bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Ageing on the Oral Absorption of d-Xylose in Rats: Analysis of Gastrointestinal Disposition
Authors: Yuasa Hiroaki , Kawanishi Koji , Watanabe Jun 
Published: April 2011

Abstract
The effects of ageing on the oral (gastrointestinal) absorption of d-xylose were investigated by analysing the gastrointestinal disposition after oral administration to young (9 weeks) and old (53 weeks) rats. A linear model assuming first-order gastric emptying followed by first-order intestinal absorption was fitted to remaining fraction vs time profiles for the stomach and small intestine to estimate the gastric emptying rate constant (kg) and the intestinal absorption rate constant (ka).
In young and old rats, kg values were 0·087 ± 0·008 and 0·070 ± 0·007 min−1, respectively, and ka values were 0·020 ± 0·002 and 0·018 ± 0·002 min−1 suggesting an insignificant effect on ageing on the rate of oral absorption. The average intestinal lumen volume (Vav) was unchanged with ageing, and so was the apparent intestinal membrane permeability clearance (CLapp) as the product of ka and Vav. However, the small intestinal transit time (Tsi) was suggested to be twice that in older rats (171 min) than in young rats (78 min) by the analysis of gastrointestinal disposition of inulin, a non-absorbable marker. It was also shown that our preceding finding of an increase in the fraction absorbed of D-xylose with ageing can be solely ascribable to the delay in intestinal transit.
Thus, among various determinants of oral absorption, only Tsi was found to be altered with ageing. The CLa,app and ka of passively absorbed drugs such as D-xylose may be generally unchanged, and the fraction absorbed may increase with ageing by the delay in intestinal transit.
Effect of Oleanolic Acid on Complement in Adjuvant- and Carrageenan-induced Inflammation in Rats
Authors: Kapil Aruna , Sharma Shalini 
Published: April 2011

Abstract
The present work was aimed at evaluating the influence of oleanolic acid on complement-related inflammation.
In adjuvant-induced arthritis and carrageenan-induced paw oedema in rats, oleanolic acid was found to possess significant anti-inflammatory and complement-inhibitory activities. The intraperitoneal injection of oleanolic acid (60 mg kg−1, twice a day), before and after Freund's Complete Adjuvant challenge and thereafter repeated for several days, significantly reduced foot-pad thickness of experimental animal models and simultaneously reduced complement activity. Oleanolic acid also produced marked reduction in complement levels and inflammatory effects on carrageenan-induced paw oedema in rats when injected intraperitoneally (60 mg kg−1 twice a day).
Antiarrhythmic and Electrophysiological Effects In-vivo of the Major Metabolite of Org 7797 Found in Canine and Rodent Liver Homogenate Preparations
Authors: Winslow E , Campbell J K , Delbressine L 
Published: April 2011

Abstract
Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo.
Org 20781 (0·5–2·0 mg kg−1 i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5–6-day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2–4mg kg−1) associated with suppression of late arrhythmias were 6–18 μm, whilst the mean plasma elimination half-life (in normal dogs) was 107 min.
It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.
Effects of Ginsenosides on Vasodilator Nerve Actions in the Rat Perfused Mesentery are Mediated by Nitric Oxide
Authors: Peng Chang-Fu , Li Yu-Jie , Li Yuan-Jian , Deng Han-Wu 
Published: April 2011

Abstract
This study was designed to explore the effect of ginsenosides, saponins from Panax ginseng, on the vasodilator nerve actions in the rat perfused mesentery and the mechanism of this effect.
In the rat perfused mesentery, when adrenergic nerves were blocked by guanethidine (5 × 10−6 M) and vascular muscle tone was increased with methoxamine (5 × 10−6-10−5 M), transmural field stimulation produced a frequency-dependent vasodilator response, which is due to the release of calcitonin generelated peptide; ginsenosides significantly suppressed this vasodilator response in a concentration-dependent manner (3–30 μg mL−1). After pretreatment with saponin (50 μg mL−1, 3min) to damage endothelial cells, this suppressing effect of ginsenosides was unaltered. However, the effect was abolished by Nω-nitro-l-arginine methyl ester (L-NAME) (10−4 M), an inhibitor of nitric oxide synthesis and addition of l-arginine (3 × 10−4 M) restored this suppressing effect. Methylene blue (10−5 M), an inhibitor of guanylate cyclase, also abolished the suppressing effect of ginsenosides. However, ginsenosides did not alter the relaxation responses caused by exogenous calcitonin gene-related peptide administration.
We conclude that ginsenosides can produce an inhibitory effect on the vasodilator response prejunctionally in the rat perfused mesentery and that this effect of ginsenosides may be mediated by nitric oxide released from non-adrenergic, non-cholinergic nerves.
Chemical and Pharmacological Studies of Phyllanthus caroliniensis in Mice
Authors: Filho Valdir Cechinel , Santos Adair R S , De Campos Rafael O P , Miguel Obdulio G , Yunes Rosendo A , Ferrari Franco , Messana Irene , Calixto João B 
Published: April 2011

Abstract
The aim of this study was to isolate and characterize the constituents of the hydroalcoholic extract (HE) of the leaves, stems and roots from P. caroliniensis, and also to evaluate the preliminary antinociceptive action of the HE and purified compounds in mice.
Phytosterols, quercetin, gallic acid ethyl ester and geraniin were identified in P. caroliniensis on the basis of 1H and 13C NMR spectral data and by mixed co-TLC and co-HPLC injection with authentic samples. The HE of P. caroliniensis (10-100 mg kg−1, i.p.) inhibited, in a dose-related manner, acetic acid-induced abdominal constrictions in mice, with a mean ID50 value of 23.7 mg kg−1. In the formalin test, the HE given intraperitoneally (1-30 mg kg−1) or orally (25-600 mg kg−1) caused graded inhibitions of both the neurogenic (first phase) and the inflammatory response (late phase) of formalin-induced licking. The HE was 54-fold more effective in inhibiting the late phase than it was in inhibiting the first phase of the formalin test, with mean ID50 values of 3.6 and 196.4 mg kg−1, respectively. The HE failed, however, to affect the oedematogenic response associated with the late phase of formalin-induced pain. In addition, the reference drug, aspirin, given intraperitoneally (1-100 mg kg−1) or orally (100-600 mg kg−1), caused significant inhibition of the late but not the first phase of the formalin test. Pharmacological analysis also revealed that quercetin, gallic acid ethyl ester and a semi-purified fraction of flavonoids (1-100 mg kg−1, i.p.) exhibited graded and significant antinociception against acetic acid-induced abdominal constriction. The mean ID50 values (mg kg−1) for these effects were: 18.8, 34.7 and 5.3, respectively.
It is concluded that quercetin, gallic acid ethyl ester and some as yet unidentified flavonoids might account for the antinociceptive action reported for the HE of P. caroliniensis.
Influence of the Carrier on the Intrinsic Rate of Dissolution of Diazepam in Interactive Mixtures
Authors: Supabphol Roongtawan , Stewart Peter J 
Published: April 2011

Abstract
The use of interactive mixtures of drugs adhering to the surface of carriers can promote drug dissolution. The mechanism of dissolution of such mixtures has been studied using the rotating-disc method under conditions eliminating secondary influences such as carrier surface characteristics and drug particle aggregation. Levich plots were used to characterize the dissolution behaviour.
Diazepam-compactrol interactive mixtures had initial dissolution rates similar to that of pure diazepam owing to the deposition of a continuous layer of diazepam on the disc surface from the interactive mixture. Linear Levich plots were produced at all drug loadings and the presence of compactrol in the disc slightly enhanced dissolution rates. Dissolution rates for diazepam-emcompress interactive mixtures were lower than those of pure diazepam. The Levich plots for these systems were non-linear with increasing negative curvature as the diazepam loading decreased. The rate of dissolution of diazepam in the lactose interactive mixture was markedly higher than that of pure diazepam, but high diazepam loadings in the lactose mixtures inhibited diazepam dissolution. Rapid carrier dissolution caused surface retraction of the disc, enhancing the dissolution rate. The Levich plots showed an upward curvature due to turbulence.
Linear Levich plots for diazepam and other benzodiazepines and for diazepam-compactrol interactive mixtures showed that their dissolution in pH 5 phosphate buffer was diffusion-controlled. The Levich plots for diazepam-emcompress interactive mixtures were indicative of some interfacial control during dissolution, but the hypothesis of common ion precipitation of dissolved carrier, calcium phosphate, onto the disc surface did not fully explain this effect.
A Pharmacokinetic Study of Sublingual Aerosolized Morphine in Healthy Volunteers
Authors: Watson Neil W , Taylor Kevin M G , Joel Simon P , Slevin Maurice L , Eden Osborn B 
Published: April 2011

Abstract
A pharmacokinetic study was undertaken to compare the pharmacokinetics of morphine after an intravenous dose with the pharmacokinetics after a sublingual dose administered from an aerosol.
Plasma levels of morphine, morphine-3-glucuronide and morphine-6-glucuronide were measured in five normal volunteers after morphine administration by the intravenous route and from a novel sublingual pressurized aerosol formulation. The mean (± s.d.) bioavailability of the sublingual aerosol morphine was 19.7 ± 6.7%. The morphine-3-glucuronide/morphine and the morphine-6-glucuronide/morphine ratios were 5.1 ± 1.6 and 1.2 ± 0.4, respectively, for the intravenous route and 28.3 ± 11.3 and 5.2 ± 1.4, respectively, for the sublingual route. The combined total areas under the plots of systemic concentration against time (AUC) for the metabolites after the two routes was not significantly different.
When compared with published data for oral administration the results demonstrate that the sublingual aerosol morphine might provide an alternative to conventional methods of morphine delivery, and has similar pharmacokinetics to a sublingual morphine tablet. It has no particular pharmacokinetic advantages over oral morphine, except a potential for a faster onset of analgesia. Bioavailability, maximum plasma concentration, Cpmax, and the time at which the maximum plasma concentration is reached, Tmax, are equivalent to those for orally administered morphine.
Pharmacokinetic Analysis of the Absorption Characteristics of Diclofenac Sodium in Man by use of a Multi-segment Absorption Model
Authors: Mahmood Iftekhar 
Published: April 2011

Abstract
The pharmacokinetic analysis of an oral sustained-release preparation of diclofenac sodium has been investigated using multi-segment absorption models in which it has been assumed that the gastrointestinal tract can be divided into several segments in each of which the drug has its own lag-time and absorption rate constants.
Plasma concentration-time data for sustained release diclofenac sodium in man were fitted both by a conventional pharmacokinetic method assuming first-order absorption and by a multi-segment absorption model. The plasma concentration of diclofenac sodium calculated on the basis of the multi-segment absorption model was found to correlate with the observed plasma concentration.
It was concluded that diclofenac sodium data can be better described by a multi-segment absorption model than by a conventional pharmacokinetic model. The results also show that multi-segment absorption models are suitable for pharmacokinetic analysis of plasma drug-concentration data with irregular or multiple peaks in the absorption profiles, and also for the pharmacokinetic analysis of sustained-release preparations.
Bioavailability and In-vitro/in-vivo Correlation for Propranolol Hydrochloride Extended-release Bead Products Prepared Using Aqueous Polymeric Dispersions
Authors: Rekhi Gurvinder Singh , Jambhekar Sunil S 
Published: April 2011

Abstract
The influence of formulation and extrinsic factors has been investigated for the in-vitro release of propranolol hydrochloride from controlled-release beads prepared using aqueous polymeric dispersions, Aquacoat and Surelease. A single-dose three-way crossover bioavailability study of two extended-release experimental formulations (80 mg), Inderal LA (80 mg) and an Inderal immediate-release dosage form (2 × 40 mg) was also conducted and a comparative analysis of pharmacokinetic parameters and the in-vitro release profiles was performed to assess in-vitro/in-vivo correlation.
Analysis showed that the in-vitro release data appeared to follow zero-order release kinetics. Intensity of agitation and dissolution method were found to have no significant effect on drug release from beads prepared using either of the coating dispersions studied or Inderal LA. Release of drug from beads coated with Aquacoat was faster in basic media than in acidic media; Surelease-coated beads, however, showed release characteristics that were less sensitive to changes in the pH of the dissolution fluid, and Inderal LA beads showed slower release profiles in acidic medium than in other dissolution media studied. Pharmacokinetic analysis of the data revealed sustained-release absorption characteristics without any evidence of dose-dumping from any of the extended-release dosage forms studied. Regression analysis of the fraction of drug absorbed against the percentage of the drug released in-vitro, at the corresponding times, yielded good in-vitro/in-vivo correlation (level A) for all the extended-release formulations studied.
The results showed that there was no dose-dumping from any of extended-release formulations and that the relative bioavailabilities of the experimental formulations were superior to that of the marketed formulation.
Effectiveness and Toxicity Screening of Various Absorption Enhancers in the Rat Small Intestine: Effects of Absorption Enhancers on the Intestinal Absorption of Phenol Red and the Release of Protein and Phospholipids from the Intestinal Membrane
Authors: Yamamoto Akira , Uchiyama Tomomi , Nishikawa Reiko , Fujita Takuya , Muranishi Shozo 
Published: April 2011

Abstract
Sodium glycocholate, sodium taurocholate, sodium deoxycholate, EDTA, sodium salicylate, sodium caprate, diethyl maleate, N-lauryl-β-D-maltopyranoside, linoleic acid polyoxyethylated (60 mol) mixed micelles (all 20 mM) have been ranked in order of their effectiveness as enhancers of the absorption of drugs in the rat small intestine, by use of an in-situ loop model with phenol red as a model drug. Local toxicity in rats was examined by assessing protein and phospholipid release as biological markers.
Of the absorption enhancers, sodium deoxycholate, EDTA and N-lauryl-β-D-maltopyranoside were the most effective; sodium deoxycholate and EDTA, however, caused significant release of protein and phospholipids. N-lauryl-β-D-maltopyranoside, on the other hand, did not damage the small intestinal membrane. Sodium taurocholate enhanced phenol red absorption from the small intestine and resulted in little or no protein and phospholipids release. Sodium salicylate, diethyl maleate and the mixed micelles had no absorption-promoting effects on phenol red. There was good correlation between the area under the plasma concentration-time curve for phenol red and the amounts of protein and phospholipid released in the presence of absorption enhancers.
From these results it might be concluded that N-lauryl-β-D-maltopyranoside and sodium taurocholate are effective absorption enhancers which have low toxicity levels at a concentration of 20 mM.
Characterization of α-Adrenoceptor Activity in Term-newborn Piglet Mesentery
Authors: Ferrara J J , Hoang T V , Choe E U , Lippton H L , Hyman A L , Flint L M 
Published: April 2011

Abstract
For further characterization of neonatal mesenteric α1-adrenoceptor populations, an extracorporeal perfusion circuit was established to control intestinal blood flow in 0-2 day old piglets.
Activation of α1-adrenoceptors was first documented by observing dose-dependent increases in mesenteric perfusion pressure after intra-mesenteric arterial injection of methoxamine and noradrenaline. Peripheral intravenous injections of WB 4101 (a competitive α1A-adrenoceptor antagonist), but not clorethylclonidine (CEC, an α1B-adrenoceptor antagonist), significantly (P &lt; 0.05, analysis of variance) blunted mesenteric vasoconstrictor responses to those agonists.
That the mesenteric vasoconstrictor response to mesenteric plexus stimulation was unaltered by CEC, but was muted by both WB 4101 and SK&F 104856 (a post-junctional α1- and α2-adrenoceptor antagonist) suggests that pre- and post-junctional α1A-adrenoceptors are present and functional at birth.
The Failure of Substrate pKa to Influence the Microsomal Formation of Amides from N-Benzylamines: the Microsomal Metabolism of N-Benzyl Pyrrolidine, N-Benzyl Carbazole and N-Acetyl-N-benzyl-4-methylaniline
Authors: Ulgen Mert , Gorrod John W 
Published: April 2011

Abstract
The in-vitro hepatic microsomal metabolism of N-benzylpyrrolidine (NBP), N-benzylcarbazole (NBC) and N-acetyl-N-benzyl-4-methylaniline (NANBMA) has been studied, using hamster microsomal preparations, to establish whether the corresponding amide is formed.
Amide formation was not observed with any of the substrates utilized, although several metabolic products were detected by HPLC with UV detection. These included the oxidative debenzylation products (for all substrates), ring hydroxylated products (for NBC) and a lactam metabolite (for NBP).
The results support the concept that the metabolic conversion of benzylic amines to the corresponding amide involves an N-oxidative step.
Age-dependent Alteration of the Serum-unbound Fraction of Nicardipine, a Calcium-channel Blocker, in Man
Authors: Sugioka Nobuyuki , Koyama Hikaru , Kawakubo Mariko , Ohta Toshio , Kishimoto Hideki , Mori Satoru , Nakajima Kenji 
Published: April 2011

Abstract
To determine whether the age-dependent increase in the pharmacological effect of calcium-channel blockers is a result of age-dependent alteration of the unbound fraction the drug in serum, the unbound fraction of the nicardipine was investigated in the serum of 38 adults.
The unbound concentration of nicardipine in serum to which nicardipine (205.4 ng mL−1) had been added was determined by ultracentrifugation to range from 0.49 to 4.01% (mean±s.d., 1.55 ± 0.78%). Non-glycosylated albumin was most strongly correlated with age (r = 0.901). Total bilirubin was weakly correlated with age whereas levels of α-1-acid glycoprotein, triglycerides and glycosylated albumin were not correlated with age. A significant (P &lt; 0.01) linear correlation was obtained between the unbound fraction of nicardipine and parameters such as age, albumin, albumin/globulin ratio, albumin/glycosylated albumin ratio, non-glycosylated albumin and total bilirubin. To assess the relative effect of each variable on the unbound fraction of nicardipine, stepwise multiple linear regression was performed using age and biochemical parameters. The three variables (non-glycosylated albumin, total bilirubin and age) were entered into the regression equation.
The results of this study showed that the major ligand of nicardipine in serum was non-glycosylated albumin, which decreased with age. It was, moreover, shown that the serum-unbound concentration of nicardipine increased with age. This finding would be one factor accounting for the increase in the pharmacological effect of nicardipine with age. In addition, our predicted model for the unbound fraction of nicardipine might be useful in determining the appropriate nicardipine dose for the elderly.
Chemical Stability of Artesunate Injection and Proposal for its Administration by Intravenous Infusion
Authors: Batty Kevin T , Ilett Kenneth F , Davis M E , Timothy  
Published: April 2011

Abstract
Artesunate, the only artemisinin analogue that can be given intravenously, produces rapid parasite and fever clearance in falciparum malaria. A significant therapeutic problem is a high, late recrudescence rate, probably due to short half-lives of both artesunate and its active metabolite dihydroartemisinin relative to conventional dosing intervals. One method of extending the duration of action of artesunate could be to administer the drug by infusion rather than bolus injection, provided that it is chemically stable at ambient temperature.
Artesunate was found to be stable in 0&#x006d;̇9% w/v sodium chloride at 9°C, 23°C and 36&#x006d;̇5°C for 130, 10&#x006d;̇6 and 1&#x006d;̇6 h, respectively. Interpolating from an Arrhenius plot, artesunate should be stable for approximately 4 h at 30°C, a temperature representative of ambient conditions in tropical countries. Exposure to light did not affect the degradation rate. Single compartment pharmacokinetic modelling was used to evaluate potential differences in artesunate and dihydroartemisinin plasma concentrations following administration of artesunate by intravenous bolus or infusion. A bolus injection of artesunate at a dose of 4 mg kg−1 gives a peak concentration of 5&#x006d;̇3 mg L−1, falling to 0&#x006d;̇005 mg L−1 at 5 h. The same dose infused over 4h results in a peak concentration of 0&#x006d;̇92 mg L−1 falling to 0&#x006d;̇005 mg L−1 at 8h. Simultaneous modelling of dihydroartemisinin showed that while its peak plasma concentration was reduced by 27% and the peak delayed by 2.5 h following artesunate administration by infusion, substantially higher concentrations were maintained compared with those predicted after bolus artesunate.
These data indicate that artesunate can be administered as a high-dose intravenous infusion, thus avoiding high plasma concentrations. This strategy also has the potential to prolong the duration of antimalarial effect and reduce toxicity, and consequently improve clinical outcome in seriously ill patients.
In-vitro Evaluation of Biphenylyl Acetic Acid-β-Cyclodextrin Conjugates as Colon-targeting Prodrugs: Drug Release Behaviour in Rat Biological Media
Authors: Hirayama Fumitoshi , Minami Kunihiro , Uekama Kaneto 
Published: April 2011

Abstract
Biphenylyl acetic acid was selectively conjugated to one of the primary hydroxyl groups of β-cyclodextrin through an ester- or amide-linkage, and the physicochemical properties (aqueous solubility and hydrolysis) were investigated.
Aqueous solubility of the conjugates was lower than those of either drug or parent β-cyclodextrin. The amide conjugate was stable in aqueous solution and in rat biological fluids and gastrointestinal contents. The ester conjugate was hydrolysed to β-cyclodextrin and biphenylyl acetic acid at moderate rates resulting in a V-shaped rate-pH profile in aqueous solution. The ester conjugate released the drug preferentially when incubated with the contents of caecum or colon, whereas no appreciable drug release was observed on incubation with contents of stomach or intestine, nor on incubation with intestinal or liver homogenates, nor on incubation with rat blood.
The present results suggest that the ester-type drug conjugate of β-cyclodextrin may serve as a colon-targeting prodrug.