Pharmacokinetics of a hematoregulatory peptide (SK&F107647) in healthy male volunteers and in patients with colorectal or pancreatic adenocarcinoma not amenable to standard therapy.

PURPOSE: To describe the pharmacokinetics of SK&F 107647, a synthetic hematoregulatory peptide, in healthy volunteers and in patients with adenocarcinoma. METHODS: SK&F 107647 pharmacokinetics were evaluated in 2 dose-escalation studies. Volunteers received SK&F 107647 as single 15-minute iv infusion doses of 1, 10, 100, 500, and 1,000 microg/kg. Cancer patients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1 microg/kg once daily for 10 days. Drug concentrations were quantified in plasma and urine of healthy volunteers and on days 1 and 10 in plasma of cancer patients receiving the two top dose levels. RESULTS: In volunteers, mean clearance (CL) ranged from 76.7 to 101 ml/hour/kg; mean volume of distribution at steady-state (Vss) ranged from 175 to 268 ml/kg. Most of the administered dose was renally excreted as intact peptide within 24 hours postinfusion. In patients, mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150 ml/kg and terminal half-life from 2.1 to 3.4 hours. There was little accumulation of drug. In both studies, linear pharmacokinetics was observed. Clearance approached normal glomerular filtration rate (GFR) in volunteers and correlated with creatinine clearance in cancer patients. CONCLUSIONS: SK&F 107647 exhibits linear pharmacokinetics, a small Vss, and clearance, primarily renal, approaching normal GFR.

Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.

BACKGROUND: Interleukin-5 (IL-5) is essential for the formation of eosinophils, which are thought to have a major role in the pathogenesis of asthma and other allergic diseases. We aimed to assess the effects of monoclonal antibody to IL-5 on blood and sputum eosinophils, airway hyper-responsiveness, and the late asthmatic reaction to inhaled allergen in patients with mild asthma. METHODS: We did a double-blind randomised placebo-controlled trial, in which a single intravenous infusion of humanised (IgG-K) monoclonal antibody to IL-5 (SB-240563) was given at doses of 2.5 mg/kg (n=8) or 10.0 mg/kg (n=8). The effects of treatment on responses to inhaled allergen challenge, sputum eosinophils, and airway hyper-responsiveness to histamine were measured at weeks 1 and 4 with monitoring of blood eosinophil counts for up to 16 weeks. FINDINGS: Monoclonal antibody against IL-5 lowered the mean blood eosinophil count at day 29 from 0.25x10(9)/L (95% CI 0.16-0.34) in the placebo group to 0.04x10(9)/L (0.00-0.07) in the 10 mg/kg group (p<0.0001), and prevented the blood eosinophilia that follows allergen challenge. After inhaled allergen challenge, 9 days after treatment, the percentage sputum eosinophils were 12.2% in the placebo group and lowered to 0.9% (-1.2 to 3.0; p=0.0076) in the 10 mg/kg group, and this effect persisted at day 30 after the dose. There was no significant effect of monoclonal antibody to IL-5 on the late asthmatic response or on airway hyper-responsiveness to histamine. INTERPRETATION: A single dose of monoclonal antibody to IL-5 decreased blood eosinophils for up to 16 weeks and sputum eosinophils at 4 weeks, which has considerable therapeutic potential for asthma and allergy. However, our findings question the role of eosinophils in mediating the late asthmatic response and causing airway hyper-responsiveness.

Plasma antioxidant potential in severe sepsis: a comparison of survivors and nonsurvivors.

OBJECTIVE: To determine the plasma antioxidant potential of patients in the intensive care unit (ICU) with severe sepsis and secondary organ dysfunction and relate these findings to outcome. DESIGN: A prospective, cohort study. SETTING: A nine-bed ICU in a university teaching hospital. PATIENTS: Fifteen consecutive patients, who were within 16 hrs of development of severe sepsis and secondary organ dysfunction. INTERVENTIONS: Plasma samples were obtained within 16 hrs of the onset of secondary organ dysfunction and subsequently on days 2, 3, 4, 6, 8, 10, and 15 until patients either left the ICU or died. Plasma antioxidant potential was determined by an ultraviolet spectrophotometric technique. MEASUREMENTS AND MAIN RESULTS: The mean initial plasma antioxidant potential was lower than our range for healthy volunteers (p < .05). Survivors had an initial plasma antioxidant potential that was greater than nonsurvivors (p < .01), and serial subset analysis demonstrated that survivors, despite having a low initial plasma antioxidant potential rapidly attained normal or supranormal values. While plasma antioxidant potential also increased in nonsurvivors over time, values in this subset never reached the normal range and remained below values in survivors at all time points studied (p < .05). CONCLUSIONS: Plasma antioxidant potential is initially decreased in patients with sepsis who develop organ dysfunction, and it increases over time. While we have no clear evidence to prove that this reduction has a causal relationship, failure to achieve a normal plasma antioxidant potential is strongly associated with an unfavorable outcome.

Decreased antioxidant status and increased lipid peroxidation in patients with septic shock and secondary organ dysfunction.

OBJECTIVE: To determine antioxidant vitamin concentrations, lipid peroxidation, and an index of nitric oxide production in patients in the intensive care unit (ICU) with septic shock and relate the findings to the presence of secondary organ failure. DESIGN: A prospective, observational study. SETTING: A nine-bed ICU in a University teaching hospital. PATIENTS: Sixteen consecutive patients with septic shock, defined as: a) clinical evidence of acute infection; b) hypo- or hyperthermia (< 35.6 degrees C or > 38.3 degrees C); c) tachypnea (> 20 breaths/min or being mechanically ventilated); d) tachycardia (> 90 beats/min); e) shock (systolic pressure < 90 mm Hg) or receiving inotropes. Fourteen patients also had secondary organ dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Antioxidant vitamin concentrations were significantly lower in the patients than the reference range obtained from a comparable group of healthy controls. The mean plasma retinol (vitamin A) concentration was 26.5 +/- 19.3 micrograms/dL compared with 73.5 +/- 18.3 micrograms/dL in healthy subjects (p < .01). Additionally, 13 (81%) patients had retinol values below the lower limit of our reference range (< 37.0 micrograms/dL). Tocopherol (vitamin E) plasma concentrations were below the reference range in all patients (< 9.0 mg/L), with a mean value of 3.6 +/- 2.0 mg/L compared with 11.5 +/- 1.3 mg/L in healthy subjects (p < .001). Plasma beta carotene and lycopene concentrations were undetectable (< 15 micrograms/L) in eight (50%) patients, and below our reference range (< 101 micrograms/L and < 154 micrograms/L, respectively) in the remaining patients. In the five patients with three or more dysfunctional secondary organs, plasma thiobarbituric acid-reactive substances were significantly increased (p < .05), suggesting increased lipid peroxidation. Concentrations of thiobarbituric acid-reactive substances correlated negatively with both plasma retinol and plasma tocopherol (r2 = .42, p < .01 and r2 = .48, p < .005, respectively). In the five patients from whom we were able to collect urine, nitrite excretion was increased approximately 400-fold (p < .001). CONCLUSIONS: These data indicate decreased antioxidant status in the face of enhanced free radical activity, and suggest potential therapeutic strategies involving antioxidant repletion.

Increased circulating adhesion molecule concentrations in patients with the systemic inflammatory response syndrome: a prospective cohort study.

OBJECTIVE: To investigate the relationship between the soluble derivatives of endothelial adhesion molecules liberated by activated vascular endothelium and the development of the systemic inflammatory response syndrome and organ dysfunction in septic patients. DESIGN: Prospective cohort study with controls. SETTING: University hospital intensive care unit. PATIENTS: Healthy volunteers (controls, n = 85), patients with the systemic inflammatory response syndrome (n = 21), patients with systemic inflammatory response syndrome and organ dysfunction (n = 14), and miscellaneous, severely ill patients (n = 5). INTERVENTIONS: Plasma samples were collected from consecutive patients who satisfied the criteria for inclusion in the groups listed above. MEASUREMENTS AND MAIN RESULTS: The plasma was assayed by enzyme-linked immunosorbent assay (ELISA) for each of the three soluble adhesion molecules: sE-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1. There were low basal amounts of these adhesion molecules in the healthy volunteers, while plasma concentrations of all three adhesion molecules were increased in the sepsis groups. The median soluble E-selectin concentration was higher in those patients with organ dysfunction compared with the concentrations in patients with uncomplicated sepsis (p < .01 at first and p < .001 when comparing peak values attained). No patient survived when the amount of soluble E-selectin was > 30 units/mL. CONCLUSIONS: Concentrations of circulating vascular endothelial adhesion molecules, especially soluble E-selectin, are increased in patients with systemic inflammatory response syndrome and these concentrations are more increased in patients with organ dysfunction. High plasma concentrations of soluble E-selectin were closely associated with multiple-organ dysfunction and death. Measurement of adhesion molecules, especially soluble E-selectin, might be used to advantage in the management of patients with sepsis.