Potentially harmful excipients in neonatal medicines: A pan-European observational study

Objectives We aimed to describe administration of eight potentially harmful excipients of interest (EOI)-parabens, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol and benzalkonium chloride-to hospitalised neonates in Europe and to identify risk factors for exposure. Methods All medicines administered to neonates during 1 day with individual prescription and demographic data were registered in a web-based point prevalence study. Excipients were identified from the Summaries of Product Characteristics. Determinants of EOI administration (geographical region, gestational age (GA), active pharmaceutical ingredient, unit level and hospital teaching status) were identified using multivariable logistical regression analysis. Results Overall 89 neonatal units from 21 countries participated. Altogether 2095 prescriptions for 530 products administered to 726 neonates were recorded. EOI were found in 638 (31%) prescriptions and were administered to 456 (63%) neonates through a relatively small number of products (n=142; 27%). Parabens, found in 71 (13%) products administered to 313 (43%) neonates, were used most frequently. EOI administration varied by geographical region, GA and route of administration. Geographical region remained a significant determinant of the use of parabens, polysorbate 80, propylene glycol and saccharin sodium after adjustment for the potential covariates including anatomical therapeutic chemical class of the active ingredient. Conclusions European neonates receive a number of potentially harmful pharmaceutical excipients. Regional differences in EOI administration suggest that EOI-free products are available and provide the potential for substitution to avoid side effects of some excipients.

Abnormal alterations in the Ca2+/CaV1.2/calmodulin/caMKII signaling pathway in a tremor rat model and in cultured hippocampal neurons exposed to Mg2+-free solution

Voltage-dependent calcium channels (VDCCs) are key elements in epileptogenesis. There are several binding-sites linked to calmodulin (CaM) and several potential CaM-dependent protein kinase II (CaMKII)-mediated phosphorylation sites in CaV1.2. The tremor rat model (TRM) exhibits absence‑like seizures from 8 weeks of age. The present study was performed to detect changes in the Ca2+/CaV1.2/CaM/CaMKII pathway in TRMs and in cultured hippocampal neurons exposed to Mg2+‑free solution. The expression levels of CaV1.2, CaM and phosphorylated CaMKII (p‑CaMKII; Thr‑286) in these two models were examined using immunofluorescence and western blotting. Compared with Wistar rats, the expression levels of CaV1.2 and CaM were increased, and the expression of p‑CaMKII was decreased in the TRM hippocampus. However, the expression of the targeted proteins was reversed in the TRM temporal cortex. A significant increase in the expression of CaM and decrease in the expression of CaV1.2 were observed in the TRM cerebellum. In the cultured neuron model, p‑CaMKII and CaV1.2 were markedly decreased. In addition, neurons exhibiting co‑localized expression of CaV1.2 and CaM immunoreactivities were detected. Furthermore, intracellular calcium concentrations were increased in these two models. For the first time, o the best of our knowledge, the data of the present study suggested that abnormal alterations in the Ca2+/CaV1.2/CaM/CaMKII pathway may be involved in epileptogenesis and in the phenotypes of TRMs and cultured hippocampal neurons exposed to Mg2+‑free solution.

Identification of diagnostic biomarkers for infection in premature neonates

Infection is a leading cause of neonatal morbidity and mortality worldwide. Premature neonates are particularly susceptible to infection because of physiologic immaturity, comorbidity, and extraneous medical interventions. Additionally premature infants are at higher risk of progression to sepsis or severe sepsis, adverse outcomes, and antimicrobial toxicity. Currently initial diagnosis is based upon clinical suspicion accompanied by nonspecific clinical signs and is confirmed upon positive microbiologic culture results several days after institution of empiric therapy. There exists a significant need for rapid, objective, in vitro tests for diagnosis of infection in neonates who are experiencing clinical instability. We used immunoassays multiplexed on microarrays to identify differentially expressed serum proteins in clinically infected and non-infected neonates. Immunoassay arrays were effective for measurement of more than 100 cytokines in small volumes of serum available from neonates. Our analyses revealed significant alterations in levels of eight serum proteins in infected neonates that are associated with inflammation, coagulation, and fibrinolysis. Specifically P- and E-selectins, interleukin 2 soluble receptor alpha, interleukin 18, neutrophil elastase, urokinase plasminogen activator and its cognate receptor, and C-reactive protein were observed at statistically significant increased levels. Multivariate classifiers based on combinations of serum analytes exhibited better diagnostic specificity and sensitivity than single analytes. Multiplexed immunoassays of serum cytokines may have clinical utility as an adjunct for rapid diagnosis of infection and differentiation of etiologic agent in neonates with clinical decompensation.