Pazdur R, Redman B G, Corbett T, Phillips M, Baker L H
Cancer Res. 1987 Aug 1;47(15):4213-7.
Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly X 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly X 3. Concurrent murine studies confirmed spiromustine as a schedule independent drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.
采用每3周一次的给药方案和每周一次共3周的给药方案对螺旋莫司汀进行了I期评估。神经毒性是剂量限制性毒性，表现为皮质整合功能（定向、语言、协调）改变，导致意识水平下降。传统的神经毒性分级标准难以描述这些毒性。最大耐受剂量为每3周6mg/m²和每周一次共3周，每次3mg/m²。同期的小鼠研究证实螺旋莫司汀是一种给药方案不相关的药物，其毒性与血浆峰值水平相关。毒扁豆碱对减轻小鼠模型中的神经毒性作用不大。所用的溶剂不是神经毒性的原因。采用分剂量给药方案注射螺旋莫司汀可降低小鼠的急性神经毒性，并允许给予更大的总剂量（与单次推注剂量相比）。基于这些结果，建议在未来的临床试验中采用分剂量给药方案。
