bluuebunny/crossref_metadata_2025_split huggingface dataset:
Frontal accretion and thrust wedge evolution under very oblique plate convergence: Fiordland Basin, New Zealand
Authors: Barnes P. M. , Davy B. , Sutherland R. , Delteil J. 
Published: March 2003

ABSTRACTA thrust wedge with unusual geometry has developed under very oblique (50–60°) convergence between the Pacific and Australian Plates, along the 240‐km length of the Fiordland margin, New Zealand. The narrow (25 km‐wide) wedge comprises three overlapping components, lying west of the offshore section of the Alpine Fault, and straddles a change of > 30° in the regional strike of the plate boundary. Swath bathymetry, marine seismic reflection profiles, and dated samples together reveal the stratigraphy, structure, and evolution of the wedge and the underthrusting, continental, Caswell High (Australian Plate). Lateral variations in the composition and structure of the accretionary wedge, and the depth of the décollement thrust, result partly from variations in crustal structure and basement relief of the underthrust plate, and from associated variations in the thickness of turbidites available for frontal accretion. In the southern Fiordland Basin the underthrust plate is undergoing flexural uplift and extension, and a thick turbidite section is available for accretion. Along‐strike, a structurally elevated portion of the underthrust plate is very obliquely colliding with the central part of the accretionary wedge, the turbidite section available for accretion is condensed, and structural inversion occurs in the underthrust plate.  Growth of the thrust wedge is inferred to have commenced in the Pliocene prior to 3 ± 1 Ma, but much of the wedge developed in the Quaternary. The spatial distribution of thrusting has varied through time, with most late Quaternary shortening occurring on structures within 10 km of the right‐stepping deformation front. Estimates of the magnitude and rates of deformation indicate that the wedge accommodates a significant component of the oblique convergence between the Pacific and Australian Plates. Shortening of up to 7.3 ± 1.4 km and 9.1 ± 1.8 km within the southern and central parts of the wedge, respectively, represent about 5–15% of the total 70–140 km of shortening predicted across the plate boundary since 6.4 Ma, and about 10–30% since 3 Ma. Late Quaternary shortening rates of the order of 1–5 mm yr−1, estimated across both the northern and southern parts of the wedge, represent about 10–50 and 5–21% of the total NUVEL‐1 A shortening across the plate boundary at these respective latitudes, implying that most shortening is occurring onshore. Furthermore, possible oblique‐slip thrusting within the wedge may be accommodating boundary‐parallel displacement of 0–6 mm yr−1, representing 0–17% of the total predicted within the plate boundary.
Quantifying the sequence stratigraphy and drowning mechanisms of atolls using a new 3‐D forward stratigraphic modelling program (CARBONATE 3D)
Authors: Warrlich G. M. D. , Waltham D. A. , Bosence D. W. J. 
Published: March 2003

ABSTRACTThis paper describes a new 3‐D forward numerical model (CARBONATE 3D) that simulates the stratigraphic and sedimentological development of carbonate platforms and mixed carbonate–siliciclastic shelves by simulating the following sedimentary processes: (1) Carbonate shallow, open‐marine production, dependent on water depth, restriction and sediment input; (2) Carbonate shallow, restricted‐marine production, dependent on water restriction; (3) Pelagic sediment production and deposition; (4) Coarse and fine siliciclastic input; (5) Erosion, transport and redeposition of sediment, dependent on currents, slope, depth and restriction as well as sediment grain‐size and composition; (6) Dissolution of subaerially exposed carbonate. In this paper the model is used to investigate the controlling mechanisms on the sequence stratigraphy of isolated carbonate platforms and atolls and to predict distinctive architectural signatures from different drowning mechanisms. Investigation of the mechanisms controlling atoll strata shows that although relative sea‐level is the major control, antecedent topography, environmental setting and early diagenesis have profound influence on what stratigraphic geometries and facies develop. Hence care must be taken if sea‐level curves are interpreted from real stratigraphies. Atoll drowning by fast sea‐level rise, by lowered production and by repeated exposure and fast subsequent sea‐level rises are investigated and different stratigraphic signatures for the respective mechanisms predicted. A fast relative sea‐level rise results in a bucket‐shaped morphology developed prior to drowning and a sharp transition from the platform margin facies to a pelagic cover. Drowning caused by lowered platform margin production is predicted to result in the development of a dome‐shaped, shallow‐water shoal over the whole platform top prior to drowning. Fourth order amplitudes of several tens of metres, typical of ‘icehouse’ settings, cause atoll drowning at subsidence rates where atolls subject to fourth order amplitude of only a few metres, typical of ‘greenhouse’ settings, can keep up with the rising sea‐level. In the resultant strata, vertical facies belts are less well developed but horizontally extensive facies bands are more prominent. High fourth order amplitudes (up to 80 m) without sufficient third order scale subsidence will not lead to drowning, however, as the platform can recover in each fourth order lowstand. These results suggest that atolls might be easier to drown in ‘icehouse’ rather than in ‘greenhouse’ conditions but only in situations with suitably high rates of longer‐term relative sea‐level rise or sufficient lag times.
Assembling the stratigraphic record: depositional patterns and time‐scales in an experimental alluvial basin
Authors: Sheets B. A. , Hickson T. A. , Paola C. 
Published: March 2003

ABSTRACTOur understanding of sedimentation in alluvial basins is best for very short and very long time‐scales (those of bedforms to bars and basinwide deposition, respectively). Between these end members, the intermediate time‐scales of stratigraphic assembly are especially hard to constrain with field data. We address these ‘mesoscale’ fluvial dynamics with data from an experimental alluvial system in a basin with a subsiding floor. Observations of experimental deposition over a range of time‐scales illustrate two important properties of alluvial systems. First, ephemeral flows are disproportionately important in basin filling. Lack of correlation between flow occupation and sedimentation indicates that channelized flows serve mainly as conduits for sediment, while most deposition occurs via short‐lived unchannelized flow events. Second, there is a characteristic time required for individual depositional events to average to basin‐scale stratal patterns. This time can be scaled in terms of the time required for a single channel‐depth of aggradation, and in this form is constant through a four‐fold variation of experimental subsidence rate.
The stratigraphic and structural evolution of the Dzereg Basin, western Mongolia: clastic sedimentation, transpressional faulting and basin destruction in an intraplate, intracontinental setting
Authors: Howard J. P. , Cunningham W. D. , Davies S. J. , Dijkstra A. H. , Badarch G. 
Published: March 2003

ABSTRACTThe Dzereg Basin is an actively evolving intracontinental basin in the Altai region of western Mongolia. The basin is sandwiched between two transpressional ranges, which occur at the termination zones of two regional‐scale dextral strike‐slip fault systems. The basin contains distinct Upper Mesozoic and Cenozoic stratigraphic sequences that are separated by an angular unconformity, which represents a regionally correlative peneplanation surface. Mesozoic strata are characterized by northwest and south–southeast‐derived thick clast‐supported conglomerates (Jurassic) overlain by fine‐grained lacustrine and alluvial deposits containing few fluvial channels (Cretaceous). Cenozoic deposits consist of dominantly alluvial fan and fluvial sediments shed from adjacent mountain ranges during the Oligocene–Holocene. The basin is still receiving sediment today, but is actively deforming and closing. Outwardly propagating thrust faults bound the ranges, whereas within the basin, active folding and thrusting occurs within two marginal deforming belts. Consequently, active fan deposition has shifted towards the basin centre with time, and previously deposited sediment has been uplifted, eroded and redeposited, leading to complex facies architecture. The geometry of folds and faults within the basin and the distribution of Mesozoic sediments suggest that the basin formed as a series of extensional half‐grabens in the Jurassic–Cretaceous which have been transpressionally reactivated by normal fault inversion in the Tertiary. Other clastic basins in the region may therefore also be inherited Mesozoic depocentres. The Dzereg Basin is a world class laboratory for studying competing processes of uplift, deformation, erosion, sedimentation and depocentre migration in an actively forming intracontinental transpressional basin.
Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP‐105,696 in man following single oral administration
Authors: Liston Theodore E. , Conklyn Maryrose J. , Houser Janet , Wilner Keith D. , Johnson Arlene , Apseloff Glen , Whitacre Caroline , Showell Henry J. 
Published: March 2003

Aims
CP‐105,696, (+)‐1‐(3S,4R)‐[3‐(4‐phenylbenzyl)‐4‐hydroxy‐chroman‐7‐yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP‐105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg.
Methods
Forty‐eight subjects participated in a randomized, double‐blind, parallel group study. Plasma and urine concentrations of CP‐105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP‐105,696, the inhibiton of LTB4‐induced upregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration using an ex vivo whole blood flow cytometry assay.
Results

C
max and AUC(0,∞) increased in a dose‐related manner. Respective mean Cmax values were 0.54 to 30.41 μg ml−1 following doses of 5 to 640 mg. Respective mean AUC(0,∞) values were 1337 to 16819 μg ml−1 h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half‐lives ranging from 289 to 495 h. Group mean terminal elimination half‐lives were dose‐independent. Urinary excretion of unchanged drug accounted for <1% of the administered dose. A linear relationship was observed between CP‐105,696 plasma concentrations and inhibition of LTB4‐mediated CD11b upregulation on human neutrophils in whole blood. CP‐105,696 plasma concentrations of 5–6 μg ml−1 were necessary to elicit a two‐fold shift to the right of the LTB4 concentration response curve for CD11b upregulation.
Conclusions
These studies demonstrate pharmacologically significant LTB4‐receptor antagonism following a single dose of CP‐105,696 and pharmacokinetics consistent with once‐daily dosing.
Effect of protease inhibitors on nucleoside analogue phosphorylation in vitro
Authors: Hoggard P. G. , Manion V. , Barry M. G. , Back D. J. 
Published: March 2003

Aims
Combination antiretroviral therapy for human immunodeficiency virus (HIV) infection now involves both nucleoside analogues and protease inhibitors. Since intracellular phosphorylation is essential for the activity of all the nucleoside analogues this study was designed to investigate interactions with protease inhibitors at the intracellular level which may alter antiviral efficacy.
Methods
PHA‐stimulated PBMCs (3×106 cell/plate) and U937 cells (4×106 cells/plate) were incubated with either radiolabelled zidovudine (ZDV), stavudine (d4T), zalcitabine (ddC), lamivudine (3TC) or didanosine (ddI) in the presence and absence of the protease inhibitors, indinavir, ritonavir, and saquinavir (0.1−10 μm ) for 24 h. Cells were extracted overnight prior to analysis by radiometric h.p.l.c. Intracellular phosphates were standardised to pmol per million cells.
Results
None of the three protease inhibitors tested had any significant effect on the intracellular phosphorylation of the five nucleoside analogues. It is particularly important to focus on the active triphosphate anabolites and data for control vs ritonavir (10 μm ) incubations in U937 cells were as follows: ZDVTP, 0.19±0.02 vs 0.21±0.02 pmol/106 cells (mean±s.d.; n=5); d4TTP, 0.30±0.13 vs 0.27±0.26; 3TCTP, 0.32±0.12 vs 0.26±0.19; ddCTP, 0.07±0.04 vs 0.06±0.02; ddATP, 0.014±0.003 vs 0.018±0.006 pmol/106 cells.
Conclusions
The protease inhibitors, indinavir, ritonavir and saquinavir have no effect on the enzymes responsible for phosphorylation. Combining protease inhibitors and nucleoside analogues should not lead to any intracellular interactions in vivo.
Differential selectivity of cytochrome P450 inhibitors against probe substrates in human and rat liver microsomes
Authors: Eagling Victoria A. , Tjia John F. , Back David J. 
Published: March 2003

Aims
Chemical inhibitors of cytochrome P450 (CYP) are a useful tool in defining the role of individual CYPs involved in drug metabolism. The aim of the present study was to evaluate the selectivity and rank the order of potency of a range of isoform‐selective CYP inhibitors and to compare directly the effects of these inhibitors in human and rat hepatic microsomes.
Methods
Four chemical inhibitors of human cytochrome P450 isoforms, furafylline (CYP1A2), sulphaphenazole (CYP2C9), diethyldithiocarbamate (CYP2E1), and ketoconazole (CYP3A4) were screened for their inhibitory specificity towards CYP‐mediated reactions in both human and rat liver microsomal preparations. Phenacetin O‐deethylation, tolbutamide 4‐hydroxylation, chlorzoxazone 6‐hydroxylation and testosterone 6β‐hydroxylation were monitored for enzyme activity.
Results
Furafylline was a potent, selective inhibitor of phenacetin O‐deethylation (CYP1A2‐mediated) in human liver microsomes (IC50=0.48 μm ), but inhibited both phenacetin O‐deethylation and tolbutamide 4‐hydroxylation (CYP2C9‐mediated) at equimolar concentrations in rat liver microsomes (IC50=20.8 and 24.0 μm respectively). Sulphaphenazole demonstrated selective inhibition of tolbutamide hydroxylation in human liver microsomes but failed to inhibit this reaction in rat liver microsomes. DDC demonstrated a low level of selectivity as an inhibitory probe for chlorzoxazone 6‐hydroxylation (CYP2E1‐mediated). DDC also inhibited testosterone 6β‐hydroxylation (CYP3A‐mediated) in man and rat, and tolbutamide 4‐hydroxylase activity in rat. Ketoconazole was a very potent, selective inhibitor of CYP3A4 activity in human liver (IC50=0.04 μm ). Although inhibiting CYP3A in rat liver it also inhibited all other reactions at concentrations ≤5 μm.
Conclusions
It is evident that CYP inhibitors do not exhibit the same selectivity in human and rat liver microsomes. This is due to differential selectivity of the inhibitors and/or differences in the CYP isoform responsible for metabolism in the different species.
Terfenadine–antidepressant interactions: an in vitro inhibition study using human liver microsomes
Authors: Jurima‐Romet Malle , Wright Marcy , Neigh Scott 
Published: March 2003

Aims
Inhibition of the metabolism of terfenadine has been associated with torsades de pointes ventricular arrhythmias. The aim of this study was to assess in vitro the potency of the antidepressants nefazodone, sertraline and fluoxetine in inhibiting terfenadine biotransformation.
Methods
Human liver microsomes were incubated with terfenadine and the antidepressants at various concentrations. Formation of the two major metabolites of terfenadine was determined by h.p.l.c.
Results
The apparent Km for microsomes from four human livers was 11±5 and 18±3 μm (mean±s.e.mean) for the N‐dealkylation and C‐hydroxylation pathways, respectively. Nefazodone, sertraline and fluoxetine inhibited terfenadine N‐dealkylation with Ki values of 10±4, 10±3 and 68±15 μm respectively. Inhibition of the C‐hydroxylation pathway yielded noncompetitive Ki values of 41±4, 67±13 and 310±40 μm respectively.
Conclusions
Nefazodone and sertraline were moderately weak in vitro inhibitors of terfenadine metabolism while fluoxetine was a very weak inhibitor. Clinically significant interaction of terfenadine is more likely with nefazodone than sertraline or fluoxetine since therapeutic plasma levels of nefazodone are comparatively higher.
Trying to improve compliance with prophylactic penicillin therapy in children with sickle cell disease
Authors: Berkovitch Matitiahu , Papadouris Dimitrios , Shaw Dianne , Onuaha Nzenalu , Dias Carla , Olivieri Nancy F. 
Published: March 2003

Aims
To evaluate compliance with prophylactic penicillin therapy in sickle cell disease (SCD) in children.
Methods
Forty‐five children aged 37±19 (9–84) months [mean±s.d; range] with homozygous SCD were recruited. After a baseline period of 2 months the patients were randomized to either the intervention or non‐intervention group. The intervention consisted of a slide show explaining the pathogenesis of sickle cell disease and its complications; weekly phone calls by the clinic social worker; and a calendar. Compliance was again evaluated after the 2 month intervention period and after a further 2 month monitoring period without intervention. Compliance was monitored using the Medication Event Monitoring System. At the end of the 6 months, parents in both groups completed a questionnaire the aims of which were to determine knowledge and understanding of sickle cell disease and previous experience with infection. Patient admissions to the hospital during the study were recorded.
Results
Compliance during the 2 month baseline assessment was 66.0±32.5 (1.3–98.2)% and 69.3±25.4 (19.8–96.5)% in the intervention (n=13) and non‐intervention (n=10) groups respectively (P=0.79). During the next 2 months, compliance in the intervention group (n=11) was 79.0±31.4 (11.0–100.0)% and in the non‐intervention group (n=9) was 66.0±20.2 (42.2–96.8)% (P=0.297). In the final 2 month monitoring period compliance was 82.0±34.7 (3.8–100.0)% and 65.8±25.3 (25.0–98.2)% in the intervention (n=7) and the non‐intervention (n=6) groups respectively (P=0.366). No statistically significant differences were found when comparing compliance between the groups.
Conclusions
Compliance with prophylactic antibiotic therapy in children with sickle cell disease is highly variable and its evaluation is problematic.
Effect of ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers
Authors: Ouellet* Daniele , Hsu Ann , Qian Jiang , Locke Charles S. , Eason Carolyn J. , Cavanaugh John H. , Leonard John M. , Granneman G. Richard 
Published: March 2003

Aims To assess the effects of the protease inhibitor ritonavir on the pharmacokinetics of ethinyl oestradiol in healthy female volunteers.Methods This was an open‐label, single centre study in 23 subjects who received two single doses of oral contraceptive containing 50 μg ethinyl oestradiol on Day 1 (alone) and on Day 29 during concomitant ritonavir. Each subject received 16 days of every 12 h doses of ritonavir from Day 15 through Day 30. Blood samples were collected for serum ethinyl oestradiol concentrations for 48 h after each dose and for plasma ritonavir on Day 29 at 0 and 4 h postdose.Results Statistically significant decreases in ethinyl oestradiol meanCmax(−32%) and mean AUC (−41%), and a statistically significant increase in the mean terminal elimination rate constant (+31%) were observed during concomitant ritonavir. The harmonic mean terminal half‐life decreased from 17 h to 13 h during concomitant ritonavir. No statistically significant change was noted intmax. The ratios of means (95% confidence intervals) forCmaxand AUC were 0.682 (0.612–0.758) and 0.595 (0.506–0.694), respectively. The changes in ethinyl oestradiol pharmacokinetics were consistent with an increase in clearance from enzymatic induction of glucuronidation and/or cytochrome P450 hydroxylation. Mean steady‐state ritonavir concentrations of 6.5 and 13.4 μg ml−1were observed at 0 and 4 h postdose, respectively.Conclusions Considering the extent of the decrease in ethinyl oestradiol concentrations, the use of alternate contraceptive measures should be considered when ritonavir is being administered.
Bias in reporting clinical trials
Authors: Bardy A. H. 
Published: March 2003

Aims
The primary aim of the present study was to identify possible occurrence of selective reporting of the results of clinical trials to the Finnish National Agency for Medicines. Selective reporting may lead to poorly informed action or inaction by regulatory authorities.
Methods
In 1987, 274 clinical drug trials were notified to the Finnish National Agency for Medicines. By December 1993, final reports had been received from 68 of these trials and statements that the trial had been suspended from 24 trials. The sponsors of the non‐reported trials were requested to report the outcome. The outcomes, if any, of all reported and non‐reported trials were classified as positive, inconclusive or negative.
Results
The total number of trials with positive, inconclusive or negative outcome were 111, 33 and 44, respectively; the outcomes of 86 trials could not be assessed. Final reports were received from 42/111 (38%) trials with positive, 6/33 (18%) with inconclusive and 9/44 (20%) with negative outcomes.
Conclusions
Substantial evidence of selective reporting was detected, since trials with positive outcome resulted more often in submission of final report to regulatory authority than those with inconclusive or negative outcomes.
Induction of zidovudine glucuronidation and amination pathways by rifampicin in HIV‐infected patients
Authors: Gallicano Keith D. , Sahai Jan , Shukla Vijay K. , Seguin Isabelle , Pakuts Attila , Kwok David , Foster Brian C. , Cameron D. William 
Published: March 2003

Aims
The objective of the study was to determine the effect of multiple doses of rifampicin on the steady‐state pharmacokinetics of zidovudine and its 5′‐glucuronosyl (GZDV) and 3′‐amino (AMT) metabolites.
Methods
Eight asymptomatic HIV‐infected patients (seven male, one female) participated in this three‐period longitudinal study. Each patient received zidovudine (200 mg every 8 h) for 14 days (period 1), followed by rifampicin (600 mg every 24 h) with zidovudine for 14 days (period 2), and then zidovudine alone for a further 14 days (period 3). Blood and urine samples were collected over 6 h on the last day of each period for measurements of zidovudine and GZDV by h.p.l.c.‐u.v. and AMT by h.p.l.c.‐m.s‐m.s.
Results
Compared with zidovudine‐alone values in period 1, 14 days of coadministration with rifampicin significantly increased zidovudine oral clearance (89%) and formation clearances to GZDV (100%) and AMT (82%). Correspondingly, there were decreases in maximum plasma concentration (43%), AUC (47%) and urine recovery (37%) of zidovudine. GZDV/zidovudine and AMT/zidovudine AUC ratios increased by 99% and 36%, respectively, despite a significant 29% decrease in AMT AUC. After stopping rifampicin for 14 days, values of these pharmacokinetic parameters returned to within 26% of baseline. Over the three periods AMT plasma levels were <18 ng ml−1 (n=6) and <40 ng ml−1 (n=2), and molar AMT/zidovudine AUC ratios ranged from 1.7% to 4.5%.
Conclusions
Rifampicin induced zidovudine glucuronidation and amination pathways resulting in decreased plasma and urine exposures to zidovudine. AMT plasma exposure decreased because induction was more pronounced for the major GZDV metabolite. The magnitude of the residual inductive effect was minimal at 14 days after stopping rifampicin.