bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Effect of Oren-gedoku-to on Experimental Colitis in Rats
Authors: Zhou Haiyan , Mineshita Satoru 
Published: October 2002

Abstract
In Japan and China, Oren-gedoku-to (a complex mixture of ingredients derived from plants) has been used as a herbal medicine in the treatment of inflammatory and ulcerative diseases. In other countries salicylazosulfapyridine has been used to treat inflammatory bowel disease. In this study, we have compared the effect of Oren-gedoku-to with salicylazosulfapyridine on trinitrobenzene-sulphonic acid-induced colonic damage in rats, a model representative of ulcerative colitis and Crohn's disease in man.
Oren-gedoku-to was administered orally for one or two weeks over a range of doses. Tissue damage scores, body weight, spleen weight, colon wet weight and colon wall thickness were measured, and colonic tissue levels of interleukin-8 (IL-8), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and myeloperoxidase activity were examined.
The results indicated that Oren-gedoku-to was effective in the treatment of inflammatory bowel disease in the rat model. Histological observation showed a quicker healing process of the lesions, and a reduction of inflammatory cell infiltration following administration of Oren-gedoku-to.
The precise mechanism of action for Oren-gedoku-to is still unclear; however, the reduction of IL-8, LTB4, and PGE2 observed suggests that the mechanism may be different from salicylazosulfapyridine (which has no effect on IL-8). There may be a potential benefit in offering combination therapy for the treatment of inflammatory bowel disease.
Effects of Sho-saiko-to Extract on Liver Fibrosis in Relation to the Changes in Hydroxyproline and Retinoid Levels of the Liver in Rats
Authors: Ono Masahide , Miyamura Mitsuhiko , Kyotani Shojiro , Saibara Toshiji , Ohnishi Saburo , Nishioka Yutaka 
Published: October 2002

Abstract
To examine the effects of Sho-saiko-to extract on liver fibrosis, the drug was administered to rats with dimethylnitrosamine-induced liver-injury at various doses. Hydroxyproline and retinoid levels in the liver were measured as indicators of liver function.
In liver-injured rats, the hydroxyproline level in the liver (957 ± 154nmol g−1) was about 4.16-times that found in normal liver (230 ± 11 nmol g−1), but administration of Sho-saiko-to extract (0.75%, 1.5% or 3%) reduced the hydroxyproline level significantly (554 ± 58, 356 ± 51, 374 ± 66 nmol g−1, P &lt; 0.01). Single administration of the active constituents of Sho-saiko-to extract, glycyrrhizin, baicalin or baicalein, decreased the hydroxyproline level significantly compared with the ordinary food group (P &lt; 0.05), but the decrease was smaller compared with the Sho-saiko-to extract group. The liver retinoid level was higher in the Sho-saiko-to extract group than the ordinary food group and the value increased dose-dependently. A significant negative correlation, r = −814 (P &lt; 0.001) was detected between the hydroxyproline level and retinoid level in the liver of liver-injured rats. Significant negative correlations, r = 0.728 (P &lt; 0.001) and r = −0.873 (P &lt; 0.001), were also detected between the liver hydroxyproline level and the liver concentrations of the active constituents (glycyrretic acid, baicalin and baicalein) in the liver-injured rats.
From these findings, it was considered that the liver concentrations of hydroxyproline and retinoid as well as the active constituents were involved in the improvement of liver fibrosis in the liver-injured rats administered Sho-saiko-to extract. Administration of Sho-saiko-to extract inhibited collagen production while an increase in retinoid level inhibited activation of Ito cells leading to inhibition and prevention of liver fibrosis.
The Maximum Pharmacodynamic Effect as a Response Parameter: Pharmacokinetic Considerations
Authors: Leopold Claudia S 
Published: October 2002

Abstract
In previous human in-vivo studies measuring the maximum pharmacodynamic response to characterize cutaneously applied ointment preparations, it was observed that differences between various formulations caused by penetration enhancement led to different enhancement factors depending on the method used for determination of these factors from activity-reponse curves. To clarify this discrepancy, pharmacokinetic simulations have been performed based on an open one-compartment model with either first- or zero-order drug penetration kinetics and first-order elimination kinetics.
Under the assumption that the maximum pharmacodynamic response corresponds to the maximum effective drug concentration in the receptor compartment, which represents the difference between the maximum drug concentration and the threshold concentration, drug concentration vs time profiles and dose-reponse curves were simulated. In addition, maximum effective concentrations were calculated and plotted against the logarithm of the thermodynamic drug activity to obtain activity-reponse curves. Relative bioavailability and enhancement factors were determined either from the horizontal distance between the curves of a standard and a test preparation, or as the ratio of the maximum effective concentration of test and standard formulations.
A significant difference between the first-order and the zero-order input kinetics with regard to the evaluation of bioavailability and drug penetration enhancement was shown. Under finite dose conditions, i.e. first-order input kinetics from solution-type preparations, a misestimation of the factors usually occurs. Only under infinite dose conditions, i.e. if large preparation volumes are applied to achieve zero-order input kinetics, is the determination of bioavailability and enhancement factors from dose- and activity-reponse curves accurate.
Age-related Alteration of Carbamazepine-serum Protein Binding in Man
Authors: Koyama Hikaru , Sugioka Nobuyuki , Uno Akira , Mori Satoru , Nakajima Kenji 
Published: October 2002

Abstract
To determine whether biological maturation influences the kinetics of carbamazepineserum protein binding, the carbamazepine free fraction (%) was investigated in the serum of 66 patients, ranging from 4 to 83 years, with epilepsy or trigeminal neuralgia, treated with carbamazepine alone or carbamazepine in combination with phenytoin, phenobarbital, and/or valproic acid, over a relatively long period.
Biochemical parameters such as levels of albumin and non-glycated albumin showed a significant relationship with carbamazepine free fraction (r=-0.521, P &lt; 0.001 for albumin; r=-0.700, P &lt; 0.001 for non-glycated albumin). Non-glycated albumin was more strongly correlated with carbamazepine free fraction. The biochemical parameters showed a significant relationship with age (r=-0.243, P &lt; 0.1 for albumin; r= 0.666, P &lt; 0.001 for glycated albumin; r=-0.459, P &lt; 0.001 for non-glycated albumin; r= 0.640, P &lt; 0.001 for carbamazepine free fraction). Glycated albumin (%), non-glycated albumin and carbamazepine free fraction (%) were strongly correlated with age, whereas albumin showed only a weak correlation with age. To evaluate the effects of ageing on carbamazepine-serum protein binding, the patients were divided into three groups according to age: children, 4–15 years; adults, 16–64 years; elderly, 65–83 years. Albumin and non-glycated albumin were much lower, and glycated albumin (%) and carbamazepine free fraction (%) much higher in the elderly group than in the other two groups.
The results of this study showed that the major ligand of carbamazepine in the serum was non-glycated albumin, which decreased with age. These observations suggested that in elderly patients, the elevation of free carbamazepine concentrations in the serum caused by reduced non-glycated albumin levels, induces increases in the sensitivity of the pharmacological effects of carbamazepine and the risk of drug interactions.
An In-vitro Study on the Metabolism of Rokitamycin and Possible Interactions of the Drug with Rat Liver Microsomes
Authors: Zhao Xue-Jun , Ishizaki Takashi 
Published: October 2002

Abstract
This in-vitro study was designed to identify the enzyme(s) involved in the major metabolic pathway of rokitamycin, i.e. the formation of leucomycin A7, and to assess possible interactions of the drug with rat liver microsomes.
Formation of leucomycin A7 was NADPH-independent and was not appreciably inhibited by anti-rat NADPH cytochrome P-450 reductase serum or cimetidine, a nonspecific inhibitor of cytochrome P-450 isoforms. Eadie-Hofstee plots for the formation of leucomycin A7 were indicative of apparently monophasic behaviour for six rat liver microsomes tested. The mean (± s.d.) kinetic parameters, Km, Vmax and Vmax/Km, for the formation of leucomycin A7 from rokitamycin were 47 ± 13 μm, 390 ± 56 nmol min−1 (mg protein)−1 and 8.6 ± 1.6 mL min−1 (mg protein)−1, respectively. Three esterase inhibitors (100 μM), bis-nitrophenylphosphate, physostigmine and metrifonate inhibited the formation of leucomycin A7 by more than 60%. Metabolism of rokitamycin was inhibited by terfenadine, but not by mequitazine, whereas chlorpheniramine and theophylline activated the formation of leucomycin A7. Rokitamycin, leucomycin A7, leucomycin V, erythromycin and clarithromycin were weak inhibitors of CYP3A-catalysed 3-hydroxylation of quinine with mean IC50 values ranging from 71 to &gt; 100 μM.
It is concluded that in rat liver microsomes the formation of leucomycin A7 from rokitamycin is catalysed mainly by an esterase (possibly cholinesterase, EC3.1.1.8), but not by cytochrome P-450 enzyme(s). Although in this in-vitro animal study CYP3A activity was barely inhibited by rokitamycin, the possibility cannot be totally discounted in man when rokitamycin is co-administered with drugs metabolized by CYP3A.
Differences between the Vasorelaxant Activity of Adenosine-receptor Agonists on Guinea-pig Isolated Aorta Precontracted with Noradrenaline or Phenylephrine
Authors: Ford William R , Maddock Helen L , Buckingham Robin E , Broadley Kenneth J 
Published: October 2002

Abstract
The relaxant effect of adenosine and 5′-(N-ethylcarboxamido)adenosine (NECA) against α-adrenoceptor-mediated contractile tone in guinea-pig isolated aortic rings has been examined to determine if this A2B-receptor-mediated relaxation was dependent upon the contracting agent, and whether the contractions were dependent upon intracellular or extracellular calcium.
Relaxation responses were consistently greater for aortic rings pre-contracted with phenylephrine (3 times 10−6M) than for rings pre-contracted with noradrenaline (3 times 10−6M). Maximum inhibition by NECA was significantly greater for phenylephrine-contracted aortae than for noradrenaline-contracted (81.9 ± 2.8% compared with 25.0 ± 1.5%). These differences persisted in the presence of β- and α2-adrenoceptor blockade and could not, therefore, be attributed to stimulation of these receptors by noradrenaline. The ratio of the contractions obtained before and in the presence of adenosine or NECA was compared with the control ratio obtained before and after vehicle. Experiments were performed both in the presence of normal calcium levels and under calcium-free conditions. In normal-calcium medium, NECA inhibited phenylephrine-induced contractions (test ratio, 76.7 ± 3.9%; control ratio, 133.1 ± 9.8%) to a greater extent than noradrenaline-induced contractions (108.4 ± 4.1 and 123.4 ± 4.9%); adenosine similarly inhibited phenylephrine-induced contractions more than those induced by noradrenaline. Under calcium-free conditions, adenosine (36.7 ± 11.9 and 110.7 ± 26.6%) and NECA (55.2 ± 9.1 and 87.1 ± 14.9%) were only effective against phenylephrine-induced contractions. This suggests that activation of the A2B-receptor by these agonists inhibited intracellular mobilization of calcium for phenylephrine-induced contractions only. The effects on extracellular calcium influx were examined for phenylephrine- and noradrenaline-induced contractions in normal-calcium medium but in the presence of ryanodine to prevent intracellular calcium mobilization. NECA inhibited phenylephrine-induced contractions (77.3 ± 12.4 and 111.4 ± 9.3%), presumably by interfering with influx of calcium through receptor-operated calcium channels. In contrast, NECA failed to reduce noradrenaline-induced contractions (121.5 ± 10.7 and 122.4 ± 11.6%), suggesting that the effect on noradrenaline is predominantly via interaction with intracellular calcium. Adenosine was consistently a more effective relaxant than NECA, possibly because of an additional intracellular component of the response.
We conclude that adenosine receptor agonists inhibit phenylephrine-induced contractions of guinea-pig aorta more selectively than noradrenaline-induced contractions. A2B-receptor stimulation might reveal a fundamental difference between the modes of contraction elicited by these two α-adrenoceptor agonists.
Himehabu Lectin, a Novel Inducer of Ca2+-release from the Venom of the Snake Trimeresurus okinavensis, in Sarcoplasmic Reticulum
Authors: Hirata Yutaka , Ito Masaaki , Nikai Toshiaki , Kato Saori , Komori Yumiko , Sugiura Hisayoshi , Ohizumi Yasushi 
Published: October 2002

Abstract
The lectin himehabu lectin (HHL) has recently been isolated from crude venom of the snake Trimeresurus okinavensis.
Ca2+-electrode and fluorescent Ca2+-indicator experiments showed that HHL induced release of Ca2+ from the heavy fraction of skeletal muscle sarcoplasmic reticulum (HSR). The release of Ca2+ induced by caffeine from HSR was abolished by ryanodine, Mg2+ and ruthenium red, typical inhibitors of Ca2+-release channels, whereas that induced by HHL was only partially reduced by these inhibitors. HHL, unlike caffeine, had no effect on [3H]ryanodine binding to HSR.
These results suggest that HHL induces release of Ca2+ which is at least partially mediated through Ca2+-release channels with novel pharmacological properties.
Validation of a Pharmacokinetic Model of Colon-specific Drug Delivery and the Therapeutic Effects of Chitosan Capsules Containing 5-Aminosalicylic Acid on 2,4,6-Trinitrobenzenesulphonic Acid-induced Colitis in Rats
Authors: Tozaki Hideyuki , Fujita Takuya , Odoriba Tomokazu , Terabe Akira , Okabe Susumu , Muranishi Shozo , Yamamoto Akira 
Published: October 2002

Abstract
A pharmacokinetic model of colon-specific drug delivery developed in a previous study has been validated by use of 5-aminosalicylic acid (5-ASA) as a model anti-inflammatory drug.
The simulation curves obtained from the pharmacokinetic model were in good agreement with experimental data obtained after oral administration of 5-ASA-containing chitosan capsules. The concentrations of 5-ASA in the large intestinal mucosa after drug administration were higher than after administration of the drug in carmellose suspension. We then attempted colon-specific delivery of an anti-ulcerative colitis drug, in chitosan capsules, to accelerate healing of 2,4,6-trinitrobenzenesulphonic acid sodium salt (TNBS)-induced colitis in rats. To confirm this therapeutic model, salazosulphapyridine (SASP), a commercially available 5-ASA prodrug, was used as positive control. Colonic injury and inflammation were assessed by measuring myeloperoxidase activity and visual assessment (damage score), respectively. Because SASP is effective against TNBS-induced colitis in rats, use of the SASP-sensitive TNBS-induced colitis model validated the therapeutic effects of 5-ASA-containing chitosan capsules, which were signiicantly better than those of a suspension of the drug in carmellose.
These findings suggest that our pharmacokinetic model of colon-specific drug delivery can accurately evaluate this colon-specific delivery system and that 5-ASA-containing chitosan capsules are more effective than other 5-ASA formulations for treatment of TNBS-induced colitis in rats.
Enterohepatic Circulation Model for Population Pharmacokinetic Analysis
Authors: Funaki Tomoo 
Published: October 2002

Abstract
An enterohepatic circulation model based on physiological aspects of biliary excretion has been developed for population pharmacokinetic analysis. Mycophenolate mofetil was selected as a model drug for validation of the model. As a secondary objective, the model was used for pharmacokinetic comparison among different races.
The post-hoc plasma concentration-time course was well described by the newly developed enterohepatic model and a secondary peak arising from enterohepatic circulation was also well defined. The covariates predicted by the model agreed well with literature results.
The model is useful for evaluation of the covariates of an enterohepatically circulated drug. The population pharmacokinetic approach is of benefit for evaluating racial differences for a pharmacokinetic bridging package.
Application of a Loading Wash-out Method for Investigating the Hepatocellular Efflux of a Hepatically-generated Metabolite, Morphine-3-glucuronide
Authors: Evans Allan M , O'Brien Josephine , Nation Roger L 
Published: October 2002

Abstract
Previous studies using the rat isolated perfused liver demonstrated that the hepatic disposition of morphine-3-glucuronide is membrane permeability-rate limited, and that the movement of the metabolite across hepatic sinusoidal and canalicular membranes is partly via carrier-mediated transport systems. As a consequence of the membrane permeability-limitation, the biliary excretion of hepatically-generated morphine-3-glucuronide is much more efficient than that of morphine-3-glucuronide reaching the liver via the vasculature. We have quantitated the cellular efflux kinetics (cell-to-blood and cell-to-bile) of morphine-3-glucuronide in the rat isolated perfused liver using a loading wash-out design. In the ‘loading’ phase, morphine was infused into the liver (2.7 μM) and the biliary excretion and sinusoidal efflux of morphine-3-glucuronide was assessed under steady-state conditions. Subsequently, the infusion was stopped and the concentration vs time profile of morphine-3-glucuronide in outflow perfusate (the wash-out phase) was determined. A physiologically-based pharmacokinetic model was used to determine the rate-constants for the movement of hepatically-generated morphine-3-glucuronide into the sinusoidal and canalicular spaces of the liver, and the associated membrane permeability terms.
The mean (±s.d.) rate constants for the biliary excretion and sinusoidal efflux of morphine-3-glucuronide were determined to be 0.160±0.043 and 0.169 ± 0.068 min−1, respectively, and the corresponding membrane permeability parameters were 1.12 and 1.18 mL min−1, respectively. The sinusoidal membrane permeability term was significantly less than hepatic blood flow in the rat. The volume of distribution of hepatically-generated morphine-3-glucuronide (207.5 ± 74.8 mL) was found to be approximately 50-times the intracellular space of the rat liver, suggesting that hepatically-generated morphine-3-glucuronide accumulates within hepatocytes. The results indicate that hepatically-generated morphine-3-glucuronide undergoes intracellular accumulation, probably as a consequence of poor membrane permeability.
Novel Weight-Reducing Activity ofGalega officinalisin Mice
Authors: Palit P , Furman B L , Gray A I 
Published: October 2002

AbstractGalega officinalis (galega, Goat's Rue, French Lilac) is well known for its hypoglycaemic action and has been used as part of a plant mixture in the treatment of diabetes mellitus. During pharmacological investigations of an ethanolic extract of a powdered mixture of equal proportions of G. officinalis, Cressa cretica, Mangifera indica and Syzygium jambolanum, a weight reducing effect of galega was discovered. In this study we have investigated the novel weight reducing effect of galega in mice.Galega herb (10% w/w in the diet) caused a significant reduction in body weight in both normal and genetically obese (ob/ob) animals treated for 28 days when compared with respective controls (P &lt; 0.01). In normal mice, the weight loss was reversible and initially associated with a transient reduction in food intake but was then maintained even in the presence of increased eating above the control level. Pair-fed normal mice receiving galega for seven days also showed significant weight loss (P &lt; 0.01, compared with the control) in the presence of increasing food intake. In sharp contrast, weight loss in galega-treated ob/ob mice was accompanied by a persistent reduction in food intake over the 28-day treatment period. Post-mortem examinations of all galega-treated mice revealed a striking absence of body fat. Serum glucose was significantly reduced in both strains of mice receiving galega for 28 days (P &lt; 0.01), whereas serum insulin was significantly reduced only in obese mice (P &lt; 0.01).In summary, together with its established hypoglycaemic effects, galega has a novel weight reducing action that, in normal mice, is largely independent of a reduction in food intake. The mechanism of the weight reducing action of galega is unclear but involves loss of body fat.
Effects of Green Tea Tannin on Cisplatin-induced Nephropathy in LLC-PK1 Cells and Rats
Authors: Yokozawa Takako , NAKAGAWA Takako , Lee Kyeoung Im , Cho Eun Ju , Terasawa Katsutoshi , Takeuchi Shigeya 
Published: October 2002

Abstract
A study was conducted to clarify whether green tea tannin ameliorated cisplatin-induced renal injury in terms of lactate dehydrogenase and malondialdehyde leakage from a renal epithelial cell line, swine-derived LLC-PK1 cells in culture. Green tea tannin was shown to suppress the cytotoxicity of cisplatin, the suppressive effect increasing with the dose of green tea tannin. The effect of cisplatin was then investigated in rats given green tea tannin for 40 days before cisplatin administration and in control rats given no green tea tannin.
In control rats, blood, urinary and renal parameters and the activities of antioxidative enzymes in renal tissue deviated from the normal range, indicating dysfunction of the kidneys. In contrast, rats given green tea tannin showed decreased blood levels of urea nitrogen and creatinine, and decreased urinary levels of protein and glucose, reflecting less damage to the kidney. In this group, the activity of catalase in the renal tissue was increased, while the level of malondialdehyde was decreased, suggesting the involvement of radicals in the normalizing of kidney function.
Based on the evidence available it appeared that green tea tannin eliminated oxidative stress and was beneficial to renal function.