Pediatric Drugs最新文献

Childhood epilepsies comprise a group of heterogeneous conditions associated with diverse aetiologies, seizure severities/types, comorbidities, degrees of impairment and prognoses. Seizures are refractory to antiseizure medications (ASMs) in around one-third of cases. Alternatives to medication, for example surgical resection, are not always feasible, implying that new treatments are needed. In the past decade, new ASMs have been approved for specific childhood-onset epilepsy syndromes, notably cannabidiol for Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS) and tuberous sclerosis complex (TSC); fenfluramine for LGS and DS; everolimus for TSC; and ganaxolone for cyclin-dependent kinase-like deficiency disorder. However, seizure freedom with these medications has rarely been achieved in randomised controlled trials. Alongside ASM development, and surgical strategies such as laser interstitial therapy, neurostimulation modalities have evolved towards responsive systems, such as autostimulation vagus nerve stimulation (VNS) and responsive neurostimulation, and non-invasive devices such as transcutaneous VNS and transcranial direct current stimulation; these have achieved similar decreases in seizure frequency to traditional neurostimulation in some studies. However, data for paediatric epilepsy are limited. Focused ultrasound is being developed not only for seizure focus ablation but also for other approaches to seizure control. In parallel with these developments, accumulating research in the areas of genetic testing, including genetic and related therapies designed to correct or compensate for underlying genetic causes of seizures, suggests that these technologies may have the potential to transform epilepsy treatment in the future. This review summarises major recent developments and current research in the treatment of epilepsy in children.

Background and objectives: Ustekinumab (USTE) and vedolizumab (VEDO) are increasingly used in paediatric patients with inflammatory bowel diseases (pIBD). However, data on the usefulness of therapeutic drug monitoring (TDM) in children are scarce. The primary objective of this study was to evaluate the association between disease activity, measured by faecal calprotectin (F-CPT), and serum trough levels (TLs) of USTE and VEDO. Secondary outcomes were to explore factors potentially associated with the outcome and exposure, to determine the optimal USTE or VEDO dose that predicts remission (defined as F-CPT < 250 µg/g), to validate our hypothesis using a proof-of-concept cohort (POCC) and to assess the occurrence of serum antibodies to USTE and VEDO.

Methods: This was a prospective single-centre observational study performed at the University Hospital Motol, Prague, Czech Republic. Of the 87 patients (51 Crohn's disease (CD), 30 ulcerative colitis (UC), and 6 IBD unclassified (IBD-U)), drug serum TLs and antibodies were measured in 282 observations (49 treatment courses) of USTE and 359 observations (38 courses) of VEDO. Serum and stool samples were collected before each study drug application during both the induction and maintenance phases of the treatment throughout the entire study period (January 2020 to June 2024). Clinical and laboratory data were obtained from the nationwide prospective registry CREdIT. Patients with perianal disease and those with previous major bowel surgery were not excluded from the study. As a POCC, we analysed a group of pIBD treated at our centre with anti-TNF agents-adalimumab or infliximab.

Results: In a linear multiple regression mixed model, an association was observed between logF-CPT levels and USTE treatment duration (β -0.0010, 95% confidence interval (CI) -0.0015 to -0.0006, p < 0.001) but not with USTE TLs (p = 0.12). VEDO TLs and logF-CPT levels were negatively associated both in the linear (β -0.0173, 95% CI -0.0292 to -0.0053, p = 0.005) and categorical models (p = 0.026), even after adjusting for time. A VEDO TL of 15.1 µg/mL showed the best, though still poor, combination of sensitivity (0.82) and specificity (0.32) to predict F-CPT < 250 µg/g (area under the curve (AUC) 0.56, 95% CI 0.49-0.63). Intensification, induction phase, undetectable TLs, and type of IBD (CD, UC, IBD-U) were not associated with logF-CPT. Slightly elevated anti-drug antibodies were detected in 5 USTE and 16 VEDO observations, with no clinical implications.

Conclusions: TDM of USTE does not appear to be useful in pIBD. TDM of VEDO may assist in therapeutic strategy decisions, although establishing clinically useful cut-offs remains challenging.

Introduction: Congenital capillary-lymphatic-venous malformations (CLVMs) often result in life-threatening complications, which may begin in utero. Sirolimus, a mammalian target of rapamycin (mTOR) inhibitor, has been successfully used in children and adults with CLVMs due to its antiproliferative and antiangiogenic properties. However, only two cases of prenatal sirolimus treatment of fetal CLVMs have been published to date, with very limited data on optimal therapeutic scheme and drug dosing.

Case reports: Here we report two cases of effective prenatal and postnatal sirolimus treatment of extensive, complicated fetal CLVMs. The CLVMs were diagnosed prenatally by ultrasound and confirmed by magnetic resonance. The pregnancies were complicated with intralesional bleeding in both cases and polyhydramnios in one. The pregnant women received oral sirolimus from the 32nd and 33rd weeks of gestation to delivery (for 11 and 31 days, respectively). The dose of oral sirolimus for the pregnant women ranged from 2 to 6 mg/day, with a target trough whole-blood level of 7-12 ng/mL, which resulted in the umbilical cord arterial blood levels of 3.8 and 6.4 ng/mL, respectively. Therapeutic effects of prenatal sirolimus were observed in both fetuses: one experienced reduced intralesional bleeding, while the other had a significant decrease in CLVM size. The sirolimus treatment has been continued postnatally in both children, currently aged 20 and 9 months. The mothers and children experienced no adverse events from the treatment.

Conclusions: Administration of sirolimus during pregnancy with maternal blood drug-level monitoring seems to be an efficient and safe treatment option that should be considered in high-risk fetal CLVMs.

Background: Pulmonary hypertension (PH) is a common chronic complication of sickle cell disease (SCD), and patients at risk for PH can be identified by measuring tricuspid regurgitant jet velocity (TRJV). We looked for the possible efficacy of L-arginine for children with SCD who have elevated TRJV.

Methods: In total, 50 children with SCD who had TRJV higher than 2.5 m/s were randomly divided into two groups, each with 25 patients: group 1 (control group) and group 2 (treatment group). Group 2 received L-arginine at a dose of 0.1-0.2 g/kg/day for 3 months. Transthoracic echocardiography was conducted to measure TRJV at baseline and after 3 months, and blood samples were collected at baseline and after 3 months to assess serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP), lactate dehydrogenase (LDH), nitric oxide (NO), L-arginine (LA), asymmetric dimethylarginine (ADMA), and LA/ADMA ratio.

Results: After 3 months of treatment, the L-arginine-treated group had significantly lower TRJV levels than the control group, and compared with baseline. They also had significantly lower NT-proBNP and significantly higher NO, LA and LA/ADMA ratios than the control group and compared with baseline. No significant differences in side effects were observed between the two groups, indicating that L-arginine is safe for these patients.

Conclusions: L-arginine is associated with a reduction in TRJV, NT-proBNP, and improvements in NO biomarkers, suggesting it may be beneficial for reducing the risk of pulmonary hypertension in children with sickle cell disease.

Clinical trial registration: ClinicalTrials.gov identifier NCT05470998.

Although advances in the care of extremely preterm born infants have yielded improvements in survival and reductions in important morbidities, rates of bronchopulmonary dysplasia (BPD) have remained relatively unchanged. As BPD can have a long-lasting impact on the quality of life for survivors of prematurity and their families, this remains a continuing challenge. Treatments that have consistently shown efficacy in preventing either BPD or the composite outcome of BPD and death prior to 36 weeks post menstrual age (PMA) in large-scale randomized clinical trials (RCTs) include caffeine [adjusted odds ratio aOR for BPD, 0.63; 95% confidence interval (95% CI) 0.52-0.76; p < 0.001)], vitamin A [relative risk (RR) for death or BPD 0.89; 95% CI 0.80-0.99], low-dose hydrocortisone in the first week of life [OR for survival without BPD, 1.45; 95% CI 1.11-1.90; p = 0.007], and post-natal dexamethasone [RR for BPD or mortality; 0.76; 95% CI 0.66-0.87]. Although early caffeine therapy is now a widely used strategy to prevent BPD, the potentially severe side effects of post-natal glucocorticoids and the concerns regarding the cost-benefit of vitamin A have led to inconsistent use of these drugs in clinical practice. Inhaled bronchodilators and diuretics provide differing degrees of symptomatic relief for patients according to their phenotypic pattern of lung injury; however, these medications do not prevent BPD. Currently available pharmaceuticals do not sufficiently address the degree of structural immaturity and immune dysregulation that is present in the growing population of survivors born prior to 25 weeks gestational age. In this article, we provide both an evidence-based summary of pharmacological treatments currently available to prevent and manage BPD and a discussion of emerging therapies that could help preserve normal lung development in infants born preterm.

Background: Carbamazepine and valproic acid (VPA) are long-standing treatments for epilepsy in children. Interestingly, they display unique drug disposition characteristics, and maturation of drug metabolizing enzymes further complicates personalized dosing. Physiologically based pharmacokinetic (PBPK) modeling includes these mechanisms so is a promising tool to optimize dosing. Our aim was to better support pediatric drug dosing of carbamazepine and VPA.

Methods: All carbamazepine and VPA dosing simulations were conducted with Simcyp, using available carbamazepine and VPA compound models linked with adult and pediatric population models. To verify model adequacy, adult and pediatric pharmacokinetic data were retrieved from the literature to compare predicted carbamazepine and VPA concentrations with observed data. Current Dutch national dosing strategies were then simulated to evaluate their appropriateness to achieve therapeutic levels. Where doses could be optimized, alternative dosing strategies were proposed based on simulations. In addition, the effect of altered albumin levels in children on VPA was explored through simulations under conditions of +20%, average, - 20%, and - 35% age normalized reference albumin levels.

Results: Therapeutic levels of carbamazepine and VPA will be reached after 1 or 2 weeks of treatment with the current dosing strategies. Simulations suggest a carbamazepine starting dose of 10 mg/kg/day for neonates rather than 7 mg/kg/day. In addition, children aged 12-18 years may receive a higher starting dose (e.g., 400 mg/day instead of 200 mg/day) to reach therapeutic levels more quickly. For VPA, mean total VPA concentrations dropped below the therapeutic target with reduced albumin levels (i.e., - 20% and - 35%), whereas unbound levels remained within the therapeutic window.

Conclusion: Our PBPK simulations support the current pediatric drug dosing recommendations of carbamazepine and VPA. In patients with hypoalbuminemia and when higher VPA doses are needed (i.e., ≥ 30 mg/kg/day), routine determination of unbound VPA concentrations is advised to monitor free VPA concentrations. We demonstrate that PBPK modeling is a valuable tool to confirm and further optimize dosing recommendations in children. PBPK modeling provides valuable comprehensive evidence for guiding clinical practice and potentially informing pediatric drug labeling.

Background and objective: Wound catheter infusion (WCI) with local anesthetics provides effective postoperative analgesia in adults, without adverse effects on wound healing. Studies on WCI in infants are scarce. The aim of this study was to investigate the efficacy and safety of WCI with ropivacaine as treatment for postoperative pain in infants.

Methods: We conducted a prospective, randomized, double-blind, placebo-controlled trial including children aged < 1 year undergoing open abdominal surgery. Informed consent was obtained. All children received a wound catheter at the end of surgery and were randomized for treatment with either ropivacaine (bolus dose of 2 mg/kg and continuous infusion of 0.2 mg/kg/h) (R-group) or placebo (C-group), for 72 h postoperatively. The C-group received morphine 100 mcg/kg intravenously at the end of surgery, the R-group received placebo. Standard analgesia postoperatively was paracetamol intravenously and rescue morphine intravenously. Primary outcome was the cumulative amount of morphine (mcg/kg) administered in the first 48 hours postoperatively. Secondary outcomes were the number of patients needing morphine, area under the curve over 24 hours of COMFORT-B and Numeric Rating Scale pain scores, incidence of adverse events, and plasma concentrations of ropivacaine.

Results: After inclusion of 30 patients, the study was discontinued because of slow recruitment. In two cases, the wound catheter was accidentally displaced directly after surgery, therefore data of 28 children were analyzed (14 R-group, 14 C-group). Median [interquartile range] cumulative amount of morphine (mcg/kg) administered within 48 hours postoperatively was 0.0 [0.0-642.2] in the R-group, compared with 240.1 [15.1-759.0] in the C-group (P = 0.068). In the R-group, 6/14 children required morphine compared with 13/14 in the C-group (P = 0.013). Pain scores were not significantly different between groups. Plasma concentrations of ropivacaine stayed below toxic thresholds.

Conclusions: Cumulative morphine use postoperatively was not significantly different between infants receiving WCI with ropivacaine or placebo, although a lower number in the R-group required morphine. Wound catheter infusion provided adequate analgesia, with no signs of local anesthetic toxicity. The study may have been underpowered because of early discontinuation.

Clinical trial registration: The study was registered in EudraCT (2015-002209-12), and the Dutch Trial Registry NTR6130 on 23 November, 2016 (International Clinical Trials Registry Platform NL-OMON20504).