bluuebunny/crossref_metadata_2025 huggingface dataset:
A Look at the Safety Profile of Over‐the‐Counter Naproxen Sodium: A Meta‐analysis
Authors: Bansal Vidhu , Dex Terry , Proskin Howard , Garreffa Stephen
Published: July 2003

As the trend for Americans to self‐medicate continues to increase, it becomes important to review the safety of over‐the‐counter (OTC) medications. This article will review the safety of an OTC analgesic, Aleve® (naproxen sodium). The objective of this meta‐analysis is to evaluate the frequency of occurrence of all adverse events in subjects taking various doses of OTC naproxen sodium as compared to placebo. These varying doses and dosage regimens were studied individually and consisted of 220 to 880 mg administered in single, multiple, and PRN (as needed) doses of naproxen sodium. This meta‐analysis confirmed the favorable safety profile of naproxen sodium at OTC doses and established that the overall occurrence of adverse events with naproxen sodium was comparable and in some cases significantly lower than placebo. These results indicate that treatment with naproxen sodium may be highly beneficial from a clinical and economical perspective and safe when adhering to labeled directions.
Pharmacokinetic/Pharmacodynamic Evaluation of the NHE Inhibitor Eniporide
Authors: Kovar Andreas , Peters Tanja , Beier Norbert , Derendorf Hartmut
Published: July 2003

The aim of this study was to investigate the pharmacokinetics and pharmacodynamics of the new cardioprotective sodium/proton exchange (NHE‐1) inhibitor eniporide in humans. Eniporide was administered intravenously to healthy volunteers in doses between 2.5 and 100 mg. Concentrations of parent drug and its metabolite were measured by HPLC, and the data were analyzed by noncompartmental and compartmental pharmacokinetic methods. Platelet‐swelling time was determined in each subject asa biomarker to assess pharmacodynamic activity. Eniporide showed linear pharmacokinetics with an average half‐life of approximately 2 hours. The mean total body clearance was 34.4 L/h. The mean volume of distribution (Vdss) was 77.5 L, and the mean residence time was 2.3 hours. An average of 43% of the dose was recovered unchanged from urine. A pharmacokinetic two‐compartment model was found suitable to provide excellent curve fits of the measured plasma concentration profiles. Plasma concentrations of the major metabolite were lower than that of the parent drug. An average of 27% of the dose was found in urine as that metabolite. The effect on platelet swelling could be well characterized by a direct Emax model. The average concentration for half‐maximum effect (IC50) was 12 ng/mL. Eniporide was found to have predictable linear pharmacokinetics in the investigated dose range. Platelet‐swelling time was shown to be a reproducible individual biomarker for pharmacodynamic activity, with great potential for a surrogate that predicts clinical outcome, since this effect is mediated through the same mechanism of action (NHE‐1 inhibition) as the desired cardioprotective activity. Pharmacokinetic/pharmacodynamic modeling allowed a first estimate of the degree of NHE inhibition in the investigated dose range.
Pharmacodynamic Modeling of Pantoprazole's Irreversible Effect on Gastric Acid Secretion in Humans and Rats
Authors: Ferron Geraldine M. , McKeand William , Mayer Philip R.
Published: July 2003

The relationship between the pharmacokinetics of pantoprazole, an irreversible proton pump inhibitor, and its effect on gastric acid secretion was evaluated in humans and rats. Pantoprazole pharmacokinetics were studied in 6 rats (5 mg/kg, IV) and 22 healthy volunteers (10 to 80 mg, IV and oral). Gastric acid secretion under maximum pentagastrin stimulation was measured after IV administration of placebo or pantoprazole in 31 rats (0.12 to 1.15 mg/kg) for 4 hours and in 31 subjects (20 to 120 mg) for 24 hours. Pantoprazole has short half‐lives of 0.5 hours in rats and 0.8 hours in humans. After administration of the highest dose, acid secretion was fully inhibited within 1 hour and for the whole observation period in both species. An irreversible pharmacodynamic response model was successfully developed and validated. The apparent reaction rate constants of pantoprazole with the proton pumps were 0.691 L/mg/h in rats and 0.751 L/mg/h in humans, and the apparent recovery rates of the pumps were 0.053 h‐1 and 0.031 h‐1, respectively. The maximum inhibition and the overall effect of pantoprazole are related to exposure, and the onset is related to initial pantoprazole concentrations. It was concluded that this irreversible response model accurately describes the effect of IV and oral pantoprazole on gastric secretion and maybe used to predict effects under other dosage regimens.
Pharmacokinetic and Pharmacodynamic Modeling of NN703, a Growth Hormone Secretagogue, after a Single po Dose to Human Volunteers
Authors: SDVM Henrik Agersø , Ynddal Lars , Søgaard Birgitte , Zdravkovic Milan
Published: July 2003

The objective of this study was to describe the pharmacokinetics and pharmacodynamics of NN703, a growth hormone (GH)‐releasing secretagogue, after po administration to healthy human male subjects. The study was designed as a randomized, placebo‐controlled, double‐blind, dose‐escalating, single‐dose trial of NN703 covering eight dose levels. Each of the dose levels had 6 subjects on active treatment and 2 subjects on placebo. NN703 was administered po as a solution. Blood samples for serum concentrations of NN703 and GH were collected before dosing and up to 24 hours after dosing. Serum concentrations of NN703 were determined using a validated analytical method, based on solid‐phase extraction and LC/MS/MS detection. A two‐compartmental model with zero‐order input was used to describe the pharmacokinetics of NN703. The parameters of the elimination phase were fitted simultaneously, whereas the parameters describing the absorption phase were allowed to vary between the dose levels. The pharmacodynamics of NN703 was described by use of an indirect‐response model containing both a threshold value and a modulator for the development of tolerance. It was concluded that the absorption of NN703 after po administration was nonlinear; the bioavailability increased with the dose. The serum concentration of NN703 required for half‐maximal stimulation of GH was determined to be 485 ng/ml. The proposed indirect‐response model requiring a threshold concentration and development of tolerance provided a useful mean of quantifying the effects of NN703. Furthermore, the development of tolerance shown based on pharmacokinetic/pharmacodynamic modeling of single‐dose data presented here has been confirmed following multiple dosing in healthy male subjects.
Effect of Low‐ and High‐Fat Meals on Tacrolimus Absorption following 5 mg Single Oral Doses to Healthy Human Subjects
Authors: Bekersky Ihor , Dressler Dawna , Mekki Qais A.
Published: July 2003

Tacrolimus (FK506, Prograf®) is a macrolide lactone antibiotic widely used by the oral route for the prophylaxis of organ rejection in patients who have received allogenic liver or kidney transplants. This study investigated the influence of a high‐ versus a low‐fat meal, relative to the fasting state (three treatments total), on the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol employed a three‐period, randomized, crossover design employing 5 × 1 mg capsules in 15 healthy male nonsmoking, drug‐free volunteers, 20 to 45 years of age, who were within 15% of their ideal body weight. Food had a clinically significant effect in reducing relative bioavailability, as well as slowing absorption, but did not affect terminal exponential half‐life (∼34 hours). Mean maximum tacrolimus blood concentration (Cmax) values were 25.6, 5.88, and 9.03 ng/mL for the fasting, high‐fat, and low‐fat treatments, respectively; mean area under the blood concentration‐time curve (AUC(0‐∞)) values were 272, 181, and 201 (ng/mL)‐h, respectively; and mean time of Cmax (tmax) values were 1.37, 6.47, and 3.20 hours, respectively. Differences in parameters between the fasting and each fed treatment were statistically significantly different (p < 0.05). Statistically significant differences also existed in tmax between the two meals. Results also indicated the safety of single 5 mg oral tacrolimus doses administered to healthy volunteers.
Race but Not Age Affects Erythromycin Breath Test Results in Older Hypertensive Men
Authors: Schwartz Janice B.
Published: July 2003

Erythromycin breath tests (ERBT) were performed to determine age and racial effects on CYP3A4‐mediated hepatic clearance in hypertensive men (n = 43) in the clinical setting. Older hypertensive African American men (n = 19: 71 ± 8 years, mean ± SD) had faster ERBT clearance compared with Caucasian (n = 20:72 ± 6 years) hypertensive men (at 20 minutes after dosing: 0.042 ± 0.01 percent dose/min exhaled vs. 0.033 ± 0.013; at 60 minutes after dosing: 0.030 ± 0.05 vs. 0.023 ± 0.007percent dose/min exhaled; ANOVA, p = 0.007), while age, smoking, and reported alcohol intake did not affect ERBT. The data suggest faster hepatic CYP3A‐mediated clearance in African American men compared with Caucasian men, and that race may significantly affect CYP3A‐mediated hepatic clearance in patients treated for hypertension.
Pharmacodynamic Modeling of Lansoprazole Using an Indirect Irreversible Response Model
Authors: Puchalski Thomas A. , Krzyzanski Wojciech , Blum Robert A. , Jusko William J.
Published: July 2003

A mechanism‐based pharmacokinetic/pharmacodynamic model was used to assess lansoprazole effects on gastric pH. The irreversible inactivation of the H+/K+‐ATPase enzyme by lansoprazole controls the secretion rate of H+ ions and gastric pH values. The basal circadian rhythm of gastric acid production was taken into account as well as the effects of food intake. A model was applied to multiple‐dose data from a crossover study of four dosage regimens of lansoprazole in two groups of normal male subjects. Model parameters were estimated by nonlinear regression and were compared to historical values reported in the literature. The predicted mean gastric ion concentration was 23.2 mM (pH 1.6) with the peak time at 12.6 hours (8:30 p.m.), and the half‐time for H+ removal from the stomach averaged 1.7 hours. The estimated half‐life of gastric food removal was 0.8 hours. The rate constant for normal H+/K+‐ATPase degradation was 0.045 h−1. The pharmacodynamic parameter describing lansoprazole action on gastric acid secretion was the second‐order enzyme inactivation constant, which averaged 0.16 μg−1•L•h−1. The parameters obtained for both the baseline and drug treatment data were consistent with the literature and physiologically relevant with the exception of effective food volume, which was large presumably due to buffer effects. The model successfully incorporated the physiological regulation of gastric acid production, the effects of food on gastric acid, and the effects of multiple‐dosing regimens of lansoprazole on gastric acid production to give reasonable profiles ofgastric pH.
Pharmacokinetics of Mycophenolic Acid after Mycophenolate Mofetil Administration in Liver Transplant Patients Treated with Tacrolimus
Authors: Jain Ashok , Venkataramanan Raman , Hamad Imad S. , Zuckerman Sheila , Zhang Shimin , Lever Jackie , Warty Vijay S. , Fung John J.
Published: July 2003

The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (± SD) maximum MPA plasma concentration of 10.6 (± 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (± SD) steady‐state area under the plasma concentration versus time curve (AUC012) was 40 (± 30.9) mg/ml/h. The mean (± SD) half‐life was 5.8 (± 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = −0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (± SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (± 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 pg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.
Abacavir/Lamivudine/Zidovudme As a Combined Formulation Tablet: Bioequivalence Compared with Each Component Administered Concurrently and the Effect of Food on Absorption
Authors: Yuen Geoffrey J. , Lou Yu , Thompson Nancy F. , Otto Victoria R. , Allsup Thurman L. , Mahony William B. , Hutman H. Wayne
Published: July 2003

A single‐center, open‐label, three‐way crossover study was conducted in 24 healthy subjects to assess (1) the bioequivalence of a combined abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg (A/L/Z) combination tablet relative to the separate brand‐name components administered simultaneously and (2) the effect of food on the bioavailability of the drugs from the combination tablet. The subjects were randomly assigned to receive each of the following three treatments, separated by a 2‐day washout period: one A/L/Z combination tablet after an overnight fast, one abacavir 300 mg tablet + one lamivudine 150 mg tablet + one zidovudine 300 mg tablet sequentially after an overnight fast, or one A/L/Z combination tablet 5 minutes after completing a standardized high‐fat breakfast (67 g fat, 58 g carbohydrate, and 33 g protein). Serial blood samples were collected up to 24 hours postdose for determination of abacavir, lamivudine, and zidovudine serum concentrations. Standard pharmacokinetic parameters were estimated. Treatments were considered bioequivalent if 90% confidence intervals (CI) for geometric least squares (GLS) mean ratios for abacavir, lamivudine, and zidovudine area under the serum concentration‐time curve (AUC∞) and maximum observed serum concentration (Cmax) fell entirely within 0.80 to 1.25 for log‐transformed parameters. The combined A/L/Z tablet was bioequivalent in the extent (AUC∞) and rate of absorption (Cmax and time of Cmax [tmax]) to the individual brand‐name drug components administered concurrently under fasted conditions. GLS ratios and 90% CI for AUC∞ and Cmax were 0.99 (0.96, 1.03) and 1.00 (0.90, 1.11), respectively, for abacavir; 0.95 (0.91, 0.99) and 0.90 (0.84, 0.99), respectively, for lamivudine; and 0.95 (0.89,1.02) and 0.96(0.80,1.15), respectively, for zidovudine. The extent of absorption of abacavir, lamivudine, and zidovudine from the combination tablet was not altered byadministration with meals, indicating that this formulation may be administered with or without food. However, food slowed the rate of absorption, delayed the tmax, and reduced the Cmax of abacavir, lamivudine, and zidovudine. These changes, which were consistent with those observed with the individual reference formulations when administered with food, were not considered clinically important. All formulations were well tolerated under fasted and fed conditions.
Effect of Alosetron on the Pharmacokinetics of Fluoxetine
Authors: D'Souza Doreen L. , Dimmitt Dan C. , Robbins Doris K. , Nezamis James , Simms Lorinda , Koch Kevin M.
Published: July 2003

Lotronex® (alosetron hydrochloride) is a 5‐HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP3A4. Fluoxetine is an antidepressant that is administered as a racemic mixture of equipotent R‐ and S‐enantiomers. Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine. This metabolite is also present as two enantiomers, of which only the S‐enantiomer exhibits comparable antidepressant activity. This study was conducted to assess the potential for an effect of alosetron on the pharmacokinetics of fluoxetine. This was an open‐label, two‐period, nonrandomized, crossover study in 12 healthy female and male volunteers. The pharmacokinetics for both enantiomers of fluoxetine and norfluoxetine were examined following single oral doses of 20 mg fluoxetine, given alone and in combination with alosetron 1 mg twice daily for 15 days. The results showed small delays in peak concentration but no clinically significant effect of alosetron on the pharmacokinetics of S‐ and R‐fluoxetine or S‐ and R‐norfluoxetine. Coadministration of alosetron and fluoxetine was well tolerated by all subjects.
Decrease of Intracranial Pressure and Weight with Digoxin in Obesity
Authors: Hannerz Jan
Published: July 2003

Fourteen obese patients (body mass index = 34–47 kg/m2; mean = 40 kg/m2) with lumbar cerebrospinal fluid pressure (Pcsf) above 20 cm water in 10 of the 14 patients were treated with digoxin with a serum concentration of at least 1.0 nmol/L(0.8 ng/ml) for 6 months. Pcsf decreased significantly during digoxin medication (p < 0.005). Although there were no diet restrictions, all patients decreased in weight (range: 3–25 kg; mean = 10.6 kg) during the 6 months (p < 0.001). When digoxin medication was stopped in 3 patients, prompt weight increase occurred. Most patients needed progressively increased digoxin doses to attain stabilized serum concentrations at the stipulated level, in 5 patients more than 0.5 mg a day. Five of 13 patients developed diabetes mellitus during the digoxin medication. The larger the dose of digoxin, the greater the risk for diabetes mellitus to occur.
Prevention of a First Myocardial Infarction
Authors: Dayspring Thomas D.
Published: July 2003

Coronary heart disease is the leading cause of morbidity and mortality in men and women in the Western world. We now have significant evidence that prevention of the first coronary event using lifestyle and pharmacologic therapies is paramount. Events are caused by inflamed arteries leading to rupture of atherosclerotic plaques that induce potentially occlusive thrombi. Analysis of event reduction trials has revealed that LDL‐C lowering is only one part of the therapy needed to stabilize plaque. HMG‐Co‐A‐reductase inhibitors, fibrates, and statins all have differing mechanisms of action that provide not only lipid but also inflammatory, rheologic, and co‐agulation benefits. Concentration and sizes of lipoprotein subfractions have emerged as important new tools with small dense LDL particles having more atherogenicity, which has led to an increasing use of aggressive combination therapy for prevention of first myocardial infarction. Proper use of lipid‐lowering therapies requires knowledge of drug metabolism drug‐drug interactions.
Time‐Variant Increase in Methylprednisolone Clearance in Patients with Acute Respiratory Distress Syndrome: A Population Pharmacokinetic Study
Authors: Yates Charles R. , Vysokanov Alexander , Mukherjee Arnab , Ludden Thomas M. , Tolley Elizabeth , Meduri G. Umberto , Dalton James T.
Published: July 2003

Methylprednisolone (MP) disposition was evaluated in 20 individuals who participated in an ongoing randomized, double‐blind, placebo‐controlled study designed to evaluate the efficacy of MP in the treatment of acute respiratory distress syndrome (ARDS). MP (1 mg/kg) was given as a loading infusion over 30 minutes followed by a 1 mg/kg/day continuous IV infusion. Patients were switched to oral MP upon restoration of oral intake. MP plasma concentrations (n=110) were determined using a specific HPLC method. Population pharmacokinetic analysis was performed using nonlinear mixed‐effects models, implemented in NONMEM, version V. MP plasma concentration data were described by a one‐compartment open model with a time‐dependent, nonlinear increase in the clearance (CL) of MP during the course of therapy. Initial clearance of MP (CL0) in ARDS patients at the start of therapy increased to a maximal value (CLmax) after approximately 7 days. The estimate of CLmax was similar to the CL of MP in healthy individuals reported previously. Population mean estimates (± SE) of parameters in the model were as follows: CL0 = 13.2 ± 2.4 L/h, CLmax = 25.0 ± 3.6 L/h, time of half‐maximal increase in CL (T50) = 41.1 ± 8.2 h, gamma (Hill coefficient) = 3.8 ± 0.6, and volume of distribution (Vd) = 137 ± 30.2 L. Disease progression indices and patient demographics were evaluated as covariates, and no significant correlation was found. Means (± SD) of plasma protein binding differed between healthy individuals (72% ± 4%) and ARDS patients (46% ± 11%) (p < 0.001). The pharmacokinetics of MP in ARDS patients has not been described previously.
Linezolid: Pharmacokinetic and Pharmacodynamic Evaluation of Coadministration with Pseudoephedrine HCl, Phenylpropanolamine HCl, and Dextromethorphan HBr
Authors: Hendershot Pamela E. , Antal Edward J. , Welshman Ian R. , Batts Donald H. , Hopkins Nancy K.
Published: July 2003

Linezolid is a novel oxazolidinone antibiotic with mild reversible monoamine oxidase inhibitor (MAOI) activity. The potential for interaction with over‐the‐counter (OTC) medications requires quantification. The authors present data evaluating the pharmacokinetic and pharmacodynamic responses to coadministration of oral linezolid with sympathomimetics (pseudoephedrine and phenylpropanolamine) and a serotonin reuptake inhibitor (dextromethorphan). Following coadministration with linezolid, minimal but statistically significant increases were observed in pseudoephedrine and phenylpropanolamine plasma concentrations; a minimal but statistically significant decrease was observed in dextrorphan (the primary metabolite of dextromethorphan) plasma concentrations. Increased blood pressure (BP) was observed following the coadministration of linezolid with either pseudoephedrine or phenylpropanolamine; no significant effects were observed with dextromethorphan. None of these coadministered drugs had a significant effect on linezolid pharmacokinetics. Minimal numbers of adverse events were reported. Potentiation of sympathomimetic activity by linezolid was judged not to be clinically significant, but patients sensitive to the effects of increased BP due to predisposing factors should be treated cautiously. No restrictions are indicated for the coadministration of dextromethorphan and linezolid.
Interactions between Simvastatin and Troglitazone or Pioglitazone in Healthy Subjects
Authors: Prueksaritanont Thomayant , Vega José M. , Zhao Jamie , Gagliano Kathleen , Kuznetsova Olga , Musser Bret , Amin Raju D. , Liu Lida , Roadcap Brad A. , Dilzer Stacy , Lasseter K. C. , Rogers J. Douglas
Published: July 2003

Two randomized, two‐period crossover studies were conducted to evaluate the effects of repeat oral dosing of troglitazone (Study I) and pioglitazone (Study II) on the pharmacokinetics of plasma HMG‐CoA reductase inhibitors following multiple oral doses of simvastatin and of simvastatin on the plasma pharmacokinetics of troglitazone (Study I) in healthy subjects. In both studies, each subject received two treatments. Treatment A consisted of once‐daily oral doses of troglitazone 400 mg (Study I) or pioglitazone 45 mg (Study II) for 24 days with coadministration of once‐daily doses of simvastatin 40 mg (Study I) or 80 mg (Study II) on Days 15 through 24. Treatment B consisted of once‐daily oral doses of simvastatin 40 mg (Study I) or 80 mg (Study II) for 10 days. In Study I, the area under the plasma concentration‐time profiles (AUC) and maximum plasma concentrations (Cmax) of HMG‐CoA reductase inhibitors in subjects who received both troglitazone and simvastatin were decreased modestly (by ∼30% for Cmax and ∼40% for AUC), but time to reach Cmax(tmax) did not change, as compared with those who received simvastatin alone. Simvastatin, administered orally as a 40 mg tablet daily for 10 days, did not affect the AUC or tmax (p > 0.5) but caused a small but clinically insignificant increase (∼25%) in Cmax for troglitazone. In Study II, pioglitazone, at the highest approved dose for clinical use, did not significantly alter any of the pharmacokinetic parameters (AUC, Cmax, and tmax) of simvastatin HMG‐CoA reductase inhibitory activity. For all treatment regimens, side effects were mild and transient, suggesting that coadministration of simvastatin with either troglitazone or pioglitazone was well tolerated. The modest effect of troglitazone on simvastatin pharmacokinetics is in agreement with the suggestion that troglitazone is an inducer of CYP3A. The insignificant effect of simvastatin on troglitazone pharmacokinetics is consistent with the conclusion that simvastatin is not a significant inhibitor for drug‐metabolizing enzymes. The lack of pharmacokinetic effect of pioglitazone on simvastatin supports the expectation that this combination may be used safely.
Coma and Seizures due to Severe Hyponatremia and Water Intoxication in an Adult with Intranasal Desmopressin Therapy for Nocturnal Enuresis
Authors: Odeh Majed , Oliven Arie
Published: July 2003

Desmopressin, a synthetic analogue of the antidiuretic hormone, is an effective medication for primary nocturnal enuresis for both children and adults. Its safety is well established. Although it has a favorable side effect profile, because of its pharmacological effect, intranasal desmopressin can rarely induce water intoxication with profound hypo‐natremia if given without adequate restriction of water intake. The authors describe an adult patient with water intoxication and severe hyponatremia accompanied byloss of consciousness and seizures after 2‐day intranasal administration of desmopressin. The present and the previously reported cases emphasize the need for greater awareness of the development of this serious and potentially fatal complication. In addition, to adjust the drugto the lowest required dosage, adequate restriction of water intake is recommended, and serum levels of sodium should be measured periodically to allow for early detection of water intoxication and hyponatremia.
Double‐Blind, Randomized Comparison of the Analgesic and Pharmacokinetic Profiles of Controlled‐ and Immediate‐Release Oral Oxycodone in Cancer Pain Patients
Authors: Stambaugh John E. , Reder Robert F. , Stambaugh Michael D. , Stambaugh Heather , Davis Maureen
Published: July 2003

Thirty patients with cancer pain completed a double‐blind crossover study comparing controlled‐release (CR) and immediate‐release (IR) oxycodone. In open‐label titration (2 to 21 days), these patients were stabilized on IR oxycodone qid. They were then randomized to double‐blind treatment with CR oxycodone q12h or IR oxycodone qid for 3 to 7 days followed by crossover at the same daily dose. Mean (± SD) pain intensity (0 = none to 10= severe) decreased from a baseline of 6.0 ± 2.2 to 2.7 ± 1.1 after titration with IR oxycodone dosed qid. Pain intensity remained stable throughout double‐blind treatment: 2.7 ± 1.9 with CR oxycodone and 2.8 ± 1.9 with IR oxycodone. Acceptability of therapy and pain scores correlated with plasma oxycodone concentrations for each interval and were similar for both medications (IR and CR oxycodone). Adverse events were similar for both formulations. Following repeat dosing under double‐blind conditions, oral CR oxycodone administered q12h provided analgesia comparable to IR oxycodone given qid.
Pharmacokinetics of CS‐866, a New Angiotensin II Receptor Blocker, in Healthy Subjects
Authors: Schwocho Lee R. , Masonson Harvey N.
Published: July 2003

CS‐866, a novel angiotensin IIreceptor blocker, is rapidly and completely metabolized to RNH‐6270, its active metabolite. The pharmacokinetics of RNH‐6270 following oral CS‐866 or intravenous RNH‐6270 administration was determined in 104 healthy male volunteers. The pharmacokinetics of RNH‐6270 was linear over dose ranges of 1 to 32 mg (intravenous RNH‐6270 administration) and 10 to 160 mg (oral CS‐866 administration). The time to maximum plasma concentration of RNH‐6270 after oral CS‐866 administration ranged from 1.4 to 2.8 hours, and the terminal elimination half‐life ranged from 12 to 18 hours. Absolute bioavailability of RNH‐6270 after oral administration of CS‐866 was 26%. Administration of CS‐866 once daily for 10 days did not result in drug accumulation. When administered intravenously, RNH‐6270 has a volume of distribution of 15 to 25 L. Approximately 35% to 50% of RNH‐6270 is excreted unchanged in the urine. CS‐866 was safe and well tolerated at doses of up to 160 mg/day.
The Bioavailability of the Novel Nonnucleoside Reverse Transcriptase Inhibitor GW420867X Is Unaffected by Food in Healthy Male Volunteers
Authors: Cass Lindsey M. , Moore Katy H. P. , Dallow Nigel S. , Jones Anne E. , Sisson Jonathan R. , Prince William T.
Published: July 2003

The effect of food on the bioavailability of GW420867X, a novel nonnucleoside reverse transcriptase inhibitor, was investigated in 15 young, healthy, male volunteers. A single oral dose of GW420867×100 mg was administered in the fasted state, after a high‐fat meal, and after a meal of normal fat composition. Tolerability and pharmacokinetic sampling were assessed at baseline and up to 600 hours. The median concentration‐time plots for each treatment group were essentially superimposable. Neither the rate nor the extent of absorption of GW420867X was significantly affected by food. The median time to peak plasma concentration was 3 to 4 hours, irrespective of treatment. Pairwise comparisons using the fasted treatment as the comparator showed no impact of food on GW420867X pharmacokinetics. GW420867X was well tolerated. There were no serious or treatment‐limiting adverse events; all episodes reported were rated as mild to moderate. The bioavailability of GW420867X was unaffected by food. GW420867X may be administered independently of food and fat intake.
Pharmaceutical Care Services for Asthma Patients: A Controlled Intervention Study
Authors: Schulz Martin , Verheyen Frank , Mühlig Stephan , Müller Jörg Michael , Mühlbauer Katrin , Knop‐Schneickert Elke , Petermann Franz , Bergmann Karl‐Christian
Published: July 2003

As asthma is associated with an enormous social, psychological, and economic burden, various patient education programs have been developed to improve outcomes, including quality of life. The authors evaluated the effectiveness of community pharmacy‐based interventions on lung function, health‐related quality of life, and self‐management in asthma patients in a 12‐month controlled intervention study in 26 intervention and 22 control pharmacies. Pharmacies opted whether to take part as intervention or control pharmacies. According to this, patients (ages 18–65) with mild to severe asthma attending the pharmacies were allocated to the intervention (n = 161) or control group (n = 81), respectively. Intervention patients were educated on their disease, pharmacotherapy, and self‐management; inhalation technique was assessed and, if necessary, corrected. Pharmaceutical care led to significantly improved inhalation technique. Asthma‐specific quality of life and the mental health summary score of the SF‐36 improved significantly in the intervention group. At 12 months, the intervention group showed significant improvements with regard to evening peak flow, self‐efficacy, and knowledge.
A Pilot Study Assessing the Impact of Heat on the Transdermal Delivery of Testosterone
Authors: Shomaker T Samuel , Zhang Jie , Ashburn Michael A.
Published: July 2003

This study evaluated the effect of locally applied heat on the transdermal delivery of testosterone. Six healthy adult volunteers were tested three times while receiving a 5 mg androgen patch, the same patch with a heat‐generating patch, and no patch at all over 12 hours. Statistically significant differences in mean maximum serum testosterone concentration values were seen. Heat plus patch resulted in a mean maximum serum testosterone concentration of 939 ng/dl versus 635 ng/dl (patch only) and 425 ng/dl (no patch). (Heat + patch vs. no patch: p < 0.001; heat + patch vs. patch: p < 0.001; patch vs. no patch: p = 0.003.) The area under the curve of plasma testosterone concentration versus time values were means of 4114 ng/dl·h versus 1985 ng/dl·h for the patch‐only group (p = 0.001). The use of heat improved absorption of transdermal testosterone and decreased time to peak serum testosterone concentrations, resulting in a statistically significant difference in mean maximum serum testosterone concentrations compared with the use of the patch without heat.
Low Molecular Weight Heparin‐Induced Liver Toxicity
Authors: Hui Chee‐Kin , Yuen Man‐Fung , Ng Irene Oi‐Lin , Tsang Kenneth Wah‐Tak , Fong Gardian Chung‐Yan , Lai Ching‐Lung
Published: July 2003

The authors report two cases of hepatotoxicity induced by low molecular weight heparin. A 26‐year‐old woman and a 33‐year‐old man were treated with low molecular weight heparin for pulmonary embolism and cerebral infarction, respectively. They both developed derangement in liver function tests a few days after commencement of the low molecular weight heparin. The derangement in liver function tests was associated with a decreased serum complement 3 activity. Their liver functions recovered over a period of 2 to 3 months after low molecular weight heparin was stopped. Liver biopsy in the woman demonstrated balloon degeneration with scattered foci of hepatocytic necrosis, suggesting a complementmediated hepatocellular damage.
The Effect of 3‐Month Ingestion of Ginkgo biloba Extract (EGb 761) on Pancreatic β‐Cell Function in Response to Glucose Loading in Individuals with Non‐Insulin‐Dependent Diabetes Mellitus
Authors: Kudolo George B.
Published: July 2003

In the first report (Journal of Clinical Pharmacology 2000; 40:647–654), it was shown that ingestion of 120 mg of Ginkgo biloba extract (EGb 761) daily for 3 months by normal glucose‐tolerant individuals caused a significant increase in pancreatic ‐cell insulin and C‐peptide response, measured as the area under the curve (AUC0→120) during a 2‐hour standard (75 g) oral glucose tolerance test (OGTT). This follow‐up study was designed to determine the effect of the same Ginkgo biloba treatment on glucose‐stimulated pancreatic ‐cell function in non‐insulin‐dependent diabetes mellitus (NIDDM) subjects. In diet‐controlled subjects (fasting plasma glucose [FPG], 117 ± 16 mg/dl; fasting plasma insulin [FPI], 29 ± 8 μU/ml; n = 6), ingestion of Ginkgo biloba produced no significant effect on the insulin AUC0 120(193 ± 53 vs. 182 ± 58 μU/ml/h, before and after ingesting Ginkgo biloba, respectively). In hyperinsulinemic NIDDM subjects taking oral hypoglycemic medications (n = 6) (FPG 143 ± 48 mg/dl; FPI 46 ± 13 μU/ml), ingestion of Ginkgo biloba caused blunted plasma insulin levels from 30 to 120 minutes during the OGTT, leading to a reduction of the insulin AUC0 120(199 ± 33 vs. 147 ± 58 pμU/ml/h, before and after Ginkgo biloba, respectively). The C‐peptide levels increased, and so the AUC0 120did not parallel the insulin AUC0 120, creating a dissimilar insulin/C‐peptide ratio indicative of an enhanced hepatic extraction of insulin relative to C‐peptide. Thus, in pancreatic cells that are already maximally stimulated, ingestion of Ginkgo biloba may cause a reduction in plasma insulin levels. Only in NIDDM subjects with pancreatic exhaustion (FPG 152 ± 46 mg/dl;FPI 16 ± 8 μU/ml; n = 8), who also took oral hypoglycemic agents, did Ginkgo biloba ingestion significantly increase pancreatic ‐cell function in response to glucose loading (insulin AUC0 120 increased from 51 ± 29 to 98 ± 20 μU/ml/h, p > 0.0001), paralleled by a C‐peptide AUC0 120increase from 7.2 ± 2.8 to 13.7 ± 6.8 (p > 0.0001). Whether this increase is due to “resuscitation” of previously exhausted islets or increased activity of only the remaining functional islets is unclear. However, not even in this group did increased pancreatic ‐cell activity cause a reduction of blood glucose during the OGTT. It is concluded that ingestion of Ginkgo biloba extract by an NIDDM subject may increase the hepatic metabolic clearance rate of not only insulin but also the hypoglycemic agents. The result is reduced insulin‐mediated glucose metabolism and elevated blood glucose.
Montelukast Dose Selection in Children Ages 2 to 5 Years: Comparison of Population Pharmacokinetics between Children and Adults
Authors: Knorr Barbara , Nguyen Ha H. , Kearns Gregory L. , Villaran Cesar , Boza Maria L. , Reiss Theodore F. , Rogers John D. , Zhang Ji , Larson Patrick , Spielberg Stephen
Published: July 2003

Montelukast, a leukotriene receptor antagonist, has demonstrated efficacy and tolerability in the treatment of asthma in patients age 6 years and older. The purpose of this open, one‐period, multicenter population pharmacokinetic study was to identify a chewable tablet (CT) dose of montelukast for administration to children ages 2 to 5 years with asthma, yielding a single‐dose pharmacokinetic profile (area under the plasma concentration‐time curve [AUC]) comparable to that of the 10 mg film‐coated tablet (FCT) dose in adults. Because patient numbers were small and the volume of blood that could be collected from individual 2‐ to 5‐year‐old patients was limited, a population pharmacokinetic approach was used to estimate population AUC (AUCpop). The 4 mg CT dose of montelukast was well tolerated and yielded an AUCpop(2721 ng·h/mL) similar to that of the adult AUCpop (2595 ng·h/mL) observed after a 10 mg FCT dose. These results support the selection of a 4 mg once‐daily CT dose of montelukast for future efficacy and safety studies in children ages 2 to 5 years with asthma.
Comparative Tacrolimus Pharmacokinetics: Normal versus Mildly Hepatically Impaired Subjects
Authors: Bekersky Ihor , Dressler Dawna , Alak Ala , Boswell Gary W. , Mekki Qais A.
Published: July 2003

Tacrolimus (FK506, Prograf®), marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation, is virtually completely metabolized. The major metabolic pathways are P450 3A4‐mediated hydroxylation and demethylation. Since P450 hepatic drug‐metabolizing enzymes may be impaired din hepatic dysfunction, a study was conducted to characterize oral and intravenous tacrolimus pharmacokinetics in 6 patients with mild hepatic dysfunction and compared with parameters to those from normal subjects obtained in a separate study. Patients received two treatments: a single 0.020 mg/kg ideal body weight (IBW) IV dose infused over 4 hours and ∼0.12 mg/kg IBW orally; normal subjects were dosed at 0.02 mg/kg 4‐hour IV and 5 mg(0.065 mg/kg) PO. Mean blood pharmacokinetic parameters with mild hepatic dysfunction were as follows: clearance = 0.035 L/h/kg, terminal exponential volume of distribution = 2.59 L/kg, terminal exponential half‐life = 60.6 hours (IV), PO maximum blood concentration = 48.2 ng/mL, time of PO maximum blood concentration = 1.5 hours, and absolute bioavailability = 22.3%. The respective parameters in normal subjects were as follows: 0.040 L/h/kg, 1.91 L/kg, 34.2 hours (IV), 29.7 ng/mL, 1.6 hours, and 17.8%. Inasmuch as clearance and bioavailability were not substantially different from that in normal subjects, patients with mild hepatic impairment may initially be treated with conventional tacrolimus doses, with subsequent dosage adjustments based on response, toxicity, and therapeutic drug monitoring.
Pharmacokinetics of Metformin Gastric‐Retentive Tablets in Healthy Volunteers
Authors: Gusler G. , Gorsline J. , Levy G. , Zhang S. Z. , Weston I. E. , Naret D. , Berner B.
Published: July 2003

The single‐dose pharmacokinetics of two gastric‐retentive, extended‐release tablet formulations of metformin hydrochloride in fed, healthy volunteers were compared with those of the currently marketed immediate‐release metformin hydrochloride product. The plasma concentration‐time profiles demonstrated extended‐release characteristics from the gastric‐retentive tablets. The mean bioavailability from each gastric‐retentive tablet was approximately 115%, relative to the immediate‐release (IR) product. Cmax values were lower and tmax values were greater for the gastric‐retentive tablets compared with the IR product. In contrast to conventional extended‐release metformin tablets reported in the literature, these gastric‐retentive tablets showed extended‐release plasma concentration profiles of metformin hydrochloride and increased bioavailability compared with the immediate‐release tablet.
Single‐Dose Pharmacokinetics of Bupropion in Adolescents: Effects of Smoking Status and Gender
Authors: Stewart John J. , Berkel Hans J. , Parish Roy C. , Simar M. Renee , Syed Azeem , Bocchini Joseph A. , Wilson John T. , Manno Joseph E.
Published: July 2003

Sustained‐release (SR) bupropion (Zyban®) is approved as a smoking cessation aid for adults. Since smoking often begins in adolescence, we determined the single‐dose pharmacokinetics of bupropion SR in 75 adolescent subjects ranging from 13 to 18 years old. Subjects self‐reported their smoking status. Urinary cotinine concentration was used to verify smoking status. Thirty‐seven subjects (18 males, 19 females) were classified as cigarette smokers and 38 were nonsmokers (19 males, 19 females). Fasted subjects received one tablet (150 mg) of bupropion SR, and plasma samples were collected before (0) and 1/2, 1, 2, 3, 4, 6, 8, 24, 48, and 72 hours after dosing. Plasma samples were analyzed for bupropion and its three major metabolites (hydroxybupropion and the aminoalcohol isomers, erythrohydrobupropion plus threohydrobupropion, ex‐pressed as a composite) by solid‐phase extraction, followed by LC/MS/MS. Factorial analysis of variance (ANOVA) was used to evaluate the effects of smoking and gender on pharmacokinetic parameters. Smokers and nonsmokers differed significantly (p <0.05) in age and urinary cotinine (p < 0.01) concentration but did not differ significantly in mean weight, height, body surface area, or body mass index. The pharmacokinetic (PK) parameters for bupropion and hydroxybupropion did not differ between smokers and non‐smokers, but differences were found between male and female subjects. Mean values for area under the plasma concentration versus time curve (AUC0→), volume of distribution (Vdβ) normalized to body weight, maximum plasma concentration (Cmax), and elimination half‐life (t1/2β) for bupropion were significantly (p < 0.05) greater in females than males, while clearance of bupropion normalized to body weight (CL/f) did not differ between males and females. Females also exhibited significantly (p < 0.05) larger values for hydroxybupropion mean AUC0→ and Cmax than males. The mean ratio of hydroxybupropion to bupropion AUC for adolescents was approximately 4 to 5, which is lower than that previously reported for adults. In conclusion, smoking status does not affect the single‐dose pharmacokinetics of bupropion SR in adolescents. However, females differ from males in several potentially important PK parameters for bupropion and its major metabolite, hydroxybupropion.
P‐glycoprotein Interactions of Nefazodone and Trazodone in Cell Culture
Authors: Störmer Elke , von Moltke Lisa L. , Perloff Michael D. , Greenblatt David J.
Published: July 2003

This study investigated the effects of nefazodone (NFZ) and trazodone (TZD) on P‐glycoprotein (P‐gp) activity and expression in cell culture. NFZ and TZD showed no differential transport between the basolateral to apical and apical to basolateral direction across Caco‐2 cell monolayers. Transport in either direction was not affected by verapamil. NFZ was a potent inhibitor (IC50 = 4.7 M) of rhodamine123 (Rh123)B to A transport across Caco‐2 cell monolayers, while TZD had minimal effect. Following 72‐hour exposure of LS180V cells to NFZ and TZD (10 M), a twofold increase in immunoreactive P‐gp was observed. Rh123 accumulation into these cells was reduced to 65% and 74% of control by NFZ and TZD (10 M), respectively. It was concluded that differential rates of transport of NFZ and TZD in Caco‐2 cells were not evident. However, NFZ is an inhibitor of P‐gp activity at clinically relevant in vivo concentrations and may have the potential to increase bioavailability of coadministered compounds that are substrates for transport. Concentrations of NFZ and TZD achieved in the intestine after chronic oral dosing may induce P‐gp expression and reduce absorption of coadministered drugs.
Effects of Oral Vitamin K on S‐ and R‐Warfarin Pharmacokinetics and Pharmacodynamics: Enhanced Safety of Warfarin as a CYP2C9 Probe
Authors: Kim Jooran S. , Nafziger Anne N. , Gaedigk Andrea , Dickmann Leslie J. , Rettie Allan E. , Bertino Joseph S.
Published: July 2003

Evidence for the selectivity of S‐warfarin metabolism by CYP2C9 is substantial, suggesting that warfarin may be a potential CYP2C9 phenotypingprobe. It is, however, limited by its ability to elevate the international normalized ratio (INR) and potentially cause bleeding. The effect of vitamin K to attenuate the elevation of INR may enable the safe use of warfarin as a probe. The objective of this study was to investigate the pharmacokinetics and pharmacodynamics of S‐ and R‐warfarin in plasma following the administration of warfarin alone versus warfarin and vitamin Kin CYP2C9 homozygotes. Healthy adults received, in a randomized crossover fashion in a fasted state, warfarin 10 mg orally or warfarin 10 mg plus vitamin K10 mg orally. Blood samples were obtained over 5 days during each phase. INR measurements were obtained at baseline and day 2 in each phase. INR, AUC0‐∞, and t1/2 of plasma S‐ and R‐warfarin were examined. Eleven CYP2C9*1 homozygotes (3 men, 8 women) were enrolled. INR at day 2 following warfarin 10 mg was 1.18 0.19, which differed significantly from baseline (INR = 1.00 0.05) and warfarin with vitamin K (INR = 1.06 0.07).INR at baseline was not significantly different from warfarin with vitamin K. t1/2 and AUC0 of both enantiomers did not significantly differ between the phases. It was concluded that INR is apparently attenuated by concomitant administration of a single dose of vitamin K without affecting the pharmacokinetics of either warfarin stereoisomer. Warfarin 10 mg may be safely used as a CYP2C9 probe in homozygotes when given concomitantly with 10 mg of oral vitamin K.