bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of the Role of Nitric Oxide in the Relaxant Effect of the Crude Extract and Fractions from Eugenia uniflora in the Rat Thoracic Aorta
Authors: Wazlawik Elisabeth , da Silva Marco Antônio , Peters Rodrigo Rebelo , Correia João Francisco Gomes , Farias Mareni Rocha , Calixto João Batista , Ribeiro-do-Valle Rosa Maria 
Published: April 2011

Abstract
This study has evaluated the possible role played by the l-arginine-nitric oxide pathway in the vasorelaxant action of the hydroalcoholic extract from Eugenia uniflora, and fractions from the extract, in rings of rat thoracic aorta.
The addition of an increasing cumulative concentration of hydroalcoholic extract from E. uniflora (1–300 μg mL−1) caused a concentration-dependent relaxation response in intact endothelium-thoracic aorta rings pre-contracted with noradrenaline (30–100 nm). The IC50 value, with its respective confidence limit, and the maximum relaxation (Rmax) were 7.02 (4.77–10.00) μg mL−1 and 83.94 ± 3.04%, respectively. The removal of the endothelium completely abolished these responses. The nitric oxide synthase inhibitors Nω-nitro-l-arginine (l-NOARG, 30 μm) and Nω-nitro-l-arginine methyl ester (l-NAME, 30 μm), inhibited the relaxation (Rmax) to −10.43 ± 7.81% and −3.69 ± 2.62%, respectively. In addition, l-arginine (1 mm), but not d-arginine (1 mm), completely reversed inhibition by l-NOARG. Methylene blue (30 μm), a soluble guanylate cyclase inhibitor, reduced the relaxation induced by the extract to 14.60 ± 7.40%.
These data indicate that in the rat thoracic aorta the hydroalcoholic extract, and its fractions, from the leaves of E. uniflora have graded and endothelium-dependent vasorelaxant effects.
A Comparative Pharmacokinetic-Pharmacodynamic Study of the Electrocardiographic Effects of Epinastine and Terfenadine in Rats
Authors: Ohtani Hisakazu , Kotaki Hajime , Sawada Yasufumi , Iga Tatsuji 
Published: April 2011

Abstract
The effects of epinastine hydrochloride and terfenadine on electrocardiographic (ECG) parameters in rats were investigated from a pharmacokinetic and pharmacodynamic perspective.
Epinastine hydrochloride (1 or 3 mg kg−1 h−1) or terfenadine (5, 10 or 15 mg kg−1 h−1) was intravenously infused into rats anaesthetized with urethane and α-chloralose. The changes in the QT interval derived from limb lead II and the chest lead, heart rate and PR interval were analysed. The time-course of the plasma drug-concentration of each drug was also investigated. Terfenadine prolonged the QT interval in an infusion-rate-dependent manner; its EC50 value was 792–1039 ng mL−1. An obvious QT prolongation was, moreover, observed even at a plasma terfenadine concentration of 100–200 ng mL−1, which is clinically quite high, but might be achieved under a definite condition such as a restrained terfenadine metabolism. Terfenadine also induced PR prolongation and bradycardia in an infusion-rate dependent manner. Epinastine slightly increased the heart rate, but did not affect any of the other ECG parameters even at a plasma concentration of 400 ng mL−1, which is more than 10 times the maximum concentration attained after an ordinary dosage regimen in man.
We conclude that epinastine might have an advantage over terfenadine in avoiding adverse electrocardiographic reactions.
Characterization and Trypanocidal Activity of Nifurtimox-containing and Empty Nanoparticles of Polyethylc y anoacrylates
Authors: Gonzalez-Martin Guillermo , Merino Isabel , Rodriguez-Cabezas M Nieves , Torres Marisa , Nuáez Rebeca , Osuna Antonio 
Published: April 2011

Abstract
The aim of this study was to evaluate the utility of nanoparticles of polyalkylcyanoacrylate as a targeted delivery system for nifurtimox against Trypanosoma cruzi, responsible for Chagas’ disease. Ethylcyanoacrylate nanoparticles were prepared by an emulsion polymerization process and formulations containing different concentrations of nifurtimox, polyethylcyanoacrylates and surfactants were investigated and analysed for size and drug content.
The nanoparticles obtained were less than 200 nm in size, as measured by electron microscopy and cytometry. The peak percentage of nifurtimox uptake into the nanoparticles was 33.4% for use of 500 μL polyethylcyanoacrylate, 200 μL surfactant (Tween 20) and 10 mg nifurtimox in 50 mL polymerization medium. The highest release of nifurtimox from the nanoparticles was 65.4% after 6-h incubation at pH 7.4. In-vitro studies using cultures of T. cruzi epimastigotes revealed considerably increased trypanocidal activity compared with a standard solution of nifurtimox. Studies of cell cultures previously infected with metacyclic forms of the parasite showed that only 2-h treatment with solutions of 0.001% of the nanoparticle suspension reduced parasitism by 87–94% both when the nanoparticles were loaded with nifurtimox and when unloaded. Electron-microscopic examination revealed processes of degeneration and lysis, suggesting apoptotic processes, in intracellular amastigotes and free amastigotes treated with the nanoparticles. It was demonstrated that unloaded nanoparticles, by mechanisms not completely elucidated, have trypanocide activity similar to that of a standard solution of nifurtimox. It is concluded that the nanoparticles loaded with nifurtimox constitutes a good carrier of the drug against T. cruzi. The loaded-nanoparticles significantly increase trypanocidal activity.
Formulation-dependent Pharmacokinetics and Pharmacodynamics of Propofol in Rats
Authors: Dutta Sandeep , Ebling William F 
Published: April 2011

Abstract
Propofol, a highly lipophilic anaesthetic, is commercially formulated as a lipid emulsion (diprivan) for intravenous use. This formulation is characterized by rapid onset and offset of effect after rapid intravenous administration and an effect-site equilibration half-life (t 1/2 kE0) of 1.7min in rats. Paradoxically these characteristics are usually associated with relatively water-soluble anaesthetics. To test the influence of the formulation on propofol pharmacokinetics, effect-site equilibration kinetics and pharmacodynamics we performed a pharmacokinetic-pharmacodynamic study of propofol in chronically instrumented rats after administration in a lipid-free formulation. In this report we present the results of this study and compare these results with previous data obtained with rats receiving propofol in the emulsion formulation.
Compared with the emulsion formulation the distribution volumes (Vdc and Vdss) were significantly higher but the t 1/2 kE0 (2.0 min) was similar for the lipid-free formulation. The concentration-effect relationship was biphasic. Propofol effect-site concentrations required to achieve 50% activation, peak activation, 50% inhibition of peak activation effect and maximum inhibition were significantly lower, indicating a higher apparent steady-state potency for the lipid-free formulation compared with the emulsion formulation. The evanescent characteristics of propofol’s effect-time-course disappeared when the anaesthetic was administered in the lipid-free formulation.
These results suggest that the nature of the formulation can profoundly influence the clinical characteristics of intravenously administered drugs by modifying the pharmacokinetics or pharmacodynamics or both.
The Effect of Protein Binding on the Hepatic First Pass of O-Acyl Salicylate Derivatives in the Rat
Authors: Hung Daniel Y , Mellick George D , Whitehead Benjamin D , Roberts Michael S 
Published: April 2011

Abstract
In this work the in-situ perfused rat liver has been used to examine the effect of changing the protein content of the perfusate on the hepatic extraction of O-acyl esters of salicylic acid. The hepatic availability (F) of these solutes was studied at a flow-rate of 30 mL min−1 with perfusate albumin concentrations of 0, 2, and 4% w/v.
The hepatic availability of the esters was shown to decrease with increasing carbon-chain length in the O-acyl group; for all the esters the hepatic availability increased with increasing albumin concentration in the perfusate. The dispersion-model-derived efficiency number (RN) of the esters was shown to increase with increasing lipophilicity and decrease with increasing albumin concentration in the perfusate. The unbound fraction (fu) of the esters decreased with lipophilicity. RN/fu for acetylsalicylic acid remained relatively constant as the albumin concentration was increased. However, RN/fu for n-pentanoyl-and n-hexanoylsalicylic acids increased significantly as albumin concentration increased from 0% to 4%.
Thus, for the more lipophilic solutes (n-pentanoyl- and n-hexanoylsalicylic acids) the presence of albumin apparently facilitates the uptake of unbound solute relative to acetylsalicylic acid.
Inhibition of Human Platelet Aggregation by Diazeniumdiolates: Extent of Inhibition Correlates with Nitric Oxide Load Delivered
Authors: Raulli Robert 
Published: April 2011

Abstract
The profile of nitric oxide (NO) release from the diazeniumdiolate class of NO donors was evaluated using inhibition of platelet aggregation as a model.
At 37°C, the NO complexes (Z)-1-{N-methyl-N-[6-(N-methylammoniohexyl)amino]}-diazen-1-ium-1, 2-diolate (dimethylhexanediamine complex), sodium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (diethylamine complex), (Z)-1-{N-3-aminopropyl-N-[N-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate (spermine complex), and (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,22-diolate (diethylene-triamine complex) have half-lives of 1, 2 and 39min, and 20 h, respectively. All the diazeniumdiolates caused concentration-dependent inhibition of platelet aggregation; IC50 values (values for which the effect was half the maximum) were 26.0 ± 24.1, 34.9 ± 24.0 and 14.9 ± 6.4 nM for dimethylhexanediamine complex, diethylamine complex and spermine complex, respectively, when pre-incubated with platelets for one half-life. Inhibition by all compounds was time-dependent. Pretreatment of platelets with spermine complex for 5 and 39 min resulted in IC50 values of 1.7 ± 0.85 μM and 19.7 ± 0.12 nM, whereas IC50 values for sodium nitroprusside were 27.3 ± 1.25 nM and 25 nM (average, n = 2), at 5 and 39 min, respectively. Pre-incubation of each diazeniumdiolate at a concentration of 100 nM for 5 min at 37°C, which resulted in the theoretical delivery of NO loads from 96.9% down to 0.3%, resulted in decreasingly efficacious inhibition of platelet aggregation. Linear regression analysis of the theoretical NO load delivered against the actual maximum inhibition (%) showed a strong correlation (r2 = 0.975). All four diazeniumdiolates caused concentration- and time-dependent inhibition of agonist-stimulated elevation of intra-platelet Ca2+ levels; IC50 values were, respectively, 8.7 ± 1.49nM and 11.5 ± 1.36nM for dimethylhexanediamine complex and diethylamine complex at their half-lives, and 176 ± 16.9 nM and &gt; 100 μM, for spermine complex and diethylenetriamine complex at 2 min pre-incubation time. The respective nucleophiles not complexed with NO did not show anti-aggregatory properties or inhibition of agonist-induced elevation of intra-platelet Ca2+ levels. The inhibitory effects of all diazeniumdiolates tested were attenuated by 10 μm haemoglobin.
These studies indicate that these compounds induce controlled, predictable release of NO at biological pH and temperature.
ATP-sensitive Potassium-channel-opening Activity of CL-065, a 3-[(Substituted-carbonyl)amino]-2H-1-benzopyran, in the Rat
Authors: Chen Mei-Jung , Lee Yen-Mei , Sheu Joen-Rong , Hu Cheng-Tao , Yen Mao-Hsiung 
Published: April 2011

Abstract
The pharmacological activity of CL-065 (trans-3-acetamido-2, 2-dimethyl-4-hydroxy-3, 4-dihydro-2H-1-benzopyran-6-carbonitrite) was investigated in anaesthetized spontaneously hypertensive rats (SHR) and isolated thoracic aorta of Sprague-Dawley rats.
The intravenous administration of CL-065 (0.1–2.0 mg kg−1) to anaesthetized SHR induced a dose-dependent reduction of mean arterial pressure (MAP) with maximum effect approximately 5 min after injection and which persisted for over 3 h. CL-065 also induced a reflex tachycardia which seemed to parallel the time course of the hypotensive effect. The hypotensive effect of CL-065 was blocked by pretreatment with glibenclamide (5 mg kg−1, i.v.), a specific ATP-sensitive potassium (KATP) channel blocker. Moreover, CL-065 (0.01–10 μM) resulted in dose-dependent vasodilatory effects on phenylephrine (0.3 μM)-induced vasoconstriction in isolated thoracic aorta. The vasorelaxation elicited by CL-065 was antagonized competitively by pretreatment with glibenclamide (0.1–1.0 μM; pA2 = 6.90 ± 0.09; slope = 1.03 ± 0.18). Similarly, the other two KATP-channel openers cromakalim (1.0 nM–1.0 μM) and nicorandil (0.1–30 μM) also induced vasorelaxation in thoracic aorta. The EC50 of cromakalim, CL-065 and nicorandil (i.e. the doses having half the maximum effect) were approximately 0.083, 0.17, and 4.5 μM, respectively, for phenylephrine (0.3 μM)-induced vasoconstriction in isolated thoracic aorta. Moreover, increased extracellular potassium levels (20–60 mM) resulted in concentration-dependent attenuation of the vasodilator effect of CL-065.
In conclusion, CL-065 induces a depressor effect via activation of KATP channels.
Anti-proliferative Effects of Lichen-derived Inhibitors of 5-Lipoxygenase on Malignant Cell-lines and Mitogen-stimulated Lymphocytes
Authors: Ögmundsdóttir Helga M , Zoëga Gunnar Már , Gissurarson Stefán R , Ingólfsdóttir Kristín 
Published: April 2011

Abstract
Several lichen species have been used traditionally as medicinal plants. It has previously been shown that two low-molecular-weight lichen metabolites, lobaric acid isolated from Stereocaulon alpinum Laur. and protolichesterinic acid isolated from Cetraria islandica L. (Ach.), have in-vitro inhibitory effects on arachidonate 5-lipoxygenase. We have studied the effects of these compounds on cultured cells from man, including three malignant cell-lines (T-47D and ZR-75-1 from breast carcinomas and K-562 from erythro-leukaemia), as well as normal skin fibroblasts and peripheral blood lymphocytes.
Both test substances caused a significant reduction in DNA synthesis, as measured by thymidine uptake, in all three malignant cell-lines; the dose inducing 50% of maximum inhibition (ED50) was between 1.1 and 24.6 μg mL−1 for protolichesterinic acid and between 14.5 and 44.7 μg mL−1 for lobaric acid. The breast-cancer cell-lines were more sensitive than K-562. The proliferative response of mitogen-stimulated lymphocytes was inhibited with a mean ED50 of 8.4 μg mL−1 and 24.5 μg mL−1 for protolichesterinic acid and lobaric acid, respectively. These concentrations are of the same order of magnitude as the IC50 values in the 5-lipoxygenase assay. Significant cell death (assessed by the MTS (3–4, 5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay and trypan blue exclusion) occurred in the three malignant cell-lines at protolichesterinic acid and lobaric acid concentrations above 20 and 30 μg mL−1, respectively. In K-562 morphological changes consistent with apoptosis were detected. Up to 38% cell death was observed at 20 μg mL−1 for protolichesterinic acid and 15 μg mL−1 for lobaric acid in mitogen-stimulated lymphocytes but unstimulated lymphocytes were clearly less sensitive. In contrast, the DNA synthesis, proliferation and survival of normal skin fibroblasts were not affected at doses up to 20 μg mL−1 for protolichesterinic acid and 30 μg mL−1 for lobaric acid.
We conclude that the anti-proliferative and cytotoxic effects observed might be related to the 5-lipoxygenase inhibitory activity of protolichesterinic acid and lobaric acid. These results open up the opportunity for future studies of these lichen metabolites with regard to their anti-tumour and anti-inflammatory properties.
Abstract
Authors: Papakonstantinou-Garoufalia Spyroula S , Tani Ekaterini , Todoulou Ourania , Papadaki-Valiraki Aspasia , Filippatos Evagelos , De Clercq Erik , Kourounakis Panos N 
Published: April 2011

Abstract
We report the synthesis of some mercaptotriazole derivatives in an effort to discover underlying structural requirements for antiviral activity. A preliminary antiviral study was performed and the contribution of the compounds to free radical processes was investigated. Because lipophilicity influences both biological activity and antioxidant potential we calculated lipophilicity and attempted to correlate this with antioxidant activity.
Treatment of the N-(aryl)piperazineacetohydrazides (compounds 1) with 2, 4-dichloro-phenylisothiocyanate gave the N-(aryl)piperazinethiosemicarbazides (compounds 2) in good yield. Cyclization of these compounds after treatment with NaOH solution provided the corresponding 5-(4-aryl-1-piperazinylmethyl)-4-(2, 4-dichlorophenyl)-4H-1, 2, 4-triazole-3-thiols (compounds 3) in good yield. Reaction of compounds 3 with 2, 4-dichloro-or 4-fluorobenzyl chloride in acetone in the presence of potassium carbonate gave the target compounds (compounds 4) in about 70% yield. The antioxidant effect of the compounds on non-enzymatic lipid peroxidation of rat hepatic microsomal membranes was studied. Most of the examined compounds were active at concentration of 0.1 mM and most were found to prevent dimethylsulphoxide oxidation moderately (20–50%) at a concentration tenfold less than that of dimethylsulphoxide. The interaction of the synthesized compounds with 1, 1-diphenyl-2-picrylhydrazyl stable free radical was also studied. Correlation was found between the two expressions of calculated lipophilicity, antioxidant activity and the lipophilicity of the synthesized compounds, and a correlation was derived between antioxidant activity and logP, which expresses the compounds’ hydrogenbonding capacity.
Changes in Gastric Mucosal Permeability Induced by Haemorrhagic Shock in the Anaesthetized Rat: - Modulation by Acid
Authors: Calatayud Sara , Barrachina M Dolores , García-Zaragoza Eugenia , Mattsson Hillevi , Esplugues Juan Vicente 
Published: April 2011

Abstract
Gastric mucosal damage induced by haemorrhagic shock in the anaesthetized rat has been evaluated by studying changes in capillary-to-lumen clearance of fluorescein isothiocyanate (FITC)-labelled dextran.
Haemorrhagic shock (20 min ischaemia + 20 min reperfusion) induced a significant increase in blood-to-lumen permeability to FITC-dextran of different molecular weight (10 000, 40 000 and 70 000) without modifying the macroscopic integrity of the gastric mucosa. The increase in vascular permeability was dependent on the time of administration of the tracer and was correlated with an elevation of the protein content of the gastric lumen. Intravenous administration of the secretagogue pentagastrin (20 or 50 μg kg−1 h−1) did not significantly modify the vascular permeability to dextran in control animals or in animals subjected to haemorrhagic shock. When the intraluminal pH was reduced by intragastric administration of acidic saline solution, only pH 1, which itself induced the appearance of macroscopic mucosal lesions, significantly increased vascular permeability to dextran, both in control animals and in animals subjected to haemorrhagic shock.
These findings suggest that stress induced by haemorrhagic shock increases vascular gastric permeability to dextran, by an acid-independent mechanism, without affecting the macroscopic integrity of the gastric mucosa.
Neuropharmacology: Effects on Rat Brain K1- and K2-Opioid Receptors after Chronic Treatment with Non-peptide K-Agonists
Authors: McConnaughey Mona M , Zhai Qing Zhu , Ingenito Alphonse J 
Published: April 2011

Abstract
Injection of K-agonist dynorphins and non-peptide K-agonists into the hippocampus induces a reduction in blood pressure. It has been postulated that K-opioid agonists and K-receptors are important in one mechanism of antihypertension and might have clinical potential for the treatment of hypertension. We have investigated whether chronic treatment with U-50488H and U-62066E, two non-peptide K-agonists, effects brain K1- or K2-receptor numbers or affinities in areas that might correlate with changes in blood pressure.
K 1- and K2-Opioid receptor affinities and densities were determined in cortex, hippocampus, hypothalamus, midbrain and pons after 14 days subcutaneous infusion of two non-peptide K-agonists, U-50488H and U-62066E, 9.6 mg kg day−1, by means of osmotic minipumps, to spontaneously hypertensive rats (SHR) and to Wistar-Kyoto (WKY) rats. This infusion significantly reduced blood pressure. Brains were removed within 48 h of the end of drug infusion and K-receptor binding studies were performed on homogenates from each brain area using [3H]U-69593 to assay K1-receptors and [3H]bremazocine to assay K2-receptors. U-62066E treatment seemed to cause a slight decrease in the number of [3H]bremazocine binding sites (K2-receptors) from 98.2 ± 9 to 74.9 ± 8 fmol (mg protein)−1 in the hippocampus when compared with SHR controls. A small decrease in K2-receptor density in the pons of WKY rats was also observed after U-50488H treatment (control, 51.2±5; U-50488H-treated, 24.3±9 fmol (mg protein)−1). Although SHR blood pressure values were consistently reduced by treatment with K-agonists, there was little if any significant change in apparent numbers of K1- or K2-receptors or their affinities in any of the brain regions examined.
These data indicate that although chronic treatment with K-agonists reduces blood pressure in SHR, the treatment does not elicit major changes in brain K-receptors either in SHR or in WKY rats. The potential use of K-agonists for treating hypertension might not cause receptor changes in the brain and might, therefore, result in fewer side effects or negligible rebound hypertension.
Brain Extracellular Levels of the Putative Antipsychotic CI-1007 and Its Effects on Striatal and Nucleus Accumbens Dopamine Overflow in the Awake Rat
Authors: Iyer Raj N , Davis M Duff , Juneau Paul L , Giordani Anne B 
Published: April 2011

Abstract
The compound CI-1007 (R-(+)-1,2,3,6-tetrahydro-4-phenyl-1[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine maleate) has been identified as a partial dopamine agonist and putative antipsychotic in in-vitro and in-vivo neurochemical, neurophysiological and behavioural tests.
By use of microdialysis in conjunction with high-performance liquid chromatography (HPLC) with electrochemical detection, the effects of the drug on brain dopamine release, previously observed in anaesthetized animals, were shown to occur in awake animals also. Detection of peripherally administered CI-1007 in the brain, i.e. evidence of the drug’s ability to penetrate the blood-brain barrier, was achieved by use of in-vivo brain microdialysis in awake, freely moving rats and capillary HPLC in combination with tandem mass spectrometry (HPLC/MS/MS). Intravenous administration of CI-1007 (40 mg kg−1) significantly inhibits dopamine release in the nucleus accumbens, a region associated with dopamine hyperactivity in schizophrenia, while having a non-significant impact on the striatal dopamine neurotransmission which is critical to regular motor function.
The differential neurochemical profile of the drug indicates its potential usefulness in treating positive disease symptoms and implies that its extrapyramidal side effects are lower than those of typical antipsychotics.