bluuebunny/crossref_metadata_2025_split huggingface dataset:
BQ-153, a novel endothelin (ET)A antagonist, attenuates the renal vascular effects of endothelin-1
Authors: Cirino M , Motz C , Maw J , Ford-Hutchinson A W , Yano M 
Published: April 2011

Abstract
Endothelin (ET)-l, leukotriene D4 and the thromboxane analogue, U-44069, were all shown to produce dose-dependent reductions in renal blood flow after direct injection into the renal artery of anaesthetized pigs. The effects of ET-1 differed from the other two mediators in that ET-1 caused a transient vasodilator followed by a prolonged vasoconstrictor response. The pressor response was not mediated by the secondary release of either leukotriene D4 or thromboxane A2 as evidenced by the lack of effect of appropriate receptor antagonist MK571 (3-{-2(7-chloro-2 quinolinyl) ethenyl}phenyl{3-(dimethylamino-3-oxopropyl)thio}methyl thio propionic acid) and L-670,596 respectively. This response, however, could be inhibited in a dose-dependent fashion by the selective ETA antagonist, BQ-153 (cyclo-d-sulphalanine-l-Pro-d-Val-l-Leu-d-Trp-). Following blockade by BQ-153 the vasodilator response was unaffected and a residual pressor response remained, suggesting that either or both of these effects were mediated either through an ETB or a novel, as yet undefined, endothelin receptor.
Comparison of Nebuliser Efficiency for Aerosolizing Pentamidine
Authors: Smith Don , Erskine David , Steele Janice , Hills Denise , Gazzard Brian 
Published: April 2011

Abstract
Inhaled pentamidine has become an important method of treatment and prophylaxis for Pneumocystis carinii pneumonia and we have compared nebuliser efficiency in terms of drug output and droplet sizes in four brands of jet nebuliser (Acorn-22, Inspiron, Cirrus, Respirgard II) and one brand of ultrasonic nebuliser (Fisoneb), at 2 pentamidine concentrations and 3 flow rates, using a laser particle sizer. Droplet size (which varied from 1·2 to 4·7 μm mass median diameter) was dependent in all cases, except with the Respirgard II system, on the flow rate of the gas driving the equipment and the concentration of pentamidine used. Drug output varied significantly between nebuliser brands and for a 300 mg dose of pentamidine was: 61% for the Acorn-22, 62% for the Inspiron, 49% for the Fisoneb and 43% for the Respirgard II. Both droplet size and drug output are important in determining nebuliser efficiency.
The Effect of Dinoprost on Transport of Water and Imipramine Through Rat Small Intestinal Membranes
Authors: Arimori Kazuhiko , Deshimaru Megumi , Nakano Masahiro 
Published: April 2011

Abstract
The relation between transmucosal fluid movement and its effect on absorption and exsorption of imipramine was studied with the in-situ single-pass perfusion technique in rats. Dinoprost (prostaglandin F2α, PGF2α) caused a dose-related inhibition of both absorption and secretion of water across the intestinal membrane. When PGF2α was infused at a rate of 5 μmol kg−1 h−1, the absorption rate of water decreased from 51·7 to 21·5 mL h−1 and the secretion rate decreased from 48·9 to 26·8 mL h−1. Net water flux changed from net water absorption (0·9 mL h−1)tonet water secretion (5·33 mL h−1) by infusion of PGF2α. However, absorption and exsorption of imipramine were little affected by infusion of PGF2α. The absorption rates of imipramine were 3·03 and 2·36 mg h−1 in the absence and presence of PGF2α, respectively. Furthermore, the average amounts of imipramine exsorbed into the intestinal lumen in 2 h were 7·82 and 8·10% in the absence and presence of PGF2α, respectively. Infusion of PGF2α, also enhanced motility of the small intestine compared with the control. From these results, it appears that PGF2α has no effect on the absorption and exsorption of imipramine across the intestinal membrane although it is reasonable to use PGF2α in the case of patients with overdoses of drugs which decrease gastrointestinal motility.
α2-Adrenoceptor Changes During Cerebral Ageing. The Effect of Ginkgo biloba Extract
Authors: Huguet François , Tarrade Thierry 
Published: April 2011

Abstract
[3H]Rauwolscine binding to α2-adrenoceptors in cerebral cortex and hippocampus membranes of young (4 months) and aged (24 months) Wistar rats has been investigated. In aged rats, Bmax values of [3H]rauwolscine binding were significantly reduced (25–32%) in the cerebral cortex and hippocampus, as compared with the number of α2-adrenoceptors found in young rats. Chronic treatment with Ginkgo biloba extract did not alter [3H]rauwolscine binding in the hippocampus of young rats, but significantly increased (28%) the [3H]rauwolscine binding density in aged rats. These data confirm the previously described age-related noradrenergic alteration and suggest that noradrenergic activity in aged rats is more susceptible to Ginkgo biloba extract treatment.
Method for Analysis, and Distribution Profile, of Covalently-linked Ferritin-daunorubicin Conjugate in the Blood of Trypanosome-infected Mice
Authors: Brown J E , Patterson L H , Williamson J , Brown J R 
Published: April 2011

Abstract
Daunorubicin is a highly potent trypanocide in-vitro but is inactive in-vivo. When daunorubicin is conjugated to bovine serum albumin or horse spleen ferritin using Schiffs base linkages, the complex is trypanocidal in-vitro and in-vivo. We have developed novel analytical methods, using HPLC with fluorimetric detection, for the quantitation of daunorubicin and doxorubicin in biological samples, either as unconjugated drug, or when covalently linked to macromolecules or particles. Ferritin-daunorubicin conjugate (25 mg kg−1) was administered intraperitoneally to mice infected with monomorphic Trypanosoma brucei rhodesiense; peak plasma levels occurred after 1·5 h, and were 5 times higher than those resulting from administration of an equivalent amount of unconjugated daunorubicin. Plasma levels then declined rapidly (t½ for 1–6 h period was 0·58 and 0·86 h respectively for conjugated and unconjugated daunorubicin). However, higher plasma levels were seen 24 h after treatment, suggesting the distribution profile of daunorubicin when conjugated to ferritin is multiphasic with resultant high levels of daunorubicin obtained for a prolonged time period.
Potassium markedly potentiates the effect of veratridine on dopamine release from rat superfused striatal ribbons
Authors: Olivier Valérie , Miquet Jean-Marie , Aubeneau Michel , Blanchard Jean-Charles , Doble Adam , Boireau Alain 
Published: April 2011

Abstract
The effects of veratridine-induced depolarization on [3H]dopamine ([3H]DA) release in the presence of a physiological (5 Mm) or a depolarizing (25 Mm) concentration of K+ were studied in-vitro in rat superfused striatal ribbons. A combination of the two depolarizing agents induced a marked potentiation in the overflow of [3H]DA, giving an overall 3- to 5-fold increase in veratridine activity. This potentiation was completely antagonized by tetrodotoxin (100 Nm). These studies indicated that K+-induced depolarization can increase the potency of veratridine in releasing dopamine from terminals.
Similar central actions of intravenous methohexitone suspension and solution in the rabbit
Authors: Viernstein H , Stumpf C 
Published: April 2011

Abstract
The central actions of solutions of methohexitone sodium and suspensions of methohexitone given intravenously in equimolar doses have been compared. The administrations induced identical anaesthesia. Because, in general, drugs acting upon the central nervous system are poorly soluble in water, this finding should be useful for routine pharmacological investigations as it avoids the use of organic solvents which may themselves affect the central nervous system.
Partition and distribution coefficients of aryloxypropanolamine β-adrenoceptor antagonists
Authors: Recanatini M 
Published: April 2011

Abstract
n-Octanol/water partition and distribution coefficients of fifteen β-blockers have been measured and the relationships between log P (neutral species), log Pi (fully ionized species) and log D7·4 have been examined. A strict correlation exists among these three parameters, suggesting that the ionization exerts similar effects on the partition behaviour of these drugs.
An In-vitro and In-vivo Correlative Approach to the Evaluation of Ester Prodrugs to Improve Oral Delivery of Propranolol
Authors: Shameem Mohammed , Imai Teruko , Otagiri Masaki 
Published: April 2011

Abstract
A series of ester prodrugs of propranolol was synthesized by incorporating substituents (straight alkyl, branched alkyl, acyloxyalkyl and cycloalkyl) into the β-hydroxy function of propranolol with the aim of protecting the drug against first-pass metabolism following oral administration. The in-vitro hydrolysis rates of the prodrugs were, in increasing order, liver homogenate ≫ plasma &gt; buffers. The pH-rate profile of the prodrugs showed maximum stability around pH 4·0; the hydrolysis rates were drastically increased over pH 6·8. QSAR analysis revealed hydrophobic (π) and electronic (σ) effects of the substituents play the main roles for prodrug hydrolysis in buffers and plasma, while hydrolysis in liver homogenate could not be well explained by any of these parameters. Four prodrugs (O-acetyl-, O-butyryl-, O-isovaleryl- and O-cyclopropanoyl-propranolol) were selected for oral administration based on their hydrolysis in-vitro. Following oral administration of prodrugs to beagle dogs the absolute bioavailabilities (F) of propranolol were about 2–4-fold that after an equivalent dose of propranolol. The prodrugs were rapidly absorbed and regenerated propranolol to attain peak plasma levels at 0–0·5 h. Intact prodrug levels were also observed, which varied depending on their respective stabilities in in-vitro media. A linear relationship between F of propranolol and log P was obtained. F further appeared to be parabolically dependent on the observed hydrolysis rates of prodrugs in liver homogenate suggesting optimal design manipulation. The overall in-vitro and in-vivo results showed that lipophilic prodrugs having higher chemical and enzymatic stability in buffers and plasma, but susceptible to hydrolysis in the liver homogenate, to be the most promising prodrugs for improving oral bioavailability of propranolol.
A Modification of the Extended Hildebrand Approach to Predict the Solubility of Structurally Related Drugs in Solvent Mixtures
Authors: Bustamante Pilar , Escalera Begoña , Martin Alfred , Selles Eugenio 
Published: April 2011

Abstract
A modification of the extended Hildebrand equation is proposed to estimate the solubility of an organic drug in solvent mixtures. The equation accurately reproduces the solubility of four sulphonamides in dioxane-water mixtures without requiring the heat of fusion of the solute. A single equation is obtained for predicting the solubility of related drugs using the solubilities of the drugs in the pure solvents, dioxane and water, and solute-solvent interaction terms consisting of the solubility parameter, δ2, of the solute and the solubility parameter, δ1, and basic partial solubility parameter, δ1b, of the solvent mixture. By this procedure a single equation was obtained to estimate the solubilities of three xanthines in dioxane-water and another equation to obtain the solubilities of four sulphonamides. The equation obtained for sulphonamides is able to predict the experimental solubilities of two parent compounds, sulphasomidine and sulphathiazole, and the solubilities of a drug of different structure, p-hydroxybenzoic acid. This suggests that the intermolecular solute-solvent interaction of sulphonamides and p-hydroxybenzoic acid are similar. The results indicate that the solubility behaviour of drugs having different structures may be modelled using a common equation provided that they show similar solute-solvent interactions.
Stereochemical Aspects of the Molecular Pharmaceutics of Ibuprofen
Authors: Romero A J , Rhodes C T 
Published: April 2011

Abstract
Thermal analysis, thermodynamics of solution and molecular modelling of (+)-ibuprofen and (+)-ibuprofen gave information on how heterochiral or homochiral interactions would affect the processing of ibuprofen. The study confirmed that (±)-ibuprofen exists as a true racemate with a 10% eutectic pure enantiomer composition. Both the racemate and the (+)-isomer crystal unit cells include four molecules and crystallize in the P21/c and P21 space groups, respectively. Thus the intermolecular forces were different in each crystal. As a consequence the (+)-enantiomer lattice was more fragile but only slightly more soluble than the racemate in aqueous media. The solid-state structure contributions to solubility were different for the two crystals (ΔH(+) = 51·1 and ΔH(±) = 32–2 kJ mol−1) but the standard free energies of the solutions were comparable for both compounds.
A Comparative Study of the Toxicity of Chemically Reactive Xenobiotics Towards Adherent Cell Cultures: Selective Attenuation of Menadione Toxicity by Buthionine Sulphoximine Pretreatment
Authors: Riley R J , Spielberg S P , Leeder J S 
Published: April 2011

Abstract
Metabolic activation to reactive intermediates is a prerequisite for many forms of chemically-induced toxicity. Hepa lclc-9 cells were exposed to varying concentrations of several reactive metabolites implicated in adverse drug reactions and the toxicity of the compounds assessed using applied fluorescence technology. Cytotoxicity was assessed using the fluorescence of 2′, 7′-bis-(2-carboxyethyl)-5-(6)-carboxyfluorescein as an index of cell viability. The role of glutathione in cellular defence against these chemicals was investigated by pretreating the target cells overnight with buthionine sulphoximine, a specific inhibitor of glutathione synthesis. Depletion of intracellular glutathione augmented the toxicity of N-acetyl-p-benzoquinone imine (1·5–3-fold at 100 and 10 μm). Toxicity produced by the hydroxylamine of sulphamethoxazole (500 μm) was dependent entirely on pretreatment of the cells with buthionine sulphoximine (% cell death = 33 ± 16 compared with 0 ± 4 in untreated cells, P &lt; 0·05). By contrast, the lethal effects of the model quinone, menadione, were attenuated markedly following glutathione depletion. The data obtained suggest that this assay, previously used with suspension cultures, may be useful in the rapid in-vitro screening of putative reactive intermediates. Moreover, the application of such methodology should prove beneficial for the elucidation of cellular mechanisms of defence and detoxification.
Effects of Isoquinolinesulphonamide Compounds on Multidrug-resistant P388 Cells
Authors: Nakamura Shigeo , Wakusawa Shinya , Tajima Kazuo , Miyamoto Ken-Ichi , Hagiwara Masatoshi , Hidaka Hiroyoshi 
Published: April 2011

Abstract
The effects of eight isoquinolinesulphonamide compounds on resistance to vinblastine in adriamycin-resistant mouse leukaemia cells (P388/ADR) which overexpress the relative molecular weight (Mr) 140 kDa P-glycoprotein in the plasma membrane were investigated. N-[2-(Methylamino)ethyl]-5-isoquinolinesulphonamide (H-8) and N-(2-aminoethyl)-5-isoquinolinesulphonamide (H-9) did not reverse vinblastine resistance. N-[2-[N-[3-(4-Chlorophenyl)-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-86) and N-[2-[N-[3-(4-chlorophenyl)-1-methyl-2-propenyl]amino]ethyl]-5-isoquinolinesulphonamide (H-87) caused accumulation of intracellular vinblastine and inhibition of vinblastine efflux from the cells and reversed the resistance. Addition of an aminoethyl group to the nitrogen atom of the sulphonamide group (W-66) or a formyl group at the terminal amino group (H-85) of H-86 reduced those activities. Conversion of the chlorophenyl group of H-87 to pyridinyl (H-31) or furanyl (H-34) markedly decreased activities against the drug resistance. The activity against vinblastine accumulation closely correlated with the apparent partition coefficient of compounds. These compounds dose-dependently inhibited photoaffinity labelling of a photosensitive analogue of vinblastine, N-(p-azido-(3-[125I])salicyl)-N′-β-aminoethylvindesine ([125I]NASV), and there was a good correlation between inhibition of [125I]NASV-photolabelling and hydrophobicity. Although these isoquinolinesulphonamides inhibited protein kinase A with different magnitudes, this activity did not correlate with the effect on the drug resistance. These results indicate that isoquinolinesulphonamide compounds with a hydrophobic group interact with antitumour drugs on P-glycoprotein and reverse multidrug resistance without involvement of their activity on protein kinase A.
Effect of Molsidomine and Linsidomine on the Human Isolated Bronchus and the Guinea-pig Isolated Trachea
Authors: Zhang Yong , Palette-Pays Catherine , Naline Emmanuel , Varoquaux Odile , Advenier Charles 
Published: April 2011

Abstract
The effects of molsidomine and its metabolite linsidomine were studied on the guinea-pig isolated trachea and on the human isolated bronchus. These effects were compared with those of nitrate derivatives (sodium nitroprusside, isosorbide dinitrate), theophylline, zardaverine and isoprenaline. Linsidomine exerted a relaxant effect similar to that of sodium nitroprusside on the two types of preparations precontracted with acetylcholine, histamine or potassium chloride. Molsidomine was about one-hundredth as potent as linsidomine, and less efficacious. The effects of the two substances were not modified by removal of the human bronchial epithelium. The concentration-response curves of linsidomine and sodium nitroprusside were significantly shifted to the right by methylene blue (3 × 10−5 m) but the effects of isoprenaline were unmodified. The effects of linsidomine and sodium nitroprusside were potentiated specifically by zaprinast (10−6-10−5 m), an inhibitor of type Ia or V phosphodiesterases, whereas the effects of isoprenaline were potentiated by zardaverine (10−9-10−8 m), an inhibitor of class III and IV phosphodiesterases. The effects of all three substances (linsidomine, isoprenaline and sodium nitroprusside) were potentiated equally by theophylline (10−5-10−4 m), a nonspecific inhibitor of phosphodiesterases. It is concluded that linsidomine is a potent relaxant of the smooth muscle of the guinea-pig isolated trachea and human isolated bronchus. In terms of potency and efficacy, its effect is much superior to that of the parent compound molsidomine. It is suggested that linsidomine acts, like nitrate derivatives, through the guanylate cyclase-cGMP system.
Differential Vasorelaxant Effects of K+-Channel Openers and Ca2+-Channel Blockers on Canine Isolated Arteries
Authors: Iwamoto T , Nishimura N , Morita T , Sukamoto T 
Published: April 2011

Abstract
The vasorelaxant effects of the K+-channel openers, pinacidil and cromakalim, were compared with those of the Ca2+-channel blockers, verapamil and KB-2796 (1-[bis(4-fluorophenyl)methyl]-4-(2,3,4-trimethoxybenzyl)piperazine dihydrochloride), in canine isolated coronary, renal, basilar and mesenteric arteries precontracted with U46619, a thromboxane A2 mimetic. The relaxation induced by pinacidil and cromakalim was greater in coronary than in other arteries, the magnitude of relaxation being in the order of coronary &gt; renal &gt; basilar &gt; mesenteric arteries. The relaxant responses to both drugs were inhibited by glibenclamide, a blocker of ATP-sensitive K+ channels. The relaxation induced by verapamil and KB-2796, in contrast, was greater in basilar than in other arteries, the magnitude of relaxation being in the order of basilar &gt; coronary &gt; renal and mesenteric arteries. In fura-2-loaded, U46619-stimulated arteries, pinacidil and cromakalim produced a greater reduction in intracellular Ca2+ concentration and muscle tension in coronary than in mesenteric arteries, while verapamil and KB-2796 reduced these values more potently in basilar than in mesenteric arteries. These results suggest that K+-channel openers exhibit a vasorelaxant selectivity for coronary arteries, whereas Ca2+-channel blockers exhibit such selectivity for cerebral arteries. The selective vasorelaxant action induced by these drugs appears to correspond, in part, to their effects on the concentration of intracellular Ca2+.
Effect of Glutathione on Canine Myocardial Ischaemia Without Reperfusion
Authors: Such Luis , Alberola Antonio , Gil Francisco , Bendala Elena , Viña José , Morcillo Esteban J 
Published: April 2011

Abstract
The present study was to evaluate the effect of exogenous glutathione on myocardial damage resulting from permanent (no reperfusion) coronary ligation (3 or 6 h) in anaesthetized dogs. Haemodynamics, infarct size and myocardial glutathione content were determined. Erythrocyte superoxide dismutase (SOD) activity was also determined in coronary venous blood samples. Glutathione was administered by the intraperitoneal route, 100 mg kg−1 as initial dose given 5 min before coronary ligation, and successive doses of 25 mg kg−1 every 40 min throughout the study period. Saline-treated dogs showed myocardial infarction, a decrease in myocardial glutathione content, and a transient increase in SOD activity. Three hours occlusion in glutathione-treated dogs resulted in a small reduction of infarct size, and no changes in myocardial glutathione content and SOD activity. By contrast, administration of glutathione failed to reduce infarct size and failed to prevent myocardial glutathione decrease in dogs subjected to 6 h occlusion. These results indicate that exogenous glutathione is of minor beneficial effect for myocardial damage resulting from permanent coronary occlusion and suggest that endogenous glutathione has a limited role in protecting against myocardial ischaemia without reperfusion.
Suppressive Effect of Recombinant TNF-gelatin Conjugate on Murine Tumour Growth In-vivo
Authors: Tabata Yasuhiko , Uno Kazuko , Ikada Yoshito , Muramatsu Shigeru 
Published: April 2011

Abstract
A recombinant human tumour necrosis factor α (TNF) was conjugated to gelatin by means of carbodiimide to improve the in-vivo stability of TNF. About 55% of TNF activity was retained after gelatin conjugation as judged by the cytotoxicity assay using L-M cells in-vitro. Intraperitoneal injection of the TNF-gelatin conjugate significantly suppressed the in-vivo growth of murine Meth A fibrosarcoma cells (SS2 cells) in mouse peritoneum, in comparison with that of free TNF at the same dosage (P &lt; 0·05). After intraperitoneal injection, TNF activity of the conjugate was detected in both the serum and the peritoneal cavity of mice for a longer period than was free TNF, irrespective of the presence of SS2 cells. Chromatographic studies of the conjugate demonstrated that the increase in the apparent molecular weight of TNF was consistent with gelatin conjugation. It is likely that this leads to a prolonged retention of TNF activity in-vivo. In addition, the TNF-gelatin conjugate suppressed the in-vitro growth of SS2 cells to the same extent as free TNF. Thus, it is possible that the longer retention period of the conjugate brought about an increase in the chance of contact between TNF and SS2 cells, resulting in the enhanced suppressive effect of TNF on in-vivo tumour cell growth. Gelatin conjugation is an effective method for increasing the in-vivo antitumour activity of TNF.