bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of N‐Acetylation of Procainamide and Renal Clearance of N‐Acetylprocainamide by Para‐Aminobenzoic Acid in Humans
Authors: Tisdale James E. , Rudis Maria I. , Padhi I. Desmond , Svensson Craig K. , Webb Charles R. , Borzak Steven , Ware Joseph A. , Krepostman Abraham , Zarowitz Barbara J.
Published: March 2013

Procainamide administration often results in excessively high serum N‐acetylprocainamide (NAPA) concentrations and subtherapeutic serum procainamide concentrations. Inhibition of N‐acetylation of procainamide may prevent accumulation of excessive NAPA while maintaining therapeutic serum procainamide concentrations. The purpose of this randomized, two‐way crossover study was to determine if para‐aminobenzoic acid (PABA) inhibits N‐acetylation of procainamide in healthy volunteers. Eleven (7 female, 4 male) fast acetylators of caffeine received, in random order, PABA 1.5 g orally every 6 hours for 5 days, with a single intravenous dose of procainamide 750 mg administered over 30 minutes on the third day, or intravenous procainamide alone. Blood samples were collected during a 48‐hour period after initiation of the infusion. Urine was collected over a 72‐hour period. Serum procainamide and NAPA concentrations were analyzed using fluorescence polarization immunoassay. Urine procainamide and NAPA concentrations were measured with high performance liquid chromatography. PABA did not significantly influence total or renal procainamide clearance, elimination rate constant, AUC0‐∞, amount of procainamide excreted unchanged in the urine, or volume of distribution. However, concomitant PABA administration with procainamide resulted in increases in NAPA AUC0‐∞ and t1/2 and reductions in NAPA Ke, procainamide acetylation (NAPA formation) clearance, and NAPA renal clearance. Although PABA inhibits metabolic conversion of procainamide to NAPA, it also impairs the renal clearance of NAPA (but not procainamide) in healthy subjects. Therefore, PABA may not be useful for optimizing the safety or efficacy of procainamide in patients.
Estrogen Therapy for Postmenopausal Symptoms and Prevention of Osteoporosis
Authors: Sagraves Rosalie
Published: March 2013

Menopausal symptoms are noted as estrogen deficiency affects target tissues during the climacteric and after menopause. With estrogen replacement therapy (ERT), clinical signs, such as vasomotor symptoms and genitourinary atrophy, abate. Estrogen replacement therapy protects against the development of osteoporosis and is used in its treatment. In addition, ERT has a positive effect on serum lipids and appears to he protective against coronary heart disease. More than 75% of all women experience troublesome vasomotor symptoms during the climacteric years, and osteoporosis is a major cause of morbidity and mortality in postmenopausal women. In the United States, the current annual cost of treating patients with osteoporosis is $10 billion dollars. With the aging of the baby boom generation, it is estimated that osteoporosis‐associated costs may double in the next 30 years if interventions are not undertaken to reduce the incidence of osteoporosis. It is therefore important for pharmacists and other health care practitioners to educate women about ERT after menopause to reduce the risks of vasomotor symptoms, osteoporosis, and other problems. The incidence, etiology, symptoms, and therapeutic measures used to reduce vasomotor symptoms are discussed, and updates on pathophysiology, risk factors, prevention, and treatment of osteoporosis, with an emphasis on ERT, are reviewed.
Steady‐State Kinetics of Fluoxetine and Amitriptyline in Patients Treated with a Combination of These Drugs as Compared with Those Treated with Amitriptyline Alone
Authors: El‐Yazigi Adnan , Chaleby Kutaiba , Gad Ahmed , Raines Dale A.
Published: March 2013

The steady‐state kinetics of amitriptyline (AMI), fluoxetine (FLU), and their active metabolites nortriptyline (NTRIP) and norfluoxetine (NFLU) were studied in 15 patients treated once daily for long durations with 50 mg of AMI and 20 mg of FLU. These compounds were analyzed simultaneously in plasma by liquid chromatography. The means and (SEM) of the steady‐state concentrations (Css) of AMI, NTRIP, FLU, and NFLU were 80.6 (14.2), 52.6 (10.3), 85.3 (16.1), and 90 (13.6) ng/mL, respectively, and the apparent oral clearances (CLor of AMI and FLU were 42.4 (8.6) and 14.9 (2.5) L/hr, respectively. The metabolite/drug steady‐state concentration ratio (Css(m)/Css) for NTRIP/AMI was 0.75 (0.14) and for NFLU/FLU was 1.27 (0.17). There was a significant correlation (P <0.05) between Css of FLU and that of AMI or NTRIP. The Css and (Css(m)/Css) values obtained for AMI were higher (P <0.056 and P <0.0034, respectively) than those we observed in 10 patients treated solely with the same dose of AMI. The twofold increase in Css of AMI and ninefold increase in Css of NTRIP seem to be the result of inhibition of the metabolism of these compounds by FLU, particularly the ring hydroxylation. Norfluoxetine may have a small inhibitory influence on the metabolism of NTRIP but lacks this effect on the metabolism of AMI.
An Individualized Approach to the Hypertensive Patient with Renal Disease: Six Illustrative Case Studies
Authors: Elliott William J.
Published: March 2013

One of the biggest challenges in medicine is the area of therapeutics, wherein the physician attempts to match the needs of the individual patient with a specific agent from the pharmacopeia, at the dose that might be best suited to treat the individual's problem. A great deal of the art of medicine is involved in this “matching process,” in which the scientific aspects of diagnosis and therapy meet with the physician's knowledge of clinical pharmacology. The abbreviated case histories of six patients who came to the author with specific questions regarding therapy of their hypertension and renal impairment illustrate the fact that one of any number of therapies might have reduced blood pressure in these patients, but in each, there was a specific reason to attempt a single approach first. If physicians could better understand and extrapolate the results of clinical research to the treatment of specific patients, choice of therapy might become more successful.
Clinical Aspects of Cardiovascular Effects of H2‐Receptor Antagonists
Authors: Hinrichsen H. , Halabi A. , Kirch W.
Published: March 2013

In vitro studies and animal experiments as well as clinical observations in humans concerning cardiovascular effects of H2‐receptor antagonists have been published shortly after the development. Thus, clinical studies were performed to investigate these effects. The following review summarizes the results from in vitro studies up to the clinical investigations performed.
Survey Results of POPS Use in United States and Canadian Schools of Medicine and Pharmacy
Authors: Ingenito Alphonse J. , Wooles Wallace R.
Published: March 2013

Recent initiatives calling for changes in medical education, such as the General Professional Education of the Physician and Robert Wood Johnson Reports, have recommended alternative teaching approaches to the lecture format. The Patient‐Oriented Problem‐Solving (POPS) exercises, sponsored by the Upjohn Company (Kalamazoo, MI) and made available for pharmacology in 1985, offer one of many possible alternatives to lectures. The technique involves group interactions between four students in a working group, each of whom must, with the aid of their colleagues, arrive at mutual solutions to simulated cases in clinical pharmacology. The exercises are intended to complement and enhance the learning of concepts from lectures, and to help students apply these concepts practically. The system is used extensively by medical, pharmacy, and other health profession schools throughout the United States and also abroad, and many thousands of exercise booklets have been distributed free of charge by the Upjohn Company. Currently, a committee of the American Medical School Pharmacology (AMSP) group, working with Upjohn Company personnel, is responsible for overseeing the writing and educational testing of new and revised exercises. The purpose of this paper is to report the results of a survey of POPS use in medical and pharmacy schools in the United States, Canada, and Puerto Rico, completed in March 1993. The returns indicate continued strong interest in the approach, and the acquired data affirm its value in teaching principles of clinical pharmacology to students in basic pharmacology courses. Detailed data were obtained on patterns of use, and a number of advantages and disadvantages were identified. Priorities for the writing of new POPS exercises were expressed by the respondents. The information acquired will form the basis for planning new and revised POPS exercises in the future.
Effects of Hemodialysis on Plasma Protein Binding of Bepridil
Authors: Pritchard J. Frederick , Matzke Gary R. , Opsahl John A. , Halstenson Charles E. , Nayak Ramchandra K.
Published: March 2013

The effects of end‐stage renal disease (ESRD) and hemodialysis on the in vitro plasma protein binding of bepridil hydrochloride were investigated. The possible influence of bepridil metabolites on bepridil‐protein binding in ESRD patients was also examined. Plasma samples were obtained from six patients with ESRD. Bepridil‐plasma protein binding was measured by microequilibrium dialysis after addition of freshly prepared bepridil‐14C (239 μCi/mg) at a final concentration of 2 μg/mL. The percentage of free bepridil in peripheral venous samples drawn on a nondialysis day was lower (i.e., binding was greater) in the patients with ESRD relative to previous observations in healthy subjects (0.15% ± 0.04% versus 0.31% ± 0.05% (mean ± SD). The plasma concentrations of α‐1‐acid glycoprotein (AAG), the principal bepridil binding protein, were also higher in ESRD patients (110 ± 32 mg/dL) than previously reported in healthy subjects. Although hemodialysis resulted in significant increases in AAG, total protein, and albumin concentrations, no significant difference in bepridil‐plasma protein binding was detected between predialysis and postdialysis peripheral venous samples in the presence (0.16 versus 0.18) or absence (0.20 versus 0.17) of bepridil metabolites. The percentage of free bepridil in plasma from both the arterial and venous limbs of the dialyzer during hemodialysis (means of free bepridil ranged from 0.24–0.28%) was higher than in samples drawn from a peripheral vein. This displacement of bepridil from its binding sites as blood passes through the dialyzer may have been owing to the presence of high local concentrations of plasticizers. Confirmation of this hypothesis will require further investigation.
Gastrointestinal Absorption of Pravastatin in Healthy Subjects
Authors: Triscari Joseph , O'Donnell Denis , Zinny Miguel , Pan Henry Y.
Published: March 2013

The bioavailability of pravastatin, a hypocholesterolmic agent, may be enhanced by decreasing its exposure to stomach contents, where it may be converted nonenzymatically to a relatively inactive metabolite. The pharmacokinetics of pravastatin and its metabolite were determined after infusion of pravastatin directly into the stomach (locus for greatest bioavailability for the metabolite), duodenum (greastest bioavailability for pravastatin), jejunum, or ileum. An enterically coated formulation of pravastatin may increase its bioavailability.
Effects of Food on the Bioequivalence of Different Verapamil Sustained‐Release Formulations
Authors: Waldman Scott A. , Morganroth Joel
Published: March 2013

Previously, clinical studies comparing generic and reference formulations of sustained‐release (SR) verapamil tablets revealed significant increases in the PR interval in subjects given the generic formulation in the presence of food. To determine the mechanisms underlying these differences in pharmacodynamics, the present analyses examined the pharmacokinetics of these formulations in the presence and absence of food. After single or multiple doses in fasting subjects, AUCs, Cmaxs, and tmaxs were similar, suggesting that these formulations were bioequivalent in the fasted state. However, the generic formulation exhibited a higher AUC(0–6) in fed subjects, suggesting that this formulation may be absorbed more rapidly than the reference formulation when given with food. Analysis of AUC(0–6) showed that 34% of the subjects receiving the generic formulation exhibited rapid absorption, compared with only 8% receiving the reference formulation. Significant increases in the PR interval were seen in nine fed subjects receiving the generic formulation compared with two receiving the reference formulation. Similarly, three fed subjects receiving the generic drug who were rapid absorbers exhibited first‐degree heart block, whereas this conduction disturbance was seen in only one fed subject receiving the reference formulation. Thus, increased conduction disturbances seen in subjects given the generic formulation with a meal likely reflect more rapid absorption of this formulation in the presence of food, resulting in an increase in the ratio of more potent to less potent enantiomers of verapamil in the systemic circulation.
Renal and Limb Vasodilatation during Acute Beta‐Adrenoceptor Blockade with Indenolol
Authors: Poggesi Loredana , Bisi Gianni , La Cava Giuseppe , Sciagra Roberto , Del Rosso Attilio , Masotti Giulio
Published: March 2013

Indenolol is a noncardioselective beta‐adrenoceptor blocking drug with partial agonist activity. The mechanism of its acute antihypertensive activity has been evaluated in a double‐blind, inpatient, crossover, randomized study versus placebo in 12 patients (eight men, four women, mean age 53 ± 13 yr) with I and II WHO grade essential hypertension. Patients discontinued all antihypertensive and diuretic drugs at least 4 weeks before entry into the study. The effects of indenolol (120 mg) and placebo (2 weeks apart) were measured, in the same patient, 2 hours after a single oral administration. Variations of cardiac function were assessed by radionuclide angiocardiography, renal blood flow by sequential scintigraphy, and leg blood flow by strain‐gauge plethysmography. Compared with placebo, indenolol reduced systolic blood pressure by 27.9 mm Hg and diastolic blood pressure by 17.1 mm Hg. Heart rate was also significantly decreased. The hemodynamic profile of indenolol activity was characterized by a decrease of cardiac index, without significant changes in systemic vascular resistance. Both renal and leg blood flow were increased by indenolol, and vascular resistance in these districts was considerably reduced. The percent reduction of renal vascular resistance was correlated significantly with the percent reduction of mean blood pressure. In conclusion, acute administration of indenolol exerts a considerable antihypertensive activity associated with a marked vasodilation in vascular districts involved in the progression of hypertensive disease such as the renal and muscular vasculature.
Clinical Trials in Chronic Diseases
Authors: Cleophas Ton J. M. , Tavenier Piet
Published: March 2013

In spite of rather negative publicity on the crossover/self‐controlled design for clinical trials in the early 1980s, a fair number of these studies were published in that period. Using these studies as examples, we try to give an overview of major advantages and disadvantages of crossover and parallel group studies. Strengths of the crossover versus the parallel design include: (1) elimination of between‐subject variability of symptoms; (2) no need for large samples; (3) fewer ethical problems; and (4) subjects are able to express their preference for one of the compounds being given. Weaknesses include: (1) carryover effect from one treatment period into the other; and (2) time effect due to spontaneously evolving symptoms in a lengthy trial. Although routinely used for all types of therapies in phase I/II studies, the crossover/self‐controlled design cannot be used in phase III/IV studies other than for symptomatic treatments of stable disease. Treatments of chronic diseases are directed primarily to the relief of persistent symptoms rather than the cure of a rapidly evolving symptomatology. These very aspects make them particularly suitable for crossover/self‐controlled studies. Awareness of the weaknesses of clinical trials is especially important to clinical practitioners, who depend on reported clinical trials when making clinical decisions.
Relationship Between Antipyrine Metabolism and Acetylation Phenotype in Health and Chronic Liver Diseases
Authors: El‐Yazigi Adnan , Raines Dale A. , Wahab Fida Abdel , Sieck Jens O. , Ernst Peter , Ali Hatim , Dossing Martin
Published: March 2013

The authors examined the activity of N‐acetyltransferase and that of microsomal P‐450 isoenzymes in health and hepatic disease state by determining the acetylation phenotype and the total (CLAP) and metabolic clearances of antipyrine to form norantipyrine or N‐demethylantipyrine (MCLnora), 3‐hydroxymethylantipyrine (MCLhma), and 4‐hydroxyantipyrine (MCLha) in 21 healthy subjects and in 33 patients with chronic liver diseases (CLD) and investigated the relationship between the activities of these two enzyme systems. The acetylation phenotype was determined according to the urinary caffeine metabolites test. The mean and (SEM) of CLAP, MCLhma, MCLha, and MCLnoro in healthy subjects were 2.42 (0.264), 0.193 (0.031), 0.322 (0.045), and 0.288 (0.04) L/h, and those observed in patients with CLD were 0.98 (0.1), 0.076 (0.015), 0.131 (0.026), 0.103 (0.022) L/h, respectively. The prevalence of fast acetylation among the healthy subjects and patients with CLD was 38% and 39%, respectively. Although all metabolic clearances appear to be reduced in healthy slow acetylators, the reduction was only significant in MCLnora, indicating a direct association between the activity of N‐acetyltransferase and that of P‐450 IIIA3 responsible for the N‐demethylation of antipyrine. Conversely, slow acetylators with CLD exhibited significantly higher CLAP and near‐significantly larger metabolic clearances including MCLnora, which suggests that P‐450 activity in fast acetylators is more sensitive to chronic liver diseases than in slow acetylators.
Disposition of Gabapentin in Anuric Subjects on Hemodialysis
Authors: Wong M. O. , Eldon M. A. , Keane W. F. , Türck D. , Bockbrader H. N. , Underwood B. A. , Sedman A. J. , Halstenson C. E.
Published: March 2013

Gabapentin is an anticonvulsant drug, which in man is cleared solely by renal excretion and is not bound to plasma proteins. Because the clearance of gabapentin is dependent on renal function, the pharmacokinetics of gabapentin were investigated in anuric subjects maintained on hemodialysis. Plasma samples were obtained over an 8‐day period after administration of single oral 400‐mg doses of gabapentin. Pre‐ and post‐dialyzer plasma samples and dialysate samples from quantitative collection of dialyzer effluent were obtained during hemodialysis sessions performed 2, 4, and 7 days after dosing. A mean (SD) maximum gabapentin plasma concentration of 6.0 (2.4) μg/mL was achieved at 4.7 (2.1) hours post‐dose. The elimination half‐life of gabapentin on non‐hemodialysis days averaged 132 hours. Approximately 35% of the gabapentin dose was recovered in dialysate, and mean hemodialysis clearance of gabapentin was 142 (26) mL/min; approximately 93% of the dialyzer creatinine clearance. Gabapentin elimination half‐life during hemodialysis was approximately 4 hours. Systemic plasma gabapentin concentrations increased approximately 30% during the first 2 hours after hemodialysis as a result of drug redistribution in the body. It is recommended that patients with end‐stage renal disease maintained on hemodialysis receive an initial 300‐mg to 400‐mg gabapentin loading dose. Plasma gabapentin concentrations can be maintained by giving 200 to 300 mg of gabapentin after every 4 hours of hemodialysis.
Pressor Effect of Oral Tyramine During Treatment with Befloxatone, a New Reversible Monoamine Oxidase‐A Inhibitor, in Healthy Subjects
Authors: Patat Alain , Berlin Ivan , Durrieu Geneviève , Armand Pierre , Fitoussi Serge , Molinier Patricia , Caille Philippe
Published: March 2013

The interaction between tyramine and befloxatone, a new selective, reversible monoamine oxidase‐A (MAO‐A) inhibitor, was studied in a single‐blind, parallel‐group study in 30 healthy male volunteers whose fasting tyramine 30 dose (Tyr30) was 400 or 600 mg. Each subject completed a placebo run‐in period followed by a befloxatone period. Befloxatone was given in repeated doses according to one of three regimens: befloxatone 20 mg once daily at the end of a meal rich in tyramine or befloxatone 10 or 20 mg twice daily 2 hours before a meal rich in tyramine. Subjects were given increasing daily doses of tyramine mixed with the meal, until a systolic blood pressure increase of at least 30 mm Hg was achieved (Tyr30). The mean Tyr30 decreased from 1220 mg (range, 600–1800 mg) during placebo to 290 mg (range, 150–500 mg) during befloxatone 20 mg once daily, 250 mg (range, 100–300) during befloxatone 10 mg twice daily, and 155 mg (range, 100–250 mg) during befloxatone 20 mg twice daily; corresponding to a potentiation factor of 5.2‐, 6.5‐, and 7.9‐fold, respectively. The extent and the duration of the systolic blood pressure increase did not significantly differ between the placebo and the befloxatone regimens, except for a longer duration with the 20‐mg twice daily regimen. These results are similar to those reported with the therapeutic dosage of other selective MAO‐A inhibitors. They suggest that there would be little risk of hypertensive crisis in patients treated in clinical studies with befloxatone, and thus dietary restrictions appear to be unnecessary when the drug is given in a regimen of up to 20‐mg once daily after meals.
Simultaneous First‐Order and Capacity‐Limited Elimination Kinetics After Oral Administration of Verapamil
Authors: Gupta Suneel K. , Hwang Stephen , Atkinson Linda , Longstreth James
Published: March 2013

In this study of the relationship between dose and plasma concentration of verapamil, controlled‐release verapamil in doses of 120 mg, 180 mg, 360 mg, and 540 mg were examined. The 48 study subjects received verapamil daily during each of the 4 sequential 5‐day dosing segments. Blood samples were collected frequently to obtain first‐dose and steady‐state (fifth dose) concentration profiles of verapamil. Plasma concentrations of R‐and S‐verapamil and R‐ and S‐norverapamil were measured by stereospecific assay. Statistical comparisons of pharmacokinetic parameters and mean differences between doses were performed with analysis of variance models. At steady state, area under the concentration—time curve (AUC) values for R‐ and S‐verapamil at both the 120‐mg and 180‐mg doses were about 1.5 times higher than the corresponding first‐dose values. After both first and fifth doses, pharmacokinetic parameters for all four analytes were dose proportional between the 120‐mg and 180‐mg doses. A dose‐proportional relationship also was found between the 360‐mg and 540‐mg dose levels. However, nonlinearity was found between the 180‐mg dose and higher doses, suggesting saturable metabolic pathways. The dose‐proportional relationship between the 360‐mg and 540‐mg doses suggests that other first‐order metabolic pathways become dominant. Although results from this study are partially consistent with previously reported nonlinear verapamil kinetics, this is the first clinical study to demonstrate a dose‐proportional relationship for verapamil at both low and high input rates (mg/hr). In addition, first‐order disposition pathways of verapamil are probably nonexistent at medium input rates and become dominant at higher input rates.
Interaction of Meloxicam with Cimetidine, Maalox, or Aspirin
Authors: Busch Ulrich , Heinzel Gunther , Narjes Hans , Nehmiz Gerhard
Published: March 2013

Meloxicam is a new enol carboxamide nonsteroidal antiinflammatory drug (NSAID). Preclinical studies have indicated that it possesses a high antiinflammatory potency and a low ulcerogenic potency. This open, randomized, crossover study was conducted to examine the effects of aspirin, the antacid Maalox (Rhone‐Poulenc Rorer, Cologne, Germany), and cimetidine on the pharmacokinetics and bioavailability of a single oral dose of meloxicam 30 mg in healthy male volunteers. Plasma concentrations of meloxicam were determined and subjected to noncompartmental pharmacokinetic analysis. Meloxicam was well tolerated, and concomitant treatment with cimetidine or Maalox had little or no effect on the plasma concentration—time curves, maximum plasma concentration (Cmax), or the area under the plasma concentration—time curve (AUC0‐∞) of meloxicam. Concurrent treatment with aspirin increased plasma concentrations of meloxicam, increasing Cmax by approximately 25% and AUC0‐∞ by 10%. These differences were not considered to be clinically relevant, and no adjustments of meloxicam dose should be required with coadministration of aspirin, Maalox, or cimetidine.
Pharmacokinetics of Ceftriaxone in Patients Undergoing Continuous Veno‐Venous Hemofiltration
Authors: Kroh Udo Franz , Lennartz Herbert , Edwards David J. , Stoeckel Klaus
Published: March 2013

Continuous hemofiltration is used widely in the management of patients with acute renal failure, but administration guidelines for many drugs have yet to be established. In this study, the pharmacokinetics of ceftriaxone were compared in patients with normal renal function (n = 9), mild renal insufficiency (n = 5), and acute renal failure receiving continuous veno‐venous hemofiltration (n = 6). Pharmacokinetic parameters were determined under steady state conditions. Patients with mild renal insufficiency had a significantly lower renal clearance and longer half‐life of ceftriaxone; however, drug recovery in the ultrafiltrate with continuous veno‐venous hemofiltration was similar to that in the urine of patients with normal renal function. Pharmacokinetic parameters for renal, nonrenal, and systemic clearance and for volume of distribution and half‐life were also similar between patients receiving continuous veno‐venous hemofiltration and those with normal renal function. The sieving coefficient (S) of ceftriaxone (0.69) significantly exceeded the expected free fraction in plasma, confirming previous reports that protein binding does not limit the sieving of this compound. The results suggest that a reduction in the usual daily dose of ceftriaxone is not required in patients with acute renal failure receiving continuous veno‐venous hemofiltration.
Effects of Angiotensin‐Converting Enzyme Inhibition on Left Ventricular Geometric Patterns in Patients with Essential Hypertension
Authors: De Castro Stefano , Pelliccia Francesco , Cartoni Domenico , Funaro Stefania , Melillo Guido , Beni Sergio , Magni Giuseppina , Migliau Giorgio , Fedele Francesco
Published: March 2013

Although angiotensin‐converting enzyme inhibitors have been shown to affect left ventricular (LV) remodeling favorably in several conditions, it remains unclear whether they can influence LV geometric pattern in hypertension. To address this issue, 122 patients (71 men and 51 women; mean age = 51 ± 10 years) with mild to moderate hypertension were studied prospectively. All underwent clinical evaluation and Doppler echocardiography at entry and more than 2 years of quinapril therapy (10–40 mg/day). According to either LV mass (normal if <131 g/m2 for men or <100 glm2 for women) or the ratio of LV posterior wall thickness to diastolic diameter (RWT; normal if <0.45) at baseline, 58 patients had normal mass and RWT, 18 patients had concentric remodeling (i.e., normal mass but increased RWT), 24 patients had eccentric hypertrophy (i.e., increased mass but normal RWT), and 22 patients had concentric hypertrophy (i.e., increase in both mass and RWT). After 6 months of quinapril therapy, all patients with normal left ventricles showed the maintenance of mass and RWT within normal limits. Patients with concentric remodeling showed no increase in mass but had a significant decrease in RWT. Patients with eccentric hypertrophy exhibited a significant reduction in mass with no substantial change in RWT. Patients with concentric hypertrophy had a significant reduction in both mass and RWT. Changes in LV mass and geometry were maintained during the 2‐year period of treatment and were paralleled by improvements in Doppler indices of LV diastolic function in each group. It is concluded that quinapril, with its well‐known effects on LV hypertrophy, modifies the LV geometric pattern of hypertensive patients favorably, regardless of the presence of an abnormal LV mass or RWT.
Comparisons of Oxidative Metabolism and Reductive Capacity in Sulfonamide‐Tolerant and ‐Intolerant Patients with Human Immunodeficiency Virus
Authors: Lehmann David F. , Holohan Peter D. , Blair Donald C.
Published: March 2013

Hypersensitivity reactions to trimethoprim/sulfamethoxazole occur with a high frequency in human immunodeficiency virus (HIV)‐infected patients. This study tested whether differences in oxidative metabolism and plasma reductive capacity correlate with sulfonamide intolerance in patients with HIV. Eighteen stable outpatients with HIV were prospectively studied. Nine patients had documented histories of hypersensitivity reactions to trimethoprim/sulfamethoxazole and nine did not. Urinary caffeine metabolite ratios assessed the activity of two oxidative enzymatic pathways: cytochrome P‐450 1A2 (demethylation) and 8‐hydroxylation. Plasma cyst(e)ine was used as a measure of reductive capacity. The trimethoprim/sulfamethoxazole‐intolerant group showed greater rates of 8‐hydroxylation, lower rates of demethylation, and lower cyst(e)ine levels. The results of this pilot study extend previous observations of differences in oxidative metabolism and reductive capacity that exist within the population of HIV‐infected individuals. In addition, these findings lay the groundwork for future interventional studies that could use agents to inhibit sulfonamide oxidation and increase reductive capacity in sulfonamide‐intolerant patients with HIV when rechallenged with trimethoprim/sulfamethoxazole.
Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers
Authors: Shum Linyee , Pieniaszek Henry J. , Robinson Cynthia A. , Davidson Anna F. , Widner Paul J. , Benedek Irma H. , Flamenbaum Walter
Published: March 2013

Sixteen healthy male volunteers completed a nonrandomized, sequential, three‐phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration‐time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl‐diltiazem and N‐desmethyl‐diltiazem), and both when administered together. Under steady‐state conditions, there was a two‐way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration‐time curve from time 0 to the end of administration (AUCτ) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half‐life (t1/2) of moricizine was not affected, however (2.1 ± 0.5 hours versus 2.4 ± 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 ± 1.3 hours to 3.6 ± 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl‐diltiazem and N‐desmethyl‐diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.
Protracted Methemoglobinemia after Phenazopyridine Overdose in an Infant
Authors: Christensen Carla M. , Farrar Henry C. , Kearns Gregory L.
Published: March 2013

Acquired methemoglobinemia may be produced by the ingestion or absorption of certain chemicals and xenobiotics. A case of methemoglobinemia in an 8.5‐month old infant who ingested approximately 227 mg/kg of phenazopyridine is presented. Although this adverse event is often reversed with a single dose of methylene blue, this patient required three doses of methylene blue (1 mg/kg) over a 25‐hour period. It is suggested that the need for repeated doses of methylene blue in this case was not only related to the large dose of phenazopyridine, but also its metabolites (i.e., aniline), which have the potential to produce methemoglobinemia. This case illustrates the need for close observation and serial monitoring of methemoglobin levels in patients who are at increased risk for the development of protracted methemoglobinemia. Integration of knowledge of developmental pharmacology, drug metabolism, and pharmacodynamic properties are critical determinants in the evaluation and treatment of patients with drug‐induced methemoglobinemia.
Pharmacokinetics of Hydroxyurea in Patients Infected with Human Immunodeficiency Virus Type I
Authors: Villani Paola , Maserati Renato , Regazzi Mario B. , Giacchino Roberto , Lori Franco
Published: March 2013

In a prospective, randomized, controlled, three‐arm study, the pharmacokinetics of hydroxyurea administered as an antiviral agent in patients infected with human immunodeficiency virus type 1 (HIV‐1) were evaluated. The three arms of the study consisted of azidothymidine (AZT) 250 mg twice daily, hydroxyurea 500 mg twice daily, or a combination of the two. Nine patients receiving hydroxyurea in monotherapy (n = 4) or in combination with AZT (n = 5) agreed to undergo multiple venipunctures for pharmacokinetic analysis. Sample collection was performed at steady‐state conditions and serum concentration—time data for hydroxyurea were fitted using a one‐compartment model. Mean (± standard deviation) peak concentration (Cmax) was 0.135 ± 0.06 mmol/L and mean trough level (Cmin) was 0.0085 ± 0.003 mmol/L. Mean concentration at steady state was 0.045 ± 0.006 mmol/L. Apparent clearance (Cl/F) was 0.18 ± 0.005 L/hr/kg, and half‐life (t1/2) was 2.5 ± 0.5 hours. Hydroxyurea given orally to patients infected with HIV‐1 was well absorbed from the gastrointestinal tract, with a tmax of 0.85 to 0.96 hours after ingestion. Serum levels of hydroxyurea ranged from 0.01 to 0.13 mmol/L. These values are similar to the concentrations (between 0.01 and 0.1 mmol/L) demonstrated to inhibit HIV‐1 in vitro. Our data show that hydroxyurea given at a dosage of 500 mg twice daily is sufficient to yield serum concentrations potentially useful for in vivo inhibition of HIV‐1.
Pharmacodynamics of Torsemide Administered as an Intravenous Injection and as a Continuous Infusion to Patients with Congestive Heart Failure
Authors: Kramer William G. , Smith William B. , Ferguson Jeffrey , Serpas Tina , Grant Arthur G. , Black Paula K. , Brater D. Craig
Published: March 2013

The natriuretic and diuretic effects of a 100‐mg dose of torsemide administered as a continuous infusion of torsemide and as a single bolus were compared in a group of patients with stable mild‐to‐moderate congestive heart failure (CHF). Patients received in random order 100 mg of torsemide as an intravenous bolus and as a 75‐mg infusion over 24 hours started simultaneously with a 25‐mg loading bolus. Administration of torsemide to patients with CHF as a continuous infusion was an effective dosing regimen, resulting in 24‐hour diuresis and natriuresis that was numerically but not statistically greater than that observed with bolus administration. The response with continuous infusion occurred with less torsemide in the urine, resulting in a significantly greater efficiency of torsemide with this regimen. The effectiveness of torsemide as a continuous infusion does not mean that this mode of administration should be used in all patients. The response to 100 mg of torsemide in patients with mild‐to‐moderate CHF is the same whether administered as an intravenous bolus, a continuous intravenous infusion, or by mouth. This is consistent with the high bioavailability demonstrated in previous studies. The mode of therapy used should be dictated by each individual patient's needs. This study shows that continuous infusion is a viable option for administration of torsemide, and dosing guidelines for use of such a strategy are presented.
Effects of Dihydropyridine Calcium Antagonists on Albuminuria in Patients with Diabetes
Authors: Abbott Kevin , Smith Amy , Bakris George L.
Published: March 2013

The present study was designed to assess the effects of two different dyhydropyridine calcium antagonists (DHPCAs) on proteinuria in patients with noninsulin‐dependent diabetes mellitus (NIDDM). The hypothesis that similar levels of blood pressure reduction with two different DHPCAs produce similar degrees of proteinuria reduction was tested. In a prospective randomized study, 14 patients with NIDDM, hypertension, proteinuria, and renal insufficiency were given either isradipine (n = 7) or nifedipine XL (n = 7) for 6 months. After a 2‐week washout period, patients were crossed over to the other drug and observed for an additional 6 months. Drugs were titrated to lower arterial pressure to <140/90 mmHg. Patients also instructed to follow a low‐sodium diet at the initial visit. Blood pressure and 24‐hour urine values for creatinine clearance, albuminuria, proteinuria, and sodium were assessed monthly. At the end of the initial and crossover treatment periods, there were no significant reductions in the level of albuminuria from baseline with either drug. Sodium excretion was <110 mEq/L with each drug tested. The results of this study support the concept that DHPCAs do not reduce proteinuria in patients with type II diabetes. This failure to reduce albuminuria and proteinuria occurred despite adequate blood pressure reduction and an effort at dietary sodium restriction.
Pharmacokinetic/Pharmacodynamic Modeling of Cortisol Suppression after Oral Administration of Fluocortolone
Authors: Rohatagi Shashank , Täuber Ulrich , Richter Kurt , Derendorf Hartmut
Published: March 2013

Fluocortolone is a potent corticosteroid used orally for the treatment of rheumatic diseases, asthma, and immunosuppression. A clinical study of nine healthy volunteers was conducted to determine the pharmacokinetics and cortisol suppression after administration of single oral doses of 20 mg, 50 mg, and 100 mg of fluocortolone. Blood samples were collected at 8:00 AM, 12:00 PM, and 4:00 PM on the day before treatment, and 0,0.5,1,2,3, 4,6,8,12,24,28,32,48, 52, and 56 hours after administration of the drug. Concentrations of fluocortolone and cortisol were measured in plasma by a reversed phase high‐performance liquid chromatography system. Cortisol suppression was chosen as the pharmacodynamic parameter. Total concentrations were converted into unbound concentrations using a two‐protein, one‐ligand equation. The unbound concentrations were fitted using a one‐compartment body model equation with first‐order absorption. A linear release‐rate model was used to characterize the cortisol data. The data were fitted using a common E50 value of 0.95 ± 0.22 ng/mL for the mean data. The value of E50 was in close agreement with the prediction based on relative glucocorticoid receptor affinity.
Pharmacokinetics of Oral Mycophenolate Mofetil in Volunteer Subjects with Varying Degrees of Hepatic Oxidative Impairment
Authors: Parker Gerry , Bullingham Roy , Kamm Barbara , Hale Michael
Published: March 2013

Eighteen patients with compensated alcoholic cirrhosis participated in a single‐dose pharmacokinetic study of oral mycophenolate mofetil (MMF). Participants were divided into groups of 6 patients each with mild, moderate, or severe hepatic oxidative impairment as defined by the aminopyrine breath test (APBT). Clinically, hepatic disease was of mild or moderate severity. Six healthy volunteers were included as control subjects. Plasma and urine samples were collected over 96 hours and assayed for the active metabolite mycophenolic aced (MPA) and the glucuronide conjugate, MPAG. Plasma protein binding of MPA also was determined in 6 unrelated patients with cirrhosis. Cirrhosis did not grossly affect plasma pharmacokinetics or plasma binding of MPA. Maximum plasma concentrations (Cmax) and area under the curve (AUC) of MPA and MPAG consistently decreased, increased, and then decreased as oxidative impairment declined from normal to severe. Patients with cirrhosis had comparable or greater recovery of administered drug substance in urine than controls, showing that cirrhosis did not affect the extent of MMF absorption. Urine clearance of MPAG was two times higher in the group with severe impairment than in the other groups. Creatinine clearance was similar in all groups. These results suggest progressive impairment of hepatic glucuronidation of MPA and induction of renal glucuronidation in patients with severe hepatic oxidative impairment.
Lack of Effect of Orlistat on the Bioavailability of a Single Dose of Nifedipine Extended‐Release Tablets (Procardia XL) in Healthy Volunteers
Authors: Melia Angela T. , Mulligan Thomas E. , Zhi Jianguo
Published: March 2013

Orlistat, a lipase inhibitor, reduces dietary fat absorption, and thus could potentially alter the absorption of some concomitantly administered drugs, such as the nifedipine gastrointestinal therapeutic system (GITS). To assess the effect of orlistat on the bioavailability of nifedipine GITS, a third party‐blind, placebo‐controlled, randomized, two‐way crossover study was performed in 18 healthy volunteers. Each participant received single 60‐mg oral doses of nifedipine GITS (Procardia XL; Pfizer Labs, New York, NY) on the fourth day of treatment with 120 mg of orlistat or placebo three times a day for 6 days. The two treatments were separated by a washout period of at least 1 week. Serial blood samples were collected before and at appropriate intervals after each nifedipine dose to determine plasma concentrations of nifedipine. The 90% confidence intervals for the ratio of geometric least‐square means for maximum concentration (Cmax) and area under the concentration‐time curve (AUCo‐t) and for the difference of arithmetic least‐square means for time to maximum concentration (tmax) indicate that the bioavailability of nifedipine was not altered by treatment with orlistat. Therapeutic doses of 120 mg of orlistat three times daily do not significantly alter the bioavailability of a single 60‐mg oral dose of nifedipine GITS in healthy volunteers.
Pharmacodynamic Effects and Pharmacokinetics of Atorvastatin after Administration to Normocholesterolemic Subjects in the Morning and Evening
Authors: Cilla Donald D. , Gibson Donald M. , Whitfield Lloyd R. , Sedman Allen J.
Published: March 2013

The pharmacodynamic effects and pharmacokinetics of atorvastatin, a potent investigational inhibitor of HMG‐CoA reductase, were studied in 16 normolipidemic subjects after administration of 40 mg daily for 15 days in the morning or evening. Lipid and apolipoprotein parameters were determined, and plasma atorvastatin equivalent concentrations were measured according to a validated enzyme inhibition bioassay procedure. Atorvastatin was well tolerated by the participants. Overall, mean reductions of 34% in total cholesterol, 48% in low‐density lipoprotein (LDL) cholesterol, 37% in very low density lipoprotein (VLDL) cholesterol, 25% in triglycerides, 6% in apolipoprotein A‐I, and 34% in apolipoprotein B were observed. Changes in lipid and apolipoprotein values were similar after morning and evening administration of atorvastatin. In contrast, studies with other HMG‐CoA reductase inhibitors have consistently shown that evening administration results in larger reductions in total and LDL cholesterol than does morning administration. Rate and extent of equivalent absorption of atorvastatin were lower during evening than morning administration. Mean elimination half‐life values were similar, however, suggesting that there is no diurnal variation in disposition of this drug. Pharmacokinetic differences did not correlate with effects on serum lipids.
Pharmacokinetics of Meperidine in Healthy Volunteers after Short‐ and Long‐Term Exposure to High Altitude
Authors: Ritschel Wolfgang A. , Paulos Claudio , Arancibia Aquiles , Pezzani Marcela , Agrawal Mukul A. , Wetzelsberger Klaus M. , Lücker Peter W.
Published: March 2013

Increased numbers of erythrocytes have been shown ex vivo to increase meperidine uptake, and one of the major physiologic changes that occurs at high altitude is an increase in hematocrit and erythrocytes. A study was therefore conducted to evaluate the effects of high altitude on the pharmacokinetics of meperidine. Intramuscular doses (0.75 mg/kg) of meperidine were given to three groups of healthy volunteers (age range, 18–20 years): participants living at sea level (group L), those same participants the day after arrival at high altitude (4,360 m; group HA), and participants who had lived at high altitude for ≥10 months (group HC). Blood samples were collected for 12 hours after drug administration. Meperidine was measured in whole blood, plasma, and plasma water. Elimination rate constant (λz) and clearance uncorrected for bioavailability (Cl/F) were significantly lower at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Mean residence time (MRT) was significantly higher at high altitudes than at sea level in plasma (HA and HC) and in whole blood (HA only). Hematocrit was significantly increased at both time points at high altitude in comparison to values at sea level, and was also higher after a long‐term stay at high altitude than after arrival at high altitude. Erythrocyte binding increased significantly from 41.3% at sea level to 43.8% at arrival at high altitude to 50.9% after a long‐term stay at high altitude. The extent of protein binding tended to decrease with high altitude, but this decrease was not significant. Free concentrations of meperidine in plasma water measured 1, 2, and 4 hours after administration were significantly increased after 2 and 4 hours.
Pharmacokinetics and Safety of Single Oral Doses of VX‐366 (Isobutyramide) in Healthy Volunteers
Authors: Brettman Lee R. , Chaturvedi Pravin R.
Published: March 2013

VX‐366 (isobutyramide) is an orally available branched chain amide that may offer an alternative to current treatments for β‐hemoglobinopathy. A phase I, double‐blind, randomized, placebo‐controlled study was conducted to investigate four single oral doses of VX‐366 (1, 7, 14, or 28 grams or approximately 14, 100, 200 or 400 mg/kg) administered to four male volunteers each, with two other subjects in each group receiving a matching placebo. The total number of volunteers enrolled in this study was 24, with a mean age of 27 ± 6.4 years. VX‐366 was well tolerated at all dose levels studied, and peak plasma concentrations (Cmax) of 18.88 ± 1.02 μg/mL (0.2 mmol/L), 171.13 ± 32.13 μg/mL (2 mmol/L), 331.58 ± 35.48 μg/mL (3.8 mmol/L), and 538.83 ± 54.19 μg/mL (6 mmol/L) were achieved after the four respective doses. The half‐life (t1/2) of VX‐366 was more than 7 hours, and there was evidence of nonlinear pharmacokinetics. It is likely that nonrenal (metabolic) clearance plays a predominant role in elimination. Based on these data, VX‐366 given as a single daily dose of 100 to 150 mg/kg should be well tolerated and can be expected to result in peak plasma levels in excess of 170 μg/mL (2 mmol/L) and in trough plasma levels in excess of 40 μg/mL (0.5 mmol/L). These plasma levels exceed the concentrations previously shown to stimulate gamma globin synthesis both in vitro and in baboons.