Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027947 (neutropenia)
 17,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recombinant protein technology produces drugs for human therapy in unprecedented quantity and quality. Research is now focusing on the relationship between pharmacokinetic and pharmacodynamic properties of molecules, with the aim of engineering proteins that possess enhanced therapeutic characteristics in contrast to being used as simple replacements for the natural equivalent. The addition of a polyethylene glycol (PEG) moiety to filgrastim (rmetHu-G-CSF, Neupogen) resulted in the development of pegfilgrastim. Pegfilgrastim is a long-acting form of filgrastim that requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia. The covalent attachment of PEG to the N-terminal amine group of the parent molecule was attained using site-directed reductive alkylation. Pegylation increases the size of filgrastim so that it becomes too large for renal clearance. Consequently, neutrophil-mediated clearance predominates in elimination of the drug. This extends the median serum half-life of pegfilgrastim to 42 hours, compared with between 3.5 and 3.8 hours for Filgrastim, though in fact the half-life is variable, depending on the absolute neutrophil count, which in turn reflects of the ability of pegfilgrastim to sustain production of those same cells. The clearance of the molecule is thus dominated by a self-regulating mechanism. Pegfilgrastim retains the same biological activity as filgrastim, and binds to the same G-CSF receptor, stimulating the proliferation, differentiation and activation of neutrophils. Once-per-chemotherapy cycle administration of pegfilgrastim reduces the duration of severe neutropenia as effectively as daily treatment with filgrastim. In clinical trials, patients receiving pegfilgrastim also had a lower observed incidence of febrile neutropenia than patients receiving filgrastim.
 ...
PMID:The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). 1507 38

Neutropenia is a significant hematologic complication induced by cytotoxic chemotherapy. The clinical consequences of chemotherapy-induced neutropenia are often severe and can be potentially life-threatening. Patients who develop febrile neutropenia often need to be hospitalized, reducing their quality of life and increasing costs. Neutropenia can also compromise the ability to deliver chemotherapy at the full dose and on schedule. To help prevent the occurrence of neutropenia, patients with a high risk of developing chemotherapy-related infections may be given prophylactic colony-stimulating factors. Filgrastim is a recombinant human granulocyte colony-stimulating factor that has been widely used (in over 3 million patients) for over 12 years in the management of neutropenia. Pegfilgrastim is an approved, long-acting, next generation of granulocyte colony-stimulating factor that has similar clinical benefits to filgrastim but has novel pharmacokinetic properties. Pegfilgrastim shows at least comparable safety and efficacy to filgrastim, with the added benefit of simplified once-per-chemotherapy-cycle dosing. In addition, two randomized, controlled pivotal trials have shown that a single dose of pegfilgrastim given once per cycle led to a lower observed incidence of febrile neutropenia following myelosuppressive chemotherapy, compared with daily injections of filgrastim. Clinical trials are currently expanding the clinical experience with pegfilgrastim in a variety of solid tumors and hematologic malignancies. In addition to prevention of chemotherapy-induced neutropenia in 21- and 28-day regimens, future studies are examining the suitability of pegfilgrastim in dose-dense therapy and other cancer settings.
 ...
PMID:Neulasta (pegfilgrastim): a once-per-cycle option for the management of chemotherapy-induced neutropenia. 1518 6

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.
 ...
PMID:Review: Drug-induced neutropenia--pathophysiology, clinical features, and management. 1522 23

Chemotherapy-induced neutropenia is a frequent complication in cancer patients receiving myelosuppressive chemotherapy. Chemotherapy-induced neutropenia can result in febrile neutropenia and potentially life-threatening infections requiring hospitalization and intravenous anti-infectives. Chemotherapy dose may be reduced or delayed as a result of chemotherapy-induced neutropenia, which can negatively impact treatment outcomes. Granulocyte colony-stimulating factors, such as filgrastim, stimulate neutrophil production and can therefore reduce the incidence and severity of chemotherapy-induced neutropenia. Filgrastim undergoes rapid renal clearance and needs to be administered daily. The development of pegfilgrastim represents a significant advance in the management of chemotherapy-induced neutropenia as the longer serum half-life allows once-per-chemotherapy administration, and evidence supports increased prophylactic effectiveness in reducing the incidence of febrile neutropenia. This paper reviews the development of pegfilgrastim and summarizes recent clinical data on the use of this simple, effective and well-tolerated option for the management of chemotherapy-induced neutropenia in patients with cancer.
 ...
PMID:Pegfilgrastim: a recent advance in the prophylaxis of chemotherapy-induced neutropenia. 1530 6

Chemotherapy-induced myelosuppression is the most common dose-limiting side effect of cancer chemotherapy. Neutropenia is a serious risk with chemotherapy, associated with infectious complications, use of intravenous antibiotics, hospitalization, and even death. The occurrence of febrile neutropenia can lead to dose reductions and delay in subsequent cycles of chemotherapy that may have a detrimental affect on overall survival and disease-free survival. Granulocyte colony-stimulating factors (G-CSF) can reduce the duration of severe neutropenia, the incidence of febrile neutropenia, and allow planned dosing and timing of chemotherapy. Filgrastim is a G-CSF that has demonstrated benefit for the treatment and prophylaxis of chemotherapy-induced neutropenia (CIN), but its short half-life requires repeated daily subcutaneous injection. Pegfilgrastim is a recombinant G-CSF created by attaching a polyethylene glycol (PEG) molecule to the filgrastim protein. Once-per-cycle dosing of pegfilgrastim has been evaluated in clinical trials using myelosuppressive chemotherapy in breast cancer, Hodgkin's lymphoma, and non-Hodgkin's lymphoma. Trials have demonstrated that pegfilgrastim is comparable in safety and efficacy to filgrastim for decreasing the duration of severe neutropenia after chemotherapy in patients with nonmyeloid malignancy. This review will summarize recent clinical trial results and novel uses of pegfilgrastim.
 ...
PMID:Pegfilgrastim use during chemotherapy: current and future applications. 1549 75

Primary systemic therapy (ie, preoperative or neoadjuvant) increases the possibility for breast-conserving surgery in patients with primary breast cancer. Patients with pathologic complete response to primary systemic therapy have improved survival compared with those with persistent tumors. Several phase II trials have evaluated gemcitabine-containing doublet or triplet regimens as primary systemic therapy for breast cancer, results of which have shown promising clinical and pathologic response rates with manageable toxicity. Results of a phase I/II study of gemcitabine (Gemzar)/epirubicin (Ellence)/docetaxel (Taxotere), or GEDoc, with prophylactic filgrastim (Neupogen), as primary systemic therapy in 77 evaluable patients with primary breast cancer are reported herein. Dose-limiting toxicities were grade 3 febrile neutropenia (n = 1) and grade 3 diarrhea (n = 2) at the fourth dose level of GEDoc tested (gemcitabine at 800 mg/m2 days 1 and 8, epirubicin at 90 mg/m2 day 1, and docetaxel at 75 mg/m2 day 1). As assessed by ultrasound, 92% of patients responded overall (22% complete response), and 79% of patients could undergo breast-conserving surgery. The pathologic complete response rate in resected breast tissue was 26%.
 ...
PMID:Neoadjuvant therapy with gemcitabine in breast cancer. 1568 23

Dose densification and dose escalation of cytotoxic chemotherapy may be important in improving the cure rates of chemotherapy-responsive cancers. We conducted two phase I studies, in non-small cell lung cancer (NSCLC) and in lymphoma, to explore the possibility of intensifying chemotherapy by compressing the delivery of and escalating the dose of standard combination chemotherapy. One study used etoposide and cisplatin chemotherapy in patients with unresectable stage III or IV NSCLC, intensifying chemotherapy by reducing the cycle length. The second study used cyclophosphamide, doxorubicin, vincristine, and prednisone, CHOP chemotherapy, in the treatment of stage II-IV intermediate or immunoblastic high-grade lymphoma, intensifying chemotherapy first by reducing the cycle length and then by escalating the dosages of cyclophosphamide and doxorubicin. Filgrastim support was used during dose intensification. Fifty-five patients with NSCLC and 49 with non-Hodgkin's lymphoma (NHL) were enrolled and treated in successive cohorts. At standard dosages and intervals of chemotherapy, filgrastim support resulted in incidences of grade 3 and 4 neutropenia that were between 62% and 77% lower than those in the no-filgrastim control; the mean duration of neutropenia was, likewise, more than 80% lower. Absolute neutrophil counts were >/=2 x 10(9)/l at day 14 in virtually 100% of patients receiving filgrastim. In the NSCLC trial, etoposide and cisplatin were intensified by >50%, and in the lymphoma trial, cyclophosphamide was intensified by 270% and doxorubicin was intensified by 87%. Chemotherapy reductions or delays for neutropenia were rare in the groups receiving filgrastim; but at higher chemotherapy intensities, dose-limiting thrombocytopenia was encountered. We conclude that the delivery of myelosuppressive chemotherapy in both a dose-intense and a dose-dense manner is feasible with filgrastim support.
 ...
PMID:Increasing chemotherapy dose density and intensity: phase I trials in non-small cell lung cancer and non-Hodgkin's lymphoma. 1570 16

Alemtuzumab (anti-CD52; Campath-1H) is effective in fludarabine-refractory chronic lymphocytic leukemia (CLL), but is associated with infection and early onset neutropenia. To reduce toxicity, filgrastim (G-CSF) was administered concurrently with alemtuzumab. In total, 14 CLL patients (median age 59) with a median of 3.5 prior regimens (range 1--12) received i.v. alemtuzumab, stepped up from 3 to 30 mg the first week, then 30 mg thrice weekly for 12 weeks. Filgrastim 5 microg/kg was administered daily 5 days before and throughout alemtuzumab therapy. Six patients developed cytomegalovirus (CMV) reactivation 3--6 weeks into treatment; six patients developed fever, three neutropenia, and one pneumonia. The patient with CMV pneumonia died; ganciclovir cleared CMV in the other patients. Five patients developed early neutropenia (weeks 2--5). Four patients developed delayed neutropenia (weeks 10--13) unassociated with CMV reactivation. Nine patients ceased therapy because of infectious and hematologic toxicity. Five partial responses were noted, all in patients with lymph nodes>cm, lasting a median of 6.5 months (range 5--13). Filgrastim and alemtuzumab were given concurrently with manageable infusion toxicity and clinical activity, but the efficacy of this regimen was limited by delayed neutropenia of unclear etiology and CMV reactivation. Filgrastrim should not be administered prophylactically during alemtuzumab therapy outside clinical trials.
 ...
PMID:Filgrastim and alemtuzumab (Campath-1H) for refractory chronic lymphocytic leukemia. 1585 11

The use of the recombinant human granulocyte colony-stimulating factor filgrastim to shorten the duration of severe neutropenia after cytotoxic chemotherapy has become an integral part of supportive care. However, due to its short serum half-life, filgrastim must be injected daily. Pegfilgrastim, a new long-lasting form of filgrastim administrated once per cycle, has been shown in adults to be as effective in reducing the duration of severe neutropenia as daily filgrastim. The aim of this study was to evaluate the effects of pegfilgrastim in pediatric patients. Five children with Ewing sarcoma were alternately treated with a single 100 microg/kg pegfilgrastim dose or daily doses of 10 microg/kg Filgrastim after a total number of 58 chemotherapy cycles. Pegfilgrastim was well tolerated. The duration of severe neutropenia and the incidence of febrile neutropenia after pegfilgrastim and filgrastim were comparable. By using pegfilgrastim, the number of subcutaneous injections could be reduced to one single injection per cycle.
 ...
PMID:Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. 1609 30

Granulocyte colony-stimulating factors such as filgrastim (Neupogen, Amgen, Inc.) and pegfilgrastim (Neulasta, Amgen, Inc.) are frequently used in clinical practice for the prevention of chemotherapy-induced neutropenia and its potentially life-threatening complications. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have shown that a single, fixed subcutaneous dose of pegfilgrastim 6 mg is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Postregistrational trials have been conducted to evaluate the use of pegfilgrastim with emerging dose-dense regimens, in myeloid cancers and for mobilisation and engraftment of autologous stem cells. Ongoing clinical trials continue to explore further potential uses for pegfilgrastim.
 ...
PMID:Pegfilgrastim: a granulocyte colony-stimulating factor with sustained duration of action. 1631 27


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>