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

Granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates production of neutrophils in bone marrow and may decrease the incidence of infection during neutropenia. We evaluated the protective role of recombinant GM-CSF against Pseudomonas aeruginosa challenge in neutropenic mice. CD-1 mice treated with cyclophosphamide on days 1 and 2 of the experiment were given GM-CSF (1, 2, or 4 micrograms/day) starting at day 4 of the experiment according to the following protocol: 1) 1 microgram of GM-CSF 2 hr and 24 hr after challenge; 2) 1 microgram 24 hr before challenge, 2 hr and 24 hr after challenge; 3) 2 micrograms injected 24 hr before and 2 hr after challenge; 4) 2 micrograms given 24 hr before and 2 micrograms given 2 hr and 24 hr after challenge; 5) 4 micrograms administered 2 hr and 24 hr after challenge; and 6) saline and bovine albumin controls. The number of blood neutrophils by days 4 and 5 was similar for GM-CSF-treated and untreated animals. Survival was significantly greater in animals given 2 micrograms of GM-CSF at 24 hr before and at 2 hr and 24 hr after challenge with Pseudomonas. Neutrophils and splenic macrophages obtained from GM-CSF-treated mice (2 micrograms/animal) produced significantly greater amounts of O2- (204 +/- 36 nmoles/10(5) cells) than controls (21 +/- 10 nmoles/10(5) cells). Additionally, neutrophils and macrophages from GM-CSF-treated mice killed significantly more bacteria (P. aeruginosa) in vitro and had a greater number of C3b and Fc receptors (78 +/- 12% and 89 +/- 8%) than did cells obtained from control animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytokine 1990 Jul
PMID:Protection against gram-negative bacteremia in neutropenic mice with recombinant granulocyte-macrophage colony-stimulating factor. 196 50

The purpose of the study was to evaluate the toxicity and biological activity of highly purified lipopolysaccharide (LPS) administered intravenously to cancer patients in order to establish an optimum dosage scheme. An initial subtoxic dose was increased in weekly increments in accordance with individual regimens that maintained patient reaction at a safe and acceptable level. Purified LPS from Salmonella abortus equi was administered to 11 patients with advanced solid tumors on a weekly schedule with intraindividually escalating dosage as determined by patient response. Biological response was monitored by complete blood count, C-reactive protein, and cytokine measurements at different time points after LPS injection. Tumor necrosis factor-alpha (TNF) and interleukin-1 beta serum levels were measured by enzyme-linked immunosorbent assay and interleukin-6 (IL-6) by bioassay. Dose-limiting toxicities including chills and fever (WHO grade III) were reached at 1.0 ng/kg of body weight (maximal tolerated dose-1, MTD-1). Pretreatment with ibuprofen (1,600 mg) abrogated these side effects, allowing further escalation of LPS doses up to 10 ng/kg of body weight. At dose levels greater than 8.0 ng/kg of body weight (MTD-2), the aforementioned side effects occurred again and, additionally, hepatic toxicity (WHO grade III) was observed. Hematological changes included neutropenia followed by a pronounced neutrophilia contributed to by up to 30% bands, marked monocytopenia for 3 h, and retarded lymphopenia. By 24 h, all hematological parameters returned to pretreatment values. TNF serum levels increased from 10 pg/ml before treatment to 7,000 pg/ml as a function of dosage. Maximum serum levels were reached at 60 to 90 min after LPS injection. Similarly, IL-6 serum concentrations increased from less than 4 to 2,500 U/ml; peak levels were obtained 30 min after TNF peak values. Prior administration of ibuprofen had no effect on the above-mentioned hematological changes nor on cytokine release. LPS can be administered intravenously in weekly intervals at escalating doses from 0.15-10.0 ng/kg of body weight, when patients are protected by pretreatment with ibuprofen at dose levels above 1.0 ng/kg of body weight. Cytokine release as measured by TNF and IL-6 increased in a dose-dependent manner although the constitutional symptoms are completely attenuated.
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PMID:Biological response to intravenously administered endotoxin in patients with advanced cancer. 225 60

Haemopoietic growth factors (HGFs) are being administered to patients with neutropenic fever; however, little is known about the endogenous HGF response in these patients. Specific assays were used to study four HGFs, granulocyte (G-) CSF, granulocyte-macrophage (GM-) CSF, macrophage (M-) CSF and interleukin (IL-) 6 levels in the blood of patients with neutropenic fever (46 episodes). For comparison, levels were also measured in three control populations: normals (20), afebrile neutropenic (14), and bacteraemic but not neutropenic patients (20). In febrile patients, levels of G-CSF (median, range) (0.46, < 0.10-142 ng/ml). IL-6 (0.054, 0.005-24.3 ng/ml) and M-CSF (18.5, 9.9-79.1 ng/ml) were elevated compared with afebrile subjects (< 0.10, < 0.10-1.62 ng/ml). (0.008, 0.002-0.024 ng/ml) and (6.45, < 5.0-31.3 ng/ml) respectively. GM-CSF was not elevated (< 0.02, < 0.02-8.0 ng/ml) compared with afebrile subjects (0.021, < 0.02-0.20 ng/ml). Variables significantly associated (P < 0.05) with elevated cytokine levels were determined by multiple regression analyses. Factors associated with G-CSF elevation were fever, neutropenia, pathogen type and raised bilirubin and creatinine. In contrast, neutropenia was not associated with IL-6 elevation although there was an association between IL-6 elevation and fever, Gram-negative and fungal infections and raised creatinine and bilirubin. M-CSF elevation was associated with fever, renal impairment and known pathogen. Elevated G-CSF and IL-6 levels normalized rapidly (hours-days) with the resolution of infection, whereas M-CSF concentrations remained elevated for up to 10 d. Cytokine levels remained elevated in septic neutropenic patients who did not recover. In summary, G-CSF, IL-6 and M-CSF levels were significantly elevated in sepsis. In contrast, GM-CSF levels were not elevated. These studies should assist the development of therapeutic strategies using HGFs in the treatment of sepsis.
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PMID:Endogenous haemopoietic growth factors in neutropenia and infection. 751 65

Haematopoiesis is regulated by unrelated, pleiotropic, and diverse regulatory molecules, cytokines, whose membrane receptors are related and restricted to a few families manifesting sequence homology. Most members of the cytokine receptor family which lack tyrosine kinase activity are composed of multiple chains. An accessory signal transducer can be shared by members of the receptor family. Cytokine receptor oligomerisation is required for signal transduction, which includes phosphorylation of receptors and cytoplasmic proteins. Upon ligand binding, the receptors for erythropoietin and G-CSF form homodimers, whereas other members of the receptor family form hetero-oligomers in order to generate high-affinity receptor and signal transduction. In their cytoplasmic part, cytokine receptors contain distinct functional domains, proximal and distal to the membrane, that generate separate signals. Cytokines can be used to minimise chemotherapy-induced neutropenia and treat chronic neutropenia, and to shorten the period of aplasia following bone marrow transplantation.
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PMID:[Hematopoiesis. Biological mass production closely regulated by cytokines]. 770 97

Picryl chloride-induced irritant reaction (IR) was shown to be mediated by tumor necrosis factor (TNF). Anti-TNF monoclonal antibodies, but not interleukin 1 receptor antagonist (IL-1 Ra), had a protective effect. Chlorpromazine (CPZ), an inhibitor of TNF synthesis, protected against IR and inhibited the IR-associated TNF induction in ear homogenates. Investigation of the role of polymorphonuclear leukocyte (PMN) in neutropenic mice showed that neutropenia did not prevent the development of the IR.
Eur Cytokine Netw
PMID:Protective effect of chlorpromazine on TNF-mediated hapten-induced irritant reaction. 779 76

The therapeutic efficacy of recombinant human leukemia inhibitory factor (LIF) was examined in a nonhuman primate model of radiation-induced marrow aplasia. Rhesus monkeys received 450 cGy of total-body, 1:1 mixed neutron:gamma radiation. For 23 days thereafter, each monkey received a daily subcutaneous injection of LIF or human serum albumin (HSA) at a dose of 15 micrograms/kg body weight. Complete blood counts and white blood cell differentials were monitored for 60 days postirradiation. Administration of LIF significantly decreased (P < or = .05) the duration of thrombocytopenia (platelet count < 30,000 or 20,000/microL), ie, 9.3 days or 6.3 days, respectively, versus the HSA-treated control monkeys, 12.2 days or 10.2 days, respectively. Treatment with LIF did not alter the duration of neutropenia (absolute neutrophil count < 1,000/microL) as compared with the HSA-treated control monkeys. Cytokine administration did not exacerbate the radiation-induced anemia observed in the HSA-treated control monkeys.
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PMID:Therapeutic efficacy of recombinant human leukemia inhibitory factor in a primate model of radiation-induced marrow aplasia. 794 22

Using a bioassay for hematopoietic progenitor cells we looked for mechanisms causing clozapine induced neutropenia and agranulocytosis. Micro-agar-cultures of normal peripheral blood mononuclear cells (MNC) of eight patients currently treated with clozapine and of eight probands not receiving any kind of pharmacological treatment were incubated with increasing concentrations of clozapine (0, 7.5, 15, 30 micrograms/ml). Erythropoiesis and megakaryopoiesis were totally unaffected by clozapine. A biologically relevant suppression of granulopoiesis (CFU-GM) could only be shown in cultures incubated with 30 micrograms/ml clozapine. Cytokine analysis presented a strictly dose-dependent suppression of GM-CSF and neopterin release in all cultures. There was no difference between patients and controls at any clozapine concentration. The data support a possible role for cytokines as one mediator of the agranulocytosis producing effects of clozapine.
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PMID:Effects of clozapine on hematopoiesis and the cytokine system. 827 81

We studied the effect of erythropoietin (EPO) and interleukin 3 (IL-3), either alone or in combination, on the hematopoietic toxicity associated with zidovudine in vivo, as determined by peripheral blood indices, and assay of hematopoietic progenitors, i.e. erythroid (CFU-E/BFU-E), myeloid (CFU-GM) and megakaryocyte (CFU-Meg) from bone marrow and spleen. Previous studies from this laboratory have established that dose escalation of zidovudine to normal mice induced a dose-dependent decrease in hematocrit, white blood cells and platelets with altered populations of marrow and splenic erythroid, myeloid and megakaryocyte progenitors. Daily administration of EPO (50 U/animal, i.p.) and/or IL-3 (5 U/animal, i.p.) was associated with altered peripheral blood indices and progenitor cells. In general, use of EPO and IL-3 alone reduced zidovudine-induced toxicity, notably in erythropoiesis; however, combination EPO/IL-3 was associated with enhanced toxicity with an observed rebound only with the use of < 2.5 mg/ml drug; 2.5 mg/ml drug in the presence of combination EPO/IL-3 accelerated zidovudine-erythroid toxicity. A similar response was noted with circulating platelets and megakaryocyte progenitors. Use of EPO or IL-3, either alone or in combination, failed to reverse zidovudine-induced neutropenia. These studies demonstrate that use of EPO or IL-3, either alone or in combination may serve as an effective adjuvant therapy to modulate the erythroid toxicity associated with lower doses of zidovudine; however, this cytokine therapy was ineffective modulating zidovudine-induced myelosuppression when used in vivo. A reversal in zidovudine-induced myeloid toxicity, therefore may require the use of a myelopoiesis inducing cytokine.
Cytokine 1993 Jan
PMID:In-vivo effect of interleukin 3 and erythropoietin, either alone or in combination, on the hematopoietic toxicity associated with zidovudine. 848 6

Studies were carried out to determine whether the combination of IL-1 + M-CSF, similar to the effect of these cytokines on neutropenia, was able to reduce the duration of thrombocytopenia in the 5-fluorouracil (5-FU)-myelosuppressed mouse. In addition, comparisons were made between the in vivo effects of IL-1 + M-CSF and other "thrombopoietic" cytokines (e.g., IL-3, IL-6, and GM-CSF) that demonstrate some form of megakaryocytopoietic activity in vitro. Of the five cytokines studied, only IL-1 and IL-6, by themselves, were able to effect thrombopoietic recovery in the myelosuppressed mouse. IL-1, either when acting alone or interacting synergistically with M-CSF, was able to reduce significantly the period of thrombocytopenia, but the effects of IL-6 were restricted to enhancing platelet production during the period of rebound thrombocytopenia without altering the kinetics of thrombopoietic recovery. Moreover, none of the cytokine combinations studied were found to interact to reduce further the duration of thrombocytopenia beyond that observed with IL-1 + M-CSF. Nonetheless, IL-3, IL-6, and, to a lesser extent, GM-CSF were each able to interact with IL-1 + M-CSF to extend further the period of enhanced platelet production in the animal. However, scheduling studies suggested that these thrombopoietic cytokines interacted in sequence, rather than in concert, with IL-1 + M-CSF to enhance platelet production during thrombopoietic recovery. Furthermore, the data presented are consistent with the hypothesis that IL-1 + M-CSF initially acts on a multilineage, 5-FU-resistant target cell and that IL-6 (and possibly IL-3 and GM-CSF) serves as a secondary cytokine further to enhance platelet production during rebound thrombopoiesis in the 5-FU-treated mouse.
J Interferon Cytokine Res 1996 Mar
PMID:Enhanced platelet recovery in myelosuppressed mice treated with interleukin-1 and macrophage colony-stimulating factor: potential interactions with cytokines having megakaryocyte colony-stimulating activity. 869 40

This single arm, open labeled, non randomized study was aimed to evaluate the toxicity of 3 cycles of MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) with rhG-CSF (5 micrograms/kg/day from day 3 to day 14), on 14 patients with previously untreated infiltrating bladder carcinoma, 42 cycles were administered. Chemotherapy toxicity was very low, with 7% of neutropenia grade 3 or 4.4% of thrombocytopenia grade 2, no mucositis above grade 2 and no nadir sepsis. Bone pain related to rhG-CSF occurred in 14% of cycles. 88% of the cycles were given at full dose without any delay and mean relative dose intensity was 96.4% (RDI was 100% for 9 patients). One patient achieved a complete pathological response (cystectomy: 1) and 6 clinical responses with negative transurethral resection. Addition of rhG-CSF to MVAC chemotherapy allows a high dose intensity of MVAC with very low toxicity over 3 cycles. This association should be compared to standard MVAC or intensified regimens to evaluate efficacy, toxicity, and cost effectiveness.
Eur Cytokine Netw 1996 Sep
PMID:Impact of recombinant human granulocyte colony stimulating factor on dose intensity and toxicity of three cycles of methotrexate, vinblastine, doxorubicin and cisplatin in patients with previously untreated urothelial bladder carcinoma. 895 83


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