bluuebunny/crossref_metadata_2025 huggingface dataset:
Optimizing the Absorption of Valspodar, a P‐glycoprotein Modulator, Part II: Quantifying its Pharmacokinetic Variability and Refining the Bioavailability Estimate
Authors: Kovarik J. M. , Mueller E. A. , Richard F. , Tetzloff W.
Published: March 2013

A randomized, sequential, bioreplication study was performed with 24 healthy volunteers to assess the pharmacokinetic variability of oral and intravenous administrations of valspodar, a multidrug resistance modulator for use as a chemotherapy adjunct. Subjects received 200 mg as a 2‐hour intravenous infusion and 400 mg orally as microemulsion soft gelatin capsules each given on two separate occasions. Following replicate intravenous administrations, reproducibility in peak concentration and area‐under‐the‐curve was demonstrated by interoccasion equivalence testing. Low to moderate inter‐ and intra‐subject pharmacokinetic variability were observed with coefficients of variation ranged from 9% to 19%. Absolute bioavailability from the microemulsion formulation was 60%. Replicate oral administrations demonstrated uniform and repeatable absorption with interoccasion equivalence in peak concentration, time to reach the peak concentration, and area‐under‐the‐curve. Coefficients of inter‐ and intra‐subject variation for these parameters ranged from 10% to 20% indicating low to moderate pharmacokinetic variability. When variabilities were compared between the two routes of administration, the absence of differences indicated that the rate and extent of drug absorption from the microemulsion formulation was as uniform and repeatable as by intravenous infusion.
The Effect of Erythromycin on the CYP3A Component of Sertindole Clearance in Healthy Volunteers
Authors: Wong Shekman L. , Cao Guoliang , Mack Randall J. , Witt  , Granneman G. Richard
Published: March 2013

The effect of erythromycin on the pharmacokinetic disposition of oral sertindole, a new antipsychotic compound, was investigated. Ten subjects who completed the study received a single 4‐mg dose of sertindole without or with concomitant erythromycin 250 mg taken orally 4 times daily. Coadministration of sertindole and erythromycin led to a 33% decrease (P < 0.05) in mean (±SD) time to reach maximum plasma concentration (tmax) value and a 15% elevation (P < 0.05) in the mean maximum plasma concentration (Cmax) value of sertindole. The mean area under the concentration—time curve (AUC) value of sertindole did not change significantly in the presence of erythromycin (alone: 159 ± 111 ng.hr/mL, in combination: 179 ± 144 ng.hr/mL, P >0.05). The presence of erythromycin also significantly increased the dehydrosertindole Cmax and AUC means by 16% and 21%, respectively, possibly due to inhibition of the CYP3A metabolic isozyme responsible for the elimination of this metabolite. The rate of absorption of sertindole and the rate of appearance of dehydrosertindole in the systemic circulation after a 4‐mg sertindole single dose were slightly enhanced by concomitant dosing of erythromycin. In conclusion, there is a small but noticeable effect of erythromycin on the pharmacokinetic disposition of sertindole. The effects are believed to have little clinical significance.
Relationship Between Serum and Free Interstitial Concentrations of Cefodizime and Cefpirome in Muscle and Subcutaneous Adipose Tissue of Healthy Volunteers Measured by Microdialysis
Authors: Müller Markus , Rohde Beate , Kovar Andreas , Georgopoulos Apostlos , Eichler Hans‐Georg , Derendorf Hartmut
Published: March 2013

Microdialysis is a suitable method to monitor unbound concentrations of antimicrobial drugs in the interstitial tissue space which is the site of many infections. The aim of this investigation was to examine whether free tissue levels of cefodizime (81% plasma protein binding) and cefpirome (10% plasma protein binding) in muscle and subcutaneous adipose tissue of healthy volunteers obtained by microdialysis are consistent with the extent of their respective plasma protein binding. Healthy volunteers were given cefodizime and cefpirome at a single intravenous 2‐g dose in a randomized crossover design. Microdialysis probes were inserted into a medial vastus muscle and into the periumbilical subcutaneous layer. After calibration of the probe, samples of serum and microdialysis fluid were obtained and drug concentrations were measured using a microagar diffusion‐bioassay. There was a reasonable agreement between plasma protein binding data and the tissue penetration of both cephalosporins (AUC0‐∞ tissue, free/ AUC0‐∞ Serum, total — ratios) into the interstitial fluid of the muscle tissue, but not for the subcutaneous tissue layer. Furthermore, the serum and tissue concentrations of both drugs were fitted to an open two‐compartment body model. The measured free‐tissue concentrations were compared with calculated unbound concentrations in the peripheral compartment. Good agreement was observed for the free muscle concentrations, but unbound concentrations in the subcutaneous tissue was somewhat higher (cefpirome) or lower (cefodizime) than predicted. This may be due to the different lipophilicities of the two compounds.
Transdermal Testosterone Administration in Hypogonadal Men: Comparison of Pharmacokinetics at Different Sites of Application and at the First and Fifth Days of Application
Authors: Yu Zhiling , Gupta Suneel K. , Hwang Stephen S. , Cook David M. , Duckett Melvin J. , Atkinson Linda E.
Published: March 2013

In this study of 13 hypogonadal men (25–69 years of age), three open‐label, randomized treatments were administered to determine the pharmacokinetics of serum testosterone after application of an investigational testosterone transdermal system to the upper buttocks, upper arm, and back. Testosterone in vivo input kinetics profiles were estimated by DeMonS, a recently developed numerical deconvolution method for estimating drug absorption at different time intervals and/or drug disposition model parameters, and compared on the first and fifth days of system application. Area under the concentration‐time curve from 0 to 27 hours (AUC0–27) values for testosterone after one‐day applications to the upper buttocks, upper arm, and back were 9,560 ng · hr/dL, 8,651 ng · hr/dL, and 8,988 ng · hr/dL, respectively. Maximum observed concentration (Cmax) values were 482 ng/dL, 462 ng/dL, and 499 ng/dL, respectively. Serum testosterone concentrations were equivalent to each other, and Cmax values fell within the normal range. No drug accumulation was seen with repeated dosing over 5 days.
Oxaprozin and Piroxicam, Nonsteroidal Antiinflammatory Drugs with Long Half‐Lives: Effect of Protein‐Binding Differences on Steady‐State Pharmacokinetics
Authors: Karim Aziz , Noveck Robert , McMahon F. Gilbert , Smith Margo , Crosby Sharon , Adams Marijke , Wilton John
Published: March 2013

The nonsteroidal antiinflammatory drugs (NSAIDs) oxaprozin and piroxicam have long elimination half‐lives (t1/2 ∼55 hours), permitting once‐daily dose regimens. The protein‐binding characteristics of these drugs, however, vary widely. This study examines the effect of these binding differences on the drugs' disposition kinetics at steady state. A total of 52 participants (26 young healthy volunteers and 26 elderly osteoarthritic patients, 15 men and 37 women (2 of them poor metabolizers of debrisoquine [CYP2D6]) completed the two‐period, two‐treatment, randomized, single‐dose and 21‐day, once‐daily multiple‐dose, crossover study. Doses of oxaprozin and piroxicam were 1,200 mg once daily and 20 mg once daily, respectively. Mean single‐dose kinetic parameters of oxaprozin versus piroxicam did not differ more than ±14% (t1/2, 53.0 versus 57.4 hours; apparent oral clearance adjusted for 70‐kg body weight [Clpo], 0.139 versus 0.121 L/hr; apparent volume of distribution adjusted for 70‐kg body weight [Vd/F], 10.2 L versus 9.13 L). Protein binding was plasma‐concentration dependent with oxaprozin (range, 10–400 mg/L) but not with piroxicam (range, 1–30 mg/L). Steady‐state conditions were established within 3 days with oxaprozin but took almost 12 days with piroxicam. Compared with the single‐dose values, steady‐state Clpo (Clpo, ss) and Vd/F of total drug increased with oxaprozin by almost 127% but remained within ±10% with piroxicam. Post—steady‐state apparent t1/2 of the total and unbound drugs of approximately 62 hours were similarly prolonged with piroxicam but differed substantially with oxaprozin (50.6 hours [total drug] versus 23.8 hours [unbound drug]). Single dose Clpo (Clpo, sd) values of both NSAIDs were significantly correlated in the study populations. With both NSAIDs, Clpo in the two poor metabolizers of debrisoquine was within ±20% of mean values for the population. Clinically important age‐ and gender‐dependent decreases were not observed in the weight‐adjusted, Clpo, sd or Vd/F values of the total drug for either NSAID. Clearances of the two NSAIDs were significantly correlated, suggesting that a common P450 isozyme (most likely CYP2C9, in that piroxicam is a known substrate of this isozyme) may be at least partly involved in the oxidative metabolism of these NSAIDs.
Negligible Systemic Absorption of Topical Isotretinoin Cream: Implications for Teratogenicity
Authors: Chen Chao , Jensen Bradford K. , Mistry Goutam , Wyss Ronald , Zultak Maurice , Patel Indravadan H. , Rakhit Ashok K.
Published: March 2013

The objective of the study was to assess the extent of systemic exposure of retinoic acid metabolites after excessive application of 0.1% isotretinoin cream in patients with photodamaged skin. This was a single‐center, open‐label, noncomparative, multiple‐dose study of isotretinoin cream. Eighteen female patients with photodamaged skin received a 10 g topical application of isotretinoin cream once daily to a surface area of ∼2,300 cm2 for 42 days. The patients were not allowed to have high vitamin A—containing foods, vitamin A supplements, or concomitant medications during the entire study period. Plasma levels of four retinoic acids (isotretinoin, tretinoin, 4‐oxo‐isotretinoin, and 4‐oxo‐tretinoin) were evaluated after 42 days of isotretinoin application and compared with baseline (pretreatment) levels. The mean area under the curve (AUC) in plasma increased by 48% (± SE 9.2) and 77% (± 13) from the 24‐hour pretreatment baseline level for isotretinoin and 4‐oxo‐isotretinoin, respectively, after treatment with excessive amounts of isotretinoin cream, suggesting systemic absorption of isotretinoin cream. This increase in systemic exposure of retinoic acids was less than that reported earlier after the U.S. recommended daily allowance of 5,000 IU of vitamin A supplementation (isotretinoin 141 ± 19% and 4‐oxo‐isotretinoin 171 ± 27%). The minimal systemic availability of isotretinoin cream compared with the U.S. recommended daily allowance for vitamin A supplements provides reasonable evidence for lack of its potential teratogenic risk.
Selecting and Validating Biologic Markers for Drug Development
Authors: Colburn Wayne A.
Published: March 2013

Biochemical and clinical markers are critical for efficient development of new molecular entities. Biologic markers of drug effect, sometimes referred to as “surrogate” markers, are used when such clinical outcome measures as survival are substantially delayed relative to predictive biochemical changes or clinical effects of the new molecular entity. Biologic markers have generally been used for early‐phase decision‐making studies and accelerated regulatory approvals for much‐needed drugs to treat cancer and acquired immune deficiency syndrome (AIDS). The rationale for these two uses of biologic markers is different and therefore the foundation required for establishing and validating each may be different. The theoretical foundation required for a marker that will be used to justify the regulatory approval of a treatment for a life‐threatening disease should be greater than that required for an early decision‐making study with an angiotensin II antagonist that will be used to treat mild to moderate hypertension. Use of CD4 counts as “surrogate markers” for prolonged survival was inappropriate. In contrast, changes in angiotensin‐II concentrations and other renin—angiotensin system biochemical markers, observed for the first time in a study in humans, with a purported angiotensin‐II receptor antagonist indicate that the new molecular entity is working as hoped. This is a good decision‐making tool, because theory indicates that these changes should lead to reduced blood pressure, which is a predictive “surrogate” for reduction in subsequent cardiovascular events. Surrogate, biologic markers should be used only if they have a rational theoretical basis, are proven in preclinical or clinical experience, and are measured with validated methods. Different validation—acceptance criteria for decision‐making markers compared with markers used for regulatory approval must be prospectively acknowledged and delineated.
Using Student Feedback on Examination Questions to Promote Fairness, Item Validity, and Learning
Authors: Smith Cedric M.
Published: March 2013

Ten years' experience with a system of modifying the scoring of examinations in pharmacology based on feedback comments from students on individual questions are analyzed. Each examination (3 per year for 10 years), approximately 100 items in length, was subjected to rigorous editing by a faculty committee and an independent reviewer. Putatively correct answers were posted after the examination, and students submitted comments anonymously on questions they thought justified alternative answers. Those comments accepted as valid by faculty were used to modify final scoring. A mean of 7.17 ± 0.85 questions per examination (±SE) had valid alternative answers (range, 2–17 questions; median, 6–7 questions; n = 30 examinations). No examination escaped with fewer than two items that had alternative answers accepted in response to students' comments. The mean number of deleted items was 1.63 ± 0.34 (range, 0–6). This feedback comments system has received consistently high praise from students who say that it improves fairness and validity in examinations. It has now been adopted for use in objective examinations in the major courses in this school of medicine.
Pharmacokinetics of Sirolimus in Stable Renal Transplant Patients after Multiple Oral Dose Administration
Authors: Zimmerman James J. , Kahan Barry D.
Published: March 2013

In this 2‐week, ascending dose study, the pharmacokinetic activity of sirolimus was examined in 40 stable renal transplant patients treated with cyclosporine and prednisone. Nine dose levels (range, 0.5–6.5 mg/m2/12 hr) of sirolimus were studied in a parallel design. Mean values for the pharmacokinetic parameters of sirolimus calculated in all dose groups were as follows: time to peak blood concentration, 1.4 ± 1.2 hours; terminal half‐life, 62 ± 16 hours; oral dose clearance, 208 ± 95 mL/h/kg; apparent oral steady‐state volume of distribution, 12 ± 5 L/kg; and blood/plasma ratio, 38 ± 13. The intersubject variabilities in dose clearance, steady‐state volume of distribution, and blood/plasma ratio were 4.5‐fold. Preliminary assessments suggested linear dose proportionality. An excellent correlation existed between area under the concentration—time curve and trough blood concentration at steady state. Sirolimus did not produce any significant changes in area under the concentration—time curve of cyclosporine. Preliminary analysis suggested that values for the pharmacokinetic parameters of sirolimus vary among races (black versus nonblack) but not among genders.
Effect of Valproate on the Pharmacokinetics and Pharmacodynamics of Lorazepam
Authors: Samara Emil E. , Granneman Richard G. , Witt Galen F. , Cavanaugh John H.
Published: March 2013

The pharmacokinetic—pharmacodynamic interaction between valproate and lorazepam was evaluated in this randomized, double‐blind, placebo‐controlled crossover study. Sixteen healthy male volunteers enrolled in the study to receive either divalproex sodium (500 mg every 12 hours) or matching placebo for 12 days in the first period, and then to receive the other regimen for an identical second 12‐day period. In both periods, lorazepam (1 mg every 12 hours) was administered on days 6 through 9 and on the morning of day 10. Concomitant administration of divalproex sodium with lorazepam resulted in an 8%, 20%, and 31% increase in steady‐state maximum plasma concentration, area under the concentration—time curve, and trough plasma concentrations of lorazepam, respectively. The apparent clearance of lorazepam through the formation of lorazepam glucuronide was reduced by 31% during coadministration of divalproex sodium. Pharmacokinetic properties of valproate did not change significantly in the ten available participants during coadministration of lorazepam. Sedation scales revealed no statistically significant differences in sedation between the two regimens. It is concluded that valproate increases plasma concentrations and reduces clearance of lorazepam, most likely by impairing hepatic glucuronidation, and that coadministration of lorazepam does not affect the steady‐state pharmacokinetic properties of valproate.
Stability and Performance of a Population Pharmacokinetic Model
Authors: Ette Ene I.
Published: March 2013

This study aimed to determine the stability (in terms of covariate selection) of a population pharmacokinetic model and evaluate its performance in the absence of a test data set. Data from 88 full‐term infants, 11 of whom were human immunodeficiency virus (HIV)–seropositive, taking an antiinfective agent were analyzed using exploratory data analysis methods and the nonlinear mixed‐effects modeling (NONMEM) program to obtain the final population pharmacokinetic model. The stability of the population pharmacokinetic model was tested using the nonparametric bootstrap approach in four steps: 1) with the base pharmacokinetic model, 100 bootstrap replicates of the original data were generated by sampling with replacement; 2) ascertainment that each bootstrap data replicate was described by the basic structural model using the NONMEM objective function; 3) generalized additive modeling (GAM) applied to empiric Bayesian estimates for covariate selection at α = 0.05 and a frequency (f) cutoff value of 0.50; and 4) NONMEM population model building using covariates selected in the third step with α = 0.005. Performance of the population pharmacokinetic model was evaluated using 200 additional bootstrap replicates of the data by fitting the model obtained in step 4 to them. Parameters obtained were compared with those obtained in the model stability step, and improved prediction error, a measure of predictive accuracy as an index of internal validation, was computed. The reciprocal of serum creatinine (RSC; f = 0.73) and HIV (f = 0.70) were selected by GAM as predictors of clearance (Cl). The population pharmacokinetic model obtained without the determination of model stability included RSC as a predictor of Cl, but the final model from the model stability step included both HIV and RSC as predictors of Cl. Final population pharmacokinetic parameters were obtained with this model fitted to the original data; however, the 95% confidence interval on the HIV status regression coefficient included zero, indicating no significance. The mean parameter estimates obtained with the additional 200 bootstrap replicates of data were within 15% of those obtained with the final model at the regression stability step. Bootstrap resampling procedure is useful for evaluating the stability and performance of a population model by repeatedly fitting it to the bootstrap samples when there is no test data set.
Steady‐State Pharmacokinetic Properties of Pramipexole in Healthy Volunteers
Authors: Wright C. Eugene , Sisson Theresa Lasher , Ichhpurani Avneet K. , Peters Gary R.
Published: March 2013

Pramipexole is a dopamine receptor agonist that has proved effective in the treatment of Parkinson's disease. The pharmacokinetic properties of pramipexole at steady‐state concentrations were studied in 16 healthy men and women at four dose levels throughout the range recommended for Parkinson's patients. Plasma and urine samples collected within the four dose intervals were assayed for concentrations of pramipexole, using high‐performance liquid chromatography. The total oral clearance for all participants was 419 mL/min. The mean volume of distribution and elimination half‐life for all participants was 486 ± 93.2 L and 12.9 ± 3.27 hours. Concentrations of pramipexole were proportional to dose, although the drug's pharmacokinetic properties differed between men and women. The area under the concentration—time curve for each dose level was 35% to 43% greater in women, mainly because of a 24% to 27% lower oral clearance. The mean creatinine clearance in men and women was 112 ± 12.8 mL/min/1.73 m2 and 80.9 ± 15.6 mL/min/1.73 m2, respectively. The renal clearance of pramipexole accounts for approximately 80% of oral clearance, and there was a significant correlation between renal and creatinine clearances. The influence of gender could not be distinguished from the influence of age and the resulting reduced creatinine clearance, but the measurement of pharmacokinetic properties produced linear results in both men and women.
Desmethylselegiline, a Metabolite of Selegiline, Is an Irreversible Inhibitor of Monoamine Oxidase Type B in Humans
Authors: Heinonen Esa H. , Anttila Markku I. , Karnani Hari L. , Nyman Leena M. , Vuorinen Jouni A. , Pyykkö Kaija A. , Lammintausta Risto A. S.
Published: March 2013

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO‐B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO‐B. This study investigated the inhibitory potential of MAO‐B and the pharmacokinetics of desmethylselegiline in humans. A double‐blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO‐B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO‐B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO‐B by both compounds. Desmethylselegiline caused a 63.7 ± 12.7% inhibition of platelet MAO‐B compared with 96.4 ± 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 ± 20 hours) than after selegiline administration (tmax, 1.4 ± 1.4 hours). The platelet MAO‐B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48‐hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration—time curve from time 0 to 24 hours (AUC0–24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO‐B and could possibly be used to treat Parkinson's disease in the same way as selegiline.
Dose Proportionality of Cisatracurium
Authors: Schmith Virginia D. , Fiedler‐Kelly Jill , Phillips Luann , Grasela Thaddeus H.
Published: March 2013

The dose proportionality of cisatracurium pharmacokinetics was assessed using a population approach by incorporating the collection of sparse blood samples from patients in clinical trials. Plasma concentration—time data from 131 patients with limited concentration—time data and 38 patients with full sampling were pooled and analyzed using nonlinear mixed‐effects modeling (NONMEM). Dose proportionality was assessed using dichotomous parameterization and a linear model. The population pharmacokinetic approach revealed that the pharmacokinetics of cisatracurium are independent of dose between 0.1 mg/kg and 0.4 mg/kg, as was expected based on the importance of Hofmann elimination, a chemical process dependent on pH and temperature.
Potentiation of Mivacurium by Rocuronium Is Age‐ and Time‐Dependent: A Study in Children, Adolescents, and Young and Elderly Adults
Authors: Goudsouzian Nishan , Martyn Jeevendra A.
Published: March 2013

Potentiation occurs when the steroidal muscle relaxant, rocuronium, is coadministered with the benzylisoquinolinium relaxant, mivacurium. The effect of time and age on this interaction was evaluated in four predetermined groups: children, adolescents, young adults, and elderly adults (15 per group) by monitoring the ulnar nerve—evoked force of contraction of the adductor pollicis (twitch response). During recovery from paralysis induced by 600 μg/kg of rocuronium, an infusion of mivacurium was started and maintained for at least 90 minutes to retain the twitch response at 1% to 9% of baseline tension (95 ± 4% paralysis). Rocuronium at 600 μg/kg induced greater than 95% paralysis in 57 of the 60 patients within 2.2 ± 0.4 (mean ± SE) minutes. The period of recovery from rocuronium‐induced paralysis to 5% of baseline twitch height was longest in the elderly (30.1 ± 2.9 minutes) and shortest in the adolescents (16.5 ± 2.4 minutes). The mivacurium infusion requirements to maintain 95 ± 4% paralysis was highest in children and progressively increased with time. In young and elderly adults, the infusion rates remained lower than that of children and did not change with time. The incidence of satisfactory spontaneous recovery within 20 minutes (train‐of‐four ratio >75%) was the highest in children, followed by adolescents and young adults, and was least in the elderly. The residual neuromuscular effect of rocuronium on the subsequent mivacurium infusion was most pronounced in the elderly, followed by young adults, then adolescents, and was least in children.
Selection of Doses for Phase II Clinical Trials Based on Pharmacokinetic Variability Consideration
Authors: Yu Dale K. , Bhargava Vijay O. , Weir Scott J.
Published: March 2013

Pharmacokinetic variability is an important component of the total variability in drug response, but Phase II dose‐response trials frequently are designed without considering this important factor. Mixed‐effects model simulation was performed to examine overlap of patient area under the concentration‐time curve (AUC) values between doses for drugs with differing inter‐ and intrapatient pharmacokinetic variability. Based on the results of this simulation, a dose increment of at least threefold is needed to ensure that drug exposure does not overlap in at least 50% of the patient population for a drug that exhibits greater than 25% variability. In contrast, an increment factor of 2 is normally sufficient to produce the same degree of resolution when the variability is less than 25%. These results suggest that a more aggressive choice of administration increments could lead to a better separation in systemic drug exposure between doses. This needs to be balanced against the therapeutic window of an individual drug product.
Dose‐Dependent Pharmacokinetics and Psychomotor Effects of Caffeine in Humans
Authors: Kaplan Gary B. , Greenblatt David J. , Ehrenberg Bruce L. , Goddard Jill E. , Cotreau Monette M. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and 500 mg of caffeine in a randomized, double‐blind, single‐dose crossover study. Caffeine kinetics were nonlinear, with clearance significantly reduced and elimination half‐life prolonged at the 500‐mg compared to the 250‐mg dose. The lower dose of caffeine produced more favorable subjective effects than the higher dose (elation, peacefulness, pleasantness), whereas unpleasant effects (tension, nervousness, anxiety, excitement, irritability, nausea, palpitations, restlessness) following the 500‐mg dose exceeded those of the 250‐mg dose. The lower dose of caffeine enhanced performance on the digit symbol substitution test and a tapping speed test compared to placebo; high‐dose caffeine produced less performance enhancement than the lower dose. The plasma concentration versus response relationship revealed concentration‐dependent increases in anxiety and improvements in cognitive and motor performance at low to intermediate concentrations. Both caffeine doses reduced electroencephalographic amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8–11 Hz) and beta (12–30 Hz) ranges; however, effects were not dose‐dependent. While favorable subjective and performance‐enhancing stimulant effects occur at low to intermediate caffeine doses, the unfavorable subjective and somatic effects, as well as performance disruption, from high doses of caffeine may intrinsically limit the doses of caffeine used in the general population.
Pharmacokinetics and Safety of the Novel Amino‐3‐Hydroxy‐5‐Methylisoxazole‐4‐Propionate Receptor Antagonist YM90K in Healthy Men
Authors: Umemura Kazuo , Kondo Kazunao , Ikeda Yasuhiko , Teraya Yukari , Yoshida Hisatomo , Homma Mariko , MD Toshihiko Uematsu , Nakashima Mitsuyoshi
Published: March 2013

YM90K is a novel, selective and competitive α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptor antagonist with neuroprotective properties, and it is currently under development for the intravenous treatment of stroke and other conditions of acute neuronal degeneration. The safety and pharmacokinetics of YM90K in healthy men was investigated after single doses up to 36 mg and repeated doses of 24 mg given by intravenous infusion over 3 hours. YM90K was well tolerated in healthy men and induced only mild changes in kidney function markers. Unchanged plasma drug concentration reached a near steady state during 3‐hour infusion and rapidly decreased in a biphasic manner after the completion of infusion. YM90K showed linear pharmacokinetics. In the repeated‐dose study, no significant differences were observed in pharmacokinetics of YM90K between the first and fifth dose. Unchanged urinary drug excretion was as high as 63.2% to 78.3% of the dose, most of which was excreted within 1 hour after the completion of infusion. YM90K is thought to be excreted mainly by renal tubular secretion. YM90K showed neither significant adverse reactions nor severe abnormalities in physical and laboratory examinations of the study participants and demonstrated safety and pharmacokinetic profiles compatible with clinical use.
Valsartan, a New Angiotensin II Receptor Antagonist: A Double‐Blind Study Comparing the Incidence of Cough with Lisinopril and Hydrochlorothiazide
Authors: Benz Joan , Oshrain Carl , Henry Dan , Avery Christine , Chiang Yann‐Tong , Gatlin Marjorie
Published: March 2013

The present study compares the occurrence of a dry, persistent cough with doses of 80 mg of valsartan, 10 mg of lisinopril, or 25 mg of hydrochlorothiazide in patients with a history of angiotensin‐converting enzyme inhibitor—induced cough. This was a randomized, double‐blind, active‐controlled, parallel group, multicenter trial involving 129 adult outpatients with essential hypertension. After confirmation of angiotensin‐converting enzyme inhibitor—induced cough during a 2 to 4 week challenge with lisinopril (followed by a washout period of 2 weeks), patients were randomized to receive 6 weeks of double‐blind treatment once daily with 80 mg valsartan, 10 mg lisinopril, or 25 mg hydrochlorothiazide. Assessments were made at baseline and after 3 and 6 weeks of treatment. Comparability of response to treatment was assessed by mean sitting diastolic and systolic blood pressure at the end of treatment. The occurrence of a dry, persistent cough was significantly less (P < 0.001) at 3 and 6 weeks with valsartan (19.5%) than with lisinopril (68.9%), with no significant difference between valsartan and hydrochlorothiazide (19.0%). There were no statistically significant differences in reduction of blood pressure among the three treatment groups. The overall incidence of adverse experiences, whether or not treatment‐related, was highest for lisinopril (86.7%) compared with valsartan (57.1%), and hydrochlorothiazide (61.9%). A dry cough in the lisinopril group accounted for this difference. There were no clinically significant changes in physical signs or in results of clinical laboratory evaluations during double‐blind treatment, except for from metabolic changes in 3 patients receiving hydrochlorothiazide. In hypertensive patients with a history of angiotensin‐converting enzyme inhibitor—induced cough, a single daily dose of 80 mg of valsartan produced therapeutic efficacy comparable to lisinopril but with significantly less cough.
Administration of H1 and H2 Antagonists for Chemoprophylaxis: A Double‐Blind, Placebo‐Controlled Study in Healthy Volunteers
Authors: Doenicke Alfred , Moss Jonathan , Toledano Alicia , Hoernecke Rainer , Lorenz Wilfried , Ostwald Philipp
Published: March 2013

A double‐blind, placebo‐controlled trial was performed to establish the duration of action of antihistamines and their ability to attenuate the adverse effects associated with histamine release. Thirty volunteers were assigned randomly to receive either placebo or a combination of the H1 blocker dimetindene maleate (0.1 mg/kg) and the H2 blocker cimetidine (5 mg/kg). A bolus dose of histamine (450 ng/kg) was given 15 minutes after antihistamine or placebo treatment and repeated after 2, 4, and 6 hours. Cardiovascular variables, plasma histamine levels, cutaneous manifestations, and objective and subjective signs and symptoms associated with histamine release were determined before and after each histamine injection. Although many of the signs of histamine release, including erythema and metallic taste, could be attenuated effectively for 6 hours with antihistamine treatment, the protection against histamine‐induced flush and headache diminished after 2 hours. Statistically significant protection against histamine‐mediated tachycardia persisted for only 2 hours. Antihistamine treatment significantly reduced the increase in plasma histamine levels after the first histamine injection but did not alter the levels after subsequent histamine injections. The currently recommended administration regimen for prophylaxis with antihistamines is insufficient to prevent histamine‐mediated side effects, and additional doses may be required after 4 hours to achieve appropriate chemoprophylaxis.
Clinical Significance of Methohexital, Meperidine, and Diazepam in Breast Milk
Authors: Borgatta Lynn , Jenny Richard W. , Gruss Leslie , Ong Chongkiat , Barad David
Published: March 2013

Concentrations in breast milk of medications used during general anesthesia were measured to determine whether interruption of breast‐feeding was indicated. Breast milk and maternal blood samples were obtained from nine women undergoing tubal sterilization under general anesthesia. Concentrations of methohexital, meperidine, diazepam, and nordiazepam were determined for each sample by gas chromatography. Methohexital levels declined rapidly after the first hour and were undetectable at 24 hours. Meperidine was present in both milk and blood during the recovery period but not at 24 hours. Infant‐exposure indices for methohexital were less than 1% and ranged from 1.2% to 3.5% for meperidine. The maximum doses of methohexital and meperidine to an infant in a 100 mL feeding 1 hour after induction of anesthesia were estimated to be 0.04 mg and 0.06 mg, respectively. Diazepam and nordiazepam were not detectable in any sample of milk or blood. The maximum possible infant‐exposure index for diazepam would be 3%. The amounts of methohexital, meperidine, and diazepam excreted into breast milk do not warrant interruption of breast‐feeding.
Comparative Central Nervous System Effects and Pharmacokinetics of Neu‐metoclopramide and Metoclopramide in Healthy Volunteers
Authors: Rotmensch Heschi H. , Mould Graham P. , Sutton J. Andrew , Kilminster Shaun , Moller Claus , Pero Ronald W.
Published: March 2013

Metoclopramide, a drug used for the relief of nausea and emesis, is currently under development as a radio‐ and chemosensitizing agent. Its usefulness in high doses, however, is limited by its central nervous system side effects. Neu‐metoclopramide (Neu Sensamide), a novel, concentrated, phosphate‐buffered, pH‐adjusted (pH = 6.5–7.0) formulation of metoclopramide, has been shown to have an improved side‐effect profile in animal studies. The present double‐blind, four‐way crossover study compared the central nervous system effects and pharmacokinetics of neu‐metoclopramide (intravenously and intramuscularly at 1.8 mg/kg) with intravenous metoclopramide and intramuscular placebo in 19 healthy male volunteers. Eight participants withdrew from the study, one because of noncompliance and seven because of adverse events. A total of 28 central nervous system events were observed with intravenous metoclopramide administration, whereas 16, 15, and 6 such events were attributed to intravenous neu‐metoclopramide, intramuscular neu‐metoclopramide, and placebo, respectively. Extra pyramidal effects occurred on 10 occasions: 7 after intravenous metoclopramide, 2 after intravenous neu‐metoclopramide, and 1 after intramuscular neu‐metoclopramide. No significant differences were observed in the pharmacokinetic profiles of the three formulations of metoclopramide. It may be speculated, therefore, that the molecular conformational changes inherent to neu‐metoclopramide result in a reduced side‐effect profile compared with conventional metoclopramide formulations.
Double‐Blind Comparison of Losartan, Lisinopril, and Metolazone in Elderly Hypertensive Patients with Previous Angiotensin‐Converting Enzyme Inhibitor‐Induced Cough
Authors: Chan Paul , Tomlinson Brian , Huang Tsuei‐Yuen , Ko Jiing‐Tang , Lin Tz‐Shing , Lee Ying‐Shiung
Published: March 2013

This study compared the incidence of cough with the angiotensin‐converting enzyme (ACE) inhibitor lisinopril and the diuretic metolazone with the angiotensin II receptor antagonist losartan in elderly hypertensive patients with previous histories of ACE inhibitor‐induced cough. A randomized, double‐blind, stratified, parallel‐group comparison of lisinopril at 10 mg, losartan at 50 mg, and metolazone at 1 mg, each given once daily for a maximum of 10 weeks, was performed in four hypertension clinics in four centers in two countries. Cough was detected by a questionnaire (the primary end point) given to elderly patients with hypertension, and the cough frequency was quantified by a visual analog scale (a secondary end point). A total of 84 elderly patients with hypertension, all who were nonsmokers with ACE inhibitor‐induced cough and were confirmed by lisinopril rechallenge then placebo dechallenge, were randomized to the three treatment groups. The incidence of cough with losartan (18%) was significantly lower than with lisinopril (97%) and similar to that for metolazone (21%). Cough frequency evaluated by the visual analog scale was significantly lower for losartan than for lisinopril and similar to that for metolazone. The specific, selective angiotensin II receptor antagonist losartan is associated with a decrease in the incidence of cough in patients with previous ACE inhibitor‐induced cough.
A Dose Proportionality Study of Eprosartan in Healthy Male Volunteers
Authors: Chapelsky Martha C. , Martin David E. , Tenero David M. , Ilson Bernard E. , Boike Steven C. , Etheredge Rickey , Jorkasky Diane K.
Published: March 2013

The present study investigated the proportionality of exposure after single oral doses of 100, 200, 400, and 800 mg of eprosartan, a nonpeptide, nonbiphenyl angiotensin II receptor antagonist, in 23 healthy young men. Eprosartan was safe and well tolerated. Exposure to eprosartan increased with dose but in a less than proportional manner. For each two‐fold dose increase, area under the concentration—time curve (AUC) increased an average of 1.6 to 1.8 times and maximum plasma drug concentration (Cmax) increased an average of 1.5 to 1.8 times. For both parameters, the greatest difference from the dose multiple was observed between the 400‐ and 800‐mg doses. Dose proportionality of eprosartan, as assessed by an equivalence‐type approach using the 100‐mg dose as the reference and a 30% acceptance region (0.70, 1.43), was achieved for the 200‐ and 400‐mg doses for AUC and the 200‐mg dose for Cmax. The observed changes in the pharmacokinetics of eprosartan suggest slight saturation of absorption of eprosartan over the 100‐ to 800‐mg dose range, most likely due to the physicochemical properties of the drug (pH‐dependent aqueous solubility and lipophilicity).
Pharmacokinetics and Safety of a Novel Recombinant Soluble Human Thrombomodulin, ART‐123, in Healthy Male Volunteers
Authors: Nakashima Mitsuyoshi , Kanamaru Mitsutaka , Umemura Kazuo , Tsuruta Kazuhisa
Published: March 2013

The safety and pharmacokinetics of a novel recombinant soluble human thrombomodulin, ART‐123 were evaluated in single‐ and multiple‐dose studies involving 16 healthy male volunteers. ART‐123 was administered by intravenous infusion over 2 hours. The single‐dose study indicated that plasma ART‐123 levels at doses of 0.03, 0.1, and 0.3 mg declined biexponentially and those half‐lives were approximately 4 hours (t1/2α) and 20 hours (t1/2β), respectively. The mean plasma peak concentration and area under the plasma concentration—time curves increased in proportion to the given doses. Mean urinary recovery within the first 48 hours was between 54.3% and 59.8% of dose. In the multiple‐dose study, ART‐123 was administered at a dose of 0.2 mg once daily for 3 days. ART‐123 did not accumulate as judged from plasma concentrations and urinary recovery. There were no abnormal findings in objective symptoms and laboratory findings, including blood pressure, heart rate, electrocardiogram, body temperature, hematology, bleeding time, coagulation and hemostatic parameters, blood chemistry, and urinalysis. There were no significant adverse reactions or abnormalities in physical and laboratory examinations that could definitely be attributed to the drug at a dose of 0.3 mg as a single administration and at a dose of 0.2 mg once daily for 3 days. These results indicate that ART‐123 is safe at doses up to 0.2 mg once daily for 3 days and may have clinical application. Further studies are needed, however, to evaluate the safety and pharmacokinetics of ART‐123 in the targeted population.
Multiple‐Dose Pharmacokinetics and Pharmacodynamics of OROS and Immediate‐Release Amitriptyline Hydrochloride Formulations
Authors: Gupta Suneel K. , Shah Jaymin , Guinta Diane , Hwang Stephen
Published: March 2013

The pharmacokinetics and pharmacodynamics of amitriptyline hydrochloride after oral administration of an OROS osmotic system, which provides controlled drug delivery, and an immediate‐release (IR) tablet, were evaluated in 24 healthy volunteers after repeated administration for 14 days. Each morning, subjects received either 75 mg of the OROS (amitriptyline HCl) controlled‐release formulation or the 75 mg IR amitriptyline tablet for 14 days on two separate occasions with a washout period of 21 days according to a randomly assigned sequence. Serial blood samples were collected for a period of 58 hours after the day 14 dose, then these samples were analyzed by the gas chromatography method for amitriptyline and nortriptyline. Subjective ratings of dry mouth and drowsiness were collected at specific times throughout each treatment period. Administration of the OROS formulation resulted in much more consistent plasma concentrations of the drug and metabolite compared with the IR formulation at steady state. The mean maximum concentration (Cmax) of amitriptyline was significantly lower after administration of OROS than the IR formulation. Mean values for area under the concentration—time curve (AUC0–24) for the OROS and IR formulations were 1,265 and 1,393 ng·hr/mL, respectively. The drug‐to‐metabolite ratio was found to be similar for both treatments, suggesting that there was no difference in metabolism between treatments. Incidence and severity of the anticholinergic effects were similar for the two treatments. A clockwise hysteresis between baseline‐corrected drowsiness and drug concentration suggests development of tolerance of the anticholinergic effects after both treatments. Using a hypothetical anatagonist metabolite model to explain tolerance development, the shape of the hysteresis curves of the two treatments could be explained by differences in dosing frequency.
Levofloxacin Does Not Alter Cyclosporine Disposition
Authors: Doose D. R. , Walker S. A. , Chien S. C. , Williams R. R. , Nayak R. K.
Published: March 2013

Certain fluoroquinolones have been shown to elevate the serum concentrations of the immunosuppressant cyclosporine. It is thus important to investigate the potential interaction between levofloxacin, a new fluoroquinolone anitmicrobial agent, and the pharmacokinetics of cyclosporine. Twelve healthy subjects (6 men, 6 women) were enrolled in and completed a placebo‐controlled, randomized, double‐blind, two‐phase crossover study. Subjects were given a single oral 10‐mg/kg dose of cyclosporine solution during multiple‐dose twice‐daily oral treatment with placebo or 500 mg of levofloxacin. Blood cyclosporine concentrations were measured for 48 hours after each cyclosporine dose for pharmacokinetic evaluation. Cyclosporine pharmacokinetic parameters were comparable and not significantly different in the absence and presence of levofloxacin. Results of this study suggest that a clinically important pharmacokinetic interaction between levofloxacin and cyclosporine is unlikely to occur during concurrent therapy.