bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanism for Synergism between Sulphonamides and Trimethoprim Clarified
Authors: Richards R M E , Taylor R B , Zhu Z Y 
Published: April 2011

Abstract
Pseudomonas aeruginosa, Escherichia coli, Pseudomonas cepacia and Moraxella catarrhalis were selected for their markedly different resistance patterns to sulphonamides and trimethoprim. In addition, strains of E. coli and P. cepacia were selected having different resistance profiles to the inhibition of dihydropteroate synthetase and dihydrofolate reductase.
All inhibitors of dihydropteroate synthetase combined in any combination with inhibitors of dihydrofolate reductase resulted in mutual enhancement of bacterial uptakes of the inhibitors and corresponding increased antibacterial activity of the combinations. High concentrations of sulphonamides or p-aminobenzoic acid plus trimethoprim caused a decrease in overall activity of the combination and indicated that both sulphonamides and p-aminobenzoic acid at high concentrations can interact with dihydrofolate reductase. The antibacterial activity of p-aminobenzoic acid at high concentrations is considered to be a blocking effect on dihydrofolate reductase even though p-aminobenzoic acid at low concentrations is an essential part of the synthesis of dihydrofolic acid.
These findings support an alternative hypothesis for the mechanism of antibacterial action of individual antifolates and their mechanism of synergism in combination.
Magnetizable Solid-phase Supports for Purification of Nucleic Acids
Authors: Bruce I J , Davies M J , Howard K , Smethurst D E , Todd M 
Published: April 2011

Abstract
A simple, small scale non-hazardous procedure for the production of magnetizable solid-phase support (MSPS) beads has been developed based on the extrusion of agarose/iron oxide mixtures.
The MSPS beads were derivatized using various amine ligands. Derivatized MSPS beads were used to adsorb nucleic acids from aqueous solution and to separate RNA/DNA mixtures.
Synthesis and Biological Evaluation of 3-(Prop-2-enyl)- and 3-(Prop-2-ynyl)pyrrolidine-2,5-dione Derivatives as Potential Aromatase Inhibitors
Authors: Barrell K J , Woo W L , Ahmadi M , Smith H J , Nicholls P J 
Published: April 2011

Abstract
3-(4′-Aminophenyl)pyrrolidine-2,5-dione (WSP3), a known reversible inhibitor of P450 aromatase, was modified using molecular graphics and our model of reversible inhibitor and substrate binding to resemble 10β-prop-2-ynylestr-4-ene-3,17-dione (PED), a mechanism-based inactivator of the enzyme.
The analogues prepared were 3-substituted 3-(prop-2-enyl) or 3-(prop-2-ynyl) pyrrolidine-2,5-diones and their N-alkyl derivatives.
The reported compounds demonstrated no irreversible (time-dependent) inhibition of the human placental P450 aromatase enzyme. However, some reversible activity was seen in several of the 3-(prop-2-ynyl) compounds.
Efficient Syntheses of Polyamine and Polyamine Amide Voltage-Sensitive Calcium Channel Blockers: FTX-3.3 and sFTX-3.3
Authors: Moya Eduardo , Blagbrough Ian S 
Published: April 2011

Abstract
Efficient syntheses of FTX-3.3 and sFTX-3.3, voltage-sensitive calcium channel blockers are described. These modified polyamines were prepared from selectively protected polyamines and purified on a practical scale.
Studies with Type I Aldolase to Understand Fructose Intolerance and Combat Parasitic Disease
Authors: Dalby Andrew , Littlechild Jennifer A 
Published: April 2011

Abstract
A structural study of the type I aldolases has been carried out to examine the isozyme specificity of these enzymes and the potential for designing specific inhibitors. Natural mutations in these aldolase enzymes are associated with haemolytic anaemia and fructose intolerance. It has also been proposed that inhibition of the parasitic version of the enzyme may provide a new lead in the design of drugs against malaria and sleeping sickness. X-ray crystallographic data is used with molecular modelling techniques to investigate the structural properties of these enzymes.
A Hydrogel Based on a Polyaspartamide: Characterization and Evaluation of In-vivo Biocompatibility and Drug Release in the Rat
Authors: Giammona G , Pitarresi G , Tomarchio V , Cacciaguerra S , Govoni P 
Published: April 2011

Abstract
This paper deals with the characterization of a new microparticulate hydrogel obtained by gamma irradiation of α,β-poly[N-(2-hydroxyethyl)-dl-aspartamide] (PHEA).
When enzymatic digestion of PHEA hydrogel was evaluated using various concentrations of pepsin and α-chymotrypsin no degradation occurred within 24 h. In-vivo studies showed that this new material is biocompatible after oral administration to rats. PHEA hydrogel was also studied as a system for delivery of diflunisal, an anti-inflammatory drug. In-vitro release studies in simulated gastrointestinal juice (pH 1 or 6.8) showed that most of the drug was released at pH 6.8. In-vivo studies indicated that diflunisal-loaded PHEA microparticles significantly improved the gastric tolerance and oral bioavailability of the drug in comparison with free diflunisal.
These results suggest the potential application of PHEA hydrogel as a new delivery system for the oral administration of anti-inflammatory drugs.
Stereoselectivity of Butylidenephthalide on Voltage-dependent Calcium Channels in Guinea-pig Isolated Ileum
Authors: Ko Wun-Chang , Sheu Joen-Rong , Leu Yi-Rong , Tzeng Shu-Huey , Chen Chi-Ming 
Published: April 2011

Abstract
Two geometric isomers, the Z- and the E- forms, can be separated from synthetic mixtures of butylidenephthalide (Bdph).
Z-Bdph (50–100 μm) non-competitively inhibited Ca2+-induced contractions in depolarized (K+, 60 mm) guinea-pig ileum longitudinal smooth muscle, with a pD2' value of 3.88 ± 0.20 (n = 5). However, E-Bdph (20–100 μm) competitively inhibited these contractions with a pA2 value of 4.56 ± 0.18 (n = 5) which was significantly (P &lt; 0.05) greater than the pD2' value of Z-Bdph. In contrast, the two isomers had no stereoselective inhibitory action on Ca2+ influx through pre- or post-junctional membranes of cholinergic nerve endings from which the transmitter acetylcholine is released or on Ca2+ release from intracellular stores.
Therefore, the trans-Z and cis-E forms of Bdph might have geometric stereoselectivity for voltage-dependent calcium channels (VDC) in guinea-pig longitudinal smooth muscle. Both isomers might inhibit more selectively the contractile twitch responses evoked by electrical stimulation than by cumulative acetylcholine-or carbachol-induced transient contractions in guinea-pig ileum longitudinal smooth muscle.
Molecular Factors Influencing Drug Transfer across the Blood-Brain Barrier
Authors: Gratton Julie A , Abraham Michael H , Bradbury Michael W , Chadha Harpreet S 
Published: April 2011

Abstract
A recently reported approach to the prediction of blood-brain drug distribution uses the general linear free energy equation to correlate equilibrium blood-brain solute distributions (logBB) with five solute descriptors: R2 an excess molar refraction term; π2H, solute dipolarity or polarizability; α2H and β2H, the hydrogen bond acidity or basicity, and VX, the solute McGowan volume. In this study we examine whether the model can be used to analyse kinetic transfer rates across the blood-brain barrier in the rat.
The permeability (logPS) of the blood-brain barrier to a chemically diverse series of compounds was measured using a short duration vascular perfusion method. LogPS data were correlated with calculated solute descriptors, and octanol-water partition coefficients (logPoct) for comparison.
It is shown that a general linear free energy equation can be constructed to predict and interpret logPS values. The utility of this model over other physicochemical descriptors for interpreting logPS and logBB values is discussed.
Synthesis and Biological Activity of Two New Calcium-channel Blockers, Mebudipine and Dibudipine
Authors: Mahmoudian M , Mirkhani H , Nehardani Z , Ghiaee S 
Published: April 2011

Abstract
Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine.
The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K+-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mm)–treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine &gt; nifedipine &gt; dibudipine.
It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.
Bakkenolide G, a Natural PAF-receptor Antagonist
Authors: Liao Chang-Hui , Ko Feno-Nien , Wu Tian-Shung , Teng Che-Ming 
Published: April 2011

Abstract
Because platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) participates in many physiopathological responses, including inflammatory reaction, endotoxic shock, allergic diseases and platelet aggregation, PAF-receptor antagonists are important in the treatment of these diseases.
A biologically active compound, bakkenolide G, extracted from the plant Petasites formosanus selectively and concentration-dependently inhibited PAF-induced platelet aggregation and ATP release. The IC50 of bakkenolide G for PAF (2 ng mL−1)-induced platelet aggregation was 5.6 ± 0.9 μm. Bakkenolide G also concentration-dependently inhibited PAF-induced intracellular signal transductions, including thromboxane B2 formation, and increased intra-cellular calcium concentration and phosphoinositide breakdown without affecting those caused by thrombin (01 units mL−1), collagen (10 μg mL−1), arachidonic acid (100 μm) and U46619 (1 μm). Bakkenolide G shifted the concentration-response curves of PAF-induced platelet aggregation parallel to the right; the Schild plot slope and the pA2 value were 1.31 ± 0.31 and 6.21 ± 0.75, respectively. Moreover, bakkenolide G concentration-dependently competed with [3H]PAF binding to platelets, with an IC50 value of 2.5 ± 0.4 μm.
These data strongly indicate that bakkenolide G is a specific PAF-receptor antagonist as an antiplatelet aggregatory agent.
Potential Efficacy of a Delta 5-Aminolevulinic Acid Bioadhesive Gel Formulation for the Photodynamic Treatment of Lesions of the Gastrointestinal Tract in Mice
Authors: Vonarx V , Eleouet S , Carre J , Ioss P , Gouyette A , Leray A M , Merle C , Lajat Y , Patrice T 
Published: April 2011

Abstract
A delta 5-aminolevulinic acid (ALA) bioadhesive gel has been developed and evaluated in an in-vivo mouse model for photodynamic treatment of gastric cancer or Barrett's oesophagus. Four gels were tested: noveon AA-1, keltrol T, lutrol and blanose.
An initial in-vitro study of gel adhesion showed that noveon and keltrol had longer polyethylene transit times than lutrol and blanose. In-vivo assays indicated that protoporphyrin IX was synthesized by gastric mucosa when ALA-noveon and ALA-lutrol were used (preferable results for noveon). Keltrol was eliminated from the study after these investigations. Only ALA-noveon gel was retained for studies of the relationship between ALA dose and fluorescence. Fluorescence measurements in-vivo showed that ALA concentration and application time had an influence on protoporphyrin IX synthesis. Maximum intensity (2091 counts s−) was found with 2 mg mL− ALA, and fluorescence intensities differed with application time, reaching 1805 counts s− after 240 min.
ALA-noveon, showing good adhesion and enabling efficient diffusion of ALA at a pH &lt; 6, was considered the best formulation for maintaining ALA stability.
Biodistribution of Cyclosporin Encapsulated in Liposomes Modified with Bioadhesive Polymer
Authors: Yoshikawa Yukako , Miyazaki Masaya , Houjou Takeshi , Komuta Yutaka , Yoshikawa Hiroshi , Takada Kanji 
Published: April 2011

Abstract
The purpose of this investigation was to study the possibility of renewing the immunosuppressive activity of cyclosporin by formulating the compound in liposomes modified with bioadhesive polymers. The liposomes prepared were evaluated both pharmacokinetically and pharmacodynamically. Tissue distribution and plasma pharmacokinetics of cyclosporin and model dye, sudan black, which is as hydrophobic as cyclosporin, were studied in rats after intravenous infusion (10 mg kg−). The immunosuppressive efficacy of liposomal cyclosporin preparations was studied in the allogenic rat-heart-transplantation model, where cyclosporin therapy (10 mg kg−) continued for one week.
The entrapment of sudan black in liposomes modified with bioadhesive polymers resulted in higher sudan black delivery to the spleen and the liver than with standard sudan-black-loaded liposomes. Among the modified liposomes, those modified with carbopol 941 showed the most remarkable enhancing effect on the delivery of sudan black to these organs and total plasma clearance of sudan black decreased to 38.6 ± 7.8 mL h− kg− (standard liposomes, 58.9 ± 64 mL h− kg−). Delivery of cyclosporin to the spleen and the liver was increased approximately twofold by modifying the liposomes with carbopol 941. In the preliminary study on the allogenic rat-heart-transplantation model, the mean survival days of the graft were 18.8 ± 2.9 days for the group receiving cyclosporin liposomes modified with carbopol 941, 14.2 ± 4.4 days for the group receiving standard cyclosporin liposomes and 7.6 ± 0.5 days for the group receiving cyclosporin solution.
The encapsulation of cyclosporin in liposomes modified with bioadhesive polymer enhanced the residence time of cyclosporin in the systemic circulation, resulting in approximately twofold greater delivery of cyclosporin to the spleen and liver. However, in the allogenic rat-heart-transplantation model no significant difference was detected between the immunosuppressive efficacy of cyclosporin encapsulated in bioadhesive polymer-modified liposomes and that encapsulated in standard liposomes.
Antiplatelet Effects of Some Aporphine and Phenanthrene Alkaloids in Rabbits and Man
Authors: Teng Che-Ming , Hsueh Cheung-Mei , Chang Ya-Ling , Ko Feng-Nien , Lee Shoei-Sheng , Liu Karin Chiung-Sheue 
Published: April 2011

Abstract
Two aporphines (boldine and laurolitsine) and five phenanthrene alkaloids (litebamine, secoboldine, N-cyanosecoboldine, N-methylsecoglaucine and N-methylsecopredicentrine) were evaluated in-vitro for their ability to inhibit platelet aggregation.
All seven alkaloids inhibited aggregation of rabbit platelets and inhibited the release of ATP induced by arachidonic acid and collagen in rabbit platelets. Those aggregations induced by platelet-activating factor (PAF), thrombin, U46619 and ADP were inhibited by the three N-substituted secoboldine derivatives only. Thromboxane B2 formation caused by arachidonic acid was also suppressed by these compounds. They did not affect the generation of [3H]inositol monophosphate caused by collagen, PAF and thrombin in the presence of indomethacin. Platelet cyclic AMP level was unaffected by litebamine, but was increased by N-methyl-secoglaucine. Litebamine suppressed the secondary aggregation, but not the primary aggregation, induced by ADP and adrenaline in platelet-rich plasma from man, whereas N-methylsecoglaucine inhibited both primary and secondary aggregation.
It is concluded that the antiplatelet effect of these seven aporphine and phenanthrene alkaloids is mainly a result of inhibition of thromboxane A2 formation; N-methylsecoglaucine has additional antiplatelet activity as a result of increasing the levels of platelet cyclic AMP.
A Comparison of the Standard Approach and the NONMEM Approach in the Estimation of Bioavailability in Man
Authors: Combrink M , McFadyen M L , Miller R 
Published: April 2011

Abstract
There has recently been concern about confidence intervals calculated using the standard error of parameter estimates from NONMEM, a computer program that uses a non-linear mixed-effects model to calculate relative bioavailability (F), because of possible downward bias of these estimates. In this study an alternate approach, the log-likelihood procedure, was used to calculate the confidence intervals for F from NONMEM. These were then compared with those calculated using the standard error of the parameter estimates, the traditional NONMEM approach, and the standard model-independent method, to determine whether bias exists.
By use of data from a single dose, open cross-over study of ibuprofen using 14 healthy male volunteers, NONMEM was shown to give results consistent with those obtained using the standard model-independent method of analysis and could be a useful tool in the determination of F where conditions for using the standard method of analysis are not optimum. The width of the confidence interval for F using the log-likelihood procedure was narrower and non-symmetrical when compared with that obtained using the traditional NONMEM approach. The width of the confidence interval obtained using the traditional NONMEM method was similar to that from the standard approach, however the parameter estimate for F was higher than that obtained from the standard method. This could have been because of an outlier in the data set to which the standard approach is more sensitive.
No downward bias was found in the confidence intervals from NONMEM. The bioavailability data set was of relatively low variability and more research with highly variable data is necessary before it can be concluded that the confidence intervals calculated from NONMEM can be used for hypothesis testing.
The Synergistic Purgative Action of Aloe-emodin Anthrone and Rhein Anthrone in Mice: Synergism in Large Intestinal Propulsion and Water Secretion
Authors: Yagi Teruyo , Yamauchi Kazuko , Kuwano Shigeaki 
Published: April 2011

Abstract
This study aimed to explore the mechanism involved in the synergistic purgative action of aloe-emodin anthrone and rhein anthrone, the active metabolites of sennoside C.
Aloe-emodin anthrone and rhein anthrone, and their equimolar mixture, induced excretion of an approximately equal number of faeces by intracaecal administration at a dose of 23.2 μmol kg−1 in mice (= 10 standard dose). The number of wet faeces induced by aloe-emodin anthrone was less than those of rhein anthrone and the mixture. At the same dose, rhein anthrone and the mixture significantly stimulated large intestinal propulsion, though aloe-emodin anthrone had little stimulatory effect. Aloe-emodin anthrone and rhein anthrone decreased net water absorption but could not reverse it to the net secretion at 1/2 dose. The mixture significantly decreased net water absorption and reversed it to the net secretion at this dose. These anthrones did not stimulate mucus secretion in the colon at 1/2 dose.
We concluded that the synergistic purgative effect of aloe-emodin anthrone and rhein anthrone in mice results from synergistic stimulation of large intestinal transit and large intestinal water secretion.
VB20B7, a Novel 5-HT-ergic Agent with Gastrokinetic Activity. II. Evaluation of the Gastroprokinetic Activity in Rats and Dogs
Authors: García-Garayoa E , Monge A , Roca J , Del Río J , Lasheras B 
Published: April 2011

Abstract
The gastrokinetic activity of 2[l-(4-piperonyl)piperazinyl]benzothiazole (VB20B7), a new compound with 5-HT4 receptor agonist and weak 5-HT3 receptor antagonist properties has been studied in rats and dogs.
The effects of VB20B7 were investigated in physiological conditions and in a model of gastroparesis induced by the α2-adrenergic agonist UK-14304 and compared with cisapride.
In rats, both VB20B7 and cisapride enhanced gastric emptying of indigestible solids (steel spheroids) and liquids (phenol red) at doses of 5–10 mg kg−1 by mouth. Gastric emptying of solid radiopaque markers in fasted beagle dogs was enhanced significantly by VB20B7 (0.25–1 mg kg−1 p.o.) whereas the effect of cisapride (0.5–2 mg kg−1 p.o.) did not reach statistical significance. Similar results were found when the radiopaque markers were given to the dogs following a standard solid meal The delayed gastric emptying of indigestible solids and radiopaque markers by UK-14304 was reversed by oral administration of VB20B7 in both rats and dogs. Cisapride, however, was only effective in rats. In addition, gastric emptying of a digestible solid/liquid meal was assessed by quantitating the rate of appearance of the radioactive markers in the duodenum of dogs. VB20B7 (0.2–1 mg kg−1, i.v.) enhanced gastric emptying of both solid and liquid phases while cisapride only enhanced emptying of the solid phase.
The present study indicates that acute oral and intravenous administration of VB20B7 accelerates gastric emptying of both solids and liquids in different animal models.
Portal Hypotensive Effects of Tetrandrine and Verapamil in Portal Hypertensive Rats
Authors: Liu Tsun-Bin , Lin Han-Chieh , Huang Yi-Tsau , Sun Chang-Ming , Hong Chuang-Ye 
Published: April 2011

Abstract
The portal hypotensive effects of tetrandrine and verapamil (both calcium-channel blockers) were assessed in portal hypertensive rats.
Portal hypertension was induced by partial portal vein ligation in Sprague–Dawley rats. Both tetrandrine (4, 8, 16 and 24 mg kg−1) and verapamil (0.5, 10, 1.5 and 2.0 mg kg−1) induced dose-dependent decreases of portal venous pressure and mean arterial pressure after intravenous infusion. For example, infusion of tetrandrine (16 mg kg−1) induced a maximum reduction of portal venous pressure and mean arterial pressure approximately 1 min after the start of infusion. Portal venous pressure decreased from baseline (12.5 mmHg) to 100 mmHg, and mean arterial pressure from baseline (90 mmHg) to 80 mmHg. Heart rate decreased from 250 to 240 beats min−1. At 24 mg kg−1, tetrandrine reduced portal venous pressure and mean arterial pressure to 20.3 ± 2.4% and 28.4 ± 1.4% of baseline, respectively.
Our results show that both tetrandrine and verapamil induce portal pressure reduction in portal hypertensive animals.