Pediatric Drugs最新文献

Background: Vamorolone has recently been approved for the management of Duchenne muscular dystrophy to replace glucocorticosteroids, which theoretically have more side effects. However, its efficacy and safety profile is unclear.

Objective: We aimed to assess the efficacy of vamorolone in Duchenne muscular dystrophy through the 6-minute walk test (6MWT), the North Star Ambulatory Assessment (NSAA), time to stand velocity (TTSTAND), time to run 10 m (TTRW), time to climb four stairs (TTCLIMB) and a safety profile.

Methods: A systematic search was conducted in MEDLINE, Scopus, Web of Science and the Cochrane Library from inception to June 2024 (PROSPERO: CRD42024558413) for studies evaluating the effect or safety profile of vamorolone in a population with Duchenne muscular dystrophy on 6MWT, NSAA and TTSTAND. TTRW, TTCLIMB and a safety profile were included. The risk of bias was assessed using the Cochrane Collaboration's risk of bias tool (RoB2) and the Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group from the US National Institutes of Health National Heart, Lung, and Blood Institute, depending on the type of design. Results were expressed as mean differences or proportions with 95% confidence intervals (CIs), depending on the outcome.

Results: Six studies with a total of 145 individuals with Duchenne muscular dystrophy and a baseline age between 4.7 and 5.5 years were included in the systematic review. Overall, the most effective dose was 6 mg/kg/day. At 24 weeks, this dose showed a statistically significant effect compared with the untreated cohorts of 41.60 m (95% CI 14.30, 68.90) on the 6MWT, 3.57 points (95% CI 1.89, 5.25) on the NSAA, 0.06 events/s (95% CI 0.02, 0.10) on the TTSTAND, approximately 0.25 m/s on the TTRW and 0.04 (95% CI -0.00, 0.08) to 0.07 events/s (95% CI 0.03, 0.11) on the TTCLIMB. There was some discrepancy in the statistical significance of some studies, although the direction of the effect was usually similar. In general, the effect was maintained in the extension studies. Adverse events were less frequent than in historical cohorts treated with glucocorticoids. Finally, the risk of bias in the included studies was low.

Conclusions: According to our results, vamorolone offers a statistically and clinically significant benefit in the management of Duchenne muscular dystrophy, with fewer side effects than glucocorticoids. However, the number of studies limits the interpretability and generalisability of these data, requiring more studies with more participants to perform a meta-analysis.

Distal renal tubular acidosis (dRTA) is characterized by a primary defect in proton secretion by α-intercalated cells of the collecting duct, leading to impaired urine acidification and resulting in metabolic acidosis, hypokalemia, and hypercalciuria. Inherited forms of dRTA are currently associated with variants in five genes (SLC4A1, ATP6V1B1, ATP6V0A4, FOXI1, and WDR72), each being associated with specific extra-renal manifestations. Acquired forms can result from autoimmune diseases or drug side effects. Classical complications include nephrolithiasis, nephrocalcinosis, reduced glomerular filtration rate (GFR), bone demineralization, and growth failure. Treatment focuses on correcting the acid-base imbalance through alkali supplementation (potassium, sodium, or magnesium bicarbonate or citrate) to reduce renal disease progression and promote normal growth and mineralization. Traditional treatments (alkali and potassium supplementation) often suffer from poor adherence due to frequent day and night administrations, gastrointestinal discomfort, and unpleasant taste. A novel investigational drug, ADV7103, which contains potassium citrate and potassium bicarbonate in an extended-release formulation, has recently been approved by the European Medicine Agency (EMA) for dRTA. Recent studies support its use as a first-line treatment, given its efficacy and safety profile.

Myasthenia gravis (MG) is an antibody-mediated disorder of the neuromuscular junction affecting children and adults. MG is a treatable condition with most patients requiring immunosuppression for disease control and/or remission. Juvenile myasthenia gravis (JMG) is rare in comparison with adult-onset MG but given the same underlying pathophysiology, treatment strategies are similar to those in adults. Until recently, there were only a few randomised controlled trials (RCTs) for MG treatments in adults and none in children, and management strategies were primarily based on expert consensus. In addition, treatment options for refractory MG cases have been severely limited, resulting in poor long-term quality of life in such patients due to the significant disease burden. Recently, there have been several RCTs focussing on novel therapeutic strategies with potentially promising outcomes, suggesting a change in MG management over the coming years and access to more effective and faster-acting drugs for MG patients. This paper will review current and new MG treatments including efgartigimod, eculizumab, rozanolixizumab, ravulizumab, and zilucoplan, with a focus on juvenile myasthenia gravis.

Background: Acetaminophen, ibuprofen, and indomethacin are widely used as first-line drugs for patent ductus arteriosus (PDA) closure in preterm neonates. However, their relative safety profiles remain unclear.

Methods: Adverse event reports related to the first-line drugs used in PDA and neonates in general were retrieved from the US Food and Drug Authority (FDA) Adverse Event Reporting System. Deduplicated reports were analyzed using proportional reporting ratios and reporting odds ratios to identify disproportionality safety signals between drugs.

Results: A total of 969 unique reports related to the first-line drugs used in PDA and 499 reports in the neonatal period were included. Acetaminophen signals primarily involved the liver, while ibuprofen and indomethacin signals pertained to gastrointestinal, renal, vascular, and mortality outcomes. Higher occurrences of death were reported with indomethacin and ibuprofen compared with acetaminophen.

Conclusion: This first comparison of PDA drug safety profiles from spontaneous reports highlights some differences, with acetaminophen potentially conferring a safer adverse effect profile overall. While limitations include missing data and reporting biases, the signals warrant further validation. Given its comparable efficacy to ibuprofen, as demonstrated in other studies, acetaminophen has the potential to be preferred as an initial medical therapy for PDA.

Daily, children undergo countless investigations and interventions, which require sedation and immobilization to ensure safety and accuracy. This remains associated with a persistent risk of sedation-induced life-threatening events as children are particularly vulnerable to adverse medical events and complications. Consequently, there is an urgent need to increase the safety of pediatric sedation and anesthesia. An ideal approach involves the use of drugs with fewer intrinsic side effects. In this context, on the basis of their pharmacokinetic properties, remimazolam (RMZ) and dexmedetomidine (DEX) were evaluated for their suitability as ideal sedatives. RMZ and DEX, both of which are currently available in pediatric medicine, have shown great promise in initial publications. To date, only very limited data concerning RMZ in small children are available. RMZ is a novel, ultrashort-acting benzodiazepine that is metabolized by tissue esterase, largely independent of organ function. It has a context-sensitive half-life of approximately 10 min, with minimal accumulation even with prolonged use. Its effects can be completely reversed with flumazenil. DEX, an isomer of medetomidine, is a potent α2-receptor-agonist with multiple indications in anesthesia and intensive care medicine. It has coanalgesic potential, allows for 'arousal sedations' and has a low profile for cardiorespiratory side effects. DEX is metabolized in the liver and is predominantly excreted renally. Both drugs show potential in the prevention and treatment of delirium, with DEX having additional neuroprotective effects. DEX and RMZ possess several properties of an optimal sedative, including clinically insignificant main metabolites and a broad dosage range, indicating their potential to reduce the incidence of sedation-related life-threatening events in children. However, further clinical research is necessary to better evaluate their potential risks.

Purpose: The purpose of this study was to review the pharmacokinetic profile of gentamicin among neonates with hypoxic ischemic encephalopathy (HIE) undergoing therapeutic hypothermia (TH) treatment.

Methods: This was a retrospective study of neonates with HIE undergoing TH in the neonatal intensive care unit who received gentamicin between 2009 and 2014. Demographic information, diagnoses, laboratory test results, and medication administration and monitoring information were collected, and data were analyzed using SciPy.

Results: A total of 57 neonates were analyzed. The median birth weight was 3.25 kg (interquartile range [IQR] 2.8-3.68), and median gestational age was 39 weeks (IQR 38-40). An elevated gentamicin trough level (defined as > 2 mg/L) was observed in 61% (35/57) of neonates. Half of the neonates (49%) had multiple gentamicin trough levels obtained, and 4% of the neonates were switched to an alternate agent. There was a significant difference in the number of dosing interval changes in neonates with elevated gentamicin trough levels compared with those with therapeutic gentamicin trough levels (P < 0.001). Of the neonates with elevated gentamicin trough levels, 14% (5/35) failed their hearing screen (P = 0.389).

Conclusions: Neonates with HIE undergoing TH may have an altered pharmacokinetic profile, requiring multiple blood draws so medication levels can be monitored and doses adjusted. Traditional gentamicin dosing regimens may not be ideal for this patient population, and further guidance is required for alternative treatment regimens.

Juvenile dermatomyositis is a rare systemic inflammatory autoimmune disease involving muscle, skin, and vessels. Most patients do not fully respond to initial therapy, instead having a chronic refractory or polycyclic disease course. Pathogenesis is not completely understood, but immune cell dysregulation, particularly of B cells, mitochondrial dysfunction, changes in neutrophils and neutrophil extracellular traps (NETs), and increased type I and type II interferon (IFN) signaling have been described. There are limited randomized controlled trials of drugs in juvenile dermatomyositis (JDM), and treatment is largely based on lower-quality data such as case series, retrospective studies, and open-label prospective studies. These data have been compiled into expert recommendations or consensus treatment plans, which help guide therapy. While initial therapy is more standard with most including corticosteroids (high-dose oral and/or pulse intravenous methylprednisolone) and methotrexate, for refractory patients, guidelines are more varied with multiple options or combinations, including biologic therapies. There is a clear need for more efficacious and personalized therapy in JDM. Emerging treatment options worthy of further study in JDM include targeting IFN-signaling (JAK, IFNAR1, IFN beta), B-cells (CD20, CD19, BAFF, TACI, CD38, BCMA) including Chimeric Antigen Receptor (CAR)-T cell therapy, mitochondrial dysfunction, and NETs.

Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of hematological malignancies, inducing notable and durable clinical responses. However, for solid tumors, including but not limited to pediatric tumors, several peculiar biological features posed substantial challenges for achieving comparable results. Despite sound pre-clinical evidence of the ability of CAR T cells to eradicate solid malignancies, their activity remains suboptimal when facing the in vivo complexity of solid tumors, characterized by antigen heterogeneity, scarce T-cell infiltration, and an immunosuppressive microenvironment. Neuroblastoma was amongst the first tumors to be evaluated as a potential candidate for GD2-targeting CAR T cells, which recently documented promising results in high-risk, heavily pre-treated patients. Moreover, innovative engineering strategies for generating more potent and persistent CAR T cells suggest the possibility to reproduce, and potentially improve, these promising results on a larger scale. In the next years, harnessing the full therapeutic potential of CAR T cells and other immunotherapeutic strategies may open new possibilities for effectively treating the most aggressive forms of pediatric tumors.