Kochi M, Kuratsu J, Mihara Y, Takaki S, Inoue N, Sueyoshi N, Uemura S, Ushio Y
Department of Neurosurgery, Kumamoto University Medical School, Japan.
Cancer Res. 1990 May 15;50(10):3119-23.
To test the feasibility of intrathecal perfusion of ACNU (3-[(4-amino-2-methyl-5-pyrimidinyl)methyl]-1-(2-chloroethyl)-1-nitro sou rea hydrochloride) in the treatment of subarachnoid dissemination of malignant glioma, the neurotoxicity and pharmacokinetics of ACNU were studied in dogs. ACNU [1-2 mg dissolved in 10-20 ml of lactated Ringer's solution or artificial cerebrospinal fluid (CSF)] was administered via the right lateral ventricle by constant drip infusion and CSF was drained by lumbar puncture. The infusion time was from 15 to 71 min. For the control, a bolus injection was given. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord revealed only mild denudation of ependyma in the wall of the ventricles in a dog treated three times with 2 mg ACNU (perfusion twice, bolus injection once) and in 2 dogs perfused with 1 mg ACNU once a week for 10 weeks. ACNU was not detected in lumbar CSF after bolus injection into the lateral ventricle. When 1 mg of ACNU, dissolved in 10 ml of artificial CSF, was perfused for a duration of 22 to 31 min, it started to appear in the lumbar CSF 10 to 15 min after the start of perfusion, reaching a maximum concentration of 13.88 to 22.31 micrograms/ml. The area under the drug concentration-time curve was 344 to 706 micrograms x min/ml; the half-time was 15.5 to 19.5 min. The distribution volume was 30.6 to 54.1 ml. These findings suggest the feasibility of intrathecal perfusion of ACNU in the treatment of patients with subarachnoid dissemination of glioma.
为了测试鞘内灌注嘧啶亚硝脲（3-[(4-氨基-2-甲基-5-嘧啶基)甲基]-1-(2-氯乙基)-1-亚硝基脲盐酸盐）治疗恶性胶质瘤蛛网膜下腔播散的可行性，在犬类中研究了嘧啶亚硝脲的神经毒性和药代动力学。将嘧啶亚硝脲[1 - 2毫克溶解于10 - 20毫升乳酸林格氏液或人工脑脊液（CSF）中]通过右侧脑室持续滴注给药，并通过腰椎穿刺引流脑脊液。输注时间为15至71分钟。作为对照，进行了一次大剂量注射。灌注后未观察到神经和全身症状。对脑和脊髓进行组织学检查发现，在一只接受2毫克嘧啶亚硝脲治疗三次（两次灌注，一次大剂量注射）的犬以及两只每周一次接受1毫克嘧啶亚硝脲灌注共10周的犬中，仅脑室壁室管膜有轻度剥脱。向侧脑室内进行大剂量注射后，在腰段脑脊液中未检测到嘧啶亚硝脲。当将1毫克嘧啶亚硝脲溶解于10毫升人工脑脊液中灌注22至31分钟时，灌注开始后10至15分钟开始在腰段脑脊液中出现，最高浓度达到13.88至22.31微克/毫升。药物浓度 - 时间曲线下面积为344至706微克·分钟/毫升；半衰期为15.5至19.5分钟。分布容积为30.6至54.1毫升。这些结果表明鞘内灌注嘧啶亚硝脲治疗胶质瘤蛛网膜下腔播散患者具有可行性。
