bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Human Serum Albumin Content in Formulations on the Bioequivalency of Interferon Alfa‐2a Given by Subcutaneous Injection in Healthy Male Volunteers
Authors: Zhi Jianguo , Teller Stuart B. , Satoh Hiroko , Koss‐Twardy Susan G. , Luke David R.
Published: March 2013

To determine the influence of human serum albumin (HSA) content in formulations on the bioequivalency of recombinant interferon alfa‐2a, a double‐blind, randomized, two‐way crossover study was conducted in 24 healthy male volunteers. Subjects received a single subcutaneous injection of 18 million IU of Roferon‐A reconstituted with either the diluent containing 10 mg of HSA or the HSA‐free diluent; final HSA contents in the 2 formulations were 15 mg and 5 mg, respectively. Administration of the 2 formulations resulted in similar 48‐hour Roferon‐A serum concentration‐time profiles and comparable frequency and intensity of adverse events. The statistical analysis using the two one‐sided tests procedure showed that both formulations were bioequivalent for pharmacokinetic parameters such as Cmax, tmax, AUC48, and AUC. We conclude that a threefold change in HSA content in formulations does not alter the bioequivalency of Roferon‐A.
Use of a Eutectic Mixture of Local Anesthetics for Prolonged Subcutaneous Drug Administration
Authors: Berkovitch Matitiahu , Davis Susan , Matsui Doreen , Donsky Judy , Koren Gideon , Olivieri Nancy F.
Published: March 2013

The efficacy of a eutectic mixture of local anesthetics (EMLA) in alleviating the pain associated with subcutaneous needle insertion for infusion of the iron‐chelating agent, deferoxamine, was examined in 12 patients with homozygous β‐thalassemia. As reported by the patient using a 100‐mm visual analogue scale, the pain of insertion was rated as significantly less after application of EMLA (mean ± SD, 1.5 ± 2.2 mm) than the pain associated with needle insertion without EMLA (34.8 ± 33.5 mm, P = .005). Subsequently, in a double‐blind randomized trial of 10 β‐thalassemia patients, EMLA was significantly better (5.7 ± 8.2 mm) than placebo (27.0 ± 22.8 mm, P = .01) in reducing the pain of needle insertion for deferoxamine infusion. No adverse effects were reported with the use of EMLA cream. These results suggest that EMLA may be effective in reducing the pain associated with needle insertion for subcutaneous deferoxamine infusion in β‐thalassemia patients, which may lead to improved compliance with this irritating, prolonged therapy. The safety of EMLA use in these patients, and others receiving regular parenteral therapy, should now be examined.
Risk Factors for the Development of Specific Noncardiovascular Adverse Effects Associated With Amiodarone
Authors: Tisdale James E. , Follin Sheryl L. , Ordelova Alina , Webb Charles R.
Published: March 2013

Noncardiovascular adverse effects associated with amiodarone result in substantial morbidity. Adverse effects involving the skin, liver, thyroid, and lungs have been reported in as many as 57%, 55%, 11%, and 13% of patients, respectively. Although risk factors for some amiodarone‐induced adverse effects have been identified, risk factors for these specific side effects have not been systematically evaluated. Therefore, risk factors for development of amiodarone‐induced dermatologic, hepatic, thyroid, or pulmonary adverse effects were identified using univariate analysis in 44 patients receiving the drug for supraventricular or ventricular arrhythmias (mean duration of therapy 99.5 ± 110.8 weeks). Dermatologic side effects occurred in 4 (9.1%) patients. Patients who experienced dermatologic side effects were younger than patients who did not (mean age, 48.3 ± 15.8 years versus 60.1 ± 9.5 years, respectively; P = .03). Patients younger than 60 years of age were more likely to develop photosensitivity or blue‐gray skin discoloration than those aged 60 or older (P = .05). Hepatic adverse effects occurred in 3 (6.8%) patients. Left ventricular ejection fraction was lower in those who developed hepatic adverse effects than in those who did not (15.0 ± 4.0% versus 39.1 ± 13.9%, P = .005). Adverse thyroid effects occurred in 6 (13.6%) patients; and pulmonary fibrosis occurred in 2 (4.5%) patients. No specific risk factors for adverse thyroid effects or pulmonary fibrosis were revealed. In conclusion, age less than 60 may be a risk factor for amiodarone‐induced dermatologic adverse effects, whereas severely depressed left ventricular ejection fraction may be a risk factor for hepatic side effects associated with amiodarone.
Disposition of Phenylbutyrate and its Metabolites, Phenylacetate and Phenylacetylglutamine
Authors: Piscitelli Stephen C. , Thibault Alain , Figg William D. , Tompkins Anne , Headlee Donna , Lieberman Ronald , Samid Dvorit , Myers Charles E.
Published: March 2013

Phenylacetate, an inducer of tumor cytostasis and differentiation, shows promise as a relatively nontoxic antineoplastic agent. Phenylacetate, however, has an unpleasant odor that might limit patient acceptability. Phenylbutyrate, an odorless compound that also has activity in tumor models, is known to undergo rapid conversion to phenylacetate by beta‐oxidation in vivo. This phase I study examined the pharmacokinetics of phenylbutyrate and characterized the disposition of the two metabolites, phenylacetate and phenylacetylglutamine. Fourteen patients with cancer (aged 51.8 ± 13.8 years) received a 30‐minute infusion of phenylbutyrate at 3 dose levels (600, 1200, and 2000 mg/m2). Serial blood samples and 24‐hour urine collections were obtained. Samples were assayed by high‐performance liquid chromatography. A model to simultaneously describe the pharmacokinetics of all three compounds was developed using ADAPT II. Data were modeled as molar equivalents. The model fit the data well as shown by mean (±SD) coefficients of determination (r2) for phenylbutyrate, phenylacetate, and phenylacetylglutamine, which were 0.96 ± 0.07, 0.88 ± 0.10, and 0.92 ± 0.06, respectively. The intrapatient coefficient of variation percentage (CV%) around the parameter estimates were small (range 7.2–33.5%). Phenylbutyrate achieved peak concentrations in the range of in vitro tumor activity (500–2000 μmol/L) and exhibited saturable elimination (Km = 34.1 ± 18.1 μg/mL and Vmax = 18.1 ± 18 mg/h/kg). Metabolism was rapid; the times to maximum concentration for phenylacetate and phenylacetylglutamine were 1 and 2 hours, respectively. The conversion of phenylbutyrate to phenylacetate was extensive (80 ± 12.6%), but serum concentrations of phenylacetate were low owing to rapid, subsequent conversion to phenylacetylglutamine. The ratio of phenylbutyrate AUC to phenylacetate AUC was 2.66. Thus, phenylbutyrate may not be a prodrug for phenylacetate and should be pursued as an independent antitumor agent.
Comparative Pharmacokinetics and Bioavailability of Nitroglycerin and its Metabolites from Transderm‐Nitro, Nitrodisc, and Nitro‐Dur II Systems Using a Stable‐Isotope Technique
Authors: Sun Jim X. , Piraino Anthony J. , Morgan John M. , Joshi Jill C. , Cipriano Alessandra , Chan Keith , Redalieu Elliot
Published: March 2013

The pharmacokinetics and bioavailability of nitroglycerin (GTN) and its metabolites, 1,2‐glyceryl dinitrate (1,2‐GDN) and 1,3‐glyceryl dinitrate (1,3‐GDN), were compared after a single 14‐hour application of Transderm‐Nitro (Ciba‐Geigy, Summit, NJ), Nitrodisc (GD Searle, Chicago, IL), and Nitro‐Dur II (Key Pharmaceuticals, Kenilworth, NJ) systems to 18 healthy male subjects on 3 separate occasions. A 14‐hour intravenous infusion of 15N‐labeled GTN was given simultaneously to correct for changes in systemic clearance during the application of each system. Plasma concentrations of 15N‐labeled GTN, unlabeled GTN, and their corresponding dinitrate metabolites were measured using a gas chromatography/mass spectrometry method. Results showed that the plasma concentration profiles of nitroglycerin and its metabolites for the three systems were similar during and after system removal. Mean (SD) total amounts (AUCp × CLiv) of GTN transdermally available after adjustment for 15N‐labeled GTN clearance were 5.3 (2.1), 5.3 (2.0), and 5.4 (2.6) mg for Transderm‐Nitro, Nitrodisc, and Nitro‐Dur II, respectively. Mean (SD) AUC values for 1,2‐GDN were 44.6 (15.8), 44.3 (16.1), and 42.8 (19.3) ng • h/mL for the 3 systems. Corresponding AUC values for 1,3‐GDN were 9.3 (2.9), 9.7 (2.9), and 8.7 (3.0) ng • h/mL. Statistical analysis of the log‐transformed data based on 90% conventional confidence interval showed that all 3 systems delivered equivalent amounts of nitroglycerin into the systemic circulation. The AUC ratios for 1,3‐GDN to GTN, but not 1,2‐GDN to GTN, were statistically different for the intravenous and transdermal routes during all 3 system applications, indicating that the formation and metabolism of 1,3‐GDN was dependent on route of administration.
The Influence of Adrenalin on the Pharmacokinetics of Interpleurally Administered Lidocaine in Patients With Pancreatic Neoplasia
Authors: Calvo Begoña , Pedraz José L. , Gascón Alicia R. , Hernández Rosa M. , García‐Ortega E. , Vara F. , Muriel Clemente , Domínguez‐Gil Alfonso
Published: March 2013

The influence of adrenalin on the pharmacokinetics of lidocaine given interpleurally to 10 patients with pancreatic neoplasia was studied. Five patients received an interpleural dose of lidocaine (200 mg; control group), and 5 patients received an interpleural dose of lidocaine (200 mg) plus adrenalin (1:200,000). Plasma and cerebrospinal fluid (CSF) levels of lidocaine were measured before and at specified times (up to 8 hours) after the dose. The analytical technique was radioimmunoassay; and plasma and CSF data were assessed using noncompartmental analysis. The drug was quickly absorbed into the plasma in the control group (Cmax = 2.76 ± 0.10 μg/mL at 0.33 ± 0.14 hours after administration); whereas drug access to CSF was decreased and occurred slowly (Cmax = 0.32 ± 0.07 μg/mL at 1.66 ± 1.35 hours). The drug was eliminated more quickly from plasma than from CSF, with half‐lives of 1.71 ± 0.43 hours and 3.86 ± 1.27 hours, respectively. The simultaneous administration of adrenalin delayed absorption (tmax = 0.91 ± 0.52 hours). The drug elimination half‐lives in plasma and CSF of this group increased to 3.22 ± 1.22 hours and 8.71 ± 3.28 hours, respectively. The duration of the analgesia, evaluated as the time until the patient needed another dose, increased from 8.2 ± 1.5 hours in the control group to 9.7 ± 1.3 hours in the group that received adrenalin. From these results the levels that would be reached on a multiple‐dose regimen (D = 200 mg, r = 8 hours) were predicted. In the second group, the drug accumulated in the CSF. This may lead to adverse central nervous system (CNS) side effects when adrenalin is given simultaneously with lidocaine.
Controlled Study of the Putative Interaction Between Famotidine and Theophylline in Patients with Chronic Obstructive Pulmonary Disease
Authors: Bachmann Kenneth , Sullivan Timothy J. , Reese James H. , Jauregui Luis , Miller Kristen , Scott Mary , Yeh K. C. , Stepanavage Michael , King Joyce D. , Schwartz Jules
Published: March 2013

The effects of famotidine (80 mg per day), cimetidine (1600 mg per day), and placebo on theophylline pharmacokinetic parameters in chronic obstructive pulmonary disease (COPD) patients were compared. This was an open‐label, randomized, three‐period crossover study, in which each subject first underwent a seven‐day theophylline washout period, and thereafter received three single intravenous doses of theophylline (5 mg/kg infused over 30 minutes) during the study. Each of the experimental treatments was administered orally every 12 hours for a total of 9.5 days (19 doses). Theophylline was infused after the 17th dose of each treatment. Fourteen serial blood samples were collected before the start of each infusion, and for 30 hours after the end of each infusion. Plasma samples were assayed for theophylline, pharmacokinetic parameters were estimated, and treatment effects on each parameter were compared. Fourteen COPD patients completed all three periods of the investigation. Famotidine treatment had virtually no effect on any of theophylline's pharmacokinetic parameters. In contrast, cimetidine treatment significantly altered every pharmacokinetic parameter of theophylline as follows: Cimetidine decreased theophylline geometric mean CL from 2.74 L/h to 2.07 L/h (P < .001), and prolonged theophylline harmonic mean half‐life from 6.6 to 9.6 hours (P < .001) and mean residence time from 10.8 to 15.0 hours (P < .001). Cimetidine treatment slightly increased theophylline volume of distribution by approximately 10%, and that change also was statistically significant (P = .032). The authors conclude that the treatment effects of cimetidine on theophylline pharmacokinetic parameters were in accord with those reported by others, and that famotidine treatment had no effect on any of theophylline's pharmacokinetic parameters in COPD patients.
Pharmacokinetic‐Based Ticarcillin/Clavulanic Acid Dose Recommendations for Infants and Children
Authors: Reed Michael D. , Yamashita Toyoko S. , Blumer Jeffrey L.
Published: March 2013

The pharmacokinetic characteristics of ticarcillin and clavulanic acid were determined after the first dose (n = 22) and again under steady‐state conditions (n = 16) in a group of infants and children. Study subjects ranged in age from 1 month to 9.3 years; all but 3 study patients were 6 months of age or older. Each patient received 50 mg of ticarcillin and 1.7 mg of clavulanic acid (30:1 ratio) per kg of body weight given intravenously every 4 hours. Elimination half‐life, steady‐state volume of distribution, and body clearance averaged 1.1 hours, 0.22 L/kg, and 2.7 mL/min/kg, respectively, for ticarcillin, and 0.9 hours, 0.4 L/kg, and 6.2 mL/min/kg, respectively, for clavulanic acid. A total of 71% of the ticarcillin and 50% of the clavulanic acid dose were excreted unchanged in the urine over the 4‐hour sampling period. Corresponding renal clearances averaged 2.1 and 3.2 mL/min/kg for ticarcillin and clavulanic acid, respectively. No differences were observed between first dose and steady‐state evaluations in the pharmacokinetic behavior of either agent. In contrast, the pharmacokinetic behavior of clavulanic acid was significantly different from that observed for ticarcillin. These pharmacokinetic data combined with known in vitro susceptibilities of important clinical pathogens support a dose of 80 mg of ticarcillin and 2.7 mg/kg clavulanic acid per kg body weight given as a fixed dose combination every 8 hours for the treatment of most systemic infections that occur outside the central nervous system.
Pharmacokinetics of Orally Administered Cyclosporine in Patients with Crohn's Disease
Authors: Flückiger Simone S. , Schmidt Christoph , Meyer Ansgar , Kallay Zoltan , Johnston Atholl , Kutz Klaus
Published: March 2013

Cyclosporine pharmacokinetics were reported to be influenced in patients with Crohn's disease. To explore the relationship between Crohn's disease and cyclosporine pharmacokinetics, this investigation was performed in 20 patients with varying Crohn's Disease Activity Index (CDAI). A single oral dose of 300 mg of cyclosporine was given and serial blood samples were obtained over 52 hours. Cyclosporine whole blood concentrations were determined by a specific monoclonal radioimmunoassay. Pharmacokinetic parameters were comparable with those of healthy volunteers. No statistically significant difference between the pharmacokinetic parameters of the patients with CDAI values less than 150 and those with CDAI values 150 or greater could be shown. Although several factors associated with the pathology of Crohn's disease theoretically could influence the pharmacokinetics of orally administered cyclosporine, this investigation did not identify statistically significant differences in cyclosporine pharmacokinetics in Crohn's disease patients with different disease activities or different localization of inflammation as compared with healthy volunteers. However, if large parts of the small bowel were removed, a decrease of absorption of cyclosporine could be observed. In any case, it is important to be aware of the clinical variability of Crohn's disease and its potential implications in cyclosporine absorption.
The Pharmacokinetics and Cardiovascular Pharmacodynamics of HP 749 (Besipirdine HCl) and Metabolite P86–7480 in the Conscious Monkey
Authors: Hubbard John W. , Hsu Robert S. , Griffiths Lynne , Natarajan Chandra , Dean Roosevelt , Dileo Eva M. , Hintze Thomas H.
Published: March 2013

HP 749 was absorbed slowly in the conscious monkey after single oral doses (10, 20, and 40 mg/kg), with gradual metabolism to the N‐despropyl metabolite, P86–748Q. The tmax was 2 to 4 hours after dosing, with nonlinear increases in Cmax and the AUC0–4h for HP 749. The calculated elimination half life (t1/2) after oral administration was 7.4 ± 2.1 hours; however, absorption appeared to influence the terminal phase because the t1/2 after intravenous administration of 10 mg/kg was 1.5 hours. Plasma concentration of HP 749 2 minutes after intravenous bolus was 26.08 μg/mL. The HP 749 was rapidly distributed (t1/2α = 0.064 ± 0.033 hours) after intravenous administration, and displayed a VZ of 2.6 ± 0.85 L/kg. The CL of HP 749 was 20.8 ± 6.9 mL/min/kg, whereas renaJ clearance (CLR) of unchanged drug was only 0.13 ± 0.04 mL/min/kg. Thus, only about 1% of the administered dose was excreted unchanged by the kidney. The P86–7480 also was rapidly distributed and eliminated after an intravenous bolus, but was less extensively distributed than HP 749. HP 749 administered either as an intravenous bolus or orally caused a significant pressor effect soon after dosing. A significant tachycardia resulted from intravenous administration, but not after oral administration of the drug. An intravenous bolus of P86–7480 (0.1 mg/kg) resulted in an immediate increase in MAP and decreased heart rate. The duration of these cardiovascular events was significantly shorter after intravenous administration of P86–7480 than with intravenous or oral administration of the parent drug. These results support findings of previous studies in rats and dogs, demonstrating that high doses of HP 749 and its metabolite P86–7480 exert significant cardiovascular effects.
Impact of a Four‐Day Head‐Down Tilt (–6°) on Lidocaine Pharmacokinetics Used as Probe to Evaluate Hepatic Blood Flow
Authors: Saivin S. , Traon A. Pavy‐Le , Cornac A. , Güell A. , Houin G.
Published: March 2013

The impact of a microgravity simulation using a head‐down tilt (–6°) on lidocaine pharmacokinetics used as a probe to evaluate hepatic blood flow is discussed. Eight healthy male subjects were selected for a 7‐day study, including a 4‐day head‐down tilt from day 2 to day 5. Subjects were given 1 mg/kg of lidocaine on days 1 through 5 and 7. Blood sampling, cardiac output, and hepatic artery blood flow velocity measurements were done within 6 hours after administration. Cardiac output increased significantly during head‐down tilt, and returned to basal values during the recovery period. Blood flow velocity in the hepatic artery increased during the first day of the down tilt. Slight side effects (buzzing noise in the ears and sleepy feeling) were reported within minutes after the injection of lidocaine. Lidocaine disposition was modified during head‐down tilt: a significant decrease in maximal concentration (1.47 ± 0.26 mg/L on day 1 and 0.96 ± 0.30 mg/L on day 2); an increase in elimination clearance from 8.24 ± 3.22 mL/kg • minutes−1 to 11.63 ± 3.00 mL/kg • minutes−1; an increase in volume of distribution on day 2 and a decrease to lower than basal value on the other days (2.77 ± 1.73 L/kg on day 1 and 2.33 ± 0.48 L/kg on day 7). Half‐life regularly decreased from 264 ± 210 minutes to 160 ± 60 minutes between day 1 and day 7. With the exception of day 1, no correlation was found between blood flow in the hepatic artery and lidocaine clearance, probably owing to the lack of precision of echo Doppler measurement, which only permitted indirect assessment. The reported pharmacokinetic modifications suggested that the dosage of drugs such lidocaine must be adapted during long‐term administration in microgravity conditions by increasing the dose or reducing the interval of drug intake.
Effects of Phenytoin on Plasma High‐Density Lipoprotein Cholesterol Levels in Men with Low Levels of High‐Density Lipoprotein Cholesterol
Authors: Goerdt Chris , Keith Mary , Rubins Hanna Bloomfield
Published: March 2013

A low level of high‐density lipoprotein cholesterol (HDL‐C) is an important and common risk factor for coronary heart disease. Cross‐sectional studies and uncontrolled clinical trials have suggested that phenytoin can significantly raise HDL‐C levels. This study was undertaken to determine whether phenytoin can raise HDL‐C levels in men with low levels of HDL‐C. Ninety‐two men currently receiving outpatient care at a Veterans Affairs medical center and with baseline HDL‐C levels ≤ 1.16 mmol/L (45 mg/dL) were recruited to participate in this randomized, placebo‐controlled, double‐blind clinical trial. Participants received a placebo or 100 mg, 200 mg, or 300 mg of phenytoin once daily for 14 weeks. Lipid levels were measured at baseline and at 6, 10, and 14 weeks. After 14 weeks of treatment, the 200‐mg and 300‐mg phenytoin groups together achieved a significant 10% increase in HDL‐C levels compared with placebo after adjusting for differences in baseline HDL‐C levels, age, and body mass index. Other lipid levels did not significantly change in the phenytoin groups compared with placebo. Average compliance was 98% or greater for each of the treatment groups. Eighteen participants dropped out of the study with similar numbers from each treatment group. Side effects were mild and mostly transient. Low doses of phenytoin are well tolerated and can effectively increase HDL‐C levels in men with low levels of HDL‐C.
Effect of Losartan, an Angiotensin II Receptor Antagonist, on Response of Cortisol and Aldosterone to Adrenocorticotrophic Hormone
Authors: Sasaki Masato , Fujimura Akio , Harada Kazuhiro , Sunaga Ken‐ichiro , Ebihara Akio
Published: March 2013

Many imidazole derivatives are shown to inhibit adrenal steroid biosynthesis. The present study was undertaken to examine an effect of another imidazole derivative, losartan (an angiotensin II receptor antagonist), on responses of cortisol and aldosterone to adrenocorticotrophic hormone (ACTH). Nine patients with essential hypertension were given placebo orally for 7 days and 50 mg of losartan for the next 9 days. Responses of serum cortisol and plasma aldosterone to intramuscular ACTH injection were determined before and at the end of the treatment with losartan. Serum cortisol and plasma aldosterone significantly increased after ACTH injection in both periods of treatment (placebo and losartan). The increments in these parameters during treatment with losartan were not significantly different from those during treatment with placebo. These results suggest that the inhibitory effect of losartan on adrenal steroid biosynthesis is negligible.
Effect of Aging on Atenolol Pharmacokinetics and Pharmacodynamics
Authors: Sowinski Kevin M. , Forrest Alan , Wilton John H. , II Alan M. Taylor , Wilson Michael F. , Kazierad David J.
Published: March 2013

A study was conducted to characterize and compare the pharmacodynamics and pharmacokinetics of atenolol in young and elderly men. Six young (mean ± SD, 25.0 ± 3.0 years) and six elderly (63.0 ± 3.2 years) healthy men took atenolol 100 mg orally once daily for 6 days. Heart rate response to submaximal exercise was measured at selected times for 48 hours, and plasma and urine samples were collected over the same time interval. The Sigmoid Emax model was fit to percent reductions in exercise heart rate and atenolol plasma concentrations. The younger men had significantly lower values for area under the steady‐state plasma concentration—time curve and higher values for systemic clearance/F and renal clearance. EC50 values showed a trend toward greater sensitivity to the negative chronotropic effects of atenolol among the elderly men. Model‐derived percent reductions in heart rate were greater at all concentrations among the elderly men. These data suggest that group differences in atenolol pharmacokinetics were likely a result of age‐related decline in renal function, and that the elderly subjects were at least as sensitive as, and maybe even more sensitive than, the younger subjects to the negative chronotropic effects of atenolol.
Pharmacokinetics and Pharmacodynamics of Ro 41–3696, a Novel Nonbenzodiazepine Hypnotic
Authors: Dingemanse Jasper , Bury Michèle , Roncari Gaetano , Zell Manfred , Gieschke Ronald , Gaillard Anthony W. K. , Odink Jaap , Van Brummelen Peter
Published: March 2013

This report describes the first evaluation in humans of Ro 41–3696. Based on its preclinical profile, Ro 41–3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo‐controlled, double‐blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41–3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41–3696 was absorbed and eliminated rapidly (tmax = ∼1 hour; t1/2 = ∼4 hours). At all times plasma levels of Ro 41–3290, the desethylated derivative of Ro 41–3696, were higher than those of the parent drug (tmax and t1/2 values = ∼2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose‐proportional pharmacokinetics for both Ro 41–3696 and Ro 41–3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long‐term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41–3696 in doses up to ∼5 mg and further exploration of the characteristics of Ro 41–3290.
Nonlinear Pharmacokinetics of Nefazodone After Escalating Single and Multiple Oral Doses
Authors: Kaul Sanjeev , Shukla Umesh A. , Barbhaiya Rashmi H.
Published: March 2013

The single‐ and multiple‐dose pharmacokinetics of nefazodone and its metabolites, hydroxynefazodone, p‐hydroxynefazodone, and m‐chlorophenylpiperazine were investigated in two groups of 18 healthy male volunteers, employing three‐period complete crossover designs. In one group, single 50‐mg, 100‐mg, and 200‐mg oral doses of nefazodone hydrochloride were administered with a 1‐week washout between treatments. In the other group, doses of 50 mg, 100 mg, and 200 mg were administered twice a day (every 12 hours) for 7.5 days (15 doses) with a 1‐week washout between treatments. Serial plasma samples were obtained in both groups and assayed for nefazodone, hydroxynefazodone, m‐chlorophenylpiperazine, and p‐hydroxynefazodone. Cmax plasma levels of nefazodone and hydroxynefazodone were attained within 2 hours of administration of nefazodone; tmax for m‐chlorophenylpiperazine was more delayed, and p‐hydroxynefazodone levels were generally below the assay limit. On repeated twice‐daily dosing of nefazodone, steady‐state levels of the drug and its metabolites were reached within 3 days. Mean single‐dose plasma half‐life (t1/2) values for nefazodone increased from ∼1 hour at a 50‐mg dose to ∼2 hours at a 200‐mg dose; at steady state, t1/2 values increased from ∼2 hours at 50 mg twice daily to ∼3.7 hours at 200 mg twice daily. Whereas dose increased in the proportion of 1:2:4, mean single‐dose AUC0‐∞ for nefazodone increased in the proportion of 1:3.3:8.9 and mean steady‐state AUC0‐r for nefazodone increased in the proportion of 1:4.2:16.8. Plasma levels of hydroxynefazodone paralleled those of nefazodone and were approximately 33% of nefazodone levels at each dose level. Plasma levels of m‐chlorophenylpiperazine were only ∼10% those of nefazodone. Within the dosage range of 50–200 mg of nefazodone hydrochloride, nefazodone and hydroxynefazodone exhibited nonlinear pharmacokinetics; m‐chlorophenylpiperazine, a minor metabolite, appeared to exhibit linear pharmacokinetics.
The Influence of Reduced Dietary Fat Absorption Induced by Orlistat on the Pharmacokinetics of Digoxin in Healthy Volunteers
Authors: Melia Angela T. , Zhi Jianguo , Koss‐Twardy Susan G. , Min Bo H. , Smith Bettye L. , Freundlich Nancy L. , Arora Sujata , Passe Sharon M.
Published: March 2013

To assess the influence of an orlistat‐induced reduction in dietary fat absorption on the pharmacokinetics of digoxin, an open‐label, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers. Each subject received single 0.4‐mg doses of digoxin (soft gelatin capsules) administered orally on the fourth day of orlistat (120 mg three times daily for 6 days) and placebo (three times daily for 6 days) treatment, separated by at least an 11‐day washout period. Serial blood samples were collected before and at appropriate intervals after each digoxin dose to determine plasma concentrations of unchanged digoxin. The 90% confidence intervals for the ratio of geometric least‐squares means (for Cmax, AUC0–48, AUC0‐t, and AUC) and for the difference of arithmetic least‐squares means (for tmax and Λz) indicate that the pharmacokinetics of digoxin was not altered by treatment with orlistat. This result suggests that a ∼30% reduction in dietary fat absorption will not change the efficacy of digoxin in cardiac patients.
Pharmacokinetic and Pharmacologic Variation Between Different Estrogen Products
Authors: O'Connell Mary Beth
Published: March 2013

Due to the complex nature of endogenous and exogenous hormone concentrations, formation, and metabolism and assay complexity, the pharmacokinetics of estrogens are difficult to study. Oral estrogens have minimal systemic bioavailability (2% to 10%) due to gut and liver (first‐pass) metabolism. High concentrations of estrone are achieved with oral administration, whereas higher concentrations of estradiol are generally achieved after percutaneous absorption. Although vaginal products (such as gel, rings, etc.) are administered locally, they achieve high serum concentrations. Estradiol and estrone concentrations and estradiol‐to‐estrone ratios vary with different estrogen therapies. Approximately 95% to 98% of estradiol is bound loosely to albumin or tightly to sex hormone binding globulin, the major binding protein. The terminal half lives for the different estrogen compounds (after oral or intravenous administration) vary from 1–12 hours. Some conversion rates have been calculated between estrogen and its metabolites. Smoking decreases achievable estrogen concentrations, and has a greater effect on oral products. Oral contraceptives have been found to decrease antipyrine clearance. In the one study evaluating conjugated estrogens, antipyrine clearance was not altered. Oral contraceptives have a variable effect on the elimination of medications. Acetaminophen clearance is increased, whereas clearance of some benzodiazepines, caffeine, and prednisolone is decreased. Phenytoin increases the metabolism of conjugated estrogens. The various estrogen products may produce different clinical effects based on composition. The metabolites (minor components) of conjugated estrogens have been found to have significant effects on lipid concentrations, uterine weight, liver generated compounds, and bone resorption. Because transdermal products bypass the first‐pass effect, delayed or decreased effects on lipid profiles and liver generated compounds have been observed.
Single‐Dose Pharmacokinetics, Safety, and Tolerance of Linopirdine (DuP 996) in Healthy Young Adults and Elderly Volunteers
Authors: Pieniaszek Henry J. , Fiske William D. , Saxton Timothy D. , Kim Yong S. , Garner Dennis M. , Xilinas Mikis , Martz Robert
Published: March 2013

The pharmacokinetics, safety, and tolerance of linopirdine ([3,3‐bis(4‐pyridinylmethyl)‐1‐phenylindolin‐2‐one];DuP 996) a potential therapeutic agent for Alzheimer's disease, were assessed in double‐blind, placebo‐controlled, randomized studies in which single oral doses were given to 64 healthy young or elderly males. Young subjects received escalating doses of 0.5 to 55 mg, whereas elderly subjects were given doses of 20 to 45 mg. Linopirdine plasma and urine samples were quantified after liquid extraction by a specific HPLC method using UV detection. In both groups, linopirdine disposition was characterized by rapid absorption (mean Tmax, <1 hr) and elimination (mean t1/2, 0.4–3.2 hr). Urinary excretion of unchanged drug was negligible. The pharmacokinetic parameters showed large inter‐ and intrasubject variability. Linopirdine was well‐tolerated in both young and elderly volunteers. The most frequently reported adverse event was headache. The subjects who received linopirdine did not experience clinically important changes in vital signs, electrocardiograms (ECGs), electroencephalograms (EEGs), or clinical laboratory evaluations.
Dosing of Antihypertensive Medications in Patients with Renal Insufficiency
Authors: Carter Barry L.
Published: March 2013

The use of antihypertensive agents in patients with renal insufficiency necessitates careful consideration of dosages, titration, and monitoring. Renal function must be estimated to appropriately make dosage adjustments for antihypertensives that exhibit extensive renal elimination. Thiazide diuretics are useful in mild degrees of renal insufficiency but loop diuretics become necessary as renal function deteriorates further. With either class, low dosages should be used to prevent hypovolemia, hyponatremia, and hypokalemia which may worsen renal blood flow. Angiotensin‐converting enzyme (ACE) inhibitors have become popular because they may have unique renal protective properties. All ACE inhibitors except fosinopril require reduced dosages and/or less frequent administration in patients with renal insufficiency. It is often necessary to use a diuretic with an ACE inhibitor and special dosing considerations are important. Due to demographic and physiologic characteristics of patients with renal insufficiency, beta blockers are often reserved for patients with other indications for beta blockers such as ischemic heart disease. Several beta blockers are eliminated primarily by the kidney and dosage reductions are necessary for these agents. Calcium antagonists may also have renal protective effects. Because calcium antagonists are metabolized extensively, significant dosage adjustments are not necessary. Data suggest that antihypertensives may slow the decline in renal insufficiency. The pharmacokinetics of several antihypertensives change with renal impairment because of reduced elimination. Therefore, dosage adjustments, slower titration, and less frequent administration are often necessary.
Effect of Food on the Oral Bioavailability of Isosorbide‐5‐Mononitrate Administered as an Extended‐Release Tablet
Authors: Kosoglou Teddy , Kazierad David J. , Schentag Jerome J. , Patrick James E. , Heimark Larry , Radwanski Elaine , Christopher David , Flannery Brian E. , Affrime Melton B.
Published: March 2013

We evaluated the effect of a high‐fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide‐5‐mononitrate (5‐ISMN) controlled‐release tablet formulation (IMDURTrade; 60‐mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5‐ISMN 60‐mg solution, absorption was rapid with mean peak plasma 5‐ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDURTrade; 60‐mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5‐ISMN from IMDURTrade; tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDURTrade; tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5‐ISMN from this controlled‐release tablet formulation, however this effect is not clinically relevant.
Evaluation of Diurnal Variation in Fentanyl Clearance
Authors: Gupta Suneel K. , Southam Mary A. , Hwang Stephen S.
Published: March 2013

Drug disposition kinetics are commonly assumed to be time‐invariant as a first approximation. In a preliminary study, 6 healthy volunteers received a constant intravenous infusion of 50 μg/h for 48 hours; the serum fentanyl concentration at 36 hours was lower than that at 24 hours for all 6 subjects. This suggested possible diurnal variations in fentanyl clearance. In 2 subsequent studies, with healthy volunteers receiving short infusions of fentanyl (n = 9, 150 μg/h for 0.33 hours every 4 hours; n = 12, 150 μg/h for 0.33 hours every hour, respectively), the area under the serum fentanyl concentration curve appeared to be independent of the time of infusion. Thus, there was no evidence to support a large diurnal change in fentanyl clearance. The serum fentanyl concentration‐time profiles, corrected for carryover from previous doses, within each study were superimposable. This suggests that there are no diurnal changes in the distribution kinetics of fentanyl.
The Effect of Verapamil on the Nephrotoxic Potential of Gentamicin as Measured by Urinary Enzyme Excretion in Healthy Volunteers
Authors: Kazierad David J. , Wojcik Gregory J. , Nix David E. , Goldfarb Allen L. , Schentag Jerome J.
Published: March 2013

The effects of verapamil on the nephrotoxic potential of multiple‐dose gentamicin were studied in healthy adult male volunteers. Subjects received a gentamicin infusion every 8 hours for 19 doses. Gentamicin dosage was adjusted to maintain peak concentrations of 5.5 mg/L and trough concentrations of 0.5 mg/L. Verapamil was given as a sustained release preparation of 180 mg twice daily starting 2 days before the aminoglycoside, and continued for 4 days post‐gentamicin therapy. Nephrotoxicity was assessed by measuring 24‐hour urinary alanine aminopeptidase excretion (AAP). The urinary AAP results of six subjects given gentamicin with verapamil were compared with urinary AAP from nine subjects treated with gentamicin alone. These nine subjects were matched with the verapamil‐treated subjects on the basis of gentamicin area‐under‐the‐curve (AUC). After matching AUC, gentamicin exposure was virtually identical between the two groups with an average gentamicin AUC of 26.61 ± 1.49 and 27.51 ± 1.25 mg · hr/L for the gentamicin/ve‐rapamil and gentamicin only groups respectively. Verapamil retarded the rise in mean daily AAP excretion on days 1 to 6 of gentamicin therapy, with a significant difference with respect to AAP urinary excretion (P < .05) observed on day 2. There was no significant difference in total cumulative AAP excretion or in the time to return to baseline AAP excretion. Therefore, verapamil was effective in reducing AAP excretion associated with gentamicin therapy.
Noninvasive Assessment of Mitoxantrone Cardiotoxicity in Relapsing Remitting Multiple Sclerosis
Authors: De Castro Stefano , Cartoni Domenico , Millefiorini Enrico , Funaro Stefania , Gasperini Claudio , Morino Stefania , Tallarico Demetrio , Beni Sergio
Published: March 2013

Multiple sclerosis is the most common cause of neurologic disability in young adults. Recent reports have suggested that Mitoxantrone might be a candidate for clinical trials in multiple sclerosis patients. The authors studied 20 patients with relapsing remitting multiple sclerosis to evaluate cardiac toxicity during a one‐year follow‐up period. Patients were divided into 2 groups: group A, mitoxantrone treated patients (cumulative dose of 96 mg/m2); group B, placebo patients. The clinical course of multiple sclerosis was assessed using the Expanded Disability Status Scale and the number of relapses during the follow‐up. Each patient had an electrocardiogram and a spectral and color flow Doppler echocardiographic examination at enrollment, and 6 and 12 months later, to investigate cardiac toxicity. The mean exacerbation rate was reduced significantly in group A patients. No significant differences in the electrocardiograms or the echocardiographic parameters of systolic and diastolic function were noted between the two groups or in group A during the follow‐up. Mitoxantrone treatment seems able to improve the clinical course of relapsing remitting multiple sclerosis patients. It does not show any cardiac toxicity in selected patients at this dosage.
Pharmacokinetics and Pharmacodynamics of AC137 (25,28,29 Tripro‐Amylin, Human) After Intravenous Bolus and Infusion Doses in Patients with Insulin‐Dependent Diabetes
Authors: Colburn Wayne A. , Gottlieb Alan B. , Koda Joy , Kolterman Orville G.
Published: March 2013

A study was conducted to evaluate the effect of 30‐μg, 100‐μg, and 300‐μg 2‐minute bolus doses and 2‐hour infusion doses of AC137 (25,28,29 tripro‐amylin, human) on plasma AC137 concentrations and plasma glucose and lactate responses in patients with insulin‐dependent diabetes mellitus (IDDM). The study design was an imbedded two‐way crossover wherein patients received placebo and active boluses in one period and placebo and active infusions in the other period. Two patients in each dose group received placebo throughout the two periods. Pharmacokinetics and pharmacodynamics (PK/PD) were determined during the 6‐hour period after initiation of dosing. Data were fitted with a linked PK/PD model. Pharmacokinetics were linear over the dose range studied, and attenuation of glucose and lactate responses to a mixed meal was dose and concentration dependent. The results of the PK/PD model indicate that the attenuation of glucose and lactate responses was greater after AC137 infusion doses than after the same doses given as a bolus. Glucose and lactate responses to a mixed meal were essentially negated by the 300‐μg infusion dose.
Pharmacokinetics and Pharmacodynamics of Famotidine in Children
Authors: James Laura P. , Marshall James D. , Heulitt Mark J. , Wells Thomas G. , Letzig Lynda , Kearns Gregory L.
Published: March 2013

The pharmacokinetics and pharmacodynamics of intravenous famotidine were studied in 12 children (1.1–12.9 years of age; mean weight ± standard deviation = 27.6 ± 21.2 kg) who were given the drug for prophylactic management of stress ulceration. After a 0.5‐mg/kg infusion of famotidine, timed blood (n = 10) and urine (n = 6) samples and repeated evaluations of intragastric pH (n = 13) were obtained from each subject. Pharmacokinetic parameters were determined from curve fitting of serum concentration data. The mean (± SD) maximum serum concentration (Cmax) was 527.6 ± 281.2 ng/mL, the elimination half‐life (t1/2) was 3.2 ± 3.0 hours, and the apparent steady‐state volume of distribution (Vdss) was 2.4 ± 1.7 L/kg. Plasma clearance (Cl) and renal clearance (ClR) were 0.70 ± 0.34 L/hr/kg and 0.43 ± 0.24 L/hr/kg, respectively. Over 24 hours, 73.0 ± 27.3% of the dose was excreted unchanged in the urine (Fel). Pharmacodynamic analysis of gastric pH data using the sigmoid Emax model predicted that 50% of the maximal effect of famotidine (EC50) occurs at a serum concentration of 26.0 ± 13.2 ng/mL. Children who did not have an initial intragastric pH ≤4 did not have a significant response in pH after receiving famotidine. Although Vdss and Cl were higher in these children than those seen in adults, statistically significant relationships between these parameters and age were not observed in the study population. The pharmacodynamics and pharmacokinetics of famotidine in children older than one year of age appear to be similar to those noted in adults.
Pharmacokinetics of Prednisolone During Administration of Sirolimus in Patients with Renal Transplants
Authors: Jusko William J. , Ferron Geraldine M. , Mis Suzette M. , Kahan Barry D. , Zimmerman James J.
Published: March 2013

The pharmacokinetic interaction of multiple oral doses of sirolimus (rapamycin) and prednisone were evaluated in 40 stable patients with renal transplants receiving concomitant multiple doses of cyclosporine. Nine sirolimus dosage levels from 1 mg/m2/ day to 13 mg/m2/day were studied and compared with placebo. Plasma concentrations of prednisone, prednisolone, and cortisol were measured by high‐performance liquid chromatography and analyzed by noncompartmental methods. Mean pharmacokinetic values of prednisolone found before sirolimus administration were as follows: peak plasma concentration (Cmax) was 187 ng/mL; time to peak plasma concentration (tmax) was 2.03 hours; rate of reaching peak plasma concentration (Cmax divided by the area under the concentration‐time curve [AUC]) was 0.149 hour−1; terminal half‐life (t1/2) was 3.60 hours; AUC was 1206 ng · hour/mL; and apparent clearance (Cl/F) was 0.094 L/hour/kg. During the 2 weeks of concomitant administration, prednisolone elimination decreased in relation to sirolimus dosages. These changes were modest, with mean increases of 18% in Cmax and 27% in t1/2 and mean decreases of 27% in Cl/F for the groups receiving 6 mg/m2/day to 13 mg/m2/day. Most patients initially had plasma cortisol concentrations indicative of adrenal suppression. With sirolimus treatment, the Cmax of cortisol did not decrease further, but the AUC (8:00 am‐8.00 pm) values were significantly lower, independent of sirolimus exposure. The AUC for cyclosporine did not correlate with sirolimus and prednisolone exposure. A 2‐week course of sirolimus showed a slight pharmacokinetic interaction between sirolimus and prednisolone/prednisone/cortisol in stable patients with renal transplants.
Imidazoline Receptor Agonist Drugs: A New Approach to the Treatment of Systemic Hypertension
Authors: Yu Austin , Frishman William H.
Published: March 2013

The imidazoline receptors have recently been discovered to be involved in central nervous system control of blood pressure (I‐1 receptor) and in neuroprotection for cerebral ischemia (I‐2 receptor). A new class of central‐acting antihypertensive agents has been developed, the imidazoline receptor agonists (rilmenidine and moxonidine), which control blood pressure effectively without the adverse effects of sedation and mental depression that are usually associated with central‐acting antihypertensives. This new generation of central‐acting antihypertensive agents are highly selective for the imidazoline receptor, while having a low affinity for α2‐adrenergic receptors.