bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue distribution of and species differences in deacetylation of N-acetyl-L-cysteine and immunohistochemical localization of acylase I in the primate kidney
Authors: Yamauchi Aiko , Ueda Nobuhiko , Hanafusa Sayuri , Yamashita Eri , Kihara Masaru , Naito Shinsaku 
Published: October 2002

Abstract
Species differences in the biotransformation of N-acetyl-L-cysteine (NAC) have been investigated to evaluate the usefulness of NAC as a constituent in parenteral nutrition solutions in place of cysteine. The activity of NAC-deacetylating enzyme (acylase) was measured in various tissues of different species (rat, rabbit, dog, monkey, and man). Acylase activity was highest in the kidney in all species studied. Enzyme activity in the liver was 10%-22% of that in the kidney in the rat, rabbit, monkey, and man, but almost no hepatic activity was seen in the dog. NAC-deacetylating activity was very low in other organs. The tissue distribution of acylase I was determined by Western blotting and an immunohistochemical method employing specific antibody against porcine acylase I (EC 3.5.1.14). The immunoblotting study showed a 46-kDa protein band corresponding to porcine acylase I in the kidney of all species. In liver cytosol, 46 kDa and/or 29 kDa bands were observed in the rat, rabbit, monkey, and man, but not in the dog. In the immunohistochemical study, positive staining with anti-acylase I antibody was observed clearly in the renal proximal tubules in the monkey and man. These results suggested that the kidney and liver were the main organs responsible for the biotransformation of NAC to cysteine in mammals other than the dog.
Transport of D-glucose across cultured stratified cell layer of human oral mucosal cells
Authors: Kimura Toshikiro , Yamano Hitoshi , Tanaka Akihiro , Matsumura Tomohiro , Ueda Minoru , Ogawara Ken-ichi , Higaki Kazutaka 
Published: October 2002

Abstract
To evaluate the role of several specialized mechanisms for D-glucose transport in human oral mucosa, a cultured stratified cell layer derived from human oral mucosa was employed. Although this culture system has been used for reconstructive surgery, we, for the first time, tried to apply this system to the evaluation of nutrients and drug transport. Cell number and transepithelial electrical resistance (TEER) reached steady state 7–8 days after inoculation on the Transwell and TEER values at steady state were 130–140 Ω cm2, which was higher or lower than that of small intestine or Caco-2 cells, respectively. The transport studies were carried out using the cultured epithelium on the Transwell. The transport of D-glucose across the cultured stratified layer of oral epithelial cells was much more extensive than L-glucose, and was inhibited by 2-deoxy-D-glucose, a substrate of facilitative glucose transporters, and α-methyl-D-glucoside, a specific substrate of a Na+/glucose cotransporter (SGLT1). The results indicate that the sugar transporters function not only to take up D-glucose by the epithelial cells but also to transport the sugar across the stratified epithelial layer.
In-vitro and in-vivo pharmacokinetic interactions of amprenavir, an HIV protease inhibitor, with other current HIV protease inhibitors in rats
Authors: Shibata Nobuhito , Gao Weihua , Okamoto Hiroyuki , Kishida Tomoyuki , Yoshikawa Yukako , Takada Kanji 
Published: October 2002

Abstract
The drug interactions between a new human immune deficiency virus (HIV) protease inhibitor, amprenavir, and four other protease inhibitors which are presently used have been characterized by in-vitro metabolic studies using rat liver microsomal fractions and in-vivo oral administration studies. The metabolic clearance rates (Vmax/Km) of amprenavir, saquinavir, indinavir and nelfinavir in rat liver microsomes were 50.67 ± 3.77, 170.88 ± 15.34, 73.01 ± 2.76 and 126.06 ± 6.23 μL min−1 (mg protein)−1, respectively, and the degree of metabolic clearance was in the order of saquinavir &gt; nelfinavir &gt; indinavir &gt; amprenavir &gt; ritonavir. The inhibition constants (Ki) of ritonavir for amprenavir, indinavir, nelfinavir and saquinavir were 2.29, 0.95, 1.01 and 1.64 μM, respectively, and that of indinavir for amprenavir was 0.67, indicating that amprenavir metabolism in rat liver microsomes was strongly inhibited by indinavir. The Ki values of amprenavir for indinavir, nelfinavir and saquinavir were 7.41, 2.13 and 16.11 μM, respectively, and those of nelfinavir and saquinavir for amprenavir were 9.15 and 34.57 μM, respectively. The area under the concentration vs time curve (AUC) of amprenavir after oral co-administration with saquinavir, indinavir, nelfinavir or ritonavir (20 mg kg−1 for each oral dose in rats) was increased by 1.6-, 2.0-, 1.2- and 9.1-fold, respectively. The AUC values of saquinavir, indinavir and nelfinavir by co-administration with amprenavir showed about 7.3-, 1.3-, and 7.9-fold increase, respectively. These observations suggested that the oral bioavailability of amprenavir was not so affected by co-administration with saquinavir, nelfinavir or indinavir, compared with ritonavir, whereas amprenavir markedly affected the oral bioavailability of saquinavir and nelfinavir. In addition, the in-vivo effects after coadministration of two kinds of HIV protease inhibitors cannot always be predicted from in-vitro data, suggesting the presence of other interaction processes besides metabolism in the liver. However, these results provide useful information for the treatment of AIDS patients when they receive a combination therapy with two kinds of HIV protease inhibitor.
Metabolism of sulphobromophthalein II. Species differences between rats, guinea-pigs and rabbits
Authors: Sano Kazumi , Totsuka Yukari , Ikegami Yoji , Uesugi Takashi 
Published: October 2002

Abstract
Interesting species differences in the metabolism of sulphobromophthalein sodium have been observed between rats, guinea-pigs and rabbits. The species difference was measured in terms of sulphobromophthalein monoglutathione conjugate (mGSH) positional isomer formation. After an intravenous injection of sulphobromophthalein to rats, 92% of sulphobromophthalein-mGSH excreted into bile was the α -isomer. In contrast, in guinea-pigs the three isomers α, β and δ were excreted in equivalent amounts. In rabbits, the majority of sulphobromophthalein-mGSH was excreted as the β-isomer. The formation ratio of glutathione (GSH) conjugates in-vitro using cytosolic glutathione S-transferases (GSTs) prepared from livers generally accounted for the biliary excretion ratio of α-, β - and δ-monomercaptide isomers in-vivo. GSTs from the livers of rat, guinea-pig, and rabbit were purified and characterized. Although their main GSTs produced different isomers, their 20 amino acid residues showed that they belonged to the same class mu of GSTs. The results suggested differences of the three-dimensional structure of GSTs that formed sulphobromophthalein-mGSH isomers between the three animal species.
Synthesis and physicochemical assessment of novel 2-substituted 3-hydroxypyridin-4-ones, novel iron chelators
Authors: Moridani Majid Y , Tilbrook Gary S , Khodr Hicham H , Hider Robert C 
Published: October 2002

Abstract
Novel 3-hydroxypyridin-4-one containing tridentate ligands were synthesised and their physicochemical properties characterised, including ionisation constants and stoichiometric titration with Fe(III). There is an urgent demand for orally active iron chelators with potential for the treatment of thalassaemia. In principle, tridentate ligands are likely to be more kinetically stable than bidentate molecules, but to date no satisfactory molecules have been identified. Fe(III) stability constants were assessed by competition with the hexadentate ligand EDTA. In all cases no evidence was found for a tridentate mode of iron chelation; instead the ligands behaved as bidentate hydroxypyridinones. As a consequence they provide no advantage over the more simple alkyl hydroxypyridinones.
Distribution kinetics of solutes in the isolated in-situ perfused rat head using the multiple indicator dilution technique and a physiological two-barrier model
Authors: Foster K A , Weiss M , Roberts M S 
Published: October 2002

Abstract
The purpose of this study was to determine the pharmacokinetics of [14C]diclofenac, [14C]salicylate and [3H]clonidine using a single pass rat head perfusion preparation. The head was perfused with 3-[N-morpholino] propane-sulfonic acid-buffered Ringer's solution. 99mTc-red blood cells and a drug were injected in a bolus into the internal carotid artery and collected from the posterior facial vein over 28 min. A two-barrier stochastic organ model was used to estimate the statistical moments of the solutes. Plasma, interstitial and cellular distribution volumes for the solutes ranged from 1.0 mL (diclofenac) to 1.6 mL (salicylate), 2.0 mL (diclofenac) to 4.2 mL (water) and 3.9 mL (salicylate) to 20.9 mL (diclofenac), respectively. A comparison of these volumes to water indicated some exclusion of the drugs from the interstitial space and salicylate from the cellular space. Permeability-surface area (PS) products calculated from plasma to interstitial fluid permeation clearances (CLPI) (range 0.02-0.40 mL s−1) and fractions of solute unbound in the perfusate were in the order: diclofenac &gt;salicylate &gt;clonidine &gt;sucrose (from 41.8 to 0.10 mL s−1). The slow efflux of diclofenac, compared with clonidine and salicylate, may be related to its low average unbound fraction in the cells. This work accounts for the tail of disposition curves in describing pharmacokinetics in the head.
Cloned human EP1 prostanoid receptor pharmacology characterized using radioligand binding techniques
Authors: Sharif Najam A , Davis Terry L 
Published: October 2002

Abstract
Prostaglandins such as prostaglandin E2 (PGE2) interact with EP-class prostanoid receptors including EP1, EP2, EP3 and EP4 subtypes. We have conducted a detailed pharmacological characterization of the binding of [3H]-PGE2 to recombinant human EP1 prostanoid receptors expressed in human embryonic kidney (HEk-293) cells using a broad panel of natural and synthetic prostanoids. The receptor displayed high affinity (kd = 16.0 ± 0.69 nM; n = 3) for [3H]-PGE2, and was expressed at high levels (Bmax = 3.69 ± 0.30 pmol (mg protein)−1 in cell membranes of HEk-293 cells. Specific binding constituted 97.5 ± 1.4% (n = 12) of the total binding. In competition assays, the rank order of affinities of natural prostanoids for the receptor was PGE2 &gt; PGE1 &gt; PGF2 &gt; PGI2 &gt; PGD2. PGE2 was more effective than PGE1 at displacing bound [3H]-PGE2 (ki for PGE2 = 14.9 ± 2.2 nM; ki for PGE1 = 165 ± 29 nM). The affinities of enprostil (ki = 14.5 ± 3.1 nM) and 17-phenyl-ω-trinor-PGE2 (ki = 7.3 ± 2.7 nM) for the receptor were quite similar to that of PGE2, while that of sulprostone (ki = 137 ± 13 nM) more closely resembled PGE1. Some compounds historically classified as specific for DP prostanoid receptors bound with relatively high affinity to the recombinant human EP1 receptor (e.g. Zk118182 (ki = 73.4 ± 8.6 nM) and Zk110841 (ki = 166 ± 20 nM)). All FP (e.g. travoprost acid, fluprostenol), IP (iloprost) and TP (SQ29548) receptor-specific ligands exhibited low affinity (ki ≥ 1μM).
Gastroprotective activity of oleanolic acid derivatives on experimentally induced gastric lesions in rats and mice
Authors: Astudillo Luis , Rodriguez Jaime A , Schmeda-Hirschmann Guillermo 
Published: October 2002

Abstract
The gastroprotective effect of the triterpene oleanolic acid (OA) was assessed on gastric ulceration in rats. The effect of a single oral dose of OA was evaluated at 50, 100 and 200 mg kg−1 in the following models: pylorus ligature (Shay), and aspirin- and ethanol-induced gastric ulcers. A single oral administration of OA at doses of 50, 100 and 200 mg kg−1 inhibited the appearance of gastric lesions induced by ethanol, aspirin and pylorus ligature. In the pylorus ligature and aspirin models, the effect of OA at the selected concentrations was comparable with that of ranitidine at 50 mg kg−1. In the ethanol-induced gastric lesion model, OA showed a dose-dependent activity, and at 100 and 200 mg kg−1 was as active as omeprazole at 20 mg kg−1. The effect of OA, its acetylated and methoxylated derivatives, oleanonic acid and its methyl ester were assessed on HCl/ethanol-induced ulcers in mice at 200 mg kg−1. OA and its methoxylated (OAM) and acetylated (OAAM, OAA) derivatives proved to be active in this animal model. The semisynthetic derivatives OAM and OAAM had the greatest gastroprotective activity, but their effect was not significantly greater than OA. In an acute toxicity test on mice, intraperitoneal administration of OA showed no toxicity at doses up to 600 mg kg−1.
Formation of a disulfide protein conjugate of the SH-group-containing metabolite (M-I) of esonarimod (kE-298) and its elimination in rats
Authors: Hasegawa Masatoshi , Omi Naoko , Endo Hiromi , Yoshida Hideo , Higuchi Shohei 
Published: October 2002

Abstract
The reactivity of the thiol moiety of the active main metabolite (M-I) of esonarimod (kE-298), a novel anti-rheumatic agent, was investigated in rats. After repeated oral administration of 14C-kE-298, the radioactivity decreased rapidly and no tendency towards accumulation was found, in marked contrast to other common SH-group-containing drugs. At 30 min after intravenous administration of 14C-M-I to rats, the concentration of the 14C-M-I plasma protein conjugate in plasma was extremely low at 0.143 nmol mL−1 (0.66% of total plasma radioactivity). The 14C-M-I plasma protein conjugate that formed in rat plasma was mixed disulfide with plasma protein. After intravenous administration of synthetic 14C-M-I plasma protein conjugate to rats, the radioactivity in plasma decreased rapidly, with the terminal half-life at 6.90 h. In-vitro, the 14C-M-I plasma protein conjugate was readily dissociated by the endogenous thiol compounds, cysteine and glutathione. These results suggest that the reactivity of the thiol moiety of M-I is extremely low. Furthermore, the 14C-M-I plasma protein conjugate decreased rapidly in-vivo, which would be related to interaction with endogenous thiol compounds. These properties of M-I are principally responsible for the zero accumulation in rat tissues. kE-298 could therefore be expected to have reduced adverse effects compared with other SH-group-containing anti-rheumatic drugs.
Effect of heparinoid on the production of tissue inhibitor of metalloproteinases (TIMP)-3 in rheumatoid synovial fibroblasts
Authors: Watanabe Hideki , Wada Hiromi , Itoh Masayuki , Kataoka Masanori , Kido Hiroko , Naruse Tomohiro 
Published: October 2002

Abstract
Heparinoid is one of the major contents of Mobilat widely used as an antirheumatic drug. To clarify the precise mechanisms of the antirheumatic effect of heparinoid, we investigated its effects on the production of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) from rheumatoid synovial fibroblasts stimulated (or not) with interleukin-1 alpha (IL-1α) at 100 units mL−1. The expression of TIMP-3 mRNA was also investigated in a similar manner. The production of both MMPs and TIMPs and the expression of TIMP-3 mRNA were investigated by western-blot analysis and northern-blot hybridization, respectively. Under the stimulation of IL-1α, heparinoid increased the production of TIMP-3 in a concentration-dependent manner, but not TIMP-1, TIMP-2, MMP-1 or MMP-3. Heparinoid did not affect the expression of TIMP-3 mRNA that was increased by the stimulation of IL-1α. These findings suggest that the anti-rheumatoid effect of heparinoid may be due to increased production of TIMP-3. This increase in TIMP-3 may help redress the imbalance between the amounts of MMPs and TIMPs as observed in the joint tissues of rheumatoid arthritis and osteoarthritis patients.
Influence of nicardipine and nifedipine on plasma carvedilol disposition after oral administration in rats
Authors: Hokama Nobuo , Hobara Norio , Sakai Masayuki , Kameya Hiromasa , Ohshiro Susumu , Sakanashi Matao 
Published: October 2002

Abstract
The effect of two kinds of 1,4-dihydropyridine calcium-channel blockers, nicardipine hydrochloride and nifedipine, on the disposition of carvedilol, was studied in rats. Blood samples were assayed for carvedilol levels using solid-phase extraction and high-performance liquid chromatography. The plasma carvedilol concentration was found to be significantly higher, and the area under the concentration-time curve up to 24 h (AUC0→24) was 6.7 and 3.0 times higher after simultaneous oral administration of 20 mg kg−1 carvedilol with 40 mg kg−1 nicardipine hydrochloride, or with 40 mg kg−1 nifedipine, respectively, than after administration of carvedilol alone. The pharmacokinetic interaction between carvedilol and dihydropyridine calcium-channel blockers is thought to be attributable to vasodilator-induced changes in hepatic first-pass metabolism, inhibition in the absorption barrier by P-glycoprotein and in the metabolism of carvedilol.
Free radical scavengers, anti-inflammatory and analgesic activity of Acaena magellanica
Authors: Feresin Gabriela Egly , Tapia Alejandro , Angel Gutierrez R , Delporte Carla , Erazo Nadine Backhouse , Schmeda-Hirschmann Guillermo 
Published: October 2002

Abstract
Extracts of the whole plant Acaena magellanica (Rosaceae) were assessed for anti-inflammatory, antipyretic and analgesic activity in animal models. At 600 mg kg−1, the global ethanolic extract (GEE), dichloromethane (DCM) and defatted methanol (MeOH) fractions showed a mild anti-inflammatory effect in the carrageenan-induced guinea-pig paw oedema. The GEE, DCM and defatted MeOH fractions significantly reduced inflammation by 43.2, 40.5 and 42.1%, respectively. The GEE did not showed any significant antipyretic activity in doses up to 600 mg kg−1. A 20% w/v infusion administered orally at 16 mL kg−1 presented analgesic effect in the acetic acid-induced abdominal constriction test in mice. The GEE and MeOH extract of A. magellanica showed free radical scavenging activity in the diphenylpicrylhydrazyl decolouration assay. Assay-guided isolation led to quercetin, Q-3-O-β-D-glucoside, Q-3-O-β-D-galactoside, ellagic acid and catechin as the free radical scavengers. The saponins tormentic acid 28-O-β-D-galactopyranoside and 28-O-β-D-glucopyranoside were isolated from the polar extract. The structures were determined by spectroscopic methods.
Mechanisms involved in the relaxant action of the ethanolic extract of propolis in the guinea-pig trachea in-vitro
Authors: Paulino Niraldo , Scremin Fernando M , Raichaski Lisiane B , Marcucci Maria Cristina , Scremin Amarilis , Calixto João B 
Published: October 2002

Abstract
This study examines the mechanisms by which the standardised ethanolic extract of propolis induces relaxation of the guinea-pig trachea in-vitro. In guinea-pig trachea with or without epithelium and contracted by histamine, the propolis extract caused reproducible and graded relaxation, with a mean EC50 value of 3.8 or 10.5 μg mL−1 and Emax of 100%, respectively. The propolis extract-induced relaxation was markedly reduced (26 ± 9 and 96 ± 3%) when guinea-pig tracheas were exposed to Krebs solution containing elevated K+ in the medium (40 or 80 mM). Pre-incubation of guinea-pig tracheas with tetraethylamonium (100 mM) or with 4-aminopyridine (10 mM) reduced the propolis extract-induced relaxation by 31±10% and 28 ± 2%. Likewise, apamin (0.1 μM), charybdotoxin (0.1 μM) or iberiotoxin (0.1 μM) caused marked inhibition of propolis extract-mediated relaxation in guinea-pig trachea (percentage of inhibition: 65 ± 3%, 60 ± 5% and 65 ± 9%, respectively). Also, glibenclamide (1 μM) inhibited the relaxant response caused by the propolis extract by 57 ± 4%. ω-Conotoxin GIVA (0.1 μM) or capsaicin (1 μM) produced small but significant inhibition (30 ± 5% or 47 ± 7%, respectively) of the propolis extract-induced relaxation. The vasoactive intestinal peptide (VIP) antagonist D-P-CI-Phe6, Leu17[VIP] porcine (0.1 μM) inhibited relaxation by 55 ± 5%, while propranolol (1 μM) induced a parallel rightward displacement (about 20 fold) of the propolis extract concentration-response curve. Finally, the propolis extract-induced relaxation was inhibited by the nitric oxide synthase inhibitor L-NG-nitroarginine (L-NOArg, 100 μM) (48 ± 6%), and by the soluble guanylate cyclase inhibitor methylene blue (10 μM) (37 ± 6%), while the more selective soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolol[4,3-a]quinoxalin-1-one (ODQ, 1 μM) produced only a parallel (about 3 fold) rightward displacement of the propolis extract concentration-response curve. Collectively, these results support the notion that the propolis extract-mediated relaxation in the guinea-pig trachea involves the release of nitric oxide, probably from sensory neurons, besides the activation of soluble guanylate cyclase and activation of Ca2+- and ATP-sensitive K+channels. Furthermore, the stimulation of β2-adrenergic and VIP receptors also seems to account for its relaxant action.
Clearance and disposition of indometacin in chronically instrumented fetal lambs following a 3-day continuous intravenous infusion
Authors: Krishna Rajesh , Riggs K Wayne , Kwan Eddie , Wong Harvey , Szeitz Andras , Walker Martin P R , Rurak Dan W 
Published: October 2002

Abstract
Indometacin is used in pregnancy for the treatment of premature labour, but there are limited data on the disposition of the drug in the fetus. In order to elucidate fetal indometacin pharmacokinetics at plasma levels and duration comparable with those occurring with use of the drug for tocolysis in humans, indometacin was administered at doses of 1.9 (low dose, LD; n = 5) or 7.5 (high dose, HD; n = 9) μg min−1 to steady state over a 3-day period in chronically instrumented fetal lambs. Indometacin concentrations in biological fluid samples were analysed by a sensitive capillary gas chromatography-electron capture detection method. The mean steady-state fetal arterial plasma indometacin concentrations were 68.6 ± 16.5 ng mL−1 in the LD infusion and 230.3 ± 28.8 ng mL−1 in the HD infusion. Indometacin concentrations in amniotic fluid were ∼10% of those in fetal plasma, and below assay detection limits in tracheal fluid. Total body clearance (TBC) in the LD and HD infusions were not different and the overall mean was 11.3 ± 1.2 mL min−1 kg−1. In the 11 experiments where paired fetal arterial and umbilical venous samples were collected, the extraction of indometacin across the placenta averaged only 5.2 ± 1.1%, indicating low placental permeability to the drug in sheep. However, fetal placental clearance (CLpl) of indometacin (10.0 ± 2.5 mL min−1 kg−1, n = 10) averaged 115.1± 41.2% of TBC in these animals and the calculated value for fetal non-placental clearance (0.6 ± 2.8 mL min−1 kg−1) was not significantly different from zero. Fetal renal clearance of intact indometacin (3.8 ± 1.1 μL min−1 kg−1; n = 12) was also very low. However, treatment of fetal urine with glucuronidase indicated the presence of glucuronide conjugates and these comprised 69.9 ± 8.2% of the total drug concentration (i.e. intact + conjugated) in urine. Thus, the fetal lamb appears to be able to glucuronidate indometacin, but the contribution of this and other non-placental routes to overall fetal elimination of the drug appear minimal. CLpl of the drug is also low owing to the physicochemical properties of indometacin (high polarity) and the permeability characteristics of the sheep placenta.