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。     

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.     

动脉血质子自旋标记与动态磁敏感对比MRI在急性脑缺血患者中的应用价值

目的对比研究动脉血质子自旋标记（ASL）与动态磁敏感对比（DSC）MRI在急性脑缺血诊断中的应用价值。方法27例发病3d内的急性脑卒中患者，均采用3．0TMR行脉冲式ASL和DSCMR检查。观察2种技术的灌注表现，包括灌注不足、正常灌注、延迟灌注、过度灌注等，采用Mann—Whitney检验做定性分析。在扩散加权成像显示的病变部位及对侧正常半球的镜像区域分别确定3个感兴趣区（ROI），测量信号强度并计算信号强度比（病侧／对照侧），并将结果做配对t检验。结果定性分析显示27例患者中，2l例2种技术检查结果一致（灌注不足14例，正常灌注5例，过度灌注2例）。6例2种技术不一致，其中4例ASL显示灌注不足而DSC显示延迟灌注，2例ASL显示正常灌注而DSC显示延迟灌注，两者间差异无统计学意义（P〉0．05）。定量分析示，2种技术的病侧与对照侧信号强度比值ASL为0．7l±0．46，DSC为0．73±0．42，两者间差异无统计学意义（P〉0．05）。结论无创性ASL技术在检测灌注异常时与DSCMRI有相似的敏感性；ASL可与常规MR检查相结合，为临床诊断急性缺血性卒中提供有价值的信息。     

A quantitative evaluation of sealing ability of 4 obturation techniques by using a glucose leakage test.

OBJECTIVE: The aim of this study was to evaluate the sealing ability of 4 different obturation techniques by using a glucose leakage test. STUDY DESIGN: Eighty extracted single-rooted maxillary incisors were selected for the study. The teeth were decoronated and the root canals prepared using ProFile rotary instruments to an apical dimension of size 40 (0.06 taper). The specimens were then randomly divided into 4 experimental groups (n = 15) and filled with gutta-percha and sealer by using either cold lateral compaction, warm vertical compaction, Thermafil, or the E & Q Plus system. Another 10 teeth each served as the positive and negative controls. A glucose leakage model was used for quantitative evaluation of the coronal-to-apical microleakage at 24 hours, 1, 2, 3, 5, 8, and 12 weeks. RESULTS: No significant difference in the cumulative amount of leakage was found among the 4 groups at 24 hours and 1 week (Kruskal-Wallis test, P > .05). Lateral compaction showed significantly more leakage than the other 3 techniques at longer intervals (Mann-Whitney U test, P < .008). No significant difference was found between vertical compaction, Thermafil, and E & Q Plus at all observation times. CONCLUSIONS: Warm vertical compaction, Thermafil, and the E & Q Plus system showed a better sealing result than cold lateral compaction of gutta-percha at extended observation periods. The glucose leakage method used in this study was able to provide a nondestructive, quantitative, and long-term evaluation of the sealing ability of root canal fillings.     

张琪教授从肝论治疑难病的经验探讨

中医治疗现代医学难治疾病的经验报导颇多,显示出中医治疗疑难病的优势.因此,如实整理名老中医治疗疑难病的特点和规律,势必为今后深入细致地探索攻克疑难病奠定基础.张琪教授行医六十余载、学验俱丰,以善治疑难病而著称于杏林.脏腑辨证是中医辨证体系的重要组成部分,张琪教授治疗疑难病重视脏腑辨证,今将其从肝辨治疑难病的经验论述于下,加以探讨.     

pH值对IFN-α2b、rIL-2、ADM合用维拉帕米对人肝癌细胞杀伤作用的影响

目的　观察培养液在 pH值为 6 .8、7.3、7.6条件下rIL - 2、IFN -α2b、ADM及合用维拉帕米对人肝癌细胞 74 0 4杀伤作用的影响。方法　MTT法于 96孔培养板上进行杀伤实验 ,测定培养液pH值分别为 6 .8、7.3、7.6状态下 ,rIL - 2、IFN -α2b、ADM、及与维拉帕米联合杀伤人肝癌细胞 70 4 0的差异。结果　pH值为 7.6状态下rIL - 2、IFN -α2b、ADM及合用维拉帕米杀伤效果最佳。pH值为 6 .8、7.3、7.6时 ,IFN -α2b都能增加ADM抗肿瘤作用 ,但pH值为 7.6时 ,IFN -α2b +ADM杀伤效果最佳。结论　在偏硷性环境下 ,rIL - 2、IFN -α2b、ADM及合用维拉帕米对肿瘤细胞杀伤效果最佳