgesic activity in human volunteers. We describe an improved method for producing and recording tooth pulp evoked potentials in six healthy subjects. Only 16 EEG epochs were necessary to get a reproducible EP response from the participants. The approach was applied to study the efficacy of codeine (60 mg administered orally); a decrease in the evoked potential amplitudes after codeine administration was observed. The data were consistent with results from visual analog pain ratings given by the subjects.
Effect of Food on the Relative Bioavailability of Oral Ganciclovir
Authors: Lavelle James , Follansbee Stephen , Trapnell Carol B. , Buhles William C. , Griffy Kay Gaines , Jung Donald , Dorr Albert , Connor James
Published: March 2013

The steady‐state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two‐way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602‐calorie, high‐fat (46.5%) breakfast. Serial blood samples were obtained over the 8‐hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration—time curve from time 0 to 8 hours (AUC0–8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food.
Effect of Age and Gender on Pharmacokinetics of Atorvastatin in Humans
Authors: Gibson Donald M. , Bron Nicola J. , Richens MPhil Alan , Hounslow Neil J. , Sedman Allen J. , Whitfield Lloyd R.
Published: March 2013

Atorvastatin is a new 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor that reduces plasma cholesterol by inhibiting cholesterol synthesis and increasing cellular uptake of low density lipoproteins. The effects of age and gender on the pharmacokinetics of atorvastatin after administration of single 20‐mg tablets of atorvastatin were studied in 16 young and 16 elderly volunteers (8 men and 8 women in each age group). Plasma equivalent concentrations of atorvastatin were quantitated by a validated enzyme inhibition bioassay. Atorvastatin was well tolerated by the participants. The equivalent maximum concentration (Cmax) of atorvastatin was 42.5% higher in elderly participants (age, 66–92 years) than in young participants (age, 19–35 years) and 17.6% higher in women than in men. In addition, mean area under the concentration—time curve (AUC0‐∞) and half‐life (t1/2) were 27.3% greater and 36.2% longer, respectively, in elderly adults than in young adults and 11.3% lower and 19.9% shorter, respectively, in women than in men. Because the primary site of action for HMG‐CoA reductase inhibitors is the liver and atorvastatin is subject to extensive first‐pass hepatic metabolism, it is unclear whether these age‐ and gender‐related differences in the pharmacokinetics of atorvastatin will be clinically important. Results of subsequent safety and efficacy trials should help clarify the clinical significance of these pharmacokinetic differences.
Human Pharmacokinetics and Tolerability of L‐365,260, a Novel Cholecystokinin‐B Antagonist
Authors: Grasing Kenneth , Murphy M. Gail , Lin Juinn , Swigar Mary , Freedholm Debra , Clarke Laura , Zhang Ji , Wolkowitz Owen M. , Weingartner Herbert , Putnam Karen , Seibold James R.
Published: March 2013

A study was conducted to examine the tolerability and pharmacokinetics of single and multiple oral doses of L‐365,260, a novel antagonist for type B cholecystokinin (CCK) receptors and to quantify effects of selective blockade of type B CCK receptors through treatment with L‐365,260 on measures of anxiety, hunger, and cognitive performance. Healthy volunteers were given single oral doses of up to 50 mg of L‐365,260 and multiple oral doses of up to 25 mg every 6 hours for 10 days. Plasma concentrations of L‐365,260 were quantified by means of high‐performance liquid chromatography. Anxiety and hunger were assessed by visual analog scale and the Spielberger State Anxiety Index. Cognitive testing was used to evaluate attention level and short‐term memory. L‐365,260 was rapidly absorbed and a biphasic pattern of elimination was demonstrated with a terminal half‐life (t1/2) of 8 to 12 hours. The mean (n = 6) values for peak plasma concentration (Cmax) and time to peak concentration (tmax) of L‐365,260 were 503 ng/mL and 1.25 hours, respectively, after a single 50‐mg oral dose. Accumulation of L‐365,260 plasma concentrations was seen after the prescribed multiple‐dose regimens. Steady state was achieved after 3 days of oral administration. L‐365,260 had an acceptable tolerability profile after oral administration. No changes in measures of anxiety, hunger, or short‐term memory were observed at doses of L‐365,260 shown to have antagonist activity at the CCK‐B receptor.
Nonparametric Expectation Maximization Population Modeling of Ganciclovir
Authors: Preston Sandra L. , Drusano George L.
Published: March 2013

The use of the nonparametric expectation maximization (NPEM2) program to estimate pharmacokinetic parameters of ganciclovir in a group of patients with human immunodeficiency virus (HIV) and cytomegalovirus (CMV) infection was evaluated. A 10‐point data set per patient obtained over 8 hours was analyzed. Mean pharmacokinetic parameters obtained included rate constant from the central to the peripheral compartment (KCP, 3.1 hr−1), rate constant from the peripheral to the central compartment (KPC, 0.824 hr−1), slope of the volume of distribution to body weight (VS, 0.246 L/kg), and slope of clearance to creatinine clearance (Clcr) and body weight (CLS, 0.222 L/hr/kg/100 mL/min Clcr). Use of NPEM2 led to identification of a subset of patients with CMV retinitis who had a more rapid clearance of ganciclovir of 0.51 to 0.54 L/hr/kg/100 mL/min Clcr. Use of smaller, optimally timed samples of five, four, and three data points per patient produced mean pharmacokinetic parameter results consistent with the full ten‐point data set. When Bayesian‐derived parameter estimates using a five‐point data set were compared with a traditional, nonlinear, least‐square analysis of the entire ten‐point data set, estimates of clearance were determined to be relatively unbiased and precise. The ability of NPEM2 to estimate pharmacokinetic parameters and to determine the population distribution of the parameters was demonstrated. By using points in the analysis chosen by D‐optimal design theory, NPEM2 was able to give consistent parameter estimates with as few as three data points. Determination of the distribution appeared to have been dependent on the time points used, however. The approach of MAP‐Bayesian analysis to derive patient‐specific estimates using optimal samples and prior estimates from a previous population pharmacokinetic analysis for inclusion in subsequent pharmacodynamic analyses of drug exposure (area under the concentration‐time curve) may enable development of exposure‐response and exposure‐toxicity relationships.
Effect of Angiotensin‐Converting Enzyme Inhibition on Bronchial Responsiveness
Authors: Dicpinigaitis Peter V. , Dobkin Jay B.
Published: March 2013

The effect of angiotensin‐converting enzyme (ACE) inhibition on bronchial responsiveness has not been clearly established. Because ACE degrades bradykinin and substance P, inhibition of the enzyme may lead to accumulation of these potent bronchoconstrictors in the lung, potentially leading to enhanced bronchial reactivity or bronchospasm. Previous studies of the effect of ACE inhibition on airway responsiveness have yielded conflicting results. A randomized, double‐blind, placebo‐controlled study was therefore conducted to evaluate the effect of a 14‐day course of oral lisinopril (10 mg for days 1–3, 20 mg for days 4–14) on bronchial responsiveness to inhaled methacholine in a group of healthy volunteers. No significant change in methacholine responsiveness occurred in any of the participants receiving lisinopril. The mean (±SD) concentration of methacholine producing a decrease in FEV1 of 20% from baseline (PC20; mg/mL) was 23.3 ± 5.0 before the study and 23.5 ± 4.5 at the end of the study for the lisinopril group, and 23.0 ± 4.6 before the study and 21.8 ± 6.9 after the study for the placebo group. The 14‐day course of ACE inhibitor therapy did not enhance nonspecific bronchial responsiveness in healthy volunteers.
Presenting and Publishing Case Reports
Authors: Iles Robert L. , Piepho Robert W.
Published: March 2013

The educational value of case reports and the four main categories of information they include are described. Checklists and directions for effective spoken presentations are detailed, so the presenter knows not only the information the audience is likely to expect, but the techniques that will help convey the information. A typical case as it might be presented during rounds is shown with questions for discussion. Guidelines for writing case reports for publication also are included, such as journal selection, descriptions of the standard and nonstandard case formats, the content of the three main sections of the typical case report, and the directions that journal editors typically ask reviewers to follow.
Pharmacokinetics of Cyclosporine after Renal Transplant in Children
Authors: Mochon Manuel , Cooney Gerard , Lum Bert , Caputo G. Craig , Dunn Stephen , Goldsmith Barbara , Baluarte H. J. , Polinsky Martin S. , Kaiser Bruce A.
Published: March 2013

The pharmacokinetics of cyclosporine and the relationship between blood levels and average drug concentration were prospectively evaluated in 18 children 1 month after renal transplantation. All children had normal renal function and no hepatic or gastrointestinal dysfunction. Cyclosporine was administered after an overnight fast, and serial blood samples were drawn over a 24‐hour period. Analysis of cyclosporine levels was performed by means of monoclonal radio immunoassay on whole blood. Children were divided into three age groups for comparison: 2–5 years, 5–10 years, and >10 years. There were no differences between age groups in serum protein, serum lipids, or hemoglobin levels, or in the pharmacokinetic parameters of cyclosporine except as follows: significant differences were noted in cyclosporine dose based on body weight, apparent steady‐state volume of distribution, and apparent blood clearance, with the youngest children (2–5) requiring higher doses, a relative greater distribution, and exhibiting more rapid drug clearance than those > 10 years of age. In addition, we observed diurnal variation in trough levels, with morning levels (0 hr) significantly higher than those obtained in the evening (12 hours after administration of cyclosporine). Trough levels demonstrated a fair correlation with area under the concentration‐time curve (AUC) and average concentration (Cav), but an abbreviated kinetic profile using cyclosporine levels 1 and 3.5 hours after administration accurately predicted AUC.
The Effect of Orlistat on the Pharmacokinetics of Phenytoin in Healthy Volunteers
Authors: Melia Angela T. , Mulligan Thomas E. , Zhi Jianguo
Published: March 2013

To assess the effect of an orlistat‐induced reduction in dietary fat absorption on the pharmacokinetics of phenytoin, a third‐party blind, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each participant received single 300‐mg oral doses of phenytoin administered on the fourth day of treatment with 120 mg orlistat (treatment A) or placebo (treatment B) three times a day for 7 days. The two treatments were separated by a 2‐week washout period. Serial blood samples were collected before and up to 96 hours after each dose of phenytoin to determine serum concentrations of phenytoin. The 90% confidence intervals (CI) for the ratio of geometric least‐squares means for maximum concentration (Cmax) and area under the concentration‐time curve (AUC) and for the difference of arithmetic least‐squares means for time of maximum concentration (tmax) and elimination rate constant (λg) showed the two treatments of phenytoin to be equal by analysis of variance. An approximately 30% reduction in dietary fat absorption induced by orlistat administered at doses of 120 mg three times daily did not significantly alter the pharmacokinetics of a single 300‐mg oral dose of phenytoin in healthy volunteers.
Evaluation of Sex Differences in the Pharmacokinetics of Ranitidine in Humans
Authors: Abad‐Santos Francisco , Carcas Antonio J. , Guerra Pedro , Govantes Carlos , Montuenga Carlos , Gómez Estrella , Fernández Antonio , Frias Jesus
Published: March 2013

A bioequivalence study of two oral formulations of 300 mg ranitidine was carried out in 16 healthy volunteers (8 men and 8 women), and the pharmacokinetics in both sexes were compared. There was bioequivalence of both formulations. The terminal half‐life of ranitidine was 7% shorter and the oral apparent clearance 10.5% higher in women (1.44 L/h/kg) than in men (1.29 L/h/kg), although this difference did not reach statistical significance. No differences were observed in maximum concentration (Cmax) or the time of its occurrence (tmax). Sex, age, and weight did not correlate significantly with oral clearance. These results suggest that there are no sex differences in the pharmacokinetics of ranitidine, or that any differences would not be of clinical relevance. It also should be emphasized that bioequivalence trials also can be used to study other pharmacokinetic or pharmacodynamic characteristics of drugs without damaging the main endpoint of the study.
Chronopharmacologic Considerations When Treating the Patient with Hypertension: A Review
Authors: Straka Robert J. , Benson Steven R.
Published: March 2013

Recognition of the existence of circadian variation in exacerbation of cardiovascular disease may have relevance to clinical use of cardioactive agents. Physiologic rational for the chronobiology of cardiac disease exists and can provide a basis on which to examine the efficacy of agents to manage cardiac disease. The use of 24‐hour ambulatory blood pressure monitoring (ABPM) devices have advanced our ability to describe the interplay of chronobiologic rhythms and pharmacodynamic response to antihypertensive medications. This review summarizes the studies evaluating the use of various antihypertensive medications in the context of using 24‐hour blood pressure monitoring devices. The studies are described in an attempt to increase awareness of chronobiology and potential implications of designing chronotherapeutic regimens.
Oral Absorption Characteristics and Pharmacokinetics of Colchicine in Healthy Volunteers after Single and Multiple Doses
Authors: Ferron Geraldine M. , Rochdi Myriam , Jusko William J. , Scherrmann Jean‐Michel
Published: March 2013

Colchicine is an antimitotic drug used to treat gout and familial Mediterranean fever. Absolute bioavailability, pharmacokinetics, and absorption characteristics of colchicine after single 1.0‐mg doses in oral solution or tablet form or 0.5‐mg intravenous doses were compared in 6 subjects. This study was combined with 14 days of multiple‐dose administration of 1.0‐mg colchicine tablets in 6 subjects. Serial blood samples were collected for 48 hours after administration of single doses and for 120 hours after the last dose in the multiple‐dose regimen. Plasma colchicine profiles as measured by radioimmunoassay were analyzed using deconvolution and compartmental methods. After intravenous bolus injection of colchicine, the area under the concentration‐time curve (AUC) was 61.2 ± 12.7 ng · hr/mL, steady‐state volume of distribution (V88) was 419 ± 95 L, systemic clearance (Cl) was 8.5 ± 1.8 L/hr, and the terminal half‐life (t1/2) was 57.8 ± 10.7 hours. After oral administration in solution form, peak plasma concentrations (Cmax) of 6.50 ± 1.03 ng/mL were reached at time (tmax) 1.07 ± 0.55 hours, with a rate of 0.109 ± 0.024 hr−1 (Cmax/AUC); bioavailability was 47 ± 14%. Oral tablets yielded similar Cmax, tmax, and Cmax/AUC values, but AUC was significantly lower. Most participants exhibited a secondary peak within 6 hours of administration, possibly in relation to a second absorption site or enterohepatic recirculation. This second absorption process was significantly longer than the first one, and accounted for a similar amount of colchicine absorbed. From the multiple‐dose study, a model including an alteration of colchicine absorption due to possible drug‐induced gastrointestinal modifications allowed better determination of steady‐state plasma concentrations of colchicine.
Influences of Bathing and Hot Weather on the Pharmacokinetics of a New Transdermal Clonidine, M‐5041T
Authors: Fujimura Akio , Sasaki Masato , Harada Kazuhiro , Kumagai Yuji , Ohashi Kyo‐ichi , Ebihara Akio
Published: March 2013

The influences of bathing and hot weather on plasma concentrations of clonidine were examined during application of a new transdermal clonidine system, M‐5041T, in eight healthy volunteers. An M‐5041T patch containing 6 mg of clonidine was applied on the right chest for 96 hours during winter with or without bathing (40°C for 5 minutes) and also during summer without bathing. Plasma concentrations and urinary excretion of clonidine were determined for a 160‐hour period after application. Plasma concentrations of clonidine in the winter trials did not differ significantly with or without bathing. Plasma drug concentration as a whole was significantly higher in the summer trial than in the winter trial, however. The maximum plasma concentration (Cmax), area under the plasma concentration‐time curve (AUC), and urinary excretion (Ae) of clonidine also tended to be higher in the summer trial. These results suggest that plasma levels of clonidine are higher after application of M‐5041T during hot weather. Although the period of bathing used in this study was short, the influence of bathing seems to be negligible.
Influence of Food on the Oral Bioavailability of Loratadine and Pseudoephedrine from Extended‐Release Tablets in Healthy Volunteers
Authors: Nomeir Amin A. , Mojaverian Parviz , Kosoglou Teddy , Affrime Melton B. , Nezamis Jim , Radwanski Elaine , Lin Chin‐Chung , Cayen Mitchell N.
Published: March 2013

The effect of a high‐fat breakfast on the bioavailability of the components of an extended‐release tablet containing 10 mg loratadine in the immediate‐release coating and 240 mg pseudoephedrine sulfate in the extended‐release core was studied in 24 healthy male volunteers in a single‐dose, two‐way crossover study. The drug was administered after a 10‐hour overnight fast or within 5 minutes of consuming a standardized high‐fat breakfast. Serial blood samples were collected over a 48‐hour period, and plasma was analyzed for loratadine and its active metabolite descarboethoxyloratadine (DCL), and pseudoephedrine. For pseudoephedrine, maximum concentration (Cmax) and area under the concentration—time curve extrapolated to infinity (AUC0‐∞) were similar after both treatments, indicating no relevant food effect on the bioavailability of pseudoephedrine. Also, the absorption profiles of pseudoephedrine (from Wagner‐Nelson analysis) were similar for the fed and fasted treatments, indicating no apparent differences in absorption. Plasma concentration—time profiles and values for Cmax and AUC0‐∞ of DCL were similar for the two treatments, indicating no relevant food effect on the pharmacokinetics of DCL. In contrast, for loratadine, administration with food resulted in a significantly increased mean Cmax (53%) and AUC from time zero to the final quantifiable sample (AUCtf) (76%). However, the resultant Cmax and AUC of loratadine under fed conditions were well below those previously obtained at steady‐state after multiple‐dose administration of loratadine (40 mg/day) that were shown to be safe and well‐tolerated in several clinical studies. The effect of food on the bioavailability and pharmacokinetic profiles of the components of a combination loratadine/pseudoephedrine extended‐release tablet is not likely to be clinically significant.
Acetaminophen Toxicity in Children: Diagnostic Confirmation Using a Specific Antigenic Biomarker
Authors: Webster Patricia A. , Roberts Dean W. , Benson R. Wayne , Kearns Gregory L.
Published: March 2013

Chronic acetaminophen (APAP) toxicity poses a difficult diagnostic challenge to the clinician. Signs and symptoms are nonspecific and no currently available laboratory study can confirm APAP as the causative agent of hepatic injury. In this study an antigenic biomarker for APAP toxicity was used to confirm the diagnosis of APAP‐induced hepatic failure in two children with chronic APAP toxicity. APAP that has been metabolized to N‐acetyl‐benzoquinone imine (NAPQI) reacts with cellular proteins to form 3‐(cystein‐S‐yl)‐APAP protein adducts (3‐Cys‐A). Serum from both patients was submitted for quantitation of 3‐Cys‐A by a competitive inhibition enzyme‐linked immunosorbent assay (ELISA). Concentrations of 3‐Cys‐A in the two patients were 1.97 and 2.77 nmol/mg protein, which are similar to concentrations found in adults with hepatic injury secondary to an overdose of APAP. Individuals with no exposure to APAP have no detectable 3‐Cys‐A in serum. It was concluded that 3‐Cys‐A is a useful marker of APAP intoxication after long‐term ingestion of APAP when total dose and time course of ingestion are uncertain, and may prove to be a useful clinical and investigative tool in the study of APAP intoxication.
Pharmacokinetics and Pharmacodynamics of Multiple‐Dose Terbinafine
Authors: Nedelman Jerry R. , Gibiansky Ekaterina , Robbins Bruce A. , Cramer Jeffrey A. , Riefler John F. , Lin Thomas , Meligeni John A.
Published: March 2013

Data from clinical trials of terbinafine for the treatment of onychomycosis were analyzed with the following two objectives: 1) to identify demographic predictors of the duration and extent of systemic drug exposure;and 2) to explore whether increased systemic exposure or demographic predictors of increased exposure were associated with altered safety or efficacy. Demographic predictors of exposure were identified by a model‐free, nonparametric approach applied to the sparse pharmacokinetic data from the onychomycosis studies. Those covariates were then incorporated into a multicompartmental nonlinear mixed effects model. Post hoc parameter estimates from the nonlinear mixed effects model provided individual measures of exposure. Safety scores were derived for adverse events that were frequently attributed to drug exposure and for liver function tests. Terbinafine was found to have an average terminal half‐life (t1/2) of approximately 3 weeks. That terminal elimination phase contributed so little to the total exposure, however, that average concentrations accumulated only approximately two‐fold at steady state with once daily dosing. Age and concomitant hypertension were predictors of higher plasma concentrations of terbinafine; smokers had lower levels than nonsmokers. Although some statistically significant associations between adverse events and systemic exposure were found, in all cases the actual frequency of the adverse events was low, and there were no trends in severity with respect to exposure. Above‐normal levels of gamma‐glutamyl transferase were associated with exposure, but there was no trend in severity with respect to exposure. No other liver function test abnormalities were associated with exposure, nor were there any significant associations between adverse events or liver function abnormalities and demographic subgroups that differed with respect to exposure. Among patients taking the active drug there were no significant associations between exposure levels and efficacy, nor were there differences in efficacy between demographic subgroups that differed with respect to exposure.
New Insights into the Site and Mode of Antinociceptive Action of Flurbiprofen Enantiomers
Authors: Geisslinger Gerd , Schaible Hans‐Georg
Published: March 2013

The S‐enantiomer of flurbiprofen has been shown to have both antiinflammatory and antinociceptive effects, whereas R‐flurbiprofen is antinociceptive but not antiinflammatory. Importantly, only S‐flurbiprofen inhibited prostaglandin biosynthesis in vitro at therapeutic concentrations. R‐flurbiprofen did not undergo significant chiral inversion to S‐flurbiprofen in rats and humans. A study was conducted to gain new insight into the possible sites and modes of action of flurbiprofen enantiomers. In a modified Randall Selitto assay, both enantiomers were antinociceptive in a dose‐dependent manner after systemic administration. After local administration into the inflamed paw, only S‐flurbiprofen produced significant dose‐related antinociception. In a physiologic study, we recorded extracellularly from nociceptive spinal cord neurons that were rendered hyperexcitable. Intravenous administration of R‐ and S‐flurbiprofen reduced responses of neurons to pressure applied to the inflamed knee and the noninflamed ankle and paw in a dose‐dependent manner. When injected directly into the knee joint, only S‐flurbiprofen but not R‐flurbiprofen reduced responses to pressure. These results suggest a central site of antinociceptive action for R‐ and S‐flurbiprofen and an additional peripheral site for S‐flurbiprofen. The findings may be of clinical relevance, as it was demonstrated that both enantiomers also were antinociceptive in humans. Because R‐flurbiprofen caused less toxicity in rats than the S‐enantiomer or the racemic compound, a reduction in the quantitatively most important side effects in the gastrointestinal tract might be achieved with the use of R‐flurbiprofen for pain therapy.
Pharmacokinetic/Pharmacodynamic Aspects of Aerosol Therapy using Glucocorticoids as a Model
Authors: Hochhaus Günther , Möllmann Helmut , Derendorf Hartmut , Gonzalez‐Rothi Ricardo J.
Published: March 2013

Glucocorticoids are predominantly prescribed in asthma therapy as aerosols to achieve high pulmonary effects with reduced systemic spill‐over and pronounced pulmonary selectivity. A variety of pharmacokinetic parameters are potentially important for determining pulmonary selectivity. The intent of this article, is to provide a practice‐relevant theoretical approach to put the importance of these parameters on pulmonary targeting using pharmacokinetic/pharmacodynamic modeling as a tool in perspective. The applied pulmonary pharmacokinetic/pharmacodynamic model revealed that, in addition to recognized parameters such as systemic clearance, oral bioavailability, and efficiency of pulmonary deposition, other factors, such as the pulmonary release (dissolution) rate and dose, are relevant. However, the volume of distribution (for effect parameters not undergoing a diurnal rhythm) and the receptor affinity of a given glucocorticoid are not important for achieving lung targeting. J Clin Pharmacol 1997;37:881–892.
Optimizing the Absorption of Valspodar, a P‐glycoprotein Modulator, Part I: Selecting an Oral Formulation and Exploring its Clinical Pharmacokinetics/Dynamics
Authors: Mueller E. A. , Kovarik J. M. , Üresin Y. , Preisig‐Flückiger S. S. , Hensel S. , Lücker P. W. , Holt B.
Published: March 2013

Valspodar is a cyclosporine D analog used as a chemotherapy adjunct for modifying multidrug resistance. Two studies were sequentially performed to select an optimal oral formulation and to characterize selected aspects of its clinical pharmacokinetics/dynamics. An initial four‐way crossover study with 20 volunteers compared the pharmacokinetics of single fasting administrations of 200 mg by intravenous infusion and 600 mg orally as a conventional oral solution, a microemulsion oral solution, and a microemulsion soft gelatin capsule. The two microemulsion dosage forms demonstrated significantly faster and less variable rates of absorption compared with the conventional oral solution. The microemulsion dosage forms were bioequivalent with absolute bioavailability nearly double that of the conventional oral solution. Based on these results, the microemulsion capsule was further investigated in a four‐way randomized crossover study with 24 volunteers who received single fasting administrations of 200, 400, and 600 mg and a 400‐mg administration after a fat‐rich meal. Dose proportionality in area under the curve (AUC) was demonstrated over this dose range. Administration after a fat‐rich meal caused a slight time lag until absorption began, a delay in time to reach the peak concentration, and a moderate increase of 24% in AUC. Serial determinations of total bilirubin were explored as a potential pharmacodynamic marker for P‐glycoprotein inhibition. A similar magnitude of reversible hyperbilirubinemia was seen at all dose levels suggesting that P‐glycoprotein inhibition in the biliary canaliculi was maximal even at the lowest dose tested. The microemulsion formulation (oral solution or soft gelatin capsule) represents an improved and less variable oral delivery form providing dose‐proportional drug exposure over a clinically relevant dose range.
The Pharmacokinetics of Tiagabine in Healthy Elderly Volunteers and Elderly Patients with Epilepsy
Authors: Snel Sonja , Jansen Jens A. , Mengel Helle B. , Richens Alan , Larsen Soeren
Published: March 2013

The pharmacokinetics of tiagabine after single‐dose (8 mg) and multiple‐dose (3 mg, three‐times daily for four days) administration of tiagabine HCl were investigated in healthy elderly volunteers (n = 8; Group 1), elderly patients with epilepsy receiving at least one hepatic enzyme‐inducing antiepileptic drug (AED) (n = 8; Group 2), and healthy young volunteers (n = 8; Group 3). Participants were matched by gender, age (Groups 1 and 2), alcohol intake, body weight, and whether they smoked tobacco. The pharmacokinetic parameters of tiagabine following single‐ and multiple‐dose administration were similar in both healthy elderly and young volunteers except for a small but significant difference in the area under the concentration—time curve after multiple‐doses (103 ± 29 ng.hr/mL/mg in the elderly versus 72 ± 20 ng.hr/mL/mg in younger participants). This is not expected to have any clinical relevance because of the large intersubject variability in this parameter. In contrast, and as expected, the pharmacokinetics of tiagabine were altered in the presence of enzyme‐inducing antiepileptic drugs: Time to reach maximum plasma concentration, area under the concentration—time curve, and elimination half‐lives were significantly lower (e.g. 39 ± 13 ng.hr/mL/mg for AUC after multiple‐dose) compared with corresponding values in the healthy volunteers. These findings suggest that adjusting the dose of tiagabine on the basis of the age of the patient is not necessary, although, irrespective of age, higher doses and/or more frequent administrations will be required in patients taking concomitant enzyme‐inducing antiepileptic drugs.
Meta‐Analysis of Steady‐State Pharmacokinetics of Troglitazone and Its Metabolites
Authors: Loi Cho‐Ming , Alvey Christine W. , Randinitis Edward J. , Abel Robert , Young Malcolm A. , Koup Jeffrey R.
Published: March 2013

The object of this study is to evaluate the effects of age, gender, age‐by‐gender interaction, Type II diabetes, body weight, race, smoking, and formulation on steady‐state pharmacokinetics of troglitazone, Metabolite 1 (sulfate conjugate), and Metabolite 3 (quinone metabolite) following multiple‐dose oral administration of troglitazone. Pharmacokinetic parameter estimates [Cl/F (apparent oral clearance), AUC0–24 (area under plasma concentration—time curve), and ratio of AUC for troglitazone to Metabolite 1 and to Metabolite 3] obtained from 84 healthy volunteers and 171 patients with Type II diabetes in 8 studies were analyzed using a graphical method (for race and smoking) or a weighted ANCOVA model incorporating gender, health status (healthy vs Type II diabetes), and formulation as main effects; age, age‐by‐gender interaction, and body weight as continuous covariates. Ratio of AUC for troglitazone to metabolites was also examined by inspection of log‐probit plots. Age, gender, age‐by‐gender, Type II diabetes, and formulation had negligible effects on troglitazone Cl/F, AUC0–24 (all analytes), and AUC ratio of troglitazone to metabolites. Race and smoking did not appear to influence steady‐state pharmacokinetics of troglitazone and its metabolites. Although body weight was a significant covariate for AUC0–24 and Cl/F, the explanatory power of the overall model was weak (R2 < 0.2). Log‐probit plots did not reveal a polymorphic distribution in AUC ratio of troglitazone to Metabolite 1 or Metabolite 3. Based on pharmacokinetics, dose adjustment for troglitazone in relation to the demographic factors examined is not required due to their poor predictive ability on steady‐state pharmacokinetics of troglitazone and its metabolites.
Effect of Glycosylation on Carbamazepine‐Serum Protein Binding in Humans
Authors: Koyama Hikaru , Sugioka Nobuyuki , Uno Akira , Mori Satoru , Nakajima Kenji
Published: March 2013

Effect of glycosylation on carbamazepine‐serum protein binding was investigated in vitro using the serum from 24 diabetics and 10 healthy subjects, and in vivo using the serum from 49 patients receiving carbamazepine. In both binding studies, nonglycosylated albumin levels were strongly correlated with the carbamazepine free fraction (%). To evaluate the effect of glycosylation in vivo, the patients were divided into two groups according to glycosylated albumin levels (%): a healthy group (10–15) and a high group (15 and over). The high group had decreased nonglycosylated albumin levels and an increased carbamazepine free fraction. Our results suggest that one should not use total concentrations for the monitoring of serum carbamazepine concentrations, but free concentrations, especially in poorly controlled diabetics.
Lack of Effect of Azelastine and Ketoconazole Coadministration on Electrocardiographic Parameters in Healthy Volunteers
Authors: Morganroth J. , Lyness W. H. , Perhach J. L. , Mather G. G. , Harr J. E. , Trager W. F. , Levy R. H. , Rosenberg A.
Published: March 2013

Azelastine, an antihistamine with additional pharmacologic properties, was evaluated for a possible influence on pharmacokinetic and electrocardiographic parameters due to its coadministration with CYP3A4 inhibitor ketoconazole (200 mg every 12 hrs). Twelve volunteers entered this three‐period, open‐label study. Electrocardiographic parameters (PR, QRS and QTc intervals and U‐wave morphology) were monitored after 14 days of azelastine HCl (4.4 mg every 12 hrs), after 7 days of either azelastine/ketoconazole or azelastine/placebo, and after a 21‐day washout period, which was then followed by a 7‐day administration of ketoconazole alone. None of the treatments resulted in meaningful alterations of electrocardiographic variables. Pharmacokinetic parameters could not be estimated because ketoconazole metabolites interfered with azelastine assay procedures. In vitro tests with human liver microsomes were used to characterize azelastine's inhibition spectrum. Azelastine did not inhibit CYP3A4 activity but it did inhibit CYP2D6 and CYP2C19 activity with Ki values exceeding maximum plasma concentration by 120 to 800‐fold. Therefore, in vitro tests and the absence of electrocardiographic effects suggests azelastine can be safely administered with CYP3A4 inhibitors.
Prediction of In Vivo Drug Interaction from In Vitro Systems Exemplified by Interaction Between Verapamil and Cimetidine Using Human Liver Microsomes and Primary Hepatocytes
Authors: Fischer Ulrike , Rohde Beate , Wacke Rainer , Stange Jan , Nitschke Frank P. , Adam Ulrich , Drewelow Bernd
Published: March 2013

Emphasis on drug safety is increasing as newly developed drugs become more potent. Interest in the prediction and description of drug interactions is growing accordingly. The study of potential interactions at a very early stage of drug development requires suitable in vitro models that describe drug interactions both qualitatively and quantitatively. The purpose of the work described here was to help assess the predictive value of in vitro drug interaction tests with liver microsomes and hepatocytes by means of the interaction between verapamil and cimetidine. The in vitro inhibition of verapamil metabolism by cimetidine observed during the studies was quantitatively similar to the results reported in published clinical studies after intravenous application. Studies using liver microsome fractions showed that the intrinsic clearances for the formation of various metabolites could be used to predict drug interactions. In addition, work with hepatocyte cultures revealed that an in vitro system covering both phase I and phase II reactions should be included in such studies to permit quantitative prediction of the various metabolic pathways. Both human hepatocyte cultures and human microsomes offer certain advantages for predicting the degree of drug metabolism and interactions in humans at the biotransformation level. Therefore, it seems likely that the simultaneous application of both systems will yield conclusions that most closely approximate the situation in humans.
Population‐Based Investigation of Valproic Acid Relative Clearance Using Nonlinear Mixed Effects Modeling: Influence of Drug‐Drug Interaction and Patient Characteristics
Authors: Yukawa Eiji , To Hideto , Ohdo Shigehiro , Higuchi Shun , Aoyama Toshinobu
Published: March 2013

Nonlinear mixed effects modeling (NONMEM) was used to estimate the effects of drug‐drug interaction on valproic acid relative clearance values using 792 serum levels gathered from 400 pediatric and adult patients with epilepsy (age range, 0.3–54.8 years) during their clinical routine care. Patients received valproic acid as monopharmacy or in combination with either the antiepileptic drugs, phenobarbital, or carbamazepine. The final model describing valproic acid relative clearance was CL (mL/hr/kg) = 15.6 · TBW (kg)−0.252 · DOSE (mg/kg/day)0.183 · 0.898GEN · COPB · COCBZ, where COPB equals 1.10 if the patient is treated with phenobarbital, a value of unity otherwise, and COCBZ equals 0.769 · DOSE (mg/kg/day)0.179 if the patient is treated with carbamazepine, a value of unity otherwise. Valproic acid relative clearance was highest in the very young and decreased in a weight‐related fashion in children, with minimal changes observed in adults. This pattern was consistent whether valproic acid was administered alone or coadministered with phenobarbital or carbamazepine. When valproic acid was coadministered with phenobarbital or carbamazepine, valproic acid relative clearance increased as compared with that in monopharmacy. Its magnitude in the presence of carbamazepine increased in a valproic acid daily dose‐related fashion. Concomitant administration of phenobarbital and valproic acid resulted in a 10% increase on valproic acid relative clearance. The clearance in female patients was approximately 10% less than that in male patients.
Pharmacokinetics of Pamidronate Disodium in Patients with Cancer with Normal or Impaired Renal Function
Authors: Berenson James R. , Rosen Lee , Vescio Robert , Lau Henry S. , Woo Margie , Sioufi Antoine , Kowalski M. Ortu , Knight Robert D. , Seaman John J.
Published: March 2013

Pamidronate is a second‐generation bisphosphonate that undergoes negligible biodegradation and is eliminated exclusively by renal excretions. Nineteen cancer patients were stratified according to baseline creatinine clearance (Clcr): group I, Clcr >90 mL/min (n = 6); group II, Clcr 61 mL/min to 90 mL/min (n = 6); group III, Clcr 30 mL/min to 60 mL/min (n = 3); group IV, Clcr <30 mL/min (n = 4). All patients received a single, 90‐mg dose of pamidronate disodium administered in a 4‐hour intravenous infusion. Plasma and urine samples were collected at intervals up to 36 and 120 hours, respectively, after the start of infusion and were assayed for pamidronate, using validated high‐performance liquid chromatography. Pamidronate's pharmacokinetics were characterized by a short distribution phase (2–3 hours) followed by rapid elimination of the drug in urine. Elimination of pamidronate was slower in patients in group IV with a mean ± standard deviation area under the plasma concentration—time curve (AUC0–36) of 19.0 ± 4.60 μg·hr/mL compared with 8.1 ± 3.13 μg·hr/mL in patients in group I. A linear relationship in Clcr was observed for AUC0–36 (r = 0.67), urinary excretion (r = 0.69), and renal clearance (r = 0.81). Renal clearance was proportional to Clcr for patients in all four renal‐function groups. In the treatment of bone metastases of malignancy, successive doses of pamidronate are generally separated by weeks; thus, plasma accumulation in patients with renal impairment is not expected to be clinically relevant. A reduction in dose of pamidronate disodium should not be necessary in cancer patients with renal impairment.