bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Chronic Oral H2‐Antagonist Therapy on Left Ventricular Systolic Function and Exercise Capacity
Authors: Hilleman Daniel E. , Mohiuddin Syed M. , Williams Mark A. , Gannon Joan M. , Mathias Richard J. , Thalken Lisa J.
Published: March 2013

It has been suggested that H2‐antagonists may adversely affect left ventricular systolic junction. To assess the effects of cimetidine, famotidine, and ranitidine on exercise capacity and left ventricular systolic function, the authors conducted a randomized, double‐blind, four‐way crossover study in 15 healthy male volunteers with placebo control. Each subject underwent a maximal upright treadmill exercise test, aerobic metabolic assessment, and two‐dimensional stress echocardiography on six separate occasions. The initial two treadmill exercise tests with aerobic metabolic assessment and stress echocardiography were performed to minimize the learning effect. In the final four evaluations, subjects were randomized to receive 7 days of oral treatment with cimetidine 400 mg twice daily, famotidine 40 mg daily, ranitidine 150 mg twice daily, and placebo. A comparison of exercise tests, aerobic metabolic assessment, and stress echocardiography results found no significant differences between any of the H2‐antagonists and placebo. In addition, there were no significant differences in test results between cimetidine, famotidine, and ranitidine. Specifically, exercise treadmill time, maximal oxygen consumption, respiratory quotient, maximal exercise systolic and diastolic blood pressure, maximal exercise heart rate, left ventricular end‐diastolic dimension, left ventricular end‐systolic dimension, and ejection fraction were not different between treatments. The authors conclude that 7 days of oral treatment with cimetidine, famotidine, or ranitidine has no deleterious effect on exercise capacity or left ventricular systolic function in healthy subjects.
Clarithromycin Pharmacokinetics in Healthy Young and Elderly Volunteers
Authors: Chu Sou‐yie , Wilson David S. , Guay David R. P. , Craft Carl
Published: March 2013

The pharmacokinetics of clarithromycin and its active 14(R)‐hydroxy metabolite were assessed in 12 healthy young and 12 healthy elderly volunteers after oral administration of a multiple dose regimen of oral clarithromycin (500 mg every 12 hours for 5 doses). Plasma and urine clarithromycin and 14(R)‐hydroxyclarithromycin concentrations were determined using high‐performance liquid chromatography. The elderly subjects exhibited significantly elevated clarithromycin peak (Cmax) and trough (Cmin) plasma concentrations and area under the plasma concentration‐time curve (AUC) compared with young subjects. In addition, the elderly group exhibited a significantly reduced apparent total body clearance (300 ± 97 versus 476 ± 112 mL/min, respectively) and renal clearance (CLR) (84 ± 31 versus 168 ± 35 mL/min, respectively). Similar results were noted for the 14(R)‐hydroxy metabolite, with significantly elevated Cmax, Cmin, and AUC and reduced CLR in the elderly compared with the young group. Because the differences in parent and metabolite pharmacokinetic parameters were small and the increase in circulating drug concentrations was well tolerated (no increase in incidence or severity of adverse events), adjustments in clarithromycin dosing regimens may not be necessary solely on the basis of age.
Lack of Effect of Pentoxifylline on Red Blood Cell Deformability
Authors: Cummings Doyle M. , Ballas Samir K. , Ellison Mark J.
Published: March 2013

The proposed mechanism of action for pentoxifylline's beneficial effect in peripheral vascular disease is an improvement in red blood cell deformability. Likewise, single doses of pentoxifylline in healthy volunteers have been shown to improve whole blood filterability, which was suggested to occur as a result of augmented red blood cell deformability. To further assess this, the authors studied the effects of short‐term pentoxifylline administration (400 mg three times daily for 7 days) on red blood cell deformability in ten healthy, methylxanthine‐free, nonsmoking volunteers. Blood samples were obtained at baseline and after 1 week of therapy (steady‐state). Samples were analyzed for red blood cell deformability by ektacytometry, which showed no significant change in deformability in any subject. Despite the improvement in whole blood filterability associated with both single‐dose and short‐term administration of pentoxifylline, the current study demonstrates no effect on red blood cell deformability after short‐term administration in healthy volunteers.
Dose‐Dependent Aspirin Hydrolysis and Platelet Aggregation in Patients with Atherosclerosis
Authors: Akopov Sergey S. , Grigorian George S. , Gabrielian Emil S.
Published: March 2013

In a double blind, randomized trial the effects of aspirin (1, 5, and 15 mg/kg) were compared with the changes in platelet aggregation at 6 and 24 hours after dosage. It is found that there is a negative correlation between aspirin hydrolysis velocity in blood and capability of aspirin to decrease platelet aggregation with ADP and collagen in patients with atherosclerosis. Relationship between these parameters depends on aspirin dosage. The correlation was more marked for low doses of aspirin. It is suggested that the effect of aspirin in low dosage on platelet aggregation might be ineffective in many patients without control of aspirin hydrolysis velocity in blood.
Comparative Pharmacokinetics of Lovastatin, Simvastatin and Pravastatin in Humans
Authors: Pentikainen Pertti J. , Saraheimo Markku , Schwartz Jules I. , Amin Raju D. , Schwartz Michael S. , Brunner‐Ferber Francoise , Rogers J. Douglas
Published: March 2013

Twelve healthy male volunteers received single market‐image 40‐mg oral doses of lovastatin and simvastatin (both lactone prodrugs), or pravastatin (α β‐hydroxyacid) at 1 week intervals in a three‐way crossover study to quantify HMG‐CoA reductase inhibitors in plasma. Multiple plasma samples were collected up to 24 hours after the dose and assayed for active and total HMG‐CoA reductase inhibitors. After equal oral doses, higher plasma concentrations of HMG‐CoA reductase inhibitory activity after pravastatin than after either lovastatin of simvastatin (2–3 fold greater area under the concentration‐time curve) suggest a greater potential availability of pravastatin‐related inhibitory activity to peripheral tissues.
Influence of Food on the Absorption of Beta‐Methyldigoxin
Authors: Tsutsumi Kimiko , Nakashima Hajime , Kotegawa Tsutomu , Nakano Shigeyuki
Published: March 2013

Nine healthy subjects received 0.2 mg of beta‐methyldigoxin (β‐MD) orally in the fasting state, 30 minutes after and before a standard breakfast. The time‐to‐peak serum glycoside concentration was delayed and the peak concentration was lower in the postprandial state compared with the other regimens (P <.01). The absorption rate constant was significantly reduced when β‐MD was given after a meal (1.55 ± 1.75 hr−1) than before a meal (5.54 ± 2.16 hr−1) and in the fasting state (5.22 ± 3.06 hr−1)(P <.01). Although the area under the serum glycoside concentration‐time curve and the cumulative urinary excretion (CUE) of β‐MD, digoxin, and total drug (β‐MD plus digoxin) was not significantly different between three regimens, the CUE∞ tended to be smaller in the postprandial state compared with before a meal. The results indicate that the timing of drug administration in relation to a meal is an important factor leading to the fluctuations of serum glycoside concentration after oral β‐MD, which might be of some clinical importance.
Evolving Pathogens in Vulvovaginal Candidiasis: Implications for Patient Care
Authors: Horowitz Benson J. , Giaquinta Diane , Ito Susan
Published: March 2013

Over the past two decades, an increasing trend in the number of vaginal infections attributable to yeasts other than Candida albicans has emerged. Of these non‐albicans species, C. tropicalis and C. glabrata appear to be the most important. The change in incidence pattern of yeast vaginitis can be expected to impact greatly on the treatment of this condition, because many currently used drug therapies (e.g., imidazoles) for C. albicans vaginitis do not adequately eradicate non‐albicans species. A possible explanation for the recent increased selection of these species may be the shortened antifungal therapies that have been introduced during the past decade. These 1‐ to 3‐day regimens with the older imidazoles may suppress C. albicans, but create an imbalance of flora that facilitate an overgrowth of non‐albicans species. The recognition of yeast speciation and the need for use of a broad‐spectrum antifungal preparation that covers these organisms is now apparent.
Single‐ and Multiple‐Dose Pharmacokinetics of Intravenous Cefpirome (HR810) to Healthy Volunteers
Authors: Nakayama Issei , Akieda Yozo , Yamaji Emiko , Nitta Yoshisuke , Ohishi Masahiko , Katagiri Kinya , Imamura Naoto , Takase Kenichi
Published: March 2013

The safety and pharmacokinetics of single and multiple administrations of cefpirome (HR810), a new cephalosporin antibiotic agent with a broad antibacterial spectrum, were studied in healthy male volunteers. The single administration protocols included a 3‐minute intravenous injection of 0.5 g or 1 g, and a 1‐hour intravenous drip infusion of 0.5 g, 1 g, or 2 g. The multiple administration protocols included nine intravenous injections and 1‐hour intravenous drip infusions of 1 g of cefpirome twice a day at intervals of 12 hours. Cefpirome was tolerated, and only a few mild, subjective and hepatic‐function side effects were observed. There were no severe abnormalities. The drug concentrations in the plasma and the urine were determined by means of HPLC and bioassay, and the results correlated well (r = 0.99). The pharmacokinetic parameters were calculated using a two‐compartment model. The elimination half‐life (t1/2β) was about 1.7 hours for both intravenous injection and intravenous drip infusion and was not dose‐dependent AUC and Cmax were dose‐dependent in this study, although an accumulation due to multiple administrations was not observed, and there were no changes in the pharmacokinetic parameters after the initial and the final administrations. The recovery rate of the unchanged compound in the urine was more than 80% in the 24 hours after a single administration and was the same after multiple administrations. Bioautography did not show any active metabolites in the plasma or the urine. The results, for safety and pharmacokinetics, show that cefpirome can be expected to have excellent clinical efficacy for bacterial infections.
Pharmacokinetics of Terfenadine in Healthy Elderly Subjects
Authors: Eller Mark G. , Walker Barbara J. , Westmark Patricia A. , Ruberg Stephen J. , Antony Kelly K. , McNutt Bruce E. , Okerholm Richard A.
Published: March 2013

The pharmacokinetics of the terfenadine active metabolite, metabolite I, was examined in ten healthy elderly adults and ten younger adults after single‐dose oral administration of 120‐mg terfenadine. All subjects successfully completed the study without reporting sedation or other adverse events. Absorption was rapid in both the young and elderly. The mean Cmax was the same for both groups, 501 ng/mL, and occurred at 2.3 hours in the young subjects and 2.5 hours in elderly subjects. However, the apparent clearance was reduced by about 25% in the elderly. After correcting clearance for bodyweight, this difference was not statistically significant.
Impact of an Electronic Medication Compliance Aid on Long‐Term Blood Pressure Control
Authors: McKenney James M. , Munroe Wendy P. , Wright Jackson T.
Published: March 2013

A two‐phase study was conducted to assess the effect of an electronic medication compliance aid on hypertension control and pharmaceutical compliance in ambulatory patients. In Phase I (12 weeks), 36 patients were randomly assigned to a medication vial equipped with a cap containing a digital timepiece that displays the last time the cap was removed. The control group included 34 patients randomly assigned to a standard medication vial. Subjects using the timepiece cap showed an average compliance rate of 95.1%, an average decrease in systolic pressure of 7.6 mm Hg (P = .006), and an average decrease in diastolic pressure of 8.8 mm Hg (P < .001). Controls had an average compliance rate of 78% and decreases of 2.8 mm Hg and 0.2 mm Hg in systolic and diastolic pressures, respectively. Phase 11 (12 weeks) combined use of the timepiece cap with other compliance aids: a pocket‐size card for recording blood pressure and a blood pressure cuff for self‐monitoring. Patients using the timepiece cap and the card had an average compliance rate of 98.7% with mean decreases of 11 mm Hg in systolic pressure (P < .01) and 7.64 Hg mm in diastolic pressure (P = .0001). The combined use of the cap, the card, and the blood pressure cuff resulted in an average 100.2% compliance rate with mean decreases of 15 mm Hg (P = .0006) and 6.60 mm Hg (P = .0006) in systolic and diastolic pressures, respectively. Results of the two‐phase study showed statistically significant increases in medication compliance associated with statistically and clinically significant reductions in blood pressure for all patients using the timepiece cap.
Nitrendipine and Renal Tubular Function in Human Volunteers
Authors: Forsyth D. R. , Roberts C. J. C.
Published: March 2013

Nine normotensive, water‐loaded subjects received 10 mg oral nitrendipine, and eight subjects received placebo in a double‐blind randomized manner. Urine and plasma were collected at fixed time points for 1 hour before and for 4 hours after drug administration for biochemical measurements. Glomerular filtration rate was measured by inulin clearance and effective renal blood flow was measured by para‐amino hippurate clearance. Absolute sodium excretion increased by 25.9% from 0.27 ± 0.03 mmol/min to 0.34 ± 0.02 mmol/min (P = .02), and fractional sodium excretion increased by 32.3% from 18.9 ± 3.0% to 25.0 ± 1.9% (P = .03) after nitrendipine, but both were unchanged after placebo. There was no change in inulin clearance, para‐amino hippurate clearance, urine volume, or fractional excretion of uric acid, which made an effect on glomerular filtration, renal blood flow, or proximal tubular junction an unlikely explanation of the natriuresis. Fractional excretion of magnesium increased after both placebo and nitrendipine administration, from 5.0 ± 0.6% to 6.8 ± 0.7% (P = .027) and 5.7 ± 0.8% to 8.8 ± 1.0% (P = .006), respectively. Fractional excretion of phosphate also increased after both placebo and nitrendipine, from 9.5 ± 2.3% to 12.9 ± 3.9% (P =.05) and 9.7 ± 1.7% to 14.2 ± 1.9% (P = .002), respectively. These changes are likely to be due to the effects of the water load rather than due to a drug effect. There was no change in clearance of solute free water, which made a direct effect on the loop of Henle or cortical diluting segment unlikely. Fractional excretion of potassium (FEK%) appeared to be inhibited by the water load in both groups. FEK% decreased by 24.2% from 5.8 ± 0.3% to 4.4 ± 0.3% (P = .009) after nitrendipine administration and by 34.8% from 6.9 ± 0.8% to 4.5 ± 0.3% (P = .04) after placebo administration. The continuing natriuresis in the face of potassium retention may indicate a distal tubular action of nitrendipine.
The Pharmacokinetics of Quinapril and Its Active Metabolite, Quinaprilat, in Patients with Various Degrees of Renal Function
Authors: Halstenson Charles E. , Opsahl John A. , Rachael Karen , Olson Stephen C. , Horvath Ann Marie , Abraham Paul A. , Posvar Edward L.
Published: March 2013

Single‐ and multiple‐dose pharmacokinetics of quinapril and its active metabolite, quinaprilat, were determined after oral administration of 20 mg quinapril HCl on day 1 and days 4 through 10 in 17 normotensive subjects with various degrees of renal function. Blood and urine samples were collected over 72‐ and 24‐hour periods, respectively, after the first single dose and last multiple dose for measurement of quinapril and quinaprilat concentrations. The renal clearance of quinapril and quinaprilat decreased with increasing renal insufficiency but did not result in significant changes in quinapril pharmacokinetics in patients with renal impairment. In contrast, quinaprilat maximum plasma concentration, trough and peak steady‐state plasma concentrations, area under the plasma concentration‐time curve, and half‐life increased significantly with increasing renal insufficiency. The disposition of quinapril and quinaprilat was unchanged from single to multiple doses. Small changes in the pharmacokinetic disposition of quinapril, together with a decreased rate of quinaprilat elimination, resulted in increased quinaprilat plasma concentrations following administration of both single and multiple quinapril doses to normotensive patients with renal impairment. Thus, quinapril dosage adjustment may be required in some patients with renal impairment.
Clinical Pharmacology Training at the Food & Drug Administration
Authors: Nelson Robert C. , Peck Carl C.
Published: March 2013

Challenged with the clearly demonstrated need for highly trained clinical pharmacologists for new drug development and review activities, the FDA Center for Drug Evaluation and Research (CDER) established an internal Staff College. This organizationally unique and innovative unit addressed the educational needs of both the new and the veteran CDER scientists. A multileveled strategy was conceptualized and implemented as described.
Pharmacokinetic Comparison of a Slow‐Release Clonidine with a Conventional Formulation After Acute and Chronic Administration in Hypertensives
Authors: Conway E. L. , Anavekar S. N. , Howes L. G. , Louis W. J.
Published: March 2013

The pharmacokinetic characteristics of a slow‐release formulation of clonidine (150 pg) were compared with those of a conventional formulation (75 μg) after acute and chronic (2 week) administration to 12 hypertensive subjects. The Tmax of the slow‐release formulation was significantly later than for the conventional formulation after both acute (8.3 ± 6 hr vs. 2.1 ±2 hr) and chronic administration (4.0 ± 3 hr vs. 2.5 ± 2 hr). Although the Tmax did not change significantly with acute and chronic administration of the conventional preparation, it was significantly shorter after chronic administration of the slow‐release formulation when acute and chronic administration were compared. The Cmax was approximately 60% lower for the slow‐release formulation (1 × 150 μg; 0.42 ± 0.09 ng/mL) compared with the conventional formulation (2 × 75 pg; 0.70 ± 0.12 ng/mL) after acute administration, whereas in the steady state, in which the dose of the conventional preparation was halved (75 μg), the Cmax values were comparable: 1 × 150 pg‐0.99 ± 0.27 ng/mL, 1 × 75 pg‐0.84 ± 0.20 ng/mL and the dose‐normalized interdose AUC were identical for the conventional (16.2 ± 4.3 ng/mL · hr) and slow release (16.6 ± 5.3 ng/mL · hr) products. T1/2 values for the conventional formulation of clonidine exceeded 20 hours in all but one subject and were considerably longer than those in previous reports, including those of the authors, in which a less sensitive assay was used. T1/2 was even longer for the slow‐release formulation after both acute and chronic dosing and was consistent with the continuing release of clonidine from the slow‐release product throughout the 48‐hour sampling time. The results confirm the slow‐release nature of the formulation and suggest that the elimination half‐life of clonidine does not correlate closely with the duration of the antihypertensive effect of the drug.
Transdermal Clonidine as an Adjunct to Enalapril: An Evaluation of Efficacy and Patient Compliance
Authors: Weidler Donald , Wallin John D. , Cook Eileen , Dillard Daniel , Lewin Andrew , Matzek Kandace
Published: March 2013

This four‐center, 20‐week, open‐label study evaluated transdermal clonidine as an adjunct to enalapril 10 mg daily and demonstrated patterns of compliance. Seventy‐four mildly to moderately hypertensive patients (mean seated blood pressure, 150/101 mm Hg) received enalapril 10 mg once daily as initial monotherapy. In 66 patients, the seated diastolic blood pressure remained 90 mm Hg at the trough blood levels of enalapril. Transdermal clonidine (3.5 cm2, 7.0 cm2, or 10.5 cm2, equivalent to 0.1 mg, 0.2 mg, and 0.3 mg clonidine/day, respectively) then was added as needed to achieve blood pressure control. Forty‐eight patients achieved diastolic blood pressures < 90 mm Hg on concomitant therapy; 44 patients completed 8 weeks of maintenance dosing with a mean blood pressure of 134/85 mm Hg. Oral compliance, as measured by an electronic device that was actuated each time the medication vial was opened, varied from 48 to 140%. Compliance with the transdermal clonidine regimen was excellent; the patch was worn as directed during 96% of the patient‐weeks of therapy. The authors conclude that blood pressure can be controlled by a combination of transdermal clonidine and enalapril in patients that do not adequately respond to enalapril monotherapy. Patients poorly complying with oral regimens may be candidates for a trial of transdermal clonidine monotherapy.
Increases in Methyldopa Absorption and Renal Excretion After Multiple Doses
Authors: Campbell N. R. C. , Patrick W.
Published: March 2013

A retrospective analysis of previous studies examining methyldopa absorption suggested the possibility that the absorption of methyldopa might increase on repeat methyldopa ingestion. A prospective study was undertaken to determine the effect of repeated oral doses of methyldopa on methyldopa absorption. Thirteen healthy subjects ingested single 250 mg methyldopa doses on days 0, 7, 14, 28, 56, and 112; 24 urine samples were collected and analyzed for methyldopa and its major metabolites on each study day and methyldopa plasma levels were measured over 8 hours at days 0 and 56. There were significant increases in the absorption of methyldopa (as estimated by the urinary excretion of methyldopa and the measured metabolites over 24 hours) at day 56 (33.4 ± 8.9%, P < .025) compared with day 0 (26.0 ± 10.8%). There was also a significant increase in renal clearance of unmetabolized methyldopa (62.7 ± 13.6 vs. 99.3 ± 29.1 mL/min, P < .01) and a decrease in the plasma half‐life of methyldopa at day 56 (2.22 ± 0.91 vs. 1.56 ± 0.68 hr, P < .05). There was a tendency toward increases in methyldopa absorption at day 7, 14, 28, and 112. Several possible explanations for the changes in methyldopa disposition are discussed.
Can Fluoroquinolones Be Considered Once‐Daily Therapy?
Authors: Neu Harold C.
Published: March 2013

Fluoroquinolone antimicrobial agents inhibit most Enterobacteriaceae at extremely low concentrations, ≤0.5 μg/mL. The half‐lives of the agents range from 4 to 18 hours. Most of the available fluoroquinolones can be administered once daily to treat urinary tract and diarrheal infections. Newer agents with long half‐lives that inhibit gram positive organisms at lower concentrations than the older fluoroquinolones, ≤1 μg/mL, and have a long postantibiotic effect have the potential to be used once daily as treatment of respiratory, skin‐structure and selected bone infections as well. Careful clinical studies are needed to establish the efficacy of once daily use of fluoroquinolones, to determine that clinical efficacy is equivalent to multiple doses, and that once‐daily dosing does not select more resistant bacteria. Single‐dose therapy with quinolones would be an improvement in cost and patient compliance.
Cost Effectiveness of Once‐Daily Oral Antimicrobial Therapy
Authors: Davey Peter , Parker Sharon
Published: March 2013

Once daily dosing of oral antimicrobials achieves significantly better patient compliance than three or four times daily dosing, and limited data suggest that this is associated with greater efficacy. Comparison of once daily and twice daily dosing is less consistent, and most studies show only marginally better compliance with once daily dosing versus twice daily dosing. Detection of urinary antimicrobial activity provides a simple method for checking compliance with oral antimicrobials and deserves wider study. Counts of residual tablets have been shown to overestimate compliance. Intravenous formulations are always more expensive than equivalent oral formulations, and preparation and administration of intravenous drugs adds significant additional costs. Moreover, intravenous regimens are complex, and a number of studies have shown that serious errors occur in both preparation and administration of intravenous drugs. There is increasing evidence that serious infections can be adequately treated with oral drugs, and the excellent bioavailability of quinolones makes them particularly attractive for these indications. Clinicians require a method for checking absorption by patients with severe infection, and the Serum Bactericidal Test may provide a practical method for monitoring a wide variety of drugs.
BOOK REVIEWS
Authors: Maggio Beth
Published: March 2013

Book reviewed in this article:

Manual of Quantitative Pathology in Cancer Diagnosis and Prognosis Baak JPA, Editor.

Drugs in Gastroenterology Braga P, Guslandi M, Tittobello A, Editors.

Excitatory Amino Acids (Fidia Research Foundation Symposium Series, Vol. 5) Meldrum BS, Moroni F, Simon RP, Woods JH, Editors.

Retinoids: 10 Years On Saurat JH, Editor.

The Design of Analgesic Clinical Trials (Advances in Pain Research and Therapy, Vol. 18), Mitchell B. Max, Russell K. Portenoy, and Eugene M. Laska, Editors

Patient Compliance in Medical Practice and Clinical Trials, Joyce A. Cramer and Bert Spilker, Editors

Clinical Drug Therapy, Anne Abrams, Editor
Dr. N‐Acetylation Polymorphism and Diabetes Mellitus among Saudi Arabians
Authors: El‐Yazigi Adnan , Johansen Klaus , Raines Dale A. , Dossing Martin
Published: March 2013

The acetylator phenotypes of 200 Saudi diabetics and an equal number of control subjects of the same origin were determined by measuring the peak height ratio of two urinary caffeine metabolites, 5‐acetylamino‐6‐formylamino‐3‐methyluracil (AFMU) and 1‐methylxanthine (1MX), using a simplified high‐performance liquid chromatographic method. Urine samples were collected from the diabetics and the control subjects who regularly drink coffee, tea, or caffeinated beverages as part of their normal daily diet. The patients were classified as either type 1 (insulin‐dependent) (28 patients) or type 2 (insulin‐independent) diabetics (172 patients) according to standard criteria. The reproducibility of acetylator phenotype was established by examining the peak height ratio of AFMU/1MX in 18 diabetics and 6 control subjects on different days. Significant differences in the proportion of rapid acetylators were observed between type 1 (53.6%) and type 2 (33.7%) diabetics (P ≤ .0436), and between the control group (26%) and the overall diabetics (36.5%) (P ≤ .024) or those with type 1 disease (P ≤ .0028). Also, there was a significant (P ≤ .0436) association between rapid acetylator status and type 1 diabetes mellitus.
Arithmetic Versus Harmonic Mean Values for Cyclosporin‐A Pharmacokinetic Parameters
Authors: Lum Bert L. , Tarn Janice , Kaubisch Sonja , Flechner Stuart M.
Published: March 2013

The harmonic and arithmetic mean values for volume of distribution at steady state, half‐life, and clearance of intravenous cyclosporin‐A were calculated using an index set of 22 renal transplant candidates to determine if harmonic mean values provide a less biased estimate of central tendency than arithmetic mean values. Cyclosporin‐A was measured using a nonspecific radioimmune assay method. The arithmetic mean value for volume of distribution was 16% larger than calculations by the harmonic mean method. Similarly, the arithmetic mean half‐life and clearance values were larger than harmonic mean values by 10% and 15%, respectively. However, 95% confidence intervals for these pharmacokinetic parameters overlapped. When these mean pharmacokinetic parameter values were used to predict actual values in a test group of 22 renal transplant candidates receiving cyclosporin‐A, similar levels of precision were demonstrated by either method. Both methods produced positively biased predictions for volume of distribution and clearance. However, these differences were not significant. These findings suggest there is little practical value for the use of harmonic mean calculations to describe the central tendency of pharmacokinetic parameters of cyclosporin‐A under the conditions studied. The value of harmonic mean values for pharmacokinetic parameters in other patient populations or with other assay methods for cyclosporin remain to be studied.
Bioequivalence of Racemic Drugs
Authors: Nerurkar Shriniwas G. , Dighe Shrikant V. , Williams Roger L.
Published: March 2013

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a race‐mate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case‐by‐case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.
Single‐Dose Pharmacokinetics of Cetirizine in Patients With Chronic Liver Disease
Authors: Horsmans Y. , Desager J. P. , Hulhoven R. , Harvengt C.
Published: March 2013

The pharmacokinetics of the H1‐receptor antagonist cetirizine were studied from 0 to 72 hours after a single dose of 20 mg in 5 patients with chronic hepatocellular liver disease (group A), in 5 patients with chronic cholestatic liver disease (group B), and in 16 healthy volunteers. The renal function of patients and volunteers was normal (creatinine clearance ≥ 70 mh/min). Cetirizine pharmacokinetics were similar in the two groups of patients. The elimination t1/2 was prolonged in patients (mean ± standard deviation; group A: 14.32 ± 2.30 hours; group B: 13.86 ± 3.14 hours) in comparison with the values observed in volunteers (9.42 ± 2.4 hours). A reduced apparent oral body clearance also was observed in patients (group A: .48 ± .23 mL/min/kg; group B: .41 ± .09 mL/min/kg) in comparison with volunteers (.74 ± .19 mL/min/kg). No differences were observed in the mean cumulative urinary excretion between patients (group A: 69 ± 15%; group B: 69 ± 13%) and volunteers (70.7 ± 7.8%).
Pharmacokinetics of Cyclosporine and Multiple‐Dose Diclofenac During Coadministration
Authors: Mueller Edgar A. , Kovarik John M. , Koelle Ernst U. , Merdjan Henri , Johnston Atholl , Hitzenberger Gerhart
Published: March 2013

Pursuant to anecdotal case reports of a possible drug‐drug interaction between cyclosporine and diclofenac, an open, two‐period crossover study in 24 healthy male volunteers was undertaken in which a single oral dose of 300 mg cyclosporine was administered alone and on day 8 of multiple oral dosing of 50 mg diclofenac every 8 hours. Serial blood samples were obtained over 48 hours after each cyclosporine dose and over a dosing interval for diclofenac on day 7 (diclofenac alone) and day 8 (coadministration of diclofenac with cyclosporine). The mean pharmacokinetic characteristics of cyclosporine were unchanged during coadministration with diclofenac. Based on area under the curve comparison, lack of a pharmacokinetic interaction was conclusively demonstrated for the extent of cyclosporine absorption. The diclofenac maximum plasma concentration and area under the curve over a dosing interval were significantly increased during coadministration; however, a straightforward interpretation of the statistical results was confounded by pronounced variability in diclofenac pharmacokinetics. The results underscore the need for continued caution when cyclosporine and diclofenac are coadministered.
Angiotensin II Receptor Blockade: An Innovative Approach to Cardiovascular Pharmacotherapy
Authors: Eberhardt Robert T. , Kevak Rudolph M. , Kang Peter M. , Frishman William H.
Published: March 2013

Through the multiple actions of angiotensin II (AII), the renin‐angiotensin system (RAS) participates in cardiovascular homeostasis. Angiotensin II acts by binding to specific membrane‐bound receptors, which are coupled to one of several signal transduction pathways. These AII receptors exhibit heterogeneity, represented by AT1 and AT2 receptor subtypes. The AT1 receptor mediates the major cardiovascular action of the RAS. This receptor has been cloned from multiple species, disclosing features consistent with a transmembrane, G‐protein‐linked receptor. Further AII receptor heterogeneity is evident by the cloning of isotypes of the AT1 receptor. Blocking the interaction of AII with its receptor is the most direct site to inhibit the actions of the RAS. Many AII receptor antagonists, including peptide analogs of AII and antibodies directed against AII, possess unfavorable properties that have limited their clinical utility. The discovery and further development of imidazole compounds with AII antagonist properties and favorable characteristics, however, has promise for clinical utility. The leader in this field is a selective AT1 receptor antagonist losartan (previously known as DuP 753 or MK‐954). Losartan was demonstrated to be an effective antagonist of many AII‐induced actions and an effective antihypertensive agent in many animal models of hypertension (HTN). Losartan also demonstrated secondary benefits in preventing stroke, treating congestive heart failure (CHF), and delaying the progression of renal disease in animal models. Clinical studies confirm the AII antagonist action of losartan and suggest that losartan will be effective in the treatment of essential HTN. AII antagonism is likely to provide useful treatment in essential HTN and CHF, conditions in which the RAS is known to play a major role. The utility of AII antagonism may extend beyond that of HTN and CHF, as suggested by the potential usefulness of angiotensin‐converting enzyme (ACE) inhibition in the treatment or prevention of many other diseases. The key advantage AII antagonists provide over ACE inhibitors is that they may avoid unwanted side effects, related to bradykinin potentiation with the latter drugs. The AII antagonists will help determine the role of the RAS in physiologic regulation and in the pathophysiology of various disease states.
Comparison of the Pharmacokinetics of E2020, A New Compound for Alzheimer's Disease, in Healthy Young and Elderly Subjects
Authors: Ohnishi Akihiro , Mihara Mitsuo , Kamakura Hirotoshi , Tomono Yoshiro , Hasegawa Jiro , Yamazaki Katsuhiko , Morishita Nobumichi , Tanaka Teruji
Published: March 2013

E2020, a central‐acting cholinesterase inhibitor, is now under clinical development as a potential therapeutic agent for senile dementia of Alzheimer type. In the current study, the authors compared the pharmacokinetics of this drug after single oral administration in 12 healthy young volunteers (20–27 years of age) and 6 elderly volunteers (65–82 years of age). The subjects received a single 2‐mg oral dose of E2020 after a meal. Blood samples for determination of the drug level were collected over 168 hours after drug administration and were measured by specific high‐pressure liquid chromatography methods with ultraviolet detection. E2020 was generally well tolerated by all subjects of both groups. The plasma elimination half‐life of the β‐phase (t1/2β) and time to maximum peak plasma concentration (tmax) were significantly longer in the elderly than in the young: t1/2β, 103.8 ± 40.6 versus 59.7 ± 16.1 hours; and tmax, 5.2 ± 2.8 versus 3.4 ± 1.5 hours, respectively. There were no statistically significant differences in maximum peak plasma concentration and area under the curve between the two groups. The mean (± standard deviation) oral clearance (Cl/F) in the elderly (9.1 ± 2.4 L/h) was similar to that in the young (10.6 ± 2.7 L/h). The volume of distribution in the steady state (Vdss/F) was significantly larger in the elderly than that in the young: 1217.2 ± 223.2 versus 852.5 ± 147.7 L, respectively. These results suggested that the drug was absorbed more slowly and distributed more widely and thoroughly, but that its clearance from the body is essentially unaffected by age. It is concluded that a modification of the dose of E2020 in the elderly is unnecessary.
A Study of Pharmacokinetic Interaction Between Buspirone and Alprazolam at Steady State
Authors: Buch A. B. , Van Harken D. R. , Seidehamel R. J. , Barbhaiya R. H.
Published: March 2013

The steady‐state pharmacokinetic interaction between buspirone and alprazolam was evaluated in a parallel study with two groups of 12 male volunteers each. On days 1 to 7, group I subjects received a 1‐mg alprazolam tablet every 8 hours (q8h) (TRT 1) and group II subjects received 2 × 5‐mg buspirone tablets qdh (TRT 2). On days 8 through 14, all subjects received a combination of 1‐mg alprazolam and 2 × 5‐mg buspirone tablets q8h (TRT 3). Plasma samples, collected 0 to 8 hours after the morning dose on days 7 and 14, were analyzed for buspirone, alprazolam and their metabolites, 1‐PP, and α‐HO‐alprazolam, respectively. Additional samples were collected before the morning dose on days 5 and 6 of each session to monitor the attainment of steady state. Steady‐state pharmacokinetic parameters Cmax, Tmax, AUC0–8, and Cmin were calculated. The results indicated that for alprazolam, there was a small (<10%) increase in Cmax and AUC when coadministered with buspirone. For buspirone, there was a 10% and 29% increase in Cmax and AUC, when coadministered with alprazolam. These values were within the normal variability observed with this class of drugs. Except for a 14% decrease in Cmin for α‐HO‐alprazolam, coadministration of buspirone and alprazolam did not affect the parameters for the metabolites. The results of this study suggest that coadministration of buspirone and alprazolam did not markedly affect the steady‐state pharmacokinetics of either drug.
Aldose Reductase Inhibitory and Uricosuric Activities of FK366 in Healthy Volunteers
Authors: Kanamaru Mitsutaka , Uematsu Toshihiko , Nagashima Satoru , Mizuno Atsuhiro , Terakawa Masato , Sugiyama Akira , Nalcashima Mitsuyoshi
Published: March 2013

The pharmacokinetics, and aldose reductase (AR) inhibitory and uricosuric activities of FK366 were studied in healthy volunteers given a single oral dose of 150, 300, or 600 mg after fasting, 600 mg after a meal, or 300 mg twice a day for 8 days after meals. The AR inhibition was assessed by the percent reduction from the predrug dulcitol values in red blood cells converted from exogenous galactose by AR. Aldose reductase inhibition paralleled the plasma concentrations of FK366, with maximum inhibitions of 31.6, 48.0, and 56.9% at doses of 150, 300, and 600 mg, respectively. With multiple dosing, the inhibition scarcely differed between the first (41.8%) and last doses (41.5%). Serum uric acid decreased dose dependency, with a minimum concentration of 4.0 mg/dL (predrug: 5.5 mg/dL) 8 hours after receiving 600 mg. With multiple dosing, serum uric acid levels declined rapidly and remained at a concentration of 3.1 mg/dL beginning at day 3. Urinary excretion of uric acid was high on day 1 (879 mg/day), but decreased significantly to 654 mg/day on day 2 and then stabilized. The pharmacokinetics of FK366 were linear over the dose range studied, with an elimination half‐life of 8.2 hours and urinary recovery of 27.2% as unchanged drug. FK366 was well tolerated by all subjects.
Drug Therapy of the Fetus
Authors: Ward Robert M.
Published: March 2013

The fetus has become an intended object of drug therapy administered through the mother with the successful prevention of hyaline membrane disease with glucocorticoids. Maternal drug treatment has now been undertaken for a variety of fetal problems, including arrhythmias, congestive heart failure, infections, and inborn errors of adrenal metabolism. Interestingly, this planned maternal drug exposure during pregnancy coincided with increasing concerns during the last two decades about inadvertent transplacental exposure of the fetus to licit and illicit drugs. Efforts to direct drug therapy to the fetus have pointed out important gaps in knowledge of the pharmacology of the maternal‐placental‐fetal‐unit (MPFU), whereas other observations illustrated recognized principles of the pharmacology of the MPFU. Many of these principles fit the basic framework of pharmacokinetics: absorption, distribution, metabolism and excretion. Rapid changes in maternal‐placental physiology and fetal development during gestation, however, lead to dramatic variations in these processes throughout pregnancy.
Effects of Pyrazinoylguanidine on the Glucose‐Fatty Acid Cycle in Normal Subjects and Patients with Non‐Insulin‐Dependent Diabetes Mellitus
Authors: Vesell Elliot S. , Chambers Charles E. , Passananti G. Thomas , Demers Laurence M. , Beyer Karl H.
Published: March 2013

Pyrazinoylguanidine (PZG) reduced the hyperglycemia, hyperinsulinemia, and hyperlipidemia of patients with non‐insulin‐dependent diabetes mellitus (NIDDM) as well as of normal subjects receiving hydrochlorothiazide (HCTZ). Mechanisms are proposed by which PZG downregulated the elevated glucose‐fatty acid cycle toward a more normal level in NIDDM patients and in non‐diabetic subjects maintained on HCTZ. Despite maintenance of these NIDDM patients on their current antihypertensive medication, PZG reduced further their systolic and diastolic pressures. PZG was well tolerated by both normal and NIDDM patients.
Once‐Daily Trandolapril Compared with the Twice‐Daily Formulation in the Treatment of Mild to Moderate Essential Hypertension: Assessment by Conventional and Ambulatory Blood Pressures
Authors: Poirier Luc , Bourgeois Joanne , Lacourcière Yves
Published: March 2013

A double‐blind, crossover study was carried out to compare the antihypertensive efficacy of the long‐acting ACE inhibitor trandolapril 1 mg administered once daily and 0.5 mg twice daily in 31 patients with mild to moderate essential hypertension. After randomization, patients entered a single‐blind placebo period of 4 weeks. After a double‐blind treatment of 4 weeks with either of the dosage regimens, patients were then crossed over to the alternate regimen for the last 4 weeks of the study. Conventional BP and heart rate were measured on each visit and ambulatory BP monitoring was done at baseline and at the end of each treatment phase. Conventional as well as 24‐hour and awake ambulatory systolic and diastolic BPs were significantly (P < 0.001) and almost identically decreased by both once‐ and twice‐daily formulations. Moreover, the clinical response rates (reduction in seated diastolic BP ≥ 10% or diastolic BP ≤90 mm Hg) were similar with both treatment regimens (42% vs. 45% with the once‐ and twice‐daily formulations, respectively). However, trandolapril twice daily exerted a significantly (P = 0.03) greater antihypertensive effect on systolic BP during sleep as compared with the once‐daily formulation. Due to the fact that the minimal effective dose was used in this trial, further studies with higher doses should demonstrate effective 24‐hour control of BP as described with other long‐acting ACE inhibitors. In addition, our results suggest that ambulatory BP measurements should be done in dose‐response studies.
The Effect of Phenobarbital on Autonomic Function and Epileptogenic Activity Induced by the Hippocampal Injection of Penicillin in Cats
Authors: Lathers Claire M. , Schraeder Paul L. , Turner Nihal
Published: March 2013

This study addressed whether penicillin‐induced epileptiform discharges in the right hippocampus produced associated autonomic dysfunction. The study also examined the effect of phenobarbital on the heart rate and blood pressure changes that were induced by the epileptiform discharges. The delay in onset of epileptiform activity at the site of injection ranged from 1 second to 16 minutes, and consisted of interictal discharges or ictal discharges. With the onset of epileptiform activity, blood pressure and heart rate increased significantly from control (P < .05). Electrocardiogram alterations included: P‐R interval changes; increased P‐wave amplitude; QRS complex changes; T‐wave inversion; and ST elevation. Phenobarbital 20 mg/kg intravenously suppressed the epileptogenic activity and depressed the blood pressure and heart rate below control (P < .05). In an additional series of experiments, penicillin G injected into the right hippocampus in five cats produced epileptiform activity and increased the blood pressure and the heart rate significantly from the control (P < .05). Phenobarbital (20 mg/kg, intravenously, and 40 mg/kg, intravenously) also prevented the penicillin‐induced epileptiform activity. Phenobarbital (40 mg/kg, intravenously) reversed the effect of penicillin on the blood pressure and heart rate, to levels significantly below that of control (P < .05). Phenobarbital diminished both epileptiform activity and autonomic dysfunction. The autonomic dysfunction related to epileptiform activity induced by focal hippocampal administration of penicillin was similar to that induced by the intravenous administration of pentylenetetrazol.