Application of watershed deposition tool to estimate from CMAQ simulations the atmospheric deposition of nitrogen to Tampa Bay and its watershed.

UNLABELLED: The US. Environmental Protection Agency (EPA) has developed the Watershed Deposition Tool (WDT) to calculate from the Community Multiscale Air Quality (CMAQ) model output the nitrogen, sulfur and mercury deposition rates to watersheds and their sub-basins. The CMAQ model simulates from first principles the transport, transformation, and removal of atmospheric pollutants. We applied WDT to estimate the atmospheric deposition of reactive nitrogen (N) to Tampa Bay and its watershed. For 2002 and within the boundaries of Tampa Bay's watershed, modeled atmospheric deposition rates averaged 13.3 kg N ha(-1) yr(-1) and ranged from 6.24 kg N ha(-1) yr(-1) at the bay's boundary with Gulf of Mexico to 21.4 kg N ha(-1) yr(-1) near Tampa's urban core, based on a 12-km x 12-km grid cell size. CMAQ-predicted loading rates were 1,080 metric tons N yr(-1) to Tampa Bay and 8,280 metric tons N yr(-1) to the land portion of its watershed. If we assume a watershed-to-bay transfer rate of 18% for indirect loading, our estimates of the 2002 direct and indirect loading rates to Tampa Bay were 1,080 metric tons N and 1,490 metric tons N, respectively, for an atmospheric loading of 2,570 metric tons N or 71% of the total N loading to Tampa Bay. To evaluate the potential impact of the US. EPA Clean Air Interstate Rule (CAIR, replaced with Cross-State Air Pollution Rule), Tier 2 Vehicle and Gasoline Sulfur Rules, Heavy Duty Highway Rule, and Non-Road Diesel Rule, we compared CMAQ outputs between 2020 and 2002 simulations, with only the emissions inventories changed. The CMAQ-projected change in atmospheric loading rates between these emissions inventories was 857 metric tons N to Tampa Bay, or about 24% of the 2002 loading of 3,640 metric tons N to Tampa Bay from all sources. IMPLICATIONS: Air quality modeling reveals that atmospheric deposition of reactive nitrogen (N) contributes a significant fraction to Tampa Bay's total N loading from external sources. Regulatory drivers that lower nitrogen oxide emissions from power plants and motor vehicles are important to bay management strategies, which seek to improve water quality through N load reduction.

Parental perceptions regarding mandatory mouthguard use in competitive youth soccer.

OBJECTIVE: To understand factors that influence parental perceptions regarding mandatory mouthguard use in competitive youth soccer. SETTING AND SUBJECTS: A web based survey of parents whose 8-14 year old children participated in outdoor competitive youth soccer during the fall of 2002. Questions focused on: previous injury, education provided, dentist/physician recommendations, and parental perceptions of mouthguard use. MAIN OUTCOME MEASURE: The outcome variable was parental agreement with the statement "mouthguards should be mandatory for competitive youth soccer". Logistic regression and chi(2) were performed using STATA 8.0. RESULTS: Altogether 120 parents participated. The children had a mean (SD) age of 11.8 (1.5) years and 48% were female; 14% wore mouthguards and 11% suffered orofacial injuries. Nineteen percent of parents reported receiving educational material from the youth soccer organization. Although 92% of parents believed that mouthguards were effective in reducing orofacial injuries, only one half agreed that mouthguards should be mandatory. Thirty percent of respondents reported that their dentist/physician recommended mouthguards for competitive youth soccer. Logistic regression showed that dentist/physician recommendation and parental female gender were independently associated with parental agreement for mandatory mouthguard use (odds ratio 2.9, 95% confidence interval (CI) 1.2 to 7.3; odds ratio 3.0, 95% CI 1.1 to 6.5). CONCLUSIONS: Few athletes wear mouthguards during competitive youth soccer. Health care professionals in this study did not capitalize on the apparent influence they have on parental beliefs regarding mouthguard use. Efforts are needed by both health professionals and soccer organizations to educate parents about orofacial injuries and mouthguard use in competitive youth soccer.

IC14, a CD14 specific monoclonal antibody, is a potential treatment for patients with severe sepsis.

CD14 is a pattern recognition receptor for the bacterial cell wall components from Gram-positive and Gram-negative bacteria as well as mycobacteria. Binding of lipopolysaccharide (LPS) or other cell wall constituents to CD14 initiates signal transduction through the Toll-like receptors resulting in the release of pro-inflammatory cytokines and the initiation of the systemic inflammatory response. In rabbits and non-human primates, CD14 specific antibodies were shown to attenuate responses to LPS or Escherichia coli challenge including pro-inflammatory cytokine release, acute lung injury, hypotension and changes in lung, liver, spleen and adrenal gland morphology. In healthy human subjects, single doses of a chimeric CD14 antibody (IC14) have been shown to be well tolerated and result in a dose-related degree of saturation of CD14 receptors on monocytes and granulocytes. Pretreatment of healthy subjects with IC14 2 h prior to LPS resulted in an attenuation of the LPS-induced fever, clinical symptoms, and leukocyte activation and degranulation. IC14 inhibited the release of TNF-alpha, IL-6, and IL-10 and delayed the release of sTNFR(I) and IL-1ra. Further studies are in progress to characterize the safety and clinical pharmacology of IC14 in patients with severe sepsis.

IC14, an anti-CD14 antibody, inhibits endotoxin-mediated symptoms and inflammatory responses in humans.

CD14 is a receptor for cell wall components of Gram-negative and Gram-positive bacteria that has been implicated in the initiation of the inflammatory response to sepsis. To determine the role of CD14 in LPS-induced effects in humans, 16 healthy subjects received an i.v. injection of LPS (4 ng/kg) preceded (-2 h) by i.v. IC14, a recombinant chimeric mAb against human CD14, at a dose of 1 mg/kg over 1 h, or placebo. In subjects receiving IC14, saturation of CD14 on circulating monocytes and granulocytes was >90% at the time of LPS injection. IC14 attenuated LPS-induced clinical symptoms and strongly inhibited LPS-induced proinflammatory cytokine release, while only delaying the release of the anti-inflammatory cytokines soluble TNF receptor type I and IL-1 receptor antagonist. IC14 also inhibited leukocyte activation, but more modestly reduced endothelial cell activation and the acute phase protein response. The capacity of circulating monocytes and granulocytes to phagocytose Escherichia coli was only marginally reduced after infusion of IC14. These data provide the first proof of principle that blockade of CD14 is associated with reduced LPS responsiveness in humans in vivo.

Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock.

Plasma endotoxin and lipopolysaccharide-binding protein (LBP) levels were measured in a group of 253 patients at the onset of severe sepsis and/or septic shock. Endotoxin levels were significantly greater than control levels (n=33; mean +/- SD, 5.1+/-7.3 pg/mL) in 78.3% of patients. Median endotoxin levels in patients with sepsis were 300 pg/mL (25%-75% interquartile range, 110-726 pg/mL). LBP levels were elevated in 97% of patients compared with normal control values of 4.1+/-1.65 microgram/mL. Median LBP levels in patients with sepsis were 31.2 microgram/mL (interquartile range, 22.5-47.7 microgram/mL). Median endotoxin levels at study entry were more highly elevated (515 vs. 230 pg/mL; P<.01), and LBP levels were less highly elevated (28.0 vs. 33.2 microgram/mL; P<.05) in nonsurvivors than survivors over the 28-day study period. No correlation was found between endotoxin and LBP levels. The quantitative level of both endotoxin and LBP may have prognostic significance in patients with severe sepsis.

ST segment elevation and the prediction of hospital life-threatening complications: the role of right ventricular and posterior leads.

UNLABELLED: Accurate prognosis in suspected acute myocardial infarction (AMI) is essential for appropriate use of thrombolytic therapy and primary angioplasty. However, previous models may be limited because the 12-lead electrocardiogram (ECG) does not examine the right ventricular (RV) and posterior myocardium. We evaluated ST segment elevation (STSE) in posterior (V7-V9) and RV (V4R-V6R) leads to determine their predictive value for hospital life-threatening complications (HLTCs). METHOD AND RESULTS: This prospective trial of seven Midwestern hospital emergency departments (EDs) had inclusion criteria of age 35 years, chest pain suggestive of ischemia, and coronary care unit (CCU) admission. ECG leads were test positive if STSE was > 0.1 mV. Patients were positive for HLTCs if ED or inpatient hospital course included: ventricular fibrillation or tachycardia, second- or third-degree block, shock, arrest, or death. Univariate and multivariate analyses were performed to test each lead's association with HLTCs. Of 533 patients, 64.7% (345/533) had AMI and 15.8% (85/533) had HLTCs. The sensitivity of 18 leads for HLTCS was increased by 5.8%, but specificity decreased by 8.2%. ECG subgroups by STSE were associated with the following HLTC rates: inferior/+RV (32.4%); anterior (29.5%), lateral (23.1%), inferior RV (17.9%), and posterior (16.2%). V1 (odds = 3.2) and V6R (odds = 3.1) were statistically significant independent predictors. CONCLUSION: Posterior and RV leads did not increase the ECG's overall prognostic value, but in the presence of inferior STSE, were associated with low and high complication rates, respectively. Right and left precordial leads were the best predictors of HTLCs.

Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group.

OBJECTIVE: To determine the therapeutic efficacy and safety of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) in the treatment of patients with severe sepsis. DESIGN: Prospective, randomized, double-blind, placebo-controlled, multicenter trial with a planned, midstudy, interim analysis. SETTING: Ninety-one academic medical center intensive care units in North America and Europe. PATIENTS: Patients with severe sepsis or septic shock (n = 696) received standard supportive care and antimicrobial therapy for sepsis, in addition to rhIL-1ra or placebo. INTERVENTIONS: Patients were randomized to receive either rhIL-1ra (100 mg) or placebo (vehicle) by intravenous bolus, followed by a 72-hr continuous intravenous infusion of either rhIL-1ra (2.0 mg/kg/hr) or placebo. MEASUREMENTS AND MAIN RESULTS: The study was terminated after an interim analysis found that it was unlikely that the primary efficacy end points would be met. The 28-day, all-cause mortality rate was 33.1% (116/350) in the rhIL-1ra treatment group, while the mortality rate in the placebo group was 36.4% (126/346), yielding a 9% reduction in mortality rate (p = .36). The patients were well matched at the time of study entry; 52.9% of placebo-treated patients were in shock while 50.9% of rhIL-1ra-treated patients were in shock at the time of study entry (p = .30). The mortality rate did not significantly differ between treatment groups when analyzed on the basis of site of infection, infecting microorganism, presence of bacteremia, shock, organ dysfunction, or predicted risk of mortality at the time of study entry. No excess number of adverse reactions or microbial superinfections were attributable to rhIL-1ra treatment in this study. CONCLUSIONS: A 72-hr, continuous intravenous infusion of rhIL-1ra failed to demonstrate a statistically significant reduction in mortality when compared with standard therapy in this multicenter clinical trial. If rhIL-1ra treatment has any therapeutic activity in severe sepsis, the incremental benefits are small and will be difficult to demonstrate in a patient population as defined by this clinical trial.

Use of predicted risk of mortality to evaluate the efficacy of anticytokine therapy in sepsis. The rhIL-1ra Phase III Sepsis Syndrome Study Group.

OBJECTIVES: To investigate a novel anticytokine therapy in patients with sepsis syndrome, and the relationship between a patient's baseline mortality risk and survival benefit. DESIGN: Data from a recent phase III, double-blind, placebo-controlled, multicenter clinical trial with patients randomized to three treatment arms: an intravenous loading dose of recombinant human interleukin-1-receptor antagonist (rhIL-1ra) or placebo, followed by a continuous infusion of rhIL-1ra (1.0 mg/kg/hr, or 2.0 mg/kg/hr), or placebo for 72 hrs. SETTING: Sixty-three investigative centers in eight countries. PATIENTS: The study population consisted of 893 patients: 302 placebo patients; 298 patients treated with 1.0 mg/kg/hr of rhIL-1ra; and 293 patients treated with 2.0 mg/kg/hr of rhIL-1ra. MEASUREMENTS AND MAIN RESULTS: An independent, sepsis-specific, log-normal regression model that predicts the risk of mortality over 28 days was applied to all patients enrolled into the rhIL-1ra sepsis study. The ability of the Predicted Risk of Mortality model to predict 28-day mortality in the placebo patients was determined and the relationship between mortality risk and efficacy of rhIL-1ra was investigated. The trial data were also analyzed using two other risk-assessment models for comparison with Predicted Risk of Mortality. A significant increase in survival time was demonstrated for all patients treated with rhIL-1ra (n = 893, p < .02 Predicted Risk of Mortality log-normal), but patients with a Predicted Risk of Mortality of < 24% derived little benefit. Retrospective examination of time-to-death data demonstrated that rhIL-1ra reduced risk of death in the first 2 days for patients with > or = 24% Predicted Risk of Mortality (n = 580, p < .005 Predicted Risk of Mortality log-normal). This same effect was not present in patients with a Predicted Risk of Mortality of < 24% on entry into the study. The Predicted Risk of Mortality model predicted a 28-day mortality rate of 35% for placebo patients compared with 34% observed and accurately stratified patients along the full range of risks. There was a wide distribution of individual patient risks for 28-day mortality for all patients, as well as within categorical subgroups, such as shock and organ system dysfunction. Two alternate risk models were assessed and the Acute Physiology Score of Acute Physiology and Chronic Health Evaluation III also demonstrated a statistically significant survival benefit for rhIL-1ra (p = .04 Predicted Risk of Mortality log-normal) for all patients treated. CONCLUSIONS: Using an appropriate analytic model, a statistically significant increase in survival time from rhIL-1ra was measured. A direct relationship was found between a patient's Predicted Risk of Mortality at study entry to efficacy of rhIL-1ra. Individual risk or severity assessment may be a useful tool for evaluating the clinical benefit of new therapeutic approaches to sepsis and for monitoring outcomes at the bedside.

Interleukin-1 contributes to increased concentrations of soluble tumor necrosis factor receptor type I in sepsis.

Studies were done in baboons and humans to assess the role of interleukin (IL)-1 on the release of soluble tumor necrosis factor receptors (sTNFRs) during sepsis. In baboons, IL-1 alpha induced increased levels of sTNFR types I and II. Infusion of Escherichia coli into baboons also led to higher sTNFR levels. Treatment with IL-1 receptor antagonist (ra) attenuated the rise in sTNFR-I, which was positively correlated with a partial preservation of renal function by IL-1ra. In patients with sepsis, treatment with IL-1ra also was associated with lower levels of sTNFR-1 but did not influence plasma creatinine levels. IL-1ra did not affect sTNFR-II in baboons or humans. These data suggest that IL-1 produced during sepsis is involved in increases in sTNFR-I. Such increases during rapidly fatal septic shock may in part be explained by an effect on the renal clearance of sTNFR-I.

In vitro binding of lithium using the cation exchange resin sodium polystyrene sulfonate.

Sodium polystyrene sulfonate, a cation exchange resin, should be useful in the treatment of lithium overdosage. This in vitro study was conducted to assess the ability of sodium polystyrene sulfonate to bind lithium, effects of pH on binding, binding efficacy in comparison to charcoal, and affinity for lithium versus potassium. Stock solutions of lithium were added to fixed amounts of sodium polystyrene sulfonate and charcoal. Lithium and potassium concentrations in supernatant were measured by flame photometry. Increasing concentrations of sodium polystyrene sulfonate bound more lithium. Changes in pH had little effect on lithium binding. Lithium is bound to sodium polystyrene sulfonate more readily than to charcoal. Potassium is preferentially bound to sodium polystyrene sulfonate over lithium. Sodium polystyrene sulfonate may provide a useful therapeutic modality in the treatment of lithium overdosage.

Interleukin-1 receptor blockade does not affect endotoxin-induced changes in plasma thyroid hormone and thyrotropin concentrations in man.

Interleukin-1 (IL-1) has been implicated as a mediator of the euthyroid sick syndrome. The effects of IL-1 can be blocked by the naturally occurring IL-1 receptor antagonist (IL-1ra). In the present study, iv administration of endotoxin was used as a human model of the euthyroid sick syndrome. To assess the role of endogenous IL-1 in endotoxin-induced changes in plasma thyroid hormone and TSH concentrations, 18 healthy postabsorptive humans were studied on a control study day, followed 3 days later by a study day on which they were randomly assigned to one of three treatments: a 6-h infusion of recombinant human IL-1ra alone (133 mg/h), endotoxin alone (lot EC-5; 20 U/kg), or both endotoxin and IL-1ra. Administration of IL-1ra alone did not affect the plasma concentrations of thyroid hormones or TSH compared with those on the control day. Endotoxin injection was associated with decreases in T4 (P = 0.06 vs. the control day), free T4 (P = 0.02), T3 (P < 0.001), and TSH (P < 0.0001) and a rise in rT3 (P < 0.001), reproducing the major features of the euthyroid sick syndrome. Coinfusion of IL-1ra did not influence these endotoxin-induced changes. Our results suggest that endogenous IL-1 does not play an important role in the alterations in plasma thyroid hormone and TSH concentrations induced by mild endotoxemia in healthy humans.

Influence of IL-1 receptor blockade on the human response to endotoxemia.

Although the experimental administration of IL-1 induces several aspects of the inflammatory response, such as fever, tachycardia, and acute phase proteinemia, the contribution of IL-1 to the human responses to injury or infection remains unclear. A specific IL-1R antagonist (IL-1ra), which effectively blocks the actions of IL-1, was utilized to evaluate the influence of endogenous IL-1 during experimental human endotoxemia. Eighteen healthy volunteers each underwent one control study day, followed 3 days later by one of three randomly chosen treatments: a 6-h infusion of IL-1ra alone (133 mg/h), 20 U/kg national reference endotoxin alone, or both endotoxin and IL-1ra infusion. IL-1ra administration alone was not associated with any observable response. Despite achieving high circulating levels of IL-1ra (34 +/- 3 micrograms/ml), there were no significant differences in hemodynamic parameters, core temperature, or resting energy expenditure in those endotoxemic volunteers receiving IL-1ra when compared with those who did not. Furthermore, leukocyte kinetic and circulating cytokine, acute phase protein, and endocrine responses were similar in both endotoxemic groups. However, IL-1 blockade did significantly reduce the subjective severity of symptoms experienced by the endotoxemic volunteers (p < 0.05). This study demonstrates that an endogenous IL-1 response does not play a significant role in the hemodynamic, immunologic, and metabolic responses to mild endotoxemia in humans.

Evaluation of two wound measurement methods in a multi-center, controlled study.

Methods for measuring wound size and healing have ranged from simple measurement with a ruler to sophisticated automated image analysis. As part of a multicenter, double-blind evaluation of a growth factor for wound healing, we evaluated the predictability and accuracy of two measurement systems. Four hundred and fifty paired comparisons (900 observation points) of lower extremity ulcers of either diabetic or venous stasis origin were evaluated weekly for at least four weeks. Wound size was determined by computer digitization of either color slide photographs (photo method) or acetate tracings (tracing method). Measurements of wound surface area for both methods were very similar, with a correlation coefficient of 0.97. The standard deviation of the methods, stratified by wound size and study center, were low (10 percent to 20 percent). Inter-site variability accounted for only 5.4 percent of the total variability noted in these observations. We have found that both the photo method and the tracing method may be useful in large, multi-center clinical trials when measurements of wound size are utilized to evaluate responsiveness to therapy.

Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis.

Clinical trials of anticytokines in sepsis have not been as straightforward as had been anticipated from results in animal models of sepsis and the role of cytokines in sepsis is now in question. Retrospective analysis of the results of a phase III trial of interleukin-1 (IL-1) receptor antagonist suggests that sepsis-induced adult respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), renal dysfunction, and shock are valuable markers of patients in whom IL-1 is a pathogenic mediator and in whom IL-1ra can reduce mortality. A re-examination of the effects of IL-1ra in animal models of sepsis supports the validity of this analysis. A new phase III clinical trial will confirm or disprove the hypothesis that IL-1 is a mediator of pathology, and IL-1ra is a valuable therapy for sepsis complicated by ARDS, DIC, renal dysfunction, or shock.

Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group.

OBJECTIVE: To further define the safety and efficacy of recombinant human interleukin 1 receptor antagonist (rhIL-1ra) in the treatment of sepsis syndrome. STUDY DESIGN: Randomized, double-blind, placebo-controlled, multicenter, multinational clinical trial. POPULATION: A total of 893 patients with sepsis syndrome received an intravenous loading dose of rhIL-1ra, 100 mg, or placebo followed by a continuous 72-hour intravenous infusion of rhIL-1ra (1.0 or 2.0 mg/kg per hour) or placebo. OUTCOME MEASURE: Twenty-eight-day all-cause mortality. RESULTS: There was not a significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication (n = 893; generalized Wilcoxon statistic, P = .22) or among patients with shock at study entry (n = 713; generalized Wilcoxon statistic, P = .23), the two primary efficacy analyses specified a priori for this trial. Results from secondary analyses suggest an increase in survival time with rhIL-1ra treatment among patients with dysfunction of one or more organs (n = 563; linear dose-response, P = .009). Retrospective analysis demonstrated an increase in survival time with rhIL-1ra treatment among patients with a predicted risk of mortality of 24% or greater (n = 580; linear dose-response, P = .005) as well as among patients with both dysfunction of one or more organs and a predicted risk of mortality of 24% or greater (n = 411; linear dose-response, P = .002). CONCLUSIONS: There was not a statistically significant increase in survival time for rhIL-1ra treatment compared with placebo among all patients who received the study medication or among patients with shock at study entry. Secondary and retrospective analyses of efficacy suggest that treatment with rhIL-1ra results in a dose-related increase in survival time among patients with sepsis who have organ dysfunction and/or a predicted risk of mortality of 24% or greater.

Initial evaluation of human recombinant interleukin-1 receptor antagonist in the treatment of sepsis syndrome: a randomized, open-label, placebo-controlled multicenter trial.

OBJECTIVES: To evaluate the safety, pharmacokinetics, and efficacy of human recombinant interleukin-1 receptor antagonist (IL-1ra) in the treatment of patients with sepsis syndrome. DESIGN: Prospective, open-label, placebo-controlled, phase II, multicenter clinical trial using three different doses of human recombinant IL-1ra. SETTING: Twelve academic medical center intensive care units in the United States. PATIENTS: Ninety-nine patients with sepsis syndrome or septic shock who received standard supportive care and antimicrobial therapy, in addition to infusion with escalating doses of IL-1ra or placebo. INTERVENTIONS: Patients received an intravenous loading dose of either human recombinant IL-1ra (100 mg) or placebo, followed by a 72-hr intravenous infusion of either one of three doses of IL-1ra (17, 67, or 133 mg/hr) or placebo. All patients were evaluated for 28-day, all-cause mortality. MEASUREMENTS AND MAIN RESULTS: A dose-dependent, 28-day survival benefit was associated with IL-1ra treatment (p = .015), as indicated by the following mortality rates: 11 (44%) deaths among 25 placebo patients; eight (32%) deaths among 25 patients receiving IL-1ra 17 mg/hr; six (25%) deaths among 24 patients receiving IL-1ra 67 mg/hr; and four (16%) deaths among 25 patients receiving IL-1ra 133 mg/hr. A dose-related survival benefit was observed with infusion of IL-1ra in patients with septic shock at study entry (n = 65; p = .002) and in patients with Gram-negative infection (n = 45; p = .04). Patients with an increased circulating interleukin-6 (IL-6) concentration of > 100 pg/mL at study entry demonstrated a dose-related survival benefit with IL-1ra treatment (p = .009). In patients with an increased IL-6 concentration at study entry, the magnitude of the decrease in IL-6 concentration 24 hrs after the initiation of therapy was correlated with increasing the IL-1ra treatment dose (p = .052). A significant dose-related reduction in the Acute Physiology and Chronic Health Evaluation (APACHE II) score was achieved by the end of infusion (p = .038). A renal elimination mechanism for IL-1ra was suggested by the positive correlation between IL-1ra plasma clearance and estimated creatinine clearance (p = .001; r2 = .51). Human recombinant IL-1ra was well tolerated. CONCLUSIONS: This initial evaluation suggests that human recombinant IL-1ra is safe and may provide a dose-related survival advantage to patients with sepsis syndrome. A larger, definitive clinical trial is needed to confirm these findings.

Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans.

A phase I study of human recombinant interleukin-1 receptor antagonist (IL-1ra) was conducted in healthy males between the ages of 18 and 30. Twenty-five volunteers received a single, 3 h continuous intravenous infusion of doses ranging between 1 mg/kg and 10 mg/kg IL-1ra. At 3 h into the infusion, plasma IL-1ra levels were 3.1 micrograms/ml and 29 micrograms/ml for the 1 mg/kg and 10 mg/kg doses, respectively. Post-infusion plasma IL-1ra levels declined rapidly, exhibiting an initial half-life of 21 min and a terminal half-life of 108 min. Clinical, hematological, biochemical, endocrinological and immunomodulatory effects were monitored over 72 h and compared to those of four subjects receiving a 3 h infusion of saline. There were no clinically significant differences between the drug and saline groups in symptoms, physical examinations, complete blood counts, mononuclear cell phenotypes, blood chemistry profiles, serum iron and serum cortisol levels. Peripheral blood mononuclear cells (PBMC) obtained after completion of the IL-1ra infusion synthesized significantly less interleukin 6 ex vivo than PBMC from saline-injected controls. These data suggest that transient blockade of interleukin 1 receptors is safe and does not significantly affect homeostasis.