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

Enzymatic hydrolysis of nitrile was performed under mild conditions and afford high efficiency and selectivity,thus being highly potential for the synthesis of optically active carboxylic acids and their derivatives.The type of nitrile-hydrolyzing enzymes and hydrolysis reactions,reaction characteristics,factors influencing the hydrolysis and the prospect for its application to industrial production were reviewed in this paper.

Objective To examine the clinical effect of heat sensitive moxibustion in treating simple obesity with spleen-kidney deficiency type.Methods Ninety simple obesity patients with spleen-kidney deficiency type were randomized into a acupuncture group,a heat sensitive moxibustion group and a combination group,with 30 cases in each group.The heat sensitive moxibustion group was given moxibustion by self-made heat sensitive moxa stick.Heat sensitization acupoints were sought at patients' lumbosacral portion and hypogastrium.Two or three heat sensitization acupoints were selected each time.Patients were treated for 5 times each week,each time for 45min.In the acupuncture group,acupoints of Zhongwan (RN12),Shuifen (RN9),Qihai (RN6),Guanyuan (RN4),Mingmen (DU4),Yaoyangguan (DU3),bilateral Tianshu (ST25),Daheng (SP15),Daimai (GB26),Pishu (BL20),Weishu (21) and Shuidao (ST28) were selected.Seven to ten acupoints were selected each time.Even reinforcingreducing method was used.Needle was retained for 30min.During needle retention,manipulating the needles once every 10min.Patients were treated by 5 times each week.The combination group was given both acupuncture and heat sensitive moxibustion.The methods were the same as above.One month was a course.Each group was treated for 3 courses.Patients' body weight,waistline and height were recorded before and after treatment.Body mass index (BMI),body fat percent and waist to height ratio were calculated before and after treatment.The clinical effect was evaluated.Results After treatment,body weight,BMI,body fat percent and waist to height ratio in each group decreased (P ＜ 0.05).After treatment,body weight,BMI,body fat percent and waist to height ratio in the combination group was lower than those in the acupuncture group and the heat sensitive moxibustion group (P ＜ 0.05);while the difference between the acupuncture group and the heat sensitive moxibustion group was not significant (P ＞0.05).The total effective rate in the acupuncture group was 73.3％,with 76.7％ in the heat sensitive moxibustion group,and 86.7％ in the combination group.The clinical effect in the combination group was superior to that in the acupuncture group and in the heat sensitive moxibustion group.Conclusion Heat sensitive moxibustion therapy might be effective in treating simple obesity with spleen-kidney deficiency type.Moreover,the clinical effect seemed better if combined with acupuncture.

Objective To explore the operative procedure and perioperative management of gastric cancer with liver cirrhosis.Methods Clinical data of 28 cases of gastric cancer with liver cirrhosis who were surgically treated in our hospital during the last seven years were retrospectively analyzed.Preoperatively,a detailed examination,and improvement of their nutritional status,liver function,and prothrombin time were aggressively made,and the possibility of tumor removal was estimated.Seven patients underwent radical proximal subtotal gastrectomy,and 4 of these cases underwent splenectomy and pericardial devascularizaion simultaneously.Five cases underwent total gastrectomy,and 3 of them had splenectomy and pericardial devascularizaion simultaneously.Twelve patients underwent radical distal subtotal gastrectomy,and 5 of these cases had splenectomy and suture of pericardial varices simultaneously.Four patients had palliative distal subtotal gastrectomy.The support of liver function and intense monitoring and management of complications were carried out postoperatively.Results Varying degrees of ascites occurred in all the 28 patients postoperatively,and other complications such as early liver coma occurred in five patients,extensive wound bleeding in three patients,left subdiaphragmatic abscess in one patient and wound infection in two patients.The morbidity rate was 100%(28/28).However,all the complications were recovered by non-surgical treatment.There were no perioperative deaths in this series.Conclusions Gastric cancer patients with liver cirrhosis are at a significant risk of developing postoperative complications.The surgical procedure should the "individual" principle based on liver function,history of upper gastrointestinal bleeding and the location of gastric carcinoma.Good hepatic reserve and perioperative care,meticulous hemostasis during operation,and prevention and treatment of postoperative complications are the likely determinants of operative prognosis.

Objective To explore the serum level of Glucagon like peptide-1 in late-onset Alzheimer′s patients and its clinical significance.Methods Case control study.Collecting cerebral vascular disease fifty-five cases, diagnosed with late-onset Alzheimer′s disease sixty-one cases, type 2 diabetes mellitus fifty-one cases , type 2 diabetic patients combined with late-onset Alzheimer′s disease thirty-seven patients from the Shanghai East Hospital and partly Pudong area elderdly hospital during October 2013 to March 2014, and forty healthy persons as normal control from physical examination center of Shanghai East Hospital during September 2013 to February 2014.Measuring the concentrations of GLP-1,β-amyloid, Tau protein and other routinely used clinical tests in the serum of patients from the normal controls , cerebrovascular disease , late-onset Alzheimer′s disease, type 2 diabetes and type 2 diabetes mellitus combined with late-onset Alzheimer′s disease by ELISA method developed in our laboratory.The blood samples were also collected at three fixed time including fasting time ,1 hour after taking glucose , 2 hour after taking glucose, the concentrations of GLP-1 were determined in the LOAD group , T2DM group and the T2DM combined with LOAD group and normal control group.The concentrations of serum GLP-1 among groups were compared with single factor analysis of variance , and the concentrations of serum GLP-1 between the two groups were compared using LSD-t test.Analysing the correlation between GLP-1 and other indicators with Pearson analysis.Results The fasting GLP-1 levels of LOAD group were ( 123.4 ±20.8 ) nmol/L, and they were highest between the normal control group (78.6 ±6.0) nmol/L and the cerebral blood vessel disease group(89.0 ±8.7)nmol/L (F values were 3.46 and 1.98, P<0.05).The fasting GLP-1 levels of T2DM combined with LOAD group (157.9 ±28.6) nmol/L were higher than the LOAD group (123.4 ± 20.8) nmol/L (t =1.63,P <0.05), but there were no difference of the fasting GLP-1 levels between T2DM combined with LOAD group (157.9 ±28.6) nmol/L and T2DM group(153.8 ±18.0)nmol/L(t=0.96,P>0.05).Deficient secretion of GLP-1 after taking glucose 1 hour in most of the patients of T2DM combined with LOAD group (99.1 ±14.2) nmol/L, LOAD group(73.9 ±6.6 ) nmol/L and T2DM group (96.3 ±7.0 ) nmol/L could be concluded .The GLP-1 levels of T2DM combined with LOAD group after taking sugar 2 hour were (115.4 ±18.6)nmol/L ,and were higher than that of normal levels (63.3 ±6.2) nmol/L after taking sugar 2 hour(t=4.49,P<0.05).There were no difference between the GLP-1 levels of the LOAD group (73.6 ±5.8 )nmol/L and the GLP-1 levels of the normal group(63.3 ±6.2)nmol/L after taking sugar 2 hour (t=0.94,P>0.05).Pearson correlation analysis showed that the relationship of the levels of GLP-1 with Aβ( 1-42 ) and the levels of GLP-1 after taking glucose 1 h and 2 h were positively relative, and its coefficients of correlation were 0.401,0.436,0.722.Conclusions LOAD and T2MD are similar, and they have GLP-1 secretion shortage phenomenon after taking glucose , so monitoring dynamic change of GLP-1 after taking glucose may contribute to the auxiliary diagnosis of LOAD.

Purpose To investigate the relationship between Epstein-Barr virus (EBV) and lymphoepithelioma-like carcinoma (LELC) of the parotid gland and detect the gene expression products of EBV harbouring in LELC cells. Methods Thirty-two parotid LELCs were collected from the Departments of Pathology, Sun Yat-sen University of Medical Sciences, Guangzhou, China during the period of January 1986 and December 1995. All the 32 formalin-fixed paraffin-embedded blocks had been consecutively re-sectioned again. Immunohistochemical and in situ nucleic acid hybridization methods for detection of EBV gene encoded products were performed. Results (1) 32 LELCs were found out of 125 parotid gland carcinomas, the frequency was 25.6% (32/125). (2) All of the 32 specimens contained a variable number of EBNA-1 and EBERs positive neoplastic cells. (3) Twenty-seven out of 32 specimens (27/32, 84.4%) had a portion of carcinoma cells expressing LMP-1. (4) No ZEBRA positive cell could be found. (5) EA-D, VCA and MA positivity rates for these 32 parotid LELCs reached to 71.9%(23/32), 68.8%(22/32), and 12.5%(4/32), respectively. Conclusions (1) The parotid gland LELC is frequently to be seen in Guangzhou locale of China, where is a high-incidence area of nasopharyngeal carcinoma (NPC). The parotid gland LELC and NPC are co-prevalent in Guangzhou locale. (2) This disease is also consistently associated with EBV infection. (3) The EBV infection of the parotid gland LELCs is essentially the type of latency Ⅱ, expressing EBNA-1, EBERs and LMP-1. (4) The latent infected EBV harbouring in LELC cells could in part be switched over to lytic cycle, producing EA-D, VCA or/and MA.

Objective To explore the changes of nitric oxide(NO) and superoxide dismutase(SOD) in the serun and intestine mucosal and the treatment of ulcerative colitis(UC) with tanshinon in rats,Methods 30 mg of trinitro-benzene-sulfonic acid (TNBS) dissolved in 0.85ml of 50% ethanol was administrated intrarectally in Sprague-Dawley female rats to induce experimental colitis.After 7 days,the rats were divided into normal control, 0.9% saline and treatment group tanshinon 2ml?kg~(-1)?d~(-1) were intravenously.The therapeutic effect was evaluated by measuring the ponderal index,the surface area of the ulcers,macroscopical and histological score,activity of NO and SOD were measured in colonic tissue and serum all rats.Results Compared with the saline group,the ponderal index,the surface area of the ulcers,macroscopical and histological score,activity of NO level in the serum and intes- tine mucosal was decreased and the SOD increased of significantly in the treatment group(P

The technique conditions of decolonization of fermentation broth were successively optimized using single factor assay and orthogonal layout method in Cordyceps jiangxiensis. The optimal condition of decolorization was investigated to be 3g/100mL active carbon, 5 min absorption time, pH5 of fermented broth and 25℃absorption temperature. Under the optimal condition, the maximum decolorization rate of fermented broth reached 89. 6% , simultaneously 10. 7% consuming rate of exopolysaccahride was minimum. Subsequently, the extract condition of exopolysaccharide of C. jiangxiensis was further optimized by orthogonal layout design. The maximum exopolysaccharide production was 0. 38 g/L under the optimal condition, i. e. firstly fermented filtrate decolorized and deproteined was concentrated to 1/7 of its total volume, secondly concentration broth was mixed with four times its volume of absolute ethanol and stirred vigorously, lastly precipitation of exopolysaccharide proceeded at 4℃for 16 hrs and the exopolysaccharide collected by centrifugal ion and dryness.

The methyl group plays an important role in the rational drug design. Introducing methyl into small molecules has become an important strategy of lead compound optimization. The application of methyl in drug design is reviewed in this paper. Methyl can modulate the physicochemical, pharmacodynamic, and pharmacokinetic properties by ortho effect, inductive effect, and conformational effect. It also improves the metabolic stability as a soft metabolic point. In addition, introducing methyl into drug molecules can also be applied as a strategy in new uses of old drugs and generate me-too drugs.
Drug Design ; Hydrophobic and Hydrophilic Interactions ; Lipid Metabolism ; Methylation ; Pharmaceutical Preparations ; chemical synthesis ; chemistry ; metabolism ; Solubility ; Stereoisomerism ; Structure-Activity Relationship

Adolescent ; Bone Plates ; Fracture Fixation, Internal ; instrumentation ; Fractures, Bone ; diagnostic imaging ; pathology ; physiopathology ; surgery ; Humans ; Male ; Patella ; injuries ; surgery ; Radiography