Bioavailability of Oniria®, a Melatonin Prolonged-Release Formulation, Versus Immediate-Release Melatonin in Healthy Volunteers.

BACKGROUND: Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro. OBJECTIVES: The main objective of the present study was to evaluate the relative oral bioavailability of Oniria®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin. METHODS: We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria® and the reference melatonin (periods 2 and 3). RESULTS: Two phases were clearly differentiated in the PK profile of Oniria®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a Cmax value close to 4000 pg/mL. However, in the delayed phase, Oniria® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria®, not only in the induction of sleep, but also in the maintenance. CONCLUSION: Oniria® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.

Real-World Cost-Effectiveness Analysis of Spinal Cord Stimulation vs Conventional Therapy in the Management of Failed Back Surgery Syndrome.

PURPOSE: Failed back surgery syndrome (FBSS) causes disability and lowers health-related quality of life (HRQoL) for patients. Many patients become refractory to conventional medical management (CMM) and spinal cord stimulation (SCS) is advised. However, comparative cost-effectiveness research of both clinical approaches still lacks further evidence. This probabilistic cost-effectiveness analysis compares CMM versus SCS plus CMM in FBSS patients for a 5-year period in Spain. PATIENTS AND METHODS: Patient-level data was obtained from a 2-year real-world study (SEFUDOCE) of adults diagnosed with FBSS who were treated with CMM or SCS. Incremental cost-effectiveness ratios (ICER) were estimated in terms of direct clinical cost and quality-adjusted life years (QALYs). Costs (€ for 2019) were estimated from the Spanish National Health Service (NHS) perspective. We applied a yearly discount rate of 3% to both costs and outcomes and performed a probabilistic sensitivity analysis using bootstrapping. RESULTS: After 2 years, the health-related quality of life measured by the EQ-5D displayed greater improvements for SCS patients (00.39) than for improved CMM patients (0.01). The proportion of SCS patients using medication fell substantially, particularly for opioids (-49%). In the statistical model projection, compared with the CMM group at year 5, the SCS group showed an incremental cost of € 15,406 for an incremental gain of 0.56 0.56 QALYs, for an ICER of € 27,330, below the €30,000 willingness-to-pay threshold for Spain. SCS had a 79% of probability of being cost-effective. CONCLUSION: SCS is a cost-effective treatment for FBSS compared to CMM alone based on real-world evidence.

Improvement and validation of a high-performance liquid chromatography in tandem mass spectrometry method for monitoring of omeprazole in plasma.

BACKGROUND: Omeprazole (OME) is a proton pump inhibitor with a 58% bioavailability after a single oral dose. It is subject to marked interindividual variations and significant drug-drug interactions. The authors developed a simple and rapid method based on liquid chromatography in tandem with mass spectrometry with solid phase extraction and isotope-labeled internal standard to monitor plasma levels of OME in pharmacokinetics and drug-drug interaction studies. METHODS: OME and its internal standard (OME-D3) were eluted with a Zorbax Extend C-18 rapid resolution column (4.6 × 50 mm, 3.5 µm) at 25°C, under isocratic conditions through a mobile phase consisting of 1 mM ammonium acetate, pH 8.5 (55%), and acetonitrile (45%). The flow rate was 0.8 mL/min, and the chromatogram run time was 1.2 minutes. OME was detected and quantified by liquid chromatography in tandem with mass spectrometry with positive electrospray ionization, which operates in multiple-reaction monitoring mode. RESULTS: The method was linear in the range of 1.5-2000 ng/mL for OME. The validation assays for accuracy and precision, matrix effect, extraction recovery, and stability of the samples for OME did not deviate more than 20% for the lower limit of quantification and no more than 15% for other quality controls. CONCLUSIONS: These findings are consistent with the requirements of regulatory agencies. The method enables rapid quantification of OME concentrations and can be used in pharmacokinetic and drug-drug interaction studies.

A simple assay for the simultaneous determination of human plasma albendazole and albendazole sulfoxide levels by high performance liquid chromatography in tandem mass spectrometry with solid-phase extraction.

A simple, reproducible and fast (4 min chromatogram) method of liquid chromatography in tandem with mass spectrometry (LC/MS-MS) was developed to determine simultaneously the plasma levels of albendazole (ABZ) and its metabolite albendazole sulfoxide (ABZOX) for pharmacokinetic and clinical analysis. Each plasma sample was extracted by solid phase extraction (SPE) using phenacetin as internal standard (IS). The extracted sample was eluted with a Zorbax XDB-CN column using an isocratic method. The mobile phase consisting of water with 1% acetic acid (40%, A) and MeOH (60%, B), was used at a flow rate of 1 mL/min. ABZ and ABZOX were detected and identified by mass spectrometry with electrospray ionization (ESI) in the positive ion and multiple-reaction monitoring (MRM) mode. The method was linear in the range of 5-1000 ng/mL for ABZ and 10-1500 ng/mL (full validation) or 10-5000 ng/mL (partial validation) for ABZOX, with 5 and 10 ng/mL lower limit of quantification (LLOQ) for ABZ and ABZOX, respectively. The tests of accuracy and precision, matrix effect, extraction recovery and stability of the samples for both ABZ and ABZOX did not deviate more than 20% for the LLOQ and no more than 15% for other quality controls (QCs), according to regulatory agencies.