Doherty N, Hancock S L, Kaye S, Coleman C N, Shulman L, Marquez C, Mariscal C, Rampling R, Senan S, Roemeling R V
Joint Center for Radiation Therapy, Harvard Medical School, Boston, MA 02115.
Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):379-82. doi: 10.1016/0360-3016(94)90293-3.
Tirapazamine (SR 4233) is a benzotriazine di-N-oxide which acts as a hypoxic cytotoxic agent and as a radiation enhancer when given shortly before or after radiation. Three Phase I clinical trials were designed to determine the maximum tolerated dose, toxicities, pharmacokinetics, and effects on irradiated tumors and normal tissues.
Tirapazamine 9 mg/m2 to 21 mg/m2 was given i.v. 1/2 to 1 h prior to irradiation on a multiple dose schedule of 10 consecutive doses. This was later revised to a three times-per-week schedule for 12 doses. In a second clinical trial, tirapazamine was given in a single dose of 18 mg/m2 to 293 mg/m2 i.v. after irradiation. In a third trial, tirapazamine was administered without irradiation in single doses of 36 mg/m2 to 250 mg/m2, with an option for retreatment.
Subjects reported muscle cramping of varying degrees of severity on all three dose schedules. One patient experienced Grade 3 cramping and treatment was discontinued. The most frequent site of cramping were the lower extremities. Creatine phosphokinase (CPK) values were elevated in three patients with associated muscle soreness in one patient. MB (cardiac) isoenzymes were elevated in one patient with no evidence of cardiac muscle damage, and returned to baseline at drug completion. No consistent abnormalities in clinical laboratory values were found. Stretching of the muscle was most effective in relieving the cramping.
Muscle cramping has been the most frequently reported toxicity in Phase I studies of tirapazamine, though it does not appear to be dose limiting. Dose escalation on the three clinical trials continues. In vitro studies to investigate the cramping are ongoing.
替拉扎明（SR 4233）是一种苯并三嗪二-N-氧化物，在放疗前或放疗后不久给药时，可作为一种乏氧细胞毒性剂和放疗增强剂。三项I期临床试验旨在确定最大耐受剂量、毒性、药代动力学以及对受照射肿瘤和正常组织的影响。
在放疗前1/2至1小时静脉注射替拉扎明，剂量为9mg/m²至21mg/m²，采用连续10剂的多剂量方案。后来改为每周三次，共12剂的方案。在第二项临床试验中，放疗后静脉注射替拉扎明，单剂量为18mg/m²至293mg/m²。在第三项试验中，不进行放疗，单剂量给予替拉扎明36mg/m²至250mg/m²，可选择再次给药。
在所有三种剂量方案中，受试者均报告有不同程度的肌肉痉挛。一名患者出现3级痉挛，治疗中断。痉挛最常见的部位是下肢。三名患者的肌酸磷酸激酶（CPK）值升高，其中一名患者伴有肌肉酸痛。一名患者的MB（心脏）同工酶升高，但无心肌损伤证据，在停药后恢复至基线水平。临床实验室值未发现一致的异常。肌肉伸展对缓解痉挛最有效。
在替拉扎明的I期研究中，肌肉痉挛是最常报告的毒性反应，尽管它似乎不是剂量限制性的。三项临床试验的剂量递增仍在继续。正在进行体外研究以调查痉挛情况。
