bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of Venodilatory Effect of Amrinone and Theophylline In Human Subjects
Authors: Harada Kazuhiro , Ohashi Kyoichi , Kumagai Yuji , Fujimura Akio
Published: March 2013

Amrinone, a positive inotropic agent, is a selective phosphodiesterase III inhibitor and exerts vasodilatory effect on venous vessels. The present study was undertaken to compare the venodilatory effect of amrinone and theophylline, a nonselective phosphodiesterase inhibitor, in eight healthy male subjects. In a randomized crossover design, one of these drugs was infused into the dorsal hand vein preconstricted by phenylephrine and its diameter was measured using a linear variable differential transformer. The value of maximum vasodilation for amrinone (mean ± standard deviation, 106% ± 17%) was similar to that for theophylline (mean ± standard deviation, 108% ± 14%). However, the infusion rate of amrinone needed to induce 50% of maximum vasodilation was significantly less than that of theophylline (25 ±15 μg/minute vs. 192 ± 87 μg/minute, respectively; P < 0.01). These findings suggest that the venodilatory activity of amrinone is more potent than that of theophylline in human subjects.
Pharmacokinetic and Pharmacodynamic Evaluation of Triamcinolone Acetonide After Intravenous, Oral, and Inhaled Administration
Authors: Rohatagi Shashank , Hochhaus Günther , Möllmann Helmut , Barth Jürgen , Galia Eric , Erdmann Martina , Sourgens Hildegard , Derendorf Hartmut
Published: March 2013

Triamcinolone acetonide (TCA) is a corticosteroid that is frequently used in the treatment of asthma. After inhalation, TCA can become systemically available when the inhaled formulation is swallowed, causing undesirable systemic effects. A clinical study was conducted to determine the systemic side effects of TCA after intravenous (2 mg as phosphate ester), oral (5 mg), and inhaled (2 mg) administration. Blood samples were collected at appropriate times over 24 hours, and TCA concentrations in plasma were measured by high‐performance liquid chromatography and radioimmunoassay. Free drug concentrations were determined by ultrafiltration for correlating pharmacokinetics and pharmacodynamics. The free fraction of TCA (± standard deviation) was 29.0 ± 1.3% and was independent of the investigated concentration range up to 1,000 ng/mL. Pharmacodynamic parameters were determined by monitoring lymphocytes, granulocytes, and cortisol. Pharmacokinetic/pharmacodynamic modeling was performed using a modified Emax model for lymphocytes and granulocytes. A novel linear release rate model was used to characterize the cortisol data. The E50 values determined from all three pharmacodynamic endpoints were not significantly different for the three treatments, indicating that these effects can be explained based on systemic steroid concentrations.
The Expanding Role of Angiotensin Converting Enzyme Inhibitors in the Management of Hypertension
Authors: Burris James F.
Published: March 2013

Angiotensin converting enzyme (ACE) inhibitors are increasingly important in antihypertensive therapy because of their efficacy, tolerability, and specific benefits in subsets of patients. They are pharmacologically diverse. Whereas most benefits have been proven with older agents (captopril, enalopril), newer agents, such as benazepril, quinapril, and ramipril, offer potential advantages that remain to be proven.
Cibenzoline Versus Flecainide in the Prevention of Paroxysmal Atrial Arrhythmias: A Double‐Blind Randomized Study
Authors: Babuty D. , D'Hautefeuille B. , Scheck F. , Mycinsky C. , Pruvost P. , Peraudeau P.
Published: March 2013

In a randomized, double‐blind, parallel clinical trial, the authors tested and compared flecainide and cibenzoline, a new antiarrhythmic drug, on atrial arrhythmias. Sixty‐eight patients (36 men, 32 women, mean age 62.5 ± 1.6 years) with documented symptomatic paroxysmal atrial arrhythmias (fibrillation in 56, flutter in 12) were recruited and received either cibenzoline 260 mg/day (n = 33) or flecainide 200 mg/day (n = 35). Patients were assessed with physical examination, resting ECG, 24‐hour ambulatory ECG recording, two‐dimensional echocardiography, and standard biologic titrations before the inclusion day, and 3 months and 6 months after the randomization day. Sixteen patients were withdrawn (7 were lost to follow‐up, 7 had side effects, 2 had another medical event). Seventeen patients had documented recurrence of atrial arrhythmia (9 in the cibenzoline group, 8 in the flecainide group) during the study. The efficacy of cibenzoline and flecainide for preventing recurrence of atrial arrhythmias was not significantly different (62.5% versus 71.4%). Eleven patients complained of one or more side effects (cibenzoline, n = 6; flecainide, n = 5), justifying leaving the trial in 6 cases (cibenzoline, n = 3; flecainide, n = 3). Two ventricular proarrhythmic effects were observed. No atrial proarrhythmic effects were reported. The efficacy of cibenzoline and flecainide for preventing atrial arrhythmia is good and similar during a follow‐up period of 6 months. In view of these results, cibenzoline may be administered first to prevent atrial arrhythmia.
Alpha‐1‐Acid Glycoprotein Concentration and the Protein Binding of Disopyramide in Healthy Subjects
Authors: Kishino Satoshi , Nomura Akikazu , Di Zhai Suo , Sugawara Mitsuru , Iseki Ken , Kakinoki Shigeo , Kitabatake Akira , Miyazaki Katsumi
Published: March 2013

Age‐ and gender‐related changes in serum α1‐acid glycoprotein (AAG) concentration and the serum protein binding of disopyramide were examined after intensive medical examination. Based on the clinical chemistry tests over 51 points, 245 subjects were diagnosed as healthy and 71 subjects (22.5%) revealed an abnormal value for at least one item. In the healthy subjects, serum AAG concentration in men was significantly higher than in women (men, 0.78 ± 0.18 mg/mL, mean ± SD; women, 0.67 ± 0.16 mg/mL). In contrast, there were no significant differences in the AAG concentration between age groups for men and women and in the unbound fraction of disopyramide. Gender changes AAG concentration. Age, however, does not change AAG concentration and the protein binding of the basic drug.
Human Plasma Protein Binding of the Angiotensin II Receptor Antagonist Losartan Potassium (DuP 753/MK 954) and Its Pharmacologically Active Metabolite EXP3174
Authors: Christ David D.
Published: March 2013

The in vitro protein binding characteristics of the prototypical angiotensin II receptor antagonist losartan potassium (DuP 753/MK 954) and its pharmacologically active metabolite EXP3174 were determined by ultrafiltration ivith plasma from naive donors, volunteers dosed with losartan, and purified human plasma proteins. The binding of losartan was high, with a percent unbound (free) of 1.4 ± 0.2% to 1.2 ± 0.1% at concentrations ranging from 0.5 to 5.0 μg/mL; that ist approximately 98.6 to 98.8% bound. EXP3174 was more highly bound than losartan (P < .05) ivith 0.2 ± 0.0% free at concentrations ranging from 0.1 to 10.0 μg/mL; or, greater than 99.7% bound. The binding in the plasma from volunteers given oral losartan was similar to that determined with plasma from naive donors, with 1.5 ± 0.3 versus 1.4 ± 0.1% free for losartan, and 0.5 ±0.1 versus 0.4 ± 0.0% for EXP3174, respectively. This extensive plasma binding of both acidic compounds occurs primarily to albumin, with negligible binding to the α1‐acid glycoprotein. Although highly bound, neither losartan nor EXP3174 were displaced in vitro by pharmacologically relevant concentrations of non‐steroidal antiinflammatory drugs (NSAlDs), warfarin, or diazepam; however, suprapharmacologic concentrations of the NSAIDs increased the free fraction of both compounds. These data show that the angiotensin II receptor antagonists losartan and EXP3174 are highly bound to plasma albumin in humans, although clinically significant drug interactions due to displacement from binding sites are unlikely. Moreover, these data may be used to estimate the unbound plasma concentrations in published and subsequent pharmacokinetic studies, an important parameter because it is generally recognized that only the unbound drug is available for distribution into tissues and binding to receptors.
Glyburide Protein Binding and the Effect of Albumin Glycation in Children, Young Adults, and Older Adults with Diabetes
Authors: Olsen K. M. , Kearns G. L. , Kemp S. F.
Published: March 2013

Because glyburide is a weak acid that is more than 98% bound to albumin, the authors evaluated the binding in vitro and the influence of albumin glycation in children, young adults, and older adults with diabetes mellitus. Glyburide binding to non‐glycated albumin was greater than 98%, and remained constant over a total concentration range of 50 to 1000 ng/mL. Increasing the albumin concentration from 0.5 to 5.0 g/dL was logarithmically related to the free fraction of glyburide. After the in vitro glycation of albumin (range, 5.7–15.6%), mean (±SD) glyburide binding was 99.05 ± 0.082%, a value in agreement with that obtained from control serum. Serum samples from 57 subjects with type I and 16 patients with type II diabetes were incubated with 300 ng/mL of unlabeled glyburide and 200 ng/mL of 14C‐glyburide. The extent of albumin glycation varied from 5 to 22% for the type I subjects and 5 to 14% for the type II subjects. The free fraction from these groups ranged from 1.07 to 1.75% and 0.66 to 0.88% for the type I and type II subjects, respectively. Although these values did not differ significantly from those of the control samples, the glyburide free fraction in patients with type I diabetes (1.39 ± 0.85%) was significantly greater than that found for the 16 elderly patients with type II diabetes (0.78 ± 0.05%). A significant linear relationship was not found between glyburide free fraction and the degree of albumin glycation for either group. Glyburide protein binding did not appear to be influenced by the extent of albumin glycation.
Management of Hypertensive Urgencies and Emergencies
Authors: Abdelwahab Waiel , Frishman William , Landau Andre
Published: March 2013

Hypertensive emergency is a condition in which there is elevation of both systolic and diastolic blood pressure with the presence of acute target organ disease. Hypertensive urgency is a condition where the blood pressure is elevated (diastolic > 120 mmHg) with the absence of acute target organ disease. Hypertensive emergencies are best managed with parenteral drugs and careful intraarterial blood pressure monitoring. Hydralazine has been widely used in treatment of hypertension in eclampsia and preeclampsia, and its safety has been demonstrated in these patients. Sodium nitroprusside (SNP) has the most reliable antihypertensive activity, which begins immediately after its administration and ends when the infusion is stopped. As with diazoxide, it should be used with caution in patients with impaired cerebral flow. SNP is the preferred drug in obtaining controlled hypotension in patients undergoing neurovascular surgery. Intravenous nitroglycerin is useful in patients prone to myocardial ischemia, but should be avoided in patients with increased intracranial pressure. Esmolol is effective in controlling both supraventricular tachyarrhythmias and severe hypertension. Its short onset of duration of action make it useful in the emergent setting, but because of its negative inotropic effect its use should be avoided in patients with low cardiac output. Verapamil should not be used in patients with preexisting conduction abnormalities. Nicardipine is a potent arteriolar vasodilator without a significant direct depressant effect on myocardium. As with other afterload reducing agents, it should not be used in patients with severe aortic stenosis. Because angiotensin‐converting enzyme (ACE) inhibitors generally cause cerebral vasodilatation, enalaprilat may be particularly beneficial for patients who are at high risk of developing cerebral hypotensive episodes secondary to impaired cerebral circulation. Fenoldopam, a selective post‐synaptic dopaminergic receptor (DA1) has been shown to be effective in treating severe hypertension with a lower incidence of side effects than SNP. Hypertensive urgencies can usually be managed with oral agents. Oral nifedipine, captopril, clonidine, labetalol, prazosin, and nimodipine have all been shown to be effective in these situations.
Antianginal and Antiischemic Efficacy of Monotherapy Extended‐Release Nisoldipine (Coat Core) in Chronic Stable Angina
Authors: Glasser Stephen P. , Ripa Steven , Garland W. Thomas , Weiss Robert , Nademanee Koonlawee , Singh Steven , Bittar Neville
Published: March 2013

A double‐blind, randomized, placebo‐controlled study was conducted to test the peak and trough antianginal and antiischemic monotherapy efficacy and safety of a new extended‐release formulation of nisoldipine (nisoldipine Coat Core [Bayer Corporation], 20 mg, 40 mg, and 60 mg once daily compared to placebo). Study patients had a history of chronic, stable angina pectoris, exercise‐induced angina in association with ST segment depression, and exercise test reproducibility. Of the 483 patients enrolled in the study, results were valid for safety analysis for 312 and for efficacy analysis for 284. There was a statistically significant improvement in total exercise time at both peak and trough for patients taking 20 mg and 60 mg of nisoldipine compared with patients taking placebo, but the group taking 60 mg was not better than the group taking 20 mg (33.9 and 33.7 seconds, respectively, at trough). The results were similar for the secondary endpoints (time to onset of angina and time to 1 mm ST segment depression). No correlation was evident between plasma nisoldipine levels and total exercise duration. Headache and peripheral edema were the most frequently reported adverse events and were dose related. There were no discontinuations due to adverse events in patients randomized to the 20‐mg nisoldipine group. No deaths occurred while patients were receiving active nisoldipine therapy. Therapy with this extended‐release formulation of nisoldipine is an effective once‐daily treatment for chronic stable angina pectoris. It represents one of the few dihydropyridine calcium channel antagonists that has shown efficacy when administered as monotherapy to patients with angina.
Invasive Pharmacodynamics of Fosinopril in Patients with Congestive Heart Failure
Authors: Ford Neville F. , Natarajan Chandra , Fulmor I. Edgar , Smith R. A. , Hui Ka Kit
Published: March 2013

Five patients with NYHA Class III CHF received 5 mg of fosinopril on each of 4 days. Hemodynamics were measured with a Swan‐Ganz catheter after dosing on day 1. Measurements of plasma fosinoprilat, ACE activity, renin, and aldosterone were obtained. An Emax model was used to fit the effect‐site concentration and mean arterial pressure change. A linear model was used to fit the effect‐site concentration and the pulmonary artery wedge pressure (PAWP) change. At steady state on day 4, AUC0–24 was 1668 ± 476 ng.hr/mL and Cmax was 143.5 ± 33.6 ng/mL. The mean elimination half‐life of fosinoprilat was 11.3 ± 0.7 hours, and median Tmax occurred at 3 hours, corresponding to maximum plasma ACE inhibition. Plasma renin activity was unchanged, and mean plasma aldosterone level declined. Emax modeling using fosinoprilat concentrations and mean arterial pressure showed good prediction of the pharmacodynamic effects from the effect‐site concentration. A linear relationship was observed between the effect‐site concentrations of fosinoprilat and PAWP. When expressed in an Emax model, the pharmacodynamic actions of fosinopril in patients with CHF are a reflection of its pharmacokinetics.
Effects of Aging on Antipyrine Clearance: Predictive Factors of Metabolizing Capacity
Authors: Jorquera F. , Almar M. M. , Pozuelo M. , Sansegundo D. , González‐Sastre M. , González‐Gallego Javier
Published: March 2013

The purpose of this study was to identify variables that can account for the decline of antipyrine clearance (ClAP) in elderly adults and that may help predict a reduction in metabolizing capacity. For comparison, ClAP was determined in 177 elderly (mean age 82 years) and 25 young (mean age 29 years) volunteers. Antipyrine (1 g) was administered orally and ClAP was determined by the one‐sample saliva method. Mean ClAP was reduced by 38% and antipyrine half‐life increased by 64% in old subjects. Multiple regression analysis of ClAP revealed an independent value for age, serum aspartate transaminase (AST), and height in the elderly. The independent variables collectively accounted for 27% of the variance explained. Age, high serum AST, use of diuretics, and no consumption of drugs known to stimulate oxidative metabolism were selected by multivariate analysis (logistic model) as independent predictors of a low metabolizing capacity. The findings indicate that factors other than age may contribute to impaired hepatic oxidative metabolism in the elderly.
Single‐Dose and Steady‐State Pharmacokinetics of Fosinopril and Fosinoprilat in Patients with Hepatic Impairment
Authors: Ford Neville F. , Lasseter Kenneth C. , Van Harken Donald R. , Hammett Janis L. , Raymond Ralph , Manning James
Published: March 2013

The single‐dose and steady‐state pharmacokinetics of the angiotensin‐converting enzyme (ACE) inhibitor fosinopril and its active diacid, fosinoprilat, were evaluated in 6 healthy volunteers and 12 patients with alcoholic cirrhosis. Fosinopril was administered at a dosage of 10 mg once daily for 14 days. Results in the two groups were similar, with no evidence of accumulation of fosinoprilat in hepatically impaired patients. Mean (±SD) maximum observed plasma concentrations of fosinoprilat in the healthy subjects were 112.0 ± 67.2 ng/mL after the first dose and 144.1 ± 61.7 ng/mL at steady‐state. Corresponding values for the hepatically impaired patients were 111.4 ± 40.1 ng/mL and 140.2 ± 50.9 ng/mL. The area under the serum concentration versus time curve for healthy volunteers was 790.7 ± 431.0 ng · hr/mL after the first dose and 940.3 ± 400.4 ng · hr/mL at steady‐state. Similar values were noted in hepatically impaired patients: 926.0 ± 293.9 ng · hr/mL and 1,255.4 ± 434.0 ng · hr/ mL for first dose and steady‐state, respectively. No statistically significant differences were detected in fosinoprilat pharmacokinetic values between healthy and hepatically impaired subjects. Absence of accumulation can be attributed to the dual route of elimination of fosinoprilat reported in previous studies. Renal excretion of fosinoprilat in hepatically impaired patients prevents increased accumulation. The present findings suggest that the starting dose of fosinopril used in hypertensive patients with normal renal and hepatic function can also be used in patients with hepatic impairment secondary to cirrhosis.
Losartan: First of a New Class of Angiotensin Antagonists for the Management of Hypertension
Authors: Carr Albert A. , Prisant L. Michael
Published: March 2013

Angiotensin receptor antagonists represent a new class of drugs for the treatment of patients with hypertension. Reduction of blood pressure in patients with essential hypertension requires increased activity of the renin—angiotensin system. Losartan, the first orally active, nonpeptide angiotensin antagonist, specifically competes with angiotensin II (Ang II) for the AT1 receptor and reversibly alters the receptor. Maximum blood pressure reductions occur after doses of approximately 50 mg, although some patients will require 100 mg; the parent compound and a metabolite are responsible for a smooth 24‐hour effect on blood pressure. Once‐daily dosing with losartan has been documented to be safe. The drug's safety has been evaluated in 4,058 patients; of these patients, more than 1,200 were treated for longer than 6 months and more than 800 were treated for longer than 1 year with doses of 10 mg to 150 mg. Overall, no hypertensive patients were withdrawn from treatment because of elevated serum creatinine or potassium levels, and there were no reports of angioedema. In addition, some reductions in plasma uric acid levels were noted. Cough occurred significantly less often in patients treated with losartan than in those treated with hydrochlorothiazide or lisinopril. In contrast to angiotensin‐converting enzyme (ACE) inhibitors, losartan does not activate bradykinin—nitric oxide—prostanoid vasodilation.
Disposition of Procainamide in Patients with Chronic Congestive Heart Failure Receiving Medical Therapy
Authors: Tisdale James E. , Rudis Maria I. , Padhi I. Desmond , Borzak Steven , Svensson Craig K. , Webb Charles R. , Acciaioli Joseph , Ware Joseph A. , Krepostman Abraham , Zarowitz Barbara J.
Published: March 2013

Dosage reduction of procainamide has been recommended in patients with congestive heart failure (CHF). However, these recommendations are based primarily on studies with unmatched control groups, suboptimal blood sampling, and in patients not receiving angiotensin‐converting enzyme (ACE) inhibitors. These agents increase renal blood flow, which theoretically may offset alterations in drug disposition in patients with CHF. The pharmacokinetics of procainamide in patients with chronic CHF and in matched controls were compared. A single intravenous dose of 750 mg of procainamide was administered to 9 patients with chronic New York Heart Association (NYHA) class II or III CHF (mean ± SD left ventricular ejection fraction 22 ± 9%) receiving medical therapy and 7 control subjects matched for age and gender. Blood and urine samples were collected at intervals over a period of 48 and 72 hours, respectively. Patients with CHF and control subjects were demographically similar, with the exception of concomitant medications, including ACE inhibitors (8/9 versus 1/7, respectively). There were no significant differences between patients with CHF and control subjects in mean ± SD peak serum concentrations (Cmax), area under the serum concentration—time curve (AUC0‐∞), total clearance, renal clearance, half‐life (t1/2), or volume of distribution (Vd) of procainamide. Similarly, there were no significant differences between patients with CHF and control subjects in the mean ± SD Cmax, AUC0‐∞, renal clearance, or t1/2 of N‐acetylprocainamide (NAPA). Procainamide dosage reduction may not be necessary in patients with chronic stable CHF who are receiving medical therapy.
Assessment of the Pharmacokinetic ‐Pharmacodynamic Interaction Between Terazosin and Finasteride
Authors: Samara Emil E. , Hosmane Bala , Locke Charles , Eason Carolyn , Cavanaugh John , Granneman G. Richard
Published: March 2013

The pharmacokinetic‐pharmacodynamic interaction between terazosin and finasteride was evaluated in an 18‐day, parallel, open‐label, randomized study. Forty‐eight nonsmoking, healthy, adult male volunteers entered the study. One third of the participants received terazosin alone, one third received terazosin and finasteride, and one third received finasteride alone. Multiple‐dose coadministration of terazosin and finasteride did not alter the central values of steady‐state pharmacokinetic parameters of either drug in a statistically significant manner. Compared with the single‐agent groups, however, the group taking finasteride and terazosin had higher variability in the pharmacokinetic parameters of both drugs. Testosterone concentrations were not altered after administration of finasteride and terazosin alone or in combination. Terazosin administered alone did not affect the dihydrotestosterone concentrations. The significant reduction in dihydrotestosterone concentrations induced by administration of finasteride was not affected by coadministration of terazosin. Mean changes in blood pressure and pulse rate in these normotensive volunteers were generally slight; therefore, concurrent administration of multiple doses of terazosin and finasteride did not produce significant clinical concern.
Lack of Diurnal Variation in Glomerular Filtration Rates in the Elderly
Authors: Sunaga Ken‐ichiro , Sudoh Toshiaki , Fujimura Akio
Published: March 2013

The present study was undertaken to examine the effect of age on diurnal variation in glomerular filtration rate (GFR). The GFR, as estimated by creatinine clearance (Clcr), was determined during a 24‐hour period in 10 younger (mean ± SD age 42 ± 9 years) and 10 older (mean age 75 ± 4 years) patients with hypertension. Significant diurnal variations in Clcr were observed in the younger patients, with a peak during the day and trough during the night. Such were not observed in the older patients, however. These results suggest that diurnal variation in GFR is affected by age. Chronopharmacologic profiles of drugs, which are mainly excreted in urine by glomerular filtration, might be altered in these patients.
Pharmacodynamics and Pharmacokinetics of Two Dose Regimens of Befloxatone, a New Reversible and Selective Monoamine Oxidase Inhibitor, at Steady State in Healthy Volunteers
Authors: Patat Alain , le Coz Franck , Dubruc Catherine , Gandon Jean‐Marc , Durrieu Geneviève , Cimarosti Isabelle , Jezequel Sylvie , Curet Olivier , Zieleniuk Isabelle , Allain Hervé , Rosenzweig Pierre
Published: March 2013

The pharmacodynamic equipotency of 2 dose regimens (5 mg twice daily versus 10 mg once daily) of befloxatone, a new reversible and selective monoamine oxidase A (MAO‐A) inhibitor, after single and multiple doses for 6 days was examined in a randomized, double‐blind, three‐way crossover, placebo‐controlled trial of 12 healthy volunteers. Plasma levels of the deaminated metabolite 3–4 dihydroxyphenylglycol (DHPG), as measured by high‐performance liquid chromatography (HPLC) with coulometric electrochemical detection, were used as an index of MAO inhibition. A single dose of befloxatone produced a significant dose‐related reduction in plasma DHPG levels, as shown by the decrease in the 24‐hour area under the concentration‐time curve (AUC0–24) of DHPG, which peaked 2 hours after administration and persisted over 24 hours. Both dose regimens provided equipotent extent and duration of MAO‐A inhibition at steady state, suggesting a once daily dosage should be sufficient for most patients. The pharmacokinetic bioavailability at steady state of both dose regimens was also similar. The concentration‐time effect curve after a single dose revealed a hysteresis corresponding to the delay necessary to elicit MAO inhibition and/or elimination of DHPG. The relationship between plasma levels of DHPG and/or elimination of plasma concentrations of DHPG and befloxatone after a single dose can be modeled using the Emax model with a mean EC50 of 4.75 ng/mL, and suggests the presence of a maximal response from the single dose. This model permits prediction of steady‐state levels of DHPG.
The Effects of Epoprostenol on Drug Disposition I: A Pilot Study of the Pharmacokinetics of Digoxin 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 influence of epoprostenol on the pharmacokinetics of drugs administered concurrently to patients with congestive heart failure (CHF) receiving epoprostenol was evaluated as a secondary objective of a Phase II pilot study. A total of 278 blood samples were collected from 30 patients with end‐stage CHF receiving conventional therapy alone or conventional therapy plus epoprostenol. Estimates of oral clearance (CI), v olume of distribution, and absorption rate constant of digoxin were generated from plasma digoxin concentrations using nonlinear mixed effects modeling, and the effect of epoprostenol on Cl of digoxin was evaluated by univariate analysis. Additional factors that were evaluated by univariate analysis included age, obesity, time since study entry, cardiac output, concomitant use of angiotensin‐converting enzyme (ACE) inhibitor, concomitant dobutamine, and estimated creatinine clearance. Backward elimination was used to arrive at a final model that included concomitant epoprostenol as a covariate. The final model revealed an approximate 15% decrease in Cl of digoxin in response to short‐term administration of epoprostenol that was no longer apparent by the end of the 12‐week treatment phase. Simulations revealed that this effect, although statistically significant, would not be clinically significant in most patients; however, the potential exists for short‐term elevation of digoxin concentrations in response to concurrent administration of epoprostenol.
Effect of Felbamate on the Pharmacokinetics of Lamotrigine
Authors: Colucci Robert , Glue Paul , Holt Beverley , Banfield Christopher , Reidenberg Pascale , Meehan Jeffrey W. , Pai Sudhakar , Nomeir Amin , Lim Josephine , Lin Chin‐Chung , Affrime Melton B.
Published: March 2013

To assess the possible interaction between lamotrigine and felbamate, a double‐blind, randomized, placebo‐controlled, two‐way crossover study was conducted in 21 healthy male volunteers. Volunteers were given lamotrigine (100 mg every 12 hours) and felbamate (1,200 mg every 12 hours) or matching placebo for 10 days during each period of the crossover. After morning administration on day 10, blood samples were obtained over 12 hours for measurement of lamotrigine. Felbamate increased the maximum concentration (Cmax) and and area under the concentration‐time curve from time 0 to 12 hours (AUC0–12) of lamotrigine by 13% and 14%, respectively, compared with placebo. The 90% confidence intervals of the log‐transformed pharmacokinetic parameters were within the 80–125% bioequivalence limits, however. Felbamate had no significant effect on the urinary excretion of lamotrigine (total), unconjugated lamotrigine, or the N‐glucuronide. One volunteer discontinued the study after developing a rash while taking lamotrigine and placebo. All other adverse events were primarily related to the central nervous system and gastrointestinal tract, with a higher incidence reported during coadministration of lamotrigine and felbamate than with placebo. Overall, felbamate appears to have no clinically relevant effects on the pharmacokinetics of lamotrigine.
A Classification of Drug Action Based on Therapeutic Effects
Authors: Bjornsson Thorir D.
Published: March 2013

A systematic classification system has been developed for the categorization of therapeutic effects of individual drugs based on their relationships to the underlying disease processes being treated or prevented, rather than on the pharmacologic or biochemical effects of the individual drugs. This system involves a total of six categories of different therapeutic specificities, involving four categories based on disease process‐oriented mechanisms of drug action (Categories I through IV), and two additional ones (Categories 0 and V) to complete the classification system. Category 0 includes drugs or drug uses that prevent the development of a disease when none exists; Category I, those that affect etiologic factors of a disease; Category II, those that affect specific disease processes; Category III, those that affect specific disease manifestations; Category IV, those that affect non‐specific disease manifestations or symptoms; and Category V includes drug uses or drugs used to diagnose or facilitate treatment of a disease. Examples are provided for each category as well as for applications of the classification system.
Acebutolol Overdose Treated with Hemodialysis and Extracorporeal Membrane Oxygenation
Authors: Rooney M. , Massey K. L. , Jamali F. , Rosin M. , Thomson D. , Johnson D. H.
Published: March 2013

A case involving a 27‐year‐old woman who ingested an overdose of acebutolol is presented. Extracorporeal membrane oxygenation was initiated to stabilize the patient's condition before commencing hemodialysis. S‐diacetolol (the N‐acetelation product of acebutolol) was cleared with hemodialysis. It is suggested that extracorporeal membrane oxygenation may be of short‐term benefit in the treatment of overdoses with β‐adrenergic agents such as acebutolol when accelerated clearance with hemodialysis is anticipated.
Pharmacokinetic Profile and Endocrine Effects of Posatirelin Treatment in Healthy Elderly Subjects
Authors: Reboldi Gianpaolo , Parnetti Lucilla , Santeusanio Fausto , Ambrosoli Laura , Palumbo Barbara , Cherubini Antonio , Girardello Roberto , Poli Aldo , Lowenthal David T. , Senin Umberto
Published: March 2013

The pharmacokinetics and endocrine effects of a therapeutic dose (10 mg/day) of posatirelin (L‐pyro‐2‐aminoadipyl‐L‐leucyl‐L‐prolinamide) were investigated in healthy elderly subjects. Posatirelin was given once daily by intramuscular injection for 7 days. Pharmacokinetic parameters were estimated using a model‐independent approach. The plasma concentrations of free triiodotyronine (FT3), free thyroxine (FT4), and thyroid‐stimulating hormone (TSH) and the circadian rhythms of prolactin and cortisol were considered as indicator variables of endocrine response to posatirelin administration. Posatirelin was well tolerated and no significant adverse effects were observed during the study. Peak plasma concentration (Cmax), time of peak plasma concentration (tmax), area under the plasma concentration—time curve from time zero to infinity (AUC0‐∞), elimination half‐life (t1/2), and total clearance (Cl/F) were measured after single‐dose intramuscular injection (day 1) and after multiple‐dose administration (day 7). There were no significant changes in these parameters after multiple‐dose administration (day 7). Posatirelin induced a progressive reduction in basal TSH levels and maximum response. There were no significant changes during treatment in the time at which basal levels of FT3 and FT4 occurred, and these levels remained within the normal range throughout the study. The circadian rhythms of cortisol and prolactin were not influenced by posatirelin treatment. The pharmacokinetics of posatirelin were not time dependent, and the drug did not accumulate after multiple‐dose administration. Short‐term treatment with posatirelin did not induce clinically relevant endocrine consequences in healthy elderly subjects.
Tonsillar Tissue Penetration of Dirithromycin after Multiple Doses
Authors: Benson John M. , Arnold James , Manning Scott C. , Coleman Dennis L. , Conforti Paul M. , Lemon Eloise , Watkins Vish S. , Sides Gregory D.
Published: March 2013

Dirithromycin is a new macrolide antibiotic that is effective against group A β‐hemolytic streptococcal pharyngotonsillitis. This prospective, multicenter, randomized study compared the serum and tonsil tissue concentrations of erythromycylamine (to which dirithromycin is rapidly converted by nonenzymatic hydrolysis during absorption) and erythromycin after 5‐ and 10‐day regimens of dirithromycin and erythromycin, respectively. Thirty‐nine patients undergoing elective tonsillectomy but without active tonsillitis were assigned in randomized fashion to receive dirithromycin 500 mg orally once daily (n = 22) or erythromycin base 250 mg orally four times daily (n = 17). Data from 12 patients receiving dirithromycin and 10 receiving erythromycin were eligible for analysis. Mean serum concentrations (± standard deviation) of erythromycylamine and erythromycin were 0.20 ± 0.07 μg/mL and 0.12 ± 0.25 μg/mL, respectively, after the 5‐day regimen and 0.17 ± 0.10 μg/mL and 1.57 ± 3.16 μg/mL, respectively, after the 10‐day regimen. The mean serum concentration of erythromycin after 10 days was skewed by the data for one of the six patients in the group (concentration of >8 μg/mL). Mean concentrations of erythromycylamine in tonsil tissue were 4.62 ± 0.97 μg/g after 5 days and 3.47 ± 2.84 μg/g after 10 days. Concentrations in tonsillar tissue were undetectable in all patients given erythromycin for 5 days and in 4 of the 6 patients given erythromycin for 10 days. The high concentrations of erythromycylamine in tonsillar tissue agree with the clinical efficacy seen in the treatment of group A β‐hemolytic streptococcal tonsillopharyngitis with dirithromycin.
Pharmacokinetics of Trapidil in Patients with Chronic Liver Disease
Authors: Berndt Annette , Looby Michael , Pönicke Klaus , Zipprich Berndt , Weiss Michael
Published: March 2013

The pharmacokinetics of trapidil were studied in 15 patients with chronic liver disease (12 with hepatic cirrhosis, 2 with alcoholic fatty liver, 1 with liver fibrosis). Trapidil was administered intravenously as a 100‐mg bolus. Serum samples were analyzed for trapidil by means of high‐performance liquid chromatography. Mean pharmacokinetic parameters were compared with those found in a previous study of 12 healthy volunteers. Total plasma clearance was decreased significantly in patients with hepatic cirrhosis (96 mL/min versus 258 mL/min in healthy individuals and 252 mL/min in patients with noncirrhotic liver disease). No difference in clearance was observed between patients with compensated or decompensated cirrhosis, and portal hypertension did not affect this clearance of trapidil. It can be concluded that trapidil clearance is a parameter that is very sensitive to alterations in hepatic clearance caused by liver cirrhosis, and that the dosage of trapidil should be adjusted accordingly in such patients.
Effects of Befloxatone, a Reversible Selective Monoamine Oxidase‐A Inhibitor, on Psychomotor Function and Memory in Healthy Subjects
Authors: Warot Dominique , Berlin Ivan , Patat Alain , Durrieu Geneviève , Zieleniuk Isabelle , Puech Alain J.
Published: March 2013

Befloxatone is a new reversible and selective monoamine oxidase (MAO‐A) inhibitor that has been shown to have antidepressant activity in various animal models. To assess the effects of single oral doses of befloxatone (5, 10, and 20 mg) on psychomotor performance and memory, a randomized, double‐blind, five‐way, crossover study with both placebo and amitriptyline (50 mg) was carried out in 15 healthy male volunteers. Psychomotor and cognitive functions were evaluated using both objective measures, including Critical Flicker Frequency (CFF), Choice Reaction Time (CRT), Digit Symbol Substitution Test (DSST), and a picture memory test, and subjective measures, including Visual Analog Scales (VAS) and Addiction Research Center Inventory (ARCI), before and 2, 4, and 8 hours after administration. Pupil diameter was recorded by videopupillography. Single doses of befloxatone from 5 to 20 mg did not result in any detrimental effects on skilled performance and memory. In contrast, amitriptyline significantly impaired arousal (CFF), speed of reaction (CRT), information processing (DSST) and long‐term memory (delayed free recall of pictures) and produced subjective sedation from 2 to 8 hours after administration. At the doses studied amitriptyline induced miosis but befloxatone did not modify pupil diameter. There was no evidence in this study to suggest that befloxatone, at the doses studied, has any sedative or amnesic effects in healthy subjects.
A Pharmacodynamic and Pharmacokinetic Comparison of Intravenous Quinaprilat and Oral Quinapril
Authors: Breslin Elaine , Posvar Edward , Neub Martin , Trenk Dietmar , Jahnchen E.
Published: March 2013

Quinaprilat is the active metabolite of quinapril, an orally active angiotensin‐converting enzyme (ACE) inhibitor. The dose‐response and duration‐of‐effect after single intravenous doses of quinaprilat and placebo (part A) and after administration of oral quinapril solution and intravenous quinaprilat (part B) were assessed in a randomized, crossover study of two groups of 12 healthy volunteers. Pharmacodynamic effects of quinaprilat and oral quinapril were assessed by measurement of blood pressure changes after an infusion of angiotensin I (A‐I) at a dose previously determined to produce an increase in diastolic blood pressure of 25 mmHg under standardized conditions (A‐I pressor response). A clear dose‐response relationship was demonstrated for quinaprilat in this pharmacodynamic model, with 0.5 mg as the lowest effective dose. Doses of 1.0 mg and higher partially suppressed A‐I pressor response for at least 6 hours. Onset of action was observed within 15 minutes of intravenous administration of quinaprilat and was independent of dose, whereas peak effect and duration of action appeared to be dose related. Quinaprilat doses of 2.5 mg and 10 mg achieved approximately 50% and >80% inhibition of the A‐I pressor response, respectively. In part B, these doses of intravenous quinaprilat were compared with oral doses of quinapril previously found to produce 50% (2.5 mg) and 90% (10 mg) inhibition of the A‐I pressor response. The magnitude of effect was similar after administration of 20 mg quinapril orally and 10 mg quinaprilat intravenously. Duration of action was longer, however, after administration of intravenous quinaprilat (10 mg) than after oral quinapril (20 mg), due to the higher maximum plasma concentration (Cmax) of quinaprilat. Mean area under the plasma concentration‐time curve extrapolated to infinity (AUC0‐∞) of quinaprilat was similar after the 10‐mg dose of intravenous quinaprilat and the 20‐mg dose of oral quinapril. Based on the concentrations of quinaprilat observed in this study, the absolute bioavailability of quinapril was approximately 50%; intravenous quinaprilat should therefore produce a pharmacodynamic response similar to that obtained with oral quinapril at approximately half the dose.
Lack of Effect of Type II Diabetes on the Pharmacokinetics of Troglitazone in a Multiple‐Dose Study
Authors: Loi Cho‐Ming , Randinitis Edward J. , Vassos Artemios B. , Kazierad David J. , Koup Jeffrey R. , Sedman Allen J.
Published: March 2013

Twelve patients with type II diabetes and 12 age‐, weight‐, and gender‐matched healthy subjects participated in a study comparing the pharmacokinetics of troglitazone, metabolite 1 (sulfate conjugate), and metabolite 3 (quinone) after oral administration of 400 mg of troglitazone every morning for 15 days. Serial plasma samples collected after the dose on days 1 and 15 were analyzed for troglitazone, metabolite 1, and metabolite 3 using a validated HPLC method. Steady‐state plasma concentrations of troglitazone and its metabolites were achieved by the fifth day of troglitazone administration in both groups. Mean day 15 Cmax, tmax, AUC0–24, and Cl/F values of troglitazone were 1.54 μg/mL, 3.25 hours, 15.6 μg · hr/mL, and 461 mL/min, respectively, in patients with type II diabetes. Corresponding parameter values were 1.42 μg/mL, 2.63 hours, 12.5 μg · hr/mL, and 558 mL/min, respectively, in healthy subjects. Elimination t1/2 was approximately 24 hours in both groups. Mean day 15 pharmacokinetic parameter values for metabolite 1 and metabolite 3 were similar in the two groups. Ratio of AUC of metabolite 1 to troglitazone was 6.2 and 6.7, respectively, in patients and in healthy subjects. Ratio of AUC of metabolite 3 to troglitazone was 1.1 in both groups. Thus, steady‐state pharmacokinetics and disposition of troglitazone and its metabolites in patients with type II diabetes were similar to those in healthy subjects.
Evaluation of the Diurnal Variation in the Pharmacokinetics of Zileuton in Healthy Volunteers
Authors: Awni Walid M. , Locke Charles , Dube Louise M. , Cavanaugh John H.
Published: March 2013

The diurnal variation in the pharmacokinetic parameters of zileuton were evaluated in 12 healthy male volunteers in a three‐period study. Periods I and II constituted a balanced, randomized, crossover study in which a participant received a single dose of 600‐mg zileuton either at 7 am or 11 pm. In period III all participants received 600‐mg doses four times daily for 5 days. The differences between the pharmacokinetics of single doses of zileuton administered at 7 am and at 11 pm were not statistically significant. Plasma concentration—time profiles of zileuton during the four daily dose intervals at steady state were also similar. Values for the pharmacokinetic parameters of zileuton after multiple doses were similar to those after single doses, with a minimal accumulation of the drug after multiple doses. Overall, there was little or no diurnal variation in the pharmacokinetic parameters of zileuton after single and multiple doses.
Carotenoids and Retinoids: A Review of Research, Clinical, and Public Health Applications
Authors: Hinds Tanya S. , West William L. , Knight Enid M.
Published: March 2013

Traditionally, the carotenoids and retinoids have been regarded as dietary sources of vitamin A and have been evaluated regarding their respective physiologic roles in vision, growth, immune system integrity, and prevention of vitamin A deficiency. In the 1990s, however, vitamin A deficiency is no longer widespread in Western countries. Therefore, the role of carotenoids and retinoids is evolving to encompass treatment and prevention of conditions such as cancer and cardiovascular disease, which are prevalent in Western societies. This review summarizes current research concerning the therapeutic utility of vitamin A and its analogues and their roles in the prevention of cancer and cardiovascular disease.
Visual Symbolization as a Learning Tool: Teaching Pharmacology to International Audiences
Authors: Giannini A. James , Giannini Juliette N. , Melemis Steven M.
Published: March 2013

Medieval and Renaissance teaching techniques used linkage between course content and tangentially related visual symbols to reinforce lectures. This technique was adopted in teaching pharmacologic principles of addiction to international audiences. It produced significant results with non‐English‐speaking audiences using concurrent or consecutive translation. This technique may be useful for non‐English‐speaking audiences because of enhancement of all three areas of memory: attention, storage, and retrieval.
Pharmacokinetics and Pharmacodynamics of 9‐cis‐Retinoic Acid in Healthy Men
Authors: Weber Cornelia , Dumont Etienne
Published: March 2013

A double‐blind, placebo‐controlled, randomized study using single ascending oral doses of 5 mg, 15 mg, 40 mg, 80 mg, and 150 mg of 9‐cis‐retinoic acid was performed to assess the single‐dose pharmacokinetics, tolerability, and pharmacodynamic effects of 9‐cis‐retinoic acid in healthy men. Forty participants received treatment (six taking the active treatment and two taking placebo for each dose level). The pharmacokinetics of 9‐cis‐retinoic acid were linear over the dose range studied. Peak plasma concentrations were achieved within 3 to 4 hours on average. The half‐life was in the range of 1.3 to 2.4 hours. Metabolism was the major pathway of elimination. 4‐Oxo‐9‐cis‐retinoic acid, one of four metabolites measured, which included all‐trans‐retinoic acid and 13‐cis‐retinoic acid, was the main metabolite in plasma, achieving peak plasma levels of 41% to 83% of those of 9‐cis‐retinoic acid. Dose‐/concentration‐dependent reductions of retinol in plasma, with a maximum of 30% from baseline, were observed 24 hours after administration. Baseline levels were recovered after 5 days. Concentrations of retinol binding protein remained unchanged. Overall, the drug was well tolerated at all dose levels. Adverse events observed were consistent with findings of other retinoids (all‐trans‐retinoic acid and 13‐cis‐retinoic acid) and included headache and xeroderma at high dose levels.