bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic characterization of the interaction between abciximab or tirofiban with unfractionated or a low molecular weight heparin in healthy subjects
Authors: Klinkhardt Ute , Graff Jochen , Westrup Dagmar , Kirchmaier Carl M. , Esslinger Hans‐Ulrich , Breddin Hans Klaus , Harder Sebastian 
Published: March 2003

Aims  The objective of our study was to define the interaction between either unfractionated heparin (UFH) or a low molecular weight heparin, reviparin (REV), and the pharmacodynamic profile of the GPIIb/IIIa‐antagonists abciximab (ABC) or tirofiban (T).Methods  Two studies each containing 18 healthy subjects were performed, and all were pretreated with aspirin (ASA) for 3 days. Volunteers then received UFH (5000 IU bolus/infusion 7 IU kg−1 h−1 for 7 h, n = 6), REV (4200‐anti‐Xa‐IU s.c., n = 6) or placebo (n = 6). One hour later, ABC (study I) or T (study II) were given by i.v. infusion for 6 h. The pharmacodynamic effects measured were bleeding time (BT), fibrinogen‐binding at the GPIIb/IIIa‐receptor (FIB), expression of the platelet secretion marker CD62, and ADP (20 µm)‐ and collagen (5 µg ml−1)‐induced platelet aggregation.Results  After treatment with both GPIIb/IIIa‐antagonists, prolongation of BT occurred to a similar magnitude (approximately 25–30 min) and was not affected by UFH or REV‐comedication. ABC or T with ASA alone resulted in nearly the same magnitude of reduction in FIB and platelet aggregation. After coadministration with UFH, FIB was significantly higher (thus less inhibited) than after after T + ASA alone (19 ± 16% vs 55 ± 36%) or ABC + ASA alone (8 ± 9% vs 32 ± 11%). This attenuation of FIB was not seen with REV. Inhibition of ADP‐and collagen‐induced aggregation tended to be attenuated by treatment with UFH (e.g. ADP‐induced aggregation at 0.25 h after ABC + ASA alone =13 ± 4%; after coadministration with UFH = 40 ± 26%). No such changes were noted with REV. Minor reductions in CD62‐expression were seen in subjects given ABC or T alone, but expression was not affected by UFH or REV.Conclusions  Co‐medication with UFH attenuated platelet inhibition during treatment with GPIIb/IIIa‐antagonists, but these effects were not seen with the low molecular weight heparin reviparin. The results show that administration of reviparin together with abciximab or tirofiban did not adversely affect the pharmacodynamic profile of these GPIIb/IIIa‐antagonists.
Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example
Authors: Ferner R. E. , Langford N. J. , Anton C. , Hutchings A. , Bateman D. N. , Routledge P. A. 
Published: March 2003

Aims  The nature and incidence of errors in prescribing and giving medicines have previously been estimated by trained observers, or by retrospective analysis of incidents in which patients have come to harm. We have examined prospectively in routine clinical practice the concentrations of intravenous infusions of a drug (acetylcysteine) which is given according to a complicated dosing schedule.Methods  We prospectively collected samples before and, where possible, after the infusion of acetylcysteine in 66 anonymous patients requiring treatment for acetaminophen (paracetamol) overdose in four centres in the United Kingdom. We measured the concentration in each infusion bag, and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given.Results  The experimentally determined dose was within 10% of the anticipated dose in 68 of 184 individual bags (37%), and within 20% of the anticipated dose in 112 bags (61%). Doses in 17 bags were more than 50% from the anticipated doses. In three patients, values in all three bags appeared to be systematically wrong by 50% or more; in a further seven cases, individual bags differed by 50% or more from the anticipated value. The median difference between pre‐ and post‐infusion samples was 0% [interquartile range −5.2% to +14.6%], but 9% showed a disparity of greater than ± 50%.Conclusions  Our data suggest that there is large random variation in administered dosage of intravenous infusions. Systematic calculation errors occur in about 5% [95% confidence interval 2, 8%] of cases, and major errors in drawing up in a further 3% [1, 7%], with inadequate mixing in 9% [4, 14%]. While we have no evidence that patients were adversely affected, and while the regime of administration of the drug studied (acetylcysteine) is complicated, these data suggest that the delivered dose often deviates from the intended dose, and that methods of quality control are needed.
Pharmacokinetics and systemic activity of fluticasone via Diskus® and pMDI, and of budesonide via Turbuhaler®
Authors: Thorsson Lars , Edsbäcker Staffan , Källén Anders , Löfdahl Claes‐Göran 
Published: March 2003

Aims To determine the basal pharmacokinetics, lung uptake and plasma cortisol suppression for two commonly prescribed inhaled corticosteroids.
Methods
Twenty‐one subjects (13 healthy and 8 mild asthmatic patients) received fluticasone propionate via a chlorofluorocarbon‐propelled pressurized metered‐dose inhaler (pMDI) (healthy subjects only) and Diskus® and budesonide via Turbuhaler®, 1000 µg twice daily for 7 days. Intravenous doses (200 µg) of both compounds were used as references. Plasma concentrations of fluticasone and budesonide were determined during 48 h by liquid chromatography plus tandem mass spectrometry (LC‐MS‐MS). Plasma concentrations of cortisol were determined by LC‐MS every second hour for 24 h at baseline, and following each treatment.
Results
The volume of distribution was found to be larger and the elimination half‐life and mean absorption time longer for fluticasone than for budesonide. The systemic availability of budesonide via Turbuhaler (39%) was significantly higher than that of fluticasone via Diskus (13%) (ratio 3.0 [2.5, 3.6] with 95% confidence interval [CI]), and via pMDI (21%) (ratio 1.8 [1.3, 2.3]). In addition, at steady state the systemic availability of fluticasone via pMDI was significantly higher than via Diskus (ratio 1.6 [1.1, 2.2]). The lung deposition of budesonide via Turbuhaler was 2.2‐fold [1.7, 2.9] higher than that of fluticasone pMDI and 3.4‐fold [2.8, 4.0] higher than that of fluticasone Diskus. In addition, the lung deposition of fluticasone via pMDI was 1.5‐fold [1.1, 2.9] higher than that via the Diskus inhaler. Plasma cortisol (24 h) was significantly reduced vs baseline for all three treatments. The cortisol concentration vs baseline was 12% for fluticasone pMDI, which was significantly lower (ratio 0.32 [0.24, 0.42]) than that for fluticasone Diskus (39%), and for budesonide Turbuhaler (46%) (ratio 0.27 [0.21, 0.37]). The plasma cortisol concentration did not differ significantly between treatments with fluticasone Diskus and budesonide Turbuhaler (ratio 0.87 [0.65; 1.15]).
Conclusions
Budesonide and fluticasone differ in their pharmacokinetic properties in that although clearance is the same, the rate of uptake and elimination is slower for fluticasone. Despite a significantly higher pulmonary availability of budesonide via Turbuhaler, the plasma cortisol suppression is less than that of fluticasone via pMDI and similar to that of fluticasone via Diskus. There is no indication of any difference between healthy subjects and mild asthmatic patients in the pharmacokinetics and plasma cortisol suppression of fluticasone and budesonide.
Opioid analgesic prescribing and use – an audit of analgesic prescribing by general practitioners and The Multidisciplinary Pain Centre at Royal Brisbane Hospital
Authors: Nissen L. M. , Tett S. E. , Cramond T. , Williams B. , Smith M. T. 
Published: March 2003

Aims  This study evaluated the use of and need for opioids in patients attending the Multidisciplinary Pain Centre at the Royal Brisbane Hospital (RBH).Methods  All consecutive in‐patient admissions in 1998 were reviewed. A 10‐point scoring system based on the World Health Organization (WHO) analgesic ladder was devised to facilitate comparison of analgesic prescribing on admission and at the time of discharge. A conversion table was used to standardize opioid analgesic doses to an oral morphine equivalent.Results  Of the 370 patients reviewed, 233 (81%) were by their general practitioners. Records of 288 (78%) were available for full review and 270 (94%) of these had noncancer pain. On admission, 239 (83%) were taking an opioid analgesic, with 135 (47%) taking strong opioids (e.g. morphine, oxycodone, methadone). There was a significant decrease in the mean total daily oral morphine equivalent prescribed on discharge 36.9 mg (95% CI: 33.4, 40.4) compared with that on admission 88.7 mg (95% CI: 77.6, 99.8) (P < 0.001). There was a significant decrease (P < 0.05) in the proportion of patients taking a primary opioid on discharge 153 (58%) compared with admission 239 (83%), although the proportion of patients taking a strong opioid on discharge 150 (52%) compared with admission 135 (47%) was not significantly different (P > 0.05). The proportion of patients taking a laxative showed a significant increase on discharge 110 (73%) compared with admission 38 (28%) (P < 0.05).Conclusions  Our analgesic prescribing scoring system and opioid conversion table have the potential to be developed further as tools for assessing opioid analgesic prescribing. The significant decrease in total daily oral morphine equivalents signifies the value of prescribing in accordance with the WHO analgesic ladder, and the necessity of general practitioner education. The management of chronic pain is complex, and it requires interventions additional to pharmacological therapy. Evaluation by a multidisciplinary team, coupled with experience in and an understanding of analgesic prescribing and rehabilitation provides an effective basis for improving the management of patients with chronic pain.
Allometric plasticity in a polyphenic beetle
Authors: Moczek Armin P. 
Published: March 2003

Abstract1. Environmental conditions, such as variation in nutrition, commonly contribute to morphological variation among individuals by affecting body size and the expression of certain morphological traits; however the scaling relationship between a morphological trait and body size over a range of body sizes is generally assumed not to change in response to environmental fluctuation (allometric plasticity), but instead to be constant and diagnostic for a particular trait and species or population. The work reported here examined diet‐induced allometric plasticity in the polyphenic beetleOnthophagus taurusSchreber (1759) (Coleoptera: Scarabaeidae).2. MaleO. taurusvary in body size depending on larval nutrition. Only males above a critical body size threshold express fully developed horns; males smaller than this threshold develop only rudimentary horns or no horns at all.3. Field populations that naturally utilise two different resources for feeding larvae (horse dung vs. cow manure) exhibited significant differences in the average scaling relationship between body size and male horn length over the same range of body sizes. Males collected from cow manure populations expressed consistently longer horns for a given body size than males collected from horse dung populations.4. Males reared in the laboratory on horse dung or cow manure also exhibited significant differences in the average scaling relationship between body size and horn length. Differences between laboratory populations reared on horse dung or cow manure were of the same kind and magnitude as differences between field populations that utilise these different resources naturally.5. These findings suggest that between‐population differences in scaling relationships between horn length and body size can be the product of differences in the quality of resources available to developing larvae. Results are discussed in the context of onthophagine mating systems and recent insights in the developmental and endocrine control of horn polyphenisms.
Brain natriuretic peptide increases urinary albumin and alpha‐1 microglobulin excretion in Type 1 diabetes mellitus
Authors: McKenna K. , Smith D. , Moore K. , Glen A. , Tormey W. , Thompson C. J. 
Published: March 2003

AbstractAtrial natriuretic peptide (ANP) increases urinary albumin excretion in Type 1 diabetes mellitus (DM). Brain natriuretic peptide (BNP) is structurally and functionally related to ANP, but its effect on urine albumin excretion rate (UAER) is unknown.Aims  To compare the albuminuric effects of intravenous infusion of ANP and BNP, and to assess the effect of both peptides on tubular protein excretion.Methods  Eight subjects with Type 1 DM were randomised to a three leg, double blind, and placebo controlled study. On each study day, subjects were euglycaemic clamped and subsequently water loaded (20 mL/kg orally, plus urine losses) to steady state diuresis. When in steady state, creatinine clearance was estimated in three separate 1 hour periods. At the end of the first period, a 1 hour intravenous infusion of either placebo, ANP 0.025 μg/kg/min, or BNP 0.025 μg/kg/min was administered. There followed a 1 hour recovery period. Urine was collected at 15 min intervals for estimation of urine albumin (ACR) and α1 microglobulin creatinine ratio (MCR). Results were analysed by anova.Results  Creatinine clearance was similar on the three study days, and was unaltered by any infusion. ACR was unaltered by placebo (1.3 ± 0.5–1.2 ± 0.4 mg/mmol, mean ± SD, p = 0.81), but increased compared to placebo with infusion of both ANP (1.2 ± 0.4–9.8 ± 8.4 mg/mmol, P = 0.0004), and BNP (1.1 ± 0.4–13.4 ± 8.6 mg/mmol, P = 0.0001). The MCR was unaltered by placebo infusion (P = 0.89), but increased compared with placebo after infusion of ANP (5.4 ± 0.9–12.3 ± 4.2 mg/mmol, P < 0.0001), and BNP (5.4 ± 0.8–12.1 ± 2.5 mg/mmol, P < 0.0001).Conclusions  Intravenous infusion of BNP and ANP both increase the urine excretion of albumin and the tubular protein α1 microglobulin, independent of creatinine clearance.Diabet. Med. 18, 973–978 (2001)
Double‐blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients
Authors: Gæde P. , Poulsen H. E. , Parving H.‐H. , Pedersen O. 
Published: March 2003

AbstractAims  Elevated levels of urinary albumin excretion rate (AER) predict high risk for progressing to end‐stage renal disease. In streptozotocin‐induced diabetes, supplementation with vitamin C or E reduces albuminuria and glomerular hypertrophy. We tested the hypothesis that supplementation of both vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with persistent micro/macroalbuminuria.Methods  Thirty Type 2 diabetic patients with AER 30–300 mg/24 h were included in a double‐blind randomised, cross‐over trial. Patients received vitamin C (1250 mg) and vitamin E (680 IU) per day or matching placebo for 4 weeks with a 3‐week wash‐out period between treatment periods in random order.Results  Combined treatment with vitamin C and E reduced AER by 19% (95% CI 6–34%) (p = 0.04), geometric mean 197 mg/24 h (95% CI 114–341 mg/24 h) vs. 243 mg/24 h (146–404 mg/24 h). No changes were seen in serum creatinine, haemoglobin A1C or blood pressure. Fasting plasma concentrations of vitamin C and E increased in all patients during active treatment (mean vitamin C 79.4 μmol/L (SD 27.8) vs. 41.9 μmol/L (18.4) and vitamin E 47.0 μmol/L (19.8) vs. 29.5 μmol/L (15.3), P < 0.000001). Except for two patients that started additional blood pressure lowering treatment during the run‐in period, no changes in medication, food and exercise habits or in the number of smokers occurred during the study.Conclusion  Short‐term treatment with vitamin C and E in pharmacological doses lowers AER in Type 2 diabetic patients with micro/macroalbuminuria. Further long‐term, large‐scale studies of this albuminuria reducing treatment modality are warranted.Diabet. Med. 18, 756–760 (2001)
Control of secretion by mitochondria depends on the size of the local [Ca2+] after chromaffin cell stimulation
Authors: Montero Mayte , Alonso Maria Teresa , Albillos Almudena , Cuchillo‐Ibáñez Inmaculada , Olivares Román , G. García Antonio , García‐Sancho Javier , Alvarez Javier 
Published: March 2003

AbstractIn chromaffin cells, plasma membrane calcium (Ca2+) channels and mitochondria constitute defined functional units controlling the availability of Ca2+ nearby exocytotic sites. We show here that, when L‐/N‐type Ca2+ channels were inhibited with nisoldipine and ω‐conotoxin GVIA, cytosolic [Ca2+] ([Ca2+]c) peaks measured in fura‐4F‐loaded cells were reduced by 36%; however, mitochondrial Ca2+ uptake was unaffected and secretion was potentiated by protonophores as in control cells. By contrast, when non L‐type Ca2+ channels were inhibited with ω‐conotoxin MVIIC, [Ca2+]c peaks induced by high K+ were reduced by 73%, mitochondrial Ca2+ uptake was abolished, and secretion was not modified by protonophores. However, if Ca2+ entered only through L‐type channels activated by FPL64176, high K+ stimulation induced fast mitochondrial Ca2+ uptake and catecholamine secretion was strongly increased and potentiated by protonophores. These results confirm the close association of catecholamine secretion to mitochondrial Ca2+ uptake, and indicate the sharp threshold of local [Ca2+]c (about 5 µm) required for triggering fast mitochondrial Ca2+ uptake that is able to modulate secretion. The entry of Ca2+ through L‐type channels generated local [Ca2+]c increases just below that, inducing little mitochondrial Ca2+ uptake unless FPL64176 was present. By contrast, Ca2+ entry through P/Q‐type channels fully activated mitochondrial Ca2+ uptake. Control of secretion by mitochondria therefore depends critically on the ability of the stimulus to create large local [Ca2+]c microdomains.
Effects of post‐inhalation treatment with interleukin‐12 on airway hyper‐reactivity, eosinophilia and interleukin‐18 receptor expression in a mouse model of asthma
Authors: Kuribayashi K , Kodama T , Okamura H , Sugita M , Matsuyama T 
Published: March 2003

SummaryBackground  Correcting Th1/Th2 imbalance with administration of IL‐12 before and during antigen challenge holds therapeutic promise in asthma. However, the effects of IL‐12 on the established asthmatic responses have not fully been examined.Objective  We investigated whether IL‐12 administered after antigen challenge could diminish airway hyper‐reactivity (AHR) and eosinophilia in mice actively sensitized to ovalbumin. We also have investigated the ability of administered IL‐12 to induce IL‐18 receptor (IL‐18R) expression that may lead possible synergic action of IL‐12 with endogenous IL‐18.Methods  C57BL/6 mice immunized to ovalbumin (OVA) by intraperitoneal (i.p.) injection, were challenged three times with an aerosol of OVA every second day for 8 days. Recombinant IL‐12 (500 ng) was intravenously administered on a single occasion 1 h after the final challenge of mice. Mice were analysed for effects of IL‐12 on AHR, inflammatory cell infiltration and cytokine levels in lung tissue as well as serum immunoglobulin (Ig) E levels. Immunohistochemistry for IL‐18R was performed using rat monoclonal antibody specific for murine IL‐18Rα (IL‐1 receptor related protein; IL‐1Rrp).Results  An intravenous IL‐12 administration diminished AHR, pulmonary eosinophilia and T lymphocyte infiltration, serum IgE, IL‐4 and IL‐13 in lung tissue. Expression of IL‐18R was induced in the mononuclear cells in the lung of mice exposed to OVA. IL‐12 administration enhanced the IL‐18R expression compared with the control.Conclusion  These data indicate that IL‐12 can attenuate established antigen‐induced AHR and inflammation. In this mechanism it would be interpreted as follows: IL‐12 administration in OVA‐challenged mice decreased IL‐4 production and IgE production thereafter through direct effect on inhibiting the activation of established Th2 cells response and also combined effect with up‐regulation of IL‐18R expression by inflammatory cells in the lung.
Depth distribution of earthquakes in the Baikal rift system and its implications for the rheology of the lithosphere
Authors: Déverchère Jacques , Petit Carole , Gileva Nadejda , Radziminovitch Natalia , Melnikova Valentina , San'Kov Vladimir 
Published: March 2003

AbstractThe correspondence between the predicted brittle–plastic transition within the crust and the maximum depth of earthquakes is examined in the case of the Baikal rift, Siberia. Although little accurate information on depths is available through large- and moderate-size earthquakes, there are frequent indications of foci at 20 km depth and more. We have relocated 632 events recorded at nearby stations that occurred between 1971 and 1997, with depth and epicentral uncertainties less than 5 km, over the eastern and southern parts of the Baikal rift. We have compared these results with other depth distributions obtained in previous studies from background seismicity in the NE rift (1365 events in the Kalar-Chara zone and 704 events in the Muya region). The relative abundance of earthquakes is generally low at depths between 0 and 10 km (7–15 per cent) and high between 15 and 25 km (∼50 per cent). Earthquake activity is still significant between 25 and 30 km (9–15 per cent) and persists between 30 and 40 km (7–13 per cent). Very few earthquakes are below the Moho. We use empirical constitutive laws to obtain the yield-stress limits of several layers made of dominant lithologies and to examine whether the observed distribution of earthquakes at depth (519 events controlled by a close station and located within the extensional domain of the Baikal rift system) can match the predicted crustal strength proportion with depth and the deeper brittle–ductile transition in the crust. A good fit is obtained by using a quartz rheology at 0–10 km depth and a diabase rheology at 10–45 km depth with a moderate temperature field which corresponds to a ∼100 Myr thermal lithosphere. No dioritic composition of the crust is found necessary. In any case, earthquakes occur at deep crustal levels, where the crust is supposed to be ductile, in a way very similar to what is found in the East African Rift System. From these results we conclude that the seismogenic thickness is ∼35–40 km in the Baikal rift system and that the depth distribution of earthquakes is at first order proportional to the strength profile found in a rheologically layered crust dominated by a mafic composition in the ∼10–45 km depth range. An upper mantle core with high strength, however, generally prevents it from reaching stress failure at greater depth.