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PubMed2002

Accelerated recovery from irradiation injury by angiotensin peptides.

PURPOSE: Angiotensin peptides have been shown to affect the proliferation and chemotaxis of multiple cell types. More recent studies in this laboratory have shown that angiotensin II (AII) can increase colony formation and proliferation by hematopoietic progenitors and mesenchymal cells in vitro. As white blood cell (WBC) recovery after bone marrow injury requires progenitor proliferation, the effect of AII and angiotensin (1-7) [A(1-7)], a non-hypertensive fragment of AII, on recovery from total body irradiation was evaluated in C57Bl/6 mice. MATERIALS AND METHODS: The effect of angiotensin peptides on hematopoietic recovery and the number of progenitors in the bone marrow of irradiated C57Bl/6 mice was evaluated. RESULTS: Treatment of animals with angiotensin peptides accelerated hematopoietic recovery and increased the number of hematopoietic progenitors in bone marrow and in the blood. The increase in WBC concentration continued for a longer time after cessation of AII therapy than after treatment with filgrastim. Specifically, the number of WBCs continued to increase 21 days after irradiation with 7 days of angiotensin peptide administration. In contrast, the number of WBCs increased through day 13 with 7 days of filgrastim administration. On day 35 after irradiation (28 days after the last treatment), AII was shown to have increased the number of CFU-GM in the bone marrow of irradiated mice, whereas filgrastim administration had not. Angiotensin peptides also reduced the drop in platelet concentration after irradiation and increased the number of megakaryocyte precursors and megakaryocytes in the bone marrow. Receptor blocking studies indicated that losartan, an antagonist of the angiotensin type 1 receptor, blocked recovery of WBC levels in response to treatment with AII. In contrast, the increase in WBC levels in response to treatment with A(1-7), a ligand for other angiotensin receptors, was not affected by losartan. CONCLUSIONS: These findings suggest that these peptides utilize distinct receptors in the stimulation of hematopoietic recovery. In summary, systemic administration of angiotensin peptides led to an acceleration in hematopoietic recovery after irradiation. These peptides act to stimulate the formation of bone marrow progenitors, thereby facilitating recovery after myelosuppressive irradiation.

Angiotensin I↗

PubMed2005

Glycosylated or non-glycosylated G-CSF differently influence human granulocyte functions through RhoA.

Granulocyte function may be altered after in vivo G-CSF administration and this has been related to both an immaturity of mobilized cells and to a defect in F-actin polymerization. In this paper we show that in resting Filgrastim (non-glycosylated G-CSF)-pulsed cells, F-actin polymerization, membrane-linked RhoA and cell polarization are enhanced compared to those found in resting Lenograstim (glycosylated G-CSF)-cells. The basal hyper-activation of RhoA could be responsible for the morphological and functional modifications of Filgrastim-mobilized cells. Moreover, Filgrastim-mobilized cells, but not Lenograstim-mobilized cells, are unable to correctly respond to LPS stimulation, as demonstrated by minor further RhoA activation and cell elongation.

Actins↗

PubMed2003

Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy.

BACKGROUND: Myocardial regeneration via stem-cell mobilisation at the time of myocardial infarction is known to occur, although the mechanism for stem-cell homing to infarcted tissue subsequently and whether this approach can be used for treatment of ischaemic cardiomyopathy are unknown. We investigated these issues in a Lewis rat model (ligation of the left anterior descending artery) of ischaemic cardiomyopathy. METHODS: We studied the effects of stem-cell mobilisation by use of granulocyte colony-stimulating factor (filgrastim) with or without transplantation of syngeneic cells. Shortening fraction and myocardial strain by tissue doppler imaging were quantified by echocardiography. FINDINGS: Stem-cell mobilisation with filgrastim alone did not lead to engraftment of bone-marrow-derived cells. Stromal-cell-derived factor 1 (SDF-1), required for stem-cell homing to bone marrow, was upregulated immediately after myocardial infarction and downregulated within 7 days. 8 weeks after myocardial infarction, transplantation into the peri-infarct zone of syngeneic cardiac fibroblasts stably transfected to express SDF-1 induced homing of CD117-positive stem cells to injured myocardium after filgrastim administration (control vs SDF-1-expressing cardiac fibroblasts mean 7.2 [SD 3.4] vs 33.2 [6.0] cells/mm2, n=4 per group, p<0.02) resulting in greater left-ventricular mass (1.24 [0.29] vs 1.57 [0.27] g) and better cardiac function (shortening fraction 9.2 [4.9] vs 17.2 [4.2]%, n=8 per group, p<0.05). INTERPRETATION: These findings show that SDF-1 is sufficient to induce therapeutic stem-cell homing to injured myocardium and suggest a strategy for directed stem-cell engraftment into injured tissues. Our findings also indicate that therapeutic strategies focused on stem-cell mobilisation for regeneration of myocardial tissue must be initiated within days of myocardial infarction unless signalling for stem-cell homing is re-established.

Animals↗

PubMed2002

Novel effects with polyethylene glycol modified pharmaceuticals.

Proteins undergo extensive hydrolysis in the gastrointestinal tract and have short circulating half-lives in the blood. For optimal clinical efficacy, therefore, they must be given by daily injections. Attaching a polyethylene glycol (PEG) moiety (pegylation) improves the pharmacokinetic and pharmacodynamic profiles of proteins. Pegfilgrastim (pegylated filgrastim) has a longer half-life than unmodified filgrastim and, when administered as a single dose, has been shown to be at least as efficacious as daily filgrastim. Because of its reduced renal clearance, the elimination of pegfilgrastim is predominantly neutrophil-mediated, so its clearance is self-regulated. In addition, pegfilgrastim can be administered at a fixed dose instead of in weight-based doses. For these reasons, pegfilgrastim can potentially increase patient adherence and acceptance of treatment, thus having a beneficial effect on their quality of life. Furthermore, treatment is likely to cost less because of the reduced need for medical interventions. Similarly, pegylated liposomal doxorubicin has a longer half-life than unmodified doxorubicin and has been shown, because of its reduced reticuloendothelial system clearance, to produce higher concentrations of doxorubicin in tumours and to have greater clinical efficacy than doxorubicin in the treatment of some solid tumours. Pegylated liposomal doxorubicin is also associated with less myelosuppression and febrile neutropenia.

Animals↗

PubMed2002

Clinical uses of pegylated pharmaceuticals in oncology.

A number of agents that are used in the treatment of cancer have a suboptimal pharmacokinetic profile that necessitates prolonged or repetitive administration. Pegylation of these agents may help overcome these shortcomings without compromising the agents' efficacy. Several such pegylated agents have now been developed and evaluated in patients with oncology-related disorders. Pegfilgrastim (a pegylated form of filgrastim) has shown efficacy and tolerability that are at least equivalent to those of filgrastim in patients with chemotherapy-induced neutropenia and, unlike unmodified filgrastim, is effective with only one administration per chemotherapy cycle. Other promising pegylated agents are pegylated liposomal doxorubicin, which appears to be more effective and less cardiotoxic than unmodified or liposome-encapsulated doxorubicin, and peginterferon alpha-2a, as once-weekly treatment for renal cell carcinoma. Pegylated agents are likely to be more convenient for patients than the standard formulations, and the improved pharmacokinetics will enhance the clinical utility of these agents.

Adult↗

PubMed1996

Immediate hypersensitivity to human recombinant granulocyte-macrophage colony-stimulating factor associated with a positive prick skin test reaction.

BACKGROUND: Recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF), also known as sargramostim, is used to accelerate myeloid recovery following bone marrow transplantation or cytotoxic chemotherapy. "Anaphylactic" reactions to sargramostim have been reported on a limited basis and are poorly characterized. OBJECTIVE: It is the purpose of this report to describe an adverse reaction to sargramostim treatment involving palmar itching, urticaria, angioedema, and throat tightness and to demonstrate the utility of prick skin testing to determine type I sensitization. METHODS: Prick skin testing with 100 and 250 micrograms/mL sargramostim and 300 micrograms/mL rhu G-CSF (filgrastim) was performed in the patient and four control subjects. RESULTS: The patient experienced an immediate wheal and flare reaction with both concentrations of sargramostim while the control subjects demonstrated no reaction. There was also no reaction with filgrastim (rhu G-CSF) in either group and the patient subsequently tolerated filgrastim therapy. CONCLUSION: Prick skin testing with rhu GM-CSF and rhu G-CSF may be useful to demonstrate type I sensitization. Additional studies are needed to determine the incidence and prevalence of skin test reactions in larger numbers of patients with cytokine therapy exposure.

Adult↗

PubMed2004

The transepithelial transport of a G-CSF-transferrin conjugate in Caco-2 cells and its myelopoietic effect in BDF1 mice.

PURPOSE: The purpose of this study was to investigate the transferrin-receptor (TfR)-mediated transepithelial transport of G-CSF-transferrin (Tf) conjugate in cultured enterocyte-like Caco-2 monolayers and the myelopoietic effect of subcutaneously and orally administered G-CSF-Tf in BDF1 mice. METHODS: Caco-2 monolayers exhibiting a minimum transepithelial electrical resistance of 500 ohms-cm2 and BDF1 mice were used as in vitro and in vivo models, respectively. TfR-mediated transcytosis wa measured by using 125I-G-CSF-Tf and analyzing the downstream compartment by gamma counter. The efficacy of subcutaneously and orally administered G-CSF-Tf was determined by performing daily absolute neutrophil counts. RESULTS: Transport experiments in Caco-2 cells revealed that the monolayers that received 125I-G-CSF-Tf exhibited significantly higher apical-to-basolateral transport rates compared to the monolayers that received 125I-G-CSF. Inclusion of 100-fold excess unlabeled Tf reduced the extent of 125I-G-CSF-Tf transport by 80%. Chromatographic and bioactivity assays revealed that the protein recovered from the basolateral compartment was the intact conjugate, and it retained full ability to stimulate the proliferation of the granulocyte-colony stimulating factor (G-CSF) dependent cell line, NFS-60, upon reduction. Subcutaneous administration of G-CSF-Tf in BDF1 mice demonstrated that the conjugate is able to elicit a statistically significant enhancement in therapeutic effect relative to filgrastim, which includes a longer duration of action with higher absolute neutrophil counts. Oral administration of G-CSF-Tf in BDF1 mice demonstrated that G-CSF-Tf is able to elicit a significant, and apparently dose-dependent, increase in absolute neutrophil counts whereas filgrastim had no effect. CONCLUSIONS: Our data indicate that G-CSF-Tf is transported across Caco-2 monolayers by TfR-specific processes at a rate that is significantly higher than the nonspecific flux of G-CSF. G-CSF-Tf is also able to elicit a prolonged myelopoietic effect relative to filgrastim when administered subcutaneously or orally in BDF1 mice. The development of an orally bioavailable G-CSF has the potential to provide great benefit to patients under sustained G-CSF dosing regimes.

Administration, Oral↗

PubMed1999

The utilization of cytokines in stem cell mobilization strategies.

High-dose myeloablative chemotherapy supported by peripheral blood progenitor cell (PBPC) transplant is rapidly replacing bone marrow transplant to treat a number of chemosensitive cancers. Numerous investigators have studied the relationship of CD34+ cell dose and engraftment kinetics in an effort to help define minimum and optimum target stem cell doses. A number of studies suggest that reinfusion of > or = 5 x 10(6) CD34+ PBPCs results in prompt and durable platelet engraftment. Mobilization of stem cells can be accomplished through use of chemotherapy alone, colony-stimulating factors, or a combination of the two. Strategies to improve PBPC yields include filgrastim in combination with chemotherapy or with other hematopoietic growth factors. In this paper, the advantages and disadvantages of these strategies will be discussed, and the results of a recently conducted, randomized, controlled phase 3 clinical trial in breast cancer patients receiving either SCF plus filgrastim or filgrastim alone for PBPC mobilization will be reviewed.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Effect of two forms of granulocyte-colony-stimulating factor on hepatic regeneration after 70% partial hepatectomy in rats.

1. The purpose of this study was to determine whether the commercially available forms of granulocyte-colony-stimulating factor exert the same beneficial effect on hepatic regeneration after 70% partial hepatectomy in rats. Adult male Wistar rats received either the two commercially available forms of granulocyte-colony-stimulating factor (Filgrastim or Lenograstim), or saline, simultaneously with partial hepatectomy. Hepatic regeneration was documented by determining [3H]thymidine incorporation into hepatic DNA, liver thymidine kinase activity, mitotic index and proliferating cell nuclear antigen immunostaining, at various time points after partial hepatectomy. 2. DNA biosynthesis, liver thymidine kinase activity and mitotic index of hepatocytes were not only enhanced (P < 0.001) in rats that received 150 micrograms of Filgrastim or Lenograstim/kg of body weight, but occurred earlier than in saline-treated partially hepatectomized rats. The administration of both forms of granulocyte-colony-stimulating factor, at the dose of 15 micrograms/kg of body weight, did not affect liver proliferative capacity, compared with observations in simply partially hepatectomized rats. High mitotic and proliferating cell nuclear antigen indices appeared earlier than those estimated in simply partially hepatectomized rats, when 150 micrograms of Filgrastim or Lenograstim/kg of body weight were administered. 3. These findings suggest that both pharmacologically available forms of granulocyte-colony-stimulating factor at a dose of 150 micrograms/kg of body weight are able to augment liver regenerative capacity, to the same extent, in this animal model of controlled hepatic proliferation.

Adjuvants, Immunologic↗

PubMed2000

Neutropenia, neutrophil dysfunction, and bacterial infection in patients with human immunodeficiency virus disease: the role of granulocyte colony-stimulating factor.

Neutropenia frequently complicates infection due to human immunodeficiency virus (HIV). The etiology of neutropenia in this setting includes bone marrow infection or infiltration, myelosuppressive therapies, the presence of antibodies to HIV, and accelerated apoptosis. Protection against microbial invaders by neutrophils is further compromised by impaired chemotaxis and phagocytosis, production of toxic oxygen species, and expression of cellular adhesion molecules. Neutropenia is a significant risk factor for bacterial infection in HIV-infected patients. Endogenous cytokines, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor, regulate neutrophil count and function. Treatment with recombinant human methionyl G-CSF (filgrastim) has lessened neutropenia in patients with HIV infection. Clinical trials have shown that the incidence of bacterial infections and the number of consequent days of hospitalization for HIV-infected patients receiving filgrastim therapy are lower. Filgrastim treatment also allows administration of larger doses of myelosuppressive agents.

AIDS-Related Opportunistic Infections↗

PubMed2000

Impact of colony-stimulating factor therapy on clinical outcome and frequency rate of nosocomial infections in intensive care unit neutropenic patients.

OBJECTIVES: To determine whether the use of recombinant human granulocyte colony-stimulating factor (G-CSF, filgrastim) reduces the mortality rate and the frequency rate of nosocomial infections in neutropenic patients requiring intensive care unit (ICU) admission. DESIGN: Retrospective consecutive case series analysis. SETTING: Medical ICU of a teaching hospital. PATIENTS: We compared two groups of patients, according to whether or not they received G-CSF. In the ICU, 28 leukopenic patients received filgrastim (5 microg of body weight per day intravenously). In all these patients, G-CSF was continued until recovery from leukopenia, defined as a leukocyte count >1,000/mm3. A total of 33 ICU leukopenic patients did not receive G-CSF. End points included leukocyte count, bone marrow recovery, frequency of ICU nosocomial infections (pneumonia, urinary tract, and catheter-related infections), and mortality rate. MEASUREMENTS AND MAIN RESULTS: There were no differences in number of patients who recovered from leukopenia or in whom blood leukocyte count increased. Nosocomial infections occurred in the same percentage in both groups. The percentage of patients who died was identical in both groups. The percentage of patients with and without filgrastim therapy who recovered from leukopenia but died, was 86% and 78%, respectively. CONCLUSION: In the ICU, clinical outcome of neutropenic patients was not changed by G-CSF therapy. It is possible that G-CSF therapy may not be helpful in improving the ICU clinical outcome of neutropenic patients. Additional controlled studies designed to address this question are warranted.

Adult↗

PubMed2005

Superior mobilisation of haematopoietic progenitor cells with glycosylated G-CSF in male but not female unrelated stem cell donors.

Granulocyte colony-stimulating factor (G-CSF) effectively mobilises haematopoietic stem cells to the peripheral blood. It is unclear whether the mobilisation of stem cells with lenograstim (glycosylated G-CSF) or filgrastim (non-glycosylated G-CSF) leads to a higher cell number of collected engraft able progenitor cells. Thus, we investigated harvesting efficiency of the licensed G-CSF preparations in mobilising peripheral stem cells in a randomised study. A total of 501 healthy unrelated donors, including 339 males and 162 females received either lenograstim (n = 261) or filgrastim (n = 240) at 10 microg/kg body weight (BW) per day. Aphaeresis was performed on day 5 and, if necessary, on day 6 of mobilisation. The number of CD34+ cells collected was 11.5% higher in the lenograstim group (7.19 x 10(6) vs. 6.44 x 10(6)/kg BW donor; P < 0.03). Univariate variance analysis revealed that this effect was caused by male donors: more progenitors cells per kg BW of the donor (7.73 x 10(6) vs. 6.88 x 10(6); P < 0.017) and of the recipient (10.1 x 10(6) vs. 8.88 x 10(6), P < 0.029) could be harvested. There was no significant difference in the percentage of donors in whom a second aphaeresis was required (9.6% vs. 11.6%). Lenograstim mobilises progenitor cells into the peripheral blood more effectively in males than filgrastim.

Adult↗

PubMed2006

Fixed-dose single agent pegfilgrastim for peripheral blood progenitor cell mobilisation in patients with multiple myeloma.

High-dose chemotherapy and autologous peripheral blood progenitor cell transplantation is an effective treatment for multiple myeloma. Progenitor cells are generally mobilised into the peripheral blood by administration of filgrastim. Pegfilgrastim is a covalent conjugate of filgrastim with a longer half-life. The results of a phase II study of pegfilgrastim, administered as a single injection to mobilise autologous peripheral blood progenitor cells in patients with multiple myeloma, is reported. All patients (n = 19) received 12 mg of pegfilgrastim. Leukaphaeresis was started when the peripheral blood CD34(+) count was >0.015 x 10(9)/l. Daily, leukaphaeresis was performed until the target progenitor cell dose was obtained. The median number of leukaphaeresis procedures required to collect the target CD34(+) cell dose was 2 (range 1-5). A median of 8.4 x 10(6) CD34(+) cells/kg (range 4.1-15.8) was collected. The most common toxicity was bone pain/myalgia. Sustained haematological recovery occurred in all the patients who underwent high-dose chemotherapy followed by autologous peripheral blood progenitor cell transplantation with pegfilgrastim-mobilised cells. A single fixed dose of pegfilgrastim was effective in mobilising adequate peripheral blood progenitor cells in patients with multiple myeloma. The efficacy and toxicity profile was similar to that described with filgrastim treatment.

Adult↗

PubMed2006

Efficacy of single-dose pegfilgrastim after chemotherapy for the mobilization of autologous peripheral blood stem cells in patients with malignant lymphoma or multiple myeloma.

BACKGROUND: A single injection of pegfilgrastim has been shown to be equivalent to daily filgrastim in enhancing neutrophil recovery after chemotherapy, whereas the experiences with pegfilgrastim in mobilization of peripheral blood progenitor cells (PBPCs) are limited. STUDY DESIGN AND METHODS: Forty unselected patients with lymphoma or multiple myeloma were treated with different chemotherapy regimens followed by 6 mg of pegfilgrastim for mobilization of autologous PBPCs. Patients with an inadequate mobilization (blood CD34+ cells <or= 10/microL after nadir) were given additional daily doses of 10 microg per kg unconjugated filgrastim. RESULTS: A median blood CD34+ peak concentration of 81 per microL (range, 10-565/microL) was found in 30 patients, who had only received pegfilgrastim, compared to 13 per microL (median, range 4-71/microL; p < 0.001) in 10 poor mobilizing patients with additional filgrastim. The median yield of CD34+ cells was 9.8 x 10(6) per kg (range, 1.5-88.1) after pegfilgrastim only versus 2.5 x 10(6) (range, 1.7-7.0) in poor mobilizers. Patients who needed additional cytokine administration were those with a more extensive previous antineoplastic treatment and mobilizing regimens containing PBPC toxic agents. CONCLUSION: The results confirm the efficacy and feasibility of PBPC mobilization with chemotherapy and single-dose pegfilgrastim in patients with lymphoproliferative malignacies. In less heavily pretreated patients, 6 mg of pegfilgrastim after chemotherapy induced an adequate mobilization, whereas dose and schedule in patients after numerous cytotoxic regimens need further investigation.

Adult↗

PubMed2002

Mobilization, collection, and processing of peripheral blood stem cells in individuals with sickle cell trait.

Mobilized peripheral blood is increasingly used as the source of hematopoietic stem cells for allogeneic transplantation, currently the only curative approach for sickle cell anemia. However, the safety and feasibility of stem cell mobilization in individuals with sickle cell trait (SCT) has not been documented. This study is a prospective controlled trial to evaluate the safety and feasibility of peripheral blood stem cell (PBSC) mobilization in 8 SCT subjects and 8 control subjects matched for age and race. Mobilization with filgrastim 10 microg/kg subcutaneous daily for 5 days was followed by 12-L apheresis on the fifth day. Filgrastim administration was accompanied by similar symptoms in all subjects; no untoward adverse events occurred in either group, including sickle cell crises. CD34+ cell mobilization response was not significantly different between SCT and control subjects. Median CD34+ cell content was also similar in PBSCs collected from SCT versus control subjects, 6.8 versus 3.9 x 10(6) CD34+ cells/70 kg, P =.165. Red cell depletion from SCT products was not possible by using hydroxyethyl starch sedimentation but was achievable with ammonium chloride lysis. There was no evidence of gelling of SCT products after thaw, and no difference in cell recovery was seen among red cell-depleted versus nondepleted products. Cryopreservation in 5% dimethyl sulfoxide/6% pentastarch was associated with superior cell recovery (both SCT and control subjects) compared with 10% dimethyl sulfoxide (P =.001). The study concluded that filgrastim mobilization, large volume apheresis, processing, and cryopreservation appears to be safe in donors with SCT, allowing PBSC use for transplantation in patients with sickle cell anemia.

Adult↗

PubMed2000

Phase II trial of docetaxel and vinorelbine in patients with advanced non-small-cell lung cancer.

PURPOSE: Docetaxel and vinorelbine are active agents in advanced non-small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m(2)) and vinorelbine (45 mg/m(2)) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS: Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS: We delivered median doses of 450 mg/m(2) of vinorelbine and 600 mg/m(2) of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION: Docetaxel 60 mg/m(2) and vinorelbine 45 mg/m(2), both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.

Adult↗

PubMed2001

Pharmacodynamic model of topotecan-induced time course of neutropenia.

Pharmacodynamic measures of neutropenia, such as absolute neutrophil count at nadir and neutrophil survival fraction, may not reflect the overall time course of neutropenia. We developed a pharmacokinetic-pharmacodynamic model to describe and quantify the time course of neutropenia after administration of topotecan to children and to compare this with nonhuman primates (NHPs) as a potential preclinical model of neutropenia. Topotecan was administered as a 30-min infusion daily for 5 days, repeated every 21 days. As part of a Phase I Pediatric Oncology Group study, topotecan was administered at 1.4 and 1.7 mg/m(2)/day without filgrastim (POG), and at 1.7, 2, and 2.4 mg/m(2)/day with filgrastim (POG+G). In NHPs, topotecan was administered at 5, 10, and 20 mg/m(2)/day without filgrastim. A pharmacokinetic-pharmacodynamic model was fit to profiles of topotecan lactone plasma concentrations and neutrophil survival fraction from cycle 1 and used to calculate topotecan lactone area under the plasma concentration-versus-time curve from 0 to 120 h (AUC(LAC)) and the area between the baseline and treatment-related neutrophil survival fraction (ABC) from 0 to 700 h. The mean +/- SD neutrophil survival fraction at nadir for the POG, POG+G, and NHP groups was 0.12 +/- 0.09, 0.11 +/- 0.17, and 0.09 +/- 0.08, respectively (P > 0.05). The mean +/- SD for the ratio of ABC to AUC(LAC) for the POG and NHP groups was 1.02 +/- 0.38 and 0.16 +/- 0.09, respectively (P < 0.05). The model estimate of ABC and the ratio of ABC to AUC(LAC) in children and NHPs may better reflect sensitivity to chemotherapy-induced neutropenia.

Animals↗

PubMed2004

Review: Drug-induced neutropenia--pathophysiology, clinical features, and management.

Drug therapy plays a significant role in causing neutropenia. The neutropenia may be immune mediated or due to direct inhibition of the bone marrow precursors. Recently, due to wide use of chemotherapy, febrile neutropenia has become a common and devastating problem. Neutropenia predisposes to many bacterial and fungal infections with organisms including gram negative bacilli such as E. coli, Klebsiella, and Pseudomonas; gram positive organisms such as Staphylococcus, Streptococcus viridans, and Enterococcus species; and fungi, like Candida and Aspergillus. In addition to the customary supportive care for neutropenic patients, therapy with recombinant human granulocyte colony-stimulating factor (rG-CSF) (filgrastim) has been shown to be beneficial. Filgrastim was a significant advance in the management of drug induced neutropenia in the past decade, but therapy with pegfilgrastim (a pegylated, long-acting form of filgrastim) ushers in the current decade. Pegfilgrastim (Neulasta) is administered as a single s.c. injection once per chemotherapy cycle. This results in fewer injections, fewer patient visits to the physician's office, and better patient compliance with therapy.

Bacterial Infections↗