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 systematically investigate the efficacy and safety of sublingual immunotherapy( SLIT) in the treatment of a-dults with seasonal allergic rhinitis( SAR) .Methods Literature was retrieved online in CNKI,CBM,VIP,Wanfang data,PubMed,EMBase, Medline,Cochrane Library,et al.After screening literature,data collection and assessment quality,randomized controlled trials relevant to our study were selected independently based on inclusion and exclusion criteria by two researchers.Statistical analyses were conducted by RevMan 5.2 software.Results A total of 13 RCTs were enrolled.The meta-analysis revealed that SLIT provided a significant improvement in aspect of reducing Symptom Scores(SS) and Medication Scores (MS)of adults with SAR,the difference had statistical significance(P<0.000 01). Compared to placebo,SLIT could increase the rate of adverse events( AEs) in the treatment of adults with SAR compared to placebo.The fre-quently reported AEs during clinical trials were oral pruritus,tongue edema,ear pruritus,throat irritation,et al.Conclusion Sublingual im-munotherapy could improve the symptoms significantly and reduce the SS and MS in the treatment of adults with SAR.And its safety could be well tolerated.

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

OBJECTIVE:To establish a New Vierordt method for assaying ingredients in compound fleroxacin suppositories and compound fleroxacin ear drops METHODS:New Vierordt method was applied to determination of fleroxacin and tinidazole in compound fleroxacin suppositories and fleroxacin and metronidazole in compound fleroxacin ear drops with no need of separation RESULTS:The fleroxacin and tinidazole in compound fleroxacin suppositories were detected at wavelength 286nm and 317nm respectively The average recoveries were 100 17% and 99 96% with RSDs=0 44% and 0 37% respectively The fleroxacin and metronidazole in the compound fleroxacin ear drops were detected at wavelength 286nm and 318nm respectively The average recoueries were 100 65% and 99 92% with RSDs=0 65% and 0 21% respectively CONCLUSION:The New Vierordt method can be used for quality control of the two compound preparations because of its convenience,accuracy and good repeatability and can eliminate mutual interference of two ingredients in preparations

Genetic Therapy ; Mouth Neoplasms ; therapy

Objective To evaluate the role of Janus kinase 2-signal transducer and activator of transcription 3 (JAK2-STAT3) signaling pathway in sevoflurane postconditioning-induced inhibition of mitochondrial permeability transition pore (mPTP) opening during myocardial ischemia-reperfusion (I/R)in rats.Methods Sixty pathogen-free healthy male Sprague-Dawley rats,weighing 250-300 g,were divided into 4 groups (n=15 each) using a random number table:I/R group,sevoflurane postconditioning group (group SP),AG-490 group (group AG) and sevoflurane postconditioning plus AG-490 group (group SP+AG).Myocardial I/R was induced by 30 min ligation of the left anterior descending branch of coronary artery followed by 120 min reperfusion.In group SP,2.8％ sevoflurane was inhaled for 15 min starting from 2 min before reperfusion.JAK2 inhibitor AG-490 3 mg/kg was intravenously injected at 10 min before reperfusion in group AG.In group SP+AG,AG-490 3 mg/kg was intravenously injected at 10 min before reperfusion,and 2.8％ sevoflurane was inhaled for 15 min starting from 2 min before reperfusion.At 15 min of reperfusion,5 rats were sacrificed and myocardial specimens were obtained for determination of the expression of JAK2,phosphorylated JAK2 (p-JAK2),STAT3 and phosphorylated STAT3 (p-STAT3)in myocardial tissues by Western blot.The ratios of p-JAK2 to JAK2 expression (p-JAK2/JAK2) and pSTAT3 to STAT3 expression (p-STAT3/STAT3) were calculated.Five rats were sacrificed at the end of reperfusion for measurement of myocardial infarct size.The left 5 rats were selected and sacrificed,myocardial specimens were obtained,and the opening of mPTP was detected by a calcein-cobalt quenching method.Results Compared with group I/R,the myocardial infarct size and mPTP opening were significantly decreased,and JAK2/p-JAK2 and STAT3/p-STAT3 were increased in group SP (P＜0.05),and no significant change was found in the parameters mentioned above in SP+AG and AG groups (P＞0.05).Compared with group SP,the myocardial infarct size was significantly enlarged,the extent of mnPTP opening was aggravated,and JAK2/p-JAK2 and STAT3/p-STAT3 were decreased in SP+AG and AG groups (P＜0.05).Conclusion The mechanism by which sevoflurane postconditioning inhibits the opening of mPTP during myocardial I/R is related to activation of JAK2-STAT3 signaling pathway in rats.

Objective To explore genes expression of adiponectin receptors during differentiation of SW872 preadipocytes. Met-(hods) SW872 preadipocytes were cultured in vitro and induced to differentiate by 0.6 mmol/L oleic acid. During the progress of diffe-(rentiation), the morphological changes of SW872 cells were observed and the differentiation rate was assayed by oil-red O staining. Adiponectin receptors mRNA was measured by reverse transcription-polymerase chain reaction during differentiation of SW872 preadipocytes. Results 1.After stimulated by 0.6 mmol/L oleic acid for 72 hours, almost all SW872 cells were differentiated,and there were lots of fat droplets in the cells.2.There were adiponectin receptors genes expressions in SW872 preadipocytes.After 72 hours,and the levels of adiponectin receptor(AdipoR) 1 mRNA and AdipoR 2 mRNA were markedly increased up to 2.54 and 4.09 times,respectively. Conclusion There are AdipoR1 and AdipoR2 genes expressions in fat cells and the expressions are differentiation-dependent.

Objective To study the effect of oleic acid on the differentiation of SW872 preadipocytes.Methods SW872 prea-(dipocytes) were cultured and induced to differentiate by 0.6 mmol/L oleic acid in vitro.After 24 h,48 h and 72 h of differentiation,the morphological changes of SW872 preadipocytes were observed and the differentiation rate was assayed by oil-red O staining.In addition,triglyceride(TG) mass was detected by chemical colorimetry methods.During the differentiation of SW872 preadipocytes,transcription factors including peroxisome proliferator activated receptor-?_2(PPAR-?_2) and CAAT/enhancer binding protein-?(C/EBP-?)(mRNA) were also measured by reverse transcription-polymerase chain reaction(RT-PCR).Results 1.SW872 preadipocytes were fibroblastic and had no obvious fat droplet in cytoplasm.However,when stimulated for 72 hby 0.6 mmol/L oleic acid,SW872 preadipocytes became more bigger and rounder and differentiated into mature adipocytes with lots of fat droplets in the cells.2.Compared with that of predifferentiation,the concentration of TG mass increased by 14 folds after 72-hour differentiation(P

The samples of experimental and control groups were obtained by 1 ∶ 1 matching method and divided into development (242 pairs) and sign (156 pairs) groups.Through a 10-month group and case type intervention,Gesell test was performed for 5 zone development quotients of large motor,fine motor,adaptability,speech and personal-social to determinate the effectiveness of interventions.Before intervention,t values of the development group were 1.07,1.42,0.78,0.62 and 1.67 while those of sign group-1.48,-1.96,1.82,1.78 and-1.73 respectively.The inter-group comparison of various developmental quotient differences had no statistical significance (P ＞ 0.05).After intervention,t values of the development group were 9.85,8.92,3.57,11.21 and 9.30 for inter-group comparison and-31.65,-36.94,-46.26,-37.56 and-49.85 for intra-group comparison.The results of sign group were 10.91,9.61,10.75,12.01 and 14.36 for inter-group comparison and-23.20,-31.75,-44.94,-33.58 and-54.58 for intra-group comparison.Between intra-group and inter-group,the comparison of the developmental quotient differences had statistical significance (P ＜ 0.01).In two experimental groups,the post-intervention developmental quotients in 5 zones are better than those pre-intervention levels.It shows that preventive intervention of infant mental health is effective.

Objective To evaluate the theraputic effect of transcatheter arterial chemoembolization (TACE)for hepatocellular carcinoma with tumor thrombosis of portal vein.Methods One hundred and six patients of hepatocellular carcinoma with tumor thrombosis of portal vein under treament of TACE were observed before and after the procedure.Results After TACE tumor size reduced＞50% in 23 patients,＜50% in 25, no significant change in 44.The size of tumor enlarged in 12.The disappearance of portal vein tumor thrombosis accessed in 14,with reduction in 39,and no significant change in 51.Two patients died within one week.Conclusion TACE provides good therapeutic effect on hepatocellular carcinoma with tumor thrombosis of portal vein.