bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of Application Volume and Area on the Absorption of Phenol Red, as a Model Drug, from the Liver Surface in Rats
Authors: Nishida Koyo , Sato Norihito , Nakakoga Yuki , Mukai Takahiro , Sasaki Hitoshi , Nakamura Junzo 
Published: April 2011

Abstract
To determine the influence of the method of administration of a pharmaceutical formulation we have examined the importance of application volume and area in the absorption of phenol red, as a model drug, from the rat-liver surface.
When 1 mg phenol red was applied to the rat-liver surface, in-vivo, in three volumes (0.1, 0.2 or 0.334 mL) using a cylindrical glass cell (i.d. 9 mm), the shape of the plasma concentration profile differed greatly, particularly the maximum concentration. These patterns were well fitted by a two-compartment model with first-order absorption, and the absorption-rate constant Ka obtained was inversely proportional to the application volume. The absorption ratio and biliary recovery of phenol red after 6 h increased with glass cell area (i.d. 6, 9 or 14 mm; area 0.28, 0.64 or 1.54 cm2). Furthermore, the permeability coefficient Papp derived from Ka did not depend on application area, indicating no difference in the absorption characteristics of the liver surface. This also implies transport of the drug by passive diffusion from the liver surface. After intraperitoneal administration to the rat-liver surface for clinical application, increasing the application volume resulted in the delayed disappearance of phenol red from the plasma. However, the difference was not as marked as that obtained by use of the glass cell. The assumption that the effective area relating to the absorption changed with the application volume enabled us to estimate Papp. Consequently, we speculate that absorbability can be estimated precisely by consideration of application volume and area.
Nitric Oxide Modulates the Acute Increase of Gastrointestinal Transit Induced by Endotoxin in Rats: a Possible Role for Tachykinins
Authors: Martínez-Cuesta M A , Barrachina M D , Beltrán B , Calatayud S , Esplugues J 
Published: April 2011

Abstract
Because of the evidence that endogenous nitric oxide (NO) plays an essential role in the physiological regulation of gastrointestinal motility we have investigated, by use of the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), the role of endogenous NO in the acute endotoxin-induced changes of gastrointestinal transit.
Pre-treatment with E. coli endotoxin (100 μg kg−, i.v.) induced a significant increase in the gastrointestinal transit of a charcoal suspension in anaesthetized rats. Previous administration of the NO synthase inhibitor, l-NAME (10 mg kg−, i.v.) significantly prevented the effects of endotoxin. l-arginine (200 mg kg−, i.v.) and the substance P antagonist [d-Pro2, d-Trp7,9]-substance P (SPA), significantly reversed the effects of l-NAME on gastrointestinal transit in rats treated with endotoxin. Pre-treatment with dexamethasone (5 mg kg−, s.c., twice), an inhibitor of the expression of inducible NO synthase, did not affect the increase in the gastrointestinal transit through constitutive NO synthesis.
The results suggest that constitutive nitric oxide is involved in the increase of gastrointestinal transit induced by endotoxin and that the reduction in transit induced by l-NAME in endotoxin-treated rats is mediated by endogenous tachykinins.
Impulse-response Studies on Tracer Doses of [14C]Lignocaine and its Multiple Metabolites in the Perfused Rat Liver
Authors: Mellick George D , Roberts Michael S 
Published: April 2011

Abstract
The outflow-concentration-time profiles for lignocaine (lidocaine) and its metabolites have been measured after bolus impulse administration of [14C]lignocaine into the perfused rat liver.
Livers from female Sprague-Dawley rats were perfused in a once-through fashion with red-blood-cell-free Krebs-Henseleit buffer containing 0 or 2% bovine serum albumin. Perfusate flow rates of 20 and 30 mL min− were used and both normal and retrograde flow directions were employed. Significant amounts of metabolite were detected in the effluent perfusate soon after lignocaine injection. The early appearance of metabolite contributed to bimodal outflow profiles observed for total 14C radioactivity. The lignocaine outflow profiles were well characterized by the two-compartment dispersion model, with efflux rate «influx rate. The profiles for lignocaine metabolites were also characterized in terms of a simplified two-compartment dispersion model. Lignocaine was found to be extensively metabolized under the experimental conditions with the hepatic availability ranging between 0.09 and 0.18. Generally lignocaine and metabolite availability showed no significant change with alterations in perfusate flow rate from 20 to 30 mL min− or protein content from 0 to 2%. A significant increase in lignocaine availability occurred when 1200 μm unlabelled lignocaine was added to the perfusate. Solute mean transit times generally decreased with increasing flow rate and with increasing perfusate protein content.
The results confirm that lignocaine pharmacokinetics in the liver closely follow the predictions of the well-stirred model. The increase in lignocaine availability when 1200 μm unlabelled lignocaine was added to the perfusate is consistent with saturation of the hydroxylation metabolic pathways of lignocaine metabolism.
Synthesis of Several Substituted Phenylpiperazines Behaving as Mixed D2/5HT1A Ligands
Authors: Dukić Sladjana , Kostić-Rajačić Sladjana , Dragović Deana , Šoškić Vukic , Joksimović Jelena 
Published: April 2011

Abstract
Twenty-two different compounds have been synthesized with the aim of creating new, mixed D2/5HT1A ligands. For this purpose 1-substituted phenylpiperazines attached by the N-4 nitrogen to dopaminergic pharmacophores of the 2-(5-benzimidazole)ethyl-, 2-(5-benztriazole)ethyl-, 2-[5-(benzimidazole-2-thione)]ethyl- and 2-[6-(1,4-dihydroquinoxaline-2,3-dione)]ethyl-type were selected according to known structure-affinity requirements of 1-arylpiperazines.
All the new compounds were evaluated for in-vitro binding affinity at the dopamine (D1 and D2) and 5-HT1A receptors. Synaptosomal membranes prepared from fresh bovine caudate nuclei and hippocampi were used as a source of dopamine and 5-hydroxytryptamine receptors, respectively. [3H]SCH 23390 (D1 selective), [3H]spiperone (D2 selective) and 8-OH-[3H]DPAT (5-HT1A selective) were employed as the radio-ligands. None of the compounds expressed affinity for binding at D1 dopamine receptors. Compounds 3b and 4b were inactive 8-OH-[3H]DPAT competitors whereas 1b, 2b and 4b were inactive in the [3H]spiperone-binding assay. The other compounds tested showed fair (1c, 1e, 1f, 2c, 2f, 3b, 3c and 4c) to high (1a, 1d, 2a, 1d, 3a, 3d–3f, 4a, and 4d) affinity in the [3H]spiperone-binding assay, the most potent representative being 4-[2-(5-benzimidazole-2-thione)ethyl]-1-(2-methoxyphenyl)piperazine, 3a (Ki = 1.7 nm). In the 8-OH-[3H]DPAT-displacement assay compounds 1b, 1d, 1f, 2b, 2f and 3f behaved as moderate competitors and 1a, 1c, 1e, 2a, 2c, 2d, 3a, 3c–3e, 4a, 4c, 4d and 4f as rather strong competitors; 4-[2-(5-benztriazole)ethyl]-1-(2-methoxyphenyl)piperazine, 2a had the highest binding affinity at the 5-HT1A receptors (Ki = 2.6 nm).
Because many antipsychotic and anxiolytic agents behave as mixed dopaminergic and serotonergic ligands, the high affinity of several of these new ligands for binding at both D2 and 5-HT1A receptors make them promising candidates deserving further pharmacological evaluation as antipsychotic or anxiolytic pharmaceuticals.
Pharmacokinetic and Pharmacodynamic Response after Intranasal Administration of Diazepam to Rabbits
Authors: Bechgaard Erik , Gizurarson Sveinbjörn , Hjortkjær Rolf K 
Published: April 2011

Abstract
Nasal application of drugs might be an alternative to intravenous administration in acute situations such as epileptic or fever seizures. In the search for a nasal formulation leading to a peak plasma concentration of diazepam at a tmax ≤5 min bioavailability in rabbits has been studied after intranasal administration of the drug in ten vehicles of different polarity.
The animals were dosed with 3 mg diazepam, dissolved in 100 μL vehicle, the solution being administered into both nostrils. The bioavailability, measured during the first 30 min, because periods after this are not relevant for acute treatment, was found to be between 49 and 62% for the four most promising vehicles, pure glycofurol 75, tetraethyleneglycol, poly(ethylene glycol) 200 and 30% glycofurol in tetraethyleneglycol. The tmax for these vehicles was achieved after 5 min, and they induced a very rapid pharmacodynamic response after 1.5 to 3.5 min. The bioavailability was reduced when more polar liquids such as ethanol and tween 20, or lipid oils, e.g. vegetable oil and miglyol 840 were added to the glycofurol. There was a good correlation between tmax and the induction of pharmacodynamic response.
These results suggest that nasal application of diazepam in a water-free low-molecular-weight glycol might be of clinical importance as an alternative to intravenous injection, especially in acute situations.
Detection of Carbamazepine-induced Changes in Valproic Acid Relative Clearance in Man by Simple Pharmacokinetic Screening
Authors: Yukawa Eiji , Honda Tomoo , Ohdo Shigehiro , Higuchi Shun , Aoyama Toshinobu 
Published: April 2011

Abstract
Selecting the optimum dose of valproic acid is difficult because the pharmacokinetics are complicated by inter-patient variability and by effects arising as a result of co-administration with other antiepileptic drugs. The multiple peak approach has been used to evaluate the effect of age, total body weight, dose, gender and co-medication (carbamazepine-induced change) on population estimates of valproic acid relative clearance.
Routine clinical pharmacokinetic data (n = 479) were collected from 207 epilepsy patients on combination therapy. The data were analysed by a simple steady-state pharmacokinetic model with the use of NONMEM, a computer program designed for population pharmacokinetic analysis that enables pooling of data. NONMEM estimates suggested that the rate of valproic acid clearance in patients receiving concomitant administration of valproic acid and carbamazepine decreased non-linearly with increasing total body weight in the maturation process, and increased non-linearly with increasing valproic acid dose. The clearance in females was 5.7% less than in males. NONMEM estimates also suggested that the rate of valproic acid clearance increased non-linearly with increasing carbamazepine dose. Concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs resulted in an increase in valproic acid clearance of 10%. The final regression model of valproic acid relative clearance was CL = 606TBW0.168 ×DOSE0.414 × CBZDOSE0.095 × 0.943GEN × 1.10CO, where CL is the clearance (mL kg− h−), TBW is the total body weight (kg), DOSE is the dose of valproic acid, CBZDOSE is the dose of carbamazepine, GEN = 0 for males and 1 for females and CO = 0 for concomitant administration of valproic acid and carbamazepine and 1 for concomitant administration of valproic acid and carbamazepine with other antiepileptic drugs.
This technique can be used to estimate the pharmacokinetic parameters of a population from sparse data collected during routine clinical care and to determine the extent to which patient characteristics influence drug pharmacokinetics.
Prediction of Changes in the Clinical Pharmacokinetics of Basic Drugs on the Basis of Octanol-Water Partition Coefficients
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Ichimura Fujio 
Published: April 2011

Abstract
A physiologically based pharmacokinetic model for basic drugs has been established on the basis of octanol-water partition coefficients of the non-ionized, unbound drugs (Poct).
The parameters for the physiological model in man were estimated from a regression equation obtained for the relationships between the Poct and the tissue-plasma partition coefficient, the hepatic intrinsic clearance (CLint,h) and the blood-to-plasma concentration ratio in rabbits. The plasma concentrations observed after intravenous administration of ten basic drugs (3.2 mg kg−) to rabbits agreed with the levels predicted using the physiological model (r = 0.710–0.980). In man, the predicted plasma concentrations of basic drugs were in good agreement with reported values (r = 0.729–0.973), except for diazepam and pentazocine. Variations in plasma and brain-concentration profiles of clomipramine and nitrazepam in various disease states were simulated using the model. We assumed that the changes in unbound fraction of drug in serum (fp), CLint,h and the hepatic blood flow rate were from 0.25- to 4-fold that of the control and that fat volume changed by 0.2- to 5-fold. With regard to changes in fp, we predicted that the brain-plasma concentration ratio of clomipramine was 1.5- to 25-fold that of the control 24 h after intravenous administration, although the variations in the plasma concentration-time profiles were less marked.
Plasma concentrations predicted for several basic drugs were in good agreement with reported values and this physiological model could be useful for predicting drug-disposition kinetics in man.
Relationships between the Hepatic Intrinsic Clearance or Blood Cell-Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs
Authors: Ishizaki Junko , Yokogawa Koichi , Nakashima Emi , Ichimura Fujio 
Published: April 2011

Abstract
The relationships between drug lipophilicity and hepatic intrinsic clearance (CLint,h) or red blood cell-plasma partition coefficients (D) have been elucidated for ten highly lipophilic basic drugs with apparent octanol-water partition coefficients at pH 7.4 (Papp, oct) of 150 or above.
The true octanol-water partition coefficients of the non-ionized drugs (Poct) were used to determine CLint,h and D for the unbound drugs (CLint,h,f and Df, respectively), and CLint,h,f and Df for the non-ionized and unbound drugs (CLint,h,fu and Dfu, respectively). The total clearance values were determined at steady state by infusion studies of individual drugs in rabbits. There was better correlation between log Poct, and log CLint,h,fu (r = 0.974) than between log Poct, and log CLint,h,f (r = 0.864). The D values were calculated from the blood-plasma concentration ratio. There was a better correlation between log Poct and log Dfu (r = 0.944) than between log Poct, and log Df (r = 0.612). The regression equations obtained were CLint,h,fu = 0.0875 × Poct1.338 and Dfu = 0.0108 × Poct0.970, respectively.
These results show that the CLint,h and D of highly lipophilic basic drugs can be predicted from Poct by taking fu into consideration. By applying these parameters to a physiologically based pharmacokinetic model it might be possible to predict the pharmacokinetics of unknown basic drugs.
In-vivo Microdialysis Study of the Distribution of Cisplatin into Brain Tumour Tissue after Intracarotid Infusion in Rats With 9L Malignant Glioma
Authors: Nakashima Mikiro , Shibata Shobu , Tokunaga Yoshiharu , Fujita Hideshi , Anda Takeo , Arizono Koji , Tomiyama Naoki , Sasaki Hitoshi , Ichikawa Masataka 
Published: April 2011

Abstract
Simultaneous brain microdialysis in tumour and non-tumour tissues has been used for kinetic determination of the local distribution of an anticancer agent, cisplatin, in rats.
Rat brain was implanted with 9L malignant glioma and cisplatin (3.5 mg kg−) was administered as a selective intracarotid infusion for 30 min to rats prepared for brain microdialysis. The amount of platinum in the dialysate collected from tumour and non-tumour brain tissues was determined by atomic absorption spectrophotometry, as representative of cisplatin. Total and free platinum concentrations in plasma were also measured. Free platinum is accumulated preferentially in the tumour tissue and the brain tumour distribution coefficient (the ratio of brain tumour platinum AUC to plasma free platinum AUC, where AUC is the area under the platinum concentration-time curve) was 0.69, although there was little distribution into normal brain tissue. Drug binding to plasma proteins was 65%.
It is concluded that simultaneous microdialysis is an easy and available method for assessing in-vivo local pharmacokinetics and distribution of cisplatin in tumour and non-tumour tissues of the brain.
Application of an Allosteric Ternary Complex Model to the Technique of Pharmacological Resultant Analysis
Authors: Christopoulos Arthur , Mitchelson Fred 
Published: April 2011

Abstract
A simple ternary complex model of drug-receptor interaction has been used to extend the procedure of pharmacological resultant analysis, enabling the quantitation of interactions between allosteric modulators and orthosteric antagonists.
Equations derived in the theoretical treatment were used to analyse functional data for the interaction between the allosteric modulator gallamine and the orthosteric antagonist scopolamine, with oxotremorine as the agonist, at rat tracheal muscarinic acetylcholine receptors. Quantitative estimates of the affinity of gallamine for the allosteric site (pKZ = 4.7) and the extent of negative, heterotropic co-operativity between gallamine and scopolamine (α′ = 13.1) were obtained. Furthermore, an alternative direct, model-fitting approach, that does not rely on the determination of concentration ratios, was also developed, and yielded similar results.
It is suggested that the approach presented in this paper is useful for quantifying interactions between orthosteric antagonists and allosteric modulators, particularly when the extent of co-operativity is low or the modulators possess multiple pharmacological properties, or both.
Degradation Pathways of Ampicillin in Alkaline Solutions
Authors: Robinson-Fuentes V A , Jefferies T M , Branch S K 
Published: April 2011

Abstract
Ampicillin trihydrate, sodium salt, in aqueous solution has a pH of about 8. No complete degradation pathway has been proposed to explain the degradation of ampicillin under alkaline conditions and the information available explains the formation of only certain products. The present work was carried out with the aim of providing this information.
The formation of degradation products of ampicillin trihydrate, sodium salt, produced in aqueous solutions (pH 12 and 37°C) have been studied as an accelerated form of the possible degradation that may occur in aqueous solutions at pH 8. Some of the degradation products formed under these conditions were then obtained either by synthesis or by degradation of ampicillin sodium followed by isolation using semi-preparative HPLC. These compounds were characterized by 1H NMR spectroscopy.
The information obtained from the experiments by HPLC and NMR spectroscopy made it possible to propose a degradation pathway for ampicillin under the conditions described above. 5R-penicilloic acid is the first degradation product of ampicillin and subsequently undergoes epimerization at C-5 to form the 55 isomer via the imine tautomer. Mechanisms for the formation of compounds previously believed to form only under acidic conditions are proposed, i.e. ampicillin penilloic acid and 2-hydroxy-3-phenylpyrazine. The formation of ampicillin polymers was detected in dilute solutions (1% w/v) within a few hours of dissolution. The presence of ampicillin penicillenic acid and ampicillin penamaldic acid was detected by 1H NMR and their main spectroscopic features determined.
Effects of Thyrotrophin-releasing Hormone Tartrate and its Sustained Release Formulation on Cerebral Glucose Metabolism in Aged Rats
Authors: Nakayama Takahiro , Nagai Yasuo 
Published: April 2011

Abstract
The effects of a sustained release formulation of thyrotrophin-releasing hormone (TRH) over two weeks (TRH-SR, 10 or 50 mg kg− equivalent to 0.56 or 2.80 mg kg− free TRH, respectively) and repeated treatment with TRH tartrate (TRH-T, 0.3, 1.0 or 3.0 mg kg−, equivalent to 0.2, 0.7 or 2.0 mg kg− free TRH, respectively) on the rate of local cerebral glucose utilization (LCGU) were investigated using the quantitative autoradiographic 2-deoxy-[14C]d-glucose method in various brain regions of aged rats.
In aged rats (28 months old), the LCGU was significantly reduced as compared with young adult rats (3 months old), while treatment with TRH-SR ameliorated the reduction of the LCGU in a dose-dependent manner. The brain regions ameliorated by TRH-SR were the auditory cortex, septal nucleus, substantia nigra, cerebellar cortex and cerebellar nucleus. In contrast, once-daily repeated treatment over one week with TRH-T at a dose of 0.3 mg kg− (equivalent to 50 mg kg− of TRH-SR) had no effect on the reduced LCGU in various brain regions in aged rats (27 months old), whereas treatment with a higher dose of TRH-T (0.7 or 2.0 mg kg− free TRH) significantly ameliorated the reduction.
The comparison of the ameliorating potencies between TRH-T and TRH-SR indicated that TRH-SR had a potency about 7 times greater than TRH-T.
Nitric Oxide is a Regulator of Bone Remodelling
Authors: Chae Han-Jung , Park Rae-Kil , Chung Hun-Taeg , Kang Jang-Sook , Kim Myung-Sun , Choi Du-Young , Bang Byung-Gwan , Kim Hyung-Ryong 
Published: April 2011

Abstract
Nitric oxide (NO) is known to be implicated in the metabolism of bone, especially as a mediator of cytokine effects on the remodelling of bone tissue. In this study we examine whether NO affects the osteoblast activation or the osteoclast differentiation of primary mouse osteoblast-like and osteosarcoma ROS 17/2.8 cell lines.
Primary osteoblast and ROS 17/2.8 cells released NO upon stimulation of interleukin-1β, tumour necrosis factor-α, and interferon-γ. Sodium nitroprusside, a donor of nitric oxide, increased the activity of alkaline phosphatase in ROS 17/2.8 cells as well as the number of calcified nodule formations in primary mouse osteoblast-like cells. Sodium nitroprusside also completely inhibited 1α,25-(OH)2D3-induced osteoclast generation in a high concentration (100 μm). However, a low concentration of sodium nitroprusside (3–30 μm) significantly increased the generation of osteoclasts.
These results indicated that NO appears to be an important regulatory molecule in the processes of bone formation and resorption. Hence, NO may be involved in the pathogenesis of bone loss in diseases associated with cytokine activation, such as periodontal disease and rheumatoid arthritis.
Evidence for α2-Adrenoceptor Agonist Activity of Minoxidil
Authors: Sharma Nitin , Mehta Anita A , Santani Dev D , Goyal Ramesh K 
Published: April 2011

Abstract
The present investigation was undertaken to study the mechanism of action of minoxidil using various smooth muscle preparations.
Minoxidil (4.7 × 10−6 m to 4.7 × 10−4 m) produced a concentration-dependent inhibition of field stimulation-evoked responses in rat anococcygeus muscle and vas deferens. The inhibition produced by minoxidil was antagonized by yohimbine (2.5 × 10−7 m). Minoxidil (1.4 × 10−5 m to 4.7 × 10−4 m) also produced a concentration-dependent relaxation in oestrogen-primed potassium chloride-depolarized rat uterus. These responses were blocked not only by yohimbine but also by glibenclamide (202 × 10−8 m).
Our results suggest that minoxidil possesses α2-adrenoceptor agonist activity in addition to potassium-channel-opening activity.