Computational modeling to predict effect of treatment schedule on drug delivery to prostate in humans.

PURPOSE: To evaluate a computational approach that incorporates experimental data in preclinical models to depict doxorubicin human tissue pharmacokinetics. EXPERIMENTAL DESIGN: Beagle dogs were given 2 mg/kg doxorubicin as i.v. bolus, 4-h infusion, or 96-h infusion. Concentrations in plasma, prostate (target tissue), heart (toxicity), and major tissues for disposition were determined and modeled. Model parameters were obtained after the bolus injection with model validation based on the 4-h and 96-h infusion data. Clinical pharmacokinetic data and scale-up gave doxorubicin profiles in human prostate and heart. RESULTS: In agreement with in vitro results, tissues were best modeled with two compartments, one rapidly and one slowly equilibrating. The developed tissue distribution model predicted concentrations for all three administration regimens well, with an average deviation of 34% (median, 29%). Interspecies scale-up to humans showed that the change from a bolus injection to a slow, 96-h infusion (a) had different effects on the drug partition and accumulation in heart and prostate, and (b) lowered the peak concentration in the plasma by approximately 100-fold but had relatively little effect on maximal heart concentration ( approximately 33% lower). The simulated drug exposure in a human prostate was above the exposure required to inhibit tumor proliferation but was 30 to 50 times below that needed for cell death. CONCLUSION: The present study shows a computation-based paradigm for translating in vitro and in vivo preclinical data and to estimate and compare the drug delivery and pharmacokinetics in target tissues after different treatment schedules.     

儿童频繁瞬目征的病因及综合治疗

[目的]探讨儿童频繁瞬目征的发病原因及其治疗措施。[方法]随机抽取148例门诊频繁瞬目征患儿，对其生活习惯、眼部情况进行详细询问并进行病因分析及综合治疗。[结果]通过克服不良生活习惯、去除谤因、调节心理和综合治疗措施，148例频繁瞬目征惠患儿经2周～5周的治疗，115例患儿治愈，28例好转，5例无效。[结论]频繁瞬目征与玩电脑、看电视及偏食有一定关系，针对性综合治疗可获得较满意的疗效。     

急诊右半肝活体肝移植治疗急性肝衰竭

目的 探讨急诊右半肝活体肝移植（living donor liver transplantation，LDLT）治疗急性肝衰竭（acute liver failure，ALF）的价值。方法 同顾性分析我院自2006年11月至2007年2月6例接受急诊LDLT的ALF患者临床资料，评价转归和疗效。结果 全部供体术后均未发生严重并发症或死亡，3周后恢复日常生活。全部受体均接受不含肝中静脉的右半肝，手术顺利，术后48h内苏醒，未发生神经系统并发症。与术前水平相比，血氨术后第1天明显下降至（53.3±21.6）μmol/L （P〈0.05）；总胆红素（TB）术后第1天即可恢复至（212±130）μmol/L（P〈0.05），以后呈继续下降趋势；凝血酶原时间（PT）术后1周内即可降至正常水平（13±1）s（P〈0.05）；国际标准化比值（INR）变化与PT类似；丙氨酸转氨酶（ALT）和天冬氨酸转氨酶（AST）术后1周内持续下降，至术后第7天降至较低水平。1例患者术后第10天发生急性排斥反应经激素冲击疗法治愈，其余5例均未发生严重并发症。全组受体均于术后1月内康复出院。结论 急诊右半肝LDLT能有效治疗ALF。     

Performance and comparison of the Cockcroft-Gault and simplified Modification of Diet in Renal Disease formulae in estimating glomerular filtration rate in a Chinese Type 2 diabetic population.

AIMS: Our aim was to assess performances of the Cockcroft-Gault and simplified Modification of Diet in Renal Disease (MDRD) formulae in estimating glomerular filtration rate (GFR) in Chinese diabetic populations and their association with vascular risks. METHODS: A total of 1009 patients with Type 2 diabetes were categorized into low estimated GFR groups (GFR < 60 ml/min/1.73 m(2)) and control groups by the two equations. The performances of these formulae were assessed at different stages of kidney function. Carotid artery intima-media thickness (IMT) and the prevalence of diabetic retinopathy or albuminuria were compared among the groups. The ability of these formulae to identify established vascular risk markers using sensitivity, specificity, positive and negative predictive values were also compared. RESULTS: The prevalence of low estimated GFR was 32.7% with the Cockcroft-Gault formula and 5.2% with the MDRD formula, respectively. In low estimated GFR subjects by the MDRD formula, IMT was significantly thicker than those by the Cockcroft-Gault formula (1.2 mm vs. 1.0 mm; P < 0.05), with a higher prevalence of albuminuria (78.4 vs. 52.8%, P < 0.05) and diabetic retinopathy (46.5 vs. 30.5%; P < 0.05). The Cockcroft-Gault formula gave a specificity of 71.7% and a sensitivity of 37.0%, and the MDRD formula gave a specificity of 96.6% and a sensitivity of 7.9% in estimating low GFR relevant for established vascular risks. CONCLUSIONS: These formulae performed differently in Chinese diabetic populations. The simplified MDRD formula is minimally superior to the Cockcroft-Gault formula for its high specificity and positive predictive values in estimating low GFR relevant for vascular risks.     

Intraprostatic chemotherapy: distribution and transport mechanisms.

PURPOSE: The present study evaluated the tissue distribution and targeting advantage of intraprostatic chemotherapy. EXPERIMENTAL DESIGN: We studied the delivery and spatial distribution of a fluorescent drug, doxorubicin, in the prostate of beagle dogs, after intraprostatic or i.v. administration. Drug concentrations were measured using high-performance liquid chromatography and confocal fluorescence microscopy. RESULTS: I.v. and intraprostatic injections yielded qualitatively and quantitatively different doxorubicin distribution in the prostate. A relatively homogeneous distribution was found after i.v. administration, whereas intraprostatic injection yielded a highly heterogeneous distribution with >10-fold higher concentrations localized in a cone-shaped glandular lobule bound by fibromuscular stroma, compared with other parts of the prostate. Compared with i.v. injection, intraprostatic injection yielded, on average, approximately 100-fold higher tissue-to-plasma concentration ratio, ranging from 963-fold near the injection site to 19-fold in the contralateral half of the prostate. The drug distribution within the prostate further suggests an important role for acinar flow in intraprostatic drug transport. CONCLUSIONS: Intraprostatic administration represents a viable option to deliver high drug concentrations within the prostate. The results further suggest the fibromuscular stroma separating the prostatic lobules as a major barrier to drug transport and convective flow as an important drug transport mechanism in the prostate.     

曼氏血吸虫与日本血吸虫交叉免疫原性的血清学实验研究

以曼氏血吸虫的虫卵和成虫免疫家兔后所产生的特异性抗体,可用以日本血吸虫虫卵、尾蚴和成虫为抗原分别进行的COP,CHR和ELACIEP测出,表明两种人体血吸虫存有显著的交叉抗原成分。应用此种血清交叉反应性,以检测抗异种人体血吸虫的抗体,似有效而可取的,可用以辅助诊断援外回国人员是否感染国外人体血吸虫病。     

Trade Herbal Products and Induction of CYP2C19 and CYP2E1 in Cultured Human Hepatocytes

Abstract: The aim of this study was to evaluate in vitro the dose‐dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S‐mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP‐modulating herb, showing a dose‐dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log‐linear dose‐dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non‐inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug‐herb interactions with selected CYP2C19 substrates.     

Induction of apoptosis in human hepatocarcinoma SMMC-7721 cells in vitro by flavonoids from Astragalus complanatus

Aim of the study

Flavonoids extracted from the seeds of Astragalus complanatus R.Br. reduce the proliferation of many cancer cells. The present study was carried out to evaluate the effects of these flavonoids from Astragalus complanatus (FAC) on human hepatocarcinoma cell viability and apoptosis and to investigate its mechanisms of action in SMMC-7721 cells.

Materials and methods

Cell viability was measured using the MTT assay. To detect apoptotic cells, SMMC-7721 cells treated with FAC were stained with Hoechst 33258 and subjected to agarose gel electrophoresis. Quantitative detection of apoptotic cells was performed by flow cytometry. The effects of FAC on apoptosis and cell cycle regulatory genes and proteins in SMMC-7721 cells were examined using an S series apoptosis and cell cycle gene array and Western blot analysis.

Results

The growth of SMMC-7721 and HepG2 cells was inhibited by treatment with FAC. Cell death induced by FAC was characterized by nuclear condensation and DNA fragmentation. Moreover, the cell cycle was arrested in the G0/G1 and S phases in FAC-treated SMMC-7721 cells. A sub-G1 peak with reduced DNA content was also formed. The activity of caspase-3 was significantly increased following FAC treatment. Microarray data indicated that the expression levels of 76 genes were changed in SMMC-7721 cells treated with FAC: 35 genes were up-regulated and 41 were down-regulated. Western blot analysis showed that caspase-3, caspase-8, Bax, P21, and P27 protein levels in SMMC-7721 cells were increased after 48 h of FAC treatment, while cyclinB1, cyclinD1, CDK1, and CDK4 protein levels were decreased.

Conclusions

These results suggest that FAC may play an important role in tumor growth suppression by inducing apoptosis in human hepatocarcinoma cells via mitochondria-dependent and death receptor-dependent apoptotic pathways.     

结直肠癌预后影响因素分析 ：附112例报告

摘要：为探讨影响结直肠癌预后的因素，笔者对112例结直肠癌患者的临床资料作回顾性分析。结果示，112例患者5年生存率为48%。Ducks A，B期组的生存期明显长于C，D期组，腺癌组生存期明显长于黏液腺癌组和未分化癌组；根治术组生存期长于未切除组及姑息手术组；化疗组生存期明显长于未化疗组。提示：结直肠癌的病理类型、临床分期、手术方式、是否化疗是影响结直肠癌预后的重要因素。     

中药泡足佐治糖尿病周围神经病变疗效观察

目的 探讨糖尿病周围神经病变的有效治疗方法.方法 将274.例糖尿病周围神经病变患者随机分成观察组(138例)和对照组(136例).两组均行常规控制血糖、改善循环、营养神经等治疗,对照组同时采用腿浴治疗器进行磁疗和热疗,观察组在对照组治疗基础上行中药泡足.结果 观察组总有效率为100%,对照组为83.1%,两组比较,差异有显著性意义(X2=25.48,P＜0.01).结论 应用中药泡足佐治糖尿病所致周围神经病变疗效显著,可降低糖尿病足的发生率,提高患者生活质量.