大剂量口服白消安在异基因造血干细胞移植预处理患者体内药动学研究

 目的 研究异基因造血干细胞移植（ allo-HSCT ）预处理患者口服大剂量白消安 (Bu) 的药动学特征。 方法 allo-HSCT 预处理患者口服 Bu 1 mg· kg^-1 , q6h ,共 16 剂。在首剂和第 9 剂给药时,分别于给药前及给药后不同时间点采集血样,用高效液相色谱法测定血浆 Bu 浓度;用 DAS 软件进行药动学房室模型拟合,计算药动学参数。 结果 首剂和第 9 剂给药后 Bu 在 allo-HSCT 预处理患者体内血药浓度 - 时间曲线均符合一室模型,其主要药动学参数分别为： <> t _1/2 ( 133.0 ± 30.6) 与 (131.4 ± 28.2)min , <> K _e （ 0.005 ± 0.001 ）与（ 0.006 ± 0.001 ） min^-1 , <> V _d /<>F （ 0.56 ± 0.12 ）与（ 0.46 ± 0.08 ） L·kg^-1 , <> CL /<>F （ 0.003 ± 0.001 ）与（ 0.002 ± 0.001 ） L·min^-1·kg^-1 , AUC_0-t （ 910.3 ± 146.9 ）与（ 1 158.5 ± 139.0 ） μmol·min·L^-1 , AUC_{0- ∞} （ 1 401.9 ± 243.2 ）与 （ 1 689.0 ± 312.4 ） μmol·min·L^-1 ; Bu 平均稳态血浆浓度为（ 3.29 ± 0.39 ） μmol·L^-1 。 结论 口服大剂量 Bu 在 allo-HSCT 预处理患者体内过程符合一室药动学模型,主要药动学参数个体差异大,多次给药后药物清除率发生改变。     

Antitumor Activity and Neutrophil-selective Hematopoietic Toxicity of Busulfan Analogs in Mice

The antitumor activity and hematopoietic toxicity of two busulfan analogs were evaluated in comparison with those of busulfan. Although a program of five daily ip treatments with busulfan was not effective in treating sarcoma 180-bearing mice, a fluorine-containing busulfan analog, 1,4-butanediol di-2,2,2-trifluoroethanesulfonate (BFS), and a water-soluble analog, 1,4-butanediol diisethionate (BIT), were significantly effective when given on the same schedule. Busulfan did not appreciably prolong the life span of either P388- or Meth A-bearing mice, whereas BFS and BIT produced significant increases in the life span. It is worth noting that both the analogs were definitely less toxic to the host mice than busulfan. All the drugs examined exhibited suppressive effects on the counts of total WBCs, neutrophils, and lymphocytes. Relative toxicity toward neutrophils versus lymphocytes was increased significantly in the BFS and BIT treatments compared with busulfan treatment. It seems that the toxicity of busulfan in host mice might be due to unidentified side effects other than bone marrow suppression. These results suggest that BFS and BIT could be improved substitutes for busulfan.     

Testicular quantitative ultrasound: A noninvasive monitoring method for evaluating spermatogenic function in busulfan-induced testicular injury mouse models

Busulfan-induced testicular injury mouse models are commonly used for experiments on spermatogonial stem cell transplantation, treatments for azoospermia due to spermatogenic failure and preserving male fertility after chemotherapy. Here, we investigated the value of testicular quantitative ultrasound for evaluating spermatogenic function in this model. In this study, testicular ultrasound was performed on mice from day 0 to 126 after busulfan treatment (n = 48), and quantitative data, including the testicular volume, mean pixel intensity and pixel uniformity, were analysed. The results revealed that from day 0 to 36, the testicular volume was positively associated with the testicle-to-body weight ratio (r = .92). On day 63, the pixel uniformity, which remained stable from day 0 to 36, declined significantly compared with that on day 36 (p < .01). On day 126, when the whole progression of spermatogenesis could be observed in most tubules, the mean pixel intensity also returned to normal (p > .05). In conclusion, testicular quantitative ultrasound could be used as a noninvasive and accurate monitoring method for evaluating spermatogenic function in busulfan-induced testicular injury mouse models.     

The effectiveness of busulfan‐based conditioning regimens for stem cell transplantation against lymphomas in children,adolescents, and young adults in Japan

Conditioning regimens for stem cell transplantation (SCT) involving total body irradiation (TBI) are generally preferred over busulfan (BU)‐based ones for lymphoid malignancies. However, reports of favorable results using BU against lymphomas have recently emerged. This study sought to compare the effectiveness of BU and TBI regimens for SCT against lymphomas. We retrospectively analyzed 893 lymphoma patients who underwent primary SCT in Japan between 1980 and 2015. The median age of all patients was 18 years (range, 0–30 years) with 589 males, 303 females, and 1 patient whose sex was unknown. Overall survival (OS) was not different between those receiving BU and TBI (P = 0.672). OS in patients receiving autologous SCT was significantly better with BU over TBI regimens (P = 0.038), particularly in children (0–15 years) (P = 0.024). Conversely, OS in adolescents and young adults (AYAs; 16–30 years) receiving allogeneic SCT was significantly worse with BU over TBI regimens (P = 0.035). Overall, BU regiments had comparable effectiveness to TBI conditioning regimens, and, although less effective for AYAs with allogeneic SCT, were particularly more effective than TBI regimens for children who received autologous SCT.     

Integration of modelling and simulation into the development of intravenous busulfan in paediatrics: an industrial experience

Busulfan (Bu) is commonly used in preparative conditioning regimen prior to bone marrow transplantation in infants (< 1 year old), children and adolescents (up to 17 years old). The clinical development of an intravenous form of busulfan (Busilvex^®) was based on pharmacokinetic (PK) modeling and simulation techniques. A retrospective population PK analysis was initially performed from a first study in 24 pediatric patients (0.45–16.7 years old) and a log‐linear relationship between body weight and Busilvex^® clearance was demonstrated with no age‐dependency. For an optimal area under the curve (AUC) targeting, a new Bu dosing regimen [i.e. 5 dose levels (0.80 to 1.20 mg/kg) adjusted to 5 discrete weight categories] was developed and assessed through population PK‐based simulations. The benefit from this new dosing strategy was validated in a second trial including 55 children (0.30–17.2 years old). This prospective trial confirmed the previous simulations: an efficient therapeutic targeting whatever the patient's age or body weight. Over 80% of the children were within the desired plasma exposure window, and the initial PK model was validated on the confirmatory dataset.     

Daily bone marrow cell transplantations for the management of fast neurodegenerative processes

Cell therapy has been proven to be a promising treatment for fighting neurodegenerative diseases. As neuronal replacement presents undeniable complications, the neuroprotection of live neurons arises as the most suitable therapeutic approach. Accordingly, the earlier the diagnosis and treatment, the better the prognosis. However, these diseases are commonly diagnosed when symptoms have already progressed towards an irreversible degenerative stage. This problem is especially dramatic when neurodegeneration is aggressive and rapidly progresses. One of the most interesting approaches for neuroprotection is the fusion between healthy bone marrow‐derived cells and neurons, as the former can provide the latter with regular/protective genes without harming brain parenchyma. So far, this phenomenon has only been identified in Purkinje cells, whose death is the cause of different diseases like cerebellar ataxias. Here we have employed a model of aggressive cerebellar neurodegeneration, the Purkinje Cell Degeneration mouse, to optimize a cell therapy based on bone marrow‐derived cell and cell fusion. Our findings show that the substitution of bone marrow in diseased animals by healthy bone marrow, even prior to the onset of neurodegeneration, is not fast enough to stop neuronal loss in time. Conversely, avoiding bone marrow replacement and ensuring a regular supply of healthy cells through continuous, daily transplants, the neurodegenerative milieu of PCD is enough to attract those transplanted elements. Furthermore, in the most affected cerebellar regions, more than a half of surviving neurons undergo a process of cell fusion. Therefore, this method deserves consideration as a means to impede neuronal cell death.     

造血干细胞移植中白消安血药浓度监测及其临床意义

目的 综述白消安在造血干细胞移植预处理方案中的应用及其血药浓度监测研究进展.方法 查阅国内外相关文献,对有代表性的文献进行分析、归纳、总结.结果 白消安的血药浓度与治疗结果相关,适宜的治疗窗能提高疗效,减少药物不良反应和降低移植后并发症的风险.结论 对白消安进行血药浓度监测和剂量调整有重要的临床意义.     

Origin and Significance of Intranuclear Tubular Inclusions in Type II Pulmonary Alveolar Epithelial Cells of Patients with Bleomycin and Busulfan Toxicity

Abundant intranuclear tubular structures were observed in type II alveolar pneumocytes in lung biopsies from patients with bleomycin and busulfan toxicity. It is proposed that since chromatin-membrane interactions in eukaryotic cell nuclei do occur, the intranuclear proliferation of the tubular structures occurs as a result of the interaction of the drug with peri-chromatin.     

Effect of protopanaxatriol saponin on spermatogenic stem cell survival in busulfan-treated male mice

Background and aims:  Panax ginseng C.A. Meyer is a medicinal herb widely used in Asian countries. Many of its pharmacological actions are attributed to ginsenosides (saponin). However, the pharmacological effects or functions of ginsenosides on mammalian spermatogenesis are unclear.
Methods:  In the present study study, we investigated the therapeutic and prophylactic effects of protopanaxatriol saponin (PT) on testicular organ weight and morphology, testicular germ cells, proliferation, differentiation and spermatogenesis after induction of toxicity by a chemotherapeutic agent, busulfan, in male mice.
Results:  Intraperitoneally (IP) busulfan treatment markedly decreased the organ weight of testis, caput and cauda epididymis. After the treatment, the testes had collapsed seminiferous tubules with incomplete spermatogenesis. However, a single dose of busulfan treatment followed by PT injection showed milder damage on seminiferous tubules than busulfan alone.
Conclusion:  These results suggest that PT is effective in recovery of the male reproductive organ, and induced an increase in the number and viability of germ cells overcoming busulfan toxicity. PT might have applications in the recovery of male infertility arising from azoospermia and oligospermia.     

Cytogenetic Remission in a Ph1-Positive Case of Chronic Myelogenous Leukaemia

Unusual cytogenetic findings in a case of chronic myelogenous leukaemia in the course of an aplastic crisis induced by busulfan therapy are reported. The proportion of Ph¹-positive cells in bone marrow aspirates fell from 100 % before treatment to 8.6 % following aplasia. It increased gradually during recovery, and normal cells still represented 25.7 % of the metaphases 20 months later. After a 38-months' remission without therapy the disease relapsed and the Ph¹ chromosome was found in 100 % of the bone marrow cells.