bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of clotrimazole on microsomal metabolism and pharmacokinetics of albendazole
Authors: Merino G , Molina A J , García J L , Pulido M M , Prieto J G , Alvarez A I 
Published: June 2003

Abstract
Albendazole is a broad spectrum anthelmintic drug widely used in human and veterinary medicine. Intestinal and hepatic albendazole metabolism leads to albendazole sulfoxide (active metabolite) and albendazole sulfone (inactive metabolite) formation. Microsomal sulfonase activity can be abolished by in-vitro interaction with clotrimazole and pharmacokinetic studies confirm this interaction. After albendazole incubation, albendazole sulfone formation was completely inhibited by 50 μm clotrimazole in intestinal incubations and a 50% inhibition was observed in hepatic incubations. The lower inhibition constant (Ki) value observed in the intestinal incubations (9.4 ± 1.0 μm) compared with the hepatic counterparts (23.3 ± 15.8 μm) pointed to a greater affinity of the enzymatic systems in the intestine. Regarding the formation of albendazole sulfoxide, an inhibition close to 50% was observed in liver and intestine at 10 μm clotrimazole. The pharmacokinetic parameters obtained following the oral co-administration of albendazole sulfoxide and clotrimazole corroborated the in-vitro inhibition of albendazole sulfone formation, since the ratio of the area under the plasma concentration-time curves for the sulfoxide/sulfone (AUCABZSO/AUCABZSO2) was significantly higher (38.1%). In addition, the AUC and Cmax for albendazole sulfone were significantly lower. The effect of clotrimazole was also studied after prolonged treatment. Hepatic microsomal metabolism of albendazole was induced after 10 days of clotrimazole administration, with significant increases in formation of albendazole sulfoxide (40%) and sulfone (27%). These results offer further insight into the metabolism of benzimidazole drugs and highlight the difficulty involved in human therapy with these anthelmintics, since after prolonged treatment the drug interactions are affected differentially.
Evaluation of the estimation of midazolam concentrations and pharmacokinetic parameters in intensive care patients using a bayesian pharmacokinetic software (PKS) according to sparse sampling approach
Authors: Bolon M , Bastien O , Flamens C , Paulus S , Salord F , Boulieu R 
Published: June 2003

Abstract
The aim of the study was to assess the performance of a bayesian program (PKS System, Abbott) for predicting midazolam concentrations and pharmacokinetic parameters in intensive care patients by comparing the pharmacokinetic parameters estimated by PKS to those calculated according to rich data. The study involved 42 patients receiving midazolam infusion for two hours or for several days. The program was used to predict plasma midazolam concentrations after feedback of 1, 2 or 3 concentrations. High correlation between observed and estimated concentrations was shown (r2 &gt; 0.992). Mean prediction error, mean absolute prediction error and root mean squared error were low for the patients of the reference and validation groups. From two or three feedback concentrations, midazolam pharmacokinetic parameters estimated by PKS were statistically comparable with those obtained using a rich pharmacokinetic analysis (P &gt; 0.05 paired Wilcoxon test). Thus, PKS is useful for predicting midazolam concentrations and pharmacokinetic parameters when at least two feedback concentrations are known. This software seems to be appropriate for providing significant help to the clinician for midazolam dosage adjustment, according to midazolam concentrations and clinical sedation.
The effects of mebendazole on P4501A activity in rat hepatocytes and HepG2 cells. Comparison with tiabendazole and omeprazole
Authors: Baliharová V , Skálová L , Maas R F M , de Vrieze G , Bull S , Fink-Gremmels J 
Published: June 2003

Abstract
Mebendazole is a benzimidazole anthelmintic widely used in veterinary and human therapy. Among benzimidazole derivatives, several drugs with inducing effect on cytochromes P450 can be found. However, the induction capacity of mebendazole on P450s has not been explored yet. In this study, the effects of mebendazole on P4501A activity was tested in primary cultures of rat hepatocytes and in human hepatoma HepG2 cell line. Two known P4501A inducers with benzimidazole structure, tiabendazole and omeprazole, were also included in the experiments with the aim of studying structure-induction relationships. After 24-, 48- and 72-h incubation of rat hepatocytes and HepG2 cells with drugs in various concentrations (0.1–100μm), enzyme activity associated with P4501A1/2 (EROD, MROD) was measured. In addition, the P4501A1/2 protein levels in both in-vitro systems were determined by Western-blotting. Mebendazole provoked a significant increase in P4501A1/2 protein expression and P4501A activity in both in-vitro systems. Omeprazole caused a significant dose-dependent increase of P4501A activity only in HepG2 cells. Although tiabendazole treatment led to significant increase of P4501A protein level, no effect on P4501A activity was observed in either system. The results demonstrate that mebendazole possesses the ability to significantly induce P4501A. Thus, pharmacological and toxicological consequences of P4501A induction should be taken into account in human therapy. The structure-induction relationships and differences between in-vitro systems used are discussed.
Relaxation of rat arteries by urocortin: effects of gender and diabetes
Authors: Sanz Elena , Fernández Nuria , Monge Luis , Climent Belén , Diéguez Godofredo , Garcia-Villaló Angel Luis 
Published: June 2003

Abstract
Urocortin is a peptide recently identified, structurally related to corticotropin releasing factor (CRF). We have compared the effects of urocortin in different vascular beds, and have investigated whether there are gender differences in these effects or whether they are altered by diabetes. We have studied the response of isolated segments (2-mm long) from basilar, coronary and tail arteries to urocortin. The segments were obtained from male and female, normoglycaemic and strepto-zotocin-induced diabetic rats. In the arterial segments precontracted with endothelin-1, urocortin produced concentration-dependent relaxation, and the order of sensitivity was: tail &gt; basilar &gt; coronary. This relaxation was similar in arteries from male and female, diabetic and normoglycaemic rats. In tail arteries from normoglycaemic male rats, the cyclooxygenase inhibitor meclofenamate (10−5M) increased the relaxation to urocortin, and the inhibitor of nitric oxide synthesis Nω-nitro-L-arginine methyl ester (L-NAME, 10−4M) or the potassium-channel-blocker charybdotoxin (10−7M) did not modify it. In tail arteries from normoglycaemic female rats meclofenamate, charybdotoxin or L-NAME did not modify the relaxation to urocortin. These results suggested that urocortin produced vasodilation which showed regional differences between basilar, coronary and tail arteries, but was not affected by diabetes. The mechanisms underlying this relaxation in tail arteries might differ between males and females.
A novel D2-dopaminergic and α2-adrenoceptor receptor agonist induces substantial and prolonged IOP decrease in normotensive rabbits
Authors: Savolainen Jouko , Rautio Jarkko , Razzetti Roberta , Järvinen Tomi 
Published: June 2003

Abstract
The effects of a novel and selective D2-dopaminergic/α2-adrenoceptor agonist, CHF1035, and its metabolite CHF1024 on intraocular pressure (IOP) were determined in rabbits. Because CHF1035 is a mixture of two enantiomers, CHF1800 (+) and CHF1810 (-), pure enantiomers were also studied to determine possible differences in IOP-decreasing ability depending on the stereochemistry of the molecule. CHF1035, CHF1800 (+), CHF1810 (-), CHF1024, brimonidine and 0.9% NaCl were administered topically to rabbits and IOP was then measured at fixed time intervals. The dose-response profile (0.01–1.0% w/v) was determined for CHF1035. CHF1035 and its metabolite CHF1024 significantly lowered IOP in the treated eyes. CHF1035 showed a maximum IOP decrease (7.6 ± 1.5 mmHg) 5 h post-dosing, whereas the metabolite CHF1024 showed a maximum decrease in IOP (7.0 ± 0.8 mmHg) 3 h post-dosing. The maximum IOP decrease produced by CHF1035 in the treated eye was comparable with that produced by brimonidine (7.8 ± 0.9 mmHg), but CHF1035 had a significantly longer duration of action. Unlike brimonidine, CHF1035 and CHF1024 did not decrease IOP in the untreated eye. CHF1810 (-) lowered the IOP more than CHF1800 (+). No irritation, evaluated as eyelid closure, was observed after topical administration of any of the compounds. Only in the case of CHF1035 1% solution, two rabbits out of six closed the eye for 30–45s. In conclusion, CHF1035 and its metabolite CHF1024 significantly decreased the IOP in rabbits, and are potential novel IOP lowering agents. Especially, CHF1035 produced a substantial decrease in IOP for a prolonged period of time, and thus may prove useful in glaucoma therapy.
Evaluation of the synergistic adverse effects of concomitant therapy with statins and fibrates on rhabdomyolysis
Authors: Matzno Sumio , Tazuya-Murayama Keiko , Tanaka Hiromi , Yasuda Shinya , Mishima Motohiro , Uchida Takahiro , Nakabayashi Toshikatsu , Matsuyama Kenji 
Published: June 2003

Abstract
Rhabdomyolysis is a severe adverse effect of hypolipidaemic agents such as statins and fibrates. We evaluated this muscular cytotoxicity with an in-vitro culture system. Cellular apoptosis was determined using phase-contrast and fluorescein microscopic observation with Hoechst 33342 staining. L6 rat myoblasts were treated with various statins and bezafibrate under various conditions. With statins only, skeletal cytotoxicity was ranked as cerivastatin &gt; fluvastatin &gt; simvastatin &gt; atorvastatin &gt; pravastatin in order of decreasing potency. Combined application of fibrates enhanced ator-vastatin-induced myopathy, which causes little apoptosis alone. These results suggest that statins and fibrates synergistically aggravate rhabdomyolysis.
Dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity in rats
Authors: To Hideto , Ohdo Shigehiro , Shin Mikiko , Uchimaru Hiroki , Yukawa Eiji , Higuchi Shun , Fujimura Akio , Kobayashi Eiji 
Published: June 2003

Abstract
Cardiac toxicity caused by doxorubicin (adriamycin) is a serious dose-limiting factor in the clinical situation. However, the influence of doxorubicin dosing time has not been clarified from the viewpoints of cardiotoxic development and its mechanism. In this study, we have investigated the dosing time dependency of doxorubicin-induced cardiotoxicity and bone marrow toxicity after repeated administration of doxorubicin in rats. When doxorubicin (5 mg kg−1, i.p.) was administered every seven days (total of 30 mg kg−1) at 3, 9, 15 or 21h after the light was turned on (HALO), toxic death was significantly higher in the 9 HALO treated group than the other groups. When doxorubicin was injected every seven days for 28 days at 9 or 21 HALO, we measured the levels of creatine kinase, malondialdehyde (MDA; an index of lipid peroxide), and glutathione peroxidase (GPx) as markers of cardiotoxicity. On days 14 and 28, creatine kinase levels were significantly higher in the 9-HALO group compared with the 21-HALO group (P &lt; 0.01, respectively). On day 14, MDA levels increased significantly in the 9 HALO group compared with the 21 HALO group (P &lt; 0.01). A single dose of doxorubicin was administered at 9-h or 21-h after the light was turned on to investigate the dosing-time-dependent difference of the pharmacokinetics. The area under the plasma time-concentration curve showed a significant increase at 9 HALO compared with 21 HALO (P &lt; 0.05). These results suggested that the dosing-time-dependent difference of cardiotoxicity induced by doxorubicin was closely related to the daily variation of doxorubicin pharmacokinetics. In conclusion, the choice of optimal dosing time based on the chronopharmacokinetics of doxorubicin may decrease the cardio-toxicity and enable the practice of effective and safe chemotherapy of doxorubicin.
Effects of glycyrrhetinic acid derivatives on hepatic and renal 11β-hydroxysteroid dehydrogenase activities in rats
Authors: Shimoyama Yoshihito , Hirabayashi Kazuhiro , Matsumoto Hiroatsu , Sato Toshitsugu , Shibata Shoji , Inoue Hideo 
Published: June 2003

Abstract
The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11β-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11β-HSD activity. 18β-Glycyrrhetinic acid (Ia) potently inhibited 11β-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 μm) and renal (IC50 = 0.36 μm) homogenate. The inhibitory effect of 18β-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18β-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18β-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11β-HSD activity, but less effect on renal 11β-HSD activity. Furthermore, the inhibitory activity of 18β-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18β-olean-9(11), 12-diene-3β, 30-diol (IIIa) and olean-11, 13(18)-diene-3β, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11β-HSDs. While glycyrrhetinic acid (200 mg kg−1, p.o.) significantly inhibited 11β-HSD activity in rat liver and kidney at 3 h after administration, compound IVb (100 mg kg−1, p.o.) had no effect on either enzyme activity. In addition, the circulating corticosterone level was slightly increased by glycyrrhetinic acid but not by compound IVb. These results suggest that the anti-inflammatory effects of compound IVb, derived from glycyrrhetinic acid, are not due to accumulation of steroids induced by the inhibition of 11β-HSD activity. Our data also showed that the 11-, 24- and 30-positions of glycyrrhetinic acid may play important roles in the differential inhibitory effects on 11β-HSD isozyme activity.
Effect of monensin liposomes on the cytotoxicity of anti-My9-bR immunotoxin
Authors: Shaik Madhu Sudhan , Jackson Tanise L , Singh Mandip 
Published: June 2003

Abstract
The purpose of the study was to evaluate the utility of monensin liposomes in the enhancement of in-vitro cytotoxicity, apoptosis and in-vivo antitumour activity of anti-My9-bR immunotoxin. Monensin liposomes were prepared and studied for the enhancement of in-vitro cytotoxicity and apoptotic response of anti-My9-bR immunotoxin against both sensitive and resistant human promyelocytic leukemia HL-60 cells by MTS/PES method and acridine orange staining, respectively. Further, the in-vivo cytotoxicity enhancement of anti-My9-bR immunotoxin by monensin liposomes was studied in a survival model of severe combined immunodeficient (SCID) mice bearing intraperitoneal HL-60 tumours. The in-vitro cytotoxicity of anti-My9-bR immunotoxin was enhanced 580 fold and 4.7 fold against sensitive and resistant HL-60 cells, respectively, by monensin liposomes (5 times 10−8m). The combination of anti-My9-bR immunotoxin (50 ng mL−1) with monensin liposomes (5 times 10−8m) produced apoptosis in 40% of cells, whereas the apoptotic response was minimal (&lt; 10%) in anti-My9-bR immunotoxin- or monensin liposome (alone)-treated HL-60 (resistant) cells. In SCID mice bearing HL-60 tumours, anti-My9-bR immunotoxin (75 μg kg−1 administered intravenously every other day for a total of five courses) showed a median survival time of 20 days, which was no different than that of vehicle control- or monensin liposome-treated mice. However, anti-My9-bR immunotoxin (75 μg kg−1) in combination with monensin liposomes (4 μg kg−1 monensin), administered every other day for a total of five courses, was found to prolong the survival of 20% of mice for more than 46 days. Our results indicate that, despite anti-My9-bR immunotoxin being ineffective in the HL-60 tumour model, its combination with monensin liposomes could improve the antitumour response.
Insurmountable antagonism of AT-1015, a 5-HT2 antagonist, on serotonin-induced endothelium-dependent relaxation in porcine coronary artery
Authors: Rashid Mamunur , Nakazawa Mikio , Nagatomo Takafumi 
Published: June 2003

Abstract
The purpose of this study was to examine the inhibitory effects of AT-1015, a newly synthesized 5-HT2 receptor antagonist, on serotonin-induced endothelium-dependent relaxation in U 46619 (5 times 10−9m)-precontracted porcine coronary artery pre-incubated with ketanserin (3 times 10−6m), and then compare its effects with another potent 5-HT2 antagonist, ritanserin. The investigation showed that AT-1015 (10−8−10−6m) caused rightward shift with significant inhibition of maximum relaxation response induced by serotonin in porcine coronary artery with endothelium. Ritanserin caused a rightward shift of serotonin-induced relaxation without decreasing maximum response at 10−9 and 10−8m, but it inhibited the maximum relaxation response at 10−7m. The study showed that AT-1015 and ritanserin had no inhibitory effect on bradykinin-induced relaxation in porcine coronary artery with endothelium. Thus, these findings suggested that AT-1015 at concentrations of 10−8−10−6m caused noncompetitive blockade of serotonin-induced endothelium-dependent relaxation in porcine coronary artery. The antagonistic effects of AT-1015 on serotonin-induced relaxation were different from that of ritanserin, except at 10−7m ritanserin. The variation of inhibitory effects between these two 5-HT2 antagonists may be due to the different chemical structure and/or interaction sites at the receptor.
Stimulatory effect of cinnamic acid analogues on α1A-adrenoceptors in-vitro
Authors: Chang Huang-Kuang , Hsu Feng-Lin , Liu I-Min , Cheng Juei-Tang 
Published: June 2003

Abstract
We have characterized the effects of cinnamic acid and its derivatives on α1-adrenoceptor subtypes. The cinnamic acid with a methoxyl group and/or a hydroxyl group showed the ability to stimulate radioactive glucose uptake into C2C12 cells, a cell line that specifically expresses the α1A-adrenoceptor subtype of α1-adrenoceptors. However, cinnamic acid without chemical modification diminished the glucose uptake into C2C12 cells. It was shown that methoxylation and/or hydroxylation of cinnamic acid had higher affinities for α1A-adrenoceptors investigated using [3H]prazosin binding experiments in C2C12 cells. The effect of these derivatives on α1A-adrenoceptors was further characterized using the displacement of [3H]prazosin binding in rat prostate. We found that 3,5-dimethoxy-4-hydroxycinnamic acid, the cinnamic acid derivative with two methoxyl groups and hydroxylation at the fourth carbon on the benzene ring, had a higher affinity for the α1A-adrenoceptor subtype, showing a smaller IC50 value (the concentration for production of 50% inhibition) to displace [3H]prazosin binding in rat prostate. Affinity of these compounds for α1B-adrenoceptors was identified using [3H]prazosin-binding experiments in rat spleen. However, we found no marked differences in the IC50 values between these cinnamic acid analogues to displace the [3H]prazosin binding in rat spleen. In conclusion, our data indicated that methoxylation and/or hydroxylation of cinnamic acid might raise the affinity for α1A-adrenoceptors.
Si-Ni-San, a traditional Chinese prescription, and its drug-pairs suppress contact sensitivity in mice via inhibition of the activity of metalloproteinases and adhesion of T lymphocytes
Authors: Sun Yang , Chen Ting , Xu Qiang 
Published: June 2003

Abstract
In this paper, the effect of Si-Ni-San, a famous traditional Chinese prescription, on ear contact sensitivity was examined. Si-Ni-San significantly inhibited the ear swelling when administered during the induction phase of picryl-chloride-induced ear contact sensitivity in mice. The adhesion to type I collagen of isolated spleen cells was significantly decreased in the Si-Ni-San group, especially in the presence of protein kinase C activator, phorbol 12,13-dibutyrate. The inhibition of adhesion was seen in purified T cells from the spleen, as well as in Jurkat cells. Furthermore, the adhesion to collagen involves the production of matrix metalloproteinase-2 and −9 in spleen cells, and the oral administration of Si-Ni-San remarkably reduced the matrix metalloproteinase production. Three drug-pairs composed in Si-Ni-San were used for comparison. The combination of Chaihu and Shaoyao showed a similar effect to Si-Ni-San, while Chaihu and Zhishi, and Shaoyao and Gancao only showed a tendency in most situations. These results suggest that Si-Ni-San may contribute to the treatment of immunologically related diseases by down-regulating the activation and function of T lymphocytes, especially the cell adhesion and matrix metalloproteinase production. Its effect is mainly displayed by the combination of Chaihu and Shaoyao.
Antioxidant activity of Smoke Shield in-vitro and in-vivo
Authors: Sreekanth Kavitha Sivaraman , Sabu Mandumpal Chacko , Varghese Leyon , Manesh Chittezhath , Kuttan Girija , Kuttan Ramadasan 
Published: June 2003

Abstract
Smoke Shield is a proprietory formulation containing extract of turmeric (Curcuma longa), obtained by supercritical carbon dioxide gas extraction and post-supercritical hydroethanolic extraction, together with extracts of green tea and other spices whose presence synergistically increases the activity of turmeric. This study evaluates the antioxidant potentials of Smoke Shield in-vitro and in experimental animals, as well as in human models. Smoke Shield was found to scavenge superoxide radicals generated by photoreduction of riboflavin (50% inhibitory concentration = 91 μg mL−1) and hydroxyl radicals generated by Fenton reaction (50% inhibitory concentration = 95 μg mL−1) and reduced lipid peroxidation. Administration of Smoke Shield to mice was found to elevate antioxidant enzymes such as catalase and superoxide dismutase in blood as well as in liver and kidney. Glutathione-S-transferase activity was found to be significantly elevated in liver and kidney of animals treated with Smoke Shield. Glutathione levels were also significantly elevated in blood. Glutathione reductase was significantly elevated in kidney. Administration of Smoke Shield decreased the lipid peroxidation in serum, liver and kidney, as well as reduced the levels of conjugated dienes and hydroperoxides. Administration of Smoke Shield to smokers was found to increase the superoxide dismutase and glutathione in blood and decrease glutathione peroxidase. Smoke Shield inhibited phase I enzymes as represented by aniline-hydroxylase and aminopyrene-demethylase in-vitro. These results indicate that Smoke Shield has potent antioxidant activity, could inhibit phase I enzymes and increase detoxifying enzymes, which makes it an effective chemoprotective herbal formulation.