bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of Acute Phase Response on Phenytoin Metabolism in Neurotrauma Patients
Authors: McKindley David S. , Boucher Bradley A. , Hess Mary M. , Rodman John H. , Feler Claudio , Fabian Timothy C.
Published: March 2013

The purpose of this prospective study was to correlate measures of the acute phase response, associated therapeutic interventions, and other clinical variables with the process of altered drug metabolism previously observed in patients with severe neurotrauma. Nine patients with severe head injury (Glasgow Coma Scale ≤ 8) requiring intravenous phenytoin were included in the study. A loading dose of phenytoin was followed by daily maintenance doses. Serial blood samples were taken after the loading dose and every even‐numbered study day for 10 to 14 days for measurement of total and unbound concentrations of phenytoin, interleukin‐1 β, interleukin‐6 (IL‐6), tumor necrosis factor α, α1‐acid‐glycoprotein, C‐reactive protein, and albumin. Time‐invariant and time‐variant Michaelis‐Menten models were fit to the phenytoin concentration—time data. Protein intake was closely monitored. The mean (± SEM) unbound fraction of phenytoin increased from 0.17 ± 0.02 on day 1 to 0.24 ± 0.04 on day 10 (P < 0.05). The time‐variant model was superior in describing the concentration—time data of unbound phenytoin in eight of nine patients. Mean (± SEM) pharmacokinetic parameter estimates for unbound phenytoin were: VmaxΔ = 605 ± 92 mg/day, VmaxB = 149 ± 26.3 mg/day, kind = 0.013 ± 0.004 hr−1. Interleukin‐6 was the only cytokine with significant concentration changes over time; it was inversely correlated with Vmax,t. Peak concentrations of interleukin‐6 also proved to be inversely correlated with VmaxB. The daily amount of protein administered was significantly correlated with Vmax,t. Significant alterations in the metabolism of phenytoin occur after severe neurotrauma. The etiology of these changes is probably multifaceted. These results suggest that low initial phenytoin Vmax may be explained by the presence of interleukin‐6. An increase in oxidative metabolism that correlated with nutritional protein administration was observed later in these patients.
Evaluation of Pharmacokinetic Interaction Between Bromfenac and Phenytoin in Healthy Males
Authors: Gumbhir‐Shah Kavita , Cevallos William H. , DeCleene Sheryl A. , Korth‐Bradley Joan M.
Published: March 2013

An open‐label, nonrandomized, multiple‐dose, inpatient study was conducted in healthy male volunteers to compare the pharmacokinetics of bromfenac and phenytoin when the drugs are given individually and concomitantly. Twelve men received multiple oral doses of bromfenac for 4 days and then oral phenytoin for up to 14 days followed by concomitant administration of bromfenac and phenytoin for 8 days. Concomitant administration of the two drugs caused an approximate 40% decrease in the mean peak plasma concentration (Cmax) and the interdose area under the concentration—time curve (AUC) of bromfenac. The oral clearance (Clpo) of bromfenac doubled and the volume of distribution increased by 77%. For phenytoin, the mean peak serum concentration and the AUC increased by 9% and 11%, respectively, in the presence of bromfenac. The only change in unbound phenytoin was a 16% increase in the AUC. Although statistically significant, the changes in the pharmacokinetic parameters of phenytoin and unbound phenytoin were small. Adjustments in the dose of phenytoin should not be required during concomitant administration of bromfenac, although each patient's clinical status should be evaluated individually.
Relationship Between the Prescriber's Instructions and Compliance with Antibiotherapy in Outpatients Treated for an Acute Infectious Disease
Authors: Favre Olivier , Delacrétaz Etienne , Badan Michel , Glauser Michel , Waeber Bernard
Published: March 2013

Antibiotics are frequently prescribed in everyday practice for the management of acute microbial infections. The present study was designed to assess the relationship between the prescriber's instructions and the patient's adherence to a prescribed schedule of twice‐daily doses of antibiotic for at least 5 days to treat an infectious disease. The trial was conducted by ten practicing physicians on ambulatory patients. Compliance with the antibiotic regimen was evaluated using a microelectronic device, the Medication Event Monitoring System (MEMS). Seventy patients were prescribed an antibiotic in twice‐daily doses for 5 to 14 days (mean = 8). Data were available for analysis from 68 of them, aged 18 to 84 years (mean = 44). The “taking compliance” for the whole study group, which corresponded to the ratio of the number of times the bottle was opened and the total number of doses prescribed during the monitoring period, was nearly perfect at 99.6%. However, only 32.6% of the medications was taken within 1 hour before or after the 12‐hour interval expected to be optimal for a twice‐daily regimen. It therefore seems highly desirable that physicians give more detailed recommendations to their patients regarding the drug regimens they prescribe.
Protein Binding in Plasma of Valsartan, a New Angiotensin II Receptor Antagonist
Authors: Colussi Danielle M. , Parisot Carole , Rossolino Maria L. , Brunner Linda A. , Lefèvre Gilbert Y.
Published: March 2013

The protein‐binding characteristics of the angiotensin II receptor antagonist valsartan were determined in vitro by equilibrium dialysis, using 14C‐labeled valsartan with serum from healthy donors, plasma from patients who had received valsartan, serum or plasma from animals, and purified human plasma proteins. The binding of valsartan was high (96 ± 2%) in human serum at concentrations ranging from 0.05 μg/mL to 5 μg/mL. A comparable extent of binding (85–99%) was recorded in plasma from patients after repeated administration of valsartan. Albumin (binding 92%) is the main protein involved in the binding to plasma proteins, while the binding to α‐acid glycoprotein was low (22%) and to gamma globulins, negligible. Although highly bound, valsartan was not displaced in vitro by hydrochlorothiazide, diclofenac, furosemide, and warfarin. A high extent of binding was found in rat, dog, and rabbit serum and in marmoset plasma, while a lower binding was found in mouse serum.
First Pharmacokinetic—Pharmacodynamic Study in Humans with a Selective 5‐Hydroxytryptamine4 Receptor Agonist
Authors: Appel Silke , Kumle Anette , Hubert Martine , Duvauchelle Thierry
Published: March 2013

This report describes the first study in humans with SDZ HTF 919 (HTF), a novel, selective 5‐hydroxytryptamine4 (5‐HT4) receptor partial agonist and investigates its tolerability, pharmacokinetics, and pharmacodynamics. Three cohorts of 12 men, of whom 8 were treated with active drug and 4 with placebo, participated in the double‐blind, randomized, parallel‐group, ascending‐dose study. A single dose and subsequently twice‐daily multiple doses of 25, 50, and 100 mg were given for 14 days. Adverse events, clinical laboratory variables, electrocardiogram, vital signs, and psychometric effects were recorded. Basic pharmacokinetic characteristics of HTF were derived. Loose stool and total colonic transit time were assessed. Mild to moderate adverse gastrointestinal events, predominantly loose stools, occurred at all dose levels and reflect the pharmacologic properties of HTF. The incidence of headache increased with dose. Dose‐normalized (to 25 mg) systemic exposures were 25 ± 12, 19 ± 11, and 26 ± 10 hr‐· ng/mL in single doses and 26 ± 12, 23 ± 12, and 33 ± 12 hr· ng/mL in multiple doses for the three doses. Steady‐state concentrations of HTF were reached after 8 days of daily administration and moderate accumulation was observed. Loose stool occurred on average between 2 and 4 hours after drug administration. The overall HTF‐mediated median decrease from baseline (26 and 38 hours) in total colonic transit time was 4.8 hours, versus 1.8 hours with placebo. In conclusion, the novel 5‐HT4 receptor agonist HTF was tolerated at oral doses of 25 mg to 100 mg administered twice daily. Pharmacokinetics in both single and multiple doses indicate no deviation from dose proportionality. The applicability of the total colonic transit time as a measurement of surrogate prokinetic effect warrants further investigation in patient populations.
Pressor Response to Tyramine after Single 24‐Hour Application of a Selegiline Transdermal System in Healthy Males
Authors: Barrett Jeffrey S. , Hochadel Thomas J. , Morales Richard J. , Rohatagi Shashank , DeWitt Kimberly E. , Watson Sara K. , Darnow John , Azzaro Albert J. , DiSanto Anthony R.
Published: March 2013

Orally administered selegiline hydrochloride is a selective monoamine oxidase type B inhibitor at the recommended regimen of 10 mg/day, but it loses selectivity at higher doses. In bypassing first‐pass metabolism, a 24‐hour application of transdermally administered selegiline (7.8 mg/24 hr) yields fifty times greater systemic exposure than is provided by single oral doses. The current study was designed to demonstrate that, similar to the oral regimen, transdermally administered selegiline is devoid of the pressor effects associated with tyramine and classic monoamine oxidase type A inhibitors. A single‐blind, staggered, parallel‐group study of pressor response to tyramine during a single 24‐hour application of one‐quarter, one‐half, or one selegiline transdermal system relative to baseline (drug‐free) response to tyramine was conducted in three groups, each with five healthy male volunteers. The end point of pressor response was declared if a participant's systolic blood pressure rose by >30 mmHg, heart rate decreased by >25 bpm with an associated >20‐mmHg rise in systolic blood pressure, or a clinically significant change was observed in the electrocardiogram. Doses up to 600 mg were administered during the baseline phase and up to 200 mg during the active‐treatment phase. Participants received escalating tyramine doses every 4 hours until the maximum or threshold dose was achieved. Doses up to 200 mg were tolerated without apparent increase in sensitivity in participants receiving one‐quarter, one‐half, or one selegiline transdermal system. All participants completed the trial, and no significant adverse events were reported. Monoamine oxidase type B inhibition was complete (100%) by 12 hours after initial application in all treatment groups while plasma levels of 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) after 24‐hour application were unaffected relative to baseline. These results suggest that systemic selegiline levels may not predict the propensity for a hypertensive crisis associated with presumed nonselective doses and that the avoidance of peripheral monoamine oxidase type A inhibition in the gut via the selegiline transdermal system may provide a safe vehicle for administering selegiline at plasma levels beyond that which can be safely obtained after oral administration. These findings will need to be confirmed in a long‐term dose setting.
Bioequivalence Assessment of a Single 5 mg/day Testosterone Transdermal System Versus Two 2.5 mg/day Systems in Hypogonadal Men
Authors: Wilson Douglas E. , Meikle A. Wayne , Boike Steven C. , Fairless Amanda J. , Etheredge Rickey C. , Jorkasky Diane K.
Published: March 2013

A novel, nonscrotal, transdermal delivery system for testosterone therapy has been marketed for treatment of hypogonadal men. The usual dose of this system is two 2.5 mg/day systems applied daily. A new system has been developed that administers a dose of 5 mg/day using a single patch rather than two patches. A randomized, steady‐state, four‐period, replicate‐design, open‐label, crossover study was conducted to assess the bioequivalence of the two testosterone transdermal delivery systems in postpubertal, hypogonadal men: two 2.5 mg/day patches as the reference regimen (R) and one 5 mg/day patch as the test regimen (T). 21 men were enrolled, and 20 completed the study. Each subject was randomly assigned to one of four sequences (R1‐R2‐T1‐T2, T1‐T2‐R1‐R2, R1‐T1‐T2‐R2, T1‐R1‐R2‐T2), such that each subject received each regimen during two study sessions. Two subjects were inadvertently treated according to the sequence T1‐R1‐T2‐R2. Patches were applied to the upper arm, thigh, and back in the evening on days 1, 2, and 3, respectively, of each study session. Serial blood samples were obtained for pharmacokinetic analysis of testosterone for 24 hours after patch application on day 3 of each study session. The two formulations would be considered bioequivalent if the 90% confidence intervals (CI) for the ratios of the adjusted geometric means for T:R for both area under the concentration—time curve from 0 to 24 hours (AUC0–24) and maximum concentration (Cmax) were completely contained in the interval (0.80, 1.25). Mean values for AUC0–24 and Cmax were similar for the two formulations. The T and R formulations were found to be bioequivalent based on both AUC0–24 (90% CI 0.96, 1.08) and Cmax (90% CI 0.92, 1.07). The median time to Cmax was also similar, indicating comparable rates of testosterone absorption for both formulations. Based on this analysis, the testosterone transdermal system 5 mg/day patch is bioequivalent to two of the 2.5 mg/day patches. Both systems were safe and well tolerated in hypogonadal men.
Short‐Term Effects of Nicardipine and Propranolol on Ocular and Systemic Hemodynamics in Healthy Japanese Subjects
Authors: Yatsuka Yoko Ishii , Matsukubo Seiichirou , Kotegawa Tsutomu , Nakamura Koichi , Nakano Shigeyuki , Nakatsuka Kazuo
Published: March 2013

Ocular perfusion is a critical factor in ischemic ocular diseases, and blood flow in the ophthalmic artery has a pronounced effect on perfusion. To evaluate the effects of dihydropyridine calcium channel blocker and nonselective beta‐adrenergic antagonist on ocular perfusion, we investigated the short‐term effects of single oral doses of nicardipine (40 mg) and propranolol (40 mg) on the blood flow velocity in the ophthalmic artery, intraocular pressure (IOP), systemic blood pressure, and heart rate in nine healthy Japanese male volunteers in a double‐blind, placebo‐controlled study using color Doppler imaging. Parameters were evaluated before and 60 and 120 minutes after administration. Nicardipine significantly increased the maximum systolic velocity and time‐averaged blood flow velocity compared with placebo without significant increase in the resistance index. Propranolol had no significant effects on Doppler parameters. Propranolol exhibited a great reduction in IOP from placebo values. Systolic blood pressure and heart rate were significantly reduced by propranolol. Nicardipine significantly increased heart rate. These results suggest that nicardipine increased ophthalmic blood flow, but propranolol did not.
Regulating Angiogenesis: A New Therapeutic Strategy
Authors: Gibaldi Milo
Published: March 2013

Angiogenesis is the proliferation of endothelial and smooth muscle cells to form new blood vessels. Largely muted after adolescence, angiogenesis may be reignited by cancerous cells. Neoangiogenesis plays a primary role in tumor growth and metastases. Antiangiogenic therapy to limit and even reverse the growth of tumors are under investigation and showing promise. A derivative of fumagillin, TNP 470, is the first angiogenesis inhibitor to be given to humans. Surprisingly, several potent inhibitors are derived from tumors themselves. Researchers now recognize that stimulation of angiogenesis may have a place in the treatment of cardiovascular disease. Reestablishing blood flow to ischemic tissue through angiogenesis may provide a biologic “bypass” for patients with ischemic heart disease. The same applies to the treatment of peripheral vascular disease.
When Are Bioavailability Studies Required? A German Proposal
Authors: Gleiter Christoph H. , Klotz Ulrich , Kuhlmann Jochen , Blume Henning , Stanislaus Fritz , Harder Sebastian , Paulus Hanns , Poethko‐Müller Christine , Holz‐Slomczyk Maria
Published: March 2013

The Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM), the German drug regulation authority, issued guidelines for determining whether bioavailability/bioequivalence studies are required for certain drugs. This decision tree is based on pharmacodynamic, pharmacokinetic, and physicochemical criteria. Details of this decision tree were worked out by an expert panel, the Bioavailability Commission at the BfArM. The decision tree has been in use by German regulatory authorities for more than 10 years. In the meantime, its essentials were adopted by the European Committee for Proprietary Medicinal Products (CPMP) and by the World Health Organization (WHO) for their “Guidelines on interchangeability of multisource pharmaceutical products.” This article reviews the original decision tree of the BfArM and provides examples of drugs that have been assessed according to its rules. The current procedure of the German regulatory authorities for judging the necessity of bioavailability trials, which reflects the status quo of regulatory practice in Germany, is also discussed.
The Serotonin Uptake‐Enhancing Drug Tianeptine Suppresses Asthmatic Symptoms in Children: A Double‐Blind, Crossover, Placebo‐Controlled Study
Authors: Lechin Fuad , van der Dijs Bertha , Orozco Beatriz , Jara Hector , Rada Isais , Lechin Marcel E. , Lechin Alex E.
Published: March 2013

Studies have shown that levels of free serotonin in plasma are increased in symptomatic patients with asthma. In addition, the concentration of free serotonin in symptomatic patients with asthma correlates positively with clinical status and negatively with pulmonary function. Thus, reducing the concentration of free serotonin in plasma might be useful in treating patients with asthma. We studied the effectiveness of tianeptine in treating patients with asthma. Tianeptine is the only drug known to be able to reduce levels of free serotonin in plasma and to enhance uptake by platelets. In this study, 69 children with asthma were assigned in randomized fashion to receive tianeptine and/or placebo in a double‐blind crossover trial that lasted 52 weeks. Tianeptine provoked a dramatic and sudden decrease in both clinical rating and free serotonin plasma levels and an increase in pulmonary function.
Comparison of the Single‐Dose Pharmacokinetics and Tolerability of Modafinil and Dextroamphetamine Administered Alone or in Combination in Healthy Male Volunteers
Authors: Wong Y. Nancy , Wang Lixia , Hartman Linda , Simcoe Donna , Chen Yusong , Laughton Watson , Eldon Richard , Markland Colin , Grebow Peter
Published: March 2013

An open‐label, randomized, crossover study was performed in healthy male volunteers to evaluate the potential pharmacokinetic and pharmacodynamic interactions and tolerability of single oral doses of modafinil (200 mg) and dextroamphetamine (10 mg). Blood samples were collected for determination of plasma levels of modafinil, the acid and sulfone metabolites of modafinil, and dextroamphetamine at intervals through 48 hours after administration for each treatment. Vital signs (blood pressure and pulse rate) were measured through 48 hours, and electrocardiograms were measured through 24 hours after administration. Pharmacokinetic parameters were determined using noncompartmental methods. The data collected in this study of 24 healthy volunteers suggest that concomitant administration of single oral doses of modafinil and dextroamphetamine has no clinically significant effects on the pharmacokinetic profile of either agent. Although there was a slightly greater incidence of adverse events when modafinil and dextroamphetamine were administered together, the concomitant administration of the two drugs was well tolerated.
Preclinical Enantioselective Pharmacology of (R)‐ and (S)‐ Ketorolac
Authors: Handley Dean A. , Cervoni Peter , McCray John E. , McCullough John R.
Published: March 2013

Many of the nonsteroidal anti‐inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)‐ and (S)‐ enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)‐ enantiomers, as the (R)‐ enantiomers do not exhibit COX inhibition. However, the (R)‐ enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential. To extend these observations, we examined the (R)‐ and (S)‐ enantiomers of RS‐ketorolac. (S)‐ ketorolac exhibited potent COX1and COX2enzyme inhibition, whereas (R)‐ ketorolac was > 100‐fold less active on both COX subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate any affinity for opioid receptors (μ, δ, or κ). In experimental models, (S)‐ ketorolac exhibited about 10‐fold greater activity than (R)‐ ketorolac in the murine phenylquinone writhing model. In this model, morphine sulfate was effective at much lower doses, however, and neither (R)‐ nor (S)‐ ketorolac showed any morphine‐sparing effect. In the rat gait test for analgesia in the foot paw after injection of brewers yeast suspension, neither (R)‐ nor (S)‐ ketorolac affected paw volume. However, both provoked changes in gait scores, the (S)‐ enantiomer being 30‐fold more potent than the (R)‐ enantiomer. A similar reduction was observed with respect to ulcerogenic potential, measured by direct microscopic changes after test conclusion. These findings suggest that (R)‐ ketorolac may possess analgesic activity that is independent of COX inhibition and may be associated with reduced ulcerogenic potential compared to effects exhibited by (S)‐ ketorolac. J Clin Pharmacol 1998;38:25S‐35S.
Ignorability and Parameter Estimation in Longitudinal Pharmacokinetic Studies
Authors: Ette Ene I. , Sun He , Ludden Thomas M.
Published: March 2013

In the analysis of longitudinal pharmacokinetic data, both balanced (equal number of samples per subject) and unbalanced data are used. It is implicitly assumed that the process that caused the missing data can be ignored. A simulation study was performed to determine the effect of ignoring the missing data (i.e., “ignorability”) on the accuracy and precision of parameter estimation in longitudinal pharmacokinetic studies. A two‐compartment model with multiple intravenous bolus inputs was assumed. Subjects with balanced data sets had six samples, and those with unbalanced data had 1 to 5 samples missing (i.e., supplied in a decreasing order from 5 to 1 samples). The proportion of subjects with 1 to 5 samples missing varied from 25% to 75% in a fixed sample size of 100. The effect of ignorability was studied at intersubject variability ranging from 15% to 60% for a drug assumed to be dosed at its elimination half‐life. One hundred replicate data sets of 100 subjects each were simulated for each missing data scenario. The accuracy of parameter estimation was not significantly affected by the amount of ignorable missing data at any given level of variability. However, the precision of parameter estimation was affected by the degree of “missingness.”
Pharmacokinetics and Pharmacodynamics of Irbesartan in Healthy Subjects
Authors: Marino Maria R. , Langenbacher Kathleen , Ford Neville F. , Uderman Howard D.
Published: March 2013

The safety, pharmacokinetics, and pharmacodynamics of single and multiple doses of the angiotensin II (AII) AT1 blocker irbesartan were assessed in healthy subjects. In this single‐center, placebo‐controlled, double‐blind within dose group, sequential, dose‐ascending study, 48 men were randomized to receive irbesartan at doses of 150 mg, 300 mg, 600 mg, or 900 mg daily. Subjects received a single dose of irbesartan (n = 9 per group) or placebo (n = 3 per group), followed by 3 days of placebo, and then multiple doses of irbesartan or placebo once daily for 7 days. The values for plasma area under the concentration—time curve (AUC) of irbesartan were dose proportional up to 600 mg. There were no significant differences between the dose groups in time to maximum concentration (tmax) or half‐life (t1/2) after single and multiple doses. After multiple doses, urinary recovery was significantly lower in the 600‐mg and 900‐mg dose groups compared with the 150‐mg and 300‐mg dose groups. Steady‐state concentrations of irbesartan were achieved within 3 days of administration with no clinically important accumulation. Irbesartan produced dose‐dependent increases in plasma renin activity and AII levels. Irbesartan was well tolerated at doses from 150 mg to 900 mg daily; a maximally tolerated dose was not reached. Modest decreases in blood pressure without orthostatic symptoms were observed at irbesartan doses of 300 mg or higher. These results demonstrated the dose‐proportionality of irbesartan 150 mg to 600 mg and indicated that doses up to 900 mg daily were well tolerated.
Paradoxical Hypotension and Bradycardia after Intravenous Arginine Vasopressin
Authors: Kraft Walter , Greenberg Howard E. , Waldman Scott A.
Published: March 2013

Standard therapy for variceal bleeding includes endoscopic sclerotherapy and esophageal balloon tamponade. In addition, pharmacologic therapies, including arginine vasopressin (AVP), are frequently used in hemodynamically unstable patients or where sclerotherapy has been unsuccessful. A case is described herein of a 30‐year‐old woman with a history of ethanol abuse, hematemeisis, and biopsy‐proven hepatic cirrhosis in which the addition of AVP to an antivariceal regimen of octreotide was associated with a paradoxical episode of hypotension, bradycardia, and hypoxia. Indeed, within 15 minutes after initiation of an AVP infusion, the patient exhibited hypotension with a systolic blood pressure of 80 mmHg, a relative bradycardia to 76 beats per minute, and a desaturation of blood oxygen to 84%. The AVP infusion was discontinued 2 hours later and blood pressure, heart rate, and oxygen saturation rapidly returned to baseline. This temporal correlation between the onset and termination of the physiologic effects and the initiation and discontinuation of the AVP infusion suggests a causal relationship. The paradoxical physiologic effects might reflect cardiac ischemia secondary to vasospasm and/or central suppression of the autonomic nervous system induced by AVP.
Application of Population Pharmacokinetics to the Phase II Development of an Anti‐Alzheimer's Disease Compound, S12024
Authors: Laveille C. , Lachaud‐Pettiti V. , Neuman E. , Jochemsen R.
Published: March 2013

Steady‐state concentrations of S12024, a novel compound for treatment of Alzheimer's disease, were studied to determine the pharmacokinetic parameters of S12024 in Phase IIa patients and to assess the effect of patient characteristics on those pharmacokinetics. A prospective sparse sampling strategy was used to obtain oral repeated data (n = 285) from 89 patients, which were analyzed using a one‐compartment model and the NONMEM computer program. The model suggested that apparent clearance of S12024 was influenced by the study and by patient age. In the Spanish study, apparent clearance was increased by 68% and 26% for doses of 100 mg and 300 mg, respectively, and patient age decreased oral clearance by approximately 10% per decade in the patient age range (50 to 90 years). Data from only a few patients in the Spanish study were probably responsible for the observed study influence on apparent clearance of S12024, and no measured covariates could explain this effect. The model provided an excellent characterization of the observed data and it predicted correctly the plasma concentrations from an earlier Phase I trial and a subsequent Phase IIb study. The present model, built from Phase IIa data, provides a basis for examining the influence of patient covariates and the magnitude of their effects on the pharmacokinetics of S12024. The study effect is probably an artefact that will disappear by further expanding of the population model in the future.
Pharmacokinetics and Pharmacodynamics of Irbesartan in Patients with Hepatic Cirrhosis
Authors: Marino Maria R. , Langenbacher Kathleen M. , Raymond Ralph H. , Ford Neville F. , Lasseter Kenneth C.
Published: March 2013

The effect of hepatic impairment on the clinical pharmacology of the angiotensin II (AII) receptor antagonist irbesartan was assessed by comparing pharmacokinetic and pharmacodynamic parameters in 10 patients with hepatic cirrhosis with a matched group of 10 healthy volunteers. The pharmacokinetics and pharmacodynamics of irbesartan, 300 mg taken orally once daily, were evaluated after single‐ and multiple‐dose (7 consecutive days) administration to normotensive subjects in an open‐label, multiple‐dose, parallel group study. Pharmacokinetic data obtained after administration of single and multiple doses of irbesartan showed no significant difference between the two groups in time to maximum observed plasma concentration of drug (tmax), half‐life (t1/2), area under the plasma concentration‐time curve (AUC), apparent oral clearance (Clt/F), renal clearance (Clr), and accumulation index (AI). Steady‐state levels of irbesartan were reached within 3 days in both treatment groups. After irbesartan administration on day 1, mean increases from baseline in plasma AII levels and plasma renin activity (PRA) were greater in the group with cirrhosis than in the control group. On day 7, mean increases from baseline in PRA were greater in the control group than in the group with cirrhosis. No discontinuations or serious adverse events occurred during the study. The pharmacokinetics of irbesartan after repeated oral administration were not significantly affected in patients with mild‐to‐moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.
Brompheniramine, Loratadine, and Placebo in Allergic Rhinitis: A Placebo‐Controlled Comparative Clinical Trial
Authors: Druce Howard M. , Thoden William R. , Mure Patti , Furey Sandy A. , Lockhart Earle A. , Xie Tailiang , Galant Stanley , Prenner Bruce M. , Weinstein Steven , Ziering Robert , Brandon Milan L.
Published: March 2013

A double‐blind, randomized, placebo‐controlled, parallel‐group, multicenter study was conducted to compare the effectiveness of an extended‐release formulation of a classical antihistamine, brompheniramine, and a second‐generation compound, loratadine, in the treatment of allergic rhinitis. Subjects with symptoms of allergic rhinitis received brompheniramine 12 mg twice daily (n = 112), loratadine 10 mg once daily (n = 112), or placebo twice daily (n = 114) for 7 days. Study medications were blinded using a double‐dummy technique. Subjects completed an overall evaluation of symptom relief on a daily basis and returned on treatment days 3 and 7, at which times the investigator assessed symptom severity. The investigator and subject each completed a global efficacy evaluation, and subjects were interviewed regarding adverse experiences. The primary efficacy variable was the physicians' global efficacy evaluation on day 3. Symptoms also were analyzed as summed severity scores for all symptoms and for the nasal symptom cluster of rhinorrhea, sneezing, and nasal blockage. At all post‐baseline evaluations (days 3, 7, and averaged over the two days), brompheniramine was significantly better than loratadine and placebo for both sets of summed symptom scores and all three global assessments. Loratadine was significantly better than placebo for physician ratings of total symptom severity averaged over the two days and for the physician and subject ratings of the nasal cluster on day 3. Central nervous system‐related symptoms were the most frequently reported adverse experiences; somnolence was reported most frequently by patients taking brompheniramine, and its occurrence was less frequent as treatment continued. A nonprescription, extended‐release formulation of brompheniramine 12 mg twice daily provided significantly better relief of symptomatic allergic rhinitis than loratadine 10 mg once daily.
Independence and Statistical Inference in Clinical Trial Designs: A Tutorial Review
Authors: Bolton Sanford
Published: March 2013

The requirements for statistical approaches to the design, analysis, and interpretation of experimental data are now accepted by the scientific community. This is of particular importance in medical studies where public health consequences are of concern. Investigators in the clinical sciences should be cognizant of statistical principles in general, but should always be wary of the pursuing their own analyses and engage statisticians for data analysis whenever possible. Examples of circumstances that require statistical evaluation not found in textbooks and not always obvious to the lay person are pervasive. Incorrect statistical evaluation and analyses in such situations will result in erroneous and potentially serious misleading interpretation of clinical data. Although a statistician may not be responsible for any misinterpretations in such unfortunate circumstances, the quote often cited about statisticians and “damned liars” may appear to be more truth than fable. This article is a tutorial review and describes a common misuse of clinical data resulting in an apparently large sample size derived from a small number of patients. This mistake is a consequence of ignoring the dependency of results, treating multiple observations from a single patient as independent observations.
Single‐ and Multiple‐Dose Pharmacokinetic Comparison of a Sustained‐Release Tablet and Conventional Tablets of Naproxen in Healthy Volunteers
Authors: Zhou Diansong , Zhang Qiang , Lu Wei , Xia Qing , Wei Shuli
Published: March 2013

The pharmacokinetics of a new sustained‐release tablet of naproxen (500 mg once daily) were compared with a conventional tablet (250 mg twice daily) after single‐ or multiple‐dose oral administration in healthy volunteers using an open, randomized two‐way crossover experimental design. Naproxen was well absorbed from the sustained‐release tablet (∼ 97%) compared with the conventional tablet. Pharmacokinetic data showed that the sustained‐release formulation reached significantly delayed mean peak plasma levels (Cmax) in both single‐ and multiple‐dose studies and lower Cmax in a single‐dose study than the conventional formulation. However, there were no statistically significant differences in other pharmacokinetic parameters, including area under the concentration—time curve (AUC), elimination half‐life (t1/2), and elimination rate constant (Ke), in either single‐ or multiple‐dose studies between the two treatments. In addition, there were no significant differences between formulations in Cmax, minimum plasma concentration (Cmin), and fluctuation index in the multiple‐dose study.
Assessment of Drug Accumulation in the Evaluation of Pharmacokinetic Data
Authors: Meineke Ingolf , Gleiter Christoph H.
Published: March 2013

The evaluation of drug accumulation is approached from a practical point of view. Estimates of accumulation indices as obtained from standard estimators—AUC, peak levels, and trough levels (RAUC, Rmax, and Rmin, respectively)—are compared and differences analyzed. The estimators are based on the concentration‐time curve characteristics area under the concentration‐time curve (AUC), maximum concentration, and trough level. Simulated data are used for the analysis, both noise‐free and with random error added. The data are based on pharmacokinetic parameters derived from a clinical study. The numerical procedures can be reproduced by the interested reader with little effort. It is shown empirically that if Rmin > RAUC then simple kinetic behavior cannot be safely assumed, but accumulation is a complex function of time. Rmax as obtained from the data and an estimate of this value based on time to peak concentration (tmax) and apparent elimination rate constant (λz) after a single dose and at steady state can then be compared in an attempt to exclude time‐dependent kinetics. This new numerical procedure can provide valuable and even pivotal information regarding the accumulation kinetics of a compound under investigation. Recommendations on how to use the available concentration‐time information to the best advantage are presented. It is concluded that the assessment of drug accumulation should not be confined to the calculation of just one estimate, because the three estimators RAUC, Rmax, and Rmin reflect different aspects of accumulation. Moreover, all information about accumulation should be carefully analyzed in the clinical context. This way the relevant accumulation can be identified for safe and efficacious drug treatment.
Oral Bioavailability and Disposition Characteristics of Irbesartan, an Angiotensin Antagonist, in Healthy Volunteers
Authors: Vachharajani Nimish N. , Shyu Wen Chyi , Chando Theodore J. , Everett Donald W. , Greene Douglas S. , Barbhaiya Rashmi H.
Published: March 2013

Absolute oral bioavailability and disposition characteristics of irbesartan, an angiotensin II receptor antagonist, were investigated in 18 healthy young male volunteers. Subjects received [14C] irbesartan as a 30‐minute intravenous infusion (50 mg), [14C] irbesartan orally as a solution (50 mg or 150 mg), or irbesartan capsule (50 mg). Irbesartan was rapidly and almost completely absorbed after oral administration, and exhibited a mean absolute oral bioavailability of 60% to 80%. Mean total body clearance was approximately 157 mL/min, and renal clearance was 3.0 mL/min. Volume of distribution at steady state was 53 L to 93 L, and terminal elimination half‐life was approximately 13 to 16 hours. Hepatic extraction ratio was low (0.2). There were no major circulating metabolites, and approximately 80% of total plasma radioactivity was attributable to unchanged irbesartan. Regardless of route of administration, approximately 20% of dose was recovered in urine and the remainder in feces.
Synthesis and Herbicidal Activities of Sulfonylureas Bearing 1,3,4‐Thiadiazole Moiety
Authors: Song Xiang‐Hai , Ma Ning , Wang Jian‐Guo , Li Yong‐Hong , Wang Su‐Hua , Li Zheng‐Ming
Published: March 2013

In this article, we report the synthesis and herbicidal activities of sulfonylureas bearing the 1,3,4‐thiadiazole moiety. The target compounds 9a, 9b, 9c, 9d, 9e, 9f, 9g, 9h, 9i, 9j, 9k, 9l were synthesized using 2‐hydrazinocarbonyl benzenesulfonamide (4) and phenyl pyrimidinecarbamates as starting materials. The key intermediate, 2‐(4,5‐dihydro‐5‐thioxo‐1,3,4‐thiadiazol‐2‐yl)benzenesulfonamide (5), was prepared from 4 and CS2 via a conventional method or an improved method. The improved method, in which sulfonamido group acts as a directing group for the cyclization reaction, is more concise and efficient. The structures of the target compounds were determined by IR, 1H‐NMR, 13C‐NMR, MS, and elemental analysis. Their herbicidal activities were screened by Petri dish tests and pot tests. As the results, sulfonylureas 9h and 9j inhibited Brassica napus, Amaranthus retroflexus, and Echinochloa crusgalli at the 15 g/ha level, which is at the same level as azimsulfuron. Moreover, the safety tests showed that 9j was safe to wheat at dosage of 60 g/ha and might develop further into a herbicide in wheat field.
Synthesis and Fungicidal Activity of 5‐Aryl‐1‐(aryloxyacetyl)‐3‐(tert‐butyl or phenyl)‐4‐(1H‐1,2,4‐triazol‐1‐yl)‐4,5‐dihydropyrazole
Authors: Mao Hui‐Yu , Song Hong , Shi De‐Qing
Published: March 2013

A series of novel 5‐aryl‐1‐(aryloxyacetyl)‐3‐(tert‐butyl or phenyl)‐4‐(1H‐1,2,4‐triazol‐1‐yl)‐4,5‐dihydropyrazole3a–3nwere synthesized by the annulation of 2‐aryloxyacetohydrazides with 3‐aryl‐1‐t‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)prop‐2‐en‐1‐ones (2) in the presence of a catalytic amount of acetic acid. Compounds2were obtained by the Knoevenagel reactions of 1‐t‐butyl (or phenyl)‐2‐(1H‐1,2,4‐triazol‐1‐yl)ethanone (1) with aromatic aldehydes in the presence of piperidine. Their structures were confirmed by IR,1H‐NMR, ESI‐MS, and elemental analyses. The preliminary bioassay indicated that some compounds displayed moderate to excellent fungicidal activity. For example, compounds3l,3m, and3npossessed 100% inhibition againstCercospora arachidicolaHori at the concentration of 50 mg/L.
Facile and Efficient Synthesis of Indol‐3‐yl Substituted Pyran Derivatives via One‐Pot Multicomponent Reactions under Ultrasonic Irradiation
Authors: Chen Tao , Xu Xiao‐Ping , Ji Shun‐Jun
Published: March 2013

A series of polysubstituted indol‐3‐yl substituted pyran derivatives have been synthesized via one‐pot multicomponent reactions of aldehydes, malononitrile with 3‐cyanoacetyl indoles under ultrasonic irradiation. This method has the advantages of high yield, easy operation, short‐reaction time, mild‐reaction condition, and catalyst recyclability.
Hyperbranched Conjugated Polyelectrolytes for Biological Sensing and Imaging
Authors: Feng Guangxue , Liang Jing , Liu Bin
Published: March 2013

Over the recent decades, conjugated polyelectrolytes have attracted great research interests due to their unique physical and chemical properties. In this feature article, we summarize the recent advances of hyperbranched conjugated polyelectrolytes (HCPEs) in biological sensing and imaging applications. The HCPEs possess three‐dimensional core‐shell architectures with plenty of functional groups at the peripheries. Through further bioconjugation, the obtained functional HCPEs have wide applications in biomolecules sensing in solution, in vitro cell detection and imaging, specific protein detection in live cells, real‐time cell apoptosis detection, gene delivery, and in vivo dual‐modal fluorescence and magnetic resonance imaging. Some further outlooks are also highlighted at the end of the feature article.

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Effect of curauá fiber content on the properties of poly(hydroxybutyrate‐co‐valerate) composites
Authors: Rossa Lilian Vanessa , Scienza Lisete Cristine , Zattera Ademir José
Published: March 2013

Poly(hydroxybutyrate‐co‐valerate) (PHBV), a biodegradable polymer produced from a renewable microbiological source, was reinforced with varying amounts of curauá fibers (CFs). The composites were produced using a twin‐screw extrusion and injection process. Scanning electron microscopy showed poor adhesion between the matrix and fiber; however, mechanical testing showed that the addition of the fiber improved the mechanical properties. Composites with 20 and 30 wt% CF displayed the best properties; however, because of the difficulties in processing composites with a CF content of 30 wt%, it was concluded that the ideal content of CF was 20 wt%. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
Effect of insulation layer for thermal shock in cryogenic composite laminates
Authors: Oh Bong Taek , Lagoudas Dimitris C. , Moon Sung Cheal
Published: March 2013

The structural weight of a cryogenic propellant tank for reusable launch vehicles (RLVs) can be effectively reduced by the use of advanced composite materials. However, microscopic damage such as transverse matrix cracks (TMC) and delaminations are prone to develop in composites well below the load levels that would result in mechanical failure. This microscopic damage leads to a leakage path for the fuel. The leakage is influenced by many factors including connectivity of the cracks, residual and service‐induced stresses, and composite stacking sequence. This article is concerned with the effect of thermal gradients due to sudden exposure to a cryogenic temperature with and without insulation layer. An investigation of the insulation layer for sudden exposure to cryogenic temperatures is conducted numerically. The exposure of the harsh environment could make the damages such as delaminations, TMC, and leakage path. The defects from manufacturing could be formed, and they are critical parts under sudden exposure to cryogenic temperature. Therefore, the qualitative analysis for insulation technique is needed. The results from this article are very important because the stress levels which cause damages can be predicted and also controlled using the insulating techniques. The insulation skill which can suppress the stress levels is newly introduced in this article for RLV cryogenic fuel tank. Moreover, the effect of lay‐ups is also investigated in this article. The thermal gradient can be controlled by using different lay‐ups. POLYM. COMPOS., 2013. © 2013 Society of Plastics Engineers
A reactive extrusion process for the free radical grafting of silanes onto polypropylene: Effects of processing conditions and properties of water cross‐linked silane‐grafted polypropylene
Authors: Li Zheng‐Hui , Hu Guo‐Hua , Corriou Jean‐Pierre , Hoppe Sandrine , Fonteix Christian , Laine Richard , Habimana Jean , Deheunynck Damien
Published: March 2013

Silane grafting and water cross‐linking of polypropylene (PP) are a recent method to modify its properties, such as melt strength, heat, and chemical resistance. This work aims at grafting silanes onto PP by reactive extrusion. The occurrence of the grafting of silane onto PP was confirmed by Fourier transform infrared (FTIR) and a method based on FTIR was developed to quantify the amount of polymerized silane and that of silane grafted onto PP. The molar mass of the silane‐grafted PP and its melt viscosity were also measured. A multiobjective optimization strategy was used to study the effects of processing conditions on the quality of the silane‐modified PP. It was concluded that to maximize the amount of silane grafted on PP and minimize the amount of polymerized silane and the decrease in PP chain scission, screw speed and barrel temperature should be low and feed rate high. POLYM. ENG. SCI., 2013. © 2013 Society of Plastics Engineers
Putative cholesterol‐binding sites in human immunodeficiency virus (HIV) coreceptors CXCR4 and CCR5
Authors: Zhukovsky Mikhail A. , Lee Po‐Hsien , Ott Albrecht , Helms Volkhard
Published: March 2013

Using molecular docking, we identified a cholesterol‐binding site in the groove between transmembrane helices 1 and 7 near the inner membrane‐water interface of the G protein‐coupled receptor CXCR4, a coreceptor for HIV entry into cells. In this docking pose, the amino group of lysine K67 establishes a hydrogen bond with the hydroxyl group of cholesterol, whereas tyrosine Y302 stacks with cholesterol by its aromatic side chain, and a number of residues form hydrophobic contacts with cholesterol. Sequence alignment showed that a similar putative cholesterol‐binding site is also present in CCR5, another HIV coreceptor. We suggest that the interaction of cholesterol with these putative cholesterol‐binding sites in CXCR4 and CCR5 is responsible for the presence of these receptors in lipid rafts, for the effect of cholesterol on their conformational stability and function, and for the role that cell cholesterol plays in the cell entry of HIV strains that use these membrane proteins as coreceptors. We propose that mutations of residues that are involved in cholesterol binding will make CXCR4 and CCR5 insensitive to membrane cholesterol content. Cholesterol‐binding sites in HIV coreceptors are potential targets for steroid drugs that bind to CXCR4 and CCR5 with higher binding affinity than cholesterol, but do not stabilize the native conformation of these proteins. Proteins 2013. © 2012 Wiley Periodicals, Inc.
Oxidizing Borcherds symmetries
Authors: Kleinschmidt Axel , Palmkvist Jakob
Published: March 2013

Abstract

The tensor hierarchy of maximal supergravity in D dimensions is known to be closely related to a Borcherds (super)algebra that is constructed from the global symmetry group E
11−D
. We here explain how the Borcherds algebras in different dimensions are embedded into each other and can be constructed from a unifying Borcherds algebra. The construction also has a natural physical explanation in terms of oxidation. We then go on to show that the Hodge duality that is present in the tensor hierarchy has an algebraic counterpart. For D > 8 the Borcherds algebras we find differ from the ones existing in the literature although they generate the same tensor hierarchy.