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991.
The objective of this study was to evaluate the effects of DX-9065a, a nonpeptide, direct inhibitor of factor Xa (FXa), in a novel experimental model of venous thrombosis. The experiments were conducted on anesthetized rabbits in which a veno-venous shunt with cotton threads was inserted into the vena cava. DX-9065a was administered intravenously to the rabbits as an initial bolus followed by a maintenance infusion using the following dosing schedules: DX-I: 0.25 mg/kg + 3 micrograms/kg/min.; DX-II: 0.75 mg/kg + 9 micrograms/kg/min.; DX-III: 1.5 mg/kg + 18 micrograms/kg/min.; DX-IV: 3.0 mg/kg + 36 micrograms/kg/min.; DX-V: 6.0 mg/kg + 72 micrograms/kg/min. DX-9065a induced a dose-dependent increase in the time to occlusion and a dose-dependent decrease in thrombus weight. Because of the unique character of the model, we were also able to show a dose-dependent increase in blood flow through the shunt. In addition, there were dose-dependent increases in prothrombin time (PT) and activated coagulation time (ACT) with more variable responses in the activated partial thromboplastin time (APTT). DX-9065a had little effect on thrombin time (TT) or bleeding time at all doses tested. In conclusion, dose-dependent antithrombotic efficacy was documented with DX-9065a in this new model of venous thrombosis. Although the in vivo potency of the compound was not striking, the results support the utility of FXa inhibition in venous thrombosis and demonstrate the utility of this experimental model for evaluating the efficacy of novel anticoagulants. 相似文献
992.
Functional reentry has been hypothesized to be an underlying mechanism of ventricular fibrillation (VF); however, its contribution to activation patterns during fully developed VF is unclear. We applied new quantitative pattern analysis techniques to mapping data acquired from a 21 x 24 unipolar electrode array (2-mm spacing) located on the ventricular epicardium of 7 open-chest, unsupported pigs. Data epochs 4 seconds long beginning 1, 10, 20, 30, and 40 seconds after electrical induction were analyzed. Reentrant circuits were automatically identified and quantified. We found that 2.3% of activation pathways could unambiguously be classified as reentrant. From scaling analysis, an additional 28% of the pathways may also have been reentrant. Reentry was short-lived with 1.5+/-1.5 (mean+/-SD) complete cycles per circuit. The fraction of reentrant pathways, number of cycles per circuit, cycle duration, and area and perimeter of the cores all increased significantly as VF progressed. Core drift speed decreased significantly. Neither the orientation of the cores nor the direction of drift was well predicted by the epicardial fiber orientation (r2=0.108 and 0.138, respectively, by linear regression). Reentrant circuits were clustered in regions of the epicardium. We conclude the following: (1) Epicardial reentry is relatively uncommon and short-lived during VF, suggesting either that sustained reentry is transmural or that mechanisms governing sustained reentry are relatively unimportant to the dynamics of VF. (2) Reentrant circuits become more common, larger, and longer-lived as VF progresses, which may explain a recently observed increase in VF organization during the first minute of VF. (3) The conditions necessary to induce and sustain reentry are distributed nonuniformly. 相似文献
993.
Understanding diet and energy balance as risk factors for breast, colon,
and other cancers requires information on the contribution of each factor
and of interactions among factors to cancer risk. Rodent models for breast
cancer provide extensive data on effects of dietary fat and calories,
energy balance, body weight gain, and physical activity on tumor
development. Analyses of the combined data from many studies have shown
clearly that quality and quantity of dietary fat and energy balance
contribute independently to increased mammary gland tumorigenesis. These
findings were seen in female rats fed diets high in fat (35-40% of
calories) compared to rats fed control diets, with approximately 10% of
calories as fat (Fay and Freedman, 1997, Breast Cancer Res. Treat. 46,
215-223). The methods used permit comparison of experimental and
epidemiological data, and they may be useful in extrapolating between
species and developing public health recommendations. In addition to the
contributions of lifetime-diet composition, intake, energy balance, and
physical activity to cancer risk, there are questions about the timing and
duration of alterations in these factors and about the "dose-response"
characteristics of cancer risk to the factors. Endocrine mechanisms may be
significant in mammary gland tumor risk, but experimental and
epidemiological data indicate that cancers at other sites, such as colon
and liver, also are influenced by the factors listed. Other diet and
lifestyle factors that influence energy, or specifically fat, metabolism
may also affect risk for cancers that are promoted by increased intake of
fat and calories. Studies of separate and interactive effects of dietary
fat, black tea, weight gain, and mammary gland tumorigenesis (Rogers, et
al, 1998, Carcinogenesis 19, 1269-1273) have been analyzed. Using
adjustment of carcinogenesis endpoints for body weight, tumor burden, and
latency, they were found to be related to weight gain within treatment
groups in 2 of 3 experiments.
相似文献
994.
N M Marina B Cushing R Giller L Cohen S J Lauer A Ablin R Weetman J Cullen P Rogers C Vinocur C Stolar F Rescorla E Hawkins S Heifetz P V Rao M Krailo R P Castleberry 《Journal of clinical oncology》1999,17(7):2137-2143
PURPOSE: To determine whether the 3-year event-free survival (EFS) of children with completely resected immature teratomas is greater than 85%. PATIENTS AND METHODS: Patients with immature teratomas treated at Pediatric Oncology Group or Children's Cancer Group institutions were eligible. Pathology was centrally reviewed to confirm diagnosis and tumor grading. Follow-up included physical examination, measurement of tumor markers (alpha fetoprotein and human chorionic gonadotropin), and imaging. All patients were monitored for events, defined as tumor recurrence, second malignancy, or death. RESULTS: Seventy-three children (median age, 7.8 years) with extracranial immature teratomas were enrolled on study. Primary tumor sites included ovarian (n = 44), testicular (n = 7), and extragonadal (n = 22). However, on review, 23 patients had foci of yolk sac tumor (n = 21) or primitive neuroectodermal tumor (n = 2), whereas 50 had pure immature teratomas. Twenty-five patients had increased alpha fetoprotein (n = 18), human chorionic gonadotropin (n = 5), or both (n = 2); nine had foci of yolk sac tumor on review. Pathology review identified 23 patients with grade 1, 29 with grade 2, and 21 with grade 3 immature teratomas. With a median follow-up of 35 months, the overall 3-year EFS was 93% (95% confidence interval, 86% to 98%), with 3-year EFS of 97.8%, 100%, and 80% for patients with ovarian, testicular, and extragonadal tumors, respectively. Only four of 23 patients with immature teratoma and malignant foci developed recurrence, suggesting that surgical resection followed by close observation are effective treatment. Overall, five patients had disease recurrence 4 to 7 months from diagnosis, and four (80%) are disease free after platinum-based therapy. The fifth patient has residual tumor after cisplatin, etoposide, and bleomycin treatment requiring further therapy. CONCLUSION: Surgical excision is safe and effective treatment for 80% to 100% of children with immature teratoma. 相似文献
995.
Robert T. Koda Agustin A. Garcia Dhruba J. Chatterjee Wen Yen Li Deepika Parimoo Susan Jeffers Marion Rogers C. Gail Leichman Lawrence Leichman Ellen Y. Wu Bhasker V. Shetty Stephanie Webber Neil Clendinnin Franco M. Muggia 《Cancer chemotherapy and pharmacology》1999,43(6):489-496
Purpose: This was a phase I study of AG 331 to determine systemic tolerance and pharmacokinetics following single and multiple escalating
intravenous doses. Methods: The study was an open-label phase I trial that was divided into two components. In phase IA (single dose), six dose levels
from 12.5 to 225 mg/m2 were administered to 18 patients (3 at each dose level) and serial blood samples were collected for 72 h. Upon achieving
satisfactory pharmacologic parameters, the multiple dosing component (phase IB) was initiated. Six dose levels from 50 to
800 mg/m2 per day were administered for 5 consecutive days to 18 patients. Pre- and postdose blood samples were obtained on days 1–4
and serial blood samples were collected over 24 h following dose 5. Nonhematologic and hepatic toxicities were assessed, serum
AG 331 concentrations were measured and pharmacokinetic parameters determined. Results: Other than fatigue, no severe toxicities were encountered in phase IA. Liver toxicity was manifested by elevations in transaminase
first noted at multiple doses of 200 mg/m2 per day for 5 days. Fever and malaise but no myelosuppression were noted. The mean terminal t1/2 following single doses was significantly shorter than the t1/2 following multiple dosing (6.8 vs 9.9 h) and clearance was significantly faster following single doses than following multiple
dosing (81.7 vs 30.4 1/h), but no significant difference in Vd was noted. Conclusions: The dose-related toxicity profile precludes further clinical development at this time. The pharmacokinetics of AG 331 following
single and multiple doses showed significant differences.
Received: 11 July 1997 / Accepted: 18 September 1998 相似文献
996.
Rosalind M. Turnbull Emma L. Meczes M. Perenna Rogers Richard B. Lock Daniel M. Sullivan Graeme J. Finlay Bruce C. Baguley Caroline A. Austin 《Cancer chemotherapy and pharmacology》1999,44(4):275-282
Purpose: Methyl N-(4′-(9-acridinylamino)-phenyl)carbamate hydrochloride (AMCA) and methyl N-(4′-(9-acridinylamino)-2-methoxyphenyl)carbamate
hydrochloride (mAMCA) are analogues of the topoisomerase II (topo II) poison amsacrine, and are distinguished from amsacrine
by their high cytotoxicity towards non-cycling cells. Since mammalian cells contain two forms (α and β) of topo II and the
α isoform is down-regulated in non-cycling cells, we have considered whether these carbamate analogues target topo IIβ selectively.
Methods: A drug permeable yeast strain (JN394 top2-4) was transformed using a shuttle vector containing either human top2α, human top2α or yeast top2 under the control of a GAL1 promoter. The strain was analysed at a non-permissive temperature, where only the plasmid-borne
topo II was active. Results: AMCA and mAMCA produced comparable levels of cell killing with human DNA topo IIα, human DNA topo IIβ and yeast DNA topo
II. Two other acridine derivatives N-[2-(dimethylamino)ethyl]acridine-4-carboxamide (DACA) and its 7-chloro derivative, which
like AMCA and mAMCA are able to overcome multidrug resistance mechanisms, were much more active against human DNA topo IIα
than against human DNA topo IIβ and yeast DNA topo II. A series of mutant Chinese hamster and human lines with defined topo
lesions, including the HL60/MX2 line that lacks topo IIβ expression, was also used to compare resistance to amsacrine, AMCA
and etoposide. Loss of topo IIβ activity had a greater effect on amsacrine and AMCA than on etoposide. Resistance of murine
Lewis lung cultures in exponential and plateau phase was also measured. Loss of topo IIα activity, as measured in both mutant
cells expressing lower amounts of enzyme and in cells in plateau phase, resulted in concomitant acquisition of resistance
that was greatest for etoposide and least for AMCA. Conclusion: We conclude that the carbamate analogues of amsacrine recognize both topo IIα and β in cells.
Received: 7 September 1998 / Accepted: 29 January 1999 相似文献
997.
998.
Polascik TJ Manyak MJ Haseman MK Gurganus RT Rogers B Maguire RT Partin AW 《Cancer》1999,85(7):1586-1592
BACKGROUND: The pretherapy prediction of occult lymph node involvement and the avoidance of otherwise futile and potentially morbid definitive local therapy is paramount in men with newly diagnosed prostate carcinoma. To identify patients with prostate carcinoma who likely have lymph node involvement and would benefit from staging lymphadenectomy prior to definitive local therapy, the authors compared the ability of several predictive staging algorithms and a radiolabeled monoclonal antibody scan to predict lymphatic metastases prior to treatment. METHODS: Between August 1991 and June 1994, 198 men with clinical T2 or T3 classified (TNM) prostate carcinoma (bone scan negative) who were at high risk of lymph node involvement underwent a 111In-capromab pendetide scan prior to staging lymphadenectomy. Several predictive models based on preoperative prostate specific antigen level, biopsy Gleason score, and clinical stage were selected to predict those men having a > or =20% probability of lymph node involvement. The ability to predict pathologic stage using several clinical algorithms and the monoclonal antibody scan was compared with pathologic examination of the lymph nodes. RESULTS: Overall, 39% of the pelvic lymph node specimens were positive for metastatic disease by pathologic analysis. Published algorithms predicting lymph node metastases had a positive predictive value (PPV) ranging from 40.5% to 46.6% and an area under the receiver operating characteristic curve (AUC) ranging from 0.52 to 0.61. The monoclonal antibody scan had a PPV of 66.7% and an AUC of 0.71. The differences between the PPV and the AUC for the individual clinical algorithms when compared with immunoscintigraphy were statistically significant. Combining the radiolabeled monoclonal antibody scan with clinical predictive models, a PPV of up to 72.1% could be obtained. CONCLUSIONS: These data suggest that the PPVs for the clinical predictive algorithms are similar and that the PPV of the radiolabeled monoclonal antibody scan alone or in combination with the algorithms has additional value in predicting lymph node involvement in prostate carcinoma patients at high risk of regional disease spread. These algorithms and the 111In-capromab pendetide scan may be used for the appropriate selection of candidates for definitive local therapy in men with clinically localized prostate carcinoma and significant risk of lymph node involvement. 相似文献
999.
1000.
Age, sex, and estimated time of onset of insulin-dependent diabetes were determined for children in Pittsburgh (N = 673), Gainesville (N = 976), Galveston (n = 741), and Melbourne (N = 851). The US cities had a decrease in new cases during the summer and peak incidence in January through April. In Melbourne, monthly trends were reversed: there were more cases during May through August. In US cities, but not in Melbourne, children less than 6 years old showed a greater variation by season than children 6 years old and older. Observations of the same fall and winter onset (in different calendar months) of insulin-dependent diabetes in Australia and the United States, and exaggeration of seasonal differences in young US children, suggest that onset of insulin-dependent diabetes is associated with seasonally varying viral diseases. Mumps and rubella infections do not seem to be responsible for much of the seasonal variation. Seasonal peaks of mumps and rubella are later than those observed for insulin-dependent diabetes, and immunization with live mumps and rubella viruses has not been associated with changes in incidence of insulin-dependent diabetes. An increase in disease incidence in boys over girls below age 6 years and in girls over boys at ages 6 through 11 years was consistently observed but not explained. 相似文献