bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate of Low‐Density Lipoprotein Cholesterol and Apolipoprotein B Changes on Initiation and Discontinuation of Atorvastatin Treatment
Authors: Stern Ralph H. , Abel Robert B.
Published: March 2013

In a clinical trial, the changes in LDL cholesterol and in total apolipoprotein B with time were analyzed using a one‐compartment model with constant input rate and first order elimination rate constant after the initiation and discontinuation of treatment with atorvastatin. After initiation of treatment, input rate for total apoplipoprotein B (21 mg/dL/day) and elimination rate constants for both total apoplipoprotein B (0.36 days−1) and low‐density lipoprotein (LDL) cholesterol (0.24 days−1) were similar to those reported for LDL—apolipoprotein B at steady state during treatment with other HMG—CoA reductase inhibitors. However, after discontinuation of treatment, very low elimination rate constants of 0.09 days−1 for LDL cholesterol and 0.07 days−1 for total apolipoprotein B are obtained. A likely explanation is that the model incorrectly assumes an immediate return to the pretreatment state, whereas transient stimulation of hepatic cholesterol synthesis on discontinuation of therapy with HMG—CoA reductase inhibitors is known to occur.
Cortisol Pharmacodynamics after Methylprednisolone Administration in Young and Elderly Males
Authors: Tornatore Kathleen M. , Logue Gerald , Venuto Rocco C. , Davis Paul J.
Published: March 2013

Glucocorticoids are commonly prescribed in the elderly on an empiric basis with little consideration for the age‐related alterations in pharmacologic response. The objectives of this study were to compare the effect of methylprednisolone on cortisol patterns in elderly and young healthy men, to define the relationship between pharmacokinetic parameters of methylprednisolone and pharmacodynamics of cortisol in the elderly and young men. Seven healthy, elderly males (69–82 years old) and five healthy, young males (24–37 years old) participated in a 24‐hour pharmacodynamic trial with randomized assignment to a control period (Phase I) and a methylprednisolone period (Phase II). Serial blood samples were obtained throughout both study periods. Cortisol measurements included the total area under the concentration—time curve (AUC), return AUC, and suppression ratio. During Phase I, a circadian pattern was noted in both groups. After exposure to methylprednisolone (Phase II), a linear decline in serum concentrations of cortisol was observed in both groups. The return AUC of cortisol (425 ± 357 ng·hr/mL [elderly] versus 854 ± 216 ng·hr/mL [young]) and the total AUC 764 ± 340 g·h/mL [elderly] versus 1,230 ± 258 g·hr/mL [young]) were significantly lower in the older men. In addition, a significant decline in total AUC and nadir concentration of cortisol from Phase I to Phase II was noted within both groups. The suppression ratio was significantly greater in the elderly men (mean, 0.38 versus 0.58 in young), which indicates a greater degree of adrenal suppression after administration of methylprednisolone. Exposure to methylprednisolone, as measured by AUC, was 554 ± 215 ng·hr/kg (elderly) and 389 ± 102 ng·hr/kg (young). The greater exposure to methylprednisolone noted in the elderly yielded significant combined correlations for both groups with AUC, return AUC, and suppression ratio of cortisol. A more significant response of cortisol to the exogenous glucocorticoid was apparent in the elderly men. In addition, a slower clearance of methylprednisolone was noted in the elderly group compared with their young counterparts. The effect of reduced clearance of methylprednisolone on the suppression ratio indicates the interrelationship between the disposition of a single dose of an exogenous glucocorticoid and response patterns of cortisol.
Time of Peak Drug Concentration after a Single Dose and a Dose at Steady State
Authors: Greenberg Howard E. , England Michael J. , Hellriegel Edward T. , Bjornsson Thorir D.
Published: March 2013

The time of peak concentration after administration of oral drug is an often quoted and used pharmacokinetic parameter. It is not well appreciated, however, that the peak times after a single dose and a dose at steady state during a multiple administration regimen can differ significantly. This article derives the mathematical relationships that determine how a peak time at steady state differs from that after a single or first dose. These relationships are then evaluated using three different approaches: 1) graphic simulations of time courses of drug concentration for three hypothetical drugs; 2) comparisons of predicted and observed peak times using examples from the literature; and 3) comparisons of predicted and simulated peak times based on different sampling schedules for three hypothetical drugs. The key finding is that peak times after a dose at steady state can occur considerably earlier after administration than after a single dose. However, the manner by which peak times are usually determined, that is, the sampling time corresponding to the highest measured drug concentration, imposes significant limitations on the usefulness of this parameter.
Short‐Term Safety and Efficacy of Low‐Dose Simvastatin in Elderly Patients with Hypertensive Hypercholesterolemia and Fasting Hyperinsulinemia
Authors: Chan Paul , Huang Tsuei‐Yuen , Tomlinson Brian , Lee Clarita , Lee Ying‐Shiung
Published: March 2013

To evaluate the short‐term safety and efficacy of low‐dose (10 mg) simvastatin in hypercholesterolemic, hypertensive elderly Chinese patients receiving antihypertensive treatment, a randomized, double‐blind, placebo‐controlled, 3‐month trial was conducted. The patients had a total plasma cholesterol level of at least 250 mg/dL and had been, for at least 3 months, consuming a standard lipid‐lowering diet (American Heart Association Step 1 Diet). Elderly hypertensive patients (n = 76) were randomized to receive treatment with either placebo (n = 38) or simvastatin (n = 38). The dosage consisted of 10 mg simvastatin daily during the 3‐month trial. During that period, in the simvastatin group, plasma levels of total cholesterol and low‐density lipoprotein cholesterol decreased significantly (27% and 33%, respectively) compared with those levels in plasma in the placebo group. The plasma levels of high‐density lipoprotein cholesterol increased (7%), whereas triglyceride levels slightly decreased (8%). There were no serious side effects, and simvastatin was generally well tolerated. Fasting hyperinsulinemia also improved (–21%) after 3 months of simvastatin therapy. Results of this study confirmed that a low dose (10 mg) of simvastatin daily is a safe and effective method of reducing plasma levels of total and low‐density lipoprotein cholesterol in hypercholesterolemic, hypertensive elderly patients receiving concurrent antihypertensive drug therapy, and that it has the additional potential benefit of reducing plasma levels of insulin.
Comparison of Enalapril to Captopril by 24‐Hour Ambulatory Blood Pressure Monitoring
Authors: Bental Tamir , Lishner Michael , Lalkin Arieh , Elis Avishai , Ravid Mordchai
Published: March 2013

The efficacy of a once‐daily dose of enalapril was compared with a thrice‐daily dose of captopril in an open‐label, randomized parallel group study of 27 hypertensive patients. The patients were monitored using conventional measurements of blood pressure and with 24‐hour ambulatory blood pressure monitoring at baseline and after 12 weeks of therapy. The end points were 24‐hour, daytime, and nighttime mean blood pressure values and the percentage of elevated systolic and diastolic measurements, reflecting the “hypertensive load.” Enalapril reduced mean 24‐hour systolic blood pressure by 18 mmHg and diastolic blood pressure by 11 mmHg. The comparative values for captopril were 9 mmHg and 2 mmHg, respectively. The mean daytime systolic blood pressure was reduced by 20 mmHg with enalapril versus 7 mmHg with captopril; the diastolic values were lowered by 11 mmHg with enalapril versus 4 mmHg with captopril. The mean nighttime systolic blood pressure was lowered by 16 mmHg with enalapril versus 12 mmHg with captopril; the diastolic values were reduced by 10 mmHg with enalapril and 5 mmHg with captopril. No major side effects were recorded in either group. A single daily 20‐mg dose of enalapril, therefore, proved to be equipotent or superior to 75 mg of captopril administered in three divided doses.
Effect of a Cola Beverage on the Bioavailability of Itraconazole in the Presence of H2 Blockers
Authors: Lange David , Pavao Jennifer Hardin , Wu Jane , Klausner Mark
Published: March 2013

Thirty‐three healthy individuals participated in an open‐label, randomized, three‐way crossover study designed to compare the bioavailability of a single 200‐mg oral dose of itraconazole when administered alone or after treatment with ranitidine, both with and without coadministration of a cola beverage. Each treatment phase was separated by a 2‐week washout period. Participants pretreated with ranitidine were required to have a gastric pH of at least 6.0 before receiving itraconazole. An analysis of the area under the curve (AUC) and peak plasma concentration (Cmax) data indicated that the bioavailability of itraconazole was significantly reduced when the gastric pH was increased by pretreatment with ranitidine but showed that this effect was counteracted by the coadministration of an acidic solution (e.g., a cola beverage) that transiently reduced the gastric pH. These findings suggest that the coadministration of an acidic beverage with itraconazole may be an effective approach in improving the bioavailability of itraconazole in patients who are hypochlorhydric or who are taking gastric acid suppressants.
Population Pharmacokinetics of Intravenous Amiodarone and Comparison with Two‐Stage Pharmacokinetic Analysis
Authors: Vadiei Kiumars , Troy Steven , Korth‐Bradley Joan , Chiang Soong T. , Zimmerman James J.
Published: March 2013

The disposition of amiodarone, an antiarrhythmic agent was evaluated after a single intravenous infusion (5 mg/kg over 15 minutes) in patients of various ages and with various degrees of renal function and left ventricular function. The plasma concentration—time data were obtained from three clinical studies with similar protocols. The data were analyzed by nonlinear mixed‐effects modeling (NONMEM) to estimate the population pharmacokinetic parameters of amiodarone and to determine the significant demographic covariates affecting these parameters. The pharmacokinetic parameters of amiodarone (weight‐corrected) also were calculated using two‐stage analysis and were compared with the results obtained from the mixed‐effects analysis. The population plasma concentration—time profile of amiodarone was best described by a four‐compartment model. Demographic covariates (i.e., creatinine clearance and ejection fraction) did not improve the final pharmacostatistical model significantly. The results from the two‐stage analysis showed no significant relationship between amiodarone pharmacokinetic parameters and age, gender, renal function, or ejection fraction. The results from one study, however, demonstrated that advanced age (≥65 years) resulted in reduced amiodarone clearance coupled with a prolonged elimination half‐life. No such correlation was detected with NONMEM analysis, which may be partly attributable to the small number of elderly patients. Overall, the results from NONMEM analysis validated the results obtained from the two‐stage analysis.
Sinistrin Clearance for Determination of Glomerular Filtration Rate: A Reappraisal of Various Approaches Using a New Analytical Method
Authors: Buclin Thierry , Pechère‐Bertschi Antoinette , Séchaud Romain , Décosterd Laurent A. , Munafo Alain , Burnier Michel , Biollaz Jérôme
Published: March 2013

Several approaches are available to estimate the glomerular filtration rate (GFR) from the sinistrin clearance. To compare such approaches, GFR was estimated in six healthy volunteers, both after a bolus injection and a bolus dose followed by a 6‐hour infusion. A recently developed high‐performance liquid chromatography method was used for the determination of sinistrin levels, enabling precise measurements in plasma and urine samples with high sensitivity. Blood and urine were sampled up to 6 hours. Four calculation methods for estimating GFR were applied: 1) classical ratio of urinary excretion rate over plasma concentration (UV/P); 2) two‐point (log‐linear regression slope times monocompartmental volume of distribution) after bolus; 3) ratio of dose over area under the curve (D/AUC) after bolus; and 4) ratio of infusion rate over steady‐state concentration during infusion (Rinf/P). The results obtained by fitting a pharmacokinetic model to all the plasma and urine data served as the standard against which the performance of the respective calculation methods were examined. The UV/P method performed poorly on bolus data, mainly by underestimating GFR at late times; on both bolus and infusion data, it suffered from important imprecisions on the urinary volume. The two‐point method appeared applicable only between 2 and 4 hours after the bolus dose. The D/AUC method with extrapolation to infinity was highly reliable when integrating the concentrations up to 3 hours or more after the bolus dose. The Rinf/P method was satisfactory if applied later than 2 to 3 hours after the loading dose. The advantages and drawbacks of each method have to be evaluated in relation to the particular clinical setting in which GFR is to be estimated.
Pharmacokinetics and Pharmacodynamics of Midazolam After Intranasal Administration
Authors: Burstein Aaron H. , Modica Rosanne , Hatton Michael , Forrest Alan , Gengo Fran M.
Published: March 2013

This study aimed to characterize the pharmacokinetics and pharmacodynamics of midazolam after intranasal administration to healthy volunteers. Eight participants were given 0.25 mg/kg intranasally and 2 mg intravenously in a randomized, crossover fashion. Blood samples for determination of plasma concentrations of midazolam and measures of cognitive function (using the digit symbcl substitution test) were obtained at baseline and 5, 10,20,30,45,60, 90, 120, 180,240, and 360 minutes after administration of study medications. Plasma samples were analyzed by gas chromatography (% coefficient of variation < 10%). Pharmacokinetic data were fitted using iterative two‐stage analysis to a two‐compartment model. Pharmacodynamic data were fitted by a baseline subtraction Hill‐type model. The mean (SD)for total clearance, distributional clearance, volume of distribution in the central compartment, volume of distribution in the peripheral compartment, absorption rate constant, bioavailability, and half‐life were 0.57 (0.26) L/hr/kg, 0.31 (0.29) L/hr/kg, 0.27 (0.14) L/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr‐1, 50% (13%), and 3.1 (0.84) hours, respectively. The mean (SD) for the concentration at which the effect is half maximal (EC50) and the maximal effect or the maximal change in effect measure from baseline (Emax) were 63.1 (21.2) ng/mL and 52.8 (21.1) correct substitutions, respectively. After in tranasal administration, midazolam concentrations rapidly achieve values considered sufficient to induce conscious sedation and produce predictable changes in digit symbol substitution score.
Plasma Levels of Nicotine and Safety of Smokers Wearing Transdermal Delivery Systems During Multiple Simultaneous Intake of Nicotine and During Exercise
Authors: Homsy Walid , Yan Kerry , Houle Jean‐Marie , Besner Jean‐Guy , Gossard Denis , Pierce Charles H. , Caillé Gilles
Published: March 2013

Although transdermal nicotine patches have been studied extensively under recommended conditions, the present studies were designed to assess the nicotine plasma levels and the safety of transdermal nicotine patches in smokers undergoing situations suspected to result in increased nicotine plasma levels. The first study examined the effects of increasing nicotine intake through sequential administration of a nicotine patch (day 2), a patch followed by consumption of nicotine gum (day 3), and a patch followed by gum consumption and cigarette smoking (day 4). In this study, nicotine plasma levels increased transiently after the addition of each nicotine source. Mean areas under the concentration‐time curves from 0 to 24 hours +AUC0–24) for nicotine were 453 ± 120 ng · hr/mL (day 2), 489 ± 143 ng · hr/mL (day 3), and 485 ± 143 ng · hr/mL (day 4). The second study evaluated the effects of physical exercise on the kinetics and the safety of two different types of nicotine transdermal devices: Nicoderm and Habitrol. The mean delivered dose of nicotine was higher with Nicoderm compared with Habitrol, and the two products were not considered to be bioequivalent. During a 20‐minute exercise period, nicotine plasma levels increased by 13 ± 9% for Nicoderm and 30 ± 20% for Habitrol. This increase in nicotine plasma levels was probably related to the exercise‐induced increase in peripheral circulation at the patch site. Results from both studies indicate a clinically nonsignificant increase in blood pressure and heart rate after the administration of nicotine. After exercise, subjects taking Habitrol tended to have a higher incidence of adverse events compared with baseline values. Safety profiles remained acceptable in both studies despite the increases in nicotine plasma levels. It was concluded that both superimposed nicotine sources and physical exertion result in short‐lived plasma nicotine elevations and temporarily increase nicotine pharmacodynamic parameters without increased risk to the volunteers.
Absence of a Pharmacokinetic Interaction Between Intravenous Theophylline and Orally Administered Levofloxacin
Authors: Gisclon Lee G. , Curtin Christopher R. , Fowler Cynthia L. , Williams R. Rex , Hafkin Barry , Natarajan Jaya
Published: March 2013

A randomized, placebo‐controlled, two‐way crossover study in 16 healthy men was performed to determine the effect of orally administered levofloxacin at steady‐state conditions, given at 500 mg every 12 hours, on the pharmacokinetics of theophylline given as a single 4.5‐mg/kg intravenous infusion. Participants were assigned randomly to receive theophylline with levofloxacin in one study period and theophylline with placebo in the other period. Fourteen individuals completed the study. Mean (± SD) values for theophylline pharmacokinetic parameters for the levofloxacin and placebo treatments, respectively, were peak plasma concentrations (Cmax) of 11.4 (1.8) μg/mL and 10.7 (1.3) μg/mL; areas under the concentration time curve from time 0 extrapolated to infinity (AUC0‐∞) of 124 (32) μg · hr/mL and 126 (30) μg · hr/mL; volumes of distribution at steady state (Vdss) 31.7 (3.5) L and 32.0 (3.9) L; clearances (Cl) of 48.6 (11.6) mL/min and 47.4 (10.3) mL/min; and half‐lives (t1/2) of 8.1 (1.9) hours and 8.2 (1.8) hours. There were no statistically significant differences between treatments for any of these parameters. There was no pharmacokinetic interaction between levofloxacin administered orally at steady‐state conditions and intravenously administered theophylline.
Acetylator Phenotype in Relation to Age and Gender in the Baltimore Longitudinal Study of Aging
Authors: Korrapati Madhu R. , Sorkin John D. , Andres Reubin , Muller Denis C. , Loi Cho‐Ming , Vesell Elliot S. , Vestal Robert E.
Published: March 2013

This study investigated in healthy Caucasians the possible occurrence of age and gender‐associated differences in NAT2 acetylator phenotype. Acetylator phenotype was determined after a single oral dose of 100 mg dapsone during testing of oral glucose tolerance in 510 Caucasian volunteers aged from 19 to 93 years, 339 men and 171 women, from the Baltimore Longitudinal Study of Aging. Participants were classified as slow or rapid acetylators according to the ratio of monoacetyldapsone to dapsone concentration in plasma. The ratio dividing the two groups, 0.30, was chosen after inspection of a probit plot and histogram of the monoacetyldapsone/dapsone ratios. Fifty‐one percent of the participants were slow acetylators and 49% were rapid acetylators. Because there was no significant difference between the sexes in the monoacetyldapsone/dapsone ratios, all 510 participants were pooled into a single group for further analysis. In the combined analysis, there was a small decline in the prevalence of the slow acetylator phenotype with age, but this age effect accounted for less than 1% of the total variance in the monoacetyldapsone/dapsone ratio (r2 = 0.009). Also, it was shown in a group of 20 participants that administration of glucose with dapsone does not influence the determination of acetylator phenotype. In a large healthy Caucasian‐American population, there was no biologically important effect of age or sex on the distribution of NAT2 acetylator phenotype.
Phase I Pilot Study of the Effects of Trovafloxacin (CP‐99,219) on the Pharmacokinetics of Theophylline in Healthy Men
Authors: Dickens George R. , Wermeling Daniel , Vincent John
Published: March 2013

This study examined the effect of trovafloxacin (CP‐99,219) on the pharmacokinetics and pharmacodynamics of a single dose of theophylline, when administered to steady‐state concentrations. Twelve healthy, nonsmoking male volunteers participated. A 450‐mg dose of theophylline was administered at 7:00 am on day 1. On day 4, volunteers received 300 mg of trovafloxacin (CP‐99,219) daily in the morning for 7 days. The 450‐mg dose of theophylline was repeated on day 8 at 7:00 am concomitantly with 300 mg of trovafloxacin. Theophylline concentrations in plasma and trovafloxacin in serum were determined using reverse‐phase high‐performance liquid chromatography. There was no significant difference between the geometric mean values for Cmax of theophylline, 6.42 μg/mL and 6.00 μg/mL on days 1 and 8, respectively. A change (P = 0.032) in the geometric mean of the area under the concentration‐time curve extrapolated to infinity (AUC0‐x) for theophylline was noted after trovafloxacin was administered. Mean terminal phase elimination rate constants (KeS) were reduced (P = 0.001) by 13% after administration of trovafloxacin from day 1 to day 8. In general, changes in theophylline clearance of less than 20% are unlikely to be of clinical significance. In this study, oral administration of trovafloxacin in 300‐mg doses to achieve steady‐state concentration resulted in an 8.4% increase in the extent of systemic exposure (AUC0‐x) to theophylline. Assuming that this AUC change is based on oral clearance and not absorption, one would not expect to see clinically significant changes in the pharmacokinetics of theophylline. No pharmacodynamic changes resulted from the pharmacokinetic changes of theophylline.
Single‐Dose Pharmacokinetics and Pharmacodynamics of Alprazolam in Elderly and Young Subjects
Authors: Kaplan Gary B. , Greenblatt David J. , Ehrenberg Bruce L. , Goddard Jill E. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

The pharmacokinetics and pharmacodynamics of the benzodiazepine anxiolytic alprazolam (1 mg orally) were compared between young and elderly healthy volunteers. Eight young subjects (mean age 29.8 years) and eight elderly volunteers (mean age 68.4 years) received oral placebo and alprazolam (1.0 mg) in a randomized, double‐blind, single‐dose crossover study. In the elderly subjects, plasma concentrations were higher, although not significantly so, than in young volunteers 0.25, 0.5, and 0.75 hours after dosage. Apparent elimination half‐life, time of maximum concentration, maximum concentration, volume of distribution, and apparent clearance were similar for the two groups. In both groups, alprazolam treatment (versus placebo) produced significant changes in typical benzodiazepine agonist effects, such as increased sedation and fatigue, reduced excitement, increased feelings of spaciness, and perception of thinking slowed. For some measures, the alprazolam‐placebo difference was greater in young than in elderly subjects. In both groups, alprazolam significantly impaired performance on the digit‐symbol substitution test (DSST). EEG studies indicated significant increases in relative beta amplitude (13–30 Hz range) after alprazolam compared to placebo. Percent DSST decrement and percent EEG change were highly correlated with plasma alprazolam concentrations for both groups. There were modest increases in alprazolam plasma concentration in the elderly compared to the younger group shortly after drug administration, but there was no evidence of increased sensitivity to the pharmacodynamic effects of alprazolam in the elderly. J Clin Pharmacol 1998;38;14–21.
Comparative Efficacy and Safety of Controlled‐Release Morphine Suppositories and Tablets in Cancer Pain
Authors: Babul Najib , Provencher Louise , Laberge Francis , Harsanyi Zoltan , Moulin Dwight
Published: March 2013

Although the oral route is the preferred method of opioid therapy in patients with cancer pain, many patients will require an alternate route of analgesic administration at some point during the trajectory of their illness. This study compared the efficacy and safety of a novel, controlled‐release suppository of morphine (MSC‐R) and controlled‐release morphine tablets (MSC‐T) in patients with cancer pain. In a double‐blind crossover study, 27 patients with cancer pain were randomized to receive MSC‐R or MSC‐T every 12 hours for 7 days each, using a 1:1 analgesic equivalence ratio. Pain intensity was assessed using a visual analog scale (VAS) and the Present Pain Intensity Index of the McGill Pain Questionnaire. Nausea and sedation were also assessed with a VAS. Pharmacodynamic assessments were made by the patient at 8:00 am, 12:00 pm, 4:00 pm, and 8:00 pm and rescue morphine use recorded in a daily diary. There were no significant differences between MSC‐R and MSC‐T in overall scores for pain intensity VAS, ordinal pain intensity, and sedation. There was a small but significant difference in overall nausea VAS score in favor of MSC‐R. Mean daily rescue analgesic use did not differ significantly during between treatment with MSC‐R and MSC‐T. MSC‐R provides pain control comparable to that provided by MSC‐T when given every 12 hours at a 1:1 dose ratio, and represents a reliable alternative method of pain control for patients unable to take oral opioid agents.
Steady‐State Pharmacokinetics of Isotretinoin and its 4‐Oxo Metabolite: Implications for Fetal Safety
Authors: Nulman Irena , Berkovitch Matitiahu , Klein Julia , Pastuszak Anne , Lester Robert S. , Shear Neil , Koren Gideon
Published: March 2013

Isotretinoin is the most potent human teratogen on the market. Women for whom contraception fails may conceive during or soon after discontinuing isotretinoin therapy, making its elimination kinetics a crucial determinant of fetal safety. The steady‐state pharmacokinetics of isotretinoin and its major 4‐oxo metabolite were studied in 16 adult patients treated for acne who were receiving doses that ranged from 0.47 to 1.7 mg/kg daily. This is the first study of the pharmacokinetics of isotretinoin in women of childbearing age (n = 11). The clinical efficacy and tolerability of isotretinoin was investigated, and the correlation between these data and steady‐state serum concentrations of isotretinoin was tested. The concentration‐time data best fitted a two‐compartment open model with linear elimination. There was no correlation between efficacy and tolerability of isotretinoin and steady‐state serum concentrations. There was no correlation between dose of isotretinoin and steady‐state concentration, due to the large variability in apparent clearance. Values for elimination half‐life (t1/2) of isotretinoin and its metabolite were 29 ± 40 hours and 22 ± 10 hours, respectively. These data suggest a longer elimination t1/2 of the parent drug than previously reported. This is probably due to the longer sampling time used in this study (as long as 28 days). This study suggests that a greater variability exists in the safe time after discontinuation of the drug for onset of conception.
Gut Motility and Transit Changes in Patients Receiving Long‐Term Methadone Maintenance
Authors: Yuan Chun‐Su , Foss Joseph F. , O'Connor Michael , Moss Jonathan , Roizen Michael F.
Published: March 2013

This study was conducted to survey gut motility and transit in 19 volunteers receiving methadone maintenance who were opioid‐dependent, and to measure the oral‐cecal transit time in these individuals using the lactulose hydrogen breath test. None of these patients reported constipation problems before use of illicit drugs. During current long‐term methadone therapy, 58% of patients experienced some degree of constipation, and two of these 19 patients reported that constipation was a very serious problem. Mean ± standard deviation (SD) oral‐cecal transit time in these individuals was 159 ± 49.2 minutes, which is significantly longer than the transit time recorded in two previous studies of healthy volunteers (P < 0.01). These results indicate that tolerance to opioids does not appear to extend to gastrointestinal motility and transit. It seems that patients receiving long‐term methadone therapy are a good model for use in evaluating gastrointestinal effects of opioid antagonists.
Pharmacokinetics of Mitomycin C in Pelvic Stopflow Infusion and Hypoxic Pelvic Perfusion with and without Hemofiltration: A Pilot Study of Patients with Recurrent Unresectable Rectal Cancer
Authors: Guadagni Stefano , Aigner K. R. , Palumbo G. , Cantore M. , Fiorentini G. , Pozone T. , Deraco M. , Clerico M. , Chaudhuri P. K.
Published: March 2013

This pilot study was conducted to evaluate the advantage in drug delivery for regional chemotherapy in patients with unresectable recurrent rectal carcinoma by different methods. For this research, the pharmacokinetic advantages of mitomycin C delivery by four different methods were compared: intraaortic infusion with aortic stopflow; intraaortic infusion with inferior vena cava stopflow; intraaortic infusion with aortic and inferior caval vein stopflow (hypoxic pelvic perfusion); and hypoxic pelvic perfusion with hemofiltration. The results of this study indicate that pelvic stopflow infusion followed by hypoxic pelvic perfusion significantly increases mitomycin C concentrations in the blood coming from the tumor site. Also, use of hemofiltration reduces mitomycin C levels in peripheral blood after high‐dose regional chemotherapy. Further investigations involving more patients should be carried out in the future to validate these results.
Fentanyl Delivery from an Electrotransport System: Delivery is a Function of Total Current, Not Duration of Current
Authors: Gupta Suneel K. , Bernstein Keith J. , Noorduin Henk , Van Peer Achiel , Sathyan Gayatri , Haak Ron
Published: March 2013

This open‐label, parallel study of 28 men was conducted to evaluate the pharmacokinetics and safety of fentanyl delivered by the E‐TRANS (fentanyl) electrotransport transdermal system (ALZA Corporation, Palo Alto, CA). The E‐TRANS (fentanyl) system provided electrically assisted, transdermal, continuous delivery of fentanyl. Treatments consisted of no current (group A); a constant current of 100 μA for 26 hours plus 4 additional doses at varying currents for varying times during hour 25 (groups B, C, D); a constant current of 100 μA for 26 hours plus 4 additional doses at 1,200 μA over 2.5 minutes during hour 1 (group E); or 500 μA for 0.5 hours and 100 μA for 3.5 hours (group F). No fentanyl was detected in serum when no current had been applied. Mean serum fentanyl concentrations were similar regardless of current duration during hour 25 (treatments B, C, D). Increases in mean serum fentanyl concentrations were significantly lower during additional dosing for treatment E compared with treatments B, C, and D. Serum fentanyl concentrations sufficient for analgesia (1–3 ng/mL) were attained in treatments using the E‐TRANS (fentanyl) system with basal current of 100 μA for 26 hours. There were no safety issues after treatment with E‐TRANS (fentanyl) system with concurrent opioid antagonist (naltrexone) administration. The only adverse event requiring treatment was a headache (n = 1). The majority of subjects had no or barely perceptible erythema at the application site 24 hours after system removal. Application of E‐TRANS (fentanyl) resulted in therapeutically significant serum fentanyl concentrations over a range of applied currents. Overall serum fentanyl concentrations were higher when the skin had been primed by constant‐current fentanyl delivery.
Effect of Grapefruit Juice on the Pharmacokinetics of Microemulsion Cyclosporine and its Metabolite in Healthy Volunteers: Does the Formulation Difference Matter?
Authors: Ku Yi‐Min , Min David I. , Flanigan Michael
Published: March 2013

This study was conducted to determine the effect of grapefruit juice on the pharmacokinetics of microemulsion cyclosporine and its major metabolites, M1 and M17, in 12 healthy volunteers. Each subject received two oral doses of microemulsion cyclosporine with water or grapefruit juice. Each subject also received intravenous cyclosporine on a separate occasion. Blood samples were collected for assay of cyclosporine, M1, and M17 during a 24‐hour period, and were analyzed by a high‐performace liquid chromatography method. Compared with water, administration with grapefruit juice significantly increased peak concentration (Cmax) and area under the concentration‐time (AUC) of cyclosporine. Administration with grapefruit juice increased the absolute bioavailability of microemulsion cyclosporine by 45%. For cyclosporine metabolites, administration with grapefruit juice decreased the Cmax and AUC of M1 by 21% and 15%, respectively. These findings suggest that concurrent administration with grapefruit juice increases the bioavailability of microemulsion cyclosporine significantly compared with water in healthy volunteers. The grapefruit juice affects each metabolite formation and its pharmacokinetics differently, which suggests that the major site of its formation is different.
Chelation Therapy in Cardiovascular Disease: Ethylenediaminetetraacetic Acid, Deferoxamine, and Dexrazoxane
Authors: Elihu Nadia , Anandasbapathy Sharmila , Frishman William H.
Published: March 2013

This review was conducted to assess whether there is sufficient evidence for the clinical use of chelation therapy in cardiovascular disease based on original articles and abstracts published in the last 30 years, with emphasis placed on the most recent placebo‐controlled studies. Articles postulating the mechanisms of chelation also were included. The majority of the literature focused on three chelators in particular, ethylenediaminetetraacetic acid (EDTA), deferoxamine, and dexrazoxane (ICRF‐187). Historically, much has been written on the beneficial effects of EDTA. However, there are few controlled studies, and the mechanism of action of EDTA is poorly understood. Although studies of deferoxamine are more recent, most of the research is limited to animals and ex vivo models. Recently, dexrazoxane was approved, but only for parenteral use for reducing the incidence and severity of cardiomyopathy associated with doxorubicin administration in women with metastatic breast cancer. Given these limitations, it is concluded that more controlled studies are required to determine the efficacy of chelation therapy in cardiovascular disease before it can be used broadly in the clinical setting.
Five Distinct Human Cytochromes Mediate Amitriptyline N‐Demethylation In Vitro: Dominance of CYP 2C19 and 3A4
Authors: Venkatakrishnan Karthik , Greenblatt David J. , von Moltke Lisa L. , Schmider Jürgen , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

The human cytochromes P450 (CYPs) mediating amitriptyline N‐demethylation have been identified using a combination of enzyme kinetic and chemical inhibition studies. Amitriptyline was N‐demethylated to nortriptyline by microsomes from cDNA transfected human lymphoblastoid cells expressing human CYPs 1A2, 2C9, 2C19, 2D6, and 3A4. CYP 2E1 showed no detectable activity. While CYP 2C19 and CYP 2D6 showed high affinity, CYP 3A4 showed low affinity; CYP 2C9 and 1A2 showed intermediate affinities. Based on these kinetic parameters and estimated relative abundance of the different CYPs in human liver, CYP 2C19 was identified as the major amitriptyline N‐demethylase at low (therapeutically relevant) amitriptyline concentrations, whereas CYP 3A4 may be more important at higher amitriptyline concentrations. Chemical inhibition studies with ketoconazole and omeprazole indicate that CYP 3A4 is the major amitriptyline N‐demethylase at 100 μmol/L amitriptyline, while CYP 2C19 is equally important at a substrate concentration of 5 μmol/L. The CYP 1A2 inhibitor α‐naphthoflavone and the CYP 2C9 inhibitor sulfaphenazole produced much less inhibition of amitriptyline N‐demethylation at both substrate concentrations. Quinidine produced no detectable inhibition. The kinetics of amitriptyline N‐demethylation by human liver microsomes were consistent with a two enzyme model, with the high affinity component exhibiting Michaelis Menten kinetics and the low affinity component exhibiting Hill enzyme kinetics. No difference was apparent in the kinetics of amitriptyline N‐demethylation in two liver samples with low levels of CYP 2C19 activity compared with two other samples with relatively normal 2C19 activity. This may reflect the importance of higher substrate concentration values in estimation of kinetic parameters in vitro.
Stereoselective Pharmacokinetics and Inversion of (R)‐ Ketoprofen in Healthy Volunteers
Authors: Rudy Anita C. , Liu Yingxian , Brater D. Craig , Hall Stephen D.
Published: March 2013

The pharmacokinetics of ketoprofen enantiomers were evaluated after 25‐, 50‐, and 100‐mg doses of (R)‐ ketoprofen and 100 mg of racemic ketoprofen in 25 healthy volunteers (12 male and 13 female). The fractional inversion (Finv) of (R)‐ ketoprofen was 8.9 ± 3.3% using plasma data and 10.0 ± 2.2% using urine data. There were small (<5%) but significant differences between the enantiomers for areas under the plasma concentration‐time curve (AUC) after the racemic dose (P < 0.005). Half‐lives were 130–144 minutes for (R)‐ ketoprofen and 132–209 minutes for (S)‐ ketoprofen. Dose proportionality in AUC and maximum plasma concentration (Cmax) values was noted for both enantiomers. A total of 69% of the dose was recovered in the urine as (R)‐ and (S)‐ ketoprofen and conjugates. The elimination rate constant of (R)‐ ketoprofen was significantly different (P < 0.05) between men and women. Exposure to cyclooxygenase inhibiting (S)‐ ketoprofen was approximately 10% of the dose after the administration of pure (R)‐ ketoprofen and was independent of gender. J Clin Pharmacol 1998;38:3S‐10S.
Clinical Endoscopic Evaluation of the Gastroduodenal Tolerance to (R)‐ Ketoprofen, (R)‐ Flurbiprofen, Racemic Ketoprofen, and Paracetamol: A Randomized, Single‐Blind, Placebo‐Controlled Trial
Authors: Jerussi Thomas P. , Caubet Jean‐François , McCray John E. , Handley Dean A.
Published: March 2013

Ketoprofen, a nonsteroidal anti‐inflammatory drug (NSAID) of the 2‐arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10–15% of patients. The (S)‐ enantiomer exhibits most of the anti‐inflammatory properties, with concomitant gastrointestinal toxicity. The (R)‐ enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition. Seventy‐two healthy male volunteers not receiving NSAIDs, alcohol, or anti‐ulcer drugs, were enrolled in a randomized, investigator‐blind, placebo‐controlled trial to evaluate the gastroduodenal tolerance of (R)‐ ketoprofen 100 mg b.i.d., (R)‐ flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5 days of dosing were used to detect newly occurring hemorrhages and erosions. Adverse events were also recorded. The incidence of submucosal hemorrhages was 4/16 in the (R)‐ ketoprofen group, 5/16 in the (R)‐ flurbiprofen group, 12/16 in the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the placebo group. The incidence of erosions was 2/16 in the (R)‐ ketoprofen group, 4/16 in the (R)‐ flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16 in the paracetamol group, and 2/8 in the placebo group. The differences in hemorrhages and erosions among treatments were statistically significant (gastric hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P = 0.0004; duodenal erosions P = 0.0062, Kruskal‐Wallis test). At 100 mg b.i.d., (R)‐ ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal hemorrhages and gastric, duodenal erosions, respectively). The difference between 100 mg b.i.d. (R)‐ ketoprofen and 100 mg b.i.d (R)‐ flurbiprofen was not statistically significant. The dissociation between analgesic and anti‐inflammatory properties for (R)‐ ketoprofen suggests that it may represent a unique analgesic with a favorable safety profile. J Clin Pharmacol 1998;38:19S‐24S.
Single‐Dose Pharmacokinetics of Modafinil and Methylphenidate Given Alone or in Combination in Healthy Male Volunteers
Authors: Wong Y. Nancy , King S. Peter , Laughton Watson B. , McCormick George C. , Grebow Peter E.
Published: March 2013

Modafinil is a novel wake‐promoting agent being developed for treatment of excessive daytime sleepiness associated with narcolepsy. An open, 3 × 3 Latin square, randomized, cross‐over study was performed in healthy males to compare the pharmacokinetics of single‐dose oral modafinil (200 mg) and methylphenidate (40 mg) administered alone or in combination. Blood samples were obtained for analysis of d‐ and l‐threo‐methylphenidate and modafinil and its acid and sulfone metabolites. Pharmacokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels that were close to the assay quantitation limit. Although sporadic differences in plasma concentrations were observed between treatments, coadministration of modafinil and methylphenidate did not significantly alter the plasma concentrations of modafinil, modafinil acid, modafinil sulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half‐life (t1/2), maximum concentration (Cmax), area under the concentration—time curve (AUC0–∞), total clearance (Cl/F), and apparent volume of distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0–∞ for modafinil acid were not affected by concomitant administration of methylphenidate. Small but statistically significant increases in time to Cmax (tmax) were observed for modafinil and modafinil acid after methylphenidate coadministration compared with modafinil alone. Modafinil coadministration did not significantly alter the pharmacokinetics of d‐ or l‐threo‐methylphenidate, except for a small decrease in Vd/F of l‐threo‐methylphenidate. Concomitant methylphenidate may cause a delay in the oral absorption of modafinil, but this delay might not be relevant clinically. Coadministration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between modafinil and methylphenidate would be unlikely.
The Influence of Cimetidine on the Disposition Kinetics of the Antidepressant Venlafaxine
Authors: Troy Steven M. , Rudolph Richard , Mayersohn Michael , Chiang Soong T.
Published: March 2013

The influence of cimetidine on the disposition pharmacokinetics of the antidepressant drug, venlafaxine, and its active metabolite, O‐desmethylvenlafaxine, was examined in 18 healthy young men and women. The steady‐state pharmacokinetic profiles of venlafaxine and O‐desmethylvenlafaxine were evaluated during a 24‐hour period after 5 days of treatment with venlafaxine (50 mg three times a day) and during a second 24‐hour period after 5 days of combination treatment with venlafaxine (50 mg three times a day) and cimetidine (800 mg once a day). The apparent oral clearance of venlafaxine decreased significantly in the presence of cimetidine and the average steady‐state plasma concentration of venlafaxine increased significantly in the presence of cimetidine, but there were no changes in the corresponding concentrations of the active metabolite. However, O‐desmethylvenlafaxine exhibits pharmacologic activity that is approximately equimolar to that of venlafaxine, and the sum of venlafaxine plus O‐desmethylvenlafaxine plasma concentrations was increased by an average of only 13%. Therefore, the effect of cimetidine coadministration is not expected to result in clinically important alterations in the response to venlafaxine in patients with depression. This may not be true, however, for patients with compromised hepatic metabolic function.
Inflammation, Inflammatory Mediators, and Mediator Antagonists in Asthma
Authors: Lazarus Stephen C.
Published: March 2013

Asthma is an inflammatory disease that involves mast cells, antigen‐presenting cells, eosinophils, neutrophils, and TH2‐lymphocytes. These cells produce a broad array of mediators and cytokines that lead to the bronchoconstriction, mucosal edema, mucus secretion, and bronchial hyperresponsiveness that characterize asthma. Current guidelines for therapy recommend that all patients whose asthma is more severe than mild intermittent receive chronic treatment with drugs that interrupt this inflammatory cascade. Corticosteroids have been the gold standard for treatment, but a greater understanding of the specific cells and mediators involved in the pathogenesis of asthma has led to more focused, specific therapy. Pharmacologic agents that interrupt the synthesis of action of leukotrienes, and monoclonal antibodies directed against intracellular adhesion molecules or immunoglobulin E are examples of the new generation of specific targeted therapy for use in asthma.