bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enantioselective Structure-pharmacokinetic Relationships of Ring Substituted Warfarin Analogues in the Rat
Authors: Baars L G M , Schepers M T , Hermans J J R , Dahlmans H J J , Thijssen H H W 
Published: April 2011

Abstract
The enantiomer specific pharmacokinetics of ring substituted warfarin analogues have been studied in the rat after the administration of 2 mg kg−1 of the racemates. The stereoselective differences observed were due to stereoselective plasma protein binding and stereoselective intrinsic hepatic clearance. Greater binding was observed for the S-enantiomers except for 2′-substituted analogues where the R-enantiomers were more tightly bound. The stereoselectivity in the binding ranged up to a factor of about 4. All substituted warfarins showed a higher intrinsic clearance than warfarin. Enantiomer selectivity depended on the position of the substituent; warfarin and 3′-substituted analogues showed R &gt; S; 4′-and 2′ substituted warfarins showed S &gt; R stereoselectivity. Exceptions to this generality were seen for 4′-methoxy-and 4′-methylwarfarin which did not show stereoselective hepatic clearance.
Specific binding and clearance of [3H]dynorphin (1–13) in the perfused rat lung: an application of the multiple-indicator dilution method
Authors: Sato Hitoshi , Terasaki Tetsuya , Tsuji Akira 
Published: April 2011

Abstract
The clearance and binding of a κ-selective opioid peptide, dynorphin (1–13), in the perfused rat lung has been examined, using the multiple indicator dilution method. More than 50% of [3H]dynorphin (1–13) entering the pulmonary circulation was eliminated by the lung during a single passage of a tracer dose. By contrast, when a high dose (100 μM) of dynorphin (1–13) was concomitantly injected, [3H]dynorphin (1–13) behaved like [14C]sucrose, an extracellular marker. The kinetic analyses of the pulmonary venous outflow curves of [3H]dynorphin (1–13) and [14C]sucrose at low and high doses of dynorphin (1–13) indicated that the initial uptake rate constant, extraction ratio and distribution volume of [3H]dynorphin (1–13) decreased significantly in the presence of a high concentration of unlabelled dynorphin (1–13). These results suggest that [3H]dynorphin (1–13) is eliminated by a saturable process and binds to a specific binding site in the perfused lung, which may be the κ-type binding site. The multiple indicator dilution technique, in combination with a moment analysis, was successfully applied to demonstrate the specific binding and clearance of dynorphin (1–13) in the perfused lung.
Tissue Distribution of Amphotericin B Lipid Complex in Laboratory Animals
Authors: Olsen Steven J , Swerdel Mavis R , Blue Barbara , Clark Junius M , Bonner Daniel P 
Published: April 2011

Abstract
Amphotericin B lipid complex (ABLC), under development for the treatment of serious fungal disease, is not a true liposome but a complex of amphotericin B, dimyristoyl phosphatidylcholine and dimyristoyl phosphatidylglycerol with a particle size range of 1·6–6·0 μm. Tissue distribution of ABLC was determined in mice and rats after i.v. or i.p. administration. ABLC resembles typical liposomal preparations with amphotericin B concentrating in the reticuloendothelial system. After a single i.v. treatment with ABLC, amphotericin B was present in high concentrations in liver, lung and spleen of mice and rats while plasma levels were consistently low. Mouse liver contained 48% of the administered dose 1 h after treatment and always contained the largest amount of amphotericin B after ABLC treatment. In mice treated once daily for 7 consecutive days with 10 mg kg−1 ABLC, liver amphotericin B concentration reached 377 μg g−1. Tissue concentrations of amphotericin B were substantially lower when ABLC was given i.p. instead of i.v. with reticuloendothelial tissues containing 2- to 7-fold more after i.v. treatment. Animals treated with 10 mg kg−1 ABLC for 14 consecutive days showed no overt signs of toxicity and had only transient changes in liver and kidney function after treatment.
In-vitro Skin Pharmacokinetics of Acitretin: Percutaneous Absorption Studies in Intact and Modified Skin from Three Different Species using Different Receptor Solutions
Authors: Surber Christian , Wilhelm Klaus-P , Maibach Howard I 
Published: April 2011

Abstract
The aromatic synthetic retinoid acid derivative, acitretin, is efficacious in several cutaneous diseases. Its toxicological profile makes a topical form with no or reduced systemic adverse effects desirable. Direct application of a topical acitretin formulation might result in therapeutic skin concentrations at the site of the disease while minimizing systemic exposure. The present studies define the percutaneous absorption characteristics of acitretin from an isopropylmyristate formulation. We investigated, in-vitro, (1) the role of receptor solution variations, (2) the role of skin modifications, (3) the influence of skin from three different species on the absorption of topically applied acitretin and (4) the drug distribution within the skin. Addition of solubilizers (Polyethylenglycol-20 and albumin) to the receptor solutions improved the flux of acitretin through monkey skin, whereas the acitretin concentration in the skin was not affected by the various receptor solutions used. Acitretin flux through tape-stripped monkey skin and dermis was only slightly higher than through intact skin. Acitretin concentration in human skin was significantly higher than in rhesus monkey or guinea-pig skin. Topical application of acitretin can produce dermal concentrations in excess of those achieved by therapeutic oral doses.
Ambroxol Inhibits Na+ Absorption by Canine Airway Epithelial Cells in Culture
Authors: Tamaoki Jun , Chiyotani Atsushi , Yamauchi Fumiko , Takeuchi Satomi , Takizawa Takao 
Published: April 2011

Abstract
To study the effect of ambroxol on ion transport functions of airway mucosa, we measured bioelectric properties of canine cultured tracheal epithelium under short-circuit conditions in-vitro. Addition of ambroxol to the submucosal but not to the mucosal solution in an Ussing chamber decreased short-circuit current, transepithelial potential difference and cell conductance. The ambroxol-induced decrease in short-circuit current was not affected by bumetanide or diphenylamine-2-carboxylate, but it was abolished by pretreatment of cells with amiloride. These results suggest that ambroxol may selectively inhibit Na+ absorption by airway epithelium, thereby increasing water composition in airway surface fluid and reducing mucus viscosity.
N
G-Nitro-l-arginine methyl ester attenuates vasodilator responses to acetylcholine but enhances those to sodium nitroprusside
Authors: Ralevic Vera , Mathie Robert T , Alexander Barry , Burnstock Geoffrey 
Published: April 2011

Abstract
The effects of NG-nitro-l-arginine methyl ester (l-NAME), an inhibitor of the synthesis of the endothelium-derived relaxing factor nitric oxide, were studied in two isolated perfused vascular beds: the rat mesenteric arterial bed and the hepatic arterial bed of the rabbit liver. The tone of both preparations was raised with noradrenaline (10 and 30 μm for rabbit and rat preparations, respectively). In both preparations, L-NAME (30 μm) significantly attenuated vasodilator responses to the endothelium-dependent vasodilator acetylcholine, but enhanced responses to sodium nitroprusside (a direct smooth muscle dilator). The evidence supports the view, previously established from work carried out in isolated vessels, that in addition to acting as an inhibitor of nitric oxide, l-NAME enhances the responsiveness of smooth muscle to direct relaxation by nitrovasodilators.
Pharmacokinetics and brain entry of alaptide, a novel nootropic agent, in mice, rats and rabbits
Authors: Lapka R 
Published: April 2011

Abstract
Pharmacokinetics of a novel nootropic agent, alaptide, have been examined in plasma and brain of mice, rats and rabbits following an intravenous dose (1 mg kg−1). First-order equilibration rate constants between plasma and brain (kBO) were calculated by a two-compartment model with a linked compartment (brain). Brain alaptide equilibrates rapidly with the central compartment in mice and rats due to the high kBO/β ratio. In rabbits the equilibration is much slower (kBO/β∼ 1). Partition coefficients between brain and plasma calculated from areas under the brain and plasma concentration-time curves, are 0·479, 0·549 and 0·864, in mice, rats and rabbits, respectively.
Effect of Diltiazem and its Metabolites on the Uptake of Adenosine in Blood: an In-vitro Investigation
Authors: Yeung Pollen K F , Mosher Susan J , Macrae Dennis A , Klassen Gerald A 
Published: April 2011

Abstract
Using whole blood from man and rabbits, the effect of diltiazem, its metabolites, and other calcium antagonists on the uptake of adenosine has been described. The uptake and metabolism of adenosine was extremely rapid with a half-life in plasma of less than 30 s. Adenosine is rapidly and extensively metabolized to hypoxanthine. Metabolites of diltiazem, deacetyl diltiazem and deacetyl O-desmethyl diltiazem were considerably more potent than the parent drug. Diltiazem was one-tenth as active as verapamil, but more active than nifedipine or amlodipine. Dipyridamole was the most potent uptake-inhibitor tested (IC50 &lt; 1 μm), whereas the angiotensin converting enzyme inhibitor enalapril was virtually devoid of any inhibitory activities (IC50&gt; 1000 μm). The results obtained from both man and rabbit were similar.
Effects of a Polysaccharide Fraction from the Roots of Bupleurum falcatum L. on Experimental Gastric Ulcer Models in Rats and Mice
Authors: Sun X-B , Matsumoto T , Yamada H 
Published: April 2011

Abstract
Effects of an acidic polysaccharide fraction, BR-2, from the roots of Bupleurum falcatum L., on HCl-ethanol, ethanol and water immersion stress-induced gastric lesions in mice and pylorus-ligated ulcers in rats have been studied. Oral administration of BR-2 at doses of 50 to 200 mg kg−1 inhibited the formation of the gastric lesions induced by necrotizing agents such as HCl-ethanol and ethanol, in a dose dependent manner. This protective effect was observed after oral, intraperitoneal, and subcutaneous administration of BR-2 (25–100 mg kg−1). BR-2 also inhibited the formation of gastric ulcers which were induced by water immersion stress or pylorus-ligation. Prostaglandin E2 in gastric juice from rats and in gastric mucosa from mice was not influenced by oral administration of BR-2. The protective action of BR-2 against HCl-ethanol-induced gastric lesions was not abolished by pretreatment with indomethacin (20 mg kg−1, i.p.). The amount of alcian blue binding to mucosa also increased after administration of BR-2 (100 mg kg−1, p.o.); however, the amount of hexosamine and N-acetylneuraminic acid in mucosa did not change significantly.
A Two-compartment Dispersion Model Describes the Hepatic Outflow Profile of Diclofenac in the Presence of its Binding Protein
Authors: Evans Allan M , Hussein Ziad , Rowland Malcolm 
Published: April 2011

Abstract
The residence-time distribution (RTD) of diclofenac in the rat single-pass isolated perfused in-situ liver (n = 4) was determined after bolus input into the hepatic portal vein. Addition of human serum albumin (5 g L−1) ensured extensive (&gt;98%) binding of diclofenac within the perfusate. The one-compartment form of the axial dispersion model of hepatic elimination, which assumes instantaneous radial distribution of substrate within the accessible spaces of the liver, failed to describe adequately the RTD of diclofenac. In contrast, the two-compartment form of this model, which assumes that the radial transfer of unbound substrate between the vascular and cellular space is non-instantaneous, provided an excellent description of the diclofenac data. Moreover, the mean (±s.d.) value for the hepatic dispersion number (DN) for diclofenac (0·354 ± 0·076) compared well with that determined for simultaneously injected [125I]human serum albumin (0·456 ± 0·078) using the one-compartment dispersion model. These estimates of DN, a stochastic parameter which characterizes the axial spreading of individual elements during transit through the liver, were similar in magnitude to those reported for other tracers in the rat perfused liver. The findings suggest that common factors influenced the RTD of diclofenac and its binding protein, and indicate that the two-compartment dispersion model may be a valuable tool for interpreting hepatic impulse-response data for solutes whose hepatic distribution and elimination is influenced by membrane permeability.
Mechanism of paraquat-stimulated lipid peroxidation in mouse brain and pulmonary microsomes
Authors: Hara Shuichi , Endo Takahiko , Kurhwa Fumi , Kano Sadao 
Published: April 2011

Abstract
Paraquat-stimulated NADPH-dependent lipid peroxidation in mouse brain and pulmonary microsomes was inhibited by superoxide dismutase and singlet oxygen quenchers, but not by catalase or hydroxyl radical scavengers. MnCl2, which might form a salt with unsaturated lipid, inhibited the lipid peroxidation in brain microsomes, but not that in pulmonary microsomes. These findings suggest that activated oxygen species, especially superoxide and singlet oxygen, may play a major role in the stimulation of microsomal lipid peroxidation by paraquat in both brain and lung, and that the nature of the lipids exposed to peroxidative attack may be different in microsomes of the two organs.
Gastrointestinal absorption of quaternary ammonium compounds correlated to their binding to small intestinal brush border membrane in rat
Authors: Saitoh Hiroshi , Saitoh Nobutaka , Iseki Ken , Miyazaki Katsumi 
Published: April 2011

Abstract
The relationship between absorption of quaternary ammonium compounds (QACs) from rat intestine and their in-vitro binding to isolated brush-border membrane has been examined, using a series of n-alkyltrimethylammoniums. The binding of these QACs gradually increased with each extension of unbranched hydrocarbon chain from octyltrimethylammonium to tetradecyltrimethylammonium. However, hexyltrimethylammonium and heptyltrimethylammonium failed to bind to the membrane. On the other hand, the disappearance of these QACs from rat jejunal loop also increased with the length of hydrocarbon chain over the range of 8·9 to 71·3%. A good correlation was found between binding to the brush-border membrane and disappearance from jejunal loop. From these results, it was suggested that the size of the hydrophobic part of a QAC molecule was a principal determinant of both absorption and membrane binding, and that the absorption of QACs, with an appropriate sized hydrophobic part, was closely associated with the degree of binding to the membrane.
Effects of nifedipine on renal responses to several diuretic agents in rats
Authors: Rao V S , Fonteles M C 
Published: April 2011

Abstract
The influence of the dihydropyridine calcium antagonist nifedipine has been studied on the diuretic response to frusemide, acetazolamide and hydrochlorothiazide in water-loaded (25 mL kg−1) conscious rats. Oral administration of nifedipine (10 mg kg−1) markedly inhibited frusemide- and hydrochlorothiazide-induced diuresis as evidenced by a reduction in 5 h urine volume and urinary sodium and potassium elimination. However, it neither significantly enhanced nor limited urine and electrolyte excretion promoted by acetazolamide. Nifedipine, 5 and 10 mg kg−1 but not 1 mg kg−1, significantly (P &lt; 005) inhibited the diuretic response of hydrochlorothiazide. At doses which affect hydrochlorothiazide diuresis (5 and 10 mg kg−1), nifedipine was found to depress the mean arterial pressure by 32% in normotensive rats. These results are of interest in view of the often reported clinical side effect of nifedipine in promoting peripheral oedema in hypertensive patients and its use in combination with a thiazide or loop diuretic.
Instrumentation of a Gravity Feed Extruder and the Influence of the Composition of Binary and Ternary Mixtures on the Extrusion Forces
Authors: Baert L , Fanara D , De Baets P , Remon J P 
Published: April 2011

Abstract
A gravity feed extruder was adapted to monitor the extrusion forces, the temperature during processing and the rotational speed of the extruding cylinders. The extruder was used to evaluate the influence of particle size of insoluble material and of product solubility on the extrusion forces. Microcrystalline cellulose, dicalcium phosphate dihydrate and different lactoses were used as model compounds. Difference in lactose and microcrystalline cellulose particle size did not influence extrusion forces. The amount of water in the mixtures to be processed and the initial difference in solubility for some of the lactose types investigated influenced the extrusion forces dramatically. Extrusion forces recorded during processing of a mixture previously granulated in a high shear granulator were higher than when processed in a planetary mixture. Loss of water during high shear granulation is probably the main cause of this phenomenon.
Distribution of Protein Kinase C in the Hippocampus of the Gerbil and Rat: Autoradiographic Analysis by [3H]Phorbol 12,13-Dibutyrate
Authors: Kawagoe Jun-Ichi , Hara Hideaki , Kogure Kyuya 
Published: April 2011

Abstract
In-vitro quantitative receptor autoradiography with [3H]phorbol 12,13-dibutyrate (PDBu) was used to determine the affinity constant (Kd) and the maximum number of receptor sites (Bmax) for protein kinase C (PKC) in subregions of the gerbil hippocampus, and to compare the distribution of [3H]PDBu binding sites in the gerbil hippocampus with that in the rat hippocampus. The Kd and Bmax values in the subregions of the gerbil hippocampus were estimated at 2·6–3·8 nM and 2·38–2·54 pmol (mg tissue)−1, respectively. The distribution of hippocampus [3H]PDBu binding sites was uniform in the gerbil but not in the rat. The [3H]PDBu binding activities in the strata oriens of the CA1 and CA3 subfields and the molecular layer of the dentate gyrus in the rat hippocampus were significantly higher than in the gerbil hippocampus. However, binding activity in the stratum lacunosum-moleculare of the rat CA1 subfield was statistically lower. These data demonstrate a difference in the distribution of [3H]PDBu binding activity in the hippocampus between the gerbil and rat.
In-vivo Release of a GnRH Agonist from a Slow-release Poly(lactide-glycolide) Copolymer Preparation: Comparison in Rat, Rabbit and Guinea-Pig
Authors: Heinrich Nadja , Fechner Klaus , Berger Hartmut , Lorenz Dorothea , Albrecht Erika , Rafler Gerald , Schäfer Heinz , Mehlis Burkhard 
Published: April 2011

Abstract
Different batches of 50:50 poly((±)-lactide-glycolide) copolymer (PLG) were used as biodegradable carriers for D-Phe6-gonadotropin-releasing hormone (GnRHa) in the form of injectable long-acting implants loaded with 10% GnRHa and tracer amounts of [125I]GnRHa. After their injection subcutaneously into rats, rabbits, and guinea-pigs, the release kinetics of the peptide were determined by counting the radioactivity remaining in the implants (i) after recovery from the rats after death or (ii) directly on the skin above the injection site of rabbits and guinea-pigs in-vivo. No significant differences in the release pattern of the peptide amongst the three species whether the release process was controlled by diffusion or by degradation of the polymeric matrix were found. It is concluded that the results of in-vivo release tests using laboratory animals are valid for man and that enzymes are not involved in the degradation of the polymeric matrix. The results may be of general importance for the use of long-term release PLG formulations of highly active drugs, especially peptides and proteins.
Differential Effects of Potassium Channel Blockers on Dopamine Release from Rat Striatal Slices
Authors: Boireau Alain , Richard Fabien , Olivier Valérie , Aubeneau Michel , Miquet Jean-Marie , Dubédat Pierre , Laduron Pierre , Doble Adam , Blanchard Jean-Charles 
Published: April 2011

Abstract
The effects of different potassium channel blockers on tritiated dopamine ([3H]DA) release were investigated in rat striatal slices in the presence of pargyline and nomifensine (10 μM each). 4-Aminopyridine (4-AP; 10 and 30 μM) and 3,4-diaminopyridine (3,4-DAP; 30 μM) markedly increased the basal tritium outflow, whereas tetraethylammonium (TEA; 100–1000 μM) was without effect. The facilitating effect of 4-AP (10 μM) on spontaneous release was Ca2+- and K+-dependent. Moreover, the 4-AP-induced increase in spontaneous release was abolished in the presence of tetrodotoxin, indicating that voltage-dependent Na+ channels were involved in the release mechanism. 4-AP (10 and 30 μM) induced a dose-dependent decrease in K+-evoked [3H]DA release. This effect was confirmed with 3,4-DAP (30 μM). When striatal slices were depolarized with veratridine (5 μM), these two aminopyridines increased the evoked release of [3H]DA. TEA increased both K+- and veratridine-evoked [3H]DA release. These biochemical results are consistent with electrophysiological differences between the mechanism of action of aminopyridines and that of TEA.
The plasma kinetics of digoxin-specific Fab fragments and digoxin in the rabbit
Authors: Timsina M P , Hewick D S 
Published: April 2011

Abstract
The plasma kinetics of total and free digoxin, and digoxin-specific antibody fragments (DSFab) in rabbits which had been given [3H]digoxin one hour before DSFab has been studied over a 5 day period. Injection of DSFab caused a 4- to 5-fold rise in total digoxin and reduced elimination half-life (t½β), apparent volume of distribution at steady-state (Vdss) and systemic clearance (CL) by 40, 90 and 75% respectively. Early in the experimental period, DSFab reduced free digoxin concentration (measured by ultrafiltration) from 4·1 ng mL−1 to a minimum of 1·3 ng mL−1 at 15 min. However, the concentration had rebound to 2·5 ng mL−1 by 60 min. Subsequently, free digoxin fell to 0·63 ng mL−1 and remained relatively constant over a 7 to 90 h period. The distribution half-life, t½β, Vdss and CL for DSFab (concentrations measured by enzyme-linked immunosorbent assay) were 0·3 h, 3·2 h, 185 mL kg−1 and 57 mL kg−1 h−1, respectively. A considerable molar excess (about 5) of DSFab in the plasma was necessary to maintain minimum free digoxin concentrations. When the DSFab:digoxin molar ratio was less than 4 during the initial treatment period, free (toxicologically active) concentrations increased. With the elevation in total digoxin, however, an opposite situation appeared to apply. By 24 h the relatively short DSFab t½β meant that the plasma DSFab concentration was &lt; 0·05 μg mL−1 giving a DSFab:digoxin molar ratio of below 006, yet the antibody-induced rise in total digoxin concentration was still detectable at 100 h.
Influence of standard and nicotine-reduced cigarette smoke on plasma concentrations of isosorbide dinitrate and its metabolites in rats
Authors: Gomita Yutaka , Furuno Katsushi , Araki Yasunori 
Published: April 2011

Abstract
Rats dosed orally with isosorbide dinitrate (1 mg kg−1) were exposed to smoke from standard and nicotine-reduced cigarettes for 8 min using a smoking machine. Plasma concentrations of isosorbide dinitrate and 5-isosorbide mononitrate, one of its major metabolites were approximately equal in the exposed groups, but were lower than in the non-smoking control group. The 2-isosorbide mononitrate concentration was also lower in the group exposed to smoke from standard cigarettes. Since the pharmacokinetics were influenced by smoke from both types of cigarette smoke, the effect may be attributed in large part to non-nicotine components of the smoke.