抗疟药伯喹的肝微粒体体外代谢的研究

以硅胶薄层层析和高效液相色谱分析法研究了伯喹的肝微粒体体外代谢的主要代谢产物谱。结果表明肝微粒体代谢可同时产生伯喹的喹啉环氧化代谢产物——5-羟基伯喹(5-OH PQ)与侧链氧化脱氨基代谢产物——羧酸伯喹(CPQ);定量比较研究表明在微粒体代谢中前者的生成量远大于后者。     

结合代谢的抗疟药溶血毒性体外检测法

以苯巴比妥i.p.60mg/kg×3d及单剂苯并黄酮i.p.80mg/kg诱导雄性Sprague-Dawley大鼠,摘肝制微粒体,加氧化型辅酶Ⅱ(NADP)等辅助因子,组成体外代谢系统。选取6-磷酸葡萄糖脱氢酶(G6PD)偏低的兔血,制成1％红细胞悬液。不同剂量的伯喹、氯喹或三氟乙酰伯喹(M8506)分别于体外和肝微粒体代谢系统在37℃共同温育后,再取其上清液与1％红细胞悬液共同温育,测定温育后各管上清液的OD值。结果表明,在3×10~1～3×10~3μmol/L的浓度范围内,伯喹和M8506均可测出明显的溶血毒性,并呈一定的剂量一反应关系;而氯喹则无溶血毒性。提示本方法可用作抗疟药溶血毒性的快速初筛试验。     

瑞香素的抗溶血和抗膜脂质过氧化作用

目的：研究瑞香素的抗溶血与抗红细胞膜脂质过氧化作用。方法：用常规的溶血毒性体外检测法及高效液相层析定量测定脂质过氧化产物法,检测不同浓度瑞香素对伯氨喹（ＰＱ）溶血毒代谢产物５,６－二羟基８－氨基喹啉（ＡＱＤ）诱发溶血与红细胞膜脂质过氧化的抑制率。结果：１０至８０μｍｏｌ／Ｌ瑞香素对ＡＱＤ溶血毒性与红细胞膜脂质过氧化的抑制率分别为３３．０％－６９．２％和１１．９％－５８．２％,且呈一定的剂量－反应关系。结论：瑞香素具有抗溶血与抗红细胞膜脂质过氧化作用。     

重症肺炎患者血清25-羟基维生素D水平及其影响因素分析

正研究认为机体的免疫功能紊乱在重症肺炎病程中起着重要作用~([1])。维生素D是一组具有生物活性的脂溶性类固醇衍生物,其活性形式之一25-羟基维生素D(25-OH Vit D)可调节机体代谢、免疫及炎症反应过程~([2,3])。Barker等~([4])报道患者血清25-OH Vit D水平低下与呼吸系统感染的病情严重程度存在一定相关性。Cava等~([5])认为低水平25-OH     

红细胞6-磷酸葡萄糖脱氢酶与伯喹溶血关系的临床研究

伯氨喹啉现今仍为根治间日疟的首选药物,但对遗传性红细胞6-磷酸葡萄糖脱氢酶(G6PD)缺陷者可致急性血管内溶血,使其在间日疟的常规应用中受限制。为寻求防止伯喹溶血反应措施,我们于1984年7～8月对海南岛127例疟疾患者作G6PD活性测定,观察G6PD缺陷与伯喹溶血关系,并在1985年给治前检测G6PD正常的104,例进行伯喹治疗反应观察,取得了满意效果~[1]。     

贵州省罗甸县人群及服伯喹溶血患者G6PD活性的测定

鉴于在我区服用伯氨喹啉后发生溶血反应的病例不断增多,我们收集了我县近年来发生的96例伯氨喹啉溶血患者和经严格挑选的3936名男性学生作了红细胞6-磷酸葡萄糖脱氢酶(G6PD)活性测定,探讨其溶血发生的原因与G6PD缺乏的关系,并     

高强度聚焦超声波对细粒棘球绦虫原头节酶活性的影响

目的探索高强度聚焦超声波(HIFU)对体外分离的细粒棘球绦虫原头节的酶活性的影响作用。方法用不致原头节即刻杀伤的高强度聚焦超声剂量照射原头节,行酶组织化学染色观察酸性磷酸酶(ACP)、葡萄糖6-磷酸酶(G-6-P)和琥珀酸脱氢酶(SDH)的活性,了解高强度聚焦超声对体外培养的原头节3种代谢酶活性的影响作用。结果细粒棘球绦虫原头节具有酸性磷酸酶、葡萄糖6-磷酸酶和琥珀酸脱氢酶活性。不致原头节即刻杀伤的高强度聚焦超声波作用后,辐照组原头节葡萄糖6-磷酸酶和琥珀酸脱氢酶活性较对照组明显减弱,而酸性磷酸酶反应产物与对照组相比无明显变化。阴性对照组无酶反应产物产生。结论高强度聚焦超声波辐照对原头节酸性磷酸酶活性无影响,而对葡萄糖6-磷酸酶和琥珀酸脱氢酶的活性有明显的抑制,这可能是影响原头节的代谢功能,最终抑制其增殖的原因之一。     

伯氨喹在G-6-PD缺乏和正常的间日疟病人体内的药物动力学

伯氨喹因其具杀灭肝内休眠子的特有药 效,作为临床上唯一有效的间日疟和卵形疟根治药物使用了近50年。药物严重的毒性是在葡萄糖-6磷酸脱氢酶(G-6-PD)缺乏的病人引起溶血。尚不清楚除易感病人红细胞的     

广西少数民族地区口服伯喹发生227例溶血反应分析

广西境内有16个民族聚居地区,其中壮族占全区人口33.88％。本文根据1975～1991年16个县(市)资料统计,共发现227例溶血反应病例,均经及时处理治愈,无死亡病例。所服伯氨喹啉(伯喹)系上海天平制药厂(沪卫药准字第0284号)产品,每片含量7.5mg(基质),成人每日口服伯喹22.5mg(基质),儿童按年龄递减,其疗程不等,服药天数为1、2、3、4、5和8d。据227例溶血反应发生时间来看,口服伯喹后第1～6d出现     

瑞香素抗红外期疟原虫作用的研究

目的　研究瑞香素 (DPNT)抗红外期疟原虫的作用。方法　于ICR小鼠腹腔注射约氏疟原虫子孢子后 0 5h灌胃给药 ,连续 4d。不同剂量的DPNT及DPNT伍用伯氨喹 (PQ)的抗疟作用 ,分别以d7ICR小鼠阴性率及d1 1 或d1 2 ICR小鼠每千个红细胞被原虫感染数作评价 ,并观察DPNT对ICR小鼠血红蛋白浓度的影响。结果　DPNT的剂量范围为每天 10～ 10 0mg/kg ,连服 4d ,d7原虫阴性小鼠数及d1 1 红细胞被感染程度与对照组相比其差异均无显著性 ;DPNT每天 5 0mg/kg和每天PQ5mg/kg配伍组的d7小鼠阴性率与PQ每天 10mg/kg组相当。ICR小鼠DPNT每天 5 0mg/kg组与对照组血红蛋白浓度在d8天有差异。结论　DPNT单独用药 ,无明显抗红外期疟原虫作用 ,但DPNT每天 5 0mg/kg与PQ每天 5mg/kg伍用的抗疟效果与PQ每天 10mg/kg相当。DPNT在短期内可致小鼠贫血。     

Atrial repolarization as observable during the PQ interval

Objective

We aimed to study the involvement of atrial repolarization in body surface potentials.

Methods

Electrocardiograms of healthy subjects were recorded using a 64-lead system. The data analysis focused on the PQ intervals while devoting special attention to the low-amplitude signals during the PQ segment: the segment from the end of the P wave until onset QRS. The data were analyzed by inspecting body surface potential maps and the XYZ signals of the vectorcardiogram.

Results

Standard P-wave features exhibited normal values. The local potential extremes were found at positions not sampled by the standard leads. The PQ segment was found to be not isoelectric, the time course of the potential distribution being very similar to that during the P wave but for a reversed polarity and about 3-fold lower magnitudes.

Conclusion

The results demonstrate a significant involvement of atrial repolarization during the PQ interval and essentially discordant “atrial T waves,” suggesting a small dispersion of atrial action potential durations.     

老年女性2型糖尿病患者骨代谢标志物变化研究

目的 探讨老年女性2型糖尿病患者骨代谢标志物的特征. 方法 对我院内分泌科住院44例老年女性2型糖尿病患者(均为绝经后)的骨代谢标志物进行检测.糖尿病患者根据病程分为耱尿病1组(糖尿病病程＜10年)及糖尿病2组(糖尿病病程≥10年);根据糖化血红蛋白水平(HbA1c)分为糖尿病3组(HbA1c＜8％)及糖尿病4组( HbA1c≥8％),目前临床上建议老年患者HbA1c水平控制在＜8％为宜.同时选取我院50例体检健康女性作为对照组.结果 (1)耱尿病组25-羟维生素D3、Ⅰ型前胶原氨基末端(C端)前肽(PICP)明显低于正常对照组,而抗酒石酸碱性磷酸酶(TrACP-5b)较对照组明显升高,且有统计学差异(P＜0.05).(2)糖尿病2组患者血Ⅰ型前胶原氨基末端(N端)前肽(PINP)和PICP水平明显低于糖尿病1组患者(P＜0.05),而TrACP-5b水平高于1组,雌二醇、25-羟维生素D3则无明显统计学差异.(3)糖尿病3组血PINP、PICP明显高于糖尿病4组,TrACP-5b低于4组,差异存在统计学意义(P＜0.05).(4) HbA1c与HNP、PICP和TrACP-5b存在显著相关性,而雌二醇与PINP、PICP、25-羟维生素D3、TrACP-5b无明显相关性. 结论 2型糖尿病患者的骨形成降低,而骨吸收增加.这提示糖尿病患者的骨质形成减弱、骨质破坏增加.随着糖尿病病程的延长,患者的骨质形成速率减慢,骨吸收增加.血糖控制不佳会对骨的形成及骨质的吸收产生影响,因而严格的血糖控制可有效延缓骨质疏松进展.     

云南南部恶性疟原虫对氯喹、咯萘啶、青蒿琥酯、哌喹敏感性的体外测定

1988及1990年在滇南恶性疟流行区用体外微量法测得恶性疟原虫对氯喹、咯萘啶、青蒿琥酯及哌喹的抗性率分别为98.7％(75/76)、27.6％(16/58)、13.8％(9/65)及97.7％(43/44);半数抑制量(ID_(50))分别为125.0、19.0、4.7及243.3nmol/L,抗氯喹恶性疟原虫对哌喹有明显的交叉抗性;对咯萘啶及青蒿琥酯则未见明显的交叉抗性。抗青蒿琥酯恶性疟原虫对以上3种药均有一定程度的交叉抗性。抗咯萘啶恶性疟原虫对青蒿琥酯无交叉抗性,而对氯喹及哌喹有一定程度的交叉抗性。     

迟缓爱德华氏菌溶血相关基因的克隆

目的 研究迟缓爱德华菌（Ｅｄｗａｒｄｓｉｅｌｌａ ｔａｒｄａ Ｅｔ．）重要毒力因子的溶血素。方法 用鸟枪法将Ｅｔ－１２株的染色体经Ｓａｕ３Ａ酶切后,连接在质粒ｐＡＣＹＣ１８４上。结果 在抗性绵羊红细胞平板上,筛选出７株溶血相关克隆子,其中２株能稳定表达,并将１株重组质粒经酶切后,发现其酶谱和大小和国外报告的不同。经斑点杂交,证实该溶血相关基因在Ｅｔ－１２染色体上,结论 可能克隆到新的Ｅｔ－１２溶血     

蒿苯酯预防日本血吸虫病的实验研究

本文报道了蒿苯酯预防动物血吸虫病的实验结果。小鼠、免及犬在单次感染日本血吸虫尾蚴后第7d开始服蒿苯酯,每wkl次,连服4-6次,对宿主体内的血吸虫童虫有明显杀灭效果,减虫率达90％—100％,该药对不同感染度小鼠体内血吸虫童虫的杀灭作用相同。对连续感染14d(每d1次)的家兔减虫率亦达93.5％,蒿苯酯皮下注射给药效果比口服好,但毒性大。比较蒿苯酯、呋喃丙胺和吡喹酮3种药物杀灭血吸虫童虫的效果,以蒿苯酯为最佳。同样,蒿苯酯优于其他两种青蒿衍生物一蒿甲醚和还原青蒿素。     

Abnormalities of intermediary metabolism following a gestational diabetic pregnancy

OBJECTIVE--The aim of this study was to compare intermediary metabolism in glucose tolerant women with previous gestational diabetes and control women without a history of gestational diabetes. SUBJECTS--Fifteen women with previous gestational diabetes and 15 controls individually matched for race, age and body mass index were included. Only subjects with normal glucose tolerance were included in this study. METHODS--Plasma glycerol, 3-OH butyrate, non-esterified fatty acids (NEFA), glucose and insulin were measured fasting and following a 75 g oral glucose load. RESULTS--The women with previous gestational diabetes and their matched controls were of similar racial origin, age and body mass index. There was no difference between those with previous gestational diabetes and controls in fasting glycerol, 3-OH butyrate, NEFA, glucose or insulin concentrations. Following the oral glucose load, glycerol, 3-OH butyrate and NEFA concentrations fell in both groups. However, compared with controls at 120 minutes, those with previous gestational diabetes had significantly higher concentrations of glycerol (median 57, range 24-216 vs 27, range 8-89 mumols/l, P less than 0.005) and 3-OH butyrate (9, range 1-18 vs 5, range 2-11 mumols/l, P less than 0.01). NEFA concentrations were similar in the two groups. Despite similar glucose concentrations during the oral glucose tolerance test the insulin response during the first 60 minutes following oral glucose was significantly reduced in the subjects with previous gestational diabetes when compared with controls (insulin area, 0-60 minutes; 2172, range 788-4767 vs 2830, range 996-4784 pmol min/l, P less than 0.05). CONCLUSIONS--Women with a previous history of gestational diabetes, despite having normal glucose tolerance, have defective insulin release with resultant abnormalities of intermediary metabolism.     

Humanized mouse model of glucose 6-phosphate dehydrogenase deficiency for in vivo assessment of hemolytic toxicity

Individuals with glucose 6-phosphate dehydrogenase (G6PD) deficiency are at risk for the development of hemolytic anemia when given 8-aminoquinolines (8-AQs), an important class of antimalarial/antiinfective therapeutics. However, there is no suitable animal model that can predict the clinical hemolytic potential of drugs. We developed and validated a human (hu)RBC-SCID mouse model by giving nonobese diabetic/SCID mice daily transfusions of huRBCs from G6PD-deficient donors. Treatment of SCID mice engrafted with G6PD-deficient huRBCs with primaquine, an 8-AQ, resulted in a dose-dependent selective loss of huRBCs. To validate the specificity of this model, we tested known nonhemolytic antimalarial drugs: mefloquine, chloroquine, doxycycline, and pyrimethamine. No significant loss of G6PD-deficient huRBCs was observed. Treatment with drugs known to cause hemolytic toxicity (pamaquine, sitamaquine, tafenoquine, and dapsone) resulted in loss of G6PD-deficient huRBCs comparable to primaquine. This mouse model provides an important tool to test drugs for their potential to cause hemolytic toxicity in G6PD-deficient populations.Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme deficiency, with an estimated 400 million people worldwide affected by this enzymopathy (1). G6PD-deficient RBCs are uniquely sensitive to oxidative stress. Several drugs induce oxidative stress in G6PD-deficient RBCs, including the antimalarial drug primaquine (PQ), an 8-aminoquinoline (8-AQ) (2). The damaged G6PD-deficient RBCs are subsequently cleared from the peripheral circulation, resulting in “hemolytic” anemia (2). 8-AQs are the only approved drug class able to eliminate the hypnozoite stages of the malaria parasite (3), as well as stage V Plasmodium falciparum gametocytes (4, 5). These characteristics make them an ideal drug class for malaria elimination campaigns (6, 7). However, because of the hemolytic toxicity associated with PQ, this drug has sharply limited utility in public health programs for the treatment of malaria. Although new 8-AQs have been developed (8), the lack of a relevant animal model to predict hemolytic toxicity in the context of G6PD deficiency has hindered further development of this class of antimalarial drugs (2).SCID mice have routinely been used as models of human disease (9–12). Lacking in functional immune responses, and therefore able to accept xenogenic transplants, SCID mice have been widely used as hosts for the engraftment of both normal and malignant human cells including human RBCs (huRBCs) (13, 14). Subsequent studies on the engraftment of huRBCs improved the degree and persistence of engraftment by using sublethal irradiation, chemical treatment protocols, or inclusion of denatured human serum and repeated administration of huRBCs to enhance engraftment efficiency (15–18). Recent advances in the development of immunodeficient mouse models have yielded mice with higher engraftment capacities and with minimal manipulation before engraftment. SCID mice developed on the nonobese diabetic (NOD) background (NOD/SCID) are able to support huRBCs for prolonged periods after repeated i.p. injections of huRBCs (19–21).We report here the development of an NOD/SCID mouse model engrafted with G6PD-deficient huRBCs. Treatment with PQ and other drugs known to induce hemolytic anemia in humans produced hemolytic responses in mice engrafted with G6PD-deficient huRBCs, suggesting that this model can be used for testing drugs for the prediction of the hemolytic toxicity. Use of this model will expedite the development of safer drugs for malaria treatment and prophylaxis, as well as other antiparasitic diseases for which 8-AQs have demonstrated efficacy.     

ATP depletion as a consequence of adenosine deaminase inhibition in man.

Hereditary deficiency of the enzyme adenosie deaminase (adenosine aminohydrolase, EC 3.5.4.4) results in an immunodeficiency syndrome characterized by a marked reduction in circulating lymphocytes. We have administered 2'-deoxycoformycin, a potent inhibitor of adenosine deaminase, to a patient with a lymphoproliferative malignancy. The clinical consequences of pharmacologic inhibition of adenosine deaminase activity included an abrupt decrease in the lymphocyte count, abnormalities of renal and hepatic function, and hemolytic anemia. The plasma concentrations of adenosine and deoxyadenosine rose to peak values of 13 microM and 5 microM, respectively, and erythrocyte dATP levels increased to 110 pmol/10(6) cells over 9 days. There was a corresponding decrease in erythrocyte ATP levels from 128 to < 6 pmol/10(6) cells. A similar profound reductin in ATP occurred in the erythrocytes of a second patient. The rapid and unexpected depletion of ATP associated with dATP accumulation may account, at least in part, for the toxicity associated with 2'-deoxycoformycin administration. The inverse relationship of ATP and dATP raises major questions about the control of energy metabolism in erythrocytes.