Recombinant Methionyl Granulocyte Colony-stimulating Factor Research Articles

Filgrastim, a Recombinant Form of Granulocyte Colony-stimulating Factor, Ameliorates 3-nitropropionic Acid and Haloperidol-induced Striatal Neurotoxicity in Rats.

Striatal neurotoxicity is the pathological hallmark for a heterogeneous group of movement disorders like Tardive dyskinesia (TD) and Huntington's disease (HD). Both diseases are characterized by progressive impairment in motor function. TD and HD share common features at both cellular and subcellular levels. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor (GCSF), shows neuroprotective properties in in-vivo models of movement disorders. This study seeks to evaluate the neuroprotective effect of filgrastim in haloperidol and 3-NP-induced neurotoxicity in rats. The study was divided into two: in study one, rats were administered with haloperidol for 21days, filgrastim at the dose of (20, 40, 60µg/kg,s.c.) was administered once a day before haloperidol treatment and the following parameters (orofacial movements, rotarod, actophotometer) were performed to assess TD. Similarly, in the second study, rats were administered with 3-NP for 21days, filgrastim at a dose of (20 and 40µg/kg, s.c.) was administered, and the following parameters (rotarod, narrow beam walk, and open field test) were assessed for HD. On the 22nd day, animals were sacrificed and cortex and striatum isolated for oxidative stress (LPO, GSH, SOD, catalase, and nitrate) marker assessment. Results revealed that haloperidol and 3-NP treatment significantly impaired motor coordination, and oxidative defense inducing TD and HD-like symptoms. Treatment with filgrastim significantly averted haloperidol and 3-NP-induced behavioral and biochemical alterations. Conclusively, the neuroprotective effect of filgrastim is credited to its antioxidant properties. Hence, filgrastim might be a novel therapeutic candidate for the management of TD and HD.

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects.

All current treatments of Parkinson's disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.

A Phase 3, Randomized, Placebo-Controlled Trial of Filgrastim in Patients (Pts) with Hematologic Malignancies (HM) Treated with a Myeloablative Conditioning Regimen and Allogenic Bone Marrow Transplantation (allo BMT).

Background. Recombinant methionyl granulocyte colony-stimulating factor (methuG-CSF; Filgrastim) is commonly used to reduce the duration of neutropenia that follows allo BMT performed after high-dose chemo-/radiotherapy (HDT) in pts with HM. Recently, a retrospective chart review suggested that leukemic pts treated with G-CSF after allo BMT had faster neutrophil recovery, but slower platelet engraftment, increased risk of graft vs host disease (GvHD), and reduced survival relative to pts who did not receive G-CSF (Ringdén et al, 2004). The present double-blind, randomized, placebo-controlled, multicenter phase 3 study was designed to evaluate the effects of Filgrastim treatment on neutrophil recovery. Pts were to be followed for 2 years.Methods. Eligible pts were aged 12–55 and scheduled for allo BMT from a sibling donor preceded by high-dose chemotherapy +/− total body irradiation for treatment of acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL), high-risk non-Hodgkin's lymphoma (NHL), acute myeloid leukemia (AML), or chronic myeloid leukemia (CML). Pts were randomized to receive either Filgrastim (5μg/kg/day) or placebo from transplant until recovery of an absolute neutrophil count (ANC) of ≥0.5x109/L or for a maximum of 42 days. Randomization was stratified by age (<18 and ≥18 years) and remission status (1st complete remission/subsequent remissions) within each center. The primary endpoint was the time to ANC of ≥0.5x109/L. Assuming a standard deviation of 3.8 days, the study was powered to have a probability of at least 80% of detecting a difference of at least 3.6 days between the groups for the endpoint of time to ANC ≥0.5x109/L using a two-tailed significance of 5%.Results. The first pt was enrolled in 1993; however, the planned sample size of 100 pts (50 per arm) was not reached due to slow enrollment and the study was terminated in 1996. A total of 66 pts were enrolled; of these, 51 were analysed (25 Filgrastim, 26 placebo). Filgrastim-treated pts achieved an ANC of ≥0.5x109/L at a median (quartiles) time of 15 (13, 16) days compared with 19 (17, 22) days for placebo; ANC ≥1.0x109/L was reached by 16 (15, 17) and 22 (21, 28) days, respectively. Median (quartiles) time to discharge from hospital was 30 (26, 43) days for Filgrastim vs 36 (28, 42) days for placebo. The number of pts with platelet count ≥25x109/L within 56 days was 16 for Filgrastim vs 23 for placebo, and 12 vs 18, respectively, for platelet count ≥50x109/L within 56 days. The incidence, maximum severity and number of days to onset of acute GvHD were similar across the groups. No difference in adverse events was reported; 4 Filgrastim pts died (0 of disease progression) and 8 placebo pts died (3 of disease progression).Conclusion. The results of this phase 3, double-blind, placebo-controlled, randomized trial in pts with HM receiving allo BMT may suggest that Filgrastim treatment enhances neutrophil engraftment with no negative impact on platelet recovery or GvHD.

Reduction by Granulocyte Colony-Stimulating Factor of Fever and Neutropenia Induced by Chemotherapy in Patients with Small-Cell Lung Cancer

Background. Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Methods. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, <1.0×10 9 per liter, with a temperature ≥38.2 o C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide

Effective stimulation of donors for granulocyte transfusions with recombinant methionyl granulocyte colony-stimulating factor [see comments

Effective granulocyte transfusion (GT) therapy has been hampered by the low yield of neutrophil granulocytes (PMN) obtainable from normal donors even by use of corticosteroid prestimulation, hydroxyethyl starch (HES), and modern leukapheresis (LA) techniques. To increase the PMN yield we performed LA in 22 healthy volunteer donors after a single subcutaneous administration of 300 micrograms of granulocyte colony- stimulating factor (G-CSF) 12 to 16 hours before LA. Five to 7 L of blood was processed within 1.9 to 3 hours using the standard CS- 3000Plus (Baxter, Deerfield, IL) LA protocol including HES. The mean number of PMN harvested was 44.32 +/- 15.5 x 10(9), corresponding to 6.88 +/- 2.1 x 10(9)/L of blood processed. In the final product PMN functions (in vitro: chemotaxis, phagocytosis, chemiluminescence, superoxide anion production; in vivo: chemiluminescence, half-life) were at least normal. In all donors G-CSF induced a consistent increase of white blood cell (mean 16.46 +/- 3.8 x 10(9)/L) and PMN counts (15.94 +/- 3.6 x 10(9)/L). No G-CSF-related side effects were observed and LA was well tolerated. G-CSF prestimulation allows to harvest three to five times higher numbers of functionally normal PMN by LA compared with corticosteroid pretreatment. This may help to overcome one of the major limitations of an effective PMN support.

Reduction by Granulocyte Colony-Stimulating Factor of Fever and Neutropenia Induced by Chemotherapy in Patients with Small-Cell Lung Cancer

Neutropenia and infection are major dose-limiting side effects of chemotherapy. Previous studies have suggested that recombinant methionyl granulocyte colony-stimulating factor (G-CSF) can reduce chemotherapy-related neutropenia in patients with cancer. We conducted a randomized clinical trial to test this hypothesis and the clinical implications. Patients with small-cell lung cancer were enrolled in a multicenter, randomized, double-blind, placebo-controlled trial of recombinant methionyl G-CSF to study the incidence of infection as manifested by fever with neutropenia (absolute neutrophil count, less than 1.0 x 10(9) per liter, with a temperature greater than or equal to 38.2 degrees C) resulting from up to six cycles of chemotherapy with cyclophosphamide, doxorubicin, and etoposide. The patients were randomly assigned to receive either placebo or G-CSF, with treatment beginning on day 4 and continuing through day 17 of a 21-day cycle. The safety of the study treatment could be evaluated in 207 of the 211 patients assigned to either drug, and its efficacy in 199. At least one episode of fever with neutropenia occurred in 77 percent of the placebo group, as compared with 40 percent of the G-CSF group (P less than 0.001). Over all cycles of chemotherapy, the median duration of grade IV neutropenia (absolute neutrophil count, less than 0.5 x 10(9) per liter) was six days with placebo as compared with one day with G-CSF. During cycles of blinded treatment, the number of days of treatment with intravenous antibiotics, the number of days of hospitalization, and the incidence of confirmed infections were reduced by approximately 50 percent when G-CSF was given, as compared with placebo. Mild-to-moderate medullary bone pain occurred in 20 percent of the patients receiving G-CSF. The use of G-CSF as an adjunct to chemotherapy in patients with small-cell cancer of the lung was well tolerated and led to reductions in the incidence of fever with neutropenia and culture-confirmed infections; in the incidence, duration, and severity of grade IV neutropenia; and in the total number of days of treatment with intravenous antibiotics and days of hospitalization.