Study On The Pharmacokinetinetic And Pharmacodynamic Of Glargine

objective and background:Diabetes mellitus is a common form ofchronic disease that affects many peopler worldwide. Without a doubt,diabetes is an alarming threat to the public health and economy in the world[1,2] . Optimal glucose control is the primary goal for treating diabetesmellitus and preventing long-term complications of diabetes, such ascoronary heart disease, nephropathy, neuropathy and retinopathy.Exogenous insulin is required in type 1 diabetic patients and in type 2diabetic patients whose glucose levels are not controlled by diet, exerciseand oral antidiabetic drugs. Unfortunately at present human insulin analogssuch as Neutral Protamine Hagedorn (NPH) insulin has a quicker onset, ashorter duration of action, and lacks 24-hour duration of action, and gives ainsulin concentration peak that predisposes patients to nocturnalhypoglycemia and daytime hyperglycemia when administered at bedtime.activity[3～7]. So we need a human insulin analogs which has a slower onset,a longer duration of action, and no peak in metabolic activity. Insulinglargine is a novel, long-acting human insulin analog Insulin glargine is arecombinant human insulin with the substitution of asparagine with glycineat position A21 and the elongation of the carboxyl-terminus of the B-chainwith 2 arginines. structural changes shifted the isoelectric point of insulinglargine from pH 5.4 to 6.8. When injected into the subcutaneous tissuewith a neutral pH, insulin glargine forms microprecipitates. The glycinesubstitution also gives insulin glargine a dense crystal structure with aslower dissociation rate [8,9]. In order to make a scientific and rational assessment for the Glargine,in this study, we stusdy the toxicology, pharmacokinetic andpharmacodynamic toxicokinetic of Glargine then further investigate themechanism of a flat pharmacokinetic profile, with a duration of action of atleast 24 hours. Meathod:The pharmacodynamics, pharmacokinetics, acute toxiceffect,chronic toxic effect, General Pharmacological Studies , localstimulate test and immunologenic charaterization ,toxicokinetic arereviewed to prove Glargine is a good drug for treating diabetes mellitus andpreventing long-term complications of diabetes. Results: (1) The result of acute toxic test: the LD50 of Glargine forsubcutaneous injection on mice is 38.42mg/kg, the confidence limit(95%)is 33.90~43.54mg/kg. the LD50 of Glargine for injection of vien on mice is17.89mg/kg, the confidence limit(95%) is 16.35~19.57mg/kg. (2) The result of general pharmacological studies: There is obviousdifference in the effect of Glargine on the climb time, the irritation,theclimb pole time, the independence activities in mice. but there was nosignificant difference( p > 0.05 )of the ECG,HR and respiration rangebetween the Glargine group and the control group. But there wassignificant difference( p < 0.05 )of the respiratory rate between theGlargine group and the control group and between the different dosesgroups. (3)The result of local stimulate test and immunologeniccharaterization: Beagle dogs were immunized with Glargine thesubcutaneous tissue injections, then the serum antibody titer was measuredwith ELISA. Results: the serum antibody Glargine antibody was notdetected. The subcutaneous tissue injection of Glargine induced obviouserythema and edema on subcutaneous tissue of Beagle dogs. But when westop injection there was no obvious erythema and edema on subcutaneoustissue. (4)The result of long term toxicity: After the12 weeks of thesubcutaneous tissue injection determine blood regular and bloodbiochemistry of the tested animals, maked viscera index and examiningtheir pathological changes. Results: during the12 weeks of thesubcutaneous tissue injection of Glargine and recovering dogs do notexpress any toxicity. (5)The result of the pharmacodynamic: Glargine could obviouslydecrease the serum glucose, TG, TC, BUN and Alb concentrations ofstrptozotocin-induced diabetic rats(p < 0.05), the effects were related to thedoses of administration Glargine can improve the TP, Alb concentrati...