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  • bilateral breast cancer  (1)
  • complement  (1)
  • thrombosis  (1)
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  • 1
    ISSN: 1573-742X
    Keywords: thrombosis ; electrolytic injury ; thrombin inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Direct thrombin inhibitors represent a new class of drug that may offer a therapeutic alternative for the treatment and prevention of thrombembolic conditions, especially on the venous side of the systemic circulation. CI-1028 (PD 172524/LB30057) is a potent, highly selective inhibitor of thrombin that is orally bioavailable. The efficacy of this compound has been demonstrated in animal models in which intra-venous administration was used. The objective of this study was to evaluate the efficacy of CI-1028 after oral administration in a canine electrolytic injury model of venous and arterial thrombosis. CI-1028 was administered via oral gavage, and animals received either saline or 10, 15, 20, or 30 mg/kg of drug. Fifteen minutes later, the dogs were anesthetized and a femoral artery and vein were exposed and instrumented to induce electrolytic injury and thrombosis while continuously monitoring blood flow in the vessels. Maximum blood CI-1028 concentrations of 0.88±0.27, 1.8±0.3, 2.2±0.5, and 3.2±0.5 μg/mL were generally achieved 15 to 30 minutes after administering the compound in the 10-, 15-, 20-, and 30-mg/kg groups, respectively. Administration of CI-1028 increased the time to occlusion (TTO), the principal efficacy end point, in a dose-dependent manner in both arteries and veins. The TTO in the control group (n=8) averaged 66±11 minutes in the arteries and 69±6 minutes in the veins. In dogs treated with 10 mg/kg (n=8), the TTO was not significantly different from that of the control group. In the 15-mg/kg group (n=9) TTO averaged 140±27 minutes in the arteries (p=not significant) and 125±15 minutes (p〈0.05) in the veins. In the 20-mg/kg group (n=8), TTO was significantly longer than controls in both types of vessels, averaging 168±30 minutes in the arteries (p=0.05) and 155±21 minutes (p〈0.05) in the veins. Likewise, at 30 mg/kg (n=8) both the arterial (179±17 minutes) and venous (188±15 minutes) TTO was significantly prolonged compared with controls. Surgical blood loss and template bleeding times tended to increase in a dose-dependent manner but a statistically significant elevation was detected for template bleeding time only at the highest dose. Dramatic changes in thrombin time were detected, consistent with the CI-1028 mechanism of action. Virtually no changes were detected in prothrombin time. Maximum activated partial thromboplastin time (aPTT) and activated clotting time changes were detected approximately 30 minutes after dosing, and they were approximately twofold and fivefold baseline values, respectively, at the highest dose. In conclusion, these results demonstrate that CI-1028 provides dose-dependent antithrombotic efficacy after oral administration in a canine model of venous and arterial thrombosis.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-7217
    Keywords: bilateral breast cancer ; genetic predisposition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Our purpose was to determine whether bilateral breast cancer depends upon genetic predisposition to multiple tumors or, alternatively, represents two independent sporadic events. Biological concordance of hormone receptors and histopathology in bilateral tumors, family history of breast cancer, age at diagnosis, and survival were evaluated in 88 patients. The immunoreactivity of paired tumors from 51 patients to six different immunocytochemical markers was compared. Neither histologic patterns nor immunocytochemical reactions showed concordance between bilateral tumors. Absence of concordance (other than for estrogen receptors) and lack of associations with positive family history and early age of onset support an interpretation of independent tumor origins and does not suggest a major role for genetic determinants in the majority of cases of bilateral breast cancer.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-6903
    Keywords: Alzheimer's disease ; antibodies ; cerebrospinal fluid ; complement ; hippocampus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunocytochemical staining was performed to investigate the presence of anti-hippocampal antibodies in cerebrospinal fluid (CSF) from patients with probable Alzheimer's disease (AD) (n = 19), aged normal controls (n = 9), and young normal controls (n = 10). Marked staining of neurons in the granule cell layer of the dentate gyrus and in pyramidal neurons in CA1-3 of the rat hippocampus was observed in 5 AD CSF samples (26%), 1 aged control sample (11%), and 1 young control sample (10%). These differences were not statistically significant. One of the immunoreactive AD CSF specimens also contained high concentrations of C5b-9, the membrane attack complex. The infrequent occurrence of anti-hippocampal antibodies in AD CSF, and the detection of similar immunoreactivity in control CSF specimens, suggest that these antibodies are unlikely to play a role in the neurodegenerative process in most individuals with AD. However, elevated C5b-9 concentration in an AD CSF specimen with marked immunoreactivity to hippocampal neurons suggests the possibility that anti-neuronal antibodies may contribute to complement activation in some AD patients.
    Type of Medium: Electronic Resource
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