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Biomedical subjects

Charles Natanson

Publications and source records attributed to Charles Natanson.

At least 19 recordsLinked to original sources
PubMed2006

Effective dosing of lipid A analogue E5564 in rats depends on the timing of treatment and the route of Escherichia coli infection.

BACKGROUND: E5564, a competitive lipid A antagonist, inhibits endotoxin-stimulated inflammation and is under study in patients with sepsis. METHODS: We tested whether clinically relevant variables, including the timing of treatment and the route of infection, influenced the effective dosing of E5564 in Escherichia coli-challenged rats. RESULTS: All E5564 doses (0.3, 1.0, 2.0, and 3.0 mg/kg intravascular bolus followed by 10% of the bolus dose infused hourly for 24 h) administered 1 h before intravascular E. coli challenge similarly reduced the risk of death. Delaying the start of E5564 to 1 or 3 h after intravascular E. coli challenge significantly reduced the beneficial effect of the doses tested. However, increasing the dose of E5564 reversed some loss of efficacy for delayed treatment (P=.004, for increasing benefit with increasing dose at 1 h). During intrabronchial or intraperitoneal (extravascular) E. coli challenge, the pattern of effective E5564 dosing was the inverse of that for intravascular E. coli challenge (P=.001, for the interaction)--lower doses of E5564 were beneficial and higher doses were not (0.03, 0.3, 1.0, 2.0, and 3.0 mg/kg bolus followed by infusion) (P=.05, for decreasing benefit with increasing dose at 1 h). CONCLUSION: These findings suggest that, for maximal clinical benefit, E5564 should be given early and that dosing should be adjusted upward for intravascular infection and downward for extravascular infection.

Animals↗
PubMed2006

Preclinical trial of L-arginine monotherapy alone or with N-acetylcysteine in septic shock.

OBJECTIVE: L-arginine supplementation in sepsis is controversial. Septic shock has been alternatively viewed as an L-arginine-deficient state or as a syndrome caused by excess nitric oxide, an end-product of L-arginine metabolism. DESIGN: Randomized, placebo-controlled, and double-blinded (investigators, veterinarians, and pharmacists). SETTING: Laboratory. SUBJECTS: Purpose-bred, 1- to 2-yr-old, 10- to 12-kg beagles. INTERVENTIONS: The effects of parenteral L-arginine alone or in combination with N-acetylcysteine were compared with vehicle alone in a well-characterized canine model of Escherichia coli peritonitis. Two doses were studied that delivered approximately 1.5-fold (10 mg x kg(-1) x hr(-1)) and 15-fold (100 mg x kg(-1) x hr(-1)) the L-arginine dose typically administered with standard total parenteral nutrition. Animals in the low- and high-dose L-arginine arms were further randomized to receive vehicle alone or N-acetylcysteine (20 mg x kg(-1) x hr(-1)) as an antioxidant to prevent peroxynitrite formation. MEASUREMENTS AND MAIN RESULTS: The main measurements were hemodynamics, plasma arginine and ornithine, serum nitrate/nitrite, laboratory studies for organ injury, and survival. Both doses of L-arginine similarly increased mortality (p = .02), and worsened shock (p = .001 for reduced mean arterial pressure). These effects were associated with significant increases in plasma arginine (p = .0013) and ornithine (p = .0021). In addition, serum nitrate/nitrite (p = .02), liver enzymes (p = .08), and blood urea nitrogen/creatinine ratios (p = .001) rose, whereas arterial pH (p = .001) and bicarbonate levels (p = .001) fell. N-acetylcysteine did not significantly decrease any of the harmful effects of L-arginine. Thus, parenteral L-arginine monotherapy was markedly harmful in animals with septic shock. CONCLUSIONS: These findings suggest that supplemental parenteral L-arginine, at doses above standard dietary practices, should be avoided in critically ill patients with septic shock.

Acetylcysteine↗
PubMed2005

Hemolysis-associated endothelial dysfunction mediated by accelerated NO inactivation by decompartmentalized oxyhemoglobin.

During intravascular hemolysis in human disease, vasomotor tone and organ perfusion may be impaired by the increased reactivity of cell-free plasma hemoglobin (Hb) with NO. We experimentally produced acute intravascular hemolysis in a canine model in order to test the hypothesis that low levels of decompartmentalized or cell-free plasma Hb will severely reduce NO bioavailability and produce vasomotor instability. Importantly, in this model the total intravascular Hb level is unchanged; only the compartmentalization of Hb within the erythrocyte membrane is disrupted. Using a full-factorial design, we demonstrate that free water-induced intravascular hemolysis produces dose-dependent systemic vasoconstriction and impairs renal function. We find that these physiologic changes are secondary to the stoichiometric oxidation of endogenous NO by cell-free plasma oxyhemoglobin. In this model, 80 ppm of inhaled NO gas oxidized 85-90% of plasma oxyhemoglobin to methemoglobin, thereby inhibiting endogenous NO scavenging by cell-free Hb. As a result, the vasoconstriction caused by acute hemolysis was attenuated and the responsiveness to systemically infused NO donors was restored. These observations confirm that the acute toxicity of intravascular hemolysis occurs secondarily to the accelerated dioxygenation reaction of plasma oxyhemoglobin with endothelium-derived NO to form bioinactive nitrate. These biochemical and physiological studies demonstrate a major role for the intact erythrocyte in NO homeostasis and provide mechanistic support for the existence of a human syndrome of hemolysis-associated NO dysregulation, which may contribute to the vasculopathy of hereditary, acquired, and iatrogenic hemolytic states.

Animals↗
PubMed2005

Neutrophil inhibition with L-selectin-directed MAb improves or worsens survival dependent on the route but not severity of infection in a rat sepsis model.

Both route and severity of infection may influence immunomodulator agents in sepsis. We studied the effect of each variable on HRL-3, an L-selectin-directed MAb that inhibits neutrophil function, in a rat sepsis model. Animals (n = 800) were randomized to be treated with either HRL-3 or placebo and to receive Escherichia coli either intravenously (IV) or intrabronchially (IB) in doses producing low or high mortality rates. Animals received antibiotics and were observed for 168 h. Route but not dose of E. coli altered the effects HRL-3 on mortality rate (mean hazards ratio +/- SE). With IV E. coli, compared with control, HRL-3 was beneficial and reduced the hazards ratio both early (0 to 6 h; -0.75 +/- 0.23) and late (6 to 168 h; -0.72 +/- 0.36) (P = 0.001 and 0.04, respectively, over all E. coli doses). In contrast, with IB E. coli HRL-3 reduced the hazards ratio early (-1.1 +/- 0.36) but worsened it late (0.87 +/- 0.23) (P = 0.002 for both effects over all E. coli doses) in patterns significantly different from IV E. coli (P < 0.0001). Compared with control, although HRL-3 did not alter lung neutrophil numbers or injury score at 6 or 168 h with IV E. coli (P = ns for all), it reduced both early and increased them late with IB E. coli (P </= 0.05 for all comparing 6 with 168 h). Thus immunomodulators inhibiting neutrophil function, although potentially beneficial with sepsis due to intravascular infection, may be harmful with extravascular infection regardless of severity.

Animals↗
PubMed2005

Novel therapies for sepsis: a review.

BACKGROUND: Over the past 30 years, efforts have been made to identify therapeutic targets in the host response to infection. METHODS: A review of the randomized controlled clinical sepsis trials and meta-analyses of glucocorticoids, mediator-specific anti-inflammatory agents, and anticoagulant agents was performed. RESULTS: The effects of glucocorticoids in sepsis appear to be dose-dependent, with high doses decreasing survival and low doses improving survival. As a class, the mediator-specific anti-inflammatory agents have a small beneficial effect on survival; however, no single agent has demonstrated significant benefit. The treatment effects of these agents appear to be related to the patient's risk of death. As a class, the anticoagulant agents do not improve survival; however, the efficacy of these agents may have been confounded by concurrent heparin therapy. Activated protein C demonstrated a beneficial effect on survival that was dependent on severity of illness. CONCLUSION: Trials of agents directed at altering the host's response during sepsis have had variable results, and it appears that several different factors may alter the efficacy of these agents.

Animals↗
PubMed2005

Prophylactic high-dose N(omega)-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs.

We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-alpha (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 microg kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-alpha-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P = 0.02). These data suggest that TNF-alpha initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha.

Animals↗
PubMed2004

Differing effects of epinephrine, norepinephrine, and vasopressin on survival in a canine model of septic shock.

During sepsis, limited data on the survival effects of vasopressors are available to guide therapy. Therefore, we compared the effects of three vasopressors on survival in a canine septic shock model. Seventy-eight awake dogs infected with differing doses of intraperitoneal Escherichia coli to produce increasing mortality were randomized to receive epinephrine (0.2, 0.8, or 2.0 microg.kg(-1).min(-1)), norepinephrine (0.2, 1.0, or 2.0 microg.kg(-1).min(-1)), vasopressin (0.01 or 0.04 U/min), or placebo in addition to antibiotics and fluids. Serial hemodynamic and biochemical variables were measured. Increasing doses of bacteria caused progressively greater decreases in survival (P <0.06), mean arterial pressure (MAP) (P <0.05), cardiac index (CI) (P <0.02), and ejection fraction (EF) (P=0.02). The effects of epinephrine on survival were significantly different from those of norepinephrine and vasopressin (P=0.03). Epinephrine had a harmful effect on survival that was significantly related to drug dose (P=0.02) but not bacterial dose. Norepinephrine and vasopressin had beneficial effects on survival that were similar at all drug and bacteria doses. Compared with concurrent infected controls, epinephrine caused greater decreases in CI, EF, and pH, and greater increases in systemic vascular resistance and serum creatinine than norepinephrine and vasopressin. These epinephrine-induced changes were significantly related to the dose of epinephrine administered. In this study, the effects of vasopressors were independent of severity of infection but dependent on the type and dose of vasopressor used. Epinephrine adversely affected organ function, systemic perfusion, and survival compared with norepinephrine and vasopressin. In the ranges studied, norepinephrine and vasopressin have more favorable risk-benefit profiles than epinephrine during sepsis.

Animals↗
PubMed2004

Meta-analysis: the effect of steroids on survival and shock during sepsis depends on the dose.

BACKGROUND: Previous meta-analyses demonstrated that high-dose glucocorticoids were not beneficial in sepsis. Recently, lower-dose glucocorticoids have been studied. PURPOSE: To compare recent trials of glucocorticoids for sepsis with previous glucocorticoid trials. DATA SOURCES: Systematic MEDLINE search for studies published between 1988 and 2003. STUDY SELECTION: Randomized, controlled trials of sepsis that examined the effects of glucocorticoids on survival or vasopressor requirements. DATA EXTRACTION: Two investigators independently collected data on patient and study characteristics, treatment interventions, and outcomes. DATA SYNTHESIS: The 5 included trials revealed a consistent and beneficial effect of glucocorticoids on survival (I2 = 0%; relative benefit, 1.23, [95% CI, 1.01 to 1.50]; P = 0.036) and shock reversal (I2 = 0%; relative benefit, 1.71 [CI, 1.29 to 2.26]; P < 0.001). These effects were the same regardless of adrenal function. In contrast, 8 trials published before 1989 demonstrated a survival disadvantage with steroid treatment (I2 = 14%; relative benefit, 0.89 [CI, 0.82 to 0.97]; P = 0.008). In comparison with the earlier trials, the more recent trials administered steroids later after patients met enrollment criteria (median, 23 hours vs. <2 hours; P = 0.02), for longer courses (6 days vs. 1 day; P = 0.01), and in lower total dosages (hydrocortisone equivalents, 1209 mg vs. 23 975 mg; P = 0.01) to patients with higher control group mortality rates (mean, 57% vs. 34%; P = 0.06) who were more likely to be vasopressor-dependent (100% vs. 65%; P = 0.03). The relationship between steroid dose and survival was linear, characterized by benefit at low doses and increasing harm at higher doses (P = 0.02). LIMITATIONS: We could not analyze time-related improvements in medical care and potential bias secondary to nonreporting of negative study results. CONCLUSIONS: Although short courses of high-dose glucocorticoids decreased survival during sepsis, a 5- to 7-day course of physiologic hydrocortisone doses with subsequent tapering increases survival rate and shock reversal in patients with vasopressor-dependent septic shock.

Adrenal Insufficiency↗
PubMed2004

Severity of sepsis alters the effects of superoxide anion inhibition in a rat sepsis model.

Previous analysis showed that selective inhibitors of five different host inflammatory mediators administered for sepsis, although beneficial with severe sepsis and high-control mortality rates, were ineffective or harmful with less severe sepsis. We hypothesized that severity of sepsis would also influence inhibition of superoxide anion, another inflammatory mediator. To test this, 6-h infusions of M40401, a selective SOD mimetic, or placebo were given to antibiotic-treated rats (n=547) starting 3 h after challenge with differing doses of intravenous Escherichia coli designed to produce low- or high-control mortality rates. There was a positive and significant (P=0.0008) relationship between the efficacy of M40401 on survival rate and control mortality rates. M40401 increased or decreased the log (odds ratio of survival) (means +/- SE), dependent on whether control mortality rates were greater or less than the median (66%) (+0.19 +/- 0.12 vs. -0.25 +/- 0.10, P=0.01). In a subset of animals examined (n=152) at 9 h after E. coli challenge, M40401 increased (mean effect +/- SE compared with control) mean arterial blood pressure (8 +/- 5 mmHg) and decreased platelets (-37 +/- 22 cells x 10(3)/ml) with high-control mortality rates but had opposing effects on each parameter (-3 +/- 3 mmHg and 28 +/- 19 cells x 10(3)/ml, respectively) with low rates (P < or = 0.05 for the differing effects of M40401 on each parameter with high- vs. low-control mortality rates). A metaregression analysis of published preclinical sepsis studies testing SOD preparations and SOD mimetics showed that most (16 of 18) had control mortality rates >66%. However, across experiments from published studies, these agents were less beneficial as control mortality rate decreased (P=0.03) in a relationship not altered (P=not significant) by other variables associated with septic challenge or regimen of treatment and which was similar, compared with experiments with M40401 (P=not significant). Thus, in these preclinical sepsis models, possibly related to divergent effects on vascular function, inhibition of superoxide anion improved survival with more severe sepsis and high-control mortality rates but was less effective or harmful with less severe sepsis. Extrapolated clinically, inhibition of superoxide anion may be most efficacious in septic patients with severe sepsis and a high risk of death.

Animals↗
PubMed2004

Recombinant human activated protein C in sepsis: assessing its clinical use.

Based on the results of the phase III PROWESS trial, recombinant human activated protein C (rhAPC) was approved by the Food and Drug Administration (FDA) for use in severely septic patients. Concerns regarding rhAPC's inconsistent effects, incomplete understanding of its mechanism of action, and its safety in particular subgroups were raised during the FDA's evaluation. This study attempts to assess the cost-effectiveness rhAPC by comparing its effects during recent clinical use to its prior phase III trial testing and by considering other potentially less expensive treatments with effects that may overlap those of rhAPC. In patients with similar numbers of injured organs, mortality rates may be higher with rhAPC during clinical use compared with the phase III trial. There may also be an increased risk of hemorrhage and other adverse events that necessitate early discontinuation of treatment. Many of the patients receiving rhAPC during clinical use may have otherwise been excluded from its phase III trial testing. Data from several recent phase III trials as well as a recent meta-analysis suggest that heparin and physiologic dose steroids offer substantially less expensive alternatives to rhAPC. Further phase IV testing will be required to confirm such possibilities.

APACHE↗
PubMed2004

Activated protein C in sepsis: emerging insights regarding its mechanism of action and clinical effectiveness.

PURPOSE OF REVIEW: Dysregulation of endogenous coagulant and anticoagulant systems is now believed to play an important role in the pathogenesis of sepsis and septic shock. Reductions in host activated protein C levels and resultant microvascular thrombosis provided a basis for the use of recombinant human activated protein C in sepsis. Although controversial, the findings from an initial phase III trial testing this agent resulted in its approval for use in patients with severe sepsis and high risk of death. This review highlights emerging insights into the biology of protein C and activated protein C in sepsis, summarizes additional analysis growing out of the phase III trial testing recombinant human activated protein C, and assesses the cost-effectiveness that the clinical use of the agent has had thus far. RECENT FINDINGS: Binding of activated protein C to the endothelial cell protein C receptor is recognized to result in a growing number of actions including increased activity of activated protein C itself and inhibition of both nuclear factor-kappaB, a central regulator in the host inflammatory response, and apoptosis. Additional analysis of the original phase III trial testing recombinant human activated protein C appears to emphasize one of the US Food and Drug Administration's original concerns regarding an association between severity of sepsis and this agent's effects. Postmarketing analysis and growing experience with other anticoagulant agents and corticosteroids in sepsis raise questions regarding the ultimate cost-effectiveness of activated protein C. SUMMARY: The protein C pathway is important both to coagulant and inflammatory pathways during sepsis. Based on emerging investigations, its actions appear to be increasingly complex ones. Despite potentially promising results in an initial phase III trial, the role of recombinant human activated protein C in the treatment of septic patients must continue to be evaluated.

Blood Coagulation↗