bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pituitary Homeobox 1 Activates the Rat FSHβ (rFSHβ) Gene through Both Direct and Indirect Interactions with the rFSHβ Gene Promoter
Authors: Zakaria Marjorie M. , Jeong Kyeong-Hoon , Lacza Charlemagne , Kaiser Ursula B. 
Published: October 2002

AbstractMolecular mechanisms underlying gonadotrope-specific and hormonal regulation of FSHβ gene expression remain largely unknown. We have studied the role of pituitary homeobox 1 (Ptx1), a transcription factor important for regulation of many pituitary-specific genes, in the regulation of rat FSHβ (rFSHβ) gene transcription. We demonstrate that Ptx1 activates the rFSHβ gene promoter both basally and in synergy with GnRH. The effect of Ptx1 was localized to −140/−50, a region also important for basal activity of the promoter. Two putative Ptx1 binding sites (P1 and P2) homologous to consensus Ptx1 binding elements were identified in this region. We demonstrate specific binding of Ptx1 to the P2 but not to the P1 site. Furthermore, functional studies indicate that the P2 but not the P1 site mediates activation of the promoter by Ptx1. Residual activation of the promoter by Ptx1 was observed independent of the P2 site. However, no additional Ptx1 binding sites were identified in this region, indicating that the residual activation observed is likely independent of direct Ptx1 binding to the promoter. These results identify a functional Ptx1 binding site in the rFSHβ gene promoter and suggest the presence of an additional activating pathway that is independent of direct binding of Ptx1 to the promoter.
Controlled Transdermal Delivery of Propranolol Using HPMC Matrices: Design and In-vitro and In-vivo Evaluation
Authors: Verma P R P , Iyer Sunil S 
Published: October 2002

Abstract
To improve bioavailability and achieve a smoother plasma-concentration profile as compared with oral administration, a matrix-dispersion-type transdermal delivery system was designed and developed for propranolol using different ratios of hydroxypropyl-methylcellulose (HPMC) K4M, K15M and K100M. Formulations were evaluated for in-vitro dissolution characteristics using a Cygnus' sandwich-patch holder.
Drug release followed Higuchi rather than zero-order or first-order kinetics. In-vivo evaluation was carried out on healthy volunteers (21 ± 1.41 years; 60.89 ± 5.35 kg) following the balanced incomplete block design. The dissolution rate constant (k) and data generated from plasma and urine (Cmax, maximum plasma concentration; tmax, time to reach peak plasma concentration; AUC, area under the curve; ke, elimination rate constant; t½e, elimination half-life; ka, absorption rate constant; t½a, absorption half-life) were evaluated statistically by two-way analysis of variance. Statistically excellent correlation was found between the percentage of drug absorbed and Cmax, AUC0–24 and AUC0-∞. A highly significant difference (P &lt; 0.001) was observed when Cmax and AUC0-∞ generated from plasma and urine were compared, but ke, t½e, ka and t½a did not differ significantly (P &gt; 0.1).
We conclude that urinary excretion data may be used as a simpler alternative to blood level data in studying the kinetics of absorption and deriving the absorption parameters.
Effects of Some Non-ionic Surfactants on Transepithelial Permeability in Caco-2 Cells
Authors: Dimitrijevic Dejana , Shaw Andrew J , Florence Alexander T 
Published: October 2002

Abstract
The effects of the non-ionic surfactants polysorbate 20, polysorbate 60, polysorbate 85, cholesteryl poly (24) oxyethylene ether (Solulan C24) and the lanolin-based poly (16) oxyethylene ether (Solulan 16) on the epithelial integrity of monolayers of human intestinal epithelial (Caco-2) cells has been studied using metformin as a model drug. The aim was to identify the surfactants and their optimal concentrations capable of enhancing drug transport while causing no, or only minor, cellular damage. Effects on cell permeability were assessed by measurements of the transport of metformin, a hydrophilic drug, by monitoring transepithelial electrical resistance. Cell viability was determined by the diphenyltetrazolium bromide test (the MTT test).
All the surfactants studied demonstrated concentration-dependent effects on cell permeability and cell viability. The effects on transepithelial electrical resistance correlated with cell viability, i.e. increased transepithelial electrical resistance and increased cell-monolayer permeability for metformin corresponded to decreased cell viability. The results indicate that the Solulan and polysorbate surfactants were active as absorption enhancers, Solulan C24 and 16 being more effective than polysorbates 20, 60 or 85, causing an increase in metformin transport at lower concentrations than the polysorbates. Polysorbate 20 exerted its greatest effect at a concentration of 5%—increasing the flux of metformin after 3h by a factor of around 20 over the control. Large increases in the transport of metformin, especially at surfactant levels of 0.05%, 0.1% and 0.5%, were related to the effect of Solulan C24 and Solulan 16 on the cell permeability.
The Caco-2 cell monolayer experiments confirmed the ability, especially of polysorbate 20, Solulan C24 and Solulan 16, to increase the absorption of metformin. The polysorbates increased permeability as a result of solubilisation of membrane components, while Solulans did so by penetrating and solubilising the membrane. Correlation between increase in membrane permeability and the toxicity of the surfactants towards the cell membrane has been established.
Inhibitory Effects of Glibenclamide on the Contraction of Human Arterial Conduits used in Coronary Artery Bypass Surgery
Authors: Crosbie Alan E , Vuylsteke Alain , Ritchie Andrew J , Latimer Raymond D , Callingham Brian A 
Published: October 2002

Abstract
Glibenclamide has been shown to inhibit prostanoid-induced contraction in a number of blood vessel types. In this study, the effects of glibenclamide on the contraction of human peripheral arteries in response to both prostanoid and non-prostanoid agonists were compared and possible mechanisms of action were investigated.
Segments of left internal mammary artery (LIMA) and radial artery, taken from patients undergoing coronary artery bypass graft (CABG) surgery, were mounted in organ baths containing physiological saline solution aerated with 95% O2/5% CO2 at 37°C. Contractions were obtained by either the use of a thromboxane analogue (U46619), l-phenylephrine, KCl or CaCl2. The effects of glibenclamide on these contractions were observed and pEC50 values were determined after manipulation of a logistic curve-fitting equation. Concentration-dependent relaxation of U46619-contracted LIMA and radial artery was observed in the presence of glibenclamide, with calculated pEC50 values of 4.2±0.17 (n = 7) for LIMA and 3.26 ±0.48 (n = 5) for radial artery. Incubation of both LIMA and radial artery with glibenclamide (50 μm) caused the concentration-response curves for U46619 and l-phenylephrine to shift significantly to the right. Similarly the KCl tension relationship was caused to shift to the right. Finally, glibenclamide (100 μm) also had an inhibitory effect on Ca2+-induced tension in radial artery.
These results show that the inhibitory effects of glibenclamide on human peripheral blood vessels are not restricted to prostanoid-induced contractions. Furthermore, evidence has been provided to suggest that these effects might be mediated through an interaction with voltage-sensitive Ca2+ channels.
Pharmacodynamics of S-2150, a Simultaneous Calcium-blocking and α1-Inhibiting Antihypertensive Drug, in Rats
Authors: Ishibashi Toru , Yano Yoshitaka , Oguma Takayoshi 
Published: October 2002

Abstract
The in-vivo pharmacodynamics of S-2150, a newly developed dual-blocking type antihypertensive drug, was evaluated following intravenous infusion to rats. Previous in-vitro studies showed that the drug has two distinct mechanisms of antihypertensive effect—calcium-channel blocking activity and α1-adrenoceptor antagonism—which could be explained by a combination of two different pharmacodynamic models.
The present in-vivo study showed that S-2150 also displays a complex pharmacodynamic profile (as measured by the decrease in mean blood pressure), which could be described by a combination of two sigmoid Emax models independently connected with the central compartment and the effect compartment.
These results suggested that the dual-blocking mechanism of S-2150, which has been observed in in-vitro experiments, was also evaluated by the pharmacodynamic analysis of in-vivo experimental data.
Anti-inflammatory Effect of FR140423, a Novel Selective Cyclo-oxygenase-2 Inhibitor, in Rat Adjuvant Arthritis Without Gastrointestinal Side Effects
Authors: Ochi Takehiro , Goto Toshio 
Published: October 2002

Abstract
We investigated the effect of FR140423 (3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulphinyl)phenyl]pyrazole), a novel and selective cyclo-oxygenase (COX)-2 inhibitor, in rat adjuvant arthritis. The results were compared with that of indomethacin.
We tested the inhibitory effects of FR140423 on paw oedema and the formation of the arachidonic acid metabolites prostaglandin (PG) E2 and leukotriene (LT) B4 in inflamed paws immunized with heat-killed and dried Mycobacterium tuberculosis. Oral administration of FR140423 showed a dose-dependent anti-inflammatory effect. This effect was two- to threefold more potent than that of indomethacin. The increase of PGE2 and LTB4 in inflamed paws was associated with the development of paw swelling. FR140423 and indomethacin dose-dependently suppressed the level of PGE2 but not LTB4 in arthritic paws. Unlike indomethacin, FR140423 did not induce gastric lesions even at doses up to 10 mg kg−1 in arthritic rats.
FR140423 has a potent anti-inflammatory effect mediated by inhibition of PGE2 produced by COX-2 in inflamed tissues. The safety profile of FR140423 appears to be an improvement on the safety profile of indomethacin.
Benidipine Inhibits Apoptosis During Ischaemic Acute Renal Failure in Rats
Authors: Yao Kozo , Sato Hitoshi , Ina Yasuhiro , Nagashima Ken , Nishikawa Satoshi , Ohmori Kenji , Ohno Tetsuji 
Published: October 2002

Abstract
We have investigated the effects of benidipine (hydrochloride), a calcium antagonist, against ischaemic acute renal failure in rats. Using histological examination, we studied whether the inhibition of apoptosis was associated with the protective effects of benidipine on the ischaemic renal injury.
Acute renal failure was induced by the unilateral clamping of the left renal artery for 60 min, followed by reperfusion and contralateral nephrectomy. Drugs were given intravenously 5 min before the unilateral clamping. Prophylactic administrations of benidipine (10 μg kg−1, i.v.) significantly ameliorated the development of renal failure as estimated by the measurements of serum creatinine and blood urea nitrogen 24 h after the reperfusion. Amlodipine (besilate, 100 and 300 μg kg−1, i.v.) tended to attenuate renal dysfunction. Lisinopril (300 and 1000 μg kg−1, i.v.), an angiotensin converting enzyme inhibitor, was ineffective in this acute renal failure model. Histological examination using the terminal transferase-mediated dUTP-biotin nick end-labelling (TUNEL) method to detect apoptotic cells revealed that the TUNEL-positive tubular epithelium was prominent in the renal cortex 24 h after the reperfusion. The TUNEL-positive cells were significantly reduced by pretreatment with benidipine.
The results demonstrate that benidipine can ameliorate the ischaemic acute renal failure in rats and suggest that the renoprotective effect of benidipine was at least partly attributable to the reduction of apoptosis in tubular epithelial cells.
Effect of Lamivudine on Uptake of Organic Cations by Rat Renal Brush-Border and Basolateral Membrane Vesicles
Authors: Takubo Takatoshi , Kato Toshihiro , Kinami Junji , Hanada Kazuhiko , Ogata Hiroyasu 
Published: October 2002

Abstract
The effect of lamivudine on uptake of a representative organic cation, tetraethylammonium (TEA), by rat renal brush-border membrane vesicles (BBMV) and basolateral membrane vesicles (BLMV) has been investigated.
The pH-driven uptake of TEA by BBMV (pHin = 60, pHout = 7.5) was inhibited by lamivudine. The IC50 value (concentration resulting in 50% inhibition) for the concentration-dependent effect of lamivudine on TEA uptake by BBMV after 30 s was 2668 μm whereas IC50 values for cimetidine and trimethoprim were &lt;2.5 μm and &lt; 25 μm, respectively. The early uptake of TEA by BLMV was also reduced significantly by lamivudine. The IC50 value for the concentration-dependent effect of lamivudine on uptake of TEA by BLMV at 30 s was &gt; 25 mm, whereas the IC50 values for Cimetidine and trimethoprim were 2116 μm and 445 μm, respectively.
These findings suggest that compared with other cationic drugs, such as trimethoprim and Cimetidine, lamivudine is a weak inhibitor of organic cation transport into the tubules by the brush-border and basolateral membranes of renal epithelial cells. It is unlikely lamivudine will have any significant effect on the excretion of co-administered cationic drugs by the renal tubules.
Reduction of the Potential Anticancer Drug Oracin in the Rat Liver In-vitro
Authors: Szotáková Barbora , Skálová Lenka , Wsól Vladimír , Kvasnièčková Eva 
Published: October 2002

Abstract
Studies on the metabolism of the potential cytostatic drug oracin have shown that a principal metabolite of oracin is 11-dihydrooracin (DHO). We conducted in-vitro experiments to investigate the extent of oracin carbonyl reduction in microsomal or cytosolic fractions and to find out the enzymes involved under these conditions.
Among several inducers of rat cytochrome P450 only 3-methylcholanthrene caused a significant (P &lt; 0.01) stimulation (1.9 times) of DHO production in microsomal fraction and the specific P4501A inhibitor α-naphthoflavone significantly (P &lt; 0.01) decreased (twice) the induced reduction activity. Cytochrome P4501A participates in oracin reduction in microsomes. 18β-Glycyrrhetinic acid, a specific inhibitor of hydroxysteroid dehydrogenase, significantly (P &lt; 0.01) inhibited the production of DHO in the microsomal fraction (&gt;95% inhibition) in comparison with the non-inhibited reaction. Statistically significant (P &lt; 0.01) inhibition (95%) of DHO formation was caused by metyrapone, which is also the substrate of 11β-hydroxysteroid dehydrogenase.
The main microsomal enzyme which catalyses the carbonyl reduction of oracin is probably 11β-hydroxysteroid dehydrogenase. Important oracin reduction to DHO in the cytosolic fraction was found. According to its specific sensitivity towards quercitrin (inhibition by 99%, P &lt; 0.01), the enzyme responsible for DHO formation in the rat liver cytosol is postulated to be carbonyl reductase.
Structure-Activity Relationships for the Ca2+-releasing Activity of 6-Hydroxy-β-carboline Analogues in Skeletal Muscle Sarcoplasmic Reticulum—The Effects of Halogen Substitution at C-5 and C-7
Authors: Seino-Umeda Asami , Ishibashi Masami , Kobayashi Jun'Ichi , Ohizumi Yasushi 
Published: October 2002

Abstract
This study of structure-activity relationships of 6-hydroxy-β-carboline analogues has been performed on the basis of quantitative measurement of Ca2+-releasing activity in the sarcoplasmic reticulum of skinned fibres of skeletal muscle.
Substitution of halogens for hydrogens at the C-5 and C-7 positions and further introduction of a methyl group into the N-9 position of 6-hydroxy-β-carboline resulted in Ca2+-releasing activity. The 50% effective concentrations of 5,7-dibromoeudistomin D, 5,7-dichloroeudistomin D, 5,7-diiodoeudistomin D, 9-methyl-5,7-dibromoeudistomin D, 9-methyl-5,7-dichloroeudistomin D, 9-methyl-5,7-diiodoeudistomin D, and caffeine were 5.6 times 10−6, 6.3 times 10−6, 7.8 times 10−6, 2.1 times 10−6, 2.0 times 10−5, 3.7 times 10−5, and 4.7 times 10−4 m, respectively, indicating that these analogues are 10–200 times more potent than caffeine. Substitution of bromine by chlorine or iodine at the C-5 and C-7 positions markedly reduced the activity of the analogues with a methyl group at the N-9 position.
These results suggest that halogens at the C-5 and C-7 positions in the β-carboline skeleton are essential for Ca2+-releasing activity and that an N-9 methyl group also affects the activity of these analogues. Thus, these 6-hydroxy-β-carboline analogues might become powerful tools for studying the molecular mechanism of Ca2+ release in the sarcoplasmic reticulum.
Antioxidant Properties of Novel Lipophilic Ascorbic Acid Analogues
Authors: Weber Valerie , Coudert Pascal , Rubat Catherine , Duroux Eliane , Leal Fernand , Couquelet Jacques 
Published: October 2002

Abstract
Structural modifications of ascorbic acid by the introduction of lipophilic moieties has led to derivatives with increased stability against thermal and oxidative degradation. Two series of new lipophilic ascorbic analogues were synthesized to obtain antioxidants devoid of autooxidant properties: 4-benzoyl-3-hydroxyfuran-2(5H)-ones (3a-j) and 4-acetyl-5-aryl-3,4-dihydrofuran-2(5H)ones(5a-f).
These compounds were submitted to three different tests: reduction of the stable free radical, 1,1-diphenyl-2-picrylhydrazyl (DPPH); superoxide-anion scavenging assay; and lipid-peroxidation assay. Most compounds interacted with DPPH: at a concentration of 5 times 10−3 M, the reducing activity of 4-benzoyl derivatives, 3c and 3h, was more than 50%; under the same conditions, the rate of inhibition for 4-acetylbutanolides, 5a and 5f, reached 60.6% and 87.3%, respectively; 93.3% inhibition was observed with ascorbic acid. In the superoxide-anion scavenging assay, at a concentration of 1 mg mL−1, 4-benzoyl derivatives, 3g and 3i, exhibited a good activity, with IC50 (dose resulting in 50% inhibition) values of 1.45 and 1.35 times 10−3 M, respectively. 4-Acetylbutanolide, 5f, significantly inhibited the Fe2+/ADP/ascorbate-induced lipid peroxidation of rat liver microsomes with an IC50 of 4.9 times 10−4 M.
This study demonstrates that enol functions in the structure of ascorbic acid analogues are not absolutely essential to bring about antioxidant effects.
Effects of ZNC-2381, a New Oral Compound, on Several Hepatic Injury Models and on Hepatocellular Apoptosis in Mice and Rats
Authors: Itokazu Yoshihiko , Segawa Yoshihide , Omata Takeshi , Inoue Naonori , Tsuzuike Naoki , Nagasawa Masaaki , Nishioka Hiroyasu , Kobayashi Tadashi , Nakano Yoshihisa , Kanda Takashi 
Published: October 2002

Abstract
The hepatoprotective effect of ZNC-2381 (1-(4-aminophenyl) methyl-3-(3-nitrophenyl)-1,3-dihydroimidazo[4,5-b]pyridine-2-one), a novel 2-one dihydroimidazopyridine derivative, has been evaluated in several experimental models of hepatic injury.
In mice, oral ZNC-2381, administered at doses of 3, 10 or 30 mg kg−1, 1 h before induction of hepatic injury with concanavalin A, dose-dependently inhibited increases in serum alanine aminotransferase (ALT) activity. Apoptosis of liver cells, as indicated by DNA fragmentation (nucleosome assay) and DNA-ladder formation (electrophoresis), was also inhibited dose-dependently. ZNC-2381 dose-dependently inhibited concanavalin A-induced increases in serum tumour necrosis factor (TNF)-α levels, and TNF-α mRNA expression in the liver. Oral ZNC-2381 also dose-dependently inhibited increases in serum ALT activity in mice with hepatic injury induced by Propionibacterium acnes and a bacterial lipopolysaccharide (LPS) or d-galactosamine-LPS, and in rats with d-galactosamine-induced hepatic injury.
These results indicate that oral ZNC-2381 inhibits cytokine (TNF-α) production and cytokine-related hepatocellular apoptosis, and might thus prevent different types of hepatic injury.
Influence of Immunogenicity on the Pharmacokinetics of BMS-191352, a Pseudomonas Exotoxin Immunoconjugate, in Rats and Dogs
Authors: Damle Bharat , Tay Lee , Comereski Charles , Warner William , Kaul Sanjeev 
Published: October 2002

Abstract
BMS-191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS-191352 and its influence on the pharmacokinetics in rats and dogs.
BMS-191352 was administered intravenously at doses of 0.75, 1.5, and 3 mg m−2 once every two days for a total of five doses in rats, and 1.2, 2.4, and 4.8 mg m−2 once every three days for a total of five doses in dogs. Blood samples were collected on days 1 and 9 in rats, and on days 1, 7, and 13 in dogs to monitor pharmacokinetics and anti-BMS-191352 immune response. Plasma concentrations of BMS-191352 and serum anti-BMS-191352 antibody titre were determined using ELISA assays. Pharmacokinetics were assessed using a non-compartmental method.
Anti-BMS-191352 antibodies were not observed in rats within the drug administration interval. In all dogs, except one, markedly higher anti-BMS-191352 antibody titres were observed on day 13 compared with days 1 and 7, and its magnitude was independent of BMS-191352 dose. The single dose kinetics of BMS-191352 in rats and dogs were linear and the drug exposures were generally dose proportional. Mean half-life, total body clearance, and volume of distribution were 1.74 h, 3.35 mL min−1 m−2, and 0.27 L m−2 in rats, respectively, and 4.27 h, 6.28 mL min−1 m−2, 1.19 L m−2 in dogs, respectively. The multiple-dose (day 9) kinetics in rats were similar to the single-dose kinetics. In dogs, the disposition of BMS-191352 on day 7 was similar to that on day 1; however, there was a precipitous reduction in the systemic drug exposure (by 5- to 110-fold) and marked increase in drug clearance on day 13. These changes in the kinetics of BMS-191352 were attributed to the generation of anti-BMS-191352 antibodies. In the one dog that did not develop anti-BMS-191352 antibodies, the pharmacokinetics were unchanged.
The pharmacokinetics of BMS-191352 may be perturbed due to an immune response thus restricting the therapeutic utility of the immunotoxin.
Ranolazine Attenuates Palmitoyl-l-carnitine-induced Mechanical and Metabolic Derangement in the Isolated, Perfused Rat Heart
Authors: Maruyama Kazuyasu , Hara Akiyoshi , Hashizume Hiroko , Ushikubi Fumitaka , Abiko Yasushi 
Published: October 2002

Abstract
The effect of ranolazine, a novel anti-ischaemic drug that stimulates the activity of pyruvate dehydrogenase, on palmitoyl-l-carnitine-induced mechanical dysfunction and metabolic derangement in isolated perfused rat hearts has been studied and compared with the effect of dichloroacetate, an activator of pyruvate dehydrogenase. Rat hearts paced electrically were perfused aerobically at constant flow by the Langendorff technique. Palmitoyl-l-carnitine (4 μm) increased left ventricular end-diastolic pressure and reduced left ventricular developed pressure (i.e. induced mechanical dysfunction); it also reduced tissue levels of adenosine triphosphate and increased tissue levels of adenosine monophosphate (i.e. induced metabolic derangement). These functional and metabolic alterations induced by palmitoyl-l-carnitine were attenuated by ranolazine (5, 10, and 20 μm) in a concentration-dependent manner. In contrast, dichloroacetate (1 and 10 mm) did not attenuate palmitoyl-l-carnitine-induced mechanical and metabolic derangement. In the normal (palmitoyl-l-carnitine-untreated) heart, however, ranolazine did not modify mechanical function and energy metabolism.
These results suggest that ranolazine attenuates palmitoyl-l-carnitine-induced mechanical and metabolic derangement in the rat heart, and that the beneficial action of ranolazine is not because of the energy-sparing effect or activation of pyruvate dehydrogenase.