Analysis of Reporting Adverse Drug Reactions in Paediatric Patients in a University Hospital in the Netherlands

AIMS: The risk to develop adverse drug reactions (ADRs) is high for paediatric patients. This is, amongst other reasons, due to the inevitable use of off-label and unlicensed medicines. Moreover, there is limited knowledge on ADRs in children. Thus, adequate recognition may be challenging. The lack of dedicated studies and the voluntary nature of pharmacovigilance systems used to gain insight into the characteristics of ADRs contribute to this problem. The goal of this study is to identify whether ADRs in paediatric patients are adequately documented by the medical team and whether they are subsequently reported to the national pharmacovigilance system. METHODS: All patients admitted to the paediatric medium care of the Radboudumc Amalia Children's hospital during 1 month, and using one or more drugs, were included. Two researchers analysed retrospectively and independently the number of possible ADRs in the medical records. The ADRs were listed per paediatric subspecialty, to evaluate any differences in documentation and reporting of the ADRs. Subsequently, the causality, severity, and seriousness of the ADRs were assessed. The ADRs were categorised by system organ class and drug class. The national pharmacovigilance centre was consulted to check if there were any reports coming from our hospital and to collect the total number of reports. RESULTS: The medical records of 301 patients were analysed, 81 patients were suffering from one or more ADRs. In total 132 suspected ADRs were found, divided among 19 different paediatric subspecialties. Numbers were too small to investigate the differences in ADR documentation. Of these found ADRs, 55% were not explicitly noted as such in the medical records by the treating physician. None of the ADRs were reported to the national pharmacovigilance centre. Most ADRs scored 'possible' in the causality assessment, were mild or moderate, and a small number were serious. The ADRs occurred in 25 different organ systems. In total 25 different drug classes were involved. CONCLUSIONS: The results of the present study show that a large number of ADRs are not registered in the medical records and are not reported to the national pharmacovigilance system. Furthermore, it is shown that the number of ADRs occurring at our centre is much higher than the number reported to the national pharmacovigilance centre. Only an average of 513 ADRs in paediatric patients are reported per year nationwide, suggesting that there is extensive underreporting

Evaluation of the pharmacokinetics of prednisolone in paediatric patients with acute lymphoblastic leukaemia treated according to Dutch Childhood Oncology Group protocols and its relation to treatment response

Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0–18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research.</p

Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants

Aims Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. Methods A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m(2) every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. Results In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. Conclusion Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments

The role of tunneling in enzyme catalysis of C–H activation

AbstractRecent data from studies of enzyme catalyzed hydrogen transfer reactions implicate a new theoretical context in which to understand C–H activation. This is much closer to the Marcus theory of electron transfer, in that environmental factors influence the probability of effective wave function overlap from donor to acceptor atoms. The larger size of hydrogen and the availability of three isotopes (H, D and T) introduce a dimension to the kinetic analysis that is not available for electron transfer. This concerns the role of gating between donor and acceptor atoms, in particular whether the system in question is able to tune distance between reactants to achieve maximal tunneling efficiency. Analysis of enzyme systems is providing increasing evidence of a role for active site residues in optimizing the inter-nuclear distance for nuclear tunneling. The ease with which this optimization can be perturbed, through site-specific mutagenesis or an alteration in reaction conditions, is also readily apparent from an analysis of the changes in the temperature dependence of hydrogen isotope effects

The effect of high dose inhaled corticosteroids on wheeze in infants after respiratory syncytial virus infection: randomised double blind placebo controlled trial

Objective To determine whether early initiated anti-inflammatory therapy with prolonged high dose inhaled glucocorticoids influences the occurrence and severity of recurrent wheeze after respiratory syncytial virus related lower respiratory tract infections

Minimally invasive and endoscopic versus open necrosectomy for necrotising pancreatitis: a pooled analysis of individual data for 1980 patients

Minimally invasive surgical necrosectomy and endoscopic necrosectomy, compared with open necrosectomy, might improve outcomes in necrotising pancreatitis, especially in critically ill patients. Evidence from large comparative studies is lacking. We combined original and newly collected data from 15 published and unpublished patient cohorts (51 hospitals; 8 countries) on pancreatic necrosectomy for necrotising pancreatitis. Death rates were compared in patients undergoing open necrosectomy versus minimally invasive surgical or endoscopic necrosectomy. To adjust for confounding and to study effect modification by clinical severity, we performed two types of analyses: logistic multivariable regression and propensity score matching with stratification according to predicted risk of death at baseline (low: <5%; intermediate: ≥5% to <15%; high: ≥15% to  <35%; and very high: ≥35%). Among 1980 patients with necrotising pancreatitis, 1167 underwent open necrosectomy and 813 underwent minimally invasive surgical (n=467) or endoscopic (n=346) necrosectomy. There was a lower risk of death for minimally invasive surgical necrosectomy (OR, 0.53; 95% CI 0.34 to 0.84; p=0.006) and endoscopic necrosectomy (OR, 0.20; 95% CI 0.06 to 0.63; p=0.006). After propensity score matching with risk stratification, minimally invasive surgical necrosectomy remained associated with a lower risk of death than open necrosectomy in the very high-risk group (42/111 vs 59/111; risk ratio, 0.70; 95% CI 0.52 to 0.95; p=0.02). Endoscopic necrosectomy was associated with a lower risk of death than open necrosectomy in the high-risk group (3/40 vs 12/40; risk ratio, 0.27; 95% CI 0.08 to 0.88; p=0.03) and in the very high-risk group (12/57 vs 28/57; risk ratio, 0.43; 95% CI 0.24 to 0.77; p=0.005). In high-risk patients with necrotising pancreatitis, minimally invasive surgical and endoscopic necrosectomy are associated with reduced death rates compared with open necrosectom

Population Pharmacokinetics and Pharmacodynamics of Ciprofloxacin Prophylaxis in Pediatric Acute Lymphoblastic Leukemia Patients

Background. Ciprofloxacin is used as antimicrobial prophylaxis in pediatric acute lymphoblastic leukemia (ALL) to decrease infections with gram-negative bacteria. However, there are no clear guideline

Ischemic Preconditioning in the Animal Kidney, a Systematic Review and Meta-Analysis

Ischemic preconditioning (IPC) is a potent renoprotective strategy which has not yet been translated successfully into clinical practice, in spite of promising results in animal studies. We performed a unique systematic review and meta-analysis of animal studies to identify factors modifying IPC efficacy in renal ischemia/reperfusion injury (IRI), in order to enhance the design of future (clinical) studies. An electronic literature search for animal studies on IPC in renal IRI yielded fifty-eight studies which met our inclusion criteria. We extracted data for serum creatinine, blood urea nitrogen and histological renal damage, as well as study quality indicators. Meta-analysis showed that IPC reduces serum creatinine (SMD 1.54 [95%CI 1.16, 1.93]), blood urea nitrogen (SMD 1.42 [95% CI 0.97, 1.87]) and histological renal damage (SMD 1.12 [95% CI 0.89, 1.35]) after IRI as compared to controls. Factors influencing IPC efficacy were the window of protection (<24 h = early vs. ≥24 h = late) and animal species (rat vs. mouse). No difference in efficacy between local and remote IPC was observed. In conclusion, our findings show that IPC effectively reduces renal damage after IRI, with higher efficacy in the late window of protection. However, there is a large gap in study data concerning the optimal window of protection, and IPC efficacy may differ per animal species. Moreover, current clinical trials on RIPC may not be optimally designed, and our findings identify a need for further standardization of animal experiments

On the Early Digging of Peanut Fruits

1. The flowering period of peanut is about 100 days or more, which differentiates very much the respective maturity of each fruit of peanut, so it is difficult that growers catch its exact yielding time. 2. By the factors of climate, especially temperature, the flowering or maturing period is controlled, and the yielding period is from the middle of September to the end of October. 3. The effective flowering period was until the end of August, and the seeded plant at the beginning of July had its effective flowering period of only about one month, and so the July-seeded plant had only half of the product of the optimum seeded plant at the beginning of May. The seeded plant after July had the common pods, but brought no grain. 4. Immature grains decreased rapidly after about 90 days from the first flowering of each plant, or about 40 days from the maximum flowering time. 5. The plants harvested after the middle of October, which passed over the 110 days from the first flowering of each plant, produced many over-mature grains and germinating grains. 6. The early harvesting time is better than the customary time, and when the immature pods are many, the mature fruits should be harvested and the plants with immature pods should be gathered at the corner of the field and planted temporarily. After they were laid on till the frost time, the Secondly harvest should be done. 7. The optimum harvesting time was about after one month from the end of effective flowering period, or after one month and a half from the maximum of fertile percentage