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

Granulocyte-colony stimulating factor in experimental stroke and its effects on infarct size and functional outcome: a systematic review

Background Granulocyte-colony stimulating factor (G-CSF) shows promise as a treatment for stroke. This systematic review assesses G-CSF in experimental ischaemic stroke. Methods Relevant studies were identified with searches of Medline, Embase and PubMed. Data were extracted on stroke lesion size, neurological outcome and quality, and analysed using Cochrane Review Manager using random effects models; results are expressed as standardised mean difference (SMD) and odds ratio (OR). Results Data were included from 19 publications incorporating 666 animals. G-CSF reduced lesion size significantly in transient (SMD -1.63, p4 weeks post ischaemia) was not (SMD 0.76, p=0.35). Death (OR 0.27, p<0.0001) was reduced with G-CSF. Median study quality was 4 (range 0-7/8); Egger’s test suggested significant publication bias (p=0.001). Conclusions G-CSF significantly reduced lesion size in transient but not permanent models of ischaemic stroke. Motor impairment and death were also reduced. Further studies assessing dose-response, administration time, length of ischaemia and long-term functional recovery are needed

Antithymocyte Globulin Plus G-CSF Combination Therapy Leads to Sustained Immunomodulatory and Metabolic Effects in a Subset of Responders With Established Type 1 Diabetes.

Low-dose antithymocyte globulin (ATG) plus pegylated granulocyte colony-stimulating factor (G-CSF) preserves β-cell function for at least 12 months in type 1 diabetes. Herein, we describe metabolic and immunological parameters 24 months following treatment. Patients with established type 1 diabetes (duration 4-24 months) were randomized to ATG and pegylated G-CSF (ATG+G-CSF) (N = 17) or placebo (N = 8). Primary outcomes included C-peptide area under the curve (AUC) following a mixed-meal tolerance test (MMTT) and flow cytometry. "Responders" (12-month C-peptide ≥ baseline), "super responders" (24-month C-peptide ≥ baseline), and "nonresponders" (12-month C-peptide &lt; baseline) were evaluated for biomarkers of outcome. At 24 months, MMTT-stimulated AUC C-peptide was not significantly different in ATG+G-CSF (0.49 nmol/L/min) versus placebo (0.29 nmol/L/min). Subjects treated with ATG+G-CSF demonstrated reduced CD4+ T cells and CD4+/CD8+ T-cell ratio and increased CD16+CD56hi natural killer cells (NK), CD4+ effector memory T cells (Tem), CD4+PD-1+ central memory T cells (Tcm), Tcm PD-1 expression, and neutrophils. FOXP3+Helios+ regulatory T cells (Treg) were elevated in ATG+G-CSF subjects at 6, 12, and 18 but not 24 months. Immunophenotyping identified differential HLA-DR expression on monocytes and NK and altered CXCR3 and PD-1 expression on T-cell subsets. As such, a group of metabolic and immunological responders was identified. A phase II study of ATG+G-CSF in patients with new-onset type 1 diabetes is ongoing and may support ATG+G-CSF as a prevention strategy in high-risk subjects

G-CSF Prevents the Progression of Structural Disintegration of White Matter Tracts in Amyotrophic Lateral Sclerosis: A Pilot Trial

Background: The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) has neuroprotective and regenerative properties. The G-CSF receptor is expressed by motoneurons, and G-CSF protects cultured motoneuronal cells from apoptosis. It therefore appears as an attractive and feasible drug candidate for the treatment of amyotrophic lateral sclerosis (ALS). The current pilot study was performed to determine whether treatment with G-CSF in ALS patients is feasible.Methods: Ten patients with definite ALS were entered into a double-blind, placebo-controlled, randomized trial. Patients received either 10 mu g/kg BW G-CSF or placebo subcutaneously for the first 10 days and from day 20 to 25 of the study. Clinical outcome was assessed by changes in the ALS functional rating scale (ALSFRS), a comprehensive neuropsychological test battery, and by examining hand activities of daily living over the course of the study (100 days). The total number of adverse events (AE) and treatment-related AEs, discontinuation due to treatment-related AEs, laboratory parameters including leukocyte, erythrocyte, and platelet count, as well as vital signs were examined as safety endpoints. Furthermore, we explored potential effects of G-CSF on structural cerebral abnormalities on the basis of voxel-wise statistics of Diffusion Tensor Imaging (DTI), brain volumetry, and voxel-based morphometry.Results: Treatment was well-tolerated. No significant differences were found between groups in clinical tests and brain volumetry from baseline to day 100. However, DTI analysis revealed significant reductions of fractional anisotropy (FA) encompassing diffuse areas of the brain when patients were compared to controls. On longitudinal analysis, the placebo group showed significant greater and more widespread decline in FA than the ALS patients treated with G-CSF.Conclusions: Subcutaneous G-CSF treatment in ALS patients appears as feasible approach. Although exploratory analysis of clinical data showed no significant effect, DTI measurements suggest that the widespread and progressive microstructural neural damage in ALS can be modulated by G-CSF treatment. These findings may carry significant implications for further clinical trials on ALS using growth factors

Eradication of chronic myeloid leukemia stem cells: a novel mathematical model predicts no therapeutic benefit of adding G-CSF to imatinib

Imatinib mesylate induces complete cytogenetic responses in patients with chronic myeloid leukemia (CML), yet many patients have detectable BCR-ABL transcripts in peripheral blood even after prolonged therapy. Bone marrow studies have shown that this residual disease resides within the stem cell compartment. Quiescence of leukemic stem cells has been suggested as a mechanism conferring insensitivity to imatinib, and exposure to the Granulocyte-Colony Stimulating Factor (G-CSF), together with imatinib, has led to a significant reduction in leukemic stem cells in vitro. In this paper, we design a novel mathematical model of stem cell quiescence to investigate the treatment response to imatinib and G-CSF. We find that the addition of G-CSF to an imatinib treatment protocol leads to observable effects only if the majority of leukemic stem cells are quiescent; otherwise it does not modulate the leukemic cell burden. The latter scenario is in agreement with clinical findings in a pilot study administering imatinib continuously or intermittently, with or without G-CSF (GIMI trial). Furthermore, our model predicts that the addition of G-CSF leads to a higher risk of resistance since it increases the production of cycling leukemic stem cells. Although the pilot study did not include enough patients to draw any conclusion with statistical significance, there were more cases of progression in the experimental arms as compared to continuous imatinib. Our results suggest that the additional use of G-CSF may be detrimental to patients in the clinic

Effect in supralethally irradiated rats of granulocyte colony- stimulating factor and lisofylline on hematopoietic reconstitution by syngeneic bone marrow or whole organ passenger leukocytes

We have previously shown the existence of migratory hematopoietic stem cells in adult solid organs. This study demonstrates that granulocyte colony- stimulating factor (G-CSF) and lisofylline, a phosphatidic acid inhibitor that suppresses hematopoiesis-inhibiting cytokines, can enhance the engraftment of organ-based hematopoietic stem cells. When syngeneic heart grafts or liver nonparenchymal cells were transplanted into lethally irradiated (9.5 Gy) Lewis rats, complete hematopoietic reconstitution and animal survival were significantly improved by treating the recipient with G- CSF or, to a lesser extent, with lisofylline. Pretreatment of hepatic nonparenchymal cell donors with G-CSF, but not lisofylline, also resulted in striking improvement of recipient survival which was associated with an augmented subpopulation of donor stem cells. The results suggest that these drugs can be used to enhance the chimerism that we postulate to be the basis of organ allograft acceptance

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in patients with non-Hodgkin's lymphoma in the United Kingdom (UK)

Introduction: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for prevention of febrile neutropenia (FN) following chemotherapy for non-Hodgkin’s lymphoma (NHL) in the United Kingdom (UK). Methods: A mathematical model was constructed simulating the experience of patients with NHL undergoing chemotherapy. Three strategies were modelled: primary prophylaxis (G-CSFs administered in all cycles); secondary prophylaxis (G-CSFs administered in all cycles following an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim; lenograstim and pegfilgrastim. Costs were taken from UK databases and utility values from published sources with the base case analysis using list prices for G-CSFs and a willingness to pay (WTP) threshold of £20,000 per QALY gained. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. Results: In the base-case analysis the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 22%, secondary prophylaxis with pegfilgrastim for baseline FN risk 8-22%, and no G-CSFs for baseline FN risk less than 8%. Using a WTP threshold of £30,000, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 16%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. Conclusions: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on underlying FN risk level, patient age, and G-CSF price

Cost-effectiveness of granulocyte colony-stimulating factor prophylaxis for febrile neutropenia in patients with non-Hodgkin's lymphoma in the United Kingdom (UK)

Introduction: We report a cost-effectiveness evaluation of granulocyte colony-stimulating factors (G-CSFs) for prevention of febrile neutropenia (FN) following chemotherapy for non-Hodgkin’s lymphoma (NHL) in the United Kingdom (UK). Methods: A mathematical model was constructed simulating the experience of patients with NHL undergoing chemotherapy. Three strategies were modelled: primary prophylaxis (G-CSFs administered in all cycles); secondary prophylaxis (G-CSFs administered in all cycles following an FN event), and no G-CSF prophylaxis. Three G-CSFs were considered: filgrastim; lenograstim and pegfilgrastim. Costs were taken from UK databases and utility values from published sources with the base case analysis using list prices for G-CSFs and a willingness to pay (WTP) threshold of £20,000 per QALY gained. A systematic review provided data on G-CSF efficacy. Probabilistic sensitivity analyses examined the effects of uncertainty in model parameters. Results: In the base-case analysis the most cost-effective strategy was primary prophylaxis with pegfilgrastim for a patient with baseline FN risk greater than 22%, secondary prophylaxis with pegfilgrastim for baseline FN risk 8-22%, and no G-CSFs for baseline FN risk less than 8%. Using a WTP threshold of £30,000, primary prophylaxis with pegfilgrastim was cost-effective for baseline FN risks greater than 16%. In all analyses, pegfilgrastim dominated filgrastim and lenograstim. Sensitivity analyses demonstrated that higher WTP threshold, younger age, or reduced G-CSF prices result in G-CSF prophylaxis being cost-effective at lower baseline FN risk levels. Conclusions: Pegfilgrastim was the most cost-effective G-CSF. The most cost-effective strategy (primary or secondary prophylaxis) was dependent on underlying FN risk level, patient age, and G-CSF price

Predictive value of hematological and phenotypical parameters on postchemotherapy leukocyte recovery

Background: Grade IV chemotherapy toxicity is defined as absolute neutrophil count &lt;500/μL. The nadir is considered as the lowest neutrophil number following chemotherapy, and generally is not expected before the 7th day from the start of chemotherapy. The usual prophylactic dose of rHu-G-CSF (Filgrastim) is 300 μg/day, starting 24-48 h after chemotherapy until hematological recovery. However, individual patient response is largely variable, so that rHu-G-CSF doses can be different. The aim of this study was to verify if peripheral blood automated flow cytochemistry and flow cytometry analysis may be helpful in predicting the individual response and saving rHu-G-CSF. Methods: During Grade IV neutropenia, blood counts from 30 cancer patients were analyzed daily by ADVIA 120 automated flow cytochemistry analyzer and by Facscalibur flow cytometer till the nadir. "Large unstained cells" (LUCs), myeloperoxidase index (MPXI), blasts, and various cell subpopulations in the peripheral blood were studied. At nadir rHu-G-CSF was started and 81 chemotherapy cycles were analyzed. Cycles were stratified according to their number and to two dose-levels of rHuG-CSF needed to recovery (300-600 vs. 900-1200 μg) and analyzed in relation to mean values of MPXI and mean absolute number of LUCs in the nadir phase. The linear regressions of LUCs % over time in relation to two dose-levels of rHu-G-CSF and uni-multivariate analysis of lymphocyte subpopulations, CD34+ cells, MPXI, and blasts were also performed. Results: In the nadir phase, the increase of MPXI above the upper limit of normality (&gt;10; median 27.7), characterized a slow hematological recovery. MPXI levels were directly related to the cycle number and inversely related to the absolute number of LUCs and CD34 +/CD45+ cells. A faster hematological recovery was associated with a higher LUC increase per day (0.56% vs. 0.25%), higher blast (median 36.7/μL vs. 19.5/μL) and CD34+/CD45+ cell (median 2.2/μL vs. 0.82/μL) counts. Conclusions: Our study showed that some biological indicators such as MPXI, LUCs, blasts, and CD34 +/CD45+ cells may be of clinical relevance in predicting individual hematological response to rHu-G-CSF. Special attention should be paid when nadir MPXI exceeds the upper limit of normality because the hematological recovery may be delayed. © 2009 Clinical Cytometry Society