A concise review on lipidomics analysis in biological samples

Lipids are a complex and critical heterogeneous molecular entity, playing an intricate and key role in understanding biological activities and disease processes. Lipidomics aims to quantitatively define the lipid classes, including their molecular species. The analysis of the biological tissues and fluids are challenging due to the extreme sample complexity and occurrence of the molecular species as isomers or isobars. This review documents the overview of lipidomics workflow, beginning from the approaches of sample preparation, various analytical techniques and emphasizing the state-of-the-art mass spectrometry either by shotgun or coupled with liquid chromatography. We have considered the latest ion mobility spectroscopy technologies to deal with the vast number of structural isomers, different imaging techniques. All these techniques have their pitfalls and we have discussed how to circumvent them after reviewing the power of each technique with examples

Solar-Combined Thermoelectric Power Generation Simulator

Photovoltaic (PV) devices are gaining popularity in harnessing solar energy as a form of sustainable energy source to generate electricity. However, these devices including tandem PV cells are limited to utilizing only high energy photons from the solar spectrum. This curtails their efficiency restricting them from being employed in mega Watts scale power generation. This study develops a software tool that allows engineers to tap into the wasted wavelengths of the spectrum by adding a thermoelectric (TE) module and a bottoming steam turbine cycle thus spreading the use of the spectrum. The tool allows investigating how power output and thus overall efficiency can be enhanced by combining these systems. In the TE device, solar heat develops a temperature gradient to generate electricity via the Seebeck effect. A steam-driven Rankine cycle through a heat exchanger connects to thermal storage at the bottom side of the TE. This storage allows dispatchability for off-sunlight power demand at a modest cost. The simulation tool built computes expected power output and efficiency at each individual stage of the combined system. The user is at liberty to manipulate material properties such as the band gap of PV materials which is a key parameter to optimize the PV efficiency. Test runs indicate that overall efficiency of power generation has increased up to 50% by the combined system for 1000 suns using optimized band gap and TE module design. This system can be used as a basis for future models in high efficiency distributed energy production

Validated DBS method for filgotinib quantitation in rat dried blood spots and its application to a pharmacokinetic study in rats

Filgotinib is a selective JAK1 (Janus kinase) inhibitor, showed efficacy in patients suffering from moderate-to-severe rheumatoid arthritis. In this paper, we present the data on the development and validation of a sensitive, selective and high-throughput LC-MS/MS (liquid chromatography with tandem mass spectrometry) method for the quantitation of filgotinib from rat dried blood spot (DBS) cards. To the DBS disc cards, 0.2 % formic acid enriched with internal standard (IS) was added and sonicated. Thereafter the extraction of filgotinib and the IS (tofacitinib) was accomplished using ethyl acetate as an extraction solvent. The resolution of filgotinib and the IS was achieved on a Gemini C18 column with an isocratic mobile phase, which is a mixture of 0.2 % formic acid:acetonitrile (20:80, v/v) at a flow-rate of 0.9 mL/min. The total run time was 2.90 min and the retention time of filgotinib and the IS was ~1.31 and 0.89 min, respectively. Filgotinib and the IS were analyzed using positive ion scan mode and parent-daughter mass to charge ion (m/z) transition of 426.3291.3 and m/z 313.2149.2, respectively, for quantitation. The calibration range was 1.37-1937 ng/mL. No matrix effect and carry over were observed. All the validation parameters met the acceptance criteria. The validated method has been applied to a pharmacokinetic study in rats. A good correlation between DBS and plasma concentrations for filgotinib was observed

Bioenhancing effects of naringin on atorvastatin

Naringin (CAS no: 10236-47-2) is a flavonone glycoside obtained from Citrus paradisi (grapefruit), a natural bioenhancer and reported to enhance the bioavailability of drugs by inhibiting cytochrome P450 and P-glycoprotein (P-gp). The aim of the present study was to investigate the effect of naringin on antihyperlipidemic properties of atorvastatin (AST) in tyloxapol induced hyperlipidemic rats and the effects were supported with measurement of plasma concentrations of AST by HPLC method. Animals received AST along with naringin (15 and 30 mg/kg) shown higher percent reduction in both cholesterol and triglycerides levels, when compared to animals received AST alone at dose of 25 and 50 mg/kg and it was found that the higher percent reduction in cholesterol and triglycerides was proportional to increase in plasma concentration of AST. From the results it is evident that the co-administration of naringin along with AST increased the plasma concentration of AST. The findings of the present study confirmed that naringin could be used as bioenhancer. The co-administration of AST and the diet with naringin (grapefruit) to the patients may potentiate the therapeutic efficacy of AST

Validated HPLC method for quantification of copanlisib in mice plasma: application to a pharmacokinetic study

Copanlisib is a pan phosphatidylinositol 3-kinase (PI3K) inhibitor approved for follicular lymphoma. In this paper, we present the data of development and validation of a high-performance liquid chromatography (HPLC) method for the quantitation of copanlisib in mice plasma as per the FDA regulatory guideline. The method involves the extraction of copanlisib along with internal standard (IS, enasidenib) from mice plasma (100 µL) using ethyl acetate as an extraction solvent. The chromatographic resolution of copanlisib and the IS was achieved on a Hypersil Gold C18 column maintained at 40 °C using a binary gradient mobile phase [10 mM ammonium formate (pH 4.0) and acetonitrile]. The flow-rate was 0.8 mL/min. For the detection of copanlisib and the IS, the photo-diode array detector was set at λmax 310 nm. Copanlisib and the IS eluted at 6.60 and 7.80 min, respectively with a total run time of 10 min. The calibration curve was linear over a concentration range of 50 to 5000 ng/mL for copanlisib (r2 0.998). The results of intra- and inter-day accuracy and precision studies were within the acceptable limits. Copanlisib was stable on bench-top, in auto-sampler, up to three freeze/thaw cycle and long-term storage at -80 °C. The application of the validated method was shown in a mice pharmacokinetic study

Development and validation of a novel method for simultaneous quantification of enzalutamide, darolutamide and their active metabolites in mice dried blood spots using LC-MS/MS: Application to pharmacokinetic study in mice

A simple, sensitive and rapid assay method has been developed and validated for the estimation of enzalutamide, N-desmethylenzalutamide (active metabolite of enzalutamide), darolutamide and ORM-15341 (active metabolite of darolutamide) on mice dried blood spots (DBS) using liquid chromatography coupled to tandem mass spectrometry with electro spray ionization in the positive-ion mode. The method utilizes liquid extraction of enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 from 3 mm punched disks from DBS cards (spiked or study samples). The extracted sample was chromatographed using an isocratic mobile phase (0.2 % formic acid : acetonitrile; 30:70, v/v) on an Atlantis dC18 column. The total run time was 2.5 min. The MS/MS ion transitions monitored were m/z 465 → m/z 209, m/z 451 →  m/z 195, m/z 399 → m/z 178, m/z 397 →  m/z 194 and m/z 481 → m/z 453 for enzalutamide, N-desmethyl­enzalutamide, darolutamide, ORM-15341 and the IS (apalutamide-d3), respectively. Method validation was performed as per regulatory guideline. The assay had a good linearity over the range of 0.93-2000 ng/mL. The intra- and inter-batch accuracy and precision (%RE & RSD) across quality controls met the acceptance criteria for all the analytes. Stability studies showed that all the analytes were stable on DBS cards for one month. This novel method has been applied to analyze the DBS samples of enzalutamide, N-desmethylenzalutamide, darolutamide and ORM-15341 obtained from a pharmacokinetic study in mice

Razvoj samoemulzifirajućeg sustava za isporuku albendazola (SEDDS) s pojačanom sistemskom apsorpcijom

The aim of the study was to develop and evaluate a self-emulsifying drug delivery system (SEDDS) formulation to improve solubility and dissolution and to enhance systemic exposure of a BCS class II anthelmetic drug, albendazole (ABZ). In the present study, solubility of ABZ was determined in various oils, surfactants and co-surfactants to identify the microemulsion components. Pseudoternary phase diagrams were plotted to identify the microemulsification existence area. SEDDS formulation of ABZ was prepared using oil (Labrafac Lipopfile WL1349) and a surfactant/co-surfactant (Tween 80/PEG-400) mixture and was characterized by appropriate studies, viz., microemulsifying properties, droplet size measurement, in vitro dissolution, etc. Finally, PK of the ABZ SEDDS formulation was performed on rats in parallel with suspension formulation. It was concluded that the SEDDS formulation approach can be used to improve the dissolution and systemic exposure of poorly water-soluble drugs such as ABZ.Cilj rada bio je razvoj i evaluacija samoemulzifirajućeg sustava za isporuku lijekova (SEDDS) povećane topljivosti i oslobađanja, te povećane sistemske apsorpcije anthelmintika albendazola (ABZ), lijeka iz klase BCS II. Odabir sastojaka za pripravu mikroemulzija izvršen je na temelju topljivosti albendazola u različitim uljima, surfaktantima i kosurfaktantima. Kako bi se odredilo područje u kojem dolazi do mikroemulzifikacije izrađeni su pseudoternarni fazni dijagrami. SEDDS formulacija albendazola pripravljena je pomoću smjese ulja (Labrafac Lipopfile WL1349) i surfaktanta/kosurfaktanta (Tween 80/PEG-400). Dobivenom pripravku određena su mikroemulzifirajuća svojstva, veličina kapljica, oslobađanje in vitro, itd. Osim toga, određeni su farmakokinetički parametri za ABZ SEDDS u štakora i uspoređeni sa suspenzijom albendazola. Zaključeno je da se pomoću SEDDS-a može povećati topljivost i sistemska apsorpcija lijekova slabo topljivih u vodi kao što je ABZ

Preclinical assessment of ulixertinib, a novel ERK1/2 inhibitor

Ulixertinib (BVD-523) is a novel and selective reversible inhibitor of ERK1/ERK2. In xenograft studies it inhibited tumor growth in BRAF-mutant melanoma and colorectal xenografts as well as KRAS-mutant colorectal and pancreatic models. Ulixertinib is currently in Phase I clinical development for the treatment of advance solid tumors. The objective of the study is to assess the metabolic stability (in various pre-clinical and human liver microsomes/hepatocytes), permeability, protein binding, CYP inhibition, CYP induction and CYP phenotyping of ulixertinib. We have also studied the oral and intravenous pharmacokinetics of ulixertinib in mice, rats and dogs. Ulixertinib was found to be moderately to highly stable in various liver microsomes/hepatocytes tested. It is a medium permeable (2.67 x 10-6 cm /sec) drug and a substrate for efflux (efflux ratio: 3.02) in Caco-2 model. Ulixertinib was highly bound to plasma proteins. CYPs involved in its limited metabolism and it is CYP inhibition IC50 ranged between 10-20 μM. Post oral administration ulixertinib exhibited early Tmax (0.50-0.75 h) in mice and rats indicating absorption was rapid, however in dogs Tmax attained at 2 h. The half-life (t½) of ulixertinib by intravenous and oral routes ranged between 1.0-2.5 h across the species. Clearance and volume of distribution by intravenous route for ulixertinib were found to be 6.24 mL/min/kg and 0.56 L/kg; 1.67 mL/min/kg and 0.36 L/kg and 15.5 mL/min/kg and 1.61 L/kg in mice, rats and dogs, respectively. Absolute oral bioavailability in mice and rats was > 92 %, however in dogs it was 34 %

Validated LC-ESI-MS/MS method for the determination of ivosidenib in 10 µL mice plasma: application to a pharmacokinetic study

A simple, selective and rapid LC-ESI-MS/MS method has been developed and validated for the quantification of ivosidenib in mice plasma using warfarin as an internal standard (I.S.) as per regulatory guideline. Sample preparation was accomplished through a simple protein precipitation process. Chromatography of ivosidenib and the I.S. was achieved on an Atlantis dC18 column using an isocratic mobile phase comprising 0.2 % formic acid in water and acetonitrile (25:75, v/v) delivered at a flow rate of 1.0 mL/min. LC-MS/MS was operated under the multiple reaction-monitoring mode (MRM) using the electrospray ionization technique in positive ion mode and the transitions of m/z 583.1→186.1 and m/z 309.2→251.3 were used to quantitate ivosidenib and the I.S, respectively. The total chromatographic run time was 2.0 min. Linearity was established in the concentration range of 1.10-3293 ng/mL (r2>0.99). The intra- and inter-day accuracy and precision for ivosidenib in mice plasma were in the range of 5.72-9.91 and 5.90-10.7 %, respectively. Ivosidenib was found to be stable on bench-top for 6 h, up to three freeze-thaw cycles, in in-injector for 24 h and for one month at -80 °C. The applicability of the validated method has been demonstrated in a mice pharmacokinetic study. Following intravenous (2 mg/kg) and oral (5 mg/kg) administration of ivosidenib to mice, concentrations were quantifiable up to 24 and 48 h, respectively. The bioavailability was 61 %