bluuebunny/crossref_metadata_2025 huggingface dataset:
Outpatient Dobutamine Therapy: The Rhyme and the Riddle
Authors: Sacher Howard L. , Sacher Michael L. , Landau Stuart W. , Araghi Ali , Mene Matthew , Dooley Frances , Dietrich Kathleen A.
Published: March 2013

Advances in critical care medicine have increased survival for victims of myocardial infarction and other acute cardiac events so that increasingly patients are receiving long‐term, labor‐intensive, and costly medical care. Innovations in drug delivery systems and skyrocketing health care costs have fostered the growth of home health care which has blossomed into a $2.8 billion industry. There is evidence that outpatient dobutamine therapy produces definite physical and possibly psychological improvements of variable degree and duration. Hemodynamic improvements are generally associated with improvement in functional class, and the financial savings are recognizably substantial. However, three major problems confront therapies with beta‐adrenergic agonists: tendency for tolerance, ventricular arrhythmias, and increased myocardial oxygen consumption. There is a dire need for establishment of exclusionary patient criteria and for risk stratification, as well as for development of a portable radionuclide nonimaging monitor. Given the current fund of knowledge, outpatient dobutamine therapy should be undertaken cautiously after meticulous patient selection reflecting an awareness of the tremendous complexities and inherent risks. The therapeutic implications are dependent on the nature of the underlying cardiomyopathy and the fact that beta‐adrenergic receptor desensitization is unlikely to be overcome by progressive dosage increases. Therapy is initiated with the understanding that treatment will remain blindly empirical and conjectural in the absence of a continuous physiologic monitor and an expanded comprehension of the molecular pathophysiology of the failing ventricle.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Handbook of Psychiatric Drug Therapy, Second Edition

Lithium and the Blood (Karger) Vincent S. Gallicchio, Editor

Triglycerides: Their Role in Diabetes and Atherosclerosis (Atherosclerosis Reviews, Vol. 22). Antonio M. Gotto, Jr., and Rodolfo Paoletti, Editors

Handbook of Therapy in Liver and Kidney Disease (Little, Brown and Company), Robert W. Schrier, MD, and John G. Gambertoglio, Pharm, D, Editors
New Drugs in Acute Myelogenous Leukemia: A Review
Authors: Berman Ellin
Published: March 2013

Numerous clinical trials in adult patients with newly diagnosed acute myelogenous leukemia indicate that the survival rate is approximately 20%. A limited number of favorable prognostic features have been identified; patients who present with specific cytogenetic abnormalities such as t(15; 17), t(8; 21) and inv (16) tend to have survival rates approaching 40%. However, such patients constitute only a small proportion of the total denominator and it has therefore been a major focus of scientific endeavor to develop new drugs for the treatment of this disease. A wide variety of agents have undergone preliminary testing in this regard and include both natural substances such as homoherringtonine, a drug that has demonstrated modest complete remission rates in this disease and all‐trans retinoic acid, a compound that has revolutionized the treatment of acute promyelocytic leukemia. This review will put in perspective some of the newer drugs for the treatment of acute myelogenous leukemia and allow for some conclusions to be drawn as to their impact in the treatment of this disease.
Intraindividual Variability in Nifedipine Pharmacokinetics and Effects in Healthy Subjects
Authors: Soons P.A. , Schoemaker H.C. , Cohen A.F. , Breimer D.D.
Published: March 2013

The intraindividual variability in pharmacokinetics and effects of oral nifedipine (10 mg), administered with 1 week intervals, was investigated in twelve young healthy subjects. The population estimate of the coefficient of intraindividual variability (CVw) in AUC of nifedipine (13%) was much smaller than the pure between‐subject variability (CVb 54%). The long‐term (1 1/2 year) intraindividual variability was much larger than the short‐term variability. Maximum changes from baseline‐values of mean blood pressure (SBP −5%, DBP −4%) and mean heart rate (HR +21%) were small. Individual maximum changes in systolic blood pressure, diastolic blood pressure, and heart rate (SBP, DBP, and HR) and areas under effect curves were highly variable (CVw 34–250%, CVb 8–88%). For most subjects a significant positive linear relation was observed between nifedipine plasma concentration and the change in HR (mean r=0.63). The CVw in slope (106%) and intercept (685%) were even larger than the high CVb in these parameters (38% and 252%). Changes in blood pressure were not significantly related to nifedipine plasma concentrations within these healthy subjects. The small intraindividual variability in nifedipine pharmacokinetics allows crossover studies to detect pharmacokinetic relationships between nifedipine and other dihydropyridine calcium entry blockers.
The Effects of Pentoxifylline on the Plasma Membrane Ca2+ ATPase in Age‐Separated Rat and Human Erythrocytes
Authors: Seidler Norbert W. , Swislocki Norbert I.
Published: March 2013

Pentoxifylline, a dimethyl xanthine derivative given to patients with peripheral vascular disorders, increases erythrocyte deformability, diminishes Ca2+ entry, inhibits Ca2+‐dependent transglutaminase activity and elevates ATP levels. The present study examined the effects of pentoxifylline on the Ca2+ pump ATPase, an enzyme which regulates intracellular Ca2+ levels. Studies were carried out with inside‐out vesicles (IOVs) prepared from young (Ey) and old (Eo) human and rat erythrocytes. The pumping of Ca2+ depends on the concomitant hydrolysis of ATP; the two processes were measured using radiolabeled substrates. The catalytic properties of IOVs from young and old erythrocytes were stimulated by pentoxifylline when added directly to the assay medium. Pentoxifylline (0.5 to 5.0 mM) significantly activated the rates of Ca2+ dependent ATP hydrolysis in Ey and Eo IOVs of rat erythrocytes. The percent of activation was greater in the IOVs from older erythrocytes. The Ca2+ translocation was also affected by pentoxifylline. The early burst of Ca2+ uptake into IOVs decreased in the presence of pentoxifylline in Ey IOVs prepared from either species whereas steady state rates of Ca2+ transport only declined at 5.0 mM pentoxifylline. This pattern was not evident in the corresponding Eo IOVs. The response of Ey and Eo IOVs to pentoxifylline may be the basis of the difference in sensitivity of young and old erythrocytes to the drug in regulating intracellular Ca2+ concentrations.
Dose‐Dependent Effects of Betaxolol in Hypertension: A Double‐Blind, Multicenter Study
Authors: Williams Roger L. , Goyle Krishan K. , Herman Theodore S. , Rofman Barry A. , Ruoff Gary E. , Hogan Leo B.
Published: March 2013

This study determined the dose‐response relationship among three doses of betaxolol compared with placebo in patients with mild‐to‐moderate hypertension. In this double‐blind, placebo‐controlled trial, 317 hypertensive patients were randomly assigned to receive placebo or betaxolol 5, 10, or 20 mg once daily for 4 weeks. A significant (P < .05) decrease in supine diastolic blood pressure (BP) compared with concurrent placebo was evident with all three doses of betaxolol after 1 week of active treatment. Each dose of betaxolol maintained a significant reduction in diastolic and systolic BP and heart rate responses throughout the 4‐week treatment period. At the fourth week (final treatment evaluation), BP and heart rate were significantly (P < .05) reduced by all three doses of betaxolol compared with placebo. For supine systolic and diastolic BP, the decreases with betaxolol 20 mg were significantly (P < .05) greater than with the 5 mg dose, but there was no statistically significant difference between the 10‐mg and either the 5‐ or 20‐mg doses. For standing diastolic BP, the effect of betaxolol 5 mg once daily was significantly (P < .05) less than that of 10 and 20 mg. The overall supine diastolic BP response to betaxolol was dose dependent, and more patients responded to the 10‐ and 20‐mg doses of betaxolol (66% and 76%, respectively) than to the 5‐mg dose (59%). For each efficacy variable, the absolute magnitude of the reduction was greater with increasing dose. In subgroup analyses, BP responses were analyzed by race, age, baseline BP, and age combined with baseline BP. Whites responded better than blacks. Headache occurred significantly more often in the placebo group than in the betaxolol group. The frequency of bradycardia (<50 beats/min) was low (3.8% with 10 mg and 7.5% with 20 mg). The frequency of other adverse events was not significantly different between the placebo and betaxolol groups. Betaxolol is safe and effective for the treatment of essential hypertension and exhibits a dose‐response relationship over the dose ranges studied.
Once‐A‐Day Beta‐Lactam Antibiotic Administration
Authors: Rubinstein Ethan , Lang Ruth
Published: March 2013

Single daily administration of antibiotics has always been a desired goal of many physicians, scientists, medical economists, and last but not least, patients. The ease of administration coupled with reduced need for hospital stay, and consequently with reduced hospital costs, is naturally an important issue at a period of shrinking financial resources. The beta‐lactam antibiotics have been around for almost half the century, and because of their superb record of safety and activity against many bacteria, were the ideal candidates for the early experiments in the test tube, in animals and in humans for the once‐a‐day administration attempts.
Pharmacokinetic Interactions of Cefprozil With Food, Propantheline, Metoclopramide, and Probenecid in Healthy Volunteers
Authors: Shukla Umesh A. , Pittman Kenneth A. , Barbhaiya Rashmi H.
Published: March 2013

Cefprozil, a new oral cephalosporin antibiotic, is composed of cis and trans isomers in an approximate 90:10 ratio. The objectives of this study were: (1) to assess the effects of alterations in gastrointestinal motility by metoclopramide and propantheline on the pharmacokinetics of cis and trans isomers of cefprozil, and to compare them with the effects of food on the pharmacokinetics of cefprozil; (2) to assess the effects of inhibition of renal tubular secretion by probenecid on the pharmacokinetics of cefprozil isomers. In this four‐way crossover study, 15 healthy male volunteers received a 1000‐mg dose of cefprozil after fasting, pretreatment with metoclopramide or propantheline, after breakfast, or after probenecid in an incomplete, balanced block design. There was a 1‐week washout period between each treatment. Blood and urine samples collected over a 24‐hour period were assayed for the cis and trans isomers. The concentrations of the trans isomers were generally 1/10 of the cis isomer. The means and variances of the pharmacokinetic parameters of the cis and trans isomers of cefprozil were similar in fasting subjects and were affected in a parallel manner by food, metoclopramide, propantheline, and probenecid. The pharmacokinetics of the cis isomer under the fasting condition were as follows: maximum peak plasma concentration (Cmax), 14.0 ± 2.7 μg/mL; median time to reach Cmax (tmax), 1.5 (range, 1.0–3.5) hours; half‐life (t 1/2), 1.24 ± 0.27 hours; area under the concentration (AUC0‐∞), 47.3 ± 7.7 μg · hour/mL; mean residence time after oral administration (MRTpo), 2.9 ± 0.4 hours; CLB, 219 ± 60 mL/minute; and Xu% (percent cumulative urinary excretion in 0–24 hours), 68.1 ± 12.5. Propantheline delayed the tmax and significantly increased the MRTpo of the cefprozil isomers, relative to the fasting state, but other pharmacokinetic parameters were not significantly altered. Metoclopramide reduced the tmax and significantly decreased the MRTpo of both isomers of cefprozil, but other pharmacokinetic parameters were not significantly altered. Food slightly delayed the tmax but did not have a significant effect on other pharmacokinetic parameters of either isomer. Pretreatment with probenecid resulted in a significant increase in the t1/2, Cmax, AUC0‐∞, and MRTpo, and in a significant decrease in the CLR of each isomer, indicating that probenecid competitively inhibits renal tubular secretion of cefprozil. In summary, the extent of absorption of cefprozil was not affected by drugs that change gastric motility nor by concurrent administration of food. Probenecid significantly decreased the renal clearance and prolonged the t1/2 of cefprozil, indicating that renal tubular secretion is a significant pathway in elimination of cefprozil.
The Site of Gastrointestinal Absorption of Gepirone in Humans
Authors: Tay L. K. , Dixon F. , Sostrin M. B. , Barr W. H. , Farmen R. H. , Pittman K. A.
Published: March 2013

This study was conducted in seven healthy male subjects and was performed over four sessions with a 1‐week washout between sessions. It was designed to compare the bioavailability of an oral 20‐mg gepirone dose (treatment 1) with that obtained after application of the same dose by gastric intubation to the distal (treatment 2) and proximal (treatment 3) regions of the small intestine, and after 4 consecutive 5‐mg gepirone doses given orally at hourly intervals (treatment 4). Serial blood samples were taken over 24 hours after dose after each treatment. Plasma concentrations of gepirone and 1‐(2‐pyrimidiriyl)‐piperazine (1‐PP), a metabolite of gepirone, were quantitated by gas chromatography‐mass spectrometry. Mean gepirone time to reach peak concentration (tmax) after treatments 1, 2, and 3 ranged between 0.57 and 1.07 hours. There were no significant differences between sites and treatments for gepirone t1/2, which ranged between 2.8 and 3.3 hours. The mean gepirone maximum peak plasma concentration (Cmax) was significantly higher (P < .05) after treatment 2 (12.92 ± 7.24 ng/mL) compared with treatment 1 (6.79 ± 3.54 ng/mL) or treatment 3 (6.33 ± 2.26 ng/mL). Gepirone area under the curve (AUCinf) was also significantly higher (P < .05) after treatment 2 (29.83 ± 17.42 ng · h/mL) compared with treatment 1 (18.07 ± 6.10 ng·h/mL) or treatment 3 (17.74 ± 7.69 ng·h/mL). There were no significant differences in gepirone AUCinf between treatments 1 and 4. For 1‐PP, treatment 2 Cmax (19.25 ± 6.64 ng/mL) was significantly higher (P < .05) compared with treatment 1 (13.55 ± 3.26 ng/mL), but not treatment 3 (15.56 ± 4.31 ng/mL). Significant differences were not observed between sites and treatments with respect to 1‐PP t1/2 and AUCinf. Mean 1‐PP t1/2 values ranged between 4.85 and 6.73 hours, and mean tmax between 0.82 and 1.29 hours. These results suggest that even though gepirone may be more bioavailable in the lower regions of the small intestine, gepirone is absorbed throughout the entire length of the small intestine. In addition, differences were not observed in gepirone AUCinf between treatments 1 and 4, suggesting that the bioavailability of gepirone was not affected by changes in the rate of oral administration.
Chronopharmacology of Furosemide in the Elderly
Authors: Fujimura Akio , Ohira Hiroshi , Shiga Tsuyoshi , Ohashi Kyo‐ichi , Ebihara Akio
Published: March 2013

The authors have previously reported the time‐dependent change in the diuretic effects of Furosemide, a loop diuretic agent, in young and middle‐aged subjects. The current study was undertaken to examine an influence of aging on this chronopharmacologic phenomenon. Ten milligrams furosemide was given intravenously to 12 elderly subjects (>70 years of age) at 9:00 am (day trial) or at 9:00 pm (night trial) by a cross‐over design. One‐hour urine samples were collected for 3 hours after each administration, and urine volume and urinary excretions of sodium and furosemide were determined. Urine volume and urinary sodium excretion increased after furosemide administration. Contrary to the findings in the young and middle‐aged subjects, no significant differences were observed in these parameters at any observation period between the day and night trials in the elderly subjects. Urinary furosemide excretion of the day and night trials did not significantly differ. These results suggest that the chronopharmacologic profiles of furosemide are altered in the elderly.
Stereochemistry and Bioequivalence
Authors: Jamali Fakhreddin
Published: March 2013

Despite the fact that many important drugs are chiral, for a variety of reasons they are marketed as racemates (i.e., an equal proportion of two enantiomers). Although enantiomers of racemic drugs often differ from one another in their pharmacodynamic and pharmacokinetic properties, bioequivalence assessments are made using nonstereospecific assays. Such an approach may provide a poor assessment of therapeutic equality. This can be true particularly for drugs with complicated pharmacokinetics and those that exhibit extensive stereoselectivity in their disposition kinetics. Accordingly, examples of bioequivalence studies based on stereospecific assays have started to appear in the literature. Fortunately, facile stereospecific assays have become available in the last several years for many drugs. Consequently, regulatory agencies have started to take the issue of stereochemistry into consideration in the assessment of bioequivalence, particularly from the standpoint of generic substitution.
Pharmacokinetics of Didanosine and Ketoconazole After Coadministration to Patients Seropositive for the Human Immunodeficiency Virus
Authors: Knupp Catherine A. , Brater D. Craig , Relue Julie , Barbhaiya Rashmi H.
Published: March 2013

The steady‐state pharmacokinetics of didanosine (DDI) and ketoconazole (KET) were evaluated when the agents were administered alone or concurrently to patients seropositive for the human immunodeficiency virus. Using a randomized, three‐way crossover design, multiple oral doses of DDI (375 mg twice daily for 4 days), KET (200 mg daily for 4 days) or the combination were administered under fasting conditions. When DDI and KET were coadministered, KET was given 2 hours before the morning dose of didanosine. Serial blood samples and total urine output were a collected after the administration of a final single dose on day 5 of each treatment session. Samples were analyzed using high‐pressure liquid chromatography (HPLC)/ultraviolet (UV) or fluorescence methods specific for unchanged DDI (plasma and urine) or KET (plasma only). Pharmacokinetic parameters were calculated using noncompartmental methods. The average DDI maximum peak plasma concentration (Cmax) value at steady state was significantly less when DDI was administered with KET (1836 ng/mh) than when DDI was administered alone (2094 ng/mL), although the magnitude of the decrease was only 12%. Didanosine area under the curve (AUC(0 — τ))for the combination (2872 hr.ng/mL) was 8% less than when DDI was given alone (3107 hr.ng/mL); the difference was not significant. There were no significant differences among the other evaluated parameters (time to reach peak concentration [tmax], half‐life [t1/2], renal clearance [CLR], or urinary recovery [UR]) between the two DDI treatments. There were no significant differences among any of the pharmacokinetic parameters between the two KET treatments. It is concluded that the pharmacokinetics of DDI and KET are not affected to a clinically significant degree by coadministration of multiple oral doses of the two agents under the current study conditions. It is not necessary to alter the dosing regimen of either drug so long as KET is administered 2 hours before DDI.
Comparison of Vancomycin Pharmacokinetics in Hospitalized Elderly and Young Patients Using a Bayesian Forecaster
Authors: Guay David R. P. , Vance‐Bryan Kyle , Gilliland Susan , Rodvold Keith , Rotschafer John
Published: March 2013

Limited data have been published that compare the pharmacokinetic parameters of vancomycin in elderly versus young patients. This study was designed to assess vancomycin pharmacokinetics in 148 elderly (≥60 years of age) and 140 young (18–59 years of age) hospitalized infected patients. Serum vancomycin concentrations were determined using fluorescence polarization immunoassay. Serum concentration‐versus‐time data were fitted to a two‐compartment Bayesian forecasting program. Elderly versus young vancomycin pharmacokinetic parameters derived were as follows (patients with serum creatinine ≤.1.5 mg/dL): mean ± standard deviation terminal disposition half‐life (t1/2) of 17.8 ± 11.8 versus 7.5 ± 6.7 hours, respectively, P < .05; volume of distribution (Vz) of 74.2 ± 32.3 versus 67.0 ± 30.7 L, respectively, P = .16; and total body clearance (CL) of 0.71 ± 0.41 versus 1.22 ± 0.50 mL/min/kg, respectively, P < .05. Comparing subjects with normal serum creatinine values (≤1.5 mg/dL), the elderly required smaller daily doses as compared with the young group to maintain target peak and trough vancomycin serum concentrations (18.2 ± 5.8 versus 25.2 ± 7.8 mg/kg/day, P < .05). Stepwise multiple regression models for the pharmacokinetic parameters were developed to assess the predictive power of age, controlling for the effects of gender, total body weight, serum creatinine, and creatinine clearance. Age was consistently an independent and significant predictor of t1/2, Vz, and CL. These data demonstrate that elderly patients exhibit significant differences in vancomycin pharmacokinetic parameters compared with young patients and constitute a patient population in need of individualized vancomycin dosing due to substantial heterogeneity in physiologic and pharmacokinetic parameters.
Acadesine (AICA‐Riboside): Disposition and Metabolism of an Adenosine‐Regulating Agent
Authors: Dixon Ross , Fujitaki James , Sandoval Tamie , Kisicki James
Published: March 2013

Acadesine (AICA‐riboside) is a purine nucleoside analog with anti‐ischemic properties that is currently being studied (Phase 3) for the prevention of adverse cardiovascular outcomes in patients undergoing coronary artery bypass graft (CABG) surgery. The safety, tolerance, and pharmacokinetics of the drug have previously been reported in this journal (J Clin Pharmacol 1991;31:342–347). Recently, the authors studied the disposition and metabolism of acadesine in healthy males (n = 4) after a 15‐minute intravenous infusion of 25 mg/kg of 2‐14C‐acadesine. The postinfusion total 14C concentrations in plasma declined in a multiexponential manner, and the terminal phase had an apparent t1/2 of about 1 week. Intact acadesine was only measurable for 2 hours after infusion. Total plasma clearance was 2.2 ± 0.2 L/hour/kg, the acadesine blood/plasma ratio was unity, and plasma protein binding was negligible (∼1%). Uric acid, the end product of purine metabolism in humans, was the major metabolite of acadesine in plasma and accounted for all of the total plasma 14C at 6 hours after infusion. In whole blood, acadesine 5′‐monophosphate was present in the red blood cells, and the nucleotide represented 30% of the total blood 14C at the end of the infusion. The nucleotide was confined to the RBCs and was not present in plasma. Urine and fecal recoveries over 2 weeks accounted for 48% of the total 14C dose, with 44% excreted in urine and 4% in feces. Only 5% of the dose was excreted in urine as intact acadesine. Uric acid was the major metabolite in urine together with small amounts of hypoxanthine. There was no evidence of conjugation of acadesine or its metabolites with glucuronic acid. Our study indicates that acadesine is metabolized to uric acid through normal purine pathways. Acadesine metabolites also enter the endogenous purine pools and are distributed throughout the body.
Integrating Worldwide Marketing Needs and Clinical Research
Authors: Kaniecki Diana J. , Arnold Renée J. Goldberg
Published: March 2013

In this era of globalization, expanding research needs, and the necessity of sharing global technologies and worldwide data evaluation techniques, a challenging environment has been created for multinational drug development, clinical testing, and marketing. Integrating worldwide marketing needs and clinical research will become even more significant in the future as harmonization of pharmaceutical industry research and regulatory requirements increase with the unification of the European Economic Community. Marketing and research teams within a pharmaceutical company must work closely together to make the drug being developed appropriate to a global market.
Postmarketing Surveillance: Curriculum for the Clinical Pharmacologist. Part II: Clinical and Regulatory Considerations
Authors: Johnson Joyce M. , Tanner L. Ann
Published: March 2013

This is the second of a two‐part series that develops a curriculum on postmarketing surveillance. With the ongoing emphasis on drug safety and possible earlier marketing of drugs, this becomes an essential element of clinical pharmacology training. The usual educational focus on drug safety is a pharmacokinetic or pharmacodynamic perspective on a specific drug or drug class, perhaps in the context of clinical trial study design and analysis. This curriculum complements this approach and provides an overview of drug safety surveillance from regulatory and epidemiologic perspectives.
External Imaging of Atherosclerosis in Rabbits Using an 123I‐Labeled Synthetic Peptide Fragment
Authors: Hardoff Ruth , Braegelmann Frank , Zanzonico Pat , Herrold Edmund M. , Lees Robert S. , Lees Ann M. , Dean Richard T. , Lister‐James John , Borer Jeffrey S.
Published: March 2013

The oligopeptide fragment of apolipoprotein B, SP‐4, has demonstrated pronounced uptake in the healing edges of balloon‐injured rabbit aortic endothelium. To assess 123I‐labeled SP‐4 for identification of atherosclerotic plaques by gamma camera imaging, 14 Watanabe heritable hyperlipidemic (WHHL) and 5 normal rabbits were imaged 5 minutes and 12 and 24 hours after intravenous injection of123I‐SP‐4. In addition, two WHHL and two normal rabbits were injected with 125I‐SP‐4 for autoradiography. Twelve of the 14 WHHL, but none of the normal, rabbits had visually apparent focal radioiodine accumulation in the region of the aorta. Focus‐to‐lung and focus‐to‐heart count ratios were 2.4 ± 1.3 and 1.0 ± 0.4, respectively. Five of the visually positive WHHL rabbits were reimaged 4 and 8 weeks later with 123I‐NaI and 123I‐SP‐2 (an apo E peptide), respectively, as negative controls. Perceptible, but faint, aortic localization of 123I‐NaI and of 123I‐SP‐2 was seen in only one animal each. The distributions of atherosclerotic lesions on photographs of the opened WHHL aortas and of film blackening on 125I‐SP‐4 autoradiograms were identical. In contrast, the two normal rabbit aortas did not exhibit plaques on photographs or film blackening on autoradiograms. Thus, in an animal model closely simulating human atherosclerotic disease, SP‐4 localizes specifically in aortic atherosclerotic lesions.
Evidence of a Partial Escape of Renin‐Angiotensin‐Aldosterone Blockade in Patients with Acute Myocardial Infarction Treated with Ace Inhibitors
Authors: Borghi Claudio , Boschi Stefano , Ambrosioni Ettore , Melandri Giovanni , Branzi Angelo , Magnani Bruno
Published: March 2013

Angiotensin‐Converting enzyme (ACE) inhibitors have been designed to block the renin‐angiotensin system and can represent an effective therapeutic approach in those settings where such a system is active, such as myocardial infarction. In a randomized placebo‐controlled study, 10 patients with acute myocardial infarction allocated to treatment with increasing doses of zofenopril calcium and 10 patients allocated to placebo were studied in hospital, within 24 hours from symptoms, during 11 sampling periods to assess the time course of ACE inhibition and renin‐angiotensin‐aldosterone blockade. Zofenopril administration was followed by a dose‐dependent inhibition of in vitro ACE activity (7.5 mg, 65%; 15 mg, 89%; 30 mg, 94.5%) and a progressive increase in plasma active renin. Conversely, plasma aldosterone decreased during the first 3 days of treatment and then returned toward baseline values, as did blood pressure, despite a persistent inhibition of ACE. The present data suggest the existence of an interesting dissociation between the time‐course of ACE inhibition and that of blockade of the renin‐angiotensin system in patients with acute myocardial infarction. This discrepancy could arise from the combination of an only partial in vivo ACE inhibition and the compensatory increase in plasma renin that occurs during treatment with ACE inhibitors. A better understanding of this relationship would seem to be useful in addressing the correct use of ACE inhibitors in patients with acute myocardial injury.
Effects of Oral Cimetidine or Ranitidine on the Pharmacokinetics of Intravenous Enoxacin
Authors: Misiak Paul M. , Eldon Michael A. , Toothaker Roger D. , Sedman Allen J.
Published: March 2013

Enoxacin is a quinolone antibacterial agent currently being developed for oral and intravenous treatment of bacterial infections. Ten healthy subjects received a single 400‐mg intravenous dose of enoxacin alone, with 300 mg (four times daily) oral Cimetidine and with 150 mg (twice daily) oral ranitidine. Serial blood and urine samples were collected over a 48‐hour period. Plasma and urine enoxacin concentrations were determined using a validated high‐performance liquid chromatographic method. Mean enoxacin plasma concentrations were higher after administration of enoxacin with Cimetidine than those measured after enoxacin alone or enoxacin with ranitidine. Cimetidine coadministration reduced enoxacin renal clearance by 26% and systemic clearance by 20%, and resulted in a 30% increase in elimination half‐life. In contrast, concurrent ranitidine therapy did not significantly alter the pharmacokinetics of intravenous enoxacin.
Influence of Application Site of a New Transdermal Clonidine, M‐5041T, on its Pharmacokinetics and Pharmacodynamics in Healthy Subjects
Authors: Ebihara Akio , Fujimura Akio , Ohashi Kyo‐ichi , Shiga Tsuyoshi , Kumagai Yuji , Nakashima Hajime , Kotegawa Tsutomu
Published: March 2013

Influence of application site of a new transdermal clonidine, M‐5041T(M), on its pharmacokinetics and pharmacodynamics were evaluated in eight human subjects. One patch of M‐6 mg was applied for 3 days on the right chest (first trial), on the left arm (second trial), and on the upper abdomen (third trial). Blood samples for clonidine concentration were taken, and blood pressure (BP) was measured for a 120‐hour postapplication period. Plasma concentrations of clonidine increased after application of M in each trial. This parameter in the second trial was significantly greater than that of the first and third trials. The values of maximum plasma concentration and area under the plasma concentration‐time curve in the second trial were greater than those of other trials, but the differences did not reach significance. The BP‐lowering effect of M in the second trial was significantly greater than that of the third trial. These results suggest that the plasma concentrations of clonidine after application of M and its hypotensive effect are affected by the site of application in human subjects.
Itraconazole Affects Single‐Dose Terfenadine Pharmacokinetics and Cardiac Repolarization Pharmacodynamics
Authors: Honig Peter K. , Wortham Dale C. , Hull Robert , Zamani Kaveh , Smith Julie E. , Cantilena Louis R.
Published: March 2013

The object of this study was to examine prospectively the effects of itraconazole on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics (QTc intervals) of single‐dose terfenadine in six healthy volunteers. It was designed as a prospective cohort study with each subject serving as his own control, set in an outpatient cardiology clinic. The participants were six healthy volunteers (two men, four women; ages 24–35) not taking any prescription or over‐the‐counter medications. Single‐dose terfenadine administration (120 mg) was accompanied by pharmacokinetic profiles and serial determination of the QTc interval for 12 hours. The subjects then began daily oral itraconazole (200 mg each morning) for 7 days. Repeat pharmacokinetic and pharmacodynamic determinations were made after administration of a second dose (120 mg) of terfenadine while receiving itraconazole. The main outcome measures were terfenadine and acid metabolite serum concentrations; corrected QT intervals as determined by 12‐lead electrocardiogram (ECG); and presence or absence of late potentials as determined by signal‐averaged ECGs over 150 cardiac cycles. There were significant changes in the pharmacokinetic parameters of acid metabolite after treatment with itraconazole. All subjects had detectable levels of unmetabolized terfenadine after addition of itraconazole, which was associated with QT prolongation. There was no evidence of late depolarization as manifested by an increase in QRS duration found using signal‐averaged electrocardiography. Itraconazole influences the metabolism of terfenadine in normal volunteers and results in the accumulation of unmetabolized parent drug associated with altered cardiac repolarization. This drug combination should be avoided.
Pharmacokinetics of Orally Administered Levocabastine in Patients with Renal Insufficiency
Authors: Zazgornik Jan , Huang May Lynn , Van Peer Achiel , Woestenborghs Robert , Heykants Jos , Stephen Adrian
Published: March 2013

The effects of renal insufficiency and hemodialysis on the pharmacokinetics of orally administered levocabastine were studied in six nondialysis patients and in six patients undergoing regular hemodialysis. Levocabastine .5 mg, supplied as a solution, was administered orally to each patient 1 hour after breakfast Compared with data in healthy volunteers, the oral absorption and disposition of levocabastine were impaired in patients with renal insufficiency. The time to reach peak plasma concentration was increased and the peak plasma concentration was decreased in the patients with renal insufficiency compared with healthy volunteers. Urinary excretion of the unchanged drug, which is the major elimination pathway of levocabastine, was reduced in the patients with renal insufficiency. The decreased urinary excretion most likely contributed to the prolonged half‐life (from 36 hours to 95 hours) and increased area under the plasma concentration‐time curve (+56%) in the patients with renal insufficiency as compared with the healthy volunteers. Although the 6‐hour hemodialysis procedure starting 4 hours after dosing eliminated 10% of the oral dose, the terminal half‐life and the total area under the plasma concentration‐time curve did not differ significantly between the hemodialysis and the nonhemodialysis patients. In conclusion, the current study showed that the initial oral absorption of levocabastine is reduced and that levocabastine elimination is prolonged in patients with renal insufficiency.
Evaluation of the Renal Protective Effect of Misoprostol in Elderly, Osteoarthritic Patients at Risk for Nonsteroidal Anti‐inflammatory Drug‐Induced Renal Dysfunction
Authors: Fullerton Terence , Sica Domenic A. , Blum Robert A.
Published: March 2013

An age greater than 60 and diuretic use have been implicated as risk factors for nonsteroidal anti‐inflammatory drug (NSAID)‐induced decreases in renal function. Misoprostol, a prostaglandin E1 analog, was studied in nine elderly osteoarthritic patients at risk for NSAID‐induced renal dysfunction to determine whether it could prevent NSAID‐induced renal dysfunction. Subjects received ibuprofen 2400 mg/day and either misoprostol 800 meg/day or placebo for 14 days in a randomized, double‐blinded, crossover trial Glomerular filtration rate (GFR) and elective renal plasma flow (ERPF) studies using inulin and PAH plasma clearance, urinary prostaglandin E2 (PGE2) and protein excretion, and serum electrolytes were obtained at baseline, after the first dose, and on day 7 and 14 of each treatment period. Prostaglandin E2 excretion was significantly reduced after the first dose of ibuprofen and throughout the 14 days in both the misoprostol and placebo treatment groups. No statistically significant differences in GFR, ERPF, protein excretion, serum potassium, or serum sodium were detected between misoprostol and placebo treatment during the 14 days of ibuprofen treatment. However, a subset of two patients who exhibited a decrease of greater than 20% in GFR during placebo treatment, appeared to demonstrate an attenuation of this decline when treated with misoprostol. Effect of time, independent of treatment group, indicated that ERPF was significantly decreased from baseline after the first dose of ibuprofen (P ≤ 0.05), whereas GFR was notably diminished from baseline on day 14 only (P ≤ 0.05). Misoprostol does not influence GFR and ERPF in unselected subjects purportedly at risk for NSAID‐induced renal dysfunction. However, further study is necessary in preselected patients in whom a NSAID‐induced decrease in GFR has been documented.
Effect of Milk on Absorption of Norfloxacin in Healthy Volunteers
Authors: Minami Rumiko , Inotsume Nobuo , Nakano Masahiro , Sudo Yoshihisa , Higashi Akimasa , Matsuda Ichiro
Published: March 2013

The authors studied the effect of milk on the bioavailability of norfloxacin in six healthy male volunteers in a randomized crossover trial. After an overnight fast, 200 mg of norfloxacin was given with 200 mL of water or milk. Area under the curve (AUC) of norfloxacin with milk was significantly (P < 0.01) smaller than that with water. The mean peak serum concentration was decreased to 60% after oral administration of norfloxacin with milk (P < 0.01). The apparent volume of distribution at central compartment (Vc/f) value of norfloxacin was significantly (P < 0.05) increased with milk. Milk exhibits a clinically significant effect on norfloxacin absorption.
The Effect of Naproxen and Interleukin‐1 on Proteoglycan Catabolism and on Neutral Metalloproteinase Activity in Normal Articular Cartilage In Vitro
Authors: Glazer Paul A. , Rosenwasser Melvin P. , Ratcliffe Anthony
Published: March 2013

The events in inflammatory and degenerative joint diseases involve major changes in the metabolic events in the articular cartilage. The effects of nonsteroidal anti‐inflammatory drugs (NSAIDs) on articular cartilage metabolism remain unclear, however. The objective of this study was to determine the effect of one commonly used NSAID, naproxen sodium, on the catabolism of proteoglycans in articular cartilage expiants maintained in culture. Release of proteoglycan from the cartilage was compared with release of neutral metalloproteinase activity. The effect of the drug also was determined on the IL‐1‐stimulated release of proteoglycan and neutral metalloproteinase activity from the expiants. At concentrations that included those present in synovial fluids of patients treated with the drug, naproxen sodium was found to suppress the release of proteoglycan and neutral metalloproteinase activity from the articular cartilage extracts. This is in contrast to the well‐documented effect of interleukin‐1 (IL‐1), which was shown to stimulate release of proteoglycan and neutral metalloproteinase activity from articular cartilage. The effect of naproxen sodium on the IL‐1‐stimulated release was to suppress, but not totally overcome, the increased release of proteoglycan and neutral metalloproteinase activity. In summary, these in vitro studies of cartilage metabolism indicate that naproxen sodium has the potential to suppress catabolic activities in articular cartilage, including those that are motivated by IL‐1.
Effect of Ethanol on Metabolic Responses to Treadmill Running in Well‐Trained Men
Authors: Kendrick Zebulon V. , Affrime Melton B. , Lowenthal David T.
Published: March 2013

The metabolic effects of ethanol on treadmill performance were determined in four trained runners. Ethanol in doses of 25 mL in 150 mL of grapefruit juice (total volume) or grapefruit juice was randomly administered 10 minutes before and at 30 minutes of a 60‐minute treadmill run. The speed and grade of the treadmill was adjusted to elicit an average oxygen consumption (VO2) of 80 to 85% of the subjects' VO2max. Three of the four subjects could not complete the treadmill run after the administration of ethanol. Administration of ethanol resulted in significant increases in the heart rate responses to treadmill running above those for the placebo grapefruit treatment. VO2 was higher after ethanol administration than the placebo grapefruit juice treatment, but these values were not significant. Blood glucose content rose significantly between 0 and 30 minutes of treadmill running for both the ethanol and placebo grapefruit juice treatments. Between 30 minutes of treadmill running and the termination of the exercise, the blood glucose level decreased significantly by 24% after the second ethanol treatment at 30 minutes of exercise. Plasma fatty acid, triglyceride, creatine phosphokinase, and renin contents followed expected exercise changes. It was concluded that the administration of ethanol adversely influenced treadmill exercise performance by eliciting a hypoglycemic effect between 30 minutes and the termination of the exercise.
Pharmacokinetics of Oral Nifedipine in Different Populations
Authors: Castañeda‐Hernández G. , Hoyo‐Vadillo C. , Palma‐Aguirre J. A. , Flores‐Murrieta F. J.
Published: March 2013

Nifedipine disposition varies among populations. Reports on oral nifedipine pharmacokinetics show that peak plasma levels and AVC values are higher in Mexican and Japanese than in European and North American subjects. Increased nifedipine bioavailability in the nonwhite populations is likely due to nutritional habits. Certain flavonoids that inhibit the first‐pass metabolism of dihydropyridines are present in the diets of both Mexican and Japanese. Differences in phenotypes may play a role in interethnic variability.
Continuous Intravenous Dosing with Ciprostene Using a Portable Pump in Ambulatory Patients
Authors: Wolf Daniel L. , Metzler Carl M. , Froeschke Monica O. , Luderer Jack R.
Published: March 2013

Parenteral compounds present special drug delivery challenges. This open‐label study evaluated a portable infusion pump as a means to deliver intravenous ciprostene, a stable prostacyclin analog. Ten patients with peripheral vascular disease and claudication received ciprostene (titrated to 120 ng/kg/min) infused over 8 hours 1 day per week for 4 consecutive weeks. Patients successfully maintained the pump strapped to the waist. The mean ± standard deviation delivery error, with volumes of 6 to 10 mL over 8 hours, was −0.895 ± 3.177%. Accordingly, the pump performed well with a potent drug under these clinical conditions. Headache, flushing, and infusion site irritation during infusion were the most frequent side effects. Blood pressure remained unchanged during infusion; however, heart rate increased significantly (P < .05, maximum increase was 13.9 ± 2.1 beats per minute [mean ± standard error of the mean]. Mean (± standard error of the mean) relative claudication times on treadmill remained unchanged; however, absolute claudication times increased (P < .05) from 6.6 ± 1.8 to 10.0 ± 2.2 minutes. Ciprostene inhibited adenosine diphosphate‐induced platelet aggregation by 56.0 ± 12.7% (mean ± standard error of the mean). Mean template bleeding times and plasma concentrations of platelet‐specific proteins (beta‐thromboglobulin, platelet factor 4) did not change.
Single‐ and Multiple‐Dose Pharmacokinetics of Nicoderm® (Nicotine Transdermal System)
Authors: Gupta Suneel K. , Okerholm Richard A. , Coen Pat , Prather Richard D. , Gorsline Jane
Published: March 2013

The pharmacokinetics and tolerability of single and multiple applications of Nicotine Transdermal Systems (NTS), designed to deliver 14 mg of nicotine per 24 hours, were investigated in 20 healthy adult male smokers. After a single application, mean Cmax and tmax for plasma nicotine were 12.2 ng/mL and 4.4 hours, respectively. Plasma nicotine concentrations rose rapidly and then remained steady between 12 and 24 hours after application. The apparent nicotine half‐life (t 1/2) after system removal was 3.2 hours. Steady state was attained by the second day of multiple application, and mean steady‐state nicotine Cavg was 25% higher on day 5 compared with the first NTS application. Steady‐state plasma cotinine was reached by the fourth day of multiple application and, as with nicotine, Cavg and Cmax increased, tmax decreased, and t 1/2 did not change compared with single application. The mean ratios of cotinine‐to‐nicotine area under the curve (AUC) values for single and multiple NTS applications were 14.0 and 15.8, respectively. The pharmacokinetics of nicotine and cotinine were linear between single and multiple NTS applications. The nicotine transdermal systems were generally well tolerated.
Evaluation of the Pharmacokinetics and Tolerability of Tirilazad Mesylate, a 21‐Aminosteroid Free Radical Scavenger: I. Single‐Dose Administration
Authors: Fleishaker J. C. , Peters G. R. , Cathcart K. S.
Published: March 2013

The single‐dose tolerability and pharmacokinetics of tirilazad mesylate, a 21‐aminosteroid free radical scavenger, were assessed in 47 healthy male subjects. Subjects were randomized to receive citrate vehicle (n = 12) or 0.25 mg/kg (n = 9), 0.5 mg/kg (n = 9), 1.0 mg/kg (n = 8), or 2.0 mg/kg (n = 9) tirilazad mesylate by 0.5‐hour intravenous infusion. Injection site pain was observed with approximately equal frequency in both vehicle and tirilazad mesylate treatment groups. No statistically significant effects of tirilazad mesylate on blood pressure, heart rate, electrocardiograms, liver enzymes, or renal function were apparent. Tirilazad mesylate did not significantly affect measures of glucocorticoid activity (blood glucose, adrenocorticotropic hormone, cortisol eosinophil, or lymphocyte levels). Maximal plasma concentrations of tirilazad mesylate increased linearly with dose. Limited assay sensitivity at the lower two doses prevented determination of the dose proportionality of tirilazad area under the curve. The apparent elimination half‐life at the higher doses was 3.7 hours. Clearance of tirilazad mesylate approached liver blood flow. Results indicate that intravenous infusions at these doses are well tolerated and devoid of glucocorticoid effects. Tirilazad mesylate appears to be efficiently cleared by the liver, and its pharmacokinetics are apparently linear over the dosage range studied.
Book Reviews
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

β‐Adrenoceptors: Molecular Biology, Biochemistry and Pharmacology Ruffolo RR Jr., Editor.

β‐Adrenoceptors: Molecular Biology, Biochemistry and Pharmacology Ruffolo RR Jr., Editor.

Advances in Drug Therapy of Gastroesophageal Reflux Disease Scarpignato C, Editor.

Immunological and Pharmacological Aspects of Atopic and Contact Eczema Czernielewski JM, Editor.

Bacterial Meningitis Schönfeld H and Helvig H, Editors.

Atrial Fibrillation: Mechanisms and Management Falk RH and Podrid PJ, Editors.

USAN and the USP Dictionary of Drug Names United States Pharmacopeial Convention, Inc.