Inactivation of purified human alpha 2-antiplasmin and purified human C1 inhibitor by synthetic fibrinolytic agents

3-Hydroxypropyl flufenamide (Flu-HPA) is one of a series of flufenamic acid derivatives that enhances blood clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The profibrinolytic activity of Flu-HPA in clot lysis assays was found to be dependent on plasminogen. The influence of Flu-HPA on the ability of purified alpha 2-antiplasmin to inhibit purified plasmin was studied. Plasmin activity was determined using 125I-fibrin plates or the spectrophotometric tripeptide substrate, Val-Leu-Lys-paranitroanilide. At Flu-HPA concentrations greater than 1 mM, the inhibitory activity of alpha 2-antiplasmin was abolished in a time-dependent and concentration- dependent manner. The influence of Flu-HPA on the ability of purified Cl inhibitor to inhibit purified plasma kallikrein and beta-Factor XIIa was also studied. Cl inhibitor activity was abolished by Flu-HPA at concentrations greater than 2 mM. Notably, Flu-HPA up to 60 mM did not affect the amidolytic activities of plasmin, kallikrein, or beta-Factor XIIa. Flu-HPA did not release enzyme activity from preformed complexes of either alpha 2-antiplasmin and plasmin of Cl inhibitor and kallikrein. A water-soluble derivative of flufenamic acid, N-flufenamyl- glutamic acid, also inactivated alpha 2-antiplasm and Cl inhibitor. This inactivation was shown to be reversible. These results indicate that synthetic fibrinolytic compounds such as flufenamic acid derivatives may promote fibrinolysis by directly inactivating alpha 2- antiplasmin and Cl inhibitor.     

白细胞介素1及白细胞介素8在心肌缺血再灌注损伤中的动态演变及药物干预效果

目的:在心肌缺血再灌注损伤中,炎症细胞因子参与其过程的多个环节。实验拟验证白细胞介素1、白细胞介素8因子在此过程中的动态变化,并分析其与药物干预的关系。方法:实验于2005-10/2006-11在新乡医学院形态学实验室完成。①实验分组:选择健康Wistar成年大鼠70只,按随机数字表法分为3组:对照组(n=10)、模型组(n=30)和药物组(n=30)。后两组又分为缺血0.5h,再灌注2,4,8,12,24h6个时相点,每个时相点5只。对照组只设12h一个时相点作为总体对照。②实验方法:大鼠麻醉后,药物组在右股静脉注入甲泼尼龙(30mg/kg),对照组及模型组注入生理盐水(0.75mg/kg)。采用夹闭左冠状动脉前降支建立大鼠心肌缺血再灌注损伤模型。对照组只开胸不夹闭。③实验评估:在各时相点观察各组大鼠缺血再灌注后的心肌细胞改变;血清学检测白细胞介素1、白细胞介素8因子的动态表达。结果:①模型组缺血再灌注12h炎细胞浸润最显著,药物组炎细胞呈散在浸润。②模型组和药物组白细胞介素1、白细胞介素8因子质量浓度明显高于对照组[缺血再灌注8h为例,白细胞介素1分别为(99.21±14.37),(85.77±11.31),(21.87±10.32)ng/L;白细胞介素8分别为(794.85±24.07),(536.95±19.72),(103.94±11.59)ng/L,P<0.05],峰值分别在缺血再灌注4,8h;同时相点药物组白细胞介素1、白细胞介素8因子质量浓度明显低于模型组(P<0.05)。结论:白细胞介素1和白细胞介素8因子在心肌缺血再灌注损伤的炎症反应中发挥着重要作用;甲泼尼龙对缺血再灌注损伤心肌有保护作用。     

Muscle necrosis in the extremities: evaluation with Tc-99m pyrophosphate scanning--a retrospective review

A retrospective review was done of 34 extremities studied between 1981 and 1985 with technetium-99m pyrophosphate scanning; 22 were subsequently amputated. Results of detailed pathologic examination or immediate postoperative examination of the resected extremity were available in 16 cases. In these cases, scanning had allowed correct prediction of the level of amputation and of the specific areas of muscle infarction in 13 cases. In the one case in which amputation was performed for infection rather than muscle necrosis, the lack of necrosis was correctly predicted with the scan. The limited results of this study indicate that the Tc-99m pyrophosphate scan allows the location of necrotic muscle to be predicted accurately and may therefore be a useful adjunct in determining the best level for ultimate amputation. Special caution is required in those cases in which muscle necrosis is due to acute causes (e.g., traumatic thrombosis) rather than chronic vascular disease.     

Expression and immunogenicity of oncofetal antigen-immature laminin receptor in human renal cell carcinoma

PURPOSE: The 32 to 44 kDa. oncofetal antigen-immature laminin receptor (OFA-iLR) is a multifunctional protein expressed by various tumors, including breast, lung, ovary and prostate carcinoma as well as lymphoma. OFA-iLR has been implicated in tumor invasiveness, metastasis and growth. Interferon-gamma producing effector T cells and interleukin (IL)-10 producing suppressor T cells specific for OFA-iLR have been described. MATERIALS AND METHODS: The 43515 IgG2a anti-OFA-iLR monoclonal antibody was used to detect OFA-iLR expression in human renal cell carcinoma tissue by flow cytometry and immunoblotting. Spontaneous or therapy induced immune responses against OFA-iLR were determined in patients with metastatic renal cell carcinoma. Proliferative and cytokine (interferon-gamma and IL-10) responses of peripheral blood mononuclear cells from patients with renal cell carcinoma against recombinant OFA-iLR were assessed. RESULTS: Using flow cytometry OFA-iLR was detected in all 13 tumors tested. Immunoblotting revealed differences in OFA-iLR expression in renal cell carcinoma and normal kidney tissue. OFA-iLR specific proliferative and cytokine responses of mononuclear cells were detected in all 6 patients tested. Importantly evidence was also obtained that treating metastatic renal cell carcinoma with tumor lysate pulsed dendritic cells would enhance OFA-iLR specific immunity. CONCLUSIONS: This study demonstrates that OFA-iLR is an immunogenic tumor associated antigen in human renal cell carcinoma. OFA-iLR specific effector T cells producing interferon-gamma may have a role in the control of tumor growth, whereas suppressor T cells producing IL-10 may promote tumor tolerance and, thus, tumor progression.     

Population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients: a study by the EORTC-PAMM-NDDG

AIMS: To investigate the population pharmacokinetics and pharmacodynamics of doxorubicin and cyclophosphamide in breast cancer patients. PATIENTS AND METHODS: Sixty-five female patients with early or advanced breast cancer received doxorubicin 60 mg/m(2) over 15 minutes followed by cyclophosphamide 600 mg/m(2) over 15 minutes. The plasma concentration-time data of both drugs were measured, and the relationship between drug pharmacokinetics and neutrophil counts was evaluated using nonlinear mixed-effect modelling. Relationships were explored between drug exposure (the area under the plasma concentration-time curve [AUC]), toxicity and tumour response. RESULTS: Fifty-nine patients had complete pharmacokinetic and toxicity data. In 50 patients with measurable disease, the objective response rate was 60%, with complete responses in 6% of patients. Both doxorubicin and cyclophosphamide pharmacokinetics were associated with neutrophil toxicity. Cyclophosphamide exposure (the AUC) was significantly higher in patients with at least stable disease (n = 44) than in patients with progressive disease (n = 6; 945 micromol . h/L [95% CI 889, 1001] vs 602 micromol . h/L [95% CI 379, 825], p = 0.0002). No such correlation was found for doxorubicin. Body surface area was positively correlated with doxorubicin clearance; AST and patient age were negatively correlated with doxorubicin clearance; creatinine clearance was positively correlated with doxorubicinol clearance; and occasional concurrent use of carbamazepine was positively correlated with cyclophosphamide clearance. CONCLUSIONS: The proposed inhibitory population pharmacokinetic-pharmacodynamic model adequately described individual neutrophil counts after administration of doxorubicin and cyclophosphamide. In this patient population, exposure to cyclophosphamide, as assessed by the AUC, might have been a predictor of the treatment response, whereas exposure to doxorubicin was not. A prospective study should validate cyclophosphamide exposure as a predictive marker for the treatment response and clinical outcome in this patient group.     

Identification of Candida species in the clinical laboratory: a review of conventional,commercial, and molecular techniques

In healthy individuals, Candida species are considered commensal yeasts of the oral cavity. However, these microorganisms can also act as opportunist pathogens, particularly the so‐called non‐albicans Candida species that are increasingly recognized as important agents of human infection. Several surveys have documented increased rates of C. glabrata, C. tropicalis, C. guilliermondii, C. dubliniensis, C. parapsilosis, and C. krusei in local and systemic fungal infections. Some of these species are resistant to antifungal agents. Consequently, rapid and correct identification of species can play an important role in the management of candidiasis. Conventional methods for identification of Candida species are based on morphological and physiological attributes. However, accurate identification of all isolates from clinical samples is often complex and time‐consuming. Hence, several manual and automated rapid commercial systems for identifying these organisms have been developed, some of which may have significant sensitivity issues. To overcome these limitations, newer molecular typing techniques have been developed that allow accurate and rapid identification of Candida species. This study reviewed the current state of identification methods for yeasts, particularly Candida species.     

Relevance of in vitro and clinical data for predicting CYP3A4-mediated herb–drug interactions in cancer patients

The use of complementary and alternative medicines (CAM) by cancer patients is increasing. Concomitant use of CAM and anticancer drugs could lead to serious safety issues in patients. CAM have the potential to cause pharmacokinetic interactions with anticancer drugs, leading to either increased or decreased plasma levels of anticancer drugs. This could result in unexpected toxicities or a reduced efficacy. Significant pharmacokinetic interactions have already been shown between St. John’s Wort (SJW) and the anticancer drugs imatinib and irinotecan.     

抗胆碱药3-(2-苯基-2-环戊基-2-羟基-乙氧基)奎宁环烷的立体化学和构效关系

研究了强效抗胆碱药dl-3-(2-苯基-2-环戊基-2-羟基-乙氧基)-奎宁环烷的四个光学异构体的两种不对称合成方法,用HPLC检测了异构体含量,讨论了构效关系。