Pediatric Drugs最新文献

Behçet's disease is a rare and poorly understood vasculitis affecting blood vessels of all types and sizes. Uveitis and oral and genital ulcers represent the typical clinical triad. Populations along the ancient trading route connecting the Mediterranean basin with the Middle and Far East are most affected. Up to a quarter of the cases has a pediatric onset, typically around puberty. The aim of the treatment is early intervention to control inflammation, with symptom relief and prevention of relapses, damage, and complications. The heterogeneous clinical presentation often requires a multidisciplinary and tailored approach. Ocular, neurological, gastrointestinal, and vascular involvement is associated with a worse prognosis and needs more aggressive treatments. In young patients with expected prolonged disease, treatment should also focus on preventive measures and lifestyle advice. In recent years, the pharmacological armamentarium has grown progressively, although only a limited number of drugs are currently authorized for pediatric use. Most evidence for these drugs still derives from adult studies and experience; these are prescribed as off-label medications and are only available as adult formulations. Corticosteroids frequently represent the mainstay for the management of the initial acute phases, but their potential serious adverse effects limit their use to short periods. Different conventional disease-modifying anti-rheumatic drugs have long been used. Many other biologic drugs targeting different cytokines such as interleukin-1, interleukin-6, and interleukin-17 and treatments with small molecules including the phosphodiesterase 4 and Janus kinase inhibitors are emerging as novel promising therapeutic agents. In recent years, a growing interest has developed around anti-tumor necrosis factor agents that have often proven to be effective in severe cases, especially in those with a gastrointestinal and ocular involvement.

Background: Cytomegalovirus (CMV) infection is a frequent event in patients undergoing allogeneic haematopoietic cell transplantation (HCT) and is associated with increased morbidity and mortality due to eventual progress to end-organ disease. Letermovir prophylaxis for CMV infections has become a standard of care in adult HCT recipients due to its efficacy and high tolerability. However, it is not yet approved for paediatric patients.

Objective: In a retrospective single-centre observational study we evaluated the use of letermovir for prophylaxis or pre-emptive treatment of cytomegalovirus (CMV) infection in seropositive paediatric HCT recipients receiving the compound outside of clinical trials. The primary endpoint was CMV reactivation requiring a change of medication.

Methods: A total of 17 patients (seven female/ten male; median age 12.2 [range 3.5-19] years, median body weight 39.5 [range 15-63] kg; median follow-up time 463.7 [range 41-1022] days) were identified who were started on oral (14) or intravenous (3) followed by oral (2) letermovir shortly after neutrophil engraftment at doses determined on the basis of age, weight, and concomitant cyclosporine use.

Results: Five patients had no evidence of viral replication (prophylactic use), while 12 patients had varying extents of viral replication (pre-emptive therapy). A change of therapy was required in one patient due to a sustained increase in CMV viral load, and in two patients, letermovir was stopped without later reactivation after initiation of palliative care for recurrent leukaemia. Of the 14 patients who completed treatment, 3 had evidence of transient viral replication after end of treatment that required no further antiviral treatment. No patients (of 17) discontinued letermovir due to an adverse event.

Conclusion: Letermovir was effective in controlling CMV infection in seropositive paediatric allogeneic HCT recipients and was overall well tolerated. Pending completion of the still ongoing paediatric investigation plans, letermovir will be an important adjunct to our options for control of infectious complications in this special population.

Atypical hemolytic uremic syndrome is a thrombotic microangiopathy characterized by hemolysis, thrombocytopenia, and acute kidney injury, usually caused by alternative complement system overactivation due to pathogenic genetic variants or antibodies to components or regulatory factors in this pathway. Previously, a lack of effective treatment for this condition was associated with mortality, end-stage kidney disease, and the risk of disease recurrence after kidney transplantation. Plasma therapy has been used for atypical hemolytic uremic syndrome treatment with inconsistent results. Complement-blocking treatment changed the outcome and prognosis of patients with atypical hemolytic uremic syndrome. Early administration of eculizumab, a monoclonal C5 antibody, leads to improvements in hematologic, kidney, and systemic manifestations in patients with atypical hemolytic uremic syndrome, even with apparent dialysis dependency. Pre- and post-transplant use of eculizumab is effective in the prevention of atypical hemolytic uremic syndrome recurrence. Evidence on eculizumab use in secondary hemolytic uremic syndrome cases is controversial. Recent data favor the restrictive use of eculizumab in carefully selected atypical hemolytic uremic syndrome cases, but close monitoring for relapse after drug discontinuation is emphasized. Prophylaxis for meningococcal infection is important. The long-acting C5 monoclonal antibody ravulizumab is now approved for atypical hemolytic uremic syndrome treatment, enabling a reduction in the dosing frequency and improving the quality of life in patients with atypical hemolytic uremic syndrome. New strategies for additional and novel complement blockage medications in atypical hemolytic uremic syndrome are under investigation.

Background: Adverse drug reactions (ADRs) and medication errors in children may result from a lack of appropriate drugs, dosages, and pharmaceutical forms. In addition, children may respond differently to drugs than adults. Reporting of ADRs in the pediatric population is therefore of importance in order to increase the amount of safety data. However, different methodological approaches are used to collect ADRs.

Objective: The aim of the present study was to analyze whether there were differences in the ADRs collected in the KiDSafe project (845 ADR reports) compared with the spontaneous ADR reports sent to EudraVigilance (697 reports) in the same time period. The strengths and limitations of these two different approaches should be discussed.

Methods: The same inclusion criteria were applied for the systematically collected ADRs in the KiDSafe project and the spontaneous reports from EudraVigilance, and only reports of ADRs coded with hospitalization were considered. In both datasets, the number of reports (related to number of hospitals), their documentation quality (VigiGrade), causal relationship (World Health Organization-Uppsala Monitoring Centre [WHO-UMC] criteria), most frequently reported drugs and ADRs, demographical parameters of the patients, reported medical histories, and the seriousness of ADR reports were analyzed descriptively. The results of the two analyses were compared.

Results: There was considerable underreporting of ADRs via the spontaneous reports (0.4 reports per hospital; 697/1902) compared with 70.4 reports per hospital (845/12) in the systematically collected KiDSafe reports. Documentation quality assessment yielded similar results in both datasets. Among the 10 most frequently reported drugs, anticonvulsants such as levetiracetam (6.6%), valproic acid (5.6%), oxcarbazepine (3.6%), and lamotrigine (3.4%) were mainly reported in the KiDSafe reports, while in the EudraVigilance reports, mite allergen extract (4.4%) and allergens (3.6%) were preferentially reported. Seizures were the most frequently reported clinically specific ADRs in the KiDSafe reports, whereas anaphylactic reactions and urticaria were prominent in the spontaneous reports from EudraVigilance. Notably, the proportion of reports referring to medication errors and other medication safety related issues were more prominent in KiDSafe than in the spontaneous reports (27.8% vs. 12.6% and 46.0% vs. 29.0%, respectively).

Conclusion: In general, reports from both data sources contributed to the identification of ADRs and dedicated issues related to drug therapy. However, these differed by nature and strength of the signal, likely due to the characteristics of the individual method. A combined approach could likely compensate for limitations inherent to the single approaches, but will most likely only be applied to dedicated pharmacovigilance topics o

Pityriasis rubra pilaris represents a group of familial and acquired disorders of cornification that affect both adult and pediatric patients. Treatment options are difficult to assess through clinical trials, given the rarity of the disorder and its tendency for spontaneous remission. Case reports and case series are therefore the primary means of assessment. Because of the heterogeneity of the disease, there is no universal approach to treatment, and multiple agents may need to be trialed to achieve disease control. At present, topicals are used for most pediatric patients, though monotherapy with topicals is only effective for less severe disease. Despite concerns over their side-effect profiles, oral retinoids are generally accepted as a first-line systemic therapy. However, interleukin-17 inhibitors and ustekinumab, an interleukin-12 and interleukin-23 inhibitor, may soon become first-line systemic treatment as well, given their efficacy and relative safety in trials thus far. Ustekinumab, in particular, is emerging as a first-line agent for patients with pityriasis rubra pilaris with CARD14 gene variations. When these therapies fail, second-line and adjunctive therapies to consider include tumor necrosis factor-alpha inhibitors, methotrexate, and phototherapy. However, further investigation is necessary to assess the safety and efficacy of many of these agents in juvenile pityriasis rubra pilaris.

Background and objective: Previous studies of dupilumab for the treatment of moderate-to-severe atopic dermatitis in adults and adolescents, and severe atopic dermatitis in children aged 6 to < 12 years demonstrate no clinically important changes in laboratory parameters. The objective of this study was to assess laboratory outcomes in children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis treated with dupilumab.

Methods: In this randomized, placebo-controlled, phase III trial of dupilumab, 161 children aged 6 months to < 6 years with moderate-to-severe atopic dermatitis were enrolled from 31 sites in Europe and North America and randomized 1:1 to receive subcutaneous placebo or dupilumab (5 kg to < 15 kg: 200 mg; 15 kg to < 30 kg: 300 mg) every 4 weeks plus topical corticosteroids for 16 weeks. Hematology, serum chemistry, and urinalysis assessments were analyzed on blood and urine samples collected at screening and weeks 4 and 16; descriptive statistics are provided.

Results: No clinically meaningful changes in laboratory parameters were observed. While two cases of eosinophilia and one case each of neutropenia and leukocytosis were reported as treatment-emergent adverse events in the dupilumab plus topical corticosteroids group, these events were not associated with clinical symptoms and did not lead to treatment discontinuation or study withdrawal.

Conclusions: These results suggest that routine laboratory monitoring of children aged 6 months to < 6 years treated with dupilumab plus topical corticosteroids is not required. Limitations of this study include short study duration, and exclusion of patients with abnormalities in laboratory test results at screening.

Clinical trial registration: ClinicalTrials.gov: NCT03346434, part B.

Physiologically based pharmacokinetic (PBPK) modeling can be an attractive tool to increase the evidence base of pediatric drug dosing recommendations by making optimal use of existing pharmacokinetic (PK) data. A pragmatic approach of combining available compound models with a virtual pediatric physiology model can be a rational solution to predict PK and hence support dosing guidelines for children in real-life clinical care, when it can also be employed by individuals with little experience in PBPK modeling. This comes within reach as user-friendly PBPK modeling platforms exist and, for many drugs and populations, models are ready for use. We have identified a list of drugs that can serve as a starting point for pragmatic PBPK modeling to address current clinical dosing needs.

Objectives: Current irritable bowel syndrome (IBS) treatments have limited efficacy and probiotics like Bacillus clausii (B. clausii) were found to be effective in the management of several gastrointestinal disorders. This phase III trial assessed the efficacy and safety of adding B. clausii (four strains: O/C, N/R, SIN, T), versus placebo, to conventional treatment of pediatric IBS in Mexico.

Methods: Patients aged 6-17 years 11 months with IBS (Rome IV) for at least 2 months were randomized to receive either B. clausii (oral suspension, total dose 4 billion spores/day) or placebo once daily for 8 weeks. All patients also received conventional treatment. The primary endpoint was the difference in the proportion of patients with clinical improvements at Week 8 (Global Assessment Questions [GAQ]). Secondary endpoints included responders by Subject's Global Assessment of Relief for Children with IBS (SGARC); number/consistency of stools; abdominal distention/bloating; abdominal pain/intensity; and IBS behavior.

Results: 73.6% (95% confidence interval [CI] 67.3-80.0; B. clausii n = 129) and 78.5% (95% CI 72.5-84.4; placebo n = 130) of patients had symptom improvement (p = 0.8182). For Week 8 SGARC, 19.2% (B. clausii) and 20.9% (placebo) reported complete symptom relief. Stool evaluations, bloating, abdominal pain/intensity, and IBS behavior were similar between groups. Both treatments were well tolerated.

Conclusion: No significant differences in efficacy between B. clausii and placebo were demonstrated in addition to conventional treatment. The sample size calculation was based on an expected placebo/conventional treatment response of 30-40%. However, the actual treatment response observed was 80% and, thus, a study with larger population would be warranted. In addition, this study was conducted during the COVID-19 pandemic, when such controlled social conditions may have resulted in better diet, greater family stability, less psychological stress, and lower risk of infections exacerbating IBS, thereby improving symptoms in both groups.

Eudract number: 2018-004519-31.

The addition of anti-disialoganglioside-2 (GD2) monoclonal antibodies (mAbs) such as dinutuximab and naxitamab to standard therapies for high-risk (HR) neuroblastoma has significantly improved outcomes for children with this devastating disease. The care for these young patients receiving treatment for HR neuroblastoma is complex, with need for the involvement of a multidisciplinary team. Clinical implementation of anti-GD2 mAb treatment requires the same harmonized team approach. The authors share the development process of this coordinated team method and practical recommendations for administration of anti-GD2 mAbs and adverse event (AE) management. Successful collaboration between nurses and other team members ensures optimal treatment and comfort of patients and their families. The primary focus of this approach is to mitigate and manage AEs associated with anti-GD2 mAb treatments, such as pain, hypotension, allergic reactions, and hypertension, and to ensure safe and effective use of anti-GD2 mAbs. The two treatments approved for use in patients with neuroblastoma, dinutuximab for patients with HR disease following a partial response or better to frontline multimodal therapy and naxitamab for refractory or relapsed HR disease in the bone or bone marrow, were studied in different administration settings and follow different regimens and infusion schedules. Therefore, AE management requirements are specific to each treatment. The awareness of these differences and implementation of appropriate AE management strategies in clinical practice are important to ensure the best possible outcomes for patients with HR neuroblastoma.

Background: Newborn infants undergoing therapeutic hypothermia (TH) are exposed to multiple painful and stressful procedures. The aim of this systematic review was to assess benefits and harms of pharmacological and non-pharmacological interventions for the management of pain and sedation in newborn infants undergoing TH for hypoxic-ischemic encephalopathy.

Methods: We included randomized and observational studies reporting any intervention (either drugs or non-pharmacological interventions) to manage pain and sedation in newborn infants (> 33 weeks' gestational age) undergoing TH. We included any dose, duration and route of administration. We also included any type and duration of non-pharmacological interventions. Our prespecified primary outcomes were analgesia and sedation assessed using validated pain scales in the neonatal population; circulatory instability; mortality to discharge; and neurodevelopmental disability. A systematic literature search was conducted in the PubMed, Embase, CINAHL, Cochrane CENTRAL, Scopus, and Web of Science databases, with no language restrictions. Included studies underwent risk-of-bias assessment (Cochrane risk-of-bias tool and ROBINS-I) and data extraction performed by two authors independently. The plan had been to use effect measures such as mean difference for continuous outcomes and risk ratio for dichotomous outcomes, however the included studies are presented in a narrative synthesis due to their paucity and heterogeneity.

Results: Ten studies involving 3551 infants were included-one trial and nine observational studies. Most studies examined the use of phenobarbital or other antiepileptic drugs with primary outcomes related to seizure activity. The single trial that was included compared pentoxifylline with placebo. Among the primary outcomes, six studies reported circulatory instability and five reported mortality to discharge without relevant differences; two studies reported on neurodevelopmental disability and one study reported on pain scale. Three studies were ongoing.

Conclusions: We found limited evidence to establish the benefits and harms of the interventions for the management of pain and sedation in newborn infants undergoing TH. Long-term outcomes were not reported. Given the very low certainty of evidence-due to imprecision of the estimates, inconsistency and limitations in study design (all nine observational studies with overall serious risk of bias)-for all outcomes, clinical trials are required to determine the most effective interventions in this population.

Systematic review registration: PROSPERO registration number: CRD42020205755.