bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of initial depth at basin margins in sequence architecture: field examples and computer models
Authors: Uličný David , Nichols Gary , Waltham Dave 
Published: March 2003

ABSTRACTA delay in the onset of sedimentation during fault‐related subsidence at a basin margin can occur in both extensional settings, where footwall tilting may cause a diversion of drainage patterns, and in strike‐slip basins, where a source area may be translated along the basin margin. The ‘initial depth’ created by this delay acts as pre‐depositional accommodation and is a partly independent variable. It controls the geometry of the first stratal units deposited at the basin margin and thus modifies the response of the depositional system to subsequent, syndepositional changes in accommodation. In systems with a sharp break in the depositional profile, such as the topset edge in coarse‐grained deltas, the initial depth controls the foreset height and therefore the progradational distance of the topset edge. The topset length, in turn, influences topset accommodation during cyclical base level variations and therefore is reflected in the resulting stacking patterns at both long‐ and short‐term time scales. In the simplified cases modelled in this study, it is the relationship between the initial depth and the net increase in depth over the interval of a relative sea‐level cycle (ΔH) that governs long‐ and short‐term stacking patterns. In situations where the initial depth is significantly larger than ΔH, the topset accommodation of the first delta is insufficient to contain the volume of sediment of younger sequences formed during subsequent relative sea‐level cycles. Therefore, the depositional system tends to prograde over a number of relative sea‐level cycles before the topset area increases so that the long‐term stacking pattern changes to aggradation. Stacking patterns of high‐frequency sequences are influenced by a combination of topset accommodation available and position of the short‐term relative sea‐level cycles on the rising or falling limb of a long‐term sea‐level curve. This determines whether deposits of short‐term cycles are accommodated in delta topsets or foresets, or in both. Variations in stacking pattern caused by different initial depths may be misinterpreted as due to relative sea level or sediment supply changes and it is necessary to consider initial bathymetry in modelling and interpretation of stacking patterns, especially in fault‐bounded basins.
The long‐term thermal consequences of rifting: implications for basin reactivation
Authors: Sandiford M. , Frederiksen S. , Braun J. 
Published: March 2003

ABSTRACTThe attenuation of the continental crust during rifting and the subsequent filling of the rift‐related accommodation alter the long‐term thermal and mechanical state of the lithosphere. This is primarily because the Moho is shallowed due to density contrasts between the sediment fill and the crust, but also reflects the attenuation of the pre‐existing crustal heat production and its burial beneath the basin, as well the thermal properties of the basin fill. Moho shallowing and attenuation of pre‐existing heat production contribute to long‐term cooling of the Moho and thus lithospheric strengthening, as has been pointed out in many previous studies. In contrast, basin filling normally contributes to significant Moho heating allowing the possibility of long‐term lithospheric weakening, the magnitude of which is dependent on the thermal properties of the basin‐fill and the distribution of heat sources in the crust. This paper focuses on the thermal property structure of the crust and basin‐fill in effecting long‐term changes in lithospheric thermal regime, with particular emphasis on the distribution of heat producing elements in the crust. The parameter space appropriate to typical continental crust is explored using a formalism for the heat production distributions that makes no priori assumptions about the specific form of the distribution. The plausible parameter space allows a wide range in potential long‐term thermal responses. However, with the proviso that the accommodation created by the isostatic response to rifting is essentially filled, the long‐term thermal response to rift basin formation will generally increase average crustal thermal gradients beneath basins but cool the Moho due to its reduction in depth. The increase in the average crustal thermal gradient induces lateral heat flow that necessarily heats the Moho along basin margins, especially in narrow rift basins. Using coupled thermo‐mechanical models with temperature sensitive creep‐parameters, we show that such heating may be sufficient to localise subsequent deformation in the vicinity of major basin bounding structures, potentially explaining the offset observed in some stacked rift basin successions.
Pharmacokinetics of recombinant human interleukin‐2 in advanced renal cell carcinoma patients following subcutaneous application
Authors: Kirchner G. I. , Franzke A. , Buer J. , Beil W. , Probst‐Kepper M. , Wittke F. , Övermann K. , Lassmann S. , Hoffmann R. , Kirchner H. , Ganser A. , Atzpodien J. 
Published: March 2003

Aims
The aim of the study was to investigate the pharmacokinetics of recombinant human interleukin‐2 (rhIL‐2) in patients with metastatic renal cell carcinoma following different subcutaneous (s.c.) administration regimens.
Methods
RhIL‐2 was administered subcutaneously to 10 patients according to two different dosing regimens: group A received 20×106 IU m−2 once daily and group B 10×106 IU m−2 twice daily (every 12 h). Additionally, in all patients the influence of soluble interleukin‐2 receptor (sIL‐2R) on the pharmacokinetics of rhIL‐2 was investigated.
Results
The mean area under the serum concentration‐time curve to 24 h (AUC(0,24 h)) was 627 IU ml−1 h in treatment group A and 1130 IU ml−1 h (P=0.029) in treatment group B. In both study groups Cmax and AUC(0,12 h) were not significantly different. Seventy‐two hours after the beginning of s.c. rhIL‐2 therapy the sIL‐2R increased significantly (P=0.016), and sIL‐2R levels over 1200 pmol l−1 seemed to reduce the AUC.
Conclusions
In patients with metastatic renal cell cancer administration of 20×106 IU m−2 of rhIL‐2 s.c. in two daily doses (10×106 IU m−2 every 12 h) provides better bioavailability and is preferable to the single dose administration.
Exogenous L‐arginine does not affect angiotensin II‐induced renal vasoconstriction in man
Authors: Wolzt Michael , Ugurluoglu Ara , Schmetterer Leopold , Dorner Guido , Zanaschka Gabriele , Mensik Christa , Eichler Hans‐Georg 
Published: March 2003

Aims
It has been suggested that provision of the substrate of nitric oxide (NO) synthesis, l‐arginine, might influence the effects of renal vasoconstrictors. We have therefore studied the effects of pretreatment or concomitant administration of l‐arginine on angiotensin II (ANG II)‐increased renovascular resistance.
Methods
The study was conducted in a double‐blind, randomized, cross‐over design. Eight healthy subjects were assigned to placebo or a continuous intravenous coinfusion of ANG II (5.0 ng kg−1 min−1, infusion period 75 min) with l‐arginine (17 mg kg−1 min−1, infusion period 30 min). Nine further subjects received a continuous infusion of ANG II with or without pretreatment of l‐arginine. Changes in renal plasma flow (RPF) were estimated by the steady state clearance of PAH.
Results
l‐arginine alone increased RPF to 110±10% over baseline (P<0.003). The ANG II‐induced decrease in RPF was not affected by pretreatment or coinfusion of l‐arginine.
Conclusions
Our results demonstrate that a counterregulatory response of the renal vasculature to high levels of ANG II does not depend on exogenous l‐arginine. In healthy subjects, this lack of functional antagonism at the renal vasculature is therefore not a result of NO substrate availability.
Concomitant administration of cholestyramine influences the absorption of troglitazone
Authors: Young M. A. , Lettis S. , Eastmond R. 
Published: March 2003

Aim
Troglitazone is an orally active anti‐diabetic agent. Cholestyramine is an orally administered lipid‐lowering agent which acts by binding to bile acids and removing them from enterohepatic circulation. Preclinical studies suggesting the potential for an interaction between troglitazone and cholestyramine require confirmation in a clinical setting.
Methods
In vitro and in vivo experiments in the dog were carried out prior to a clinical study. Twelve healthy volunteers (mean age 32 years, range 20–44 years) each received a single oral dose of troglitazone 400 mg alone and with cholestyramine 12 g (taken 1 h after troglitazone) in an open, two‐way crossover study.
Results
In vitro, about 99% of troglitazone was adsorbed by cholestyramine at an incubate concentration of 3 μg ml−1 whilst at 500 μg ml−1 adsorption fell to about 90%. In vivo, AUC of troglitazone was reduced by an average of 42% (22.7 vs 12.2 μg ml−1 h (95% CI for difference 28–57, P=0.01) in 11 beagle dogs receiving troglitazone 200 mg and cholestyramine 1 g compared with control values. Mean maximum plasma concentration (Cmax ) was 49% of control values (7.08 vs 3.42 μg ml−1 (95% CI for difference 14–85, P=0.05)). In the clinical study median AUC for troglitazone and its two major metabolites were statistically significantly lower when troglitazone was administered with cholestyramine (17.9 vs 5.2 μg ml−1 h (95% CI for difference −20.5, −8.7), 133.7 vs 27 1 μg ml−1 h (−166.4, −67.8) and 18.4 vs 2.5 μg ml−1 h (−21.6, −10.6) for troglitazone, sulphate and quinone metabolite respectively (all P<0.01) representing percentage decreases of 71, 80 and 86% respectively. A statistically significant reduction was also observed in Cmax for the sulphate metabolite (4.56 vs 1.28 μg ml−1 (95% CI for difference −4.42, −1.99, P<0.01)), but not for troglitazone (1.85 vs 1.23 μg ml−1 (−1.13, 0.49) or the oxidative metabolite (0.84 vs 0.45 μg ml−1 (−0.77, 0.09)).
Conclusions
The results were indicative of an alteration in the extent of troglitazone's absorption. Concomitant administration of troglitazone and cholestyramine could severely impair troglitazone's clinical utility as an antihyperglycaemic agent.
Studies with iontophoretic administration of drugs to human dermal vessels in vivo: cholinergic vasodilatation is mediated by dilator prostanoids rather than nitric oxide
Authors: Noon Joseph P. , Walker Brian R. , Hand Malcolm F. , Webb David J. 
Published: March 2003

Aims
Impaired function of the vascular endothelium has been well documented in hypertension and hypercholesterolaemia. However, the ‘gold standard’ method for assessing endothelial function, using intra‐arterial drug infusion, is invasive and has only been applied in the forearm and coronary circulations in vivo. The aim of the present study was to establish the non‐invasive technique of transdermal drug iontophoresis to assess endothelial function in human dermal vessels in vivo.
Methods
In healthy male volunteers, we delivered acetylcholine (ACh) and sodium nitroprusside (SNP) to dermal vessels of the forearm using iontophoresis, and measured vasodilatation using laser Doppler fluximetry. Drugs were diluted in a methylcellulose gel vehicle which did not induce vasodilatation. To assess the contribution of nitric oxide and vasoactive prostanoids to cholinergic dilatation, the procedure was repeated during brachial artery infusion of the nitric oxide synthase inhibitor, l‐NG‐monomethyl‐arginine (l‐NMMA) and after intravenous administration of the cyclooxygenase inhibitor, aspirin. As a control for the vasoconstrictor effect of l‐NMMA, which was measured by venous occlusion plethysmography, iontophoresis was repeated during brachial artery infusion of noradrenaline.
Results
Flux increased in response to iontophoresis of ACh (from 45±9 to 499±80 units; P<0.0001) and SNP (from 32±11 to 607±82 units; P<0.0001). Brachial artery infusions of l‐NMMA or noradrenaline caused reductions in forearm blood flow (by 43±2% and 44±2%, respectively) but did not inhibit vasodilatation in response to iontophoresis of ACh or SNP. In contrast, aspirin inhibited the response to iontophoresis of ACh (from 473±81 to 222±43 units; P<0.0001) but did not affect the response to SNP (from 348±59 to 355±58).
Conclusions
We conclude that in healthy subjects, in contrast to the forearm circulation, dermal vasodilatation in response to iontophoresis of ACh is mediated predominately by a dilator prostanoid rather than by nitric oxide generation. Furthermore, the non‐invasive technique of iontophoresis could complement existing invasive tests of endothelial function in future clinical studies.
Terfenadine and risk of acute liver disease
Authors: Wald Myers Marian , Jick Hershel 
Published: March 2003

Aims
To estimate the risk of idiopathic acute liver disease among users of terfenadine.
Methods
We conducted a population‐based cohort study based on the General Practice Research Database (GPRD) in the U.K. All persons who received at least one prescription for terfenadine during the period 1991 through 1995 were eligible for the study. Among these patients we identified all those with a diagnosis of a liver disorder requiring hospitalization or referral to a consultant within 60 days of a prior prescription for terfenadine. We obtained clinical records, including hospital discharge summaries, consultant reports and relevant laboratory results in order to identify a potentially drug‐inducible liver illness.
Results
From a cohort of 210 683 recipients of terfenadine, we found only three cases of acute liver disease where a causal connection to terfenadine could not be ruled out, yielding a risk estimate of 1.4/100 000 users (95% CI 0.5, 4.2) and 0.5/100 000 prescriptions (95% CI 0.2, 1.4). All cases were receiving a concomitant hepatotoxic drug and all had a full recovery.
Conclusion
The use of terfenadine is rarely associated with idiopathic acute liver disease.
A comparison of the cardiovascular effects of levobupivacaine and rac‐bupivacaine following intravenous administration to healthy volunteers
Authors: Bardsley Hazel , Gristwood Robert , Baker Helen , Watson Norma , Nimmo Walter 
Published: March 2003

Aims
The aim of this study was to compare the cardiovascular effects of levobupivacaine with those of rac‐bupivacaine following i.v. administration to 14 healthy male volunteers.
Methods
Drugs were infused (at 10 mg min−1 ) using a randomized, double‐blind, complete crossover procedure with a washout period of at least 1 week. The administration of drug was discontinued on the appearance of defined CNS symptoms or when a total of 150 mg had been given. Parameters measured were arterial blood pressure, heart rate, ECG, ejection fraction, acceleration index, stroke index and cardiac index.
Results
The mean doses administered were 56.1 mg and 47.9 mg for levobupivacaine and rac‐bupivacaine respectively and the maximum mean plasma concentrations were 2.62 and 2.25 μg ml−1 respectively. Despite the dose and plasma concentrations being comparable, levobupivacaine produced a statistically significant smaller reduction in mean stroke index (−5.14 vs−11.86 ml m−2, P=0.001), acceleration index (−0.09 vs−0.20 s−2, P=0.011) and the ejection fraction (−2.50 vs−4.29%, P=0.024). Both levobupivacaine (non significant) and rac‐bupivacaine (significant) produced small increases in the PR interval and the corrected QT interval and although the effects of rac‐bupivacaine appeared to be greater the difference between the two drugs was not significant.
Conclusions
In conclusion, this study has shown that following i. v. administration levobupivacaine produces significantly less effects on cardiovascular function than does rac‐bupivacaine. In particular the negative inotropic effect for levobupivacaine was less than that for rac‐bupivacaine as indicated by changes in stroke index, acceleration index and ejection fraction.
Caffeine based measures of CYP1A2 activity correlate with oral clearance of tacrine in patients with Alzheimer's disease
Authors: Fontana Robert J. , DeVries Tina M. , Woolf Thomas F. , Knapp Margaret J. , Brown AS , Kaminsky Laurence S. , Tang Bing‐Kuo , Foster Norman L. , Brown Richard R. , Watkins Paul B. 
Published: March 2003

Aims
To study the potential utility of caffeine based probes of CYP1A2 enzyme activity in predicting the pharmokinetics of tacrine in patients with Alzheimer's disease.
Methods
The pharmokinetics of a single 40 mg oral dose of tacrine were measured in 19 patients with Alzheimer's disease. Each patient also received 2 mg kg−1 [13C‐3‐methyl] caffeine orally and had breath and urine samples collected.
Results
Tacrine oral clearance (CL F−1 kg−1 ), which varied 15‐fold among the patients, correlated significantly with the 2 h total production of 13CO2 in breath (r=0.56, P=0.01), and with each of two commonly used urinary caffeine metabolite ratios: the raxanthine/caffeine ratio’ (1,7X+1, 7U)/1,3,7X) (r=0.76, P=0.0002) and the ‘caffeine metabolic ratio’ (AFMU+1X+1U)/1, 7U)(r=0.76, P=0.0001). Conclusions These observations support a central role for CYP1A2 in the in vivo disposition of tacrine and the potential for drug interactions when tacrine treated patients receive known inducers or inhibitors of this enzyme. The magnitude of the correlations we observed, however, are probably not suffcient to be clinically useful in individualizing tacrine therapy.
Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects
Authors: Turnheim  , Krivanek  , Oberbauer  
Published: March 2003

Aims The prevalence of hyperuricaemia and gout increases with age as does the incidence of adverse effects to allopurinol, the major uric acid lowering drug. The present study was performed to compare the disposition and effects of allopurinol and its active metabolite oxipurinol in elderly and young subjects without major health problems.Methods Ten elderly (age range 71–93 years) and nine young subjects (24–35 years) received an oral dose of 200 mg allopurinol in an open, single dose, cross sectional design. Four of these individuals were additionally dosed with 200 mg allopurinol intravenously. Plasma and urine concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid were measured by h.p.l.c.Results Total clearance of allopurinol was not different in elderly (15.7±3.8 ml min−1 kg−1, mean±s.e. mean) and young subjects (15.7±2.1), whereas total clearance of oxipurinol was significantly reduced in the aged (0.24±0.03) compared with young controls (0.37±0.05) as was the distribution volume of oxipurinol (0.60±0.09 and 0.84±0.07 l kg−1, respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by metabolism. Fractional peroral bioavailability of allopurinol was 0.81±0.16 (n=4, two elderly and two young subjects). Although maximal plasma concentrations of oxipurinol were significantly higher in elderly (5.63±0.83 μg ml−1 ) than in young persons (3.75±0.25) as was the area under the oxipurinol plasma concentration‐time curve, AUC (260±46 and 166±23 μg ml−1h, respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly than young subjects (time‐dependent decrease of plasma uric acid 83±30 μg ml−1 h in elderly compared with 176±21 in young controls). Oxipurinol increased the renal clearance of xanthine, suggesting inhibition of tubular xanthine reabsorption by oxipurinol.Conclusions Although allopurinol elimination is not reduced in the aged, that of its active metabolite oxipurinol is because of an age‐dependent decline in renal function. Xanthine oxidase inhibition by oxipurinol appears to be reduced in old age. In addition to its uricostatic action, oxipurinol has a xanthinuric effect which is also diminished in the elderly.
Rapid development of tolerance to dipyridamole‐associated headaches
Authors: Theis  , Deichsel  , Marshall  
Published: March 2003

Aims In the Second European Stroke Prevention Study headaches associated with dipyridamole frequently (8% of patients taking dipyridamole or dipyridamole plus acetylsalicylic acid (ASA) vs2% of patients taking ASA or placebo) led to discontinuation of therapy. We have now used data from a recent trial comparing the bioequivalence of two formulations of the fixed combination of 200 mg dipyridamole in an extended release formulation and 25 mg ASA to explore predicting factors for headaches associated with this drug combination.Methods The bioequivalence trial employed a two‐way crossover, randomised, open design. Trial medication was given for two periods of five days separated by a 72 h washout period. Statistical methods were employed to explore the prevalence, the time course, and the relation to individual pharmacokinetic parameters of treatment associated headaches.Results Headache episodes, being mostly mild and transient, rapidly declined from 67% of the volunteers on the first day of treatment to 3% on the final days of treatment (days 4–5 of the second period). During the first days the prevalence of the headaches peaked 2–3 h after the morning administration, which coincided with the peak of the plasma concentrations of dipyridamole. The occurrence of headaches was not related to interindividual differences of the pharmacokinetic parameters.Conclusions The rapid decrease in the incidence of headaches over time implies that most patients quickly develop tolerance to dipyridamole‐associated headaches. Appropriate information given to the patient when prescribing and dispensing dipyridamole/ASA may reduce early withdrawals from treatment and increase compliance.
Phenotypic polymorphism and gender‐related differences of CYP1A2 activity in a Chinese population
Authors: Ou‐Yang Dong‐Shen , Huang Song‐Lin , Wang Wei , Xie Hong‐Guang , Xu Zhen‐Hua , Shu Yan , Zhou Hong‐Hao 
Published: March 2003

Aims To investigate the distribution characteristics of CYP1A2 in a Chinese population, and to examine gender‐related differences in CYP1A2 activity. Methods Two hundred and twenty‐nine healthy subjects, 120 men and 109 women, were enrolled in this study. CYP1A2 activity was measured by plasma paraxanthine/caffeine (1,7X/1,3,7X) ratio 6 h after administration of 300 mg caffeine. The concentrations of paraxanthine and caffeine in plasma were detected by h.p.l.c. Results A 16‐fold variation of CYP1A2 activity (range 0.09 to 1.46) was shown in this study. The coefficient of variation (CV %) of CYP1A2 activity was 62.9%. Non‐normal distribution of CYP1A2 activity was indicated by the Shapiro‐Wilk test (P<0.001). Probit plots of CYP1A2 activity revealed a bimodal distribution with breakpoint of 1,7X/1,3,7X ratio of 0.12. The percentage of poor metabolizers (PMs) was 5.24% (95% CI: 2.35%~8.13%) in this Chinese population. Residual analysis of the data also supported bimodality (P<0.01). The CYP1A2 activity of men was higher than that of women (median: 0.33 vs 0.23, P<0.001). A probit plot of CYP1A2 activity in men was shifted to the left compared with that in women. Based on phenotype, the gender‐related difference was observed in extensive metabolizers (EMs) (P<0.001), but not in PMs (P >0.1). In addition, there was no sex‐related difference in the incidence of PMs (P >0.1). Conclusions There is a phenotypic polymorphism in CYP1A2 activity in this Chinese population, and CYP1A2 activity is higher in men than that in women.