bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Action of 5-Hydroxytryptamine on Normal and Cystic Fibrosis Mouse Colon: Effects on Secretion and Intracellular Calcium
Authors: Hardcastle J , Hardcastle P T , Klaren P H M , Taylor C J , White S J 
Published: October 2002

Abstract
The ability of mouse colon to generate a secretory response to stimulation by 5-hydroxytryptamine (5-HT) was investigated in intact colonic sheets mounted in Ussing chambers. A preparation of intact isolated crypts was used to determine whether 5-HT action was associated with an elevation of cytosolic calcium levels, measured using the calcium-sensitive fluorescent dye, fura-2.
5-HT increased the short-circuit current, an effect that was inhibited by 55% in the absence of chloride and by 83% in the presence of serosal frusemide, consistent with the stimulation of electrogenic chloride secretion. This was confirmed by the observation that colonic tissue from transgenic cystic fibrosis mice (n = 4) failed to respond to 5-HT, although wild-type tissues generated an increased short-circuit current of 52.4 ± 11.1 μA cm−2 (n = 9). The electrical response to 5-HT was calcium-dependent. 5-HT action was unaffected by tetrodotoxin and was not mimicked by the 5-HT3 agonist 1-phenylbiguanide, indicating that neural mechanisms are not involved. The cyclooxygenase inhibitor indomethacin, however, reduced the 5-HT-induced rise in short-circuit current by 73%, suggesting that prostaglandin production contributes to the response. Stimulation of crypts with acetylcholine elicited an increase in cytosolic calcium levels, but no such response was detected on application of 5-HT (10−6 to 10−4 M), suggesting that 5-HT does not directly modulate intracellular calcium in colonic crypt cells.
It is concluded that mouse colon responds to 5-HT challenge with a stimulation of electrogenic chloride secretion and that this effect is mediated by indirect mechanisms that might involve immune elements within the colonic wall.
The Long-lasting Effect of TU-199, a Novel H+,K+-ATPase Inhibitor, on Gastric Acid Secretion in Dogs
Authors: Uchiyama Kazuyuki , Wakatsuki Daisuke , Kakinoki Bunpei , Takeuchi Yoshishige , Araki Tsutomu , Morinaka Yasuhiro 
Published: October 2002

Abstract
We have used Heidenhain-pouch dogs to investigate the effects of (±)-5-methoxy-2-{[(4-methoxy-3,5-dimethylpyrid-2-yl)methyl]sulphinyl}-1H-imidazo[4,5-b]pyridine (TU-199), an imidazopyridine derivative, on gastric acid secretion stimulated by histamine, carbachol and tetragastrin. We have also investigated the duration of the antisecretory effect of TU-199 using a measurement of intragastric pH for 24 h in gastric fistula dogs whose gastric acid secretion was stimulated by histamine.
Single oral administration of TU-199 (0.1, 0.2 and 0.4 mg kg−1) dose-dependently suppressed gastric acid secretion stimulated by histamine infusion. Oral treatment with TU-199 (0.2, 0.4 and 0.8 mg kg−1) also dose-dependently inhibited acid secretion induced by carbachol and tetragastrin. The inhibitory effect of TU-199 on stimulated gastric acid secretion was more potent than that of omeprazole, a well-known H+,K+-ATPase inhibitor in dogs. Repeated oral treatment with TU-199 at a dose of 0.2 mg kg−1 once a day for seven days markedly suppressed histamine-stimulated gastric acid secretion in dogs. This inhibitory effect of TU-199 reached a maximum level after three or four doses and was more pronounced than that of omeprazole or lansoprazole. In gastric fistula dogs, the duration of intragastric pH-elevation by administration of TU-199 (0.3 mg kg−1) was much longer than that of omeprazole (0.6 mg kg−1) or lansoprazole (0.9 mg kg−1). The IC50 values (doses resulting in 50% inhibition) of TU-199, omeprazole and lansoprazole with regard to H+,K+-ATPase activity in dog gastric mucosal microsomes were 8.6, 8.8 and 9.9 μM, respectively.
These results indicate that TU-199 inhibits gastric acid secretion via suppression of a H+,K+-ATPase activity. Our findings also suggest that TU-199 might have potent and long-lasting effects on gastric acid secretion.
In-vivo and In-vitro Metabolic Clearance of Midazolam, a Cytochrome P450 3A Substrate, by the Liver under Normal and Increased Enzyme Activity in Rats
Authors: Higashikawa Fumiko , Murakami Teruo , Kaneda Tatsuya , Takano Mikihisa 
Published: October 2002

Abstract
The metabolic clearance of midazolam, a cytochrome P450 (CYP) 3A substrate, by the liver under normal and increased enzyme activity in rats was determined in-vivo and in-vitro to elucidate the reproducibility of the in-vivo hepatic extraction ratio of midazolam from the in-vitro study. The hepatic enzyme activity was modified by pretreating rats with a CYP inducer such as dexamethasone and clotrimazole.
The in-vivo hepatic extraction ratio (ERh,obs) of midazolam under a steady-state plasma concentration (approx. 3 nmol mL−1) in untreated (control) rats was 0.864. This value increased to 0.984 in dexamethasone-pretreated rats and to 0.964 in clotrimazole-pretreated rats. The in-vitro hepatic intrinsic clearance (CLint,in-vitro), expressed as mL min−1 (mg microsomal protein)−1, of midazolam was estimated as Vmax (Km)−1 by in-vitro metabolism studies using liver microsomes. The CLint,in-vitro value was converted to the CLint,cal value, expressed as mL min−1 kg−1, by considering the microsomal protein content (g liver)−1 and the microsomal protein content (g liver)−1 kg−1. The estimated CLint,cal value was then converted to the ERh value (ERh,cal) according to the well-stirred, the parallel-tube and the dispersion models. The ERh,cal values obtained by the parallel-tube model were in good agreement with corresponding in-vivo ERh,obs values.
In conclusion, it was demonstrated that high hepatic clearances of midazolam under normal and increased CYP3A activity were reasonably predicted from in-vitro metabolism studies using liver microsomes.
Characteristics of L-Carnitine Transport in Cultured Human Hepatoma HLF Cells
Authors: Yokogawa Koichi , Miya Kazuhiro , Tamai Ikumi , Higashi Yasuhiko , Nomura Masaaki , Miyamoto Ken-Ichi , Tsuji Akira 
Published: October 2002

Abstract
The recently cloned organic cation transporter, OCTN2, isolated as a homologue of OCTN1, has been shown to be of physiological importance in the renal tubular re-absorption of filtered L-carnitine as a high-affinity Na+ carnitine transporter in man. Although the mutation of the OCTN2 gene has been proved to be directly related to primary carnitine deficiency, there is little information about the L-carnitine transport system in the liver. In this study, the characteristics of L-carnitine transport into hepatocytes were studied by use of cultured human hepatoma HLF cells, which expressed OCTN2 mRNA to a greater extent than OCTN1 mRNA.
The uptake of L-carnitine into HLF cells was saturable and the Eadie—Hofstee plot showed two distinct components. The apparent Michaelis constant and the maximum transport rate were 6.59± 1.85 (mean ± s.d.) and 78.5 ± 21.4 pmol/5 min/106 cells, respectively, for high-affinity uptake, and 590 ± 134 μM and 1507 ± 142 pmol/5 min/106 cells, respectively, for low-affinity uptake. The high affinity L-carnitine transporter was significantly inhibited by metabolic inhibitors (sodium azide, dinitrophenol, iodoacetic acid) and at low temperature (4°C). Uptake of [3H]L-carnitine also required the presence of Na+ ions in the external medium. The uptake activity was highest at pH 7.4, and was significantly lower at acidic or basic pH. L-Carnitine analogues (D-carnitine, L-acetylcarnitine and γ-butyrobetaine) strongly inhibited uptake of [3H] L-carnitine, whereas β-alanine, glycine, choline, acetylcholine and an organic anion and cation had little or no inhibitory effect.
In conclusion, L-carnitine is absorbed by hepatocytes from man by an active carrier-mediated transport system which is Na+-, energy- and pH-dependent and has properties very similar to those of the carnitine transporter OCTN2.
Protamine Induces Elevation of Cytosolic Free Ca2+ in Cultured Porcine Aortic Endothelial Cells
Authors: Sato Nobuyoshi , Az-Ma Toshiharu , Fujii Kohyu , Yuge Osafumi 
Published: October 2002

Abstract
To test the hypothesis that protamine influences calcium movement in endothelial cells, we measured the concentration of intracellular free calcium ([Ca2+]i) in cultured porcine aortic endothelial (PAE) cells in Krebs solution (2-5mM Ca2+, pH7.4) at 37°C, by fura-2 fluorimetry.
The basal [Ca2+]i of PAE cells was 113 ± 18 nM (n − 6). Protamine increased [Ca2+]iin a concentration-dependent manner (EC50, the concentration having 50% of the maximum effect, 1.4 ± 0.3 μg mL−1, n = 6). The response of PAE cells to 100 μg mL−1 protamine (330 ± 80 nM, n = 6) was blocked by a Ca2+ chelator, 5 mM glycoletherdiaminetetraacetic acid (EGTA; 131 ± 16 nM, n = 6), and by a non-selective Ca2+ channel blocker, 3 mM Co2+ (134 ± 14 nM, n = 6).
These results suggest that Ca2+ influx through cell-membrane Ca2+ channels is mainly responsible for the protamine-induced Ca2+ elevation.
Pharmacokinetics of a New Proton-pump Inhibitor, YJA-20379-8, after Intravenous and Oral Administration to Rats with Streptozotocin-induced Diabetes Mellitus
Authors: Chung Su Y , Han Kye S , Shon Sang K , Chang Man S , Lee Myung G 
Published: October 2002

Abstract
Because physiological changes occurring in diabetes mellitus patients could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of a new proton pump inhibitor, YJA-20379-8, were investigated after intravenous and oral administration of the drug (50 mg kg−1) to control rats and to rats with streptozotocin-induced diabetes mellitus (SIDM).
After intravenous administration of YJA-20379-8 to SIDM rats, plasma concentrations of the drug were significantly higher and this resulted in a significantly greater AUC (area under the concentration-time curve; 2520 ± 366 compared with 1870 ± 272 min mL−1). This was because of significantly slower clearance (CL; 19.5 ± 2.88 compared with 27.2 ± 3.93 mL min−1 kg−1) in SIDM rats. The significantly slower metabolism of YJA-20379-8 in SIDM rats was confirmed by an in-vitro tissue metabolism study; the amounts of YJA-20379-8 remaining in the liver (27.1 ± 5.19 compared with 18.9 ± 8.24 μg (g tissue)−1) were significantly greater after 30-min incubation of the drug (50 μg) with supernatant fractions obtained from the tissues by centrifugation at 9000 g. After oral administration of YJA-20379-8 to SIDM rats the plasma concentrations of the drug were significantly lower and this resulted in significantly smaller AUC (128 ± 31.0 compared with 219 ± 45.6 μg min mL−1). This was because of reduced gastrointestinal absorption of YJA-20379-8 in SIDM rats; the amounts of the oral dose recovered as unchanged drug from the entire gastrointestinal tract after 24 h were significantly greater (32.9 compared with 19.2%) in SIDM rats.
The tissue distribution of YJA-20379-8 was not affected by SIDM.
Relative Blood-Brain Barrier Permeabilities of the Cholecystokinin Receptor Antagonists Devazepide and A-65186 in Rats
Authors: Woltman Todd A , Hulce Martin , Reidelberger Roger D 
Published: October 2002

Abstract
The blood-brain barrier permeabilities of the type-A cholecystokinin receptor antagonists devazepide and A-65186 (Nα-3-quinolinoyl-D-Glu-N,N-dipentylamide) have been compared with those of the reference compounds iodoantipyrine, which readily penetrates the blood-brain barrier, and mannitol, which does not.
Anaesthetized rats received a bolus injection into the left carotid artery of [14C]iodoantipyrine (0.25 μCi) combined with [3H]mannitol, [3H]devazepide or [3H]A-65186 (1 μCi each). Rats were decapitated 12 s after injection and the brains were removed. Four samples of left cerebrum (ca 100 mg each) were solubilized overnight and 14C and 3H activity were measured. The brain-uptake index for each test compound was determined as [(3H/14C for sample)]/[(3H/14C for injectate)] × 100, with a value of 100 representing blood-brain barrier permeability equal to that for iodoantipyrine. The brain-uptake index (mean ± s.e.m.) was 1.6 ± 0.3 for [3H]mannitol (n = 5), 90.6 ± 4.1 for [3H]devazepide (n = 7, P &lt; 0.001 compared with mannitol) and 3.5 ± 0.7 for [3H]A-65186 (n = 4, P &gt; 0.05 compared with mannitol, P &lt; 0.001 compared with devazepide). Thus, devazepide readily penetrated the blood-brain barrier whereas A-65186 did not.
It is concluded that devazepide and A-65186 are likely to be useful pharmacological tools for determining whether cholecystokinin is acting peripherally or at brain sites beyond the blood—brain barrier to produce satiety or any other function mediated by the type A cholecystokinin receptor.
Rabbit Corneal and Conjunctival Permeability of the Novel Aldose Reductase Inhibitors: N-{[4-(Benzoylamino)phenyl] sulphonyl}glycines and N-Benzoyl-N-phenylglycines
Authors: Kompella Uday B , Sunkara Gangadhar , Thomas Erica , Clark C Randall , Deruiter Jack 
Published: October 2002

Abstract
Corneal and conjunctival permeability has been investigated for novel aldose reductase inhibitors (ARIs) of the N{[4-(benzoylamino)phenyl]sulphonyl}glycine (benzoylaminophenylsulphonylglycine) and N-benzoyl-N-phenylglycine (benzoylphenylglycine) series, compounds developed for prevention of cataract formation in diabetic subjects.
Six benzoylaminophenylsulphonylglycines were synthesized with modifications either of the phenyl group or of the glycine structure and three benzoylphenylglycines were synthesized with modification in the phenyl group of the benzoyl moiety. Transport of ARIs in the mucosal to serosal direction was evaluated across rabbit cornea and conjunctiva bathed in glutathione-bicarbonate Ringer's solution maintained at pH 7.4 and 37°C. The permeability coefficients of the novel ARIs across cornea and conjunctiva ranged from 1.87 to 8.95 times 10−6 cms−1 and from 4.6to19.15 times 10−6cms−1, respectively. The ratio of corneal to conjunctival permeability ranged from 0.12 to 0.79. The calculated log partition coefficient (log P) values for the ARIs were in the range 0.84 to 2.78. The log distribution coefficients (log D) were in the range −2.87 to −0.89. There was no apparent relationship between log P or log D and the permeability coefficients of the ARIs for either tissue. Cornea was more resistant to ARI transport than was conjunctiva. Substitution of a phenyl group for hydrogen in the glycine methylene group reduced the permeability coefficient. Permeability coefficients were different for different stereoisomers. Compared with the permeability coefficient of benzoylaminophenylsulphonylglycine, that of 4-fluorobenzoylaminophenylsulphonylglycine was lower in the cornea but similar in the conjunctiva. In both tissues, the permeability coefficient of 2-nitrobenzoylaminophenylsulphonylglycine was less than that of 4-nitrobenzoylaminophenylsulphonyl-glycine. There was no significant difference between the permeability coefficients of 3-nitro- and 4-nitrobenzoylphenylglycines through either tissue and the permeability coefficients of these compounds were greater than that of the more lipophilic 4-methylbenzoylphenylglycine.
The lack of dependence of the permeability coefficients on log P or log D and the different permeabilities of stereoisomers imply the existence of specialized transport processes for the ARIs tested in this study.
Inhibition of Na+ Channel or Na+/H+ Exchanger Attenuate the Hydrogen Peroxide-induced Derangements in Isolated Perfused Rat Heart
Authors: Hara Akiyoshi , Arakawa Johji , Xiao Chun-Yang , Hashizume Hiroko , Ushikubi Fumitaka , Abiko Yasushi 
Published: October 2002

Abstract
The effect of tetrodotoxin, a specific inhibitor of the Na+ channel, and 5-(N,N-dimethyl)-amiloride, a specific inhibitor of the Na+/H+ exchanger, on the mechanical and metabolic derangements induced by hydrogen peroxide (H2O2) was studied in the isolated perfused rat heart. The isolated rat heart was perfused aerobically at a constant flow rate and driven electrically.
H2O2 (600 μM) decreased the left ventricular developed pressure and increased the left ventricular end-diastolic pressure (i.e. mechanical dysfunction), decreased the tissue levels of adenosine triphosphate and adenosine diphosphate (i.e. metabolic derangement), and increased the tissue level of malondialdehyde (i.e. lipid peroxidation). These mechanical and metabolic derangements induced by H2O2 were significantly attenuated by tetrodotoxin (3 μM) or 5-(N,N-dimethyl)-amiloride (15 μM). Neither tetrodotoxin nor 5-(N,N-dimethyl)-amiloride modified the tissue malondialdehyde level, which was increased by H2O2. In the normal (H2O2-untreated) heart, neither tetrodotoxin nor 5-(N,N-dimethyl)-amiloride affected the mechanical function and energy metabolism.
These results suggested that inhibition of the Na+ channel or Na+/H+ exchanger was effective in attenuating the H2O2-induced mechanical dysfunction and metabolic derangements in the isolated perfused rat heart.
Antioxidant Activity of Tannin Components from Vaccinium vitis-idaea L.
Authors: Ho K Y , Huang J S , Tsai C C , Lin T C , Hsu Y F , Lin C C 
Published: October 2002

Abstract
Reactive oxygen molecules have been implicated as important pathological mediators in many clinical disorders and periodontal disease. To provide possible alternative treatment of periodontal disease, six tannins isolated from Vaccinium vitis-idaea L. were evaluated for anti-lipid peroxidation, anti-superoxide formation and free radical scavenging activity.
The results showed that cinnamtannin B1 displayed the strongest anti-lipid peroxidation activity, proanthocyanidin A-1 displayed the strongest superoxide scavenging activity, and epicatechin-(4βr&#x030a; 6)-epicatechin-(4β 8, 2r&#x030a; O r&#x030a; 7)-catechin had the strongest anti-superoxide formation effect.
We conclude that tannins isolated from V. vitis-idaea L. exhibited multiple antioxidant activity, and could be used for the treatment of periodontal disease.
Enhancement of Blood-brain Barrier Permeability by Sodium Caprate
Authors: Ohnishi Toshimasa , Aida Kazunosuke , Awazu Shoji 
Published: October 2002

Abstract
We examined the effect of sodium caprate on the integrity of the tight junctions of brain capillary endothelial cells, using a modified in-situ brain perfusion technique. Model hydrophilic compounds used were [3H]mannitol, [14C]sucrose, [3H]PEG900, [3H]PEG4000, FITC-dextran 4000, FITC-dextran 20000 and FITC-dextran 70000.
The brain distribution volume of [14C]sucrose was significantly increased by sodium caprate in a concentration-dependent manner. The effective minimum concentration was 10 mM. Furthermore, the effects of sodium caprate on the distribution volumes of hydrophilic compounds, [3H]mannitol, [14C]sucrose, [3H]PEG900, [3H]PEG4000, FITC-dextran 4000, FITC-dextran 20 000 and FITC-dextran 70 000, showed a molecular weight dependence. A plot of apparent permeation clearance against diffusion coefficient values suggested that 20 mM sodium caprate induced pores so large that the above compounds could pass through the blood-brain barrier with negligible friction within the pore.
Our results showed that intracarotid sodium caprate perfusion could enhance the permeation of hydrophilic compounds through the blood-brain barrier.
Gastrointestinal Absorption of a New Reversible Proton Pump Inhibitor, YJA-20379-8, and its Pharmacokinetics after Oral Administration in Acetic Acid-induced Gastric Ulcer in Rats
Authors: Chung Su Y , Han Kye S , Kim Ho J , Kim Jonghan , Chang Man S , Lee Myung G 
Published: October 2002

Abstract
The absorption of YJA-20379-8 (3-butyryl-4-[5-(R)-(+)-methylbenzylamino]-8-ethoxy-1,7-naphthyridine) from various rat gastrointestinal segments was evaluated using in-situclosed-loops. The pharmacokinetics of the drug were also evaluated after oral administration to rats with acetic acid-induced gastric ulcer (AIURs). The concentrations of YJA-20379-8 in the biological samples were analyzed by HPLC.
The absorption of YJA-20379-8 from stomach and jejunum was fast, but approximately 50% of the drug was recovered from each segment at 24 h. The total areas under the plasma concentration-time curves from time zero to 24 h (AUC0-24h) were 161, 392, 233, 365, and 226 μg min mL−1 for stomach, duodenum, jejunum, ileum, and colon, respectively. After oral administration of the drug, the plasma concentrations and the resultant AUC0-12h were not significantly different between control and AIURs. The detection limits of YJA-20379-8 in human plasma and urine were 50 and 100ng mL−1, respectively.
The results suggest that modification of the oral dose of YJA-20379-8 may not be required in gastric ulcer patients if the present rat pharmacokinetic data could be extrapolated to man.
High-performance Liquid-chromatographic-Atmospheric-pressure Chemical-ionization Ion-trap Mass-spectrometric Identification of Isomeric C6-hydroxy and C20-hydroxy Metabolites of Methylprednisolone in the Urine of Patients Receiving High-dose Pulse Therapy
Authors: Vree Tom B , Maljers Louis , Van Den Borg Noud , Nibbering Nico M M , Verwey-Van Wissen Corrien P W G M , Lagerwerf Aart J , Maes Robert A A , Jongen P Jozef H 
Published: October 2002

Abstract
Fourteen metabolites of methylprednisolone have been analysed by gradient-elution high-performance liquid chromatography coupled with tandem mass spectrometry (LC-MS-MS).
The compounds were separated on a Cp Spherisorb 5 μm ODS column connected to a guard column packed with pellicular reversed phase. The mobile phase was an acetonitrile-1.0% aqueous acetic acid gradient at a flow rate of 1.5 mL min−1.
The analysis gave a complete picture of parent drug, prodrugs and metabolites, and the α/β stereochemistry was resolved. The short (1-2h) elimination half-life of methylprednisolone is explained by extensive metabolism. The overall picture of the metabolic pathways of methylprednisolone is apparently simple—reduction of the C20 carbonyl group and further oxidation of the C20, C21 side chain (into C21COOH and C20COOH), in competition with or in addition to oxidation at the C6 position.
Chromatographic Resolution, Chiroptical Characterization and Preliminary Pharmacological Evaluation of the Enantiomers of Butibufen: a Comparison with Ibuprofen
Authors: Hoult J R S , Jackson B R , Benicka E , Patel B K , Hutt A J 
Published: October 2002

Abstract
Enantiomeric resolution of butibufen has been achieved on a cellulose tris(3,5-dimethylphenylcarbamate) chiral stationary phase with hexane-isopropanol-trifluoroacetic acid, 100: 1.2: 0.02 (v/v/v) as mobile phase at a flow rate of 1.0 mL min−1.
Semi-preparative isolation of the enantiomers then chiroptical characterization indicated that the order of elution was (-)-R- before (+)-S-butibufen. When tested for their effects on the cyclooxygenase and 5-lipoxygenase pathways of eicosanoid metabolism in calcium ionophore-activated rat peritoneal leukocytes it was found that (+) -S-butibufen inhibited generation of thromboxane B2 (TXB2) and prostaglandin E2 (PGE2) (cyclooxygenase pathway), with an IC50 of 1.5 μ (approx.), whereas the (-)-R enantiomer was essentially inactive. Neither enantiomer inhibited the 5-lipoxygenase pathway. In this regard, (+)-S-butibufen was approximately five times less potent as a cyclooxygenase inhibitor than (+)-S-ibuprofen.
These results show the enantiomeric specificity and pathway selectivity of this novel non-steroidal anti-inflammatory drug.