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 investigate the role of Stathmin in pancreatic cancer invasion and metastasis and its relationship with DNA methylation. Methods Immunohistochemical detection of MBDI and Stathmin protein expression in 40 cases of pancreatic cancer and 15 cases ot normal pancreatic tissue were performed,followed by analysis of their clinical and pathological relationship with pancreatic cancer; Human pancreatic cancer cell line BxPC-3 was treated with 5-Aza-2-dC (AZA).Both qRT-PCR and Western blot analysis of Stathmin expression were used before and after AZA treatment; Stathmin-siRNA transfected BxPC-3 cells were divided into the Stathmi-siRNA group and the empty vector control group.Transwell chamber invasion assay and animal experiment were performed to measure the changes in cell invasion and metastatic capability. Results lmmunohistochemistry showed positive MBDI and Stathmin expressions in 28 (70％) and 24 (60％) out of 40 cases of pancreatic cancer,respectively,which were significantly higher than that in the normal pancreatic tissue (P＜ 0.05); MBDI and Stathmin protein expressions were positively correlated (r =0.356,P =0.037),so were MBDI expression and lymph node metastasis (P=0.023).Stathmin expression was significantly correlated with clinical staging and lymph node metastasis (P =0.002,and P =0.001,respectively).After AZA treatment,both Stathmin mRNA and protein expression in BxPC-3 were significantly decreased.Transwell chamber invasion assay showed that compared with the control group,the cell invasion capability of the Stathmin-siRNA group was significantly decreased (P＜0.05).Animal experiment showed that the incidence of liver metastasis was significantly lower in the Stathmin-siRNA transfected group than the empty vector control group (P＜0.05).Conclusion Demethylation may contribute to the reduction of Stathmin expression in pancreatic cancer and further improve the prognosis of pancreatic cancer patients.

Objective To explore the antitumor mechanism of xianhe yanling recipe( XHYLR ). Methods The mechanism of action of 241 compounds contained in the Chinese medicine, XHYLR was studied by using computational pharmacological. Methods including molecular docking,biotechnology network,chemical space technology and the prediction of absorption,distribution,metabolism,excretion and toxicity( ADME/T). Results Most of the compounds in XHYLR had good drug-like properties. Distribution of 241 compounds in chemical space also revealed that these compounds showed similar anti-tumor activity. It suggested that the prescription of XHYLR was reasonable. The phenomena that one molecular interacted with multiple target proteins and several molecules interact with one target protein were observed in XHYLR. For example,the COX-2 interacted with 40 micromolecules,and catechin interacted with five targets including COX-2. Conclusion These results are helpful for understanding the complicated mechanism of anti-tumor activity of XHYLR.

Objective To evaluate the effects of high intensity focused ultrasound (HIFU) on hepatic cancer cells spreading in blood.Methods AFP mRNA in peripheral blood of 19 patients with hepatocellular carcinoma was detected before and after HIFU therapy by RT PCR.Results ①Before HIFU therapy, 11 of 19 cases were AFP mRNA positive (57.9%), while the control group were all negative. AFP mRNA was correlated with some clinical parameters such as serum AFP level, tumor size, portal vein embolism and extrahepatic metastasis ( P 0.05). ③After one week of HIFU therapy, the AFP mRNA positive rate of the group with tumor size less than 8 cm was much lower than that of tumor size larger than 8 cm ( P

Animals ; Beverages ; Macrophages ; drug effects ; metabolism ; Mice ; Mice, Inbred Strains ; Receptors, Complement 3b ; metabolism

Objective To observe the adverse reaction of dexmedetomidine(Dex)combined with dezocine in gynecological laparoscopic surgery after general anesthesia.Methods 120 cases of gynecologic laparoscopic surgery,ASA Ⅰ-Ⅱ,according to random number table method were divided into three groups,40 cases in each group.A group was intravenously injected Dex 1μg/kg 10min before induction,intravenously injected dezocine 5mg+ ondansetron 4mg 30min before the end of the operation.B group was intravenously injected dezocine 5mg+ ondansetron 4mg 30min before the end of surgery.C group was intravenously injected saline 1mL+ ondansetron 4mg.Before induction(T0),5min before extubation(T1),extubation(T2),10min after extubation(T3),the MAP,HR,SpO2 of three groups were recorded.The postoperative recovery time,degree of agitation,extubation and Ramsay sedation score,VRS analgesia 24h score,postoperative adverse reaction were compared among three groups.Results There was no difference in the recovery time among the three groups(t=0.94,0.97,1.02,all P>0.05).Compared with T0,the MAP of the three groups at the time of T2 increased,but the MAP of B group and C group was significantly higher(t=4.65,5.201,all P<0.01),HR was significantly higher(t=2.382,2.915,all P<0.05).Compared with A group and B group,the agitation rate of C group was higher(u=5.54,3.47,all P<0.01).The ramsay sedation score of 1 in A group was lower than C group,the VRS score of painless rate in A,B group was higher than that of C group(all P<0.05).Postoperative 24h,there were 19,23,24 cases of the three groups with nausea and vomiting,and the incidence rates were 47.5%,57.5%,60%,respectively,the differences were not statistically significant among the three groups(all P>0.05).Conclusion General anesthesia in gynecological laparoscopic surgery using Dex combined with dezocine can make patients more stable circulation,improve patients'' recovery quatity,it is a safe and effective method for prevention of adverse reaction after general anesthesia.

Objective To investigate the effect of metabolic syndrome and its components on imaging of brain impairment in subcortical ischemic vascular disease.Methods 120 patients with subcortical ischemic vascular disease (SIVD) including 25 cases without metabolic syndrome,25 cases with the risk of metabolic syndrome,70 cases with metabolic syndrome.The diagnostic criteria of metabolic syndrome was the National Cholesterol Education Program Adult Treatment Panel Ⅲ (NCEP-ATP Ⅲ).Brain MRI was assessed by the Scheltens scale,and divided into 3 regions:periventricular hyper intensities (PVH),leukoaraiosis (LA),basal ganglia hyper-intensities (BG).Results The assessment scores of PVH,LA,BG and Scheltens scores were higher in patients with the risk of metabolic syndrome and patient with metabolic syndrome than in patient without metabolic syndrome [(3.75±1.60),(4.21±1.09) us.(2.76±1.62),(10.67±5.26),(13.79±5.25) us.(6.36±3.93),(3.21±2.62),(6.90±4.25) us.(1.52±1.50),(17.62±8.32),(24.90±9.25)vs.(10.58± 5.89),respectively,all P＜0.05].Waist circumference had positive correlations with LA and Scheltens scores (r=0.185,P=0.046; r=0.488,P＜0.001).Positive correlation was found between triglyceride (TG) and LA,BG scores (r=0.188,P=0.042; r=0.311,P =0.001).The positive correlations of impaired glucose tolerance (IGT) with LA,BG and Scheltens scores were found (r=0.235,P=0.011; r=0.229,P=0.013; r=0.206,P=0.027).High density lipoproteincholesterol (HDL-C) was correlated negatively with LA,BG and Scheltens scores (r=-0.238,P=0.010;r=-0.189,P=0.042; r=-0.335,P＜0.001).The further multivariate linear regression analysis showed that IGT,HDL-C had significant correlations with LA assessment score (both P＜0.05),TG had significant correlation with BG assessment score (P＜0.05),and waist circumfernce,IGT,HDL-C had significant correlations with Scheltens scores (all P＜ 0.05).Conclusions Metabolic syndrome and its components correlate with the imagings of cerebral damage in SIVD.Abdominal obesity,TG,IGT,HDL-C are the important risk factors for SIVD.

Age of Onset ; China ; epidemiology ; Dust ; Humans ; Occupational Exposure ; analysis ; Pneumoconiosis ; epidemiology

Objective The study was designed to investigate the serum levels of HE4 in patients with lung cancer,and explore its prognostic value.Methods Blood samples of 106 healthy adults and 191 patients with lung cancer before treatment were measured by means of ELISA for HE4 levels in different stages and pathological types,for analyzing prognostic effect of HE4.Results The serum levels of HE4 in patients with lung cancer (median level 91.63 pmol/L) were significantly higher than control group (median level 56.42 pmol/L) (U =3 081.00,P ＜ 0.05).AUC of serum HE4 was 0.85,with a cut-off value of 82.70 pmol/L (specificity =95.31％,sensitivity =62.32％).HE4 expression was not statistically related to clinical stage and pathological types of lung cancer.The median overall survival (mOS) was 36.87 months in the HE4-low group and 30.43 months in the HE4-high group (P ＜0.05),respectively.HE4 level was an independent prognostic factor for overall survival (HR =2.15,95％ CI 1.49-3.12,P ＜ 0.05).Conclusions The prognosis of patients with high HE4 expression is poor.Therefore,it might be necessary for patients with high level of HE4 to receive more aggressive adjuvant therapy.

Objective To explore the causes of postoperative recurrence in patients of nodular goiter,the selection of method for reoperation and the postoperative complications. Methods The clinical data of 278 nodular goiter patients admitted in the first affiliated hospital of Harbin Medical University between 2001 and 2008 were analyzed retrospectively,including the methods and complications for first operation and reoperation. Results In the first operation,79 eases received simple eminectomy and 167 cases received partial lobectomy,accounted for 28.4% and 60.1%,respectively. Unilateral subtotal lobectomy plus contralateral eminectomy was performed in 23 cases and subtotal thyroideetomy was conducted in 9 cases,accounted for 8.3% and 3.2%,respectively. Postoperative complications occurred in one hundred and twenty-three cases,the incidence being 8.2% (23/278). Unilateral subtotal Iobectomy plus contralateral partial iobectomy was reperformed in 37 cases and bilateral subtotal thyroidectomy in 241 cases. Postoperative complications occurred in 12 cases,the incidence being 4.2%(12/278). No postoperative recurrence of nodular goiter was found. Conclusions Recurrence of nodular goiter is closely associated with the scope of previous surgical treatment,and correct operative manipulation may reduce the recurrent rate.