Effect Of Filgrastim Research Articles

Breast tumor metastasis following filgrastim administration due to the SDF-1/CXCR4 pathway.

Filgrastim, a recombinant type of granulocyte-colony stimulating factor (G-CSF), has a high potential to manage chemotherapy-induced leukopenia. It can increase stromal cell-derived factor 1 (SDF-1) which may stimulate C-X-C chemokine receptor type 4 (CXCR4) to migrate bone marrow-derived stem/progenitor cells to the bloodstream. Here, we aimed to investigate in vitro and in vivo effects of filgrastim on cell migration, invasion, and metastasis. A lentivirus vector of the anti-CXCR4 receptor was first used for the CXCR4 knockout. Effects of filgrastim on cell proliferation and migration were then investigated on 4T1 cells by Transwell migration and wound healing assay. At last, the effects of filgrastim on cell metastasis and the possible involved mechanisms have been investigated in a metastatic murine breast tumor. The knockout of the CXCR4 receptor could lead to a decrease in cell proliferation, migration, and invasion of the 4T1 cells. Filgrastim could directly target SDF-1 and upregulate the expression of the CXCR4 receptor. The knockout of the CXCR4 receptor reduced cell metastasis in an animal model of breast cancer. CXCR4 receptor stimulation by the filgrastim-affected pathways is a conserved evolutionary response that could increase cancer cell proliferation and consequent cell metastasis. Our results suggest that the activation of the CXCR4 receptor is a conserved evolutionary response that can increase cell proliferation, migration, and consequent metastasis. It seems that filgrastim may increase the chance of cancer cell metastasis in people continuously receiving it to increase the number of neutrophils. Filgrastim induces the SDF-1/CXCR4 axis on tumor cell growth. SDF-1 and its receptor CXCR4 are vital targets for filgrastim. The CXCR4 can stimulate the PI3K/AKT, NF-κB, and JAK/STAT signaling pathways. The SDF-1/CXCR4 pathway promotes cell chemotaxis and proliferation via MAPKs signaling. It also enhances cell survival, proliferation, and angiogenesis, increasing tumor cell metastasis. The STAT3-mediated inflammation is essential for tumorigenesis processes, and Akt, Wnt, STAT3, and CXCR4 signaling pathways are all correlated. CXCR4 = C-X-C chemokine receptor type 4, SDF-1 = stromal-derived-factor-1, MAPK = mitogen activated protein kinase; NF-κB = nuclear factor-κB, PI3K = phosphoinositide 3-kinase, JAK = Janus kinase, STAT = signal transducer and activator of transcription, PLC = phospholipase C, PKC = Protein kinase C, GRK = G protein-coupled receptor kinase.

Comparative study on the effects of filgrastim and pegfilgrastim in the treatment of fever and neutropenia in patients with leukemia in the west of Iran

Background: The current research seeks to present a comparative study of the effect of filgrastim and pegfilgrastim in the treatment of fever and neutropenia in leukemia patients.
 Materials and Methods: The present study is a blind randomized clinical trial. The study population is comprised of 120 children with acute lymphoblastic leukemia (ALL) who were admitted to the hospital due to mild febrile neutropenia during 2019. Included patients were divided into two groups. Filgrastim (10 micrograms/ kilogram, daily subcutaneously) and pegfilgrastim (100 micrograms per kilogram of a subcutaneous dose) were used for groups, respectively. Fever monitored every 6 hours, and neutrophil count was performed every 48 hours. The questionnaire designed in the study included age, type of drug side effects, number of days of neutropenia, and fever cessation time. Then, the data were analyzed by SPSS software.
 Result: Leukemic children with fever and neutropenia (N=120) were included in the study, which was 59 (49.1%) male and 61 (50.9%) female by the mean age of 79±44 months. The mean days of neutropenia correction in the filgrastim and pegfilgrastim groups were 5 and 4 days, respectively, which was not significantly different (p =0.08). There was no correlation between patients’ complications and types of treatments (p>0.05). Muscular pain was the most common complication observed among 4 cases and 1 case following filgrastim and pegfilgrastim administration, respectively. Furthermore, hyperleukocytosis following pegfilgrastim consumption was observed in two cases.
 Conclusion: There was no significant correlation between the duration until the cessation of fever and the number of neutropenia days in the two groups receiving pegfilgrastim and filgrastim. Therefore, the fever and neutropenia improve with pegfilgrastim earlier than filgrastim; besides, fewer injections, patient comfort, and less musculoskeletal pain can be observed.

Effects of Ocimum tenuiflorum on Induced Testicular Degeneration by Filgrastim in Wistar Rats.

Since the creation of man on earth, herbal remedies have been used as an invaluable, safe, and available natural source of medicine for the treatment of several dysfunctions in living animals and human beings. The pharmacological properties of these herbs are commonly known to include analgesic, antidiabetic, antispasmodic, hepatoprotective, reproductive, and cardioprotective potentials. Various nutritional, environmental, and physiological factors can affect the male reproductive system. Several herbal remedies are reported to target the testis at the spermatogenesis and hormonal level. Most of the chemotherapy drugs used for treating cancers cause adverse effects on male reproductive functions. Filgrastim is used for the treatment of cancer in patients suffering from neutropenia. Ocimum tenuiflorum is one of the herbal remedies used as a natural antioxidant substance for protecting the body organs against the toxic effects of chemotherapy drugs. Therefore, the current study was designed to investigate the possible productive effects of the O. tenuiflorum against adverse effects of filgrastim on testicular tissues in male Wistar rats. In total, 40 adult male rats were selected and randomly divided into four groups (n=10). Group 1 was treated with intraperitoneal administration of filgrastim at a dose of 30.83 µg/kg/day for 1 week. Group 2 received O. tenuiflorum suspended in corn oil and administered by gavages at 20 mg/kg/day for 1 week. Group 3 was intraperitoneally injected with filgrastim at a dose of 30.83 µg/kg/day for 1 week and treated with O. tenuiflorum at similar manure to group 2. Finally, group 4 was treated with placebo (0.9% saline solution). The results showed that filgrastim administration leads to the degeneration of spermatozoa and germ cells in the testicles of rats. The results of the current study showed that O. tenuiflorum has some ameliorating effects on the testicles and fertility of the rats which were treated with filgrastim. Finally, the recorded data showed that O. tenuiflorum has protective effects on testis tissues and reproductive functions in male rats.

Analysis of ANC Levels after Filgrastim Therapy in Acute Leukemia Children with Neutropenia

Cytotoxic chemotherapy suppresses the hematopoietic system, and the most serious hematologic toxicity is neutropenia. This can decrease a risk of infection that causes delays in treatment and reduction of dose intensity, which reduces therapeutic outcome. Filgrastim is used to increase neutrophils level whose therapeutic effect is unknown. The effectiveness of filgrastim is based on the ANC level pre- and post-therapy. This study aimed to analyze the use of filgrastim on ANC level changes in acute leukemia children with neutropenia, and to analyze the patient that achieve ANC level’s targeted therapy = 1000 cell/mm3. A prospective observational study with a longitudinal design was conducted from June to October 2016. The inclusion criteria of the study were patients who diagnosed acute leukemia with neutropenia and received filgrastim 10 µg/kgBW for 3, 4, 5 days. Patients’ ANC levels were measured before and after filgrastim therapy. This study has been approved its ethical clearance by Dr. Saiful Anwar Hospital, Malang. Data were obtained on the basis of neutropenic episodes, followed by 7 episodes of obtaining filgrastim for 3 days, 1 episode of obtaining filgrastim for 4 days, and 7 episodes of obtaining filgrastim for 5 days. Thus, it consists of 15 episodes. In 3 days, ANC levels increased by 9.5 fold from 381.3 ± 91.8 cell/mm3 to 3984.9 ± 426.8 cell/mm3, but in 5 days, ANC levels decreased by 0.9 fold from 200.9 cell/mm3 ± 98.2 to 189.7 ± 14.2 cell/mm3. Filgrastim was able to increased the ANC levels around nine fold for 3 days of theraphy. There were 53% neutropenia patients who achieved the goal of therapy. Filgrastim therapy with dose 10 µg/kgBW for 3 to 5 days has been able to reach the therapeutic target of 53% in acute leukemia children with neutropenia. The increased levels of ANC maximum was reached on the third day with increased levels of 9.5 fold.

Analysis of ANC Levels after Filgrastim Therapy in Acute Leukemia Children with Neutropenia

Cytotoxic chemotherapy suppresses the hematopoietic system, and the most serious hematologic toxicity is neutropenia. This can decrease a risk of infection that causes delays in treatment and reduction of dose intensity, which reduces therapeutic outcome. Filgrastim is used to increase neutrophils level whose therapeutic effect is unknown. The effectiveness of filgrastim is based on the ANC level pre- and post-therapy. This study aimed to analyze the use of filgrastim on ANC level changes in acute leukemia children with neutropenia, and to analyze the patient that achieve ANC level’s targeted therapy = 1000 cell/mm3. A prospective observational study with a longitudinal design was conducted from June to October 2016. The inclusion criteria of the study were patients who diagnosed acute leukemia with neutropenia and received filgrastim 10 µg/kgBW for 3, 4, 5 days. Patients’ ANC levels were measured before and after filgrastim therapy. This study has been approved its ethical clearance by Dr. Saiful Anwar Hospital, Malang. Data were obtained on the basis of neutropenic episodes, followed by 7 episodes of obtaining filgrastim for 3 days, 1 episode of obtaining filgrastim for 4 days, and 7 episodes of obtaining filgrastim for 5 days. Thus, it consists of 15 episodes. In 3 days, ANC levels increased by 9.5 fold from 381.3 ± 91.8 cell/mm3 to 3984.9 ± 426.8 cell/mm3, but in 5 days, ANC levels decreased by 0.9 fold from 200.9 cell/mm3 ± 98.2 to 189.7 ± 14.2 cell/mm3. Filgrastim was able to increased the ANC levels around nine fold for 3 days of theraphy. There were 53% neutropenia patients who achieved the goal of therapy. Filgrastim therapy with dose 10 µg/kgBW for 3 to 5 days has been able to reach the therapeutic target of 53% in acute leukemia children with neutropenia. The increased levels of ANC maximum was reached on the third day with increased levels of 9.5 fold.

Effectiveness of filgrastim and polyethylene glycol-filgrastim in the treatment of postchemotherapy neutropenia in children: Phase I clinical trial

Abstract Background: One of the most common side effects of chemotherapy in cancer patients is neutropenia that can result in hospitalization. The purpose of this study was to evaluate the efficacy and tolerability of polyethylene glycol (PEG)-filgrastim compared with filgrastim in the recovery of neutropenia. Methods: This study was a Phase I clinical trial conducted among patients with acute lymphoblastic leukemia aged <16 years who were referred to the Ali Asghar Hospital, Tehran, Iran, from April 2012 until October 2013. Eleven patients were selected, and filgrastim and PEG-filgrastim were injected subcutaneously at a dose of 5–10 μg/kg/day for 7 days and 100 μg/kg as a single dose, respectively. Absolute neutrophil count (ANC) was checked 7 days after the last injection in the two groups. Results: The mean age of the patients was 8.82 ± 4.36 years (3–15 years). Six boys (54.5%) and five girls (45.5%) participated in the study. ANC increase among patients treated with PEG-filgrastim or filgrastim was analyzed separately, and the results showed statistically significant differences between the study groups (P = 0.038). Conclusions: According to the findings, it can be concluded that the PEG-filgrastim is better than filgrastim alone to improve neutropenia induced by chemotherapy in patients with acute lymphoblastic leukemia.

Pharmacokinetic-pharmacodynamic modelling of neutrophil response to G-CSF in healthy subjects and patients with chemotherapy-induced neutropenia.

The objective of the present study was to use pharmacokinetic-pharmacodynamic modelling to characterize the effects of chemotherapy on the granulopoietic system and to predict the absolute neutrophil counts (ANCs) for patients with chemotherapy-induced neutropenia treated with filgrastim and pegfilgrastim. Data were extracted from 10 phase I-III studies conducted in 110 healthy adults, and 618 adult and 52 paediatric patients on chemotherapy following administration of filgrastim or pegfilgrastim. The structural model accounted for ANC dynamics and the effects of filgrastim and pegfilgrastim, chemotherapy and corticosteroids. The impact of neutrophils on drug disposition was based on a drug receptor-binding model that assumed quasi-equilibrium and stimulation of the production and maturation of neutrophils upon treatment. The chemotherapy and corticosteroid effects were represented by kinetic-pharmacodynamic-type models, where chemotherapy stimulated elimination of neutrophil precursors at the mitotic stage, and corticosteroids stimulated neutrophil production. The systemic half-lives of filgrastim (2.6h) and pegfilgrastim (10.1h) were as expected. The effective half-life of chemotherapy was 9.6h, with a 2-day killing effect. The rate of receptor elimination from mitotic compartments exhibited extreme interindividual variability (% coefficient of variation >200), suggesting marked differences in sensitivity to chemotherapy effects on ANCs. The stimulatory effects of pegfilgrastim were significantly greater than those of filgrastim. Model qualification confirmed the predictive capability of this model. This qualified model simulates the time course of ANC in the absence or presence of chemotherapy and predicts nadir, time to nadir and time of recovery from different grades of neutropenia upon treatment with filgrastim and pegfilgrastim.

Effects of Filgrastim on Thrombocytopenia in Patients with Dengue Fever: A Retrospective Study

Effects of Filgrastim on Thrombocytopenia in Patients with Dengue Fever: A Retrospective Study

Effects of filgrastim on gene expression of cholinergic system in the rat hippocampus

Background: Filgrastim is a granulocyte colony-stimulating factor (G-CSF), which also showed effects on memory and cognation. Although recent studies have begun to explore G-CSF-related mechanisms of action in memory, little is known about its effects on cholinergic system. Since the cholinergic system has a key role in memory and some studies reported effects of G-CSF on cholinergic activity. Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) gene expression was examined in the rat frontal cortex and hippocampus. Aims and Objectives: This study was designed to investigate the effect of G-CSF treatment on gene expression of AChE and ChAT in the frontal cortex and hippocampus during learning. Materials and Methods: In this study, male Wistar rats were treated for 2 week with filgrastim intraperitoneally at doses of 10, 50, 70 μg/kg/day. All rats received Morris water maze training (4 trials/day for 5 days). Moreover, ChAT and AChE gene expression was assessed by real-time polymerase chain reaction in the rat frontal cortex and hippocampus. Results: Over 5 days of training, filgrastim at doses 10, 50 and 70 μg/kg/day did not change the gene expression of ChAT and AChE in frontal cortex and hippocampus although at dose of 50 ug/kg a little changes but not significant observed. Conclusions: The findings observed in this study propose that G-CSF memory enhancer effects doesn’t only cholinergic and other mechanism may be involve.

A cell-level model of pharmacodynamics-mediated drug disposition.

We aimed to develop a cell-level pharmacodynamics-mediated drug disposition (PDMDD) model to analyze in vivo systems where the PD response to a drug has an appreciable effect on the pharmacokinetics (PK). An existing cellular level model of PD stimulation was combined with the standard target-mediated drug disposition (TMDD) model and the resulting model structure was parametrically identifiable from typical in vivo PK and PD data. The PD model of the cell population was controlled by the production rate k in and elimination rate k out which could be stimulated or inhibited by the number of bound receptors on a single cell. Simulations were performed to assess the impact of single and repeated dosing on the total drug clearance. The clinical utility of the cell-level PDMDD model was demonstrated by fitting published data on the stimulatory effects of filgrastim on absolute neutrophil counts in healthy subjects. We postulated repeated dosing as a means of detecting and quantifying PDMDD as a single dose might not be sufficient to elicit the cellular response capable of altering the receptor pool to visibly affect drug disposition. In the absence of any PD effect, the model reduces down to the standard TMDD model. The applications of this model can be readily extended to include chemotherapy-induced cytopenias affecting clearance of endogenous hematopoietic growth factors, different monoclonal antibodies and immunogenicity effects on PK.

The effect of filgrastim or pegfilgrastim on survival outcomes of patients with cancer receiving myelosuppressive chemotherapy

Primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) is associated with higher chemotherapy relative dose intensity, which may lead to improved outcomes; however, the association between G-CSF primary prophylaxis and overall survival (OS) is not well characterized. This study assessed the effect of G-CSF primary prophylaxis on patient outcomes in randomized, controlled, registrational clinical trials of filgrastim and pegfilgrastim. Three placebo-controlled and two non-inferiority clinical trials of filgrastim and/or pegfilgrastim in patients receiving myelosuppressive chemotherapy for lung, breast, or colorectal cancer were included. The median OS, 6- and 12-month survival rates, and hazard ratios [HRs; unadjusted Cox model with 95% confidence intervals (CIs)] were estimated for patients receiving ≥1 dose of filgrastim, pegfilgrastim, or placebo. Comparisons were based on a log-rank test. A fixed-effect meta-analysis assessed the effect of primary prophylaxis with filgrastim/pegfilgrastim on OS in the placebo-controlled trials. In patients with lung cancer receiving filgrastim versus placebo, the median OS was 14.1 versus 11.1 months (HR, 0.81; 95% CI 0.48-1.35; P = 0.412); in patients who crossed over to filgrastim from placebo after cycle 1, the median OS was 16.9 months (HR, 0.75; 95% CI 0.43-1.28; P = 0.286). The median OS was inestimable in at least one treatment arm in the other studies because of the small number of OS events. Where estimable, 6- and 12-month survival rates were generally greater among patients receiving filgrastim/pegfilgrastim versus placebo. In the meta-analysis of placebo-controlled studies comparing G-CSF primary prophylaxis with placebo in the as-treated analysis sets, the HR (95% CI) for OS was 0.77 (0.58-1.03). In this retrospective analysis, OS point estimates were greater among patients receiving filgrastim versus placebo, but the differences were not statistically significant. Further studies evaluating patient outcomes with G-CSF prophylaxis are warranted. NCT00035594, NCT00094809.

Effect of filgrastim (recombinant human granulocyte colony stimulating factor) on spatial memory in aged rats

Background: Apart from functioning as a multimodal hematopoietic growth factor, granulocyte colony-stimulating factor (G-CSF) causes intense consequences on the brain. It has been viewed that G-CSF boosts the improvement from the neurologic deficits in rodent models of central nervous system diseases. Aims and Objective: To evaluate the efficacy of G-CSF as an intervention for improving cognitive deficits commonly associated with aging. Materials and Methods: In this study, male Wistar rats aged 21 months were treated for 2 weeks with G-CSF intraperitoneally at doses of 10, 50, and 70 mg/kg/day. The learning process was assessed by the reference memory task in the Morris water maze, by comparing the G-CSF–treated group with the control animals. All the rats received Morris water maze training (four trials/day for 5 days) in order to assess the hippocampal-dependent spatial learning and received a 60-s probe trial test of spatial memory retention 24 h after the twentieth trial. Result: Over 5 days of training, G-CSF (10, 50, and70 mg/kg/day) significantly reduced the latency and path length to finding the escape platform (P < 0.01). In probe trials (without platform), on the last day of training, the G-CSF–treated group spent significantly longer time in the platform quadrant when compared with the control animals (P < 0.01). Among the treated groups, the 50-mg/kg dosage of G-CSF induced the best rehearsals memory. Conclusion: The findings observed in this study support G-CSF as a promising therapeutic aid for cognitive enhancement in the aging phenomenon. © 2015 Hamid Sepehri.

Effect of filgrastim (recombinant human granulocyte colony stimulating factor) on IgE responses in human asthma: A case study

RationaleThe role of peripheral blood progenitor cell mobilization on Immunoglobulin E (IgE) responses has not been studied. MethodsDistributions of blood lymphocytes (CD4+, CD8+, CD8+CD60+, CD19+, CD23+, CD16/56+, CD25, CD45RA+, CD45RO+, CD34+), and levels of serum immunoglobulins (IgM, IgG, IgA, IgE) were studied in an allergic asthmatic serum IgE+ (181IU/mL) adult (m/45 y/o) donor undergoing routine stem cell mobilization protocol (American Society of Hematology) before (day-30), during (day 4), and after (1wk post last dose) filgrastim (subcutaneous, 480 mcg, 2qd) treatment (flow cytometry, nephelometry, UniCAP Total IgE Fluoro enzyme immunoassay). ResultsOn day 4 of filgrastim treatment, numbers of CD8+CD60+T cells and CD23+ blood cells dramatically increased (98% and 240% respectively) compared with pre treatment. In contrast on day 4 of treatment, serum IgE levels decreased (>50%) compared with pre treatment. CD8+CD60+T cells and CD23+ blood cells and serum IgE levels approached pre-treatment levels at 1week post treatment. ConclusionsFilgrastim treatment transiently increases numbers of CD8+CD60+T and CD23+ expressing cells, which are known to regulate human IgE responses, while also transiently suppressing ongoing IgE responses. These results suggest that filgrastim affects IgE related responses, and may be useful in modulating allergic responses.

Comparative effectiveness of pegfilgrastim, filgrastim, and sargramostim prophylaxis for neutropenia-related hospitalization: two US retrospective claims analyses

Objective:Few studies have compared the effectiveness of filgrastim (FIL), pegfilgrastim (PEG), and sargramostim (SAR) to reduce the risk of febrile neutropenia (FN) associated with myelosuppressive chemotherapy (M-CT). Two large commercial database analyses were separately conducted to examine the incidence of neutropenia-related and all-cause hospitalizations associated with FIL, PEG, and SAR prophylaxis for patients receiving M-CT for non-Hodgkin lymphoma (NHL), Hodgkin lymphoma, or solid tumors.Methods:Separate retrospective US claims database analyses utilized patient data from January 1, 2004 to April 30, 2010 using the HealthCore Integrated Research Database (HIRDSM) and January 1, 2001 to August 31, 2009 using OptumInsight’s (formerly Ingenix) database. Patients were ≥18 years old and treated with M-CT for NHL, Hodgkin lymphoma, and solid tumors. All identified M-CT cycles with prophylactic (first 5 days of cycle) FIL, PEG, or SAR were included in the analysis. Patterns of administration and incidence rates of all-cause and neutropenia-related hospitalization were examined on a per-cycle basis.Results:In total, 9330 and 8762 patients with cancer, representing 30,264 and 24,215 chemotherapy cycles (28,189 and 22,649 (PEG), 1669 and 1351 (FIL), 406 and 215 (SAR)) from the HIRDSM and OptumInsight databases, respectively, were included in the separate database analyses. Both the HIRDSM and OptumInsight analysis showed that SAR and FIL prophylaxis had a higher risk of neutropenia-related hospitalization (SAR: OR = 3.48 [95%CI = 2.11, 5.74] and 2.81 [1.62, 4.87]; FIL: 1.78 [1.28, 2.48] and 2.36 [1.82, 3.06], respectively) and all-cause hospitalization (SAR: 2.18 [1.41, 3.36] and 2.41 [1.58, 3.68]; FIL:1.57 [1.25, 1.97] and 1.95 [1.60, 2.38], respectively) vs PEG.Limitations:Medical claims do not contain information about chemotherapy dose, and hospitalizations were not validated against the patient’s chart.Conclusion:In this comparative effectiveness study, use of PEG was associated with a lower risk of neutropenia-related and all-cause hospitalizations compared to use of FIL or SAR prophylaxis.

Effect of filgrastim (recombinant human granulocyte colony stimulating factor) on IgE responses in human asthma (48.1)

Abstract Rationale: The role of peripheral blood progenitor cell mobilization on IgE responses has not been studied. Methods: Distributions of blood lymphocytes (CD4+, CD8+, CD8+CD60+, CD19+, CD23+, CD16/56+, CD25, CD45RA+, CD45RO+, CD34+), and levels of serum immunoglobulins (IgM, IgG, IgA, IgE) were studied in an allergic asthmatic serum IgE+ (181 IU/mL) adult (m/45 y/o) donor undergoing routine stem cell mobilization protocol (American Society of Hematology) before (day -30), during (day 4), and after (1 wk post last dose) filgrastim (subcutaneous, 480 mcg, 2qd) treatment (flow cytometry, nephelometry, UniCAP Total IgE Fluoroenzymeimmunoassay). Results: On day 4 of filgrastim treatment, numbers of CD8+CD60+ T cells and CD23+ blood cells dramatically increased (&amp;gt;2 fold); CD34+ cell numbers also increased. One week after treatment, numbers of these cells decreased to pre-treatment levels. On day 4 of treatment, serum IgE levels decreased (&amp;gt;50%). However, one week after treatment, IgE levels approached pre-treatment levels. Conclusions. Filgrastim treatment transiently increases numbers of CD8+CD60+ T cells known to regulate human IgE responses (Smith-Norowitz, et al., JI, 2008), while also transiently suppressing ongoing IgE responses. These results suggest that filgrastim might be useful in modulating allergic responses.

Effects of filgrastim on granulopoietic cells of mice pretreated with methotrexate

We have evaluated the effect of filgrastim on proliferation and differentiation activity of granulopoietic cells in mice pretreated with methotrexate. Filgrastim was injected daily, from day 8 to 28 after cytotoxic agent administration. The granulopoiesis changes were measured by assessment of GM-CFU cells content, marrow and spleen granuloid cells pool as well as circulating neutrophils. In MTX pretreated mice, bone marrow GM-CFU oscillating values were higher than normal values, but these changes were not followed by high proliferative activity in granuloid precursor cell compartment. After MTX treatment, filgrastim administration was unable to stimulate marrow granulopoiesis as observed in normal mice. In the spleen, MTX led to dramatic changes in the proliferative activity of GM-CFU cells, but did not result in spleen granuloid cell changes. However, filgrastim treatment induced a spleen granuloid amplification, similar to the changes observed in circulating neutrophils values. We suggest that these findings can be explained by inhibition of differentiation of marrow GM-CFU cells into the more mature granulopoietic cells and/or by an inhibited proliferative activity of marrow granuloid cells. They can be also explained in terms of an unfavorable marrow microenvironment for granulopoiesis, contrary to a supportive spleen microenvironment.

Effect of Filgrastim on Serum Lactate Dehydrogenase and Alkaline Phosphatase Values in Early Breast Cancer Patients

To improve chemotherapy dose intensity and to optimize the use of granulocyte-colony stimulating factor, 506 patients with early breast cancer were randomly assigned to high dose epirubicin and cyclophospamide (EC) with or without prophylactic subcutaneously filgrastim, according to 5 different schedules: 480 µg or 300 µg daily or every other day, on day 8 through day 14, and 300 µg daily on days 8 and 12 of each chemotherapy course, Serum levels of lactate dehydrogenase (LDH) and alkaline phosphatase (AP) were significantly higher in patients given EC plus filgrastim than EC alone (P + 0.0001), the rate of G1-3 toxicity being 33.4% and 13.1% vs. 1.6% and 1%, respectively. No clinical evidence of filgrastim-related hepatic damage or significant difference in transaminase and γ-GT elevation was seen between the two groups. LDH and AP closely resembled peripheral blood leukocytes count and increased with increasing leucocytosis, throughout the 5 schedules. Although no patient continued treatment for filgrastim-related side effects, and LDH and AP rises resolved spontaneously within 3 weeks following the chemotherapy course, physicians should be aware of the transient and innocuous change in serum chemistry associated to leucocytosis, since it could be misinterpreted as expression of disease activity.

Effect of filgrastim on dose intensity of adjuvant CMF with concomitant radiotherapy in patients with operable breast cancer. A prospective randomized study

Effect of filgrastim on dose intensity of adjuvant CMF with concomitant radiotherapy in patients with operable breast cancer. A prospective randomized study

Neutrophil Adhesion Molecules in Colorectal Surgery: Effect of Filgrastim given Perioperatively

To assess whether the postoperative expression of neutrophil adhesion molecules CD11b/CD18 (Mac-1) and CD62L (L-selectin) would differ in peripheral blood, peritoneal fluid and wound fluid in patients operated on for colorectal conditions, and to analyse the effect of perioperative filgrastim on their expression. Prospective randomised double-blind placebo-controlled clinical study. University hospital, Finland. Thirty consecutive patients undergoing elective colorectal operations (15 in each group). The patients were prospectively randomised to receive either filgrastim or placebo. Expression of neutrophil adhesion molecules was measured 48 hours postoperatively in peripheral blood, peritoneal fluid, and wound fluid by flow cytometry. Postoperative neutrophil CD11b/CD18 expression was higher in both wound fluid and peritoneal fluid than in peripheral blood in the placebo group. Simultaneously, the expression of neutrophil CD62L was higher in peripheral blood than in peritoneal fluid or wound fluid in both groups. Filgrastim caused increased postoperative expression of neutrophil CD11b/CD18 in peripheral blood but not in peritoneal fluid or wound fluid. Postoperative expression of neutrophil adhesion molecules differs at the local operation site from that in peripheral blood. Filgrastim increases only blood neutrophil CD11b/CD18 expression.

Population pharmacokinetic-pharmacodynamic modeling of filgrastim (r-metHuG-CSF) in healthy volunteers.

The pharmacokinetic-pharmacodynamic (PK-PD) relationship of the granulopoietic effects of Filgrastim in healthy volunteers was characterized via a population approach. Healthy male volunteers were enrolled into a four-way crossover clinical trial. Subjects received four single doses of Filgrastim (375 and 750 micrograms i.v. and s.c.) with an intervening washout period of 7 days. Serum concentrations of Filgrastim were determined using an enzyme-linked immunosorbent assay. Absolute neutrophil count (ANC) was determined. Data analysis was performed using mixed-effects modeling as implemented in the NONMEM software package. The final PKPD model incorporates a two-compartment PK model with bisegmental absorption from the s.c. site, first-order and saturable elimination pathways, and an indirect PD model. A sigmoidal Emax model for the stimulation of ANC input rate (kin) was superior to the conventional Emax model (mean +/- SE: Emax = 12.7 +/- 1.7; EC50 = 4.72 +/- 0.72 ng/ml; Hill = 1.34 +/- 0.19). In addition, a time-variant scaling factor for ANC observations was introduced to account for the early transient depression of ANC after Filgrastim administration. The absolute bioavailability of subcutaneously administered Filgrastim was estimated to be 0.619 +/- 0.058 and 0.717 +/- 0.028 for 375 micrograms and 750 micrograms s.c. doses, respectively. The time profiles of concentration and ANC, as well as the concentration approximately ANC relationship of Filgrastim in healthy volunteers were well described by the developed population PK-PD model.