Fitzgerald J, de la Iglesia F, Goldenthal E I
J Toxicol Environ Health. 1982 Dec;10(6):879-96. doi: 10.1080/15287398209530303.
The long term effects of the oral contraceptive, Norlestrin, were evaluated in sexually mature female rhesus (Macaca mulatta) monkeys over a 10 year period. Norlestrin, a combination of norethindrone acetate and ethinylestradiol (50:1) was given orally on a continuous cyclic regimen of 21 d of dosing followed by 7 d without treatment. Groups of 16 monkeys each received the drug at dose levels of 0.05, 0.51, and 2.55 mg/kg representing multiples of 1, 10, and 50 times the human dose, respectively. A comparable group of 16 animals remained untreated and served as controls. Selected clinical and laboratory parameters were monitored throughout the study and all animals were necropsied and evaluated for gross and histopathologic changes. All dose levels were well tolerated and survival was not affected. There were no consistent treatment-related alterations in coagulation or other clinical laboratory parameters. Ophthalmologically, macular pigmentary anomalies were observed in all groups. Treatment-associated pathologic findings, representing exaggerated pharmacological responses with superimposed senile changes, including ovarian and uterine atrophy and dilatation of acini and ducts in the mammary gland. Periodic vaginal cytologic examination and mammary gland palpation did not demonstrate drug related changes. A small number of neoplasms was seen in all groups and a granulosa cell carcinoma of the ovary occurred in a control animal. The benign tumors consisted of three cutaneous papillomas: one in a low dose and one in a high dose animal, a uterine leiomyoma in one high dose animal, and a pancreatic duct adenoma in one low dose animal. The results of this study indicate that Norlestrin had no significant toxic manifestations or tumorigenic potential when administered on a cyclic regimen to female rhesus monkeys at levels up to 50 times the human dose for ten yr.
在10年期间，对性成熟的雌性恒河猴（猕猴）评估了口服避孕药诺雷得林（Norlestrin）的长期影响。诺雷得林是醋酸炔诺酮和炔雌醇（50:1）的复方制剂，采用连续周期给药方案，给药21天，随后停药7天。每组16只猴子分别接受0.05、0.51和2.55毫克/千克剂量的药物，分别相当于人类剂量的1倍、10倍和50倍。一组16只可比动物未接受治疗作为对照。在整个研究过程中监测选定的临床和实验室参数，并对所有动物进行尸检，评估大体和组织病理学变化。所有剂量水平均耐受性良好，生存率未受影响。凝血或其他临床实验室参数没有与治疗相关的一致变化。在眼科方面，所有组均观察到黄斑色素异常。与治疗相关的病理发现，表现为药理学反应过度并伴有叠加的衰老变化，包括卵巢和子宫萎缩以及乳腺腺泡和导管扩张。定期阴道细胞学检查和乳腺触诊未显示与药物相关的变化。所有组均发现少量肿瘤，一只对照动物发生了卵巢颗粒细胞瘤。良性肿瘤包括三个皮肤乳头状瘤：一只低剂量动物和一只高剂量动物各一个，一只高剂量动物有一个子宫平滑肌瘤，一只低剂量动物有一个胰管腺瘤。本研究结果表明，当以高达人类剂量50倍的水平对雌性恒河猴进行周期给药10年时，诺雷得林没有明显的毒性表现或致瘤潜力。
