Study of Linearization of Hill Dose-Effect Curve with Metabolic Velocity Instead of Drug Concentration

Objective To explore the velocity-effect relationship in order to the establish linearization of effect on an equation with regard to the consistency of the Hill dose-effect expression with the metabolic kinetics of receptors.Methods The linear velocity-effect expression was obtained by solving multivariant differential equation groups,which were established to compare the coincidences and basic relations between the Hill dose-effect and metabolic kinetic Michaelis-Menten equation for receptors.The validation test was conducted with acetylcholine,adrenaline,and their mixture as model drugs.Results The linear velocity-effect modelling was represented in vivo or in vitro,for single and multidrug systems.Pharmacodynamic parameters,especially suitable for multicomponent CMM formulas,could be determined and calculated for single or multicomponent formulas at high saturating or low linear concentration for receptors.The validation test showed that the pharmacodynamic parameters of acetylcholine were:k,2.675×10^-3s^-1;ka,5.786×10^-9s^-1;km,2.500×10^-7s^-1;α,4.619×10^9张s·mg^-1;E0,13张(P<0.01)and those of adrenaline were:k,1.415×10^-3s^-1;ka,5.846×10^-9s^-1;km,2.300×10^-7s^-1;α,-1.627×10^9张s·m g^-1;E0,9.2张(P<0.01).For the mixture of the two components,the values were:α,1.375×1010张s·m g^-1;-6.150×10^9张s m g^-1for acetylcholine and adrenaline,respectively,and E0was7.08张in both,with the other parameters unchanged(P<0.01).Conclusion The velocity-effect equation can linearize the Hill dose-effect relationship,which can be applied to study the pharmacodynamics and availability of CMM formulations in vivo and in vitro.

Effects of triterpenic acid from Prunella vulgaris L. on glycemia and pancreas in rat model of streptozotozin diabetes

Background The effects of triterpenic acid from Prunella vulgaris L. （TAP） on diabetes and its mechanism are uncertain. The aim of this study was to investigate the effects of TAP on antihyperglycemic, antioxidant, and pancreas-protective in streptozotozin （STZ）-diabetic rats. Methods The diabetic model was produced by injection of 60 mg/kg STZ. Blood was drawn from the tail vein of rats after 72 hours. Rats with blood glucose 〉16.7 mmol/L were considered diabetic. Diabetic rats were randomly divided into four groups： （1） Diabetes rat （STZ）, （2） Diabetic rats treated with 50 mg/kg of triterpenic acid from Prunella vulgaris L （STZ＋TAP50）, （3） Diabetic rats treated with 100 mg/kg TAP （STZ＋TAP100）, and （4） Diabetic rats treated with 200 mg/kg TAP （STZ＋TAP200）. Normal rats （n=10） acted as the control group （NC）. TAP was administered by the intragastric route once each day for six weeks. Body weight and the concentration of blood glucose （BG） were measured after three and six weeks. Fructosamine （FMN）, malondialdehyde （MDA）, and nitric oxide （NO）, and the activities of nitric oxide synthase （NOS） and superoxide dismutase （SOD） in serum were determined after six weeks using commercially available kits following the manufacturer＇s instructions. Pathologic changes in pancreatic β-cells were also investigated by microscopic examination after hematoxylin-eosin （HE） staining. The level of SOD mRNA in pancreatic β-cells was measured by polymerase chain reaction （PCR）. Results The levels of BG, FMN, NO, and MDA and the activities of NOS in serum in the four diabetes groups were significantly increased compared with the control group （P 〈0.01）. The activity of SOD in serum and the body weight was significantly decreased compared with the control group （P 〈0.01）. After administration of TAP to diabetic rats for six weeks, the body weight and the levels of BG, FMN, MDA, NO and the activity of NOS in serum decreased significantly compared with the STZ group in a dose-dependent manner. The activity of SOD in serum and body weight increased significantly compared with the STZ group in a dose-dependent manner. In addition, diabetic rats showed a significant decrease in SOD mRNA expression in pancreatic β cells. However, these changes were reversed by TAP. Histopathological examination also showed the protective effect of TAP on pancreatic β cells. Conclusions Triterpenic acid from Prunella vulgaris L. has an anti-diabetic effect, by controlling blood glucose and antioxidants, and has a protective effect on the pancreas.