Namba K, Otani T, Osada Y
Exploratory Research Laboratories 1, Daiichi Pharmaceutical Co, Ltd, Tokyo, Japan.
Blood. 1994 May 1;83(9):2480-8.
The response of megakaryocytes and platelets to the administration of romurtide, a synthetic muramyl dipeptide derivative, was investigated in normal and irradiated guinea pigs. Romurtide was administered subcutaneously in a single dose or daily doses at levels of 1 to 100 micrograms/animal/day to normal animals to assess the dose response. Subsequently, dosage at 100 micrograms/animal/d for 8 consecutive days was initiated in separate groups of animals immediately after 1 Gy total body x-irradiation. In normal animals, a significant dose-dependent increase in the platelet count was noted, and a prolonged thrombocytopoiesis was detectable from 7 through 15 days after the initiation of romurtide administered for 8 days at a dose of 100 micrograms/animal/d. A significant increase in the white blood cell (WBC) count was also observed during days 1 through 11 after beginning romurtide treatment. In the irradiated animals, the treatment with romurtide increased platelet counts during the recovery phase of thrombocytopenia, thus apparently decreasing the time required for recovery to a normal platelet level. Before the rapid recovery of platelet counts by romurtide treatment, a marked increase in the number of megakaryocytes was noted as early as 7 days after irradiation. This increase was accompanied by an accelerated shift of the size distribution of megakaryocytes toward larger size class. Thus, the mean megakaryocyte size was significantly greater in guinea pigs receiving romurtide than in controls. Preceding the increase in the number of megakaryocytes, the serum interleukin-6 levels were found to be approximately 5 times greater than those in control animals. Treatment with romurtide diminished the WBC count nadir, resulting in significantly higher WBC count levels than in controls. Elevation of the plasma fibrinogen level was observed in the treated animals, and normalized gradually after discontinuation of romurtide treatment. These results indicate a possible therapeutic potential of romurtide in the management of thrombocytopenia associated with myelosuppression.
在正常和受辐照的豚鼠中研究了巨核细胞和血小板对合成的胞壁酰二肽衍生物罗穆肽给药的反应。以1至100微克/动物/天的剂量对正常动物皮下给予单剂量或每日剂量的罗穆肽以评估剂量反应。随后，在1 Gy全身X线照射后，立即对不同组的动物连续8天给予100微克/动物/天的剂量。在正常动物中，观察到血小板计数有显著的剂量依赖性增加，并且在以100微克/动物/天的剂量给予罗穆肽8天后的第7至15天可检测到血小板生成延长。在开始罗穆肽治疗后的第1至11天也观察到白细胞（WBC）计数显著增加。在受辐照的动物中，罗穆肽治疗在血小板减少症的恢复阶段增加了血小板计数，从而明显缩短了恢复到正常血小板水平所需的时间。在罗穆肽治疗使血小板计数迅速恢复之前，早在照射后7天就注意到巨核细胞数量显著增加。这种增加伴随着巨核细胞大小分布向更大尺寸类别的加速转变。因此，接受罗穆肽的豚鼠的平均巨核细胞大小显著大于对照组。在巨核细胞数量增加之前，发现血清白细胞介素-6水平比对照动物高约5倍。罗穆肽治疗使白细胞计数最低点降低，导致白细胞计数水平显著高于对照组。在接受治疗的动物中观察到血浆纤维蛋白原水平升高，在停止罗穆肽治疗后逐渐恢复正常。这些结果表明罗穆肽在治疗与骨髓抑制相关的血小板减少症方面可能具有治疗潜力。
