Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A phase IIb trial using liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) in combination with ifosfamide (IFX) for patients with relapsed osteosarcoma was undertaken to determine (a) the tolerability of the combination therapy, (b) if L-MTP-PE increased the toxicity of IFX, and (c) whether IFX altered or suppressed the in vivo immune response to L-MTP-PE. Patients had histologically proven osteosarcoma and pulmonary metastases that either developed during adjuvant chemotherapy or were present at diagnosis, persisted despite chemotherapy, and recurred following surgical excision. Stratum A patients were rendered clinically free of disease within 4 weeks of study entry prior to receiving combination therapy. IFX was administered at 1.8 g/m2 for 5 days every 21 days for up to eight cycles. L-MTP-PE was administered twice weekly for 12 weeks, then once weekly for 12 weeks. Once cycle of combination therapy was defined as 5 days of IFX and 3 weeks of L-MTP-PE therapy. Stratum B patients had measurable disease at study entry that was judged to be amenable to surgical resection. Stratum B patients received three cycles of combination therapy prior to surgery to judge clinical and histologic response. Postoperatively, patients received an additional five cycles. A total of nine patients were entered into the protocol: six on stratum A and three on stratum B. Serial blood samples were collected and assayed for cytokine levels (tumor necrosis factor-alpha [TNF alpha], interleukin-6 [IL-6], IL-8, neopterin, C-reactive protein). In addition, peripheral blood monocyte tumoricidal activity was evaluated pre- and post-combination therapy. Complete blood counts with differential and platelet counts were followed weekly. No increase in the toxic side effects of IFX was demonstrated when administered with L-MTP-PE nor were delays in IFX administration due to neutropenia experienced. The toxic side effects of L-MTP-PE were also not increased. Elevations of serum C-reactive protein, plasma neopterin, IL-6, IL-8, and TNF alpha following combination therapy were similar to those observed in patients treated with L-MTP-PE alone. Monocyte-mediated tumoricidal activity was elevated 24 and 72 h following L-MTP-PE and IFX therapy, similar to what has been reported following L-MTP-PE alone. Tumor specimens obtained from stratum B patients showed the histologic characteristics consistent with a "chemotherapy effect," i.e., dead, amorphous, acellular osteoid with cell drop-out.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Combination therapy with ifosfamide and liposome-encapsulated muramyl tripeptide: tolerability, toxicity, and immune stimulation. 761 44

The influence of pentoxifylline (PTX) on mortality and some important mediators was studied in a model of cecal perforation with fulminant intra-abdominal sepsis in rats. Cumulative mortality was registered in three groups of animals: untreated sepsis (n = 36), sepsis + PTX 20 mg/kg/24 h (n = 24), and sepsis + PTX 80 mg/kg/24 h (n = 24). PTX therapy was started at sepsis induction or after 4 h, and mortality was reduced from 89% in untreated sepsis to 60-66% in the PTX groups. Levels of sepsis mediators were studied in two groups: untreated sepsis and sepsis + PTX 40 mg/kg started 1 h after sepsis induction. In both groups 6-10 animals were sacrificed at 4 and 8 h to measure blood levels of bacteria, endotoxin, tumor necrosis factor (TNF), interleukin-6 (IL-6), endothelin-1, lactate, neutrophils, and packed cell volume. Cecal perforation gave high levels of bacteria, endotoxin, TNF, IL-6, and endothelin-1, leading to dehydration, lactacidosis, neutropenia, and death. Treatment with PTX did not modify dehydration, neutropenia, or concentrations of bacteria and endotoxin. Release of endothelin-1 was delayed, TNF burst was nearly abolished, and levels of IL-6 and lactate were substantially suppressed. In summary, PTX improves survival and reduces blood concentrations of TNF, IL-6, lactate, and endothelin-1 in fulminant intra-abdominal sepsis in rats. The primary effect of PTX in this sequence is probably reduction of TNF.
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PMID:Pentoxifylline improves survival and reduces tumor necrosis factor, interleukin-6, and endothelin-1 in fulminant intra-abdominal sepsis in rats. 777 1

Serum endotoxin, interleukin-6 (IL-6) and C-reactive protein (CRP) were serially determined in 26 patients with hematological malignancies and chemotherapy-induced neutropenia who developed fever. Endotoxin in serum was detected in 69% of the patients, with the highest values being recorded in patients with gram-negative (Gr-) bacteremia. High levels of IL-6 were found after start of fever, and in 6/9 patients with Gr- bacteremia levels exceeded 200 ng/l in samples drawn within the first 72 hours. However, only in 2/17 patients with gram-positive bacteremias and blood culture-negative fever episodes did IL-6 exceed this concentration (p < 0.05). High CRP values (exceeding 100 mg/l) did not discriminate between Gr- and non-Gr- episodes (7/9 versus 10/17, respectively). In patients with fever at day 3-5 (n = 15), IL-6 values > 100 ng/l were associated with fever continuing for more than 7 days after start of the episode; contrarily, CRP values did not indicate the persistence of fever. Determination of IL-6 may be a better test than CRP in monitoring the acute response to infection in the neutropenic patient. A combination of high endotoxin and IL-6 values may indicate a Gr- bacteremia. This could have therapeutic implications before results of blood cultures are obtained.
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PMID:Monitoring of endotoxin, interleukin-6 and C-reactive protein serum concentrations in neutropenic patients with fever. 778 67

Interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF) are important mediators of fever and inflammation, and are involved in the pathogenesis of sepsis. There is only limited data on serum concentrations of these proinflammatory cytokines in patients with fever and neutropenia, and their interrelationship and correlation with body temperature and clinical disease early in the febrile response during neutropenia have not been studied. Immunoreactive TNF, IL-1 beta, IL-6, and IL-8 in serum samples serially obtained from 14 adult patients with neutropenia and fever considered or documented to be due to infection were measured. IL-6 and Il-8 were consistently elevated in all patients, and correlated well with each other and with body temperature. Median peak concentration of IL-6 and IL-8 were 400 pg/ml (range: 100 to 41,000 pg/ml), and 1,025 pg/ml (range: 600 to 26,000 pg/ml), respectively, and levels of both cytokines rapidly declined in patients responding to antimicrobial therapy. Despite frequent sampling before and after the temperature peaks TNF and IL-1 beta, conversely, were less frequently detectable, with median peak values of < 10 pg/ml (range: < 10 to 150 pg/ml) for TNF, and 17 pg/ml (range: < 10 to 36 pg/ml) for IL-1 beta, respectively. The role of neutro- and monocytopenia with depletion of important cytokine producing and target cells in this particular cytokine response pattern needs to be further studied.
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PMID:Kinetics and correlation with body temperature of circulating interleukin-6, interleukin-8, tumor necrosis factor alpha and interleukin-1 beta in patients with fever and neutropenia. 792 10

Previous reports have indicated that immunological priming of animals will result in increased cytokine production and enhanced susceptibility to the toxicity of cytokines. We primed mice with complete Freund's adjuvant and challenged 2 weeks later with 1 mg/mouse of lipopolysaccharide. Primed mice produced less tumor necrosis factor than naive mice (35 +/- 8 vs 108 +/- 20 ng/ml) and also less interleukin-6 (182 +/- 37 vs 6.39 +/- 155 ng/ml). Leukopenia developed only in the naive mice. Although neutropenia and lymphocytosis developed in both groups, the alterations manifested themselves more quickly in primed mice. Primed mice had substantially greater pulmonary neutrophil sequestration determined both enzymatically and histologically but no lung damage. However, primed mice had significantly less small bowel damage than naive mice. Mortality was substantially reduced in primed mice compared with unprimed mice. These results demonstrate that immunological priming in vivo decreases cytokine production in response to lipopolysaccharide challenge, decreases organ injury, and reduces mortality.
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PMID:Immunological priming attenuates the in vivo pathophysiological response to lipopolysaccharide. Comparison of cytokine production, tissue injury, and lethality in complete Freund's adjuvant-primed mice and in unprimed mice. 812 45

Serum concentrations of tumour necrosis factor alpha (TNF-alpha), interleukin-1 receptor antagonist (IL-1ra), interferon gamma (IFN-gamma), interleukin-6 (IL-6) and interleukin-10 (IL-10) were studied in 31 patients with haematological malignancies during febrile neutropenia. Samples were obtained when blood cultures were performed (time 0) and, when possible, after 2, 4, 6, 12 and 24 h. Increased levels of all cytokines were detected after start of fever with peak values in gram-negative (Gr-) bacteraemias after 2 h (TNF-alpha, IL-1ra and IFN-gamma), 4 h (IL-6) and 6 h (IL-10), respectively. At time 0 the median TNF-alpha value was higher in the Gr- group (80 pg/ml; range 54-516 pg/ml) as compared to both gram-positive bacteraemias (Gr+, 14 pg/ml; range 7-60 pg/ml; P < 0.05) and blood culture negative episodes (BCN, 8 pg/ml; range 0-87 pg/ml; P < 0.05). Furthermore, the peak values of TNF-alpha, IL-1ra, IL-6 and IL-10 during the 24 h study period were significantly and/or numerically higher in the Gr- group in comparison to the Gr+ and BCN groups, respectively. It may be concluded that neutropenic patients have increased levels of both pro- and anti-inflammatory cytokines at start of fever, with the highest values recorded during the first hours in Gr- bacteraemias. Prospective studies will show whether monitoring of serum cytokines may be used as an early diagnostic tool before results of blood cultures are available, which may have important therapeutic implications.
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PMID:Clinical significance of serum cytokine patterns during start of fever in patients with neutropenia. 890 7

Pretransplant and posttransplant use of hematopoietic growth factors in bone marrow transplantation (BMT) has shortened the time to engraftment. Severe neutropenia and thrombocytopenia have been the major clinical problems associated with autologous BMT. Efforts to maintain posttransplant levels of circulating neutrophils have focused on exploiting the synergistic action between various hematopoietic growth factor families. Ex vivo generation of distinct populations of expanded cells through simultaneous and sequential addition of hematopoietic growth factors was attempted. Cultures of CD34-selected cells with combinations of growth factors consisting of either recombinant human stem cell factor (rhSCF), recombinant human interleukin-6 (rhIL-6), and recombinant human interleukin-3 (rhIL-3) or rhSCF, rhIL-3, and recombinant human granulocyte-colony stimulating factor (rhG-CSF) generated two distinct but overlapping populations of cells. Delayed addition (on day 7) of rhIL-3 and rhIL-6 to cells cultured with rhSCF generated a population of cells significantly less mature than those cultured with continuous rhSCF, rhIL-3, and rhIL-6 alone. It appears that optimal generation of immediate and delayed cell populations can be achieved by simultaneous culture with rhSCF, rhIL-3, and rhG-CSF; and with rhSCF, rhIL-6, and rhIL-3. Questions remain regarding the cell populations most effective for generating and sustaining the required neutrophil numbers.
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PMID:The biology of the cytokine sequence cascade. 860 May 44

The use of granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in order to abrogate chemotherapy-induced neutropenia has become a routine part of many cancer treatment regimes. However, there are still very few data available about possible complications related to repeated or prolonged use of these agents in patients with malignant solid tumors. The authors report a child with brainstem glioma who received repeated cycles of multiagent chemotherapy with G- or GM-CSF support. During this period of 10 months, no clinical side effects were observed that could have been attributed to growth factor administration. However, postmortem histological examination revealed the presence of diffuse plasmacytosis, a rare hematological disorder in childhood. Undifferentiated plasma cells of nonmonoclonal origin could be demonstrated infiltrating bone marrow, lungs, and lymph nodes of the patient. Based on previously published in vitro and in vivo evidence on the interleukin-6 (IL-6)-mediated stimulatory effect of G- and GM-CSF on myeloma cell proliferation, the authors suggest a possible link between extensive growth factor support and the development of plasmacytosis in this patient.
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PMID:Diffuse plasmacytosis in a child with brainstem glioma following multiagent chemotherapy and intensive growth factor support. 861 71

Prolonged thrombocytopenia is a frequent clinical problem in cancer patients undergoing high-dose chemotherapy and autologous transplantation. The use of GM-CSF as an adjuvant to autologous bone marrow transplantation (ABMT) has significantly reduced the duration of neutropenia after high-dose chemotherapy but failed to accelerate platelet recovery in transplanted patients. The more rapid hematopoietic reconstitution obtained by autologous mobilized peripheral blood progenitor cell transplantation (PBPCT) after high-dose chemotherapy has resulted in its increasing use instead of ABMT. However, PBPCT does not always produce faster platelet engraftment after high-dose chemotherapy, and persistent thrombocytopenia remains a significant clinical problem in PBPC-transplanted patients. The duration of severe thrombocytopenia (requiring frequent platelet transfusions) until platelet recovery varies widely depending on the quality of the autograft and previous radiotherapy or chemotherapy. The median days to reach 20,000/microliters platelets ranged from 10 to 32 days. Pilot clinical studies in which cancer patients were transplanted with enriched CD34+ cell autografts, obtained from G-CSF-mobilized PB, showed a similar platelet recovery after high-dose chemotherapy but also wide variation among the patients. The median days to reach 20,000/microliters platelets ranged from 9 to 38 days. The dose of CFU-GM in the autograft has been identified as the best predictive factor for hematopoietic recovery (p < 0.0001) after high-dose chemotherapy and autologous PBPCT in 118 patients with hematologic malignancies. A similar assessment of the megakaryocyte progenitor cells (BFU-MK and CFU-MK) in the autograft not only could predict time to platelet recovery but also could help to optimize the number and method of mobilization of the PBPC required to shorten the problematic obligatory 2-week duration of thrombocytopenia after high-dose chemotherapy. A routine assessment of the number of BFU-MK and CFU-MK present in each autograft and correlation with platelet recovery after transplantation would enable us to define the clinical threshold cell dose required for rapid platelet recovery. Recently, several non-specific cytokines with thrombopoietic activity have been evaluated in phase I clinical trials, including interleukin-1, interleukin-3 followed by GM-CSF, interleukin-6, and interleukin-11 in cancer patients, showing an encouraging trend toward a decrease in thrombocytopenia after chemotherapy. The recently cloned specific platelet cytokine, thrombopoietin, is currently undergoing phase I clinical studies, and the results are awaited with interest.
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PMID:Thrombocytopenia after high-dose chemotherapy and autologous stem cell transplantation: an unresolved problem and possible approaches to resolve it. 887 16

To date, six hematopoietic growth factors, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), interleukin-1 (IL-1), interleukin-6 (IL-6) and erythropoietin (Epo), have been used in the treatment of patients with aplastic anemia (AA). Among them, G-CSF and GM-CSF are effective in correcting neutropenia in some patients with AA, but in general, patients with very severe hypoplasia do not respond to conventional doses of either agent. These factors have been used in the treatment of AA as follows: (1) as adjuvant therapy for severe infections; (2) as adjuvant therapy to immunosuppressive therapy (IS); and (3) as second-line therapy for patients refractory to IS. The results of clinical trials with antilymphocyte globulin, cyclosporine combined with G-CSF have been remarkable both in Europe and in Japan. Ongoing randomized studies with long-term follow-up will reveal the effects of hematopoietic growth factors on both hematopoiesis and the long-term course of the disease, including the later development of clonal disorders.
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PMID:Use of hematopoietic growth factors for treatment of aplastic anemia. 897 6


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