bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic Disposition of Loracarbef in Healthy Young Men and Women at Steady State
Authors: Sitar Daniel S. , Hoban Daryl J. , Aoki Fred Y.
Published: March 2013

The pharmacokinetic disposition of 200‐ and 400‐mg doses of a novel carbacephem, loracarbef, was determined over a dose interval on day 8, after ingestion of drug doses twice daily for 7 days, in 20 young, healthy volunteers of both genders. Drug was analyzed in plasma, urine, saliva, vaginal secretions, and fecal filtrate. Peak plasma concentration was proportional to dose for both men (4.0 ± 1.3 and 8.8 ± 3.4 mg/L) and women (8.0 ± 5.6 and 15.3 ± 3.3 mg/L), and the observed time to peak increased from 1 to 2 hours with the increased dose. Apparent volume of distribution was greater in men than women (0.385 ± 0.114 versus 0.270 ± 0.075 L/kg; P < .03). The drug was virtually quantitatively excreted unchanged in urine, and its renal clearance exceeded creatinine clearance in all subjects. Renal loracarbef clearance correlated with neither weight‐corrected dose nor creatinine clearance in these healthy subjects. There was no evidence for drug accumulation in the body with chronic ingestion. Loracarbef was detected in the fecal filtrate of seven volunteers, but did not account for more than 7% of the daily dose. Loracarbef was detected in vaginal secretions of two of five volunteers who ingested the 400‐mg dose. No drug was detected in saliva obtained just before dose ingestion. These data are consistent with complete bioavailability for an oral beta‐lactam antibiotic drug that is virtually completely eliminated unchanged by the kidney.
Primary Care Physicians and the Cost of Drugs: A Study of Prescribing Practices Based on Recognition and Information Sources
Authors: Walzak Doris , Swindells Susan , Bhardwaj Ajay
Published: March 2013

Rapidly inflating health care costs limit patient care, and prescription drug costs constitute a major component of this expenditure. This study examines attitudes toward and knowledge of prescription drug costs of primary care physicians. Access to information about drug costs and implications for medical education are also explored. A questionnaire survey was sent to 137 internists, family, and general practitioners, randomly selected from a list provided by the Ohio State Medical Board. The questionnaire elicited information on demographic characteristics of respondents, influence of drug costs on prescribing habits, actual knowledge of prices of the 20 most commonly used drugs, attitudes toward generic drug use, sources of information on costs, and desire for emphasis on drug costs in medical education. Responding physicians indicated consideration of drug costs in therapeutic decisions, but lacked information and often made inaccurate assumptions about costs of drugs prescribed. Most felt they could provide better service and reduce costs if information about drug prices was readily available. Most agreed medical education should address drug costs. Drug cost estimates varied widely; correct responses ranged from 9% to 53%. No statistically significant pattern emerged regarding demographics of respondents or information sources used. Primary care physicians consider drug costs important and realize that cost‐effective prescribing may lower health care costs. However, because physician knowledge of drug costs is inadequate and costs are not readily accessible, implications for better physician education and improved access are substantial.
Pharmacokinetics of Tazobactam M1 Metabolite After Administration of Piperacillin/Tazobactam in Subjects with Renal Impairment
Authors: Halstenson Charles E. , Wong Marietta O. , Johnson Curtis A. , Zimmerman Stephen W. , Onorato James J. , Keane William F. , Doepner M. , Sia L. , Tantillo K. , Bansal S. , Kuye Olatunde , Yacobi A. , Faulkner Robert , Lathia C. D.
Published: March 2013

Tazobactam is a new derivative of penicillinic acid sulfone, which functions as an irreversible inhibitor of many β‐lactamases. The disposition of tazobactam M1 metabolite after intravenous (IV) infusion of 3 g of piperacillin/0.375 g of tazobactam was evaluated in 26 subjects with various degrees of renal impairment. Participants in the study were 18 subjects with creatinine clearances (ClCR) ranging from 7.4–41.8 mL/min, 4 subjects maintained on continuous ambulatory peritoneal dialysis (CAPD), and 4 subjects undergoing chronic hemodialysis (HD). The pharmacokinetic parameters of piperacillin and tazobactam were evaluated and were similar to previous reports. Tazobactam M1 metabolite maximum plasma concentration increased as renal function declined. The terminal elimination half‐life and area under the plasma concentration—time curve of the tazobactam M1 metabolite increased as renal function declined. The mean rate of recovery of the tazobactam M1 metabolite in hemodialysate during a 3‐ to 4.2‐hour HD session 1 hour after the IV infusion of piperacillin/tazobactam was 25.3%. However, when HD was performed at 36–48 hours after the IV infusion, 57.6% of the tazobactam dose was recovered as M1 metabolite, suggesting further conversion of tazobactam to M1 metabolite. Peritoneal dialysis removed 15.8% (n=2) of the tazobactam dose as the M1 metabolite. Using a dose of 3 g of piperacillin/0.375 g of tazobactam, the predicted maximum steady‐state plasma concentrations of the tazobactam M1 metabolite are 14.6 μg/mL, 34.8 μg/mL, and 48.8 μg/mL for subjects with ClCR 20–40 mL/min (every 6 hour dosing), ClCR <20 mL/min (every 8 hour dosing), and on CAPD (every 12 hour dosing), respectively.
Sleep and Circadian Rhythms in Space
Authors: Stampi Claudio
Published: March 2013

This paper presents a detailed critical review of the knowledge accumulated in the last three decades concerning research on sleep, work—rest schedules, and circadian rhythms in space. The focus of the paper is preceded by a brief review of the basic principles of the human circadian system and the physiology of the sleep—wake cycle, relevant to understanding the problem of astronaut work—rest scheduling. Much of what is known is based on anecdotal reports, mission log books, and debriefing of astronauts after flights. The broad literature reviewed, which includes studies from American and Soviet space missions, as well as some studies conducted under simulated weightlessness, offers just a handful of objective studies on the physiology of sleep and circadian rhythms in space. Nevertheless, the data are remarkably consistent, and indicate that sleep can be of reasonably good quality in space. The risk of sleep loss and associated performance degradation appears to be a manageable one. However, one clear conclusion arises from this review: whatever the type of mission or flight plan, its success will depend on whether the principles of circadian and sleep—wake regulation have been taken into account during the planning phase of work—rest schedules. That is, satisfactory sleep and alertness is more likely to occur if crews maintain a reasonable (i.e., constant) relation with their normal terrestrial rhythm. This is not as easy a task as it may appear; indeed, unexpected, high‐intensity operational demands have been the major cause of acute problems of sleep loss and performance degradation in space. Moreover, the growing complexity of space missions indicate that emergencies will never disappear. Therefore, one of the most important research challenges for future space missions is the development of strategies that could permit astronauts to function closest to maximal efficiency during intensive and prolonged work. Countermeasures for optimizing astronaut performance, as well as other factors affecting sleep and performance in space, are reviewed and discussed in detail in this paper.
First‐Time‐in‐Human Dose Selection: Allometric Thoughts and Perspectives
Authors: Boxenbaum Harold , DiLea Clifford
Published: March 2013

Some of the many factors that influence dose selection in first‐time‐in‐human studies are examined. These include animal toxicology, toxicokinetics, allometric scaling, pharmacokinetics, body surface area correlations, and integration of preclinical pharmacologic and toxicologic data. Appropriate preclinical evaluation and analysis may reduce the frequency and severity of unexpected toxic events arising during single‐dose, phase I testing. However, significant intrinsic uncertainties in this process presently exist and will continue to exist well into the foreseeable future. With our present state of knowledge, we cannot provide a realistic and reasonable algorithm for ascertaining first‐time‐in‐human doses: any decision tree would be too unwieldy. There are several rules of thumb that do have a place in the evaluation and decision‐making process, however.
Immunopharmacodynamic Studies of Cyclosporine in Patients Awaiting Renal Transplantation
Authors: d'Uscio Claudia H. , Aweeka Francesca T. , Prueksaritanont Thomayant , Tomlanovich Stephen J. , Gupta Suneel K. , Lantz Marianne V. , Gambertoglio John G. , Garovoy Marvin R. , Benet Leslie Z.
Published: March 2013

The immunopharmacodynamics of cyclosporine were investigated in eight hemodialysis patients awaiting renal transplantation. cyclosporine was administered orally (10 mg/kg) and intravenously (4 mg/kg), with both administrations separated by at least one week. Plasma samples were processed at 37°C and analyzed for specific cyclosporine and its four major metabolites (AM1, AM1c, AM9, and AM4N) using high‐performance liquid chromatography. In addition, the in vitro immunosuppressive activity of these serial plasma samples was estimated as a relative percentage inhibition of third party mitogenic lymphocyte proliferation stimulated with phytohemagglutinin. The relationships between concentration and effect of cyclosporine versus time were noted. These results suggest that unchanged cyclosporine concentrations in plasma correlate with mitogen‐induced lymphocyte suppression yielding significant immunosuppressant activity of cyclosporine. Control studies with plasma from healthy volunteers spiked with cyclosporine in the concentration range of 0–10,000 ng/mL were developed. A sigmoidal Emax model was fitted to the effect versus plasma concentration data. The ratio of effect versus predicted effect were calculated for intravenous cyclosporine dosing. There was a good correlation between the observed and predicted inhibitory effect.
A Model for Estimating Individualized Valproate Clearance Values in Children
Authors: Botha J. H. , Gray A. L. , Miller R.
Published: March 2013

To evaluate the population pharmacokinetics of valproic acid in children, 97 steady‐state serum valproate concentration measurements were gathered during normal, routine, outpatient care of 52 children with epilepsy (1.2–16 years of age). Levels were obtained from patients receiving valproate monotherapy (49%) or valproate with concomitant carbamazepine (32%), phenytoin (11%), or phenobarbitone (8%). A one‐compartment model was used to fit the data with the Nonlinear Mixed Effects Model (NONMEM) computer program. The final model for clearance (L/hr) was CL = [EXP (0.022WT − 1.38)] × M, where EXP = the base of the natural logarithm, WT = patient weight (kg) and M = a scaling factor for concomitant medication with a value of 1 for patients on valproate monotherapy and 1.61 for those receiving concomitant carbamazepine. Although phenytoin and phenobarbitone also were expected to increase valproate clearance, this could not be demonstrated, possibly because of the small number of samples taken from patients receiving these agents. Weight‐adjusted values of valproate clearance decreased with increasing age. The actual mean value of 0.021 L/hr/kg for children taking monotherapy was slightly higher than values shown in most previously published reports, whereas the mean value of 0.028 L/hr/kg for patients taking concomitant carbamazepine was similar to those found previously in children taking other antiepileptic drugs.
Pharmacokinetics of Verapamil and Norverapamil Enantiomers After Administration of Immediate and Controlled‐Release Formulations to Humans: Evidence Suggesting Input‐Rate Determined Stereoselectivity
Authors: Bhatti M. Masood , Lewanczuk Richard Z. , Pasutto Franco M. , Foster Robert T.
Published: March 2013

Verapamil is a racemic calcium channel‐blocking drug that undergoes extensive hepatic first‐pass metabolism to an active metabolite, norverapamil. The enantiomers of verapamil and norverapamil have differing negative inotropic, chronotropic, and dromotropic activities and differing effects on vascular smooth muscles; the S‐enantiomers having greater activity. It is hypothesized that the R/S concentration ratio of verapamil enantiomers may be input‐rate dependent. The pharmacokinetics of verapamil and norverapamil enantiomers were studied in 11 young, healthy male and female volunteers after oral administration of 80 mg immediate‐release (IR) verapamil every 8 hours, and a 240 mg dose once daily of controlled‐release (CR) formulation on two separate occasions. Both dosage regimens were continued for 1 week with a minimum 1‐week period between the two drug treatments. After the last dose of each regimen, plasma samples were collected over the period corresponding to the dosing interval. Enantiomer concentrations were determined using a microwave‐facilitated precolumn derivatization with high performance liquid chromatographic quantification. Stereospecific assay revealed that: (1) stereoselective R‐ and S‐enantiomer disposition occurred regardless of formulation administered; (2) a trend of R:S concentration ratios of verapamil differed between the two formulations; and (3) fluctuations between Cmax and Cmin values of the two formulations were statistically different over respective dosing intervals (greater fluctuation after CR administration). Using nonstereospecific data analyses, however, the pharmacokinetic parameters for verapamil and norverapamil were similar for both formulations over a 24‐hour period. We suggest that kinetic differences can be attributed to differences in release rates of drug from the tablet matrices. The relative bioavailabilities of verapamil and norverapamil from the two products may, therefore, be subject to input rate‐dependent processes.
Absence of a Pharmacokinetic Interaction between Losartan and Hydrochlorothiazide
Authors: McCrea Jacqueline B. , Lo Man‐Wai , Tomasko Lisa , Lin Charles C. , Hsieh John Y.‐K. , Capra Nancy L. , Goldberg Michael R.
Published: March 2013

To support the use of a combination of losartan, a highly specific and selective AT1 angiotensin II receptor antagonist, and hydrochlorothiazide for treatment of hypertension, a pharmacokinetic drug interaction study was conducted. In this open‐label, randomized, three‐period, crossover study, patients with mild to moderate hypertension received a 12.5‐mg tablet of hydrochlorothiazide, a 50‐mg losartan tablet, or a combination tablet of 12.5 mg of hydrochlorothiazide and 50 mg of losartan for 7 days. Twelve patients (age range, 35–55 years; mean age, 44 years) were allocated to treatment. Drug interactions were evaluated by comparing the 24‐hour area under the concentration‐time curve (AUC24) for losartan and its active metabolite, E‐3174, when losartan (50 mg) was given alone or in combination with 12.5 mg hydrochlorothiazide. The urinary recovery over the 24‐hour period of hydrochlorothiazide was compared for hydrochlorothiazide (12.5 mg) given alone or in combination with 50 mg losartan. A clinically significant interaction was defined as a treatment difference of more than 35%. There was no evidence of a clinically significant effect of hydrochlorothiazide on the pharmacokinetics of losartan or E‐3174, as the geometric mean AUC24 ratio (90% confidence interval [CI]) was 1.02 (0.95, 1.09) for losartan and 1.02 (0.96, 1.09) for E‐3174. Based on urinary recovery over a 24‐hour period of hydrochlorothiazide, losartan did not affect the pharmacokinetics of hydrochlorothiazide, as the geometric mean ratio of urinary hydrochlorothiazide recovery (90% CI) was 0.898 (0.79, 1.20). There was a minor (17%) decrease in the AUC24 of hydrochlorothiazide after administration of the combination tablet. Coadministration of hydrochlorothiazide and losartan was well tolerated.
Novel Galactose Single Point Method as a Measure of Residual Liver Function: Example of Cefoperazone Kinetics in Patients with Liver Cirrhosis
Authors: Hu Oliver Yoa‐Pu , Tang Hung‐Shang , Chang Ching‐Ling
Published: March 2013

A novel, simple, clinically useful quantitative liver function test, called the galactose single point (GSP) method, was developed to assess residual liver function by measuring galactose blood concentration 1 hour after galactose was administered (0.5 g/kg). This method was applied to the study of cefoperazone kinetics in patients with hepatic cirrhosis. To study the influence of hepatic cirrhosis on the residual liver function and the correlation between the residual liver function and the pharmacokinetics of cefoperazone, a dose of 1 g of cefoperazone was administered to 11 healthy volunteers and 12 patients with liver cirrhosis. The GSP method, the galactose elimination capacity (GEC) test, and the modified galactose elimination capacity (MGEC) test were done for each volunteer and patient to measure residual liver function. The galactose concentrations were determined enzymatically. Cefoperazone was administered intravenously, and blood and urine samples were collected at appropriate intervals after drug administration. All blood and urine samples were stored at −30°C until high‐performance liquid chromatography analysis. Cefoperazone plasma concentrations were much higher in cirrhosis patients than in normal subjects at all times. The elimination half‐life, hepatic clearance, mean residence time, and renal clearance of cirrhosis patients differed significantly from those of healthy volunteers. The plasma protein binding was unaltered in both groups. Urinary excretion of cefoperazone was significantly increased in cirrhosis patients (23.95 ± 5.06% for normal men and 51.09 ± 11.50% in cirrhosis patients). Hepatic clearance, fraction excreted in urine, and total clearance significantly correlated with GSP, GEC, and MGEC (P < .001). These results suggest that (1) cefoperazone kinetics was significantly altered in patients with cirrhosis; and (2) the GSP method can predict the cefoperazone clearances in patients with liver dysfunction.
No Pharmacokinetic or Pharmacodynamic Interaction Between Rivastatin and Warfarin
Authors: Schall Robert , Müller F. Otto , Hundt H. K. L. , Ritter W. , Duursema Linda , Groenewoud Gerhard , Middle Michelle V.
Published: March 2013

Twenty‐one healthy, male volunteers completed this double‐blind, randomized, two‐period, crossover study to determine the possible pharmacodynamic and pharmacokinetic interaction of the concomitant administration of rivastatin and warfarin sodium in healthy volunteers. The study comprised 2 treatment periods of 8 days each, with a medication‐free period of 14 days between the 2 treatment periods.

According to the randomization, the volunteers received either 300 μg of rivastatin or matching placebo once daily during the treatment periods. On day 4 of each treatment period, the volunteers also received a single oral dose of 25 mg of warfarin sodium together with rivastatin or matching placebo. The effect of rivastatin on both the pharmacokinetics and pharmacodynamics (prothrombin time and clotting factor VII activity) of warfarin sodium, and the effect of warfarin sodium on the pharmacokinetics of rivastatin were investigated. Blood sample assays included the analysis of both R‐ and S‐warfarin, because it is known that the enantiomers differ in anticoagulant potency.

The study results indicate that the concomitant administration of rivastatin and warfarin does not affect the pharmacokinetics of R‐ and S‐warfarin, or the pharmacodynamics of warfarin. Furthermore, the administration of warfarin sodium does not affect the pharmacokinetics of rivastatin.
Cyclic Antidepressant Toxicity in Children and Adolescents
Authors: James Laura Phillips , Kearns Gregory L.
Published: March 2013

We retrospectively evaluated the clinical and laboratory findings of all patients admitted to our facility during a 6.5‐year period with a history of cyclic antidepressant ingestion (CAD). Outcome parameters [admission CAD concentration, arterial pH, and corrected QT (QTc) and QRS intervals] used in adult populations to predict morbidity after CAD ingestion were applied to our study population. During the study period, 45 patients (mean ± SD age of 11.8 ± 5.6 years) were admitted with CAD ingestion. Conduction delays were present in 17 patients, 9 of whom had QTc intervals greater than 0.43 seconds. Seven patients had generalized seizures; 7 required mechanical ventilation; 14 had Glasgow Coma Scores of 8 or lower on presentation; and one required pharmacologic support for hypotension. In our cohort, the mean admission serum CAD concentration was 461.5 ± 477.4 ng/mL. Correlations were found between the arterial pH, the QRS interval, the QTc interval, and the admission CAD serum concentration. In an analysis of three subsets of patients (i.e., those with seizures, coma, and respiratory insufficiency), only patients who presented with seizures were found to have a significant prolongation in the QRS and QTc intervals. Pediatric patients who have ingested CADs and present with seizures would appear to be at increased risk for having conduction delays, cardiac dysrhythmias, and, presumably, attendant morbidity and mortality associated with an ingestion.
Novel Oral Medication Delivery System for Famotidine
Authors: Schwartz Jules I. , Yeh Kuang C. , Berger Marc L. , Tomasko Lisa , Hoover Monica E. , Ebel David L. , Stauffer Laura A. , Han Ronald , Bjornsson Thorir D.
Published: March 2013

A famotidine wafer that rapidly disperses on the tongue without water is a novel alternative to other histamine2 (H2)‐antagonist dosage forms. Benefits associated with such a dosage form include convenience and potentially improved compliance for patients who dislike or have difficulty taking tablets and capsules. This report describes the research of three studies on the famotidine wafer dosage form. In the first trial, the bioequivalence and tolerability of the new 40‐mg famotidine wafer and the marketed 40‐mg famotidine tablet were studied in a 2‐period crossover study (n = 18). The two formulations were bioequivalent as assessed by area under the plasma concentration versus time curve and maximum plasma concentration of famotidine. The plasma concentration of famotidine associated with 50% inhibition of pentagastrin stimulated gastric acid secretion (EC50; 10 ng/mL) was attained on average within 0.5 hours post‐dose for the wafer and tablet. In a second trial, the tolerability of the famotidine 20‐mg and 40‐mg wafers or placebo given twice daily (bid) for 14 days were evaluated (n = 192). Both wafer strengths were well and equally tolerated. In a third trial of 450 subjects, the 40‐mg wafer was preferred over tablets by 75% of the subjects, when they were asked to consider the method of administration and flavor. When used as an alternative to tablets and other conventional dosage forms, the wafers have the potential therapeutic benefit of improved compliance. It is concluded that similar systemic exposure, excellent tolerability, palatability, and preference make the famotidine wafer a clinically acceptable and convenient dosage form for patients on H2‐antagonist therapy.
Pharmacokinetics of Bepridil and Two of its Metabolites in Patients With End‐Stage Renal Disease
Authors: Awni Walid M. , Halstenson Charles E. , Nayak Ramchandra K. , Opsahl John A. , Desiraju Ravi K. , Minn Fredrick L. , Matzke Gary R.
Published: March 2013

The pharmacokinetics of bepridil and 2 of its major metabolites (McN‐A‐2600 and McN‐6303) were studied in 6 patients with end‐stage renal disease (ESRD) before and after hemodialysis. Patients underwent dialysis 1 day after a single oral 200‐mg dose of bepridil hydrochloride; blood was sampled for up to 7 days. The mean (±SD) peak plasma concentration, time of peak concentration, and area under the plasma concentration‐time curve (0–168 hours) for each agent were as follows: bepridil, 806 ± 321 ng/mL, 2.6 ± 1.6 hours, 4.87 ± 1.21 μg h/mL; McN‐A‐2600, 57 ± 16 ng/mL, 4.2 ± 2.0 hours, 0.53 ± 0.29 μg h/mL; McN‐6303, 284 ± 120 ng/mL, 4.7 ± 1.5 hours, 4.06 ± 1.11 μg h h/mL. The bepridil area under the curve corrected for dose was similar to that in healthy volunteers, suggesting that plasma clearance was unaffected by severe renal impairment. None of the compounds were removed by dialysis, and no rebound in plasma concentrations was observed after the end of dialysis. The disposition of bepridil appears to be unchanged in patients with ESRD; and is unaffected by hemodialysis. Thus, no dosage adjustment will be required for ESRD patients and those receiving hemodialysis with cuprophane filters.
Renal Effects of Over‐the‐Counter Analgesics
Authors: Whelton Andrew
Published: March 2013

Recent case reports have shown that over‐the‐counter (OTC) analgesics, which are generally considered to be a safe treatment for minor aches and pains and fever, may cause adverse renal effects. Many renal syndromes induced by nonsteroidal antiinflammatory drugs (NSAIDs) can be attributed to prostaglandin inhibition. Fluid and electrolyte disturbances, acute renal failure, and acute interstitial nephritis also occur predominantly with NSAIDs. Acetaminophen lacks significant peripheral prostaglandin inhibition and may be a preferred first‐line agent, particularly in patients susceptible to the induction of renal impairment. Apart from obvious clinical overdosage situations, limited reports of adverse renal effects exist with acetaminophen. Some studies have reported an association between analgesic nephropathy, one of the most severe analgesic‐related adverse renal effects, and long‐term abuse of phenacetin, acetaminophen, aspirin, ibuprofen, analgesic combinations, or other NSAIDs, although for some of these agents, this relationship is controversial. The overall risk for serious renal effects with OTC analgesics appears to be low, but given the accessibility and vast number of persons taking these agents, the absolute number of patients affected may be substantial. Therefore, it is important that healthcare providers recognize the risk factors for adverse analgesic‐related renal effects.
Comparison of the Pharmacokinetics of Two Nicotine Transdermal Systems: Nicoderm and Habitrol
Authors: Gupta Suneel K. , Okerholm Richard A. , Eller Mark , Wei Greg , Rolf Clyde N. , Gorsline Jane
Published: March 2013

This randomized, crossover study compared the nicotine and cotinine pharmacokinetic parameters and plasma concentration profiles of two different nicotine transdermal products: Nicoderm (Alza, Palo Alto, CA; and Marion Merrell Dow, Kansas City, MO) and Habitrol (Basel Pharmaceuticals, Summit, NJ). The two treatments were randomly assigned to each of 24 male smokers and worn for 24 hours each day for 5 days, with a 6‐day washout between treatments. Plasma nicotine and cotinine concentrations were measured on day 1 and day 5 of each treatment. Mean delivered dose differed significantly between products, and the two products were not bioequivalent. The Nicoderm system provided higher mean plasma nicotine concentrations, particularly during the first 8 hours after system application. The mean steady state Cmax, AUC, and degree of fluctuation (DF) values were significantly greater for the Nicoderm system than for Habitrol. The mean nicotine tmax value for the Nicoderm system was significantly shorter (P < .001) than that for Habitrol (2.7 versus 8.6 hours). Steady state cotinine AUC values and plasma concentrations were significantly lower for Habitrol than for the Nicoderm system. The incidence of adverse events was similar for both products.
Lisinopril Versus Placebo in the Treatment of Heart Failure: The Lisinopril Heart Failure Study Group
Authors: Beller Barry , Bulle Thomas , Bourge Robert C. , Colfer Harry , Fowles Robert E. , Giles Thomas D. , Grover John , Whipple James P. , Fisher Mary B. , Jessup Mariell , Naggar Charles , Alexander Sidney , Parker Brent M. , Smith Ellen , Weidler Donald J. , Wertheimer John
Published: March 2013

Lisinopril, a long‐acting, angiotensin‐converting enzyme inhibitor, was compared with placebo in a randomized, parallel, double‐blind, 12‐week study of 193 patients with heart failure. All patients were New York Heart Association Functional Class II, III, or IV and had remained symptomatic despite optimal dosing with digoxin and diuretics. After 12 weeks of therapy, the improvement in treadmill exercise duration was greater in the lisinopril group (113 seconds) compared with the placebo group (86 seconds). This improvement in exercise duration was particularly evident in patients with left ventricular ejection fractions less than 35% (lisinopril = 130 seconds; placebo = 94 seconds). In patients receiving lisinopril, the increase in exercise duration was accompanied by an improvement in quality of life as measured by the Yale Scale Dyspnea/Fatigue Index and in signs and symptoms of heart failure. In addition, the lisinopril group had a larger mean increase (3.7%) in left ventricular ejection fraction when compared with the placebo group (1.3%). Thus, lisinopril, administered once daily for 12 weeks, was well tolerated and efficacious in the treatment of heart failure when used concomitantly with diuretics and digoxin.
Safety, Tolerability, and Effect of Food on the Pharmacokinetics of Iloperidone (HP 873), a Potential Atypical Antipsychotic
Authors: Sainati Stephen M. , Hubbard John W. , Chi Eric , Grasing Kenneth , Brecher Martin B.
Published: March 2013

Iloperidone (HP 873) is a D2 and 5‐HT2 receptor‐antagonist that is under development as a potential atypical antipsychotic agent. Two studies on iloperidone evaluated its safety and tolerability, made a preliminary pharmacokinetic assessment of single 3‐ and 5‐mg doses, and determined the effect of food on its tolerability and pharmacokinetics in healthy volunteers after single 3‐mg doses. Iloperidone was well absorbed orally in fasted subjects. The Cmax occurred approximately 2 to 3 hours after administration of a single 3‐ or 5‐mg dose. The pharmacokinetic parameters increased with the dose between 3 and 5 mg (from 2.2 to 5.2 ng/mL for Cmax, and 16 to 50 ng/mL•h for AUC). Iloperidone was eliminated slowly, with a mean t1/2 of 13.5 to 14.0 hours. Coadministration with food did not significantly affect AUC, tmax, or Cmax. These results indicate that the rate of iloperidone's absorption is decreased, but the overall bioavailability is unchanged, when the drug is taken with food. Orthostatic hypotension, dizziness, and somnolence were the most commonly reported adverse events. Coadministration of food reduced the incidence and severity of these events.
Pharmacokinetic and Pharmacodynamic Evaluation of Warfarin and Nefazodone Coadministration in Healthy Subjects
Authors: Salazar Daniel E. , Dockens Randy C. , Milbrath Rochelle L. , Raymond Ralph H. , Fulmor I. Edgar , Chaikin Philip C. , Uderman Howard D.
Published: March 2013

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady‐state warfarin concentrations and a stable prothrombin ratio. Nefazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double‐blind, randomized design. No serious or unexpected adverse events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady‐state pharmacokinetics of R‐warfarin based on within‐subject or comparison to placebo‐treated subjects. The steady‐state AUCTAUover the dosing interval and Cmaxof S‐warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady‐state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well‐tolerated with no clinically significant interactions.
The Safety and Tolerance of Xanomeline Tartrate in Patients with Alzheimer's Disease
Authors: Sramek John J. , Hurley Daniel J. , Wardle Thomas S. , Satterwhite Julie H. , Hourani Jameel , Dies Federico , Cutler Neal R.
Published: March 2013

Xanomeline tartrate (active ingredient xanomeline) is a muscarinic agonist that has demonstrated specificity for the M1 receptor in preclinical studies and has been well tolerated at dosages up to 50 mg three times a day in healthy elderly subjects. To define the maximum tolerated dose (MTD) of xanomeline tartrate in patients with Alzheimer's disease, 48 patients (20 men, 28 women) with probable Alzheimer's disease were enrolled in a double‐blind, placebo‐controlled inpatient study to determine the safety and tolerability of 8 fixed dosages of xanomeline tartrate (25, 35, 50, 60, 75, 90, 100, and 115 mg, all three times a day) given for 7 days. For each dosage the treatment panel consisted of six patients (four taking xanomeline tartrate and two taking placebo). With the discontinuation of two patients because of severe intolerable adverse events, a minimum intolerated dose was reached at 115 mg three times a day, and 100 mg three times a day was defined as the MTD. This MTD in patients was two‐fold greater than the MTD previously determined in healthy elderly volunteers.
Pharmacokinetics of Lansoprazole in Hemodialysis Patients
Authors: Karol Michael D. , Machinist Joseph M. , Cavanaugh John M.
Published: March 2013

The pharmacokinetics of the new benzimidazole proton pump inhibitor lansoprazole and five of its metabolites were assessed after single oral dose administration to five hemodialysis patients. Patients were studied on dialysis and nondialysis days. Multiple blood and dialysate samples were collected after dosing and were assayed for lansoprazole and metabolite content via high‐performance liquid chromatography. The degree of lansoprazole plasma protein binding was lower in hemodialysis patients than in subjects with normal renal function or patients with renal impairment not requiring dialytic therapy, although this tended to moderate when assessed immediately after dialysis. Examination of venous plasma concentration, paired arterial‐venous concentration, and dialysate data revealed that lansoprazole and its metabolites were poorly dialyzable. No dosage adjustment of lansoprazole is necessary in hemodialysis patients nor is supplementation after hemodialysis sessions necessary.
5‐HT3 Receptors: Pharmacologic and Therapeutic Aspects
Authors: Gyermek Laszlo
Published: March 2013

The serotonin 5‐HT3 receptor is unique among the seven serotonin receptor “families” that have been recognized so far. It functions not as a G‐protein coupled but as a direct ion channel gated receptor. Because of the varied neural functions linked to this receptor, intensive research interest has developed in recent years about its basic and clinical pharmacology, which are summarized in this review. Some new agonists and many new antagonists have been developed. These agents have a useful role as selective pharmacologic research probes, and some of them can be used therapeutically as potent and selective antinausea and antiemetic drugs, particularly in patients undergoing cancer chemotherapy treatment or general anesthesia procedures. Potential applications of these agents include the treatment of some behavioral disorders in mental disease, drug addiction, and certain types of pain syndromes.
Pharmacokinetics of Single‐ and Multiple‐Dose Bupropion in Elderly Patients with Depression
Authors: Sweet Robert A. , Pollock Bruce G. , Kirshner Margaret , Wright Bruce , Altieri Linda P. , DeVane C. Lindsay
Published: March 2013

A study of a dopaminergic antidepressant that may have an advantageous profile for use in elderly patients, bupropion, was conducted to determine the pharmacokinetics of bupropion in the elderly. Pharmacokinetics of single‐ and multiple‐dose bupropion were examined in six elderly patients (five women and one man) diagnosed with depression. Mean (±SD) CLapp of bupropion was 1.6 ± 0.4 L/hr/kg, approximately 80% of the corresponding value reported for younger patients. Mean bupropion t1/2 was 34.2 ± 8.7 hours, and average apparent Vd (Vdapp) was 79.3 ± 29.4 L/kg. Apparent half‐lives (t1/2 app) of the metabolites hydroxybupropion, erythrobupropion, and threohydrobupropion were 34.2 ± 4.6 hours, 61.4 ± 21.6 hours, and 38.8 ± 7.6 hours, respectively. After multiple dosing, the mean t1/2 for bupropion and its metabolites did not change significantly, although in some patients the t1/2app of the metabolites was substantially prolonged. There was also evidence of inordinate accumulation of metabolites. The elderly are at risk for accumulation of bupropion and its metabolites. Specification of therapeutic drug monitoring parameters for bupropion treatment of the elderly is needed.
Pharmacokinetics and Bioavailability of Flucloxacillin in Elderly Hospitalized Patients
Authors: Gath J. , Charles B. , Sampson J. , Smithurst B.
Published: March 2013

The pharmacokinetics and oral bioavailability of flucloxacillin were studied in five female and two male patients (age 68–87 yr) who had been hospitalized for orthopedic surgeries. A single dose of intravenous or oral flucloxacillin sodium (500 mg) was administered in random order on different occasions separated by at least 2 days. Blood and urine samples were taken up to 24 hours after drug administration and levels of flucloxacillin and 5‐hydroxymethylflucloxacillin (5‐HMF), a major metabolite, were measured by high‐performance liquid chromatography. Flucloxacillin elimination, but not oral absorption, was reduced in the elderly, compared with data from young healthy subjects reported elsewhere. Total clearance, renal clearance, and volume of distribution were 0.083 ± 0.013 L/kg/hr, 0.038 ± 0.01 L/kg/hr, and 0.184 ± 0.034 L/kg, respectively. Regression of flucloxacillin renal clearance (CLcr) on estimated creatinine clearance (CLcr) gave the relationship: Clr = 0.755 (CLcr + 10.6 (r = 0.91; P = 0.004). Terminal half‐lives for flucloxacillin and 5‐HMF were 2.21 ± 0.51 hr and 3.0 ± 0.75 hr, respectively, after intravenous administration. Flucloxacillin was absorbed rapidly after oral administration, with a mean absorption time of 0.95 ± 0.34 hr, and time to reach peak concentration of 1.20 ± 0.29 hr. The absolute bioavailability of flucloxacillin from capsules was 54.4 ± 18.8%.
Treatment of Mild Hypertension with Low Once‐Daily Doses of a Sustained‐Release Capsule Formulation of Verapamil
Authors: Davis Pamela J. , Fagan Timothy C. , Topmiller Mary J. , Levine Jon H. , Ferdinand Keith C.
Published: March 2013

The efficacy and safety of a low dose (120 mg) of a sustained‐release capsule formulation of verapamil administered once daily in the treatment of 42 patients with mild hypertension were assessed in this clinical trial. After a 4‐week placebo washout period (baseline), patients with diastolic clinic blood pressures of 91 to 100 mm Hg inclusive were treated for 4 weeks with once‐daily verapamil sustained‐release 120 mg capsules. Clinic blood pressure was measured and 24‐hour ambulatory blood pressure monitoring was performed at the end of both the baseline and the 4‐week treatment periods. Twenty‐four hour, day, and night systolic and diastolic ambulatory blood pressures were significantly (P <0.01) reduced in the entire study population (24‐hour, −5/−4 mm Hg; day, −6/−4 mm Hg; night, −4/–3 mm Hg). On the basis of mean daytime (6 AM to 6 PM) ambulatory diastolic blood pressure, patients were stratified into subgroups of patients with confirmed (>85 mm Hg) and unconfirmed mild hypertension (≤85 mm Hg). The magnitude of the mean change in systolic and diastolic blood pressure was greater in the group of patients with confirmed mild hypertension than the group with unconfirmed hypertension. The incidence of adverse experiences was low in frequency and events were of mild severity; quality of life scores improved (P = 0.02). Low daily doses (120 mg) of verapamil sustained‐release capsules provide a well‐tolerated and sustained antihypertensive effect over 24 hours in patients with mild hypertension.
Local and Systemic Phentolamine Antagonism of Norepinephrine‐Induced Hand Vein Constriction
Authors: Goldberg M. J. , Collins J. F. , Rowe H. M. , Cerimele B. J.
Published: March 2013

The dorsal hand vein distention technique has been used to study the effects of α‐adrenergic receptor antagonists on α‐agonist‐induced venoconstriction. Using this technique, we investigated the dose‐effect relationships between different intravenous routes of phentolamine (an α‐antagonist) administration on norepinephrine (an α‐agonist)‐induced hand vein constriction. Hand vein studies were done on healthy men; each man was studied on up to four occasions. On one occasion for each man, graded doses of phentolamine were infused into a hand vein preconstricted (submaximally) with norepinephrine. The dose of phentolamine producing a half maximal response (ED50) for reversal of venoconstriction, and the maximal reversal were calculated. On the other three occasions (randomly allocated) for each man, graded doses of norepinephrine were infused into a hand vein before and during intravenous infusions of (1) control (vehicle solutions); (2) systemic (other arm vein) phentolamine; and (3) local (hand vein) phentolamine. Systemic and local phentolamine dose ratios (ED50 of norepinephrine during phentolamine, divided by ED50 of norepinephrine before phentolamine; divided by the control dose ratio) were calculated. These studies show that phentolamine (administered directly into a preconstricted hand vein) can completely reverse norepinephrine‐induced venoconstriction. Phentolamine, administered by either local or systemic intravenous infusion, induces a significant right‐ward shift (approximately 10‐fold) in responsiveness to norepinephrine‐induced venoconstriction. To achieve comparable degrees of α‐antagonism, however, systemic phentolamine must be administered intravenously at a dose approximately 3,000‐fold higher than that of local phentolamine. Implications of these dose‐effect relationships, and their possible application to the treatment of norepinephrine extravasation and to hand vein studies with other receptor agonist‐antagonist combinations, are discussed.
First‐Line Therapy Option with Low‐Dose Bisoprolol Fumarate and Low‐Dose Hydrochlorothiazide in Patients with Stage I and Stage II Systemic Hypertension
Authors: Frishman William H. , Burris James F. , Mroczek William J. , Weir Matthew R. , Alemayehu Demissie , Simon Joseph S. , Chen Shun‐Yi , Bryzinski Brian S.
Published: March 2013

This 30‐center, randomized, double‐blind, placebo‐controlled, parallel‐group study was designed to (1) establish that 6.25 mg of hydrochlorothiazide (HCTZ) given once daily with 5 mg of bisoprolol fumarate can contribute to antihypertensive effectiveness in patients with stage I and stage II (mild to moderate) systemic hypertension; and (2) assess whether this formulation was more effective or possessed a safety advantage over standard monotherapy with bisoprolol or 25 mg of HCTZ. Results showed that HCTZ 6.25 mg contributed significantly to the antihypertensive effectiveness of bisoprolol 5 mg. Bisoprolol 5 mg/HCTZ 6.25 mg (B5/H6.25) produced significantly greater mean reductions from baseline in sitting systolic and diastolic blood pressure (−15.8 mm Hg/−12.6 mm Hg) than bisoprolol 5 mg alone (−10.0 mm Hg/−10.5 mm Hg) and HCTZ 25 mg alone (−10.2 mm Hg/−8.5 mm Hg). A 73% response rate was achieved with the low‐dose formulation compared with 61% for the bisoprolol 5 mg (B5) group and 47% for the HCTZ 25 mg (H25) group. B5/H6.25 was found to be significantly more effective than B5 or H25 in all subgroups of patients, regardless of gender, race, age, or smoking history. Antihypertensive effects were maintained during the 24‐hour dosing interval. The incremental effectiveness of B5/H6.25 was not accompanied by an increase in the frequency or severity of adverse experiences; the incidence of adverse experiences in the B5/H6.25 group was comparable to that in the placebo group. B5/H6.25 was shown to provide safety advantages over H25, as shown by less hypokalemia (<1% with B5/H6.25 versus 6.5% with H25). Treatment effects on triglycerides were similar to placebo, although small decreases in high‐density lipoprotein (HDL) cholesterol were observed in the bisoprolol‐treated groups. The benefits of low‐dose bisoprolol 5 mg/HCTZ 6.25 mg provide a rational basis for the use of this medication in the first‐line treatment of patients with stage I and stage II systemic hypertension.
Effect of Alosetron (a New 5‐HT3 Receptor Antagonist) on the Pharmacokinetics of Haloperidol in Schizophrenic Patients
Authors: Gupta Samir K. , Kunka Robert L. , Metz Alan , Lloyd Tom , Rudolph George , Perel James M.
Published: March 2013

Alosetron is under clinical development for the treatment of schizophrenia. This study evaluated the effect of oral alosetron dosing on the pharmacokinetics of haloperidol, the latter being administered daily to 13 schizophrenic patients for 56 days. Alosetron 1 mg daily or placebo was given by random assignment for 2 weeks. After a two‐week alosetron washout period (during which patients received placebo), patients received the alternate treatment for another two weeks. Serial blood samples were collected for high‐performance liquid chromatography determination of plasma haloperidol, reduced haloperidol, and alosetron at selected times for 24 hours after administration of haloperidol and alosetron on study days 21 and 49. Mean pharmacokinetic parameters of haloperidol in the presence of alosetron and placebo treatments were not significantly (P > .05) different: dose‐normalized Cmax (6.40 versus 5.75 ng/mL), dose‐normalized Cmin (2.00 versus 1.90 ng/mL), dose‐normalized AUC (85.97 versus 68.48 ng·hr/mL), and CL/f (78.23 versus 104.7 L/hr). A two‐compartment model was used to assess the concentration‐ and time‐independent pharmacokinetics of haloperidol after multiple dosing. The model confirmed that there was no change in the pharmacokinetics of haloperidol when alosetron was administered concomitantly. Mean AUC ratios of reduced haloperidol to haloperidol (0.18) in the presence of alosetron were similar to values obtained in the absence of alosetron, indicating that alosetron had no influence on the metabolism of haloperidol. Mean pharmacokinetic parameters of alosetron were similar to those in previous studies in healthy subjects.