Experimental Study On The Therapy Of Cerebral Vasospasm With Ibuprofen Polylactide Microspheres

Objective: Preparation of biodegradable materials poly(d,l-lactide) and synthesis the ibuprofen polylactide microspheres. Investigate the physical chemistry characters and release in vitro with microspheres. Method: The three batch poly(d,l-lactide) with varied molecular weight of 9400, 15000 and 21000 were made by two-step method. PDLLA microspheres containing dexoibuprofen were made by oil/water solvent evaporation method. Investigate the best preparative techniques and the physical chemistry characters; study the release speed in artificial cerebrospinal fluid. Result: The concentration of PLA and gelatin, ratio of ibuprofen/PLA could affect particulate size, drug encapsulation and drug content of microspheres. Studies on the release in vitro showed that nearly no initial burst release could be seen, drug could release slowly in two weeks. The greater molecular weight of PDLLA, the more slowly the drug release. Conclusion: Ibuprofen polylactide microspheres can release slowly in artificial cerebrospinal fluid, the size of microspheres is related to release speed as well as the molecular weight ofPLA to some extent.Part two: Experimental study in vivo with ibuprofen polylactidemicrospheres.Objective: Study the toxic effect and release efficiency with ibuprofen polylactide microspheres implantation in subarachnoid. Method: Preparation the vary concentration of ibuprofen polylactide microspheres (3%, 5%, 10%, 20%), inject into skull base cistern in New Zealand rabbits, then observed the symptom and mortality rate. Examined the pathology changes in cerebral vascular and nerve. Study the release efficiency in vivo according to the safe dosage with ibuprofen polylactide microspheres and simplicial dexoibuprofen. Result: There is no death happened in rabbits with microspheres under the concentration of 5%, and haven't found obvious pathology changes and inflammation response in cerebral, nerve and vascular. The microspheres can release persistently until two weeks in subarachnoid. Compared with simplicial dexoibuprofen, the releasing time of microspheres was prolonged and the Cma, was less obviously. Conclusion: The ibuprofen polylactide microspheres could be used as a local slow release drug in cranial under a certain concentration.Part three: Experimental study on the therapy of cerebral vasospasm with ibuprofen polylactide microspheresObjective: Study the effect on therapy cerebral vasospasm withibuprofen polylactide microspheres, and discuss the possible mechanism with ibuprofen treat CVS. Method: The primary SAH model of rabbit is made by which the blood was injected into subarachnoid. Treatment group was injected 1ml ibuprofen polylactide microspheres with concentration of 3% into subarachnoid. Observed the effect of therapy on CVS after SAH. The expression of TNF- a , IL-1 0 , IL-6 in cerebral and vascular was stained by immunohistochemistry. The concentration of TNF- a , IL-1 ?, IL-6 in cerebrospinal fluid were analyzed with ELISA. Result: The microspheres can release persistently until two weeks in subarachnoid, and have definitely effect with treat CVS. There was obviously pathology changes happened to the wall of BA in group of SAH, and the expression of TNF- a , IL-1 jB, IL-6 was Up-regulation in cerebral , vascular endothelial and cerebrospinal fluid. The group of treatment was on the contrary. Conclusion: The ibuprofen polylactide microspheres could treat CVS effectively and the technique with polymer should guide the therapy of cerebral vascular disease to some extent. The possible mechanisms with treat CVS by ibuprofen maybe related to inhibiting the inflammatory cytokine.