全球药品研发进展(2012.06)

本月全球药品研发进展取得成效的药物有50个,较上月增加了7个,除进入Ⅲ期临床阶段的药品数量略有减少外,进入其他研发阶段的药品数量均有所增加.进入注册阶段的有22个,比上月大幅增加7个.其中6个为全球首次注册的药品,在新市场补充注册的药品有14个.进入注册前阶段的有11个,比上月增加1个.进入Ⅲ期临床研究的有17个,比上月减少1个.     

全球药品研发进展(2010.07)

本月全球药品研发进展取得成效的药物有46个,比上月增加了7个,除进入注册阶段的药品数量大幅增加外,进入注册前和Ⅲ期临床研究的药品数量均有所减少.进入注册阶段的有25个,比上月大幅增加了11个.其中10个为全球首次注册的新活性物质和新制剂,其余15个均为在新市场补充注册.     

全球药品研发进展(2012.11)

本月全球药品研发进展取得成效的药物有52个,较上月大幅减少14个.除进入注册前阶段的药品数量略有增加外,其他阶段药品数目均有一定下降.进入注册阶段的有24个,比上月增加1个.其中,6个为全球首次注册的药品,在新市场补充注册的为18个.进入注册前阶段的有7个,比上月减少11个.进入Ⅲ期临床研究阶段的有21个,比上月减少4个.     

全球药品研发进展(2010.10)

本月全球药品研发进展取得成效的药物有47个,比上月增加7个,进入注册前阶段的药品数量较上月大幅下降,进入注册阶段的药品数量则较上月大幅增加,进入Ⅲ期临床研究的药品数量较上月也略有上升.进入注册阶段的有30个,较上月大幅增加11个.其中9个为全球首次注册的新活性物质和新制剂,其余21个为在新市场补充注册.     

全球药品研发进展(2011.07)

本月全球药品研发进展取得成效的药物有51个,较上月增加了9个,除进入Ⅲ期临床研究阶段的药品量比上月略有下降外,进入注册阶段和注册前阶段的药品数量均比上月增多.进入注册阶段的有26个,比上月增加9个.其中5个为全球首次注册的新活性物质、新制剂和新适应证,其余21个均为在新市场补充注册.     

全球药品研发进展(2012.10)

本月全球药品研发进展取得成效的药物有66个,较上月增加4个.除进入注册阶段的药品大幅减少外,其他阶段药品数量均有一定幅度增加.进入注册阶段的有23个,比上月减少10个.其中,8个为全球首次注册的药品,在新市场补充注册的为13个.进入注册前阶段的有18个,比上月增加4个.进入Ⅲ期临床研究阶段的有25个,比上月增加10个.     

全球药品研发进展(2012.12)

本月全球药品研发进展取得成效的药物有61个,较上月增加9个.除进入Ⅲ期临床研究阶段的药品数量大幅下降外,其他各阶段药品数目均有一定幅度的上升.进入注册阶段的有38个,比上月大幅增加14个.其中,14个为全球首次注册的药品,在新市场补充注册的为24个.进入注册前阶段的有11个,较上月增加4个.进入Ⅲ期临床研究阶段的有12个,较上月大幅减少9个.     

全球药品研发进展(2012.09)

本月全球药品研发进展取得成效的药物有62个,较上月增加6个.除进入Ⅲ期临床研究阶段的药品有所减少外,其他阶段药品数量均有一定幅度增加.进入注册阶段的有33个,比上月增加4个.其中,8个为全球首次注册的药品,在新市场补充注册的为25个.进入注册前阶段的有14个,比上月增加9个.进入Ⅲ期临床研究阶段的有15个,比上月减少7个.     

全球药品研发进展(2009.03)

本月全球药品研发进展取得成效的药物有43个,与上月持平,各个研发阶段的药品数量与上月相近. 进入注册阶段的有24个(9个为全球首次注册,其余15个均为在新市场补充注册),比上月增加3个.     

全球药品研发进展(2009.04)

本月全球药品研发进展取得成效的药物有53个,较上月增加了10个,各个研发阶段的药品数量均较上月有所增长. 进入注册阶段的有29个(8个为全球首次注册,其余21个均为在新市场补充注册),比上月增加了5个.     

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.     

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.     

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。     

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.     

Deoxynivalenol in cereals in Russia

A survey of the occurrence of deoxynivalenol (DON) and zearalenone (ZEN) in wheat, rye, barley and maize harvested in 1989-2001 in several regions of Russia has been conducted. A total of 5652 samples of cereals were analysed for DON and ZEN by using TLC and normal-phase HPLC with UV-detector. DON was detected in 69% of 2166 samples from Krasnodar region which is considered to be the major Fusarium endemic region of Russia. The contamination levels ranged from 0.1 till 8.6 ppm, MTEL was exceeded in 37% of these samples. The positive correlation between DON concentration and a percentage of Fusaria-damaged wheat kernels has been shown. DON occurrence and contamination levels were much lower that for wheat. Based on the results of monitoring and the data of average actual consumption of wheat products in Russia, the estimated daily intake of DON per 1 kg of body weight (EDI)was calculated. EDI varied from 0.07 ug in 1990-1991 till 1.40 ug in 1992. Although average EDI were lower than adopted tolerable daily intake (TDI, 3 ug/kg body weight) EDIs for the North-Caucasian region in some cases exceeded TDI.