Pharmacokinetics and pharmacodynamics of hydroxychloroquine enantiomers in patients with rheumatoid arthritis receiving multiple doses of racemate

Hydroxychloroquine, a slow acting antirheumatic drug, is administered as the racemic mixture. Blood concentrations of the two enantiomers of hydroxychloroquine were measured in two studies, one study of eight patients, in whom blood and urine concentrations were measured during the first 6 months of therapy with rac-hydroxychloroquine, and one of 43 patients who had received rac-hydroxychloroquine therapy for at least 6 months. In the latter study rheumatoid disease activity was also measured. The pharmacokinetics of hydroxychloroquine were found to be enantioselective. The concentrations of (?)-(R)-hydroxychloroquine were higher than those of the (+)-(S)-antipode in all patients at all time points, although the ratios of the two enantiomers did display a two to three fold variability between patients. Both total and renal clearance were greater for the (+)-(S)-enantiomer. From the observational, cross-sectional study design used, it was not possible to differentiate concentration–effect relationships of the two enantiomers. The 11-fold range of drug concentrations swamped any effect of variability between patients in enantiomer proportions. Blood concentrations of both enantiomers were significantly higher in groups of patients with less active disease. © 1994 Wiley-Liss, Inc.     

国产人尿激酶原的药效学、药理学和毒理学研究

通过对重组人尿激酶原（rhRhpro-UK）不同剂量（8万IU/kg和16万IU/kg）对家兔纤溶功能的影响并与尿激酶（UK）（8万IU/kg）比较实验显示,rhpro-UK和UK都能明显缩短兔优球蛋白溶解时间,rhpro-UK对纤溶参数影响比UK小.rhpro-UK对体外血栓的溶解作用随剂量增加而增加,与同剂量UK比较有显著差别.rhpro-UK和UK对猪冠脉血栓都有明显的溶栓作用,对猪的纤溶指标纤维蛋白原（FG）、纤溶酶原（PLG）和α2抗纤溶酶（α2-AP）无明显影响.rhpro-UK对出血时间、凝血时间、单位时间内出血量均明显低于UK.表明rhpro-UK的副作用明显低于UK.rhpro-UK对小鼠、大鼠、犬和豚鼠回肠的一般药理学实验表明,rhpro-UK对受试动物的一般行为、状态及中枢神经系统、心血管系统、呼吸系统、消化系统等均无明显影响.仅发现犬实验中手术创面有渗血现象,对全身血液有类似肝素化状态.rhpro-UK的毒理实验表明,rhpro-UK的半数致死量为97.5mg/kg;Beagle犬接受2,8,28mg/kgrhpro-UK后,除8mg和28mg组有一过性牙龈充血,凝血时间明显延长,Tchol,TP和Alb含量有升高趋势外,未观察到明显毒性反应,病理学检查也未观察到药物造成直接的脏器损伤,2mg/kg组未观察到任何毒副反应.特殊毒性实验表明,rhpro-UK没有致突变和致畸作用.     

人参皂苷Rg3药代动力学及抗肿瘤作用的研究进展

人参皂苷Rg3是存在于天然药物人参中的一种四环三萜皂苷,研究表明人参皂苷Rg3具有确切的抗肿瘤活性,在诱导肿瘤细胞凋亡、抑制肿瘤细胞增殖、增强免疫功能等方面具有显著作用。本文通过查阅近年来相关文献,概括人参皂苷Rg3药效学及药代动力学研究进展,探讨人参皂苷Rg3抗肿瘤的作用机理以及体内吸收、分布、代谢、排泄规律,并在此基础上结合现代中药理论对今后人参皂苷Rg3的研究方向进行了展望。     

Bioanalytical strategy used in development of pharmacokinetic (PK) methods that support biosimilar programs

The development of biosimilar products is expected to grow rapidly over the next five years as a large number of approved biologics reach patent expiry. The pathway to regulatory approval requires that similarity of the biosimilar to the reference product be demonstrated through physiochemical and structural characterization, as well as within in vivo studies that compare the safety and efficacy profiles of the products. To support nonclinical and clinical studies pharmacokinetic (PK) assays are required to measure the biosimilar and reference products with comparable precision and accuracy. The most optimal approach is to develop a single PK assay, using a single analytical standard, for quantitative measurement of the biosimilar and reference products in serum matrix. Use of a single PK assay for quantification of multiple products requires a scientifically sound testing strategy to evaluate bioanalytical comparability of the test products within the method, and provide a solid data package to support the conclusions. To meet these objectives, a comprehensive approach with scientific rigor was applied to the development and characterization of PK assays that are used in support of biosimilar programs. Herein we describe the bioanalytical strategy and testing paradigm that has been used across several programs to determine bioanalytical comparability of the biosimilar and reference products. Data from one program is presented, with statistical results demonstrating the biosimilar and reference products were bioanalytically equivalent within the method. The cumulative work has established a framework for future biosimilar PK assay development.     

藏药西藏棱子芹抗炎镇痛药效学研究

本文采用二甲苯致小鼠耳廓肿胀法、棉球致小鼠肉芽肿法观察藏药西藏棱子芹的抗炎作用,采用热板法、醋酸扭体法观察藏药西藏棱子芹的镇痛作用。结果表明藏药西藏棱子芹能明显抑制二甲苯所致小鼠耳廓肿胀和棉球所致小鼠肉芽肿;能提高小鼠对热板疼痛的阈值,减少小鼠扭体反应的次数,延长醋酸所致小鼠扭体反应的潜伏时间。藏药西藏棱子芹具有显著的抗炎镇痛作用,值得开发研究。     

Intra-Species Extrapolation in Risk Assessment of Different Classes of Antimicrobials

The risk assessment process for non-carcinogens incorporates all available scientific information, including toxicokinetic and toxicodynamic data. A 10-fold uncertainty factor (UF) is most commonly used to account for underlying variability within the human species. The purposes of this investigation are to evaluate whether the magnitude of the 10X-UF can be reduced when pharmacokinetic and pharma-codynamic data are incorporated to characterize interindividual variability and whether another UF is needed for the children group. An extensive literature search was conducted on seven antimicrobials in order to incorporate information on kinetics and dynamics to allow extrapolation among susceptible humans. The drugs are cefaclor, cefuroxime, erythromycin, clarithromycin, ampicillin, gentamicin and amikacin. The composite factor was calculated using the highest ratio for appropriate parameters and default subfactor. According to the data, we concluded that when relevant kinetic and dynamic data are available, replacing the default factors with actual data-derived values was possible for the antimicrobials evaluated and that there is no need to add another UF to the children group.     

Dose Scaling and Extrapolation Across Age Groups

This paper considers how the logic of cross-species dose scaling applies (or does not apply) when extrapolating among differently sized humans, and specifically, when extrapolating to children. Scaling children's doses by a power of body weight predicts that they would be less sensitive to chemicals than adults, owing to faster clearance. Possible countervailing factors, however, are the role of quicker pharmacodynamic processes, differences between interspecific and ontogenetic allometry, and the complex role of inherent differences in the metabolism and physiological system of immature bodies, the last leading to uncertainty in extrapolation but not necessarily to systematic sensitivity among children. The issue of scale per se does not appear to provide a basis for positing a systematically greater sensitivity of children to toxic substances     

Monitoring the dynamics of Src activity in response to anti-invasive dasatinib treatment at a subcellular level using dual intravital imaging

Optimising response to tyrosine kinase inhibitors in cancer remains an extensive field of research. Intravital imaging is an emerging tool, which can be used in drug discovery to facilitate and fine-tune maximum drug response in live tumors. A greater understanding of intratumoural delivery and pharmacodynamics of a drug can be obtained by imaging drug target-specific fluorescence resonance energy transfer (FRET) biosensors in real time. Here, we outline our recent work using a Src-FRET biosensor as a readout of Src activity to gauge optimal tyrosine kinase inhibition in response to dasatinib treatment regimens in vivo. By simultaneously monitoring both the inhibition of Src using FRET imaging, and the modulation of the surrounding extracellular matrix using second harmonic generation (SHG) imaging, we were able to show enhanced drug penetrance and delivery to live pancreatic tumors. We discuss the implications of this dual intravital imaging approach in the context of altered tumor-stromal interactions, while summarising how this approach could be applied to assess other combination strategies or tyrosine kinase inhibitors in a preclinical setting.     

Implications of chirality on pharmacodynamic modeling

Although the implications of stereochemistry for pharmacokinetics are relatively well appreciated only recently has its influence on pharmacodynamics begun to be examined. The implications of different pharmacological interactions between enantiomers with similar and different kinetic properties are examined through the use of simulation of the pharmacological effect vs. time profile. The influences of assuming that the pharmacological effect is solely the result of the more active enantiomer are also discussed. The simulations demonstrate that the less pharmacologically active enantiomer may have a significant influence on the observed effect vs. time profile and that the assumption that all of the observed pharmacological activity arises from the more active enantiomer may lead to highly inaccurate prediction of the pharmacodynamic parameters. Finally, these observations suggest that the pharmacodynamic profiles of a drug administered as a racemate or as a “pure” formulation of the more active enantiomer may be significantly different. © 1994 Wiley-Liss, Inc.