bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of an alginate suspension on pepsin and bile acids – key aggressors in the gastric refluxate. Does this have implications for the treatment of gastro-oesophageal reflux disease?
Authors: Strugala Vicki , Avis Jeanine , Jolliffe Ian G , Johnstone Lesley M , Dettmar Peter W 
Published: October 2010

Abstract

Objectives
During a reflux event the oesophagus is exposed to a heterogeneous mixture of gastric juice components. The role of non-acid components of the refluxate in causing damage to the oesophagus is now well established but no therapeutic option exists to address this.

Methods
The role of Gaviscon Advance (GA), a raft-forming alginate suspension, in protecting the oesophagus from damage by pepsin and bile acids (aggressors) was investigated using a series of in-vitro models.

Key findings
GA was able to dose-dependently inhibit pepsin activity over and above the neutralisation effect of the formulation. This was evident against both protein and collagen substrates using two distinct colorimetric assays. GA was able to retard the diffusion of pepsin and multiple bile acids using a Franz cell model. Using the raft-forming mode of action GA was able to remove both pepsin and multiple bile acids from a simulated reflux event. There was capacity in the GA raft to accommodate aggressors from multiple reflux events.

Conclusions
GA can specifically remove both pepsin and bile acids from the refluxate, limit their diffusion and affect enzymatic activity of pepsin. There is a role for GA to reduce the damaging potential of the refluxate and thus protect the oesophagus.
Synthesis and in-vitro antitumour activity of new naphthyridine derivatives on human pancreatic cancer cells
Authors: Banti Irene , Nencetti Susanna , Orlandini Elisabetta , Lapucci Annalina , Breschi Maria Cristina , Fogli Stefano 
Published: October 2010

Abstract

Objectives
The aim of the study was to evaluate the antitumour effect in vitro of newly synthesized 7-substituted 2,3-dihydro-1,8-naphthyridines.

Methods
Characterization tools included cell viability assay, caspase 3/7 induction, DNA fragmentation, fibroblast growth factor type 1 receptor kinase inhibition, and in-vitro antiangiogenic analysis.

Key findings
Treatment of MIA PaCa-2 human pancreatic cancer cells with test compounds showed time- and concentration-dependent cytotoxicity with IC50 values in the micromolar range. Compounds with an aminoalkyl or a diaminoalkyl side chain at the 7-position exhibited remarkable cytotoxicity, whereas the presence of a methyl group or a cyclic amine in the same position led to a significant decrease in their biological activity. Cytotoxicity screening demonstrated that the most active was compound 11 (mean 50% inhibition of cell proliferation (IC50) 11 μM). This compound had an in-vitro antitumour efficacy superior to 5-fluorouracil (the lowest cell viability value after treatment (Emax) 0.2% and 19%, respectively) and proved to be less toxic than 5-fluorouracil against non-cancerous human oral epithelial cells. In addition, compound 11 induced apoptosis in MIA PaCa-2 cells and it was able to promote antiangiogenic effects in vitro. Finally, its cytotoxicity was enhanced in pancreatic cancer cells stimulated with fibroblast growth factor, while no substantial effect was observed on human bronchial smooth muscle cells stimulated with the same growth factor.

Conclusions
These findings suggest that 1,8-naphthyridine derivatives are a promising class of compounds in cancer research. In particular, the antitumour activity of compound 11 is worth further investigation.
Acute effect of Copaifera reticulata Ducke copaiba oil in rats tested in the elevated plus-maze: an ethological analysis
Authors: Curio Mateus , Jacone Hellena , Perrut Jaime , Pinto Âengelo C , Filho Valdir F Veiga , Silva Regina C B 
Published: October 2010

Abstract

Objectives
Copaiba oil oleoresin exuded from Copaifera reticulata Ducke (CRD) is commonly used in anti-inflammatory, healing and anti-tumoral folk medicines. The purpose of this study was to investigate the putative anxiolytic effect of acute administration of CRD.

Methods
CRD was administered (100, 400 and 800 mg/kg, p.o.) to male Wistar rats submitted to the elevated plus-maze model of anxiety using an ethopharmacological analysis.

Key findings
In comparison with control rats, CRD increased the percentage of entries in the open arms over the entire dose range tested (vehicle, 33.6 ± 4.5; CRD 100 mg/kg, 44.67 ± 3.68; CRD 400 mg/kg, 47.2 ± 2.3; CRD 800 mg/kg, 50.7 ± 2.2) and the percentage of time spent in the open arms of the elevated plus-maze at the highest dose (800 mg/kg) (vehicle, 26.4 ± 5.7; CRD 800 mg/kg, 52.0 ± 2.7). A standard anxiolytic, diazepam (3 mg/kg, p.o.), was used as a positive control. In a similar way, diazepam increased the percentage of entries and time spent in the open arms when compared with vehicle (% open entries: vehicle, 45.4 ± 1.3; diazepam, 50.7 ± 1.9; % time spent in open arms: vehicle, 28.2 ± 0.9; diazepam, 38.9 ± 1.2). Regarding ethological measures, CRD at the highest dose (800 mg/kg) reduced peeping out (anxiety-related behaviour) (vehicle, 3.1 ± 0.6; CRD, 0.9 ± 0.2) and increased end-arm activity (vehicle, 0.2 ± 0.2; CRD, 2.0 ± 0.4), indicating an enhanced tendency of the rats to explore actively the potentially dangerous areas of the maze. Diazepam decreased peeping out (vehicle, 3.3 ± 0.3; diazepam, 1.0 ± 0.2) and flat-back approach (vehicle, 0.8 ± 0.2; diazepam, 0.2 ± 0.1) and increased end-arm activity (vehicle, 0.3 ± 0.1; diazepam, 2.5 ± 0.3) and head-dipping (vehicle, 8.2 ± 0.4; diazepam, 12.0 ± 0.5).

Conclusions
These data showed, for the first time, that acute treatment with CRD copaiba oil produced a dose-dependent anxiolytic-like effect over the dose range tested, on conventional and ethological parameters, without adversely affecting general activity levels.
Modulatory effect of Inula racemosa Hook. f. (Asteraceae) on experimental atherosclerosis in guinea-pigs
Authors: Mangathayaru Kalachaveedu , Kuruvilla Sarah , Balakrishna Kedike , Venkhatesh Jayakothandaramaswamy 
Published: October 2010

Abstract

Objectives
Inula racemosa Hook. f. is indicated for precordial chest pain in Ayurveda. In this study, the effects of a hexane (IrH) and an alcohol extract (IrA) of Inula racemosa on atherosclerosis induced by a high-fat diet in guinea-pigs were investigated.

Methods
After 30 days on a high-fat diet (guinea-pig pellet diet + 0.2% w/w cholesterol) six animals were killed and evaluated for the onset of early atherosclerotic changes in coronary artery, aorta and major organs. The remaining animals were assigned to 5 groups of six animals each and fed for the following 90 days with a pellet diet + 0.15% w/w cholesterol (positive control) along with 100 mg/kg IrA, 100 mg/kg IrH or 10 mg/kg atorvastatin calcium. The normal control group received only the pellet diet. At the end of experimental period, serum lipid levels, heart and liver antioxidant status, area of lipophilic aortic lesions and histopathology of coronary artery were estimated.

Key findings
IrA decreased total cholesterol, triglycerides, low-density lipoprotein cholesterol and the atherogenic index, and increased high-density lipoprotein cholesterol compared with the positive control. It scavenged thiobarbituric acid reactive substances and increased reduced glutathione in liver, and enhanced superoxide dismutase and glutathione peroxidase in heart. Aortic lesion area and % bodyweight increase was least in the IrA-treated group. Coronary artery changes due to the high-fat diet were reversed by the extracts. The observed effects are presumably mediated by phenolics in IrA and sesquiterpene lactones in IrH.

Conclusions
The results demonstrate the anti-atherogenic effect of I. racemosa, thus validating the cardioprotective and anti-obesity claims in traditional medicine.
Aminolevulinic acid-loaded Witepsol microparticles manufactured using a spray congealing procedure: implications for topical photodynamic therapy
Authors: Al-Kassas Rasil , Donnelly Ryan F , McCarron Paul A 
Published: October 2010

Abstract

Objectives
The aim was to enhance aminolevulinic acid (ALA) stability by incorporation into low-melting microparticles prepared using a spray congealing procedure and to evaluate temperature-triggered release, allowing topical bioavailability following melting at skin temperature.

Methods
ALA-loaded Witepsol microparticles were prepared using a novel spray congealing technique. Entrapment efficiency was compared with conventional emulsion-based methods and modelled drug release profiles determined using a membrane separation technique. Raised receiver medium temperature was used to determine triggered release. Bioavailability and lipid-mediated enhancement of ALA penetration were determined in excised murine skin.

Key findings
ALA-loaded Witepsol microparticles were spherical, with a mean diameter of 20 μm. Loading and stability studies demonstrated effective encapsulation, ranging from 91% to 100%, with no evidence of degradation to pyrazine derivatives. ALA release correlated with dissolution medium temperature, triggered at temperatures close to that of skin. Results suggested that molten Witepsol enhanced cutaneous permeation, whereas incorporation of microparticles in a semi-solid vehicle attenuated ALA penetration. Optimal use was direct application under occlusion.

Conclusions
Spray congealing is superior to the emulsion-based procedures with respect to encapsulation efficiency of ALA in Witepsol matrices, providing temperature-triggered release, enhanced stability and improved penetration of ALA through keratinised skin. These features could improve ALA delivery to superficial lesions as part of photodynamic therapy.
Diabetic neuropathy: therapies on the horizon
Authors: Mahmood Danish , Singh Bhulan Kumar , Akhtar Mohammad 
Published: October 2010

Abstract

Objectives
This is a review of emerging interventions from the recent preclinical and clinical literature that demonstrate the potential for effectiveness in the therapy of diabetic neuropathy (DN). DN is the most common complication of diabetes mellitus and up to 50% of patients with type 1 and type 2 forms have some or other form of neuropathy. The pathology of DN is characterized by progressive nerve fibre loss that gives rise to positive and negative clinical signs and symptoms such as pain, paraesthesiae and loss of sensation.

Key findings
There are very few drugs available to directly treat DN. Those that are clinically indicated provide symptomatic relief but do not repair or reverse underlying nerve damage. However, some agents are in clinical development that may support adult neurons and direct reparative processes after injury stages. Several disease modifying drugs such as aldose reductase inhibitors and protein kinase C inhibitors are in phase III development. Agents on the horizon include neurotrophic factors, growth factors, gene therapy, immunotherapy, poly(ADP-ribose) polymerase inhibitors and non-immunosuppressive immunophilin ligands.

Summary
Progress has been made toward understanding the biochemical mechanisms leading to diabetic neuropathy, and as a result, new treatment modalities are being explored. The pathogenesis, types and approaches for treating DN together with the newer therapeutic interventions on the horizon are discussed.
Retrospective population pharmacokinetic/pharmacodynamic analysis of pyridostigmine, a cholinesterase inhibitor, in Chinese males
Authors: Seng Kok-Yong , Loke Weng-Keong , Moochhala Shabbir , Zhao Bin , Lee Jon-Deoon Edmund 
Published: October 2010

Abstract

Objectives
We have characterised the population pharmacokinetics-pharmacodynamics of pyridostigmine given as pyridostigmine bromide.

Methods
Over three days 50 healthy Chinese male subjects each received seven doses of 30 mg pyridostigmine bromide orally (3 times 10 mg every 8 h). Plasma concentrations of pyridostigmine and red blood cell acetylcholinesterase (AChE) activity were determined at various times within the eight hours after the first and the seventh doses. The resulting pharmacokinetic data were fitted to a single compartment open model with first-order absorption and elimination. The pharmacodynamics were modelled using an inhibitory Emax model. The potential influence of demographic and biological covariates on the model parameters was investigated. Nonlinear mixed effects modelling was performed using NONMEM.

Key findings
The apparent clearance and volume of distribution as well as absorption rate constant of plasma pyridostigmine were estimated to be 136 1/h, 130 1 and 0.68 1/h, respectively. The maximum red blood cell AChE activity decrease (Emax) and plasma pyridostigmine concentration producing 50% of this reduction (EC50) were estimated to be 9.32 AChE units per gram haemoglobin and 51.9 ng/ml, respectively. None of the tested covariates were found to be correlated with any of the model parameters. Dosing simulations suggested that 30 mg repeated every six hours might be needed to achieve steady-state trough percentage inhibition above the recommended 10% in healthy Chinese males.

Conclusions
The pharmacokinetics and the effects of pyridostigmine on red blood cell AChE activity were described using a mixed effects model. For Chinese males, the dosing interval may have been shorter than that recommended for the Caucasian population. Additional studies are needed to confirm these findings.
Contribution of a significant first-pass effect of dimethyl-4,4′-dimethoxy-5,6,5′,6′-dimethylene dioxybiphenyl-2,2′-dicarboxylate in the liver to its poor bioavailability in rats
Authors: Yu Kyung-Ha , Lee Ye-Rie , Ahn Sung-Hoon , Kim Dae-Duk , Shim Chang-Koo , Chung Suk-Jae 
Published: October 2010

Abstract

Objectives
The objective of this study was to investigate the mechanism responsible for the poor oral bioavailability of dimethyl-4′,4′-dimethoxy-5,6,5′,6′-dimethylene dioxy-biphenyl-2,2′-dicarboxylate (DDB), a hepatoprotective agent, in rats.

Methods
DDB was intravenously administered to rats at doses of 0.2-1 mg/kg. To determine the hepatic first-pass effect in rats, DDB (1 mg/kg) was administered via the pyloric vein and the femoral vein. Direct measurement of intestinal permeability was attempted using Caco-2 cell monolayers and rat intestinal epithelium.

Key findings
A moment analysis indicated that the volume of distribution and clearance remained unchanged with the magnitude of the dose, indicating that DDB exhibited linear pharmacokinetics. When the area under the curve for DDB after administration to the pyloric vein was compared with that after femoral vein administration, the ratio (FH) was found to be 0.294, indicating a significant first-pass effect for DDB. The permeability of DDB was high in the rat intestine (1.78 ± 0.229 × 10−5 cm/s) and in Caco-2 cell monolayers (6.8 ± 0.70 × 10−5 cm/s), suggesting that DDB, in soluble form, was readily permeable across the intestinal epithelium.

Conclusions
These observations indicated that despite the fact that DDB was readily permeable to the intestinal epithelium, a significant first-pass metabolism was associated with its pharmacokinetics in rats.
Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device
Authors: Luthringer Remy , Djupesland Per G , Sheldrake Colin D , Flint Anthony , Boeijinga Peter , Danjou Philippe , Demazières Agnès , Hewson Graeme 
Published: October 2010

Abstract

Objectives
The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared.

Methods
The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design.

Key findings
Following intranasal delivery, median tmax was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean ± SD values for Cmax were 96 ± 25, 11 ± 7 and 16 ± 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure.

Conclusions
Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.
Inhibition of IgE-induced mast cell activation by ethyl tertiary-butyl ether, a bioethanol-derived fuel oxygenate
Authors: Yamaki Kouya , Yoshino Shin 
Published: October 2010

Abstract

Objectives
The effect of ethyl tertiary-butyl ether (ETBE), which is widely used as a fuel oxygenate commonly produced from bioethanol, on immunoglobulin (Ig)E-dependent mast cell activation was investigated.

Methods
The rat mast cell line RBL2H3 sensitised with monoclonal anti-ovalbumin IgE was challenged with ovalbumin in the presence or absence of ETBE, tert-butanol (TBA), which is the main metabolite of ETBE in humans, and ethanol. Degranulation of RBL2H3 was examined by the release of β-hexosaminidase. To understand the mechanisms responsible for regulating mast cell function, the effects of ETBE, TBA and ethanol on the levels of intracellular calcium, phosphorylation of Akt (as a marker of phosphatidylinositol 3-kinase) and global tyrosine phosphorylation were also measured as indicators of mast cell activation.

Key findings
In the presence of ETBE, TBA or ethanol, IgE-induced release of β-hexosaminidase was decreased. These compounds also attenuated the IgE-mediated increase in the levels of intracellular Ca2+, phosphorylation of Akt and global tyrosine phosphorylation in RBL2H3 cells.

Conclusions
ETBE, TBA and ethanol inhibited mast cell degranulation by inhibiting the increase in intracellular calcium ion concentration and activation of phosphatidylinositol 3-kinase and protein tyrosine kinase activation, suggesting that exposure to ETBE might affect immune responses, particularly in allergic diseases.
Effect of yokukansan, a traditional Japanese medicine, on social and aggressive behaviour of para-chloroamphetamine-injected rats
Authors: Kanno Hitomi , Sekiguchi Kyoji , Yamaguchi Takuji , Terawaki Kiyoshi , Yuzurihara Mitsutoshi , Kase Yoshio , Ikarashi Yasushi 
Published: October 2010

Abstract

Objectives
Yokukansan, a traditional Japanese medicine, has been approved by the Ministry of Health, Labour, and Welfare of Japan as a remedy for neurosis, insomnia or night crying and irritability in children. It has recently been reported to improve behavioural and psychological symptoms of dementia, such as hallucinations, agitation, and aggressiveness in patients with some forms of senile dementia. Little is known about the mechanism underlying the effectiveness of yokukansan. Our aim was to clarify the involvement of yokukansan in serotonergic function in para-chloroamphetamine (PCA)-induced aggressive behaviour in rats.

Methods
The effect of yokukansan on social interactions, including social and aggressive behaviour, was examined in PCA-injected rats. Concentration and release level of serotonin (5-HT) in the hypothalamus were measured.

Key findings
PCA reduced not only the 5-HT concentration but also the high K+ -induced 5-HT release in the rat hypothalamus. Social interaction tests showed a significant decrease in social behaviour and a significant increase in aggressive behaviour in the PCA-treated rats. The decrease in social behaviour was ameliorated by the 5-HT1A agonist buspirone and further decreased by a 5-HT1A antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cyclo-hexanecarboxamide trihydrochloride (WAY-100635), whereas it was further decreased by the 5-HT2A agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI), and ameliorated by the 5-HT2A antagonist ketanserin. On the other hand, the increase in aggressive behaviour was ameliorated by buspirone but not affected by WAY-100635, whereas it was enhanced by DOI and ameliorated by ketanserin. A single injection of yokukansan ameliorated the PCA-induced decrease in social behaviour but not aggressive behaviour. Chronic treatment for 14 days with yokukansan ameliorated PCA-induced abnormal behaviour, decreased social behaviour and increased aggressive behaviour, but it did not ameliorate PCA-induced decreases in the cerebral 5-HT concentration and 5-HT release. The ameliorative effects of chronic yokukansan on behaviour were counteracted by co-administration of WAY-100635.

Conclusions
These results suggest that yokukansan might have two different effects: an acute effect on social behaviour and a chronic effect on aggressive behaviour. One of the mechanisms of these effects of yokukansan may be related to the agonistic effect on 5-HT1A receptors.
Effects of iron depletion on antimicrobial activities against planktonic and biofilm Pseudomonas aeruginosa
Authors: Cai Yun , Yu Xu-Hong , Wang Rui , An Mao-Mao , Liang Bei-Bei 
Published: October 2010

Abstract

Objectives
Iron plays an important role in the development of Pseudomonas aeruginosa biofilm. Here we evaluated effects of iron depletion on the antimicrobial activity of ceftazidime, tobramycin and ciprofloxacin against planktonic and biofilm Pseudomonas aeruginosa.

Methods
We tested the sensitivities of wild-type PAO1, type-IV pilus mutant PAO-ΔpilHIJK and the quorum-sensing mutant PAO-JP2 P. aeruginosa planktonic cultures and biofilms to antibiotics under iron-depleted conditions.

Key findings
In planktonic bacteria, the minimum concentration that inhibited visible growth (MIC) of ciprofloxacin was increased slightly in an iron-depleted environment in all three strains, whereas the MIC of tobramycin was similar in iron-depleted and control environments. The MIC of ceftazidime increased in the PAO-JP2 strain when iron was depleted. Tobramycin achieved the best bactericidal effect in biofilms. Viable counts were reduced by one log under iron-depleted conditions in all three strains when tobramycin reached 4 MIC and when ceftazidime and ciprofloxacin reached 8 MIC.

Conclusions
This study suggests that once the biofilm is formed, iron depletion may only slightly promote the bactericidal effect of antibiotics on PAO1, PAO-ΔpilHIJK and PAO-JP2. Although these changes were relatively small, iron as one of the environmental factors should not be ignored when evaluating bactericidal effect of antibiotics. The combination of an iron chelator and antibiotics may have therapeutic value under certain bacterial growth conditions.