bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics and pharmacodynamics of the vasopeptidase inhibitor, omapatrilat in healthy subjects
Authors: Liao Wei‐chi , Vesterqvist Ole , Delaney Carol , Jemal Mohammed , Ferreira Irene , Ford Neville , Swanson Brian , Uderman Howard 
Published: September 2003

Aims To determine the pharmacokinetics, pharmacodynamics and tolerability of omapatrilat, a vasopeptidase inhibitor, in healthy subjects.Methods The effects of oral omapatrilat were evaluated in healthy men in two double‐blind, placebo‐controlled, dose‐escalation trials. In a single‐dose study, subjects received omapatrilat in doses of 2.5, 7.5, 25, 50, 125, 250, or 500 mg. In a multiple‐dose study, subjects received doses of 10, 25, 50, 75, or 125 mg daily for 10 days.Results In the multiple‐dose study, peak plasma concentrations (Cmax = 10–895 ng ml−1;tmax = 0.5–2 h) of omapatrilat were attained rapidly. Omapatrilat exhibited a long effective half‐life (14–19 h), attaining steady state in 3–4 days. In the single‐dose study,Cmax(1–1009 ng ml−1) and AUC(0,t) (0.4–1891 ng ml–1 h) were linear but not dose proportional. In the multiple‐dose study, based on weighted least‐squares linear regression analysesvsdose,Cmaxbut not AUC(0,t) was linear at the lower doses on day 10. The lowest dose of omapatrilat (2.5 mg) almost completely inhibited (> 97%) serum angiotensin converting enzyme activity at 2 h after dosing. In the multiple dose study, angiotensin converting enzyme activity was inhibited by more than 80% 24 h after all doses of omapatrilat. Inhibition of neutral endopeptidase activity was shown by increases in the daily urinary excretion of atrial natriuretic peptide and cyclic guanosine monophosphate at doses of more than 7.5 and 25 mg, respectively. In the single dose study, omapatrilat increased the daily urinary excretion of atrial natriuretic peptide dose‐dependently from 10.8 ± 4.1 (± SD) ng 24 h−1in the placebo group to 60.0 ± 18.2 ng 24 h−1in the 500 mg group. Omapatrilat did not affect sodium and potassium excretion or urinary volume. Compared with placebo, omapatrilat produced a decrease in mean arterial pressure at 3 h after all doses in both the single‐ and multiple‐dose studies.Conclusions Omapatrilat was generally well tolerated. The pharmacokinetic and pharmacodynamic effects of omapatrilat are consistent with once‐daily dosing.
Chest pain during use of bupropion as an aid in smoking cessation
Authors: De Graaf L. , Diemont W. L. 
Published: September 2003

Aims  To investigate the cause of chest pain during the use of bupropion as an aid to stop smoking.Methods  The Netherlands Pharmacovigilance Centre received 22 reports of chest pain, associated with the use of bupropion as an aid to smoking cessation. Additional information about long‐term follow up was collected to analyze whether these complaints herald manifest cardiac disease.Results  All but one patient recovered after withdrawal of bupropion. Seven patients were additionally investigated and in six of them, a cardiac cause could be excluded. During long‐term follow‐up, no coronary heart diseases were diagnosed.Conclusions  These reports indicate that chest pain seems to be associated with the use of bupropion, but its origin remains unclear.
Moclobemide poisoning: toxicokinetics and occurrence of serotonin toxicity
Authors: Isbister Geoffrey K. , Hackett L. P. , Dawson Andrew H. , Whyte Ian M. , Smith Anthony J. 
Published: September 2003

Aims  To investigate the spectrum of toxicity of moclobemide overdose, the occurrence of serotonin toxicity, and to estimate toxicokinetic parameters.Methods  All moclobemide overdoses presenting over a 10‐year period to the Hunter Area Toxicology Service were reviewed. Clinical features, complications, length of stay (LOS) and intensive care (ICU) admission rate were extracted from a standardized, prospectively collected database. Comparisons were made between moclobemide alone and moclobemide with a serotonergic coingestant poisoning. Serotonin toxicity was defined by a combination of Sternbach's criteria and a clinical toxicologist's diagnosis. In five patients serial moclobemide concentrations were measured. Time to maximal plasma concentration (Tmax), peak plasma concentration (Cmax) and terminal elimination half‐lives were estimated.Results  Of 106 included patients, 33 ingested moclobemide alone, 21 ingested moclobemide with another serotonergic agent (in some cases in therapeutic doses) and 52 ingested moclobemide with a nonserotonergic agent. Eleven (55%) of 21 patients coingesting a serotonergic drug developed serotonin toxicity, which was significantly more than one (3%) of 33 moclobemide‐alone overdoses (odds ratio 35, 95% confidence inteval 4, 307; P < 0.0001). In six of these 21 cases severe serotonin toxicity developed with temperature> 38.5 °C and muscle rigidity requiring intubation and paralysis. The 21 patients had a significantly increased LOS (34 h) compared with moclobemide alone overdoses (12 h) (P < 0.0001) and a significantly increased ICU admission rate of 57% vs. 3% (P < 0.0001). Time to peak plasma concentration was delayed in two patients where prepeak samples were obtained. Cmax increased slightly with dose, but all three patients ingesting ≥ 6 g vomited or had charcoal. The mean elimination half‐life of moclobemide in the five patients in whom serial moclobemide concentrations were measured was 6.3 h and elimination was first order in all cases. There was no evidence of a dose‐dependent increase in half‐life.Conclusions  The effects of moclobemide alone in overdose are minor, even with massive ingestions. However, moclobemide overdose in combination with a serotonergic agent (even in normal therapeutic doses) can cause severe serotonin toxicity. The elimination half‐life is prolonged by two to four times in overdose, compared with that found in healthy volunteers given therapeutic doses. This may be a result of wide interindividual variation in overall elimination, also seen with therapeutic doses, but appears not to be due to saturation of normal elimination pathways.
Mitogenic effects of phospholipase D and phosphatidic acid in transiently permeabilized astrocytes: effects of ethanol
Authors: Schatter Beate , Walev Ivan , Klein Jochen 
Published: September 2003

AbstractInvestigations of lipid‐mediated signalling pathways are often limited by a lack of methods for the intracellular delivery of lipid messengers. We established a procedure for the transient permeabilization of astrocytes by an oxygen‐insensitive mutant of streptolysin‐O (SLO) to investigate the participation of the phospholipase D (PLD) signalling pathway in astroglial cell proliferation. Exogenous PLD, when incubated in the presence of SLO, caused an increase in DNA synthesis (measured by thymidine incorporation) which was completely suppressed by ethanol (0.3%, v/v). In parallel experiments, phosphatidic acid also induced a dose‐dependent mitogenic response which, however, was not affected by the presence of ethanol. Phosphatidic acid was more effective in this assay than diacylglycerol but its effect was sensitive to the protein kinase inhibitor Ro 31‐8220. Our findings provide direct evidence that disruption of the PLD signalling pathway by ethanol is sufficient to suppress astroglial proliferation, an effect that might contribute to the inhibition of brain growth in alcoholic embryopathy.
Presence of functional ATP and dinucleotide receptors in glutamatergic synaptic terminals from rat midbrain
Authors: Gualix Javier , Gómez‐Villafuertes Rosa , Díaz‐Hernández Miguel , Miras‐Portugal M. Teresa 
Published: September 2003

AbstractGlutamatergic terminals from rat midbrain were characterized by immunolocalization of synaptophysin and the vesicular glutamate transporters, either VGLUT1 or VGLUT2. Terminals containing these markers represent about 31% (VGLUT1) and 16% (VGLUT2) of the total synaptosomal population. VGLUT1‐positive glutamatergic terminals responded to ATP or P1,P 5‐di(adenosine‐5′) pentaphosphate (Ap5A) with an increase in the intrasynaptosomal calcium concentration as measured by a microfluorimetric technique in single synaptosomes. Roughly 20% of the VGLUT1‐positive terminals responded to ATP, 13% to Ap5A and 11% to both agonists. Finally 56% of the terminals labeled with the anti‐VGLUT1 antibody did not show any calcium increase in response to ATP or Ap5A. A similar response distribution was also observed in the VGLUT2‐positive terminals. The Ca2+ responses induced by ATP and Ap5A in the glutamatergic terminals could be selectively inhibited by pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulfonic acid (PPADS, 80 µm) and P1,P 5‐di(inosine‐5′) pentaphosphate (Ip5I, 100 nm), respectively. Both ATP and Ap5A, once assayed in the presence of extrasynaptosomal calcium, were able to induce a concentration‐dependent glutamate release from synaptosomal populations, EC50 values being 21 µm and 38 µm for ATP and Ap5A, respectively. Specific inhibition of glutamate release was obtained with PPADS on the ATP effect and with Ip5I on the dinucleotide response, indicating that separate receptors mediate the secretory effects of both compounds.
Expression of Concern: Potent anti‐amyloidogenic and fibril‐destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer's disease
Authors: Ono Kenjiro , Yoshiike Yuji , Takashima Akihiko , Hasegawa Kazuhiro , Naiki Hironobu , Yamada Masahito 
Published: September 2003

AbstractCerebral deposition of amyloid β‐peptide (Aβ) in the brain is an invariant feature of Alzheimer's disease (AD). A consistent protective effect of wine consumption on AD has been documented by epidemiological studies. In the present study, we used fluorescence spectroscopy with thioflavin T and electron microscopy to examine the effects of wine‐related polyphenols (myricetin, morin, quercetin, kaempferol (+)‐catechin and (–)‐epicatechin) on the formation, extension, and destabilization of β‐amyloid fibrils (fAβ) at pH 7.5 at 37°C in vitro. All examined polyphenols dose‐dependently inhibited formation of fAβ from fresh Aβ(1–40) and Aβ(1–42), as well as their extension. Moreover, these polyphenols dose‐dependently destabilized preformed fAβs. The overall activity of the molecules examined was in the order of: myricetin = morin = quercetin > kaempferol > (+)‐catechin = (–)‐epicatechin. The effective concentrations (EC50) of myricetin, morin and quercetin for the formation, extension and destabilization of fAβs were in the order of 0.1–1 µm. In cell culture experiments, myricetin‐treated fAβ were suggested to be less toxic than intact fAβ, as demonstrated by 3‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide assay. Although the mechanisms by which these polyphenols inhibit fAβ formation from Aβ, and destabilize pre‐formed fAβin vitro are still unclear, polyphenols could be a key molecule for the development of preventives and therapeutics for AD.
Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and ischaemic brain damage in the endothelin‐1 rat model for focal cerebral ischaemia
Authors: Van Hemelrijck An , Vermijlen David , Hachimi‐Idrissi Said , Sarre Sophie , Ebinger Guy , Michotte Yvette 
Published: September 2003

AbstractThe relationship between glutamate and dopamine release, apoptosis and ischaemic damage was studied following induction of transient focal cerebral ischaemia under normothermic (37°C) and postischaemic (resuscitative) mild hypothermic (34°C for 2 h) conditions in sevoflurane anaesthetized male Wistar rats. Focal ischaemia was induced by infusing endothelin‐1 adjacent to the middle cerebral artery. In vivo microdialysis was used to sample glutamate and dopamine from striatum and parietal cortex of the ipsilateral hemisphere. The volume of ischaemic damage and the degree of apoptosis were determined 24 h after the insult. In both striatum and cortex of the normothermic group an initial increase in extracellular glutamate and dopamine levels following endothelin‐1 infusion was observed. Striatal glutamate levels remained enhanced (250% of baseline) throughout the experiment, while the other neurotransmitter levels returned to baseline values. Hypothermia significantly attenuated the endothelin‐1 induced glutamate release in the striatum. It also reduced apoptosis and infarct volume in the cortex. These results indicate that: (i) postischaemic mild hypothermia exerts its neuroprotective effect by inhibiting apoptosis in the ischaemic penumbral region; and (ii) this effect is not associated with an attenuation of glutamate or dopamine release in the cortex.
Hippocampal neurotrophin levels in a kainate model of temporal lobe epilepsy: a lack of correlation between brain‐derived neurotrophic factor content and progression of aberrant dentate mossy fiber sprouting
Authors: Shetty Ashok K. , Zaman Vandana , Shetty Geetha A. 
Published: September 2003

AbstractA significant upregulation of neurotrophins particularly brain‐derived neurotrophic factor (BDNF) is believed to be involved in the initiation of epileptogenic changes such as the aberrant axonal sprouting and synaptic reorganization in the injured hippocampus. However, it is unknown which of the neurotrophins are upregulated during the peak period of aberrant mossy fiber sprouting in the chronically injured hippocampus. We measured chronic changes in the levels of BDNF, nerve growth factor (NGF) and neurotrophin‐3 (NT‐3) in the adult hippocampus using enzyme‐linked immunosorbent assay (ELISA) after a unilateral intracerebroventricular administration of kainic acid (KA), a model of temporal lobe epilepsy. For comparison, neurotrophins were also measured from the control intact hippocampus. Further, to see the association between changes in neurotrophin levels and the progression of mossy fiber sprouting, chronic changes in the mossy fiber distribution within the dentate supragranular layer (DSGL) were quantified. In the KA‐lesioned hippocampus, the neurotrophins BDNF and NGF were upregulated at 4 days post‐lesion, in comparison to their levels in the intact hippocampus. However, the concentration of BDNF reached the baseline level at 45 days post‐lesion and dramatically diminished at 120 days post‐lesion. In contrast, the upregulation of NGF observed at 4 days post‐lesion was sustained at both 45 days and 120 days post‐lesion. The concentration of NT‐3 was upregulated at 45 days post‐lesion but remained comparable to baseline levels at 4 days and 120 days post‐lesion. Interestingly, analysis of mossy fiber sprouting revealed that most of the aberrant sprouting in the lesioned hippocampus occurs between 45 days and 120 days post‐lesion. Taken together, these results suggest that the period of robust mossy fiber sprouting does not correlate with the phase of post‐lesion BDNF upregulation. Rather, it shows a relationship with the time of upregulation of neurotrophins NGF and NT‐3.
Depletion of wild‐type huntingtin in mouse models of neurologic diseases
Authors: Zhang Yu , Li Mingwei , Drozda Martin , Chen Minghua , Ren Shengjun , Mejia Sanchez Rene O. , Leavitt Blair R. , Cattaneo Elena , Ferrante Robert J. , Hayden Michael R. , Friedlander Robert M. 
Published: September 2003

AbstractHuntington's disease (HD) is caused by a mutation in the gene encoding for huntingtin resulting in selective neuronal degeneration. Because HD is an autosomal dominant disorder, affected individuals have one copy of the mutant and one copy of the wild‐type allele. Huntingtin has antiapoptotic properties and is critical for cell survival. However, the important role of wild‐type huntingtin in both HD and other neurological diseases has not been fully recognized. We demonstrate disease‐associated decreased levels of full‐length huntingtin in brains of transgenic mouse models of HD, ischemia, trauma, and in spinal cord after injury. In addition, overexpression of wild‐type huntingtin confers in vivo protection of neurodegeneration after ischemia. We propose that in HD, in addition to a toxic gain‐of‐function of mutant huntingtin, a parallel depletion of wild‐type huntingtin results in a detrimental loss‐of‐function, playing an important role in disease progression.
Glutamine efflux from astrocytes is mediated by multiple pathways
Authors: Deitmer Joachim W. , Bröer Angelika , Bröer Stefan 
Published: September 2003

AbstractThe neurotransmitter glutamate, once released into the synaptic cleft, is largely recycled by the glutamate–glutamine cycle, which involves uptake into astrocytes, conversion into glutamine and subsequent release of glutamine from astrocytes as a precursor for neuroneal glutamate synthesis. We analysed glutamine efflux from cultured astrocytes by pre‐loading cells with labelled glutamine for 30 min and subsequently measured glutamine efflux for 30 min. Efflux of pre‐loaded glutamine was rapid and almost complete after 30 min with a first order rate of 0.11 ± 0.01/min. Efflux was 50% reduced when cells were depleted of intracellular Na+. Increasing intracellular Na+ concentration had a small stimulatory effect on glutamine efflux, indicating the participation of a Na+‐dependent transport mechanism. About 50% of the basal efflux could not be inhibited by depletion of the intracellular Na+, suggesting the presence of an additional Na+‐independent transport mechanism. Glutamine efflux was stimulated two‐ to threefold by addition of extracellular neutral amino acids, such as alanine or leucine. The stimulatory effects of alanine and leucine had a Na+‐dependent and a Na+‐independent component, suggesting the presence of two antiport mechanisms one involving Na+. When compared to the expression of glutamine transporter mRNAs in cultured astrocytes it appeared likely that glutamine efflux was mediated by SN1, LAT2, ASCT2 and an additional, yet unidentified, transporter that mediates about 40% of the basal efflux.
Glutamate transport, glutamine synthetase and phosphate‐activated glutaminase in rat CNS white matter. A quantitative study
Authors: Hassel Bjørnar , Boldingh Karen Astrid , Narvesen Cecilie , Iversen Evy Grini , Skrede Knut Kristian 
Published: September 2003

AbstractGlutamatergic signal transduction occurs in CNS white matter, but quantitative data on glutamate uptake and metabolism are lacking. We report that the level of the astrocytic glutamate transporter GLT in rat fimbria and corpus callosum was ∼ 35% of that in parietal cortex; uptake of [3H]glutamate was 24 and 43%, respectively, of the cortical value. In fimbria and corpus callosum levels of synaptic proteins, synapsin I and synaptophysin were 15–20% of those in cortex; the activities of glutamine synthetase and phosphate‐activated glutaminase, enzymes involved in metabolism of transmitter glutamate, were 11–25% of cortical values, and activities of aspartate and alanine aminotransferases were 50–70% of cortical values. The glutamate level in fimbria and corpus callosum was 5–6 nmol/mg tissue, half the cortical value. These data suggest a certain capacity for glutamatergic neurotransmission. In optic and trigeminal nerves, [3H]glutamate uptake was < 10% of the cortical uptake. Formation of [14C]glutamate from [U‐14C]glucose in fimbria and corpus callosum of awake rats was 30% of cortical values, in optic nerve it was 13%, illustrating extensive glutamate metabolism in white matter in vivo. Glutamate transporters in brain white matter may be important both physiologically and during energy failure when reversal of glutamate uptake may contribute to excitotoxicity.
Time‐dependent changes in gene expression profiles of midbrain dopamine neurons following haloperidol administration
Authors: Fasulo Wendy H. , Hemby Scott E. 
Published: September 2003

AbstractAntipsychotic drugs require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations in specific neuroanatomical loci are likely involved. Haloperidol‐induced changes in gene expression in various brain regions have been observed; however, alterations in distinct neuronal populations have remained elusive. The present study examined changes in gene expression profiles of ventral tegmental area (VTA) and substantia nigra (SN) tyrosine hydroxylase immunopositive neurons following 1, 10 or 21 days of haloperidol administration (0.5 mg/kg/day). Macroarrays were used to study the expression of receptors, signaling proteins, transcription factors and pre‐ and post‐synaptic proteins. Data were analyzed using conventional statistical procedures as well as self‐organizing maps (SOM) to elucidate conserved patterns of expression changes. Results show statistically significant haloperidol‐induced and time‐dependent alterations in 17 genes in the VTA and 25 genes in the SN, including glutamate and GABA receptor subunits, signaling proteins and transcription factors. SOMs revealed distinct patterns of gene expression changes in response to haloperidol. Understanding how gene expression is altered over a clinically relevant time course of haloperidol administration may provide insight into the development of antipsychotic efficacy as well as the underlying pathology of schizophrenia.
The use ofex situconserved plant genetic resources
Authors: Hodgkin Toby , Rao V. Ramanatha , Cibrian-Jaramillo Angélica , Gaiji Samy 
Published: September 2003

AbstractPlant genetic resources are conserved so that they can be used to improve crop plant pro- duction and in other ways. However, it is often asserted that use ofex situconserved germplasm is inadequate and that genetic diversity maintained in genebanks is underutilized. In part, this reflects an incomplete recognition of what constitutes use of plant genetic resources, and of the many different ways in which material from genebanks contributes to improved agricultural production. Based on recent information from surveys of distribution of germplasm from genebanks, and from surveys of users, we suggest that the evidence indicates that there is substantial use ofex situconserved materials for a wide range of different uses. We suggest that barriers to use ofex situconserved germplasm may often result from a lack in numbers of users, and from limitations in capacity to effectively utilize the genetic diversity present in genebanks to reduce genetic vulnerability and increase sustainability in modern production systems.
Effects of fall dormancy of alfalfa on seed production at a northern latitude
Authors: Fairey D. T. , Fairey N. A. , Lefkovitch L. P. , Lieverse J. A. C. 
Published: September 2003

AbstractThe agri-climatic adaptation of an alfalfa variety in North America is categorized by its Fall Dormancy Rating (FDR1 = dormant to FDR9 = non-dormant). Presently, only relatively dormant, winter-hardy varieties (FDR1–4) are grown for seed and herbage at the northern latitudes of western Canada. However, there is considerably greater demand for seed of varieties that have FDR ≥ 4. A study was conducted in the Peace River region of north-western Canada to determine the relationship between FDR and seed production of alfalfa with FDR ≥ 4. Trials were established in each of two consecutive years with four varieties representing each of six FDR categories, FDR4–9. Growth characteristics were determined for two successive years of seed crops for each year of establishment. Seed yield (as a percentage of that for FDR4) was 84, 52, 40, 29 and 39% for FDR5 to FDR9, respectively, whereas total biomass at seed maturity was 89,73, 73, 57 and 57% for FDR5 to FDR9, respectively. Seed yield was more sensitive to changes in FDR than total biomass. Short rotations of specific alfalfa varieties with FDR ≥ 4 could be an option for seed growers in the northerly latitudes of western Canada, provided greater financial compensation is given for higher FDR varieties, and provided genetic drift can be retained within acceptable limits.