bluuebunny/crossref_metadata_2025_split huggingface dataset:
Stereoselective Passage of Mefloquine Through the Blood-Brain Barrier in the Rat
Authors: Baudry S , Pham Y T , Baune B , Vidrequin S , Crevoisier CH , Gimenez F , Farinotti R 
Published: April 2011

Abstract
The pharmacokinetics of the enantiomers of mefloquine were studied in the rat after administration of a racemic mixture and of the separate enantiomers (+)-mefloquine and (–)-mefloquine.
When 50 mg kg−1 racemic mixture was administered orally for 22 days, plasma concentrations of the (+) enantiomer were 2–3 times higher than those of the (–) enantiomer whereas the opposite was true in every part of the brain (cerebellum, cortex, hippocampus, hypothalamus and striatum). Different concentrations of mefloquine were found in the different regions of the brain; the lowest concentrations of (±)-mefloquine (270 nmol g−1) were in the cerebellum and the highest (1100 nmol g−1) in the hippocampus. The main metabolite, carboxymefloquine, was detected in plasma but not in the brain.
The results indicate that mefloquine crosses the blood-brain barrier stereoselectively.
Affinity of the Miotic Drug, Dapiprazole, at α1-Adrenoceptor Subtypes A, B and D
Authors: Eltze Manfrid 
Published: April 2011

Abstract
The functional affinities of the α1-adrenoceptor antagonist, dapiprazole, currently being used to reverse diagnostic pupillary dilation, were determined at subtype A in rat vas deferens, at subtype B in guinea-pig spleen and at subtype D in rat aorta and compared with various α1-adrenoceptor subtype-discriminating antagonists.
Dapiprazole had relatively high affinity both at rat vas deferens α1A-adrenoceptors (pA2 = 7.93) and at rat aortic α1D-adrenoceptors (pA2 = 8.26), whereas its affinity at guinea-pig splenic α1B-adrenoceptors (pA2 = 7.13) was lower. The reference antagonists, 5-methylurapidil and the 5-methylurapidil/fiesinoxan hybrid, B8805–033((±)-1,3,5-trimethyl-6[[3[4(2(2,3-dihydro-2-hydroxymethyl)-1,4-benzodioxin-5-yl)-1-piperazinyl]propyl]-amino]2,4(1H,3H)-pyrimidinedione), were 40- and 1500-fold selective for the A subtype, whereas spiperone and BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione diHCl) were confirmed as selective for the B and D subtypes of α1-adrenoceptors, respectively.
Thus, in functional experiments dapiprazole seems to be moderately selective (approximately 10-fold) for the A and D over the B subtype of α1-adrenoceptors; the possible therapeutic consequence of this is discussed.
Cold-storage of Rabbit Thoracic Aorta in University of Wisconsin Solution Reduces Endothelium-independent Vasodilation
Authors: Gryf-Lowczowski J V D , Sherlock D , Salisbury J , Benjamin I S , Alexander B 
Published: April 2011

Abstract
Optimum preservation conditions for storage of donor livers and blood vessels are essential for successful transplantation. The blood vessels are used as vascular conduits to facilitate anastomosis of the liver to the recipient's systemic vasculature. Failure of some transplants has been ascribed to thrombosis of these vascular conduits possibly because of alterations in vascular reactivity owing to inadequate storage techniques. To restrict data variability previously associated with studies using a heterogeneous sample of vessels from man, this study investigated changes in vascular reactivity in segments of rabbit thoracic aorta from male, age-matched, New Zealand White rabbits stored at 4°C in either University of Wisconsin solution (UW; Du Pont Pharmaceuticals, UK) or Krebs-Bülbring buffer (KB).
Percent vasodilation to acetylcholine remained significantly greater in UW than in KB at –log (m) concentrations of 70 (UW = 47.05 ± 4.26 compared with KB = 13.20 ± 7.20%; P &lt; 0.001), 6.5 (UW = 66.82 ± 4.83 compared with KB = 26.60 ± 9.48%; P &lt; 0.01), and 60 (UW = 83.68 ± 5.26 compared with KB = 31.20 ± 9.83%; P &lt; 0.001). This was not significantly different to relaxation in unstored arteries and suggested improved endothelial function and structure, confirmed by electron microscopy. Percent vasodilation to sodium nitroprusside was significantly lower in UW than in unstored (D0) arteries at –log (M) concentrations of 7.5 (D0 = 28.27 ± 4.02 compared with UW = 15.21 ± 1.82%; P &lt; 0.01), 7.3 (D0 = 52.58 ± 5.05 compared with UW = 29.23 ± 1.94%; P &lt; 001), 70 (D0 = 69.70 ± 4.85 compared with UW = 49.72 ± 2.49%; P &lt; 005), and 6.4 (D0 = 93.16 ± 2.93 compared with UW = 71.29 ± 5.20%; P &lt; 0.05). Percent vasodilation was also lower in UW- compared with KB-stored arteries at –log (m) sodium nitroprusside concentrations of 7.0 (UW = 49.72 ± 2.49 compared with KB = 64.11 ±5.03%; P &lt; 0.05) and 6.4 (UW = 71.29 ± 5.20 compared with KB = 96.91 ± 5.96; P &lt; 0.05). Electron microscopy confirmed that this was not a result of degradation of smooth muscle structure. The nitric oxide synthase inhibitor l-NG-nitro-l-arginine methyl ester (100 μm) did not significantly modulate sodium nitroprusside-induced vasodilation in unstored arteries, when endothelial function was maximum, or in UW-stored arteries, suggesting that the reduced responses in UW-stored arteries were not because of increased synthesis of nitric oxide. This reduced relaxation to sodium nitroprusside was therefore nitric oxide-independent and not a result of competition between sodium nitroprusside and endothelial ‘nitric oxide donation’ for cGMP.
In summary, cold-storage preservation with UW reduced endothelium-independent vascular relaxation by mechanisms other than competition with NO; this requires further evaluation.
Several Receptor Subtypes Contribute to 5-Hydroxytryptamine-induced Secretion by Rat Ileum In-vitro
Authors: Hardcastle J , Hardcastle P T 
Published: April 2011

Abstract
The receptors contributing to 5-hydroxytryptamine (5-HT)-induced secretion by rat ileum were investigated in-vitro using selective agonists and antagonists.
5-HT induced a dose-dependent increase in the short-circuit current (SCC) generated by both intact and stripped sheets of rat ileum. 1-Phenylbiguanide, a selective 5-HT3 agonist, and 5-methoxytryptamine, an agonist that lacks affinity for 5-HT3 receptors, also increased the SCC. In intact sheets 5-HT was more effective than either 1-phenylbiguanide or 5-methoxytryptamine, whereas in stripped sheets 5-HT and 5-methoxytryptamine were equipotent, with 1-phenylbiguanide having little effect. Tetrodotoxin abolished the response of intact sheets to 1-phenylbiguanide but only reduced the responses to 5-HT and 5-methoxytryptamine by 57% and 54%, respectively. This inhibition was reduced to 25% in stripped sheets. The 5-HT3 antagonist granisetron abolished the response to 1-phenylbiguanide, but did not alter the effects of 5-HT. Ketanserin, a 5-HT2 antagonist, had a small effect on the actions of 5-methoxytryptamine in intact, but not stripped, sheets and no effect on the response to 5-HT in either preparation. Tropisetron, a 5-HT3 and 5-HT4 antagonist, inhibited the response to 5-methoxytryptamine, but had less effect on the response to 5-HT. Desensitization to 1-phenylbiguanide inhibited the response to 5-HT in intact, but not stripped sheets, whereas desensitization to 5-methoxytryptamine abolished the 5-HT response in stripped sheets, but induced only 42% inhibition in intact sheets. Previous exposure to a combination of both 1-phenylbiguanide and 5-methoxytryptamine abolished the 5-HT-induced increase in SCC in both preparations.
The findings suggest that 5-HT-induced ileal secretion involves more than one 5-HT receptor subtype and that both neural and non-neural mechanisms contribute to the response.
Screening of Hepatoprotective Plant Components using a HepG2 Cell Cytotoxicity Assay
Authors: Thabrew M Ira , Hughes Robin D , McFarlane Ian G 
Published: April 2011

Abstract
Identification of the active components of plants with hepatoprotective properties requires screening of large numbers of samples during fractionation and purification. A screening assay has been developed based on protection of human liver-derived HepG2 cells against toxic damage.
Various hepatotoxins were incubated with HepG2 cells in 96-well microtitre plates (30000 cells well−1) for 1 h and viability was determined by metabolism of the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy phenyl)-2-(4-sulphophenyl)-2H-tetrazolium (MTS). Bromobenzene (10 mm) and 2,6-dimethyl-N-acetyl-p-quinoneimine (2,6-diMeNAPQI, 200 mm) had greater toxic effects than tert-butyl hydroperoxide (1.8 mm) or galactosamine (10 mm), reducing mean viability to 44.6 ± 1.2% (s.e.m.) and 561 ± 21% of control, respectively. Protection against toxic damage by these agents was tested using a crude extract of a known hepatoprotective Sri Lankan plant, Osbeckia aspera, and two pure established hepatoprotective plant compounds, (+)-catechin and silymarin (1 mg mL−1). Viability was significantly improved by Osbeckia (by 37.7 ± 2.4%, P &lt; 0.05, and 36.5 ± 21%, P &lt; 0.05, for bromobenzene and 2,6-diMeNAPQI toxicity, respectively). Comparable values for (+)-catechin were 68.6 ± 2.9% and 63.5 ±11%, and for silymarin 24.9 ± 1.4% and 25.0 ± 1.6%.
This rapid and reproducible assay should prove useful for the isolation and identification of active hepatoprotective compounds in crude plant extracts.
Cisplatin-induced Changes in Adenine Nucleotides in Rat Kidney Slices: Amelioration by Tiopronin and Procaine
Authors: Zhang Jin-Gang , Lindup W Edward 
Published: April 2011

Abstract
The adenine nucleotides (ATP, ADP and AMP) in rat renal cortical slices exposed in-vitro to cisplatin, an anticancer drug, were determined by HPLC.
Cisplatin had no effect on total adenine nucleotides in the slices but caused a time- and concentration-dependent decrease in ATP levels with a concomitant increase in ADP and AMP levels. The decrease in ATP and increases in ADP and AMP concentrations became statistically significant after incubation with cisplatin (2 mm) for 90 min or after cisplatin (1 mm) for 120 min. Both tiopronin, a sulphydryl-containing drug, and procaine, an antioxidant, protected against cisplatin-induced changes in the adenine nucleotides.
The results indicate a cisplatin-induced defect in cellular energetics that occurs at a relatively late stage in the process of toxicity to the slices in this in-vitro model. Cisplatin-induced depletion of ATP in the slices might result from an increase in catabolism of ATP to ADP and AMP. Maintenance of the normal concentration of ATP in the slices might be involved in the protection afforded by tiopronin and procaine against cisplatin-induced nephrotoxicity.
Application of Muscle Microdialysis to Evaluate the Concentrations of the Fluoroquinolones Pazufloxacin and Ofloxacin in the Tissue Interstitial Fluids of Rats
Authors: Araki Harumi , Ogake Naoko , Minami Shinazburo , Watanabe Yasuo , Narita Hirokazu , Tamai Ikumi , Tsuji Akira 
Published: April 2011

Abstract
Muscle microdialysis has been used to determine the unbound concentrations of the fluoroquinolones, pazufloxacin and ofloxacin, in tissue interstitial fluids (Cisf, u) of rats under steady state conditions.
Cisf, u was estimated from the concentration in dialysate and the in-vitro permeability rate constant by the extrapolation method based on the clearance concept. Paper disks were inserted under the abdominal skin of rats, and the drug concentrations in the fluids penetrating into the disks (Cdisk) were measured and compared with Cisf, u. The Cisf, u of pazufloxacin and ofloxacin in muscle were close to their unbound concentrations in the venous plasma; these were 75.3% and 77.1%, respectively, of the total concentrations in plasma at the steady state. The Cdisk of pazufloxacin and ofloxacin were also close to their Cisf, u.
These results indicate that the unbound concentrations of the fluoroquinolones in the tissue interstitial fluids were the same as those in the venous plasma. The disk insertion technique seems to be useful for evaluating drug concentrations in tissue interstitial fluid.
Isoquinoline Derivatives Isolated from the Fruit of Annona muricata as 5-HTergic 5-HT1A Receptor Agonists in Rats: Unexploited Antidepressive (Lead) Products
Authors: Hasrat J A , De Bruyne T , De Backer J-P , Vauquelin G , Vlietinck A J 
Published: April 2011

Abstract
The fruit and the leaves of Annona muricata (Annonaceae) are used in traditional medicine for their tranquillizing and sedative properties. Extracts of the plant have been shown to inhibit binding of [3H]rauwolscine to 5-HTergic 5-HT1A receptors in calf hippocampus, and three alkaloids, annonaine (1), nornuciferine (2) and asimilobine (3), isolated from the fruit have been shown to have IC50 values of 3 μm, 9 μm and 5 μm, respectively, although in ligand-binding studies it was not possible to determine whether interaction of these ligands with the receptor was agonistic or antagonistic. This paper presents the results of functional assays of the alkaloids.
The inhibition of cAMP accumulation was tested in NIH-3T3 cells stably transfected with the 5-HT1A receptor from man. None of the alkaloids showed antagonistic properties towards the 5-HT1A receptors because in the antagonistic tests no influence on the forskolin-stimulated increase of cAMP level was detected. Full agonistic properties were measured for all three compounds; the inhibition constants (Ki) for 1, 2 and 3 were &lt; 10 μm. Inhibition of the binding of the radioligand to the 5-HT1A receptor was observed in every ligand-binding assay performed with the alkaloids; the Ki values for 1, 2 and 3 were in the μm range.
These results imply that the fruit of Annona muricata possesses anti-depressive effects, possibly induced by compounds 1, 2 and 3, and that in the past potent leads for the development of anti-depressive therapeutics have not been used.
Pharmacology of the Gastric Pro-kinetic Drug Ecabapide (DQ-2511)
Authors: Furuhama Kazuhisa , Wood Jackie D 
Published: April 2011

Abstract
The pharmacology of ecabapide (DQ-2511; 3-[2-(3,4-dimethoxyphenyl)ethylcarbamoylmethyl]amino-N-methylbenzamide) is reviewed.
Evidence from basic studies in animal models suggests that the drug acts on peripheral mechanisms of neural control. In the stomach, ecabapide acts to suppress firing in vagal afferent nerves and thereby reduce the flow of sensory information into the dorsal vagal complex.
The enhancement of the efferent discharge provoked by ecabapide was completely blocked by bilateral vagotomy, as suggested by increased firing in vagal efferent fibres, preceded by suppression of activity in the sensory limb of the putative vago-vagal reflex pathway.
The mechanism of action of ecabapide in suppressing discharge in vagal afferent terminals appears to mimic that of nitric oxide by stimulating formation of cGMP and activation of an inhibitory transduction cascade in the sensory fibres. In this respect the mechanism of its pro-kinetic action differs from other promoter agents. In addition to selective actions in the stomach, evidence from electrophysiological studies of enteric neurons in the small intestine suggests that ecabapide might have actions similar to those of other substituted benzamides on synaptic transmission in the intramural nervous system of this specialized region of the digestive tract. These actions include enhanced release of acetylcholine at excitatory synapses and suppression of the release of noradrenaline at inhibitory synapses.
The Effect of Surfactant and Suspending Agent Concentration on the Effective Particle Size of Metered-dose Inhalers
Authors: Fedina L T , Zelkó R , Fedina L I , Szabados Z S , Szántó M , Vakulya G 
Published: April 2011

Abstract
The aim of this study was to examine the influence of the concentrations of surfactant and suspending agent on the quantity of effective particles (size &lt; 10 μm) delivered by metered-dose inhalers.
A 2-factor, 3-level, face-centred central composite design was used to construct a second-order polynomial model which describes the effect of formulation factors (suspending agent, surface-active ingredient) on the therapeutically important characteristic (effective particle size) delivered by metered-dose inhalers. Oleic acid was selected as the surface-active ingredient, and the suspending agent was anhydrous alcohol. A non-linear model demonstrated with good correlation the effect of the amounts of surfactant and suspending agent on the quantity of particles of effective size.
The results obtained enable determination of the correct amount of surface-active ingredient and the optimum quantity of the suspending agent, thus enabling formulation of a therapeutically effective formulation.
Change of the Microstructure of Microcrystalline Cellulose with Grinding and Compression
Authors: Yamamura Shigeo , Terada Katsuhide , Momose Yasunori 
Published: April 2011

Abstract
The microstructure of microcrystalline cellulose was investigated by use of a radial distribution function (RDF) based on the intensity of X-ray scattering data. Changes in the microstructure of the cellulose as a result of grinding and compression were detected by use of the RDF.
The RDF of intact microcrystalline cellulose had peak maxima corresponding to distances of approximately 1.5, 2.6, 5.0, 8.2, 13.3 and 170 Å. The first two corresponded to the intramolecular atomic distances; other peaks were attributable to the intermolecular (inter-fibre) atomic distance. Changes in the RDF as a result of grinding indicated that the regular intermolecular atomic arrangement was gradually lost. Compression resulted in formation of long-range (&gt; 20 Å) ordering of the intermolecular (inter-fibre) atomic arrangement.
These results show that RDF analysis is suitable for monitoring changes in the structure of microcrystalline cellulose which occur as a result of grinding and compression.
Short-period Double-dosing for Simultaneous Evaluation of Intestinal Absorption and Hepatic Disposition in a Single Conscious Rat Using Cephalexin as Test Drug
Authors: Ito Takashi , Yamaoka Kiyoshi , Nakagawa Terumichi 
Published: April 2011

Abstract
A new method has been developed for simultaneous evaluation of local absorption from the intestine into the portal system and local disposition through the liver, and for assessment of the bioavailability of a drug in a single conscious rat. The method is based on the difference between plasma concentrations in portal and systemic blood (PS method).
Because cephalexin is known to be absorbed completely from the intestine and not to be eliminated through the liver, it was used as test drug to confirm the validity of the new method. The portal vein and the femoral artery of a rat were simultaneously cannulated and blood samples were obtained from both sites. Two methods of administration, single-dosing and double-dosing, were investigated and the efficacy of double-dosing (DD) was demonstrated. Rats received an intra-arterial (group A) or oral (group B) dose in single-dosing, whereas rats used for double-dosing received an oral dose 3 h after an intra-arterial dose (group C). After administration of cephalexin, the portal and arterial plasma concentrations were determined by HPLC. Groups A and B were monitored for 4 h and group C for 8 h. The portal-blood flow rate was measured by means of an electromagnetic flow-meter. Global and local moments were calculated by trapezoidal integration with extrapolation to infinite time. On the basis of the PS method, the local absorption ratio (Fa) and the mean local absorption time (t̄a) were estimated to be 0.975 ± 0.104 and 2.19 ± 0.51 h, respectively, in group B. By comparing the averaged moments between groups A and B, the extent of bioavailability (F), the mean absorption time (MAT) and the hepatic recovery ratio (FH) were calculated to be 1.01, 1.92 h and 1.04, respectively. The mean hepatic transit time (t̄H) was negligible. In group C, Fa = 0.936 ± 0.107, t̄H = 1.55 ± 0.32 h, F = 1.08 ± 0.07, MAT = 1.55 ± 0.40 h and FH = 1.17 ± 0.14 h, the mean values being close to those from groups A and B.
In conclusion, the PS method with short-period double-dosing (PS-DD method) can offer an effective means of evaluating the local absorption kinetics of drugs, because F, MAT and FH are obtained from a single conscious rat, and consequently the standard deviations of the quantities can be quickly estimated.
Control of the Amount of Free Molecular Iodine in Iodine Germicides
Authors: Hickey John , Panicucci Rick , Duan Yongjun , Dinehart Kirk , Murphy Joe , Kessler Jack , Gottardi Waldemar 
Published: April 2011

Abstract
Horseradish peroxidase has been used to generate iodine compositions that comprised principally free molecular iodine.
The concentration of free molecular iodine in these enzyme-based compositions ranged from 44 to 63% of the thiosulphate titratable iodine; this is substantially higher than the corresponding value for the povidoneiodine preparation betadine. The biocidal efficacy of these compositions was proportional to the concentration of free molecular iodine. Iodine compositions with relatively low total iodine concentrations but high levels of free molecular iodine (20–175 ppm) killed Staphylococcus aureus and spores of Bacillus subtilis more rapidly than betadine. The effects of normal saline and these enzyme-based iodine compositions on the rate of epidermal regeneration in superficial swine wounds were comparable.
These results suggest that an effective germicide containing a high level of molecular iodine need not be irritating or toxic.
Relationship between Plasma Concentration and Antihypertensive Effect of the Dihydropyridine Calcium Antagonist, Benidipine, in Rats
Authors: Kobayashi Hiroyuki , Kobayashi Satoshi 
Published: April 2011

Abstract
Although benidipine hydrochloride, a hydrophobic and weakly cationic dihydropyridine calcium antagonist, has slow onset but long-lasting anti-hypertensive effect in experimental animals and man, after administration it rapidly disappears from the plasma. Correlation of the plasma concentration with reduction in blood pressure has been investigated in spontaneously hypertensive rats, and concentrations in the mesenteric artery were compared with those in plasma after oral and intravenous administration of benidipine to rats.
After oral administration of benidipine to spontaneously hypertensive rats, the fall in blood pressure showed an anti-clock hysteresis phenomenon. Using concomitant analysis, plasma concentrations and anti-hypertensive activity could both be closely fitted to a one-compartment open model and the effect compartment for the pharmacological activity of benidipine could be described by a Hill equation. Concentrations in the mesenteric artery increased rapidly and then declined more slowly than in plasma. The mean residence time of benidipine in the mesenteric artery corresponded closely to the reciprocal of the rate constant for elimination of benidipine from the effect compartment.
From these results it seems that benidipine is retained longer in the plasma membrane, an effective site, because of its physicochemical properties, and thus shows a more sustained anti-hypertensive effect than would be predicted from its disposition in plasma.