Studies On Clinical Pharmacokinetics, Tolerance And Safety Of D-polymannuronicate

Objective: 1,To evaluate pharmacokinetics test of single intravenous dripping D-polymannuronicate injection in Chinese adult volunteers, in order to provide reliable drug metabolism parameter in vivo for D-polymannuronicate injection clinical dosage design test. 2,To evaluate pharmacokinetics test of multiple intravenous dripping D-polymannuronicate injection in Chinese adult volunteers, in order to provide reliable drug metabolism parameter in vivo for D-polymannuronicate injection clinical dosage design test on stageⅡof clinical research. 3,To adopt a random,double-blind,placebo comparison test about continuously multiple intravenous dripping D-polymannuronicate injection in Chinese adult volunteers, for the purpose of evaluating its safety,toleration and offering reliable experiment evidence for stageⅡof clinical research. Methods: 1,To divide 27 health adults for 3 dosage group randomly and equally, then accept different dosage D-polymannuronicate injection by single intravenous drip, determine partial thromboplastin time and blood drug level in different time after overdose, eventually calculate pharmacokinetics parameter. 2,To divide 10 Chinese healthy adults for 2 batch randomly and equally, then adopt 100mg dosage of D-polymannuronicate injection by multiple intravenous dripping continuously , determine partial thromboplastin time and blood drug level in different time after overdose, eventually calculate pharmacokinetics parameter. 3,To apply a random,double-blind,placebo comparison test, 24 Chinese healthy adults distribute 2 groups randomly and adopt different dosage D-polymannuronicate injection by multiple intravenous dripping continuously, then observe clinical symptom,physical sign and laboratory index. Results: 1,D-polymannuronicate can extend APTT time obviously in vitro and show a good linear correlation (r>0.99) during 0.05～10 mg/L concentration; recovery rate was between 91.48%～105.67%, the precision of intraday and daytime was less than 14%, drug-time plot was accord with the second compartment model, elimination rate constantβ,elimination half life T1/2βand clearance rate CL were not statistically significant between different groups, AUC0-39 increased following the drug dosage added, but C0/dose was no significant deviation and T1/2β,β,CL had nothing to do with dosage. 2,D-polymannuronicate could extend APTT time obviously in vitro and show a good linear correlation (r>0.99) during 0.05～10 mg/L concentration(r=0.9957)when D-polymannuronicate was continuously administrated by multiple intravenous drip. The main pharmacokinetic parameters of C0,t1/2β,Vc,CL and AUC0-∞after the first administration of D-polymannuronicate did not significantly differentiate from those after the last administration. The discrepancy of D-polymannuronicate's peak and valley concentration among different days had no statistical significance. Cumulative odds (R) was 0.90±0.73, and fluctuation index (FI) was 1.82±0.11. 3,The vital sign of 24 subjects had nothing abnormal detected after administration, the laboratory examination had no abnormal change of clinical significance in the first day before administration,the third day and fifth day after administration,the first day after discontinuation, the B- ultrasound examination of liver was no abnormality seen before administration and after discontinuation. The whole experimental stage had no severe and unhealthy events. Conclusions:1,D-polymannuronicate shows first class linearity dynamics and has no saturability in the physiological disposition during 100mg～300mg dosage range. The subjects have no other infaust event except APTT extending a normal therapeutic effect during administration. 2,After administration of multiple intravenous dripping of D-polymannuronicate in Chinese adult volunteers, drug-time plot was accord with the second compartment model and no accumulation occur in vivo. We recommend 100mg dosage and continuous 7 days administration by intravenous drip of D-polymannuronicate, one time per day, for stageⅡof clinical research. 3,The toleration of D-polymannuronicate injection is better below 100mg dosage and continuous 7 days administration by intravenous drip, so we suggest recommend clinical routine daily dose below 100mg, one time per day and the time of intravenous drip exceed three hours, the course of treatment can reach seven days.