bluuebunny/crossref_metadata_2025_split huggingface dataset:
Oxaliplatin in Combination with Infusional 5-Fluorouracil and Leucovorin Every 2 Weeks as First-Line Treatment in Patients with Advanced Colorectal Cancer: A Phase II Study
Authors: Kouroussis Ch. , Souglakos J. , Kakolyris S. , Mavroudis D. , Malamos N. , Kalbakis K. , Androulakis N. , Agelaki A. , Vardakis N. , Samonis G. , Georgoulias V. 
Published: April 2003

<i>Purpose:</i> To evaluate the efficacy and safety of oxaliplatin (L-OHP) in combination with leucovorin (LV)-modulated bolus plus infusional 5-fluorouracil (5-FU; de Gramont schedule) every 2 weeks in chemotherapy-naive patients with advanced colorectal cancer (CRC). <i>Patients and Methods:</i> Thirty-two patients (median age: 69 years) with histologically confirmed and two-dimensionally measurable metastatic CRC were enrolled. The patients’ performance status (WHO) was 0 in 14 (44%), 1 in 15 (47%), and 2 in 3 (9%) patients. Twenty (62.5%) patients had at least two metastatic sites. LV was administered at a dose of 200 mg/m<sup>2</sup>/day as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at the dose of 400 mg/m<sup>2</sup> and then, as a 22-hour continuous infusion at the dose of 600 mg/m<sup>2</sup>/day for 2 consecutive days. L-OHP was administered on day 1 at the dose of 85 mg/m<sup>2</sup> as a 2-hour infusion in parallel with LV but using different infusion lines. Treatment was administered every 2 weeks. <i>Results:</i> In an intention-to-treat analysis, 2 (6.2%) complete and 9 (28%) partial responses (28%; odds ratio 34.2%; 95% confidence interval 17.92–50.83%) were achieved while 8 (25%) patients had stable disease and 13 (41%) progressive disease. The median duration of response was 5 months, but the median time to progression has not yet been reached. After a median follow-up period of 11 months, the median survival has not yet been attained, but the projected probability for 1-year survival was 72%. Grade 3/4 neutropenia occurred in 16 (50%) patients while 1 (3%) of them developed febrile neutropenia. There was no treatment-related death. Peripheral neuropathy grade 2 and ≧3 occurred in 5 (16%) and 7 (21%) patients, respectively. <i>Conclusions:</i> The bimonthly administration of L-OHP in association with LV-modulated bolus plus infusional 5-FU (‘de Gramont’ regimen) is a well-tolerated and effective front-line treatment for metastatic CRC.
The Relationship between Rabbit Corneal Opacity and Immunohistochemical Expression of Heat Shock Protein 72/73 and c-<i>fos</i> after Excimer Laser Photorefractive Keratectomy
Authors: Hong Jong Wook , Lee Tae Soo 
Published: April 2003

To evaluate the etiology of corneal opacities, a study was done on the immunohistochemical staining for heat shock protein (HSP) 72/73 and c-<i>fos</i> after myopic excimer laser photorefractive keratectomy (PRK). New Zealand white rabbits (60 eyes) were divided into four groups: –6-, –9- and –15-dpt operation groups and a control group (only corneal epithelium removed). Using an excimer laser (VisX 20/20, Sunnyvale, Calif., USA), myopic PRK was performed on the rabbit’s cornea by a single or multizone technique followed by an immunohistochemical stain to detect the expression of HSP 72/73 and c-<i>fos</i> at 6, 24, 48 h, 1 week and 8 weeks. Corneal epithelia were healed within 3 days in all groups, and 8 weeks after the operation, the mean density of corneal opacity was 0.83 (–6-dpt operation group), 1 (–9-dpt operation group) and 1.67 (–15-dpt operation group). All groups exhibited HSP 73 in corneal epithelium and stroma. However, the maximal expression of c-<i>fos</i> and HSP 72 appeared in corneal epithelium at 24 and 48 h, respectively, after the operation in the –15-dpt group. These results suggest that the expressions of HSP 72 and c-<i>fos</i> in rabbit corneal epithelium are significant factors in relation to corneal opacity after excimer laser PRK.
Aqueous Dynamics in Experimental ab externo Trabeculectomy
Authors: Rossier Alain , Uffer Sylvie , Mermoud André 
Published: April 2003

<i>Purpose:</i> This study assessed the decrease in intraocular pressure (IOP), the residual outflow resistance of the trabeculum and the filtration site by histology in enucleated pig and human eyes after ab externo trabeculectomy. <i>Method:</i> Measurement of the resistance to aqueous outflow was performed using the constant pressure method before and after ab externo trabeculectomy. <i>Results:</i> The outflow facility was 0.31 ± 0.13 µl/min/mm Hg in pig eyes and 0.24 ± 0.08 µl/min/mm Hg in human eyes before surgery, and 79.0 ± 47.6 µl/min/mm Hg in pig eyes and 6.33 ± 6.67 µl/min/mm Hg in human eyes after ab externo trabeculectomy. On histological examinations the aqueous outflow pathway was seen to be at the level of the residual trabecular meshwork. <i>Conclusion:</i> This study showed that ab externo trabeculectomy significantly lowers IOP and improves outflow facility in enucleated pig and human eyes.
Protective Effects of Vitamin E and Selenium on the Renal Morphology in Rats Fed High-Cholesterol Diets
Authors: Gonca Süheyla , Ceylan Süreyya , Yardimoglu Melda , Dalçık Hakkı , Yumbul Zühal , Köktürk Sibel , Filiz Serdar 
Published: April 2003

The histopathological effects of cholesterol and the protective effects of vitamin E and selenium (Se) on renal histology were examined in Sprague-Dawley rats. Light-microscopic evaluation of the renal cortex revealed: glomerular fibrosis, cellular and mesangial proliferation, capillary obliteration and cholesterol crystals in the tubular lumina of the cholesterol-fed group. These results suggest that oxidated LDL (O-LDL) is a cytotoxic factor which stimulates mesangial cell and matrix proliferation. Ultrastructurally, small and large lipid vacuolization in intracapillary lumina, adhesion of epithelial foot processes, mesangial foam cells and polymorphonuclear leukocytes were seen in the cholesterol-fed group. In the groups fed cholesterol + vitamin E, cholesterol + Se and cholesterol + vitamin E + Se, morphological improvements were observed. It appeared that an excess in O-LDL, reactive oxygen species and growth factors might play an important role in the pathogenesis of glomerulosclerosis. In addition, it was concluded that antioxidant therapy may prevent LDL oxidation and generation of free radicals.
Antidiarrheal Activity of Wood Creosote: Inhibition of Muscle Contraction and Enterotoxin-Induced Fluid Secretion in Rabbit Small Intestine
Authors: Ogata Norio , Shibata Takashi 
Published: April 2003

Wood creosote has long been used as an antidiarrheal agent, but its mechanism of action is not well understood. To elucidate the mechanism of its antidiarrheal activity, we have addressed questions whether it inhibits fluid secretion induced by <i>Escherichia coli</i> heat-stable enterotoxin (STa) in rabbit jejunum in vivo, and whether it inhibits muscle contraction of isolated rabbit ileum ex vivo. Wood creosote (10–100 mg/l) instilled in a ligated loop of jejunum inhibited STa-induced fluid secretion (p < 0.05). It also inhibited the spontaneous phasic, acetylcholine-induced tonic and Ba<sup>2+</sup>-induced tonic contractions of longitudinal and circular muscles of ileum dose-dependently with IC<sub>50</sub> values of 130–530 mg/l. These data provide further evidence that the antidiarrheal activity of wood creosote is attributable to its antisecretory and antimotility effects.
Effects of Bergenin, the Major Constituent of <i>Mallotus japonicus</i> against <i>D</i>-Galactosamine-Induced Hepatotoxicity in Rats
Authors: Lim Hwa-Kyung , Kim Hack-Seang , Choi Hong-Serck , Choi Jongwon , Kim Seung-Hwan , Chang Myung-Jei 
Published: April 2003

The hepatoprotective effects of bergenin, a major constituent of <i>Mallotus japonicus,</i> were evaluated against <i>D</i>-galactosamine (GalN)-induced liver damage in rats. Bergenin (50, 100 and 200 mg/kg) was given orally once daily for 7 successive days and then GalN 400 mg/kg was injected intraperitoneally to rats at 24 and 96 h after the final administration of bergenin. Pretreatment with bergenin reduced the increased enzyme activities of alanine/aspartate aminotransferase, sorbitol dehydrogenase, γ-glutamyltransferase and the elevated level of malondialdehyde induced by GalN. Bergenin restored the decreased hepatic contents of glutathione as well as the decreased activities of glutathione S-transferase and glutathione reductase by GalN towards normalization, suggesting that the hepatoprotective effects of bergenin may consist in maintaining adequate levels of hepatic glutathione for the removal of xenobiotics. The present results indicate that bergenin has hepatoprotective effects against GalN-induced hepatotoxicity in rats.
In vitro and in vivo Activity of New Rhodium (III) Complexes against <i>Leishmania donovani</i>
Authors: Rodriguez-Cabezas M.N. , Mesa-Valle C.M. , Azzouz S. , Moraleda-Lindez V. , Craciunescu D. , Gutierrez-Rios M.T. , De Frutos M.I. , Osuna A. 
Published: April 2003

The activities of 17 new rhodium drug complexes were determined against <i>Leishmania donovani</i> promastigotes. The five most active salts were selected: [Rh<sup>III</sup>(2-amino-6-ethoxybenzothiazole)<sub>4</sub>Br<sub>2</sub>]<sup>+</sup>Br<sup>–</sup>; [Rh<sup>III</sup>(2-bromothiazole)<sub>4</sub>(Br)<sub>2</sub>]<sup>+</sup>Br<sup>–</sup>; [Rh<sup>III</sup>(mefloquine)<sup>4</sup>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup>; [Rh<sup>III</sup>(2-mepacrine)<sub>4</sub>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup>, and [Rh<sup>III</sup>(oxamniquine)<sub>4</sub>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup>, which induced growth-inhibition rates of more than 50% at 24 h of treatment and at the maximum dosage tested. The cytotoxicity assays on the macrophage cell line J-774 showed high cytotoxicity for the salts [Rh<sup>III</sup> (mefloquine)<sub>4</sub>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup>, [Rh<sup>III</sup>(2-mepacrine)<sub>4</sub>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup> and [Rh<sup>III</sup>(oxaminquine)<sub>4</sub>(Cl)<sub>2</sub>]<sup>+</sup>Cl<sup>–</sup> with a percentage of specific <sup>15</sup>Cr release of 49.3, 64.8 and 53.2% at 24 h of incubation and 100 µg/ml. Meanwhile, assays of the other compounds showed practically no cytotoxicity. The ultrastructural studies in the flagellates treated with the salt [Rh<sup>III</sup>(2-amino-6-ethoxybenzothiazole)<sub>4</sub>Br<sub>2</sub>]<sup>+</sup>Br<sup>–</sup> showed some alterations in the nucleus of the parasites with a very condensed chromatin and an electrodense endosome. This compound showed a high in vivo activity in parasitized Wistar rats.
Effects of Silymarin MZ-80 on Hepatic Oxidative Stress in Rats with Biliary Obstruction
Authors: González-Correa J.A. , de la Cruz J.P. , Gordillo J. , Ureña I. , Redondo L. , Sánchez de la Cuesta F. 
Published: April 2003

This study was designed to evaluate the effects of three pharmaceutical forms of silymarin (silymarin MZ-80, silybinin-β-cyclodextrin, and silybinin) on the liver oxidative status in vitro and after oral administration to rats with extrahepatic biliary obstruction (EBO) and sham-operated animals. We evaluated thiobarbituric acid-reactive substances (TBARS), glutathione (GSH + GSSG) and their related enzyme activities (GSH peroxidase, GSSG reductase and GSH transferase). All three compounds inhibited the in vitro production of TBARS (IC<sub>50</sub> 56–533 µmol/l). These compounds, mainly silymarin MZ-80, also increased GSH peroxidase and GSH transferase activities. In EBO rats we found increases in TBARS production which was inhibited by 50–70% after treatment. Glutathione was reduced by 55% and elevated by silymarin MZ-80. GSH transferase increased in the group given silymarin MZ-80. We conclude that all three derivatives of silymarin show a clear ability to reduce lipid peroxidation in the liver. Silymarin MZ-80 was the only compound that enhanced the glutathione antioxidant system.
Assessment of ex vivo Pharmacodynamic Markers during Inhibition of Thrombosis by CI-1031 (ZK-807834), a Novel Direct Factor Xa Inhibitor
Authors: Chi Liguo , Pen Yun-Wen , Potoczak Ronald , Gibson Glenn , Hicks Gary , Mertz Thomas E. , Janiczek Nancy , Juneau Paul L. , Gallagher Kim , Leadley Robert 
Published: April 2003

CI-1031 (ZK-807834) is a novel, synthetic factor Xa (FXa) inhibitor with a Ki of 0.11 n<i>M</i> against human FXa. In human plasma in vitro, CI-1031 doubled PT and aPTT at 0.23 and 0.49 µ<i>M</i>, respectively. The in vivo antithrombotic effect of CI-1031 was evaluated in a veno-venous shunt model of thrombosis in anesthetized rabbits. After thrombus formation was verified in the first shunts, rabbits received either vehicle or CI-1031 intravenously (bolus injection of 60, 240, or 480 µg/kg followed by an infusion of 2, 8, or 16 µg/kg/min for 140 min, respectively). The second shunts were inserted after 20 min of infusion of CI-1031 or vehicle. CI-1031 dose-dependently prolonged time to occlusion (TTO) in the second shunts (35 ± 21, 62 ± 24, and 120 ± 0 min for the three dose groups, respectively, vs. 10 ± 1 min for vehicle). Thrombus mass (TM) was reduced in a dose-dependent manner by CI-1031 (42 ± 7, 27 ± 6, and 18 ± 4 mg vs. 50 ± 4 mg for vehicle). Maximal TM reduction was 70% with an IC<sub>50</sub> of 0.6 µg/ml. Among all the coagulation parameters tested, PT had the best correlation with plasma CI- 1031 concentration (r = 0.97). Ex vivo plasma anti-FXa activity was also well correlated with plasma concentration of CI-1031 and with PT (r = 0.96 and 0.98, respectively). These results indicate that CI-1031, which is currently undergoing clinical evaluation, is an effective antithrombotic compound with a favorable efficacy-to-bleeding ratio. In addition, CI-1031 concentration in plasma can be monitored using PT or anti-Xa assays, thereby providing reliable methods to ensure safe and accurate dose titration of CI-1031.
Nefiracetam Improves the Impairment of Local Cerebral Blood Flow and Glucose Utilization after Chronic Focal Cerebral Ischemia in Rats
Authors: Jin Jingji , Watabe Shigeo , Yamamoto Tsuneyuki 
Published: April 2003

In this study we investigated the effects of nefiracetam (DM-9384) on local cerebral blood flow (LCBF) and local cerebral glucose utilization (LCMR<sub>glc</sub>) in the chronic phase after middle cerebral artery (MCA) occlusion in rats. Nefiracetam (10 mg/kg) was administered orally once a day for 2 weeks from day 15 after MCA occlusion. On day 28 after MCA occlusion, LCBF and LCMR<sub>glc</sub> were measured by an autoradiographic image-processing method. In MCA-occluded rats, LCBF and LCMR<sub>glc</sub> in the ischemic side of seven regions including the frontal cortex were significant decreased compared with those of the nonischemic side. Nefiracetam significantly improved the impairment of LCBF in the frontal cortex, parietal cortex, caudate putamen, ventral thalamus, amygdaloid nucleus and hippocampus. It also improved the decrease of LCMR<sub>glc</sub> in the frontal cortex, ventral thalamus and hippocampus. These results suggested that nefiracetam has ameliorating effects on chronic disorders of LCBF and LCMR<sub>glc</sub> induced by MCA occlusion.
Relationship between Prostatic α<sub>1</sub>-Adrenoceptor Binding and Reduction in Intraurethral Pressure following Continuous Infusion of KMD-3213 in Rats
Authors: Akiyama Katsuyoshi , Tatemichi Satoshi , Katayama Susumu , Nakajima Mariko , Oki Tomomi , Okura Takashi , Yamada Shizuo , Kimura Ryohei 
Published: April 2003

The relationship between α<sub>1</sub>-adrenoceptor binding in rat tissues and pharmacodynamic effects of continuous infusion of KMD-3213 was examined. In vivo specific binding of [<sup>3</sup>H]KMD-3213 after continuous intravenous infusion of the ligand (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min for 60 or 90 min) differed largely among the tissues examined. Specific binding of [<sup>3</sup>H]KMD-3213 in aorta, heart, lung, and kidney was not different in terms of infusion time in the case of continuous infusion for 10, 70 and 100 min, whereas the binding in prostate, vas deferens, and submaxillary gland by 70- and/or 100-min infusion was significantly greater than that by the 10-min infusion. A similar extent of specific binding in the prostate was observed by the infusion (100 min) of a three-fold higher dose of [<sup>3</sup>H]KMD- 3213. Continuous intravenous infusion of KMD-3213 (100 pmol/kg/min for 10 min, followed by 30 pmol/kg/min) for 70 or 100 min significantly reduced the phenylephrine-induced increase in the mean blood pressure and that in the intraurethral pressure of anesthetized rats. Extent and time course of the KMD-3213 effect reduction in the phenylephrine-induced increase in intraurethral pressure were closely associated with those in prostatic [<sup>3</sup>H]KMD-3213 binding after continuous infusion of the corresponding dosage of the radioligand. The reduction in the phenylephrine-induced increase by the infusion of a three-fold higher dose of KMD-3213 was significantly greater in the case of the intraurethral pressure than in that of the mean blood pressure, thereby suggesting a greater selectivity for the α<sub>1</sub>-adrenoceptor in the lower urinary tract than for that in the vascular tissue. In conclusion, the present study has shown that specific binding of [<sup>3</sup>H]KMD-3213 in the rat prostate after the continuous intravenous infusion of the radioligand may be closely associated with the pharmacological effect of this drug on the lower urinary tract.
Effects of SM-20550, a New Na<sup>+</sup>/H<sup>+</sup> Exchange Inhibitor, on Survival and Infarct Size in Rat Myocardial Infarction
Authors: Yamada Kazuto , Sasabe Masao , Matsui Kazuki , Yamamoto Setsuko , Ohashi Naohito 
Published: April 2003

The effect of a novel potent Na<sup>+</sup>/H<sup>+</sup> exchange inhibitor, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid], on survival after myocardial infarction was studied. Anesthetized rats underwent occlusion of the coronary artery (30 min) followed by reperfusion (14 days). SM-20550 was administered intravenously before ischemia (1-day treatment group) or before ischemia and on the 2 days following (3-day treatment group). The infarct size was significantly reduced on the 14th day after surgery by approximately 17 and 20% in 1- and 3-day treatment groups, respectively. The survival rate on day 14 was significantly enhanced in both treatment groups (96%) compared with the vehicle-treated control group (70%). These results suggest that SM-20550 improved survival after myocardial infarction, at least due to its antinecrotic effect.
Effects of Y-27632, a Rho/Rho Kinase Inhibitor, on Leukotriene D<sub>4</sub>- and Histamine-Induced Airflow Obstruction and Airway Microvascular Leakage in Guinea Pigs in vivo
Authors: Tokuyama Kenichi , Nishimura Hideko , Iizuka Kunihiko , Kato Masahiko , Arakawa Hirokazu , Saga Reiko , Mochizuki Hiroyuki , Morikawa Akihiro 
Published: April 2003

Recent in vitro studies have shown that the Rho/Rho kinase pathway is involved in the mechanism of not only airway smooth muscle contraction but also vascular endothelial permeability caused by certain stimuli. This suggests that Rho/Rho kinase inhibitors may become useful agents against asthma via reduction of increased airway microvascular leakage, one of the main features of this disease. Thus, we wanted to know the in vivo effect of Y-27632, a selective Rho kinase inhibitor, on airway microvascular leakage caused by leukotriene D<sub>4</sub> (LTD<sub>4</sub>) and histamine, potent mediators of allergic airway inflammation, by comparing its effect against airflow obstruction. For comparison, the effects of procaterol, a β<sub>2</sub>-adrenoceptor agonist, on these responses were also studied. Tracheostomized guinea pigs were given either aerosolized Y-27632 (3 or 15 mmol/l), procaterol (6 µmol/l) or vehicle (0.9% NaCl) for 5 min under spontaneous breathing. After being mechanically ventilated, the animals were given intravenous Evans blue dye 15 min after the end of inhalation. One minute later, either 2 nmol/kg LTD<sub>4</sub>, 300 nmol/kg histamine or vehicle was administered intravenously. After measurements of lung resistance (R<sub>L</sub>) for 6 min, the lungs of animals were taken out, and the amount of extravasated Evans blue dye was examined as an index of leakage. Inhaled Y-27632 dose-dependently attenuated increases in R<sub>L</sub> caused by LTD<sub>4</sub> and histamine. The degree of inhibition was almost similar between 15 mmol/l Y-27632 and 6 µmol/l procaterol. By contrast, only 15 mmol/l, but not 3 mmol/l, Y-27632 partially reduced LTD<sub>4</sub>-induced leakage. Histamine-induced Evans blue dye extravasation was not inhibited by 15 mmol/l Y-27632. Procaterol significantly inhibited the dye extravasation caused by either LTD<sub>4</sub> or histamine. These results suggest that Y-27632 is not a useful agent in attenuating airway microvascular leakage which is seen in asthma, although it is potent in inhibiting airflow obstruction.
Effects of STA<sub>2</sub>, a Thromboxane A<sub>2</sub> Mimetic, in Inducing Airflow Obstruction and Airway Microvascular Leakage in Guinea Pigs
Authors: Inoue Yoshinari , Tokuyama Kenichi , Nishimura Hideko , Arakawa Hirokazu , Kato Masahiko , Mochizuki Hiroyuki , Morikawa Akihiro 
Published: April 2003

<i>Background:</i> U-46619, a thromboxane A<sub>2</sub> (TXA<sub>2</sub>) mimetic, is shown to cause airway microvascular leakage, although the effects is weak when comparing with that to induce bronchoconstriction in guinea pigs. <i>Objective:</i> In order to know the airway effect of TXA<sub>2</sub> more accurately, we have examined the effects of STA<sub>2</sub>, a TXA<sub>2</sub> mimetic with higher affinity to TXA<sub>2</sub> (TP) receptors than U-46619, to induce airway microvascular leakage and airflow obstruction. <i>Methods:</i> Anesthetized and ventilated guinea pigs were i.v. given STA<sub>2</sub> (3–30 nmol/kg) or U-46619 (3–100 nmol/kg) 1 min after i.v. Evans blue dye. STA<sub>2</sub>- and U-46619-induced increases in lung resistance (R<sub>L</sub>) was measured for 6 min. The amount of extravasated Evans blue dye in the lower airways was, then, examined as an index of leakage. In selected animals, specific TP receptor antagonists (10 µg/kg S-1452 or 10 mg/kg ONO-3708) were pretreated i.v. <i>Results:</i> Both STA<sub>2</sub> and U-46619 induced significant increases in leakage and airflow obstruction. However, STA<sub>2</sub> induced a slow and significantly less increase in R<sub>L</sub> but caused a significantly greater increase in extravasation of Evans blue dye compared to U-46619. Specific TP receptor antagonists completely abolished both airway effects induced by STA<sub>2</sub> and U-46619. <i>Conclusion:</i> Our present results have supported a possibility that TXA<sub>2</sub> induces microvascular leakage as well as bronchoconstriction in the airways.