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81.
The sulfide metabolite of sulindac prevents tumors and restores enterocyte apoptosis in a murine model of familial adenomatous polyposis 总被引:16,自引:5,他引:11
Mahmoud NN; Boolbol SK; Dannenberg AJ; Mestre JR; Bilinski RT; Martucci C; Newmark HL; Chadburn A; Bertagnolli MM 《Carcinogenesis》1998,19(1):87-91
Sulindac, a non-steroidal anti-inflammatory drug (NSAID), is effective in
treating intestinal adenomas in humans with Familial Adenomatous Polyposis
(FAP) and in preventing intestinal tumors in the C57Bl/6J- Min+ (Min)
mouse, an animal model of FAP. Sulindac is a prodrug metabolized by the
liver and intestinal flora to a sulfone, which has no anti-inflammatory
activity, and a sulfide, which is the active anti- inflammatory metabolite.
In this study, we determined which of these metabolites is responsible for
the anti-tumor effect of sulindac in Min mice. Min mice were treated with
either sulindac sulfone or sulindac sulfide (0.5 +/- 0.1 mg/day). Min mice
and homozygous C57Bl/6J-(+/+) normal litter-mates lacking the Apc mutation
(+/+) were used as controls. At 110 days of age, all mice were euthanized
and their intestinal tracts examined. Control Min mice had 33.2 +/- 6.6
tumors per mouse compared to 0.6 +/- 0.3 tumors for sulindac
sulfide-treated Min mice (P < 0.001) and 21.9 +/- 4.5 tumors per mouse
for sulindac sulfone-treated Min mice (P > 0.05). Decreased enterocyte
apoptosis was observed in Min control mice and Min mice treated with
sulindac sulfone. Sulindac sulfide restored to normal the level of
apoptosis in the mucosa of Min animals and decreased levels of PGE2 in the
small intestine of treated Min animals by 59% (P < 0.001). These data
suggest that the anti-tumor effect of sulindac in Apc-deficient animals is
mediated by the sulfide metabolite and correlates with suppression of
tissue prostaglandin synthesis.
相似文献
82.
van Leth F Conway B Laplumé H Martin D Fisher M Jelaska A Wit FW Lange JM;NN study group 《Antiviral therapy》2004,9(5):721-728
OBJECTIVE: To assess whether differences in safety profiles between nevirapine (NVP) and efavirenz (EFV), as observed in the 2NN study, translated into differences in 'health related quality of life' (HRQoL). DESIGN: A sub-study of the 2NN study, with antiretroviral-naive patients randomly allocated to NVP (once or twice daily), EFV or NVP+EFV, in addition to stavudine and lamivudine. METHODS: Comparing differences in changes of HRQoL over 48 weeks as measured with the Medical Outcomes Study HIV Health Survey (MOS-HIV) questionnaire, using analysis of variance. RESULTS: The 2NN study enrolled 1216 patients. No validated questionnaires were available for 244 patients, and 55 patients had no HRQoL data at all, leaving 917 patients eligible for this sub-study. A total of 471 (51%) had HRQoL measurements both at baseline and week 48. The majority (69%) of patients without HRQoL measurements did, however, complete the study. The change in the physical health score (PHS) was 3.9 for NVP, 3.4 for EFV and 2.4 for NVP+EFV (P=0.712). For the mental health score (MHS) these values were 6.1, 7.0 and 3.9, respectively (P=0.098). A baseline plasma HIV-1 RNA concentration (pVL) > or = 100,000 copies/ml and a decline in pVL (per log10) were independently associated with an increase of PHS. An increase of MHS was only associated with pVL decline. Patients experiencing an adverse event during follow-up had a comparable change in PHS but a significantly smaller change in MHS, compared with those without an adverse event. CONCLUSIONS: First-line ART containing NVP and/or EFV leads to an improvement in HRQoL. The gain in HRQoL was similar for NVP and EFV, but slightly lower for the combination of these drugs. 相似文献
83.
Kappelhoff BS van Leth F MacGregor TR Lange J Beijnen JH Huitema AD;NN Study Group 《Antiviral therapy》2005,10(1):145-155
OBJECTIVE: The aim of this 2NN pharmacokinetic substudy was to investigate the population pharmacokinetics of nevirapine and efavirenz. METHODS: Treatment-naive, HIV-1-infected patients received nevirapine (once or twice daily), efavirenz or a combination with lamivudine and stavudine. Blood samples were collected on day 3 and weeks 1, 2, 4, 24 and 48. Using non-linear mixed effects modelling, pharmacokinetics of nevirapine and efavirenz and factors involved in the inter-individual variability were investigated. RESULTS: Clearance of nevirapine in the induction phase (<14 days) and at steady state (>28 days) were 2.02 I/h and 2.81 I/h, respectively. Volume of distribution and absorption rate constant were 77.0 l and 1.66 h(-1), respectively. Clearance of nevirapine was lower in females (13.8%) and in patients with hepatitis B (19.5%). Patients from South America and Western countries had higher clearance of nevirapine compared with Thai and South African patients. The clearances of efavirenz in the induction phase and at steady state were 7.95 l/h and 8.82 l/h, respectively. The volume of distribution and absorption rate constant were 4181 and 0.287 h(-1), respectively. Concomitant use of nevirapine increased clearance of efavirenz (43%). Patients from Thailand had lower clearance than the rest of the population. CONCLUSIONS: The population pharmacokinetics of nevirapine and efavirenz were assessed in the 2NN trial. For both drugs, an induction phase was distinguished from the steady-state phase. Gender, hepatitis B and geographical region were involved in the variability of the pharmacokinetics of nevirapine. Region and concomitantly used nevirapine were determinants of the pharmacokinetics of efavirenz. 相似文献
84.
研究证实表皮生长因子(EGF)不影响培养人眼视网膜色常上皮(RPE)细胞cAMP的基础水平,但促进异丙肾上腺索激活β2受体后诱导cAMP水平升高的效应,井呈量效信赖关系。EGF对腺嘌呤核苷A2受体激动剂NECA诱导cAMP水子升高的效应没有明显影响.细胞增殖分析表明,EGF刺激人眼RPE细胞增殖,而DibutyrylcAMP和异丙肾上腺素抑制RGF刺激增殖的效应。结果提示,在人眼RPE细胞EGF和β2受体之间存在受体间交互作用.
(中华眼底病杂志,1995,11:25-27) 相似文献