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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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Suppurative corneal ulceration in Bangladesh 总被引:8,自引:0,他引:8
AAS Dunlop MB BS ED Wright MRCPath † SA Howlader‡ I Nazrul‡ R Husain‡ K McClellan FRACO § FA Billson FRACO § 《Clinical & experimental ophthalmology》1994,22(2):105-110
Suppurative keratitis is an important preventable cause of blindness, particularly in the developing world. This study analyses 142 cases of suppurative keratitis referred to Chittagong Eye Infirmary, Bangladesh. Some 53.5% of cases were bacterial and 35.9% were fungal. The five most common pathogens were: Pseudomonas sp. 24%, Streptococcus pneumoniae 17%, Aspergillus sp. 13%, Fusarium sp. 7% and Curvularia sp. 6%. Gram stain and culture results were consistent in 62.6% of cases. Previous antibiotic treatment was a significant factor for failure of culture isolation and less so for Gram stain failure. On Gram stain, 55.9% of pseudomonal cases were missed, but only 2% of fungal cases were missed. Over all, Gram stain had a sensitivity of 62% and positive predictive value of 84% for bacterial cases, and 98% and 94% for fungal cases, respectively. Fungal ulcers were typically filamentous, but an antecedent history of trauma was not common. The most frequent injury was due to rice grains, but the inoculum appeared to be introduced during eye washing with contaminated water. Pseudomonal ulcers occurred most frequently in the monsoon season, and Fusarium cases were seen only in the hot, dry season. 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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. We invited Dr Peplau to provide a personal reflection on the recent history of psychiatric nursing and her thoughts on immediate challenges facing the profession. The paper is an individual scholar's commentary on the way that psychiatry has waxed and waned over the years, in relation to nursing. This historical review discovers and reports a challenge to current practice. Dr Peplau describes a professional shift that is pulling nurses toward the subordinate role observed earlier this century. The paper draws attention to how contemporary practice can be positively influenced, e.g., by giving a structure to the allocation and conduct of nurse–patient time. 相似文献
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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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W A Denny P B Roberts R F Anderson J M Brown D Phil W R Wilson 《International journal of radiation oncology, biology, physics》1992,22(3):553-556
Targeting of electron affinic radiosensitizers to DNA via reversible non-covalent intercalative binding has potential for increasing sensitizer concentrations locally at the DNA target while decreasing accessibility to reductases responsible for bioactivation and cytotoxicity. We have prepared an DNA-targeted acridine-linked 2-nitroimidazole (NLA-1) as an example of such a compound. NLA-1 binds reversibly to DNA with an affinity similar to 9-aminoacridine, and is approximately 1000 times more potent than MISO as a cytotoxin, despite a similar reduction potential. It shows less enhancement of cytotoxicity under hypoxia (5- to 6-fold) than does MISO (approximately 11-fold), but is a potent hypoxia-selective radiosensitizer in AA8 cells with a concentration for an enhancement ratio of 1.6 (C1.6) of 9 microM. The mean intracellular concentration at the C1.6 is 400 microM, on which basis its potency is about twice that of MISO. The in vitro therapeutic index (aerobic cytotoxic potency/hypoxic C1.6) of NLA-1 is approximately 6-fold lower than that for MISO. NLA-1 lacks radiosensitizing activity against SCCVII or EMT6 tumors in vivo at the maximum tolerated dose (MTD) of 100 mumol.kg-1. 相似文献
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