Pessina A, Turlizzi E, Bonomi A, Guizzardi F, Cavicchini L, Croera C, Bareggi S
Institute of Microbiology, University of Milan, Italy.
Pharmacopsychiatry. 2006 Jan;39(1):20-2. doi: 10.1055/s-2006-931475.
Atypical antipsychotics may lead to agranulocytosis because of the apoptosis caused by cells binding nitrenium molecules. Studies showing the direct myelotoxicity of clozapine were undertaken years ago using different assays, and thus it is difficult to compare them with those of clozapine's analogues that have been more recently reported as causing neutropenia, agranulocytosis, and thrombocytopenia.
We compared the direct toxicity of clozapine, olanzapine, quetiapine, and chlorpromazine using a previously standardized GM-CFU assay validated for predicting neutropenia.
The results showed that all of the drugs were characterized by dose-dependent toxicity, which was greatest in the case of chlorpromazine (IC90 = 10.02 +/- 0.69 microg/mL), followed by olanzapine (IC90 = 13.43 +/- 1.23 microg/mL), clozapine (IC90 = 44.71 +/- 4.42 microg/mL), and quetiapine (IC90 = 137.24 +/- 15.36 microg/mL).
These data agree with recent clinical reports concerning the direct or mediated toxic effects of olanzapine on progenitor and committed cells (GM-CFU) and suggest that the correlation between its plasma levels and clinical effects warrants further investigation. There are no published data concerning the bone marrow pharmacokinetics of atypical antipsychotics or their possible bioactivation by the bone marrow cell compartment, but our findings suggest that they may affect hematopoiesis in different ways, such as the direct action of them or their metabolites due to bioactivation by hematopoietic cells themselves.
非典型抗精神病药物可能因细胞与氮烯鎓分子结合导致的细胞凋亡而引发粒细胞缺乏症。多年前曾采用不同检测方法进行了显示氯氮平直接骨髓毒性的研究，因此难以将这些研究结果与最近报道的氯氮平类似物导致中性粒细胞减少、粒细胞缺乏症和血小板减少的研究结果进行比较。
我们使用先前标准化的用于预测中性粒细胞减少的GM-CFU检测方法，比较了氯氮平、奥氮平、喹硫平和氯丙嗪的直接毒性。
结果表明，所有药物均表现出剂量依赖性毒性，其中氯丙嗪的毒性最大（IC90 = 10.02 +/- 0.69微克/毫升），其次是奥氮平（IC90 = 13.43 +/- 1.23微克/毫升）、氯氮平（IC90 = 44.71 +/- 4.42微克/毫升）和喹硫平（IC90 = 137.24 +/- 15.36微克/毫升）。
这些数据与最近关于奥氮平对祖细胞和定向细胞（GM-CFU）的直接或介导毒性作用的临床报告一致，并表明其血浆水平与临床效果之间的相关性值得进一步研究。目前尚无关于非典型抗精神病药物骨髓药代动力学或其可能被骨髓细胞区室生物活化的公开数据，但我们的研究结果表明，它们可能以不同方式影响造血，例如它们或其代谢产物由于造血细胞自身的生物活化而产生的直接作用。
