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991.
The P-glycoprotein (P-gp)-deficient mouse model is used to assess the influence of P-gp-mediated efflux on the central nervous system (CNS) distribution of drugs. The steady-state unbound plasma/unbound brain concentration ratio ([plasma],(u)/[brain],(u)) is an alternative method for assessing CNS distribution of drugs independent of the mechanism(s) involved. The objective of this study was to compare the degree of CNS distributional impairment determined from the in vivo P-gp efflux ratio with that determined from the [plasma],(u)/[brain],(u) ratio. CNS distribution of 34 drugs, including opioids, triptans, protease inhibitors, antihistamines, and other clinically relevant drugs with either poor CNS distribution or blood-brain barrier efflux, was studied. Plasma and brain unbound fractions were determined by equilibrium dialysis. K(p,brain) and the P-gp efflux ratio were obtained from the literature or determined experimentally. The P-gp efflux ratio and the [plasma],(u)/[brain],(u) ratio were in concurrence (<3-fold difference) for 21 of the 34 drugs. However, the [plasma],(u)/[brain],(u) ratio exceeded the P-gp efflux ratio substantially (>4-fold) for 10 of the 34 drugs, suggesting that other, non-P-gp-mediated mechanism(s) may limit the CNS distribution of these drugs. The P-gp efflux ratio exceeded the [plasma],(u)/[brain],(u) ratio by more than 3-fold for three drugs, suggesting the presence of active uptake mechanism(s). These observations indicate that when mechanisms other than P-gp affect CNS distribution (non-P-gp-mediated efflux, poor passive permeability, cerebrospinal fluid bulk flow, metabolism, or active uptake), the P-gp efflux ratio may underestimate or overestimate CNS distributional impairment. The [plasma],(u)/[brain],(u) ratio provides a simple mechanism-independent alternative for assessing the CNS distribution of drugs. 相似文献
992.
The dialdehyde derivative of 5′-deoxyinosine (5′-deoxyinox) was prepared from 5′-deoxyadenosine by HNO2 deamination and periodate oxidation. 5′-Deoxyinox was shown to inhibit ribonucleotide reductase activity in cell-free extracts and to inhibit RNA and DNA syntheses in intact cells. Further, 5′-deoxyinox inhibited the conversion of cytidine nucleotides to deoxycytidine nucleotides in intact cells. In comparative studies with the dialdehyde derivative of inosine (Inox), 5′-deoxyinox was shown to be more active on a molar basis in inhibiting RNA or DNA synthesis in intact cells. In addition, 5′-deoxyinox was more inhibitory to the growth of Novikoff hepatoma cells in culture than was Inox. 5′-Deoxyinox, in addition to being more active than Inox, also differed from Inox in its biochemical properties. Inox did not inhibit RNA polymerase activity when added to isolated nuclei. On the other hand, 5′-deoxyinox showed a marked inhibition of the RNA polymerase activity when added to the isolated nuclei. Further, inhibition of the RNA polymerase activity in the nuclei from Inox-treated cells was reversed completely by the addition of exogenous polydeoxyadenylate-deoxythymidylate as template, whereas the inhibition caused by 5′-deoxyi nox was not reversed by this treatment. These studies show that, in addition to the variation in activity caused by altering the purine component, the nature of the dialdehyde moiety also plays a role in the mode of action of this class of compounds. 相似文献
993.
R N Cory R Osman S Maayani 《The Journal of pharmacology and experimental therapeutics》1984,230(1):162-170
Several naturally occurring and synthetic flavonoids were studied for their effects on the metabolism of zoxazolamine to 6-hydroxyzoxazolamine. Flavone, nobiletin, tangeretin and 7,8-benzoflavone (50-250 microM) stimulated the metabolism of zoxazolamine by liver microsomes obtained from 5-day-old rats. Evidence was obtained indicating that flavone changed the apparent Km and Vmax values for zoxazolamine hydroxylation. The i.p. administration of 5 mumol of flavone, nobiletin, tangeretin or 7,8-benzoflavone concurrently with 740 nmol of zoxazolamine immediately stimulated the total body metabolism of zoxazolamine to 6-hydroxyzoxazolamine. The magnitude of the flavone-mediated increases in zoxazolamine hydroxylation in vivo was dependent on the dose of flavone and the dose of zoxazolamine administered. The i.p. administration of 5 mumol of flavone caused a 3- to 5-fold stimulation in the in vivo metabolism of 740 to 3000 nmol of zoxazolamine, but flavone had little or no stimulatory effect when 74 nmol of zoxazolamine were administered. Flavone stimulated zoxazolamine metabolism both in vitro and in vivo when control or phenobarbital-treated rats were used, but flavone inhibited the in vitro and in vivo hydroxylation of zoxazolamine when rats induced with 5,6-benzoflavone were studied. Although flavone activated zoxazolamine metabolism in vivo in neonatal rats, flavone did not activate the in vivo metabolism of benzo(a)pyrene. The in vitro addition of the hydroxylated flavonoids apigenin, chrysin, fisetin, morin and quercetin inhibited the hydroxylation of zoxazolamine by liver microsomes from neonatal rats, but studies with quercetin and apigenin indicated that these flavonoids had no effect on the in vivo metabolism of zoxazolamine. 相似文献
994.
Previous work has shown endogenous cholinergic activity facilitates both GABAergic and glycinergic neurotransmission to premotor cardiac vagal neurons. Exogenous application of nicotine increases the frequency of glycinergic and GABAergic inhibitory postsynaptic currents (IPSCs) and miniature IPSCs (mIPSCs) to cardiac vagal neurons. In this study we examined whether the nicotine evoked facilitation of GABAergic and glycinergic neurotransmission to cardiac vagal neurons is dependent or independent of activation of voltage dependent calcium channels. Nicotine evoked increases in GABAergic and glycinergic mIPSCs in cardiac vagal neurons which were blocked by the non-specific calcium channel antagonist cadmium (100 microM). Application of the L (Cav 1) type calcium channel antagonist nimodipine (10 microM) had no effect. However, the increase in both GABAergic and glycinergic mIPSCs elicited by nicotine was abolished by the P/Q (Cav 2.1) voltage gated calcium channel antagonist omega-agatoxin IVA (100 nM). Omega-conotoxin GVIA (1 microM), a specific blocker of N (Cav 2.2) type voltage gated calcium currents, inhibited the nicotine elicited augmentation of GABA and abolished the increase in glycine mIPSC frequency. This work demonstrates that the nicotine evoked facilitation of GABAergic and glycinergic neurotransmission to cardiac vagal neurons is dependent upon activation of P/Q (Cav 2.1) and N (Cav 2.2) type calcium channels. 相似文献
995.
CCL3/macrophage inflammatory protein (MIP-1)-1alpha is elevated in the rectal biopsies of patients with active inflammatory bowel diseases, but its role remains undefined. The present study examined the role of CCL3/MIP-1alpha during trinitrobenzene sulfonic acid (TNBS)-induced colitis in the rat. Colonic CCL3/MIP-1alpha levels were elevated (>20-fold above control) within 24 h and remained elevated to day 7 of colitis induction by TNBS administration. In addition, significant increases in colonic neutrophil accumulation were observed within 24 h to day 7 of TNBS treatment. Pre-treatment of rats with a single dose of CCL3/MIP-1alpha antibody significantly reduced (47%) colonic neutrophil accumulation during the early (24 h) phase of TNBS-induced colitis. In contrast, chronic (repeated) administration of CCL3/MIP-1alpha antibody did not attenuate colonic neutrophil accumulation during the late phase (day 7) of TNBS-induced colitis. These results suggest a role for CCL3/MIP-1alpha in promoting colonic neutrophil accumulation during the early (24 h) phase of TNBS-induced colitis. 相似文献
996.
Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity 总被引:14,自引:0,他引:14
O'Shea CC Johnson L Bagus B Choi S Nicholas C Shen A Boyle L Pandey K Soria C Kunich J Shen Y Habets G Ginzinger D McCormick F 《Cancer cell》2004,6(6):611-623
ONYX-015 is an adenovirus that lacks the E1B-55K gene product for p53 degradation. Thus, ONYX-015 was conceived as an oncolytic virus that would selectively replicate in p53-defective tumor cells. Here we show that loss of E1B-55K leads to the induction, but not the activation, of p53 in ONYX-015-infected primary cells. We use a novel adenovirus mutant, ONYX-053, to demonstrate that loss of E1B-55K-mediated late viral RNA export, rather than p53 degradation, restricts ONYX-015 replication in primary cells. In contrast, we show that tumor cells that support ONYX-015 replication provide the RNA export function of E1B-55K. These data reveal that tumor cells have altered mechanisms for RNA export and resolve the controversial role of p53 in governing ONYX-015 oncolytic selectivity. 相似文献
997.
998.
Franklin C Rosenbloom B 《Critical care medicine》2003,31(2):663; author reply 663-663; author reply 664
999.
Rifai K Ernst T Kretschmer U Bahr MJ Schneider A Hafer C Haller H Manns MP Fliser D 《Journal of hepatology》2003,39(6):984-990
BACKGROUND/AIMS: Extracorporeal detoxification systems for supportive therapy of liver failure have recently gained much interest. We herein report results from the first clinical application of Prometheus, a new liver support system in which albumin-bound substances are directly removed from blood by special adsorber. In a simultaneous step, high-flux hemodialysis is performed. We assessed safety, adsorber efficiency and clinical efficacy of the Prometheus system. METHODS: Eleven patients with acute-on-chronic liver failure and accompanying renal failure were treated with Prometheus on 2 consecutive days for >4 h. RESULTS: Prometheus treatment significantly improved serum levels of conjugated bilirubin, bile acids, ammonia, cholinesterase, creatinine, urea and blood pH. There were no significant changes in hemoglobin and platelet levels, whereas leucocytes increased without signs of systemic infection. No treatment-related complications except a blood pressure drop in two patients with systemic infection were noted. In one patient (Child-Pugh score: 15) Prometheus treatment could not be completed due to onset of uncontrolled bleeding 16 h after dialysis. CONCLUSIONS: Prometheus is a safe supportive therapy for patients with liver failure. A significant improvement of the biochemical milieu was observed already after two treatments. Prospective controlled studies with the Prometheus system are necessary to evaluate hard clinical end-points. 相似文献
1000.