bluuebunny/crossref_metadata_2025 huggingface dataset:
Sodium Ion/Hydrogen Ion Exchange Inhibition: A New Pharmacologic Approach to Myocardial Ischemia and Reperfusion Injury
Authors: Levitsky Josh , Gurell Daniel , Frishman William H.
Published: March 2013

Over the past few years, it has been shown that the cardiac myocyte plasma membrane sodium ion/hydrogen ion exchanger (NHE) plays an important role in the maintenance of intracellular pH, sodium, and calcium ion homeostasis. From the results of various experimental studies, it is clear that this ion exchanger is an important mediator of ischemic‐reperfusion injury of the heart. During myocardial ischemia, intracellular acidosis develops quickly, activating the exchanger to extrude H+ into the extracellular environment and bring Na+ into the cell. With further progression of ischemia, the cell is unable to handle the overload of Na+, causing it to use its Na+/Ca2+ exchanger to unload intracellular Na+ into the extracellular space. At the same time, however, calcium is being transported into the cell. This can lead to detrimental cardiac injury, such as contracture and necrosis. During myocardial reperfusion, these events are magnified because the return of blood flow lowers the extracellular H+ concentration, stimulating the NHE to extrude more intracellular H+ ion. This leads to intracellular Na+ excess and eventually, intracellular Ca2+ overload and cardiac injury. In an effort to alter these pathophysiologic events, a number of investigators have studied the ability of various NHE inhibitors, such as amiloride, analogues of amiloride, and other drugs (HOE 694, HOE 642), to prevent cardiac ischemic‐reperfusion damage. Preliminary results from studies in animal models have revealed that most of these agents are able to attenuate the development of myocardial contracture, infarction, and arrhythmias during both ischemia and reperfusion. Their efficacy and cardioprotective effects in human beings have yet to be determined. These agents appear to be promising not only in the prevention and treatment of ischemic heart disease, but also in avoiding cardiac damage in situations where low‐flow states are followed by immediate recovery of flow, as in coronary artery bypass graft surgery, percutaneous transluminal coronary angioplasty, thrombolytic therapy, and coronary arterial vasospasm. This article reviews the physiology of the NHE and analyzes the potential role of NHE inhibitors in the prevention of ischemic‐reperfusion injury and other cardiac disease states.
Pharmacokinetics of 2‐Oxothiazolidine‐4‐Carboxylate, a Cysteine Prodrug, and Cysteine
Authors: Gwilt Peter R. , Radick Lorraine E. , Li Xiao‐Yan , Whalen John J. , Leaf Cynthia D.
Published: March 2013

The pharmacokinetics of both 2‐oxothiazolidine‐4‐carboxylate (OTZ), a prodrug of cysteine, and total blood cysteine (cysteine plus cystine) were investigated in 18 healthy volunteers. OTZ was given either as a single, 2‐hour intravenous infusion (56–66 mg/kg) or similarly infused (70–100 mg/kg) every 8 hours for four doses. Blood was assayed for OTZ, total blood cysteine, and glutathione. The pharmacokinetics of OTZ were analyzed alone and simultaneously with total cysteine using the NONMEM software package (University of California at San Francisco. The pharmacokinetics of OTZ were best described by Michaelis‐Menten kinetics with parallel first‐order elimination. OTZ was efficiently removed from the plasma. The Michaelis‐Menten route of elimination was attributed to conversion of OTZ to total cysteine. At plasma OTZ concentrations equal to the Michaelis constant Km, 84% of OTZ was converted to total cysteine. These findings suggest that OTZ administered intravenously is an efficient means of increasing total blood cysteine.
Protease Inhibitors as Inhibitors of Human Cytochromes P450: High Risk Associated with Ritonavir
Authors: von Moltke Lisa L. , Greenblatt David J. , Grassi Jeffrey M. , Granda Brian W. , Duan Su Xiang , Fogelman Steven M. , Daily Johanna P. , Harmatz Jerold S. , Shader Richard I.
Published: March 2013

Four protease inhibitor antiviral agents (ritonavir, indinavir, nelfinavir, saquinavir) were evaluated as in vitro inhibitors of the activity of six human cytochromes using an in vitro model based on human liver microsomes. Ritonavir was a highly potent inhibitor of P450‐3A activity (triazolam hydroxylation), having inhibitory potency slightly less than ketoconazole. Indinavir was also a potent 3A inhibitor, while nelfinavir and saquinavir were less potent. Ritonavir had high inhibition potency against cytochrome P450‐2C9 (tolbutamide hydroxylation), −2C19 (S‐mephenytoin hydroxylation), and −2D6 (dextromethorphan O‐demethylation and desipramine hydroxylation), while the other protease inhibitors had one or more orders of magnitude lower inhibitory activity against these reactions. None of the protease inhibitors had important inhibitory potency against P450‐1A2 (phenacetin O‐deethylation) or −2E1 (chlorzoxazone hydroxylation). Thus, among available protease inhibitors, ritonavir carries the highest risk of incurring drug interactions due to inhibition of cytochrome P450 activity.
Pharmacokinetics of Metoclopramide in Neonates
Authors: Kearns Gregory L. , van den Anker John N. , Reed Michael D. , Blumer Jeffrey L.
Published: March 2013

Despite its wide use as a prokinetic agent in neonates and infants with gastroesophageal reflux (GER), the pharmacokinetics of metoclopramide have not been characterized in this pediatric subpopulation. A single‐dose pharmacokinetic study of oral metoclopramide (0.1 to 0.15 mg/kg) was performed in 10 fasted premature infants (weight 1.1 to 3.2 kg) ranging from 31 to 40 weeks postconceptional age. Metoclopramide was quantitated from repeated blood samples (n = 9 over 24 hours) by high‐performance liquid chromatography. A one‐compartment open model with first‐order absorption best described the plasma concentration—time data. No correlations were observed between gestational, postnatal, or postconceptional age and any of the pharmacokinetic parameters studied. Comparison of the pharmacokinetic parameters from the study cohort and those reported previously from a similar study of older infants revealed no statistically significant differences. However, a prolonged apparent plasma clearance (Cl/F) of metoclopramide was observed in 30% of the infants studied, and the mean Cl/F and apparent steady‐state volume of distribution (Vdss/F) were approximately 1.4‐ and 2.1‐fold higher, respectively, than values reported in previous studies of metoclopramide disposition in adults. These data suggest that metoclopramide pharmacokinetics may exhibit a developmental dependency. Thus, a metoclopramide dose of 0.15 mg/kg given orally every 6 hours is recommended for the initiation of prokinetic therapy with this agent in infants who are ≤31 weeks postconceptional age.
Vasoreactivity in Pre‐ and Postmenopausal Women: Evaluation by Pharmacodynamic Modeling
Authors: Ching Marilou I. , Sung Bong Hee , Forrest Alan , Wilson Michael F. , Izzo Joseph L.
Published: March 2013

Postmenopausal women experience an increase in cardiovascular mortality and morbidity compared with their premenopausal counterparts. This study was undertaken to develop a pharmacodynamic model to determine whether vascular reactivity in postmenopausal women differed from that in premenopausal women. Eleven subjects in each group were recruited. Graded doses of norepinephrine and insulin were infused via the dorsal hand vein. Venous diameter was measured by ultrasound. Dosage and venous diameter were fit to a Hill‐type pharmacodynamic model in which norepinephrine acts as a vasoconstrictor and insulin counteracts varying fractions of norepinephrine constriction. Fitted pharmacodynamic parameters for norepinephrine did not differ uniformly between groups, but at norepinephrine infusion rates between 14 and 46 ng/mL, postmenopausal women demonstrated increased norepinephrine‐induced vasoconstriction. Also, the modeled maximal response to insulin (Emaxi) was greater in premenopausal women. By stepwise linear regression, maximal response to insulin was found to be related to menopausal status and diastolic blood pressure. Postmenopausal women showed differences in vasoreactivity that may have important implications in the pathogenesis of hypertension.
Population Pharmacokinetics and Pharmacodynamics of Pyridostigmine Bromide for Prophylaxis against Nerve Agents in Humans
Authors: Marino Mark T. , Schuster Brian G. , Brueckner Ralf P. , Lin Emil , Kaminskis Andris , Lasseter Kenneth C.
Published: March 2013

This study was conducted to determine the pharmacokinetics and pharmacodynamics of pyridostigmine given as 30 mg of pyridostigmine bromide every 8 hours in healthy subjects. Plasma pyridostigmine concentration and red blood cell acetylcholinesterase activity were measured in blood samples collected during a 3‐week period. Population analysis was performed using standard pharmacokinetic and pharmacodynamic models with the nonlinear mixed‐effect modeling software (NONMEM). The pharmacokinetic model that best fit the pyridostigmine plasma levels was a two‐compartment open model with first‐order absorption, a lag time, and first‐order elimination from the central compartment. The pharmacodynamic model that best fit red blood cell acetylcholinesterase activity was an inhibitory Emax model with an effect compartment linked to the central compartment. The results showed that the pharmacokinetics of pyridostigmine bromide are both gender and weight dependent. The pharmacodynamic effect does not lag significantly from the plasma concentration and returns to near normal within 8 hours. With the present dosage regimen of 30 mg every 8 hours, 30% of individuals may not have red blood cell acetylcholinesterase inhibition >10% at the time of the trough.
Pharmacokinetics, Pharmacodynamics, and Safety of Metrifonate in Patients with Alzheimer's Disease
Authors: Pettigrew L. Creed , Bieber Florian , Lettieri John , Wermeling Daniel P. , Schmitt Frederick A. , Tikhtman Alex J. , Ashford J. Wesson , Smith Charles D. , Wekstein David R. , Markesbery William R. , Orazem John , Ruzicka Bianca B. , Mas Janice , Gulanski Barbara
Published: March 2013

Metrifonate is converted nonenzymatically to 2,2, dimethyl dichlorovinyl phosphate (DDVP), an inhibitor of acetylcholinesterase (AChE). This 21‐day, randomized, double‐blind, placebo‐controlled trial of metrifonate in patients with Alzheimer's disease (n = 27) evaluated four doses, each administered orally once daily. All patients received a loading dose (LD) for 6 days followed by a maintenance dose (MD) for 15 days. The treatment groups were: panel 1, LD = 1.5 mg/kg (75–135 mg), MD = 0.25 mg/kg (12.5–25 mg); panel 2, LD = 2.5 mg/kg (125–225 mg), MD = 0.40 mg/kg (20–35 mg); panel 3, LD = 4.0 mg/kg (200–335 mg), MD = 0.65 mg/kg (30–60 mg); and panel 4, LD = 4.0 mg/kg (200–335 mg), MD = 1.0 mg/kg (50–90 mg). All metrifonate doses were well tolerated. Most adverse events were mild to moderate in intensity, gastrointestinal in nature, and transient. Mean area under the concentration—time curve (AUC) and maximum concentration (Cmax for both metrifonate and DDVP increased in relation to dose. Metrifonate and DDVP had similar, largely dose‐independent mean values for time to Cmax (tmax) and half‐life (t1/2). There was little or no accumulation of either metrifonate or DDVP with long‐term administration. After 21 days of treatment, mean percent erythrocyte AChE inhibition was 14%, 35%, 66%, 77%, and 82% for placebo and panels 1 through 4, respectively. Cognitive improvement was observed with the two highest metrifonate doses. These results reflect favorable safety and pharmacokinetic profiles for the use of metrifonate in the treatment of Alzheimer's disease.
Absolute Bioavailability and Electroencephalographic Effects of Conventional and Extended‐Release Formulations of Venlafaxine in Healthy Subjects
Authors: Patat Alain , Troy Steven , Burke Jim , Trocherie Suzanne , Danjou Philippe , Coz Franck Le , Allain Hervé , Gandon Jean‐Marc
Published: March 2013

Venlafaxine is currently marketed for treatment of depressive disorders as a conventional tablet formulation with a twice or three times daily dosage regimen. The absolute bioavailability of the conventional (CF) and extended‐release (XR) formulations and their effects on electroencephalograms (EEG) and on a visual analog scale (VAS) for nausea were assessed in a randomized, double‐blind, four‐way crossover, placebo‐controlled study of 16 healthy young men who were given either a single oral dose of 50 mg of CF venlafaxine, 75 mg of XR venlafaxine, or an intravenous dose of 10 mg of venlafaxine, or a placebo at 1‐week intervals. The absolute bioavailability of venlafaxine was between 40% and 45% and was similar for both the CF and XR formulations. Venlafaxine produced central effects of a desipramine‐like antidepressant. Regardless of formulation tested, the main EEG changes were an increase in fast beta (20–30 Hz) energy, which was more pronounced over the frontotemporal regions and extended within the full beta range (16–40 Hz). Maximum effect was reached at 6 hours for the CF and reached a plateau from 10 to 24 hours for the XR formulation. A dose‐proportional increase in central activity, expressed as area under the effect curve (AUE) of the beta band, was observed between the CF (50 mg) and XR (75 mg) formulations. Compared with the CF tablet, the XR formulation also produced a much less intense maximum effect and a decrease of 63% in the AUE of nausea normalized by dose. The XR formulation has the same absolute bioavailability and the same central activity as assessed by EEG, but produced less intensive nausea than CF venlafaxine. The present findings suggest that a once‐daily dosage regimen should be sufficient. This was confirmed by several clinical trials in depressive patients.
Development of a Limited Sampling Approach in Pharmacokinetic Studies: Experience with the Antiepilepsy Drug Tiagabine
Authors: Mahmood Iftekhar
Published: March 2013

A sparse sampling method is proposed to assess pharmacokinetic parameters after a single dose of the antiepilepsy drug tiagabine. Pharmacokinetic parameters obtained from two different pharmacokinetic studies were compared using sparse sampling (7 blood samples) with extensive sampling (15 to 16 blood samples). The results indicated that sparse blood samples taken at appropriate times can be used to estimate pharmacokinetic parameters as accurately as extensive blood samples. In addition, a limited sampling model (LSM) was developed using samples from 10 subjects at two time points (6 and 8 hours). The model was validated in 40 subjects and provided good population mean estimates of area under the concentration‐time curve (AUC) and maximum concentration (Cmax). The sparse sampling method described here can be used to assess pharmacokinetic parameters in drug development provided a prior knowledge of the pharmacokinetics of a drug has been obtained from extensive sampling. Further, the LSM described here may be useful in estimating AUC and Cmax of tiagabine using two samples in clinical settings. The LSM approach described here can also be used to estimate AUC and Cmax of a drug in preclinical toxicokinetic studies without detailed pharmacokinetic studies.
Do Alprazolam‐Induced Changes in Saccadic Eye Movement and Psychomotor Function Follow the Same Time Course?
Authors: Kroboth Patricia D. , Folan M. Margaret , Bauer Kenneth S. , Tullock William , Wright C. Eugene , Sweeney John A.
Published: March 2013

The purpose of this study was to determine whether short‐term tolerance develops to GABA‐agonist‐induced changes in saccadic eye movements (SEMs), and whether the time course for GABA‐agonist induced onset and offset of impairment is similar for SEMs and for psychomotor function. An additional goal was to determine whether there are differences in sensitivity between SEMs and psychomotor function. Six healthy volunteers participated in this balanced double‐blind, three‐way crossover, single‐dose study of placebo and two different dosage forms of the GABA‐agonist alprazolam: a rapidly absorbed oral 1.5‐mg compressed tablet (CT) and a 3.0‐mg sustained release (SR) tablet. Treatments were separated by a 7‐day washout period. Peak concentrations did not differ between CT and SR treatments, although area under the concentration‐time curve (AUC) of alprazolam was greater after administration of SR than after CT, because plateau concentrations were attained after SR. Both SEM and psychomotor tests showed time‐dependent responses consistent with the development of tolerance. SEMs discriminated the differences in rate of drug input of the CT and SR formulations, with impairment evident at low concentrations during absorption. SEM impairment also persisted longer than did psychomotor impairment. Peak saccade velocity is a more sensitive indicator of pharmacologic effects mediated by the GABA‐benzodiazepine receptor complex than are psychomotor responses. This is probably the result of the very high GABA dependency of SEMs, along with their limited sensitivity to motivation.
Inhibition of Capsaicin‐Induced Cough by the γ‐Aminobutyric Acid Agonist Baclofen
Authors: Dicpinigaitis Peter V. , Dobkin Jay B. , Rauf Khalid , Aldrich Thomas K.
Published: March 2013

γ‐aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA‐agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14‐day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low‐dose, oral baclofen given once daily. Forty‐one healthy volunteers were randomly assigned in a double‐blind manner to receive a 28‐day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once‐daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA‐agonists as potential therapeutic agents for chronic, nonproductive cough.
KA 672‐HCl, a Neuronal Activator Against Dementia: Tolerability, Safety, and Preliminary Pharmacokinetics after Single and Multiple Oral Doses in Healthy Male and Female Volunteers
Authors: Sourgens Hildegard , Hoerr Robert , Biber Anton , Steinbrede Heike , Derendorf Hartmut
Published: March 2013

In vitro and animal experiments have characterized KA 672‐HCl as a potent functional antagonist of excitatory amino acid‐induced convulsions and mortality. In receptor‐binding studies, the compound displayed high affinities to several serotoninergic, adrenergic, and dopaminergic receptors and to the sigma receptor. The potential for short‐ and long‐term toxicity of KA 672‐HCl in rats and dogs was found to be low. Double‐blind, randomized, placebo‐controlled studies were undertaken in healthy volunteers ranging from 52 to 74 years of age to determine tolerability, safety, and preliminary pharmacokinetics of single and repeated doses in humans. Single doses up to 40 mg were well tolerated, with no difference in effect from placebo. At 60 mg, approximately half of the volunteers experienced a moderate drug‐related orthostatic syndrome. After repeated doses of 10 or 20 mg KA 672‐HCl for 14 days only minor adverse events of mild intensity were reported with no clear relation to dose or a clinically relevant difference from placebo. A mild decrease in semisupine and standing blood pressure 4 hours after administration was observed in the 20 mg group with no occurrence of orthostasis. Linear pharmacokinetics were observed after repeated doses. However, this was not the case after single‐dose administration, as generally higher plasma concentrations were observed after the 20‐mg dose than would have been predicted from the 10‐mg data. The mean terminal phase half‐life after the 20 mg dose was 11.1 hours and 13.7 hours after repeated and single doses, respectively. The safety and tolerability data support a continuation of therapeutic trials. KA 672‐HCl is currently entering phase II development.
Pharmacokinetics and Pharmacodynamics of Ranitidine in Neonates Treated with Extracorporeal Membrane Oxygenation
Authors: Wells Thomas G. , Heulitt Mark J. , Taylor Bonnie J. , Fasules James W. , Kearns Gregory L.
Published: March 2013

The pharmacokinetics and pharmacodynamics of ranitidine were studied in 13 term neonates with stable renal and hepatic function who were treated with extracorporeal membrane oxygenation (ECMO). Ranitidine was initially administered as a single 2 mg/kg dose over 10 minutes and intragastric pH was monitored to determine response. Within 90 minutes after administration of ranitidine, intragastric pH for all of the patients whose initial reading was ≤ 4 had increased to > 5. Intragastric pH remained < 4 for a minimum of 15 hours. Mean ± 1 standard deviation elimination half‐life was 6.61 ± 2.75 hours, and 41.5 ± 22.2% of the single dose was eliminated in urine within 24 hours. Total plasma clearance of ranitidine correlated well with estimated glomerular filtration rate. Twenty‐four hours after the initial dose, a continuous infusion of ranitidine (2 mg/kg/24 hr) was started and continued for 72 hours or until ECMO was discontinued. Eleven patients completed 48 hours of continuous infusion and seven completed all 72 hours. Plasma clearance and elimination half‐life were determined from steady‐state plasma ranitidine concentrations 24, 46, and 72 hours after the start of the infusion. There were no significant differences in clearance between these intervals. These data suggest that for term neonates with stable renal and hepatic function, ranitidine does not need to be administered more frequently than every 12 hours. A continuous infusion of 2 mg/kg/24 hours maintained intragastric pH above 4 in more than 90% of our patients, and in our opinion is the preferred method for delivering ranitidine to term neonates undergoing ECMO who require H2 antagonists. Response to therapy should be monitored by repeated measurement of gastric pH and the dose should be adjusted accordingly.
Balanced Designs in Longitudinal Population Pharmacokinetic Studies
Authors: Ette Ene I. , Sun He , Ludden Thomas M.
Published: March 2013

A simulation study was performed using a balanced design to determine the sample size required for accurate and precise estimation of a parameter at a given level of intersubject variability in a longitudinal population pharmacokinetic study. A two‐compartment model parameterized in terms of clearance (Cl), volumes of the central (V1) and peripheral (V2) compartments, and intercompartmental clearance (Q) with multiple intravenous bolus inputs was assumed. Six samples were obtained from each subject using the informative profile (block) randomized design. Variability (in terms of coefficient of variation, CV) in model parameters was varied between 30% and 100%, and residual variability was fixed at 15%. Sample sizes ranging from 30 to 1,000 subjects were studied, and a hundred replicate data sets were generated and analyzed with NONMEM for each sample size at each CV. A sample size of 30 was required for accurate and precise estimation of structural model parameters when CV ≤ 75%, except for Cl where it is adequate for CV ≤ 100%. A sample size of 80 was required for intersubject variability estimation with CV ≤ 60%. Robust estimates of variability in Cl were obtained with sample sizes of 30 (CV ≤ 45%), 60 (CV 60–75%), and 100 (CV ≥ 75%). Positively biased estimates of residual variability were obtained irrespective of sample size at ≥ 60% CV. This indicates that estimates of residual variability obtained in study situations where CV ≥ 60% should be interpreted with caution. In such situations model misspecification may not be the issue, because in this simulation study concentration‐time profiles were generated and analyzed with the same model. Although these results should be interpreted within the context of the study, they provide a framework for addressing the issue of sample size in longitudinal population pharmacokinetic study with a balanced sampling design. The result of a population pharmacokinetic study can be anticipated by comparing the results of several simulations in which the various input factors have been varied.
Lack of Effect of Food on the Oral Bioavailability of Irbesartan in Healthy Male Volunteers
Authors: Vachharajani Nimish N. , Shyu Wen Chyi , Mantha M. Subbarao , Park Jong‐Soon , Greene Douglas S. , Barbhaiya Rashmi H.
Published: March 2013

This study was conducted to evaluate the effects of a high‐fat meal on the oral bioavailability of an 300‐mg irbesartan tablet in healthy male volunteers. Sixteen healthy young male volunteers participated in this single‐center, open‐label, single‐dose, crossover study. Each volunteer received a single 300‐mg irbesartan tablet under fasted conditions and 5 minutes after a high‐fat breakfast, with administrations separated by a 7‐day washout period. Serial blood samples were collected over a 72‐hour period, and plasma samples were analyzed for irbesartan using a validated high‐performance liquid chromatography/fluorescence procedure. Food had no statistically significant effects on the peak concentration (Cmax) and area under the concentration‐time curve (AUC) of irbesartan. The presence of food was associated with a slightly prolonged time to maximum concentration (tmax) and half‐life (t1/2), but the differences were not statistically significant. The results of this study indicate that food does not affect the bioavailability of irbesartan. Thus, irbesartan can be administered without regard to meals.
The Effects of Eprosartan, an Angiotensin II AT1 Receptor Antagonist, on Uric Acid Excretion in Patients with Mild to Moderate Essential Hypertension
Authors: Ilson Bernard E. , Martin David E. , Boike Steven C. , Jorkasky Diane K.
Published: March 2013

The effects of antihypertensive agents, including angiotensin II receptor antagonists, on urine uric acid excretion may have important clinical consequences. Therefore, the effects of single and repeated doses of eprosartan on uric acid excretion were evaluated in 57 male patients with mild‐to‐moderate essential hypertension in a double‐blind, randomized, placebo‐controlled, repeated dose, dose‐rising, two‐period, period‐balanced, crossover study conducted in two parts. In part 1 (n = 33), the effects of eprosartan dose regimens of of 50 mg, 100 mg, and 350 mg once daily and 150 mg every 12 hours on uric acid excretion were assessed. In part 2 (n = 24), the effects of eprosartan dose regimens of 600 mg, 800 mg, and 1,200 mg once daily on uric acid excretion were assessed. Eprosartan was well tolerated. There were no appreciable changes from predose values in fractional excretion of uric acid (FEua), urine uric acid excretion, urine uric acid to creatinine (Uua/Ucr) ratios, or serum uric acid concentrations after single or repeated doses of eprosartan. Mean Uua/Ucr ratios for eprosartan doses of 50 mg, 100 mg, or 350 mg daily or 150 mg every 12 hours were comparable to those for placebo. Mean FEua values and Uua/Ucr ratios for eprosartan doses of 600 mg, 800 mg, or 1,200 mg daily also were comparable to those for placebo. Single and repeated oral doses of eprosartan ranging from 50 mg to 1,200 mg daily had no effect on serum uric acid concentrations or urine uric acid excretion in patients with mild‐to‐moderate essential hypertension.
Cough‐Challenge Trial with a New Angiotensin‐Converting Enzyme Inhibitor, Imidapril
Authors: Shionoiri Hiroshi , Takasaki Izumi , Minamisawa Kohsuke , Ueda Shinichro , Kihara Minoru , Shindo Kunihiko , Hiroto Seiji , Sugimoto Koichi , Himeno Hideo , Naruse Masahiko , Nagamochi Isao , Yasuda Gen
Published: March 2013

This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin‐converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor‐induced dry cough were enrolled in a randomized, open‐labeled, crossover trial with two 6‐week periods to be treated with imidapril or amlodipine, a calcium‐channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough‐challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I‐ and bradykinin‐degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.
The Effect of Cimetidine on the Formation of Sulfamethoxazole Hydroxylamine in Patients with Human Immunodeficiency Virus
Authors: Lehmann David F. , Newman Nancy , Morse Philo D.
Published: March 2013

Hypersensitivity reactions from trimethoprim/sulfamethoxazole are likely caused by a reactive nitroso intermediate formed from sulfamethoxazole hydroxylamine. This pilot study tested whether cimetidine inhibits the urinary excretion of sulfamethoxazole hydroxylamine. Ten outpatients infected with human immunodeficiency virus (HIV) and currently receiving trimethoprim/sulfamethoxazole prophylaxis were randomly selected from 59 eligible patients. Five received cimetidine 800 mg twice daily for 1 week and five served as controls. Two spot urine samples one week apart were obtained after a trimethoprim/sulfamethoxazole dose for all patients. Patients taking cimetidine had a significant decrease in excretion of sulfamethoxazole hydroxylamine relative to total excreted drug in the two urine samples compared with control patients. Cimetidine likely caused this decrease in sulfamethoxazole hydroxylamine excretion through inhibition of CYP3A4. Because of potential differences between HIV‐infected patients and healthy subjects in oxidative metabolism, future studies of inhibitors of sulfamethoxazole hydroxylamine formation should be conducted in the HIV population.
AmBisome (Liposomal Amphotericin B): A Comparative Review
Authors: Boswell G. W. , Buell D. , Bekersky I.
Published: March 2013

AmBisome (NeXstar Pharmaceuticals, San Dimas, CA) is a unilamellar liposomal formulation of amphotericin B that was recently approved for use as empirical treatment for presumed fungal infections in febrile neutropenic patients and for aspergillosis, candidiasis, and cryptococcosis infections refractory to amphotericin B. It is a small closed microscopic sphere (<100 nm in diameter) with an inner aqueous core (i.e., a true liposome). AmBisome remains as an intact sphere in vitro and for prolonged periods of time in vivo during the processes of systemic transport and pharmacologic action. As a consequence of its size and in vivo stability, AmBisome has physiochemical properties and a pharmacokinetic profile that are considerably different from those of currently available lipid‐complexed amphotericin B formulations, with greatly increased area under the plasma concentration—time curve and much lower clearance at equivalent doses. AmBisome liposomes can be seen to accumulate at sites of fungal infection. Disruption of AmBisome liposomes occurs after attachment to the fungal cell wall and results in amphotericin B binding to fungal cell membrane ergosterol with subsequent cell lysis. AmBisome has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.
Effects of ABT‐761, a Novel 5‐Lipoxygenase Inhibitor, on the Pharmacokinetics of a Single Dose of Ethinyl Estradiol and Levonorgestrel in Healthy Female Volunteers
Authors: Wong Shekman L. , O'Dea Robert F. , Dube Louise M. , Awni Walid M.
Published: March 2013

ABT‐761 is a second‐generation 5‐lipoxygenase inhibitor in clinical development for the treatment of asthma. The effects of ABT‐761 on the pharmacokinetics of an oral contraceptive were assessed in 21 female adult volunteers in a phase I, multiple‐dose, open‐label study. Subjects received a single dose of oral contraceptive (30 μg ethinyl estradiol and 0.15 mg of levonorgestrel) on each of days 1 and 29. Oral doses of 300 mg of ABT‐761 were administered once daily beginning on day 15 continuing through day 29. Statistically significant decreases in maximum concentration (Cmax) and area under the concentration—time curve (AUC) of ethinyl estradiol were observed when oral contraceptive was administered concomitantly with ABT‐761 compared with administration of oral contraceptive alone. The mean elimination rate constant of ethinyl estradiol increased by 30% (a mean decrease of 3.8 hours in half‐life), and the mean apparent volume of distribution during the terminal phase (Vdβ/F) of ethinyl estradiol increased by 73% in the presence of ABT‐761. Mean Cmax and AUC values for norgestrel decreased by 12% and 10%, respectively, when administered with ABT‐761. Mean values for time to Cmax (tmax), terminal rate constant (β), half‐life (t1/2), and Vdβ/F) of norgestrel were similar when oral contraceptive was administered alone or concomitantly with ABT‐761. The mechanism responsible for the effect of ABT‐761 on the clearance of ethinyl estradiol remains undefined. Because results of previous multiple‐dose studies of ABT‐761 do not provide any evidence of autoinduction, the effects of ABT‐761 on the pharmacokinetics of ethinyl estradiol are more likely related to absorption of ethinyl estradiol.
Eprosartan Does Not Affect the Pharmacodynamics of Warfarin
Authors: Kazierad David J. , Martin David E. , Ilson Bernard , Boike Steven , Zariffa Nevine , Forrest Alan , Jorkasky Diane K.
Published: March 2013

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady‐state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14‐day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14‐day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.
Impairment of Absorption of Digoxin by Acarbose
Authors: Miura Takanori , Ueno Kazuyuki , Tanaka Kazuhiko , Sugiura Youji , Mizutani Masaru , Takatsu Fumimaro , Takano Y. Yumiko , Shibakawa Masahiko
Published: March 2013

This study was conducted to determine the effect of acarbose on serum concentrations of digoxin in healthy male volunteers. A randomized crossover design with three phases was used. In phase 1 participants received 0.5 mg of digoxin alone. In phase 2 they received 0.5 mg of digoxin 0.5 hours after a 200‐mg dose of acarbose. In phase 3 they received 100 mg of acarbose 0.5 hours before each meal three times daily for 3 days. On the fourth day, they received 0.5 mg of digoxin 0.5 hours after a 100‐mg dose of acarbose. Area under the concentration—time curve (AUC0–48) and mean maximum concentration (Cmax) were significantly lower and tmax significantly increased in phases 2 and 3 compared with phase 1. These results indicate that the absorption of digoxin is reduced by administration of acarbose, and that one of the major mechanisms of this interaction may be due to the pharmacodynamics of acarbose.
Influence of Age on the Safety, Tolerability, and Pharmacokinetics of the Novel HMG‐CoA Reductase Inhibitor Cerivastatin in Healthy Male Volunteers
Authors: Mazzu Arthur , Lettieri John , Kaiser Lee , Mullican William , Heller Allen H.
Published: March 2013

The safety, tolerability, and pharmacokinetics of cerivastatin, a novel, synthetic, potent, and highly selective HMG‐CoA reductase inhibitor, were studied in 48 young and elderly male volunteers in a randomized, double‐blind, placebo‐controlled study. Eight men ranging from 18 to 38 years of age (young) and 15 men ranging from 65 to 78 years of age (elderly) received 0.1‐mg cerivastatin tablets daily for 7 days. The remaining subjects (8 young and 17 elderly) received matching placebo tablets. Cerivastatin was well tolerated in elderly and young subjects. Adverse events were mild and occurred less frequently in the participants receiving cerivastatin than in those receiving placebo. In those participants given cerivastatin, the incidence of adverse events was similar for both age groups (4 of 8 young subjects and 8 of 15 elderly subjects). Transient and mild elevations in creatine kinase and transaminase levels were evenly distributed across the cerivastatin and placebo groups. Pharmacokinetic parameters, including area under the concentration curve (AUC), peak plasma concentration (Cmax), time to Cmax (tmax), and elimination half‐life (t1/2), were similar between the two age groups. The mean elimination t1/2 for both groups was approximately 4 hours. These results indicate that cerivastatin is well tolerated in elderly male volunteers at a dosage of 0.1 mg/day. Further, the pharmacokinetics of cerivastatin are not altered as a consequence of age. Dose adjustment is therefore not required in elderly men.
Pharmacokinetics and Pharmacodynamics of Scopolamine after Subcutaneous Administration
Authors: Ebert Ulrike , Siepmann Martin , Oertel Reinhard , Wesnes Keith A. , Kirch Wilhelm
Published: March 2013

The effects of subcutaneously administered scopolamine on quantitative electroencephalogram (qEEG) and cognitive performance were evaluated and correlated with pharmacokinetic parameters in a randomized, double‐blind placebo‐controlled crossover study of 10 healthy male volunteers. Changes in qEEG and cognition were determined for 8 hours after drug administration. Scopolamine produced dose‐ and time‐dependent impairments of attention and memory and a time‐dependent increase in delta power (1.25‐4.50 Hz) and a decrease in fast alpha power (9.75‐12.50 Hz) on qEEG compared with placebo. Maximum serum concentrations of scopolamine occurred 10 to 30 minutes after drug administration. Mean peak serum concentrations (free base) were 3.27, 8.99, and 18.81 ng/mL after administration of 0.4, 0.6 mg, and 0.8 mg scopolamine, respectively. Elimination half‐life was approximately 220 minutes. The findings indicate temporary changes in qEEG and psychometric tests, and support the possible use of such a testing model for impaired cognitive functions such as age‐related memory disturbances.
A Simple and Efficient Synthesis of Ethyl 1‐Aryl‐4‐formyl‐1H‐pyrazole‐3‐carboxylates
Authors: Matiychuk Vasyl S. , Potopnyk Mykhaylo A. , Obushak Mykola D.
Published: March 2013

A new simple and convenient method of synthesis of ethyl 1‐aryl‐4‐formyl‐1H‐pyrazole‐3‐carboxylates from aromatic amines via diazonium salts has been developed. Hydrolysis and hydrazinolyization of these compounds has been investigated.
AMR‐Me inhibits PI3K/Akt signaling in hormone‐dependent MCF‐7 breast cancer cells and inactivates NF‐κB in hormone‐independent MDA‐MB‐231 cells
Authors: Rabi Thangaiyan , Huwiler Andrea , Zangemeister‐Wittke Uwe
Published: March 2013

AMR‐Me, a C‐28 methylester derivative of triterpenoid compound Amooranin isolated from Amoora rohituka stem bark and the plant has been reported to possess multitude of medicinal properties. Our previous studies have shown that AMR‐Me can induce apoptosis through mitochondrial apoptotic and MAPK signaling pathways by regulating the expression of apoptosis related genes in human breast cancer MCF‐7 cells. However, the molecular mechanism of AMR‐Me induced apoptotic cell death remains unclear. Our results showed that AMR‐Me dose‐dependently inhibited the proliferation of MCF‐7 and MDA‐MB‐231 cells under serum‐free conditions supplemented with 1 nM estrogen (E2) with an IC50 value of 0.15 µM, 0.45 µM, respectively. AMR‐Me had minimal effects on human normal breast epithelial MCF‐10A + ras and MCF‐10A cells with IC50 value of 6 and 6.5 µM, respectively. AMR‐Me downregulated PI3K p85, Akt1, and p‐Akt in an ERα‐independent manner in MCF‐7 cells and no change in expression levels of PI3K p85 and Akt were observed in MDA‐MB‐231 cells treated under similar conditions. The PI3K inhibitor LY294002 suppressed Akt activation similar to AMR‐Me and potentiated AMR‐Me induced apoptosis in MCF‐7 cells. EMSA revealed that AMR‐Me inhibited nuclear factor‐kappaB (NF‐κB) DNA binding activity in MDA‐MB‐231 cells in a time‐dependent manner and abrogated EGF induced NF‐κB activation. From these studies we conclude that AMR‐Me decreased ERα expression and effectively inhibited Akt phosphorylation in MCF‐7 cells and inactivate constitutive nuclear NF‐κB and its regulated proteins in MDA‐MB‐231 cells. Due to this multifactorial effect in hormone‐dependent and independent breast cancer cells AMR‐Me deserves attention for use in breast cancer prevention and therapy. © 2013 Wiley Periodicals, Inc.
Induction of reactive oxygen species generation inhibits epithelial–mesenchymal transition and promotes growth arrest in prostate cancer cells
Authors: Das Trinath P. , Suman Suman , Damodaran Chendil
Published: March 2013

Oxidative stress is one causative factor of the pathogenesis and aggressiveness of most of the cancer types, including prostate cancer (CaP). A moderate increase in reactive oxygen species (ROS) induces cell proliferation whereas excessive amounts of ROS promote apoptosis. In this study, we explored the pro‐oxidant property of 3,9‐dihydroxy‐2‐prenylcoumestan (psoralidin [pso]), a dietary agent, on CaP (PC‐3 and C4‐2B) cells. Pso greatly induced ROS generation (more than 20‐fold) that resulted in the growth inhibition of CaP cells. Overexpression of anti‐oxidant enzymes superoxide dismutase 1 (SOD1), SOD2, and catalase, or pretreatment with the pharmacological inhibitor N‐acetylcysteine (NAC) significantly attenuated both pso‐mediated ROS generation and pso‐mediated growth inhibition in CaP cells. Furthermore, pso administration significantly inhibited the migratory and invasive property of CaP cells by decreasing the transcription of β‐catenin, and slug, which promote epithelial–mesenchymal transition (EMT), and by concurrently inducing E‐cadherin expression in CaP cells. Pso‐induced ROS generation in CaP cells resulted in loss of mitochondrial membrane potential, cytochrome‐c release, and activation of caspase‐3 and ‐9 and poly (ADP‐ribose) polymerase (PARP), which led to apoptosis. On the other hand, overexpression of anti‐oxidants rescued pso‐mediated effects on CaP cells. These findings suggest that increasing the threshold of intracellular ROS could prevent or treat CaP growth and metastasis. © 2013 Wiley Periodicals, Inc.
ProFit revisited
Authors: Fuchs Alexander , Boesiger Peter , Schulte Rolf F. , Henning Anke
Published: March 2013

Purpose

An enhanced version of the ProFit fitting tool was developed and validated to improve the quantification of two‐dimensional JRPESS spectroscopic data.

Methods

The proposed enhancements were achieved by flexible organization of prior knowledge, configurations for different situations, the inclusion of measured macromolecular baseline contribution, additional baseline splines and a model‐free lineshape based on self‐deconvolution. The new software was tested and tuned on simulated data and subsequently applied to in vivo intrasubject and intersubject data.

Results

Fit results of simulated and acquired spectra show good overall quality suggesting the potential reliable detection of up to 18 metabolites on a 3T system yielding Cramer‐Lower‐Bounds below 20%.

Conclusion

The proposed enhanced version of ProFit together with two‐dimensional J‐resolved spectroscopy offers the opportunity to reliably detect a wide selection of important brain metabolites on 3T. Magn Reson Med 71:458–468, 2014. © 2013 Wiley Periodicals, Inc.
Uniform spinning sampling gradient electron paramagnetic resonance imaging
Authors: Johnson David H. , Ahmad Rizwan , Liu Yangping , Chen Zhiyu , Samouilov Alexandre , Zweier Jay L.
Published: March 2013

Purpose

To improve the quality and speed of electron paramagnetic resonance imaging (EPRI) acquisition by combining a uniform sampling distribution with spinning gradient acquisition.

Theory and Methods

A uniform sampling distribution was derived for spinning gradient EPRI acquisition (uniform spinning sampling, USS) and compared to the existing (equilinear spinning sampling, ESS) acquisition strategy. Novel corrections were introduced to reduce artifacts in experimental data.

Results

Simulations demonstrated that USS puts an equal number of projections near each axis whereas ESS puts excessive projections at one axis, wasting acquisition time. Artifact corrections added to the magnetic gradient waveforms reduced noise and correlation between projections. USS images had higher SNR (85.9 ± 0.8 vs. 56.2 ± 0.8) and lower mean‐squared error than ESS images. The quality of the USS images did not vary with the magnetic gradient orientation, in contrast to ESS images. The quality of rat heart images was improved using USS compared to that with ESS or traditional fast‐scan acquisitions.

Conclusion

A novel EPRI acquisition which combines spinning gradient acquisition with a uniform sampling distribution was developed. This USS spinning gradient acquisition offers superior SNR and reduced artifacts compared to prior methods enabling potential improvements in speed and quality of EPR imaging in biological applications. Magn Reson Med 71:893–900, 2014. © 2013 Wiley Periodicals, Inc.