bluuebunny/crossref_metadata_2025 huggingface dataset:
Metoclopramide Increases the Bioavailability of Dantrolene in Spinal Cord Injury
Authors: Gilman Thomas M. , Segal Jack L. , Brunnemann Sherry R.
Published: March 2013

A study was conducted to determine the effect of metoclopramide on the disposition of dantrolene in patients with spinal cord injury (SCI) and in neurologically intact, able‐bodied volunteers. Fifteen serum samples each were collected from 6 able‐bodied volunteers and 13 patients with SCI (7 paraplegics, 6 quadriplegics) in a prospective, open‐label, pharmacokinetic study of a single 100‐mg oral dose of dantrolene. After a washout period, a single 10‐mg intravenous dose of metoclopramide was given along with dantrolene to the patients with SCI only, and the study was repeated in sequential, crossover fashion. Concentrations of dantrolene were measured by a high‐performance liquid chromatography (HPLC) assay. Numerical integration was used to calculate area under the curve (AUC) and mean residence time (MRT). Differences were studied using paired and two‐sample, nonparametric tests, with 0.05 as the significance level. Without metoclopramide, the AUC of dantrolene was larger in able‐bodied volunteers than in patients with SCI, and the MRT of dantrolene was similar both groups. When patients with SCI received metoclopramide before treatment with dantrolene, the median increase in the AUC for dantrolene was 57%, with no change in MRT. This pharmacokinetic interaction is probably attributable to augmented absorption and could alter the pharmacologic action of dantrolene. Concurrent treatment of patients with SCI with metoclopramide and dantrolene should be accompanied by careful surveillance to avoid toxicity and preserve efficacy.
Inhibition of Histamine‐Induced Skin Wheal and Flare after 5 days of Mizolastine
Authors: Pinquier Jean‐Louis , Caplain Henri , Cabanis Marie‐Josée , Dubruc Catherine , Stalla‐Bourdillon Aline , Rosenzweig Pierre
Published: March 2013

Mizolastine is a new, nonsedating antihistamine providing satisfactory symptomatic relief in allergic rhinitis and urticaria. The purpose of this study was to use inhibition of wheal and flare formation after 2‐μg intradermal histamine injections as a measure of the antihistamine effect of repeated doses of mizolastine. Eight volunteers were enrolled in this four‐arm, double‐blind, cross‐over, randomized study. Three dose levels of once‐daily mizolastine (5 mg, 10 mg, and 15 mg) were compared with placebo during 5‐day dose periods. Histamine tests were performed before drug intake on days 1 and 5, and then 2, 3, 4, 6, 8, 10, 12, 14, and 24 hours after drug intake on day 5. All 3 doses of mizolastine were more effective than placebo in suppressing wheal and flare reactions, and the antihistamine activity was highest at both the 10‐ and 15‐mg dose levels. The effect on the flare reaction appeared within 1 hour, reached a maximum effect 4 hours after administration, and persisted for as long as 24 hours. The relative changes in wheal and flare areas were correlated with mizolastine trough plasma levels on day 5. Safety was satisfactory in all groups. This study confirms that mizolastine is a rapid and potent antihistamine; and its long‐lasting effectiveness indicates that a once‐daily regimen is acceptable for clinical use.
Effects of Ofloxacin on the Pharmacokinetics and Pharmacodynamics of Procainamide
Authors: Martin David E. , Shen Jason , Griener James , Raasch Ralph , Patterson J. Herbert , Cascio Wayne
Published: March 2013

Procainamide is a class I antiarrhythmic agent that undergoes active tubular secretion through the organic cation transport system, with approximately 50% of a dose excreted in the urine as unchanged drug. The remainder is metabolized to an active metabolite, n‐acetyl procainamide (NAPA). Ofloxacin is a fluoroquinolone antibiotic that is excreted in the urine as unchanged drug via active tubular secretion and glomerular filtration. To test the hypothesis that ofloxacin may interfere with the renal elimination of procainamide, 9 healthy volunteers were randomly assigned to receive 1 g of oral procainamide as a single dose with or without pretreatment with 400 mg of ofloxacin twice a day for 5 doses. Blood and urine samples were obtained and pharmacokinetic parameters for procainamide were determined for each treatment period. Standard 12‐lead and signal‐averaged electrocardiographic recordings were used for pharmacodynamic analysis. The mean area under the concentration—time curve (AUC) and peak plasma concentration (Cmax; μg/mL) for procainamide increased by 27% and 21%, respectively, and the plasma clearance for procainamide decreased by an average of 22% with coadministration of ofloxacin. Ofloxacin did not significantly influence the pharmacokinetics of NAPA, nor were pharmacodynamics of procainamide significantly affected by coadministration of ofloxacin. These results suggest that procainamide concentrations should be monitored closely when coadministered with ofloxacin.
New Immunosuppressive Drugs in Organ Transplantation
Authors: Hughes Stephen E. , Gruber Scott A.
Published: March 2013

An examination of the mechanisms by which four new immunosuppressive drugs—rapamycin, mizoribine, mycophenolate mofetil, and 15‐deoxyspergualin—exert their effects reveals three major categories. Rapamycin binds to an intracellular immunophilin. The resulting drug‐immunophilin complex inhibits the action of cytokines, thus blocking the activation and proliferation of T cells. Mizoribine and mycophenolate mofetil are antimetabolites that inhibit a key enzyme in the de novo purine biosynthetic pathway. As a result, the proliferation of T cells and B cells is inhibited selectively compared with that of nonlymphoid cells because the salvage pathway is unavailable to lymphocytes. Finally, 15‐deoxyspergualin has a unique mechanism of action, which includes suppressive effects on macrophage function, the induction of cytolytic T cells, B‐cell reactivity, and antibody responses. The demonstrated synergism among certain immunosuppressants allows reduction in the dose of each agent to minimize the individual toxicities. As more of these new agents become available, it is likely that azathioprine will be replaced, and it may be possible to eliminate the need for long‐term maintenance steroid therapy.
Nonprescription Ibuprofen and Acetaminophen in the Treatment of Tension‐Type Headache
Authors: Schachtel Bernard P. , Furey Sandy A. , Thoden William R.
Published: March 2013

A single‐dose, double‐blind, randomized clinical trial was conducted to examine the relative analgesic effectiveness of 400 mg of ibuprofen (n = 153), 1,000 mg of acetaminophen (n = 151), and placebo (n = 151) in volunteers with muscle contraction headache. At regular intervals during a 4‐hour period, participants evaluated headache pain intensity on a 100‐mm visual analog scale and headache pain relief on a six‐category scale. Both active agents were significantly different from placebo at all time points and in reducing pain intensity and providing relief of headache overall. Similarly, ibuprofen at 400 mg differed significantly from acetaminophen at 1,000 mg on both rating scales. Participants receiving ibuprofen at 400 mg achieved complete relief of headache faster than those receiving acetaminophen at 1,000 mg or placebo, and more participants taking ibuprofen experienced complete relief of headache than those taking placebo or acetaminophen. Both ibuprofen at 400 mg and acetaminophen at 1,000 mg are efficacious analgesic agents for muscle contraction headache, and ibuprofen at 400 mg is significantly more effective than acetaminophen at 1,000 mg for treating this condition.
Cardiovascular Effects of Anabolic Steroids in Weight‐Trained Subjects
Authors: Palatini Paolo , Giada Franco , Garavelli Guido , Sinisi Francesco , Mario Luca , Michieletto Marco , Baldo‐Enzi Goretta
Published: March 2013

The effects of large doses of anabolic steroids on 24‐hour blood pressure, cardiac structure and function, and lipid profiles were studied in 10 body builders using anabolic steroids and 14 body builders who did not use steroids (control subjects). All subjects underwent noninvasive 24‐hour blood pressure monitoring, echocardiography, Doppler analysis of transmitral flow, and analysis for lipoprotein and gonadotropin levels. Anabolic steroid users were studied at the end of a steroid cycle and after a period of withdrawal. Average 24‐hour blood pressure was similar in the two groups, but anabolic steroid users exhibited a smaller pressure reduction during sleep than did nonusers. This finding was present both at the end of treatment and after the period of withdrawal. Echocardiographic dimensional and functional indexes did not differ substantially between anabolic steroid users and the nonusers, and were similar in anabolic steroid users during use and after withdrawal. Anabolic steroid users also had higher LDL and lower HDL cholesterol levels than nonusers; Lp(a) was higher in nonusers, although this difference did not attain the level of statistical significance. These differences were more striking at the end of the treatment period. The results of this study show that chronic anabolic steroid intake causes an abnormal 24‐hour blood pressure pattern, characterized by a flattening of the diurnal curve, and minor changes of the dimensional echocardiographic parameters.
Effect of Dirithromycin on Human CYP3A In Vitro and on Pharmacokinetics and Pharmacodynamics of Terfenadine In Vivo
Authors: Goldberg Mark J. , Ring Barbara , DeSante Karl , Cerimele Benito , Hatcher Barbara , Sides Gregory , Wrighton Steven
Published: March 2013

Terfenadine is metabolized by the cytochrome P‐450 3A subfamily of enzymes (CYP3A). Certain macrolide antibiotic agents inhibit CYP3A and, when coadministered with terfenadine, result in a drug interaction. The authors compared the abilities of dirithromycin (a new macrolide antibiotic agent), its major metabolite erythromycylamine, and the known CYP3A substrate terfenadine to inhibit CYP3A in vitro. The hydroxylation of midazolam in human liver microsomes was used as a probe for CYP3A activity. Dirithromycin and erythromycylamine were low affinity inhibitors of CYP3A (inhibitory binding affinities of 493 μmol/L and 701 μmol/L, respectively); conversely, terfenadine was a moderate affinity inhibitor (inhibitory binding affinity of 28 μmol/L). Based on these data, the authors tested the hypothesis that dirithromycin would not interact with terfenadine in humans. Six healthy men received terfenadine alone (60 mg twice daily) for 8 days, after which dirithromycin (500 mg once daily) was added to the terfenadine regimen for an additional 10 days. The pharmacokinetics of terfenadine (and its acid metabolite) and the QTc interval were measured during both treatments, and it was found that neither parameter was affected. In this study, dirithromycin was found to have low affinity for human CYP3A in vitro, which is in accordance with the study's finding that in vivo dirithromycin has no major effect on the metabolism of the CYP3A substrate terfenadine in humans.
Pharmacokinetics of Sematilide in Renal Failure
Authors: Shi Jun , Ripley Elizabeth , Gehr Todd W. B. , Sica Domenic A. , Dandekar Kishor A. , Hinderling Peter H.
Published: March 2013

A randomized, two‐period, two‐treatment study was conducted to investigate the effect of renal impairment on the pharmacokinetics of the Class III antiarrhythmic sematilide HCl. The pharmacokinetic—pharmacologic effect relationship and tolerability of sematilide HCl were also studied. The study included 22 subjects: 6 healthy volunteers and 16 patients with various degrees of renal impairment, including functionally anephric patients on intermittent hemodialysis. Separated by a 14‐day washout period, the subjects received a constant rate intravenous infusion of 40 mg sematilide HCl over 30 minutes and a tablet containing 100 mg of the drug. The functionally anephric patients were studied during and off dialysis after intravenous and oral administration of the drug, respectively. Blood and urine samples were collected at defined times up to 48 hours and 72 hours, respectively, after administration. Sematilide concentrations in plasma, urine, and dialysate were measured by a validated high‐performance liquid chromatography (HPLC) method with ultraviolet detection. The pharmacokinetic data analysis used a compartment model independent approach. The heart rate‐corrected Lead II QT interval was recorded as a pharmacologic end‐point. Subjective symptoms, cardiovascular parameters, routine serum chemistry, and hematology and urinalysis parameters were measured to assess tolerability. Mean renal clearance after intravenous and oral administration was reduced in patients with severe renal impairment. Statistically significant linear correlations existed between total clearance of sematilide and creatinine clearance for all subjects who could be evaluated after both intravenous and oral administration. Steady‐state volume of distribution, absolute bioavailability, and nonrenal clearance of sematilide were independent of renal function. The mean dialysis clearance was 98 mL/min, indicating effective removal of the drug by hemodialysis. In accord with the drug's Class III pharmacologic activity, the heart rate corrected Lead II QT intervals were prolonged in all subjects after intravenous and oral administration of the drug. The pharmacologic effect to plasma concentration relationship in renal patients and in healthy subjects was comparable. Based on the experimentally determined linear relationship between total clearance of sematilide and creatinine clearance, modified dose regimens for sematilide HCl in patients with renal impairment and functionally anephric patients off hemodialysis were developed.
Enhancement of Anticoagulant Action by Warfarin—Benzbromarone Interaction
Authors: Shimodaira Hideo , Takahashi Kiyoe , Kano Kimiko , Matsumoto Yusuke , Uchida Yutaka , Kudo Tatsuhiko
Published: March 2013

To investigate the interaction between warfarin potassium and benzbromarone, administration of benzbromarone to patients receiving long‐term treatment with both drugs was discontinued for 1 week and then resumed, and the resulting changes in the coagulation system were examined. Thrombotest value, activity of coagulation factors II and VIII, concentration of protein induced by vitamin K absence or antagonist‐II (PIVKA‐II), total plasma concentration of warfarin, and free warfarin concentration were measured during the period of concurrent administration of the two drugs, 1 week after discontinuation of benzbromarone, and after resumption of benzbromarone administration. After administration of benzbromarone had been discontinued for 1 week, the thrombotest value and factor II activity rose significantly whereas PIVKA‐II activity dropped significantly compared with corresponding levels before discontinuation, but these parameters tended to revert to the previously maintained levels after resumption of benzbromarone treatment. Activity of the vitamin K‐independent factor VIII displayed almost no changes, however. Total plasma warfarin concentration also decreased significantly, and free warfarin concentration was nearly unchanged. These results verified that the anticoagulant action of warfarin is enhanced by concurrent administration of benzbromarone. Accordingly, adequate consideration must be devoted to the prevention of grave hemorrhagic tendencies when these two drugs are administered concurrently.
Crossover Trials with a Binary Response: A Powerful Method Despite the Carryover Effect
Authors: Cleophas Ton J. M. , Van Lier Henk J. J.
Published: March 2013

The two‐period crossover trial has the evident advantage that, by use of within‐patient comparisons, the usual large between‐patient variability is not used as a measure to compare treatments. A prerequisite, however, is that the order of the treatments does not substantially influence the outcome of the treatment. Crossover studies with a binary response (such as yes/no or present/absent), although widely used for initial screening of new compounds, have not previously been studied for such order effects. This study uses a mathematical model based on standard statistical tests to study to what extent such order effects, here identical to carryover effects, may reduce the power of detecting a treatment effect. It is concluded that, despite large carryover effects, the crossover study with a binary response remains a powerful method and that testing for carryover effects makes sense only if the null hypothesis of no treatment effect cannot be rejected.
Explaining Variable Absorption of a Hypolipidemic Agent (CGP 43371) in Healthy Subjects by Gamma Scintigraphy and Pharmacokinetics
Authors: Sun Jim X. , Walter Brian , Sandefer Erik P. , Page Richard C. , Digenis George A. , Ryo U. Yun , Cipriano Alexandra , Maniara Wieslawa M. , Powell Mark L. , Chan Keith
Published: March 2013

The gastrointestinal absorption of a hypolipidemic agent (CGP 43371) was investigated using an external scintigraphy technique in six healthy men. After an overnight fast, subjects received a single 800‐mg oral dose of CGP 43371 (4 capsules of 200 mg each) and one capsule of radioactive samarium‐153 oxide (100–130 μCi) as a nonabsorbable marker of gastrointestinal transit and fecal recovery for CGP 43371. In vivo gastrointestinal transit of samarium‐153 was monitored via gamma scintigraphy for 48 hours after administration to coincide with blood sampling. Samarium‐153 content in whole fecal samples was determined by external gamma scintigraphy, and CGP 43371 content in both fecal and plasma samples was determined using high‐performance liquid chromatography (HPLC). The results of fecal analysis indicated that transit of the two compounds in the gastrointestinal tract were similar, and bioavailability of CGP 43371 was calculated to be 9% based on the difference between the cumulative amounts of the nonabsorbable radioactive marker and CGP 43371 found in the feces. The onset of drug absorption occurred 4 hours after administration when radioactive samarium‐153 was in the distal small bowel, and peak plasma drug level occurred 6 hours after administration, which corresponded with the arrival of samarium‐153 in the terminal ileum and ileal/cecal junction. This observation supported the concept that primary absorption of this compound was in the distal to terminal portion of the ileum. Although the onset of drug absorption was delayed, it was curious that the rate of gastric emptying also affected the extent of absorption. A positive correlation (r = 0.91) between area under the drug curve (AUC) and area under the transit curve (AUTC) of the gastric emptying showed that longer gastric residence improved oral absorption of CGP 43371.
No Evidence of a Direct Venodilatory Effect of Furosemide in Healthy Human Subjects
Authors: Harada Kazuhiro , Ohmori Masami , Fujimura Akio , Ohashi Kyoichi
Published: March 2013

The present study was undertaken to examine whether furosemide, a loop diuretic, has a direct venodilatory effect in healthy male subjects. Furosemide, or amrinone, an inotropic agent with a vasodilatory action, was infused into a dorsal hand vein that had been preconstricted by phenylephrine. The diameter of the vein was measured by a linear variable differential transformer. Venodilation was observed during the infusion of amrinone, but such a response was not detected with furosemide. These findings do not support the hypothesis that furosemide has a direct venodilatory effect in healthy human subjects.
Pharmacokinetics and Bioavailability of Mycophenolate Mofetil in Healthy Subjects after Single‐Dose Oral and Intravenous Administration
Authors: Bullingham Roy , Monroe Scot , Nicholls Andrew , Hale Michael
Published: March 2013

A randomized, crossover study of 12 healthy volunteers was conducted with single, 1.5‐g doses of mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), after oral and intravenous administration. During the intravenous infusion, phase systemic plasma clearance of MMF was ∼10 L/min and the half‐life (t1/2) was a few minutes. After oral administration, however, plasma MMF was below quantitation limits at all times. The plasma MPA profile of oral MMF showed a sharp peak at ∼1 hour and a secondary peak at 8 to 12 hours. Mean apparent plasma t1/2 of MPA was similar for both routes (∼17 hours). The area under the concentration‐time curve (AUC) from time 0 to 24 hours was statistically higher for intravenous than for oral administration, but total AUC showed statistical equivalence (80–120 rule), with mean bioavailability of MPA from oral administration of MMF estimated as 94.1% relative to the intravenous route. Total plasma AUC of mycophenolic acid glucuronide (MPAG), the sole metabolite of MPA, was four‐ to five‐fold higher than MPA. Total 48‐hour MPAG recovery in urine was statistically equivalent for the two routes and represented a mean of 70% of administered drug; corresponding MPA recovery was less than 1%. Renal clearance (CIr) values required transport mechanisms for MPAG, but not for MPA. The CIR of MPAG was statistically higher after intravenous administration than oral administration. MMF administered orally undergoes rapid, complete absorption and essentially complete presystemic deesterification. There was presystemic removal of MPA, but enterohepatic circulation compensated for the first pass loss. Renal metabolism of MPA also may have occurred.
Effect of Time of Administration on the Pharmacokinetics and Tolerance of Doxazosin in Healthy Male Volunteers
Authors: Vashi Vijay , Chung Menger , Dias Norma , Phillips Kem
Published: March 2013

A randomized, open‐label, two‐way crossover study of 24 normotensive, healthy male volunteers with nocturia was conducted to compare morning and evening administration of doxazosin in terms of pharmacokinetics and tolerance. In both the morning and evening phases, participants received doxazosin 1 mg once daily for 10 days, followed by 2 mg once daily for 5 days. Pharmacokinetic data were evaluated from blood samples serially collected for 72 hours after drug administration on the last day of each phase. Vital signs and adverse events were recorded throughout the study. Mean peak plasma concentrations (Cmax) were 16.98 and 15.76 ng/mL after morning and evening administration, respectively. Corresponding mean values of area under the plasma concentration‐time curve (AUC0–24) were 227.90 and 253.66 ng.hr/mL, respectively. Statistical analysis of the log‐transformed values for Cmax and AUC0–24 indicated that morning and evening administration of doxazosin were bioequivalent. There were no statistically or clinically significant differences between phases for mean apparent half‐life (t1/2) or total body clearance. There were no clinically relevant differences in blood pressure or in pulse rate between phases, and no occurrences of orthostatic hypotension. The incidence of adverse experiences during morning and evening administration was similar. Morning and evening administration of doxazosin are equivalent and have similar tolerance profiles.
Effects of Atorvastatin, an HMG‐CoA Reductase Inhibitor, on Hepatic Oxidative Metabolism of Antipyrine
Authors: Yang Bing‐Bing , Hounslow Neil J. , Sedman Allen J. , Forgue S. Thomas
Published: March 2013

Possible effects of multiple‐dose administration of atorvastatin on the pharmacokinetics of single‐dose antipyrine were evaluated in this drug‐drug interaction study. Twelve healthy male volunteers received three 200‐mg capsules of antipyrine on days 1 and 22, and two 40‐mg atorvastatin tablets in the morning on days 8 through 23. Serial blood and urine samples were collected after administration of each antipyrine dose. Plasma was analyzed for antipyrine, and urine samples were analyzed for antipyrine, 4‐hydroxyantipyrine, and norantipyrine by validated high‐performance liquid chromatography with ultraviolet detection. Overall, antipyrine and atorvastatin doses were well tolerated in healthy volunteers. Mean antipyrine concentrations in plasma after administration of a single, oral dose of antipyrine during coadministration of multiple doses of atorvastatin were nearly superimposible on concentrations after administration of antipyrine alone. Individual and mean parameter values for plasma pharmacokinetics of antipyrine were similar in both treatment periods. Atorvastatin did not significantly alter the fraction of clearance of antipyrine in plasma that occurred by urinary excretion of 4‐hydroxyantipyrine and norantipyrine. These results indicate that the recommended highest daily dose of atorvastatin has negligible effects on antipyrine pharmacokinetics and on oxidative pathways responsible for the metabolism of antipyrine.
Magnitude and Nature of Noncompliance with Treatment using Isosorbide Dinitrate in Patients with Ischemic Heart Disease
Authors: Straka Robert J. , Fish Jeffrey T. , Benson Steven R. , Suh J. Thomas
Published: March 2013

Isosorbide dinitrate is one of the most commonly prescribed medications for the treatment of ischemic heart disease. It has been demonstrated to be ineffective relative to placebo when taken inappropriately. This study objectively documents the magnitude and nature of compliance in 68 ambulatory patients who were prescribed isosorbide dinitrate three times a day. Each patient received a 9‐week supply of medication in a vial equipped with a computerized monitor (MEMS‐4 cap; APREX Corporation, Fremont, CA) and were informed as to the purpose of the study. Of the patients, 74% were classified into the low and 16% into the high compliance category, defined as compliant <70% and ≥85% of study days, respectively. The mean (±SD) percent days in which isosorbide dinitrate was taken three times was 66% (±29), and the mean number of days in which it was taken three times with a 10‐hour “nitrate free period” was 53% (±31). It is concluded that the magnitude of noncompliance in patients prescribed isosorbide dinitrate three times daily is substantial (74%). The nature of this noncompliance is often due to failure to observe a 10‐ to 12‐hour nitrate free period. Given the need to take isosorbide dinitrate appropriately and given the demonstrated magnitude of noncompliance, physicians should take these factors into consideration when selecting this agent for the management of coronary artery disease relative to other pharmacologic options.
Population Pharmacokinetics of Intravenous Amiodarone in Patients with Refractory Ventricular Tachycardia/Fibrillation
Authors: Korth‐Bradley Joan M. , Rose Gilbert M. , De Vane Philip J. , Peters John , Chiang Soong T.
Published: March 2013

A population approach was used to determine the pharmacokinetics of amiodarone in 245 patients receiving intravenous amiodarone for the short‐term treatment of refractory, hemodynamically destabilizing, ventricular tachycardia and/or fibrillation. A two‐compartment model employing proportional statistical models to estimate intersubject variability and an additive‐proportional model to estimate residual error were found to best describe the data. The mean (% coefficient of variation, CV) value for clearance was 0.22 L/hr/kg (13%), central volume of distribution was 0.30 L/kg (11%), peripheral volume of distribution was 10.0 L/kg (9.5%), and intercompartmental clearance was 0.71 L/hr/kg (16%). The mean (%CV) intersubject variance estimates were 1.52 (31%) for clearance, 0.37 (46%) for central volume, 0.37 (67%) for peripheral volume, and 0.44 (39%) for intercompartmental clearance. The estimate of residual error (%CV) was 0.53 (13%). Age, gender, height, serum creatinine concentration, serum alkaline phosphatase activity, ejection fraction, and therapeutic response to treatment did not contribute to the variability in patient pharmacokinetics. It was concluded that the pharmacokinetic parameters of amiodarone in these patients were similar to those reported for healthy volunteers and were similarly variable. Estimates of pharmacokinetic parameters made during short periods of observation may not be entirely consistent with parameters estimated during prolonged periods of observation of healthy volunteers who receive single doses.
Pharmacokinetics of Intravenous Amiodarone in Patients with Impaired Left Ventricular Function
Authors: Vadiei Kiumars , O'Rangers Eleanor A. , Klamerus Karen J. , Kluger Jeffrey , Kazierad David J. , Leese Philip T. , Chow Moses S. , Zimmerman James J.
Published: March 2013

To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15‐minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but ≤45%; n = 6), or severely impaired (ejection fraction ≤ 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76‐day period for estimation of pharmacokinetic parameters. With the exception of the half‐life (t1/2) of DEA, statistical comparisons revealed no significant between‐group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short‐term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.
Predominance of Slow Acetylators of N‐acetyltransferase in a Hmong Population Residing in the United States
Authors: Straka Robert J. , Hansen Shawn R. , Benson Steven R. , Walker Patricia F.
Published: March 2013

Pharmacogenetics can be an important determinant of pharmacologic response. To learn more about interpopulation differences in drug metabolism between ethnically diverse populations of subjects cared for by an International Clinic, a study was conducted to describe the prevalence of fast or slow acetylators of N‐acetyltransferase (NAT2) in a population of Hmong residing in Minnesota. Ninety‐eight healthy Hmong refugees from Laos volunteered to take caffeine as an oral probe drug to establish acetylator phenotype. Participants were classified as either rapid or slow acetylators based on the urinary molar ratio of select metabolites of caffeine. Assignment of phenotype was based on results from analysis of urine collected subsequent to ingestion of caffeine. The ratio of 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU) to the combined products of the 7‐demethylation pathway of paraxanthine [AFMU, 1‐methylxanthine (1X), and 1‐methylurate (1U)] formed the basis for this determination. A probit plot of the data collected in our subjects qualified a metabolic ratio of 0.34 as an acceptable cut point for phenotype assignment. Participants with an AFMU/(AFMU + 1X + 1U) ratio of < 0.34 were classified as slow acetylators and all others as rapid acetylators. Analysis of the data suggested a bimodal distribution with an excess (74.5%) of slow acetylators in the population. The predominance of slow acetylators found in the Hmong contrast with the prevalence of slow acetylators seen in other ethnic groups. These findings may have important clinical implications given the large number of Hmong treated each year in our International Clinic and the increasing use of medications metabolized by NAT2 in this population.
Pharmacokinetics of Tirilazad and U‐89678 in Ischemic Stroke Patients Receiving a Loading Regimen and Maintenance Regimen of 10 mg/kg/day of Tirilazad
Authors: Fleishaker Joseph C. , Peters Gary R.
Published: March 2013

The pharmacokinetics of tirilazad mesylate and its active reduced metabolite, U‐89678, were evaluated in ischemic stroke patients receiving 2.5 mg/kg tirilazad every 3 hours for the first 12 hours of dosing followed by 2.5 mg/kg every 6 hours for a total of 22 doses (5 days). Trough and serial samples drawn during the 6 hours after administration of the last dose were analyzed for plasma levels of tirilazad and U‐89678 by means of high‐performance liquid chromatography. Complete concentration—time profiles were available for 20 patients, including 12 men (mean age, 68.0 years) and 8 women (mean age, 75.0 years). Trough concentrations of tirilazad and U‐89678 were consistent with the loading regimen used. The mean area under the concentration—time curve from time 0 to 6 hours (AUC0–6) of tirilazad was 8181 ± 2398 ng · hr/mL in men and 8135 ± 3671 ng · hr/mL in women. The mean AUC0–6 of U‐89678 was 2761 ± 1834 ng · hr/mL in men and 1477 ± 903 ng · hr/mL in women. These results show that gender has a modest effect on the pharmacokinetics of U‐89678 but little effect on the pharmacokinetics of tirilazad in elderly ischemic stroke patients. These observations are consistent with previous findings in healthy young and elderly subjects.
Use of β ‐ Adrenergic Receptor Blockers in Blacks
Authors: Prisant L. Michael , Mensah George A.
Published: March 2013

Beta adrenergic receptor blockers (β‐blockers) are an important class of drugs in the management of patients with cardiovascular diseases. These drugs have been shown to reduce mortality in hypertension and prolong survival in patients with coronary heart disease. Although hypertension and coronary heart disease account for the majority of excess cardiovascular morbidity and mortality in blacks, β‐blockers continue to be underprescribed in this ethnic group. The magnitude of blood pressure reduction in black patients with hypertension has been consistently less during monotherapy with nonselective β‐blockers than with diuretics. However, the highly selective β‐blocker bisoprolol has been shown to be as effective as diuretics and is equally effective in black and nonblack patients with hypertension. In general, no racial differences in efficacy are noted when β‐blockers are used with diuretics as combination therapy for hypertension. Black patients should not be denied β‐blocker therapy because of an anticipated suboptimal response, especially when there are clear indications for treatment (e.g., for migraine, hyperthyroidism, arrhythmia control, and after myocardial infarction).
The Pharmacokinetics and Bioavailability of Clemastine and Phenylpropanolamine in Single‐Component and Combination Formulations
Authors: Schran Horst F. , Petryk Lew , Chang Cheng‐Tao , O'Connor Robert , Gelbert Mark B.
Published: March 2013

Studies were conducted in healthy male volunteers (n = 171; age range, 19–49 years; 22–27 subjects per study) to examine the following: pharmacokinetics and dose proportionality of the antihistamine clemastine; the effect of coadministration of phenylpropanolamine and clemastine on the pharmacokinetics of the two drugs; and the bioavailability of clemastine tablets and combination tablets of clemastine and sustained‐release phenylpropanolamine under fasted and fed conditions after single‐dose administration and at steady state. All studies used crossover designs, with randomized drug treatments separated by a 7‐day washout period for the single‐dose studies, and with administration every 6 or 12 hours for 7 days per treatment for the steady‐state studies. After single oral doses of clemastine solution (1, 2, and 4 mg), the area under the concentration—time curve (AUC) and maximum concentration (Cmax) were dose proportional. Clemastine showed a first‐pass reduction in the extent of absorption, with oral bioavailability calculated as 39.2 ± 12.4%. Extravascular distribution of drug was suggested by the high volume of distribution (799 ± 315 L) and low Cmax (0.577 ± 0.252 ng/mL/mg) observed at 4.77 ± 2.26 hours after administration, and by the biphasic decline in plasma concentration. The terminal elimination half‐life (t1/2) of clemastine was 21.3 ± 11.6 hours. Steady‐state concentrations of clemastine were consistent with linear pharmacokinetic processes, and clearance was unaffected by age in the range studied, or by race. Clemastine solution and tablets were bioequivalent, and food had no significant effect on rate and extent of absorption of clemastine. The 1‐ and 2‐mg clemastine tablets showed proportional bioavailability. Coadministration of clemastine with phenylpropanolamine did not significantly influence the pharmacokinetics of clemastine or the AUC and elimination t1/2 of phenylpropanolamine, but reduced the rate of absorption of phenylpropanolamine. Combination tablets containing 1 mg or 2 mg of immediate‐release clemastine plus 75 mg of sustained‐release phenylpropanolamine for twice daily administration were bioequivalent to the separate components and showed no significant interaction with food.
Dynamic Modeling of Cortisol Reduction after Inhaled Administration of Fluticasone Propionate
Authors: Rohatagi Shashank , Bye Alan , Falcoz Christine , Mackie Alison E. , Meibohm Bernd , Möllmann Helmut , Derendorf Hartmut
Published: March 2013

Fluticasone propionate (FP) is a new corticosteroid that has been developed for the treatment of asthma. The compound has a very high receptor affinity, 18 times that of dexamethasone. After inhalation, FP is systemically available because of inhaled bioavailability. In healthy subjects this may lead to measurable systemic effects, such as cortisol reduction. A clinical study was conducted in 12 healthy volunteers to determine the systemic effects after inhaled administration of single 500‐μg, 1,000‐μg, and 2,000‐μg doses of FP. Blood samples were collected over a 24‐hour period after administration. Concentrations of FP and cortisol were measured in plasma by immunoassay. Cortisol reduction was chosen as the pharmacodynamic parameter. A novel linear release rate model was used to parameterize the cortisol data. The pharmacokinetics of FP were linear over the dose range studied. The cortisol release parameters were determined from baseline data (before drug administration). Based on these results, the E50 values for cortisol reduction were then determined for each dose of FP. The average E50 was 0.134 ng/mL for total FP concentrations and 0.013 ng/mL for unbound FP concentrations; these results were not dose dependent. These in vivo pharmacodynamic values measured in healthy subjects are in good agreement with the relatively high receptor affinity of FP.
Lack of Pharmacokinetic Interaction Between Buspirone and Haloperidol in Patients with Schizophrenia
Authors: Huang Huang F. , Jann Michael W. , Wei Fu‐Chuan , Chang Teng‐Ping , Chen Jeng‐Shong , Juang Dong‐Juiing , Lin Shih‐Ku , Lam Y. W. Francis , Chien Ching‐Piao , Chang Wen‐Ho
Published: March 2013

The pharmacokinetic interaction between buspirone and haloperidol was evaluated in schizophrenic patients in two different groups. In both groups, haloperidol doses (10–40 mg/day) remained constant for 6 weeks before the addition of buspirone 10 mg three times daily. Serial blood samples were obtained from the 11 patients in group I at baseline (before addition of buspirone) and after administration for 24 hours. The pharmacokinetic parameters of haloperidol were determined alone and with coadministration of buspirone. In group II, buspirone 10 mg three times daily was added to treatment with haloperidol in 27 patients. Blood samples were obtained before addition of buspirone and at weeks 2 and 6 of treatment with buspirone. Samples were obtained 10 to 12 hours after administration of the evening dose and before the morning dose. Haloperidol and its metabolite, reduced haloperidol (RH), were assayed by means of high‐performance liquid chromatography with electrochemical detection. Significant changes in the pharmacokinetic parameters of haloperidol were not found in group I; a mean increase in the half‐life (t1/2) of haloperidol from 21.5 to 28.1 hours was observed, but this finding was not statistically significant. Under steady‐state conditions, plasma levels of haloperidol in the patients in group II did not change significantly from baseline to week 6. Plasma concentrations of RH remained unaltered in both groups. The results indicate that coadministration of buspirone does not markedly affect the pharmacokinetics or plasma concentrations of haloperidol.
Pharmacokinetics of a New Thromboxane A2 Receptor Antagonist, S‐1452, and its Effect on Platelet Aggregation in Healthy Volunteers
Authors: Fujimura Akio , Shiga Tsuyoshi , Kumagai Yuji , Ohashi Kyo‐ichi , Ebihara Akio , Kotegawa Tsutomu
Published: March 2013

To study the pharmacokinetics of a new thromboxane A2 (TXA2) receptor antagonist, S‐1452, eight healthy volunteers were given placebo or S‐1452 orally on four occasions in step‐wise increasing doses of 10 mg, 25 mg, and 50 mg separated by 2‐week intervals. Blood samples for measurement of plasma concentrations of the drug and of its inhibitory effect on platelet aggregation were obtained for 24 hours after administration. Bleeding time after administration was measured. S‐1452 was rapidly absorbed, with a peak plasma concentration at 30 minutes after administration. Thereafter, the drug was rapidly eliminated (elimination half‐life, 0.4–0.5 hours), and no drug was detected at 6 hours. The inhibitory effect of S‐1452 on platelet aggregation, which was stimulated by the TXA2 receptor agonist U‐46619, persisted more than 6 hours after drug administration. Bleeding time was slightly prolonged after a single dose of S‐1452. These results suggest that although S‐1452 is rapidly eliminated in plasma, its inhibitory effects on platelet aggregation persist for a longer period. Careful observations are needed to prevent potential bleeding episodes during repeated treatment with the drug.
Effectiveness and Safety of Low‐Dose Pravastatin and Squalene, Alone and in Combination, in Elderly Patients with Hypercholesterolemia
Authors: Chan Paul , Tomlinson Brian , Lee Ching‐Bing , Lee Ying‐Shiung
Published: March 2013

A double‐blind, placebo‐controlled study was conducted to compare the efficacy and safety of low‐dose (10 mg) pravastatin and squalene (860 mg), either alone or in combination therapy, with placebo in the treatment of elderly patients with hypercholesterolemia. Ambulatory elderly patients (N = 102) were assigned in randomized fashion to receive active treatment or placebo for 20 weeks after a single‐blind placebo lead‐in period of 8 weeks. Total cholesterol and triglyceride levels in plasma were at least 250 mg/dL and less than 300 mg/dL, respectively. Concentrations of lipids and lipoproteins were measured, and clinical laboratory tests included liver function and creatine kinase determinations. Pravastatin 10 mg daily was more effective than squalene in reducing total cholesterol, low‐density lipoprotein (LDL) cholesterol, and triglycerides and in increasing levels of high‐density lipoprotein (HDL) cholesterol. Combination therapy significantly reduced total cholesterol and LDL cholesterol and increased HDL cholesterol to a greater extent than either drug alone. Adverse events and clinical laboratory abnormalities were generally mild and transient in all groups, and all but two patients finished the study. The incidence of side effects was low; myopathy did not occur. Coadministration of pravastatin and squalene combined the specific effects of the two drugs on lipoprotein concentrations. This combination may be useful and more cost‐effective in elderly patients with hypercholesterolemia, who might have a higher incidence of side effects when using larger doses of pravastatin alone.
Pharmacokinetics of CGP 36 742, an Orally Active GABAB Antagonist, in Humans
Authors: Gleiter Christoph H. , Farger Gisbert , Möbius Hans‐Jörg
Published: March 2013

A study was conducted to evaluate the pharmacokinetics of CGP 36 742 (3‐aminopropyl‐n‐butyl‐phosphinic acid), an orally active γ‐aminobutyric acid B (GABAB) antagonist, in humans. Pharmacokinetic results after a single oral (600 mg) dose included maximum observed concentration (Cmax), 27 μmol/L (95% CI 22.9, 30.8); time to Cmax (tmax), 3 hours (median); half‐life (t1/2), 3.6 hours (95% CI 3.24, 3.9); renal clearance (CIR), 125 mL/min (95% CI 114, 136); and absolute bioavailability (Fabs), 0.44 (95% CI 0.33, 0.47). Administration with food decreased the oral systemic availability (Fre) by 30%. The volume of distribution (285 L/kg) was in the order of magnitude of extracellular body water. The absorbed fraction of the compound was excreted completely and unchanged via the kidney, thus renal function would be the limiting factor for excretion. The rate of absorption and amount absorbed did not differ significantly between elderly and young healthy male volunteers, both after single and multiple doses. There was no gender‐related difference in pharmacokinetics in healthy elderly volunteers. CGP 36 742 showed an excellent safety profile: there were no clinically relevant changes in cardiovascular variables, body temperature, or blood chemistry. In the placebo‐controlled trial, adverse experiences were rare and evenly distributed among participants receiving placebo and the study drug. In addition, a newly developed high‐performance liquid chromatography (HPLC) method for measurement of CGP 36 742 concentrations in plasma and urine using fluorescence detection is described.
Pharmacokinetics and Safety of a Novel, Long‐Acting, Prodrug‐Type Potassium Channel Opener, Y‐27152, in Healthy Volunteers
Authors: Uematsu Toshihiko , Kosuge Kazuhiro , Hirosawa Sei‐ichi , Kadobe Yukinobu , Hibi Toru , Nakashima Mitsuyoshi
Published: March 2013

The pharmacokinetics and safety of a novel, long‐acting, prodrug‐type K+‐channel opener, Y‐27152, were investigated in healthy male volunteers. In the first phase, single oral doses of 0.1, 0.25, 0.5, 0.75, and 1.0 mg of Y‐27152 (n = 3–6 per dose) were given after overnight fasts in a dose‐escalating manner. The 0.75‐mg dose was given both after an overnight fast or after food to examine the effects of food intake. In the second phase, multiple doses of Y‐27152 were taken after meals once daily for 7 consecutive days. In part A of this phase, either placebo (n = 3) or 0.5 mg of Y‐27152 (n = 6) was taken for 7 days, and in part B of this phase 0.5‐, 0.75‐, and 1.0‐mg doses were taken in a dose‐escalating manner for 1, 3, and 3 days, respectively (n = 9). In the single‐dose study, peak concentration (Cmax) and area under the plasma concentration‐time curve (AUC) of main active metabolite (Y‐26763; M1) increased in parallel with dosage. This dose‐linearity was less obvious with Y‐27152, which had an AUC approximately 6 to 10 times less than that of M1. Administration with food at 0.75 mg resulted in a small but significant decrease (∼10%) in the Cmax and AUC of M1. At doses of 0.5 mg or higher, participants experienced headaches and palpitations, which were probably due to the vasodilatory effects and did not require treatment. Mean diastolic blood pressure significantly decreased and pulse rate increased at doses of 0.5 mg or higher compared with predose values. Plasma renin activity was significantly elevated 4 hours after the administration of the 0.75‐ and 1.0‐mg doses, but showed no significant change at 0.5 mg. In the multiple‐dose study, the time profile of the plasma concentration of M1 approximately coincided with the simulation curves worked out using the pharmacokinetic parameters obtained in the single‐dose study. The incidence of headaches tended to increase with dose in part B, but drug administration was not discontinued in any case. Plasma renin activity again increased 4 hours after administration. In phase B of the multiple‐dose study, diastolic blood pressure decreased and pulse rate increased compared with predose values. Y‐27152 was metabolized to M1 and well tolerated in healthy volunteers, and its pharmacologic effects were likely caused by vasodilation, which could make it an effective antihypertensive agent.