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41.
The influence of quercetin, chlorpromazine, aristolochic acid, and indomethacin on group I phospholipase A2 (PLA2) from porcine pancreas and on group II PLA2 fromVipera russelli was compared. Quercetin and chlorpromazine were found to inhibit PLA2 activity in lower concentrations (< 100M), while aristolochic acid and indomethacin were inhibitory only in higher concentrations (> 100M). The order of potency againstVipera PLA2 was: quercetin >chlorpromazin aristolochic acid > indomethacin, while the order of potency against pancreatic PLA2 was: chlorpromazine > aristolochic acid > indomethacin> quercetin. Thus, quercetin was a potent inhibitor towards group II PLA2 (IC50=2M), but a very weak inhibitor against group I PLA2, with maximum 30% inhibition. Aristolochic acid and indomethacin were three to four times more potent towards group II PLA2 than towards group I PLA2, while chlorpromazine was equally potent towards the two PLA2 types. Quercetin and chlorpromazine were also tested against two PLA2 fractions purified from the plasma of septic shock patients; chlorpromazine was then equally potent towards the two PLA2 fractions, whereas quercetin was a potent inhibitor of only one of the two PLA2 fractions (IC50=4M). Together, these results indicate that (1) different PLA2 inhibitors have different potency depending on which type of PLA2 they are used against, (2) quercetin selectively inhibits group II PLA2 and may therefore be used to discriminate between different PLA2 forms in biological materials, and (3) both PLA2 of group I and group II are present in septic shock plasma. 相似文献
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Christel M. Olsen Elise T. M. Meussen‐Elholm Mari Samuelsen Jrn A. Holme Jan K. Hongslo 《Basic & clinical pharmacology & toxicology》2003,92(4):180-188
Abstract: Bisphenol A is extensively used in the manufacturing of epoxy resins and polycarbonate plastics, whereas several brominated and chlorinated analogues are used as flame retardants and intermediates in the plastic industry. Due to the structural relationship between these chemicals and the high production volumes, we wanted to characterize and compare their potential oestrogen‐like potency using several end‐points in MCF‐7 cells: induction of pS2 protein and progesterone receptor, reduction of oestrogen receptor level, and stimulation of cell growth. Bisphenol A, tetrachloro‐ and tetrabromo‐bisphenol A, 4‐hydroxybiphenyl and 4,4′‐dihydroxybiphenyl all showed oestrogen‐like properties in MCF‐7 cells. The chemicals tested had affinity to the oestrogen receptor isolated from MCF‐7 cells, although their EC50s were 1,000 to 80,000 times higher than the EC50 of 17β‐oestradiol. Bisphenol A and 4‐hydroxybiphenyl induced cell growth in MCF‐7 cells, and the highest test concentrations induced responses, apparently exceeding the cell growth induced by 17β‐oestradiol. The other chemicals tested induced less than 50% of the maximum 17β‐oestradiol‐stimulated cell growth. Bisphenol A, 4‐hydroxybiphenyl, tetrabromobisphenol A and tetrachlorobisphenol A all increased the level of the oestrogen‐regulated proteins, progesterone receptor and pS2, whereas 4,4′‐dihydroxybiphenyl showed no such effect. Bisphenol A was the only chemical tested that clearly mimicked 17β‐oestradiol in its ability to reduce the level of cytosolic oestrogen receptors in MCF‐7 cells. By measuring several oestrogen‐dependent endpoints it seems that some xeno‐oestrogens cause an imbalanced oestrogen‐response. Their ability and potency in mimicking 17β‐oestrogen in one parameter is not necessarily accompanied by a similar effect in another oestrogen‐linked parameter. 相似文献
45.
Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit. 总被引:5,自引:0,他引:5
Hans Herbert Steiner Matteo Mario Bonsanto Philipp Beckhove Michael Brysch Karsten Geletneky Rezvan Ahmadi Rebecca Schuele-Freyer Paul Kremer Golamreza Ranaie Dejana Matejic Harald Bauer Marika Kiessling Stefan Kunze Volker Schirrmacher Christel Herold-Mende 《Journal of clinical oncology》2004,22(21):4272-4281
PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response. 相似文献
46.
Hans Gelderblom Ramon Salazar Jaap Verweij George Pentheroudakis Maja J A de Jonge Martin Devlin Christel van Hooije Francis Seguy Rosendo Obach Joan Pru?onosa Paola Principe Chris Twelves 《Clinical cancer research》2003,9(11):4101-4107
PURPOSE: Diflomotecan (BN80915) is an E-ring modified camptothecin analogue that possesses greater lactone stability in plasma compared with other topoisomerase I inhibitors, a potential advantage for antitumor activity. As with other camptothecins, oral administration has pharmacological and clinical advantages. This Phase I study was performed to assess the feasibility of the administration of oral diflomotecan, to determine the maximum-tolerated, dose its bioavailability, and to explore the pharmacokinetics. EXPERIMENTAL DESIGN: An initial i.v. bolus was administered to assess the bioavailability of diflomotecan. Fourteen days later, diflomotecan was administered p.o. once daily for 5 days to adult patients with solid malignant tumors and repeated every 3 weeks. BN80915 and its open lactone form BN80942 were measured. RESULTS: Twenty-two patients entered the study and received a total of 57 cycles of oral diflomotecan at flat dose levels of 0.10, 0.20, 0.27, and 0.35 mg. The main toxicity was hematological, but some patients experienced alopecia, mild gastrointestinal toxicity, and fatigue. At the 0.35-mg dose level, 2 of 4 patients experienced dose-limiting toxicity comprising grade 3 thrombocytopenia with epistaxis and febrile neutropenia in 1 patient and uncomplicated grade 4 neutropenia lasting for >7 days in another. Toxicity was acceptable at the 0.27-mg dose level at which dose-limiting toxicities were observed in 3 of 12 patients (grade 4 neutropenia > 7 days, complicated by fever in 1 patient but without other signs of infection). After two cycles of diflomotecan, 6 patients had disease stabilization, which was maintained in 2 patients for 9 months and >1 year, respectively. Diflomotecan pharmacokinetics were linear over the dose range studied. Systemic exposure correlated with the fall in WBC counts. The mean oral bioavailability (+/-SD) was 72.24 +/- 59.2% across all dose levels. Urinary excretion of BN80915 was very low. CONCLUSIONS: The recommended oral diflomotecan dose for Phase II studies is 0.27 mg/day x 5 every 3 weeks. This regimen is convenient and generally well tolerated with a favorable pharmacokinetic profile and high but variable bioavailability. 相似文献
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Lindahl SG 《Acta anaesthesiologica Scandinavica》2000,44(8):906-909
During the first decade of the new millennium the intense reorganization of hospitals and of medical care will be replaced by stability and long-term goals. An anesthesiologist is now as active outside as within the operating theater, being a predominant resource in intensive care, pain management, emergency and prehospital care. The anesthesiologist will also have a key part to play in risk analysis of patients scheduled for various kinds of advanced treatment. Anesthesiologists are now also more involved in primary home care where, together with other physicians and categories of health care providers, they offer qualified treatment of various diseases at home – the environment preferred by the patient. 相似文献
48.
Human cornea construct HCC-an alternative for in vitro permeation studies? A comparison with human donor corneas. 总被引:1,自引:0,他引:1
Stephan Reichl Stefanie D?hring Jürgen Bednarz Christel C Müller-Goymann 《European journal of pharmaceutics and biopharmaceutics》2005,60(2):305-308
Transcorneal in vitro permeation studies of ophthalmic drugs are normally performed with either excised animal corneas or latterly corneal cell culture models. A good correlation between these models and excised animal corneas regarding permeation behaviour of drugs has already been shown. However, comparisons between corneal in vitro models containing human cells and excised human corneas do not exist yet. Therefore in the present study the transcorneal permeation of six different model drugs (pilocarpine hydrochloride, befunolol hydrochloride, hydrocortisone, diclofenac sodium, clindamycin hydrochloride and timolol maleate) across our previously described three-dimensional organotypic human cornea construct (HCC) was tested using Franz diffusion cells and compared with permeation data obtained from human donor corneas. The HCC showed a similar permeation behaviour compared with human donor cornea for all substances. The permeabilities (permeation coefficients P) of the human cornea equivalent versus the human donor cornea were the same in the case of diclofenac, clindamycin, timolol, but marginally decreased for hydrocortisone and slightly increased for pilocarpine and befunolol. These small differences of permeation coefficients were expressed as factors and only varied from 0.8 to 1.4. The results indicate that the HCC may be an alternative for in vitro permeation studies and appropriate for predicting drug absorption into the human eye. 相似文献
49.
Glutamate receptor subunits are altered in forebrain and cerebellum in rats chronically exposed to the NMDA receptor antagonist phencyclidine. 总被引:1,自引:0,他引:1
Phencyclidine (PCP) is a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor subtype. It produces transient psychoses in normal individuals and exacerbates psychoses in schizophrenics. When administered to rodents, PCP elicits stereotypic behaviors including unrelenting head swaying, hyperlocomotion, and social withdrawal. In this study, we examined the relative distribution of the NMDA receptor subunits, as well as the subunits of its modulating receptor, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) in the forebrain, hippocampus, and cerebellum of rats chronically exposed to PCP. Rats were injected for 30 days with PCP (10 mg/kg) and age/sex-matched controls were injected for 30 days with saline vehicle. Brain NMDA and AMPA receptor subunit distribution patterns and protein levels were then analyzed by immunocytochemistry and Western blot analysis. Chronic PCP-treated animals showed significant alterations in glutamate receptor subunits, particularly for the NR1, NR2B, NR2C, and NR2D components of the NMDA receptor. AMPA receptor subunits demonstrated few significant changes in subunit availabilities. Western blot analysis largely confirmed the immunocytochemical findings. These results support the conclusion that subunits of the NMDA receptor are selectively altered by chronic PCP antagonism, with minimal to no changes observed in AMPA receptor subunits. Our findings are consistent with the interpretation that a dysfunctional NMDA receptor complex may mediate abnormal glutamatergic neurotransmission and potentially contribute to the complex etiology of cognitive disorders. 相似文献
50.