AIM To study the experimental therapeutic effects of iptakalim hydrochloride(Ipt) on hypertensive cardiac remodeling in spontaneously hypertensive rats(SHR) and stroke prone spontaneously hypertensive rats(SHRsp). METHODS SHR at the age of 12 week old were treated ig with lisinopril 12 mg?kg -1 ?d -1 or Ipt 3 mg?kg -1 ?d -1 , once a day for 30 days. Age matched Wistar rats were used as normal control. 10 week old SHRsp were treated ig with Ipt 0 25,1 0 and 4 0 mg?kg -1 , once a day for 12 weeks. Age matched Wistar rats were used as normal control. After killing animals, the effects of Ipt on hypertensive cardiac remodeling were investigated. RESULTS During the 4 week experimental period, the systolic blood pressure(SBP) and heart rates(HR) of the untreated SHR were increased progressively. Ipt 3 mg?kg -1 ?d -1 could decrease SBP effectively and inhibit the increasing tendency of HR. Ipt had no effects on hypertensive cardiac remodeling in SHR. Under the same experimental conditions, lisinopril 12 mg?kg -1 ?d -1 could decrease SBP effe-ctively and had no effects on HR. The hypertensive cardiac remodeling could be alleviated by lisinopril. During the 12 week experimental period, the SBP of the untreated SHRsp were increased progressively. Ipt 0 25,1 0 and 4 0 mg?kg -1 could decrease the SBP of SHRsp effectively. Ipt at the doses of 0 25 and 1 0 mg?kg -1 had no effects on heart rates. But in the 4th week after administration of Ipt 4 0 mg?kg -1 , significant decrease in heart rates was observed. Compared with Wistar rats, the weight of left ventricle and septum(LV+S) and the ratio of LV+S to body weight(LV+S/BW) in untreated SHRsp were elevated significantly. Ipt 0 25, 1 0 and 4 0 mg?kg -1 ?d -1 could decrease LV+S and LV+S/BW significantly. CONCLUSION Ipt could decrease SBP of SHR and SHRsp effectively. The effects of Ipt on hypertensive cardiac remodeling were related with the experimental therapeutic period. After having been treated with Ipt for 4 weeks, the hypertensive cardiac remodeling could not be reversed. But after having been treated with Ipt for 12 weeks, the hypertensive cardiac remodeling could be reversed significantly.

AIM To investigate the effects of iptakalim hydrochloride(Ipt) on the association and dissociation kinetic processes of [ 3H]glibenclamide(Gli) binding with sulfonylurea receptor(SUR 2B ) of ATP sensitive potassium channel (K ATP ) in vascular smooth muscles derived from Wistar rats,and to compare the properties of Ipt with those of nucleotides. The interactions between Ipt and nucleotides were also determined. METHODS The experiments of the association and dissociation kinetic processes of K ATP blocker[ 3H]Gli binding with endothelium denuded aorta smooth muscles were used. RESRLTS (1)The specific bindings of[ 3H]Gli with SUR 2B were not displaced by Ipt at the concentrations of 10 pmol?L -1 ～ 0 5 mmol?L 1 . Ipt 100 ?mol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B . (2)Opposite to Ipt, ATP 1 mmol?L -1 accelerated the association kinetic process and retarded the dissociation kinetic process of [ 3H]Gli binding with SUR 2B There was an interaction between ATP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (3) Similar with Ipt, ADP 1 mmol?L -1 retarded the association kinetic process and accelerated the dissociation kinetic process of [ 3H]Gli binding with SUR 2B , there was an interaction between ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B . (4)Different from ATP and ADP, UDP had no effect on the association and dissociation kinetic process of [ 3H]Gli binding with SUR 2B . And there was not interaction between UDP and Ipt. CONCLUSION Ipt had no affinity with the binding sites of K ATP blocker in SUR 2B , but had negative allosterical modulation on it. The modulatory properties of Ipt were opposite to those of ATP, similar with those of ADP and different from those of UDP. There were interactions between ATP, ADP and Ipt in the modulation of [ 3H]Gli binding with SUR 2B , but there was not interaction between UDP and Ipt.

AIM: To investigate the changes of hemodynamic parameters and ECG in circulatory failure rats induced by organophosphate insecticides DDV and parathion.METHODS: Healthy Wistar male rats,weighing(320?20)g,were treated with organophosphate insecticides by ip.to induce circulatory failure.When the mean blood pressure(MBP) decreased to 45 mmHg,the changes of hemodynamic parameters and ECG were observed.RESULTS: In circulatory failure rats,SBP,DBP,MBP,HR,LVDP,IP,+dp/dtmax,-dp/dtmax,Vpm and +dp/dtmax/IP changed dramatically(P

Aim To investigate the effect of iptakalim on neonatal cardiomyocytes hypertrophy induced by isoprenaline(ISO).Methods Hypertrophy in neonatal rat cardiac myocytes was established via culture with ISO.Total protein content was measured by Lowrys method.The fluorescence intensity of intracellular Ca2+ was detected respectively with Fluo-3/AM loading by the laser confocal microscopy.Results ① 1?10-5mol?L-1 ISO can activated ?-AR completely;② the total protein of cardiomyocytes and intracellular i was markedly decreased by treatment with IPT and represented a dose-dependent manner.Conclusion IPT could inhibit the increase of protein content of cardiomyocytes induced by ISO,which may be contributed to the decease of intracellular Ca2+ concentration.

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 optimum target plasma concentration of propofol in preventing the adverse effects of carboprost tromethamine in the patients undergoing caesarean section.Methods One hundred and twenty-eight nulliparous parturients who were at full term with a singleton fetus,of American Society of Anesthesiologists physical status Ⅰ or Ⅱ,aged 24-37 yr,weighing 54-78kg,scheduled for elective caesarean section under combined spinal-epidural anesthesia,were randomly divided into 4 groups (n =32 each) using a random number table:control group (group C),and different concentrations of propofol groups (P1-3 groups).Carboprost tromethamine 250 μg was injected into the body of the uterus,and propofol with the target plasma concentrations of 0.8,1.2 and 1.6 μg/ml was simultaneously given by target-controlled infusion in P1,P2 and P3 groups,respectively,and normal saline was infused at a rate of 0.5 ml · kg-1 · h-1 in group C.The occurrence of cardiovascular events was recorded from the end of carboprost tromethamine administration until the end of surgery.The relatedadverse effects after carboprost tromethamine administration,and Ramsay sedation score at 15 mm after carboprost tromethamine administration were recorded,and satisfactory sedation was defined as Ramsay sedation score of 2.The occurrence of complications associated with combined spinal-epidural anesthesia was recorded during the postoperative follow-up.Results Compared with group C,the incidence of carboprost tromethamine-related adverse effects was significantly decreased in P2 and P3 groups,the rate of satisfactory sedation was significantly increased in P1 and P2 groups,the incidence of hypotension and tachycardia was significantly decreased in group P1 (P＜0.05),and no significant change was found in the incidence of carboprost tromethamine-related adv erse effects in group P1,and in the rate of satisfactory sedation in group P3 (P＞ 0.05).Compared with group P1,the incidence of carboprost tromethaminerelated adverse effects was significantly decreased in P2 and P3 groups,the rate of satisfactory sedation was significantly increased in group P2,and the rate of satisfactory sedation was significantly decreased in group P3 (P＜0.05).Compared with group P2,the rate of satisfactory sedation was significantly decreased (P＜0.05),and no significant change was found in the incidence of carboprost tromethamine-related adverse effects in group P3 (P＞0.05).No cardiovascular events were found in group P2,and the incidence of hypotension was 9％ in group P3.Conclusion The optimum target plasma concentration of propofol in preventing the adverse effects of carboprost tromethamine is 1.2 μg/ml in the patients undergoing caesarean section.

Objective To investigate the effect of dexamethasone on the pulmonary gas exchange in patients undergoing cardiac valve replacement under cardiopulmonary bypass(CPB).Methods Forty ASAⅡorⅢpatients aged 29-47 yrs weighing 50-69 kg undergoing cardiac valve replacement under CPB were randomly divided into 2 groups(n=20 each):dexamethasone group received dexamethasone 0.5 mg?kg~(-1) after induction of anesthesia and control group received normal saline(NS).Blood samples were taken before operation(T_0) immediately before CPB(T_1)and immediately after discontinuation of CPB(T_2)for determination of plasma total and active matrix metallo-proteinase-9(MMP-9)concentration(by enzyme-linked immuno-absorbent and fluorometric enzyme-linked immuno-absorbent assay respectively)and MMP-9 gene expression(RT-PCR).Blood samples were taken from radial artery at T_1 and T_2 for blood gas analysis.A-aDO_2 was calculated.Results MMP-9 gene expression and plasma total and active MMP-9 concentrations were significantly increased at T_2 as compared with those at T_0 in both groups and were significantly lower in dexamethasone group than in control group(P＜0.05 or 0.01).The A-aDO_2 at T_2 was significantly smaller in dexamethasone group than in control group.Conclusion Dexamethasone can inhibit the increase in gene expression,protein synthesis and activation of MMP-9 and decrease in gas exchange across alveolar-capillary membrane caused by CPB and protect the lungs during open heart surgery performed under CPB.

Objective To investigate prophylaxis and therapy of early complications following relatives' partial live small bowel transplantation.Methods Four relatives' partial live small bowel transplantations were carried out.Among the 4 patients,there were 3 cases of short intestine syn- drome and one case of non-function of small bowel caused by the absence of nerve ganglion of small in- testine.More than 4 antigens of HLA were completely matched between donators and receptors.In- testines of donators were got from terminal ileum with the length of (150?10) cm.After operations, tacrolimus (FK506),mycophenolate mofetil (MMF),and methylprednisolone were used to prevent rejections.Measures such as use of anticoagulation,improving microcirculation and albumin infusion, aimed at regulating the function of blood coagulation and preventing bleeding and formation of thrombus at anastomotic stoma;famotidine and omeprazole were used to prevent irritable ulcer;use of the third generation of cephalosporins antibiotics,ganciclovir and fluconazol could prevent bacteria,vi- rus and eumycete infections;disinfection and care of easily-infected organs were emphasized;receptors were encouraged to get out of their beds to move frequently;glutamine and enteral nutrition were used early to promote recovery of intestinal function.Results Three days after operation,one patient's lung was infected with baumanii,and the infection had been under control after being treated with the third generation cephalosporins antibiotics;five days after operation,haematoma was detected on an- other patient and was cleared through the second operations growth of eumycete was found in 2 pa- tients' excretion and secretion from enteron,and their situations were improved with fluconazol;acute rejections of the 4 patients were detected 20 days after operation and reversed by the increased use of FK506 combined with methylprednisolone.Among the 4 patients,2 of them have survived for a long time,and the first patient has survived for 6 years and 8 months till now and the other one for 3 years and 2 months;furthermore,other 2 patients respectively died of infections 5 months and 35 days after the operations.Conclusion Because of special constitution of intestine,early complications of rela- tives' partial live small intestine transplantation are frequent and complicated.Therefore,prophylaxis and therapy of early complications are crucial to the success of the transplantation.

AIM: To observe the effects of sapindoside on blood pressure,AngⅡ,Ald,ET in the blood plasma and NO in the serum in primary hypertension rat. METHODS: The primary hypertension rats were divided into 5 groups(high,middle and low sapindoside group,control group and captopril group,10 each) in a random fashion and drugs had been given by ig.for 32 days.The blood pressure was messured in the 1,3,7,32 day after administration.At the end of the 32 nd days,AngⅡ,Ald,ET in the blood plasma and NO in the serum were measured. RESULTS: Sapindoside could significantly lower the blood pressure,increase the levels of NO in serum,reduce the concentration of AngⅡ,Ald,ET in the blood plasma. CONCLUSION: Sapindoside plays an important role in decreasing the blood pressure of primary hypertension rat.