Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0243026 (sepsis)
 52,417 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Multiple mechanisms of drug resistance contribute to treatment failure. Although high-dose therapy attempts to overwhelm these defenses pharmacologically, this approach is only successful in a fraction of treated patients. Many drug resistance mechanisms are shared between malignant and normal cells, but the expression of various drug resistance mechanisms associated with hypoxia is largely confined to tumor tissue. Thus, reversal of this mechanism is likely to provide a therapeutic advantage to the host. This study was designed to define the dose-limiting toxicities and maximum tolerated dose of etanidazole when it is given concurrently with high-dose ifosfamide, carboplatin, and etoposide (ICE), with hematopoietic stem cell support. The maximum tolerated doses of high-dose ICE were administered concurrently with dose escalations of etanidazole, a hypoxic cell sensitizer. All agents were given by 96-h continuous i.v. infusion beginning on day -7. Mesna uroprotection was provided. Autologous marrow and cytokine mobilized peripheral blood progenitor cells were reinfused on day 0. Granulocyte colony-stimulating factor was administered following reinfusion until the granulocytes recovered to > 1000/microliter. Fifty-five adults with advanced malignancies were enrolled in cohorts of five to nine patients. Four dose levels of etanidazole between 3 and 5.5 g/m2/day (12, 16, 20, and 22 g/m2 total doses) and two doses of carboplatin (1600 and 1800 mg/m2 total doses) were evaluated. Seven patients died of organ toxicity (13%); two each from veno-occlusive disease of liver and sepsis; and one each from sudden death, renal failure, and refractory thrombocytopenic hemorrhage. Five deaths occurred at the top dose level. One additional patient suffered a witnessed cardiorespiratory arrest from ventricular fibrillation and was resuscitated. Dose-dependent and largely reversible peripheral neuropathy was observed consisting of two syndromes: severe cramping myalgic/neuralgic pain, predominantly in stocking glove distribution, occurring between day -3 and day 0, and a sensory peripheral neuropathy with similar distribution peaking around day +60. The maximal achievable dose of etanidazole (16 g/m2 dose level) resulted in a mean serum level of 38 micrograms/ml (25-55 micrograms/ml). Etanidazole significantly enhanced host toxicity of high-dose ICE. Effective modulatory doses of etanidazole could not be given with acceptable toxicity using this schedule.
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PMID:Dose escalation of the hypoxic cell sensitizer etanidazole combined with ifosfamide, carboplatin, etoposide, and autologous hematopoietic stem cell support. 962 61

In normal conditions, alveolar macrophages (AMs) are the main cells that respond to bacteria that reach lower airways. However, if the microbial inoculum is too high or too virulent to be stopped by AM alone, these cells recruit polymorphonuclear neutrophils (PMN) into the alveoli from the vascular compartment. Cytokines, such as tumour necrosis factor-alpha (TNF-alpha), interleukin-1-beta (IL-beta), interleukin-6 (IL-6), and interleukin-8 (IL-8), secreted by the AM are able to attract PMN enhanced for phagocytosis, ready to destroy the invading pathogens. However, excessive cytokine production has deleterious effects, with a systemic inflammatory response (sepsis) that can lead to multiorganic failure and death. Other cytokines, such as interleukin-10 (IL-10) balance this response, attenuating several inflammatory mechanisms. The inflammatory lung response in pneumonia has been well studied in animals, and more recently in humans, using bronchoalveolar lavage to measure some inflammatory mediators (TNF-alpha, IL-1 beta, IL-6, IL-8). From these studies, it seems that: 1) the inflammatory response to pneumonia is compartmentalized for most cytokines (in contrast to adult respiratory distress syndrome (ARDS)), except for IL-6 which is a general marker of inflammation. On the other hand, C-reactive-protein is an acute-phase protein synthesized by the liver through the stimulus of IL-6 that may also be an easy-to-measure marker of inflammation that is directly related to IL-6; 2) some of these cytokines may be useful as prognostic indices; 3) there is no clear relationship between the local lung bacterial burden and the intensity of the inflammatory response; and 4) the administration of granulocyte colony-stimulating factor (G-CSF) is a promising therapeutic approach that is still under clinical investigation. In the future, it is probable that the therapeutic goal in severe pneumonia will be to find the exact point at which inflammation is beneficial but not deleterious. The measurement of the inflammatory response may serve for this purpose.
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PMID:Lung inflammatory response in pneumonia. 963 9

Recombinant GM-CSF has been recently shown to prolong survival of elderly patients with acute myeloid leukemia (AML) by reducing the rate of induction therapy-related mortality. In a prospective, randomized, placebo-controlled, double-blind, multicenter study conducted by the Eastern Cooperative Oncology Group in the United States, granulocyte-macrophage colony-stimulating factor (GM-CSF) was given only to those patients who had hypocellular or remission marrow on day 10 of one or two cycles of standard induction therapy. Although the administration of GM-CSF significantly reduced a wide range of adverse events, the main benefit of this cytokine seems to be mediated by a reduction in sepsis. A similarly designed study, conducted by the Southwest Oncology Group in a directly comparable AML patient population with use of granulocyte colony-stimulating factor (G-CSF) as the supportive cytokine, showed no survival benefit and no reduction in the rates of serious or lethal sepsis. In most current clinical situations, GM-CSF and G-CSF are indistinguishable both in terms of efficacy and toxicity. GM-CSF and G-CSF have very different impacts on the survival of patients with AML. The stimulation of monocyte-macrophage function and proliferation by GM-CSF may mediate the selective benefit of GM-CSF in patients with AML and stem cell transplants. GM-CSF merits further study as therapy for and/or protection against opportunistic sepsis in patients with cancer and will be included in a number of International Oncology Study Group protocols.
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PMID:Monocyte-macrophages, granulocyte-macrophage colony-stimulating factor, and prolonged survival among patients with acute myeloid leukemia and stem cell transplants. 963 47

The immaturity of neonatal phagocytic immunity contributes to increased mortality during neonatal sepsis. Neonates have both quantitative and qualitative neutrophil defects with decreased bone marrow neutrophil storage pool (NSP) reserves, an inability to increase neutrophil production, and defective neutrophil functional activity. Neonates respond to overwhelming sepsis with depletion of the NSP and the development of peripheral neutropenia. The myelopoietic cytokines granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been documented to induce neutrophilia in neonatal animals and human infants, increase the NSP, and upregulate neutrophils for improved functional activity. Preclinical studies in neonatal rats demonstrate increased survival with prophylactic G-CSF during experimental group B streptococcal sepsis. In pilot phase I/II human trials, G-CSF and GM-CSF were demonstrated to be both safe and well tolerated and to induce significant increases in absolute neutrophil count and NSP. Prophylactic GM-CSF in the very low birth weight neonate may reduce the incidence of nosocomial infections. Phase III trials are needed to further delineate the clinical usefulness of these myelopoietic cytokines in neonates with a high predisposition to sepsis.
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PMID:Potential use of granulocyte colon-stimulating factor and granulocyte-macrophage colony-stimulating factor in neonates. 966 63

Polymicrobial sepsis induced by cecal ligation and puncture (CLP) reproduces many of the pathophysiologic features of septic shock. In this study, we demonstrate that mRNA for a broad range of pro- and anti-inflammatory cytokine and chemokine genes are temporally regulated after CLP in the lung and liver. We also assessed whether prophylactic administration of monophosphoryl lipid A (MPL), a nontoxic derivative of lipopolysaccharide (LPS) that induces endotoxin tolerance and attenuates the sepsis syndrome in mice after CLP, would alter tissue-specific gene expression post-CLP. Levels of pulmonary interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), IL-1 receptor antagonist (IL-1ra), and IL-10 mRNA, as well as hepatic IL-1beta, IL-6, gamma interferon (IFN-gamma), G-CSF, inducible nitric oxide synthase, and IL-10 mRNA, were reduced in MPL-pretreated mice after CLP compared to control mice. Chemokine mRNA expression was also profoundly mitigated in MPL-pretreated mice after CLP. Specifically, levels of pulmonary and hepatic macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, MIP-2, and monocyte chemoattractant protein-1 (MCP-1) mRNA, as well as hepatic IFN-gamma-inducible protein 10 and KC mRNA, were attenuated in MPL-pretreated mice after CLP. Attenuated levels of IL-6, TNF-alpha, MCP-1, MIP-1alpha, and MIP-2 in serum also were observed in MPL-pretreated mice after CLP. Diminished pulmonary chemokine mRNA production was associated with reduced neutrophil margination and pulmonary myeloperoxidase activity. These data suggest that prophylactic administration of MPL mitigates the sepsis syndrome by reducing chemokine production and the recruitment of inflammatory cells into tissues, thereby attenuating the production of proinflammatory cytokines.
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PMID:Pulmonary and hepatic gene expression following cecal ligation and puncture: monophosphoryl lipid A prophylaxis attenuates sepsis-induced cytokine and chemokine expression and neutrophil infiltration. 967 35

Infections that occur after intraabdominal surgery still cause considerable morbidity and mortality despite the administration of prophylactic antibiotics. Increasing the number of neutrophils may also be a prophylactic approach, and granulocyte colony-stimulating factor (G-CSF) has been found to be beneficial in different animal models of peritonitis and sepsis. It is the combination of G-CSF and antibiotics, however, that is clinically relevant. Treatment of mice with G-CSF that was started before cecal ligation and puncture and continued afterward with antibiotics improved survival, decreased splenic bacterial colony-forming units and serum tumor necrosis factor, and increased serum interleukin-10, compared with treatment with antibiotics alone or with saline. Compared with saline, antibiotics alone increased tumor necrosis factor and did not affect interleukin-10. Thus, G-CSF confers onto antibiotics beneficial antiinfectious and antiinflammatory properties. A prophylactic regimen combining G-CSF and antibiotics may help prevent severe infectious complications following intraabdominal surgery.
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PMID:Granulocyte colony-stimulating factor and antibiotics in the prophylaxis of a murine model of polymicrobial peritonitis and sepsis. 969 29

Diabetic patients are more prone to infection and evidence for an immunologic defect superimposed upon the metabolic abnormalities of diabetes is convincing. Neutrophils play a critical role in the host defense mechanism against various bacterial infections, and it is suggested that impaired neutrophil functions cause susceptibility to infections in diabetic patients. To explore the possibility that Granulocyte colony-stimulating factor (G-CSF) may be useful to prevent the morbidity and mortality caused by infections in diabetics. We studied the effect of G-CSF against septicemia in diabetic rats. Forty eight rats were divided into seven equal groups. The IInd, IVth-VIth groups were made diabetic by single intraperitoneal injection of streptozotocin. Fourth, VIth and VIIth groups were made septicemic by cecal ligation and perforation at the end of the second week of streptozotocin injection. G-CSF was subcutaneously injected into IIIrd, Vth and VIth groups. White blood cell count, neutrophil counts and function were determined. Rats in all groups were also observed for seven days for survival. White blood cells, neutrophil and lymphocyte counts and the neutrophil phagocytosis index decreased but neutrophil adherence rate was not different in diabetic group II (p<0.05). All these variables were significantly diminished in diabetes and sepsis-induced group IV (p<0.05). G-CSF injections improved all variables except neutrophil adherence. Cumulative survival ratio was better in G-CSF-injected group VI than in ceftriaxon-administrated group VII (p<0.05). In conclusion, G-CSF increased neutrophil counts, developed neutrophil functions and improved survival. These results suggest that G-CSF may be useful as a drug to prevent bacterial infection in diabetic patients.
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PMID:Effects of rhG-CSF on neutrophil functions and survival in sepsis induced diabetic rats. 973 93

Bacterial sepsis is still a leading cause of neonatal morbidity and mortality. Early onset sepsis in particular, presents with a different clinical course and involves other pathogens than sepsis later in life. In this study, plasma concentrations and mRNA expression of granulocyte colony-stimulating factor (G-CSF), tumor necrosis factor-alpha (TNF-alpha), IL-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 (sICAM-1) of neonates with early onset sepsis were evaluated in cord blood and during the first days of life. Irrespective of prematurity, plasma levels of G-CSF, TNF-alpha, IL-1beta, IL-6, and IL-8, but not sICAM-1, were excessively elevated in septic neonates when compared with both healthy infants and infants with clinically suspected but not confirmed sepsis. Compared with the corresponding maternal levels, neonatal cytokine cord plasma levels were likewise highly elevated, indicating the endogenous cytokine production by the neonate. With the exception of TNF-alpha, mRNA expression in blood cells from septic infants was, however, not more frequently detectable than in those from nonseptic patients. Cytokine levels decreased significantly within the first days of life, whereas levels of sICAM-1 and C-reactive protein increased during the same time period. In summary, in contrast to C-reactive protein and sICAM-1, cord blood plasma levels, but not the presence of mRNA, of G-CSF, TNF-alpha, IL-1beta, IL-6, and IL-8 can predict neonatal early onset sepsis with a high sensitivity and specificity. Cell types other than blood cells are likely to contribute considerably to the high cytokine production in septic newborns.
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PMID:Plasma levels and gene expression of granulocyte colony-stimulating factor, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-8, and soluble intercellular adhesion molecule-1 in neonatal early onset sepsis. 977 33

This was a phase I, multi-center study of 13 pediatric patients (median age, 11 years) to evaluate toxicity, hematopoietic recovery, and graft-versus-host disease (GVHD) after allogeneic transplantation of enriched blood CD34(+) cells obtained from genotypically haploidentical but partially HLA-mismatched related donors (8 parents and 5 siblings). With regard to rejection, donor HLA disparity was 1 (5), 2 (6), or 3 loci (2). With regard to GVHD, recipient HLA disparity was 0 (1), 1 (3), 2 (8), or 3 (1). The patients suffered from acute myelogenous leukemia (6), chronic myelogenous leukemia (4), acute lymphoblastic leukemia (2), or hemolytic anemia plus immunodeficiency disorder (1). To reduce the risk of graft failure through the infusion of a large amount of stem cells, peripheral blood cells (PBC) were mobilized by recombinant granulocyte colony-stimulating factor (G-CSF; lenograstim, 10 microgram/kg/d for 5 days) and collected by 2 to 5 aphereses. To both enhance engraftment and reduce GVHD, CD34(+) cells were enriched using immunomagnetic procedures with the Baxter ISOLEX 300 system (Baxter Healthcare Corp, Irvine, CA) and cryopreserved. After variable cytoreductive regimens, a median of 7.7 (range, 2.2 to 14) x 10(6)/kg of CD34(+) cells and 1.03 (0.05 to 2.09) x 10(5)/kg CD3(+) cells were infused. Using Center-specific posttransplant supportive care and immunosuppressive GVHD prophylaxis, two patients experienced early death; one from veno-occlusive disease at day 17 and one from sepsis at day 18. Nine of 11 patients showed signs of engraftment; however, subsequent rejection was seen in 4 patients, 2 of whom had autologous recovery. Eight patients were evaluated in the early phase of marrow recovery. The median number of days to achieve an absolute granulocyte count of 0.5 x 10(9)/L was 14 (range, 9 to 20) and that to achieve a platelet count of 20 x 10(9)/L was 17.5 (range, 12 to 23). Donor chimerism persisted in five patients until death or current survival. All of the surviving patients with functioning-donor-type hematopoiesis were given total body irradiation. De novo acute GVHD (grades II and IV) was observed in two of the eight evaluated patients. Scheduled donor lymphocyte infusion (DLI), using the CD34(-) fraction, was administered to four patients, free of de novo acute GVHD, beginning between 28 to 43 days after transplant. Three of these patients developed acute GVHD (grades I, II, and IV). Cytomegalovirus infection was a major infectious complication but was successfully managed with gamma-globulin and gancyclovir treatment with or without additional DLI. Five patients are currently surviving, free of disease, with a follow-up ranging from 476 to 937 days. Each survivor has functioning hematopoiesis, three of donor origin and two of autologous origin. In conclusion, our results show that enriched blood CD34(+) cells from a mismatched haploidentical donor are a feasible alternative source of stem cells, but do not appear to ensure engraftment. Because none of the patients who were administered DLI survived, the therapeutic efficacy and safety of periodic DLI, as an integrated part of such transplants, needs to be clarified in further studies.
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PMID:Partially mismatched pediatric transplants with allogeneic CD34(+) blood cells from a related donor. 978 47

The purpose of this study was to determine the maximally tolerated dose of doxorubicin administered during two cycles of intensive chemotherapy with cyclophosphamide and doxorubicin without stem cell support in patients with advanced cancer and to assess the cumulative cardiac toxicity of the regimen by noninvasive radionuclide imaging and by pre-and postchemotherapy endomyocardial biopsies. Thirty-eight patients (thirty-six with high risk or metastatic breast cancer) were treated in a dose-escalation trial using a fixed dose of i.v. cyclophosphamide (4.2 g/m2) administered over 2 h on day 5 and escalating doses of doxorubicin (50-175 mg/m2) given as a 96-h continuous i.v. infusion on days 1-4, using Filgrastim (granulocyte colony-stimulating factor) for hematological support beginning on day 6. All patients underwent pretreatment, and 28 patients underwent postchemotherapy endomyocardial biopsies. Twenty-nine of 38 patients received two cycles of treatment (median number of days between cycles, 44; range, 34-62). Twenty-one patients had received doxorubicin previously at cumulative dose levels </=150 mg/m2; all patients had pretreatment endomyocardial biopsy scores less than 1. One patient treated at the highest dose level of doxorubicin (175 mg/m2) developed symptoms of mild congestive heart failure following two cycles of chemotherapy. Pre- and posttreatment radionuclide ejection fractions were 65 and 45%, respectively; this patient had a posttreatment endomyocardial biopsy score of 1 (damage to <5% of myocytes). One additional patient at this dose level had an asymptomatic biopsy score of 1, with a decrease in ejection fraction from 62 to 43%; this recovered to 58% 5 months after completion of chemotherapy. Six additional patients treated at lower dose levels had abnormal posttreatment endomyocardial biopsies without abnormal posttreatment ejection fractions. Nine patients received only one cycle of chemotherapy: five patients due to decreased cardiac ejection fraction following cycle 1 (two of these patients had normal endomyocardial biopsies, and two patients had biopsy scores of 1); one patient secondary to tumor progression following cycle one; one patient due to persistently detectable Clostridium difficile toxin in the stool; one patient refused cycle two; and one patient died following cycle one of complications related to sepsis. A single patient experienced a grand mal seizure associated with orthostatic hypotension, which was considered the dose-limiting toxicity. The median duration (over two cycles) of granulocytopenia (absolute granulocyte count <500/microliter) at the maximally tolerated dose level of 150 mg/m2 was 8.5 days (range, 5-13 days), and the median duration of thrombocytopenia (platelets <20,000/microliter) was 2.5 days (range, 0-9 days). The median duration of hospitalization including chemotherapy administration was 23 days (range, 19-36 days). Other toxicities included stomatitis, fever, diarrhea, and emesis. One patient developed acute leukemia 54 months posttreatment. We conclude that two courses of high-dose cyclophosphamide and doxorubicin using granulocyte colony-stimulating factor are feasible and safe with tolerable myocardial toxicity as evidenced by serial endomyocardial biopsies. The dose-limiting toxicity encountered was a grand mal seizure. The recommended Phase II dose is doxorubicin 150 mg/m2 administered as a 96-h infusion on days 1-4, with cyclophosphamide 4. 2 g/m2 on day 5 and G-CSF 5 microgram/kg/day started on day 6 and administered until the total WBC is above 10,000/microliter for three consecutive days.
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PMID:High-dose infusional doxorubicin and cyclophosphamide: a feasibility study of tandem high-dose chemotherapy cycles without stem cell support. 981 32


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