Pediatric Drugs最新文献

Despite significant global reductions in cases of pneumonia during the last 3 decades, pneumonia remains the leading cause of post-neonatal mortality in children aged <5 years. Beyond the immediate disease burden it imposes, pneumonia contributes to long-term morbidity, including lung function deficits and bronchiectasis. Viruses are the most common cause of childhood pneumonia, but bacteria also play a crucial role. However, the optimal duration of antibiotic therapy for bacterial pneumonia remains uncertain in both low- and middle-income countries and in high-income countries. Knowing the optimal duration of antibiotic therapy for pneumonia is crucial for effective antimicrobial stewardship. This is especially important as concerns mount over rising antibiotic resistance in respiratory bacterial pathogens, which increases the risk of treatment failure. Numerous studies have focused on the duration of oral antibiotics and short-term outcomes, such as clinical cure and mortality. In contrast, only one study has examined both intravenous and oral antibiotics and their impact on long-term respiratory outcomes following pneumonia hospitalisation. However, study findings may be influenced by their inclusion criteria when children unlikely to have bacterial pneumonia are included. Efforts to differentiate between bacterial and non-bacterial pneumonia continue, but a validated, accurate, and simple point-of-care diagnostic test remains elusive. Without certainty that a child has bacterial pneumonia, determining the optimal duration of antibiotic treatment is challenging. This review examines the evidence for the recommended duration of antibiotics for treating uncomplicated pneumonia in otherwise healthy children and concludes that the question of duration is unresolved.

Background: This study aimed to provide a comprehensive review of adverse events (AEs) associated with factor Xa (FXa) inhibitors in pediatric patients.

Methods: We searched PubMed, Embase, Cochrane Library, ClinicalTrials.gov, and the European Union Clinical Trials Register for English-language records from the establishment of the database up to October 17, 2023. Both randomized controlled trials and single-arm trials were included. AEs were analyzed using a Bayesian hierarchical model. For the pharmacovigilance study, data from the US Food and Drug Administration Adverse Event Reporting System from January 1, 2007, to December 31, 2023, were obtained. The proportional imbalance method and the Medicines and Healthcare products Regulatory Agency method were used to detect AE signals. Further characterization of patients presenting with AEs was performed.

Results: Of 451 records identified, 12 eligible studies were included. A total of 50.6% (95% Bayesian credible interval [CrI] 33.1-67.2, τ = 0.796) of patients experienced at least one AE, and 9.9% (95% CrI 3.9-19.5, τ = 0.552) developed at least one serious AE. Major and clinically relevant non-major bleeding occurred in 2.4% (95% CrI 0.8-4.8, τ = 1.61) of patients. The most common bleeding AEs were epistaxis (8.4% [95% CrI 3.9-14.9, τ = 1.96]), subcutaneous hematoma (6.4% [95% CrI 0.5-26.2, τ = 0.54]), and wound hemorrhage (3.7% [95% CrI 0.4-13.3, τ = 0.55]). Non-hemorrhagic AEs were pyrexia (9.2% [95% CrI 4.6-15.3, τ = 1.18]), vomiting (7.8% [95% CrI 4.0-12.3, τ = 0.08]), and abdominal pain (7.4% [95% CrI 1.5-19.4, τ = 0.84]). A total of 39 AE signals were detected in the pharmacovigilance study. The top three highest overall relative odds ratio (ROR) for AEs were observed for haemorrhoidal hemorrhage at 1211.82 (95% CI, 312.69-4696.29), thrombophlebitis at 134.64 (95% CI, 42.18-429.81), and deep vein thrombosis at 68.3 (95% CI, 42.53-109.68). Patients experiencing bleeding AEs had received a mean dosage of rivaroxaban 0.16 mg/kg and apixaban 0.08 mg/kg.

Conclusions: Systematically quantified AEs of FXa inhibitors in clinical trials and real-world studies provide an important guide for clinicians. The use of FXa inhibitors in pediatric patients is associated with an acceptable rate of AEs. The most common bleeding AE was epistaxis. Pediatric patients treated with FXa inhibitors were more prone to hemorrhoidal hemorrhage. A safe approach may involve prior use of other anticoagulants followed by careful administration of FXa inhibitors, with a dosing regimen tailored to age and weight. Close monitoring is recommended for peri-procedural anticoagulation and vomiting.

Background: Anakinra is an interleukin-1 receptor antagonist (IL-1Ra). Since IL-1 has been shown to play a key role in the etiology of different autoinflammatory diseases, blocking its pathway has become an important therapeutic target, even in neonates.

Aims: We aimed to report our experience in using anakinra to treat specific neonatal inflammatory conditions.

Methods: We described the clinical management with anakinra of five cases of neonates or infants up to 3 months of age admitted to the neonatal intensive care unit (NICU) of Bambino Gesù Children's Hospital IRCCS in Rome (Italy) from 2020 onwards. Medical history and clinical data concerning NICU hospitalization were collected from the electronic medical records. Furthermore, we performed a literature review of off-label anakinra in the first 3 months of life, up to 5 April 2024. We excluded from this review cases of cryopyrin-associated periodic syndrome, deficiency of the interleukin-1 receptor antagonist, and mevalonate kinase deficiency, for which anakinra is a known treatment.

Results: We reported three off-label cardiorespiratory reasons to use IL-1Ra from our series: (i) chronic lung disease with pulmonary hypertension, (ii) interstitial lung disease with pulmonary hypertension to facilitate the weaning from respiratory support, and (iii) post-surgical polyserositis if effusions accumulate despite drainage. In all our patients, the drug was administered at a dosage of 10 mg/kg/day. The route of administration was chosen based on the patient's clinical characteristics, with the subcutaneous and intravenous routes being comparable in efficacy. The duration of therapy was modulated based on the patient's clinical response, with a minimum duration of 4 months. A total of 308 retrieved articles were screened, and then full texts of records deemed eligible for inclusion were assessed. Based on the literature search and our five cases, a total of 17 infants were treated with anakinra outside its approved indications. The major off-label use was for hemophagocytic lymphohistiocytosis/macrophage activation syndrome, followed by multisystem inflammatory syndrome in children and Kawasaki disease, as in two of our cases.

Conclusions: According to the results of our case series and review of the literature, the off-label use of anakinra in neonates with inflammatory conditions refractory to first-line therapy could be considered. Prospective, multicenter research is necessary to determine whether anakinra is a safe treatment option for these infants to prevent early inflammatory illnesses and in which situations it could enhance clinical results.

Background and objectives: Females of reproductive age are increasingly using attention deficit hyperactivity disorder (ADHD) medication, but its use during pregnancy and breastfeeding is largely unknown. The aim of this study is to examine the prevalence of ADHD medication fills during pregnancy and breastfeeding, including characteristics of these females and cohort differences over time.

Methods: We conducted a descriptive study using Danish nationwide registers. Within cohorts of pregnant and breastfeeding females, we calculated the prevalence of ADHD medication (methylphenidate, amphetamine, dexamfetamine, lisdexamfetamine, modafinil, atomoxetine, clonidine and guanfacine) fills and described sociodemographic and clinical characteristics across groups with fills, no fills and previous fills. Cohort differences in ADHD medication fills during pregnancy for 2005-2010, 2011-2016 and 2017-2022 were examined.

Results: In this cohort of 1,077,279 pregnancies, ADHD medication fills increased from 0.08 to 7.71 per 1000 individuals between 2005 and 2022. Among 446,485 breastfeeding females, fills increased from 0.55 to 3.67 per 1000 individuals from 2012 to 2022. Compared with the group with no fills, females filling ADHD medication during pregnancy and breastfeeding were younger, had lower levels of education, were more often smoking during pregnancy, utilised more psychiatric healthcare and had concurrent fills of other psychotropic medication. Cohort differences over time revealed that females filling ADHD medication during pregnancy in 2017-2022 were older, had higher levels of education, smoked less during pregnancy, had fewer psychiatric contacts and were less likely to fill other psychotropic medications compared with females in the earlier cohorts.

Conclusions: Results showed an increasing prevalence of ADHD medication fills during pregnancy and breastfeeding in Denmark over time, surpassing the increase observed generally in females of reproductive age filling ADHD medication. Results revealed a difference in characteristics of females filling ADHD medication during pregnancy over time, suggesting a shift in pregnancy treatment patterns.

Oral ganaxolone (ZTALMY^®), a synthetic analogue of the endogenous neuroactive steroid allopregnanolone, acts as a positive allosteric modulator of synaptic and extra-synaptic γ-aminobutyric acid (GABA) type A receptor function in the CNS. In the EU and the UK, it is approved for the adjunctive treatment of epileptic seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) in patients aged 2-17 years. In a multinational phase III study (Marigold), 17 weeks' therapy with adjunctive ganaxolone, administered orally three times daily with food, significantly reduced 28-day major motor seizure frequency from baseline versus placebo in patients aged 2-19 years with CDD-associated refractory epilepsy. Antiepileptic efficacy was generally sustained through 2 years of treatment. Ganaxolone was generally well tolerated in Marigold. While somnolence and sedation are related to the dose of ganaxolone, they appear early in treatment and may decrease with continued therapy. Thus, although current evidence is somewhat limited, adjunctive ganaxolone could be a valuable therapeutic option for patients aged 2-17 years with epileptic seizures associated with CDD.

Necrotizing enterocolitis (NEC) is a relatively rare but very severe gastrointestinal disease primarily affecting very preterm infants. NEC is characterized by excessive inflammation and ischemia in the intestines, and is associated with prolonged, severe visceral pain. Despite its recognition as a highly painful disease, current pain management for NEC is often inadequate, and research on optimal analgesic therapy for these patients is lacking. Insight into the mechanisms underlying intestinal pain in infants with NEC-visceral pain-could help identify the most effective analgesics for these vulnerable patients. Therefore, this comprehensive review aims to provide an overview of visceral nociception, including transduction, transmission, modulation, and experience, and discuss the implications for analgesic therapy in preterm infants with NEC. The transmission of visceral pain differs from that of somatic pain, contributing to the diffuse nature of visceral pain. Studies evaluating the effectiveness of analgesics for treating visceral pain in infants are scarce. However, research in visceral pain models highlights agents that may be particularly effective for treating visceral pain based on their mechanisms of action. Further research is necessary to determine whether agents that have shown promise for treating visceral pain in preclinical studies and adults are effective in infants with NEC as well.

Pediatric-onset multiple sclerosis (POMS) refers to multiple sclerosis with onset before 18 years of age. It is characterized by a more inflammatory course, more frequent clinical relapses, and a greater number of magnetic resonance imaging (MRI) lesions compared with adult-onset MS (AOMS), leading to significant impacts on both disability progression and cognitive outcomes in affected individuals. Managing POMS presents distinct challenges due to the unique needs of pediatric patients and the limited number of disease-modifying therapies (DMTs) approved for pediatric use. Notably, only one therapy (fingolimod) is approved by the United States (US) Food and Drug Administration (FDA) and three (fingolimod, teriflunomide, and dimethyl fumarate) by the European Medicines Agency (EMA) for use in youth with MS. However, observational evidence identifies use of almost all agents off-label in this population. This review provides a comprehensive overview of literature supporting the use of DMTs for POMS, including evidence from observational studies. In this paper, we highlight the shift in clinical practice, which has led to increased use of high-efficacy therapies (HETs) at or near disease onset. We review emerging evidence indicating better cognitive and motor outcomes in this population with early initiation of therapy. Finally, in this paper, we provide a suggested treatment algorithm for managing POMS. We underscore the need for personalized approaches in POMS management. We identify special considerations unique to pediatric care, including attention to family dynamics, and strategies to improve medication adherence and a smooth transition to adult care. Further research on DMTs in POMS is essential to optimize outcomes and improve long-term prognosis.

New drugs for Duchenne muscular dystrophy (DMD) are emerging rapidly. However, we and others believe these drugs are achieving regulatory approval prematurely. It is the cardiorespiratory complications of DMD that cause the disease's major morbidities and that determine survival. Thus, to be truly effective, a new drug must improve cardiorespiratory function; instead, new drugs are approved for patient use via accelerated regulatory pathways that rely on surrogate outcome measures with unproven clinical benefits (such as tissue levels of non-biologic, truncated dystrophin) and on scales that reflect muscle strength (such as small improvements in timed activities). In DMD, cardiorespiratory complications occur in "older" individuals who are in the non-ambulatory stage of the disease. In contrast, accelerated approvals are based on data from young, ambulatory subjects, a group that essentially never experiences cardiorespiratory complications. When drug studies do obtain cardiorespiratory data, their methodologies are suboptimal. We critically review these methodologies in detail, including problems with the use of threshold levels of respiratory function as outcome measures; problems with the use of historical controls, whose results vary widely, and are influenced by uncontrolled variables related to their observational nature; and the limitations of using percent predicted forced vital capacity (FVC %pred), and its single rate of decline across a wide range of age and function, as a preferred respiratory outcome measure. We discuss the advantages of an alternative respiratory outcome, the absolute value of FVC with aging (the "Rideau plot"). Unlike FVC %pred, the Rideau plot considers distinct phenotypes rather than aggregating all individuals into a single respiratory trajectory. Key features of the Rideau plot can show the nature and timing of a drug's effect on respiratory function, making it a potentially better outcome measure for assessing the respiratory effects of a drug. With this article, we use our respiratory perspective to critically examine the DMD drug development process and to propose improvements in study methodologies and in the regulatory processes that approve new drugs.