Idiosyncratic adverse drug reactions (IDR) induce severe medical complications or even death in patients. Alert structure in drugs can be metabolized as reactive metabolite (RM) in the bodies, which is one of the major factors to induce IDR. Structure modification and avoidance of alert structure in the drug candidates is an efficient method for reducing toxicity risks in drug design. This review briefly summarized the recent development of the methodologies for structure optimization strategy to reduce the toxicity risks of drug candidates. These methods include blocking metabolic site, altering metabolic pathway, reducing activity, bioisosterism, and prodrug.
Binding Sites ; Cytochrome P-450 Enzyme System ; metabolism ; Drug Design ; Drug Discovery ; methods ; Drug Recalls ; Drug-Related Side Effects and Adverse Reactions ; prevention & control ; Humans ; Structure-Activity Relationship

Objective To study the effect of selective COX-2 inhibitor NS-398 on IL-1α and TNF a expression in HaCaT cells induced by UVA/UVB,and further to explore the mechanism on anti human skin photo damage. Methods The subcuhured HaCaT cells were divided into three groups:simple illuminated group was exposed to UVA/UVB directly,NS-398 interfered group was exposed to UVA/UVB after being treated with NS-398 in different concentrations,and the control group was cultured in normal without any treatment.The expression of IL -1α and TNF-α in supernarant was detected by ELISA kit.Results The level of IL-1α and TNF-α expression in supernatant from simple illuminated group was remarkably higher than that in the control group,NS-398 interfered group showed much lower level than the simple illuminated one,and the expression of IL-1α and TNF-α was dependent on the concentration of NS-398.Conclusions NS-398 can reduce IL-1α and TNF-α expression in HaCaT cells induced by ultraviolet rays,suggesting the possibility of anti human skin photo- damage effect.

Objective To study the effect of selective COX-2 inhibitor NS398 on IL-10 and IFN-γexpression in human keratinocytes induced by UVA,and further to explore the effect on anti human skin photoaging.Methods HaCaT cells were divided into three groups:simple UV exposure group,NS398-intervene group and blank group.For UV radiation,simple UV exposure group and NS398-intervene group were irradiated with UVA at a dose of 30 J/cm2.In order to assess the effect of NS398,HaCat cells were treated with NS398 at the dose of 0,20,40,80μmol/L respectively and then incubated without irradiation for 2h,substrate changed and cultured for 24h,and then the expression of IL-10 and IFN-γ mRNA was detected via RT-PCR.Results Simple UV exposure group had obviously higher expression of IL-10 mRNA and lower expression of IFN-γ mRNA than that of control group,while NS398-intervened group had significantly lower expression of IL-10 mRNA and higher expression of IFN-γ mRNA than that of simple UV exposure group,and dose-dependency existed.Conclusions NS398 may delay photo-damage of human skin via inhibiting the expression of IL-10 mRNA and up-regulating the expression of IFN-γ mRNA in human keractinocytes.

Aim To investigate the effect of spinal substance P on the antinociceptive propoties of ketamine. Methods Using behaviors and Fos expression technique,the effects of intrathecal administration (it) of substance P of different dose on the ketamine induced antinociception were observed in the formalin test of mice. Results Compared with NS group, the amount of time that mice spent licking the injected paw was dose-dependently decreased in 20 and 30 mg?kg -1 groups(P

OBJECTIVE: To investigate the effects of heterogenous suberect spatholobus stem (Spatholobus suberectu, Mucuna birdwoodiana, Millettia oosperma and Millettia dielsiana) on peripheral blood cell counts of mice with bone marrow suppression induced by (60)Co gamma ray irradiation. METHODS: Bone marrow suppression was induced by sublethal dose of (60)Co gamma ray in mice. White blood cell (WBC), red blood cell (RBC) and platelet (PLT) counts in peripheral blood of the mice were detected one day, 3, 7, 14 and 21 days after intragastric administration of different doses of the four kinds of suberect spatholobus stem, respectively. RESULTS: A slowdown of the decrease of WBC, RBC and PLT counts in peripheral blood of the mice with bone marrow suppression was observed after intragastric administration. The WBC, RBC and PLT counts in the Mucuna birdwoodiana-treated and Spatholobus suberectu-treated groups were significantly higher than those in the untreated group (P<0.05). CONCLUSION: All the four kinds of heterogenous suberect spatholobus stem can accelerate the recovery of WBC, RBC and PLT counts in peripheral blood of mice with bone marrow suppression, while the effects of Spatholobus suberectu and Mucuna birdwoodiana are relatively good.

Objective To explore the relationship of stromal derived factor 1α (SDF-1α) and CD44variant isoforms (CD44v6) with progress of multiple myeloma (MM). Methods Bone marrow mononuclear cells(MNCs) and bone marrow stromal cells (BMSCs) from 24 cases of MM patients (14 cases of untreated and relapsed and 10 cases of stable MM patients) and 15 cases of subjects were investigated as potential SDF-1αand CD44v6 product. The level of SDF-1α and CD44v6 of the conditioned media from MM patients and subjects were analyzed by ELISA. Results The level of SDF-1α and CD44v6 from MNCs in untreated and relapsed MM patients [(7232.41 ± 2644.97) pg/ml and (34.34 ± 13.20) ng/ml] were significantly higher than stable MM patients [(2315.49 ± 748.29) pg/ml and (15.69 ± 5.28) ng/ml] (t =6.25, t= 7.82, P ＜0.05) and 15 subjects [(1149.52 ± 636.06) pg/ml and (4.85 ± 3.62) ng/ml] (t= 4.60, t = 7.61, P＜ 0.05). The level of SDF-1α in stable MM patients was different from healthy subjects (P ＜0.05), but the level of CD44v6 in stable MM patients was not different from controls. The level of SDF-1α and CD44v6 in stable MM patients were significantly higher than health subjects (t = 2.99, t= 4.87, P ＜0.05). The level of SDF-1α was also detected from BMSCs of MM patients. When human MM cell lines U266 were adhered to BMSCs of 9 untreated and relapsed MM patients,and added rhIL-6 to it, there was significant increase of SDF-1α, compared with BMSCs in subjects and MM patients. The expression level of SDF-lα was correlated with the level of CD44v6 (r =0.51, P =0.03). Conclusion The increase of SDF-1α (may be produced by myeloma cells and BMSCs) and CD44v6 (may be produced by myeloma cells) activity is associated with the progress or pathogenesis of MM, and may be involved with tumor invasion. The completion of these processes in vivo may need participation of myeloma cells, BMSCs, IL-6,SDF-lα and CD44v6.

Objective: By taking the holism and differentiation concepts of traditional Chinese medicine (TCM) as the guidance, physical, mental and workplace factors were recruited in the observation of depression in employees, and were systematically classified to establish a workplace-related Liver Meridian-depression scale, for providing an evaluation index for depression in employees. Methods: NVIVO 11 software was adopted to assort ancient TCM classics. Based on the holism and differentiation concepts of TCM and well-developed scales, the item pool was determined via brain storm and screened by Delphi method after classified; a Wechat questionnaire was handed out 240 times via the online system 'Wen Juan Xing', and the results were statistically analyzed by the SPSS 17.0 version software. Results: Five dimensions consisting of 80 items were obtained after classification, and 60 items were selected by Delphi method; a total of 216 questionnaires were returned and the return rate was 90%. Of which, 215 questionnaires were valid ones, and the valid rate was 99%. By exploratory factor analysis (EFA), 44 items were obtained, and the aggregate split-half reliability coefficient was 0.922. The Cronbach's alpha coefficient for the five dimensions, i.e. Liver Meridian, relevant meridians, basic psychological activities, work cognition and emotional reactions, was respectively 0.841, 0.842, 0.914, 0.836 and 0.839, indicating a content internal consistency. The score of each item was highly correlated with the corresponding dimension, and the intercommunity was between 0.474 and 0.801. Nine factors were generated, 2 in the dimension of Liver Meridian, 3 in the dimension of relevant meridians, 2 in the dimension of basic psychological activities, 1 in the dimension of work cognition, and 1 in the dimension of emotional reactions, and the load of each factor was between 0.438 and 0.859. The reliability and validity of the scale were well examined. Conclusion: The scale can be applied to evaluate the qi activities of Liver Meridian and depression symptoms related to workplace.

Objective To approach the neurobiochemical mechanism of chronic central pain (CCP) after spinal cord injury (SCI). Methods 28 SD rats were divided into four groups, the normal group (group A), the pseudosurgery group (group B), and groups with CCP (group C) and without CCP (group D) after L1 spinal cord section injured with WADE method. T13 and L2 segments of rats' spinal cord were took and concentration changes of substance P (SP) in the spinal dorsal horn between two sections were examined by immunofluorescence histochemistry staining combined with confocal laser scanning microscope. Results Concentration of SP in the group D was decreased significantly compared with groups C,A and B (P<0.05-0.01), that of the group C was less than that of group A and B (P<0.05). Conclusion The rat model established by WADE method is proper to study CCP after SCI. SP in dorsal horn of spinal cord may inhibit the CCP after SCI in some degrees.

Objective：To reseach the expression of green fluorescent protein(GFP)gene in prostate car-cinoma PC-3M cell line and the efffect of cell cycle．Methods：GFP gene recombination DNA was construct-ed and PC-3M cells were transfected with lipofectin regant．The expression of GFP was observed under in-vert fluorescence microscope．Meanwhile，the cell cycle of positive cell colon was assayed by flOw cytome-ter．Resuits：After transfection，about 10％～15％cells expressed green fluorescent protein and there wasno significant change compared the cell cycle of positive cell colon with parents cells．Conclusion：GFP sup-plys a new way in reseaching metabolic phenomenon of live cells．

Objective To review the diagnosis and treatment of epithelioid angiomyolipoma of the kidney. Methods Five cases of epithelioid angiomyolipoma of the kidney were retrospectively analyzed in the aspects of imaging and pathologic characteristics. There were 3 males and 2 females with average age of 46 years (ranging from 26-64 years). There were 3 patients complained of pains of lumber. Two cases were found renal masses in routine physical examination. The mass diameter was 2.9-10. 1 cm. Two cases were diagnosed as angiomyolipoma and three as malignant tumors as kidney cancer, tumor of the adrenal gland or tumor of the liver with ultrasound and CT scan. Four of the 5cases accepted partial nephrectomy and 1 with radical nephrectomy. Results Epithelioid angiomyolipoma of the kidney was composed of abnormal thick parietal vessel, smooth muscle and adipose tissue in different proportional. The cytoplasm of epithelioid cells was acidophilia or lucency, which had acidophilia particles and abundant blood vessels. Epithelioid cells were round or polygon, surrounded to blood vessels, distributed in lipoid. The SMA, Vimentin and HMB45 were positive by immunohistochemisty. The post-operative histological diagnosis showed that all cases were epithelioid angiomyolipoma of the kidney. All patients were followed up for 2 to 12 months. No patients had locally recurrence or distant metastasis. Conclusions The diagnosis of epithelioid angiomyolipoma of the kidney relies on histopathology results. The immunohistochemical staining could be helpful for diagnosis and differential diagnosis.