bluuebunny/crossref_metadata_2025 huggingface dataset:
UHPLC‐MS/MS and UHPLC‐HRMS identification of zolpidem and zopiclone main urinary metabolites and method development for their toxicological determination
Authors: Strano Rossi Sabina , Anzillotti Luca , Castrignanò Erika , Frison Giampietro , Zancanaro Flavio , Chiarotti Marcello
Published: March 2013

Zolpidem and zopiclone (Z‐compounds) are non‐benzodiazepine hypnotics of new generation that can be used in drug‐facilitated sexual assault (DFSA). Their determination in biological fluids, mainly urine, is of primary importance; nevertheless, although they are excreted almost entirely as metabolites, available methods deal mainly with the determination of the unmetabolized drug. This paper describes a method for the determination in urine of Z‐compounds and their metabolites by ultra‐high‐pressure liquid chromatography/tandem mass spectrometry (UHPLC‐MS/MS) and UHPLC coupled with high resolution/high accuracy Orbitrap® mass spectrometry (UHPLC‐HRMS). The metabolic profile was studied on real samples collected from subjects in therapy with zolpidem or zopiclone; the main urinary metabolites were identified and their MS behaviour studied by MS/MS and HRMS. Two carboxy‐ and three hydroxy‐ metabolites, that could be also detected by gas chromatography/mass spectrometry (GC‐MS) as trimethylsylyl derivatives, have been identified for zolpidem. Also, at least one dihydroxilated metabolite was detected. As for zopiclone, the two main metabolites detected were N‐demethyl and N‐oxide zopiclone. For both substances, the unmetabolized compounds were excreted in low amounts in urine. In consideration of these data, a UHPLC‐MS/MS method for the determination of Z‐compounds and their main metabolites after isotopic dilution with deuterated analogues of zolpidem and zopiclone and direct injection of urine samples was set up. The proposed UHPLC‐MS/MS method appears to be practically applicable for the analysis of urine samples in analytical and forensic toxicology cases, as well as in cases of suspected DFSA. Copyright © 2013 John Wiley & Sons, Ltd.
Acetonitrile Coupling at an Electron‐Rich Iridium Center Supported by a PCP Pincer Ligand
Authors: Burford Richard J. , Piers Warren E. , Parvez Masood
Published: March 2013

Aryl amido iridium complexes supported by a tridentate phosphanyl–carbene–phosphanyl pincer ligand [(PCP)Ir–N(H)Ar, Ar = C6H5, 1a; Ar = 2,6‐iPr2C6H3, 1b] react with acetonitrile to afford the dimeric complex 2, in which two (PCP)Ir fragments are bridged by a diiminato ligand derived from two molecules of CH3CN. Metrical parameters obtained from X‐ray structural determination of 2 confirm that the bridging ligand is a diiminato species rather than an enediamido moiety, which indicates that the reductive coupling is mediated by one electron per iridium center. Experiments suggest that the reaction proceeds by heterolytic cleavage of the Ir–N(H)Ar bond followed by one‐electron reduction of the resulting IrI–NCCH3 cation by the amido anion. The resulting anilino radical rapidly abstracts a hydrogen atom from the solvent. The reductive coupling of acetonitrile at a late transition metal center is unusual and in this instance occurs as a result of the highly σ‐donating, electron‐rich nature of the PCP ligand.
Chiral α‐Arylethanamines: An Organocatalyst for the Enantioselective α‐Amination of Branched Aldehydes
Authors: Fu Ji‐Ya , Wang Qi‐Lin , Peng Lin , Gui Yong‐Yuan , Wang Fan , Tian Fang , Xu Xiao‐Ying , Wang Li‐Xin
Published: March 2013

α‐Arylethanamines were investigated as organocatalysts for the α‐amination of branched aldehydes with azodicarboxylates. Optimization identified (R)‐1‐(1‐naphthyl)ethanamine (1g) as an effective and enantioselective organocatalyst; multifunctional chiral quaternary amino aldehydes were successfully obtained in excellent yields (up to 99 %) and with excellent enantioselectivities (up to 98 % ee).
A Comparative Study of Biocathodes Based on Multiwall Carbon Nanotube Buckypapers Modified with Three Different Multicopper Oxidases
Authors: Pankratov Dmitry V. , Zeifman Yulia S. , Morozova Olga V. , Shumakovich Galina P. , Vasil'eva Irina S. , Shleev Sergey , Popov Vladimir O. , Yaropolov Alexander I.
Published: March 2013

14 Single‐ and multi‐walled carbon nanotubes from different sources were characterized in detail, and the characteristics obtained were carefully analyzed. The carbon material with the highest capacitance, and also other superior properties (“Taunit‐M” from “NanoTechCenter”, Russia), was chosen for further modification and fabrication of buckypaper based electrodes. These electrodes were biomodified with plant and fungal laccases, as well as fungal bilirubin oxidase. The designed biocathodes were investigated in simple buffers and also in a complex physiological fluid (human serum). Biocathodes based on immobilized fungal laccase were bioelectrocatalytically inactive in chloride containing media at neutral pH. In spite of the quite high current densities realized using biodevices based on plant laccase and fungal bilirubin oxidase, the limited thermal stability of the enzymes renders the biocathodes inadequate for practical applications in implanted situations.
Effects of Carbon Nanotube Paper Properties on Enzymatic Bioanodes
Authors: Yu Jiang , Rasmussen Michelle , Minteer Shelley D.
Published: March 2013

Carbon papers are frequent current collectors in fuel cells, but recently carbon nanotube papers have been introduced as new types of carbon paper. They have varying thickness, surface area, density, gas permeability, and conductivity. This paper studies the effect of these properties on electrochemical performance. Electropolymerizing methylene green on each carbon nanotube papers was performed to study the papers’ ability to oxidize NADH. Secondly, glucose bioanodes were formed with carbon nanotube papers to study glucose bioelectrocatalysis. The optimal carbon nanotube paper had a high surface area, low gas permeability, and low sheet resistance. Our results showed a greater than three‐fold increase in sensitivity over commercially available Toray carbon paper.
Coupling of finite volume and finite element subdomains using different time integrators
Authors: Li Zhe , Combescure Alain , Leboeuf Francis
Published: March 2013

This paper proposes a coupling strategy that can be used for transient fluid–structure interaction. The objective of this paper is to propose a time integrator coupling strategy, which ensures good properties to couple typical solid and typical fluid time integrators in linear cases. It is evaluated on a 1‐D toy problem only dedicated to the study of the quality of time integrators coupling. The structure is discretized by the linear finite element method and solved in time by the Newmark scheme, whereas the finite difference and finite volume methods are used for the fluid subdomain. By projecting the fluid equations on the eigenvector, we obtain a compatibility relation that corresponds to the characteristic line that transfers the fluid information from the inside to the fluid–structure interface. With this appropriate compatibility relation and the solid equations, the interface status is predicted for the next time step, ensuring zero interface energy. Hence, the order of accuracy and the stability are preserved to the minimum level of the two parts, the structure and the fluid. Furthermore, the coupling strategy allows incompatible time steps. Some numerical results are obtained for the 1‐D linear problem, and a good agreement with the analytical solution has been found. Copyright © 2013 John Wiley & Sons, Ltd.
NERC Matters: NERC Followed in Canada
Authors: Carpentier Deborah
Published: March 2013

Given the interconnected nature of the North American electric grid, Section 215(h) of the United States Energy Policy Act of 2005 urged the negotiation of agreements to “provide for effective compliance with Reliability Standards and the effectiveness of the [Electric Reliability Organization (ERO)] in the United States and Canada or Mexico.”
Asian dust input in the western Philippine Sea: Evidence from radiogenic Sr and Nd isotopes
Authors: Jiang Fuqing , Frank Martin , Li Tiegang , Chen Tian‐Yu , Xu Zhaokai , Li Anchun
Published: March 2013

The radiogenic strontium (Sr) and neodymium (Nd) isotope compositions of the detrital fraction of surface and subsurface sediments have been determined to trace sediment provenance and contributions from Asian dust off the east coast of Luzon Islands in the western Philippine Sea. The Sr and Nd isotope compositions have been very homogenous near the east coast of the Luzon Islands during the latest Quaternary yielding relatively least radiogenic Sr (87Sr/86Sr = 0.70453 to 0.70491) and more radiogenic Nd isotope compositions (εNd(0) = +5.3 to +5.5). These isotope compositions are similar to Luzon rocks and show that these sediments were mainly derived from the Luzon Islands. In contrast, the Sr and Nd isotope compositions of sediments on the Benham Rise and in the Philippine Basin are markedly different in that they are characterized by overall more variable and more radiogenic Sr isotope compositions (87Sr/86Sr = 0.70452 to 0.70723) and less radiogenic Nd isotope compositions (εNd(0) = −5.3 to +2.4). The Sr isotope composition in the Huatung Basin is intermediate between those of the east coast of Luzon and Benham Rise, but shows the least radiogenic Nd isotope compositions. The data are consistent with a two end‐member mixing relationship between Luzon volcanic rocks and eolian dust from the Asian continent, which is characterized by highly radiogenic Sr and unradiogenic Nd isotope compositions. The results show that Asian continental dust contributes about 10–50% of the detrital fraction of the sediments on Benham Rise in the western Philippine Sea, which offers the potentials to reconstruct the climatic evolution of eastern Asia from these sediments and compare this information to the records from the central and northern Pacific.
High‐resolution seismic imaging in the Japan Trench axis area off Miyagi, northeastern Japan
Authors: Nakamura Yasuyuki , Kodaira Shuichi , Miura Seiichi , Regalla Christine , Takahashi Narumi
Published: March 2013

Newly obtained high‐resolution seismic data reveal the detailed structure of the Japan Trench axis off Miyagi, Japan, in the region of large shallow slip during the 11 March 2011 M9 Tohoku earthquake. Correlation of seismic images with previous drilling results identifies a possible basal chert‐rich layer and hemipelagic/pelagic mudstones overlying igneous Pacific crust. Mapping of acoustic basement depicts the subduction of horst‐and‐graben topography. The basement and basal chert are subducted beneath a seismically chaotic frontal prism, but the majority of overlying hemipelagic mudstones is offscraped and imbricated at the trench axis as a result of plate boundary compression. A possible décollement is imaged as a seaward dipping reflection at landward part of the trench graben and was likely generated by loading and failure of underthrust sediments. Collectively, these analyses provide a structural framework for understanding sedimentary inputs and the localization of shallow plate boundary slip at the Japan Trench.
Electric potentials in magnetic dipole fields normal and oblique to a surface in plasma: Understanding the solar wind interaction with lunar magnetic anomalies
Authors: Wang X. , Howes C. T. , Horányi M. , Robertson S.
Published: March 2013

We experimentally investigated the solar wind interaction with moderate‐strength lunar magnetic anomalies in which the electrons are magnetized but the ions remain unmagnetized. Previously, we studied the plasma sheaths above an insulating surface in a magnetic dipole field oriented parallel to the surface. In this paper, when the dipole field is oriented normal to the surface, the surface potential largely rises, and a potential bump forms in the sheath in the magnetic cusp region due to a significant magnetic mirror reflection of the electrons. It is also found that the electrons are shielded from the central dipole wings and diverted into the side of the wings. When the dipole field obliquely intersects the surface, an asymmetric potential distribution develops. Our experimental results indicate that lunar surface charging can be greatly modified in the magnetic anomaly regions, creating extreme local electrical environments.
Hydrophosphonylation of α‐Haloalkenals
Authors: Rulev A. Yu.
Published: March 2013

Polyfunctional β‐haloalkenyl α‐hydroxy phosphonates were synthesized chemoselectively by an economical alkali metal alkoxide catalyzed reaction of dialkyl phosphites with α‐haloenals. © 2013 Wiley Periodicals, Inc. Heteroatom Chem 24:187–190, 2013; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.21081
The Effects of Values, Work Centrality, and Organizational Commitment on Organizational Citizenship Behaviors: Evidence from Turkish SMEs
Authors: Uçanok Başak , Karabatı Serdar
Published: March 2013

Organizational citizenship behaviors (OCBs) are voluntary contributions of employees not explicitly recognized by the formal reward system and are ultimately critical for sustaining organizational effectiveness (Organ, 1988). The current study aims to investigate the effects of values, work centrality, and organizational commitment on organizational citizenship behaviors in small and medium‐sized enterprises (SMEs) in Turkey. It is predicted that work centrality, and affective and normative commitment will increase OCBs along with those values that correspond to OCBs in terms of content. A cross‐sectional survey was employed with a convenience sample of 277 SME employees. Data were collected in the midst of the 2008 global financial crisis, which allowed for elaboration on the dynamics of OCBs under difficult periods. The analyses revealed that affective commitment and normative commitment were strong predictors of OCBs. Sportsmanship dimension of citizenship was found to be a function of conservation values, work centrality, and both affective and normative commitment. Findings and suggestions for future research are discussed in light of recent OCB literature and a general HRD perspective.
Discharge of major global rivers in the late 21st century climate projected with the high horizontal resolution MRI‐AGCMs
Authors: Nakaegawa Tosiyuki , Kitoh Akio , Hosaka Masahiro
Published: March 2013

This study used an atmospheric general circulation model (AGCM) with a 20‐km grid spacing and a global river routing model with 0.5° grid resolution to project climatological mean river discharges in the late 21st century under a changing climate. We also performed an ensemble simulation with the same AGCM except with a resolution of 60 km and forced with different lower boundary conditions to quantify the level of confidence in the projections. By the late 21st century, projected annual mean river discharges increased in the high latitudes and in India and the southeastern United States but decreased in broad regions of Europe, western Asia, the western United States, Central America, and the southern half of the Amazon River basin. Projected future changes in monthly river discharges include unique seasonal details not present in the annual discharge projections: in the Amazon River, for example, river discharges were projected to increase in the high‐water season but decrease in the low‐water season. These seasonal changes suggest that monthly river discharge projections should be useful for assessing the human impacts and risks in future planning of water resources and flood control. We devised a way to measure the consistency between the various projections made by our 60‐km ensemble simulations and our standard 20‐km high‐resolution model. Wherever the projected changes were consistent, the future changes also tended to be statistically significant in our high‐resolution model. These results encourage a future projection of discharge for a specific river basin in the world. Copyright © 2013 John Wiley & Sons, Ltd.
An analysis of summer evapotranspiration based on multi‐year observations including extreme climatic conditions over a cool‐temperate evergreen coniferous forest, Takayama, Japan
Authors: Saitoh Taku M. , Tamagawa Ichiro , Muraoka Hiroyuki , Kondo Hiroaki
Published: March 2013

Five years (2006–2010) of eddy‐covariance data were used to investigate inter‐annual variation of evapotranspiration (E) under dry canopy conditions (i.e. no rainfall in the previous 24 h) in summer over a cool‐temperate evergreen coniferous forest in Japan. The data included the warmest summer (June to September) in the past 50 years (2010) and the coolest summer in the past 15 years (2009). We found significant differences between 2009 and 2010 in gas exchange properties such as equilibrium evaporation (Eeq) and surface conductance (Gs) in addition to meteorological variables such as air vapour pressure deficit (Da) and net radiation. The values of E, however, were not significantly different in these two years. Furthermore, the inter‐annual variation (coefficient of variance, CV) in E was relatively low (3.5%) as compared with higher values of inter‐annual variation in gas exchange properties (4.2–10.0%) and meteorological factors (4.3–18.3%). The relatively steady E can be explained by (1) less effective atmospheric demand (i.e. less sensitive to Eeq) because of the low decoupling coefficient (0.07–0.15) at the study site and (2) the negative response of Gs to Da and a reduced sensitivity of E to high Da values in relation to plant physiological regulation (i.e. stomatal control). Copyright © 2013 John Wiley & Sons, Ltd.
Salivary Elimination of Cyclophosphamide in Man
Authors: RITSCHEL W. A. , BYKADI Q. , NORMAN E.J. , CLUXTON R. J. , DENTON D.
Published: March 2013

Abstract: A total of 25 plasma and saliva samples were obtained from three hospital inpatients upon intravenous short‐time infusion of cyclophosphamide; total doses infused ranged from 5.3 to 13.3 mg/kg. Despite interindividual variations, a correlation was found for plasma‐to‐saliva ratio of 1.61 ± 0.53 (S.D.). Our saliva‐to‐plasma ratio of 0.62 is in agreement with a recently reported5 ratio of 0.77. The ratio stayed constant throughout the observation period (0.05 to 8.4 hours), indicating that the noninvasive method of saliva sampling seems to be a useful approach in cyclophosphamide drug concentration monitoring in patients.
A Study of the Transplacental Transfer and the Mammary Excretion of Cefoxitin in Humans
Authors: DUBOIS M. , DELAPIERRE D. , CHANTEUX L. , DEMONTY J. , LAMBOTTE R. , KRAMP R. , DRESSE A.
Published: March 2013

Abstract: Cefoxitin is a new semisynthetic cephamycin derivative with broad bactericidal activities. In order to determine the extent of the transplacental transfer of cefoxitin, 35 pregnant women received 1 Gm cefoxitin intramuscularly 15 to 180 minutes before normal or Caesarean delivery. Cefoxitin was measured microbiologically in maternal blood (multiple‐time samples), umbilical blood (one‐time sample), and amniotic fluid in the cases of Caesarean sections. The mammary excretion of cefoxitin injected at the same dose was investigated by measuring cefoxitin in the milk of 16 nursing mothers. In the maternal blood, a peak plasma level of approximately 25 μg/ml was reached 30 minutes after the 1‐Gm intramuscular injection. A clear‐cut passage of cefoxitin in the umbilical cord blood was demonstrated. In the fetal blood, a peak level of 15 μg/ml was obtained 45 minutes after the injection. No cefoxitin was detectable in any of the milk samples from 30 minutes to 24 hours after the 1‐Gm intramuscular injection.
Selected Cardiac and Metabolic Responses to Pseudoephedrine with Exercise
Authors: BRIGHT THOMAS P. , SANDAGE BOBBY W. , FLETCHER H. PATRICK
Published: March 2013

Abstract: Pseudoephedrine hydrochloride was evaluated at two dosage levels in six normal healthy males, at rest and during submaximal exercise. Although there appeared to be a dose‐related rise in resting heart rate, it was not statistically significant. The drug had no effect on the amount of time required to reach 85 per cent maximal predicted heart rates while on the treadmill or on the amount of time required to recover baseline heart rates. Also, there was no drug effect observed on blood pressure at rest, during exercise, or in the recovery period. There was a significant increase in the frequency of sinus arrhythmias after the 120‐mg pseudoephedrine dose. There appeared to be no drug effect on postexercise blood glucose and insulin levels.
Effects of Indomethacin and Carprofen on Renal Homeostasis in Rheumatoid Arthritis Patients and in Healthy Individuals
Authors: WILLIAMS ROGER L. , FURST DANIEL E. , MANDEL H. GEORGE , NICOLL DIANA , KONIKOFF JOHN J. , BENET LESLIE Z.
Published: March 2013

Abstract: The influence of carprofen and indomethacin on renal salt and water homeostasis was investigated. Carprofen is a new nonsteroidal antiinflammatory drug that is currently undergoing clinical trials in the United States. Both drugs were administered in usual clinical doses to steady state in six healthy individuals and in six individuals with rheumatoid arthritis. Blood pressure, weight, plasma renin activity, urine volume, creatinine clearance, fractional excretion of sodium and potassium, and free water reabsorption were determined. Both drugs were found to suppress plasma renin activity. Indomethacin suppressed plasma renin activity more than carprofen. Neither drug produced clinically significant changes in any of the other parameters. In healthy individuals and in patients with rheumatoid arthritis, renal homeostatic mechanisms may compensate for the salt‐ and water‐retaining effects of nonsteroidal antiinflammatory drugs.
Bumetanide—The Way to Its Chemical Structure
Authors: FEIT PETER W.
Published: March 2013

Abstract: The steps in the evolution of sulfamoyl diuretics in current clinical use are outlined. The development was initiated by the chance observation of a clinical side effect of sulfanilamide, which became the first sulfamoyl group (‐SO2NH2)‐bearing compound used for diuretic treatment of patients. Ensuing chemical synthesis over the past three decades led to the development of three types of sulfamoyl diuretics: carbonic anhydrase inhibitors, thiazides, and the loop or high‐ceiling saluretic agents represented by furosemide and bumetanide. The structural relationship of furosemide to sulfanilamide and the thiazide‐type diuretics and, for bumetanide, the more specific structure for loop diuretic activity are discussed.
Long‐Term Bumetanide Treatment of Renal Edema. Comparison with Furosemide
Authors: WHELTON ANDREW
Published: March 2013

Abstract: In an open, parallel, randomized study, bumetanide was compared with furosemide in the long‐term management of patients with severe renal edema. The doses used were: bumetanide, 1 mg; furosemide, 40 mg. Graded increases were administered to daily maxima of 10 mg bumetanide and 400 mg furosemide. The efficacy of parameters measured were: weight, recumbent and standing pulse and blood pressure, abdominal girth, and estimated degree of malaise or fatigue when present. Safety parameters included: physical examination, CBC and platelets, blood chemistry, chemical and microscopic urinalysis, creatinine clearance, air audiometry, and ophthalmic examination. Weight loss and reduction of edema and of mean arterial pressure occurred in both groups of patients. In the bumetanide‐treated group, weight loss was statistically significant at most observation times during the first eight weeks, and reduction in edema was significant throughout the trial (P < 0.05). Reduction in these parameters in the furosemide‐treated patients was not statistically significant. However, the differences between the diuresis and other changes produced by the two drugs were not significant. While reduction in the mean arterial pressure of patients on bumetanide was significant (P < 0.05), the difference with that in the furosemide treatment group was not significant. Serum electrolyte abnormalities were infrequent. All patients tolerated the drug trial well. No deterioration in audiometry occurred in any patients, including 12 who entered the trial with abnormal air audiograms. Both drugs appear to be equally safe. While a daily dose of 4.2 mg bumetanide is highly effective in severe renal edema, the design of the study did not warrant definitive conclusion regarding comparative efficacy with furosemide.
Electrolyte Excretion Patterns. Intravenous and Oral Doses of Bumetanide Compared to Furosemide
Authors: BRATER D. CRAIG , FOX W. R. , CHENNAVASIN POLAVAT
Published: March 2013

Abstract: The response to bumetanide and furosemide administered orally and intravenously was compared in normal subjects. Doses of bumetanide were 0.5 and 1 mg intravenously and 0.5, 1 and 2 mg orally. Doses of furosemide were 20 and 40 mg intravenously and 20, 40, and 80 mg orally. After intravenous doses of both drugs, peak natriuresis occurred during the first collection period of 30 minutes, and the response returned to baseline by 3.5 hours. After oral dosing, peak effect occurred at 75 minutes and returned to baseline within 4 hours. Cumulative response was assessed for volume, sodium, potassium, and chloride excretion. The response did not differ substantially between drugs. On a milligram basis, bumetanide was approximately 50 times as potent as furosemide. For both drugs, the intravenous dose was approximately three times as potent as the oral preparation. The time course of response shows that the curves are virtually superimposable. The diuretic effect was short‐lived for both diuretics. The urine volume and sodium and chloride excretion were parallel. The sodium/potassium ratio was calculated as follows: for every 200 mEq sodium excreted in 4 hours, bumetanide caused about 35 mEq and furosemide caused about 50 mEq potassium to be eliminated. Even if statistically significant, this difference does not appear to be clinically remarkable. If bumetanide offers therapeutic advantages in this regard, studies in patients with various disease states would have to be performed.
Renal Electrolyte Excretion Pattern in Response to Bumetanide in Healthy Volunteers
Authors: HUTCHEON DUNCAN E. , VINCENT MARTHA E. , SANDHU RANDHIR S.
Published: March 2013

Abstract: Renal electrolyte excretion patterns were determined in nonedematous healthy volunteers following bumetanide and furosemide in two separate clinical studies. In study 1, intravenous bumetanide was administered to 24 subjects at four dose levels. In study 2, bumetanide (1 or 2 mg) or furosemide (40 or 80 mg) was administered in a single oral dose to 32 subjects assigned at random to one of the four treatment groups. In study 1, there was a significant dose‐related increase in urine volume and sodium, potassium, and chloride excretion, with chloride exceeding sodium at all dose levels, and the Na+/K+ ratios after bumetanide were greater than 3:1. In study 2, the Na+/K+ ratio increased significantly after treatment in all four treatment groups. The relative Na+/K+ ratios showed higher natriuretic potency and lower kaliuretic potency for bumetanide than for furosemide, but the differences were not statistically significant. Additionally, all four treatment groups demonstrated elevation in titratable acidity, ammonia formation, and total acid excretion. There was a significant degree of positive correlation in the bumetanide‐treated groups between Na+/K+ and the three variables. In the furosemide‐treated groups, this positive correlation was statistically significant between the Na+/K+ ratio and ammonia and total acid secretion but not for titratable acidity. The results support the view that increased H+ formation after the administration of loop diuretics has a relative potassium‐sparing effect.
Comparison of Adverse Reactions to Bumetanide and Furosemide
Authors: TUZEL ILHAN H.
Published: March 2013

Abstract: In 58 clinical studies, adverse reactions to bumetanide were evaluated in 493 patients and compared with those in 220 patients treated with furosemide. The comparison diuretics were administered to patients with edema secondary to congestive heart failure, and renal and hepatic disease. In addition to observation of clinical variables, laboratory tests were done to evaluate the effects of the diuretics on serum electrolyte levels. The results indicate that bumetanide, as furosemide, is an effective diuretic free of significant adverse effects when administered in doses within the recommended therapeutic dose range. Audiometric studies suggest that bumetanide is possibly safer than furosemide with regard to ototoxicity.
Interaction Studies with Bumetanide and Furosemide. Effects of Probenecid and of Indomethacin on Response to Bumetanide in Man
Authors: BRATER D. CRAIG , FOX W. R. , CHENNAVASIN POLAVAT
Published: March 2013

Abstract: Bumetanide was administered intravenously in doses of 0.5 and 1.0 mg to eight normal subjects with and without pretreatment with probenecid or indomethacin. Probenecid did not affect either the cumulative response or the time course of response to bumetanide. This may mean that probenecid and potentially other exogenous or endogenous organic acids do not affect the renal handling of bumetanide in normal man. Indomethacin pretreatment decreased the cumulative 4‐hour excretion of sodium caused by 1.0 mg bumetanide from 276 ± 22.9 to 202 ± 20.9 mEq (P < 0.003). Effects on volume and chloride paralleled those of sodium, while potassium excretion was not affected. When the response was analyzed as increment in fractional excretion over basal solute excretion, determined from separate control studies, indomethacin still decreased the response, possibly indicating that endogenous prostaglandins may play a role in determining the overall response to bumetanide.
The Effect of Bumetanide on the Serum Disappearance of Warfarin Sodium
Authors: NIPPER H. , KIRBY S. , IBER F. L.
Published: March 2013

Abstract: Ten normal subjects were given 0.8 mg/kg warfarin orally, and daily blood samples were taken for one week to test for prothrombin activity and warfarin levels, the latter determined specifically by a high‐performance liquid chromatography method. Bumetanide at a dose of 1 mg/day was then administered for 14 days. A second dose of warfarin was given on the eighth day of bumetanide administration. The curves showing disappearance of warfarin from the blood were identical before and during bumetanide administration. The prothrombin times were similar in both studies. It is concluded that bumetanide does not influence anticoagulant activity or its duration when warfarin and bumetanide are given simultaneously.
Clinical Use of Diuretics in Congestive Heart Failure
Authors: HUTCHEON DUNCAN , VINCENT MARTHA E. , SANDHU RANDHIR S.
Published: March 2013

Abstract: Loop diuretics have become indispensable in the management of patients with cardiac decompensation and severe edema. To evaluate the relative potency of these agents, bumetanide and furosemide were compared in 20 patients with edema associated with congestive heart failure in a double‐blind, parallel study design. The dosage of the drugs administered daily for three days was 1 to 2 mg bumetanide or 80 mg furosemide. Both agents were highly effective in reducing the edema and relieving the symptoms of heart failure. Muscle cramps and abdominal pain as side effects were deemed not severe. Laboratory values indicative of mild hypochloremic alkalosis and hyponatremia were observed in two patients. Hypokalemia and reversible eighth‐nerve involvement were not apparent in this study.
Bumetanide: A New Diuretic. Results of Clinical Efficacy and Safety in Patients with Congestive Heart Failure
Authors: HANDLER BRUCE , DHINGRA RAMESH C. , ROSEN KENNETH M.
Published: March 2013

Abstract: A clinical study of bumetanide, a new diuretic, was conducted in outpatients of a cardiology clinic to determine its long‐term effectiveness and safety in the treatment of peripheral edema due to congestive heart failure. The drug was administered for at least 24 weeks on a selected group of 34 patients. The patients were monitored for clinical response, evidenced by changes in cardiac signs and symptoms, and by laboratory tests, as well as by slit‐lamp ophthalmic examination, electrocardiogram, and chest x‐ray. Based on the clinical evaluation of effects on body weight, chronic edema, functional physical capacity, and results of selected laboratory data, it was concluded that bumetanide is as effective as other diuretics and can be used as an initial diuretic for maintenance of body weight for long‐term use in patients with peripheral edema due to congestive heart failure. Bumetanide mobilizes peripheral edema effectively in most patients and leads to improvement in functional physical capacity. Safety and adverse reactions during treatments are discussed.
History of Clinical Pharmacy and Clinical Pharmacology
Authors: MILLER RUSSELL R.
Published: March 2013

Abstract: The purpose of the Symposium on Clinical Pharmacy and Clinical Pharmacology is to describe the present and future functional roles of clinical pharmacists and clinical pharmacologists in drug research, professional education, and patient care. Clinical pharmacy is a relatively new professional discipline, being only about 15 years old. This new breed of pharmacists is patient rather than drug product oriented. The discipline arose out of dissatisfaction with old practice norms and the pressing need for a health professional with a comprehensive knowledge of the therapeutic use of drugs. The clinical pharmacy movement began at the University of Michigan in the early 1960s, but much of the pioneering work was done by David Burkholder, Paul Parker, and Charles Walton at the University of Kentucky in the latter part of the 1960s. Clinical pharmacology is a professional discipline that combines basic pharmacology and clinical medicine. Its development began in the early 1950s, primarily as a result of the efforts of Harry Gold. It has had a slower growth than clinical pharmacy but it has made many important contributions to our knowledge of human pharmacology and the rational use of drugs.
Chloramphenicol Clearance in Infants
Authors: BURCKART GILBERT J. , BARRETT FRED F. , STRAUGHN ARTHUR B. , TERNULLO SHARON R.
Published: March 2013

Abstract: Chloramphenicol clearance was evaluated over one dosing interval in 10 infants after at least 24 hours of therapy to evaluate dosage guidelines using a specific chemical assay. Serum samples were obtained prior to and at 1, 2, 4, and 6 hours after the start of a 20‐minute infusion of 25 mg/kg chloramphenicol as the sodium succinate. The chemical assay used is technically simple and is specific for unesterified chloramphenicol. Peak serum concentrations ranged from 20.9 to 94.0 μg/ml and occurred from 1 to 4 hours after infusion. Clearances ranged from 0.058 to 0.236 1./kg · hr and paralleled previously reported results using different assay methodology. The 4‐hour serum chloramphenicol concentrations were significantly lower (P < 0.05) in infants on phenobarbital. The currently recommended dose of chloramphenicol for severe infections, 100 mg/kg per day, is excessive in some infants. Widely divergent clearance rates prohibit uniform dosage guidelines so that serum level monitoring with an assay specific for chloramphenicol is essential.
The Relationship Between Serum and Saliva Trimethobenzamide Concentrations in Man
Authors: ROBERT TIMOTHY A. , DAIGNEAULT ERNEST A. , HINTON PHILIP , HAGARDORN ANDREA N.
Published: March 2013

Abstract: Six healthy volunteers provided simultaneous serum and mixed saliva specimens at various time intervals after receiving three different concentrations of trimethobenzamide HCl (total dose 800 mg) via rectal syringe on three separate occasions. Specimens were analyzed for trimethobenzamide content and the results subjected to pharmacokinetic analysis and other statistical procedures to identify characteristics of the relationship between distribution processes in these specimen types. On the basis of linear regression analysis there was a significant correlation (P < 0.01) between saliva and serum drug content for both mean values (r = 0.94) at each sampling time and all individuals' paired data points (r = 0.72). Because of the large degree of scatter in individual pairs, the data were subjected to analysis of variance in an attempt to determine a potential source of this divergence. The relationship between serum and saliva drug concentrations was found to depend upon the time after drug administration. We conclude that a nonuniform process determines the relative degree of partitioning trimethobenzamide between serum and saliva.
Saline Catharsis: Effect on Aspirin Bioavailability in Combination with Activated Charcoal
Authors: SKETRIS INGRID S. , MOWRY JAMES B. , CZAJKA PETER A. , ANDERSON WILLIAM H. , STAFFORD DAVID T.
Published: March 2013

Abstract: The effect of a saline cathartic combined with activated charcoal or activated charcoal alone on aspirin bioavailability was characterized in six healthy volunteers. Using a random, Latin‐square design, subjects were given 975 mg aspirin followed by either water alone, 15 Gm activated charcoal (AC), or 15 Gm activated charcoal plus 20 Gm sodium sulfate (AC + SS) separated by one week. Both AC (44.16 ± 16.85 μg/ml) and AC + SS (58.61 ± 10.63 μg/ml) decreased (P < 0.001) the maximal plasma salicylate concentration (Cpmax) compared to control (86.61 ± 12.69 μg/ml). Urinary salicylate recovery was decreased (P < 0.01) for AC (57.88 ± 16.26 per cent) and AC + SS (61.00 ± 11.49 per cent) as compared to control (93.73 ± 6.83 per cent), while for area under the plasma concentration‐time curve (AUC) only AC showed a decrease (P < 0.01) compared to control. Neither AC nor AC + SS differed from each other for Cpmax, AUC, or cumulative urinary recovery. Our findings indicate that the addition of sodium sulfate to activated charcoal has no added effect on limiting aspirin absorption relative to activated charcoal alone.
The Effect of Acute and Chronic Renal Failure on Theophylline Clearance
Authors: BAUER LARRY A. , BAUER STEPHANIE PATTERSON , BLOUIN ROBERT A.
Published: March 2013

Abstract: Theophylline total body clearance was measured in 29 anuric, chronic obstructive pulmonary disease patients with acute or chronic renal failure during a continuous intravenous infusion. They were divided into two groups depending on the absence (group 1, N = 16) or presence (group 2, N = 13) of congestive heart failure and compared to normal renal function control patients with similar disease states. All study and control patients smoked cigarettes. The theophylline mean total body clearance values (± S.D.) for group 1 were 68.0 ± 14.6, 64.5 ± 12.9, and 62.6 ± 17.3 ml/kg·hr for acute renal failure patients, uremic chronic renal failure patients, and control patients, respectively. For group 2, the corresponding values were 25.6 ± 6.1, 28.6 ± 8.7, and 27.4 ± 12.9 ml/kg·hr. There was no significant difference between study and control patients in either group 1 or group 2 (P greater than 0.05, one‐way analysis of variance). Since total body clearance determines the steady‐state concentration of a drug after repeated administration, theophylline doses do not need to be reduced in acute renal failure or uremia patients.
Clobazam Kinetics: Intrasubject Variability and Effect of Food on Absorption
Authors: DIVOLL MARCIA , GREENBLATT DAVID J. , CIRAULO DOMINIC A. , PURI SURENDRA K. , HO IRWIN , SHADER RICHARD I.
Published: March 2013

Abstract: The kinetics of single 20‐mg oral doses of clobazam was determined on two occasions in 12 healthy male volunteers. Clobazam was. given in the fasting state on one occasion and following a standard breakfast on another. Compared with the fasting state, administration of clobazam with food reduced mean peak plasma concentrations (465 vs. 333 ng/ml, P < 0.01), and prolonged the time to reach peak concentration (1.7 vs. 2.5 hours after dosage, P < 0.1). Total area under the curve (AUC) was not influenced, nor was clobazam elimination half‐life (24.5 vs. 24.3 hours), nor the extent of formation of desmethylclobazam, the major metabolite. Clobazam AUC and elimination half‐life each were highly correlated within subjects between the two trials (r = 0.97 and 0.95, respectively). Thus, administration of clobazam with food slows the rate of clobazam absorption but does not alter the completeness of absorption. The rate of drug elimination is highly replicable upon repeated administration of clobazam to the same individual.
Influence of Food on Tianeptine and Its Main Metabolite Kinetics
Authors: Dresse . A. , Rosen J. M. , Brems H. , Masset H. , Defrance R. , Salvadori C.
Published: March 2013

The influence of a test meal on the absorption and disposition of tianeptine (Stablon), a new antidepressant, was investigated in 12 healthy subjects in a two‐way, randomized, open cross‐over study. Single 12.5‐mg oral doses of tianeptine were administered following a night of fasting or immediately after a standardized breakfast. When subjects received tianeptine under fasting conditions the lag time before absorption onset, and the time of the maximum plasma concentration were 0.55 ± 0.26 hours and 1.29 ± 0.29 hours, respectively. The maximum plasma concentration was 322 ± 44 ng/mL, and the total area under the curve 994 ± 248 ng/hr/mL. When tianeptine was given at the end of the meal, several significant changes were found for tianeptine kinetic parameters; the lag time increased by 0.3 hour and the maximum plasma concentration was lowered (decreased by 25%) and occurred later (tmax increased by 0.5 hour). However, no significant change was found in the area under the plasma concentration‐time curve. The trend and extent of changes in the MC5 metabolite parameters were similar to those observed for the parent drug. Absorption of tianeptine is slightly delayed and slowed down without modification of its extent when tianeptine is given at the end of a meal. These slight changes are not clinically relevant for an antidepressant administered three times a day. Despite the changes observed, tianeptine may be given at meal times to improve compliance with treatment.
Lack of Interaction Between Nizatidine and Warfarin During Chronic Administration
Authors: Cournot Antoine , Berlin Ivan , Sallord Jean Claude , Singlas Eric
Published: March 2013

Nizatidine is a new antagonist of H2 receptors. The nizatidine warfarin interaction was investigated in healthy volunteers during chronic warfarin (mean warfarin dose: 5 ± 0.9 mg/d) and nizatidine (300 mg/d) administration. Nizatidine coadministration did not increase the prothrombin time, kaolin‐cephalin clotting time, and did not modify the activity of clotting factors II, VII, IX, X. Nizatidine did not influence the steady‐state plasma warfarin concentration.
Absorption of Naproxen Controlled‐Release Tablets in Fasting and Postprandial Volunteers
Authors: Mroszczak Edward , Yee James P. , Bynum Lincoln
Published: March 2013

The absorption of naproxen in a new controlled‐release (CR) formulation (1000 mg tablet) was studied in fasting and postprandial volunteers. The total area under the plasma concentration‐time curve averaged 2221 μg · hr/mL in fasting participants and 2111 μg · hr/mL in postprandial participants; whereas the difference was statistically significant (P = .025), the 95% confidence intervals indicated equivalent values. The peak plasma concentration was lower in the fasting state (63.1 μg/mL) than in the fed state (86.1 μg/mL) (P = .0001). There were no statistically significant differences between fasting versus postprandial values for the mean absorption time (9.7 hr vs. 7.7 hr) or plasma half‐life (17.3 hr vs. 17.6 hr). Hence, the rate and extent of absorption of CR naproxen was not substantially altered by the ingestion of food.
Comparison of Excretion of Nicotinuric Acid After Ingestion of Two Controlled Release Nicotinic Acid Preparations in Man
Authors: Figge Helen L. , Figge James , Souney Paul F. , Sacks Frank M. , Shargel Leon , Janosik John E. , Kaul Alan F.
Published: March 2013

We tested an inexpensive controlled‐release nicotinic acid product (Bronson Pharmaceuticals, LaCanada, CA) and compared it with the standard, more expensive, controlled release product, Nicobid (Rorer Pharmaceuticals), by measuring the 24 hour urinary recovery of nicotinic and nicotinuric acids from ten subjects following 500 mg oral ingestion of each product Nicotinuric acid is the major detoxification product of nicotinic acid and may serve as a simple quantitative index of hepatic biotransformation of nicotinic acid. Although both products demonstrated controlled release profiles, the rate of appearance of nicotinic and nicotinuric acid in the urine as well as the rate of in vitro drug dissolution of the Bronson product were more rapid compared with Nicobid. Moreover, the total amounts of nicotinic acid and nicotinuric acid recovered in the urine after 24 hours were greater for the Bronson product (P < .05). Since sustained presentation of nicotinic acid to the liver may correlate with clinical antihyperlipidemic effects, our results suggest that the Bronson product may prove to be a clinically useful preparation.
System Approaches in Pharmacokinetics: II. Applications
Authors: Veng‐Pedersen Peter
Published: March 2013

Pharmacokinetic system approaches mathematically describe a general property of a pharmacokinetic system without modeling in specific terms the kinetic processes responsible for the general property. Certain applications of the system approach including methods for evaluating drug delivery, drug distribution, drug secretion, and biotransfor‐mation in linear and nonlinear pharmacokinetics are presented and discussed. Linear system formulae for various mean time disposition parameters and a disposition decomposition‐recomposition system approach for predicting drug levels when the drug clearance changes are presented and discussed. System approaches offer certain advantages over traditional approaches for many practical applications.
Pharmacokinetics of Roxithromycin (RU 965)
Authors: Lassman Howard B. , Puri Surendra K. , Ho Irwin , Sabo Ron , Mezzino Maurice J.
Published: March 2013

This report contains the findings of five studies performed to evaluate the pharmacokinetics of roxithromycin (RU 965), a new macrolide antibiotic. Roxithromycin was given as 150‐ and 300‐mg film‐coated tablets. The drug is rapidly absorbed after oral administration. Peak plasma levels following 150‐ and 300‐mg doses occur within two hours. Steady state is reached within four days with doses of 150 mg twice a day or 300 mg once daily. The plasma half‐life is approximately 12 hours. About 10% of the dose is excreted in urine. Although dose dependency was observed for the various pharmacokinetic parameters, dose proportionality could be demonstrated only in terms of the percentage of the dose excreted in urine. The rate of absorption is not affected by age. The rate of elimination and renal clearance are decreased in healthy elderly subjects, however, these differences should not be clinically meaningful. The bioavailability of the drug is not affected to a clinically meaningful extent when it is given with milk. Less than 0.05% of the administered dose is excreted in the breast milk of lactating women. Roxithromycin was safe and well tolerated with no clinically meaningful changes in any of the safety variables in any of the five studies reported.