An epidemiologic surveillance of Shiga-like toxin-producing Escherichia coli infection in Argentinean children: risk factors and serum Shiga-like toxin 2 values.

BACKGROUND AND AIMS: Shiga-like toxin (Stx)-producing Escherichia coli (STEC) infection is an ongoing health issue that can lead to serious complications, including hemolytic uremic syndrome (HUS) and death. This study assessed demographic and epidemiologic information of STEC infection among Argentinean children. METHODS: A prospective surveillance of 2435 screened children (age, 0.5-15 years) presenting with watery diarrhea and/or bloody diarrhea was undertaken to evaluate the clinical course of STEC infection. RESULTS: Prevalence of STEC infection was 4.1% among subjects presenting with watery diarrhea for ≤ 5 days' duration, bloody diarrhea for ≤ 36 hours' duration, or both. Incidence of STEC infection was significantly higher in the subjects with bloody diarrhea. Ninety-three STEC+ children underwent further evaluation, of whom 8 (8.6%) developed HUS. White blood cells, particularly neutrophils, were abnormally elevated at screening in 5 of 8 HUS subjects. Quantifiable serum Stx-2 values were noted within 24 to 48 hours after the onset of bloody diarrhea in 3 HUS subjects using a validated chemiluminescence assay, with levels quickly dissipating by HUS onset. CONCLUSIONS: Results suggest that young STEC-positive children with bloody diarrhea and exhibiting neutrophilic leukocytosis in the early course of their diarrhea are at risk for HUS progression. The observation of measurable concentrations of Stx-2 levels in the early post-bloody-diarrhea period and rapid dissipation at the time of HUS onset requires further evaluation.

Safety and pharmacokinetics of urtoxazumab, a humanized monoclonal antibody, against Shiga-like toxin 2 in healthy adults and in pediatric patients infected with Shiga-like toxin-producing Escherichia coli.

Shiga-like toxin-producing Escherichia coli (STEC) infection causes diarrhea, which is often bloody and which can result in potentially life-threatening hemolytic-uremic syndrome (HUS). Urtoxazumab, a humanized monoclonal antibody directed against the Shiga-like toxin 2 (Stx2) produced by STEC, has been developed as a promising agent for the prevention of HUS. Single randomized, intravenous, double-blind, placebo-controlled doses of urtoxazumab were administered to assess its safety and pharmacokinetics in healthy adults (0.1 to 3.0 mg/kg of body weight) and STEC-infected pediatric patients (1.0 and 3.0 mg/kg). No dose-related safety trends were noted, nor were antiurtoxazumab antibodies detected. The disposition of urtoxazumab showed a biexponential decline, regardless of the dose. In healthy adults, the mean terminal elimination half-life was consistent across the dose groups and ranged from 24.6 days (3.0-mg/kg dose group) to 28.9 days (0.3-mg/kg dose group). The mean maximum serum drug concentration (C(max)) ranged from 2.6 microg/ml at 0.1 mg/kg to 71.7 microg/ml at 3.0 mg/kg. The disposition of urtoxazumab following the administration of doses of 1.0 and 3.0 mg/kg in pediatric patients showed mean C(max)s of 19.6 and 56.1 microg/ml, respectively. Urtoxazumab was well tolerated, appears to be safe at doses of up to 3.0 mg/kg, and is a potential candidate for the prevention of HUS in pediatric patients.

Effectiveness of ciclesonide nasal spray in the treatment of seasonal allergic rhinitis.

BACKGROUND: Ciclesonide is an investigational corticosteroid under development for treatment of allergic rhinitis. Ciclesonide is converted to active metabolite, desisobutyryl-ciclesonide (des-CIC), by upper and lower airway esterases. In vitro studies in human nasal epithelial cells and bronchial epithelial cells have demonstrated a long duration of anti-inflammatory activity of des-CIC. OBJECTIVE: To evaluate the dose-dependent efficacy and safety of a hypotonic intranasal formulation of ciclesonide in patients with seasonal allergic rhinitis (SAR). METHODS: This was a phase 2, randomized, parallel-group, double-blind, placebo-controlled study. Adults (n = approximately 145 per treatment group) with a minimum 2-year history of SAR received placebo or ciclesonide (25, 50, 100, or 200 microg/d) for 14 days. The primary end point was change in the sum of morning and evening reflective total nasal symptom scores (TNSSs) over 2 weeks. Safety was monitored throughout the study. RESULTS: Ciclesonide, 100 microg/d (P = .04) and 200 microg/d (P = .003), significantly improved the sum of morning and evening reflective TNSS vs placebo at more than 2 weeks of treatment. Baseline values for morning and evening reflective TNSS ranged from 17.80 to 18.82 across treatment groups. The average change from baseline in reflective TNSS was -4.2 for placebo and -4.8, -4.8, -5.3, and -5.8 for ciclesonide, 25, 50, 100, and 200 microg/d, respectively. There were no dose-related differences in the incidence of adverse events among treatment groups. CONCLUSIONS: Results from this study indicate that 100-microg and 200-microg daily doses of ciclesonide are effective in the treatment of SAR. Ciclesonide, 200 microg/d, appears to be the optimal dose studied for reducing the symptoms of SAR while maintaining an acceptable safety profile.

Safety, tolerability, and exposure of ciclesonide nasal spray in healthy and asymptomatic subjects with seasonal allergic rhinitis.

Ciclesonide is an intranasal corticosteroid in development for the treatment of allergic rhinitis. To assess the safety, tolerability, and pharmacokinetics of ciclesonide, adult healthy volunteers and asymptomatic subjects with seasonal allergic rhinitis were randomized to receive intranasal ciclesonide or placebo for 14 days. Serum concentrations of ciclesonide and its active metabolite, desisobutyryl-ciclesonide, were measured using high-performance liquid chromatography assay with tandem mass spectrometric detection, with lower limits of quantification of 25 and 10 pg/mL, respectively. Adrenal function was monitored by diurnal serum free and 24-hour urine cortisol concentrations. Despite the use of a sensitive assay and a high ciclesonide dose (800 microg/d), serum levels of ciclesonide and desisobutyryl-ciclesonide were below the lower limits of quantification for the majority of samples assayed. Ciclesonide was well tolerated and did not appear to affect serum or urine free cortisol levels. The low systemic exposure and favorable safety profile support the continued clinical development of ciclesonide nasal spray.