bluuebunny/crossref_metadata_2025_split huggingface dataset:
Subsidence analyses from the Betic Cordillera, southeast Spain
Authors: Hanne D. , White N. , Lonergan L. 
Published: March 2003

ABSTRACTFifty‐four Mesozoic–Cenozoic stratigraphic sections from the Betic Cordillera of southeast Spain have been analysed in order to estimate the timing and amount of lithospheric stretching that occurred at the western end of the Tethyan Ocean since the Hercynian Orogeny. The standard backstripping technique has been used in order to calculate the water‐loaded subsidence of basement for each section. Water‐loaded subsidence curves were then inverted in order to determine the variation of lithospheric strain rate as a function of time, which yields estimates of timing, magnitude and intensity of stretching.Rifting commenced during the Late Permian/Early Triassic times and continued intermittently throughout the Mesozoic in response to the opening of the Tethyan Ocean to the east and the opening of the Atlantic Ocean to the west. Two major events in the Permo‐Triassic/Early Jurassic and the Late Jurassic/Early Cretaceous can be clearly identified. Stretching factors are generally small (1.1–1.25) probably because the Betic Cordillera was located at the westernmost end of the Tethys.Peak strain rates of ∼10−15 s−1 were obtained for Mesozoic rift events and these values are in broad agreement with those obtained throughout the Tethyan Realm. We have also analysed the Neogene extensional event, which played an important role in forming the existing Mediterranean Sea. A combination of well‐log information and calibrated seismic reflection data was modelled. Peak strain rates in these younger basins are almost one order of magnitude faster than those estimated for the Mesozoic basins. These higher values appear to be typical of back‐arc extensional basins elsewhere. To the west and north of the Betic Cordillera, the Guadalquivir foreland basin developed as extension took place further east. Backstripped sections from this basin clearly record the northward migration of foreland basin subsidence through time.
Early lung absorption profile of non‐CFC salbutamol via small and large volume plastic spacer devices
Authors: Lipworth B. J. , Clark D. J. 
Published: March 2003

Aims
To evaluate the lung dose of a non‐CFC salbutamol metered dose inhaler (MDI) formulation via three commonly used plastic spacer devices, of both large and small volume, compared with the MDI used on its own.
Methods
Ten healthy volunteers were studied in a randomized single (investigator) blind crossover design. Single 1200 μg nominal doses of salbutamol from a non‐CFC MDI (Airomir), as 12 sequential 100 μg puffs over 6 min, were delivered from the MDI alone and via two large volume spacer devices (Nebuhaler, Volumatic), and a small volume spacer (Aerochamber). All spacers were prewashed prior to each study day and mouth rinsing was performed after each drug sequence. Plasma salbutamol was measured at 5, 10, 15 and 20 min, with calculation of maximum (Cmax ) and average (Cav ) concentrations. This lung dose was assessed using the early lung absorption profile of salbutamol in the first 20 min after inhalation.
Results
Both of the large volume spacers, the Nebuhaler and the Volumatic, delivered significantly more salbutamol than the MDI alone. For Cav this amounted to a 2.07‐fold difference (95% CI 1.48–2.90) between Nebuhaler vs MDI, and a 1.49‐fold difference (95%CI 1.19–1.87) between Volumatic vs MDI. The Nebuhaler also produced greater deposition than either the Volumatic or the Aerochamber spacers; Nebuhaler vs Volumatic: 1.39‐fold difference (95% CI 1.09–1.76), Nebuhaler vs Aerochamber: 1.63‐fold difference (95% CI 1.20–2.21). There were no significant differences between the Aerochamber and the MDI alone.
Conclusions
Using the early lung absorption profile, for administration of the same nominal dose, both of the large volume spacers (Nebuhaler and Volumatic) but not the small volume spacer (Aerochamber) delivered significantly more salbutamol than the MDI alone. The Nebuhaler also produced greater delivery than either the Volumatic or the Aerochamber spacer devices. Our results show that whilst lung delivery of non‐CFC salbutamol MDI is improved by the use of a plastic spacer, there may be appreciable differences in performance, particularly between large and small volume devices.
Pharmacokinetic analysis of subcutaneous erythropoietin administration with nonlinear mixed effect model including endogenous production
Authors: Hayashi Naoto , Kinoshita Haruki , Yukawa Eiji , Higuchi Shun 
Published: March 2003

Aims
Erythropoietin, a glycoprotein hormone is produced by the kidney and targeted to erythrocyte precursors. Recombinant human erythropoietin (Epoetin β) has been utilized for therapeutic purposes in renal anaemia or anaemia occurring after auto blood donation or chemotherapy. The administration routes for erythropoietin are normally subcutaneous or intravenous. No population pharmacokinetic analysis, however, has been performed following subcutaneous administration with consideration given for endogenous production.
Methods
In the present study, we have attempted to analyze the pharmacokinetics of erythropoietin after subcutaneous administration in healthy adult male volunteers by using the Nonlinear Mixed Effect Model program (NONMEM) with a model including endogenous erythropoietin production.
Results
It has been established that the final estimation of the population mean values of the absorption rate constant (ka ), the elimination rate constant (ke ), the distribution volume (V  ) and the endogenous production are 0.0430 h−1, 0.206 h−1, 3.14 l and 15.7IU h−1, respectively. For the circadian rhythm of endogenous production, the amplitude was calculated as 9.86% and the peak appeared around 24.00 h.
Conclusions
The values for ke and V  are very similar to those previously reported for intravenous administration. The circadian rhythm of endogenous production are also able to be substantiated. The factors influencing ke were found to be serum creatinine and age.
Halofantrine and chloroquine inhibit CYP2D6 activity in healthy Zambians
Authors: Simooya O. O. , Sijumbil G. , Lennard M. S. , Tucker G. T. 
Published: March 2003

Aims
To determine the effect of therapeutic loading doses of halofantrine and chloroquine on CYP2D6 activity in healthy black Zambians.
Methods
Twenty healthy black male Zambians were phenotyped for CYP2D6 activity by measuring the debrisoquine/4‐hydroxydebrisoquine ratio in a 0–8 h urine sample after a 10 mg oral dose of debrisoquine hemi‐sulphate. The subjects (all ‘extensive metabolizer’ phenotype with respect to CYP2D6) were randomized into two groups of 10, and 24 h later one group received 1500 mg halofantrine hydrochloride and the other group 1500 mg chloroquine phosphate both orally in divided doses. All subjects were given further 10 mg doses of debrisoquine at 2 h, 1 week and 2 weeks after the last dose of the antimalarial drug, and phenotyped as described above.
Results
The median debrisoquine/4‐hydroxydebrisoquine 0–8 h urinary ratio was increased by halofantrine (1.39 to 6.05; P<0.01; 95% confidence intervals 4.00–11.7) and chloroquine (1.96 to 3.91; P<0.01; 95% confidence intervals 1.34–2.66) when debrisoquine was given 2 h after treatment. The decrease in CYP2D6 activity remained statistically significant for 1 week after both drugs. Halofantrine was a significantly more potent inhibitor of CYP2D6 than chloroquine (P=0.037). Phenocopying occurred in two subjects taking halofantrine and one taking chloroquine (i.e. the debrisoquine/4‐hydroxydebrisoquine ratios became consistent with the poor metabolizer phenotype).
Conclusions
Given in therapeutic loading doses, both halofantrine and chloroquine caused significant inhibition of CYP2D6 activity in healthy black Zambians. With respect to halofantrine, this finding reinforces the recommendation that its combination with other drugs known to prolong the QT interval should be avoided, especially those that are metabolized significantly by CYP2D6.
The reproducibility of symptoms during a submaximal exercise test in chronic heart failure
Authors: Grant S. , McMurray J. , Aitchison T. , McDonagh T. , Christie J. , Davie A. , Dargie H. J. 
Published: March 2003

Aims
The aim of this study was to evaluate the use of a submaximal test with a symptom limited endpoint and to measure the reproducibility of symptoms in patients with CHF.
Methods
Ten patients with chronic heart failure were studied. Based on two maximal treadmill tests an individual protocol using a constant work rate at a submaximal intensity was derived. The projected maximum treadmill time for the constant workrate was between 8 and 17 min. Tests were carried out 1, 2, 4 and 6 weeks after the maximum tests. Every 2.5 min during the submaximal test patients recorded their symptoms of breathlessness and fatigue using computer automated visual analogue (VAS) and Borg CR10 scales. The measure of reproducibility used was the proportion of total variability explained by the between subject variability.
Results
Using the VAS scale, general fatigue was reasonably reproducible ranging from 77–86%. For VAS breathlessness reproducibility ranged from 66% to 83%. Reproducibility for breathlessness and fatigue for the Borg CR10 scale was much lower than the VAS scale. Reproducibility for the treadmill times was 51% but increased to 76% if one test of one subject was excluded.
Conclusions
The use of the VAS during submaximal exercise offers a useful means of evaluating symptoms in CHF and potentially their response to treatment. These findings show that individual submaximal protocols can be easily prescribed for CHF patients. Using such an approach, clinically desirable tests lasting around 12 min can be developed. These tests are reasonably reproducible and may provide a useful means of assessing patient disability and the impact of treatment.
Angiotensin II antagonism and plasma radioreceptor‐kinetics of candesartan in man
Authors: Malerczyk Claudius , Fuchs Bettina , Belz Gustav G. , Roll Susanna , Butzer Raunhild , Breithaupt‐Grögler Kerstin , Herrmann Volker , Magin Steffen G. , Högemann Anette , Voith Barbara , Mutschler Ernst 
Published: March 2003

Aims
The pharmacodynamic properties of the angiotensin II antagonist candesartan in humans were assessed from the rightward shifts of angiotensin II dose‐effect curves (Schild regression technique). The pharmacokinetic characteristics were determined by radioreceptor assay (r.r.a.) and h.p.l.c.
Methods
Twelve healthy male volunteers received single oral doses of 4, 8 and 16 mg candesartan cilexetil and placebo. Plasma was obtained for h.p.l.c. and r.r.a. (receptors: rat lung; radioligand: [125I‐Sar1Ile8]‐angiotensin II).Before and up to 24 h post dosing angiotensin II was infused in ascending dose steps until blood pressure (systolic and/or diastolic) increased by +25 mmHg. Individual angiotensin II dose‐effect curves were fitted according to an Emax model and dose ratios (DR) calculated from the antagonist induced rightward shifts.
Results
Candesartan, the active metabolite of candesartan cilexetil, declined from peak concentrations at about 4 h with a t1/2 of about 6 h. A linear relation (slope 1) between h.p.l.c. and r.r.a. data revealed that there is no other active metabolite. DR at 6–9 h post dosing reached a maximum of about 30 and at 24 h still amounted to 4–7, indicating the persistence of a relevant antagonistic effect in vivo. The apparent Ki‐doses (derived from Schild regression plots) indicated a high potency (1.9 mg at 24 h) and slow decline of effect. Between plasma concentrations and antagonistic effect a counterclockwise hysteresis was visible.
Conclusions
A longer persistence of the antagonistic effect at the receptor site than expected by the presence in plasma indicates a slow off‐rate of candesartan cilexetil from in vivo receptors. This provides an additional rationale for the observed 24 h therapeutic activity of candesartan cilexetil.
Start of therapy with the angiotensin II antagonist losartan after immediate switch from pretreatment with an ACE inhibitor
Authors: Scholze Juergen , Stapff Manfred 
Published: March 2003

Aims
To evaluate initial blood pressure effects of the angiotensin II antagonist losartan (L) immediately after switching from an ACE inhibitor (captopril, C).
Methods
Two‐phase multicentre randomized study in 177 outpatients with mild to moderate essential hypertension. For 6 weeks all patients received 25 mg C twice daily. Then they were randomized double‐blind to switch for another 6 weeks to 50 mg L once daily (n=110) or to maintain C (n=55). On the first day of the switch they underwent ambulatory blood pressure measurement (ABPM).
Results
Within 12 h of first dose, 31% of patients who switched to L had two consecutive systolic BP readings of 30 mmHg below their individual baseline value compared with 24% of patients who stayed on C. In 3% of patients with L and in 6% of the C patients systolic BP readings less than 100 mmHg were recorded within 12 h of first dose. The differences were not statistically significant. There were no clinical symptoms attributable to initial hypotension. During the 6 weeks double‐blind therapy, 9% of L patients experienced at least one adverse event, compared with 16% of patients with C.
Conclusions
In this study the angiotensin II antagonist losartan was effective and generally well tolerated when administered immediately after pretreatment with an ACE inhibitor.
Chronopharmacology of intravenous and oral modified release verapamil
Authors: Dilger Karin , Eckhardt Klaus , Hofmann Ute , Kucher Klaus , Mikus Gerd , Eichelbaum Michel 
Published: March 2003

Aims Using a stable isotope technique which allows simultaneous and differential measuring of orally and intravenously administered drugs we compared the pharmacokinetics and pharmacodynamics of unlabelled modified release verapamil p.o. (steady state) and deuterated verapamil i.v. (single dose) following morning and evening administration.Methods Twelve female and 12 male healthy volunteers were studied in a randomized, crossover design. During the last day of each treatment period (day 6 and day 10) pharmacokinetics and pharmacodynamics (PR interval) of verapamil were assessed; 1 h before ingestion of a new R/S‐verapamil 240 mg modified release formulation (08.00 h vs 20.00 h) a single dose of 10 mg d7‐R/S‐verapamil was administered intravenously. Serum levels of unlabelled and labelled R/S‐verapamil were measured by gas chromatography/mass spectrometry. In selected samples of serum which were chosen at tmin,po and tmax,po the enantiomers were separated by chiral high‐performance liquid chromatography in order to calculate R‐ to S‐verapamil serum concentration ratios.Results We observed no significant differences in pharmacokinetics (AUCpo, Cmax, tmax, CLo, F and R/S enantiomer ratio) between morning and evening treatment with modified release verapamil and there was no influence of time of dosing on mean prolongation of PR interval. AUCiv, CL, Vss and d7‐R/d7‐S enantiomer ratio following verapamil i.v. did not show circadian variation. t1/2 was slightly but statistically significantly increased after the morning infusion. PR‐prolongation was significantly greater after verapamil i.v. in the morning than in the evening. The 90% confidence intervals of the differences between morning and evening administration in AUCpo, Cmax and AUCiv were within the equivalence range of 0.8–1.25.Conclusions Time of dosing has no significant influence on pharmacokinetics and pharmacodynamics of this new modified release formulation of verapamil. Circadian variation in presystemic metabolism of verapamil was not observed.
Enantiomeric disposition of inhaled, intravenous and oral racemic‐salbutamol in man — no evidence of enantioselective lung metabolism
Authors: Ward Jonathan K. , Dow James , Dallow Nigel , Eynott Paul , Milleri Stefano , Ventresca G. Pietro 
Published: March 2003

Aims To establish whether enantioselective metabolism of racemic (rac )‐salbutamol occurs in the lungs by determining its enantiomeric disposition following inhalation, in the absence and presence of oral charcoal, compared with that following the oral and intravenous routes. Methods Fifteen healthy subjects (eight male) were randomized into an open design, crossover study. Plasma and urine salbutamol enantiomer concentrations were measured for 24 h following oral (2 mg) with or without oral charcoal (to block oral absorption), inhaled (MDI; 1200 μg) with or without oral charcoal and intravenous (500 μg) rac‐salbutamol. Systemic exposure (plasma AUC(0,∞) and urinary excretion (Au24h ) of both enantiomers were calculated, and relative exposure to (R)‐salbutamol both in plasma (AUC(R)‐/AUC(S)‐ ) and urine (Au(R)‐/Au(S)‐ ) was derived for each route. Relative exposure after the inhaled with charcoal and oral routes were compared with the intravenous route. Results AUC(R)‐/AUC(S)‐ [geometric mean (95% CI)] was similar following the intravenous [0.32 (0.28, 0.36)] and inhaled with charcoal rates [0.29 (0.24, 0.36); P=0.046], but was far lower following oral dosing [0.05 (0.03, 0.07); P<0.001]. Similar results were found when relative exposure was analysed using Au24h. Conclusions These results show no evidence of significant enantioselective presystemic metabolism in the lungs, whilst confirming it in the gut and systemic circulation, indicating that the (R)‐ and (S)‐enantiomers are present in similar quantities in the airways following inhaled rac‐salbutamol.
Non‐linear pharmacokinetics of MDMA (‘ecstasy’) in humans
Authors: De La Torre R. , Farré M. , Ortuño J. , Mas M. , Brenneisen R. , Roset P. N. , Segura J. , Camí J. 
Published: March 2003

Aims 3,4‐Methylenedioxymethamphetamine (MDMA, commonly called ecstasy) is a synthetic compound increasingly popular as a recreational drug. Little is known about its pharmacology, including its metabolism and pharmacokinetics, in humans in controlled settings. A clinical trial was designed for the evaluation of MDMA pharmacological effects and pharmacokinetics in healthy volunteers. Methods A total of 14 subjects were included. In the pilot phase six received MDMA at 50 (n=2), 100 (n=2), and 150 mg (n=2). In the second phase eight received MDMA at both 75 and 125 mg (n=8). Subjects were phenotyped for CYP2D6 activity and were classified as extensive metabolizers for substrates, such as MDMA, whose hepatic metabolism is regulated by this enzyme. Plasma and urine samples were collected throughout the study for the evaluation of MDMA pharmacokinetics. Body fluids were analysed for the determination of MDMA and its main metabolites 3,4‐methylenedioxyamphetamine (MDA), 4‐hydroxy‐3‐methoxy‐methamphetamine (HMMA) and 4‐hydroxy‐3‐methoxy‐amphetamine (HMA). Results As the dose of MDMA administered was increased, volunteers showed rises in MDMA concentrations that did not follow the same proportionality which could be indicative of nonlinearity. In the full range of doses tested the constant recovery of HMMA in the urine combined with the increasing MDMA recovery seems to point towards a saturation or an inhibition of MDMA metabolism (the demethylenation step). These observations are further supported by the fact that urinary clearance was rather constant while nonrenal clearance was dose dependent. Conclusions It has previously been postulated that individuals genetically deficient for the hepatic enzyme CYP2D6 (about 10% of the Caucasian people) were at risk of developing acute toxicity at moderate doses of MDMA because the drug would accumulate in the body instead of being metabolized and inactivated. The lack of linearity of MDMA pharmacokinetics (in a window of doses compatible with its recreational use) is a more general phenomenon as it concerns the whole population independent of their CYP2D6 genotype. It implies that relatively small increases in the dose of MDMA ingested are translated to disproportionate rises in MDMA plasma concentrations and hence subjects are more prone to develop acute toxicity.
The effects of ziprasidone on steady‐state lithium levels and renal clearance of lithium
Authors: Apseloff G. , Mullet D. , Wilner K. D. , Anziano R. J. , Tensfeldt T. G. , Pelletier S. M. , Gerber N. 
Published: March 2003

Aims  To assess the potential of ziprasidone to alter the renal clearance and steady‐state serum levels of lithium.Methods  Healthy subjects who had stable serum lithium levels during the first 7 days of treatment with lithium 900 mg day− 1, given as two divided daily doses, were randomized to receive concomitant treatment with either ziprasidone, 40 mg day− 1, given as two divided daily doses, on days 9–11 followed by 80 mg day− 1, given as two divided daily doses on days 12–15 (n = 12), or placebo twice daily (n = 13). Ziprasidone or placebo was administered 2 h before each dose of lithium.Results  Ziprasidone administration was associated with a 0.07 mmol l− 1 (13%) mean increase in steady‐state serum lithium levels compared with a mean increase of 0.06 mmol l− 1 (10%) with placebo. Mean renal clearance of lithium decreased by 0.09 l h− 1 (5%) in the ziprasidone group and by 0.14 l h− 1 (9%) in the placebo group. None of these differences between the two groups was statistically or clinically significant.Conclusions  Ziprasidone does not alter steady‐state serum lithium concentrations or renal clearance of lithium.