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To explore novel antifatigue agents targeting with AMPA receptor, 10 compounds were synthesized and their structures were confirmed by 1H NMR, ESI-MS and elemental analysis. 1-BCP was treated as the leading compound. The antifatigue activities were evaluated by weight-loaded forced swimming test, and the AMPA receptor binding affinities were tested with radioligand receptor binding assays. The results unveiled that 5b appeared to possess potent antifatigue activities and high affinity with AMPA receptor, which deserved further studies.

Aim: To study the biliary excretion of genistein and its metabolite at different doses in rats., Methods: Suspended in 0.5% CMC-Na solution, genistein was orally administered to rats at the dose of 6.25, 12.5 and 50 mg x kg(-1), separately. At various time intervals, the bile was collected. The bile was treated with beta-glucuronidase. The genistein in bile was extracted twice by vortexing with 2.0 mL mixture of methyl tert-tubtyl ether and pentane (8:2). The organic phase was removed into the tubes and then evaporated in ventilation cabinet. The residue was dissolved in 50 microL of methanol. Twenty microL solution was drawn and detected by high-performance liquid chromatography., Results: The accumulative biliary excretion of genistein was (42.56 +/- 6.54) , (75.17 +/- 18.87) and (126.60 +/- 34.78) microg at the dose of 6.25, 12.5 and 50 mg x kg(-1), respectively. The total drug (genistein plus glucuronidated genistein) excreted from bile was (108.46 +/- 35.23), (423.46 +/- 158.31) and ( 853.74 +/- 320. 84) microg, and the ratio of glucuronidated genistein was 60.76% , 82.25% and 85.17% at the dose of 6.25, 12.5 and 50 mg x kg(-1), respectively., Conclusion: The genistein was excreted mainly in the form of glucuronidated genistein in rat bile. The genistein and glucuronidated genistein were excreted in a nonlinear dose-dependent manner.

Aim: To investigate the effects of Angelica sinensis polysaccharide fraction AP-3 on IL-2 and IFN-gamma induction and its further immunomodulatory feature., Methods: The percentage of CD4+ lymphocyte was detected by flow cytometric method, the production of IL-2 and IFN-gamma in cell culture supernatant were determined by ELISA, mRNA expressions of IL-2 and IFN-gamma cytokines were detected by RT-PCR., Results: At the range of 0. 6 - 2 micromol x L(-1), AP-3 significantly enhanced the percentage of CD4+ lymphocytes in total splenocytes. At the range of 2 - 6 micromol x L(-1), the treatment of AP-3 augmented both productions of IL-2 in cell culture supernatant and cell IL-2 mRNA transcription level in a time and dose dependent manner. While in the case of IFN-gamma, AP-3 stimulated at early time after exposure but down-regulated thereafter., Conclusion: Angelica sinensis polysaccharide could regulate the immune response through upregulating IL-2, IFN-gamma expression and activating Th1 cell.

Aim: To study the metabolic kinetics of MN9202 in Beagle dog liver microsome., Methods: Beagle dog liver microsomes were prepared by using ultracentrifuge method. After incubating 0.4 micromol x L(-1) MN9202 with 1 g x L(-1) microsomes for 30 min at 37 degrees C, the reaction was terminated by adding 0.5 mL alkalization. The RP-HPLC was used to determine the drug in the incubation mixture. The Michaelis-Menten parameters Km, and Vmax in Beagle dog liver microsomes were initially estimated by analyzing Lineweave-Brurk plot. Various selective CYP inhibitors were used to investigate their inhibitory effect on the metabolism of MN9202., Results: The Km, Vmax and CLint of MN9202 were (22.6 +/- 8.0) micromol x L(-1), (0.54 +/- 0.17) micromol x g(-1) x min(-1) and (0.0242 +/- 0.0009) L x g(-1) x min(-1), respectively. The metabolism of MN9202 was significantly inhibited by ketoconazole (Ket) and troleandomycin (Tro) in Beagle dog liver microsomes. Tranylcypromine (Tra) could inhibit the metabolism of drug as well. While other inhibitors showed little inhibitory effect on the metabolism of MN9202., Conclusion: It was shown that CYP3A and CYP2C19 were involved in MN9202 metabolism. The inhibitors of human CYP3A and CYP2C19 may have potential interaction with MN9202, and this can reduce the metabolism rate and increase the toxicity of MN9202.

Aim: To study the pharmacokinetics of genistein at different doses in Beagle dogs., Methods: Suspended in 0.5% CMC-Na solution, genistein was orally administered to Beagle dogs at doses of 2.67, 5.34 and 10.68 mg.kg(-1). At various time intervals, 1.5 mL of blood was drawn from the femoral vein of dogs in their front legs. The plasma was treated with beta-glucuronidase. The genistein in plasma was extracted twice by vortexing with 2.0 mL mixture of methyl tert-tubtyl ether and pentane (v/v = 8:2). The organic phase was removed into the tubes and then evaporated in ventilation cabinet. The residue was dissolved in 50 microL of methanol. 20 microL solution was drawn and detected by high-performance liquid chromatography. The pharmacokinetic parameters were calculated by 3P97 software., Results: The plasma drug concentration-time data were fitted to the two-compartment model. When the dose was 2.67 mg.kg(-1), the MRT and AUC of parent compound were 52.9 min and 6.7 mg.min. L(-1), respectively. When the dose rose to 5.34 mg.kg(-1), the MRT and AUC of parent compound became 224.8 min and 26.1 mg.min.L(-1), respectively. However, when the dose increased to 10.68 mg .kg(-1), the MRT and AUC of parent compound increased to 267.7 min and 33.2 mg.min L(-1), respectively. The AUC of glucuronidated genistein was 33.9, 70.1 and 140.5 mg.min.L(-1) at the dose of 2.67, 5.34 and 10.68 mg.kg(-1), respectively., Conclusion: Due to significant first pass metabolism, the drug was mainly existed in the form of glucuronidated genistein in the plasma. With the increase of dose, the absorption of genistein became saturated and the half life prolonged.

Aim: To study the pharmacokinetics of m-nifedipine (m-Nif) in Beagle dogs., Methods: The Beagle dogs were divided into two groups. m-Nif was intravenously administered to the Beagle dogs in group 1 at the dose of 0. 288 mg x kg(-1), and it was orally administered to the Beagle dogs in group 2, 3 and 4 at the dose of 1.152, 3.456 and 10.370 mg x kg(-1), respectively. m-Nif in plasma was detected by reversed phase high performance liquid chromatography. The pharmacokinetic parameters were calculated by 3P97 software., Results: When m-Nif was intravenously administered, the plasma concentration-time curve was fit to a two-compartment model and T1/2beta was 117 min. When m-Nif was orally administered, the plasma concentration-time curve was fit to a one-compartment model. T1/2 (Ke) and Cmax were 147 min and 20 microg x L(-1); at the low dose of 1.152 mg x kg(-1). T1/2 (Ke) was 122 min and Cmax was 36 microg x L(-1) at the middle dose of 3.456 mg x kg(-1). T1/2 (Ke) was 144 min and Cmax was 69 microg x L(-1) at the high dose of 10.37 mg x kg(-1), respectively., Conclusion: It was showed that the speed of elimination of m-Nif was high in Beagle dogs. The absolute bioavailability of m-Nif given orally was very low.

Aim: To study the pharmacokinetics of genistein in Beagle dogs., Methods: Genistein, suspended in 0.5% CMC-Na solution, was orally administered to Beagle dogs at the dose of 5.34 mg.kg-1. At various time intervals, 1.5 mL of blood was drawn from the vein of dogs in their front legs. At the same time, urine and feces were collected. After the collection, the feces were homogenized with physiological saline (to 1 g feces, 10 mL physiological saline were added). The genistein in plasma, urine and homogenized feces was extracted twice by vortexing with 2.0 mL mixture of methyl tert-butyl ether and pentane (8:2). The organic phase was transferred into tubes and evaporated in ventilation cabinet. The residue was dissolved in 50 microL of methanol and 20 microL of the solution was drawn and detected by high-performance liquid chromatography. The pharmacokinetic parameter was calculated by 3P97 software., Results: The plasma concentration-time curve was fitted to a one-open-compartment model. The peak time was 0.29 h, and the elimination half-life was 0.52 h. After genistein was administered, 10.79% of genistein were excreted from urine and 21.55% from feces within 24 h. It was also found that 13.00% genistein were excreted from urine and 52.46% from feces within 60 h., Conclusion: It showed that the speed of absorption and elimination of genistein was high in Beagle dog, and genistein was mainly excreted in the form of parent compound in urine and feces.

Aim: To evaluate the effects of molecular weight of dextran on drug-release of conjugate in vitro by screening colon-specific conjugates., Methods: The conjugates, synthesized with different molecular-weight dextran and dexamethasone, were incubated in the contents of different parts of rat gastrointestinal tract at 37 degrees C. The release of dexamethasone(Dex) and dexamethasonehemisuccinate was determined by HPLC. The mobile phase consisted of 35% acetonitrile and 65% trisodium citrate (50 mmol.L-1, adjusted to pH 4.1 with phosphoric acid)., Results: There was no release of dexamethasone or dexamethasonehemisuccinate from conjugates in the stomach contents. The amount of Dex (including dexamethasonehemisuccinate) released from DexD26 in the contents of colon and cecum was shown to be 4.0 times higher than that released in the contents of proximal and distal small intestine while the amount of Dex (including dexamethasonehemisuccinate) released from DexD50 was shown to be 3.6 times higher. The amount of Dex (including dexamethasonehemisuccinate) released from DexD2 in the contents of colon and cecum and from DexD7.6 were 2.0 times and 1.9 times higher, respectively, than that released in contents of proximal and distal small intestine., Conclusion: The molecular weight of dextran showed marked effect on drug-release of the conjugate in vitro, and the conjugates with larger molecular-weight dextran have great potential in colon-specific delivery of dexamethasone.