bluuebunny/crossref_metadata_2025_split huggingface dataset:
In-vivo and In-vitro Evidence of a Carrier-mediated Efflux Transport System for Oestrone-3-sulphate across the Blood-Cerebrospinal Fluid Barrier
Authors: Kitazawa Takeo , Hosoya Ken-Ichi , Takahashi Takeo , Sugiyama Yuichi , Terasaki Tetsuya 
Published: October 2002

Abstract
The efflux transport of oestrone-3-sulphate, a steroid hormone sulphate, across the blood-cerebrospinal fluid barrier has been examined following its intracerebroventricular administration. [3H]Oestrone-3-sulphate was eliminated from cerebrospinal fluid (CSF) with an apparent efflux clearance of 205 μL min−1 per rat. There was 25% of unmetabolized [3H]oestrone-3-sulphate in the plasma 5 min after intracerebroventricular administration, indicating that at least a part of [3H]oestrone-3-sulphate is transported from CSF to the circulating blood across the blood-CSF barrier. This efflux transport was inhibited by co-administration of excess oestrone-3-sulphate (25 mm 10 μL = 0.25 μmol) into rat cerebral ventricle.
To characterize the oestrone-3-sulphate transport process, an in-vitro uptake experiment was performed using isolated rat choroid plexus. Oestrone-3-sulphate uptake by isolated rat choroid plexus was found to be a saturable process with a Michaelis-Menten constant (Km) of 18.1 ± 6.3 μm, and a maximum uptake rate (Vmax) of 48.0± 15.1 pmol min−1 μL−1 of tissue. The oestrone-3-sulphate transport process was temperature dependent and was inhibited by metabolic inhibitors such as 2,4-dinitrophenol and rotenone, suggesting an energy dependence. This uptake process was also inhibited by steroid hormone sulphates (1 mm dehydroepiandrosterone sulphate and 1 mm oestrone sulphate), bile acids (1 mm taurocholic acid and 1 mm cholic acid) and organic anions (1 mm sulphobromophthalein and 1 mm phenolsulphonphthalein), whereas 1 mm p-aminohippuric acid, 1 mm p-nitrophenol sulphate, 0.1 mm methotrexate and the cardiac glycoside, 2.5 μm digoxin, had little effect.
In conclusion, these results provide evidence that oestrone-3-sulphate is transported from CSF to the circulating blood across the blood-CSF barrier via a carrier-mediated efflux transport system.
Effects of Lithium on the Pharmacokinetics of Valproate in Rats
Authors: Yoshioka Hiroshi , Ida Seiko , Yokota Masayuki , Nishimoto Ayako , Shibata Sachiko , Sugawara Akiko , Takiguchi Yoshiharu 
Published: October 2002

Abstract
Combined treatment with lithium and valproate has been used for bipolar disorder. However, the studied interaction between these two drugs has not been fully investigated. We therefore examined the effects of lithium on the pharmacokinetics (plasma disappearance, metabolism and urinary excretion) of valproate in rats.
Lithium (2 mEq kg−1) was administered intraperitoneally twice a day for ten days. Plasma disappearance curves of valproate (50 mg kg−1, i.v.), valproate-metabolizing activities of UDP-glucuronosyltransferase (UGT) and cytochrome P450 (CYP) in liver microsomes and urinary excretion of free valproate and valproate-glucuronide were examined. The metabolizing activity of UGT and CYP were determined by enzyme assays and a fluorescence polarization immunoassay system. Urinary valproate-glucuronide was obtained using this system by subtracting the free level from total level, which was determined after deconjugating the sample with heat and NaOH.
The half-life of plasma disappearance of valproate was 25% reduced by lithium pretreatment (0428 ± 0.031 h with repeated lithium pretreatment vs 0.578 ± 0.062 h for controls). The valproate-metabolizing activity of UGT and CYP were not altered by lithium although lithium increased the urinary excretion of valproate-glucuronide.
In conclusion, lithium pretreatment causes a decrease in plasma valproate levels and an increase in urinary excretion of valproate-glucuronide in rats.
Intestinal Transport of β-Thioglycosides by Na+/Glucose Cotransporter
Authors: Mizuma Takashi , Hagi Katsura , Awazu Shoji 
Published: October 2002

Abstract
Intestinal metabolism and transport of p-nitrophenyl β-d-thioglucoside (p-NPβSglc) and p-nitrophenyl β-d-thiogalactoside (p-NPβSgal) by the Na+/glucose cotransporter were studied in excised small intestine of the rat.
p-NPβSglc and p-NPβSgal were stable enough on the mucosal side to be transported to the serosal side. Transport of p-NPβSglc was inhibited in the presence of phloridzin (a Na+/glucose cotransporter inhibitor), glucose, or 3-O-methylglucose (3-OMG). p-NPβSglc transport was dependent on Na+ concentration in a sigmoidal manner. The activation energy for transport was 19.4 kcal mol−1. The distribution of transport activity of p-NPβSglc in each region of the small intestine correlated well with that of 3-OMG. These results indicate that p-NPβSglc is transported by the Na+/glucose cotransporter in small intestine. The order of turnover rate for glycoside transport by Na+/glucose cotransporter was 3-OMG &gt; p-nitrophenyl β-O-glucoside &gt; p-NPβSglc &gt; p-NPβSgal, indicating that the presence of a galactose moiety and a sulphur between the monosaccharide moiety and aglycone decreases the turnover rate of the Na+/glucose cotransporter in the transport of glycosides. In an inhibition study using stable p-NPβSglc as a Na+/glucose cotransporter-transportable marker glucoside, it was also shown that the Na+/glucose cotransporter recognized several types of glycosides.
In conclusion, displacement of the oxygen at carbon C-l of glucose by sulphur in thioglycosides decreases the turnover rate of the Na+/glucose cotransporter, but thioglycosides are stable in the small intestine and are transported by the Na+/glucose cotransporter.
Effect of Trimethoprim on the Renal Clearance of Lamivudine in Rats
Authors: Takubo Takatoshi , Kato Toshihiro , Kinami Junji , Hanada Kazuhiko , Ogata Hiroyasu 
Published: October 2002

Abstract
Lamivudine undergoes minimal metabolism and renal clearance of the unchanged drug is the predominant mechanism of clearance. The effect of trimethoprim on the renal clearance of lamivudine was investigated in rats in-vivo.
Total renal clearance of lamivudine was about three times higher than the glomerular filtration rate in rats receiving an infusion of tritium-labelled lamivudine. Concomitant infusion of trimethoprim reduced the renal clearance of lamivudine to about half, but did not affect the level of radioactivity in the renal cortex. When rats received an infusion of lamivudine with probenecid, cimetidine or quinidine, the renal clearance of lamivudine was only significantly reduced by co-administration of cimetidine.
These findings suggest that secretion in the renal proximal tubule takes an active part in the total renal clearance of lamivudine, and that cationic drugs such as trimethoprim and cimetidine may inhibit the secretion of lamivudine without greatly affecting the concentration of lamivudine in the renal cortex.
Characterization of Histamine Release Induced by Fluoroquinolone Antibacterial Agents In-vivo and In-vitro
Authors: Mori Kazuhiko , Maru Chikako , Takasuna Kiyoshi 
Published: October 2002

Abstract
Characterization of histamine release induced by fluoroquinolone antibacterial agents, levofloxacin and ciprofloxacin, was investigated in-vivo and in-vitro.
Intravenous injection of levofloxacin and ciprofloxacin at 1–10 mg kg−1 produced dose-related elevations in plasma histamine level in anaesthetized dogs. In contrast, levofloxacin was devoid of plasma histamine increment in anaesthetized rats at 100 mg kg−1, whereas ciprofloxacin at the same dose caused endogenous histamine release. Levofloxacin and ciprofloxacin induced non-cytotoxic secretion of histamine from all mast cells tested in a concentration-dependent manner, whereas rat skin and peritoneal mast cells were thirty- to one-hundred-times less sensitive to the effect of fluoroquinolones as compared with the canine skin mast cells.
These results suggest that the functional heterogeneity of mast cells from different species in histamine releasing activity of fluoroquinolones may exist, and that mast cells from the dog appear to be particularly sensitive to the effect of the fluoroquinolones.
Anti-leukaemic and Anti-mutagenic Effects of Di(2-ethylhexyl)phthalate Isolated from Aloe vera Linne
Authors: Lee Keyong Ho , Kim Jeong Hwan , Lim Dae Seog , Kim Chang Han 
Published: October 2002

Abstract
Extracts of Aloe vera Linne have been found to exhibit cytotoxicity against human tumour cell lines. This study examines the anti-tumour effects of di(2-ethylhexyl)phthalate (DEHP) isolated from Aloe vera Linne, in human and animal cell lines. Its anti-mutagenic effects were examined using Salmonella typhimurium TA98 and TA100 strains.
Growth inhibition was specifically exerted by DEHP against three leukaemic cell lines at concentrations below 100 μg mL−1. At 100 μg mL−1 DEHP, K562, HL60 and U937 leukaemic cell lines showed growth inhibition of 95, 97 and 95%, respectively. DEHP exhibited an inhibitory activity of 74, 83 and 81%, respectively, in K562, HL60 and U937 cell lines at a concentration of 10 μg mL−1. At a concentration of 1 μg mL−1, DEHP exerted an inhibitory activity of 50, 51 and 52%, respectively, in K562, HL60 and U937. In a normal cell line, MDBK, DEHP exerted 30% growth inhibition at a concentration of 100 μg mL−1, and showed no inhibitory activity at concentrations below 50 μg mL−1.
It was found that DEHP exerted anti-mutagenic activity in the Salmonella mutation assay. The number of mutant colonies of Salmonella typhimurium strain TA98 upon exposure to AF-2 (0.2 μg/plate) decreased in a concentration-dependent manner in the presence of different DEHP concentrations (decreasing to 90.4, 83.9, 75.4, 69.6 and 46.9%, respectively, for DEHP concentrations of 100, 50, 10, 5 and 1 μg/plate). In the case of Salmonella typhimurium strain TA100, DEHP reduced AF-2-induced mutagenicity at 1, 5, 10, 50 and 100 μg/plate to 57.4, 77.5, 80.0, 89.0 and 91.5%, respectively.
The isolated compound from Aloe vera Linne, DEHP, was considered to be the active principle responsible for anti-leukaemic and anti-mutagenic effects in-vitro.
Investigation of the Absorption of Hypericin into the Skin of Hairless Mice
Authors: Kamuhabwa Appolinary R , Geboes Karel R , De Witte Peter A 
Published: October 2002

Abstract
The skin absorption of hypericin was evaluated in hairless mice to develop an optimised hypericin topical formulation that could be used in the clinical study of psoriasis.
Hypericin (0.01–1.0%) in Beeler basis, polyethylene glycol ointment, carbopol gel, cetomacrogol cream, petrolatum or emulsifying ointment, with and without skin-absorption enhancers (isopropylidene glycerol and diethylene glycol monoethyl ether), was tested in-vivo on hairless mice skin. Using a skin-stripping technique and the intrinsic fluorescence of hypericin under standardised UV365 irradiation, it was demonstrated that the absorption of hypericin very much depended on the vehicle used. The concentrations of hypericin in the skin were then estimated by HPLC analysis. For this purpose, two vehicles were employed, with which hypericin penetrated the skin of hairless mice well (emulsifying ointment with isopropylidene glycerol) or very poorly (polyethylene glycol ointment). In the case of emulsifying ointment with isopropylidene glycerol (0.05% hypericin), a substantial concentration of hypericin (8.6±3.2 μg g−1) (mean ± s.d., n = 5) was found in the skin. With polyethylene glycol ointment, however, only a limited hypericin skin concentration (0.38 ± 0.34 μg g−1, n = 5) was achieved.
These results show that emulsifying ointment with polyethylene glycol holds promise as an effective topical vehicle for the treatment of skin diseases, such as psoriasis, with hypericin.
The Upstream Regulation of p38 Mitogen-activated Protein Kinase Phosphorylation by Arachidonic Acid in Rat Neutrophils
Authors: Chang Ling C , Wang Jih P 
Published: October 2002

Abstract
The signal transduction pathways activated by arachidonic acid that lead to p38 mitogen-activated protein kinase (MAPK) activation in neutrophils remains unclear. In this study, selective inhibitors of several signalling pathways were utilized to investigate the mechanisms of activation of p38 MAPK by arachidonic acid in rat neutrophils.
Stimulation of p38 MAPK phosphorylation by arachidonic acid and its trifluoromethyl ketone analogue AACOCF3 was transient, peaking at 1 min, and was concentration-dependent. Arachidonic acid-stimulated p38 MAPK phosphorylation was attenuated in cells pretreated with the Gi/o inhibitor (pertussis toxin), but not with the dual cyclooxygenase/lipoxygenase inhibitor (BW755C) or the leukotriene biosynthesis inhibitor (MK886). Tyrosine kinase inhibitor (genistein), but not the extracellular signal-regulated kinase kinase inhibitors (PD98059 and U0126), attenuated the phosphorylation of p38 MAPK by arachidonic acid. Phosphoinositide 3-kinase inhibitors (wortmannin and LY294002) did not affect the arachidonic acid-induced response. After pretreatment of the cells with protein kinase C inhibitors (Gö6976, Gö6983 and GF109203X), only Gö6976 significantly attenuated the phosphorylation of p38 MAPK by arachidonic acid. In addition, phosphorylation of p38 MAPK by arachidonic acid was greatly attenuated by the phospholipase C inhibitor (U73122) and the Ca2+ chelator BAPTA ((1,2-bis-o-amino-phenoxy)-ethane-N,N,N′,N′-tetraacetic acid), but not altered by the nitric oxide synthase inhibitor, N-nitro-l-arginine methyl ester. Arachidonic acid did not cause an increase in cellular cyclic GMP level.
This study revealed the involvement of pertussis toxin-sensitive G protein, non-receptor tyrosine kinase, phospholipase C/Ca2+, and probably Ca2+-dependent protein kinase C in arachidonic acid-stimulated p38 MAPK activation.
Zidovudine, Diclofenac and Ketoprofen Pharmacokinetic Interactions in Rats
Authors: Radwan Mahasen A 
Published: October 2002

Abstract
Zidovudine (AZT) is widely used for the management of human immunodeficiency virus (HIV) infections. Non-steroidal anti-inflammatory drugs (NSAIDs) are often used for relief of non-specific fever and musculoskeletal pain in patients with HIV including those with AZT-induced myopathy. The effects of single oral doses of diclofenac and ketoprofen on AZT pharmacokinetics were studied in rats. The influence of AZT on the pharmacokinetics of diclofenac or ketoprofen was also investigated.
The administration of diclofenac (3 mg kg−1) or ketoprofen (1 mg kg−1) did not significantly alter AZT (1.5 mg kg−1) pharmacokinetic parameters compared with administering AZT alone. There was no significant difference between the pharmacokinetics of ketoprofen given alone or in combination with AZT. However, the co-administration of AZT with diclofenac affected the pharmacokinetics of diclofenac. The Cmax of diclofenac was significantly (P &lt; 0.05) increased by approximately threefold within a shorter time (0.6 ± 0.2 h). The mean AUC value for diclofenac was increased from 2.29 to 5.04 μg mL−1 h in the presence of AZT. AZT decreased the mean apparent clearance of diclofenac by 54%. The increase in diclofenac concentrations could be attributed to a decrease in its clearance or delay in its metabolite formation due to a competitive effect.
The results show that diclofenac and AZT should be given with caution because of the possible increase of diclofenac toxicity, in anticipation of follow-up clinical studies to examine this finding in man. AZT and ketoprofen could be a safe combination since no pharmacokinetic interaction was detected.
Dammarane Derivatives Protect Cultured Rat Cortical Cells from Glutamate-induced Neurotoxicity
Authors: Kim So Ra , Sung Sang Hyun , Kwon Sung Won , Park Jeong Hill , Huh Hoon , Kim Young Choong 
Published: October 2002

Abstract
We previously reported that ginsenosides Rb1 and Rg3, dammarane glycosides, of Panax ginseng C. A. Meyer (Araliaceae), significantly attenuated glutamate-induced neurotoxicity in primary cultures of rat cortical cells. To seek more potent neuroprotective compounds, we attempted to modify the chemical structure of dammarane glycosides and obtained six derivatives, MA-11, PT-11, PT-111, POA-101, POA-111 and N-001. The neuroprotective activity of these dammarane derivatives were evaluated employing primary cultures of rat corticoid cells.
The glutamate-induced neuronal cell damage was significantly reduced by a pre-treatment with protopanaxadiol, MA-11 or PT-11 at concentrations ranging from 100nM to 10 μM. Both MA-11 and PT-11, preserved the levels of catalase and inhibited decreases in glutathione reductase in glutamate-injured cells. Furthermore, the dammarane derivatives reduced the content of intracellular peroxide in glutamate-intoxicated cells. Finally, they inhibited the formation of malondialdehyde, a compound produced during lipid peroxidation, in glutamate-insulted cells.
These results show that the dammarane derivatives, MA-11 and PT-11, exert significant neuroprotective effects on cultured cortical cells by a mechanism seemingly distinct from that afforded by ginsenosides Rb1 and Rg3. As such, the dammarane derivatives may be efficacious in protecting neurons from oxidative damage caused by exposure to excess glutamate.
Effect of Dimethylglycine on Gastric Ulcers in Rats
Authors: Hariganesh K , Prathiba J 
Published: October 2002

Abstract
Dimethylglycine is an anti-stress nutrient with antioxidant properties. Recently, studies have implicated the generation of oxygen-derived free radicals and lipid peroxidation as one of the mechanisms in the pathogenesis of gastric ulcer. Hence, we evaluated the antiulcer activity of dimethylglycine in various rat models of ulcer and also investigated the probable antioxidant mechanism of the anti-ulcer effect.
The results suggest that the gastroprotective effect of dimethylglycine could be mediated by its free radical scavenging activity and cytoprotection of gastric mucosa.
Dimethylglycine at a dose of 25 and 35 mg kg−1 significantly reduced ulcer number, ulcer size and ulcer index in pyloric-ligation-, ibuprofen- and stress-induced ulcers. The 35 mg kg−1 dose was more effective than 25 mg kg−1 and was comparable to famotidine. Dimethylglycine did not produce any significant change in acid secretion, unlike famotidine. There was a significant increase in plasma and tissue malondialdehyde levels in pyloric-ligated rats but these levels fell following dimethylglycine treatment. Also, there was a significant reduction in glutathione levels after dimethylglycine treatment.
Clonidine Attenuates the Carbachol-induced Contractile and Phosphatidylinositol Responses of Rat Trachea
Authors: Shibata Osamu , Saito Masataka , Hashimoto Shigeru , Sakai Kazuyuki , Makita Tetsuji , Sumikawa Koji 
Published: October 2002

Abstract
Although Clonidine is known to affect vascular smooth muscle, its effects on airway smooth muscle are not fully understood. This study was designed to examine the effects of Clonidine on carbachol-induced contractile and phosphatidylinositol responses of rat trachea.
Clonidine, at a dose of 100 μM or greater, attenuated carbachol-induced contraction and the accumulation of carbachol-induced inositol monophosphate (IP1). Clonidine also attenuated the accumulation of aluminium fluoride-induced IP1. The concentration-effect relationship of IP1 accumulation was similar to that of carbachol-induced contraction; r = 0.797, P&lt; 0001.
These results suggest that Clonidine attenuates contractile responses, at least in part, through the inhibition of phospholipase C (coupled with G-proteins) in phosphatidylinositol responses.
AL-3138 Antagonizes FP Prostanoid Receptor-mediated Inositol Phosphates Generation: Comparison with Some Purported FP Antagonists
Authors: Sharif N A , Crider J Y , Davis T L 
Published: October 2002

Abstract
The aim of this study was to pharmacologically characterize the antagonist properties of a novel prostaglandin F2α (PGF2α) analogue (11-deoxy-16-fluoro PGF2α; AL-3138) using a variety of second-messenger assays of prostaglandin receptor subtypes. A detailed comparison was made between AL-3138 and some purported FP receptor antagonists such as PGF2α dimethylamine, PGF2α dimethylamide, glibenclamide and phloretin using the FP receptor-mediated phosphoinositide turnover assay in A7r5 rat thoracic aorta smooth muscle cells and mouse Swiss 3T3 fibroblasts.
The potency and efficacy of AL-3138 as an FP receptor agonist were: EC50 = 72.2 ± 17.9 nM (Emax = 37%) (n = 3) in A7r5 cells and EC50 = 20.5 ± 2.8 nM (Emax = 33%) (n = 5) in 3T3 cells. Being a partial agonist, the antagonist potency of AL-3138 against fluprostenol in A7r5 cells was determined to be: Ki = 296 ± 17 nM (n = 3) and Kb = 182 ± 44nM (n = 5) (-log Kb = 6.79 ± 0.1). AL-3138 exhibited very minimal or no antagonistic effects at EP2, EP4, DP and TP prostaglandin receptors. Both PGF2α dimethylamide and PGF2α dimethylamine were inactive as FP receptor antagonists, whereas phloretin and glibenclamide were very weak and had -log Kb values of 5.28 ± 0.09 (n = 3) and 3.58 ± 0.32 (n = 3), respectively. However, phloretin antagonized functional responses of EP2 and DP prostanoid receptors, and also the V1 — vasopressin receptor. AL-3138 competed for [3H]PGF2α binding to FP receptors with a relatively high affinity (IC50high = 312 ± 95nM) matching its functional antagonist potency.
In conclusion, AL-3138 is a more potent and selective FP receptor antagonist than glibenclamide, phloretin, PGF2α dimethylamide and PGF2α dimethylamine and is therefore a unique and novel pharmacological tool to help characterize FP receptor-mediated functions.
Pharmacokinetics and Bioavailability of Tacrolimus in Rats with Experimental Renal Dysfunction
Authors: Okabe Hiromi , Hashimoto Yukiya , Inui Ken-Ichi 
Published: October 2002

Abstract
The effects of renal failure on the pharmacokinetics and bioavailability of tacrolimus were investigated in rats. Experimental renal dysfunction was induced by intraperitoneal injection of cisplatin (5 mg kg−1) into rats. The blood concentration of tacrolimus was measured after intravenous and intra-intestinal administration of the drug.
The blood concentration of tacrolimus after intravenous administration (1 mg kg−1) was slightly increased (up to 1.3 fold) by induction of renal dysfunction. In contrast, the peak tacrolimus concentration after intra-intestinal administration (1 mg kg−1 or 3 mg kg−1) in rats with renal failure was about 2-fold higher than that in normal controls. The bioavailability was increased by about 35% in rats with impaired renal function as compared with normal controls. These results suggested that the bioavailability of tacrolimus, which is mainly metabolized in the liver and intestine after oral administration, is also influenced by renal function.