bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potency, affinity constants and receptor reserves for noradrenaline and adrenaline on aortae from aged normo- and hypertensive rats
Authors: Doggrell Sheila A , Chen Ying-Yu 
Published: July 2003

Abstract
Previously we have determined the potency, affinity constants (KA values), and α1-adrenoceptor reserves for noradrenaline and adrenaline on the thoracic aortae of 20-week-old Wistar Kyoto normotensive (WKY) and spontaneously hypertensive rats (SHRs). This study has investigated whether these parameters were altered on the thoracic aortae by ageing, and in hypertension/heart failure. The effects of phenoxybenzamine on the contractile responses of the aortae of 20-month-old WKYs and SHRs were determined. The pD2 values for noradrenaline and adrenaline were 7.1 and 7.0, respectively, on the aortae of 20-month-old WKYs, and similar values were obtained on age-matched SHRs. On the aortae of 20-month-old WKYs, the KA values for noradrenaline and adrenaline were 1.85 and 1.95 × 10−6 M, and the receptor occupancies required for 50% maximum responses were 16 and 24%, respectively. There were lower affinities, by approximately twofold, but similar receptor reserves for noradrenaline and adrenaline on the aortae of age-matched SHRs. In comparison with the aortae of 20-week-old WKYs and SHRs, there was a 5-fold loss of sensitivity to noradrenaline and adrenaline between 20 weeks and 20 months. Between 20 weeks and 20 months there was a 50-fold loss of affinity with ageing and a further twofold loss with hypertension/heart failure, and an increase in α1-adrenoceptor reserves for noradrenaline and adrenaline between 20 weeks and 20 months. There were no differences in the sensitivity and affinity, and minor changes in the α1-adrenoceptor reserves for noradrenaline and adrenaline between the aortae of 20-month-old WKYs and SHRs. In contrast there were major changes in these parameters in the ageing of the WKY aorta from 20 weeksto 20 months. There were no additional changes in the sensitivity and α1-adrenoceptor reserves, but a small additional change in affinity for noradrenaline and adrenaline in hypertension/heart failure on the aortae of 20-month-old SHRs.
Acetylcholine induces cytosolic Ca2+ mobilization in isolated distal colonic crypts from normal and cystic fibrosis mice
Authors: Klaren P H M , Hardcastle J , Evans S , Colledge W H , Evans M J , Taylor C J , Hardcastle P T , White S J 
Published: July 2003

Abstract
In intestinal biopsies from cystic fibrosis (CF) patients acetylcholine fails to elicit a chloride secretion response, and this observation can be explained by a defect in the Ca2+ signalling pathway in CF secretory cells. We tested the hypothesis that in CF intestine, the generation of an intracellular Ca2+ signal upon cholinergic stimulation is absent. A transgenic CF mouse model was used. Electrical measurements on intact jejunum and unstripped colon were performed in Ussing chambers. Intact distal colonic crypts were isolated, and the intracellular Ca2+ concentration was monitored using the Ca2+-sensitive dye fura-2. Acetylcholine increased the short-circuit current generated by wild-type jejunum and colon, but failed to induce a response in CF tissues. Acetylcholine caused a transient elevation in the intracellular Ca2+ concentration in colonic crypts from both wild-type and CF mice; the amplitude and timing of the response in CF crypts was indistinguishable from that in wild-type crypts. The response to acetylcholine was also observed in the absence of extracellular calcium, indicating intracellular stores as the source from which the cytosolic Ca2+ concentration increased. We conclude that the absence of a cholinergically-induced secretory response in CF intestine is not due to a defect in the generation of a Ca2+ signal in intestinal cells upon cholinergic stimulation.
Cellular characterization of an in-vitro cell culture model of seal-induced cardiac ischaemia
Authors: Takahashi Kyoko , Ohyabu Yuko , Schaffer Stephen W , Azuma Junichi 
Published: July 2003

Abstract
The lack of a well-characterized in-vitro cell culture model of load-induced cardiac ischaemia has hampered investigations into the mechanism of ischemic injury. We therefore developed a new in-vitro model of cardiac ischaemia that mimics distinct features of ischaemic injury.
Neonatal rat heart cells were cultured in a sealed flask for 24–72 h. In this environment, the cells were exposed to stresses of hypoxia, acidosis and stagnant incubation medium. The pO2 and pH of the medium gradually decreased during the ischaemic insult and ultimately fell to a level of 14 mmHg and pH 6.8, respectively. The model triggered severe cell injury, including morphological degeneration, CPK release, beating impairment and ATP depletion. Apoptosis occurred in some cardiomyocytes as early as 24 h after onset of seal-induced ischaemia. This was evidenced by positive nuclear staining using Hoechst 33258 and by the induction of caspase-3 mRNA. By 72 h, internucleosomal DNA fragmentation was observed in 45% of the myocytes; however, a non-myocyte preparation subjected to the same ischaemic insult exhibited no evidence of DNA fragmentation.
These results demonstrate that neonatal cardiomyocytes subjected to the new simulated ischaemia model exhibit several similarities to cardiac ischaemia, including the simultaneous appearance of necrosis, breakdown of cellular ATP, beating cessation and apoptosis. The new model should prove useful in unravelling the molecular alterations underlying ischaemic injury and myocardial apoptosis.
Prevention of neuronal cell damage induced by oxidative stress in-vitro: effect of different Ginkgo biloba extracts
Authors: Guidetti Cristina , Paracchini Silvano , Lucchini Serena , Cambieri Maurizio , Marzatico Fulvio 
Published: July 2003

Abstract
The effect of two different Ginkgo biloba extracts (GB1 and GB4) was studied in-vitro on cultured neurons exposed to oxidative stress caused by H2O2 (50 μmol L−1) and FeSO4 (100 μmol L−1). Only about 50% of the neurons were still viable at the end of the experiment (8 h) in control conditions, while the two extracts dose dependently increased the number of viable cells, in the concentration range 10–200 μg mL−1. The two Ginkgo biloba extracts differed in their effect on hydroxyl-radical-scavenging capacity: GB1 and GB4 had an IC50 (50% inhibiting concentration) value of 78 μg mL−1 and 186 μg mL−1, respectively. However, both extracts inhibited apoptosis in cortical neurons after oxidative stress in-vitro. These observations make one suppose that different preparations of Ginkgo biloba have quantitatively different actions and outline the importance of the contribution of apoptosis prevention toward their neuroprotective action.
The effects of freeze-drying on the stability of liposomes to jet nebulization
Authors: Bridges Paul A , Taylor Kevin M G 
Published: July 2003

Abstract
Egg phosphatidylcholine liposomes were freeze-dried in the presence and absence of trehalose. The lyophilized liposomes were rehydrated and aerosolized using a Pari LC jet nebulizer. The size of the aerosols generated was determined by laser diffraction, which was also used to determine the size distribution of the liposomes before lyophilization, post-rehydration, in the nebulizer post-aerosolization and those deposited in the two stages of a twin impinger. In the absence of trehalose, large liposomes and vesicle aggregates were produced on rehydration, which were rapidly reduced in size on nebulization. Liposomes with a mean size of 1 or 2.5 μm, freeze-dried with trehalose, had a mean size less than 3 μm following rehydration and exhibited enhanced stability to nebulization. Liposomes of 1 μm before freeze-drying were evenly distributed within aerosols generated by the nebulizer, whilst aerosols generated from 2.5 μm liposomes were fractionated in the twin impinger with the largest liposomes collected in the upper stage.
The urinary excretion of γ-hydroxybutyric acid in man
Authors: Kavanagh P V , Kenny P , Feely J 
Published: July 2003

Abstract
γ-Hydroxybutyric acid (GHB) has been widely associated with drug-facilitated sexual assault (DFSA). However, its excretion profile in man has not been well characterized. To assess the detectability of GHB for forensic cases and to correlate urinary levels with dose, we have examined the excretion profiles of 1- and 2-g doses of GHB (sodium salt) in a healthy male volunteer. The urinary levels were measured by a novel, simple and highly reproducible method. The drug was found to be excreted in small amounts in the free form (0.86 and 1.16% for 1- and 2-g doses, respectively) rapidly in urine (≤ 10 h). The urinary levels were found to be in the low mg L−1 range (up to 29.1 mg L−1). The work presented demonstrates that it is of the utmost importance to collect the samples as soon as possible following the alleged assault.
Formation of a defluorinated metabolite of a quinoxaline antiviral drug catalysed by human cytochrome P450 1A2
Authors: Mutch Peter J , Dear Gordon J , Ismail Issy M 
Published: July 2003

Abstract
The in-vitro metabolism of GW420867X ((S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-1-carboxylic acid isopropyl ester), a quinoxaline drug for the potential treatment of HIV, has been studied with singly expressed human cytochromes P450 (CYP 450). No biotransformation of [14C]GW420867X was evident in the presence of any of the CYP 450 isoforms, with the exception of CYP 450 1A2, where a single metabolite was observed in the HPLC radiochromatograms of enzyme incubations with the test compound. The structure of this metabolite was determined by nuclear magnetic resonance spectroscopy and mass spectrometry, and was shown to correspond to the replacement of the aromatic fluorine of GW420867X with a hydroxyl group. Thus, it appeared that CYP 450 1A2 catalysed the specific defluorination of GW420867X, presumably during formation of an arene oxide intermediate during aromatic hydroxylation.
Effect of indinavir on the pharmacokinetics of rifampicin in HIV-infected patients
Authors: Jaruratanasirikul Sutep , Sriwiriyajan Somchai 
Published: July 2003

Abstract
Indinavir, an antiretroviral agent, has an influence on the pharmacokinetics of other drugs by acting as an inhibitor of cytochrome P450-mediated drug metabolism. The incidence of tuberculosis has increased dramatically in the past decade because of an epidemic of HIV infection. Rifampicin is still one of the most valuable drugs for the standard treatment of tuberculosis. The objective of this study was to investigate the effects of indinavir on the pharmacokinetics of rifampicin in man. Our study was conducted in eleven HIV-infected patients. All patients received a 600-mg single dose of oral rifampicin on day 1 and 15- and 800-mg oral indinavir three times a day from day 2 to day 15. Rifampicin pharmacokinetic studies were carried out on day 1 and day 15. The results showed that rifampicin concentrations were higher when it was administered with indinavir than when it was administered alone. With concomitant indinavir medication, the mean AUC0–24 of rifampicin was increased by 73%. Therefore, we conclude that indinavir has an inhibitory effect on the metabolism of rifampicin.
A rapid and sensitive method for the determination of the amount of theophylline in blood spots
Authors: Watson D G , Oliveira E J , Boyter A C , Dagg K D 
Published: July 2003

Abstract
Monitoring of drugs (such as theophylline) with a narrow therapeutic window could be simplified if patients were able to submit blood spots for analysis. This could reduce clinic attendance for venous blood sampling and save staff time. A rapid sensitive method utilizing liquid chromatography-mass spectrometry has been developed to determine the amount of theophylline in blood spots. The lowest level of theophylline analysed in a blood spot was 15 ng extracted into 250 μL and this was still considerably above the limit of quantification (3 ng in 250 μL). The levels of theophylline in blood spots correlated well with theophylline levels in plasma samples obtained from the same patients. The assay might be of use in therapeutic drug monitoring of theophylline and blood spot sampling could be applied to other drugs where therapeutic monitoring is required.
Synthesis of N-Pyridinyl(methyl)-1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides and analogues and their anti-inflammatory activity in mice and rats
Authors: Collin X , Robert J M , Duflos M , Wielgosz G , Baut G Le , Robin-Dubigeon C , Grimaud N , Lang F , Petit J Y 
Published: July 2003

Abstract
The topical anti-inflammatory activity of a series of N-pyridinyl(methyl)1,2-dihydro-4-hydroxy-2-oxoquinoline-3-carboxamides, analogues of roquinimex, has been evaluated by measuring their inhibitory effect in the phorbol myristate acetate (PMA)-induced mouse ear swelling test, used as a screening test.
All the eight carboxamides tested (9–16) exhibited significant inhibitory activity at 0.4 and 0.2 mm kg−1. The most potent compound, the 6-bromo derivative 12, induced a 73% inhibition at 0.2 mm kg−1. Pharmacomodulation was carried out by heterocycle opening and molecular simplification leading to pentafluorobenzoylacetamide 17, pentafluorocinnamamides 18 and 19, and pentafluorobenzaldimines 20 and 21. All the five compounds exerted a reduction in swelling (49–63% at 0.2 mm kg−1) comparable with ibuprofen (56%). Anti-inflammatory activity of the most efficient compounds was evaluated by carrageenan-induced rat paw oedema inhibition. The pentafluorobenzaldimine 20 showed the highest activity with an inhibition percentage of 85% at 0.2 mm kg−1.
Overcoming antimicrobial resistance by targeting resistance mechanisms
Authors: Poole Keith 
Published: July 2003

Abstract
Three mechanisms of antimicrobial resistance predominate in bacteria: antibiotic inactivation, target site modification, and altered uptake by way of restricted entry and/or enhanced efflux. Many of these involve enzymes or transport proteins whose activity can be targeted directly in an attempt to compromise resistance and, thus, potentiate antimicrobial activity. Alternatively, novel agents unaffected by these resistance mechanisms can be developed. Given the ongoing challenge posed by antimicrobial resistance in bacteria, targeting resistance in this way may be our best hope at prolonging the antibiotic era.
A novel and simple type of liposome carrier for recombinant interleukin-2
Authors: Kanaoka Eri , Takahashi Kouji , Yoshikawa Takayoshi , Jizomoto Hiroaki , Nishihara Yoshitaka , Hirano Koichiro 
Published: July 2003

Abstract
The strong interaction between recombinant interleukin-2 (IL-2) and liposome was characterized and its possible application to drug-delivery control considered. The liposomes were prepared with egg phosphatidylcholine, distearoyl-phosphatidylglycerol (DSPG), dipalmitoyl-phosphatidylcholine, dipalmitoyl-phosphatidylglycerol or distearoyl-phosphatidylcholine (DSPC). Small and hydrophobic liposomes were selected, which were composed of saturated and long-fatty-acid-chain phospholipids. When the composition and the mixture ratio of IL-2 and the liposome were optimized, more than 95% of the lyophilized IL-2 (Imunace, 350000, JRU) was adsorbed consistently onto the DSPC-DSPG liposome (molar ratio, 10:1; 25 μmol mL−1; 30 nm in size). Merely mixing IL-2 lyophilized with liposome suspension is convenient pharmaceutically. After intravenous administration to mice, liposomal IL-2 was eliminated half as slowly from the systemic circulation as free IL-2, with more than 13 and 18 times more IL-2 being delivered to the liver and spleen, respectively. After subcutaneous administration of liposomal IL-2 to mice, the mean residence time of IL-2 in the systemic circulation was 8 times that of free IL-2. These results show that IL-2 consistently adsorbs onto the surface of liposomes after optimization of its composition and mixing ratio. Intravenous and subcutaneous administration to mice demonstrates the gradual release of IL-2. Further trials are warranted using these liposomes.
Characterization of glass solutions of poorly water-soluble drugs produced by melt extrusion with hydrophilic amorphous polymers
Authors: Forster Angus , Hempenstall John , Rades Thomas 
Published: July 2003

Abstract
Indomethacin, lacidipine, nifedipine and tolbutamide are poorly soluble in water and may show dissolution-related low oral bioavailability. This study describes the formulation and characterization of these drugs as glass solutions with the amorphous polymers polyvinylpyrrolidone (PVP) and polyvinylpyrrolidone-co-vinyl acetate by melt extrusion. The extrudates were compared with physical mixtures of drug and polymer. X-ray powder diffraction, thermal analysis, infrared spectroscopy, scanning electron microscopy, HPLC, moisture analysis and dissolution were used to examine the physicochemical properties and chemical stability of the glass solutions prepared by melt extrusion at a 1:1 drug/polymer ratio. Depending on the temperature used, melt extrusion produced amorphous glass solutions, with markedly improved dissolution rates compared with crystalline drug. A significant physicochemical interaction between drug and polymer was found for all extrudates. This interaction was caused by hydrogen bonding (H-bonding) between the carbonyl group of the pyrrole ring of the polymer and a H-donor group of the drug. Indomethacin also showed evidence of H-bonding when physical mixtures of amorphous drug and PVP were prepared. After storage of the extrudates for 4–8 weeks at 25°C/75% relative humidity (RH) only indomethacin/polymer (1:1) extrudate remained totally amorphous. All extrudates remained amorphous when stored at 25°C/&lt; 10% RH. Differences in the physical stability of drug/polymer extrudates may be due to differences in H-bonding between the components.
Distribution of the methylpiperazinopyridobenzoxazepine derivative JL13, a potential antipsychotic, in rat brain
Authors: Guiso Giovanna , Caccia Silvio 
Published: July 2003

Abstract
The brain uptake and distribution of the potential antipsychotic 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3][1,5]benzoxazepine fumarate (JL13) was examined in rats after neuropharmacologically active doses. Plasma and brain concentrations of the compound were measured by reversed-phase HPLC with UV detection (210 nm). Clozapine was used as an internal standard. After an intraperitoneal dose of 10 mg kg−1, the compound attained mean maximum plasma concentrations within 5 min of dosing, then declined with a mean elimination half-life of approximately 1 h. It rapidly crossed the blood-brain barrier and equilibrated with plasma, achieving mean maximum concentrations and area under the curve approximately 20-times those in plasma, with slight regional differences. Disappearance from whole brain almost paralleled its disappearance from plasma. There was a linear relationship between JL13 concentrations in plasma and brain regions, and in all tissues the concentrations of the compound increased almost linearly with the dose over the range of 5–20 mg kg−1. It thus appears that JL13 brain pharmacokinetics parallels that in plasma, and that plasma concentrations accurately predict brain concentrations in rats.
Control of impurities in diphenhydramine hydrochloride by an ion-pairing, reverse-phase liquid chromatographic method
Authors: Henderson L , Miller J H McB , Skellern G G 
Published: July 2003

Abstract
A precise, sensitive, repeatable and robust reverse-phase liquid chromatographic method has been developed for the control of seven possible impurities of diphenhydramine hydrochloride. The robustness of the method was examined by varying, in turn, each of four mobile-phase parameters (acetonitrile content, buffer salt concentration, ion-pair reagent concentration and pH). The method was linear in the range 0–0.14 mg mL−1 for diphenhydramine hydrochloride with an acceptable precision and accuracy, and a limit of detection of 0.17 μg mL−1. Five samples of diphenhydramine hydrochloride from two sources were analysed with the developed liquid chromatographic method.
A study of the anti-invasive properties of N-α-phthalimidomethyl-ketomethylene tripeptide-based metalloprotease inhibitors
Authors: Martin S Lorraine , McDowell Andrew , Lynas John F , Nelson John , Walker Brian 
Published: July 2003

Abstract
We have developed matrix metalloprotease (MMP) inhibitors based on synthetic peptides incorporating a non-cleavable peptide-bond isostere at the site of the putative scissile bond. These inhibitors, N-α-phthaloyl-Gly-Ψ(CO-CH2)-Leu-Tyr-Ala-NH2 (Pht-G-CH2-LYA-NH2) and N-α-phthaloyl-Gly-Ψ(CO-CH2)-Leu-Tic-Ala-NH2 (Pht-G-CH2-LTcA-NH2) were kinetically evaluated against the type IV collagenases, gelatinase A (MMP-2) and B (MMP-9), and compared with an exactly analogous chelating-based inhibitor, N-α-mercaptoacetyl-Leu-Tyr-Ala-NH2 (HSCH2CO-LYA-NH2). The peptide inhibitors were also tested for their anti-invasive effects on breast carcinoma cell lines using a modification of the Boyden chamber assay. Gelatin zymography was utilized to identify gelatinolytic activities present in media removed from cultured breast cancer cells. Of the two N-α-phthalimidomethyl-ketomethylene peptide-based inhibitors, Pht-G-CH2-LYA-NH2 proved the more effective inhibitor of MMP-2 and MMP-9 (Ki 34.27 and 45.75 μm, respectively). However, when tested against two breast cancer cell lines, T47D and MDA-MB-231, both inhibitors were able to effectively reduce tumour cell invasion through a type IV collagen matrix by up to 91.2%. Of particular interest was the observation that Pht-G-CH2-LYA-NH2 was the most potent inhibitor of invasion by the highly aggressive MDA-MB-231 cells, despite the cells' relative lack of active secreted metalloprotease activity. The results obtained from this kinetic and anti-invasive analysis of the new inhibitors suggest that compounds incorporating the N-α-phthalimidomethyl-ketomethylene peptide-bond isostere may have potential for development as new agents with anti-metastatic properties.
Synthesis and hydrolytic behaviour of glycerol-1,2-diibuprofenate-3-nitrate, a putative pro-drug of ibuprofen and glycerol-1-nitrate
Authors: Ingram Matthew J , Moynihan Humphrey A , Powell Mark W , Rostron Chris 
Published: July 2003

AbstractNitroxylated derivatives of non-steroidal anti-inflammatory drugs appear to offer protection against the gastrotoxicity normally associated with non-steroidal anti-inflammatory drugs, ostensibly via local production of nitric oxide. A diester of ibuprofen and glycerol-1-mononitrate has been prepared via the condensation of ibuprofen with 3-bromopropan-1,2-diol, followed by silver-(I)-nitrate-mediated nitroxylation. The release of ibuprofen from this diester has been studied in a simulated gastric fluid model with direct analysis by reverse-phase HPLC, using an acetonitrile-water (80%:20%) mobile phase containing trifluoroacetic acid (0.005%). n-Propyl ibuprofen was found to undergo pH-dependent hydrolysis, ranging from negligible hydrolysis at pH 5 to 52% hydrolysis at pH 3, over a 2-h period in this model. The ibuprofen-glycerol mononitrate diester was subjected to the most vigorous model hydrolytic conditions and was found to undergo 50% hydrolysis during the study period. This study shows that pro-drugs of ibuprofen and glycerol mononitrate can be obtained, and can undergo degradation to the parent drugs under conditions simulating those likely to be encountered in the stomach.