Aymard N, Baldacci C, Leyris A, Smagghe P O, Tribolet S, Vacheron M N, Viala A, Caroli F
Unité de Pharmacologie, Centre Hospitalier Sainte Anne, Paris, France.
Therapie. 1997 May-Jun;52(3):227-32.
The aim of this open study was to determine a more rational therapeutic approach for psychotic patients treated with clozapine for several months, using measurement of plasma and red blood cell levels (P, RBC) of clozapine (cloza) and N-desmethylclozapine (descloza), the major metabolite of clozapine, which has been reported to be less active but more toxic (agranulocytosis) than clozapine itself. The RBC concentration may be considered as more representative of the free fraction drug. The study concerned 7 patients suffering from chronic paranoid schizophrenia according to the DSM-IV criteria. All of them were treatment-refractory schizophrenic inpatients (4 men, 3 women, mean age +/- SD: 38.2 +/- 8.4 years; mean duration of illness +/- SD: 14.4 +/- 5.1 years). They had received at least two different neuroleptics, for 6 weeks, before entering the study. Treatment started in our hospitalization unit with clozapine 25 mg up to a maximum of 900 mg/d (mean stabilized daily dose +/- SD: 507 +/- 211 mg and mean daily dose per kg: 6.91 +/- 3.08 mg). Clinical evaluations (Quality of Life Scale: QLS), regular blood monitoring and biological samples were conducted at the same time, weekly for 18 weeks and then monthly (duration of the study: 4 to 38 months; mean +/- SD: 12.9 +/- 11.5 months). Plasma and RBC (after lysis) levels were determined by reversed phase HPLC and UV detection after extraction with hexane. All the patients improved very quickly after the first week of treatment and six were able to leave the hospitalization unit and start outpatient care such as daily hospitalization, returning home or in sheltered accommodation. With the following plasma (P) and RBC levels: mean cloza +/- SD: (P = 294 +/- 146 ng/ml; RBC = 110 +/- 82 ng/ml) and mean descloza +/- SD: (P = 173 +/- 106 ng/ml; RBC = 76 +/- 54 ng/ml); none of the seven patients developed agranulocytosis. The blood levels, ensuring better surveillance, have a predictive value for clinical improvement. A linear pharmacoclinical correlation was only found between RBC cloza concentrations and the evolution of the QLS scores. Clozapine fulfils the criteria for therapeutic drug monitoring, and determination of plasma, and more particularly RBC, cloza and descloza levels may help to find the lowest effective dose with the fewest side effects.
这项开放性研究的目的是，通过测量氯氮平及其主要代谢产物N-去甲基氯氮平在血浆和红细胞中的水平（P、RBC），为接受氯氮平治疗数月的精神病患者确定一种更合理的治疗方法。据报道，N-去甲基氯氮平的活性低于氯氮平，但其毒性（粒细胞缺乏症）高于氯氮平本身。红细胞浓度可被视为更能代表游离药物部分。该研究涉及7名符合DSM-IV标准的慢性偏执型精神分裂症患者。他们均为治疗难治性精神分裂症住院患者（4名男性，3名女性，平均年龄±标准差：38.2±8.4岁；平均病程±标准差：14.4±5.1年）。在进入研究前，他们至少接受过两种不同的抗精神病药物治疗6周。治疗在我们的住院部开始，氯氮平起始剂量为25mg，最大剂量为900mg/d（平均稳定日剂量±标准差：507±211mg，平均每千克体重日剂量：6.91±3.08mg）。同时进行临床评估（生活质量量表：QLS）、定期血液监测和采集生物样本，每周进行一次，共18周，之后每月进行一次（研究持续时间：4至38个月；平均±标准差：12.9±11.5个月）。血浆和红细胞（溶血后）水平通过反相高效液相色谱法和己烷萃取后的紫外检测来测定。所有患者在治疗第一周后均迅速好转，6名患者能够离开住院部并开始门诊治疗，如日间住院、回家或入住庇护性住所。根据以下血浆（P）和红细胞水平：氯氮平平均水平±标准差：（P = 294±146ng/ml；RBC = 110±82ng/ml），N-去甲基氯氮平平均水平±标准差：（P = 173±106ng/ml；RBC = 76±54ng/ml）；7名患者均未发生粒细胞缺乏症。确保更好监测的血药浓度水平对临床改善具有预测价值。仅在红细胞氯氮平浓度与QLS评分的变化之间发现了线性药代临床相关性。氯氮平符合治疗药物监测的标准，测定血浆，尤其是红细胞中的氯氮平和N-去甲基氯氮平水平，可能有助于找到副作用最少的最低有效剂量。
