bluuebunny/crossref_metadata_2025_split huggingface dataset:
Agonist‐ and antagonist‐induced sequestration/internalization of neuropeptide Y Y1 receptors in HEK293 cells
Authors: Pheng Leng Hong , Dumont Yvan , Fournier Alain , Chabot Jean‐Guy , Beaudet Alain , Quirion Rémi 
Published: June 2003

Neuropeptide Y Y1 receptors are known to internalize following the binding of agonists. In the present study, a pseudopeptide Y1 receptor antagonist, homodimeric Ile‐Glu‐Pro‐Dpr‐Tyr‐Arg‐Leu‐Arg‐Tyr‐CONH2 (GR231118), also induced Y1 receptor internalization in human embryonic kidney (HEK293) cells.
We demonstrated first that both specifically bound radiolabeled antagonist ([125I]GR231118) and agonist ([125I][Leu31, Pro34]PYY) underwent receptor‐mediated sequestration/internalization in transfected HEK293 cells.
Agonist‐induced Y1 receptor internalization was dependent on clathrin‐coated pits and was regulated in part by Gi/o‐protein activation as revealed by pertussin toxin sensitivity. In contrast, antagonist‐induced sequestration of Y1 receptors was partly dependent on clathrin‐coated pits, but independent from Gi/o‐protein activation.
Exposure to high concentrations of agonist or antagonist caused a 50 and 75% loss of cell surface binding, respectively. The loss caused by the agonist rapidly recovered. This phenomenon was blocked by monensin, an inhibitor of endosome acidification, suggesting that cell surface receptor recovery is due to recycling. In contrast to the agonist, GR231118 induced a long‐lasting sequestration of Y1 receptors in HEK293 cells.
Immunofluorescence labeling indicated that following 40 min of incubation with either the agonist or the antagonist, Y1 receptors followed markedly different intercellular trafficking pathways.
Taken together, these findings provided evidence that a pseudopeptide Y1 receptor antagonist can induce long‐lasting disappearance of cell surface receptors through a pathway distinct from the classical endocytic/recycling pathway followed by stimulation with an agonist.

British Journal of Pharmacology (2003) 139, 695–704. doi:10.1038/sj.bjp.0705306
Peroxidation of docosahexaenoic acid is responsible for its effects on ITO and ISS in rat ventricular myocytes
Authors: Judé S , Bedut S , Roger S , Pinault M , Champeroux P , White E , Le Guennec J‐Y 
Published: June 2003

Exposure to docosahexaenoïc acid (DHA), a long‐chain polyunsaturated fatty acid, is known to block several ionic currents such as the transient outward current ITO. It has also been reported to activate certain potassium channels. It has been suggested that these effects, observed in single‐cell experiments, participate in the antiarrhythmic properties of these compounds in vivo.
DHA is highly prone to peroxidation. To investigate the influence peroxidation may have on the effects of DHA on ion channels, we studied ITO and the steady‐state outward current ISS in isolated rat ventricular myocytes under ruptured whole‐cell patch‐clamp conditions.
A measure of 10 μM DHA alone reduced ITO, evoked by a pulse to +70 mV, by 74.8±10.8% (n=7) and activated a delayed outward current with kinetic properties different from ISS.
When an antioxidant, alpha‐tocopherol (1 μM), was added together with DHA, the blockade of ITO was reduced to 38.5±7.7% (n=8) and the delayed outward current was not activated. α‐Tocopherol alone had no effect on these currents.
When an oxidant, hydrogen peroxide (1 μM), was applied together with DHA, the blockade of ITO was almost complete (98.4±1.0%, n=7) and a large delayed outward current was activated. A measure of 1 μM hydrogen peroxide alone had no effect on these currents.
Measurements of nonperoxidized DHA in experimental solutions confirmed the negative relation between DHA concentration and the effects on the currents.
We conclude that rather than DHA itself, it is the peroxidation products of DHA that block ITO and activate a delayed outward current in in vitro single‐cell experiments. These findings have important implications for the extrapolation of in vitro experimental findings to the antiarrhythmic effects of DHA in vivo because, in vivo, peroxidation of DHA is unlikely to occur.

British Journal of Pharmacology (2003) 139, 816–822. doi:10.1038/sj.bjp.0705308
Reactive oxygen species induce swelling and cytochrome c release but not transmembrane depolarization in isolated rat brain mitochondria
Authors: Galindo María F , Jordán Joaquín , González‐García Carmen , Ceña Valentín 
Published: June 2003

In this study, we have used isolated brain mitochondria to investigate the effects of superoxide anions (O2−) on mitochondrial parameters related to apoptosis, such as swelling, potential, enzymatic activity, NAD(P)H, cytochrome c release, and caspase activity.
Addition of the reactive oxygen species (ROS) generator KO2 produced brain mitochondrial swelling, which was blocked by cyclosporin A (CSA), and which was Ca2+ independent.
Calcium induced mitochondrial swelling only at high concentrations and in the presence of succinate. This correlated with the increase in O2− production detected with hydroethidine in mitochondrial preparations exposed to Ca2+ and the fact that ROS were required for Ca2+‐induced mitochondrial swelling.
Superoxide anions, but not Ca2+, decreased citrate synthase and dehydrogenase enzymatic activities and dropped total mitochondrial NAD(P)H levels.
Calcium, but not O2−, triggered a rapid loss of mitochondrial potential. Calcium‐induced Δψm dissipation was inhibited by Ruthenium Red, but not by CSA.
Calcium‐ and superoxide‐induced mitochondrial swelling released cytochrome c and increased caspase activity from isolated mitochondria in a CS A‐sensitive manner.
In summary, superoxide potently triggers mitochondrial swelling and the release of proteins involved in activation of postmitochondrial apoptotic pathways in the absence of mitochondrial depolarization.

British Journal of Pharmacology (2003) 139, 797–804. doi:10.1038/sj.bjp.0705309
Retinoids as a potential treatment for experimental puromycin‐induced nephrosis
Authors: Moreno‐Manzano V , Mampaso F , Sepúlveda‐Muñoz J C , Alique M , Chen S , Ziyadeh F N , Iglesias‐de la Cruz M C , Rodríguez J , Nieto E , Orellana J M , Reyes P , Arribas I , Xu Q , Kitamura M , Lucio Cazana F J 
Published: June 2003

Puromycin aminonucleoside (PAN)‐induced nephrosis is a model of human minimal change disease. In rats, PAN induces nephrotic‐range proteinuria, renal epithelial cell (podocyte) damage, infiltration of mononuclear leukocytes, and apoptosis of several renal cell types.
Retinoic acid (RA) modulates a wide range of biological processes, such as inflammation and apoptosis. Since renal damage by PAN is characterized by inflammatory infiltration and epithelial cell death, the effect of treatment with all‐trans RA (tRA) was examined in the PAN nephrosis model and in the cultured differentiated podocyte.
Treatment with tRA 4 days after PAN injection did not inhibit the proteinuria peak but reversed it significantly. However, treatment with tRA both before and 2 days after the injection of PAN protected the glomerular epithelial cells, diminishing the cellular edema and diffuseness of the foot process effacement. Preservation of the podocyte architecture correlated with the inhibition of proteinuria. The anti‐inflammatory effect of tRA was evidenced by the inhibition of PAN‐induced interstitial mononuclear cell infiltration and the decreased renal expression of two molecules involved in monocyte infiltration: fibronectin and monocyte chemoattractant protein‐1. TUNEL assays showed that tRA inhibited the PAN‐induced apoptosis of cultured differentiated mouse podocytes.
We conclude that tRA treatment may prevent proteinuria by protecting the podocytes from injury and diminishing the interstitial mononuclear infiltrate in the model of PAN nephrosis. Retinoids are a potential new treatment for kidney diseases characterized by proteinuria and mononuclear cell infiltration.

British Journal of Pharmacology (2003) 139, 823–831. doi:10.1038/sj.bjp.0705311
Anti‐inflammatory activity of creatine supplementation in endothelial cells in vitro
Authors: Nomura Akihiro , Zhang Minjie , Sakamoto Tohru , Ishii Yukio , Morishima Yuko , Mochizuki Mie , Kimura Toru , Uchida Yoshiyuki , Sekizawa Kiyohisa 
Published: June 2003

Creatine (CR) supplementation augments muscle strength in skeletal muscle cells by increasing intracellular energy pools. However, the effect of CR supplementation on endothelial cells remains to be clarified.
In this study, we investigated whether CR supplementation had any anti‐inflammatory activity against human pulmonary endothelial cells in culture.
We confirmed that supplementation with 0.5 mM CR significantly increased both intracellular CR and phosphocreatine (PC) through a CR transporter while keeping intracellular ATP levels constant independent of CR supplementation and a CR transporter antagonist.
In the assay system of endothelial permeability, supplementation with 5 mM CR significantly suppressed the endothelial permeability induced by serotonin and H2O2.
In cell adhesion experiments, supplementation with 5 mM CR significantly suppressed neutrophil adhesion to endothelial cells.
In the measurement of adhesion molecules, CR supplementation with more than 0.5 mM CR significantly inhibited the expressions of ICAM‐1 and E‐selectin on endothelial cells, and the inhibition was significantly suppressed by an adenosine A2A receptor antagonist.
The present study suggests that CR supplementation has anti‐inflammatory activities against endothelial cells.

British Journal of Pharmacology (2003) 139, 715–720. doi:10.1038/sj.bjp.0705316
Evidence of an interaction between nifedipine and nafcillin in humans
Authors: Lang C. C. , Jamal S. K. , Mohamed Z. , Mustafa M. R. , Mustafa A. M. , Lee T. C. 
Published: June 2003

Aims  Nafcillin (Wyeth Laboratories, Philadelphia, PA, USA) has been reported to induce the metabolism of cyclosporin and warfarin, which are known substrates of cytochrome P‐450 (CYP). However, there has not been any report to date on its possible interaction with nifedipine, an index substrate of the enzyme, CYP3A4.Methods  Nine healthy normotensive subjects participated in this randomized placebo‐controlled two‐way crossover study examining the effects of 5 days’ pretreatment of nafcillin 500 mg or placebo four times daily on the pharmacokinetics of an oral dose of nifedipine 10 mg. Plasma nifedipine concentrations were measured by gas chromatography–mass spectro.Results  The area under the plasma nifedipine concentration–time curve (AUC0–α) in nafcillin‐pretreated subjects (80.9 ± 32.9 µg l−1 h−1) was significantly decreased compared with subjects who received only nifedipine (216.4 ± 93.2 µg l−1 h−1) (P < 0.001). Total plasma clearance of nifedipine (CL/F) was significantly increased with nafcillin pretreatment (138.5 ± 42.0 l h−1vs 56.5 ± 32.0 l h−1) (P < 0.002).Conclusions  The results show that nafcillin pretreatment markedly increased the clearance of nifedipine and suggest that nafcillin is a potent inducer of CYP enzyme.
Variability of heart rate correction methods for the QT interval
Authors: Desai Mehul , Li Lang , Desta Zeruesenay , Malik Marek , Flockhart David 
Published: June 2003

Aims  To compare variability of heart rate‐corrected QT intervals (QTc) using three different methods in a study of low‐dose oral haloperidol.Methods  In a randomized, double‐blind, placebo‐controlled, crossover trial, we studied QT interval pharmacodynamics of single doses of oral haloperidol (10 mg) in 16 healthy subjects. Heart rate correction of the QT interval was performed using Bazett’s, Fridericia's and subject‐specific correction methods. The subject‐specific correction was performed using linear mixed modelling of placebo period QT vs RR data from each study subject.Results  The subject‐specific correction, in the form of QTc = QT/RRα, yielded a correction term α (slope of the log‐transformed QT vs RR relationship) that ranged from 0.23 to 0.38 in individual subjects, i.e. the fixed correction term α = 0.5 of Bazett's correction was outside and the fixed correction term α = 0.33 of Fridericia's correction inside the range of individual values. The mean absolute slope of the QTcvs RR regression line using the subject‐specific correction was significantly lower than the mean slopes obtained using either Bazett's or Fridericia's corrections. All three methods revealed a statistically significant greater mean QTc on haloperidol than on placebo at 10 h post‐drug administration. The mean QT (95% CI) was 421.6 (410.8, 432.4), and 408.4 (398.6, 417.8) on haliperidol and placebo, respectively, using the subject‐specific correction method (P = 0.0053). The mean QTc (95% CI) was 425.4 (414.3, 436.5) and 403.1 (394.3, 411.9) on haliperidol and placebo, respectively, using Bazett's correction (P = 1.7 × 10−5) and 423.1 (412.6, 433.6) and 408.2 (398.6, 417.8) on haliperidol and placebo, respectively, using Fridericia's correction (P = 7.7 × 10−4). Raw P‐values were calculated using a paired t‐test. Bonferroni‐corrected P‐values were calculated by multiplying the raw P‐values by 13.Conclusion  Haloperidol caused a statistically significant mean QTc prolongation using the three correction methods. The QTc intervals were less dependent on RR intervals using the subject‐specific method, thus decreasing the possibility of over‐ or under‐correction. The interindividual QTc changes from baseline varied significantly depending on the method of correction used.
Effects of licence change on prescribing and poisons enquiries for antipsychotic agents in England and Scotland
Authors: Bateman D. N. , Good A. M. , Afshari R. , Kelly C. A. 
Published: June 2003

Aims  To examine the effect of licence change for thioridazine at the end of 2000 on the prescription of antipsychotic drugs in England and Scotland, and investigate changes in poisons information inquiries and, for Edinburgh, poisons admissions.Methods  Prescription data for antipsychotic drugs were obtained for England and Scotland and quarterly trends examined for 2000 and 2001. Accesses to the UK National Poisons Information Service website TOXBASE for antipsychotic products were examined for the same period. For Scotland telephone enquiry data, and admission data to the Edinburgh Poisons Unit were also evaluated. Trends in poisonings were compared with prescribing change.Results  In England prescriptions for thioridazine fell rapidly in 2001 from approximately 35% of market share to less than 5%, and were replaced by risperidone, chlorpromazine and olanzapine. TOXBASE accesses fell from 39.3% of antipsychotics to 4.4%. Accesses for chlorpromazine, olanzapine and risperidone increased. In Scotland prescribing of thioridazine was similar to changes in England, but it was principally replaced by chlorpromazine. These changes were mirrored by TOXBASE accesses, telephone enquiries and in‐patient admissions. The ratio of TOXBASE accesses for thioridazine to prescription numbers for the drug increased after the licence change.Conclusions  Licence change produced rapid change in prescribing behaviour within 3 months. Prescribing behaviour in England and Scotland was different. Changes in prescribing were mirrored by changes in accesses for poisons information in both England and Scotland, and in Edinburgh by hospital admissions. The increase in the ratio of TOXBASE accesses to prescriptions for thioridazine suggests doctors may have become more aware of its potential toxicity.
Evidence for an age and gender bias in the secondary prevention of ischaemic heart disease in primary care
Authors: Williams David , Bennett Kathleen , Feely John 
Published: June 2003

Aims  To determine if a gender or age bias exists in the prescription of important secondary preventive therapies for ischaemic heart disease in primary care.Methods  We identified 15 590 patients with ischaemic heart disease on the basis that they received a prescription for nitrate therapy over a 1‐year period (September 1999 to August 2000) from the Eastern Region of the General Medical Services scheme in Ireland (population of 334 031), which provides free health service to those eligible patients in primary care. Odds ratios (OR) for the prescription of aspirin, β‐blockers, statins, calcium channel antagonists and ACE inhibitors in women and in those aged> 65 years were determined.Results  Female patients were less likely to receive a prescription for a β‐blocker [OR = 0.84, 95% confidence interval (CI) = 0.79, 0.89, P < 0.001], aspirin (OR = 0.72, 95% CI = 0.67, 0.78, P < 0.001), and ACE inhibitors (OR = 0.83, 95% CI = 0.78, 0.89, P < 0.001) compared with their male counterparts. However, women were more likely to receive anxiolytic benzodiazepines (OR = 1.71, 95% CI = 1.59, 1.85, P < 0.001) compared with their male counterparts. Elderly patients (aged> 65 years) were less likely to receive aspirin (OR = 0.92, 95% CI = 0.85, 0.99, P < 0.001), β‐blocker (OR = 0.66, 95% CI = 0.62, 0.71, P < 0.001) and a statin (OR = 0.5, 95% CI = 0.46, 0.53, P < 0.001).Conclusions  An age and gender bias exists in the prescription of important secondary preventive therapies in primary care that may lead to increased mortality from ischaemic heart disease in these groups.
Disposition of debrisoquine and nortriptyline in Korean subjects in relation to CYP2D6 genotypes, and comparison with Caucasians
Authors: Dalén P. , Dahl M‐L. , Roh H.‐K. , Tybring G. , Eichelbaum M. , Wilkinson G. R. , Bertilsson L. 
Published: June 2003

Aims  To study the influence of the CYP2D6*10 allele on the disposition of debrisoquine and nortriptyline.Methods  The pharmacokinetics of debrisoquine and nortriptyline and their main metabolites were determined in ten Koreans with the CYP2D6*1/*1 (n = 5) and CYP2D6*1/*10 (n = 5) genotypes after single oral doses of 20 mg debrisoquine and 25 mg nortriptyline, respectively. The data were compared with previously published findings from 21 Caucasians with 0, one, two, three, four or 13 functional CYP2D6 genes.Results  The AUC0−8 of 4‐hydroxydebrisoquine was significantly lower in Koreans with CYP2D6*1/*10 genotype compared with CYP2D6*1/*1[95% confidence interval (CI) for the ratio between means 1.17, 1.85]. No other genotype‐related differences were found in the plasma kinetics of nortriptyline and debrisoquine, or their hydroxy metabolites. The AUCnortriptyline/AUC10‐hydroxynortriptyline ratio did not differ between the *1/*1 and *1/*10 genotype groups (95% CI for the ratio of means 0.60, 1.26). Similarly, there was no difference between these genotypes with respect to the AUCdebrisoquine/AUC4‐hydroxydebrisoquine ratio (95% CI for the ratio of mean values 0.38, 1.46). Both Korean genotype groups had similar AUCs and parent compound/metabolite AUC ratios of debrisoquine and nortriptyline to Caucasians with two functional CYP2D6 genes.Conclusions  Heterozygosity for CYP2D6*10 decreases the CYP2D6‐dependent elimination of nortriptyline and debrisoquine to only a limited degree. Further studies in subjects homozygous for CYP2D6*10 are required to elucidate fully the pharmacokinetic consequences of this CYP2D6 genotype in Orientals.
The effects of histamine and leukotriene receptor antagonism on nasal mannitol challenge in allergic rhinitis
Authors: Lee Daniel K. C. , Haggart Kay , Currie Graeme P. , Anderson Sandra D. , Lipworth Brian J. 
Published: June 2003

Aims  It is unclear as to which mediators are involved in mediating the response to nasal mannitol challenge, a novel osmotic stimulus.Methods  A double‐blind, randomized, placebo‐controlled, crossover design was employed. Nine patients with allergic rhinitis were randomized to receive a single‐dose of desloratadine 5 mg, montelukast 10 mg or placebo, and underwent nasal mannitol challenges with nasal peak inspiratory flow recordings over 60 min. The change in peak nasal inspiratory flow was calculated as percentage change from baseline as the peak response and area under the time–response curve (AUC).Results  Desloratadine and montelukast conferred a significant degree of protection compared to placebo for peak and AUC response, but there were no significant differences between the two drugs. For the peak response as percentage fall, the mean difference (95% CI) vs placebo was 27.7 (8.0, 47.4)% for desloratadine and 17.6 (1.9, 33.3)% for montelukast.Conclusions  Our results suggest that histamine and cysteinyl‐leukotrienes are involved in mediating the response to nasal mannitol in allergic rhinitis.
C‐peptide has no effect on forearm blood flow during local hyperinsulinaemia in healthy humans
Authors: Langenberger Herbert , Schaller Georg , Pleiner Johannes , Mittermayer Friedrich , Bayerle‐Eder Michaela , Wolzt Michael 
Published: June 2003

Background  C‐peptide increases forearm blood flow (FBF) in patients with Type 1 diabetes, probably by interaction with insulin, but not in healthy subjects. It is unclear if the vasodilating effect is sealed at normal fasting insulin concentrations.Methods  The effects of C‐peptide alone and during local hyperinsulinaemia were studied in healthy young men. Subjects received intra‐arterial insulin at 6 pmol min−1 (low dose) or placebo for 60 min with subsequent coinfusion of C‐peptide at increasing doses of 2–60 pmol min−1 in a double‐blind crossover study (n = 8). In control experiments insulin at 30 pmol min−1 (high dose) was coinfused with C‐peptide (n = 3). FBF was measured by strain‐gauge plethysmography.Results  Placebo had no effect on FBF (mean percentage change from baseline at 50 min −3.1%, 95% confidence interval [CI]−14.9, + 8.7). Insulin infusion slightly enhanced FBF by + 10.2% (95% CI −6.8, + 27.2; low dose) and + 17.6% (95% CI −38.8, + 74.0; high dose), respectively. The mean individual difference of the change in FBF between low‐dose insulin and placebo was + 13.3% (95% CI −6.0, + 32.7; P = NS). Infusion of C‐peptide increased local C‐peptide concentrations from 1.8 ± 0.1 ng ml−1 to 6.1 ± 2.8 ng ml−1, but had no effect on FBF during placebo or hyperinsulinaemia (mean difference vs low dose insulin −16.0%, 95% CI −38.9, + 6.9).Conclusion  The vasodilating effect of C‐peptide seen in Type 1 diabetes is not detectable during fasting or hyperinsulinaemia in the forearm vasculature of healthy subjects. This suggests saturation of its vasodilating potency at insulin concentrations within the normal or in the supraphysiological range.
The effect of motilin on the rectum in healthy volunteers
Authors: Kamerling I. M. C. , Burggraaf J. , Van Haarst A. D. , Oppenhuizen‐Duinker M. F. , Schoemaker H. C. , Biemond I. , Jones R. , Heinzerling H. , Cohen A. F. , Masclee A. A. M. 
Published: June 2003

Aims  The role of motilin in the regulation of upper gastrointestinal (GI) motility is well defined. However, little is known about the effects on the distal GI tract. To investigate the effect of exogenous motilin on rectal function, barostat measurements in the rectum were performed and lower abdominal symptoms were scored.Methods  Eight fasted, healthy volunteers were infused intravenously with synthetic motilin or placebo over 90 min in a double‐blind, randomized, cross‐over design. Rectum volume was measured with a barostat device during constant pressure and during isobaric distensions. Lower abdominal symptoms were scored by visual analogue scales. Plasma motilin concentrations were measured by radioimmunoassay.Results  Baseline rectum volumes were similar between treatments: 185 ± 62 mL (motilin) and 136 ± 41 mL (placebo). During the constant pressure procedure, motilin increased rectum volume [area under the effect curve (AUEC)] by 6%[95% confidence interval (CI) −3, 16] of baseline, compared with placebo. During isobaric distensions motilin increased rectum volume (AUEC) by 43 mL (95% CI 0.4, 85; P < 0.05) and compliance by 10 mL mmHg−1 (95% CI 0.3, 20; P < 0.05) relative to placebo. Motilin did not induce changes in the sensation of rectal feelings.Conclusion  Exogenous motilin increased rectal compliance in healthy volunteers, without affecting rectal sensations.