Tamargo R J, Sills A K, Reinhard C S, Pinn M L, Long D M, Brem H
Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland.
J Neurosurg. 1991 Jun;74(6):956-61. doi: 10.3171/jns.1991.74.6.0956.
Controlled-release polymers have facilitated the interstitial delivery of drugs within the central nervous system. In the present study, dexamethasone was incorporated into ethylene-vinyl acetate polymers, which were then implanted adjacent to a 9L gliosarcoma in the brain of Fischer 344 rats. The effect of interstitial delivery of dexamethasone on peritumoral edema was assessed and compared to the effect of dexamethasone delivered systemically. Eighty-five rats underwent intracranial implantation of the 9L gliosarcoma. Five days later, the animals were randomly assigned to one of four treatment groups: Group 1 received intracranial implantation of controlled-release polymers containing dexamethasone; Group 2 received intraperitoneal implantation of controlled-release polymers containing dexamethasone; Group 3 received serial intraperitoneal injections of dexamethasone; and Group 4 received sham treatment. The animals were sacrificed 3 days after initiation of therapy and their brains were removed for measurement of the water content (edema) in the tumor-bearing and contralateral hemispheres. Brain and plasma samples were analyzed by reverse-phase high-performance liquid chromatography to determine the tissue and plasma concentrations of dexamethasone. Measurement of the release kinetics of dexamethasone from the ethylene-vinyl acetate polymers in an in vitro system showed that the drug was released in a controlled, tapering fashion. During the first 3 days of controlled release in vitro, 330 micrograms of a total content of 7.5 mg of dexamethasone was released into the medium. Analysis of tissue for drug levels demonstrated, however, that the interstitial delivery of this fractional amount of dexamethasone within the brain resulted in levels 19 times higher than those achieved by administering the full dose of 7.5 mg systemically over a 3-day period. Conversely, the systemic administration of dexamethasone resulted in plasma levels 16 times higher than those measured in the interstitial delivery of dexamethasone in the brain. Brain-water content determinations showed that the interstitial controlled release of the fractional amount of dexamethasone within the brain was as effective in controlling peritumoral edema as systemic administration of the full dose by serial intraperitoneal injections. The study demonstrates the following: 1) controlled-release polymeric carriers deliver biologically active dexamethasone in a sustained fashion; 2) very high concentrations of dexamethasone in brain tissue can be achieved using interstitial polymer-mediated drug delivery while minimizing plasma concentrations of this drug which are sometimes associated with serious systemic side effects; and 3) peritumoral brain edema can be effectively treated by the interstitial delivery of dexamethasone directly within the tumor bed.
控释聚合物促进了药物在中枢神经系统内的间质递送。在本研究中，将地塞米松掺入乙烯-醋酸乙烯酯聚合物中，然后将其植入Fischer 344大鼠脑内9L胶质肉瘤附近。评估了地塞米松间质递送对瘤周水肿的影响，并与全身递送地塞米松的效果进行了比较。85只大鼠接受了9L胶质肉瘤的颅内植入。5天后，将动物随机分为四个治疗组之一：第1组接受含地塞米松的控释聚合物颅内植入；第2组接受含地塞米松的控释聚合物腹腔内植入；第3组接受地塞米松的系列腹腔内注射；第4组接受假治疗。在治疗开始后3天处死动物，并取出其大脑以测量荷瘤半球和对侧半球的含水量（水肿）。通过反相高效液相色谱法分析脑和血浆样本，以确定地塞米松的组织和血浆浓度。在体外系统中测量地塞米松从乙烯-醋酸乙烯酯聚合物中的释放动力学表明，药物以可控的、逐渐减少的方式释放。在体外控释的前3天，7.5mg地塞米松总量中的330μg释放到培养基中。然而，对组织药物水平的分析表明，在脑内间质递送这部分地塞米松所产生的水平比在3天内全身给予7.5mg全剂量所达到的水平高19倍。相反，地塞米松的全身给药导致血浆水平比脑内地塞米松间质递送所测得的水平高16倍。脑含水量测定表明，脑内地塞米松部分量的间质控释在控制瘤周水肿方面与通过系列腹腔内注射全身给予全剂量一样有效。该研究表明：1）控释聚合物载体以持续的方式递送具有生物活性的地塞米松；2）使用间质聚合物介导的药物递送可在脑组织中实现非常高浓度的地塞米松，同时将有时与严重全身副作用相关的该药物的血浆浓度降至最低；3）通过在肿瘤床内直接间质递送地塞米松可有效治疗瘤周脑水肿。
