亚急性和亚慢性染砷小鼠的免疫毒性试验研究

目的了解As2O3对小鼠免疫毒性作用。方法用As2O染毒昆明种雌性小鼠,通过亚急性和亚3慢性免疫毒性实验,在0.34、0.74、1.00mg/kgBW剂量时,观察砷对小鼠脏体系数、外周血T淋巴细胞α-醋酸萘酯酶的阳性率(ANAE)、迟发型变态反应(DTH)、血清溶血素半数溶血值(HC50)、碳粒廓清吞噬指数(α)等5个指标的影响。结果在亚急性免疫毒性试验中,当As2O剂量达0.74～1.00mg/kgBW时,小鼠的免疫器官、3体液免疫功能、细胞免疫功能以及单核巨噬细胞系统均有不同程度损伤;在亚慢性免疫毒性试验中,当As2O3剂量达1.00mg/kgBW时,小鼠的体液免疫功能、单核巨噬细胞系统均有不同程度损伤。结论砷对小鼠免疫功能具有毒作用,其最小毒作用剂量为0.74￣1.00mg/kgBW。     

减低剂量地西他滨治疗骨髓增生异常综合征伴单系发育不良患者的疗效观察深圳罗湖区人民医院 龚 辉 陈 姣 杜 芳 周凌云 刘丹波 康春香1

目的 探讨减低剂量地西他滨治疗骨髓增生异常综合征伴单系发育不良(MDS-SLD)患者的临床疗效和安全性。方法 评价深圳市罗湖区人民医院2016年1月至2018年12月使用减低剂量地西他滨[15 mg /( m₂.d),连续 5d]治疗的12例MDS-SLD患者的疗效和不良反应。结果 2例(16.6%)获完全缓解,1例(8.3%)获部分缓解,5例(41.6％)达血液学改善,总反应率达66.6％。在5例可行细胞遗传学评估的患者中,1例(20.0%)获PR。Ⅳ级血液学毒性发生率 50.0%, Ⅲ～Ⅳ级感染发生率33.3%,无Ⅲ～Ⅳ级出血,无Ⅲ～Ⅳ级恶心呕吐和Ⅲ～Ⅳ级肝功能损伤。中位随访时间16(2～32月),随访期间无患者死亡。结论 减低剂量地西他滨治疗骨髓增生异常综合征完全缓解及部分缓解率高,药物不良反应发生率低。     

Intermediate dose cytarabine improves survival and relapse-free rate compared with standard-dose cytarabine as post-remission treatment for acute myeloid leukemia: A retrospection study

The exact dose of cytarabine still remain controversial for the management of patients with acute myeloid leukemia (AML) after complete remission (CR), but recent studies favor lower doses. This study aimed to investigate the toxic effects of single-intermediate dose (ID) cytarabine in patients with AML after achieving CR, compared with standard-dose cytarabine.In this retrospective study, AML patients who achieved CR after consolidation therapy before enrollment between 07/2008 and 05/2019 were included. All patients were divided into single-ID cytarabine and standard-dose cytarabine. The Kaplan-Meier method was used to compare overall survival (OS) and relapse-free time (RFS). Cox regression models were used to assess factors independently associated with OS and RFS. The toxic side effects of hematology and non-hematology were observed.52 patients were enrolled. There were 33 in ID group, 19 in Standard dose group. The 3-year RFS rate (40.4% vs 22.2%, P = .031) was better in the ID group than in the standard-dose group, while the 3-year OS rate was not different between the 2 groups (50.2% vs 27.8%, P = .074). Treatment stratage of ID cytarabine chemotherapy significantly improve the prognosis of AML regardless of patient age, risk grade, WBC count. There were no significant differences between the 2 groups in grade 3 to 4 bone marrow suppression, gastrointestinal symptoms, blood transfusion, infections.Patients with AML receiving ID cytarabine showed better survival and similar toxicity profiles compared with patients who received standard-dose cytarabine.     

Phase Ⅰ study of postoperative radiotherapy combined with capecitabine for gastric cancer

AIM:To determine the maximum tolerated dose(MTD)and dose-limiting toxicity(DLT)of capecitabine combined with postoperative radiotherapy for gastric cancer.METHODS:We enrolled patients with any T stage and node-positive gastroesophageal or gastric adenocarcinoma after complete resection with negative margins(R0)or microscopic(R1)or macroscopic(R2)resection.Intensity modulated radiotherapy(IMRT)using a fiveto-seven-field,coplanar,sliding window technique was delivered to the tumor bed(T4b),anastomosis site,duodenal stump and regional lymph nodes(LNs)to a total dose of 45 Gy(1.8 Gy/fraction,5 d/wk).Patients with R1 or R2 resection received 10.8 Gy as a boost.Capecitabine was administered twice daily on every radiotherapy treatment day in a dose-escalation schedule (mg/m2)of 625(levelⅠ,n=6),700(levelⅡ,n=6),800(levelⅢ,n=6),900(levelⅣ,n=0)and 1000(levelⅤ,n=0).DLT was defined as grade 4 leukopenia or neutropenia,grade 3-4 thrombocytopenia or anemia and grade 3-4 non-hematological toxicity.RESULTS:Between October 2007 and August 2009,18 patients(12 men,6 women;median age,54 years)were enrolled in the study.The median number of positive LNs was 6,and total number of resected LNs was19.Twelve patients underwent R0 resection(66.7%).Fifteen patients received adjuvant chemotherapy under the leucovorin,fluorouracil and oxaliplatin(FOLFOX4)regimen.Six patients each were enrolled at dose levelsⅠ,ⅡandⅢ.Grade 1-3 leukopenia(16 patients,88.9%),anorexia(15,83.3%)and nausea(15,83.3%)were the most common toxicities.Grade 3 anorexia/nausea and grade 4 vomiting occurred in one level-Ⅰpatient.Grade 3 anorexia and nausea occurred in one level-Ⅱpatient.One level-Ⅲpatient developed grade 4neutropenia,while another developed grade 3 radiation esophagitis.No abnormal liver or renal function examinations were observed.Three patients did not finish chemoradiotherapy because of DLTs and two without DLTs received sequential boosts(total dose,55.8 Gy).CONCLUSION:The MTD of capecitabine was 800 mg/m2twice daily concurrent with IMRT for gastric cancer after surgery.The DLTs were anorexia/nausea,vomiting,neutropenia and radiation esophagitis.     

Experience of once-daily aminoglycoside dosing using a target area under the concentration-time curve

Background : Many centres are changing to once-daily aminoglycoside administration. However, proposed methods for this practice often have theoretical and practical difficulties. We have developed a method in which a target area under the concentration-time curve (AUC) is used instead of traditional peak and trough serum concentrations.
Methods : Following a starting dose of 5–7 mg/kg, administered by 30-minute infusion, the AUC was calculated using two serum aminoglycoside concentrations taken at one and six-14 hours after the start of the infusion. Dose adjustment was made to correct for any difference between the calculated AUC and a target AUC (72–101 mg.1-¹.h). The method was assessed for practicality and precision in 100 courses of treatment. The incidence of aminoglycoside toxicity was documented.
Aims : To analyse our experience with the target AUC method in the first 100 courses of once-daily aminoglycoside administration in the Christchurch, New Zealand hospitals.
Results : The mean final dose of 6.68 mg/kg, and AUC of 92.8 mg. 1 -¹.h, were significantly different from the mean starting dose and AUC of 5.67 mg/kg and 74.0 mg.1-¹.h, respectively. The method appeared to be more precise than empirical dosing at achieving the target AUC even though the final recommended dose had more variability than the starting dose. Although the study was uncontrolled, observed nephrotoxicity (2%) and ototoxicity (up to 6.9%) were no greater than expected from the results of other studies. There were no deaths related to antibiotic failure.
Conclusions : The AUC method was practical, and more appropriate for once-daily dosing than the conventional method of aiming for target peak and trough concentrations. Dose adjustment can be made before the next dose.     

增大型甲亢^131I治疗给药系数与疗效分析

目的 对^131I治疗甲亢常规公式增设给药系数，以提高增大型甲亢的一次治愈率，降低甲低率。方法 对比分析增加系数组116例和常规对照组143例的治愈率、甲低率、好转率、二次服药率。结果 增加系数组较对照组一次治愈率明显提高，由75．68％提高到83.62％（P〈0.01）。增加系数后痊愈率由58.04％提高到80.17％（P〈0．01）；二次服药率由14．69％降到6．03％（P〈0．01）；一过性甲低率和甲低率未见显著性差异。结论 增加系数后提高了增大型甲亢的一次治愈率，而甲低率未见明显增高。     

Efficacy and tolerability of rituximab and reduced-dose cyclophosphamide,doxorubicin, vincristine,and prednisolone therapy for elderly patient with diffuse large B-cell lymphoma

Objectives: Chemoimmunotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with rituximab (R-CHOP) is currently the first-line therapy for diffuse large B-cell lymphoma (DLBCL). However, management of elderly patients is challenging and often requires dose reductions or prolonged treatment intervals. We investigated the proper dose of R-CHOP for them.

Methods: At our institute, for DLBCL patients aged 65–79 and ≥80 years, we had reduced CHOP dose to 5/6 and 7/12, respectively, and retrospectively evaluated the reduced-dose R-CHOP.

Results: Although the median age in the standard, 5/6, and 7/12-dose groups was 57, 73, and 84 years, respectively (p?<?0.001), the 3-year event-free survival (EFS) rate did not differ between the standard and 5/6-dose groups (60.2 and 56.7%); however, 7/12-dose group had significantly inferior survival (25.9%). When patients aged 60–80 were evaluated, no difference in EFS was observed between the standard and 5/6-dose groups using the same international prognostic index. The neutrophil nadir and the frequency of infection were comparable among the three dose groups.

Discussion and Conclusions: Reduced-dose R-CHOP chemotherapy is a promising treatment for elderly patients with DLBCL in terms of efficacy and toxicity.     

Oxidant lung injury: Intervention with sulfhydryl reagents

Intracellular pools of reduced sulfhydryl compounds are taxed in protective and repair processes during oxidant lung injury. To determine the efficacy of exogenous sulfhydryl compounds in preventing the toxic effects of high oxygen exposure on lung, the cell permeable sulfhydryl compounds, cysteamine (CYS) or N-acetylcysteine (NaC), were infused continuously in rats during exposure to 1 atm O₂. CYS caused a reduction in mortality compared to vehicle treated-oxygen exposed rats at seven days (56% vs 78% respectively). At 48 hours, CYS reduced oxidant-induced pulmonary edema, measured by wet to dry weight ratios, and prevented oxidation of lung nonprotein sulfhydryls. NaC was even more effective in reducing mortality compared to vehicle treated-oxygen exposed rats (28% vs 78% respectively). In contrast to this beneficial effect of sulfhydryl compounds in oxygen toxicity, oxidant injury due to paraquat poisoning was exacerbated. Mortality increased in mice and rats given paraquat and treated with CYS. We speculate that this effect may be due to the ability of paraquat to accept reducing equivalents directly from CYS, thereby increasing reactive oxygen generated from reduced paraquat.     

Phase II study of high dose epirubicin in combination with cyclophosphamide in patients with advanced breast cancer

Abstract Background: Combination chemotherapy for metastatic breast cancer will palliate symptoms in the majority of patients but only a small percentage will have prolonged survival. Higher doses of doxorubicin lead to increased response rates in breast cancer and early studies have shown that epirubicin could be tolerated in higher doses with less relative toxicity than doxorubicin. Aims: This study was initiated to assess the dose of epirubicin that could be tolerated by escalating its dose while maintaining a fixed dose of cyclophosphamide. Simultaneously tumour response rate, spectrum of toxicities, duration of response and overall survival in patients with metastatic breast cancer were assessed. Methods: Patients with metastatic breast cancer commenced chemotherapy with a starting dose of epirubicin of 120 milligram per metre squared (mg/m²) and cyclophosphamide 600 mg/m². The dose of epirubicin was to be escalated or reduced depending on toxicity. Results: Forty female patients were entered into this study and three patients withdrew because of toxicity. Overall tumour response rate was 75% with 27.5% of patients obtaining a complete response. Median time to progressive disease was 35 weeks and median overall survival was 48 weeks, with median survival for complete responders being 103 weeks. Thirty-one (77%) patients completed five or more courses of treatment. Haematological toxicity was the main side effect and 70% of patients required a dose reduction. No patients were eligible for a dose escalation. One patient died as a consequence of neutropenic sepsis. Four (10%) patients had treatment ceased because of decrease in left ventricular ejection fraction and one patient died as a consequence of heart failure. Four patients remain alive. Conclusions: High dose epirubicin combined with cyclophosphamide is an effective treatment regimen for metastatic breast cancer obtaining higher overall response rates with increased percentage complete responses compared to conventional dose chemotherapy. Although toxicity was increased, high dose chemotherapy was well tolerated and mortality associated with treatment was not increased. No dose escalations of epirubicin were possible and a dose of 90mg/m² of epirubicin would be the maximum dose when used in combination with cyclophosphamide. Further trials are required to determine the influence of this high dose therapy on survival duration and whether comparable benefits can be achieved with shorter durations of therapy. (Aust NZ J Med 1995; 25: 474–478.)     

2型糖尿病胰岛素治疗剂量相关因素的探讨

目的研究2型糖尿病（T2DM）患者胰岛素（Ins）治疗达标剂量的相关因素。方法回顾分析214例Ins治疗的T2DM患者资料，根据治疗前应用口服降糖药种类分为6组，比较各组达标剂量和达标时间。结果达标剂量和病程、FPG水平、合并用药及BMI显著相关（设定检测水平P=0．1；P〈0．1有统计学意义）；单纯双胍失效组达标剂量[0.53（0．35～0．62）U／kg]与联合用药失效组[0.63（0.51～0.75）U／kg]差异有统计学意义（P=0．016），后者达标时间最长。达标基础Ins剂量和FPG可用方程Y=0．255X＋7．8表示（P=0．026）。结论T2DM患者达标Ins剂量和多因素相关。联合用药失效组达标剂量更大，时间更长。可根据FPG预测达标基础Ins剂量。     

Basal insulin requirement of youth with type 1 diabetes differs according to age

We investigated the percentage of total basal insulin dose to total daily insulin dose (%TBD) among Japanese youth of different ages with type 1 diabetes. The study enrolled 69 patients with type 1 diabetes who were treated with multiple daily injections of insulin. The participants were divided into the following age groups: group A, 0 to <10 years (n = 18); group B, 10 to <20 years (n = 31) and group C, 20 to <25 years (n = 20). We found no difference in the sex ratio, body mass index, and glycated hemoglobin and 2‐h postprandial C‐peptide levels among the three groups. Participants assigned to group B had a significantly higher percentage of total daily insulin dose than those in group A and group C (49.7 ± 10.4% vs 38.5 ± 13.7% and 38.3 ± 8.2%, P = 0.0005). In conclusion, the basal insulin requirements of Japanese youth with type 1 diabetes might have an age effect that is associated with puberty.     

CCNU Toxicity After an Overdose in a Patient with Hodgkin's Disease

An overdose of CCNU (600 mg over a 15-d period) was unintentionally ingested by a patient with advanced Hodgkin's disease subjected to combination chemotherapy. A severe bone marrow depression occurred 3 weeks after the start of the CCNU treatment. The nadir of the platelet count was reached after 4 weeks and that of the granulocyte count after 5 weeks. At the nadir of the white blood cell count, colony-forming cells (CFU-C) were found in significantly reduced numbers in the bone marrow, and were not found at all in the peripheral blood; the amount of colony-stimulating activity (CSA) produced by peripheral blood cells was reduced. However, the cells producing CSA recovered earlier than the CFU-C, and the CSA peak value was reached about 1 week before the peak value for CFU-C in the bone marrow. Thus, in vivo CSA-producing cells appeared to be more resistant to CCNU than were CFU-C, and their recovery appeared to be a prerequisite for the recovery of CFU-C and myelopoietic cells.     

乌司他丁联合大剂量氨溴索治疗重症肺炎疗效观察

目的观察乌司他丁联合大剂量氨溴索治疗重症肺炎的临床疗效。方法将60例重症肺炎患者随机分为常规治疗组和乌司他丁联合大剂量氨溴索治疗组,所有患者在治疗前后均进行血气分析及6分钟步行距离测定。比较两组患者治疗前后上述指标的变化。结果乌司他丁联合大剂量氨溴索治疗组患者治疗后上述指标改善优于常规治疗组（P〈0．05）。结论乌司他丁联合大剂量氨溴索治疗重症肺炎患者可以更好的改善氧合情况,提升患者运动能力。     

Sustained Antihypertensive Effect of Captopril Combined with Diuretics and Beta-adrenergic Blocking Drugs in Patients with Resistant Hypertension

ABSTRACT Ten patients with severe hypertension and unsatisfactory blood pressure control during combined therapy with β-adrenergic blocking drugs, diuretics, and vasodilators were treated with gradually increasing doses of captopril. Vasodilators were discontinued 24 hours prior to captopril administration. Six patients had essential, two renal, and two renovascular hypertension. Mild renal impairment was observed in four patients. Captopril effectively decreased blood pressure for 3 hours in all patients after the first dose. The antihypertensive effect appeared to be triphasic and was sustained in all but one patient during 12 months of observation. Captopril doses of 25–75 mg t.i.d. were sufficient to achieve acceptable blood pressure control (RR≦160/100 mmHg) when given in the above mentioned combination. Side-effects were few and tolerable and discontinuation of captopril was not required.