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排序方式: 共有69条查询结果,搜索用时 15 毫秒
61.
Teo SK Stirling DI Hoberman AM Christian MS Thomas SD Khetani VD 《Birth defects research. Part B, Developmental and reproductive toxicology》2003,68(2):162-171
BACKGROUND: D ,L ‐threo‐Methylphenidate (D ,L ‐MPH) is marketed currently for attention deficit hyperactivity disorder in children. D ‐threo‐methylphenidate (dexmethylphenidate; D ‐MPH) is a refined formulation of D ,L ‐methylphenidate containing only the active enantiomer and was recently approved in the U.S. for the same condition. D ‐Methylphenidate has been shown to be efficacious in patients at half the dose of D ,L ‐MPH with a potentially improved therapeutic profile. The developmental toxicity of both compounds was determined and compared in rats and rabbits according to current International Conference on Harmonization (ICH) guidelines. METHODS: Groups of pregnant rats were orally dosed twice daily 6 hr apart from Days 7 to 17 of presumed gestation (DG 7–17) for total daily doses of 2, 6 and 20 mg/kg D ‐MPH and 40 mg/kg D ,L ‐MPH. Groups of presumed pregnant rabbits were similarly dosed from DG 6 to 18 for total daily doses of 4, 20 and 100 mg/kg D ‐MPH and 200 mg/kg D ,L ‐MPH. Control groups for both studies were given water vehicle. Comprehensive clinical and developmental measurements were made. Satellite groups of animals were included in the main rat and rabbit studies for toxicokinetic assessment. RESULTS: No drug‐related mortality was seen in the F0 rats and rabbits. The number of rats with repetitive pawing, dilated pupil and aggression was significantly greater for the 40 mg/kg D ,L ‐MPH compared to the 20 mg/kg D ‐MPH dosed rats. Maternal body weight and body weight gain were significantly reduced for both D ‐MPH and D ,L ‐MPH groups compared to control. Maternal reproductive and litter parameters were unaffected by both drugs. No gross external, soft tissue, or skeletal alterations related to both compounds were seen in the fetuses. In rabbits, head‐bobbing and hyperpnea were significantly greater for the 200 mg/kg D ,L ‐MPH compared to 100 mg/kg D ‐MPH. No other maternal or fetal effects related to both compounds were seen. Exposure to D ‐MPH (as assessed by AUC) showed no teratogenic effects at exposures of up to 5.6 and 1.7 times for the rat and rabbit respectively compared to children taking the maximum therapeutic dose of 20 mg/day (10 mg twice a day). No teratogenic effects were seen for D ,L ‐MPH in rat and rabbit at exposures of up to 3.7 to 11.7 times that of the maximum therapeutic pediatric dose of 60 mg/day. CONCLUSIONS: Rats and rabbits dosed with D ,L ‐MPH exhibited significantly greater incidence of maternal clinical observations at twice the dose of D ‐MPH. Both D ‐MPH and D ,L ‐MPH were not teratogenic in rats and rabbits at higher exposure levels compared to humans. © 2003 Wiley‐Liss, Inc. 相似文献
62.
S. Nishanth Kumar C Mohandas Bala Nambisan RS Sreerag CA Jayaprakas 《Folia microbiologica》2014,59(3):197-202
In continuation of our search for new antimicrobial secondary metabolites from Bacillus cereus associated with rhabditid entomopathogenic nematode, a new microbial diketopiperazine, cyclo(l-Pro-d-Arg), was isolated from the ethyl acetate extract of fermented modified nutrient broth. The chemical structures of the isolated compounds were identified based on their 1D, 2D NMR and high-resolution electrospray ionisation–mass spectroscopy data. Antibacterial activity of the compound was determined by minimum inhibitory concentration and disc diffusion method against medically important bacteria, and the compound was recorded to have significant antibacterial activity against test bacteria. The highest activity was recorded against Klebsiella pneumoniae (1 μg/mL). Cyclo(l-Pro-d-Arg) was recorded to have significant antitumor activity against HeLa cells (IC50 value 50 μg/mL), and this compound was recorded to have no cytotoxicity against normal monkey kidney cells (VERO) up to 100 μg/mL). To the best of our knowledge, this is the first time that cyclo(l-Pro-d-Arg) has been isolated from a microbial natural source. 相似文献
63.
Background
We recently observed an association of resistance with a certain enteropathogenic Escherichia coli (EPEC) serotypes and identified a conjugative plasmid, similar to plasmid pED208, that was conserved among archival O111:H2/NM and O119:H2 strains of diverse geographical origin. In this study, we sought to determine the prevalence and distribution of this plasmid among a collection of EPEC isolates from Brazil, as well as to study the susceptibilities of these isolates to antimicrobial agents. 相似文献64.
We used immunohistochemistry to quantify and compare the expression of Toll-like receptor 2 (TLR2) and cluster of differentiation 14 (CD14) in gingival tissues of both healthy individuals and patients with chronic periodontitis. We also correlated the expression of TLR2 and CD14 with the histological grades of chronic periodontitis. We examined 30 gingival specimens from chronic periodontitis patients and 10 from healthy individuals. Tissues from both groups were immunostained with antibodies against TLR2 and CD14. TLR2 and CD14 were expressed by endothelial cells, fibroblasts, lymphocytes and plasma cells. The immunohistochemical expression of TLR2 and CD14 was significantly greater in inflammatory cells of the chronic periodontitis group than in healthy individuals. Expression of these molecules was greater in the inflammatory cells of connective tissue adjacent to pocket epithelium in both groups. The expression of TLR2 and CD14 was greatest in the periodontitis group that was classified as severe grade, followed by moderate and mild grades, which suggests a role of TLR2 and CD14 in the pathogenesis of chronic periodontitis. The positive correlation of TLR2 and CD14 expression levels with the severity grades of chronic periodontitis suggests that they are correlated also with disease severity; therefore, they may be useful for predicting disease progression. Our findings are consistent with the possibility that CD14 acts as a co-receptor for TLR2. 相似文献
65.
Okechukwu Ukairo Chitra Kanchagar Amanda Moore Julianne Shi Jeannemarie Gaffney Simon Aoyama Kelly Rose Stacy Krzyzewski Jack McGeehan Melvin E. Andersen Salman R. Khetani Edward L. LeCluyse 《Journal of biochemical and molecular toxicology》2013,27(3):204-212
Primary hepatocytes display functional and structural instability in standard monoculture systems. We have previously developed a model in which primary hepatocytes are organized in domains of empirically optimized dimensions and surrounded by murine embryonic fibroblasts (HepatoPac?). Here, we assess the long‐term phenotype of freshly isolated and cryopreserved rat hepatocytes in a 96‐well HepatoPac format. The viability, cell polarity (actin microfilaments, bile canaliculi), and functions (albumin, urea, Phase I/II enzymes, transporters) of fresh and cryopreserved rat hepatocytes were retained in HepatoPac at similar levels for at least 4 weeks as opposed to rapidly declining over 5 days in collagen/Matrigel? sandwich cultures. Pulse or continuous exposure of rat HepatoPac to GW‐7647, a selective agonist of PPARα, caused reproducible induction of CYP4A1 and 3‐hydroxy‐3‐methylglutaryl‐CoA synthase over 4 weeks. In conclusion, rat HepatoPac in a 96‐well format can be used for chronic dosing of highly functional hepatocytes and assessment of perturbed hepatocellular pathways. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:204‐212, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21469 相似文献
66.
AAM Coelho-Castelo AP Trombone RS Rosada RR Santos Jr VLD Bonato A Sartori CL Silva 《Genetic vaccines and therapy》2006,4(1):1-10
In order to assess a new strategy of DNA vaccine for a more complete understanding of its action in immune response, it is important to determine the in vivo biodistribution fate and antigen expression. In previous studies, our group focused on the prophylactic and therapeutic use of a plasmid DNA encoding the Mycobacterium leprae 65-kDa heat shock protein (Hsp65) and achieved an efficient immune response induction as well as protection against virulent M. tuberculosis challenge. In the present study, we examined in vivo tissue distribution of naked DNA-Hsp65 vaccine, the Hsp65 message, genome integration and methylation status of plasmid DNA. The DNA-Hsp65 was detectable in several tissue types, indicating that DNA-Hsp65 disseminates widely throughout the body. The biodistribution was dose-dependent. In contrast, RT-PCR detected the Hsp65 message for at least 15 days in muscle or liver tissue from immunized mice. We also analyzed the methylation status and integration of the injected plasmid DNA into the host cellular genome. The bacterial methylation pattern persisted for at least 6 months, indicating that the plasmid DNA-Hsp65 does not replicate in mammalian tissue, and Southern blot analysis showed that plasmid DNA was not integrated. These results have important implications for the use of DNA-Hsp65 vaccine in a clinical setting and open new perspectives for DNA vaccines and new considerations about the inoculation site and delivery system. 相似文献
67.
Okechukwu Ukairo Michael McVay Stacy Krzyzewski Simon Aoyama Kelly Rose Melvin E. Andersen Salman R. Khetani Edward L. LeCluyse 《Journal of biochemical and molecular toxicology》2013,27(10):471-478
We have recently shown that primary rat hepatocytes organized in micropatterned cocultures with murine embryonic fibroblasts (HepatoPac?) maintain high levels of liver functions for at least 4 weeks. In this study, rat HepatoPac was assessed for its utility to study chemical bioactivation and associated hepatocellular toxicity. Treatment of HepatoPac cultures with acetaminophen (APAP) over a range of concentrations (0–15 mM) was initiated at 1, 2, 3, or 4 weeks followed by the assessment of morphological and functional endpoints. Consistent and reproducible concentration‐dependent effects on hepatocyte structure, viability, and basic functions were observed over the 4‐week period, and were exacerbated by depleting glutathione using buthionine sulfoximine or inducing CYP3A using dexamethasone, presumably due to increased reactive metabolite‐induced stress and adduct formation. In conclusion, the results from this study demonstrate that rat HepatoPac represents a structurally and functionally stable hepatic model system to assess the long‐term effects of bioactivated compounds. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:471‐478, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21512 相似文献
68.
Mitochondrial DNA variation and genetic structure in populations of Drosophila melanogaster 总被引:5,自引:0,他引:5
The understanding of the genetic structure of a species can be improved by
considering together data from different types of genetic markers. In the
past, a number of worldwide populations of Drosophila melanogaster have
been extensively studied for several such markers, including allozymes,
chromosomal inversions, and quantitative characters. Here we present
results from a study of restriction- fragment-length polymorphisms of
mitochondrial DNA (mtDNA) in 92 isofemale lines from many of the same
geographic populations of D. melanogaster. Eleven restriction enzymes were
used, of which four revealed restriction-site polymorphism. A total of 24
different haplotypes were observed, of which 18 were unique to single
populations. In many populations, the unique haplotypes have reached high
frequency without being observed in neighboring populations. A Wagner
parsimony tree reveals that mutationally close variants show geographical
clumping, suggesting local differentiation of mtDNA in populations. The
Old-World and the New-World populations are differentiated, with the
predominant Old-World haplotype being virtually absent from the New World.
These results contrast with those for the nuclear genes, in which many loci
show parallel clines in different continents, and suggest a common origin
of D. melanogaster populations in North America.
相似文献
69.