Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys
Evaluation of the toxicity of ISIS 2302, a phosphorothioate oligonucleotide, in a four-week study in cynomolgus monkeys
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DOI：
10.1016/s0300-483x(97)03661-5
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发表时间：
1997-06-27
期刊：
影响因子：
4.5
通讯作者：
Kornbrust, DJ
中科院分区：
文献类型：
--
作者：
Henry, SP;Bolte, H;Kornbrust, DJ
研究了具有反义抗人ICAM-1mRNA活性的硫代寡核苷酸ISIS 2302对食蟹猴(幼体)的毒性。给药剂量分别为0、2、10、50 mg/kg/次，隔日一次缓慢推注，共28天，共14次。基本群体规模由三只雄性和三只雌性猴子组成，在最后一次给药后2天处死。另有2只猴子；赋形剂对照组和50 mg/kg剂量组的性别继续进行研究，为期28天。在这项研究中没有发生与治疗相关的死亡，然而，IO mg/kg剂量组中有一只猴子在第一次服药后明显昏昏欲睡。其他临床观察包括研究第一天的眼周肿胀(大于或等于10毫克/公斤)，以及整个研究过程中所有剂量组的瘀伤。瘀伤与剂量依赖的凝血时间延长有关，特别是激活的部分凝血活酶时间(APTT)，本质上是一过性的。瘀伤发生在静脉给药或采血部位，镜检显示为皮下出血。包括红细胞和血小板计数在内的血液学参数没有相应的变化。其他与治疗相关的显微镜改变包括近端肾小管上皮细胞胞浆内嗜酸性颗粒和空泡化，10和50 mg/kg，肾近端小管腔内游离红细胞50 mg/kg。所有剂量组的血清生化指标包括尿素氮和肌酐水平均在正常范围内，尿检参数无明显变化。经过4周的治疗后，肾脏中的颗粒和空泡化被逆转。一般来说，10和50 mg/kg的ISIS 2302对凝血时间和肾脏产生可逆的剂量依赖性改变，而2 mg/kg的ISIS 2302没有显著的变化。(C)1997年爱思唯尔爱尔兰科学有限公司。
The toxicity of ISIS 2302, a phosphorothioate oligonucleotide with antisense activity against human ICAM-1 mRNA, was investigated in cynomolgus monkeys (young adult). The oligonucleotide was administered by slow bolus injection every other day for 28 days (14 doses) at dose levels of 0, 2, 10, and 50 mg/kg/injection. The basic group size consisted of three male and three female monkeys which were sacrificed 2 days after the last dose. An additional 2 monkeys;sex in the vehicle control and 50 mg/kg dose groups remained on study for a 28-day treatment-free period. No treatment-related deaths occurred during this study, however, one monkey in the IO mg/kg dose group was markedly lethargic after the first dose. Other clinical observations included periocular swelling (greater than or equal to 10 mg/kg) on the first day of the study, and bruising in all dose groups throughout the study. Bruising was associated with a dose-dependent prolongation of clotting times, particularly activated partial thromboplastin times (APTT), that was transient in nature. Bruises occurred around site of intravenous dosing or blood collection, and were manifested as subcutaneous hemorrhages upon microscopic evaluation. There were no corresponding alterations in hematology parameters including RBC or platelet counts. Other treatment-related microscopic alterations noted were intracytoplasmic eosinophilic granules and vacuolation in proximal tubular epithelial cells at 10 and 50 mg/kg, with free RBC in renal proximal tubular lumens at 50 mg/kg. Serum chemistry parameters including BUN and creatinine levels were normal in all dose groups and there were no notable alterations in urinalysis parameters. Granules and vacuolations in kidneys were reversed following a 4-week treatment foe period. In general, 10 and 50 mg/kg ISIS 2302 produced dose-dependent changes in clotting times and the kidney that were reversible, while 2 mg/kg ISIS 2302 produced no remarkable alterations. (C) 1997 Elsevier Science Ireland Ltd.