毒理學評估

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).

毒理學評估

與評價藥物功效的藥理學實驗類似，需確定用藥的急慢性毒副作用。只要LD50(導致50%實驗動物死亡的劑量)未接近ED50(引起50%實驗動物最大藥理學反應的劑量)，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: 慢性毒性測試與臨床應用關(guān)系更為密切，須按下列規(guī)則進行：

(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給藥途徑、劑量范圍、用藥次數(shù)和血藥濃度應該與可能的臨床指征相適應。有可能的話，應設(shè)法測定血漿濃度，確定代謝模式。

⑵至少應測試兩種動物，通常為狗和鼠(大鼠或小鼠)。應盡可能選擇一種與人代謝特點相似的動物。

(3)療程應與用于人類和具有相關(guān)預期壽命的動物的可能療程相一致。通常毒性研究需經(jīng)歷四周至一年的時間。

⑷應不斷地進行血液學測定和生化測定。對實驗組中的死亡對象的所有組織都要進行組織學檢查。應設(shè)定同窩出生的非治療用對照組以便比較。

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.

基于目標患者群及病情指征，下列各點應予以注意：

(a) 對于男性和女性的生育力影響。

(b) 對胚胎發(fā)育的畸形影響。其敏感期處于發(fā)育早期一器官形成期。

(c) 生殖細胞內(nèi)膜或非生殖細胞發(fā)生誘變或加速突變，例如骨髓。

(d) 致癌性或惡性腫瘤的的誘發(fā)或促進。

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. 對于有關(guān)一些動物致癌性研究與人類的相關(guān)問題，尚存有分歧。

現(xiàn)在大多數(shù)國家都規(guī)定，只有在廣泛的毒理學正規(guī)檢測之后，藥物才可使用于患者。由于種屬間，特別是人與鼠或狗之間的諸多差異早有報道，所以，對于常規(guī)毒理學測試的價值，人們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，反應停(此藥導致了一場悲劇，從而使得藥物管理和毒理學檢測更為嚴格)用于老鼠并未出現(xiàn)畸形現(xiàn)象，但卻在人體出現(xiàn)了致畸作用，引起肢體殘疾。

醫(yī)學英語