吡酮酸类抗菌药物的研究Ⅷ.1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其类似物的合成和构效关系

为探讨构效关系,合成了1-对氟苯基-6-氟-1,4-二氢-4-氧-7-(1-哌嗪)噌啉-3-羧酸及其喹啉、萘啶、吡啶[2,3-C]哒嗪环系类似物16个。测定了对大肠杆菌的MIC。用Hückel分子轨道理论(HMO)方法计算了四个母体环上电子密度。结果表明:环中氮的位置对药效团——3位羧基和4位羰基氧原子上电子密度的影响较大而影响其抗菌活性。喹啉、萘啶两环系的3位羧基和4位羰基氧原子上的电子密度较高,其体外抗菌活性较高;而噌啉及吡啶[2,3-C]哒嗪两环系的电子密度较低,其体外抗菌活性较低甚至消失。     

Histologic criteria for the diagnosis of erythrodermic mycosis fungoides and Sézary syndrome: a critical reappraisal

It is often difficult to make a clinical or histologic diagnosis of erythrodermic mycosis fungoides (MF) and Sézary syndrome (SS). Whereas the histologic parameters for making a diagnosis of MF with well-developed patch and plaque stage lesions are clearly defined, the same criteria appear to be less relevant for diagnosing MF in patients with erythroderma secondary to the disease. In order to better define the histologic features of erythrodermic MF and SS, we studied 28 routine histologic sections of 17 patients with known erythrodermic MF or SS. Sections were reviewed independently by 2 dermatopathologists. Each of 24 parameters was scored semi-quantitatively and the data were compared to data previously reported from a group of 64 patients with limited patch and plaque stage lesions of MF. When compared to biopsies from patients with limited patch/plaque lesions, biopsies taken from erythrodermic patients displayed more parakeratosis (p=0.0492) and acanthosis (p=0.0046), less disproportionate epidermotropism, fewer lymphocytes aligned within the basal layer (p=0.0045), fewer hyper-convoluted cells in the epidermis, more dermal hyperconvoluted cells (p=0.0191), more papillary dermal fibrosis (p=0.0002), more prominent teleangiectasias (p=0.0028) and more mitotic figures.
The histologic features of erythrodermic MF and Sézary syndrome are even more subtle than the features of patch and plaque stage MF, thus rendering the histologic diagnosis more difficult.     

硫酸多糖对体外人脐静脉内皮细胞损伤的保护作用

研究表明,硫酸多糖体外对多聚阳离子和氧自由基损伤的人脐静脉内皮细胞有保护作用。肝素、硫酸软骨素A抗多聚阳离子损伤作用比同浓度低分子肝素和甘糖酯强。肝素、硫酸软骨素A、甘糖酯抗氧自由基损伤作用优于同浓度低分子肝素。结果显示硫酸多糖有保护血管内皮的作用,其作用可能与所带阴离子基团有关。     

高效液相色谱法测定右旋儿茶素血浆浓度及药代动力学参数

本文建立了体液中右旋儿茶素的RP-HPLC测定方法。采用C_(18)键合相硅胶为填料的固相提取柱进行样品预处理,右旋儿茶素的提取回收率为79.8%.应用二极管阵列检测器对色谱峰纯度进行鉴定。该法精密度好,方法回收率近100%,日内、日间的变异系数为2.4～5.6%,血浓69.6～1160 ng/ml范围内呈线性关系,r=0.9993。家兔静注右旋儿茶素18mg/kg,其药代动力学过程符合二室模型,分布相半衰期为0.129 h,消除相半衰期为1.19h。     

Should all the N3 lymph nodes group metastasis be regarded as distant metastasis (M1) in curatively resected gastric cancer?

Recently, metastasis to N3 lymph nodes group was regarded as distant metastasis by the new TNM staging system due to poor overall survival. However, the 5-year overall survival rate of patients with metastasis to N3 groups was 34.5% after curative surgery. Moreover, in patients with metastasis to lymph node subgroups of #12, #13, #14, the overall 5-year survival rate increased upto 47.2% after curative resection and adjuvant chemotherapy. This was similar to that of the patients with metastasis to N1 and N2 lymph nodes groups. But in these highly tumor burden states, no survival benefit was found with the addition of immunotherapy to chemotherapy as we achieved in stage II and III. Therefore, we suggest that, at least, metastasis to #12, #13, #14 lymph nodes subgroups should not be categorized as a distant metastasis. And in these situations, active curative radical surgery with extended lymphadenectomy and adjuvant chemotherapy are recommended.     

Effect of dobutamine infusion on endotoxin-induced lipid peroxidation in awake sheep.

beta-agonists are known to not only increase oxygen delivery, but also attenuate the inflammatory response. We studied the effect of infusing the beta-agonist, dobutamine, on the oxidant-induced lung and liver tissue lipid peroxidation seen after endotoxemia. Twelve unanesthetized adult sheep with lung and soft tissue (prefemoral) lymph fistulae were given 5 micrograms/kg of Escherichia coli endotoxin intravenously. In six sheep, dobutamine 10 to 15 micrograms/kg/min was infused beginning 3 hours after endotoxin to increase oxygen delivery by 75% above baseline. Animals were killed at 6 hours, and lung and liver lipid peroxidation, measured as malondialdehyde, was obtained. Data were compared to six control sheep. Endotoxin alone produced increased lung and soft tissue vascular permeability as evidenced by a twofold increase in protein-rich lymph flow. Lung and liver malondialdehyde increased to 116 +/- 40 nmol/gm and 202 +/- 64 nmol/gm, respectively, compared to control values of 42 +/- 7 nmol/gm and 110 +/- 20 nmol/gm, respectively. Dobutamine infusion after endotoxin increased oxygen delivery by 75%, although changes in total oxygen consumption were not different from those seen with endotoxin alone. Lung and soft tissue lymph flow did not change with dobutamine. However, lung malondialdehyde was 41 +/- 17 nmol/gm, not different from controls. Liver malondialdehyde remained elevated at 164 +/- 26 nmol/gm. We conclude that dobutamine infusion prevents further oxidant-induced lung tissue lipid peroxidation but does not reverse the increased permeability already present. Liver lipid peroxidation was not decreased, suggesting the liver oxidant process may not be caused by the same mechanism as the lung lipid peroxidation.     

Heterogeneity of IgE response to TDI-HSA conjugates by ELISA in toluene diisocyanate (TDI) -induced occupational asthma (OA) patients.

Toluene diisocyanate (TDI), a low molecular weight reactive chemical, is known to be a main cause of occupational asthma (OA) in Korea. Although it is thought that inhaled TDI may act as a hapten, the precise mechanisms of TDI-induced OA are unknown. In this study, TDI-human serum albumin (HSA) conjugates (5, 10, 20 and 30 min) were prepared in the range of 1.5 to 5.0 TDI mole/HSA mole. Specific binding of serum IgE to TDI-HSA (30 min) was observed using IgE ELISA as well as ELISA inhibition assay. Around 40% of TDI-induced OA patients were positive for serum specific IgE by ELISA. Degrees of serum IgE binding were different depending on which TDI-HSA conjugate was used as an antigen. Moreover, binding patterns were different depending on the individuals. Interestingly, higher binding of IgE to TDI-HSA (5 min) than to TDI-HSA (30 min) which was more highly substituted was observed in some patients. Probably new antigenic epitopes on carrier proteins were targets of the specific IgE. The results of this study indicated that IgE responses to TDI-HSA conjugates were heterogeneous in TDI-induced OA patients and self-proteins modified by reactive chemicals can become a major target antigen of IgE in certain cases.     

Use of Monoclonal Antibodies That Recognize p60 for Identification of Listeria monocytogenes

Listeria monocytogenes causes major food-borne outbreaks of disease worldwide. Specific identification of this microorganism is of utmost importance to public health and industry. Listeria species are known to secrete a 60-kDa protein collectively termed p60, which is encoded by the iap (invasion-associated protein) gene and secreted in large quantities into the growth media. p60 is a highly immunogenic murein hydrolase that is essential for cell division. Due to these properties, p60 is an ideal diagnostic target for the development of immunological detection systems for L. monocytogenes. We report here two independent lines of monoclonal antibody (MAb): p6007, which specifically recognizes L. monocytogenes p60, and p6017, which reacts with a wide range of Listeria p60 proteins. By combining these antibodies with a polyclonal antibody, we developed efficient sandwich enzyme-linked immunosorbent assay (ELISA) systems which can specifically identify L. monocytogenes or generally detect Listeria species. Since an excess amount of the peptide corresponding to PepA or PepD did not interfere with the ELISA, and direct ELISAs were unable to detect both peptides, we concluded that the epitope presumed to be recognized by p6007 or p6017 could be distinguished from PepA and PepD as described by Bubert et al. (Appl. Environ. Microbiol. 60:3120-3127, 1997). To our best knowledge, this is the first example of an immunological identification system that uses p60-recognizing MAbs.     

Comparison of Different Types of Oral Adsorbent Therapy in Patients with Chronic Kidney Disease: A Multicenter,Randomized, Phase IV Clinical Trial

PurposeOral adsorbents delay disease progression and improve uremic symptoms in patients with chronic kidney disease (CKD). DW-7202 is a newly developed oral adsorbent with high adsorptive selectivity for uremic toxins. We evaluated patient preference for and adherence to DW-7202 versus AST-120 therapy and compared treatment efficacy and safety in patients with pre-dialysis CKD.Materials and MethodsA seven-center, randomized, open-label, two-way crossover, active-controlled, phase IV clinical trial was conducted. Patients with stable CKD were randomly assigned to receive DW-7202 (capsule type) or AST-120 (granule type) for 12 weeks. The groups then switched to the other adsorbent and took it for the next 12 weeks. Patient preference was the primary outcome. Secondary outcomes included changes in estimated glomerular filtration rate (eGFR) and serum creatinine, cystatin C, and indoxyl sulfate (IS) levels.ResultsSignificantly more patients preferred DW-7202 than AST-120 (p<0.001). Patient adherence improved after switching from AST-120 to DW-7202; there was no apparent change in adherence after switching from DW-7202 to AST-120. Changes in eGFR and serum creatinine, cystatin C, and IS levels were not significantly different according to adsorbent type. There was also no significant difference in the incidences of adverse events during treatment with DW-7202 and AST-120.ConclusionDW-7202 can be considered as an alternative to AST-120 in patients who cannot tolerate or show poor adherence to granule type adsorbents. Further studies to evaluate factors affecting patient preferences and improved adherence are warranted (Clinical trial registration No. {"type":"clinical-trial","attrs":{"text":"NCT02681952","term_id":"NCT02681952"}}NCT02681952).