bluuebunny/crossref_metadata_2025_split huggingface dataset:
Influence of ketoconazole on azimilide pharmacokinetics in healthy subjects
Authors: El Mouelhi Mohamed , Worley Dan J. , Kuzmak Barbara , Destefano Anthony J. , Thompson Gary A. 
Published: November 2004

Aim  To assess the influence of ketoconazole on azimilide pharmacokinetics.Methods  A two‐period randomized crossover study was conducted in healthy male and female subjects (19–45 years). Placebo or 200 mg ketoconazole were administered orally every 24 h for 29 days. On day 8, a single oral dose of 125 mg azimilide dihydrochloride was coadministered following an overnight fast. Blood samples were obtained prior to and for 22 days following azimilide dihydrochloride administration. The plasma protein binding of azimilide was also assessed at 6 h after dosing.Results  Following ketoconazole administration, a 16% increase in azimilide AUC (90% confidence interval (CI) 112%, 120%), a 12% increase in Cmax (95% CI 107%, 116%), a 13% increase in t1/2,z (95% CI 107%, 120%) and a 14% decrease in CLo (95% CI 82%, 90%) were observed.Conclusions  The changes in azimilide pharmacokinetics following ketoconazole treatment are not clinically important since the 90% CI for the AUC fell within the prespecified range of 80–125%. Thus, no clinically important drug interactions are expected when azimilide dihydrochloride is coadministered with CYP3A4 inhibitors.
A semimechanistic and mechanistic population PK–PD model for biomarker response to ibandronate, a new bisphosphonate for the treatment of osteoporosis
Authors: Pillai Goonaseelan , Gieschke Ronald , Goggin Timothy , Jacqmin Philippe , Schimmer Ralph C. , Steimer Jean‐Louis 
Published: November 2004

AimsIbandronate, a highly potent nitrogen‐containing bisphosphonate, is the subject of an ongoing clinical development programme that aims to maximize the potential of simplified, less frequent oral and intravenous (i.v.) administration in osteoporosis. A modelling and simulation project was undertaken to characterize further the clinical pharmacology of ibandronate and identify convenient intermittent oral and i.v. regimens for clinical evaluation.Methods and resultsUsing selected data from clinical studies involving 174 women with postmenopausal osteoporosis (PMO), a classical multicompartmental pharmacokinetic‐pharmacodynamic (PK‐PD) model was developed that accurately described the PK of i.v. ibandronate in plasma and urine and urinary excretion of the C‐telopeptide of the α chain of type I collagen (uCTX), a sensitive biomarker of PD response to ibandronate. To reduce processing times, the classical PK‐PD model was simplified using a ’kinetics of drug action’ or kinetic (K)‐PD model (i.e. a dose‐response model as opposed to a dose‐concentration‐response model). The performance of the K‐PD model was evaluated by fitting data simulated with the PK‐PD model under various dosing regimens. The simplified model produced a virtually indistinguishable fit of the data from that of the PK‐PD model. The K‐PD model was extended to consider the influence of supplemental therapy (calcium with or without vitamin D) on the PD response and validated by retrospectively simulating the uCTX response in a prior Phase III and Phase II/III study of i.v. ibandronate, given once every 3 months, in 3380 women with PMO. The observed median uCTX responses at the scheduled assessment points in the completed studies were within the distribution of the simulated responses. The K‐PD model for i.v. ibandronate was extended further to allow simultaneous fitting of uCTX responses after i.v. and oral administration in 676 postmenopausal women with osteoporosis, and validated by retrospectively simulating the data observed in a Phase I study of oral daily ibandronate in 180 women with PMO. The K‐PD model adequately described the uCTX response after oral dosing.ConclusionsThis validated K‐PD model is currently being used to evaluate a range of novel intermittent oral and i.v. ibandronate regimens in an ongoing clinical development programme.
Soil organic carbon stocks in Flemish grasslands: how accurate are they?
Authors: Mestdagh I. , Lootens P. , Van Cleemput O. , Carlier L. 
Published: November 2004

AbstractArticles 3·3 and 3·4 of the Kyoto protocol provide Annex I countries the possibility to reduce greenhouse gas emissions through the sequestration of carbon (C) in their terrestrial ecosystems. For such accounting, the 1990 flux is needed and, therefore, a correct knowledge of the baseline (1990) C stocks is necessary. In addition, a correct methodology should be used to investigate the capacity of ecosystems to sequester C through changes in land use or management by the end of the first commitment period (2008–2012). At national and regional scales, formulation of baseline C stocks in terrestrial ecosystems is difficult and uncertain. Differences in method of analysis, sampling depth of soil, lack of sufficient C data and the necessity to extrapolate C data to total soil organic C stocks, provide problems when comparing databases with each other. In this study, three extrapolation models were compared with the classical layer‐based method to determine the model with the best fit. The model with the best predictions, in relation to the classical layer‐based model, uses recent soil C profiles for estimating the parameter k, which represents the decrease in the proportion of soil organic C with depth, and for extrapolating the C data available for 1990 and 2000 to a depth of 1 m. The other two models gave large underestimates.
Relationships between morphological and chemical characteristics of perennial ryegrass varieties and intake by sheep under continuous stocking management
Authors: Orr R. J. , Cook J. E. , Champion R. A. , Rook A. J. 
Published: November 2004

AbstractPlots of five intermediate‐heading varieties of perennial ryegrass (Lolium perenne L.) [AberDove, Belramo and Glen (diploid); Twins (tetraploid); and AberExcel (tetraploid hybrid)] were continuously stocked with sheep to maintain a target sward surface height of 40–50 mm. Daily dry matter (DM) intake was significantly different (F‐value = 0·032) between the varieties, with the tetraploid hybrid AberExcel having the highest values for daily DM intake and intake rate during eating. Amongst the diploid varieties, intake rate tended to be higher for sheep grazing Glen. The varieties comprised a wide range in potential growth habit, from the relatively prostrate, highly tillered Glen to the more‐erect AberExcel and there were differences between them in the vertical distribution of leaves within the sward canopy. The leaves of AberExcel weighed 3·6 mg DM cm−2 leaf area in contrast to the other varieties (4·3–5·3 mg DM cm−2 leaf area) resulting in a high leaf area index (LAI) in relation to the green leaf mass. Intake rate was not significantly correlated with extended tiller and sheath tube lengths, partition of herbage mass, number of tillers per square metre or LAI. However, canonical variates analysis showed that there were significant differences between the varieties for the morphological and chemical factors examined. Other factors also need to be explored to explain these differences in ingestive behaviour in order to identify plant traits that are correlated with herbage intake rate. These are needed for varieties destined for grazing use, both during the breeding programme and their subsequent evaluation.
Genetic diversity studies in farm animals – a survey
Authors: Baumung R. , Simianer H. , Hoffmann I. 
Published: November 2004

SummaryDuring the past decade a large number of genetic diversity studies in domestic livestock based on microsatellite loci was carried out all over the world. A survey among research groups reveals that in 50% of 87 projects more than eight breeds are investigated. Breeds are chosen mainly because of their long history of isolation, unique phenotypic qualities or an evolution within a unique environment. In half of the projects the average planned sample size per breed is higher than 50. Small ruminants are investigated in the majority of projects. The most preferred type of sample is blood and the most preferred markers are microsatellite loci. To combine results from different diversity studies, the adherence to recommendations, e.g. which loci to genotype or required sample sizes per breed, is necessary. The so called International Society for Animal Genetics (ISAG)/FAO recommendations, which were developed for that purpose, are well known, but the use of recommended microsatellite loci varies between species. The highest acceptance was found in pig, and the lowest in chicken.
Effects of a structured health education programme by a diabetic education nurse on cardiovascular risk factors in Chinese Type 2 diabetic patients: a 1‐year prospective randomized study
Authors: Ko G. T. C. , Li J. K. Y. , Kan E. C. Y. , Lo M. K. W. 
Published: November 2004

AbstractAims  To assess the effect of regular diabetic health education on cardiovascular risk factors in Chinese Type 2 diabetic patients.Methods  This was a 1‐year prospective randomized study. One hundred and eighty Type 2 diabetic subjects were recruited from three regional diabetic centres in Hong Kong. Ninety received additional structured reinforcement of diabetic health education by a trained nurse after the doctors’ consultations every 3 months (intervention group). The others received the same medical care except no nursing reinforcement (control group). Outcome measures included fasting plasma glucose, HbA1c, body mass index, waist circumference, blood pressure and lipid profiles, which were assessed before the study and after 1 year.Results  Two of the controls defaulted follow‐up. The intervention group and controls had similar age and sex distribution. At the end of study, the intervention group had reducted their waist circumference, diastolic blood pressure, HbA1c, total cholesterol and low‐density lipoprotein cholesterol levels. The controls had reduced their total cholesterol and low‐density lipoprotein cholesterol levels. Other cardiovascular risk factors were not significantly changed in the controls. Addition of drugs and/or dosage increment of anti‐diabetic drugs, lipid‐lowering agents and anti‐hypertensive agents were similar between the two groups.Conclusions  Regular structured reinforcement with diabetic health education is useful. It helps to control more successfully some of the cardiovascular risk factors in Chinese Type 2 diabetic patients.
Exploring the idiotypes of insulin antibodies as markers for remission in Type 1 diabetes
Authors: Devendra D. , Galloway T. S. , Horton S. J. , Wilkin T. J. 
Published: November 2004

AbstractAims  Complete or partial remission can occur in newly diagnosed Type 1 diabetes patients. We created idiotype‐specific reagents to explore the idiotypes of insulin antibodies (IA) in a patient in remission, and to compare with a patient who was not.Methods  Phage display was used to create a library of phagotopes specific to insulin binding in four sera. Sera from a Type 1 diabetes subject deemed to have undergone remission were taken at diagnosis and again during remission. Sera from a non‐remitter were taken at diagnosis and after 3 months on insulin. Phagotopes from the four sera were randomly selected and tested for insulin specificity in a radiobinding assay by using sera from remitters and non‐remitters.Results  IA‐binding phagotope selected from serum during remission displaced insulin binding in all nine IA+ remitters and all 10 IA+ non‐remitters. IA‐binding phagotope selected from the non‐remission patient (3 months after insulin therapy) displaced insulin binding in 8/9 IA+ remitters and 8/10 IA+ non‐remitters. The consensus peptide sequences adduced from the phages were identical for both these phagotopes. Phagotopes derived from insulin autoantibody‐positive individuals at diagnosis were unable to displace insulin binding in the IA+ sera 3 months later, whether in remission or not.Conclusions  We have established the principle of using phage display in the investigation of insulin antibodies during remission in Type 1 diabetes. The immunological characteristics of IA 3 months after the introduction of insulin treatment were different from those at diagnosis of Type 1 diabetes (IAA). Using phage display technology, it was not possible to distinguish insulin antibodies according to remission status.
Emotional specificity of startle potentiation during the early stages of picture viewing
Authors: Stanley James , Knight Robert G. 
Published: November 2004

AbstractPotentiation of the startle blink reflex shortly after picture onset has only been reported in a sample of high animal‐fear participants during fear‐evoking stimuli. The experiment tested the emotional specificity of startle reflex modification at early (300 ms) and late (2–5 s) stages of picture viewing in an unselected sample (n=55). Participants viewed two negative picture categories, threat and disgust contents, in addition to neutral and positive pictures. Blink potentiation occurred for threat contents at both probe times, relative to neutral responses. Disgust contents only potentiated blinks relative to positive content responses. These results are inconsistent with a basic, prepulse interpretation of early startle modification and suggest that affective modification can be observed shortly after picture onset, depending on the specific emotional content of the picture.
Cardiovascular reactivity and adaptation to recurrent psychological stress: Replication and extension
Authors: Kelsey Robert M. , Soderlund Kathleen , Arthur Carlotta M. 
Published: November 2004

AbstractWe analyzed the effects of evaluative observation and baseline duration on cardiovascular reactivity and adaptation to recurrent psychological stress. Cardiovascular reactivity to mental arithmetic stress was assessed in college men and women (N=224) during two pretest tasks, a test task, and a posttest task. Participants were assigned randomly in a 2 × 2 design to manipulations of baseline duration before the test task (4 min vs. 12 min) and evaluative observation during the test task (observed vs. control). Repeated exposure to stress attenuated cardiac but not vascular reactivity. Evaluative observation disrupted cardiac adaptation, resulting in a resurgence of β‐adrenergic cardiac reactivity during the test task. Cardiac adaptation resumed fully during the posttest task. Baseline duration had no effect on reactivity. The results replicate and extend previous work, and support the dual process theory of habituation and sensitization.
Clinical findings and diagnostic value of post‐traumatic thoracic radiographs in dogs and cats with blunt trauma
Authors: Sigrist Nadja E. , Doherr Marcus G. , Spreng David E. 
Published: November 2004

AbstractObjective: To characterize the clinical findings in dogs and cats that sustained blunt trauma and to compare clinical respiratory examination results with post‐traumatic thoracic radiography findings.Design: Retrospective clinical study.Setting: University small animal teaching hospital.Animals, interventions and measurements: Case records of 63 dogs and 96 cats presenting with a history of blunt trauma and thoracic radiographs between September 2001 and May 2003 were examined. Clinical signs of respiratory distress (respiratory rate (RR), pulmonary auscultation) and outcome were compared with radiographic signs of blunt trauma.Results: Forty‐nine percent of dogs and 63.5% of cats had radiographic signs attributed to thoracic trauma. Twenty‐two percent of dogs and 28% of cats had normal radiographs. Abnormal auscultation results were significantly associated with radiographic signs of thoracic trauma, radiography score and presence and degree of contusions. Seventy‐two percent of animals with no other injuries showed signs of thoracic trauma on chest radiographs. No correlation was found between the radiographic findings and outcome, whereas the trauma score at presentation was significantly associated with outcome and with signs of chest trauma but not with the radiography score.Conclusion: Thoracic trauma is encountered in many blunt trauma patients. The RR of animals with blunt trauma is not useful in predicting thoracic injury, whereas abnormal chest auscultation results are indicative of chest abnormalities. Thorough chest auscultation is, therefore, mandatory in all trauma animals and might help in the assessment of necessity of chest radiographs.
Effect of sample handling on venous PCO2, pH, bicarbonate, and base excess measured with a point‐of‐care analyzer
Authors: Richey Meghan T. , McGrath Charles J. , Portillo Erin , Scott Mary , Claypool Larry 
Published: November 2004

AbstractObjective:The purpose of this study was to determine the effect of timing of analysis, collection tube type and repeated opening of sample tubes on venous PCO2, pH, HCO3, and base excess (BE) results.Design:Prospective experimental study, paired sample analysis.Setting:Veterinary Medical Teaching Hospital.Animals:Twenty dogs.Interventions:Jugular venous blood samples.Measurements and main results:PCO2, pH, HCO3, and BE were determined immediately following collection (control) and at selected times up to 30 minutes after placement in either screw top or vacuum heparin collection tubes. A different set of screw top and vacuum heparin collection tubes were sampled repeatedly over time for up to 15 minutes.In the screw top delayed analysis group, only pH changed significantly at one time point. PCO2decreased significantly in all other groups and resulted in a significant reciprocal pH change in the vacuum tubes with either delayed single analysis or repeated sampling. HCO3and BE declined significantly in multi‐sampled vacuum tubes and HCO3also decreased significantly in multi‐sampled screw top tubes.Conclusions:Analysis of acid–base status is optimally performed on freshly drawn blood. However, when it is anticipated there will be a delay in analysis of samples kept at room temperature, the use of 2.0 mL plastic screw top heparin anticoagulant tubes may result in fewer pre‐analytical errors than 3.5 mL glass vacuum tubes.
CaNdt80 Is Involved in Drug Resistance in
Candida albicans
by Regulating
CDR1
Authors: Chen Chia-Geun , Yang Yun-Liang , Shih Hsin-I , Su Chia-Li , Lo Hsiu-Jung 
Published: November 2004

ABSTRACT

Overexpression of
CDR1
, an efflux pump, is one of the major mechanisms contributing to drug resistance in
Candida albicans. CDR1 p-lacZ
was constructed and transformed into a
Saccharomyces cerevisiae
strain so that the
lacZ
gene could be used as the reporter to monitor the activity of the
CDR1
promoter. Overexpression of
CaNDT80
, the
C. albicans
homolog of
S. cerevisiae NDT80
, increases the β-galactosidase activity of the
CDR1 p-lacZ
construct in
S. cerevisiae
. Furthermore, mutations in
CaNDT80
abolish the induction of
CDR1
expression by antifungal agents in
C. albicans
. Consistently, the
Candt80
/
Candt80
mutant is also more susceptible to antifungal drugs than the wild-type strain. Thus, the gene for CaNdt80 may be the first gene among the regulatory factors involved in drug resistance in
C. albicans
whose function has been identified.
Intranasal Interleukin-12 Treatment Promotes Antimicrobial Clearance and Survival in PulmonaryFrancisella tularensissubsp.novicidaInfection
Authors: Pammit Michael A. , Budhavarapu Varija N. , Raulie Erin K. , Klose Karl E. , Teale Judy M. , Arulanandam Bernard P. 
Published: November 2004

ABSTRACTFrancisella tularensisis a highly virulent facultative intracellular bacterium and is considered a potential biological warfare agent. Inhalation tularemia can lead to the development of bronchopneumonia, which is frequently fatal without medical intervention. Treatment strategies that directly target the respiratory mucosa may extend the efficacy of therapy, particularly for the medical management of acute aerosol exposure. To this end, we describe an intranasal (i.n.) strategy for the treatment of pulmonaryFrancisellainfection in mice that uses a combinatorial approach with the conventional antibiotic gentamicin and interleukin 12 (IL-12). The i.n. administration of IL-12 alone promoted bacterial clearance and extended the time to death but did not prevent mortality against lethal pulmonary challenge withFrancisella tularensissubsp.novicida.However, i.n. treatment with gentamicin and IL-12 therapeutically at 8 and 24 h after challenge markedly enhanced the rate of survival (70 to 100%) against pulmonary infection compared to the rates of survival for animals treated with antibiotic alone (17%) or IL-12 alone (0%). A delay in combinatorial therapy over a span of 4 days progressively decreased the efficacy of this treatment regimen. This combinatorial treatment was shown to be highly dependent upon the induction of endogenous gamma interferon and may also involve the activation of natural killer cells. Together, these findings suggest that IL-12 may be a potent adjunct for chemotherapy to enhance drug effectiveness against pulmonaryFrancisellainfection.
Potent and Long-Acting Dimeric Inhibitors of Influenza Virus Neuraminidase Are Effective at a Once-Weekly Dosing Regimen
Authors: Macdonald Simon J. F. , Watson Keith G. , Cameron Rachel , Chalmers David K. , Demaine Derek A. , Fenton Rob J. , Gower David , Hamblin J. Nicole , Hamilton Stephanie , Hart Graham J. , Inglis Graham G. A. , Jin Betty , Jones Haydn T. , McConnell Darryl B. , Mason Andy M. , Nguyen Van , Owens Ian J. , Parry Nigel , Reece Phillip A. , Shanahan Stephen E. , Smith Donna , Wu Wen-Yang , Tucker Simon P. 
Published: November 2004

ABSTRACT
Dimeric derivatives (compounds 7 to 9) of the influenza virus neuraminidase inhibitor zanamivir (compound 2), which have linking groups of 14 to 18 atoms in length, are approximately 100-fold more potent inhibitors of influenza virus replication in vitro and in vivo than zanamivir. The observed optimum linker length of 18 to 22 Å, together with observations that the dimers cause aggregation of isolated neuraminidase tetramers and whole virus, indicate that the dimers benefit from multivalent binding via intertetramer and intervirion linkages. The outstanding long-lasting protective activities shown by compounds 8 and 9 in mouse influenza infectivity experiments and the extremely long residence times observed in the lungs of rats suggest that a single low dose of a dimer would provide effective treatment and prophylaxis for influenza virus infections.
Rapid, Simple In Vivo Screen for New Drugs Active against
Mycobacterium tuberculosis
Authors: Nikonenko Boris V. , Samala Rowena , Einck Leo , Nacy Carol A. 
Published: November 2004

ABSTRACT

We evaluated the use of a simple and easy-to-obtain potential marker of tuberculosis (TB) drug efficacy, body weight, and correlated weight loss or gain with the number of CFU of
Mycobacterium tuberculosis
in lungs and spleens of infected mice. C3H mice were infected intravenously with 10
6
CFU of virulent
M. tuberculosis
H37Rv, and body weight was evaluated for several weeks after infection. At day 20, infected untreated mice consistently lost more than 25% of their body weight. Chemotherapy with selected orally active anti-TB drugs was initiated 7 days following infection and continued for 13 days. Drugs that were administered daily by gavage included isoniazid (INH), ethambutol (EMB), rifampin (RIF), and moxifloxacin (MXF). At the most effective doses, each of these drugs inhibited bacterial growth and abolished infection-induced body weight loss. Chemotherapy with 1/10 the standard dose of INH determined in accepted long-term murine models of TB also prevented body weight loss, while chemotherapy with 1/10 the standard dose of RIF did not. With only 2 weeks of chemotherapy, we observed a good reverse correlation between CFU in lung or spleen and body weight of mice. The simple measurement of weight in TB-infected drug-treated mice required only a weight balance, and go/no-go drug efficacy data was available on day 20 without the necessity of prolonged drug treatment and long (3 weeks or more) in vitro culture times to obtain organ CFU values.