Effects of Renal Function on Pharmacokinetics of Recombinant Human Granulocyte Colony-Stimulating Factor in Lung Cancer Patients

Animal studies suggest that the kidney is involved in the elimination of recombinant human granulocyte colony-stimulating factor (rhG-CSF), which is used for patients with neutropenia during cancer chemotherapy. Since anticancer drugs induce nephrotoxicity, it is important to clarify the role of the kidney in the pharmacokinetics of rhG-CSF in cancer patients. Our study was designed to evaluate the relationship between the pharmacokinetics of rhG-CSF and renal function in lung cancer patients compared to the absolute neutrophil count (ANC). The pharmacokinetic studies were conducted with 25 lung cancer patients. Following chemotherapy using platinum-based compounds, a bolus 5 microg of rhG-CSF/kg of body weight was intravenously injected from the first day of leukopenia or neutropenia. Pharmacokinetic parameters were estimated by fitting the concentration in serum-time data to a two-compartment model according to the population pharmacokinetics and the Bayesian method. Creatinine clearance (CL(CR)) was predicted by the Cockcroft-Gault formula. rhG-CSF clearance (CL(G-CSF)) correlated significantly with the ANC (r = 0.613; P < 0.001) and CL(CR) (r = 0.632; P < 0.001). Multiple linear regression analysis showed that the combination of the ANC and CL(CR) accounted for 57.4% of the variation of CL(G-CSF). In patients with an ANC of <1,000/microl, CL(CR) accounted for 72.9% of the variation of CL(G-CSF) (P < 0.001). Our findings suggest that renal function and neutrophil counts correlate with CL(G-CSF) and that the role of renal function in eliminating rhG-CSF is important in lung cancer patients with neutropenia.     

MPXI and early neutrophilia: New potential therapeutic biomarkers for recombinant human granulocyte colony-stimulating factor

We evaluated the effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) given after myelosuppressive chemotherapy in 15 cancer patients. No severe neutropenia (absolute neutrophil count, ANC < 0.5 × 10³/μL) was noticed in 10 rhG-CSF primary prophylactic patients, but was noticed in two of five rhG-CSF secondary prophylactic patients. Neutrophilia characterized by shift to the left occurred within 24 hours after starting rhG-CSF prophylaxis. Thereafter, conversion to normal level occurred within 24 hours. The peak of neutrophilia occurred earlier in the primary group than in the secondary prophylactic group. The detection of myeloperoxidase (MPO) using flow cytochemistry blood autoanalyzer (Technicon^R H*1) was evaluated as mean peroxidase index (MPXI). Leukocyte alkaline phosphatase (LAP) using the method of Kaplow (Am J Clin Pathol 39:439–449, 1963) was recorded as LAP score. There was a statistically significant elevation of MPXI in the primary group over the secondary prophylactic patients. The LAP activity was in normal range. There was a slightly decreased red blood cell (RBC) count, hemoglobin (Hb), and platelet count. In conclusion, rhG-CSF induced neutrophilia with efficient enzymatic activity. These findings demonstrate the value of rhG-CSF in patients receiving chemotherapy. MPXI and early neutrophilia may serve as a potential biomarker of therapeutic efficacy of rhG-CSF. J. Clin. Lab. Anal. 41–46, 1998. © 1998. Wiley-Liss, Inc.     

Recombinant human granulocyte colony-stimulating factor. Effects on hematopoiesis in normal and cyclophosphamide-treated primates

We examined the in vivo effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) in primates (cynomolgus monkeys) treated with subcutaneous doses of rhG-CSF for 14-28 d. A dose-dependent increase in the peripheral white blood cells (WBC) was seen, reaching a plateau after 1 wk of rhG-CSF treatment. The elevation of WBC was due to an increase in the absolute neutrophil count. These results demonstrate that rhG-CSF is a potent granulopoietic growth and differentiation factor in vivo. In cyclophosphamide (CY)-induced myelosuppression, rhG-CSF was able to shorten the time period of WBC recovery in two treated monkeys to 1 wk, as compared to more than 4 wk for the control monkey. Its ability to significantly shorten the period of chemotherapy-induced bone marrow hypoplasia may allow clinicians to increase the frequency or dosage of chemotherapeutic agents. In addition, the increase in absolute numbers of functionally active neutrophils may have a profound effect in the rate and severity of neutropenia-related sepsis. Furthermore, the activities reported here indicate a potential role for rhG-CSF in the treatment of patients with myelodysplastic syndrome, congenital agranulocytosis, radiation-induced myelosuppression, and bone marrow transplantation.     

31例高龄脑出血临床特点分析

对３１例高龄脑出血病人的发病季节，病因，起病状态，发病早期血压变化，ＣＴ或ＭＲＩ扫描结果以及临床特点进行分析，结果说明４月份至８月份发病及活动中发病较高，男性发病高于女性，左右半球出血的发生率差异不大，出血部位，出血量的大小以及并发症与疾病的转归有着密切的关系。     

The impact of the CD34+ cell dose on engraftment in allogeneic peripheral blood stem cell transplantation

Forty-five patients who underwent allogeneic peripheral blood stem cell transplantation (PBSCT) were evaluated in order to investigate any relationship between CD34+ cell dose given and hematological recovery. Granulocyte counts > 1.0 x 10(9)/L and platelet > 50 x 10(9)/L were considered as hematological recovery. Three different regimens were used for mobilization, by adjusting the recombinant granulocyte colony stimulating factor (rhG-CSF, Roche) dose. The first group (n = 3), whose donors mobilized with 5 micrograms/kg/d s.c. rhG-CSF received a mean of 5.9 x 10(6)/kg (95% confidence interval for mean (CI); 2.4-9.3) CD34+ cells. The second group (n = 37), mobilized with 10 micrograms/kg/d s.c. rhG-CSF and the third group (n = 5) mobilized with 15 micrograms/kg/d s.c. rhG-CSF, received a mean of 5.7 x 10(6)/kg (95% CI; 4.6-6.75) and 6.56 x 10(6)/kg (95% CI; 4.57-8.55) CD34+ cells, respectively. CD34+ cell dose was 5.82 x 10(6)/kg (95% CI; 4.97-6.68) for all the patients. All patients received rhG-CSF from day +1 until attaining granulocyte count > 1.0 x 10(9)/L for three consecutive days. Median granulocyte and platelet engraftment days for the whole group was 15 (range; 11-44) and 14 (11-54) days respectively. There was a close correlation (r = -0.301, p < 0.05) between the CD34+ cell dose and granulocyte recovery for the whole group. When these analyses were performed separately within groups, this correlation was also found significant for the first group (r = -0.99, p < 0.05) for granulocyte recovery. On the contrary the same analysis did not reach significance for the other groups, nor for platelet recovery for the whole group (r = 0.039, p = 0.821). We calculated a minimum dose of 4 x 10(6)/kg CD34+ cells for a safe alloPBSCT. There was no difference between patients who received more than 5 x 10(6)/kg CD34+ cells, and those who received more than 2 x 10(6)/kg and less than 5 x 10(6)/kg CD34+ cells. In conclusion, we have demonstrated a correlation between the CD34+ cell dose given and faster hematological recovery for alloPBSCT patients.     

Transfusions of granulocyte-colony-stimulating factor-mobilized granulocyte components to allogeneic transplant recipients: analysis of kinetics and factors determining posttransfusion neutrophil and platelet counts

BACKGROUND: Granulocyte-colony-stimulating factor (G-CSF) is a safe and effective agent for mobilization of neutrophils in normal donors, consistently resulting in cell yields per leukapheresis (LA) procedure that are superior to those with other agents. LA components also contain platelets, whose clinical relevance is unknown. STUDY DESIGN AND METHODS: This study describes the kinetics of and analyzes the factors determining the ANC and platelet count increments seen with each of three transfusions of granulocytes collected from HLA-matched sibling donors receiving G-CSF (n=10; maximum of 3 LA procedures/donor). The transfusions were given to recipients (n=10) on alternate days beginning. Day 1 after allogeneic bone marrow transplant (BMT). RESULTS: Significant, sustained increments in the recipient ANCs were observed after the transfusion of G-CSF-mobilized LA components. The mean peak posttransfusion increments in the ANCs were 1195, 729, and 631 per microL with transfusion of donor LA components on Days 1, 3, and 5, respectively. The length of time that the mean posttransfusion ANC was at or above the baseline (pretransfusion) value was 25 to 37 hours, depending on the post-BMT day when the component was administered. No consistent relationship was observed between LA component granulocyte dose, baseline recipient ANC, or temperature elevation and post-transfusion ANC increments. Large numbers of platelets (mean, 2.55 × 10(11)) were present in LA components, and this resulted in significant increments from baseline in the mean platelet count 1 hour after LA component transfusions. Between Days 1 and 7, the duration of severe neutropenia was shorter and the percentage of patients requiring nondonor platelet transfusions was less in study patients who received LA component transfusions than in a similar historical control group who did not. CONCLUSION: The transfusion of G-CSF-mobilized, HLA-matched LA components to allogeneic BMT recipients resulted in significant and sustained increments in the ANC and the platelet count. Within the range examined, a relationship between neutrophil dose and an increment in the ANC was not demonstrated.     

The determinants of granulocyte yield in 1198 granulocyte concentrates collected from unrelated volunteer donors mobilized with dexamethasone and granulocyte–colony-stimulating factor: a 13-year experience

BACKGROUND: The combination of granulocyte–colony-stimulating factor (G-CSF [filgrastim]) and dexamethasone (G-CSF/dex) is an effective granulocyte mobilization regimen, but the variables that affect donor neutrophil response and granulocyte collection yield are not well characterized.
STUDY DESIGN AND METHODS: A computerized database containing records of 1198 granulocyte collections from 137 unrelated volunteer apheresis donors during a 13-year period was retrospectively analyzed. Donors were categorized by age, sex, and cumulative number of granulocyte donations. Complete blood counts at baseline and after G-CSF/dex stimulation were recorded. The outcome variables include the preprocedure absolute neutrophil count (preANC), which reflects G-CSF/dex stimulation, and the granulocyte product yield per liter processed (BagGranYield/L).
RESULTS: Higher baseline ANC and platelet (PLT) counts were significantly associated with higher preANC while a larger number of prior granulocytapheresis procedures was associated with lower preANC. Total filgrastim dose (used in weight-based dosing) did not significantly impact preANC or the granulocyte yield; weight-based dosing at 5 µg per kg and a uniform 480-µg dose produced equivalent preANC. PreANC and weight were the key determinants of granulocyte yield (BagGranYield/L).
CONCLUSION: Apheresis donors with higher baseline PLT counts and ANCs have higher ANCs after G-CSF/dex stimulation; donor age, weight, and sex do not have a significant impact. A uniform G-CSF dose of 480 µg is as effective as weight-based dosing at 5 µg per kg. Donor ANC monitoring should be considered after serial granulocytapheresis procedures.     

Close Association between Clearance of Recombinant Human Granulocyte Colony-Stimulating Factor (G-CSF) and G-CSF Receptor on Neutrophils in Cancer Patients

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is used to counter chemotherapy-induced neutropenia. Our previous study showed an inverse correlation between serum rhG-CSF levels and the number of circulating neutrophils in cancer patients (H. Takatani, H. Soda, M. Fukuda, M. Watanabe, A. Kinoshita, T. Nakamura, and M. Oka, Antimicrob. Agents Chemother. 40:988–991, 1996). The aim of this study was to clarify the relationship between rhG-CSF clearance and G-CSF receptors on circulating neutrophils. In five cancer patients receiving chemotherapy, a bolus dose of rhG-CSF (5 μg/kg) was injected intravenously during defined phases of posttreatment neutropenia and neutrophilia. Serum rhG-CSF levels were measured by a chemiluminescence enzyme immunoassay and analyzed by moment analysis. G-CSF receptors on neutrophils were detected by flow cytometry with biotinylated rhG-CSF. rhG-CSF clearance was significantly higher at neutrophilia than at neutropenia (1,497 ± 132 versus 995 ± 266 ml/h; P < 0.01). The percentage of G-CSF receptor-positive neutrophils, reflecting the number of G-CSF receptors per cell, was low at neutropenia without rhG-CSF therapy (44.5% ± 22.1%) and high at neutrophilia with rhG-CSF therapy (73.0% ± 11.4%; P < 0.01). rhG-CSF clearance closely correlated with the percentage of G-CSF receptor-positive neutrophils (r² = 0.91; P < 0.0001) and neutrophil count (r² = 0.72; P < 0.005). Our results indicate that, in cancer patients receiving chemotherapy, rhG-CSF increases the number of G-CSF receptors per cell as well as circulating neutrophil counts, resulting in modulation of its own clearance.     

流式细胞术检测抗中性粒细胞抗体方法的建立及临床初步应用

目的建立适用于临床的流式细胞术（FCM）检测抗中性粒细胞抗体（ANA）的方法,并作临床初步应用。方法采用FCM,以前向散射和侧向散射参数区分全血标本中的淋巴细胞和粒细胞,设定粒细胞门,用CD16b-藻红蛋白（PE）和CD177-别藻蓝蛋白（APC）单克隆抗体分别检测中性粒细胞中表面表达CD16b和CD177抗原细胞的百分率。用所建方法检测健康对照32名,确定参考范围,以此作为判断受检者血液中抗CD16b或CD177抗体存在与否的依据。检测外周血白细胞（WBC）总数〈4.0×109/L且中性粒细胞绝对计数（ANC）〈2.8×109/L的59例患者的CD16b和CD177百分率,并对其中中性粒细胞表达CD16b和/或CD177百分率低于参考范围（即判为相应抗体阳性）的患者给予激素治疗,观察疗效。结果健康人群中性粒细胞中表达CD16b和CD177的百分率分别为98.36%±1.53%和74.95%±11.07%,据此分别确定了健康人群中性粒细胞表达CD16b和CD177的参考范围分别为CD16b〉95.36%、CD177〉53.25%（即〉x珋-1.96s）。59例患者中有23例（39.0%）ANA阳性,其中ANC〈2.0×109/L患者的ANA阳性率（50.0%）远高于ANC〉2.0×109/L患者（27.6%）。ANA阳性患者经激素治疗后,WBC和ANC上升。结论 FCM检测抗中性粒细胞CD16b和CD177抗体是自身免疫性中性粒细胞减少症（AIN）实验简便、快捷的诊断方法,有助于AIN的诊断、鉴别诊断和疗效判断。     

rhG-CSF对儿童慢性再生障碍性贫血促造血及抗感染作用

目的探讨重组人粒细胞集落刺激因子（rhG-CSF）对儿童慢性再生障碍性贫血（CAA）防治感染、促进造血功能恢复的作用。方法将本院收治的40例CAA病儿随机分为2组,对照组应用环孢素、达那唑及中药治疗,治疗组在对照组基础上加用rhG-CSF（3μg/kg皮下注射,每周1次,待中性粒细胞≥1×109/L时停止皮下注射,〈1×109/L时再次皮下注射rhG-CSF）。疗程为3个月。检查血常规、骨髓常规,临床观察感染发生率、感染例次及感染严重程度。结果治疗1周时,治疗组中性粒细胞数量较治疗前、同期对照组均明显升高（t=40.00、41.30,P〈0.05）;治疗3个月时,治疗组中性粒细胞≥1×109/L例次明显高于对照组（t=6.60,P〈0.05）,外周血白细胞、中性粒细胞、血红蛋白、血小板较治疗前及同期对照组明显增高（t=3.66~60.74,P〈0.05）,骨髓增生活跃程度、粒系增生程度及巨核细胞个数明显高于治疗前及同期对照组（χ2=16.94、6.67,t=2.38~100.00,P〈0.05）,感染发生率、感染次数及抗生素应用天数均较对照组明显减少（χ2=5.58,t=2.42、2.99,P〈0.05）。结论 CAA治疗过程中,加用rhG-CSF能迅速升高中性粒细胞数量,减少感染次数,减轻感染程度,促进造血功能恢复。     

Peripheral blood stem cell collection from healthy donors for allogeneic transplantation

There is great interest in the use of peripheral blood stem cells (PBSC) for allogeneic transplantation, based on the good results seen with autologous PBSC infusion. Reasonable caution exists regarding the use of allogeneic PBSC for transplantation because of donor toxicities due to rhG-CSF administration and the risk of graft-versus-host-disease (GVHD) in the recipient because of the large number of T-cell infused. We present preliminary data on allogeneic PBSC collections and transplantation in ten patients affected by advanced leukemia (eight patients), severe aplastic anemia (one patient) and sickle cell anemia (one patient). Seven donors were HLA-identical siblings, while the other three were mismatched for three, two and one locus, respectively. All donors received rhG-CSF at a dose of 12 micrograms/kg for a mean of 5 days. Leukaphereses were performed with the aim of collecting a minimum of 5 x 10(6)/kg (recipient's weight) CD 34+ cells. Collection timing was determined by monitoring CD 34+ cells in the donor's peripheral blood from the second day of rhG-CSF therapy. The PBSC collections yielded a mean of 10.05 x 10(8) MNCs/kg and of 10.48 x 10(6) CD 34+ cells/kg (recipient's weight). PBSC were immediately infused after collection in patients given myeloablative therapy. Engraftment was observed in each patient at a mean of 13.2 days for an absolute neutrophil count (ANC) more than 0.5 x 10(9)/L and of 26.5 days for a platelet count of more than 20 x 10(9)/L. Eight patients experienced no or moderate acute GVHD, whereas two patients died of grade 4 GVHD, notwithstanding GVHD prophylaxis with cyclosporine and prednisone. Two other patients died of viral and fungal infections, respectively, despite prophylaxis. The remaining six patients are alive between 58 and 430 days after transplant. Our results document that allogeneic PBSC are capable of engraftment after a myeloablative regimen. Controlled trials are necessary to compare the potential benefits of this approach with the results obtained in allogeneic bone marrow transplantation.     

rhG-CSF对急性白血病化疗后中性粒细胞形态、功能、表型的影响

为了探讨急性白血病病人化疗后应用rhG-CSF对中性粒细胞形态、功能及表型变化的影响,采用油镜下观察细胞形态,过氧化氢释放法、琼脂糖测定法、免疫荧光技术和流式细胞术检测中性粒细胞的吞噬、趋化及氧化代谢功能;采用免疫荧光技术和流式细胞分析检测中性粒细胞表型.结果表明：应用rhG-CSF后,中性粒细胞胞浆内＂中毒＂颗粒数、空泡数和Dohle小体数增加;化疗后病人中性粒细胞吞噬、趋化及氧化代谢功能明显低于正常组,用rhG-CSF后功能均增强,基本接近正常组甚至超出;用rhG-CSF前中性粒细胞CD64、CD62L的表达明显高于正常对照组,用G-CSF后CD64表达上调,CD62L表达显著下调;CD16、CD32、CD14和CD11b则无明显改变.结论：急性白血病病人化疗后应用rhG-CSF可引起中性粒细胞形态、功能及表型出现变化,进一步增强机体的抗感染能力.     

Severe congenital neutropenia: clinical effects and neutrophil function during treatment with granulocyte colony-stimulating factor.

We studied neutrophil function and clinical responses in seven patients with severe congenital neutropenia (SCN) after they received treatment with recombinant human granulocyte colony stimulating factor (rhG-CSF). Two subpopulations of patients with SCN were defined by their pattern of absolute neutrophil response, superoxide production, and cytochrome b559 levels. One group had an oscillating absolute neutrophil count and reduced ability to produce superoxide and cytochrome b559 (n = 4), and the second group had a relatively constant absolute neutrophil count response with normal superoxide and cytochrome levels (n = 3). Neutrophils from both groups had decreased surface expression of FcRIII and abnormal upregulation of the C3bi receptor (CR3). All patient neutrophils, however, had normal contents of the primary granule constituent, beta-glucuronidase, and the specific granule constituent, vitamin B 12 binding protein. The clinical response to rhG-CSF was evident by marked improvement in the degree of periodontitis and reduction in the number of oral ulcers in both groups of patients. Although neutrophil function is not completely normal in patients with SCN, it is likely that enough redundancy exists in neutrophil bactericidal capacity to promote normal host response to inflammation.     

MAG方案对恶性血液病患者造血干细胞动员作用的研究

目的　研究米托蒽醌 (MTZ)联合大剂量阿糖胞苷 (Ara C)、重组人粒细胞集落刺激因子(rhG CSF)组成MAG方案对恶性血液病患者外周血干细胞的动员作用。方法　 1995年 12月至2 0 0 3年 4月 ,采用MAG方案对 14例恶性淋巴瘤和 2 9例急性白血病患者外周血干细胞进行动员 ,其用量为MTZ 10mg/m2 ,第 2 ,3天 ;Ara C 2 g/m2 ,每 12h 1次 ,第 1,2天 ;rhG CSF 30 0 μg/d。首先用MA方案联合化疗 ,白细胞 <1.0× 10 9/L时开始用rhG CSF ,白细胞回升时用CS 30 0 0plus或CobeSpectra血细胞分离机采集外周血干细胞。结果　 14例恶性淋巴瘤患者除 1例外周血干细胞采集失败外 ,其余 13例均 1次性采集成功 ,所得单个核细胞 (MNC) (3.91± 2 .70 )× 10 8/kg ,CD34 细胞 (17.79± 12 .90 )× 10 6/kg。采集 2 9例急性白血病患者外周血干细胞平均 2 .13次 ,2 4例采集成功 ,5例采集失败 ,所得MNC (3.6 2± 2 .89)× 10 8/kg ,CD34 细胞 (7.37± 6 .6 0 )× 10 6/kg。rhG CSF平均使用时间为 7d。经MAG方案动员后 ,除 8例患者有胃肠道反应、14例患者骨髓抑制期合并感染外无明显不良反应 ,无动员相关死亡。MAG方案动员后进行微小残留病检测 ,部分病例转为阴性。结论　MAG方案在恶性淋巴瘤和急性白血病患者外周血干细胞动员中安全     

rhG-CSF对140例恶性肿瘤化放疗所致白细胞减少的临床疗效观察

为了观察rhG CSF对恶性肿瘤放化疗所致白细胞减少的疗效 ,对 14 0例恶性肿瘤放化疗所致粒细胞减少的患者用此国产rhG CSF(粒生素 )进行治疗。白细胞 <3.0× 10 9/L或中性粒细胞绝对计数 (ANC) <2 .0× 10 9/L时开始用粒生素 75 μg,皮下注射 ,每日 1次 ,待白细胞 >4 .0× 10 9/L或中性粒细胞绝对计数 >2 .5× 10 9/L时停药。结果表明 :粒生素能使放化疗所致粒细胞减少回升至正常范围 ,平均时间为 4 8天 ,有效率 96 .4 %。结论 :粒生素可以明显减轻放化疗过程中外周血白细胞下降程度 ,缩短白细胞恢复时间 ,且毒副反应轻、安全可靠 ,有利于放化疗的顺利进行。     

Effect of recombinant human granulocyte colony-stimulating factor on Pneumocystis carinii infection in nude mice

Repeated subcutaneous (s.c.) injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF) to Pneumocystis carinii (P. carinii)-infected balb/c nude (nu/nu) mice had no effects on the number of the P. carinii cysts in the lungs, despite neutrophilic infiltration in the tissues and a marked increase in blood neutrophil count. This finding indicates that neutrophils in the absence of T cells do not play an important role in the killing of P. carinii. However, survival periods of the rhG-CSF treated mice seemed to extend to some extent compared with the controls presumably because of the prevention of mixed bacterial infections.     

无关供者24例外周血干细胞动员和采集

目的 总结无关供者外周血千细胞(PBSC)动员和采集情况.方法 24例无关供者给予重组人粒细胞集落刺激因子(rhG-CSF)5 μμg·kg-1·d-1,每天皮下注射,第4、5天或5、6天用CS-3000PLUS血细胞分离机采集外周血干细胞,计数采集物中单个核细胞(MNC)和CD34+细胞.结果 所有供者均安全顺利完成...     

Pharmacokinetics and pharmacodynamics of recombinant human granulocyte-colony stimulating factor after intravenous and subcutaneous administration in the rat

The pharmacokinetics of recombinant human granulocyte-colony stimulating factor (rhG-CSF) (produced by Kirin Brewery Co., Ltd.) in sera was studied after i.v. and s.c. administration into male Sprague-Dawley rats. Arterial blood samples were taken to determine the rhG-CSF concentrations by measuring its activities using a modified [3H]thymidine assay. After the i.v. dose of 100 micrograms/kg, the half-lives were 25 (alpha) and 102 min (beta). Subcutaneous administration at the 100-micrograms/kg dose resulted in a lower peak serum level but, after 2 hr, rhG-CSF level after the s.c. dose was higher than that of the i.v. dose. The bioavailability of the s.c. dose of 100 micrograms/kg was 78%. The effect of rhG-CSF administration in rats was a specific activity on the neutrophil lineage with increase of neutrophils in peripheral blood. Intravenous and s.c. administration of rhG-CSF had identical effects on the peak neutrophil counts in peripheral blood but, at 24 hr after injection, neutrophil counts after the s.c. dose was greater than that of the i.v. dose. These results indicate the close relationship between pharmacokinetics and pharmacodynamics of rhG-CSF in the rats.     

Levels of recombinant human granulocyte colony-stimulating factor in serum are inversely correlated with circulating neutrophil counts.

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is effective in countering chemotherapy-induced neutropenia. However, serum rhG-CSF levels cannot be maintained throughout the course of rhG-CSF therapy. The drop in serum rhG-CSF levels may vary with the duration of rhG-CSF administration or with the circulating neutrophil counts. We investigated the relationship between serum G-CSF levels and circulating neutrophil counts and the pharmacokinetics of rhG-CSF for patients with lung cancer who had been treated with myelosuppressive chemotherapy and then with subcutaneous rhG-CSF (lenograstim, 2 micrograms per kg of body weight per day). Twelve patients were randomly assigned to four groups with different rhG-CSF therapy schedules. Serum G-CSF levels were measured by an enzyme immunoassay method. Serum G-CSF levels during the rhG-CSF therapy greatly exceeded endogenous G-CSF levels and were mainly due to the presence of exogenous rhG-CSF rather than increased levels of endogenous G-CSF. Despite the duration of rhG-CSF administration, serum G-CSF levels during rhG-CSF therapy were inversely correlated with circulating neutrophil counts (r2 = 0.73, P < 0.0001). The value for the area under the concentration-time curve of rhG-CSF on the day of neutrophilia was lower than that on the day of neutropenia (P < 0.05). Our results suggest that the fall in serum G-CSF levels during rhG-CSF therapy may result from increased clearance and/or decreased absorption of rhG-CSF, two processes related to circulating neutrophil counts.     

Granulocyte transfusion therapy for infections in candidates and recipients of HPC transplantation: a comparative analysis of feasibility and outcome for community donors versus related donors

BACKGROUND: Feasibility, response to granulocyte transfusion therapy, and clinical outcome were compared among HPC transplant recipients enrolled in a prospective study of a community blood bank-based unrelated donors program, a prospective granulocyte study using family donors, and matched control patients without granulocyte transfusion therapy. STUDY DESIGN AND METHODS: Overall, 40 patients (327 collections) received granulocyte concentrates from unrelated donors, 34 patients (219 collections) received granulocyte concentrates from related donors, and 74 patients served as controls. Study entry criteria for patients included an absolute neutrophil count (ANC) of less than 200 per microL and documented invasive fungal or bacterial infections. RESULTS: There was a median delay of 3 days (range, 0-14) in patients receiving transfusions from unrelated donors between day of diagnosis of infection and start of granulocyte transfusion therapy as compared with a median delay of 5 days (range, 0-25) in patients receiving transfusions from related donors (p = 0.01). The ANC increment after the first, second, and seventh transfusions in patients who had community donors was significantly higher or comparable to patients who had family donors. Overall, clinical outcome was comparable between the three patient groups. Kaplan-Meier analysis revealed no difference between all cohorts in overall 6-month survival (p = 0.28, log-rank) or event-free survival (p = 0.17, log-rank). CONCLUSION: These results suggest that future efficacy trials should consider inclusion of unrelated community donors for timely institution of granulocyte transfusion therapy.