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991.
992.
Novel fluorine-substituted deaza analogues of 5-azacytidine (AZC) and 5-aza-2'-deoxycytidine (dAZC) (3-deazacytosines) have been synthesized and tested for antitumor activity. Thus, 4-amino-3,5-difluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (16), 4-amino-3-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (17), 4-amino-5-fluoro-1-beta-D-ribofuranosyl-2(1H)-pyridinone (18), 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,5-difluoro-2 (1H)-pyridinone (25), 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-3-fluoro-2(1H)-pyridin one (26) 4-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)-3,5-difluoro-2(1H)-++ +pyridinon e (27), and 4-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)-3-fluoro-2 (1H)-pyridinone (28) were prepared by standard glycosylation procedures. Requisite heterocycle 4-amino-3,5-difluoro-2(1H)-pyridinone (6) was prepared in five steps from pentafluoropyridine (1). Other requisite fluoro heterocycles, 4-amino-3-fluoro-2(1H)-pyridinone (7) and 4-amino-5-fluoro-2(1H)-pyridinone (8), were obtained from a bis-defluorination of 4-amino-3,5,6-trifluoro-2(1H)-pyridinone (3) with hydrazine. Acetylation of 17 provided 4-amino-3-fluoro-1-(2,3,5-tri-O-acetyl-beta-D-ribofuranosyl)-2(1H)-pyrid inone (29). Structure proof of target nucleosides and heterocyclic compounds was provided by X-ray diffraction, 19F and 1H NMR, and UV. The ID50 values of fluorine-substituted 3-deazacytosines and 3-deazacytidines were greater than 1 X 10(-5) M in L1210 lymphoid leukemia cells in culture. Nucleoside 17 and its tri- and tetraacetates were the most active compounds with ID50 values of 1.07 X 10(-5), 1.23 X 10(-5), and 1.25 X 10(-5) M, respectively. The target nucleosides and intermediate heterocycles were inactive against P388 and L1210 lymphocytic leukemia in mice, except nucleoside 17 (NSC-378066) and its triacetate 29 (NSC-382021). Nucleoside 17 exhibited confirmed DN2 activity (% T/C 169-230) at five dose levels (25-300 mg/kg). Prodrug 29 exhibited similarly confirmed L1210 in vivo activity. 相似文献
993.
994.
Correlates of headache in a population-based cohort of elderly 总被引:3,自引:0,他引:3
N R Cook D A Evans H H Funkenstein P A Scherr A M Ostfeld J O Taylor C H Hennekens 《Archives of neurology》1989,46(12):1338-1344
Data from a community-based study of 3811 persons aged 65 years and older were used to describe the characteristics of headache in the elderly. Subjects were asked whether they experienced headache in the past year, the frequency and severity of their headaches, and whether they experienced three symptoms of migraine: unilaterality, nausea or vomiting, an aura preceding the headache. Prevalence of headache in those aged more than 65 years declined with age in both men and women; women had a higher prevalence in each age group. The same was true for frequent, severe, and migrainous headache. We examined age- and sex-adjusted correlations of headache with several medical and social factors. Prevalence of any headache was strongly associated with joint pain, depression, bereavement, waking during the night, use of eyeglasses, symptoms of temporomandibular joint dysfunction, and self-assessment of health. Similar variables were associated with frequency, severity, and migrainous symptoms, and thus could not be distinguished among these various types. 相似文献
995.
Controlled discontinuation of benzodiazepine treatment for patients with panic disorder 总被引:1,自引:0,他引:1
OBJECTIVE: The purpose of this study was to compare the effects of discontinuing treatment with intermediate- and long-acting benzodiazepines. METHOD: Fifty patients with panic disorder who had taken part in a double-blind treatment study and had responded to alprazolam, diazepam, or placebo for 8 months were asked to stop taking these medications gradually. RESULTS: After a relatively rapid dose reduction, the majority of patients relapsed. Rebound anxiety and withdrawal symptoms were identified in a substantial minority of patients. Those who were taking alprazolam showed earlier and more intense rebound anxiety and withdrawal symptoms than did the patients who received diazepam. Both the level of pretreatment anxiety and the drug the patient was taking predicted the level of anxiety when drug treatment was discontinued. CONCLUSIONS: The findings indicate that withdrawal phenomena commonly occur after patients stop taking benzodiazepines and that they are more frequent after discontinuation of treatment with shorter-acting drugs. 相似文献
996.
997.
998.
OBJECT: A canine model of hemorrhagic vasospasm of the high cervical internal carotid artery (ICA) was used to study the long-term effects of transluminal balloon angioplasty (TBA) on the structure and function of the arterial wall. METHODS: Forty dogs underwent surgical exposure of both distal cervical ICAs, followed by baseline angiographic studies on Day 0. Dogs in Group A (20 animals) underwent simple exposure of one ICA and placement of a silicone elastomer cuff around a segment of the opposite artery. These animals underwent repeated angiography on Day 7, and then TBA was performed on the uncuffed ICA; the cuff was removed from the opposite vessel. For dogs in Group B (20 animals), blood clot-filled cuffs were placed around both ICAs, and on Day 7 angiography was repeated and TBA was performed on one randomly selected ICA. Four animals were then killed from each group, and in the remaining animals the cuffs were removed from both ICAs. On Days 14, 21, 28, and 56, four animals from each group underwent repeated angiography and were then killed to permit pharmacological and morphological analyses of the ICAs. This protocol yielded five study categories: cuffed nonblood-coated arteries not subjected to TBA, blood-coated arteries not subjected to TBA, blood-coated arteries subjected to TBA, normal arteries subjected to TBA, and control arteries obtained from the proximal ICA in each animal. The contractile responses of isolated arterial rings obtained from each ICA were recorded after treatment with potassium chloride, noradrenaline, and serotonin, whereas relaxations in response to the calcium ionophore A23187 and papaverine were recorded after tonic contraction to noradrenaline had been established. Morphological analysis was performed using scanning electron microscopy. Arteries surrounded by an empty cuff exhibited no angiographic, pharmacological, or morphological differences compared with normal arteries on any study day. Arteries surrounded by blood developed angiographically confirmed vasospasm on Day 7, with characteristic pharmacological and morphological features; resolution of these symptoms occurred by Day 21. Vasospastic arteries subjected to TBA on Day 7 remained dilated on angiographic studies, exhibited impaired responses to pharmacological agents (except for papaverine), and showed altered morphological features until Day 28. Normal arteries subjected to TBA on Day 7 remained dilated on angiographic studies, exhibited impaired responses to pharmacological agents (except for papaverine), and displayed altered morphological features until Day 14. CONCLUSIONS: These results indicate that the canine high cervical ICA model produces consistent and reproducible vasospasm that follows a similar time course to that seen in humans. When TBA is performed in vasospastic arteries, it results in an immediate functional impairment of vascular smooth muscle that lasts for 2 weeks, with resolution at 3 weeks; morphological changes are mostly resolved 3 weeks post-TBA. In normal vessels, TBA causes functional impairment and morphological alterations that are not as severe or as long-lasting as those seen in vasospastic arteries. 相似文献
999.
D J Cook 《The American journal of the medical sciences》1990,299(3):175-178
To evaluate the accuracy of central venous pressure (CVP) assessment in critically ill patients, and measure disagreement amongst clinicians, 50 consecutive intensive care unit (ICU) patients with right internal jugular catheters were examined. CVP was measured by the indwelling catheter, and was assessed by: (1) one of three ICU staff physicians, (2) one of six medical residents, and (3) one of six medical students. There was no significant difference in CVP assessment between medical students, residents, and staff physicians. Although all clinicians tended to underestimate CVP, only the residents did so significantly (p less than 0.05). Sensitivity and specificity, and agreement and correlation between the clinicians' assessment and catheter measurements were higher when ventilated patients were excluded. All clinicians agreed more often and were better at identifying low CVP. In summary, considerable disagreement and inaccuracy exists in the clinical assessment of central venous pressure in critically ill patients. 相似文献
1000.