Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

THE LEVEL OF REACTIVE OXYGEN SPECIES AS A MARKER OF ASTHMA SEVERITY IN CHILDREN.

OBJECTIVE: The aim of the research was to assess the reactive oxygen species (ROS) levels in granulocytes of patients with asthma. PATIENTS AND METHODS: Materials and methods: The study involved 35 children aged 5 to 17 years. 26 children with persistent asthma, partially controlled course in the period of exacerbation were divided into groups: 1 group - mild asthma (n = 12), group 2 - moderate asthma (n = 7) group 3 - severe asthma (n = 7) and control group included almost healthy children (n = 9). ROS levels in granulocytes were evaluated using BD FACSDiva™. The spirographic complex was used to assess the function of external respiration. RESULTS: Results: The level of ROS in granulocytes of patients with severe asthma was significantly reduced compared with children in the control group and patients with mild and moderate asthma (p1-3 = 0.0003, p2-3 = 0.0017, p c-3 = 0.0150). The concentration of ROS in granulocytes ≤ 285 a.u. was prognostically significant with high specificity and sensitivity with severe asthma. CONCLUSION: Conclusions: The concentration of ROS levels in neutrophils in patients with severe asthma probably reflected the suppression of their products, which suggests the depletion of the reserve capacity of neutrophils. Decreased concentrations of reactive oxygen species in children with asthma can be considered as a possible marker of asthma severity.

Semi-refined carrageenan promotes generation of reactive oxygen species in leukocytes of rats upon oral exposure but not in vitro.

AIM: To assess the ability of the common food additive E407a (semi-refined carrageenan) to enter leukocytes in vitro and generate reactive oxygen species (ROS) in leukocytes as a whole and granulocytes in particular, both during incubation and in experimental animals. METHODS: ROS production was assessed in leukocytes incubated with E407a for 2 h at the final concentrations of 5 and 10 g/L using the dye 2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), as well as in cells isolated from rats orally exposed to E407a (140 mg/kg of weight) during 2 weeks (n = 8) and control rats (n = 8), by flow cytometry. Carrageenan uptake by leukocytes was estimated by confocal microscopy using incubation of rhodamine B isothiocyanate-labelled carrageenan with leukocyte suspensions. RESULTS: Uptake of carrageenan by viable neutrophils, monocytes, and lymphocytes was confirmed. Oral administration of the food additive E407a was associated with excessive ROS formation by viable leukocytes (CD45+, 7­aminoactinomycin D- cells) and especially in granulocytes. Unexpectedly, a direct impact of semi-refined carrageenan during incubation for 2 h did not affect ROS production in leukocytes, evidenced by statistically insignificant differences in mean fluorescence intensity values of 2',7'-dichlorofluorescein, which is a ROS-sensitive product of intracellular H2DCFDA conversion. Oral intake of E407a and direct exposure of leukocyte suspensions to it decreased the viability of leukocytes. CONCLUSION: Food-grade carrageenan can enter leukocytes without affecting ROS generation as a result of incubation for 2 h with leukocyte suspensions. On the contrary, oral exposure to E407a is accompanied by ROS overproduction by white blood cells, suggesting an indirect mechanism for the stimulation of ROS synthesis in vivo. E407a promotes cell death of leukocytes both in vivo and in vitro.

Is Willebrand Factor Indicative of Chronic Inflammation in Children with Asthma?

OBJECTIVE: To improve our knowledge and to understand how the level of von Willebrand factor indicates the development of chronic inflammation in children with recurrent wheezing and asthma. MATERIAL AND METHODS: It was a prospective cohort study. This study was conducted in children with recurrent wheezing and asthma who were referred to a children's hospital during 2017-2018. Patients were divided into 3 groups depending on the number of episodes of wheezing. Patients were examined for von Willebrand factor levels at admission and after treatment. Data analysis was performed with Statsofta Statistica Version 8 (Tulsa, OK). RESULTS: WF1 levels in Group 2 and 3 children statistically significantly increased in comparison with the control group (p<0.001). WF2 levels remained elevated only in Group 3 patients (p<0.001). WF2 levels in Group 1 and 2 decreased to the indices of the control group (p>0.05). The WF2 significantly decreased after treatment in Group 2 children (p=0.0000, T=0) and Group 3 (p=0.0000, T=0). CONCLUSION: levels of Willebrand factor indicate the presence of endothelial dysfunction. The level of Willebrand factor in the peak period of wheezing depends on the number of episodes of wheezing in history. Persistent high rates of Willebrand factor, even after the relief of clinical symptoms, indicates the present of chronic inflammation and can be regarded as the formation of asthma in children.

Are level of IL-13 and IL-4 predictive for formation of chronic inflammation in children with asthma?

INTRODUCTION: Asthma diagnosis in young children may represent a clinical challenge. There are no standard prognostic and dia-gnostic methods. The aim of the study was to evaluate the clinical and prognostic assessment of IL-4 and IL-13 concentrations in children with recurrent wheezing. MATERIAL AND METHODS: The study included 96 children with recurrent wheezing. 81 patients were diagnosed as transient wheezing, 15 patients with asthma, and 25 healthy children were selected as controls. The concentrations of IL-4 and IL-13 were analyzed in exhaled breath condensate (EBC) using an enzyme-linked immunosorbent assay (ELISA). Data analysis was performed using Statsoft Statistica Version 8 (Tulsa, OK) and the statistical program MedCalc version 17.2. RESULTS: Both IL-4 and IL-13 concentrations were significantly higher in DDA (21.13 pg/mL, 26.13 pg/mL, respectively) and TW (13.86 pg/mL, 18.3 pg/mL, respectively) groups as compared to healthy controls (3.37 pg/mL, 16.35 pg/mL, respectively; p<0.001), and the highest rates were observed in children with diagnosed asthma (p < 0.001, DDW vs TW, respectively). IL-4 concentration higher than 18.45 pg/mL (with sensitivity 86.7% and specificity 80%) and IL-13 concentration higher than 20.17pg/ /mL (with sensitivity 100% and specificity 76.7%) in EBC in children with wheezing recurrence can be considered as a possible predictor of asthma development. CONCLUSIONS: The concentration of the anti-inflammatory cytokines IL-4 and IL-13 were significantly increased in children with recurrent wheezing and the highest rates were found in asthma developing children. The concentrations of IL-4 and IL-13 in chil-dren with wheezing can be considered as a possible predictor of asthma development.

Interrelationship of endothelial function parameters in children with bronchial asthma in exacerbation and remission.

INTRODUCTION: In children with asthma, endothelial dysfunction signs are observed, and their extent depends on the severity of the disease. These changes are also present in remission. High level of soluble Vascular Cell Adhesion Molecule-1 (sVCAM-1) expression causes active adhesion of inflammatory cells and can indicate direct endothelium participation in development and supporting of chronic inflammation. Bronchial asthma (BA) is characterised by airways chronic inflammation. A special role in this inflammatory process formation is played by development of endothelial dysfunction. The aim of the study was to evaluate endothelial state in children with clinically stable and exacerbated asthma. MATERIAL AND METHODS: 91 children with persistent asthma were examined. Among them there were 40 patients with mild persistent (group I), 34 subjects with moderate persistent (group II) and 17 individuals with severe persistent (group III) asthma. 20 healthy children were selected as controls. The serum levels of sVCAM-1 were determined by enzyme-linked immunosorbent assay (ELISA). The ultrasound assessment of endothelium-dependent flow-mediated dilation of the brachial artery (FMD%) has been made. Ultrasonography has been used for investigation of the intima-media thickness (I-M) complex. Data analysis was performed with the Statsoft Statistica Version 8 (Tulsa, OK). RESULTS: The serum levels of sVCAM-1 were significantly increased in the patients with asthma exacerbation (p < 0.001) and remission (p < 0.001), compared with the controls. The index of FMD% was significantly diminished in the patients of I, II, III group with exacerbation (p < 0.001) and stayed lower in the subjects with asthma in remission (p < 0.001), compared with the controls. The thickness of I-M complex was significantly increased in the patients of I, II, III group, compared with the controls (p < 0.001). The endothelium parameter levels: sVCAM-1 (H = 56.11, p = 0.0001), FMD% (H = 43.20, p = 0.0000), the thickness of I-M complex (H = 49.37, p = 0.0000) depend on the severity of the disease. Correlations between the endothelium and pulmonary function parameters were proved (p < 0.05). CONCLUSIONS: Endothelial dysfunction in children with asthma was determined. Dependence of severity of the disease on functional state of the vascular endothelium was proved.