Oral ibuprofen versus oral ketorolac for children with moderate and severe acute traumatic pain: a randomized comparative study.

This study is to compare ibuprofen and ketorolac for children with trauma-related acute pain. We conducted a multicentre randomized, double-blind, controlled trial in the Paediatric Emergency Department setting. We enrolled patients aged 8 to 17 who accessed the emergency department for pain related to a limb trauma that occurred in the previous 48 h. At the admission, patients were classified based on numeric rating scale-11 (NRS-11) in moderate (NRS 4-6) and severe (NRS 7-10) pain groups. Each patient was randomized to receive either ibuprofen (10 mg/kg) or ketorolac (0.5 mg/kg) and the placebo of the not given drug in a double dummies design. NRS-11 was asked every 30 min until 2 h after drug and placebo administration. The primary outcome was NRS-11 reduction at 60 min. Among 125 patients with severe pain, NRS-11 reduction after 60 min from drug administration was 2.0 (IQR 1.0-4.0) for ibuprofen and 1.0 (IQR 1.0-3.0) for ketorolac (p = 0.36). Ibuprofen was significantly better, considering secondary outcomes, at 90 min with a lower median of NRS-11 (p 0.008), more patients with NRS-11 less than 4 (p 0.01) and a reduction of pain score of more than 3 NRS-11 points (p 0.01). Among 87 patients with moderate pain, the NRS-11 reduction after 60 min from drug administration was 1.63 (± 1.8) for ibuprofen and 1.8 (± 1.6) for ketorolac, with no statistically significant difference.Conclusions: Oral ibuprofen and ketorolac are similarly effective in children and adolescents with acute traumatic musculoskeletal pain.Trial registration: ClinicalTrial.gov registration number: NCT04133623.

Impact of compounded drugs on the caregivers' burden of home therapy management in pediatric palliative care: A descriptive study.

BACKGROUND: Children with medical complexity need complex assistance, that considerably affects caregivers' quality of life. They often need multiple medications, with a consequent relevant risk of errors or poor compliance. Galenic (or compounded) drugs are blended in the pharmacy's laboratory worldwide according to different rules and tailoring the patient's needs. While their use may sometimes simplify these therapies, little is known about parents' attitude about this issue. AIM: This study aimed at investigating the complexity of the daily therapy management and exploring the parents' opinions about galenic compounds. DESIGN: Parents were interviewed by using a structured questionnaire. SETTING: Children followed by the Pediatric Palliative Care Network in Friuli Venezia Giulia, Italy, were included from November 2021 to April 2022. Those diagnosed with malignancies were excluded, since therapies are mainly administered through a central venous catheter. RESULTS: Thirty-four parents were interviewed. Fourteen patients took drugs orally, one via nasogastric tube (NGT), 18 via gastrostomy, and one orally + NGT. The mean number of drugs taken every day was six (2-14), in mean 10 (3-18) administrations, that overall required a mean of 44 (8-180) minutes to be delivered. Twenty-eight parents used galenic compounds, and 24 reported relevant advantages, because of a ready-to-use and safe formulation. CONCLUSIONS: The therapy management of children with medical complexity relies on parents. Galenic compounds may improve both patients' and caregivers' quality of life, either in terms of shorter time of administration or smaller risk of errors. Therefore, their use should be encouraged worldwide, according to the different reference rules.

Available information about paediatric use of onco-haematological drugs authorized by EMA since 2016.

BACKGROUND: The treatment options available to children with cancer are limited. This is why for more than 10 years, the European Medicine Agency (EMA) has stated that all drugs to be marketed must be tested on the paediatric population in accordance with the Paediatric Investigation Plan (PIP). The objective of this study is to make a cross sectional analysis of the information related to the use of cancer drugs authorised on the European market in the paediatric population. METHOD: The European Public Assessment Reports and PIPs have been considered. The following data were extracted for onco-haematological drugs approved since 2016: paediatric indications, information about the paediatric population in the Summary of Product Characteristics (SmPC) and presence and characteristics of PIPs. A descriptive analysis of the characteristics of the drugs was made from the point of view of the paediatric population. RESULTS: Forty-eight drugs with onco-haematological indications have been authorised for marketing since 2016, 7 (15%) of these have paediatric indications. Two (4%) drugs have no paediatric indication but have information related to the paediatric population within SmPC. Forty-one (85%) drugs have no reference to the paediatric population in SmPC. Seventeen (35%) drugs out of 48 do not have PIPs and 11 have been granted a waiver to present the results of paediatric studies. The other 19 active ingredients have a total of 28 PIPs. CONCLUSION AND RELEVANCE: Most of the onco-haematological drugs approved by EMA since 2016 have neither paediatric indications nor mentions about paediatric use in SmPC. PIPs represent an opportunity, but demand for the paediatric population is still huge.

Pediatric males receiving hematopoietic stem cell transplant lose their male disadvantage in disease risk after the procedure: A retrospective observational study.

Sex differences play a relevant role in cancer susceptibility, incidence and survival. Exploring such differences is difficult because of the close interplay of genetic, epigenetic and hormonal factors. However, a better understanding of the role of such disparities in cancer mechanisms could improve its prevention and therapy. Our study explores how sex differences in pediatric outcomes vary after undergoing first and advanced-line therapy for hematological malignancies. The primary goal was to evaluate if sex differences in pediatric outcomes after first-line therapy persist after allogeneic hematopoietic stem cell transplantation (HSCT). The secondary goal was to analyze sex differences in disease risk at onset and pediatric outcomes after first-line therapy to compare our results with the literature's reported results. Among a total of 485 patients (280 males, 205 females) admitted for hematological malignancies, disease risk at the onset was significantly higher in males (P < .05). One hundred and seventy-four patients (111 males and 63 females) had a high-risk disease requiring HSCT. Before HSCT, all patients underwent myeloablative conditioning, which substantially impaired gonadal function. Although the number of boys undergoing HSCT was almost double that of girls, there were no sex-related differences in overall survival, cancer relapse and complications after HSCT exposure (P > .05). These findings suggest that the existing sex differences in cancer risk ab initio can be somehow flattened by a conditioning regimen, shedding new light on the role of hormonal factors in cancer mechanism and management.

Pediatric blinatumomab preparation: Risk assessment on SmPC for software compliance.

INTRODUCTION: Blinatumomab is an anticancer drug used in the treatment of Acute Lymphoblastic Leukaemia (ALL) in both adults and children. ALL is the most common form of cancer in children and patients who are refractory to standard treatments have poor prognosis. The preparation of blinatumomab is unique and extremely complex. It's important to carry out any information to identify all the critical issues related to the preparation of blinatumomab: sharing procedure between prescribers, staff of the Centralized Chemotherapy Preparation Unit [Unità Farmaci Antiblastici (UFA)] and administering nurses aimed at reducing the clinical risk related to the management of the drug blinatumomab and to obtain correct prescriptions on the real dose to be prepared, safe worksheets with computer processing of all variables (volumes to be added and corresponding dose of drug) and complete labels containing all the information necessary for the control of the preparation and its correct infusion. METHODS: A computerized process involves the use of specific software to which precise instructions must be given. This study is divided into two phases, the first one focused on the analysis of Summary of Product Characteristics (SmPC) and the extrapolation of any unclear part of SmPC. The second phase involved the manufacturer to answer a questionnaire. RESULTS: This comparison with the company allowed to perfect the blinatumomab preparation process leading to: 1. allow the patient to be discharged and return a few times for infusions and consequently reduce the number of medical prescriptions; 2. set up the drug for each patient every 4 days; 3. reduce costs related to devices, staff employed. CONCLUSION: Computerizing the preparation of anti-blastic drugs is a necessary path for the safety of the patient and all the operators involved, however it may be necessary to make changes in the preparation process to allow the software to work correctly. The comparison between pharmacist, clinician and, where necessary, the manufacturer of the drug, was effective in the preparation of this drug.

Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: Preliminary data and computational analysis.

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 µg/mL (0.37-0.75 µM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans.

Administering analgesia sublingually is a suitable option for children with acute abdominal pain in the emergency department.

AIM: Acute abdominal pain is a frequent complaint in children attending emergency departments. The aim of this study was to investigate the pain score reductions when children with acute abdominal pain received medication sublingually. METHODS: We carried out a multicentre randomised controlled trial in three children's hospitals in Italy between March 2015 and June 2017. Children from four to 18 years of age with acute abdominal pain were recruited if their self-reported pain was at least six on a scale from 0-10. The children were randomised to receive ketorolac 0.5 mg/kg (n = 70) or tramadol 2 mg/kg (n = 70) sublingually or a melt in the mouth powder of 20 mg/kg paracetamol (n = 70). The main study outcome was the pain scores for the three drugs after two hours. RESULTS: The 210 children (58.6% girls) had a median age of 12 years with an interquartile range of 9-14.3. The median pain scores at two hours were not significantly different between ketorolac 2.0 (interquartile ranges, IQR 0.0-4.3) and tramadol 3.0 (IQR 1.0-5.0) vs paracetamol 3.0 (IQR 0.8-5.0). The median pain reductions were all 5.0 points. CONCLUSION: Delivering analgesia sublingually was a suitable option for pain relief in children with acute abdominal pain in the emergency department.

Multicenter randomized, double-blind controlled trial to evaluate the efficacy of laser therapy for the treatment of severe oral mucositis induced by chemotherapy in children: laMPO RCT.

OBJECTIVES: To demonstrate the efficacy of laser photobiomodulation (PBM) compared to that of placebo on severe oral mucositis (OM) in pediatric oncology patients. The primary objective was the reduction of OM grade (World Health Organization [WHO] scale) 7 days after starting PBM. Secondary objectives were reduction of pain, analgesic consumption, and incidence of side effects. METHODS: One hundred and one children with WHO grade > 2 chemotherapy-induced OM were enrolled in eight Italian hospitals. Patients were randomized to either PBM or sham treatment for four consecutive days (days +1 to +4). On days +4, +7, and +11, OM grade, pain (following a 0-10 numeric pain rating scale, NRS) and need for analgesics were evaluated by an operator blinded to treatment. RESULTS: Fifty-one patients were allocated to the PBM group, and 50 were allocated to the sham group. In total, 93.7% of PBM patients and 72% of sham patients had OM grade < 3 WHO on day +7 (P = 0.01). A significant reduction of pain was registered on day +7 in the PBM versus sham group (NRS 1 [0-3] vs. 2.5 [1-5], P < 0.006). Reduced use of analgesics was reported in the PBM group, although it was not statistically significant. No significant adverse events attributable to treatment were recorded. CONCLUSIONS: PBM is a safe, feasible, and effective treatment for children affected by chemotherapy-induced OM, as it accelerates mucosal recovery and reduces pain.

First-time success with needle procedures was higher with a warm lidocaine and tetracaine patch than an eutectic mixture of lidocaine and prilocaine cream.

AIM: More than 50% of children report apian during venepuncture or intravenous cannulation and using local anaesthetics before needle procedures can lead to different success rates. This study examined how many needle procedures were successful at the first attempt when children received either a warm lidocaine and tetracaine patch or an eutectic mixture of lidocaine and prilocaine (EMLA) cream. METHODS: We conducted this multicentre randomised controlled trial at three tertiary-level children's hospitals in Italy in 2015. Children aged three to 10 years were enrolled in an emergency department, paediatric day hospital and paediatric ward and randomly allocated to receive a warm lidocaine and tetracaine patch or EMLA cream. The primary outcome was the success rate at the first attempt. RESULTS: The analysis included 172 children who received a warm lidocaine and tetracaine patch and 167 who received an EMLA cream. The needle procedure was successful at the first attempt in 158 children (92.4%) who received the warm patch and in 142 children (85.0%) who received the cream (p = 0.03). The pain scores were similar in both groups. CONCLUSION: This study showed that the first-time needle procedure success was 7.4% higher in children receiving a warm lidocaine and tetracaine patch than EMLA cream.

Hepatic Gadolinium Deposition and Reversibility after Contrast Agent-enhanced MR Imaging of Pediatric Hematopoietic Stem Cell Transplant Recipients.

Purpose To determine if hepatic gadolinium deposition occurs in pediatric patients with iron overload but normal renal and hepatic function who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. Materials and Methods Design and execution of this study was approved by the Ethical Committee of Institute for Research in Maternal and Child Health Burlo Garofolo of Trieste (reference no. 1105/2015). Because of the retrospective nature of the study, the requirement to obtain informed consent was waived. Twenty-one recipients of allogeneic hematopoietic stem cell transplants who underwent GBCA-enhanced MR imaging for suspected infection or relapse followed by liver biopsy comprised the study group. The number of GBCA-enhanced MR examinations and cumulative gadolinium dose for each patient was analyzed by comparing liver histologic analysis and iron and gadolinium liver concentration (GLC). Eight patients had siderosis and underwent chelation therapy. The study group was compared with four control patients who were never exposed to GBCA. Statistical analysis was performed with Spearman rank coefficient for correlation. Results All 21 patients had positive correlations between GLC and total GBCA dose (r = 0.4486; P < .05) and between GLC and liver iron concentration (r = 0.56; P < .05). Patients who underwent deferoxamine therapy had a significant reduction of GLC (from 0.64 µg/g ± 0.29 to 0.20 µg/g ± 0.17 [standard deviation]; P < .05). Conclusion In the presence of siderosis, a transmetallation mechanism may be set off between ferric ion and gadoterate meglumine. Deferoxamine appears capable of binding to gadolinium ion. Further studies of the safety of GBCAs in severe siderosis are needed. Chelation should be considered in patients with iron overload and a history of GBCA exposure. © RSNA, 2016.

Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature.

BACKGROUND: Sickle cell disease (SCD) is a well-known multisystem illness characterized by vascular injury due to vasoocclusion and hemolysis, as well as infectious complications and iron overload, all of which contribute to high morbidity and mortality rates among children. In these patients, some authors have previously described iron cortical deposition in the kidney. We here report the first case in the literature of a girl affected by SCD showing an anomalous metal and rare element retention in the renal cortex. CASE PRESENTATION: A 10-year-old white girl affected by SCD underwent a routine magnetic resonance imaging investigation that evidenced a reduced signal intensity in the renal cortex, compatible with hemosiderin precipitation. Histologic and elemental analyses of the hepatic and the renal biotic samples, performed with inductively coupled plasma mass spectrometry, revealed that concomitant with the high iron deposition, toxic and potentially carcinogenic elements such as nickel, magnesium, rubidium, and gadolinuim were anomalously retained particularly in the kidney. CONCLUSIONS: The finding of rare and toxic elements in the kidney of SCD patients might be linked to the development of specific neoplastic transformations already described in this patient cohort. To be confirmed, our speculations need to be demonstrated in large sampling of patients.

Effect of early post-hematopoietic stem cell transplant tacrolimus concentration on transplant outcomes in pediatric recipients: One facility's ten-year experience of immunosuppression with tacrolimus.

Acute graft-versus-host disease (GVHD) is a common life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), ranking as the second leading cause of death among recipients, surpassed only by disease relapse. Tacrolimus is commonly used for GVHD prophylaxis, but achieving therapeutic blood levels is challenging, particularly in pediatrics, due to the narrow therapeutic window and the high interindividual variability. The retrospective study conducted at IRCCS "Burlo Garofolo" in Italy aimed to assess the impact of early post-HSCT tacrolimus levels on transplant-related outcomes in pediatric recipients. The population pharmacokinetic model (POP/PK) was set up to describe tacrolimus pharmacokinetics. Elevated tacrolimus (>12-15 ng/ml) levels within the initial weeks post-HSCT are associated with reduced post-transplant infections (p < 0.0001) and decreased incidence of early transplant-related events (p < 0.01), including a lower incidence of acute GVHD (p < 0.05 on day 0). High tacrolimus exposure can lead to an increased risk of chronic GVHD (p < 0.0001) and reduced overall survival (p < 0.01). Personalized dosing and therapeutic monitoring of tacrolimus are crucial to ensure optimal outcomes. POP/PK could help achieve this goal, giving us a model by which we can balance immunosuppression while looking at the patient's general well-being and providing the necessary treatment.

First description of Merkel Cell polyomavirus DNA detection in a patient with Stevens-Johnson syndrome.

Merkel Cell polyomavirus (MCPyV), a ubiquitous DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukaemia while other associations are still being explored. MCPyV sequences have also been detected in normal tissues of tumor patients and in the blood of healthy donors. This report documents a new MCPyV association with the Stevens-Johnson syndrome, a rare immune-modulated mucocutaneous process particularly associated with specific drugs and infective agents. A high MCPyV viral load was detected simultaneously in fluid from skin lesions (2.0 × 10(4) copies/ml) and in matched blood (7.4 × 10(5) copies/ml) from a young adult patient after bone marrow transplant for a relapsed T-cell acute lymphatic leukaemia. MCPyV clearance concurred with the complete resolution of skin lesions after 5 days of cidofovir treatment. DNA sequencing classified the amplicons as the European/Italian MKL-1 strain. Given its ubiquitous nature, MCPyV could account for part of Stevens-Johnson syndrome idiopathic cases.

Neutrophils engraftment delay during tigecycline treatment in 2 bone marrow-transplanted patients.

BACKGROUND: Tigecycline is the first available drug of glycylcycline family. Because of recent introduction, some of its adverse effects could be still unexplored. OBSERVATION: We report the cases of 2 boys who underwent an allogenic bone marrow transplantation for acute myeloid leukemia and were treated with tigecycline. Erythrocyte and platelet engraftment followed a normal course, but the neutrophil count remained low despite the increase in leukocyte count. After tigecycline interruption, the neutrophil count rapidly raised in both cases. CONCLUSIONS: Neutropenia was suspected to be secondary to tigecycline exposure. In vitro experiments were performed, which suggested tigecycline influence on myeloid cells survival.

Off-label prescribing patterns of antiemetics in children: a multicenter study in Italy.

UNLABELLED: Acute gastroenteritis (AG) represents both the main cause of acute vomiting in children under 3 years old and a major cause of access to the emergency department. Even if several drugs may be able to reduce the emesis, the pharmacological treatment of vomiting in children remains a controversial issue, and several drugs are prescribed outside their authorized drug label with respect dosage, age, indication, or route of administration and are named as off-label. The aim of present study was to assess the off-label use of antiemetic drugs in patients less than 18 years with vomiting related to AG. This study was carried out in eight pediatric emergency departments in Italy. The following data were obtained crossing the pharmacy distribution records with emergency departments' patient data: sex and age of the patients and detailed information for each drug used (indication, dose, frequency, and route of administration). We recorded that antiemetic drugs were prescribed in every year, particularly in children up to 2 years old, and compared with both literature data and data sheet; 30 % of the administered antiemetics were used off-label. In particular, domperidone was the only antiemetic used labeled for AG treatment in pediatric patients, while metoclopramide and ondansetron have been off-label for both age and indications (i.e., AG treatment). CONCLUSIONS: In conclusion, we documented an off-label use of antiemetics in children, and this could represents a problem of safety for the patient and a legal risk for the prescribing physician if patients have an unwanted or bad outcome from treatment.

Early rehabilitation for unilateral peripheral vestibular disorders: a prospective, randomized investigation using computerized posturography.

Patients with unilateral vestibular lesions have a set of deficits requiring compensation based on the inherent plasticity of the central nervous system. In the 1940s, it was reported that patients with unilateral vestibular dysfunctions who exercised recovered faster than those who did not. The present prospective, randomized investigation aimed to assess the role of a computerized posturography-assisted early vestibular rehabilitation protocol combined with a home-based exercise program in the treatment of patients with unilateral peripheral vestibular disorders occurring 2 weeks previously. Fifteen patients were randomly assigned to a 5-week posturography-assisted vestibular rehabilitation protocol and a home-based exercise program (Group A), while 15 simply awaited spontaneous compensation (Group B). All patients underwent computerized posturography approximately 2 weeks after their vestibular disorder was diagnosed and again after 6 weeks. Ten healthy volunteers were also studied (Group C). After rehabilitation, Group A patients improved significantly in most sensory measures [modified clinical test of sensory organization and balance (mCTSIB)] and motor parameters [limits of stability (LOS)] by comparison with preliminary outcomes, and there were no significant differences in sensory (mCTSIB) and motor (LOS) findings between Group A and the healthy volunteers. At the same time point, several motor (LOS) parameters were still altered in Group B by comparison with the healthy volunteers. These preliminary outcomes support the hypothesis that the compensation achievable after 6 weeks with a customized program of posturography-assisted vestibular rehabilitation and home-based exercises is superior to the results of physiological spontaneous compensation.