Quantitative Analysis of Cenobamate and Concomitant Anti-Seizure Medications in Human Plasma via Ultra-High Performance Liquid Chromatography-Tandem Mass Spectrometry.

Cenobamate (CNB) is a new anti-seizure medication (ASM) recently introduced in clinical practice after approval by the FDA and EMA for the add-on treatment of focal onset seizures in adult patients. Although its mechanism of action has not been fully understood, CNB showed promising clinical efficacy in patients treated with concomitant ASMs. The accessibility of CNB could pave a way for the treatment of refractory or drug-resistant epilepsies, which still affect at least one-third of the patients under pharmacological treatment.

Applications of electrophoresis for small enantiomeric drugs in real-world samples: Recent trends and future perspectives.

Separation and identification of chiral molecules is a topic widely discussed in the literature and of fundamental importance, especially in the pharmaceutical and food fields, both from industrial and laboratory points of view. Several techniques are used to carry out these analyses, but high-performance liquid chromatography is often the "gold standard." The high costs of chiral columns, necessary for this technique, led researchers to look for an alternative, and capillary electrophoresis (CE) is a technique capable of overcoming some of the disadvantages of liquid chromatography, often providing comparable results in terms of sensitivity and robustness.

Development and Validation of a New LC-MS/MS Bioanalytical Method for the Simultaneous Determination of Levodopa, Levodopa Methyl Ester, and Carbidopa in Human Plasma Samples.

Levodopa (L-DOPA) treatment, combined with the administration of dopa-decarboxylase inhibitors (DDCIs), is still the most effective symptomatic treatment of Parkinson's disease (PD). Although its efficacy in the early stage of the disease has been confirmed, its complex pharmacokinetics (PK) increases the variability of the intra-individual motor response, thus amplifying the risk of motor/non-motor fluctuations and dyskinesia. Moreover, it has been demonstrated that L-DOPA PK is strongly influenced by several clinical, therapeutic, and lifestyle variables (e.

LC-MS/MS Application in Pharmacotoxicological Field: Current State and New Applications.

Nowadays, it is vital to have new, complete, and rapid methods to screen and follow pharmacotoxicological and forensic cases. In this context, an important role is undoubtedly played by liquid chromatography-tandem mass spectrometry (LC-MS/MS) thanks to its advanced features. This instrument configuration can offer comprehensive and complete analysis and is a very potent analytical tool in the hands of analysts for the correct identification and quantification of analytes.

Development and Validation of a UHPLC-MS/MS-Based Method to Quantify Cenobamate in Human Plasma Samples.

Cenobamate (CNB) is the newest antiseizure medication (ASM) approved by the FDA in 2019 to reduce uncontrolled partial-onset seizures in adult patients. Marketed as Xcopri in the USA or Ontozry in the EU (tablets), its mechanism of action has not been fully understood yet; however, it is known that it inhibits voltage-gated sodium channels and positively modulates the aminobutyric acid (GABA) ion channel. CNB shows 88% of oral bioavailability and is responsible for modifying the plasma concentrations of other co-administered ASMs, such as lamotrigine, carbamazepine, phenytoin, phenobarbital and the active metabolite of clobazam.

Fast Quantitative LC-MS/MS Determination of Illicit Substances in Solid and Liquid Unknown Seized Samples.

Narcotic and psychotropic substances are natural, synthetic, or semisynthetic compounds that are present in both solid and liquid illicit products. The alterations effects on the central nervous system related to their use can be psycholeptic, psychoanaleptic, or psychodiseptic and are able to generate tolerance, addiction, or dependence phenomena, creating social and public order problems. In this scenario, the analytical evaluations that aim to determine these analytes in seized nonbiological samples, and which assume the character of judicial evidence, must meet high analytical requirements of reliability, transparency, and procedures uniformity at a national level.

The Effect of Plasma Protein Binding on the Therapeutic Monitoring of Antiseizure Medications.

Epilepsy is a widely diffused neurological disorder including a heterogeneous range of syndromes with different aetiology, severity and prognosis. Pharmacological treatments are based on the use, either in mono- or in polytherapy, of antiseizure medications (ASMs), which act at different synaptic levels, generally modifying the excitatory and/or inhibitory response through different action mechanisms. To reduce the risk of adverse effects and drug interactions, ASMs levels should be closely evaluated in biological fluids performing an appropriate Therapeutic Drug Monitoring (TDM).

Therapeutic Drug Monitoring of Antiseizure Medications Using Volumetric Absorptive Microsampling: Where Are We?

Therapeutic drug monitoring (TDM) of antiseizure medications (ASMs) represents a valuable tool to establish an appropriate patient therapy, to collect important information about drugs' interactions and to evaluate patient's metabolic capabilities. In recent years, a new volumetric absorptive microsampling technique using VAMS technology and Mitra devices, consisting of a sampling technique for the collection of fixed-volume capillary blood, was developed. These new devices provide a new home-sampling technique for whole blood that has been spread out to simplify sample collection from finger-pricks.

Forensic Biochemical Markers to Evaluate the Agonal Period: A Literature Review.

Currently, forensic research is multidisciplinary with new methods and parameters useful to define the cause and time of death as well as survival/agony times. The identification of biochemical markers able to estimate agonal period has been studied by many forensic researchers. It is known that the estimation of agonal time in different types of death is not always easy, hence our interest in literature's data.

Further Analytical, Pharmacokinetic, and Clinical Observations on Low-Dose Ponatinib in Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia.

Introduction: Ponatinib (PNT) is a tyrosine kinase inhibitor approved for treating patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL), or chronic myeloid leukemia, resistant or intolerant to other tyrosine kinase inhibitor or showing T315I mutation of BCR-ABL. Unfortunately, the clinical use of PNT is limited by the possible occurrence of vascular occlusive events. The incidence of vascular events seems to correlate with PNT dose intensity and plasma exposure.

A new LC-MS/MS confirmation method for the determination of 17 drugs of abuse in oral fluid and its application to real samples.

A new liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmation method for the direct analysis of 17 drugs starting from 200μL of diluted oral fluid (OF), in a single chromatographic run, was developed and validated. Cocaine, benzoylecgonine (BEG), cocaethylene, Δ-9-tetrahydrocannabinol (Δ-9-THC), buprenorphine, 6-acetylmorphine (6AM), morphine, codeine, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), methylenedioxyamphetamine (MDA), 3,4-Methylenedioxy-N-ethylamphetamine (MDE), ketamine, N-methyl-1-(1,3-benzodioxol-5-yl)-2-butanamine (MBDB) were determined in a chromatographic run of 12min only with no sample pre-treatment, after the addition of 15 different internal standards (ISs). The method met all requirements in terms of linearity, accuracy (precision and trueness), recovery, and stability requested by FDA guidelines.

Early Chronic Carbamazepine-in-Food Administration to MAM/Pilocarpine Rats Does Not Affect Convulsive Motor Seizures.

Antiepileptic drug-resistance is a major health problem in patients with cortical dysplasia (CD). Whether drug-resistant epilepsy is associated with progressive brain damage is still debated. We previously generated a rat model of acquired CD, the methylazoxymethanol-pilocarpine (MP) rat, in which the occurrence of status epilepticus and subsequent spontaneous seizures induce progressive brain damage (Nobili et al.

Novel MIPs-Parabens based SPE Stationary Phases Characterization and Application.

In this work, the synthesis, characterization, and application of novel parabens imprinted polymers as highly selective solid-phase extraction (SPE) sorbents have been reported. The imprinted polymers were created using sol-gel molecular imprinting process. All the seven parabens were considered herein in order to check the phase selectivity.

Volumetric Absorptive Microsampling: A New Sampling Tool for Therapeutic Drug Monitoring of Antiepileptic Drugs.

Background: Volumetric absorptive microsampling (VAMS) is a novel sampling technique for the collection of fixed-volume capillary blood. In this study, a new analytical method was developed and used to quantify 14 different antiepileptic drugs (AEDs) and 2 active metabolites in samples collected by VAMS. These data were compared with concentration measurements in plasma.

Laser-Synthesized SERS Substrates as Sensors toward Therapeutic Drug Monitoring.

The synthesis by pulsed laser ablation and the characterization of both the surface nanostructure and the optical properties of noble metal nanoparticle-based substrates used in Surface Enhanced Raman Spectroscopy are discussed with reference to application in the detection of anti-epileptic drugs. Results on two representative drugs, namely Carbamazepine and Perampanel, are critically addressed.

LC-MS/MS-Based Quantification of 9 Antiepileptic Drugs From a Dried Sample Spot Device.

Background: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is commonly performed on plasma or serum. The use of dried plasma spots (DPSs) could represent a useful tool to facilitate sample shipment to reference laboratories. In this article, the authors describe the application of a commercially available UHPLC-MS/MS method for the determination of 9 commonly prescribed AEDs (levetiracetam, lacosamide, topiramate, ethosuximide, lamotrigine, rufinamide, zonisamide, primidone, and oxcarbazepine and its active metabolite 10-OH-monohydroxycarbazepine) to DPS collected on dried sample spot devices (DSSDs).

A Liquid Chromatography-Mass Spectrometry Assay for Determination of Perampanel and Concomitant Antiepileptic Drugs in the Plasma of Patients With Epilepsy Compared With a Fluorescent HPLC Assay.

Background: Perampanel is a novel noncompetitive selective antagonist at the postsynaptic ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor, which is approved as an adjunctive agent for the treatment of partial-onset seizure with or without secondary generalization and for primary generalized tonic-clonic seizure in patients with epilepsy who are at least 12 years of age. Limited information is available about the clinical utility of therapeutic drug monitoring of perampanel and therapeutic ranges are so far not established. Therefore, perampanel titration should be performed especially in case of insufficient success of the drug.

Evaluation of a Novel Immunoassay for Lacosamide Therapeutic Drug Monitoring: Comparison With a Liquid Chromatography-Mass Spectrometry Assay.

Background: Monitoring serum levels of lacosamide, other than to establish individualized reference ranges may be helpful in several settings, including patients with liver and/or kidney failure or settings that may result in altered pharmacokinetic characteristics and to assess patients' compliance with therapy. In this study, the EurekaOne liquid chromatography-mass spectrometry (LC-MS/MS) method (in use method) and the ARK immunoassay method (new method) for lacosamide monitoring were compared.

Methods: Lacosamide concentrations were determined in 39 patient samples using (1) antiepileptic drug LC-MS/MS kit by EurekaOne on a Thermo Fisher Scientific TSQuantum Access Max system and (2) the lacosamide immunoassay by ARK Diagnostic Inc.

Au nanoparticle-based sensor for apomorphine detection in plasma.

Artificially roughened gold surfaces with controlled nanostructure produced by pulsed laser deposition have been investigated as sensors for apomorphine detection aiming at clinical application. The use of such gold surfaces has been optimized using aqueous solutions of apomorphine in the concentration range between 3.3 × 10(-4) M and 3.

In vitro effects of Cyberknife-driven intermittent irradiation on glioblastoma cell lines.

Radiosurgery is used increasingly upon recurrence of high-grade gliomas to deliver a high dose of focused radiation to a defined target. The purpose of our study was to compare intermittent irradiation (IIR) by using a CyberKnife (CK) with continuous irradiation (CIR) by using a conventional linear accelerator (LINAC). A significant decrease in surviving fraction was observed after IIR irradiation compared with after CIR at a dose of 8 Gy.

Intrathecal synthesis of tumor markers is a highly sensitive test in the diagnosis of leptomeningeal metastasis from solid cancers.

Background: Identification of neoplastic cells in cerebrospinal fluid (CSF) by cytological analysis is the key diagnostic feature of leptomeningeal metastasis (LM). Because of the lack of sensitivity of this test, considerable efforts have been made to identify alternative diagnostic markers. Data from the literature suggest that measurement of tumor markers (TM) in CSF may be helpful for improving the diagnosis.

Valproic acid increases the in vitro effects of nitrosureas on human glioma cell lines.

Valproic acid (VPA) has been recently investigated for its anticancer properties in different tumors, including malignant gliomas. The aim of the present work was to evaluate the effects of VPA, alone or in combination with other chemotherapeutic drugs, on in vitro growth of human glioma cell lines. A172, U373, U138, U87, and SW1783 were treated with VPA alone or in combination with mitoxantrone, etoposide, or 1,3-bis(2-chloroethyl)-l-nitrosourea (BCNU).

Rapid in vitro elimination of anesthetic doses of thiopental in the isolated guinea pig brain.

Electrophysiological and metabolic activities in brain tissue preparations maintained in vitro may be influenced by the persistent effect of anesthetic drugs utilized during tissue dissection. In order to clarify this issue, we studied elimination kinetics of the barbiturate thiopental from the brain parenchyma in the isolated guinea pig brain maintained in vitro, arterially perfused with a protein-free saline solution [M. de Curtis, G.