bluuebunny/crossref_metadata_2025_split huggingface dataset:
A flexural model for the Paradox Basin: implications for the tectonics of the Ancestral Rocky Mountains
Authors: Barbeau D. L. 
Published: March 2003

ABSTRACTThe Paradox Basin is a large (190 km × 265 km) asymmetric basin that developed along the southwestern flank of the basement‐involved Uncompahgre uplift in Utah and Colorado, USA during the Pennsylvanian–Permian Ancestral Rocky Mountain (ARM) orogenic event. Previously interpreted as a pull‐apart basin, the Paradox Basin more closely resembles intraforeland flexural basins such as those that developed between the basement‐cored uplifts of the Late Cretaceous–Eocene Laramide orogeny in the western interior USA. The shape, subsidence history, facies architecture, and structural relationships of the Uncompahgre–Paradox system are exemplary of typical ‘immobile’ foreland basin systems.Along the southwest‐vergent Uncompahgre thrust, ∼5 km of coarse‐grained syntectonic Desmoinesian–Wolfcampian (mid‐Pennsylvanian to early Permian; ∼310–260 Ma) sediments were shed from the Uncompahgre uplift by alluvial fans and reworked by aeolian‐modified fluvial megafan deposystems in the proximal Paradox Basin. The coeval rise of an uplift‐parallel barrier ∼200 km southwest of the Uncompahgre front restricted reflux from the open ocean south and west of the basin, and promoted deposition of thick evaporite‐shale and biohermal carbonate facies in the medial and distal submarine parts of the basin, respectively. Nearshore carbonate shoal and terrestrial siliciclastic deposystems overtopped the basin during the late stages of subsidence during the Missourian through Wolfcampian (∼300–260 Ma) as sediment flux outpaced the rate of generation of accommodation space. Reconstruction of an end‐Permian two‐dimensional basin profile from seismic, borehole, and outcrop data depicts the relationship of these deposystems to the differential accommodation space generated by Pennsylvanian–Permian subsidence, highlighting the similarities between the Paradox basin‐fill and that of other ancient and modern foreland basins. Flexural modeling of the restored basin profile indicates that the Paradox Basin can be described by flexural loading of a fully broken continental crust by a model Uncompahgre uplift and accompanying synorogenic sediments. Other thrust‐bounded basins of the ARM have similar basin profiles and facies architectures to those of the Paradox Basin, suggesting that many ARM basins may share a flexural geodynamic mechanism. Therefore, plate tectonic models that attempt to explain the development of ARM uplifts need to incorporate a mechanism for the widespread generation of flexural basins.
Clinical aspects of indocyanine green pharmacokinetics following portal vein administration
Authors: Nishi Shinichi , Shindo Mitsuo , Abe Junko , Asada Akira 
Published: March 2003

Aims
This study was performed to demonstrate that measurement of the clearance of indocyanine green (ICG) following portal vein administration (CLpv) is more useful than that following peripheral vein administration (CLiv) for evaluating intrinsic clearance and hepatic blood flow.
Methods
Eight patients, aged 55.9±8.8 years, who underwent partial hepatectomy were studied. ICG was administrated to all patients via peripheral and portal veins before and after enflurane anaesthesia and soon after surgery. ICG concentrations were measured by h.p.l.c. Non‐compartmental analysis was applied to the ICG time‐concentration data obtained. The area under the curve (AUC), clearance (CL), mean residence time (MRT) and volume of distribution (V  ) were calculated using this method of analysis.
Results
CLpv was significantly decreased from 26.4±13.2 ml kg−1 min−1 before anaesthesia, to 19.5±7.0 (P<0.05) and 12.7±5.3 (P<0.01) ml kg−1 min−1, respectively, during anaesthesia and after partial hepatectomy; These values were 72.1% (P<0.01) and 48.5% (P<0.01) of that observed at percutaneous transhepatic portography (PTP). CLiv was significantly decreased from 14.6±5.3 ml kg−1 min−1 before anaesthesia, to 9.4±3.6 (P<0.05) and 9.8±4.1 (P<0.05) ml kg−1 min−1, respectively, after partial hepatectomy and 12 h after operation; These values were 68.9% (P<0.05) and 73.5% (P<0.05) of the value at PTP. The other pharmacokinetic parameters examined, V  and MRT, did not change significantly during anaesthesia or after surgery.
Conclusion
The clearance of ICG after portal administration was useful for estimating hepatic blood flow and intrinsic clearance in perioperative management of liver surgery.
Nasal absorption of hydroxocobalamin in healthy elderly adults
Authors: Van Asselt D. Z. B. , Merkus F. W. H. M. , Russel F. G. M. , Hoefnagels W. H. L. 
Published: March 2003

Aims
To investigate the nasal absorption of hydroxocobalamin in 10 healthy elderly adults.
Methods
In a cross‐over study, blood samples were collected before administration of the drug and after 10, 20, 30, 40, 60, 120, 180 and 240 min. The plasma cobalamin concentration was determined by competitive radioisotope binding technique.
Results
The maximal plasma cobalamin concentration (Cmax ) after nasal administration of 750 μg hydroxocobalamin was 1900±900 pmol l−1 (mean±s.d.). The maximal plasma cobalamin concentration was reached in 35±13 min (tmax ). The Cmax after nasal administration of 1500 μg hydroxocobalamin was 3500±2500 pmol l−1 with a tmax of 28±16 min. Both the AUC(0,240 min) and AUC(0,00) increased significantly with an increase of the dose from 750 μg to 1500 μg (P=0.037 and P=0.028, respectively). The nasal spray was well tolerated. No signs of irritation or local sensitivity were noted.
Conclusions
The nasal absorption of hydroxocobalamin in healthy elderly adults is rapid, high and well tolerated.
The induction effect of rifampicin on activity of mephenytoin 4′‐hydroxylase related to M1 mutation of CYP2C19 and gene dose
Authors: Feng Hua‐Jun , Huang Song‐Lin , Wang Wei , Zhou Hong‐Hao 
Published: March 2003

Aims
To determine the induction effect of rifampicin on the activity of 4′‐hydroxylase in poor metabolizers (PMs) with m1 mutation of S‐mephenytoin 4′‐hydroxylation and the relationship of the effect with gene dose.
Methods
Seven extensive metabolizers (EMs) of S‐mephenytoin 4′‐hydroxylation and five PMs with m1 mutation were chosen to take rifampicin 300 mg day−1 orally for 22 days. Prior to and after rifampicin treatment, each subject was given racemic mephenytoin 100 mg. The 4′‐hydroxymephenytoin (4′‐OH‐MP) excreted in the 0–24 h urine and mephenytoin S/R ratio in the 0–8 h urine were determined by h.p.l.c. and GC, respectively.
Results
In all EMs, the excretion of 4′‐OH‐MP in the 0–24 h urine was increased by 146.4±17.9%, 0–8 h urinary mephenytoin S/R ratio was decreased by 77.3±8.8%, the percentage increase in the 0–24 h excretion of 4′‐OH‐MP in those CYP2C19 homozygous (wt/wt) was greater than that in those heterozygous (wt/m1 and wt/m2 ) (203.9±42.5%vs 69.6±4.1%). 0–8 h urinary mephenytoin S/R ratio of those PMs with m1 mutation was decreased by 9.6%, the amount of 4′‐OH‐MP excreted in the 0–24 h urine was increased by 80.1±48.0%.
Conclusions
The activity of 4′‐hydroxylase of PMs with m1 mutation of S‐mephenytoin 4′‐hydroxylation can be induced by rifampicin and the inducing effect of rifampicin on 4′‐hydroxylase is gene dependent.
The population pharmacokinetics of recombinant‐ and urinary‐human follicle stimulating hormone in women
Authors: Karlsson Mats O. , Wade Janet R. , Loumaye Ernest , Munafo Alain 
Published: March 2003

Aims
To characterize the pharmacokinetics of recombinant‐human follicle stimulating hormone (r‐hFSH) and urinary‐human follicle stimulating hormone (u‐hFSH) using population pharmacokinetic analysis and deconvolution techniques.
Methods
Sparse data were available from 62 female patients who received u‐hFSH intramuscularly (i.m.) and 60 female patients who received r‐hFSH subcutaneously (s.c.) as part of an in vitro fertilisation and embryo transfer (IVF‐ET) procedure. The dose of u‐hFSH and r‐hFSH was 225 International Units (IU) FSH/day for the first 5 days of treatment. The dose of u‐hFSH/r‐hFSH on subsequent days depended upon the ovarian response. Intensively sampled data were also available from 12 female volunteers who received r‐hFSH, 150 IU, on three occasions: intravenously (i.v.), i.m. and s.c., each separated by 1 week of wash‐out. The volunteers then received multiple r‐hFSH doses by the s.c. route: 150 IU once daily for 7 days. Intensively sampled data were available from a further 12 female volunteers who received u‐hFSH, 150 IU, given by the i.v. and i.m. routes.
Results
Analysis of the intensively sampled r‐hFSH and u‐hFSH data sets found that disposition could be described using a two‐compartment model and that absorption was rate limiting and essentially a first order process, for both compounds. The population estimate of clearance (CL) after i.v. administration was 0.60 and 0.44 l h−1 for r‐hFSH and u‐hFSH respectively. The calculated mean residence times (MRT) for r‐hFSH and u‐hFSH were 16 and 18 h, respectively. The different bioavailabilities (F ) and mean absorption times (MAT) determined after i.m. and s.c. administration ranged from 0.60 to 0.77 and from 27 h to 48 h, depending on compound, administration route, data type and method of analysis. Population analysis of the sparse patient data found that a one compartment model with first order absorption was adequate to describe the r‐hFSH and u‐hFSH data. The population estimates of apparent clearance (CL/F ) were 0.71 and 0.33 l h−1 for r‐hFSH and u‐ hFSH respectively. Urinary‐hFSH CL/F increased linearly with weight and was 0.33 l h−1 at the average weight of 58.5 kg. No other covariates (age, weight, height, creatinine clearance, body mass index, race) were found to influence the FSH disposition parameters. The sparse data population estimates of intersubject variability in CL/F for r‐hFSH and u‐hFSH were essentially the same, 26% and 25%, respectively.
Conclusions
The population analysis indicates that the variability in CL/F is moderate, consequently, so would be the variability in exposure, given a fixed dosage regimen.
A pharmacokinetic and pharmacodynamic study of intravenous vs oral artesunate in uncomplicated falciparum malaria
Authors: Batty Kevin T. , Anh Thu Le Thi , Davis Timothy M. E. , Ilett Kenneth F. , Xuan Mai Truong , Canh Hung Nguyen , Phuc Tien Nguyen , Powell Shane M. , Van Thien Huynh , Quang Binh Tran , Kim Nguyen Van 
Published: March 2003

Aims
To obtain comprehensive pharmacokinetic and pharmacodynamic data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following i.v. and oral administration of ARTS to patients with acute, uncomplicated falciparum malaria.
Methods
Twenty‐six Vietnamese patients with falciparum malaria were randomized to receive either i.v. ARTS (120 mg; group 1) or oral ARTS (100 mg; group 2), with the alternative preparation given 8 h later in an open crossover design. Mefloquine (750 mg) was administered at 24 h. Plasma concentrations of ARTS and DHA were determined by h.p.l.c. assay. Pharmacokinetic parameters were calculated by non‐compartmental methods. The time to 50% parasite clearance (PCT50 ) was calculated by linear interpolation of parasite density determinations. Linear least squares and multiple linear regression analyses were used to evaluate pharmacokinetic‐pharmacodynamic relationships.
Results
Following i.v. bolus, ARTS had a peak concentration of 29.5 μm (11 mg l−1 ), elimination t1/2=2.7 min, CL=2.33 l h−1 kg−1 and V=0.14 l kg−1. The Cmax for DHA was 9.3 μm (2.64 mg l−1 ), t1/2=40 min, CL=0.75 l h−1 kg−1 and V=0.76 l kg−1. Following oral ARTS, relative bioavailability of DHA was 82%, Cmax was 2.6 μm (0.74 mg l−1 ), t1/2=39 min, and MAT=67 min. Overall, the PCT50 and fever clearance time (FCT) were 6.5 h and 24 h, respectively. There was no correlation between PCT50 or FCT and AUC, Cmax or MRT for DHA.
Conclusions
Despite rapid clearance of ARTS and DHA in patients with uncomplicated falciparum malaria, prompt parasite and fever clearance were achieved. High relative bioavailability of DHA following oral ARTS administration, and clinical outcomes comparable with those after i.v. ARTS, support the use of the oral formulation in the primary care setting.
The influence of transdermal oestradiol replacement therapy and medroxyprogesterone acetate on serum lipids and lipoproteins
Authors: Bhathena R. K. , Anklesaria B. S. , Ganatra A. M. , Pinto Rosaline 
Published: March 2003

Aims
The objective of this study was to examine the effects of continuous transdermal oestradiol with or without sequential oral medroxyprogesterone acetate on serum lipids and lipoproteins in menopausal women.
Methods
Sixty‐two healthy menopausal women, attending at two menopause clinics in Western India, were recruited for this study over a period of 1 year. Group 1 included 38 hysterectomised women being treated with continuous transdermal oestradiol only (50 μg daily). Group 2 included 24 menopausal women with an intact uterus being treated with transdermal oestradiol (50 μg daily) and medroxyprogesterone acetate (10 mg daily for the first 12 days of each calendar month). Women maintained on 50 μg oestradiol throughout 6 months (group 1: n=22; group 2: n=16) were reviewed for changes in serum lipids and lipoproteins at the end of 6 months (group 1), and between days 8 and 12 of the seventh month (combined phase of treatment) (group 2).
Results
In group 1, there was a small reduction in the concentrations of total cholesterol (−5.5%, P=0.04) and a small but not significant reduction in LDL‐cholesterol (−5.7%, P=0.16). In group 2, there were no significant changes in total cholesterol (−4.2%, P=0.43) and LDL‐cholesterol (−3.9%, P=0.57). HDL‐cholesterol levels did not change significantly with unopposed transdermal oestradiol (+3.0%, P=0.53), or with additional sequential medroxyprogesterone acetate (−3.8%, P=0.32). Serum triglyceride concentrations decreased significantly in both the groups (−13.9%, P=0.01, and −13.4%, P=0.008, respectively). Serum lipid changes did not differ between the groups.
Conclusions
Transdermal oestrogen therapy appears to be of particular benefit for women with hypertriglyceridaemia. There were no significant adverse effects of medroxyprogesterone acetate on serum lipids and lipoproteins.
Gut wall metabolism of verapamil in older people: effects of rifampicin‐mediated enzyme induction
Authors: Fromm Martin F. , Dilger Karin , Busse Dagmar , Kroemer Heyo K. , Eichelbaum Michel , Klotz Ulrich 
Published: March 2003

Aims
To investigate prehepatic metabolism of verapamil and its inducibility by rifampicin in older subjects.
Methods
Eight older subjects (67.1±1.2 years mean±s.d.) received racemic, unlabelled verapamil orally for 16 days (120 mg twice daily). Rifampicin (600 mg daily) was coadministered from day 5 to 16. Using stable isotope technology (i.e. intravenous coadministration of 10 mg deuterated verapamil) during verapamil steady‐state without (day 4) and with rifampicin (day 16) bioavailability, prehepatic and hepatic extraction of verapamil were determined. The effects of verapamil on AV‐conduction were measured by the maximum PR interval prolongation (%).
Results
Bioavailability of the cardiovascularly more active S‐verapamil decreased from 14.2±4.3% on day 4 to 0.6±0.5% on day 16 (P<0.001). As a consequence, effects of orally administered verapamil on the AV‐conduction were nearly abolished (14.4±9.4%vs 2.7±2.6%, P<0.01). This could be attributed to a considerable increase of prehepatic extraction during treatment with rifampicin (41.7±22.1%vs 91.6±6.6%, P<0.01) and to a minor extent to induction of hepatic metabolism (73.7±9.4%vs 91.6±5.3%, P<0.01).
Conclusions
Prehepatic metabolism of verapamil occurred in the group of older people investigated. Induction of gut wall metabolism most likely was the major reason for the loss of verapamil effect during treatment with rifampicin in this group of older subjects.
Molecular effects of sulphonylurea agents in circulating lymphocytes of patients with non‐insulin‐dependent diabetes mellitus
Authors: Rabbone I. , Piccinini M. , Curto M. , Mostert M. , Gamba S. , Mioletti S. , Bruno R. , Rinaudo M. T. 
Published: March 2003

Aims
In circulating lymphocytes of NIDDM patients pyruvate dehydrogenase (PDH), the major determinant in glucose consumption through oxidative pathways, is poorly active. The aim of this study is to examine whether sulphonylurea drug treatment revives PDH activity in circulating lymphocytes from NIDDM patients.
Methods
Twenty normal‐weight individuals with NIDDM were enrolled in this study. They had maintained their glycaemic levels close to normal by means of a restricted diet that had no longer been successful in the proceeding 2 months. The treatment protocol consisted in 160 mg gliclazide daily for 5 weeks. Twenty healthy subjects, matched for age, body mass index and gender, were enrolled as a control group. Patients, before and after treatment, as well as controls were tested for PDH activity in their circulating lymphocytes. Nine other untreated patients and nine healthy subjects, with the above mentioned characteristics, were recruited for the assay of PDH activity in their circulating lymphocytes before and after exposure, in vitro, to gliclazide, to insulin, and to gliclazide and insulin in combination.
Results
In gliclazide‐treated NIDDM patients, PDH activity in circulating lymphocytes recovered. In vitro, in circulating lymphocytes of untreated patients and controls insulin at 5 μU ml−1 was ineffective and highly effective, respectively, in raising enzyme activity; gliclazide at 10 ng ml−1 was ineffective on PDH in both groups, but in combination with insulin at 5 μU ml−1 in both groups PDH was as active as in cells of controls exposed to insulin only. In cells of controls, gliclazide alone at 25–50 ng ml−1 caused enzyme activation, whereas above 50 ng ml−1 it caused inhibition; in cells of patients below 50 ng ml−1 it had no effects, but at 50 ng ml−1 and above raised enzyme activity to the basal level of controls.
Conclusions
This study suggests that free gliclazide concentrations determine recovery of PDH activity in circulating lymphocytes of treated patients through drug‐mediated enhanced insulin control over PDH or through the drug alone.
Constipation as an adverse effect of drug use in nursing home patients: an overestimated risk
Authors: Van Dijk K. N. , De Vries C. S. , Van Den Berg P. B. , Dijkema A. M. , Brouwers J. R. B. J. , De Jong‐van den Berg L. T. W. 
Published: March 2003

Aims
To investigate whether results from case control and cross sectional studies which suggest an association between laxative use and other drug use could be confirmed in a cohort study of nursing home patients.
Methods
A prospective cohort study of 2355 nursing home patients aged 65 years and over was performed to estimate the incidence relative risk of constipation associated with drug use. The study was conducted with prescription sequence analysis of each resident's detailed pharmacy records and data on morbidity and mobility.
Results
Use of drugs, which according to the summaries of product characteristics (SPC) and the literature on adverse drug effects have moderately to strongly constipating properties, was associated with a relative risk of 1.59 (95% CI 1.24–2.04) for the occurrence of constipation during exposure time. Use of drugs with mildly to moderately constipating effects was not associated with laxative use (RR 1.13; 95% CI 0.93–1.38). Stratification on the level of age, gender, type of nursing (psychogeriatric or somatic), morbidity, number of medications taken and mobility showed no confounding effects of these variables on outcome measurements. These variables all acted as effect modifiers. Effect of age and number of medications taken on the relative risk was nonlinear.
Conclusions
Although an association between drugs that exhibit moderately to strongly constipating effects and occurrence of constipation was found, the risk was not as high as seen in previous studies. The high prevalence of constipation in nursing home patients is only partly due to adverse drug effects.
Midazolam pharmacokinetics following intravenous and buccal administration
Authors: Schwagmeier R. , Alincic S. , Striebel H. W. 
Published: March 2003

Aims
Midazolam has good anxiolytic qualities and is a well established premedication agent before anaesthesia or short surgical procedures. The objective of the present study was to determine pharmacokinetic data from individual plasma concentration profiles obtained following intravenous and buccal administration of midazolam.
Methods
Eight young healthy volunteers received single doses of 5 mg midazolam i.v. and after a period of 1 week buccally in a cross over manner. Blood samples were obtained up to 480 min. The measurement of plasma midazolam concentrations was by gas‐chromatography.
Results
The maximum plasma concentration was 55.9 ng ml−1 (range 35.6–77.9 ng ml−1 ) at 30 min (range 15–90 min) following buccal administration. AUC was calculated to be 15 016 ng ml−1 min (s.d. 3778 ng ml−1 min) following i.v. and 11191 ng ml−1 min (s.d. 1777 ng ml−1 min) following buccal midazolam. This gave a mean midazolam bioavailabilty of 74.5%.
Conclusions
The pharmacokinetic data presented in this study demonstrate a high bioavailability and reliable plasma concentrations following buccal midazolam. The clinical benefit of buccal midazolam may be in particular patient controlled premedication or sedation in adults.
An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method
Authors: Fabre Emmanuelle , Chevret Sylvie , Piechaud Jean‐François , Rey Elisabeth , Vauzelle‐Kervroedan Françoise , D’Athis Phillippe , Olive Georges , Pons Gérard 
Published: March 2003

Aims
No drug has been demonstrated to provide simultaneously appropriate sedation, safety and lack of disturbance of the measured parameters during cardiac catheterization in infants. The objective of this study was to estimate the dose of midazolam, administered rectally, that would provide a 90% probability of adequate sedation in infants during cardiac catheterization. A sedation score ≥4 (six‐point scale) 30 to 60 min after dosing was rated as a success.
Methods
A double‐blind, continual reassessment method using a Bayesian approach has been used. Sixteen infants were administered a single midazolam dose, within a 0.1 to 0.6 mg kg−1 dose range.
Results
Consecutive failures led to allocation of the highest dose to 15 out of 16 patients. The final estimated probability of failure of the 0.6 mg kg−1 dose was 81% (95% CI: 78.5 to 84%). The time to reach a score ≥4 was longer than expected and the median duration‐time at score ≥4 was shorter (15 min) than expected.
Conclusions
Delayed absorption and low rectal bioavailability may explain these data. Higher doses or different routes of administration may lead to the expected sedation, but the safety of doses higher than 0.6 mg kg−1 administered rectally has not been evaluated. The therapeutic strategy for sedation of this category of infants in the hospital has now been changed based on the present results in that rectal midazolam has been abandoned in this indication.