Drug Repurposing: Deferasirox Inhibits the Anti-Apoptotic Activity of Mcl-1.

INTRODUCTION: With the aim of repositioning commercially available drugs for the inhibition of the anti-apoptotic myeloid cell leukemia protein, Mcl-1, implied in various cancers, five molecules, highlighted from a published theoretical screening, were selected to experimentally validate their affinity toward Mcl-1. RESULTS: A detailed NMR study revealed that only two of the five tested drugs, Torsemide and Deferasirox, interacted with Mcl-1. NMR data analysis allowed the complete characterization of the binding mode of both drugs to Mcl-1, including the estimation of their affinity for Mcl-1. Biological assays evidenced that the biological activity of Torsemide was lower as compared to the Deferasirox, which was able to efficiently and selectively inhibit the anti-apoptotic activity of Mcl-1. Finally, docking and molecular dynamics led to a 3D model for the Deferasirox:Mcl-1 complex and revealed the positioning of the drug in the Mcl-1 P2/P3 pockets as well as almost all synthetic Mcl-1 inhibitors. Interestingly, contrary to known synthetic Mcl-1 inhibitors which interact through Arg263, Deferasirox, establishes a salt bridge with Lys234. CONCLUSION: Deferasirox could be a potential candidate for drug repositioning as Mcl-1 inhibitor.

Molecular Recognition of the HPLC Whelk-O1 Selector towards the Conformational Enantiomers of Nevirapine and Oxcarbazepine.

The presence of stereogenic elements is a common feature in pharmaceutical compounds, and affording optically pure stereoisomers is a frequent issue in drug design. In this context, the study of the chiral molecular recognition mechanism fundamentally supports the understanding and optimization of chromatographic separations with chiral stationary phases. We investigated, with molecular docking, the interactions between the chiral HPLC selector Whelk-O1 and the stereoisomers of two bioactive compounds, the antiviral Nevirapine and the anticonvulsant Oxcarbazepine, both characterized by two stereolabile conformational enantiomers. The presence of fast-exchange enantiomers and the rate of the interconversion process were studied using low temperature enantioselective HPLC and VT-NMR with Whelk-O1 applied as chiral solvating agent. The values of the energetic barriers of interconversion indicate, for the single enantiomers of both compounds, half-lives sufficiently long enough to allow their separation only at critically sub-ambient temperatures. The chiral selector Whelk-O1 performed as a strongly selective discriminating agent both when applied as a chiral stationary phase (CSP) in HPLC and as CSA in NMR spectroscopy.

Accurate and simple determination of oxcarbazepine in human plasma and urine samples using switchable-hydrophilicity solvent in GC-MS.

This work presents a sensitive and rapid analytical method for the determination of oxcarbazepine in human plasma and urine samples. A vortex-assisted switchable hydrophilicity solvent-based liquid phase microextraction (VA-SHS-LPME) was used to preconcentrate oxcarbazepine from the samples before the determination by gas chromatography mass spectrometry. The switchable hydrophilicity solvent was synthesized by protonating N,N-dimethylbenzylamine with carbon dioxide to make it totally miscible with an equivalent volume of water. Parameters of the VA-SHS-LPME method including volume of switchable hydrophilicity solvent, concentration/volume of sodium hydroxide and vortex period were systematically optimized. Under the optimum conditions, good linearity ranging from 27.03 to 353.47 µg/kg was obtained for the analyte. Limit of detection and quantitation values were found to be 6.2 and 21 µg/kg (mass base), respectively. The relative standard deviation was calculated as 6.9% for six replicate measurements of the lowest concentration of the calibration plot. Satisfactory recovery results were calculated in the range of 97-100% for human plasma and urine samples spiked at five different concentrations.

Oxcarbazepine free or loaded PLGA nanoparticles as effective intranasal approach to control epileptic seizures in rodents.

The brain as a target for drug delivery is a challenge in pharmaceutical research. Among the several proposed strategies, the intranasal route represents a good strategy to deliver drugs to the brain. The goal of this study was to investigate the potential use of oxcarbazepine (OXC) to enhance brain targeting efficiency after intranasal (IN) administration. As well as attempting to use as low a dose as possible to obtain therapeutic effect. Our results showed that, after IN administrations, the dose of OXC that was effective in controlling epileptic seizures was 0.5 mg/kg (1 dose, every 20 min for 1 h) in rodents, confirmed by Cerebral Spinal Fluid (CSF) bioavailability. With the aim of reducing the number of administrations, sustaining drug release and increasing brain targeting, OXC was loaded into poly(lactide-co-glycolide) (PLGA) nanoparticles (NPs). The selected nanoformulation for in vivo studies was obtained re-suspending the freeze-dried and cryo-protected OXC loaded PLGA NPs. The translocation of 1-1'-Dioctadecyl-3,3,3',3'-tetramethylindotricarbocyanine Iodide loaded PLGA NPs, from nose to the brain, was confirmed by Fluorescence Molecular Tomography, which also evidenced an accumulation of NPs in the brain after repeated IN administrations. IN administrations of OXC loaded PLGA NPs reduced the number of administrations to 1 over 24 h compared to the free drug thus controlling seizures in rats. Immunohistochemical evaluations (anti-neurofilament, anti-beta tubulin, and anti-caspase3) demonstrated a neuroprotective effect of OXC PLGA NPs after 16 days of treatment. These encouraging results confirmed the possibility of developing a novel non-invasive nose to brain delivery system of OXC for the treatment of epilepsy.

HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion.

Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens-Johnson syndrome, or toxic epidermal necrolysis. The Food and Drug Administration-approved label for oxcarbazepine currently presents information regarding a pharmacogenomic association with the HLA antigen allele HLA-B*15:02 and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the presence of this allele is not routinely recommended before administration of oxcarbazepine. In practice, even with carbamazepine, HLA antigen testing is not always performed before initiating treatment because of lack of physician awareness of the recommendations and because of the desire to initiate treatment without delay. We present the clinical course of a pediatric patient with focal epilepsy refractory to several AEDs who developed drug reaction with eosinophilia and systemic symptoms after oxcarbazepine administration. The pharmacogenomic testing for various HLA antigen alleles was performed post hoc, and results were evaluated for structural similarities between AEDs and their molecular associations with HLA antigen proteins. In addition, we review the population-wide prevalence of various hypersensitivity reactions to AEDs and associated HLA antigen alleles. Finally, we discuss the potential utility of preemptive pharmacogenomic screening of patients before pharmacological treatment of epilepsy to assess the risk of developing hypersensitivity reactions.

Association Between HLA genotypes and Oxcarbazepine-induced Cutaneous Adverse Drug Reactions: A Systematic Review and Meta-Analysis.

PURPOSE: To systematically review and quantitatively synthesize associations between HLA genotypes and oxcarbazepine-induced cutaneous adverse drug reactions (OXC-cADRs), including Stevens-Johnson syndrome (SJS) and maculopapular rash. METHODS: Studies investigating associations between HLA genotypes and OXC-cADRs were systematically searched irrespective of language, in PubMed, HuGENet (Human Genome Epidemiology Network), and the Cochrane Library from their inception until January, 2017. Inclusion criteria were studies investigating associations between HLA genotypes and OXC-cADRs that reported sufficient data for calculating the frequency of HLA genotype carriers among cases and controls. Overall odds ratios (ORs) with corresponding 95%CIs were calculated using a random-effects model to determine the association between HLA genotypes and OXC-cADRs.  RESULTS: The initial searches identified 91 articles, of which 6 studies met the selection criteria. The studies included 229 patients with OXC-cADRs, 251 OXC-tolerant patients, and 2,358 participants from general populations of Han Chinese, Korean, and Thai ethnicities.  Associations between HLA-B*1502 and OXC-induced SJS were found in both the general population [OR=30.2 (95%CI=3.45-264)] and in OXC-tolerant individuals [OR=26.4 (95%CI=7.98-87.6)]. An association between the HLA-B*1502 and OXC-induced maculopapular rash was found in the general population [OR=5.67 (95%CI=2.03-15.9)] while HLA-A*3101 also associated with OXC-induced maculopapular rash [overall OR=29.2 (95%CI=6.70-128)].  CONCLUSIONS: Strong associations between the HLA-B*1502 and OXC-cADRs (SJS and maculopapular rash) were found in both controls from general population and OXC-tolerant groups. There was also an association between HLA-B*3101 and OXC-induced maculopapular rash. For patient safety, genetic screening especially for HLA-B*1502 prior to OXC therapy at least in these closely related ethnicities is warranted. Further studies need to better define other ethnicities at risk and a wider range of MHC gene subtypes. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.