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K K Valu T A Gourdie T J Boritzki G L Gravatt B C Baguley W R Wilson L P Wakelin P D Woodgate W A Denny 《Journal of medicinal chemistry》1990,33(11):3014-3019
Four series of acridine-linked aniline mustards have been prepared and evaluated for in vitro cytotoxicity, in vivo antitumor activity, and DNA cross-linking ability. The anilines were attached to the DNA-intercalating acridine chromophores by link groups (-O-, -CH2-, -S-, and -SO2-) of widely varying electronic properties, providing four series of widely differing mustard reactivity where the alkyl chain linking the acridine and mustard moieties was varied from two to five carbons. Relationships were sought between chain length and biological properties. Within each series, increasing the chain length did not alter the reactivity of the alkylating moiety but did appear to position it differently on the DNA, since cross-linking ability (measured by agarose gel assay) altered with chain length, being maximal with the C4 analogue. The in vivo antitumor activities of the compounds depended to some extent on the reactivity of the mustard, with the least reactive SO2 compounds being inactive. However, DNA-targeting did appear to allow the use of less reactive mustards, since the S-linked acridine mustards showed significant activity whereas the parent S-mustard did not. Within each active series, the most active compound was the C4 homologue, suggesting some relationship between activity and extent of DNA alkylation. 相似文献
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Gopala K RANGAN Yiping WANG Yuet-Ching TAY Liguang CHEN David CH HARRIS 《Nephrology (Carlton, Vic.)》1998,4(1-2):57-64
SUMMARY: The effect of mild acute tubular injury on the progression of tubulointerstitial fibrosis was studied in pair-fed uninephrectomized male Wistar rats with established adriamycin nephrosis ( n = 34). Rats were stratified into three groups according to endogenous creatinine clearance (CrCl), proteinuria (Upr) and body weight (BW): (i) group 1 (Fe, n = 12) received a single intraperitoneal injection of ferric nitrilotriacetate (5 mg Fe/kg BW); (ii) group 2 (G, n = 10) three daily subcutaneous injections of gentamicin (60 mg/kg BW) and; (iii) group 3 (C, n = 12) saline injections. Serial CrCl (day 2, day 5, weeks 2, 4, 6 and 8) and renal histology (week 8) were examined following administration of nephrotoxin. CrCl was reduced on d2 (Fe: 0.78 ± 0.23 mL/min; mean ± SD) and day 5 (G: 0.91 ± 0.36 mL/min) as compared with C (1.22 ± 0.12 mL/min; P <0.05). There was no change in the serum creatinine and functional recovery occurred by d5 (Fe) and week 2 (G). Upr decreased transiently in G at week 2 (G: 482 ± 208 mg/day vs C: 716 ± 233; P = 0.05) despite similar food intake, baseline Upr and CrCl. At week 8, CrCl in Fe (0.84 ± 0.40 mL/min) was similar to C (0.84 ± 0.58 mL/min), whereas in G it remained stable (1.27 ± 0.39 mL/min; P <0.05). By morphometric analysis, mean relative interstitial volume (RIV) and glomerulosclerosis (GS) in Fe (RIV: 28.5 ± 13.4%; GS: 10.3 ± 12.3%) was no different to C (RIV: 24.5 ± 12.5%; GS: 20.9 ± 20.0%), whereas both parameters were reduced in G (RIV: 14.1 ± 8.1%; GS: 4.0 ± 4.8%; P <0.05). Mild gentamicin nephrotoxicity therefore reduced the progression of adriamycin nephrosis. the mechanism of this finding is unclear, but it may relate to altered glomerular and tubular cell handling of protein. 相似文献
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The cytotoxicity of the anti-leukaemia drug amsacrine (m-AMSA) has been suggested to result from its oxidative metabolism to the corresponding quinonediimine, N1'-methanesulphonyl-N4'-(9-acridinyl)-3'-methoxy-2',5'-cyclohexad iene-1',4'- diimine (mAQDI). The metabolic fate of mAQDI was examined in cultured CHO cells (subline AA8) to identify the end products to be expected following oxidative metabolism of m-AMSA. [Acridinyl-G-3H]-m-AQDI was rapidly accumulated by AA8 cells in phosphate buffered saline with complete conversion in less than one minute to m-AMSA, macromolecular adducts and polar low molecular weight species, each of these three classes being formed in approximately equal amounts. Two of the polar products were chromatographically identical to those formed on reaction of m-AQDI with reduced glutathione. These were identified by 1H NMR spectroscopy as the 1,4-addition product 5'-(S-glutathionyl)-m-AMSA and the previously unreported isomeric 6'-(S-glutathionyl)-m-AMSA. These thiol adducts were also formed rapidly from m-AQDI in deproteinized cell lysates indicating a non-enzymatic process, although the possibility of enzymatic catalysis in intact cells has not been eliminated. The absence of such products in AA8 cells after treatment with m-AMSA places an upper limit of 1% per hour on the rate of its oxidative metabolism in these cells and suggests that generation of m-AQDI is unlikely to be responsible for the cytotoxicity of m-AMSA in cultured tumour cells. 相似文献
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无环鸟苷亲脂性前体药物脂质体的制备及体外抗病毒活性(英文) 总被引:2,自引:0,他引:2
本文通过将无环鸟苷(acyclovir,简称ACV)2’位羟基分别与月桂酰氯或棕榈酰氯进行酯化反应,制得亲脂性前体药物无环鸟苷月桂酸酯和无环鸟苷棕榈酸酯(分别简称为C12-ACV和C16-ACV),使脂质体包封率从ACV的29.9%提高到C12-ACV的95.6%和C16-ACV的97.1%;漏泄实验表明在4℃透析60h后,一半以上的ACV从脂质体中漏泄,而C12-ACV和C16-ACV的滞留率分别为70%和80%;体外抗疱疹病毒的试验中,在最低试验浓度0.044μmol/L时,ACV不显示抗病毒活性,而C16-ACV脂质体抑制细胞病变率达75%,说明前体药物通过与脂质体脂膜的结合增加了药物的进入细胞能力,从而提高了ACV的抗病毒能力。 相似文献
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Kundel HL; Gefter W; Aronchick J; Miller W Jr; Hatabu H; Whitfill CH; Miller W Sr 《Radiology》1997,205(3):859
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A paradigmatic shift in post-traumatic stress disorder (PTSD) research is underway. Formistic and mechanistic research designs, characterized by single-category, single-cause, single-effect models, gradually are being replaced by contextual and organistic research designs that feature multi-category, multi-cause, and multi-effect interactional models. Such changes in diagnostic and treatment outcome research require solving many methodological issues in such areas as: measuring types of traumas and stressors; measuring PTSD symptoms and subtypes; measuring subject dispositional characteristics (such as ethnic differences); assessing concurrent and/or pre-existing psychiatric (Axis I) disorders; classifying personality styles and concurrent and/or pre-existing personality (Axis II) disorders; evaluating phase in the development of PTSD as a disorder; measuring current environmental stresses and interpersonal interactions; and assessing secondary gains and readiness for treatment. These and other methodological problems must be addressed as research on PTSD shifts to longitudinal measurement of subjects randomly assigned to treatment conditions. 相似文献
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SUMMARY: Peritonitis and exit‐site infections remain the most important limitations to the delivery of continuous ambulatory peritoneal dialysis (CAPD). Contamination of the peritoneum, from endogenous or exogenous sources, is responsible for most peritonitis episodes. Patients usually present with a cloudy bag, although other causes should be distinguished. Clinical suspicion of peritonitis should be followed rapidly by microbiological examination and empirical treatment. Microbiological confirmation allows for subsequent treatment based on sensitivities. Other interventions such as catheter removal may be appropriate in some patients. Exit‐site infections should also be identified and treated early. Peritonitis may be further prevented by adequate exit‐site care, hygienic methods, and techniques to minimise early contamination of the exit site. Mupirocin may also have a role in preventing infections caused by Staphylococcus aureus. 相似文献
10.
W. N. HABRE E. F. VAN GESSEL CH. MAMIE R. CANTIENI P. M. SUTER 《Acta anaesthesiologica Scandinavica》1994,38(6):612-614
Severe aortic regurgitation was discovered in a young man 21 days after blunt chest trauma and after a prolonged febrile state with positive blood cultures. Using transoesophageal echocardiography (TEE), it was possible to make the differential diagnosis between traumatic rupture and endocarditis as the cause of valvular insufficiency. The use of TEE in the initial evaluation of severe thoracic trauma with an unclear clinical picture is recommended. This method is easy to use at the bedside and gives precise information on the aortic valve and the ascending aorta. 相似文献