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)

In a placebo-controlled double-blind dose-finding trial, 15 patients with ovarian cancer stage III or IV received daily s.c. 1.5, 3, or 6 micrograms/kg recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). At each dose step three patients received recombinant human GM-CSF, and two received placebo. Chemotherapy comprised 6 cycles of carboplatin, 300 mg/m2, and cyclophosphamide, 750 mg/m2, by i.v. bolus on day 1 every 4 weeks. GM-CSF, given on days 6-12 on an outpatient basis, raised the mean leukocyte count on days 7, 10, and 15 and the mean neutrophil count on days 7 and 10 at all dose levels as compared with the control group. Neutrophil counts of less than 0.5 x 10(9)/liter occurred in 20 of 22 cycles in the control group and in 5 of 17 cycles at the 6-micrograms/kg/day GM-CSF dose level (P less than 0.0005). In comparison with the control group, the mean eosinophil count was higher on days 10 and 15 at all GM-CSF doses, as was the mean monocyte count on day 15. The mean platelet count was raised at the 3- and 6-micrograms GM-CSF doses on days 15 and 22. Chemotherapy dose reduction or postponement due to myelotoxicity occurred in 9 of 28 cycles in the placebo groups versus 5 of 44 cycles in the GM-CSF group (not significant). Local skin infiltrates at the GM-CSF injection sites occurred in 8/9 patients, leading to premature removal of two patients from the study. Capillary leakage of 131I-albumin was increased in all patients 5 days after the first chemotherapy course but was not significantly affected by 4 days of GM-CSF treatment. Tumor necrosis factor alpha and C-reactive protein serum levels increased during GM-CSF administration at the 6-micrograms dose level, but interleukin 6 serum levels were not affected. We conclude that a dose of 3 and 6 micrograms/kg/day GM-CSF reduces the severity of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide. This GM-CSF dose does not induce additional capillary leakage.
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PMID:A double-blind placebo-controlled study with granulocyte-macrophage colony-stimulating factor during chemotherapy for ovarian carcinoma. 198 77

In long-term bone marrow cultures we studied the effect of the addition of the myelotoxic agents methotrexate (MTX) and ceftazidime (CEF) on the kinetics of cytokine production in the supernatant (SN) and on mRNA expression in the adherent stromal layer. In response to a medium change, a prompt and significant increase in colony-stimulating activity (CSA) and interleukin 6 (IL-6) concentrations in the SN occurred, peaking 12 h later. Two macrophage colony-stimulating factors (M-CSF) mRNA of 23 kb and 4 kb were identified. In response to the medium change, the 4.0-kb transcript increased significantly six h later. The 2.3-kb transcript expression was stronger than the 4-kb mRNA but did not cycle with medium change. At medium change, IL-6 mRNA was only minimally expressed; then a prompt increase occurred, which peaked six h later. The addition of 500 mg/ml (=915 microM) CEF to the culture caused a dose-dependent suppression of CSA and IL-6 supernatant concentrations and IL-6 and M-CSF mRNA expression. By contrast, 1 microM MTX had minimal effect on cytokine concentrations in the SN following medium change. mRNA expression was, however, suppressed. These results provide insights into the possible mechanisms whereby cytokines lead to increased myeloid cell proliferation following medium change. We also demonstrate that two myelotoxic agents have different effects on cytokine production. This information could be of value in developing rational approaches to the therapeutic use of cytokines in drug-induced neutropenia.
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PMID:Effects of myelotoxic agents on cytokine production in murine long-term bone marrow cultures. 970 48

Severe weight loss associated with cancer continues to be a major cause of morbidity in cases of childhood malignancy. The etiology is not completely understood but is probably multifactorial, including reduced ingestion and altered metabolism of nutrients. Changes in the host metabolism of protein, fat and carbohydrate in the cancer-bearing host have been demonstrated both in animal models and in patients. Changes include increased protein turnover and loss of the normal compensatory mechanisms seen in starvation. Additionally, increased lipid breakdown results in depletion of lipid stores and changes in carbohydrate metabolism result in an energy-losing cycle. The increase in protein turnover seen in children with leukemia may be related to the tumor, the chemotherapy administered or to related conditions such as febrile neutropenia. The role of endogenous mediators of cancer cachexia has not yet been clearly elucidated, although tumor necrosis factor, interleukin I and interleukin 6 appear to be involved. Studies of energy expenditure in children with cancer have indicated that certain patients with a raised metabolic rate are at particular risk of severe weight loss. The challenge is to identify these vulnerable patients and to provide adequate nutritional support early in treatment and therefore avoid the deleterious effects of cachexia.
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PMID:Aspects of altered metabolism in children with cancer. 987 81

Granulocyte colony-stimulating factor (GCSF) is the principal growth factor regulating the maturation, proliferation and differentiation of the precursor cells of neutrophilic granulocytes and is used to treat neutropenia. GCSF is a member of the long-chain subtype of the class 1 cytokine superfamily, which includes growth hormone, erythropoietin, interleukin 6 and oncostatin M. Here we have determined the crystal structure of GCSF complexed to the BN-BC domains, the principal ligand-binding region of the GCSF receptor (GCSFR). The two receptor domains form a complex in a 2:2 ratio with the ligand, with a non-crystallographic pseudo-twofold axis through primarily the interdomain region and secondarily the BC domain. This structural view of a gp130-type receptor-ligand complex presents a new molecular basis for cytokine-receptor recognition.
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PMID:Atomic structure of the GCSF-receptor complex showing a new cytokine-receptor recognition scheme. 1053 11

The interleukin 6 receptor antagonist tocilizumab was investigated in a 24-week, phase III randomized controlled trial for the treatment of active, DMARD-resistant rheumatoid arthritis (TOWARD study). The results indicated that the combination of tocilizumab with standard DMARDs produced a significantly higher clinical response rate than DMARDs alone, according to American College of Rheumatology and European League Against Rheumatism response criteria. Evaluation of adverse events revealed that tocilizumab had a good safety profile, although a slightly increased rate of infections, neutropenia, elevated liver enzyme levels and increased lipid levels were observed in some individuals. Further investigations will be required, however, to clarify which DMARD-tocilizumab combinations provide the best efficacy and safety profile in daily clinical practice and to exclude potential risks associated with long-term interleukin 6 blockade. In conclusion, the introduction of tocilizumab was shown to represent a safe and effective therapeutic approach for the treatment of rheumatoid arthritis refractory to treatment with DMARDs alone, which could substantially improve our treatment options for this condition.
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PMID:Is tocilizumab in combination with traditional DMARDs safe and effective for patients with active RA? 1882 91

Having found previously that high-dose, short-term dietary exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) suppresses adaptive immunity, in the present study we characterize the effects of these fluorochemicals on the innate immune system. Male C57BL/6 mice receiving 0.02% (w/w) PFOS or PFOA in their diet for 10 days exhibited a significant reduction in the numbers of total white blood cells (WBC), involving lymphopenia in both cases, but neutropenia only in response to treatment with PFOA. Moreover, both compounds also markedly reduced the number of macrophages (CD11b(+) cells) in the bone marrow, but not in the spleen or peritoneal cavity. The ex vivo production of tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6) by peritoneal macrophages isolated from animals treated with PFOA or PFOS was increased modestly. Moreover, both fluorochemicals markedly enhanced the ex vivo production of these same cytokines by peritoneal and bone marrow macrophages stimulated either in vitro or in vivo with lipopolysaccharide (LPS); whereas there was no such effect on splenic macrophages. The serum levels of these inflammatory cytokines observed in response to in vivo stimulation with LPS were elevated substantially by prior exposure to PFOA, but not by PFOS. None of these parameters of innate immunity were altered in animals receiving a dietary dose of these compounds that was 20-fold lower (0.001%, w/w). These findings reveal that in addition to suppressing adaptive immunity, high-dose, short-term exposure of mice to either PFOS or PFOA augments inflammatory responses to LPS, a potent activator of innate immunity.
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PMID:High-dose, short-term exposure of mice to perfluorooctanesulfonate (PFOS) or perfluorooctanoate (PFOA) affects the number of circulating neutrophils differently, but enhances the inflammatory responses of macrophages to lipopolysaccharide (LPS) in a similar fashion. 1954 Sep 3