毒理学评估

Toxicological assessment

In parallel with pharmacological experiments on efficacy, the toxic effects of acute and chronic dosing are determined. Acute toxicity is less important as long as LD50 (the dose that kills 50% of animals) is not close to the ED50 (the dose causing 50% of maximum pharmacological response).

毒理学评估

与评价药物功效的药理学实验类似，需确定用药的急慢性毒副作用。只要LD50(导致50%实验动物死亡的剂量)未接近ED50(引起50%实验动物最大药理学反应的剂量)，急性毒副作用便不甚重要。

Chronic toxicity testing is more relevant to clinical applications and should take place along the following lines4: 慢性毒性测试与临床应用关系更为密切，须按下列规则进行：

(1) The route of administration, dose range, dose frequency and plasma levels should be appropriate to likely clinical indications. If possible, methods should be available to measure plasma concentrations and to determine patterns of metabolism.

(2) At least two species should be studied, usually dog and rat or mouse. If possible a species should be selected with a similar profile of metabolism to man.

(3) The duration of treatment should be consistent with the likely duration of use in man and the relative life expectancy of the animal species. Usually toxicity studies are undertaken over a period of 4 weeks to at least 1 year.

(4) Hematological and biochemical measurements should be made serially. All tissues should be examined histologically at death or on sacrifice of the experimental group. An untreated control group of littermates should be maintained for comparison.

⑴给药途径、剂量范围、用药次数和血药浓度应该与可能的临床指征相适应。有可能的话，应设法测定血浆浓度，确定代谢模式。

⑵至少应测试两种动物，通常为狗和鼠(大鼠或小鼠)。应尽可能选择一种与人代谢特点相似的动物。

(3)疗程应与用于人类和具有相关预期寿命的动物的可能疗程相一致。通常毒性研究需经历四周至一年的时间。

⑷应不断地进行血液学测定和生化测定。对实验组中的死亡对象的所有组织都要进行组织学检查。应设定同窝出生的非治疗用对照组以便比较。

Depending on the proposed patient group and disease indication, attention must be paid to:

(a) Effects on fertility in both males and females.

(b) Teratogenic effects on development of the embryo. The vulnerable period is very early in development, during organogenesis.

(c) Mutagenicity or an increased rate of mutation in germ cell lines or non-reproductive cells, e.g. bone marrow.

(d) Carcinogenicity or the induction or promotion of malignant tumors.

基于目标患者群及病情指征，下列各点应予以注意：

(a) 对于男性和女性的生育力影响。

(b) 对胚胎发育的畸形影响。其敏感期处于发育早期一器官形成期。

(c) 生殖细胞内膜或非生殖细胞发生诱变或加速突变，例如骨髓。

(d) 致癌性或恶性肿瘤的的诱发或促进。

There is disagreement over the relevance of some animal carcinogenicity studies to man5.

Extensive formal toxicological tests are now required in most countries before drugs can be used on patients. There is considerable controversy as to the value of routine toxicology testing, as many differences between species, especially between man and rat, mouse, and dog, have been reported6. 对于有关一些动物致癌性研究与人类的相关问题，尚存有分歧。

现在大多数国家都规定，只有在广泛的毒理学正规检测之后，药物才可使用于患者。由于种属间，特别是人与鼠或狗之间的诸多差异早有报道，所以，对于常规毒理学测试的价值，人们在看法上有很大分歧。

Paradoxically, thalidomide, which was the cause of the tragedy that led to stricter drug regulation and toxicology tests, is not teratogenic in mice or rats but has a teratogenic effect in humans, causing gross limb deformities.

令人感到困惑的是，反应停(此药导致了一场悲剧，从而使得药物管理和毒理学检测更为严格)用于老鼠并未出现畸形现象，但却在人体出现了致畸作用，引起肢体残疾。

医学英语