bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fishing for novel angiogenic therapies
Authors: Kidd Kameha R , Weinstein Brant M 
Published: October 2003

The zebrafish has recently emerged as an important model for the study of vascular embryogenesis. Its genetic accessibility, external development, and optically clear embryo are just a few of the features that set the zebrafish apart as a particularly well‐suited model for studying vascular development. However, there is little precedent for its use as a tool for the experimental study of therapeutic angiogenesis. Here, we review the use of the zebrafish for studying vascular development and patterning, and discuss how the zebrafish might be used more directly as a model for developing and testing effective therapeutic angiogenesis approaches.British Journal of Pharmacology (2003) 140, 585–594. doi:10.1038/sj.bjp.0705496
In vitro inhibition of human neutrophil histotoxicity by ambroxol: evidence for a multistep mechanism
Authors: Ottonello Luciano , Arduino Nicoletta , Bertolotto Maria , Dapino Patrizia , Mancini Marina , Dallegri Franco 
Published: October 2003

Neutrophils are major culprits for the protease/antiprotease imbalance during various lung diseases, that is, chronic obstructive pulmonary disease, cystic fibrosis, idiopathic pulmonary fibrosis and adult respiratory distress syndrome. Thus, these cells are presently considered an ideal target for the pharmacologic control of tissue injury during these diseases.
This study was planned in order to investigate if ambroxol and its precursor bromhexine are actually capable of preventing alpha‐1‐antitrypsin (A1AT) inactivation by stimulated neutrophils and possibly to look into the mechanisms underlying this event.
Ambroxol inhibited the production of superoxide anion by activated neutrophils, whereas bromhexine had no inhibitory effect.
Ambroxol decreased the production of hypochlorous acid (HOCl) from activated neutrophils with high efficiency, whereas bromhexine had a modest activity.
Ambroxol and bromhexine were capable of limiting the chlorination of monochlorodimedon by HOCl, displaying the capacity of directly scavenging the oxidant.
Ambroxol decreased the release of elastase and myeloperoxidase from activated neutrophils, whereas bromhexine was ineffective.
Ambroxol prevented the A1AT inactivation by neutrophils, whereas bromhexine was completely ineffective.
Among drugs currently available for in vivo use in humans, ambroxol is unique by virtue of its ability to prevent neutrophil‐mediated A1AT inactivation via inhibition of HOCl production as well as HOCl scavenging. Also taking into account its capacity for curbing elastase release, the drug displays the potential to lessen the burden of oxidants/proteases and to increase the antiprotease shield at the site of inflammation. Thus, ambroxol appears to be a good candidate for raising attempts to develop new therapeutic histoprotective approaches to inflammatory bronchopulmonary diseases.

British Journal of Pharmacology (2003) 140, 736–742. doi:10.1038/sj.bjp.0705497
Mechanisms involved in the early increase of serotonin contraction evoked by endotoxin in rat middle cerebral arteries
Authors: Hernanz Raquel , Alonso María J , Briones Ana M , Vila Elisabet , Simonsen Ulf , Salaices Mercedes 
Published: October 2003

The present study investigated the mechanisms involved in the increased 5‐hydroxytryptamine (5‐HT) vasoconstriction observed in rat middle cerebral arteries exposed in vitro to lipopolysaccharide (LPS, 10 μg ml−1) for 1–5 h. Functional, immunohistochemical and Western blot analysis and superoxide anion measurements by ethidium fluorescence were performed.
LPS exposure increased 5‐HT (10 μM) vasoconstriction only during the first 4 h. In contrast to control tissue, indomethacin (10 μM), the COX‐2 inhibitor NS 398 (10 μM), the TXA2/PGH2 receptor antagonist SQ 29,548 (1 μM) and the TXA2 synthase inhibitor furegrelate (1 μM) reduced 5‐HT contraction of LPS‐treated arteries from hour one. The iNOS inhibitor aminoguanidine (0.1 mM) increased 5‐HT contraction from hour three of LPS incubation.
The superoxide anion scavenger superoxide dismutase (SOD, 100 U ml−1) and the H2O2 scavenger catalase (1000 U ml−1), as well as the respective inhibitors of NAD(P)H oxidase and xanthine oxidase, apocynin (0.3 mM) and allopurinol (0.3 mM), reduced 5‐HT contraction after LPS incubation. LPS induced an increase in superoxide anion levels that was abolished by PEG‐SOD.
Subthreshold concentrations of the TXA2 analogue U 46619, xanthine/xanthine oxidase and H2O2 potentiated, whereas those of sodium nitroprusside inhibited, the 5‐HT contraction.
COX‐2 expression was increased at 1 and 5 h of LPS incubation, while that of iNOS, Cu/Zn‐SOD and Mn‐SOD was only increased after 5 h. All the three vascular layers expressed COX‐2 and Cu/Zn‐SOD. iNOS expression was detected in the endothelium and adventitia after LPS.
In conclusion, increased production of TXA2 from COX‐2, superoxide anion and H2O2 enhanced vasoconstriction to 5‐HT during the first few hours of LPS exposure; iNOS and SOD expression counteracted that increase at 5 h. These changes can contribute to the disturbance of cerebral blood flow in endotoxic shock.

British Journal of Pharmacology (2003) 140, 671–680. doi:10.1038/sj.bjp.0705501
The Influence of Probe Fiber Distance on Laser Doppler Perfusion Monitoring Measurements
Authors: MORALES FERNANDO , GRAAFF REINDERT , SMIT ANDRIES J. , GUSH RODNEY , RAKHORST GERHARD 
Published: October 2003

ABSTRACTLaser Doppler perfusion monitoring (LDPM) is a noninvasive technique for monitoring skin microcirculation. The aim of this article was to investigate the influence of fiber separation on clinical LDPM measurements. A dual‐channel LDPM system was used in combination with a probe that consists of two sets of detection fibers, at 0.2 and 1.0 mm from the illuminating fiber. Measurements were performed at the big toe of 8 healthy subjects and 11 subjects who had vascular disorders. In most cases, fluxes detected at both fiber distances showed very similar fluctuations. For each fiber separation, flux values of healthy subjects and patients were not significantly different. Furthermore, skin temperature (range: 22–34°C) influenced the toe's pulp microcirculation markedly, increasing similarly at both probe separations, with a higher flux at a separation of 1.0 mm than at 0.2 mm. The flux ratio signal, obtained by dividing the flux at 0.2 mm by the flux at 1.0 mm, was significantly different between the two groups (p < 0.05). In conclusion, the flux detected in vivo by means of LDPM, is influenced by the distance between the optical fibers. Use of the flux ratio with a multiseparation probe deserves attention as it is a possible marker for discriminating normal tissue perfusion from pathological skin tissue perfusion, independently from tissue temperature.
Hepatic Microcirculatory Dysfunction During Cholestatic Liver Injury in Rats
Authors: ITO YOSHIYA , BETHEA NANCY W. , BAKER GREGORY L. , MCCUSKEY MARGARET K. , URBASCHEK RENATE , MCCUSKEY ROBERT S. 
Published: October 2003

ABSTRACTObjective: The present study was conducted to elucidate the sequential alterations in the hepatic microvascular inflammatory response to extrahepatic biliary obstruction.Methods: The hepatic microvasculature in anesthetized Sprague‐Dawley rats was studied by in vivo microscopy 3, 7, and 14 days after bile duct ligation (BDL) or sham operation.Results: The numbers of adhering leukocytes and swollen sinusoidal endothelial cells were significantly increased at 3, 7, and 14 days after BDL when compared with sham‐operated controls. Concomitantly, the numbers of sinusoids containing blood flow were significantly and progressively decreased by up to 30%. The phagocytic activity of hepatic macrophages was significantly elevated during the development of biliary cholestasis. In particular, centrilobular phagocytosis at 14 days after BDL was significantly increased 1.4‐ to 2.0‐fold when compared with that at 3 and 7 days after BDL. Electron microscopy also revealed evidence of activated Kupffer cells reflected by numerous filopodia and ruffles.Conclusions: These results suggest that hepatic microcirculatory dysfunction subsequent to BDL contributes to cholestatic liver injury.
A method for simultaneous determination of plasma and erythrocyte antioxidant status. Evaluation of the antioxidant activity of vitamin E in healthy volunteers
Authors: ABELLA ANNIE , MESSAOUDI CHERIF , LAURENT DENIS , MAROT DIDIER , CHALAS JACQUELINE , BREUX JOCELYNE , CLAISE CATHERINE , LINDENBAUM ALBERT 
Published: October 2003

1Since oxygen free radicals are directly involved in a variety of pathologies such as atherosclerosis, diabetes mellitus, inflammation and/or when a deficit of defences of the organism against radicals occurs, we developed a suitable and simple method to determine both the erythrocyte sensitivity to an oxidative stress and plasma antioxidant protective capacity. 2This test is based on the introduction at 37° C of a radical initiator, 2,2′‐azobis (2‐amidinopropane) dihydrochloride (AAPH), within an erythrocyte suspension leading to a membrane alteration and ultimately to haemolysis. The latter can be quantified by determining the lacticodeshydrogenase activity released in the medium. The erythrocyte sensitivity to haemolysis and the volume of plasma inhibiting 50% of the haemolysis were determined. 3Intra‐assay CVs were 1.9 % for erythrocyte sensitivity to oxidative stress and 3.4% for inhibitory 50% plasma volume. Inter‐assay CVs for both erythrocyte sensitivity and inhibitory 50% plasma volume were 4%. 4The reliability of this method was assessed and applied to test the protective effect of vitamin E, a well known antioxidant agent, in six healthy volunteers. Two weeks after daily administration of 500 mg of vitamin E, the mean plasma vitamin E concentration increased by 41% from 10.7±2.0 mg l−1 before treatment (P<0.05). As the vitamin E concentration increased, the mean inhibitory 50% plasma volume and the percentage of haemolysed erythrocytes decreased respectively by 29% from 3.35±0.5 μl (P<0.05) and 18% from 71.5±3.8% (P<0.05). No significative variation of these parameters was observed in six adult men without vitamin E supplementation. 5Thus, this global and simple test permits an antioxidant status evaluation of a patient. It can be applied to various pathologies and allows the potency of new antioxidant molecules to be evaluated.
Comparison of the effects of clonidine on tyramine‐ and methoxamine‐evoked mydriasis in man
Authors: BITSIOS P. , LANGLEY R. W. , SZABADI E. , BRADSHAW C. M. 
Published: October 2003

1 It has been reported previously that clonidine can potentiate tyramine‐evoked mydriasis on the pain‐free side of cluster headache patients. We examined whether a single oral dose of clonidine (200 μg) can also potentiate tyramine‐evoked mydriasis in healthy subjects, using mydriasis to methoxamine, a directly acting sympathomimetic amine, as a control. 2 Eight healthy male volunteers participated in four weekly sessions. In the first two sessions (Experiment 1) the effect of clonidine or placebo on the mydriasis to tyramine hydrochloride eyedrops (75 mm; 2×10 μl), and in the last two sessions (Experiment 2) the effect of clonidine or placebo on the mydriasis to methoxamine hydrochloride eyedrops (20 mm; 2×10 μl) was examined. In both experiments subjects were allocated to drugs and sessions according to a double‐blind balanced design. In both experiments, pupil diameter of both the treated and the untreated eyes was recorded in standard ambient light and in the dark, before, and 2 h after clonidine/placebo, via binocular infrared television pupillometry. Salivation (dental roll technique), systolic and diastolic blood pressure (sitting), heart rate, and self‐ratings of mood and feelings (visual analogue scales), were also measured before, and 2 h after the ingestion of clonidine or placebo. 3 Both tyramine and methoxamine produced a significant mydriasis, which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: tyramine/light 1.05±0.28; tyramine/dark: 0.73±0.15; methoxamine/light: 1.65±0.28; methoxamine/dark: 0.85±0.15). Clonidine produced a significant miosis in the untreated eye which was more prominent in the light condition (change in resting pupil size; mm±s.e.mean: Experiment 1, light: −1.34±0.19; Experiment 1, dark: −0.46±0.1; Experiment 2, light −0.97±0.18; Experiment 2, dark: −0.29±0.17). Clonidine had no significant effect on either tyramine‐ or methoxamine‐evoked mydriasis. 4 In agreement with previous reports, clonidine significantly reduced salivation (g, mean±s.e.mean; Experiment 1: −0.84±0.22; Experiment 2: −0.55±0.11), systolic blood pressure (mm Hg; Experiment 1: −17.5±3.76; Experiment 2: −23.38±4.67), diastolic blood pressure (mm Hg; Experiment 2: −12.38±2.05), alertness (mm; Experiment 2: −24.19±5.40), and anxiety (mm; Experiment 1: −13.82±4.60), indicating the presence of pharmacodynamically effective tissue levels of the drug. 5 These results show that a single oral dose (200 μg) of clonidine causes significant miosis in human subjects, and fails to potentiate tyramine‐evoked mydriasis. This indicates that the pupil on the asymptomatic side of cluster headache patients is affected differently from the pupils of healthy volunteers by tyramine and/or clonidine.
8‐Epi PGF2α: specific analysis of an isoeicosanoid as an index of oxidant stress in vivo
Authors: DELANTY N. , REILLY M. , PRATICO D. , FITZGERALD D. J. , LAWSON J. A. , FITZGERALD G. A. 
Published: October 2003

1Excessive free radical generation is thought to contribute to tissue injury in a broad spectrum of diseases. A particular constraint in addressing this hypothesis has been the inability to assess free radical generation in vivo and the lack of information on drugs or vitamins which act as effective antioxidants in vivo. 2Traditional approaches have relied upon measures of substrate oxidizability or spin trapping of free radical adducts ex vivo. It is unknown how these measurements might relate, in a quantitative fashion, to the generation of reactive oxygen species in vivo. Isoeicosanoids are free radical catalyzed products of arachidonic acid. One of these compounds, 8‐epi prostaglandin F2α (8‐epi PGF2α) exhibits biological activity and may function as an autacoid. Specific analysis of this 8‐epi PGF2α isomer indicates that it is elevated in certain syndromes thought to be associated with oxidant stress. These include vascular reperfusion, paracetamol poisoning and liver cirrhosis. Apparently healthy individuals who smoke cigarettes or consume alcohol exhibit dose dependent increments in excretion of 8‐epi PGF2α. Excretion is depressed by antioxidant vitamins, although not by the nonspecific cyclooxygenase (COX) inhibitor, aspirin, even though 8‐epi PGF2α may be formed by either COX‐1 or COX‐2. 3Specific analysis of this and other isoeicosanoids may afford an opportunity to evaluate the effects of antioxidant interventions in human diseases characterized by excessive lipid peroxidation in vivo.
Cholesterol lowering therapy inhibits the low‐flow mediated vasoconstriction of the brachial artery in hypercholesterolaemic subjects
Authors: MEGNIEN JEAN LOUIS , SIMON ALAIN , ANDRIANI ANTONIA , SEGOND PATRICK , JEANNIN SOPHIE , LEVENSON JAIME 
Published: October 2003

1We tested whether lipid lowering treatment with HMG CoA reductase inhibitor modified the flow mediated large artery reactivity in primary pure hypercholesterolaemia.2Abnormalities in arterial reactivity have been described in the presence of high blood cholesterol, in particular an enhanced constriction of the brachial artery in response to acute induction of a low flow state.3Using pulsed‐Doppler, we measured brachial artery diameter and flow velocity at rest and their changes induced by wrist occlusion before and after 3 months of double‐blind treatment by pravastatin (40 mg orally) in 13 subjects and placebo in 15 others.4The significant decrease (P<0.01) in diameter induced by wrist occlusion before (0.34±0.08 mm) placebo and pravastatin (0.39±0.10 mm) persisted after placebo (0.26±0.07 mm) but was abolished after pravastatin (0.07±0.05 mm). The absolute change in diameter induced by wrist occlusion was lower after than before pravastatin (P<0.01) and lower after pravastin than after placebo (P<0.05). Diameter during wrist occlusion was higher after pravastatin than after placebo (4.35±0.16 vs 3.89±0.09 mm); P<0.01).5These findings indicate that the lipid changes induced by pravastatin and/or some unknown but direct mechanism of the drug itself inhibit low‐flow‐mediated vasoconstriction associated with hypercholesterolaemia. Such effects may have important implications for the treatment of vasospasm often seen in the presence of high blood cholesterol.
Taste loss to terbinafine: a case‐control study of potential risk factors
Authors: STRICKER B. H. Ch. , VAN RIEMSDIJK M. M. , STURKENBOOM M. C. J. M. , OTTERVANGER J. P. 
Published: October 2003

1To identify risk factors associated with taste loss to terbinafine, we performed a case‐control study of 87 reports of probable terbinafine‐induced taste loss and 362 controls on terbinafine without taste loss, who had filled prescriptions from the same pharmacy and GP. Data on general health, diet, alcohol, smoking, drug use and medical history were collected by means of a self‐administered questionnaire. 2The mean latent period between first intake of terbinafine and taste loss was 35 days. Most patients recovered within 4 months after discontinuation. Cases were significantly older than controls. The odds ratio of taste loss in patients of 65 years and older was 4.4 in comparison with persons younger than 35 years of age (95% CI: 1.4–16.1). The risk in persons with a body mass index (BMI) below 21 kg m−2 was 4.4 times higher than in those with a BMI of more than 27 kg m−2 (95% CI: 1.6–14.2). The risk of taste loss in patients of 55 years and older with a BMI below 21 kg m−2 was 12.8 times higher than that in patients below 35 years of age (95% CI: 1.9–88.6). 3A low BMI, a history of taste loss, and ageing are risk factors for developing taste loss to terbinafine. Prescription of this drug to elderly patients with low BMI and low daily intake of nutrients requires careful follow‐up.
Estimating impossible curves using NONMEM
Authors: SCHOEMAKER RIK C. , COHEN ADAM F. 
Published: October 2003

1On fitting model equations to experimental data, the situation may arise that individual subjects provide insufficient information to obtain adequate parameter estimates due to the fact that not all aspects are exhibited by all subjects or that the models are simply too complex. This may be solved by applying nonlinear mixed effect modelling to the data, which integrates the information provided by different subjects. 2We aim to provide insight into the methodology and its use in these situations, illustrated by three examples: determination of pharmacokinetics in a rising dose design, where the lower doses provide insufficient information (due to assay limitations) to estimate terminal half‐life; determination of the kinetics of the low molecular weight heparin enoxaparine (Clexane®) using anti‐Xa activity, effectively dealing with lingering low/basal activity; simultaneous estimation of the pharmacokinetics and pharmacodynamics of the low molecular weight heparin dalteparine (Fragmin®) after subcutaneous and intravenous administration.
Influence of concurrent antiepileptic medication on the pharmacokinetics of lamotrigine as add‐on therapy in epileptic children
Authors: VAUZELLE‐KERVROËDAN F. , REY E. , CIEUTA C. , PARIENTE‐KHAYAT A. , PONS G. , D′ATHIS P. , BIDAULT R. , DULAC O. , OLIVE G. 
Published: October 2003

1 Lamotrigine is a new antiepileptic drug, chemically unrelated to currently used antiepileptic medication. Its pharmacokinetics can be influenced by concomitant antiepileptic medication. 2 This study was performed to assess the pharmacokinetic profile of lamotrigine in three groups of children treated with different types of comedication: drugs known to induce, to inhibit or to have no clinically significant influence on drug metabolism, respectively. 3 Thirty‐one children aged 6 months to 5 years were included and received a 2 mg kg−1 single oral dose. Lamotrigine plasma profiles were different between the three comedication groups. The half‐lives (mean±s.d.) were: 7.7±1.8 h, 21.9±6.8 h, 44.7±10.2 h in the ‘inducer’, ‘other’ and ‘inhibitor’ groups respectively. 4 Patients were then dosed to steady state, with the dosage adjusted on the basis of the single dose pharmacokinetics to achieve a minimum plasma concentration between 1.5 and 3 mg l−1. The mean minimum plasma concentration for the three groups was 2.54±1.28 mg l−1 at steady state. 5 Dosage of lamotrigine can be optimised with knowledge of the metabolic effects of antiepileptic comedication.
Pharmacokinetics of intravenous fluticasone propionate in healthy subjects
Authors: MACKIE A. E. , VENTRESCA G. P. , FULLER R. W. , BYE A. 
Published: October 2003

1Fluticasone propionate (FP) is a potent glucocorticoid used in the treatment of asthma. Prior to reporting the pharmacokinetics following the inhaled and oral routes, the pharmacokinetics need to be established following intravenous dosing. The present study determines the intravenous pharmacokinetics of FP, using non‐compartmental analysis, in healthy male subjects over the 250 to 1000μg dose range. 2The pharmacokinetics of FP can be regarded as being linear over this dosing range. FP was extensively distributed within the body (Vss 318 l), rapidly cleared (CL 1.1 l min−1) with a terminal elimination half‐life of 7.8 h and a mean residence time of 4.9 h. 3In order that future pharmacokinetic/pharmacodynamic and other modelling can be carried out, the plasma concentration‐time profiles were parameterized using a model based on sums of exponentials, the appropriateness of this model was justified as the secondary kinetic parameters from the model were similar to those obtained using non‐compartmental analysis.
Hypertensive cardiac hypertrophy—is genetic variance the missing link?
Authors: NUNEZ DEREK J. R. , PIERS CLIFFORD C. , AL‐MAHDAWI SAHAR , DUTKA DAVID 
Published: October 2003

1Hypertensive cardiac hypertrophy is a major independent predictor of adverse cardiovascular events. In man the cardiac response to increased afterload is very variable, even when ambulatory blood pressure monitoring is used. Analysis of breeding experiments using normotensive and hypertensive rat strains, human twin studies and other data indicate that genetic factors play a significant role in regulating cardiac mass; in other words, a large component of total variability is accounted for by genetic variance. 2The observation that some patients with only mild‐to‐moderate hypertension exhibit gross left ventricular hypertrophy (LVH) similar to the inherited hypertrophic cardiomyopathies such as familial hypertrophic cardiomyopathy (FHC) and Friedreich's ataxia (FA) has prompted us to investigate the hypothesis that genetic factors associated with excessive myocardial hypertrophy, viz. mutations in FHC and FA genes alter the hypertrophic response of the heart to pressure overload. Here we review briefly three lines of study: (i) association analysis to test whether the allele frequencies differ in hypertensive patients with or without left ventricular hypertrophy; (ii) characterization of the cardiac manifestations of FA to understand the mechanism by which the heart is affected in a disease associated with pathology in a sub‐group of neurons, and (iii) creation of transgenic models to facilitate the investigation of the interaction between hypertrophic stimuli and underlying genetic predisposition. 3Information on the nature of the cardiac‐mass‐modifying genes involved may be useful not only for selecting high risk patients in strategies aimed at preventing the development of LVH, but also in opening new avenues of research on the reprogramming of cardiac myocytes to encourage them to hypertrophy in situations where cardiac muscle has been damaged or is hypoplastic.