bluuebunny/crossref_metadata_2025 huggingface dataset:
Disposition of Intravenous Amiodarone in Subjects with Normal and Impaired Renal Function
Authors: Ujhelyi Michael R. , Klamerus Karen J. , Vadiei Kiumars , O'Rangers Eleanor , Izard Mark , Neefe D. Lynne , Zimmerman James J. , Chow Moses S. S.
Published: March 2013

In a study designed to determine the influence of renal dysfunction on the disposition of amiodarone and its metabolite, desethylamiodarone (DEA), 30 subjects received a single 5 mg/kg intravenous dose of amiodarone over 15 minutes. Of the 30, 11 had normal renal function (group I; mean ± SD glomerular filtration rate [GFR] = 118 ± 20 mL/min/1.73 m2), 9 had renal impairment (group II; GFR = 23 ± 10 mL/min/1.73 m2), and 10 were long‐term hemodialysis patients (group III; 4 of these patients were studied during dialysis). Total and free concentrations of amiodarone and DEA were measured by high‐performance liquid chromatography. There were no significant differences between the three groups in mean systemic clearance, steady state volume of distribution, or mean residence time of amiodarone. However, the area under the concentration—time curve (AUC) for amiodarone was significantly higher in group I than in group II, and this finding was related to total body weight. Free fraction was similar in groups I and III. The disposition of amiodarone and its metabolite DEA was similar in patients with normal renal function, moderate renal dysfunction, and end‐stage renal disease. Thus, dosage adjustment in patients with renal impairment is not necessary based on this pharmacokinetic analysis.
The Effect of Renal Insufficiency and Hemodialysis on the Pharmacokinetics of Nalmefene
Authors: Matzke Gary R. , Frye Reginald F. , Alexander Alicia C. M. , Reynolds Robin , Dixon Rosina , Johnston James , Rault Raymond M.
Published: March 2013

The disposition of nalmefene, an opioid antagonist intended for the reversal of opioid‐induced respiratory depression, and its primary metabolite nalmefene glucuronide, were characterized in adult volunteers with normal renal function and in patients with end‐stage renal disease (ESRD). The effect of hemodialysis on the elimination of nalmefene and nalmefene glucuronide also was assessed. Participants with normal renal function received a single intravenous dose of 2 mg, and patients with ESRD received two separate doses of 1 mg nalmefene hydrochloride. Terminal elimination half‐life (t1/2) of both nalmefene and nalmefene glucuronide was prolonged in patients with ESRD compared with that in participants with normal renal function. The steady‐state volume of distribution (Vdss) of nalmefene was significantly higher and total body clearance lower in patients with ESRD than in participants with normal renal function. Hemodialysis clearance of nalmefene was approximately 3.3% of total body clearance. Although the hemodialysis clearance of nalmefene glucuronide was 179.3 ± 24.1 mL/min and its t1/2 was significantly reduced during dialysis to 5.2 ± 2.3 hours, a dramatic rebound of nalmefene glucuronide concentrations of 75.7% was observed 7.7 ± 5.4 hours after the end of hemodialysis. Thus, hemodialysis does not result in clinically significant alterations in the disposition of nalmefene or its primary metabolite, nalmefene glucuronide. These data suggest that there is no pharmacokinetic basis for modification of the initial dosage, but maintenance doses, if needed, should be administered less frequently due to the prolonged elimination of the active moiety, nalmefene.
The Effect of Orlistat, an Inhibitor of Dietary Fat Absorption, on the Pharmacokinetics of β‐Carotene in Healthy Volunteers
Authors: Zhi Jianguo , Melia Angela T. , Koss‐Twardy Susan G. , Arora Sujata , Patel Indravadan H.
Published: March 2013

To assess the influence of orlistat, a lipase inhibitor, on the absorption of β‐carotene, an open‐label, parallel, placebo‐controlled, randomized, two‐way crossover study was performed in 48 healthy volunteers between the ages of 19 and 58 years. Each subject received a single oral dose of 0, 30, 60, or 120 mg β‐carotene (12 subjects per dose level) on the fourth day of treatment with orlistat (120 mg) or placebo 3 times a day for 6 days. The treatments were separated by a washout period of at least 5 weeks. Serial blood samples were collected before and at appropriate intervals after administration of β‐carotene to determine plasma concentrations of unchanged β‐carotene. Short‐term (3 to 6 days) treatment with orlistat did not alter endogenous profiles of β‐carotene in plasma. When β‐carotene was given during orlistat treatment, its absorption was reduced by approximately one‐third. This reduction was consistent for all three dose levels of β‐carotene studied; however, the results for the 30‐mg dose level were subject to greater variability, particularly for area under the concentration—time curve (AUC). It was concluded that two thirds of a supplemental dose of β‐carotene will be absorbed during orlistat treatment; this may be sufficient to achieve physiologic levels of β‐carotene with an appropriate dose of β‐carotene, should supplementation be needed in obese patients who have developed β‐carotene deficiency during therapy with orlistat.
Assessment of Pharmacokinetic and Pharmacodynamic Drug Interactions between Nefazodone and Digoxin in Healthy Male Volunteers
Authors: Dockens Randy C. , Greene Douglas S. , Barbhaiya Rashmi H.
Published: March 2013

The effect of nefazodone on pharmacokinetic and pharmacodynamic parameters of digoxin were evaluated in an open, randomized, multiple‐dose, three‐way crossover study of 18 healthy male volunteers. The volunteers received nefazodone alone (200 mg twice daily), digoxin alone (0.2 mg daily), or nefazodone combined with digoxin during three 8‐day treatment periods, with a single dose on the ninth day. There was a 10‐day washout period between treatment periods. Coadministration of nefazodone with digoxin had no effect on the frequency and severity of adverse events compared with those observed with either drug alone. Steady‐state area under the concentration—time curve (AUC) and peak (Cmax) and trough (Cmin) concentrations of digoxin were significantly higher (15%, 29%, and 27%, respectively) after coadministration of nefazodone/digoxin than after administration of digoxin. Despite these increases, no clinically significant changes in vital signs, heart rate, or PR, QRS, and QT intervals on the electrocardiogram occurred after coadministration from those measured after digoxin monotherapy. Coadministration did not affect the pharmacokinetics of nefazodone or its metabolites (hydroxynefazodone, m‐chlorophenylpiperazine, triazole dione). Because digoxin has a narrow therapeutic index, monitoring of plasma digoxin levels and appropriate adjustment of dosage are recommended when nefazodone and digoxin are administered concurrently.
Pharmacokinetic Interaction Between Multiple‐Dose Venlafaxine and Single‐Dose Lithium
Authors: Troy Steven M. , Parker Vernon D. , Hicks David R. , Boudino F. Douglas , Chiang Soong T.
Published: March 2013

Venlafaxine is a structurally novel antidepressant. Because lithium and antidepressants may be administered concomitantly, it is important to determine whether the disposition of venlafaxine and lithium is affected by coadministration. An open‐label study was conducted to evaluate the effects of multiple‐dose, steady‐state venlafaxine administration on the pharmacokinetics of a single oral dose of lithium. Analogously, the effects of administration of a single‐dose of lithium on the disposition of venlafaxine and its active metabolite, O‐desmethylvenlafaxine, after multiple‐dose administration of venlafaxine were assessed. Administration of 600 mg lithium carbonate did not affect venlafaxine absorption. Lithium significantly reduced the renal clearance of venlafaxine from 0.053 to 0.027 L/h/kg. However, renal excretion is not a major elimination pathway for venlafaxine; thus, lithium did not affect the total clearance of venlafaxine. Lithium administration had similar effects on elimination of O‐desmethylvenlafaxine. Multiple‐dose administration of 50 mg of venlafaxine every 8 hours produced a slight increase in the rate of lithium absorption, but did not affect the extent of lithium absorption. Total clearance (0.026 L/h/kg) and steady‐state volume of distribution (0.71 L/kg) of lithium were not affected by administration of venlafaxine. Thus, there were no clinically significant pharmacokinetic interactions between venlafaxine and lithium.
Treating Elevated Cholesterol Levels: The Great Satan in Perspective
Authors: Gibaldi Milo , Kradjan Wayne
Published: March 2013

The purpose of this review is to provide perspective on the developments leading to the recognition of high cholesterol levels as a risk factor for coronary heart disease (CHD). Another objective is to consider the unfolding controversies regarding the relative value of cholesterol‐lowering drug therapy in primary and secondary prevention. Should physicians use lipid‐lowering drugs to treat patients with elevated cholesterol levels but no clinical evidence of coronary disease, or limit intervention to patients with a previous history of angina, coronary angioplasty, coronary artery bypass surgery, or myocardial infarction? This review finds inadequate data to support a recommendation for screening large populations for the presence of elevated cholesterol levels or for primary prevention in those known to have high cholesterol. On the other hand, there is mounting evidence to support vigorous intervention in those with known coronary disease. Further study is needed to determine whether a subset of patients with one or more well‐defined risk factors would benefit from primary prevention.
Pharmacokinetics of Ondansetron in Patients with Hepatic Insufficiency
Authors: Figg William D. , Dukes George E. , Pritchard J. Fred , Hermann David J. , Lesesne Henry R. , Carson Stanley W. , Songer Stephen S. , Powell J. Robert , Hak Lawrence J.
Published: March 2013

Ondansetron is primarily eliminated via hepatic metabolism; thus, liver disease may affect its clearance. The pharmacokinetics of ondansetron in patients with different degrees of hepatic insufficiency (N = 12 with hepatic impairment, as categorized by Pugh's classification method) were assessed and the results compared with results for age‐ and gender‐matched control subjects with normal liver function (n = 12). A secondary objective was to correlate the Pugh method of assessing hepatic impairment and quantitative metabolic markers used to assess hepatic function (antipyrine clearance and indocyanine green clearance) with changes in the pharmacokinetics of ondansetron. This was an open‐label study in which 8 mg ondansetron was given orally and intravenously, following a randomized crossover design. Clearance of ondansetron was lower among patients with hepatic impairment than control subjects. After a single, oral dose of ondansetron, mean absolute bioavailability increased markedly with increased hepatic insufficiency (approaching 100% in the group with severe hepatic impairment versus 66% for control subjects). These data suggest that there is a reduced first‐pass effect in patients with liver disease resulting in a higher AUC0‐∞. A correlation existed between clearance of ondansetron and decreased antipyrine clearance; a smaller correlation existed between ondansetron clearance and indocyanine green clearance. Mean percent of ondansetron bound to plasma proteins was significantly lower in patients with liver disease than in control subjects. None of the patients experienced any severe adverse reactions attributed to ondansetron. A reduction in the clearance of ondansetron is associated with increasing degrees of hepatic insufficiency; therefore, patients with severe hepatic impairment (Pugh score of>9) should have their daily dose of ondansetron limited to 8 mg (or 0.15 mg/kg).
The Effects of Epoprostenol on Drug Disposition II: A Pilot Study of the Pharmacokinetics of Furosemide with and without Epoprostenol in Patients with Congestive Heart Failure
Authors: Carlton Lisa D. , Patterson J. Herbert , Mattson Craig N. , Schmith Virginia D.
Published: March 2013

The effect of epoprostenol on the pharmacokinetics of furosemide was investigated in 23 patients with end‐stage congestive heart failure (CHF) receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of the apparent oral clearance, volume of distribution, and absorption rate constant for furosemide were generated from 198 serum furosemide concentrations using nonlinear mixed effects modeling (NONMEM). Univariate analyses were performed to assess the effects of patient factors on the apparent oral clearance of furosemide. The final multivariate model determined by backwards elimination included concomitant digoxin therapy. When concomitant epoprostenol therapy was included in the final model, there was a 13% decrease in the apparent oral clearance of furosemide in response to short‐term administration of epoprostenol. However, the effect of concomitant epoprostenol therapy was not statistically significant and was no longer apparent by the end of the 12‐week study. These data suggest that epoprostenol may have a slight short‐term effect on the pharmacokinetics of furosemide; the interaction between epoprostenol and furosemide is not clinically significant, however.
Grapefruit Juice Alters the Systemic Bioavailability and Cardiac Repolarization of Terfenadine in Poor Metabolizers of Terfenadine
Authors: Honig Peter K. , Wortham Dale C. , Lazarev Alexander , Cantilena Louis R.
Published: March 2013

A prospective cohort study was conducted to examine the effects of double‐strength grapefruit juice on the pharmacokinetics and electrocardiographic repolarization pharmacodynamics of terfenadine in poor metabolizers of terfenadine. Six healthy volunteers who were previously found to be poor metabolizers of terfenadine were studied, with each participant serving as his or her own control. In phase I of the study, terfenadine was given to participants at recommended dosages until steady state was achieved (60 mg twice daily for 7 days). In phase II, participants began receiving concomitant twice‐daily, double‐strength servings of grapefruit juice for 7 days. Serial pharmacokinetic and pharmacodynamic determinations were made after each phase of the study. The main outcome measures were serum concentrations of terfenadine and terfenadine acid metabolite, and corrected QT intervals as determined by 12‐lead electrocardiogram. Significant changes occurred in time to maximum concentration (tmax) and area under the concentration‐time curve (AUC) of terfenadine and terfenadine acid metabolite after addition of grapefruit juice. All participants had detectable concentrations of unmetabolized terfenadine at the end of Phase I, which were quantified in three of the six participants. Further, all participants had increased and quantifiable levels of unmetabolized terfenadine after addition of grapefruit juice that were associated with prolongation of the QT interval relative to the baseline control period without terfenadine. Grapefruit juice did not alter the elimination half‐life (t1/2) of terfenadine acid metabolite. Because of the intraindividual variability in the pharmacokinetics of terfenadine, further study is needed to confirm these results.
Hypotensive Mechanisms of Amifostine
Authors: Ryan Sean V. , Carrithers Stephen L. , Parkinson Scott J. , Skurk Carsten , Nuss Charles , Pooler Patricia M. , Owen Charles S. , Lefer Allan M. , Waldman Scott A.
Published: March 2013

Amifostine, a chemo‐ and radioprotective agent developed as adjunctive therapy for malignancies, induces hypotension after ∼20% of patient administrations. This study examines the molecular mechanisms underlying hypotension induced by amifostine. Amifostine and its metabolite, WR‐1065, induced dose‐dependent hypotension in anesthetized rats that was not blocked by NG‐methyl L arginine (L‐NAME), an NO synthase inhibitor. WR‐1065 but not amifostine induced concentration‐dependent relaxation of isolated rat aortic rings in an endothelium‐independent fashion. Relaxation was not associated with increases in cGMP or cAMP and could not be blocked by L‐NAME or indomethacin. Similarly, neither amifostine or WR‐1065 activated adenylyl, particulate guanylyl, or soluble guanylyl cyclases. WR‐1065 relaxed rat aortic rings precontracted with norepinepherine, suggesting α‐adrenergic blocking activity. However, neither amifostine nor WR‐1065 altered the ability of prazosin or phentolamine to bind to α‐adrenergic receptors. Further, WR‐1065 had no effect on receptor‐mediated increases in intracellular calcium in BAL 17 murine B lymphocytes in vitro. Thus, hypotension after administration of amifostine is mediated by WR‐1065 and appears to result from direct relaxation of vascular smooth muscle. Smooth muscle relaxation induced by WR‐1065 is not related to production of nitric oxide, prostaglandins, or cyclic nucleotides; α‐adrenergic receptor antagonism; or interference with receptor‐dependent increases in intracellular calcium. Administration of ephedrine, an efficacious adrenergic agonist, attenuated hypotension induced by amifostine in anesthetized rats and may be useful in alleviating hypotension associated with amifostine administration in patients.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Neurotherapeutics: Emerging Strategies. LM Pullan, J Patel, Editors.

Oral Cephalosporins. RC Moellering, Jr., Editor.

Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition. B Spilker, Editor.

The Peroxisome: A Vital Organelle. C Masters, D Crane, Editors.

Pharmaceutical Powder Compaction Technology. G Alderborn, C Nystrom, Editors.
Nicorandil: A Potassium Channel Opening Drug for Treatment of Ischemic Heart Disease
Authors: Goldschmidt Marc , Landzberg Brian R. , Frishman William H.
Published: March 2013

Nicorandil is the first oral potassium channel activating drug to be used for the treatment of symptomatic coronary artery disease. It appears to relax vascular smooth muscle through membrane hyperpolarization via increased transmembrane potassium conductance and, like nitrates, through an increase in intracellular cyclic GMP. In addition, nicorandil, in a nitrate‐like manner, dilates normal and stenotic coronary arteries and reduces both ventricular preload and afterload. In contrast to nitrates, however, nicorandil does not appear to cause tolerance with long‐term administration. In placebo and comparison clinical trials, nicorandil has demonstrated some efficacy and safety in patients with both stable and vasospastic angina pectoris, and it was found to be a myocardial protective agent in animal studies. The antianginal activity of nicorandil, however, is relatively short lived after dosing, which will necessitate the development of extended‐release formulations of the drug.
Analgesic Efficacy of Controlled‐Release Oxycodone in Postoperative Pain
Authors: Sunshine Abraham , Olson Nancy Z. , Colon Ariel , Rivera Juana , Kaiko Robert F. , Fitzmartin Ronald D. , Reder Robert F. , Goldenheim Paul D.
Published: March 2013

The efficacy and safety of graded doses (10, 20, and 30 mg) of controlled‐release (CR) oxycodone was compared with that of immediate‐release (IR) oxycodone (15 mg), immediate‐release oxycodone 10 mg in combination with acetaminophen 650 mg (APAP), and placebo in a single‐dose, double‐blind, randomized, parallel‐group study. The participants, 182 inpatients experiencing moderate to severe pain after abdominal or gynecologic surgery, provided hourly ratings of pain intensity and relief for 12 hours after administration. All active treatments were significantly superior to placebo for many hourly measurements and for the sum of pain intensity differences (SPID) and total pain relief (TOTPAR). A dose response was found among the three levels of CR oxycodone for pain relief and peak pain intensity difference (PID), with the 20‐ and 30‐mg doses being significantly better than the 10‐mg dose. For all active treatments, peak PID and peak pain relief occurred approximately 2 to 4 hours after administration. The median time to onset of relief was 32 minutes for oxycodone plus APAP, 41 minutes for IR oxycodone, and 46 minutes for CR oxycodone 30 mg. Duration of pain relief showed that the 10‐, 20‐, and 30‐mg doses of CR oxycodone had durations of action of 10 to 12 hours compared with IR oxycodone and oxycodone plus APAP (both approximately 7 hours). Typical adverse events, particularly somnolence, occurred in all active treatment groups. Treatment with CR oxycodone was safe and effective in this study, and its characteristics will be beneficial in the treatment of pain.
Pharmacokinetic and Pharmacodynamic Comparisons of Twice Daily and Four Times Daily Formulations of Procainamide in Patients with Frequent Ventricular Premature Depolarization
Authors: Yang Bing‐Bing , Abel Robert B. , Uprichard Andrew C. G. , Smithers Jacquelyn A. , Forgue S. Thomas
Published: March 2013

A study was conducted to evaluate the pharmacokinetics of procainamide and its active metabolite, N‐acetylprocainamide (NAPA), as a function of dose and formulation and to characterize the relationship between ventricular premature depolarization (VPD) rate and plasma concentrations of procainamide and NAPA. A subset of patients (n = 43) with frequent VPD who were enrolled in a double‐blind, multicenter, activity trial were assigned in randomized fashion to receive 1 of 4 dose levels (placebo or 1,000, 2,000, or 4,000 mg/day procainamide) and to receive Procanbid (Parke‐Davis) tablets every 12 hours or Procan SR (Parke‐Davis) tablets every 6 hours during the first week of a blinded crossover phase. Patients crossed over to the alternative formulation after one week. Maximum and steady‐state average concentrations of procainamide and NAPA after administration of Procanbid tablets were equivalent to those after administration of an equivalent daily dose of Procan SR tablets. Corresponding trough concentrations of procainamide were lower after administration of Procanbid tablets than after administration of Procan SR tablets. Both formulations produced disproportionate increases in procainamide concentrations with increasing dose; concentrations of NAPA increased in proportion to dose. Assessment of the relationship between VPD rate and drug concentration in plasma indicated no substantive difference between the two formulations. It was concluded that administration of Procanbid tablets every 12 hours is essentially equivalent to administration of procainamide extended‐release tablets (Procan SR) every 6 hours with respect to pharmacokinetics of procainamide and NAPA and to VPD suppression.
The Effect of Orlistat, an Inhibitor of Dietary Fat Absorption, on the Absorption of Vitamins A and E in Healthy Volunteers
Authors: Melia Angela T. , Koss‐Twardy Susan G. , Zhi Jianguo
Published: March 2013

An open‐label, placebo‐controlled, randomized, two‐way crossover study was performed in 12 healthy volunteers (between 20 and 44 years of age) to assess the effect of orlistat, a gastrointestinal lipase inhibitor that reduces dietary fat absorption and is being developed for weight control in obesity, on the absorption of vitamins A and E. Each participant received a single oral dose of 25,000 IU vitamin A followed 24 hours later by a single oral dose of 400 IU vitamin E on two separate occasions: during oral administration of 120 mg orlistat or placebo three times daily for 9 days. The two treatments were separated by a washout period of at least 2 weeks. Serial blood samples for pharmacokinetic analysis were collected at specified times over 24 hours after each dose of vitamin A for determination of serum concentrations of retinol, and over a period of 5 days after each dose of vitamin E for determination of serum concentrations of α‐tocopherol, total cholesterol, and triglycerides. Orlistat significantly reduced the absorption of vitamin E (∼43% according to maximum concentration and ∼60% according to area under the concentration‐time curve), but not that of vitamin A, at the dose levels studied. The results of this study will aid in the implementation of a vitamin supplementation strategy, should vitamin deficiency occur in patients undergoing orlistat therapy.
A Comparison of the Antihypertensive Effectiveness of a Combination of Moexipril or Sustained‐Release Verapamil with Low‐Dose Hydrochlorothiazide
Authors: Chrysant Steven G. , Stimpel Michael
Published: March 2013

The antihypertensive effectiveness of moexipril, a new angiotensin‐converting enzyme (ACE) inhibitor, and sustained‐release verapamil (verapamil SR) in combination with low‐dose hydrochlorothiazide was investigated in patients with moderate to severe (Stages II and III) essential hypertension. Of 147 patients treated for 4 weeks with hydrochlorothiazide 25 mg/day, 108 patients with sitting diastolic blood pressure (SDBP) of 100 to 114 mmHg were randomly assigned to receive either moexipril 7.5 mg/day (n = 56) or verapamil SR 180 mg/day (n = 52) in addition to hydrochlorothiazide 25 mg/day. After 4 weeks of treatment, doses of moexipril or verapamil SR were increased to 15 and 240 mg/day respectively for patients with SDBP of ≥90 mmHg. These patients were evaluated for an additional 8 weeks. Electrocardiograms, blood chemistries, blood counts, urinalysis, plasma renin activity, and plasma aldosterone levels were monitored during the study. Moexipril or verapamil SR, in combination with low dose hydrochlorothiazide, resulted in decreased blood pressure in the sitting and standing positions. No correlation between blood pressure response and baseline plasma renin activity was demonstrated. The results of this study indicate that both moexipril and verapamil SR produced an additive hypertensive effect when added to low‐dose hydrochlorothiazide. These combinations were well tolerated by the patients and did not result in serious clinical and metabolic side effects.
Tolerance and Pharmacokinetics of Single‐Dose Atorvastatin, a Potent Inhibitor of HMG‐CoA Reductase, in Healthy Subjects
Authors: Posvar Edward L. , Radulovic Louis L. , Cilla Donald D. , Whitfield Lloyd R. , Sedman Allen J.
Published: March 2013

Tolerance and pharmacokinetics after single‐dose administration of atorvastatin, an investigational inhibitor of HMG‐CoA reductase, were examined in 22 healthy volunteers in a three‐period, partially‐blinded study. Participants received capsule and solution doses of atorvastatin (0.5 to 120 mg) and placebo at weekly intervals. Atorvastatin was well tolerated at doses as high as 80 mg. The adverse event profile was similar after administration of atorvastatin capsules and placebo. Atorvastatin solution was slightly less well tolerated. The most common side effect after administration of capsules and solution was headache, followed by sporadic reports of diarrhea, flatulence, and nausea. At the 120‐mg solution dose, one participant experienced mild, transient restlessness, euphoria, and mental confusion that were considered to be dose‐limiting side effects. Mean concentrations of atorvastatin, maximum concentration (Cmax), and area under the concentration—time curve from time 0 to the time of the last detectable concentration (AUC0‐tldc) increased with increasing dose. Plasma elimination half‐life (t1/2) ranged from 14.7 to 57.6 hours. The bioavailability of atorvastatin capsules was similar to that of solution. These results suggest that atorvastatin is well tolerated after single doses as high as 80 mg, and may require administration only once daily.
Midazolam Hydroxylation by Human Liver Microsomes In Vitro: Inhibition by Fluoxetine, Norfluoxetine, and by Azole Antifungal Agents
Authors: von Moltke Lisa L. , Greenblatt David J. , Schmider Jürgen , Duan Su Xiang , Wright C. Eugene , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Biotransformation of the imidazobenzodiazepine midazolam to its α‐hydroxy and 4‐hydroxy metabolites was studied in vitro using human liver microsomal preparations. Formation of α‐hydroxy‐midazolam was a high‐affinity (Km = 3.3 μmol/L) Michaelis‐Menten process coupled with substrate inhibition at high concentrations of midazolam. Formation of 4‐hydroxy‐midazolam had much lower apparent affinity (57 μmol/L), with minimal evidence of substrate inhibition. Based on comparison of Vmax/Km ratios for the two pathways, α‐hydroxy‐midazolam formation was estimated to account for 95% of net intrinsic clearance. Three azole antifungal agents were inhibitors of midazolam metabolism in vitro, with inhibition being largely consistent with a competitive mechanism. Mean competitive inhibition constants (Ki) versus α‐hydroxy‐midazolam formation were 0.0037 μmol/L for ketoconazole, 0.27 μmol/L for itraconazole, and 1.27 μmol/L for fluconazole. An in vitro‐in vivo scaling model predicted inhibition of oral midazolam clearance due to coadministration of ketoconazole or itraconazole; the predicted inhibition was consistent with observed interactions in clinical pharmacokinetic studies. The selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine and its principal metabolite, norfluoxetine, also were inhibitors of both pathways of midazolam biotransformation, with norfluoxetine being a much more potent inhibitor than was fluoxetine itself. This finding is consistent with results of other in vitro studies and of clinical studies, indicating that fluoxetine, largely via its metabolite norfluoxetine, may impair clearance of P450‐3A substrates.
Teaching Healthcare Professionals About Drug‐Induced Disease: An Innovative Clinical Therapeutic Approach
Authors: Goldman Stephen A. , Lieberman Ronald , Kausal David J.
Published: March 2013

An innovative conference on the general principles of recognition and management of drug‐induced disease was developed for healthcare professionals (particularly primary care). The full‐day conference used a clinical therapeutic approach and was a cooperative effort of the United States Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) Staff College and Georgetown University Medical Center (GUMC). Linked with the FDA MedWatch postmarketing surveillance initiative, the conference used multiple formats, including didactic presentations, panel discussions, and case discussions led by faculty from various disciplines (e.g., internal and family medicine, psychiatry, clinical pharmacology, dentistry, clinical pharmacy, nursing, epidemiology). Conference topics included new drug approval, pharmacokinetic/pharmacodynamic considerations, and clinical assessment of adverse drug events. Tests were administered to participants before and after the conference, and participants completed a conference evaluation. Mean scores for the pre‐ and posttests were compared globally and by professional discipline. Conference evaluations were assessed for responses to eight standardized statements and elicited comments. After the conference, mean and median test scores were improved both globally and by discipline in comparison to pretest results, with improvement on almost all individual test questions. Comparison of median scores for the pre‐ and posttests showed small differences between physicians and pharmacists. Evaluations showed markedly positive response to standardized statements, including enhancement of professional growth; elicited comments were supportive of conference effectiveness and attendee acceptance. This conference, which utilized a combination of educational formats, was designed to present material of an innovative nature. Results indicate that the conference was well‐received and fulfilled specified learning objectives, including recognition of populations particularly vulnerable to adverse drug events and understanding of how individual providers can contribute to FDA postmarketing surveillance. Continuing educational efforts using this approach are encouraged.
Clinical Pharmacology of Multiple‐Dose Losartan, an Angiotensin II Receptor Antagonist, in Patients with Essential Hypertension
Authors: Sasaki Masato , Fujimura Akio , Harada Kazuhiro , Sunaga Ken‐ichiro , Ebihara Akio
Published: March 2013

The pharmacokinetic and pharmacodynamic alterations of multiple doses of losartan, an angiotensin II receptor antagonist, were examined in nine patients with essential hypertension. Participants were given placebo once daily for the first 7 days (from day −7 to day −1), and then 50 mg of losartan for the next 9 days (from day 1 to day 9). The 24‐hour blood pressure was measured on days −1, 1, and 7 and blood samples for measurement of losartan and its active metabolite, E‐3174, were obtained on days 1 and 7. Plasma concentrations of uric acid and plasma clearance were determined before and during treatment with losartan, and at the end of the study. Pharmacokinetic parameters after the seventh dose, including maximum plasma concentration (Cmax and time to Cmax (tmax) of losartan and E‐3174, did not differ significantly from those after the first dose. The blood pressure lowering effect of losartan, however, was significantly greater after the seventh dose than after the first dose. Plasma uric acid decreased and its plasma clearance (ClUA) increased significantly during repeated administration with losartan. These values returned to pretreatment levels after the end of treatment. These results suggest that although the pharmacokinetic profiles of losartan and E‐3174 do not change during repeated administration, the blood pressure lowering effect in hypertensive patients is greater after multiple doses than after a single dose.
Vesnarinone‐Induced Granulocytopenia: Incidence in Japan and Recommendations for Safety
Authors: Furusawa Shinpei , Ohashi Yasuo , Asanoi Hidetsugu
Published: March 2013

Vesnarinone (OPC‐8212) is a new positive inotropic agent that augments myocardial contractility. A recent multi‐center randomized trial in the United States demonstrated that 60 mg/day of vesnarinone significantly reduced morbidity and mortality and improved quality of life in patients with symptomatic chronic heart failure. Vesnarinone, however, is also known for its propensity to cause granulocytopenia. In search of effective safety measures against this side effect, data have been collected in Japan as part of the post‐marketing surveillance of this drug. This article reviews the results of this post‐marketing surveillance and other works available to date, including an illustrative case report, and presents measures that should be taken with regard to safety during treatment with vesnarinone. Vesnarinone‐induced granulocytopenia has appeared in relatively early stages of vesnarinone therapy, and characteristically results in a rapid decrease in granulocyte count. Hematologic monitoring should be performed at least once a week during the initial 16 weeks of vesnarinone therapy. Granulocyte colony‐stimulating factor may contribute to recovery from severe granulocytopenia, although it should be used carefully because of its potential to cause adult respiratory distress syndrome.
Enantioselective Assays in Comparative Bioavailability Studies of Racemic Drug Formulations: Nice to Know or Need to Know?
Authors: Karim Aziz
Published: March 2013

The importance of enantiospecific assays in studying pharmacokinetic/pharmacodynamic (PK/PD) and drug‐drug interactions of racemic drugs is widely recognized. Use of such assays in comparative bioavailability studies, however, remains controversial. This commentary proposes a PK/PD‐based rationale for deciding whether an enantioselective assay is important in such studies. Racemic drugs are divided into three major categories: those with negligible or nonenantioselective first‐pass metabolism (category I), those where the first‐pass metabolism of the less‐active enantiomer is predominant (category II), and those where the first‐pass metabolism of the more active and/or toxic enantiomer is predominant (category III). In addressing the need for assay selectivity, a simple analogy is made between these drug categories and the protein‐binding phenomenon. Enantioselective assays are not essential for category I drugs, or for category II drugs in the majority of cases. A special consideration, however, is needed for those category II drugs that undergo racemic inversion that may be influenced by the dose level and/or the residence time of the drug formulation in the gastrointestinal tract. It is with category III drugs that enantioselective assays become important, especially when metabolism, distribution, and/or elimination processes of the active or toxic enantiomer are saturable, leading to variable enantiomeric ratios in the plasma. Factors contributing to these ratio changes include routes of administration, dose level, and input rate differences. Input rate differences are particularly relevant to bioavailability evaluation of category III drugs.
Calculation of Inversion Half‐Lives of Aryl Propionic Acid Class Nonsteroidal Antiinflammatory Drugs
Authors: Kantoci Darko , Wechter William J.
Published: March 2013

Although inversion of the R‐enantiomers of the aryl propionic acid (APA) class of nonsteroidal antiinflammatory drugs (NSAIDs) in humans and other mammals has been known for more than 20 years, no satisfactory method has been developed for evaluating the half‐life of the inversion process. This parameter is useful in assessing the pharmacodynamic contribution of the R‐prodrug to the cyclooxygenase‐inhihiting S‐enantiomers. Further, it provides a similar means of evaluating the analgesic contribution of R‐enantiomers to racemic mixtures. Using human and animal data, we have mathematically determined the inversion half‐life (t1/2i) for ibuprofen, ketoprofen, and fenoprofen. The relation of the sensitivity of this value to the terminal half‐life (t1/2) of the R‐enantiomers of APA class drugs also is discussed.
Antiproliferative Effects of the Enantiomers of Flurbiprofen
Authors: McCracken John D. , Wechter William J. , Liu Youjiang , Chase Resa L. , Kantoci Darko , Murray E. David , Quiggle David D. , Mineyama Yoshimitzu
Published: March 2013

Nonsteroidal antiinflammatory drugs (NSAIDs) are recognized for inhibiting growth of colon tumors in animal models, and for reducing the risk of colon cancer in humans. The mechanisms involved have not been established, but are thought to be related to reduced prostaglandin biosynthesis. The present study investigates the effect of COX‐inhibiting and non‐COX‐inhibiting enantiomers of flurbiprofen on rat colonocyte proliferation. Intestinal ulceration was used as a surrogate indicator of COX inhibition. Sprague Dawley rats were treated orally with 6.3 mg/kg of R‐ or S‐flurbiprofen or vehicle. Colonocyte labeling index and small bowel ulcer index were measured. R‐flurbiprofen and S‐flurbiprofen significantly reduced colonocyte labeling index, by 34% and 23% respectively, compared with vehicle. R‐flurbiprofen caused minimal ulcer formation (4.48 mm2) compared with S‐flurbiprofen (94.4 mm2). These findings suggest that R‐flurbiprofen‐mediated control of colonocyte proliferation is independent of prostaglandin biosynthesis.
Pharmacokinetic/Pharmacodynamic Evaluation of Systemic Effects of Flunisolide after Inhalation
Authors: Möllmann Helmut , Derendorf Hartmut , MD Jürgen Barth , Meibohm Bernd , Wagner Melanie , Krieg Michael , Weisser Heike , Knöller Jürgen , Möllmann Anja , Hochhaus Günther
Published: March 2013

The pharmacokinetics and pharmacodynamics of flunisolide were studied in healthy volunteers after inhalation. In the morning on the day the study began, volunteers inhaled 0.5 mg of flunisolide with and without oral administration of charcoal, or 1 mg, 2 mg, and 3 mg of flunisolide with concomitant administration of charcoal. A placebo group was used to assess the endogenous cortisol, granulocyte, and lymphocyte baseline levels. Flunisolide plasma levels were determined by high‐performance liquid chromatography using a tandem mass spectrometer as detector (HPLC/MS/MS). Cortisol plasma levels and differential white blood cell counts were obtained over 12 hours. An integrated pharmacokinetic/pharmacodynamic (PK/PD) model was applied to link the flunisolide plasma concentrations with the effects on lymphocytes, granulocytes, and cortisol. Maximum concentration levels of 3 to 9 ng/mL of flunisolide were observed after 0.2 to 0.3 hours for all of the investigated doses. The terminal half‐life ranged from 1.3 to 1.7 hours. There was no statistical difference between treatments in the presence or absence of orally administered charcoal. The pharmacokinetic/pharmacodynamic (PK/PD) models satisfactorily described the time‐courses of the effects on granulocytes, lymphocytes, and cortisol suppression. The resulting E50‐values (concentrations to induce 50% of the maximum effect) concurred with the reported values of in vitro receptor binding affinities. The duration of the systemic effects were short because of the short half‐life of the drug. Cumulative cortisol suppression increased with dose administration and ranged from 20% to 36%. The PK/PD simulations resulted in a smaller degree of cortisol suppression for the drug administered at 10 pm. The cumulative change from baseline was slightly smaller for the effects on granulocytes and lymphocytes than those on cortisol. This information promotes the comparison with other inhaled glucocorticoids. J Clin Pharmacol 1997;37:893–903.
Analgesic Efficacy of a Hydrocodone with Ibuprofen Combination Compared with Ibuprofen Alone for the Treatment of Acute Postoperative Pain
Authors: Sunshine Abraham , Olson Nancy Z. , O'Neill Edward , Ramos Irma , Doyle Ralph
Published: March 2013

Hydrocodone is a semisynthetic opioid with analgesic and antitussive properties qualitatively similar to other opioid agonists. Ibuprofen is a nonsteroidal antiinflammatory agent with analgesic and antipyretic activity and is an effective, primarily peripheral acting antiinflammatory analgesic. The objective of this clinical trial was to determine the additive analgesic effect of the combination of 15 mg hydrocodone bitartrate with 400 mg ibuprofen, relative to 400 mg ibuprofen alone and placebo, in the treatment of postoperative pain. The single‐dose analgesic efficacy of the combination of hydrocodone bitartrate with ibuprofen was compared with ibuprofen alone and placebo in 120 patients with moderate or severe postoperative pain after abdominal surgery. Analgesia was measured during the 6‐hour period after dosing based on onset of relief, hourly and summary variables, and duration of effect. A significantly greater proportion of patients treated with the hydrocodone/ibuprofen combination reported onset of relief compared with ibuprofen or placebo; however, the distribution functions for time to onset of relief did not differ among treatments. Hydrocodone with ibuprofen and ibuprofen alone were significantly more effective than placebo for all measures of analgesia. The combination of hydrocodone with ibuprofen was significantly superior to ibuprofen for all hourly analgesic evaluations, weighted sum of pain intensity differences (SPID), total pain relief (TOTPAR), and global rating of study medication. No patients in the hydrocodone with ibuprofen group required analgesic remedication during the 6‐hour study period, compared with 25% and 82% in the ibuprofen and placebo groups, respectively. The analgesic superiority of 15 mg hydrocodone bitartrate combined with 400 mg ibuprofen compared with 400 mg ibuprofen alone was demonstrated across many efficacy variables. J Clin Pharmacol 1997;37:908–915.
Pharmacokinetics of Dolasetron after Oral and Intravenous Administration of Dolasetron Mesylate in Healthy Volunteers and Patients with Hepatic Dysfunction
Authors: Stubbs Katherine , Martin Lorene A. , Dimmitt Dan C. , Pready Nick , Hahne William F.
Published: March 2013

In previous studies, dolasetron was shown to have both renal and hepatic elimination mechanisms. This study was conducted to determine the impact of varying degrees of hepatic dysfunction on the pharmacokinetics and safety of dolasetron and its reduced metabolites. Seventeen adults were studied: six healthy volunteers (group I), seven patients with mild hepatic impairment (Child‐Pugh class A; group II), and four patients with moderate to severe hepatic impairment (Child‐Pugh class B or C1; group III). Single 150‐mg doses of dolasetron mesylate were administered intravenously and orally, with a 7‐day washout period separating treatments. After intravenous administration, no differences were observed between healthy volunteers and patients with hepatic impairment in maximum plasma concentration (Cmax), areas under the plasma concentration—time curve (AUC), or elimination half‐life (t1/2) of intact dolasetron. No significant differences were found in Cmax, AUC, or apparent clearance (Clapp) of hydrodolasetron, the primary metabolite of dolasetron. The mean t1/2 increased from 6.87 hours in group I to 11.69 hours in group III. After oral administration, Clapp of hydrodolasetron decreased by 42%, and Cmax increased by 18% in patients with moderate to severe hepatic impairment. There were less changes in patients with mildly hepatic impairment. Total percentage of dose excreted as metabolites was similar for healthy volunteers and patients with hepatic impairment, although urinary metabolite profiles differed slightly. Dolasetron was well tolerated and there were no apparent differences in adverse effects between groups or treatments. Because hepatic impairment did not influence Clapp of hydrodolasetron after intravenous administration, and the range of plasma concentrations of hydrodolasetron after oral administration was not different from those observed in healthy volunteers, dosage adjustments are not recommended for patients with hepatic disease and normal renal function. J Clin Pharmacol 1997;37:926–936.
The Effects of Age and Gender on the Single Dose Pharmacokinetics of Avitriptan Administered to Healthy Volunteers
Authors: Marathe Punit H. , Greene Douglas S. , Kollia Georgia D. , Barbhaiya Rashmi H.
Published: March 2013

The effects of age and gender on the single dose pharmacokinetics of avitriptan and its three metabolites were assessed in 15 young men, 15 young women, 15 elderly men and 15 elderly women. Avitriptan was administered as a 150‐mg capsule after a 10‐hour fast and serial plasma and urine samples were collected up to 36 hours after the dose. Plasma samples were analyzed for avitriptan and its metabolites, N‐desmethyl avitriptan (ND048), O‐desmethyl avitriptan (OD048), and methoxypyrimidinyl piperazine (MPP). Urine samples were analyzed for only avitriptan and MPP. Avitriptan was well tolerated in all four groups. The drug was rapidly absorbed with a median time to maximum plasma concentration (tmax) between 0.5 and 1.5 hours. No significant gender‐related differences were found in the maximum plasma concentration (Cmax) and area under the concentration—time curve extrapolated to infinity (AUC0‐∞) of avitriptan. Renal clearance of avitriptan was significantly smaller in young women compared with young men, but this is clinically not relevant because only 2% to 3% of the total dose is excreted unchanged. Compared with the young volunteers, mean Cmax was approximately 50% higher in the elderly but there was no difference in the AUC0‐∞ between the 2 age groups. Plasma concentrations of ND048, OD048, and MPP were each 50 to 100 fold lower than those of avitriptan. Hence some age‐ and gender‐related differences found in the pharmacokinetics of avitriptan metabolites are probably not relevant in the assessment of overall safety and efficacy of avitriptan. Based on the pharmacokinetics and tolerability, no age or gender‐related dose adjustment is necessary for avitriptan. J Clin Pharmacol 1997;37:937–945.