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101.
Tavelin S Taipalensuu J Söderberg L Morrison R Chong S Artursson P 《Pharmaceutical research》2003,20(3):397-405
Purpose. To characterize the paracellular route of 2/4/A1 monolayers and to compare the permeabilities of incompletely absorbed oral drugs in 2/4/A1 with those in Caco-2 monolayers.
Methods. The cells were cultivated on permeable supports. The 2/4/A1 expression of genes associated with tight junctions was compared with that in the small intestine using RT-PCR. The aqueous pore radii were determined using paracellular marker molecules. The permeabilities of a series of incompletely absorbed drugs (defined as having a fraction absorbed 0 to 80%) after oral administration to humans were studied.
Results. Occludin and claudin 1 and 3 were expressed in 2/4/A1. The pore radius of 2/4/A1 was 9.0 ± 0.2 Å, which is similar to that in the human small intestine, although the pore radius was smaller (3.7 ± 0.1 Å) in Caco-2. The relationship between permeability and fraction absorbed of 13 drugs was stronger in 2/4/A1 than in Caco-2. The relationships were used to predict the intestinal absorption of another seven drugs. The prediction was more accurate in 2/4/A1 (RMSE = 15.6%) than in Caco-2 (RMSE = 21.1%). Further, Spearman's rank coefficient between FA and permeability was higher in 2/4/A1.
Conclusion. The improved 2/4/A1 cell culture model has a more in vivo-like permeability and predicted the oral absorption of incompletely absorbed drugs better than Caco-2 cells. 相似文献
102.
Månsson E Flordal E Liliemark J Spasokoukotskaja T Elford H Lagercrantz S Eriksson S Albertioni F 《Biochemical pharmacology》2003,65(2):237-247
Mechanisms of acquired resistance to three purine analogues, 2-chloro-2'-deoxyadenosine (cladribine, CdA), 9-beta-D-arabinofuranosyl-2-fluoroadenine (fludarabine, Fara-A), and 2-chloro-2'-arabino-fluoro-2'-deoxyadenosine (clofarabine, CAFdA) were investigated in a human T-lymphoblastic leukemia cell line (CCRF-CEM). These analogues are pro-drugs and must be activated by deoxycytidine kinase (dCK). The CdA and CAFdA resistant cell lines exhibited increased resistance to the other nucleoside analogues activated by dCK. This was also the case for the Fara-A resistant cells, except that they were sensitive to CAFdA and guanosine analogues. The CdA and CAFdA resistant cells displayed a deficiency in dCK activity (to <5%) while the Fara-A resistant cells showed only a minor reduction of dCK activity (20% reduction). The activity of high K(m) 5'-nucleotidase (5'-NT) (cN-II) using IMP as substrate, was 2-fold elevated in the resistant cell lines. The amount of the small subunit R2 of ribonucleotide reductase (RR) was higher in the Fara-A resistant cells, which translated into a higher RR activity, while CdA and CAFdA cells had decreased activity compared to the parental cells. Expression of the recently identified RR subunit, p53R2 full-size protein, in CAFdA cells was low compared to parental cells, but a protein of lower molecular weight was detected in CdA and CAFdA cells. Co-incubation of Fara-A with the RR inhibitor 3,4-dihydroxybenzohydroxamic acid (didox) enhanced cytotoxicity in the Fara-A resistant cells by a factors of 20. Exposure of the cells to the nucleoside analogues studied here also caused structural and numerical instability of the chromosomes; the most profound changes were recorded for CAFdA cells, as demonstrated by SKY and CGH analysis. We conclude that down-regulation of dCK in cells resistant to CdA and CAFdA and increased activity of RR in cells resistant to Fara-A contribute to resistance. 相似文献
103.
Tavelin S Hashimoto K Malkinson J Lazorova L Toth I Artursson P 《Molecular pharmacology》2003,64(6):1530-1540
The aim of this study was to investigate whether peptides from the extracellular loops of the tight junction protein occludin could be used as a new principle for tight junction modulation. Peptides of 4 to 47 amino acids in length and covering the two extracellular loops of the tight junction protein occludin were synthesized, and their effect on the tight junction permeability in Caco-2 cells was investigated using [14C]mannitol as a para-cellular marker. Lipopeptide derivatives of one of the active occludin peptides (OPs), synthesized by adding a lipoamino acid containing 14 carbon atoms (C14-) to the N terminus of the peptide, were also investigated. Peptides corresponding to the N terminus of the first extracellular loop of occludin increased the permeability of the tight junctions without causing short-term toxicity. However, the peptides had an effect only when added to the basolateral side of the cells, which could be partly explained by degradation by apical peptidases and aggregate formation. By contrast, the lipopeptide C14-OP90-103, which protects the peptide from degradation and aggregation, displayed a rapid apical effect. The l- and d-diastereomers of C14-OP90-103 had distinctly different effects. The d-isomer, which releases intact OP90-103 from the lipoamino acid, displayed a rapid and transient increase in tight junction permeability. The l-isomer, which releases OP90-103 more rapidly, gave a more sustained increase in tight junction permeability. In conclusion, C14-OP90-103 represents a prototype of a new class of tight junction modulators that act on the extracellular domains of tight junction proteins. 相似文献
104.
Andersson BE Lundstedt S Tornberg K Schnürer Y Oberg LG Mattiasson B 《Environmental toxicology and chemistry / SETAC》2003,22(6):1238-1243
Soil artificially contaminated with fluorene, phenanthrene, pyrene, and benz[a]anthracene was inoculated with the wood-rotting fungi Plrurotus ostreatus and Antrodia vaillantii. During 12 weeks of incubation, polycyclic aromatic hydrocarbon (PAH) degradation and the formation of persistent degradation products were monitored by chemical analysis. In addition, the effect on the indigenous soil bacteria was studied by plate count techniques and by measuring the concentration of bacteria-specific phospholipid fatty acids (PLFAs). In both soils inoculated with fungi, the PAH degradation was enhanced compared to the control soil without fungi. The white-rot fungus P. ostreatus accelerated the degradation rate radically the first weeks, while the effect of the brown-rot fungus was more pronounced at later stages during the 12-week study. In a soil with no amendments, the final degradation result was similar to that in the soil with added fungi, although the degradation pattern for the individual PAHs was different. Furthermore, the degradation by P. ostreatus was accompanied by an accumulation of PAH metabolites, that is, 9-fluorenone, benz[a]anthracene-7,12-dione, and two compounds identified as 4-hydroxy-9-fluorenone and 4-oxapyrene-5-one, that was not seen in the other soils. The inoculation with the white-rot fungus also had a large negative effect on the indigenous soil bacteria. This could be an important drawback of using the white-rot fungus P. ostreatus in soil bioremediation since a sequential fungal-bacterial degradation probably is needed for a complete degradation of PAHs in soil. In the soil inoculated with A. vaillantii, on the other hand, no metabolites accumulated, and no negative effects were observed on the indigenous microorganisms. 相似文献
105.
Severe hepatic adverse drug reactions have been occasionally reported in the literature for the selective serotonin reuptake inhibitors (SSRIs), venlafaxine and nefazodone. In addition, a few case reports have suggested a possible association between SSRI treatment and pancreatitis. To further investigate this issue, a Bayesian confidence propagation neural network (BCPNN) method was applied on the World Health Organization database of adverse drug reactions. This method identifies whether a drug/adverse drug reaction combination is reported more frequently to the database than expected on the basis of chance alone compared to general reporting in the database. A statistically significant unexpected high number of reports were found for nefazodone and hepatic injury, relative to the generality of the dataset but, for the other drug/adverse drug reaction combinations, no such association was found. The nefazodone finding is in accordance with data from other publications, suggesting that the risk of hepatic injury is increased. However, because of the nature of the BCPNN, the negative findings do not necessarily prove that there is no excess risk for hepatic injury/pancreatitis during treatment with drugs other than nefazodone. Further studies are required using alternative methodologies to demonstrate whether the selective serotonin reuptake inhibitors or venlafaxine may cause hepatic injury or pancreatitis. 相似文献
106.
107.
Jacobsson H Bremmer S Larsson SA 《European journal of nuclear medicine and molecular imaging》2003,30(8):1169-1172
On single-photon emission tomography (SPET) examinations with indium-111 pentetreotide, we have often observed a small "hot" spot close to the upper portion of the left kidney. While it was initially believed that this represented a tumour in the tail of the pancreas or in the left adrenal, we now understand that it represents normal adrenal uptake. Since the adrenals have not been described as normally visualised, this uptake may interfere with the interpretation of the examination. We have studied how often the normal adrenals are visualised at such examinations. One hundred consecutive clinical (111)In-pentetreotide examinations in adults including SPET of the abdomen and with normal findings were studied. All examinations with a hot spot attributable to the adrenals were, when available, compared with computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen performed on clinical grounds within 3 months before or at any time after the scintigraphy. In 11 patients both adrenals were visualised. In 27 patients only the left and in one only the right adrenal was visualised. CT or MRI examinations were available for comparison in 25 of these 39 patients. Two of these showed a pathological finding in the left adrenal. A conservative interpretation is that the normal adrenal is visualised on one or both sides in at least one-quarter of adults at SPET examination with (111)In-pentetreotide. 相似文献
108.
Ototoxicity,nephrotoxicity and pharmacokinetics of cisplatin and its monohydrated complex in the guinea pig 总被引:5,自引:0,他引:5
Ekborn A Lindberg A Laurell G Wallin I Eksborg S Ehrsson H 《Cancer chemotherapy and pharmacology》2003,51(1):36-42
PURPOSE: To evaluate and compare the ototoxicity and nephrotoxicity of cisplatin and cis-diammineaquachloroplatinum(II) ion (monohydrated complex of cisplatin, MHC, formed in vivo by hydrolysis of cisplatin) after their separate administration to guinea pigs. METHODS: A dose of 4 mg/kg body weight of MHC was deemed suitable for the toxicity evaluation after dose titration. Electrophysiological hearing thresholds (auditory brainstem response, ABR), plasma creatinine and weight were measured in three groups of animals before and after receiving MHC 4 mg/kg (0.0141 mmol/kg), cisplatin 4.24 mg/kg (0.0141 mmol/kg, i.e. equimolar dose) or cisplatin 8 mg/kg (0.0267 mmol/kg) as an i.v. bolus injection. Cisplatin and MHC were analysed using liquid chromatography with post-column derivatization. RESULTS: Administration of MHC 4 mg/kg caused a moderate ABR threshold shift, a significant increase in creatinine and a significant weight loss, changes similar to those seen after administration of cisplatin 8 mg/kg. Animals given cisplatin 4.24 mg/kg had a slight increase in creatinine, but had no ABR threshold shift and gained weight during the experiment. The pharmacokinetic parameters of cisplatin and MHC were estimated after administration of cisplatin 4.24 mg/kg and MHC 4 mg/kg. The area under the blood-ultrafiltrate concentration versus time curve (AUC) for cisplatin after administration of MHC 4 mg/kg was 23% (56+/-5.0 micro g.min.ml(-1)) (means+/-SD) of that after administration of cisplatin 4.24 mg/kg (240+/-25 micro g.min.ml(-1)). The AUC for MHC after administration of cisplatin 4.24 mg/kg was 20% (30+/-4.9 micro g.min.ml(-1)) of that after administration of MHC 4 mg/kg (149+/-26 micro g.min.ml(-1)). CONCLUSIONS: MHC 4 mg/kg causes ototoxicity, nephrotoxicity and weight loss when administered to guinea pigs. The toxic effects were similar to those seen after administration of cisplatin 8 mg/kg and higher than those seen after administration of cisplatin 4.24 mg/kg. 相似文献
109.
Pehrsson SK Eriksson MJ Lentell JC Bowald S 《Scandinavian cardiovascular journal : SCJ》2003,37(4):235-239
OBJECTIVE: A new tri-leaflet mechanical heart valve made of titanium was inserted in the mitral position to evaluate early results. METHODS AND RESULTS: Five sheep were followed between 3 and 6 months (mean 4.7 months) and performed very well clinically during the follow-up period. In three of five animals a minor para-valvular leakage without hemodynamic importance was observed. The invasive pressure measurements at the end of follow-up revealed only minor transvalvular pressure differences between 1 and 4 mmHg (mean 2.4 mmHg). Similar results were obtained by echo-Doppler technique. Histological examination of the tissue around the valve showed no signs of foreign body reaction or chronic inflammatory reaction. CONCLUSION: This new tri-leaflet heart valve has shown an excellent hemodynamic performance and good tissue compatibility, and therefore may be an alternative to other currently used valve prostheses. 相似文献
110.
Holmgren D Redfors S Rydberg A Wåhlander H 《Clinical physiology and functional imaging》2003,23(2):120-122
We report a case of recurrent syncope in association with moderate ventricular dysfunction and mild AV-valve regurgitation in an 18-year-old girl, 4 years after she underwent total cavopulmonary connection surgery. Cardiac catheterization revealed a transpulmonary gradient of 1-2 mmHg. During exercise, a dramatic fall in blood pressure and blood oxygenation was observed, paralleled by an increase in heart rate and central venous pressure. Although a slight increase in pulmonary vascular resistance could not be excluded, the reaction was interpreted in terms of an extremely low transpulmonary gradient in association with ventricular dysfunction. Five months after heart transplantation, the patient has been completely free from syncope. Fontan circulation usually involves a delicate haemodynamic situation which may necessitate haemodynamic re-evaluations, including dynamic measurements of the central venous pressure during exercise. Also a moderate ventricular dysfunction may result in compromised pulmonary circulation which in turn may lead to syncope during exercise as a result of insufficient systemic circulation. 相似文献