Infants Receiving a Single Dose of Nirsevimab to Prevent RSV Do Not Have Evidence of Enhanced Disease in Their Second RSV Season.

To characterize nirsevimab in the prevention of RSV, children from the Phase 3 MELODY trial were followed through their second RSV season. No increase in medically attended RSV lower respiratory tract infections or evidence of antibody-dependent enhancement of infection or disease severity was found for nirsevimab vs placebo recipients. Clinical Trial Registration: Clinicaltrials.gov, NCT03979313, https://clinicaltrials.gov/ct2/show/NCT03979313.

Efficacy of nirsevimab against respiratory syncytial virus lower respiratory tract infections in preterm and term infants, and pharmacokinetic extrapolation to infants with congenital heart disease and chronic lung disease: a pooled analysis of randomised controlled trials.

BACKGROUND: In a phase 2b trial and the phase 3 MELODY trial, nirsevimab, an extended half-life, monoclonal antibody against respiratory syncytial virus (RSV), protected healthy infants born preterm or at full term against medically attended RSV lower respiratory tract infection (LRTI). In the MEDLEY phase 2-3 trial in infants at higher risk for severe RSV infection, nirsevimab showed a similar safety profile to that of palivizumab. The aim of the current analysis was to assess the efficacy of nirsevimab using a weight-banded dosing regimen in infants born between 29 weeks gestational age and full term. METHODS: Infants enrolled in the phase 2b and MELODY trials were randomised (2:1) to receive a single intramuscular injection of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) or placebo before the RSV season. Infants in MEDLEY were randomised (2:1) to receive one dose of nirsevimab (infants weighing <5 kg received 50 mg; those weighing ≥5 kg received 100 mg) followed by four monthly placebo doses, or five once-a-month intramuscular doses of palivizumab. We report a prespecified pooled efficacy analysis assessing the weight-banded dosing regimen proposed on the basis of the phase 2b and MELODY trials, in addition to extrapolated efficacy in infants with chronic lung disease, congenital heart disease, or extreme preterm birth (<29 weeks' gestational age) based on pharmacokinetic data from the phase 2-3 MEDLEY safety trial. For the pooled efficacy analysis, the primary endpoint was incidence of medically attended RSV LRTI through 150 days post-dose. The secondary efficacy endpoint was number of admissions to hospital for medically attended RSV LRTI. The incidence of very severe RSV LRTI was an exploratory endpoint, defined as cases of hospital admission for medically attended RSV LRTI that required supplemental oxygen or intravenous fluids. We also did a prespecified exploratory analysis of medically attended LRTI of any cause (in the investigator's judgement) and hospital admission for respiratory illness of any cause (defined as any upper respiratory tract infection or LRTI leading to hospital admission). Post hoc exploratory analyses of outpatient visits and antibiotic use were also done. Nirsevimab serum concentrations in MEDLEY were assessed using population pharmacokinetic methods and the pooled data from the phase 2b and MELODY trials. An exposure target was defined on the basis of an exposure-response analysis. To successfully demonstrate extrapolation, more than 80% of infants in MEDLEY had to achieve serum nirsevimab exposures at or above the predicted efficacious target. FINDINGS: Overall, 2350 infants (1564 in the nirsevimab group and 786 in the placebo group) in the phase 2b and MELODY trials were included in the pooled analysis. Nirsevimab showed efficacy versus placebo with respect to the primary endpoint of medically attended RSV LRTI (19 [1%] nirsevimab recipients vs 51 [6%] placebo recipients; relative risk reduction [RRR] 79·5% [95% CI 65·9-87·7]). Consistent efficacy was shown for additional endpoints of RSV LRTI hospital admission (nine [1%] nirsevimab recipients vs 21 [3%] placebo recipients; 77·3% [50·3-89·7]) and very severe RSV (five [<1%] vs 18 [2%]; 86·0% [62·5-94·8]). Nirsevimab recipients had fewer hospital admissions for any-cause respiratory illness (RRR 43·8% [18·8-61·1]), any-cause medically attended LRTI (35·4% [21·5-46·9]), LRTI outpatient visits (41·9% [25·7-54·6]), and antibiotic prescriptions (23·6% [3·8-39·3]). Among infants with chronic lung disease, congenital heart disease, or extreme preterm birth in MEDLEY, nirsevimab serum exposures were similar to those found in the pooled data; exposures were above the target in more than 80% of the overall MEDLEY trial population (94%), including infants with chronic lung disease (94%) or congenital heart disease (80%) and those born extremely preterm (94%). INTERPRETATION: A single dose of nirsevimab protected healthy infants born at term or preterm from medically attended RSV LRTI, associated hospital admission, and severe RSV. Pharmacokinetic data support efficacy extrapolation to infants with chronic lung disease, congenital heart disease, or extreme prematurity. Together, these data suggest that nirsevimab has the potential to change the landscape of infant RSV disease by reducing a major cause of infant morbidity and the consequent burden on caregivers, clinicians, and health-care providers. FUNDING: AstraZeneca and Sanofi.

Infant Formula With a Specific Blend of Five Human Milk Oligosaccharides Drives the Gut Microbiota Development and Improves Gut Maturation Markers: A Randomized Controlled Trial.

Background: Human milk oligosaccharides (HMOs) have important biological functions for a healthy development in early life. Objective: This study aimed to investigate gut maturation effects of an infant formula containing five HMOs (2'-fucosyllactose, 2',3-di-fucosyllactose, lacto-N-tetraose, 3'-sialyllactose, and 6'-sialyllactose). Methods: In a multicenter study, healthy infants (7-21 days old) were randomly assigned to a standard cow's milk-based infant formula (control group, CG); the same formula with 1.5 g/L HMOs (test group 1, TG1); or with 2.5 g/L HMOs (test group 2, TG2). A human milk-fed group (HMG) was enrolled as a reference. Fecal samples collected at baseline (n∼150/formula group; HMG n = 60), age 3 (n∼140/formula group; HMG n = 65) and 6 (n∼115/formula group; HMG n = 60) months were analyzed for microbiome (shotgun metagenomics), metabolism, and biomarkers. Results: At both post-baseline visits, weighted UniFrac analysis indicated different microbiota compositions in the two test groups (TGs) compared to CG (P < 0.01) with coordinates closer to that of HMG. The relative abundance of Bifidobacterium longum subsp. infantis (B. infantis) was higher in TGs vs. CG (P < 0.05; except at 6 months: TG2 vs. CG P = 0.083). Bifidobacterium abundance was higher by ∼45% in TGs vs. CG at 6-month approaching HMG. At both post-baseline visits, toxigenic Clostridioides difficile abundance was 75-85% lower in TGs vs. CG (P < 0.05) and comparable with HMG. Fecal pH was significantly lower in TGs vs. CG, and the overall organic acid profile was different in TGs vs. CG, approaching HMG. At 3 months, TGs (vs. CG) had higher secretory immunoglobulin A (sIgA) and lower alpha-1-antitrypsin (P < 0.05). At 6 months, sIgA in TG2 vs. CG remained higher (P < 0.05), and calprotectin was lower in TG1 (P < 0.05) vs. CG. Conclusion: Infant formula with a specific blend of five HMOs supports the development of the intestinal immune system and gut barrier function and shifts the gut microbiome closer to that of breastfed infants with higher bifidobacteria, particularly B. infantis, and lower toxigenic Clostridioides difficile. Clinical Trial Registration: [https://clinicaltrials.gov/ct2/show/], identifier [NCT03722550].

Solithromycin in Children and Adolescents With Community-acquired Bacterial Pneumonia.

BACKGROUND: Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP. METHODS: This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy. RESULTS: Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively. CONCLUSIONS: Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP.

Nirsevimab for Prevention of RSV in Healthy Late-Preterm and Term Infants.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection and hospitalization in infants. Nirsevimab is a monoclonal antibody to the RSV fusion protein that has an extended half-life. The efficacy and safety of nirsevimab in healthy late-preterm and term infants are uncertain. METHODS: We randomly assigned, in a 2:1 ratio, infants who had been born at a gestational age of at least 35 weeks to receive a single intramuscular injection of nirsevimab or placebo before the start of an RSV season. The primary efficacy end point was medically attended RSV-associated lower respiratory tract infection through 150 days after the injection. The secondary efficacy end point was hospitalization for RSV-associated lower respiratory tract infection through 150 days after the injection. RESULTS: A total of 1490 infants underwent randomization: 994 were assigned to the nirsevimab group and 496 to the placebo group. Medically attended RSV-associated lower respiratory tract infection occurred in 12 infants (1.2%) in the nirsevimab group and in 25 infants (5.0%) in the placebo group; these findings correspond to an efficacy of 74.5% (95% confidence interval [CI], 49.6 to 87.1; P<0.001) for nirsevimab. Hospitalization for RSV-associated lower respiratory tract infection occurred in 6 infants (0.6%) in the nirsevimab group and in 8 infants (1.6%) in the placebo group (efficacy, 62.1%; 95% CI, -8.6 to 86.8; P = 0.07). Among infants with data available to day 361, antidrug antibodies after baseline were detected in 58 of 951 (6.1%) in the nirsevimab group and in 5 of 473 (1.1%) in the placebo group. Serious adverse events were reported in 67 of 987 infants (6.8%) who received nirsevimab and in 36 of 491 infants (7.3%) who received placebo. CONCLUSIONS: A single injection of nirsevimab administered before the RSV season protected healthy late-preterm and term infants from medically attended RSV-associated lower respiratory tract infection. (Funded by MedImmune/AstraZeneca and Sanofi; MELODY ClinicalTrials.gov number, NCT03979313.).

Pharmacokinetics and Safety of Ceftobiprole in Pediatric Patients.

BACKGROUND: Ceftobiprole, the active moiety of the prodrug ceftobiprole medocaril, is an advanced-generation, broad-spectrum, intravenous cephalosporin, which is currently approved for the treatment of adults with hospital-acquired or community-acquired pneumonia. METHODS: Noncompartmental pharmacokinetics and safety were analyzed from 2 recently completed pediatric studies, a single-dose, phase 1 study in neonates and infants up to 3 months of age (7.5 mg/kg) and a phase 3 study in patients 3 months to 17 years of age with pneumonia (10-20 mg/kg with a maximum of 500 mg per dose every 8 hours for up to 14 days). RESULTS: Total ceftobiprole plasma concentrations peaked at the end of infusion. Half life (median ranging from 1.9 to 2.9 hours) and overall exposure (median AUC ranging from 66.6 to 173 µg•h/mL) were similar to those in adults (mean ± SD, 3.3 ± 0.3 hours and 102 ± 11.9 µg•h/mL, respectively). Calculated free-ceftobiprole concentrations in the single-dose study remained above a minimum inhibitory concentration (MIC) of 4 mg/L (fT > MIC of 4 mg/L) for a mean of 5.29 hours after dosing. In the pneumonia study, mean fT > MIC of 4 mg/L was ≥5.28 hours in all dose groups. Ceftobiprole was well tolerated in both studies. CONCLUSIONS: Pharmacokinetic parameters of ceftobiprole characterized in the pediatric population were within the range of those observed in adults. In the pneumonia study, the lowest percentage of the dosing interval with fT > MIC of 4 mg/L was 50.8%, which suggests that pharmacokinetic-pharmacodynamic target attainment can be sufficient in pediatric patients. Ceftobiprole was well tolerated.

A Phase 3, Randomized, Investigator-blinded Trial Comparing Ceftobiprole With a Standard-of-care Cephalosporin, With or Without Vancomycin, for the Treatment of Pneumonia in Pediatric Patients.

BACKGROUND: The advanced-generation, broad-spectrum, intravenous (IV) cephalosporin, ceftobiprole, is an effective and well-tolerated treatment for adults with hospital-acquired pneumonia (HAP) or community-acquired pneumonia (CAP), but its effects in pediatric patients have not been established. METHODS: In this multicenter, investigator-blinded, active-controlled, phase 3 study, patients 3 months to <18 years old with HAP or CAP requiring hospitalization were randomized (2:1) to ceftobiprole versus standard-of-care (SoC) IV cephalosporin treatments (ceftazidime or ceftriaxone), with or without vancomycin. After at least 3 days' IV treatment, patients demonstrating clinical improvement could be switched to an oral antibiotic, to complete a minimum of 7 days' treatment. RESULTS: Overall, 138 patients were randomized to ceftobiprole (n = 94) or a SoC cephalosporin (n = 44). Median time to oral switch was 6.0 days in the ceftobiprole group and 8.0 days in the SoC cephalosporin group. While on IV therapy, adverse events and treatment-related adverse events were reported by 20.2% and 8.5% of ceftobiprole-treated patients and 18.2% and 0% of SoC cephalosporin-treated patients. Early clinical response rates at day 4 in the intention-to-treat population were 95.7% and 93.2% (between-group difference, 2.6%; 95% confidence interval, -5.5% to 14.7%) in the ceftobiprole and comparator groups, and clinical cure rates at the test-of-cure visit were 90.4% and 97.7% (between-group difference, -7.3%; 95% confidence interval, -15.7% to 3.6%), respectively. CONCLUSIONS: Ceftobiprole was well tolerated and, in this small phase 3 study, demonstrated similar efficacy to SoC cephalosporins in pediatric patients with HAP or CAP requiring hospitalization.

Magnetic Resonance Imaging of Hemophilic Joints: Correlations with the Bleeding Phenotype and Physical Examination.

INTRODUCTION: Blood-induced joint damage as a hallmark of haemophilia continues to occur despite the widespread prophylaxis. Pre-cise assessment and follow-up of joint status are crucial for tailoring their treatment. AIM: To study the correlation between the bleeding phenotype, the functional joint status, and the magnetic resonance imaging score in pediatric patients with haemophilia. MATERIALS AND METHODS: Eighty-six joints (ankles, knees, and elbows) in patients aged 10.7±0.5 (range 4 - 20) years with severe/moderate haemophilia A, severe haemophilia B and haemophilia A with inhibitors were included in the study. The joints were assessed by Haemophilia Joint Health Score 2.1 (HJHS2.1) one month after the last hemarthrosis in a non-bleeding state. The magnetic reso-nance imaging was performed on 40 (46.5%) of the examined hemophilic joints (16 ankles, 11 knees and 13 elbows). RESULTS: Joint bleeds were present in 37 (38.9%) of the joints with ankles being the most commonly affected. Sixty joints (69.8%) had normal HJHS2.1 score. Only the loss of flexion score differed significantly between the joints and the ankles had highest score. The cumulative number of hemarthrosis in the joint correlated moderately with hemosiderin deposition and strongly with the formation of subchondral cysts on magnetic resonance imaging. The magnetic resonance imaging scores for soft tissue and osteochondral domains correlated moderately with the cumulative number of hemarthrosis in the joint and only with the presence of pain and crepitus of mo-tion from the physical examination. CONCLUSIONS: Magnetic resonance imaging is more sensitive than the bleeding phenotype and physical examination in detecting early signs of haemophilic arthropathy.

Population Pharmacokinetics and Safety of Solithromycin following Intravenous and Oral Administration in Infants, Children, and Adolescents.

Solithromycin is a novel fluoroketolide antibiotic which was under investigation for the treatment of community-acquired bacterial pneumonia (CABP). A phase 1 study was performed to characterize the pharmacokinetics (PK) and safety of solithromycin in children. Eighty-four subjects (median age, 6 years [age range, 4 days to 17 years]) were administered intravenous (i.v.) or oral (capsules or suspension) solithromycin (i.v., 6 to 8 mg/kg of body weight; capsules/suspension, 14 to 16 mg/kg on days 1 and 7 to 15 mg/kg on days 2 to 5). PK samples were collected after the first and multidose administration. Data from 83 subjects (662 samples) were combined with previously collected adolescent PK data (n = 13; median age, 16 years [age range, 12 to 17 years]) following capsule administration to perform a population PK analysis. A 2-compartment PK model characterized the data well, and postmenstrual age was the only significant covariate after accounting for body size differences. Dosing simulations suggested that 8 mg/kg i.v. daily and oral dosing of 20 mg/kg on day 1 (800-mg adult maximum) followed by 10 mg/kg on days 2 to 5 (400-mg adult maximum) would achieve a pediatric solithromycin exposure consistent with the exposures observed in adults. Seventy-six treatment-emergent adverse events (TEAEs) were reported in 40 subjects. Diarrhea (6 subjects) and infusion site pain or phlebitis (3 subjects) were the most frequently reported adverse events related to treatment. Two subjects experienced TEAEs of increased hepatic enzymes that were deemed not to be related to the study treatment. (The phase 1 pediatric studies discussed in this paper have been registered at ClinicalTrials.gov under identifiers NCT01966055 and NCT02268279.).

Efficacy and safety of fluticasone propionate/formoterol fumarate in pediatric asthma patients: a randomized controlled trial.

BACKGROUND: The efficacy and safety of fluticasone propionate/formoterol fumarate pressurized metered-dose inhaler (pMDI) (fluticasone/formoterol; Flutiform®; 100/10 µg b.i.d.) was compared with fluticasone propionate (Flixotide® Evohaler® pMDI; 100 µg b.i.d.) and fluticasone/salmeterol (Seretide® Evohaler® pMDI; 100/50 µg b.i.d.) in a pediatric asthma population (EudraCT number: 2010-024635-16). METHODS: A double-blind, double-dummy, parallel group, multicenter study. Patients, aged 5-<12 years with persistent asthma ⩾ 6 months and forced expiratory volume in 1 s (FEV1) ⩽ 90% predicted were randomized 1:1:1 to 12 weeks' treatment. The study objectives were to demonstrate superiority of fluticasone/formoterol to fluticasone and non-inferiority to fluticasone/salmeterol. RESULTS: A total of 512 patients were randomized: fluticasone/formoterol, 169; fluticasone, 173; fluticasone/salmeterol, 170. Fluticasone/formoterol was superior to fluticasone for the primary endpoint: change from predose FEV1 at baseline to 2 h postdose FEV1 over 12 weeks [least squares (LS) mean difference 0.07 l; 95% confidence interval (CI) 0.03, 0.11; p < 0.001] and the first key secondary endpoint, FEV1 area under the curve over 4 hours (AUC0-4 h) at week 12 (LS mean difference 0.09 l; 95% CI: 0.04, 0.13; p < 0.001). Per a prespecified non-inferiority margin of -0.1 l, fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the primary endpoint (LS mean difference 0.00 l; 95% CI -0.04, 0.04; p < 0.001) and first key secondary endpoint (LS mean difference 0.01; 95% CI -0.03, 0.06; p < 0.001). Fluticasone/formoterol was non-inferior to fluticasone/salmeterol for the second key secondary endpoint, change from predose FEV1 over 12 weeks (treatment difference -0.02 l; 95% CI -0.06, 0.02; p < 0.001), but was not superior to fluticasone for this endpoint (LS mean difference 0.03 l; 95% CI -0.01, 0.07; p = 0.091). All treatments elicited large improvements from baseline to week 12 for the Pediatric Asthma Quality of Life Questionnaire (LS mean change 0.76 to 0.85 units) and Asthma Control Questionnaire (LS mean change -1.03 to -1.13 units). Few severe exacerbations were seen (fluticasone/formoterol: two; fluticasone/salmeterol: two). All treatments were well tolerated. CONCLUSIONS: This study supports the efficacy and safety of fluticasone/formoterol in a pediatric asthma population and its superiority to fluticasone.

Immunophenotypic Modulation of the Blast Cells in Childhood Acute Lymphoblastic Leukemia Minimal Residual Disease Detection.

UNLABELLED: Early clearance of leukemic cells during induction therapy of childhood acute lymphoblastic leukemia (ALL) is a basis for treatment optimization. Currently, the most widely used methods for the detection of minute residual malignant cells in the bone marrow and/or peripheral blood, minimal residual disease (MRD), are PCR and flow cytometry (FCM). Immunophenotypic modulation (IM) is a well known factor that can hamper the accurate FCM analysis. AIM: To report the IM detected by 8-color FCM during the BFM-type remission induction in 24 consecutive MRD-positive samples of children with B-cell precursor ALL and the possible implications for MRD detection. PATIENTS AND METHODS: Between 2010 and 2012 we prospectively followed up the MRD on days 15 and 33 of induction treatment in bone marrow (BM) samples and on day 8 in peripheral blood (PB). The IM was assessed by comparative analyses of the changes in the mean fluorescence intensity of 7 highly relevant antigens expressed by the leukemic cells and normal B-lymphocytes. RESULTS: IM occurred, to different extents, in all analyzed day 15 BM and in most day 33 BM samples. Statistically significant changes in the MFI-levels of four CDs expressed by the leukemic blasts were observed: downmodulation of CD10, CD19 and CD34 and upmodulation of CD20. No changes in the expression of CD38, CD58 and CD45 were noticed. CONCLUSIONS: Measuring the MRD by standardized 8-color flow cytometry helps improve the monitoring of the disease, leading to better therapeutic results. However, the IM of the different antigens expressed by the leukemic blasts should be taken into consideration and cautiously analyzed.

Hearing Loss in Patients with Shunt-Treated Hydrocephalus.

Hearing loss is a common manifestation of the long-term complications in patients with shunt treated hydrocephalus along with motor development disturbance, cognitive and visual impairment, epilepsy and endocrine disorders. The aim of the present study was to investigate the alterations of hearing in patients with shunt treated hydrocephalus of non-tumor etiology and at least one year after implantation of ventriculo-peritoneal shunt, as well as their impact on the quality of life of patients. The study included 70 patients (age range 1.25 years - 21.25 years) with shunted non-tumor hydrocephalus and at least one year after placement of the shunt system. Hearing alterations were proved by measuring the brainstem auditory evoked potentials (BAEP) for children up to 5 years of age and children with mental retardation; audiograms was used for children older than 5 years with normal neuro-psychological development (NPD). Of the 70 studied patients 17 (24%) had hearing loss (10 bilateral and 7-unilateral) and all of them had sensorineural hearing loss, which is associated with low weight at birth, posthemorrhagic hydrocephalus and brainstem symptoms at the time of diagnosis of hydrocephalus. Hearing pathology was found more often in shunt-treated patients with NPD retardation, poor functional status and low quality of life. Children with shunt-treated hydrocephalus have hearing loss of sensorineural type. Children with brain stem symptomatology at diagnosing hydrocephalus and children with post-hemorrhagic hydrocephalus show higher risk of hearing loss. Children with shunted hydrocephalus and hearing loss show lower NPD, lower quality of life and lower functional status.

Phase I, open-label, single-dose study to evaluate the pharmacokinetics and safety of telbivudine in children and adolescents with chronic hepatitis B.

Telbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to <6 and 6 to 12 years receiving a single 15-mg/kg dose showed similar plasma exposures. To predict the steady-state exposure, plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.).

Cystic fibrosis and celiac disease--multifaceted and similar.

Celiac disease and cystic fibrosis share a number of clinical manifestations. The comorbidity rate of these diseases is low: 1:200000. We present a case of a child aged 1 year and 5 months, born to a mixed-marriage parents, with concomitant cystic fibrosis and celiac disease manifesting initially with chronic diarrhea. Diagnosis of cystic fibrosis was made on the basis of changes in pulmonogram and three positive sweat tests with the malabsorption managed. Celiac disease was demonstrated through immunological tests (serological test of anti-transglutaminase antibodies of IgA class), histological tests (altered duodenal mucosa) and the therapeutic effect of a gluten-free diet. This case is the first ever reported case of a child with concomitant cystic fibrosis and celiac disease in Bulgaria. The case suggests the need for targeted screening for celiac disease in children with cystic fibrosis.

Psychomotor development after ganciclovir selectively treated congenital and perinatal cytomegalovirus infection.

AIM: To study the development of children with selectively treated cytomegalovirus infection. PATIENTS AND METHODS: We studied prospectively a risk group of 12 children with cytomegalovirus infection. These children were diagnosed by serological screening in the first three months after birth and are defined as congenital and perinatal infections. Thirteen infants with no serological evidence of previous or present cytomegalovirus infection at 4-12 months of age were used as controls. Ganciclovir in a dose of 10-15 mg/kg/day for at least 2 weeks followed by 5-7.5 mg/kg/day administered intravenously for at least 2 weeks more was given to 4 children from the risk group with PCR confirmed cytomegalovirus infection: to one with suspected congenital infection that presented with encephalitis, to two children with abnormal auditory evoked potentials (AEPs) and other non-neurological symptoms of a suspected congenital infection, and to one child with proven congenital infection with systemic manifestations. There was no infant with cytomegalic inclusion disease in the study. All other children in the risk group that had clinically manifested infection received isoprinosine in a dose of 50 mg/kg for one month. RESULTS: Psychomotor development delay at age three was found in two children from the risk group and in one child in the control group. There was no difference between the two groups regarding the frequency of paroxysmal events, sensory deficiency or frequent illnesses. CONCLUSIONS: The prognosis in cases of cytomegalovirus infection diagnosed at three years of age and treated selectively can be similar to that in infection free 3-year-old children (if there are no cases of CMV inclusion disease).

Efficacy and safety of three ciclesonide doses vs placebo in children with asthma: the RAINBOW study.

OBJECTIVE: To evaluate the efficacy and safety of three doses of ciclesonide (with or without spacer) in children with persistent asthma. PATIENTS AND METHODS: This was a multicentre, double-blind, placebo-controlled, 12-week study of ciclesonide 40, 80 or 160 µg (once daily pm). Children (6-11 years) were randomised 1:1 to treatment via a metered dose inhaler (MDI) or MDI plus spacer. The primary variable was change from baseline in mean morning peak expiratory flow (PEF). Secondary variables included: time to first lack of efficacy (LOE), asthma control, forced expiratory volume in 1 s (FEV(1)), asthma symptom score and quality of life (QoL). Safety assessments included: adverse events (AEs), urinary cortisol excretion and body height. RESULTS: In total, 1073 children received treatment. At endpoint, mean morning PEF significantly improved with all doses of ciclesonide vs. placebo. There was no difference over placebo in time to first LOE, but ciclesonide was superior to placebo on asthma control, symptom score, FEV(1) and QoL. There were no differences between the spacer or non-spacer subgroups. The incidences of AEs were comparable between treatment groups (approximately 35%) and there were no between-group differences in body height or urinary cortisol. CONCLUSIONS: Ciclesonide 40-160 µg once daily is effective and well tolerated in children with persistent asthma; its efficacy and safety are unaffected by the use of a spacer. clinicaltrials.gov registration number: NCT00384189.

Assessment of left ventricular structure and function in rats subjected to pressure-overload hypertrophy in time.

BACKGROUND: Left ventricular hypertrophy (LVH) is an adaptive response to increased haemodynamic load and an independent risk factor for the development of heart failure. Although the pathophysiological features during the development of cardiac hypertrophy have been extensively studied, the time course of LVH is less clearly defined. AIM: To define the time-dependency of the LVH process in vivo and compare the data by necropsy. METHODS: Using abdominal aortic banding (AAB) in male Wistar strain albino rats we assessed the changes of LV structure and function in short intervals of 5 days for a period of 45 days. We determined the changes by serial echocardiography and confirmed the results in a second echocardiographic experiment and by necropsy. RESULTS: In our model the magnitude of the pressure overload was sufficient to produce significant LVH within a 10-day time frame and further progression on the 15th day after AAB. Interestingly, on the 20th day after banding a short-lasting regression of LVH (and heart weight and LV wall thickness) was found. It was followed by an increase in the next 15 days (till the 35th day), after which LVH was roughly complete (as measured at the 45th day). CONCLUSIONS: Following the development of LVH over a relatively long period of time and providing the changes in short intervals, a short lasting regression during ongoing pressure overload was noted. Understanding and targeting the associated signalling underlying this regression may have considerable clinical consequences.