Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036690 (sepsis)
 59,461 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The cytokines interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha) have been implicated in the pathophysiology of sepsis and the systemic inflammatory response syndrome (SIRS). The anti-endotoxin antibody, HA-1A (Centoxin), introduced as a treatment for sepsis, was withdrawn because of possible toxicity in some patients. There has been little investigation of the effects of HA-1A on cytokine production. Sixty-one whole blood samples from 15 intensive care unit (ICU) patients with SIRS were incubated for 24 h with HA-1A and concentrations of cytokines determined. Concentrations of IL-6 exceeded those in samples incubated without HA-1A by more than 25% in five patients, of whom four died. One death occurred among 10 patients for whom IL-6 concentrations did not increase (P = 0.03). Incubation with HA-1A did not increase concentrations of IL-1 beta or TNF alpha. HA-1A did not affect cytokine production in whole blood from healthy subjects. HA-1A may induce IL-6 production in whole blood from some ICU patients and this response is associated with increased mortality. Immune therapies for treatment of sepsis and SIRS require careful evaluation of their ability to affect cytokine production, before they are introduced for general use.
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PMID:In vitro effects of HA-1A (Centoxin) on cytokine production in whole blood from intensive care unit patients. 788 Jun 71

The clinical syndrome sepsis has been redefined recently, and the SIRS (systemic inflammatory response syndrome) concept has been developed. In the initial phase of sepsis, different mediator systems are activated finally resulting in a generalized endothelial inflammatory reaction. This reaction may lead to a vicious circle with subsequent multiple organ failure. Standard therapeutic regimen include the surgical removal of the source of sepsis, antimicrobial therapy, optimizing oxygenation, volume resuscitation, and treatment with catecholamines. Recently, new treatment modalities have become available. Replacement of antithrombin III, continuous venovenous hemofiltration, application of high doses of immunoglobulins and of low doses of hydrocortisone have been used. A monoclonal antibody against endotoxin (Centoxin) was taken from the German market in January 1993. Experimental aspects of treatment include the administration of C1 esterase inhibitor, pharmacological inhibition of nitric oxide (NO), plasmapheresis, the application of non-steroidal anti-inflammatory agents and of high-dose naloxone as well as manipulation of cytokines.
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PMID:[Intensive care medicine aspects of infection and septic multiple organ failure]. 837 68

Passive immunization with a human anti-endotoxin monoclonal IgM antibody (Centoxin, HA-1A) was recently studied in patients with suspected Gram-negative sepsis. Comparison of the results obtained in the Amsterdam subpopulation with those in a larger international study population of which the Amsterdam patient group was a part, showed that it had been possible to select a patient population in which HA-1A has an 'intention-to-treat' effect based upon clinical criteria (a decrease in mortality compared with placebo by 42% (p = 0.04) and in the larger study by 9% (p = 0.24). Until a clinically useful test becomes available, identification of patients who have a high likelihood of Gram-negative sepsis and who would benefit from anti-endotoxin immunotherapy with HA-1A should be based upon the history and evaluation of underlying disease, infection status, severity and progression of the disease. The severely ill patients thus selected should receive treatment as early as possible.
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PMID:[Immunotherapy using the anti-endotoxin antibody HA-1A in patients with sepsis syndrome; good results in relation to treatment with placebo]. 845 66

The pharmacokinetics and safety of HA-1A (Nebacumab), a human IgM monoclonal antibody with specificity for the lipid A region of endotoxin, were evaluated in a multicenter trial of pediatric patients with sepsis syndrome or septic shock. Forty-two patients received a total of 44 infusions of drug, at a dose of 3 mg/kg (maximum 100 mg). The mean age was 7 years 10 months (range, 11 months to 16 years 7 months). The pharmacokinetic behavior of HA-1A during 36 hours was best described by a one-compartment open model. Clearance (6.1 +/- 2.0 ml/kg per hour) and apparent volume of distribution at steady state (0.11 +/- 0.03 L/kg) were larger than values reported previously in adults with sepsis syndrome. Elimination half-life (14.5 +/- 6.8 hours) and plasma concentration after infusion (30.7 +/- 14.5 mg/L) were similar to adults' values. In an additional three patients studied for 72 hours after administration, a biexponential function (i.e., two-compartment open model) best described the pharmacokinetic behavior of HA-1A: clearance (1.5 +/- 1.4 ml/hr per kilogram) and apparent volume of distribution at steady state (0.2 +/- 0.02 L/kg) were different (p < 0.002) from values observed in children's blood samples during 36 hours. Within the pediatric population, no age-related differences in pharmacokinetics could be detected. Drug disposition was unaffected by renal or hepatic dysfunction. Decreased blood pressure was the most frequently reported adverse event; 4 (9%) episodes in 44 infusions were considered possibly related to the study drug. Gram-negative bacteremia was documented in 23 (55%) of 42 patients. The overall mortality rate was 31%. Enterobacter cloacae was the most common pathogen isolated. Haemophilus influenzae type b was isolated from one child with sepsis syndrome. We conclude that infusion of HA-1A in children is associated with a low incidence of side effects. The pharmacokinetic-pharmacodynamic behavior of HA-1A in children requires further study to determine whether developmental differences exist and how these differences might affect drug administration. Efficacy remains to be studied.
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PMID:Single-dose pharmacokinetics and safety of HA-1A, a human IgM anti-lipid-A monoclonal antibody, in pediatric patients with sepsis syndrome. 850 80

P & T Committees are entering an exciting era in which the introduction of biotechnology-derived pharmaceuticals is providing life-saving opportunities for conditions for which there was little or no hope for a cure. The P & T Committee at Thomas Jefferson University Hospital has anticipated the challenge that these novel therapeutics present, and has already positioned itself for the pending approval of the first therapeutic human monoclonal antibody. Nebacumab (HA-1A, formerly known as Centoxin; by Centocor) will be used for the treatment of gram-negative sepsis. Although this antiendotoxin has a good side effect profile, its use also carries a high price tag. This will raise several difficult ethical issues once the product is introduced. In this exclusive Hospital Formulary roundtable, members of Thomas Jefferson's P & T Committee and Technology Assessment Subcommittee provide their insights for responsibly managing a high-tech, high-cost product such as nebacumab.
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PMID:P & T Committee response to evolving technologies: preparing for the launch of high-tech, high-cost products. Roundtable discussion. 1011 68

Monoclonal antibodies have been shown to reduce morbidity and mortality in selected subsets of patients with Gram-negative sepsis and/or septic shock. However, the acquisition costs of the antibody products are expected to be in the range of $US3500 to $US4000 per course of therapy and precise identification of patients who will benefit may be difficult. Therefore, the economic impact of these antibodies will be significant. We have performed a model cost-effectiveness and cost-benefit analysis specific to our institution based on previously reported mortality figures. Our data suggest that the cost-effectiveness of HA-1A (Centoxin) will be comparable with that of a variety of commonly used medical interventions, but will produce an incremental increase in costs of at least $US7000 per patient because of the acquisition cost of the drug, as well as an increase in numbers of survivors whose hospitalisation will be prolonged.
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PMID:The economic impact of HA-1A (Centoxin) against endotoxin. 1014 53