bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute and chronic diuretic effect of ethanolic extract of leaves ofCocculus hirsutus(L.) Diles in normal rats
Authors: Badole Sachin L , Bodhankar Subhash L , Patel Naimesh M , Bhardwaj Subodh 
Published: October 2010

AbstractObjectivesThe objective of this study was to evaluate the acute and chronic diuretic effect of the ethanolic extract of the leaves of Cocculus hirsutus (L.) Diles.MethodsThe ethanolic extract was administered (100, 200 and 400 mg/kg, p.o.) in Wistar rats. In the acute study, rats received drugs orally and urine was collected after 1, 2, 3, 4, 5 and 6 h. The chronic study involved repeated administration of ethanolic extract for 28 days and urine was collected on day 1, 7, 14, 21 and 28. The parameters were total urine volume, concentration of Na+, K+ and Cl- ions, creatinine in urine and serum. Urine output, electrolytes (Na+, K+ and Cl- ions) and creatinine were determined on day 7, 14, 21 and 28.Key findingsThe highest dose (400 mg/kg) of the ethanolic extract significantly (P &lt; 0.01) enhanced urine output. Excretion of cations (Na+ and K+ ions) and anions (Cl- ions) increased significantly with respect to the control (gum acacia 2% dissolved in saline, 10 ml/kg) group. The increase of cations in the urine after treatment with ethanolic extract was dose dependent. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) did not significantly change the concentration of Na+, K+ and Cl- ions in serum. The ethanolic extract of the leaves of C. hirsutus (100, 200 and 400 mg/kg) and furosemide (10 mg/kg) increased the excretion of creatinine in urine but with a corresponding decrease in serum.ConclusionsIt was concluded that the ethanolic extract of the leaves of C. hirsutus (400 mg/kg) had significant diuretic effect in rats.
Effect of rutin on warfarin anticoagulation and pharmacokinetics of warfarin enantiomers in rats
Authors: Chan Associate Professor Eli , Hegde Akhil , Chen Xin 
Published: October 2010

AbstractObjectivesThe effects of the flavonoid rutin on the anticoagulant activity of oral warfarin and the protein binding and pharmacokinetics of its enantiomers were investigated in rats.MethodsA single dose of racemic warfarin, 1.5 mg/kg, was administered orally to rats either alone or on day 5 of an 8-day oral regimen of rutin, 1 g/kg daily.ResultsRutin reduced the anticoagulant effect of racemic warfarin, evident as a 31% reduction in the area under the prothrombin complex activty–time curve (P &lt; 0.05).Key findingsRutin had no apparent effect on pre-treatment baseline blood coagulation. It enhanced the in-vitro serum protein binding of S- and R-warfarin (reflected by 40% and 26% reductions in unbound fraction, respectively), and thus restricted distribution by 33 and 21%, respectively. Treatment with rutin significantly decreased the elimination half-life of S-warfarin by 37% as a result of the 69% increase in unbound clearance of the S-enantiomer. This effect was attributed to a significant 77% increase in the unbound formation clearance of the overall oxidative and reductive metabolites, and an increase in the unbound renal clearance of the more potent S-enantiomer of warfarin.ConclusionsConcurrent rutin administration is likely to reduce the anticoagulant effect of racemic warfarin, reflecting a significant decrease in the elimination half-life of the more potent S-enantiomer.
Montmorillonite adsorbs creatinine and accelerates creatinine excretion from the intestine
Authors: Zhang Yan-ting , Wang Xiu-fang , Long Li-hui , Liu Tong , Cao Yong-xiao 
Published: October 2010

Abstract

Objectives
This study aims to evaluate the sorption by montmorillonite of creatinine and the accelerating effect of montmorillonite on creatinine excretion from the intestine.

Methods
The sorption of montmorillonite was observed in vitro. Also, rat intestinal tract and blood vessels were perfused circularly with perfusate with or without creatinine, respectively, to study the promotion of creatinine diffusion from the blood vessel to the intestine and the inhibition of creatinine absorption in the intestinal tract. The effect of decreasing the serum concentration of creatinine was studied in an acute hypercreatininaemia mouse model. The concentration of creatinine was determined by the basic picric acid method.

Key findings
Montmorillonite adsorbed creatinine markedly in the simulated intestinal solution in a concentration-dependent manner. The sorption–time curve of montmorillonite with creatinine showed that the sorption was fast. The adsorption rate reached a maximum in 10 min. The pH of the solution influenced the sorption, the rate of which was higher at a low pH than at a high pH. Creatinine could diffuse from the blood vessel to the intestine and was reabsorbed in the intestine. Montmorillonite promoted the diffusion and inhibited the absorption. Montmorillonite decreased the serum creatinine level of hypercreatininaemia mice prepared by injecting creatinine intraperitoneally.

Conclusions
Montmorillonite adsorbs creatinine and accelerates its excretion from the intestine.
Effects of co-administration of bupropion and nicotine ord-amphetamine on the elevated plus maze test in mice
Authors: Biala Grazyna , Kruk Marta 
Published: October 2010

AbstractObjectivesA variety of abused drugs, including psychostimulants, can modulate the expression of anxiety. Although the effect of nicotine and d-amphetamine on anxiety-related behaviour in animal models has been investigated, the mechanisms underlying the anxiogenic or anxiolytic actions of these drugs have not been clarified. Bupropion is an antidepressant drug which may alleviate some symptoms of nicotine withdrawal, although its effects on anxiety are not clear. We have investigated the effect of nicotine and d-amphetamine on anxiety in the elevated plus maze test in mice.MethodsWe examined the influence of acute administration of nicotine (0.1 mg/kg, s.c.) and d-amphetamine (2 mg/kg, i.p.) on anxiety level. We then evaluated the anxiety-related response after subchronic injection of both psychostimulants, including crossover effects. For this purpose, nicotine (0.1 mg/kg, s.c.) was administered daily for six days, and on the seventh day mice were challenged with nicotine (0.1 mg/kg, s.c.) or d-amphetamine (2 mg/kg, i.p.). A distinct group of mice was pretreated with d-amphetamine (2 mg/kg, i.p., 8 days), and subjected to d-amphetamine (2 mg/kg, i.p.) or nicotine (0.1 mg/kg, s.c.) challenge on the ninth day. Moreover, we investigated acute and subchronic effects of co-administration of bupropion (5, 10 and 20 mg/kg; i.p.) and nicotine or d-amphetamine.Key findingsWe observed that acute anxiogenic effects of nicotine and d-amphetamine as well as the development of tolerance and cross-tolerance to their effects were blunted by a pretreatment with a nonactive dose of bupropion (5 mg/kg, i.p.).ConclusionsThese results demonstrated that similar neural mechanisms were involved in the regulation of nicotine and d-amphetamine anxiety-like behaviour in mice. The results have provided new findings to support the use of bupropion in the treatment of nicotine and/or amphetamine addiction.
Cytochrome P450-mediated metabolism in the human gut wall
Authors: Thelen Kirstin , Dressman Jennifer B 
Published: October 2010

AbstractObjectiveAlthough the human small intestine serves primarily as an absorptive organ for nutrients and water, it also has the ability to metabolise drugs. Interest in the small intestine as a drug-metabolising organ has been increasing since the realisation that it is probably the most important extrahepatic site of drug biotransformation.Key findingsAmong the metabolising enzymes present in the small intestinal mucosa, the cytochromes P450 (CYPs) are of particular importance, being responsible for the majority of phase I drug metabolism reactions. Many drug interactions involving induction or inhibition of CYP enzymes, in particular CYP3A, have been proposed to occur substantially at the level of the intestine rather than exclusively within the liver, as originally thought. CYP3A and CYP2C represent the major intestinal CYPs, accounting for approximately 80% and 18%, respectively, of total immunoquantified CYPs. CYP2J2 is also consistently expressed in the human gut wall. In the case of CYP1A1, large interindividual variation in the expression levels has been reported. Data for the intestinal expression of the polymorphic CYP2D6 are conflicting. Several other CYPs, including the common hepatic isoform CYP2E1, are expressed in the human small intestine to only a very low extent, if at all. The distribution of most CYP enzymes is not uniform along the human gastrointestinal tract, being generally higher in the proximal regions of the small intestine.SummaryThis article reviews the current state of knowledge of CYP enzyme expression in human small intestine, the role of the gut wall in CYP-mediated metabolism, and how this metabolism limits the bioavailability of orally administered drugs. Possible interactions between drugs and CYP activity in the small intestine are also discussed.
Amitriptyline inhibits the activity of the rat glutamate transporter EAAT3 expressed in Xenopus oocytes
Authors: Baika Hee-Jung , Lee Soon-Ae , Washington Jacqueline M , Zuo Zhi-yi 
Published: October 2010

Abstract

Objectives
Evidence suggests that glutamatergic systems may be involved in the pathophysiology of major depression and the mechanism of action of antidepressants. We have investigated the effects of amitriptyline, a tricyclic antidepressant, on the activity of the excitatory amino acid transporter type 3 (EAAT3), a protein that can regulate extracellular glutamate concentrations in the brain.

Methods
EAAT3 was expressed in Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 μM l-glutamate in the presence or absence of various concentrations of amitriptyline or after application of various concentrations of l-glutamate in the presence or absence of 0.64 μM amitriptyline.

Key findings
Amitriptyline concentration-dependently reduced EAAT3 activity. This inhibition reached statistical significance at 0.38–1.27 μM amitriptyline. Amitriptyline 0.64 μM reduced the pharmacokinetic parameter Vmax, but did not affect the pharmacokinetic parameter Km, of EAAT3 for l-glutamate. The amitriptyline inhibition disappeared after a 4-min washout. Phorbol-12-myristate-13-acetate, a protein kinase C activator, increased EAAT3 activity. However, 0.64 μM amitriptyline induced a similar degree of decrease in EAAT3 activity in the presence or absence of phorbol-12-myristate-13-acetate.

Conclusions
Our results suggested that amitriptyline at clinically relevant concentrations reversibly reduced EAAT3 activity via decreasing its maximal velocity of glutamate transporting function. The effects of amitriptyline on EAAT3 activity may have represented a novel site of action for amitriptyline to increase glutamatergic neuro-transmission. Protein kinase C may not have been involved in the effects of amitriptyline on EAAT3.
Effects of quinidine on antinociception and pharmacokinetics of morphine in rats
Authors: Okura Takashi , Morita Yuki , Ito Yoshihiko , Kagawa Yoshiyuki , Yamada Shizuo 
Published: October 2010

AbstractAimThe aim of this study was to investigate the effect of quinidine, a P-glycoprotein inhibitor, on the pharmacokinetics and pharmacodynamics of morphine in rats.MethodsRats were given morphine (30 mg/kg p.o. or 30 mg/kg over 10 min i.v.) 30 min after pretreatment with quinidine (30 mg/kg p.o.). Antinociceptive effects were determined using the tail immersion test. Concentrations of morphine in plasma and brain were also determined.Key findingsThe antinociception of morphine was significantly enhanced by oral administration of quinidine, with a 3.1-fold greater area under the effect–time curve than that in vehicle-treated rats. Morphine concentrations in plasma and brain were significantly increased by quinidine. The area under the plasma concentration–time curve after oral or intravenous administration of morphine was increased 5.2- and 1.7-fold, respectively, in quinidine-pretreated rats compared with vehicle-pretreated rats. Quinidine caused a 40% decrease in the total clearance of morphine and increased the concentration of morphine in the brain, although the brain-to-plasma concentration ratio was not changed.ConclusionsOral administration of quinidine increases the absorption of morphine from the gastrointestinal tract and subsequently enhances the concentration in the brain and its antinociceptive effect. Enhanced intestinal absorption of morphine may be due largely to inhibition of intestinal P-glycoprotein by quinidine.
Pharmacological and metabolic characterisation of the potent σ1 receptor ligand 1′-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine]
Authors: Wiese Christian , Maestrup Eva Große , Schepmann Dirk , Vela Jose Miguel , Holenz Jörg , Buschmann Helmut , Wünsch Bernhard 
Published: October 2010

AbstractObjectivesThe pharmacology and metabolism of the potent σ1 receptor ligand 1′-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] were evaluated.MethodsThe compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin pain model. Metabolism by rat and human liver microsomes was investigated, and the metabolites were identified by a variety of analytical techniques.Key findings1′-Benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] (compound 1) is a potent σ1 receptor ligand (Ki 1.14 nM) with extraordinarily high σ1/σ2 selectivity (&gt;1100). It was selective for the σ1 receptor over more than 60 other receptors, ion channels and neurotransmitter transporters, and did not interact with the human ether-a-go-go-related gene (hERG) cardiac potassium channel. Compound 1 displayed analgesic activity against neuropathic pain in the capsaicin pain model (53% analgesia at 16 mg/kg), indicating that it is a σ1 receptor antagonist. It was rapidly metabolised by rat liver microsomes. Seven metabolites were unequivocally identified; an N-debenzylated metabolite and a hydroxylated metabolite were the major products. Pooled human liver microsomes formed the same metabolites. Studies with seven recombinant cytochrome P450 isoenzymes revealed that CYP3A4 produced all the metabolites identified. The isoenzyme CYP2D6 was inhibited by 1 (IC50 88 nM) but did not produce any metabolites.Conclusions1′-Benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] is a potent and selective σ1 receptor antagonist, which is rapidly metabolised. Metabolically more stable σ1 ligands could be achieved by stabilising the N-benzyl substructure.
Endothelium-independent vasorelaxation by the selective alpha estrogen receptor agonist propyl pyrazole triol in rat aortic smooth muscle
Authors: Alda José O , Valero Marta S , Pereboom Desiree , Gros Pilar , Garay Ricardo P 
Published: October 2010

Abstract

Objectives
This study investigated the signalling mechanism of the relaxant responses to the estrogen receptor alpha (ERα) agonist PPT (propyl pyrazole triol) in endothelium-denuded rat aortic rings.

Methods
Several compounds, including protein kinase G (PKG) inhibitors and potassium channel inhibitors, were tested against PPT-dependent rat aortic relaxation. Cyclic GMP and cytosolic calcium responses to PPT in isolated aortic smooth muscle were investigated in parallel.

Key findings
PPT vasorelaxation was largely reduced by the selective ERα antagonist methyl-piperidinopyrazole (MPP; −91.6 ± 2.5%), by the selective PKG inhibitor Rp-8-Br-cGMP (−78.6 ± 4.9%), by the specific soluble guanylyl cyclase inhibitor ODQ (1H-(1,2,4)-oxadiazolo[4,3-a]quinoxalin-1-one; −85.3 ± 5.2%) and to a lesser extent by the selective BKCa (large-conductance calcium- and voltage-activated potassium channel) inhibitor iberiotoxin (−59.3%), the selective IKCa (intermediate-conductance calcium-activated potassium channel) inhibitor TRAM-34 (1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole; −50.7%) and the voltage-gated potassium channel inhibitor 4-aminopyridine (−40.8%). In isolated aortic smooth muscle, PPT strongly enhanced the cyclic GMP content (+144%) and Rp-8-Br-cGMP largely reduced the PPT-dependent calcium signal (−80.8%).

Conclusions
ERα receptor stimulation in rat aortic smooth muscle evokes a PKG-signalling pathway, likely triggering relaxation by BKCa and IKCa channel opening.
Identification of in-vivo and in-vitro metabolites of palmatine by liquid chromatography–tandem mass spectrometry
Authors: Yang Qian C , Wu Wen H , Han Feng M , Chen Yong 
Published: October 2010

Abstract

Objectives
Despite its important therapeutic value, the metabolism of palmatine is not yet clear. Our objective was to investigate its in-vivo and in-vitro metabolism.

Methods
Liquid chromatography–tandem electrospray ionization mass spectrometry (LC-ESI/MSn) was employed in this work. In-vivo samples, including faeces, urine and plasma of rats, were collected after oral administration of palmatine (20 mg/kg) to rats. In-vitro samples were prepared by incubating palmatine with intestinal flora and liver microsome of rats, respectively. All the samples were purified via a C18 solid-phase extraction procedure, then chromatographically separated by a reverse-phase C18 column with methanol–formic acid aqueous solution (pH 3.5, 70: 30 v/v) as mobile phase, and detected by an on-line MSn detector. The structure of each metabolite was elucidated by comparing its molecular weight, retention time and full-scan MSn spectra with those of the parent drug.

Key findings
The results revealed that 12 metabolites were present in rat faeces, 13 metabolites in rat urine, 7 metabolites in rat plasma, 10 metabolites in rat intestinal flora and 9 metabolites in rat liver microsomes. Except for six of the metabolites in rat urine, the other in-vivo and in-vitro metabolites were reported for the first time.

Conclusions
Seven new metabolites of palmatine (tri-hydroxyl palmatine, di-demethoxyl palmatine, tri-demethyl palmatine, mono-demethoxyl dehydrogen palmatine, di-demethoxyl dehydrogen palmatine, mono-demethyl dehydrogen palmatine, tri-demethyl dehydrogen palmatine) were reported in this work.
Novel action of 7-O-galloyl-d-sedoheptulose isolated from Corni Fructus as a hypertriglyceridaemic agent
Authors: Yokozawa Takako , Park Chan Hum , Noh Jeong Sook , Tanaka Takashi , Cho Eun Ju 
Published: October 2010

Abstract

Objectives
We investigated the lipid-lowering activity of 7-O-galloyl-d-sedoheptulose, an active component of Corni Fructus, and related mechanisms.

Methods
Rats were fed a high-fructose diet for 6 days, followed by treatment with 7-O-galloyl-d-sedoheptulose, 5, 10 or 20 mg/kg per day, or fenofibrate (positive control).

Key findings
The high-fructose diet induced an increase in body weight, hypertriglyceridaemia, hyperglycaemia and hypertension. Administration of 7-O-galloyl-d-sedoheptulose significantly reduced the levels of triglyceride in the serum and liver (being more effective than fenofibrate) but did not lead to changes in liver weight or hepatic function, whereas fenofibrate increased the liver weight markedly. The preventive effect of 7-O-galloyl-d-sedoheptulose against the accumulation of triglyceride and cholesterol was related to the up-regulation of peroxisome proliferator-activated receptor α expression.

Conclusions
The present study supports the role of 7-O-galloyl-d-sedoheptulose as a promising agent against hypertriglyceridaemia without hepatic side-effects.
Silymarin inhibits melanin synthesis in melanocyte cells
Authors: Choo Soo-Jin , Ryoo In-Ja , Kim Young-Hee , Xu Guang-Hwa , Kim Won-Gon , Kim Ki-Ho , Moon Seong-Joon , Son Eui-Dong , Bae KiHwan , Yoo Ick-Dong 
Published: October 2010

Abstract

Objectives
The aim was to search for inhibitors of melanogenesis from natural resources.

Methods
The inhibitory effect of silymarin on melanogenesis in a spontaneously immortalized mouse melanocyte cell line, Mel-Ab, was studied.

Key findings
Silymarin significantly prevented melanin production in a dose-dependent manner with an IC50 value (concentration producing 50% maximal inhibition) of 28.2 μg/ml, without effects on cell viability. Also, silymarin inhibited l-DOPA oxidation activity of tyrosinase, the rate-limiting melanogenic enzyme, in cell based-systems but it did not directly affect cell-free tyrosinase activity. Furthermore, Western blot analysis indicated that silymarin decreased the expression of tyrosinase protein.

Conclusions
This study suggests that the depigmenting effect of silymarin might be attributable to inhibition of tyrosinase expression and that silymarin may be useful as a natural skin-lightening agent.
Brain targeting studies on buspirone hydrochloride after intranasal administration of mucoadhesive formulation in rats
Authors: Khan Ms Shagufta , Patil Kundan , Yeole Pramod , Gaikwad Rajiv 
Published: October 2010

Abstract

Objectives
The purpose of this study was to find out whether nasal application of buspirone could increase its bioavailability and directly transport the drug from nose to brain.

Methods
A nasal formulation (Bus-chitosan) was prepared by dissolving 15.5 mg buspirone hydrochloride, 1% w/v chitosan hydrochloride and 5% w/v hydroxypropyl β-cyclodextrin (HP-β-CD) in 5 ml of 0.5% sodium chloride solution. The formulation was nasally administered to rats and the plasma and brain concentration compared with that for buspirone hydrochloride solution after intravenous and intranasal (Bus-plain) administration. The brain drug uptake was also confirmed by gamma scintigraphic study.

Key findings
The nasal Bus-chitosan formulation improved the absolute bioavailability to 61% and the plasma concentration peaked at 30 min whereas the peak for nasal Bus-plain formulation was 60 min. The AUC0-480 in brain after nasal administration of Bus-chitosan formulation was 2.5 times that obtained by intravenous administration (711 ± 252 ng/g vs 282 ± 110 ng/g); this was also considerably higher than that obtained with the intranasal Bus-plain formulation (354 ± 80 ng/g). The high percentage of direct drug transport to the brain (75.77%) and high drug targeting index (&gt;1) confirmed the direct nose to brain transport of buspirone following nasal administration of Bus-chitosan formulation.

Conclusions
These results conclusively demonstrate increased access of buspirone to the blood and brain from intranasal solution formulated with chitosan and HP-β-CD.