Administration of Samital® in children with oral mucositis: a feasibility study.

OBJECTIVE: SAMITAL®, a botanical drug containing three highly standardized extracts (Vaccinium myrtillus, Macleaya cordata and Echinacea angustifolia), has shown promising results in treating or preventing oral mucositis (OM) in adult patients, but it has not been fully investigated in children. In this study, we assessed the feasibility of SAMITAL administration in pediatric patients receiving anticancer treatment to prevent or treat OM, focusing on identifying an appropriate dose and evaluating safety and tolerability and palatability and treatment compliance. PATIENTS AND METHODS: We conducted an open-label, monocentric, prospective study on 18 children receiving anticancer therapy to prevent or treat OM. RESULTS: No SAMITAL®-related side effects were observed or reported during the study; moreover, no systemic absorption of SAMITAL® metabolites was detected in the bloodstream. However, compliance to SAMITAL® was unsatisfactory and variable (from 2 to 100%), and patients reported low palatability (median taste of 4.8; range 1.0-8.0). CONCLUSIONS: SAMITAL® administration appears to be safe in the pediatric population, as it is not absorbed in the bloodstream and does not cause any local or systemic side effects. However, the current formulation is only partially suitable for children, and future studies on SAMITAL® in children would need an adapted formulation to increase compliance.

Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes.

ß-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 µg ml-1 and 360 µg ml-1 h-1, respectively; nonresponse AUC limit of 250 µg ml-1 h-1). Ninety-nine ß-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.

Melatonin reduces excitotoxic blood-brain barrier breakdown in neonatal rats.

The blood-brain barrier (BBB) is a complex structure that protects the central nervous system from peripheral insults. Understanding the molecular basis of BBB function and dysfunction holds significant potential for future strategies to prevent and treat neurological damage. The aim of our study was (1) to investigate BBB alterations following excitotoxicity and (2) to test the protective properties of melatonin. Ibotenate, a glutamate analog, was injected intracerebrally in postnatal day 5 (P5) rat pups to mimic excitotoxic injury. Animals were than randomly divided into two groups, one receiving intraperitoneal (i.p.) melatonin injections (5mg/kg), and the other phosphate buffer saline (PBS) injections. Pups were sacrificed 2, 4 and 18 h after ibotenate injection. We determined lesion size at 5 days by histology, the location and organization of tight junction (TJ) proteins by immunohistochemical studies, and BBB leakage by dextran extravasation. Expression levels of BBB genes (TJs, efflux transporters and detoxification enzymes) were determined in the cortex and choroid plexus by quantitative PCR. Dextran extravasation was seen 2h after the insult, suggesting a rapid BBB breakdown that was resolved by 4h. Extravasation was significantly reduced in melatonin-treated pups. Gene expression and immunohistochemical assays showed dynamic BBB modifications during the first 4h, partially prevented by melatonin. Lesion-size measurements confirmed white matter neuroprotection by melatonin. Our study is the first to evaluate BBB structure and function at a very early time point following excitotoxicity in neonates. Melatonin neuroprotects by preventing TJ modifications and BBB disruption at this early phase, before its previously demonstrated anti-inflammatory, antioxidant and axonal regrowth-promoting effects.

Influence of single-nucleotide polymorphisms on deferasirox C trough levels and effectiveness.

Deferasirox (DFX) is the only once-daily oral chelator for iron overload and its pharmacokinetic has been related with response to therapy. Our aim was to evaluate DFX plasma concentrations according to single-nucleotide polymorphisms in genes involved in its metabolism (UGT1A1, UGT1A3, CYP1A1, CYP1A2 and CYP2D6) and elimination (MRP2 and BCRP1). Further aim was to define a plasma concentration cutoff value predicting an adequate response to therapy. Plasma concentrations were determined at the end of dosing interval (C trough) using an high-performance liquid chromatography-ultraviolet method. Allelic discrimination was performed by real-time PCR. C trough levels were influenced by UGT1A1C>T rs887829, CYP1A1C>A rs2606345, CYP1A2A>C rs762551, CYP1A2C>T rs2470890 and MRP2G>A rs2273697 polymorphisms. A DFX plasma efficacy cutoff value of 20,000 ng ml(-1) was identified; CYP1A1C>A rs2606345 AA and CYP1A2C>T rs2470890 TT genotypes may predict this value, suggesting a negative predictive role in therapy efficacy. Our data suggest the feasibility of a pharmacogenetic-based DFX dose personalization.