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1.
2.
Pia Lautala Maija Kivimaa Hannele Salomies Eivor Elovaara Jyrki Taskinen 《Pharmaceutical research》1997,14(10):1444-1448
Purpose. Nitrocatechol COMT inhibitors are a new class of bioactive compounds, for which glucuronidation is the most important metabolic pathway. The objective was to characterize the enzyme kinetics of nitrocatechol glucuronidation to improve the understanding and predicting of the pharmacokinetic behavior of this class of compounds.
Methods. The glucuronidation kinetics of seven nitrocatechols and 4-nitrophenol, the reference substrate for phenol UDP-glucuronosyltrans-ferase activity, was measured in liver microsomes from creosote-treated rats and determined by non-linear fitting of the experimental data to the Michaelis-Menten equation. A new method that combined densitometric and radioactivity measurement of the glucuronides separated by HPTLC was developed for the quantification.
Results. Apparent Km values for the nitrocatechols varied greatly depending on substitution pattern being comparable with 4-nitrophenol (0.11 mM) only in the case of 4-nitrocatechol (0.19 mM). Simple nitrocatechols showed two-fold Vmax values compared with 4-nitrophenol (68.6 nmol min–1 mg–1), while all disubstituted catechols exhibited much lower glucuronidation rate. Vmax/Km values were about 10 times higher for monosubstituted catechols compared to disubstituted ones. The kinetic parameters for COMT inhibitors were in the following order: Km nitecapone >> entacapone > tolcapone; Vmax nitecapone > entacapone > tolcapone; Vmax/Km tolcapone > nitecapone > entacapone.
Conclusions. Nitrocatechols can in principle be good substrates of UGTs. However, substituents may have a remarkable effect on the enzyme kinetic parameters. The different behaviour of nitecapone compared to the other COMT inhibitors may be due to its hydrophilic 5-substituent. The longer elimination half-life of tolcapone in vivo compared to entacapone could not be explained by glucuronidation kinetics in vitro. 相似文献
3.
The aim of this study was to determine whether the use of bactericidal coatings or immersion in antibiotic solution reduces or prevents bacterial adhesion onto ureteric stents. Precut segments of full silicone, silver-coated and hydrogel-coated ureteric stents were incubated with two uropathogenic bacterial strains with and without previous immersion in antibiotic solution. Tobramycin, ceftriaxone and ciprofloxacin solutions were used, as these antibiotics are commonly administered for the prophylaxis and treatment of urinary tract infection (UTI). Microbiological analysis showed that immersion of ureteric stents in ceftriaxone and ciprofloxacin yielded a significant reduction of bacterial adhesion, whereas immersion in tobramycin did not. The surface material of the stents had no direct influence on bacterial adhesion. In this experimental study, neither the silver nor the hydrogel coat reduced bacterial adhesion onto ureteric stents whereas immersion in a suitable antibiotic solution significantly reduced and even prevented this phenomenon, probably due to the adhesion of the antibiotic onto the stent surface. Prevention of bacterial adhesion onto ureteric stents is essential to reduce the risk of UTI in connection with these devices. 相似文献
4.
Chromium supplementation in impaired glucose tolerance of elderly: effects on blood glucose, plasma insulin, C-peptide and lipid levels. 总被引:1,自引:0,他引:1
M I Uusitupa L Mykk?nen O Siitonen M Laakso H Sarlund P Kolehmainen T R?s?nen J Kumpulainen K Py?r?l? 《The British journal of nutrition》1992,68(1):209-216
Altogether twenty-six elderly subjects (aged 65-74 years) with persistent impaired glucose tolerance (World Health Organization (1985) criteria) identified in a population-based study, were randomly treated either with chromium-rich yeast (160 micrograms Cr/d) or with placebo for 6 months. The 24 h urinary Cr increased from 0.13 (SE 0.03) to 0.40 (SE 0.06) micrograms/d in the Cr group (n 13) but no change was found in the placebo group (n 11) (0.13 (SE 0.02) v. 0.11 (SE 0.02) micrograms/d). No significant change was observed in the oral glucose tolerance test (glucose dose 75 g; 0, 1 and 2 h blood glucose respectively): 5.3 (SE 0.1), 9.3 (SE 0.3), 8.2 (SE 0.3) mmol/l v. 5.0 (SE 0.1), 8.5 (SE 0.4), 7.3(SE 0.5) mmol/l in the Cr group; 4.9 (SE 0.2), 9.2 (SE 0.6), 8.1 (SE 0.3) mmol/l v. 4.8 (SE 0.2), 8.5 (SE 0.5), 7.0 (SE 0.6) mmol/l in the placebo group (baseline v. 6 months). Glycosylated haemoglobin, plasma insulin, C-peptide and apolipoprotein A1 and B levels remained unchanged, and no improvement was seen in serum total cholesterol (6.2 (SE 0.3) v. 6.4 (SE 0.3) mmol/l for the Cr group, 6.2 (SE 0.4) v. 6.5 (SE 0.3) mmol/l for the placebo group), high-density-lipoprotein-cholesterol (1.1 (SE 0.1) v. 1.2 (SE 0.1) mmol/l for the Cr group, 1.0 (SE 0.1) v. 1.1 (SE 0.1) mmol/l for the placebo group) or triacylglycerols (2.5 (SE 0.4) v. 2.0 (SE 0.4) mmol/l for the Cr group, 2.4 (SE 0.2) v. 2.5 (SE 0.2) mmol/l for the placebo group). The present results indicate that Cr supplementation does not improve glucose tolerance or serum lipid levels in elderly subjects with stable impaired glucose tolerance. 相似文献
5.
C L Holder H C Thompson A B Gosnell P H Siitonen W A Korfmacher C E Cerniglia D W Miller D A Casciano W Slikker 《Journal of analytical toxicology》1987,11(3):113-121
Elimination and metabolic profiles of doxylamine and its nonconjugated metabolites were determined after the oral administration of [14C]-doxylamine succinate (13.3 mg/kg and 133 mg/kg doses) to male and female Fischer 344 rats. Total urine and fecal recovery of the administered dose was greater than 90% regardless of sex or dose. The cumulative urinary and fecal elimination of these nonconjugated doxylamine metabolites at the 13.3 mg dose was 44.4 +/- 4.4% and 36.0 +/- 5.8% of the total recovered dose for male and female rats, respectively. The cumulative urinary and fecal elimination of the doxylamine nonconjugated metabolites at the 133 mg/kg dose was 38.7 +/- 2.7% and 41.4 +/- 1.0% of the total recovered dose for male and female rats, respectively. In order to determine the contribution of mammalian and bacterial enzymes in the overall metabolism and excretion patterns for doxylamine, two in vitro techniques were investigated. Incubation of [14C]-doxylamine succinate with human and rat intestinal microflora indicated that anaerobic bacteria were not capable of effecting the degradation of [14C]-doxylamine succinate. However, the incubation of [14C]-doxylamine succinate with isolated rat hepatocytes generated several metabolites similar to those observed in vivo. The nonconjugated doxylamine metabolites isolated and identified include: doxylamine N-oxide, desmethyldoxylamine, didesmethyldoxylamine and ring-hydroxylated products of doxylamine and desmethyldoxylamine. The studies demonstrate the role of hepatic metabolism in the elimination of doxylamine succinate in the rat. 相似文献
6.
Arto J. Turunen José A. Fernández Leena Lindgren Kaija T. Salmela Lauri E. Kyllönen Heikki Mäkisalo John H. Griffin Sanna M. Siitonen Jari Petäjä Eero J. Pesonen 《American journal of transplantation》2005,5(9):2204-2212
We studied the role of endogenous activated protein C (APC), the major physiological anti-coagulant with concomitant anti-inflammatory properties, on ischemia/reperfusion (I/R) in 45 patients participating in a larger trial comparing three immunosuppressive protocols in cadaveric renal transplantation: perioperative anti-thymocyte globulin (ATG, Fresenius AG, Bad Homburg, Germany), perioperative basiliximab and conventional triple therapy. Blood samples for assessing plasma APC, protein C, and lactoferrin concentrations, neutrophil CD11b and L-selectin expressions and blood leukocyte differential counts were obtained preoperatively and before reperfusion from central venous cannula, complemented with simultaneous samples from iliac artery and graft vein for calculation of transrenal differences (Delta) of study parameters at 1 and 5 min after reperfusion. Unlike basiliximab or conventional therapy groups, ATG infusion induced a substantial increase in plasma APC concentration (119 [88-144]% before infusion vs. 232 [85-1246]% after infusion, p<0.001), resulting in renal graft sequestration of APC at 1 min after reperfusion (Delta=-72 [-567 to 12]%, p<0.001). Graft APC consumption was associated with transrenal reduction of neutrophil activation markers (L-selectin r=0.7, p=0.01; lactoferrin r=-0.6, p=0.02; CD11b r=-0.8, p=0.001), and with both warm (r=0.6, p=0.01) and cold ischemia time (r=0.6, p=0.02) and donor age (r=0.6, p=0.01). These findings suggest that APC has an anti-inflammatory role in I/R injury in clinical renal transplantation. 相似文献
7.
Molecular follow-up of Salmonella enterica subsp. enterica serovar Agona infection in cattle and humans 下载免费PDF全文
Salmonella enterica subsp. enterica serovar Agona was not frequently encountered in Finland until an increase in rates of isolation among animal and feed was seen in 1994. A small outbreak among cattle farms in the regions of Oulu and Vaasa in northwestern Finland in 1994-1995 included eight farms. After the outbreak, an increase in the number of serovar Agona infections in humans was seen in 1999: the number of annual microbiologically confirmed cases in humans increased from about 10 from 1990 to 1998 to 84 in 1999, including an outbreak in which more than 50 people were infected. To gather epidemiological data on serovar Agona and to trace the origin of the human infections, 110 serovar Agona isolates isolated from animal, feed, and other sources as well as from humans with cases of salmonellosis of domestic and foreign origin, which were recovered from 1984 to 1999, were analyzed for their pulsed-field gel electrophoresis (PFGE), plasmid, and IS200 profiles and antibiograms. Of these typing methods, PFGE with restriction endonucleases XbaI, BlnI, NotI, and SpeI was the most useful. The PFGE profile of the strain causing an outbreak among cattle in Finland in 1994-1995 was not seen previously. The strain with this profile was later only sporadically found in human infections. The profile of the strain causing the human outbreak in 1999 was not found among isolates from cattle or any other sources. Molecular typing was valuable in showing that although the outbreaks in cattle and humans seemed to be related regionally, they were not related otherwise. 相似文献
8.
A previously healthy 15-year-old girl fell ill with febrile gastroenteritis; Plesiomonas shigelloides was isolated from the blood 6 h after she had received one tablet of trimethoprim-sulfadiazine on the third day of symptoms. She recovered uneventfully. P. shigelloides may be isolated from the blood in immunocompetent patients with mild, uncomplicated gastroenteritis. 相似文献
9.
Clinical isolates of non-O157 Shiga toxin-producing Escherichia coli: serotypes, virulence characteristics, and molecular profiles of strains of the same serotype 下载免费PDF全文
All human Shiga toxin-producing Escherichia coli (STEC) non-O157 strains (n = 56) isolated in Finland from 1990 to August 2000 were characterized for the O:H serotype, stx(1) and stx(2) genes, production of enterohemolysin, and sensitivity to 12 antimicrobial agents. Strains of the same serotype were genotyped by pulsed-field gel electrophoresis (PFGE) after XbaI restriction of total DNA. The 56 non-O157 isolates belonged to 29 serotypes. Two of the serotypes (O102:H7 and OX181:H49) have not previously been described as being associated with STEC infections in humans or isolated from animals. Thirty-four strains (61%) within seven serotypes (O103:H2 [14 isolates], O26:H11 [6 isolates], O145:H28 [4 isolates], O145:HNM [3 isolates], O15:HNM [3 isolates], OX174:H21 [2 isolates], and O Rough:HNM [2 isolates]) were represented by more than one isolate. Of these strains, O103:H2 isolates were divided into seven, O26:H11 isolates were divided into four, and the rest within a serotype were divided into two genotypes in PFGE. In PCR, 31 (55%) of the 56 strains were positive for the stx(2) gene only and 24 strains (43%) were positive for stx(1) only. One strain (O43:H2) carried both stx(1) and stx(2). Forty-two strains (75%) produced enterohemolysin, and 39 strains (70%) possessed the eae gene. Of the latter 39 strains, 36 (92%) were enterohemolytic, whereas only 6 (35%) of the 17 isolates lacking the eae gene were enterohemolytic (P < 0.001). The majority of the strains (44 strains, 79%) were sensitive to all 12 antimicrobials tested. Of the 56 strains, 20 (36%) were associated with small family outbreaks in nine families and 14 (25%) were associated with recent travel abroad. 相似文献
10.
This study examined Shiga toxin-producing Escherichia coli (STEC) O157, using phage typing, pulsed-field gel electrophoresis, and typing of Shiga toxin variant genes by PCR with restriction fragment length polymorphism in an epidemiological survey of STEC O157 isolated from humans in Finland between 1990 and 1999. 相似文献