Henry S P, Bolte H, Auletta C, Kornbrust D J
Department of Toxicology, Isis Pharmaceuticals Inc., Carlsbad, CA 92008, USA.
Toxicology. 1997 Jun 27;120(2):145-55. doi: 10.1016/s0300-483x(97)03661-5.
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 10 mg/kg dose group was markedly lethargic after the first dose. Other clinical observations included periocular swelling (> or = 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 free 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.
研究了ISIS 2302（一种对人细胞间黏附分子-1（ICAM-1）mRNA具有反义活性的硫代磷酸酯寡核苷酸）对成年食蟹猴的毒性。该寡核苷酸每隔一天通过缓慢推注给药，持续28天（14剂），剂量水平分别为0、2、10和50毫克/千克/注射。基础组每组由三只雄性和三只雌性猴子组成，在最后一剂后2天处死。在溶媒对照组和50毫克/千克剂量组中，每组额外有2只猴子（雌雄各1只）继续观察28天的无治疗期。在本研究期间未发生与治疗相关的死亡，但10毫克/千克剂量组中有一只猴子在首次给药后明显嗜睡。其他临床观察结果包括：研究第一天出现眼周肿胀（≥10毫克/千克），以及在整个研究过程中所有剂量组均出现瘀伤。瘀伤与凝血时间（尤其是活化部分凝血活酶时间（APTT））的剂量依赖性延长有关，这种延长是暂时的。瘀伤发生在静脉给药或采血部位周围，经显微镜检查表现为皮下出血。血液学参数（包括红细胞或血小板计数）无相应改变。其他与治疗相关的显微镜下改变包括：10和50毫克/千克剂量组近端肾小管上皮细胞内出现胞质嗜酸性颗粒和空泡形成，50毫克/千克剂量组肾近端小管管腔内出现游离红细胞。所有剂量组的血清化学参数（包括尿素氮和肌酐水平）均正常，尿液分析参数也无明显改变。经过4周的无治疗期后，肾脏中的颗粒和空泡形成得以逆转。总体而言，10和50毫克/千克的ISIS 2302可引起凝血时间和肾脏的剂量依赖性改变，且这些改变是可逆的，而2毫克/千克的ISIS 2302未产生明显改变。
