Topotecan (SK&F 104864) is a novel antitumor agent whose mechanism of action is inhibition of the DNA unwinding protein topoisomerase I. An analog of camptothecin, topotecan was designed to be more water soluble in an effort to decrease the severe and sporadic toxicities experienced during phase I/II trials of the parent compound. In this phase I clinical and pharmacological trial, topotecan was given as a bolus intravenous (i.v.) infusion over 30 min every 21 days. A total of 42 patients entered the study, receiving doses ranging from 2.5 to 22.5 mg/m2. The maximum tolerated dose (MTD) of topotecan given in this schedule was 22.5 mg/m2. Myelosuppression, primarily neutropenia, was dose-limiting. The extent of prior therapy did not predict for more severe neutropenia. Non-hematologic toxicities were mild and included low-grade to moderate fever, nausea, vomiting, alopecia, diarrhea and skin rashes. There were no objective partial or complete responses, although there was a suggestion of antitumor activity in three patients. Topotecan undergoes pH-dependent hydrolysis of the lactone ring; only the closed, lactone form is active. The lactone form predominated during infusion, with hydrolysis occurring rapidly following the end of infusion. There were linear relationships between dose administered and peak plasma lactone concentrations as well as AUC lactone to AUC total. The lactone was rapidly cleared from plasma with a total body clearance of 25.7 (+/- 6.7) l/h/m2. The plasma lactone concentration declined rapidly with a harmonic mean terminal half-life of 3.4 (+/- 1.1)h. Lactone hydrolysis and renal excretion were the major routes of elimination.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
A total of 492 deaths of children below 5 years of age were registered during a 2-year period of demographic surveillance in a rural population of Ethiopia, where an epidemiologic study base population of 28,780 individuals was established in 1987. Data were collected by lay-reporters using a verbal autopsy method. The under-five cumulative mortality rate was 209 per 1000 children. When sub-divided into infants and children 1-4 years, the respective yearly mortality rates were 101 and 32.3 per 1000. There were considerable variations within the district by Peasants' Associations. Rural Lowlands experienced the highest mortality rates, especially for children 1-4 years. Mortality trends over a 2-year period indicate a significant increase for the child population, but not for infants. Similar trends were observed for boys and girls although the rates for boys were generally higher especially during infancy. More deaths occurred in the months of April, June, and July, and October and November indicating two peak seasons in both years. More deaths occurred in Peasant's Associations that were furthest from the health centre. Major probable causes of death were acute respiratory infections, measles, and diarrhoea. It is concluded that even in rural areas of a developing country it is possible to collect from mothers the much needed and valid fertility and mortality data through epidemiological surveillance by using lay-reporters. 相似文献
Noninvasive techniques for the assessment of cardiac metabolism are important for the detection of potentially salvageable
tissue in jeopardized areas of the myocardium. The correct identification of hibernating and stunned myocardium in patients
with severely depressed cardiac function can have vital therapeutic consequences for the patient. Changes in myocardial fatty
acid and glucose metabolism during acute and prolonged ischemia can be traced by positron-emitting or gamma-emitting radiopharmaceuticals.
Alternatively,31P-labeled magnetic resonance spectroscopy can be used for the assessment of high-energy phosphate metabolism. It is not yet
clear which modality will emerge as the most useful in the clinical setting. Positron emission tomography (PET) that uses
combinations of flow tracers and metabolic tracers offers unique opportunities for quantification and high-resolution static
and rapid dynamic studies. Currently, assessment of glucose metabolism with18F-fluorodeoxyglucose is regarded as the gold standard for myocardial viability and prediction of improvement of impaired contractile
function after revascularization. However, preserved oxidative metabolism may be required for potential functional improvement,
and therefore assessment of residual oxidative metabolism by11C-labeled acetate PET may prove to be more accurate than18F-fluorodeoxyglucose PET, which reflects both anaerobic and oxidative metabolism. Moreover, because fatty acids are metabolized
only aerobically, they are excellent candidates for the clinical assessment of myocardial viability and prediction of functional
improvement after revascularization. Especially derivatives of fatty acids that are not metabolized but accumulate in the
myocyte are attractive for myocardial imaging. Examples are123I-beta-methyl-p-iodophenyl pentadecanoic acid and 15-(o-123I-phenyl)-pentadecanoic acid. These tracers can be detected by planar scintigraphy and single-photon emission computed tomography,
which are more economical and widely available than PET. In addition, 511 keV collimators have been developed recently, making
the detection of positron emitters by planar scintigraphy and single-photon emission computed tomography feasible. The experience
with31P-labeled magnetic resonance spectroscopy in humans is still limited. With current magnetic resonance spectroscopic techniques,
insufficient spatial resolution is achieved for clinical purposes, but the possibility of serial measurements to monitor rapid
changes of phosphate-containing molecules in time makes magnetic resonance spectroscopy very valuable for the research of
myocardial metabolism. 相似文献
Background: Sevoflurane undergoes Baralyme- or soda lime-catalyzed degradation in the anesthesia circuit to yield compound A (2-[fluoromethoxy]-1,1,3,3,3-pentafluoro-1-propene), which is nephrotoxic in rats and undergoes metabolism via the cysteine conjugate beta-lyase pathway in those animals. The objective of these experiments was to test the hypothesis that compound A undergoes beta-lyase-dependent metabolism in humans.
Methods: Human volunteers were anesthetized with sevoflurane (1.25 minimum alveolar concentration, 3%, 2 l/min, 8 h) and thereby exposed to compound A. Urine was collected at 24-h intervals for 72 h after anesthesia. Rats, which served as a positive control, were given compound A intraperitoneally, and urine was collected for 24 h afterward. Human and rat urine samples were analyzed by19 F nuclear magnetic resonance spectroscopy and gas chromatography-mass spectrometry for the presence of compound A metabolites.
Results: Analysis of human and rat urine showed the presence of the compound A metabolites [S-[2-(fluoromethoxy)-1,1,3,3,3-pentafluoropropyl]-N-acetyl-L-cysteine, (E)- and (Z)-S-[2-(fluoromethoxy)-1,3,3,3-tetrafluoro-1-propenyl]-N-acetyl-L-cyst eine, 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid, 3,3,3-trifluorolactic acid, and inorganic fluoride. The presence of 2-(fluoromethoxy)-3,3,3-trifluoropropanoic acid and 3,3,3-trifluorolactic acid in human urine was confirmed by gas chromatography-mass spectrometry. 相似文献
The variability in the concentration and biological availability of niacin in corn was investigated. Plots of both sweet and field corn were harvested at different stages. In rat growth assays for available niacin, grains harvested at the immature, "milky" stage and then dried gave values of 88 and 74 micrograms/g, respectively. These values were in contrast to the low growth assay values of 18 and 16 micrograms/g for grain harvested at maturity, and even higher than the value of approximately 56 micrograms/g obtained for each immature corn in both the Association of Official Analytical Chemists procedure of chemical analysis and a standard microbiological procedure. However, when the milky grains were precooked at neutral pH, the values from these procedures were higher and agreed with the biological assay results. It is suggested that, during the initial alkaline digestion used for these two procedures, a proportion of the niacin in NAD, the major form of niacin in milky corn, degrades. However, when the materials are first cooked at neutral pH, nicotinamide is released without loss, and the pyridine ring is then stable. The traditional American Indian practice of roasting and drying "green corn" apparently provided a valuable source of niacin. 相似文献
To establish test specific normal limits for quantitative analysis of uptake and washout of 201Tl after dipyridamole infusion combined with low level exercise, 20 healthy volunteers were studied with low likelihood of coronary artery disease (CAD) assessed by a stepwise probability analysis based on age, sex, symptoms, resting electrocardiogram, and exercise electrocardiography. Likelihood of CAD in these volunteers was calculated as 1%. After dipyridamole infusion combined with low level exercise, one volunteer complained of headache; no other side effects were observed. There were no chest pain complaints. Maximal hemodynamic changes were achieved during the 6th and 7th min of the test. No ST segment depression was recorded. Visual analysis of the 201Tl scintigrams was normal in all volunteers. Mean regional washout at 4 h was 44.37%±2.11%. The regional washout in the 70° LAO view (46.65%±1.10%) was significantly higher than in the anterior and 30° LAO views (43.44%±1.50% and 43.02%±1.45%, respectively). Profiles of uptake and washout of 201Tl were different after dipyridamole infusion combined with low level exercise as compared to maximal exercise. Thus, in quantitative analysis of 201Tl scintigraphy after dipyridamole infusion in conjunction with low level exercise as applied in the present study, it is mandatory to use normal limits of uptake and washout of 201Tl derived from healthy volunteers who underwent the same combined protocol. 相似文献
The dominant cone-rod dystrophy gene CORD6 has previously been mapped to
within an 8 cM interval on chromosome 17p12-p13. The retinal- specific
guanylate cyclase gene (RETGC-1), which maps to within this genetic
interval and previously was implicated in Leber's congenital amaurosis, was
screened for mutations within this family and in a panel of small families
and individuals with various cone and cone- rod dystrophy phenotypes. A
missense mutation (E837D) was identified in affected members of the CORD6
family, as well as a second missense mutation (R838C) in three other
families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene
to be implicated in cone-rod dystrophy and this is the first report of
dominant mutations in this gene.
相似文献