Ichihara N, Kanazawa R, Sasaki S, Ono K, Otani T, Yamaguchi F, Une T
Department of Preventive Medicine, Kousei General Hospital, Tokyo, Japan.
Arzneimittelforschung. 1988 Jul;38(7A):1043-69.
In a first part a phase I clinical study on the immunomodulator N2-[(N-acetylmuramoyl)-L-alanyl-D-isoglutaminyl]-N6-stearoyl-L-lysine (MDP-Lys(L18), muroctasin) in male healthy volunteers was performed to assess safety, immunological activities, and preliminary pharmacokinetics of the drug by subcutaneous administration. 1. Safety Slight increase (38 degrees C) in body temperature was observed in a high-dose group by subcutaneous administration. Redness was noted as a change in the injection site, but no dose-dependency was seen in this respect. No other noticeable subjective nor objective symptoms were detected. On the other hand, positive C-reactive protein (CRP) (1 case out of 35) and slight increase in gamma-glutamyl transpeptidase (gamma-GTP, 1 case out of 35) associated with the use of this drug were observed. But the causal relationship of gamma-GTP with this drug was not clear because the finding returned to normal value during the treatment. 2. Immunological activities and leucocyte count Mitogenic responses of lymphocytes were augmented after subcutaneous administration of this drug. Increase in peripheral leukocyte count was also observed. This was due to the increase in neutrophil count. 3. Pharmacokinetics Pharmacokinetic parameters (maximum serum levels, area under serum concentration-time curve, time to reach maximum blood level, biological half-life) were obtained after a single administration of 400 micrograms: Cmax: 6.93 +/- 1.32 ng/ml (mean +/- SE), AUC: 37.22 +/- 6.51 ng/ml/h, tmax: 1.32 +/- 0.26 h and t1/2: 2.7 +/- 0.8 h. The safety of subcutaneous administration of MDP-Lys (L18) injection has been confirmed in 35 male healthy volunteers. It was suggested that adequate doses for phase II studies in patients were 200 micrograms to 400 micrograms. In a second part a clinical pharmacological study (single subcutaneous administrations of 100 micrograms and 200 micrograms and multiple 5 day subcutaneous administration of 200 micrograms of MDP-Lys (L18) was performed on male healthy volunteers to assess pharmacokinetics, effect on leukocyte function and on immune system, and safety: 1. Pharmacokinetics a) serum concentration after single administration Cmax in 100 micrograms and 200 micrograms were 1.48 and 2.78 ng/ml, respectively. The AUC values were 6.71 and 15.62 ng/ml/h, respectively, with dose dependency.(ABSTRACT TRUNCATED AT 400 WORDS)
在第一部分中，对男性健康志愿者进行了免疫调节剂N2-[(N-乙酰胞壁酰)-L-丙氨酰-D-异谷氨酰胺基]-N6-硬脂酰-L-赖氨酸（MDP-Lys(L18)，mur octasin）的I期临床研究，以通过皮下给药评估该药物的安全性、免疫活性和初步药代动力学。1. 安全性 通过皮下给药，高剂量组观察到体温略有升高（38摄氏度）。注射部位出现发红，但在这方面未观察到剂量依赖性。未检测到其他明显的主观或客观症状。另一方面，观察到与使用该药物相关的阳性C反应蛋白（CRP）（35例中有1例）和γ-谷氨酰转肽酶（γ-GTP）略有升高（35例中有1例）。但γ-GTP与该药物的因果关系尚不清楚，因为该发现在治疗期间恢复到正常水平。2. 免疫活性和白细胞计数 皮下注射该药物后淋巴细胞的促有丝分裂反应增强。外周白细胞计数也增加。这是由于中性粒细胞计数增加。3. 药代动力学 单次给予400微克后获得药代动力学参数（最大血清水平、血清浓度-时间曲线下面积、达到最大血药浓度的时间、生物半衰期）：Cmax：6.93±1.32纳克/毫升（平均值±标准误），AUC：37.22±6.51纳克/毫升/小时，tmax：1.32±0.26小时，t1/2：2.7±0.8小时。在35名男性健康志愿者中已证实皮下注射MDP-Lys (L18) 的安全性。建议在患者中进行II期研究的合适剂量为200微克至400微克。在第二部分中，对男性健康志愿者进行了临床药理学研究（单次皮下注射100微克和200微克以及多次（5天）皮下注射200微克MDP-Lys (L18)），以评估药代动力学、对白细胞功能和免疫系统的影响以及安全性：1. 药代动力学 a) 单次给药后的血清浓度 100微克和200微克单次给药后的Cmax分别为1.48和2.78纳克/毫升。AUC值分别为6.71和15.62纳克/毫升/小时，具有剂量依赖性。（摘要截断于400字）
