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991.
A physiological model of propranolol disposition was designed to help explain the large increase in AUC seen when the drug is administered with food. The mass balance equation for the liver compartment used Michaelis-Menten terms to describe hepatic metabolism. Previously published pharmacokinetic and physiological parameters were used throughout. The three parameters, Qh, Kmt, and Vmax, were varied for different durations and by a factor of two to increase AUC. The parameter variations were patterned after the changes in splanchnic blood flow following a high protein meal. The model exhibits saturation kinetics for most of the absorption phase after a simulated single oral dose of 1 mg kg-1, during which hepatic extraction is decreased. As the dose is decreased, the degree of saturation lessens. Using an input rate representative of regular release, changes to Qh caused little change in AUC. While the model was moderately sensitive to Kmt changes, large increases in AUC were seen after Vmax was altered. The sensitivity of the system to Kmt and Vmax changes became greater as the duration of the changes was increased. The AUC was most sensitive to Vmax variation, leading to the conclusion that mechanisms involving this parameter should be explored further. Reducing the input rate to mimic sustained release decreased the AUC for a given dose as well as the sensitivity of AUC to changes in Kmt and Vmax. 相似文献
992.
M R Wright J E Axelson D W Rurak B McErlane G H McMorland R C Ongley Y K Tam J D Price 《British journal of clinical pharmacology》1988,26(4):469-473
The disposition of metoclopramide was studied on a four-way crossover basis in six healthy non-smoking volunteers. The linearity of kinetic parameters and absolute bioavailability of metoclopramide were examined. In contrast to previous reports, metoclopramide obeyed linear kinetics over oral doses ranging from 5 to 20 mg. The absolute bioavailability of metoclopramide was 0.76 +/- 0.38 (mean +/- s.d.) from the oral dosage forms examined in this study. 相似文献
993.
Inhibition of tumor growth and metastasis in vitro and in vivo by targeting macrophage migration inhibitory factor in human neuroblastoma 总被引:2,自引:0,他引:2
Ren Y Chan HM Fan J Xie Y Chen YX Li W Jiang GP Liu Q Meinhardt A Tam PK 《Oncogene》2006,25(25):3501-3508
Macrophage migration inhibitory factor (MIF) has been defined as a novel oncogene. Our previous results have shown that MIF may contribute to the progression of neuroblastoma by (a) inducing N-Myc expression and (b) upregulating the expression of angiogenic factors. The aim of this study was to test whether tumor growth could be inhibited by reduction of endogenous MIF expression in neuroblastoma and clarify the molecular mechanisms underlying MIF reduction on the control of neuroblastoma growth. We established human neuroblastoma cell lines stably expressing antisense MIF (AS-MIF) cDNA. These stable transfectants were characterized by cell proliferation, gene expression profile, tumorigenicity and metastasis in vitro and in vivo. Decreased MIF expression was observed after transfection with AS-MIF in neuroblastoma cells and downregulation of MIF expression significantly correlated with decreased expression of N-Myc, Ras, c-Met and TrkB at protein level. Affymetrix microarray analysis revealed that expression of IL-8 and c-met was inhibited and neuroblastoma-favorable genes such as EPHB6 and BLU were upregulated in MIF reduced cells. Neuroblastoma cell growth exhibited a nearly 80% reduction in AS-MIF transfectants in vitro. Furthermore, mice in which tumors formed after subcutaneous injection of AS-MIF transfectants showed a 90% reduction in tumor growth compared to control. Metastasis in mice was also suppressed dramatically. Our data demonstrate that targeting MIF expression is a promising therapeutic strategy in human neuroblastoma therapy, and also identifies the MIF target genes for further study. 相似文献
994.
Demaegdt H Lenaerts PJ Swales J De Backer JP Laeremans H Le MT Kersemans K Vogel LK Michotte Y Vanderheyden P Vauquelin G 《European journal of pharmacology》2006,546(1-3):19-27
Due to its high affinity for [(125)I]Angiotensin IV, cystinyl aminopeptidase (CAP) has recently been assigned as the 'angiotensin AT(4) receptor'. Since the aminopeptidase N (AP-N) activity is also susceptible to inhibition by Angiotensin IV, it might represent an additional target for this peptide. Based on [(125)I]Angiotensin IV binding and catalytic activity measurements, we compared the ligand interaction properties of recombinant human CAP and human AP-N. Both enzymes displayed distinct pharmacological profiles. Although their activity is inhibited by Angiotensin IV and LVV-hemorphin 7, both peptides are more potent CAP-inhibitors. On the other hand, substance P and l-methionine have a higher potency for AP-N. High affinity binding of [(125)I]Angiotensin IV to CAP occurs in the presence of chelators but not to AP-N in either the absence or presence of chelators. These differences were exploited to determine whether CAP and/or AP-N are present in different cell lines (CHO-K1, COS-7, HEK293, SK-N-MC and MDBK). We provide evidence that CAP predominates in these cell lines and that, comparatively, CHO-K1 cells display the highest level of this enzyme. 相似文献
995.
Letoha T Kusz E Pápai G Szabolcs A Kaszaki J Varga I Takács T Penke B Duda E 《Molecular pharmacology》2006,70(6):2027-2036
GABA(B) receptors are heterodimers of two subunits, GABA(B1) (GB1) and GABA(B2) (GB2). Agonists such as GABA and baclofen bind to the GB1 subunit only, whereas GB2 is essential for G protein activation. Positive allosteric modulators enhance the potency and efficacy of agonists at GABA(B) receptors and are of particular interest because they lack the sedative and muscle relaxant properties of agonists. In this study, we aimed to characterize the interaction of the positive modulator N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine (GS39783) with the GABA(B) receptor heterodimer. Using functional guanosine 5'-O-(3-[(35)S]thio)triphosphate binding assays, we observed positive modulation by GS39783 in different vertebrate species but not in Drosophila melanogaster. However, coexpression of D. melanogaster GB1 with rat GB2 yielded functional receptors positively modulated by GS39783. Together with data from rat/D. melanogaster GB2 subunit chimeras, this pointed to a critical role of the GB2 transmembrane region for positive modulation. We further characterized GS39783 function using point mutations. GS39783 positively modulated GABA responses but also showed considerable agonistic activity at heterodimers containing a mutant rat GB2 subunit with three amino acid substitutions in transmembrane domain VI. It was surprising that in contrast to wild-type rat GB2, this mutant subunit was also activated by GS39783 when expressed without GB1. The mutations of both G706T and A708P are necessary and sufficient for activation and identify a key region for the effect of GS39783 in the GB2 transmembrane region. Our data show that mutations of specific amino acids in GB2 can induce agonism in addition to positive modulation and facilitate GB2 activation in the absence of GB1. 相似文献
996.
BACKGROUND: Helicobacter pylori infection is common in paediatric population. To date, there is still no universally accepted recommendation on the treatment of this infection in children. Ranitidine bismuth citrate-based triple therapy has been shown to be effective in H. pylori eradication in adults but its use has rarely been validated in children. AIM: To investigate the efficacy of ranitidine bismuth citrate-based triple therapy in eradication of H. pylori in children and to determine the shortest duration of treatment required. PATIENTS AND METHODS: We conducted a prospective randomized study comparing ranitidine bismuth citrate plus amoxicillin plus clarithromycin given for 4 days vs. 7 days in H. pylori-infected children diagnosed by (13)C-urea breath test. Eradication was evaluated by repeat (13)C-urea breath test at 6 weeks after treatment. RESULTS: A total of 206 children were recruited (median age 12 years, 97 boys and 109 girls). Ninety-eight (47.6%) and 108 (52.4%) children were randomized to receive 7-day and 4-day regimen respectively. The eradication rate of 4-day treatment arm was 77.8% (both intention-to-treat and per protocol) compared with 88.8% (intention-to-treat, P = 0.036) and 89.7% (per protocol, P = 0.022) of 7-day regimen. There was no statistical difference in terms of side effects between the two groups. CONCLUSIONS: Seven-day ranitidine bismuth citrate-based triple therapy is an effective and well-tolerated treatment for eradication of H. pylori in children. 相似文献
997.
Traditional Chinese medicine causing hepatotoxicity in patients with chronic hepatitis B infection: a 1-year prospective study 总被引:2,自引:0,他引:2
Yuen MF Tam S Fung J Wong DK Wong BC Lai CL 《Alimentary pharmacology & therapeutics》2006,24(8):1179-1186
BACKGROUND: Safety of traditional Chinese medicine in patients with chronic hepatitis B is unknown. AIM: To study the clinical outcome of traditional Chinese medicine-induced hepatotoxicity in chronic hepatitis B patients. PATIENTS AND METHODS: All chronic hepatitis B patients in 2004 with liver dysfunction requiring hospitalization were screened prospectively for traditional Chinese medicine intake. The hepatotoxicity of individual traditional Chinese medicine elements was determined by extensive search of both English and Chinese publications. RESULTS: Of 45 chronic hepatitis B patients, the liver dysfunction in seven (15.6%) was attributable to traditional Chinese medicine. All had liver dysfunction pattern resembling those of acute exacerbation of chronic hepatitis B. Three patients had adverse outcomes (two deaths, one liver transplantation). One patient had accelerated course of cirrhosis now awaiting liver transplantation. The identified hepatotoxic components were Polygonum multiflorum Thunb, Cassia obtusifolia L, Melia toosendan Sieb., Rheum palmatum L., Scolopendra subspinipes mutilans L, Alisma orientale Juzepe, Glycyrrhiza uralensis Fisch. and Mentha haplocalyx Briq. One traditional Chinese medicine formula was adulterated with a highly hepatotoxic agent, N-nitrosofenfluramine. CONCLUSIONS: Traditional Chinese medicine-related hepatotoxicity resulted in high mortality in chronic hepatitis B patients. Prospective randomized-controlled trials with the same stringent criteria as western medicine clinical trials are required for Chinese medicines, to document their efficacies and safety before they can be advocated for the treatment of patients. 相似文献
998.
Guillain-Barré syndrome (GBS) is the most common cause of acute flaccid paralysis in polio-free regions. Considerable evidence links Campylobacter infection with GBS, but evidence that implicates other pathogens as triggers remains scarce. We conducted a time-series analysis to investigate short-term correlations between weekly laboratory-confirmed reports of putative triggering pathogens and weekly hospitalizations for GBS in England from 1993 through 2002. We found a positive association between the numbers of reports of laboratory-confirmed influenza A in any given week and GBS hospitalizations in the same week. Different pathogens may trigger GBS in persons of different ages; among those <35 years, numbers of weekly GBS hospitalizations were associated with weekly Campylobacter and Mycoplasma pneumoniae reports, whereas among those >35 years, positive associations were with influenza. Further studies should estimate the relative contribution of different pathogens to GBS incidence, overall and by age group, and determine whether influenza is a real trigger for GBS or a marker for influenza vaccination. 相似文献
999.
In this paper, we report a new method based on supercritical carbon dioxide (scCO(2)) to fill and distribute the porous magnetic nanoparticles with n-octanol in a homogeneous manner. The high solubility of n-octanol in scCO(2) and high diffusivity and permeability of the fluid allow efficient delivery of n-octanol into the porous magnetic nanoparticles. Thus, the n-octanol-loaded magnetic nanoparticles can be readily dispersed into aqueous buffer (pH 7.40) to form a homogenous suspension consisting of nano-sized n-octanol droplets. We refer this suspension as the n-octanol stock solution. The n-octanol stock solution is then mixed with bulk aqueous phase (pH 7.40) containing an organic compound prior to magnetic separation. The small-size of the particles and the efficient mixing enable a rapid establishment of the partition equilibrium of the organic compound between the solid supported n-octanol nano-droplets and the bulk aqueous phase. UV-vis spectrophotometry is then applied to determine the concentration of the organic compound in the aqueous phase both before and after partitioning (after magnetic separation). As a result, logD values of organic compounds of pharmaceutical interest determined by this modified method are found to be in excellent agreement with the literature data. 相似文献
1000.
A better understanding of the biological roles and the pathological consequences of thiol-dependent enzymes has emerged in recent years, and hence considerable progress has been made in identifying and delineating cysteine proteases that can be considered promising drug targets from those involved in housekeeping functions. Cysteine proteases have been implicated in a wide variety of disease processes ranging from cardiovascular, inflammatory, viral and immunological disorders to cancer. The first milestone in drug development of cysteine protease inhibitors has probably been reached, as IDN-6556 (a broad spectrum caspase inhibitor) has recently received Orphan Drug label by the U.S. Food and Drug Administration for use in the treatment of the patients undergoing liver transplantation and other solid organ transplantation. IDN-6556, which blocks apoptosis, is in Phase II human clinical trial in patients undergoing liver transplantation. In addition, more than ten cysteine protease inhibitors are presently at various phases of clinical development/trials for diverse diseases. This review emphasises on the new development from the literature reports since the year 2000 in the exploration of potential cysteine proteases as prospective drug targets, and the investigation of promising inhibitors that can potentially be developed for the treatment of human diseases. Transglutaminases, another class of thiol-dependent enzymes, are not discussed here. 相似文献