人血浆中氧氟沙星的HPLC测定及药代动力学研究

建立了人血浆中氧氟沙星含量的HPLC测定方法,以Spherisorb C18柱分离,流动相组成为甲醇-0.01mol/L磷酸盐缓冲液-0.5mol/L四丁基溴化铵(35:65:4,pH 2.5),流速为1.0 ml/min,在UV 294nm处测定。样品采用甲醇沉淀蛋白后,混旋、离心,吸取上清液在75℃下用氮气流吹干后,以0.4ml流动相稀释进样。采用内标法定量,在0.5～4.0μg/ml的浓度范围内呈线性关系,r=0.9999。最小检测浓度为20ng/ml。用本法对10名分别服用进口和国产氧氟沙星片剂的健康志愿者进行了血药浓度测定,取得了满意的结果,并对其药代动力学参数及生物利用度进行了研究。     

Efficacy of an intensive post-induction chemotherapy regimen for adult patients with Philadelphia chromosome-negative acute lymphoblastic leukemia,given predominantly in the out-patient setting

Intensification of chemotherapy in adults with acute lymphoblastic leukemia (ALL) has improved outcome. The aim of this analysis was to evaluate outcome of patients treated with an intensive regimen based on that used in the German national trials, but adapted in order to enable treatment to be given mainly on an out-patient basis, once complete remission (CR) had been achieved. Between 2000 and 2007, 53 patients with Philadelphia chromosome-negative ALL (40 with B-ALL and 13, T-ALL) received treatment. CR was achieved in 47/53 (89%), with no significant difference in CR rate between B- and T-ALL. At a median follow-up of 6.3 years, 25 patients are alive, 23 (43%) in 1st CR, and 20 have relapsed. No patient died in CR due to treatment-related toxicity. At 5 years, overall survival was 50%, and disease-free survival, 53%. Thirty four of the 47 patients in whom CR was achieved completed therapy and are evaluable for duration of hospital stay and number of Day Unit attendances. The median time in hospital during the year of treatment was 10 weeks (range, 6–44) with no significant difference between patients ≤ vs. >30 years old. It was possible to administer this intensive protocol largely on an out-patient basis without compromising patient safety.     

2,4-二氨基-5-氯-6-取代苄氨基喹唑啉类化合物的合成及其抗疟、抗肿瘤和抗菌活性

本文报道标题化合物的合成及其抗疟、抗肿瘤和抗菌活性,该类化合物是以5-氯-2,4, 6-三氨基喹唑啉与各种取代苯甲醛缩合成相应的Schiff碱,然后经NaBH₄还原,再甲酰化或亚硝化制得.经对感染伯氏疟原虫(P.berghei)的鼠抑制性治疗筛选,有八个化合物剂量20mg/kg×4d时抑制率100%,Ⅰ₃,Ⅰ₄,Ⅲ₄三个化合物剂量5mg/kg×4d时抑制率在90%以上;体外抗肿瘤试验有4个化合物的活性优于MTX和SIPl759,以Ⅰ₄最佳。对L1210白血病细胞株的IC₅₀为2.20×10^-9 m mol/L;经对18种常用菌株进行体外筛选,发现对肺炎双球菌(D.pneumoniae)有较好的活性。     

Detection of somatic mutations of the bcl-2 oncogene in B cell lymphomas with the t(14;18)

The incidence of mutations within the first 582 bp of the open reading frame of the bcl-2 gene, has been investigated in presentation lymph node samples, from 7 cases with follicular non-Hodgkin's lymphoma (NHL), 1 case with centroblactic NHL, the DOHH, cell line derived from the immunoblastic transformation of a follicular NHL and one case with benign follicular hyperplasia. A total number of 43 point mutations within the examined portion of the bcl-2 gene were detected in the cases analysed including the DOHH, cell line. Similar analysis of peripheral blood lymphocytes from 2 normal individuals that lacked the t(14;18), revealed no mutations in one case and a single 101 bp A-->G transition in clone, in the other. Missense mutations were detected in 7/8 NHLs, the DOHH2 cell line and the case of benign follicular hyperplasia. There was a significantly higher frequency of mutations within the region corresponding to the BH1, one of the two known functional domains, of the bcl-2 protein. The same position, 445 bp of the bcl-2 gene, was found to be involved in missense mutations affecting the DOHH2 cell line and 3 cases with follicular NHL.     

Depletion of T cells from human bone marrow using monoclonal antibodies and rabbit complement. A quantitative and functional analysis

Graft-versus-host-disease (GVHD) remains the principal complication of allogeneic bone marrow transplantation. In animal models mature T lymphocytes have been shown to be responsible for GVHD and, therefore, in vitro treatment of donor bone marrow using monoclonal T cell specific antibodies and complement is currently being investigated as a strategy for the prevention of GVHD. In the present studies anti-T12 and anti-T11 monoclonal antibodies and rabbit complement were used to remove T lymphocytes from normal bone marrow. The efficacy of depletion was investigated by immunofluorescence assays and by in vitro culture of the residual cells using nonspecific mitogens or allogeneic B cells as the proliferative stimulus in the presence of lymphocyte-conditioned medium containing interleukin 2 (IL-2). Immunofluorescence analysis showed complete depletion of T12+ and T11+ cells after treatment with the respective antibodies and with the combination. Nevertheless, culture of treated bone marrow with phytohemagglutinin (PHA) or concanavalin A (Con A) and conditioned media containing IL-2 resulted in the proliferation of mature T cells (T3+, T4+ or T8+, T11+). Stimulation of treated marrow with allogeneic cells (Laz 388) resulted in the growth of a population with natural killer (NK) cell phenotype (T3-, T11+, NKH1+). The latter population was found to be strongly cytotoxic against K562 cells, a standard NK target. As expected, NK cells that are T11+ and T12- appeared to be more effected by in vitro treatment with anti-T11 than with anti-T12. A clonogenic assay was then used to quantitate the efficacy of target cell depletion in vitro. Three sequential incubations of bone marrow with either anti-T12 or anti-T11 plus complement resulted in depletion of 1-2 logs of clonogenic cells. Treatment with both antibodies concurrently resulted in elimination of 2-3 logs of clonogenic target cells. Although multiple treatments with both anti-T12 and anti-T11 were more effective than similar treatment with only one antibody, it remains to be established whether such combinations will be necessary in the clinical setting or whether more selective depletion of T cells without removal of NK cells might be optimal.     

A feasibility study of simultaneous administration of gemtuzumab ozogamicin with intensive chemotherapy in induction and consolidation in younger patients with acute myeloid leukemia

The feasibility of combining gemtuzumab ozogamicin (GO) with intensive chemotherapy as first-line treatment of acute myeloid leukemia (AML) was assessed in 72 patients, aged 17 to 59 years, as a prelude to the United Kingdom Medical Research Council (MRC) AML15 trial. Sixty-four patients received induction chemotherapy (DAT [daunorubicin, ara-C, thioguanine], DA [daunorubicin, ara-C], or FLAG-Ida [fludarabine, ara-C, G-CSF, idarubicin]) with GO on day 1. It was possible to give GO 3 mg/m2 with course 1, but 6 mg/m2 with course 1 or GO in a dose of 3 mg/m2 with consecutive courses was not feasible because of hepatotoxicity and delayed hematopoietic recovery. Thirty-one patients who were treated in consolidation with MACE (amsacrine, ara-C, etoposide) or HidAC (HidAC) and GO (3 mg/m2), and 23 in induction and consolidation, tolerated GO (3 mg/m2) well. Grade 4 liver toxicity and sinusoidal obstructive syndrome was more common in thioguanine-containing schedules (P =.007). Remission with course 1 was seen in 86% of patients. DA or FLAG-Ida with GO in induction achieved complete remission in 91% of patients and 78% of these patients are in continuous complete remission at 8 months. GO given with induction (DA or FLAG-Ida) and consolidation (MACE or HidAC) was well tolerated. These schedules are now being compared in the MRC AML15 trial in patients younger than 60 years.