THE ROLE OF POLYMORPHISMS OF MATRIX METALLOPROTEINASES' POLYMORPHISMS 1 AND 12 IN THE FORMATION OF WHEEZING SYNDROME AMONG CHILDREN WITH RECURRENT BRONCHITIS.

OBJECTIVE: The aim: Matrix metalloproteinases (MMP) play an important role in the architecture and remodeling of the lungs. There are 2 gene families of MMP among significantly different genes - MMP-1 and MMP-12, which are closely related to the pathophysiological processes of allergic inflammation, damage and restoration of tissues and the body's defense against pathogens. PATIENTS AND METHODS: Materials and methods: 70 examined children were divided into 2 groups: 37 children who had acute recurrent bronchitis complicated by wheezing syndrome, the comparison group included 33 children with acute bronchitis. The determination of gene polymorphism was carried out using ELISA analysis. RESULTS: Results: In the dominant model, carriers of the 2G allele genotypes had 3,45 times lower risk of wheezing syndrome compared with patients with the 1G/1G genotype (OR = 3,45, 95% CI: 1,07-11.15, p<0,05). In the dominant model, carriers of G-allele genotypes had a 4,2-fold lower risk of wheezing syndrome compared with patients with the AA genotype (OR = 4,2; 95% CI (CI) = 1,09- 16,09; p <0,05). CONCLUSION: Conclusions: Polymorphism rs1799750 in the MMP-1 gene increases the risk of developing the wheezing syndrome among children with acute recurrent bronchitis in 3,5 times. The rs2276109 polymorphism in the MMP-12 gene reduces the risk of wheezing syndrome by 4,2 times among children with acute recurrent bronchitis.

Peculiar features of aortic wall structure among children with coarctation.

OBJECTIVE: The aim of the study to evaluate the peculiarities of the aortic wall structure at the place of coarctation. PATIENTS AND METHODS: Materials and methods: Studying of the aortic sections removed during operative correction at the place of constriction. 10 children at the age between 1 to 6 months were undergone the operation. Intraoperative aortic biopsy specimens were observed in 10% neutral formalin. Histologic sections were prepared in a conventional way followed by staining them with hematoxylin-eosin. RESULTS: Results: Histological examination in the areas of constriction revealed that the endothelium in all the preparations had poor expressiveness. The most significant changes were recorded in the middle layer of the aorta in the form of reduced development of elastic fibers, their fragmentation and chaotic arrangement. Angiomatosis with the formation of thin-layer small vessels by capillary type was found out. In all the preparations, areas of emptying of cells and fibers of the middle cover with the formation of cystic structures were revealed. CONCLUSION: Conclusions: The histological examination has revealed changes in the structure of the aorta wall, which may indicate the systemic nature of the lesion and make it possible to consider coarctation of the aorta to be a manifestation of systemic vasculopathy. The above-mentioned facts determine the need for a more detailed examination of children with the specified pathology at different stages of observation.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Macimorelin in Children with Suspected Growth Hormone Deficiency: An Open-Label, Group Comparison, Dose-Escalation Trial.

BACKGROUND/AIMS: Diagnosis of growth hormone deficiency (GHD) in children requires the use of provocative growth hormone (GH) stimulation tests, which can have limited reliability and are potentially contraindicated in some patients. This is the first paediatric study to test the safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics (PD) of macimorelin, an oral GH secretagogue, approved for diagnosis of adult GHD. METHODS: In this open-label, group comparison, single-dose escalation trial (EudraCT 2018-001988-23), sequential cohorts of patients (C1-C3) received ascending single doses of macimorelin: 0.25 (C1), 0.5 (C2), and 1.0 (C3) mg/kg. Primary endpoints were safety and tolerability, and secondary endpoints were PK/PD. RESULTS: Twenty-four patients aged between 2 and <18 with suspected GHD participated in the study. No macimorelin-related adverse events were reported, and macimorelin was well tolerated. Plasma macimorelin concentrations increased with dose: mean areas under the curve were 6.69 (C1), 18.02 (C2), and 30.92 (C3) h × ng/mL; mean maximum concentrations were 3.46 (C1), 8.13 (C2), and 12.87 (C3) ng/mL. GH concentration increased following macimorelin administration: mean times of maximum measured concentration were 52.5 (C1), 37.5 (C2), and 37.5 (C3) min. CONCLUSION: All 3 doses of macimorelin had excellent safety and tolerability with PK/PD profiles in expected ranges. These results support the use of 1.0 mg/mL macimorelin in a Phase 3 test validation trial in children.

A Randomized Phase 2 Study of Long-Acting TransCon GH vs Daily GH in Childhood GH Deficiency.

Context: TransCon Growth Hormone (GH) (Ascendis Pharma) is a long-acting recombinant sustained-release human GH prodrug in development for children with GH deficiency (GHD). Objective: To compare the pharmacokinetics, pharmacodynamics, safety, and efficacy of weekly TransCon GH to that of daily GH in prepubertal children with GHD. Design: Randomized, open-label, active-controlled study of three doses of weekly TransCon GH versus daily Genotropin (Pfizer). Setting: Thirty-eight centers in 14 European countries and Egypt. Patients: Prepubertal male and female treatment-naïve children with GHD (n = 53). Interventions: Subjects received one of three TransCon GH doses (0.14, 0.21, or 0.30 mg GH/kg/wk) or Genotropin 0.03 mg GH/kg/d for 26 weeks. Main Outcome Measures: GH and insulinlike growth factor-1 (IGF-1) levels, growth, adverse events, and immunogenicity. Results: Both GH maximum concentration and area under the curve were similar following TransCon GH or Genotropin administration at comparable doses. A dose response was observed, with IGF-1 standard deviation scores increasing into the normal range for all three TransCon GH doses. Annualized mean height velocity for the three TransCon GH doses ranged from 11.9 cm to 13.9 cm, which was not statistically different from 11.6 cm for Genotropin. Adverse events were mild to moderate, and most were unrelated to the study drug. Injection site tolerance was good. One TransCon GH subject developed a low-titer, nonneutralizing antibody response to GH. Conclusions: The results suggest that long-acting TransCon GH is comparable to daily Genotropin for GH (pharmacokinetics) and IGF-1 (pharmacodynamics) levels, safety, and efficacy and support advancement into phase 3 development.

Safety and Tolerability of Doripenem in Hospitalized Children With Complicated Intra-Abdominal Infection, Complicated Urinary Tract Infections and Pneumonia.

Three multicenter, randomized, controlled studies evaluated doripenem in children 3 months to <18 years of age, with complicated intra-abdominal or urinary tract infections and bacterial pneumonia.In the 66 patients treated with doripenem before early termination of the studies for nonsafety reasons, doripenem was safe and generally well tolerated. Low enrollment limited ability to assess benefits and risks of doripenem in children.