Lagler F, Kretzschmar R, Leuschner F, Foitzik E, Kiel H, Kuhne J, Neumann W
Arzneimittelforschung. 1976;26(42):634-43.
The chemotherapeutically effective 5:1 combination N1-(4,5-dimethyl-2-oxazolyl)-sulfanilamide (sulfamoxole) and 2,4-diamino-5-(3,4,5-trimethoxy-benzyl)-pyrimidine (trimethoprim) (CN 3123, Nevin, Supristol) was investigated to determine any evidence of toxicological potentiation or new toxic signs. It was found that CN 3123 had a very low acute toxicity when administered orally to mice, rats and dogs (oral LD50: mouse greater than 12 000 mg/kg; rat greater than 14 000 mg/kg; dog greater than 1000 mg/kg body weight). The combination was also tolerated by rats and dogs in repeated doses administered over a period of 4 or 26 weeks, that greatly exceeded the therapeutic dose. The only change observed occurred in the thyroid, which in all doses administered exhibited a dose-related increase in weight accompanied by histological changes indicating an activation of thyroid function and a hypersecretion of basophilic thyrotropic cells in the anterior lobe of the pituitary. Six weeks after discontinuation of treatment this condition showed a tendency to reversibility or had already returned to normal. In dogs there was a dose-related increase in iodine uptake by the thyroid and a decrease in serum thyroxine over a period of 6 months under the highest dosage of CN 3123 administered. Whereas the thyroid changes observed under the combination could be reproduced with sulfamoxole, no effect on thyroid weight was observed in rats and dogs in the subacute toxicity phase of a comparative investigation with trimethoprim. Moreover, trimethoprim did not increase the effect of sulfamoxole on the thyroid gland. The effect of sulfamoxole on the thyroid is discussed in detail with a review of the literature. It can be characterized as species-specific for sulfonamides in mice, rats, rabbits and dogs but not in monkeys or in man and appears to be caused by the inhibition of the organic binding of iodine in the thyroid, whereby the predisposing factors must vary considerably from species to species. The thyroid hypertrophy observed is due to the activation of the regulatory cycle via the anterior lobe of the pituitary. The following systemic changes occurred after 600 mg CN 3123/kg, a lethal-toxic dosage and the highest administered in the study: reduced body weight, decreased food consumption leading to cachexia, slightly increased SGPT and alkaline phosphatase, slight thrombocyte depression, enlargement and increased fatty degeneration of the liver, occurrence of necrotic areas in the liver, hemosiderin accumulation in Kupffer's cells, and an increase of reticular cells in the spleen. The acute toxicity of CN 3123 and all major functional and histological changes under repeated administration were due exclusively to sulfamoxole. The combination sulfamoxole/trimethoprim gives no indication of toxicological potentiation or new toxic signs.
对具有化疗效果的5:1组合N1-(4,5-二甲基-2-恶唑基)-磺胺（磺胺恶唑）和2,4-二氨基-5-(3,4,5-三甲氧基苄基)-嘧啶（甲氧苄啶）（CN 3123，内文，舒普瑞斯托）进行了研究，以确定是否存在毒理学增强或新的毒性迹象。研究发现，CN 3123经口给予小鼠、大鼠和狗时急性毒性非常低（经口半数致死量：小鼠大于12000毫克/千克；大鼠大于14000毫克/千克；狗大于1000毫克/千克体重）。大鼠和狗在4周或26周的重复给药期间也能耐受该组合，给药剂量大大超过治疗剂量。观察到的唯一变化发生在甲状腺，在所给予的所有剂量下，甲状腺重量均呈现剂量相关的增加，并伴有组织学变化，表明甲状腺功能激活以及垂体前叶嗜碱性促甲状腺细胞分泌亢进。停药6周后，这种情况有恢复正常的趋势或已恢复正常。在给予最高剂量的CN 3123的情况下，狗在6个月内甲状腺碘摄取量呈剂量相关增加，血清甲状腺素减少。虽然在联合用药时观察到的甲状腺变化可用磺胺恶唑重现，但在与甲氧苄啶的对比研究的亚急性毒性阶段，大鼠和狗的甲状腺重量未观察到影响。此外，甲氧苄啶并未增强磺胺恶唑对甲状腺的作用。结合文献综述详细讨论了磺胺恶唑对甲状腺的作用。其可被描述为对小鼠、大鼠、兔子和狗中的磺胺类药物具有物种特异性，但对猴子或人类则不然，似乎是由甲状腺中碘的有机结合受到抑制引起的，由此可见，不同物种的易感因素差异很大。观察到的甲状腺肥大是由于通过垂体前叶激活了调节循环。给予600毫克CN 3123/千克（该研究中给予的致死毒性剂量和最高剂量）后出现了以下全身变化：体重减轻、食物摄入量减少导致恶病质、血清谷丙转氨酶和碱性磷酸酶略有升高、血小板略有减少、肝脏肿大和脂肪变性增加、肝脏出现坏死区域、库普弗细胞中铁蛋白蓄积以及脾脏中网状细胞增多。CN 3123的急性毒性以及重复给药后的所有主要功能和组织学变化完全归因于磺胺恶唑。磺胺恶唑/甲氧苄啶组合未显示出毒理学增强或新的毒性迹象。
