| Hemoglobin Based Oxygen Carriers(HBOCs),a kind of oxygen carrier based on human or other mammalian hemoglobin,can maintain oxygen supply to ischemic and hypoxic tissues,and at the same time HBOCs have a low risk of pathogen infection.In addition,HBOCs do not need cross-matching,and do not cause immune reactions,which gives it great potential for development.The polymerized porcine hemoglobin(pPolyHb)synthesized by chemical modification with glutaraldehyde as the crosslinker used in this experiment possesses the advantages of polymerized hemoglobin,Furthermore,pPolyHb has been shown by many studies to have a significant effect in maintaining tissue oxygen supply and recovery from hemorrhagic shock.For further assessment of its safety and effectiveness,pharmacodynamic and pharmacokinetic characteristics of pPolyHb was studied in this thesis.For pharmacodynamic studies,based on the purpose of assessing its clinical effectiveness,requires the selection of appropriate clinical indications for a series of pharmacodynamic clinical trials.The pharmacodynamics section aims to initially explore the effectiveness of pPolyHb in traumatic and other massive blood loss situations by establishing relevant animal experimental models.We chose a blood exchange and hemorrhagic shock model of rats to simulate a series of clinical environments such as trauma and shock.In the blood exchange model of rat,we recorded MAP,Hct,and other physiological indicators at four time points.Blood was collected for arterial blood gas analysis and survival of the rats within one week after blood exchange were examined.The results showed that,compared to the control group(HES),the hemodynamic stability of pPolyHb was maintained,and pPolyHb can correct anaerobic metabolism and acid-base imbalance.In addition it also can restore tissue perfusion and oxygenation to a certain extent and significantly improved the survival rate of rats in the blood exchange model;Iin the hemorrhagic shock model of rat,the physiological indicators such as MAP and Hct were recorded,and blood was collected for arterial blood gas analysis.The quality of life and survival of rats within one week after hemorrhagic shock were examined.The results showed that compared to HES,pPolyHb can maintain stable hemodynamics,correct acidemia after blood loss,and restore perfusion and oxygenation of ischemic tissue.Compared with the control group,the survival rate in experience group improved significantly.Since pPolyHb is a kind of protein drug,a ssessment of its absorption,distribution,and metabolism is a major determinant of its safety and efficacy.In the pharmacokinetic study of this thesis,we evaluated the pPolyHb absorption,distribution and metabolism in rats by measuring and calculating pharmacokinetic parameters of pPolyHb.It is well known that clinical conditions can influence the pharmacokinetics of numerous drugs.Consequently,it is possible that the pharmacokinetics of Hemoglobin-based oxygen carriers(HBOCs)could be also altered in situations such as massive hemorrhage caused by injury,accidental blood loss,or a major surgery.Therefore,in addition to a top-load model,50% blood exchange model and 60% hemorrhagic shock model of rat were also established.The results showed that the kinetic process of pPolyHb in rats conforms to the laws of linear pharmacokinetics in vivo.The half-life of pPolyHb was superior and more stable under non-pathological conditions,but in clinical situations such as trauma and anemia,the half-life of pPolyHb may decline.The study of clearance(CL)and the apparent volume of distribution(Vd)of pPolyHb in these three different animal models demonstrated longer residence and a predominant,targeted role of pPolyHb with little accumulation in tissues.Through this study,the superior pharmacokinetic characteristics of pPolyHb have been proved and will aid in the determination of a reasonable dosing regimen and administration interval in clinical situations. |
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