非雄激素竞争型雄激素受体拮抗剂设计策略

雄激素受体(androgen receptor,AR)是前列腺癌治疗中最为重要的药物靶点,但抗雄激素药物在使用过程中产生的耐药性问题给前列腺癌患者的治疗带来了巨大挑战.本文回顾了雄激素受体的结构功能及传统治疗位点产生药物抗性的原因,并总结非雄激素竞争型的雄激素受体拮抗剂设计策略,为发展新型抗前列腺癌药物提供依据.     

间歇性与持续性雄激素阻断治疗晚期前列腺癌疗效比较

目的比较间歇性与持续性雄激素阻断治疗晚期前列腺癌的疗效以及治疗产生的副作用。方法选取我科2012年1月~2013年1月收治的晚期前列腺癌患者76例,分为观察组(38例)及对照组(38例)。观察组38例行间歇性雄激素阻断治疗即药物去势加抗雄激素药物,对照组38例行持续性雄激素阻断治疗即手术去势加抗雄激素药物。比较两组患者的副反应发生率及治疗后的生活质量。结果观察组38例患者发生潮热症状者13例(34.21%)、乳房胀痛者12例(31.58%)。对照组23例患者发生潮热症状者26例(68.42%)、乳房胀痛者25例(65.79%)。比较两组潮热症状及乳房胀痛的发生率差异均有统计学意义(P0.05)。两组患者治疗后,观察组患者在肠道症状、性功能、尿路症状、骨痛、治疗相关症状方面都较对照组有明显的改善,生活质量大大提高,两组对比差异有统计学意义(P0.01)。结论间歇性联合雄激素阻断治疗可以明显降低患者治疗的副作用并且增加治疗后的生活质量,是晚期前列腺癌患者行雄激素阻断治疗的首选方案。     

核糖核酸改善慢性活动性肝炎血清蛋白的观察

<正> 1979年,我们曾试用正常核糖核酸(RNA)治疗慢性肝炎和肝硬化取得一定的疗效,并发现其对患者血清蛋白的疗效尤为显著。由动物实验尚证明,RNA有增进正常小鼠肝细胞合成蛋白质的作用。在此基础上,我们重点观察了RNA对慢性活动性肝炎(CAH)血清蛋白的疗效。自1979至1985年间,总共以RNA治疗CAH82例,并以辅酶Q_(10)治疗CAH20例进行对照观察,进一步证明RNA有明显改善CAH患者血清蛋白的疗效。现报告如下:对象及方法一、治疗对象:选择CAH而有血清蛋白电泳异常的病例为治疗对象。CAH的诊断均参照1978年第一届全国病毒性肝炎学术会议     

21-羟化酶缺乏症患儿的生长发育及治疗

先天性肾上腺皮质增生症(congenital adrenal hyper-plasia, CAH)是一组常染色体隐性遗传疾病,由肾上腺皮质激素合成途径中酶的缺陷所引起。最常见的酶缺陷类型为21-羟化酶缺乏(21-hydroxylase deficiency, 21-OHD),占酶缺陷类型的90%,根据酶的缺陷程度又分为经典型及非经典型两种临床类型,儿童中主要为经典型。经典型21-OHD又分为完全缺乏和不完全缺乏两类。前者酶活性为0,皮质醇及醛固酮皆不足,临床表现为失盐性(salt-wasting, SW);后者酶活性为1%~10%,皮质醇及醛固酮的分泌量大致正常,在一般情况下能维持生理功能不发生失盐症状,仅表现为因高雄激素血症所引起的女性假两性畸形及男性假性性早熟,临床表现为单纯男性化型(simple virilizing, SV)。主要的治疗方法是皮质醇(糖皮质激素和盐皮质激素)替代治疗。如患儿未能及时治疗或者治疗不足,由于雄激素分泌过多,生长过快、骨成熟提前,使骨骺早闭,导致患儿身材矮小;但如患儿使用皮质激素过量,也常引起患儿矮小[1]。正常情况下,生理性糖皮质激素分泌量约为4.8~8.7 mg/ (m2·d),临床上最常用是的是生理性糖皮质激素氢化可的松片剂,常用剂量为10~20 mg/(m2·d),每日3次。超生理量的糖皮质激素能在下丘脑、垂体和靶器官水平干扰生长激素/胰岛素样生长因子-Ⅰ(growth hormone/insulin-like growth factor-I, GH/IGF-I)信号传导通路、抑制生长激素的释放、信号和基因传导与mRNA的加工等,从而抑制生长中儿童的线性生长[2]。为维持CAH 患儿理想的线性生长,治疗上应该以最低剂量的糖皮质激素适当替代,同时也能抑制肾上腺雄激素的过度分泌[3]。Nebesio T D 等[4]指出,线性生长是反映糖皮质激素治疗不当的最好指标。笔者经过查阅文献对经典型21鄄羟化酶缺乏患儿的生长发育及糖皮质激素对生长的影响进行了综述。     

芳香化酶抑制剂治疗青春期矮身材疗效及安全性研究进展

<正>矮身材患儿越早进行治疗且治疗持续时间越长,越有利于改善患儿的终身高(final adult height,FAH)^[1-2]。但临床上常遇到错过最佳治疗时期的青春期矮小患儿,他们就诊时骨龄较大,骨骺接近闭合,生长潜力小,此时开始单用重组人生长激素(recombinant human growth hormone,rhGH)或联合促性腺激素释放激素类似物(gonadotropin releasing hormone analogs,GnRHa)干预疗效不佳。因此,     

噻唑烷酸治疗慢性病毒性肝炎20例

本文报道使用噻唑烷酸(硫杂脯氨酸)治疗慢性病毒性肝炎20例,其中包括慢性迁延型肝炎(CPH)15例、慢性活动性肝炎(CAH)5例。研究结果表明,噻唑烷酸对CPH的有效率为(86％)13/15;对CAH的有效率为(80％)4/5。从乙型肝炎病毒标志(HBVM)检测结果看,似乎有一定疗效。在服用过程中未见副作用。作者等认为噻唑烷酸治疗慢性病毒性肝炎,似有进一步扩大临床研究的必要,以提供治疗慢性病毒性肝炎较好的替代药物。     

多囊卵巢综合征药物治疗的研究概况

多囊卵巢综合征(Polycystic ovary syndrome,PCOS)药物治疗是首选,西医药物治疗主要以促排卵、降低血雄激素水平、降低LH水平、改善胰岛素抵抗为治疗原则,针对肥胖、抑郁等还可采用药物对症辅助治疗.中医治疗PCOS以辩证论治处方、周期疗法、专方专药为主,辩证论治常用药物为补虚药、活血化瘀药物.     

小剂量环孢素A与小剂量雄激素在慢性再生障碍性贫血治疗中的临床效果

目的:探讨对慢性再生障碍性贫血采用小剂量环孢素A与小剂量雄激素进行联合治疗的临床疗效.方法:选取我院收治的70例慢性再障患者,随机分为对照组和观察组,两组患者均给予环孢素A与雄激素治疗,对照组为标准剂量,观察组为小剂量,治疗2个月后比较疗效.结果:治疗后,两组患者外周血中的白细胞、血红蛋白、血小板等指标均有明显改善(P＜0.05),两组比较差异无显著性(P＞0.05);两组患者的药物副作用发生情况相比,观察组低于对照组(P＜0.05);两组的治疗有效率无显著差异(P＞0.05).结论:针对慢性再障采用小剂量环孢素A与小剂量雄激素进行治疗,临床疗效显著,药物副作用的发生率明显较低,具有推广价值.     

先天性肾上腺皮质增生症的药物治疗

先天性肾上腺皮质增生症（CAH）是由于肾上腺皮质激素合成途径中所必需的一些酶遗传性缺陷,引起皮质醇合成不足,进而继发下丘脑CRH和垂体ACTH代偿分泌增加,导致肾上腺皮质增生的一组疾病。根据酶缺陷的种类不同,分为21-羟化酶缺陷症（21-OHD）、11β-羟化酶缺陷症（11β-OHD）、17α-羟化酶缺陷症（17-OHD）以及其他种类。其中以21-OHD最常见。CAH的治疗目标是补充皮质激素的不足,避免肾上腺危象。同时抑制雄性激素,减轻男性化,改善终身高或减少脱氧皮质酮等中间产物的堆积,缓解由其造成的高血压、低血钾等临床症状及其并发症。CAH的主要治疗方式为药物治疗,其中糖皮质激素最为重要,对于不同类型的患者要加用盐皮质激素,或辅以外科手术等方式进行治疗。糖皮质激素剂型有多种选择,通常对于生长发育期的患儿宜首选氢化可的松,以避免对于生长的抑制作用,而成年患者可选择氢化可的松、泼尼松或地塞米松等,酌情加用盐皮质激素。在治疗期间应监测临床症状,血电解质及肾素活性等,同时注意多血质貌、体重增加等现象,及时调整治疗,避免医源性库欣综合征的发生。     

雄激素联合环孢素治疗再生障碍性贫血的疗效分析

目的分析再生障碍贫血患者施行雄激素联合环孢素的临床疗效及不良反应。方法选2012年11月至2017年11月我院收治的再生障碍性贫血患者40例作为实验组研究对象,均采用雄激素联合环孢素治疗方法,回顾2007年10月至2012年10月我院收治的40例再生障碍性贫血患者作为对照组研究对象,均单纯采用雄激素药物治疗,对比两组患者的临床疗效及治疗后的不良反应情况。结果采用雄激素联合环孢素治疗的实验组患者临床总有效率明显高于对照组(P <0.05),且实验组不良反应发生率低于对照组(P <0.05)。结论治疗再生障碍性贫血采用雄激素联合环孢素具有良好的临床疗效,患者不良反应少,安全性高,值得临床推广应用。     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg.kg) or i.p. (50 mg.kg) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) l.h. kg in the male rat and 10.6 (95% CI: 7.5, 15.0) l.h. kg in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p 0.001) in plasma obtained from the male (8.8 2.0%) compared with the female rat (11.7 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Quantitative in vivo and in vitro sex differences in artemisinin metabolism in rat

1. The pharmacokinetics of the antimalarial compound artemisinin were compared in the male and female Sprague-Dawley rat after single dose i.v. (20 mg x kg(-1)) or i.p. (50 mg x kg(-1)) administration of an emulsion formulation. 2. Plasma clearance of artemisinin was 12.0 (95% confidence interval: 10.4, 13.0) 1 x h(-1) x kg(-1) in the male rat and 10.6 (95% CI: 7.5, 15.0) 1 x h(-1) x kg(-1) in the female rat suggesting high hepatic extraction in combination with erythrocyte uptake or clearance. Artemisinin half-life was approximately 0.5 h after both routes of administration in both sexes. Values for plasma clearance and half-lives did not statistically differ between the sexes. 3. After i.p. administration artemisinin AUCs were 2-fold higher in the female compared with male rat (p < 0.001). Artemisinin disappearance was 3.9-fold greater in microsomes from male compared with female livers and it was inhibited in male microsomes by goat or rabbit serum containing antibodies against CYP2C11 and CYP3A2 but not CYP2B1 or CYP2E1. 4. The unbound fraction of artemisinin in plasma was lower (p < 0.001) in plasma obtained from the male (8.8 +/- 2.0%) compared with the female rat (11.7 +/- 2.2%). 5. The possibility of a marked sex difference, dependent on the route of administration, has to be taken into account in the design and interpretation of toxicological studies of artemisinin in this species.     

Theophylline kinetics in peripheral tissues in vivo in humans

Several biochemical and cellular effects have been described for methylxanthines under in vitro conditions. However, it is unknown, whether threshold concentrations required to exert these effects are attained in target tissues in vivo. We therefore employed the microdialysis technique for measuring theophylline concentrations in peripheral tissues under in vivo conditions.Following in vitro and in vivo calibration, microdialysis probes were inserted into the medial vastus muscle and into the periumbilical subcutaneous adipose layer of healthy volunteers. Following single oral dose administration of 300 mg or i.v. infusion of 240 mg theophylline, in vivo time courses of theophylline concentrations were monitored in tissues and plasma. Major pharmacokinetic parameters (c_max, t_max, AUC) were calculated for plasma and tissue time courses. The mean AUC_tissue /AUC_plasma-ratio was 0.56 (p.o.) and 0.55 (i.v.) for muscle and 0.55 (p.o.) and 0.72 (i.v.) for subcutaneous adipose tissue.We conclude that microdialysis provides important information on the distribution and the tissue pharmacokinetics of theophylline.Abbreviations FPIA Fluorescence polarisation immuno assay - AUC Area under the curve - t_max Time to peak concentration - c_max Peak concentration     

休克时血中氧自由基的变化

本实验测定10名休克患者血浆和红细胞的丙二醛(MDA)、血浆总抗的氧化活性(AOA)的含量。结果表明:休克病人红细胞膜和血浆 MDA 含量(4.298±0.722;5.348±0.834)与对照组(3.235±0.682;4.356±1.081)比较明显增高(P<0.05);血浆 AOA(39.65±7.858)与对照组(48.21±10.81)比较明显降低(P<0.01)。提示:休克时,患者机体内自由基反应增强是引起组织细胞损伤的原因之一。     

Interindividual variability in metabolic activation in humans in vivo

In assessing interindividual variability in metabolic activation, the toxic metabolite is often too unstable for conventional analysis. Possible alternatives include a stable product of the reactive metabolite e.g. cysteinyl derivatives of N-acetyl-4-benzoquinoneimine, the toxic metabolite of paracetamol, adducts with DNA or protein, and indirect measurement of the activity of the enzyme(s) producing the active metabolite. An example of the last approach is the use of furafylline, a highly specific inhibitor of human CYP1A2, to determine the extent of the metabolic activation of the cooked food mutagens PhIP and MeIQx. The extent of inhibition, determined from levels of unchanged amine in urine, is an indirect measure of the activity of the activation pathway. Further refinement of this approach, allied to improved measures of the biological process of interest should prove of value in evaluating interindividual variability and its role in the risk assessment process.     

Changes in angiopoietin expression in glomeruli involved in glomerulosclerosis in rats with daunorubicin-induced nephrosis

AIM: To study the potential pathological role of endogenous angiopoietins in daunorubicin-induced progressive glomerulosclerosis in rats. METHODS: Seventy male Wistar rats were allocated randomly into a daunorubicin group (DRB; n=40) or a control group (n=30). The rats in the DRB group were injected with DRB (15 mg/kg), in their tails. Subsequently, at intervals of 1, 2, 4, 6, 8, and 12 weeks, 5 male Wistar rats in each group were chosen randomly for 24 h urinary protein quantitative measurements (24 h UPQM), and determination of plasma tumor necrosis factor alpha (TNF-alpha), angiopoietin-1 (Ang1), and angiopoietin-2 (Ang2) levels. Kidney sections were examined by electron microscopy, Periodic Acid Schiff (PAS) staining, immunohistochemical staining and in situ hybridization histochemistry. RESULTS: As glomerulosclerosis progressed in the DRB group, expression of Ang1 mRNA and protein in glomeruli decreased and expression of TNF-alpha protein, Ang2 mRNA and protein in glomeruli increased. Expression of Ang1 mRNA and protein in glomeruli were negatively correlated with 24 h UPQM, Fn protein expression, and mean area of extracellular matrix (MAECM). In comparison, expression of Ang2 mRNA and protein in glomeruli were positively correlated with 24 h UPQM, Fn protein expression and MAECM; furthermore, there was a positive correlation between plasma Ang2 and 24 h UPQM. Plasma TNF-alpha and expression of TNF-alpha in glomeruli were positively correlated with expression of Ang2 mRNA and protein in glomeruli. There was a negative correlation between Ang1 protein expression and Ang2 protein expression in glomeruli. CONCLUSION: During DRB-induced glomerulosclerosis, podocyte injury led to a shift in the balance of Ang1 and Ang2 in glomeruli. Increased TNF-alpha in plasma and glomeruli may upregulate Ang2 expression in glomeruli. Elevated Ang2 in both plasma and glomeruli may mediate protein permeability through the glomerular filtration barrier. Moreover, local expression of Ang2 may facilitate the progress of glomerulosclerosis by upregulating a component expression of extracellular matrix.     

Hyperkalaemia in patients in hospital

A survey of all laboratory blood specimens with a plasma potassium concentration greater than or equal to 5.5 mmol/L was conducted over a three month period. Of 331 specimens with hyperkalaemia, 71 were excluded because the specimens was haemolysed, old or contaminated. The laboratory served a population of 348,561 and during this time measured the plasma potassium on 25,016 occasions. Sixty-six outpatients and 20 neonates were not evaluated. The survey was undertaken on 86 of 102 inpatients (46 males), 48 of whom were over 66 years of age. Fifty-seven patients were admitted under a medical service and 29 under a surgical service. Fifty-nine had a single episode of hyperkalaemia. Thirty-two underwent a surgical procedure. The commonest contributing factor was impaired renal function which was present in 71 (83%) patients. Although a definitive causative role for drugs could be identified in only five patients, in 52 (60%) patients drugs were a contributing factor (potassium supplements 24, ACE inhibitors 16, nonsteroidal antiinflammatory drugs 12). Thirty-five of the 86 (41%) patients died during their hospital admission. Nineteen of the 35 deaths occurred within three days of the hyperkalaemia being recorded. A normal plasma potassium was eventually documented in 50 of the 86 patients. Of the remaining 36 patients, 25 (69%) subsequently died. In general the treatment of patients with hyperkalaemia focused on identifying and treating the underlying cause. Hyperkalaemia must always be considered seriously and regard given to the overall clinical status of the patient, with particular attention to drug therapy, renal and cardiac function, acid base status and the possibility of sepsis.