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101.
Marrazzo A Prezzavento O Pappalardo MS Bousquet E Iadanza M Pike VW Ronsisvalle G 《Il Farmaco; edizione pratica》2002,57(1):45-53
Selective ligands for either sigma1 (sigma1) or sigma2 binding sites are potentially useful for gaining a better understanding of the physiological functions of these proteins. Moreover, potent and selective homochiral sigma1 and sigma2 binding site ligands represent leads to potential radioligands for tumour imaging with positron emission tomography (PET). On the basis of their structural similarity to previous leads, new (+)- and (-)-cis-2-[(1-adamantylamino)-methyl]-1-phenylcyclopropane derivatives were synthesised and their binding affinities for sigma1 and sigma2 binding sites were determined. Each enantiomer showed high affinity for both sigma1 and sigma2 binding sites, but only (-)-cis-methyl-2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropane-carboxylate, (-)-4, showed appreciable selectivity for binding to sigma1 versus sigma2 sites. The enantiomers of cis-(2-[[1-adamantyl(methyl)amino]methyl]-1-phenylcyclopropyl)methanol, 6, expressed the highest affinity for sigma1 and sigma2 binding sites. Ligands (-)-4, (+)-6 and (-)-6 might be rapidly labelled in their N-methyl groups by methylation of the N-desmethyl analogues with [11C]iodomethane to provide prospective radioligands for PET. The N-desmethyl analogues, which are also high affinity ligands, were prepared and shown to undergo satisfactory methylation with iodomethane. 相似文献
102.
Bolognese A Correale G Manfra M Lavecchia A Mazzoni O Novellino E Barone V Pani A Tramontano E La Colla P Murgioni C Serra I Setzu G Loddo R 《Journal of medicinal chemistry》2002,45(24):5205-5216
The iminoquinone is an important moiety of a large number of antineoplastic drugs and plays a significant role in the nucleus of actinomycins, powerful, highly toxic, natural antibiotics that target DNA as intercalating agents. A series of polycyclic iminoquinonic compounds, 2-amino-3H-phenoxazin-3-one (1), 2-amino-1,9-diacetyl-3H-phenoxazin-3-one (2), 2-acetylamino-3H-phenoxazin-3-one (3), 3H-phenoxazin-3-one (4), 5H-pyrido[3,2-a]phenoxazin-5-one (5), and 5H-pyrido[3,2-a]phenothiazin-5-one (6), strictly related to the actinomycin chromophore, were synthesized for developing new anticancer intercalating drugs. The antiproliferative activity of these compounds, evaluated against representative human liquid and solid neoplastic cell lines, showed that 5 and its isoster 6 were the most active compounds inhibiting cell proliferation in a submicromolar range. Compound 5 was also evaluated against KB subclones (KBMDR, KB7D, and KBV20C), which overexpress the MDR1/P-glycoprotein drug efflux pump responsible for drug resistance. All the above KB subclones did not show altered sensitivity to the antiproliferative activity of 5. UV-vis and (1)H NMR spectroscopy experiments support the phenoxazinone 5/DNA binding. Molecular mechanics methods were used to build a three-dimensional model of the 5/[d(GAAGCTTC)]2 complex. Electrostatic interactions between the hydrogen of the positively charged pyridine nitrogen of 5 and the negatively charged oxygen atoms (O4' and O5') of the cytosine C5 residue together with stacking forces contribute to the high antiproliferative activity. The metal(II)-assisted synthesis procedure of 5 is described, and the formation mechanism is proposed. 相似文献
103.
104.
A 45-year-old woman experienced long-term, chronic exposure to carbon monoxide in the restaurant kitchen where she was employed as a cook. After returning to the restaurant after 5 days off work, she noticed that her symptoms returned immediately; she then aired out the room and called the gas company. Approximately 6 hr after a leak was detected, the patient went to the hospital, where her carboxyhemoglobin was found to be within normal limits and results of a neurologic examination were described as normal. Based on her symptoms, the patient believed she had been exposed to CO for at least 1 year before the leak was discovered. Initially, she experienced flu-like symptoms, which eventually resolved. At the time of her first neuropsychological evaluation (17 months after the exposure was identified), her persisting complaints included difficulties in reading, writing, speaking and word retrieval. The test results were consistent with secondary frontal lobe dysfunction associated with subcortical disorders such as those seen after CO exposure. Results of a subsequent neuropsychological examination (29 months postexposure) showed slight improvement in performance, but her performance was still consistent with mild frontal/subcortical dysfunction. Although the initial screening of a brain magnetic resonance image (MRI) performed 15 months after the exposure was interpreted as being within normal limits, two subsequent blind reviews of the same scans identified multiple bilateral lesions in the basal ganglia, which were consistent with chronic CO exposure. We present this case as an example of the utility of MRI and neuropsychological examinations in detecting central nervous system dysfunction secondary to CO exposure. 相似文献
105.
BACKGROUND AND OBJECTIVE: The pathophysiology and the neurobiology of the behavioral disturbances in Alzheimer's disease (AD) are far from understood. The aim of the study was to assess whether delusional AD patients have a specific pattern of regional brain atrophy. METHODS: The setting of the study was the outpatient facility of a memory clinic. Subjects were 41 AD patients with mild dementia severity (Mini-Mental State Exam score of 22 +/- 3, range 18 to 27). Delusions were assessed with the pertinent subscale of the UCLA Neuropsychiatric Inventory (NPI). Nondelusional (n = 22) AD and delusional (n = 19) AD were defined on the basis of absence (NPI delusions subscale = 0) or presence (NPI delusions subscale = 1 or higher) of delusions. Thirteen (68%) of the delusional patients had isolated theft delusions, and 6 (32%) had theft associated with another paranoid delusion (of jealousy or persecution). None of the patients had misidentifications or other delusions of nonparanoid content. Temporal lobe and frontal lobe atrophy were assessed with linear measures (radial width of the temporal horn, rWTH, and frontal index, FI) taken from computed tomographic films. Temporal and frontal asymmetries were computed as right/left ratio of the rWTH and FI. RESULTS: AD patients without delusions had symmetrical enlargement of both temporal (8.1 +/- 3.9 vs. 8.5 +/- 4.5) and frontal horns (35.8 +/- 4.8 vs. 35.9 +/- 4.6). On the contrary, AD with delusions showed temporal horns larger to the right (9.1 +/- 3.3 vs. 7.7 +/- 3.1, p = .06) and the frontal horn to the left (35.7 +/- 4.3 vs. 37.5 +/- 4.2, p = .02). This different pattern was confirmed with a gender-adjusted repeated measures analysis of variance model interaction term between asymmetry and group: F1,38 = 5.5, p = .03). DISCUSSION: AD patients with delusions are characterized by a specific pattern of frontal and temporal asymmetry of brain atrophy, whereas nondelusional patients are symmetric. Because the asymmetry pattern of the delusional patients is similar to the physiological pattern of asymmetry of individuals without dementia, the data indicate that the absence of theft delusions in the mild stage of AD rather than their presence is associated with an abnormal asymmetry pattern. 相似文献
106.
107.
Intralesional topotecan in advanced ovarian cancer: a clinical report,based on a preclinical study 总被引:2,自引:0,他引:2
Nicoletto MO Padrini R Palumbo M Ziade A Ragazzi RS Pratesi G Artioli G De Cesare M Zunino F 《Oncology reports》2002,9(6):1351-1354
The aim of this study was to evaluate the response of ovarian cancer to intralesionally administered topotecan. Preliminary experiments were carried out in nude mice subcutaneously grafted with three different human ovarian carcinoma cells (A2780, IGROV/DDP and SKOV-3). Topotecan was administered intravenously (i.v.: 10-15 mg/kg every 4th day for 4 times) or intralesionally (i.t.: single dose of 15-20 mg/kg) and tumor size changes/drug toxicity were evaluated. The results indicate that the sensitivity of the three tumor models was different (rank: A2780 > IGROV/DDP > SKOV-3) but, for each tumor line, the pattern of response was similar after i.v. and i.t. administration. No local toxicity was detected, but appreciable systemic toxicity (animal death rate) was observed in spite of the use of a single i.t. dose. The effects of intralesional topotecan administration were then assessed in a patient with an advanced, epithelial ovarian tumor (endometroid type, poorly differentiated histologic grade), already treated with cisplatin and paclitaxel. The treatment (7.5 mg/m(2)) was repeated three times and, although drug plasma levels were in the range generally reported following i.v. administration and typical systemic toxicity occurred, no tumor regression was observed and the patient died 14 months later. We conclude that the intralesional drug delivery is effective to achieve a rapid tumor shrinkage in large tumor lesions, but in the presence of drug resistance, either intrinsic or acquired, intratumor drug administration can not be recommended. 相似文献
108.
Milone G Di Raimondo F Gioi FL Palumbo GA Manenti GO Pafumi M Giustolisi R 《Leukemia & lymphoma》2002,43(12):2319-2324
Mitoxantrone and Epirubicin are active agents in non-Hodgkin's lymphomas (NHL). These drugs have reduced cardiotoxicity and therefore are indicated in treatment of elderly patients. Cyclophosphamide, mitoxantrone, vincristine and methylprednisone (CNOP) and cyclophosphamide, epirubicin, vincristine and methylprednisone (CEOP) are combination chemotherapy and contain Mitoxantrone and Epirubicin that have been shown to be effective in treatment of NHL of intermediate and highgrade of malignancy in the elderly. Since Mitoxantrone and Epirubicin are partially non-cross resistant their combined use may diminish emergence of resistant neoplastic clones and may be associated with enhanced anti-neoplastic activity. In this study, a polychemotherapy schedule alternating 3 cycles of CEOP and 3 cycles of CNOP, was used in a single center between December 1988 and April 1995 to treat 41 previously untreated patients, over 60 years of age affected by intermediate or high grade non-Hodgkin's lymphoma according to the Working Formulation. In treated patients, 57.5% achieved complete response, 35% partial response and 7.5% were non-responders. Overall survival was 52.4 % at 4 years, Disease free survival (DFS) for complete responders was 48.9%. Only one case of severe extrahematological toxicity (grade 3-4 WHO) was observed. Severe mucositis (grade 3-4 WHO) was absent, and delayed administration of chemotherapy was required in only 7/230 cycles. No treatment related deaths were registered. This regimen achieved results comparable to that of other anthracycline or mitoxantrone based chemotherapy, but determined lower toxicity. Alternating CEOP and CNOP may improve overall toxicity. 相似文献
109.
Sentinel lymph node biopsy was shown to be an accurate procedure in the study of axillary lymph nodes; it allowed a marked decrease in surgery-related morbidity of breast cancer and axillary dissection could be avoided. Other parameters as molecular markers, nuclear grading, patient age, tumor size, are not able to predict the axillary lymph node status and consequent local therapeutic approach similar to those provided by sentinel lymph node biopsy. The extent of sentinel lymph node metastatic involvement, the extracapsular spread, the size of primary tumor and peritumoral lymphatic/vascular infiltration are the four characteristics shown to be significant, if considered in association and not separately as predictors of the extent of axillary involvement in presence of a positive sentinel lymph node. However, so far, specific studies did not confirm concordant and reproducible results. Therefore, apart from controlled studies, axillary dissection is always required in presence of a metastatic sentinel lymph node. 相似文献
110.