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1.
Mikrochim Acta ; 189(3): 125, 2022 03 01.
Article in English | MEDLINE | ID: covidwho-1712245

ABSTRACT

A novel electrochemical sensor is reported for the detection of the antiviral drug favipiravir based on the core-shell nanocomposite of flower-like molybdenum disulfide (MoS2) nanospheres and molecularly imprinted polymers (MIPs). The MoS2@MIP core-shell nanocomposite was prepared via the electrodeposition of a MIP layer on the MoS2 modified electrode, using o-phenylenediamine as the monomer and favipiravir as the template. The selective binding of target favipiravir at the MoS2@MIP core-shell nanocomposite produced a redox signal in a concentration dependent manner, which was used for the quantitative analysis. The preparation process of the MoS2@MIP core-shell nanocomposite was optimized. Under the optimal conditions, the sensor exhibited a wide linear response range of 0.01 ~ 100 nM (1.57*10-6 ~ 1.57*10-2 µg mL-1) and a low detection limit of 0.002 nM (3.14*10-7 µg mL-1). Application of the sensor was demonstrated by detecting favipiravir in a minimum amount of 10 µL biological samples (urine and plasma). Satisfied results in the recovery tests indicated a high potential of favipiravir monitoring in infectious COVID-19 samples.


Subject(s)
Amides/analysis , Antiviral Agents/analysis , Disulfides/chemistry , Molecularly Imprinted Polymers/chemistry , Molybdenum/chemistry , Nanocomposites/chemistry , Nanospheres/chemistry , Pyrazines/analysis , Amides/blood , Amides/therapeutic use , Amides/urine , Antiviral Agents/blood , Antiviral Agents/therapeutic use , Antiviral Agents/urine , COVID-19/drug therapy , COVID-19/virology , Electrochemical Techniques/methods , Humans , Limit of Detection , Oxidation-Reduction , Pyrazines/blood , Pyrazines/therapeutic use , Pyrazines/urine , Reproducibility of Results , SARS-CoV-2/isolation & purification
2.
Int J Antimicrob Agents ; 59(2): 106516, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1611755

ABSTRACT

High concentrations of ivermectin demonstrated antiviral activity against SARS-CoV-2 in vitro. The aim of this study was to assess the safety and efficacy of high-dose ivermectin in reducing viral load in individuals with early SARS-CoV-2 infection. This was a randomised, double-blind, multicentre, phase II, dose-finding, proof-of-concept clinical trial. Participants were adults recently diagnosed with asymptomatic/oligosymptomatic SARS-CoV-2 infection. Exclusion criteria were: pregnant or lactating women; CNS disease; dialysis; severe medical condition with prognosis <6 months; warfarin treatment; and antiviral/chloroquine phosphate/hydroxychloroquine treatment. Participants were assigned (ratio 1:1:1) according to a randomised permuted block procedure to one of the following arms: placebo (arm A); single-dose ivermectin 600 µg/kg plus placebo for 5 days (arm B); and single-dose ivermectin 1200 µg/kg for 5 days (arm C). Primary outcomes were serious adverse drug reactions (SADRs) and change in viral load at Day 7. From 31 July 2020 to 26 May 2021, 32 participants were randomised to arm A, 29 to arm B and 32 to arm C. Recruitment was stopped on 10 June because of a dramatic drop in cases. The safety analysis included 89 participants and the change in viral load was calculated in 87 participants. No SADRs were registered. Mean (S.D.) log10 viral load reduction was 2.9 (1.6) in arm C, 2.5 (2.2) in arm B and 2.0 (2.1) in arm A, with no significant differences (P = 0.099 and 0.122 for C vs. A and B vs. A, respectively). High-dose ivermectin was safe but did not show efficacy to reduce viral load.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Ivermectin/pharmacokinetics , SARS-CoV-2/drug effects , Adult , Antiparasitic Agents/blood , Antiparasitic Agents/pharmacokinetics , Antiparasitic Agents/pharmacology , Antiviral Agents/blood , Antiviral Agents/pharmacology , COVID-19/blood , COVID-19/virology , Double-Blind Method , Drug Repositioning , Female , Humans , Ivermectin/blood , Ivermectin/pharmacology , Male , Middle Aged , SARS-CoV-2/growth & development , SARS-CoV-2/pathogenicity , Treatment Outcome , Viral Load/drug effects
3.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1189: 123087, 2022 Jan 15.
Article in English | MEDLINE | ID: covidwho-1587335

ABSTRACT

Favipiravir is a promising antiviral agent that has been recently approved for treatment of COVID-19 infection. In this study, a menthol-assisted homogenous liquid-liquid microextraction method has been developed for favipiravir determination in human plasma using HPLC/UV. The different factors that could affect the extraction efficiency were studied, including extractant type, extractant volume, menthol amount and vortex time. The optimum extraction efficiency was achieved using 300 µL of tetrahydrofuran, 30 mg of menthol and vortexing for 1 min before centrifuging the sample for 5 min at 3467g. Addition of menthol does not only induce phase separation, but also helps to form reverse micelles to facilitate extraction. The highly polar favipiravir molecules would be incorporated into the hydrophilic core of the formed reverse micelle to be extracted by the non-polar organic extractant. The method was validated according to the FDA bioanalytical method guidelines. The developed method was found linear in the concentration range of 0.1 to 100 µg/mL with a coefficient of determination of 0.9992. The method accuracy and precision were studied by calculating the recovery (%) and the relative standard deviation (%), respectively. The recovery (%) was in the range of 97.1-103.9%, while the RSD (%) values ranged between 2.03 and 8.15 %. The developed method was successfully applied in a bioequivalence study of Flupirava® 200 mg versus Avigan® 200 mg, after a single oral dose of favipiravir administered to healthy adult volunteers. The proposed method was simple, cheap, more eco-friendly and sufficiently sensitive for biomedical application.


Subject(s)
Amides/isolation & purification , Antiviral Agents/isolation & purification , COVID-19/drug therapy , Liquid Phase Microextraction/methods , Pyrazines/isolation & purification , Amides/administration & dosage , Amides/blood , Antiviral Agents/administration & dosage , Antiviral Agents/blood , COVID-19/blood , COVID-19/virology , Chromatography, High Pressure Liquid/methods , Humans , Liquid Phase Microextraction/instrumentation , Menthol/chemistry , Pyrazines/administration & dosage , Pyrazines/blood , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
4.
Clin Pharmacol Ther ; 108(4): 775-790, 2020 10.
Article in English | MEDLINE | ID: covidwho-1384148

ABSTRACT

There is a rapidly expanding literature on the in vitro antiviral activity of drugs that may be repurposed for therapy or chemoprophylaxis against severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). However, this has not been accompanied by a comprehensive evaluation of the target plasma and lung concentrations of these drugs following approved dosing in humans. Accordingly, concentration 90% (EC90 ) values recalculated from in vitro anti-SARS-CoV-2 activity data was expressed as a ratio to the achievable maximum plasma concentration (Cmax ) at an approved dose in humans (Cmax /EC90 ratio). Only 14 of the 56 analyzed drugs achieved a Cmax /EC90 ratio above 1. A more in-depth assessment demonstrated that only nitazoxanide, nelfinavir, tipranavir (ritonavir-boosted), and sulfadoxine achieved plasma concentrations above their reported anti-SARS-CoV-2 activity across their entire approved dosing interval. An unbound lung to plasma tissue partition coefficient (Kp Ulung ) was also simulated to derive a lung Cmax /half-maximal effective concentration (EC50 ) as a better indicator of potential human efficacy. Hydroxychloroquine, chloroquine, mefloquine, atazanavir (ritonavir-boosted), tipranavir (ritonavir-boosted), ivermectin, azithromycin, and lopinavir (ritonavir-boosted) were all predicted to achieve lung concentrations over 10-fold higher than their reported EC50 . Nitazoxanide and sulfadoxine also exceeded their reported EC50 by 7.8-fold and 1.5-fold in lung, respectively. This analysis may be used to select potential candidates for further clinical testing, while deprioritizing compounds unlikely to attain target concentrations for antiviral activity. Future studies should focus on EC90 values and discuss findings in the context of achievable exposures in humans, especially within target compartments, such as the lungs, in order to maximize the potential for success of proposed human clinical trials.


Subject(s)
Antiviral Agents/administration & dosage , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Delivery Systems/methods , Drug Repositioning/methods , Pneumonia, Viral/drug therapy , Antiviral Agents/blood , COVID-19 , Coronavirus Infections/blood , Humans , Pandemics , Pneumonia, Viral/blood , SARS-CoV-2
5.
Biomed Chromatogr ; 36(1): e5238, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1380369

ABSTRACT

Sofosbuvir is a direct-acting antiviral drug that inhibits hepatitis C virus (HCV) NS5B polymerase, which in turn affects the virus replication inside biological systems. The clinical importance of sofosbuvir is based not only on its effect on HCV but also on other lethal viruses such as Zika and severe acute respiratory syndrome coronavirus disease 2019 (SARS-COVID-19). Accordingly, there is a continuous shedding of light on the development and validation of accurate and fast analytical methods for the determination of sofosbuvir in different environments. This work critically reviews the recent advances in chromatographic methods for the analysis of sofosbuvir and/or its metabolites in pure samples, pharmaceutical dosage forms, and in the presence of other co-administered drugs to highlight the current status and future perspectives to enhance its determination in different matrixes.


Subject(s)
Antiviral Agents/blood , Chromatography/methods , Hepatitis C, Chronic/drug therapy , Sofosbuvir/blood , Antiviral Agents/therapeutic use , Hepatitis C, Chronic/blood , Humans , Plasma/chemistry , Sofosbuvir/therapeutic use
6.
Anal Bioanal Chem ; 413(23): 5811-5820, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1321733

ABSTRACT

Remdesivir is a nucleotide analog prodrug that has received much attention since the outbreak of the COVID-19 pandemic in December 2019. GS-441524 (Nuc) is the active metabolite of remdesivir and plays a pivotal role in the clinical treatment of COVID-19. Here, a robust HPLC-MS/MS method was developed to determine Nuc concentrations in rat plasma samples after a one-step protein precipitation process. Chromatographic separation was accomplished on Waters XBrige C18 column (50 × 2.1 mm, 3.5 µm) under gradient elution conditions. Multiple reaction monitoring transitions in electrospray positive ion mode were m/z 292.2 → 163.2 for Nuc and 237.1 → 194.1 for the internal standard (carbamazepine). The quantitative analysis method was fully validated in line with the United States Food and Drug Administration guidelines. The linearity, accuracy and precision, matrix effect, recovery, and stability results met the requirements of the guidelines. Uncertainty of measurement and incurred sample reanalysis were analyzed to further ensure the robustness and reproducibility of the method. This optimized method was successfully applied in a rat pharmacokinetics study of remdesivir (intravenously administration, 5 mg kg-1). The method can act as a basis for further pharmacokinetic and clinical efficacy investigations in patients with COVID-19. Graphical abstract.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Adenosine/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Adenosine/blood , Adenosine/pharmacokinetics , Adenosine/standards , Adenosine Monophosphate/blood , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/standards , Alanine/blood , Alanine/pharmacokinetics , Alanine/standards , Animals , Antiviral Agents/pharmacokinetics , Antiviral Agents/standards , Limit of Detection , Male , Quality Control , Rats , Rats, Sprague-Dawley , Reference Standards , Reproducibility of Results
7.
Molecules ; 26(13)2021 Jun 22.
Article in English | MEDLINE | ID: covidwho-1288957

ABSTRACT

In the current work, a simple, economical, accurate, and precise HPLC method with UV detection was developed to quantify Favipiravir (FVIR) in spiked human plasma using acyclovir (ACVR) as an internal standard in the COVID-19 pandemic time. Both FVIR and ACVR were well separated and resolved on the C18 column using the mobile phase blend of methanol:acetonitrile:20 mM phosphate buffer (pH 3.1) in an isocratic mode flow rate of 1 mL/min with a proportion of 30:10:60 %, v/v/v. The detector wavelength was set at 242 nm. Maximum recovery of FVIR and ACVR from plasma was obtained with dichloromethane (DCM) as extracting solvent. The calibration curve was found to be linear in the range of 3.1-60.0 µg/mL with regression coefficient (r2) = 0.9976. However, with acceptable r2, the calibration data's heteroscedasticity was observed, which was further reduced using weighted linear regression with weighting factor 1/x. Finally, the method was validated concerning sensitivity, accuracy (Inter and Intraday's % RE and RSD were 0.28, 0.65 and 1.00, 0.12 respectively), precision, recovery (89.99%, 89.09%, and 90.81% for LQC, MQC, and HQC, respectively), stability (% RSD for 30-day were 3.04 and 1.71 for LQC and HQC, respectively at -20 °C), and carry-over US-FDA guidance for Bioanalytical Method Validation for researchers in the COVID-19 pandemic crisis. Furthermore, there was no significant difference for selectivity when evaluated at LLOQ concentration of 3 µg/mL of FVIR and relative to the blank.


Subject(s)
Amides/analysis , Amides/blood , Antiviral Agents/analysis , Antiviral Agents/blood , Biological Assay/methods , COVID-19/drug therapy , Chromatography, High Pressure Liquid/methods , Liquid-Liquid Extraction/methods , Pyrazines/analysis , Pyrazines/blood , Acyclovir/analysis , Acyclovir/blood , COVID-19/blood , Calibration , Drug Stability , Freezing , Humans , Reference Standards , Reproducibility of Results , Solvents/chemistry
8.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1176: 122768, 2021 Jun 30.
Article in English | MEDLINE | ID: covidwho-1240421

ABSTRACT

Favipiravir is a broad-spectrum inhibitor of viral RNA polymerase. It is currently used as a possible treatment for coronavirus disease 2019 (COVID-19). Pre-clinical or clinical trials of favipiravir require robust, sensitive, and accurate bioanalytical methods for quantitation of favipiravir levels. Recently, several studies have been reported about developing a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring favipiravir levels. However, these methods were validated predominantly for plasma samples, electrospray ionization was operated only in negative or positive mode, and clinical application of these methods has not been applied for patients with COVID-19. This study aimed was to develop a validated LC-MS/MS method for the measurement of favipiravir levels in positive and negative electrospray ionization mode and to perform a pilot study in patients with COVID-19 receiving favipiravir to demonstrate the applicability of this method in biological samples. Simple protein precipitation was used for the extraction of favipiravir from the desired matrix. Favipiravir levels were quantitated using MS / MS with an electrospray ionization source in positive and negative multiple reaction monitoring (MRM) mode. The chromatographic detection was performed on a reverse-phase Phenomenex C18 column (50 mm × 4.6 mm, 5 µm, 100 Å) with gradient elution using 0.1% formic acid in water and 0.1% formic acid in methanol as mobile phase. The method was linear over the concentration ranges of 0.048-50 µg/mL (in negative ionization mode) and 0.062-50 µg/mL (in positive ionization mode) with a correlation coefficient (r2) better than 0.998. The total run time was 3.5 min. The intra-assay and inter-assay %CV values were less than 7.2% and 8.0%, respectively. A simple, rapid and robust LC-MS / MS method was developed for the measurement of favipiravir and validation studies were performed. The validated method was successfully applied for drug level measurement in COVID-19 patients receiving favipiravir.


Subject(s)
Amides/blood , COVID-19/drug therapy , Chromatography, Liquid/methods , Pyrazines/blood , Tandem Mass Spectrometry/methods , Amides/administration & dosage , Amides/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/blood , Drug Stability , Humans , Limit of Detection , Pyrazines/administration & dosage , Pyrazines/therapeutic use , Sensitivity and Specificity , Spectrometry, Mass, Electrospray Ionization/methods
10.
Inorg Chem ; 60(9): 6585-6599, 2021 May 03.
Article in English | MEDLINE | ID: covidwho-1195597

ABSTRACT

Silver vanadate nanorods (ß-AgVO3) with silver nanoparticles (Ag-NPs) decorated on the surface of the rods were synthesized by using simple hydrothermal technique and later anchored onto nitrogen-doped reduced graphene oxide (N-rGO) to make a novel nanocomposite. Experimental analyses were carried out to identify the electronic configuration by X-ray diffraction analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy analysis, which revealed monoclinic patterns of the C12/m1 space group with Wulff construction forming beta silver vanadate (ß-AgVO3) crystals with optical density and phase transformations. Ag nucleation showed consistent results with metallic formation and electronic changes occurring in [AgO5] and [AgO3] clusters. Transmission electron microscopy and field-emission scanning electron microscopy with elemental mapping and EDX analysis of the morphology reveals the nanorod structure for ß-AgVO3 with AgNPs on the surface and sheets for N-rGO. Additionally, a novel electrochemical sensor is constructed by using Ag/AgVO3/N-rGO on screen-printed carbon paste electrodes for the detection of antiviral drug levofloxacin (LEV) which is used as a primary antibiotic in controlling COVID-19. Using differential pulse voltammetry, LEV is determined with a low detection limit of 0.00792 nm for a linear range of 0.09-671 µM with an ultrahigh sensitivity of 152.19 µA µM-1 cm-2. Furthermore, modified electrode performance is tested by real-time monitoring using biological and river samples.


Subject(s)
Dielectric Spectroscopy/instrumentation , Dielectric Spectroscopy/methods , Levofloxacin/analysis , Nanocomposites/chemistry , Antiviral Agents/analysis , Antiviral Agents/blood , Antiviral Agents/urine , Carbon/chemistry , Electrodes , Graphite/chemistry , Humans , Levofloxacin/blood , Levofloxacin/urine , Limit of Detection , Metal Nanoparticles/chemistry , Microscopy, Electron, Transmission , Nanotubes/chemistry , Photoelectron Spectroscopy , Silver/chemistry , Silver Compounds/chemistry , Spectroscopy, Fourier Transform Infrared , Spectrum Analysis, Raman , Tablets , Vanadates/chemistry , X-Ray Diffraction
11.
Molecules ; 26(7)2021 Mar 29.
Article in English | MEDLINE | ID: covidwho-1159212

ABSTRACT

The COVID-19 pandemic has reached over 100 million worldwide. Due to the multi-targeted nature of the virus, it is clear that drugs providing anti-COVID-19 effects need to be developed at an accelerated rate, and a combinatorial approach may stand to be more successful than a single drug therapy. Among several targets and pathways that are under investigation, the renin-angiotensin system (RAS) and specifically angiotensin-converting enzyme (ACE), and Ca2+-mediated SARS-CoV-2 cellular entry and replication are noteworthy. A combination of ACE inhibitors and calcium channel blockers (CCBs), a critical line of therapy for pulmonary hypertension, has shown therapeutic relevance in COVID-19 when investigated independently. To that end, we conducted in silico modeling using BIOiSIM, an AI-integrated mechanistic modeling platform by utilizing known preclinical in vitro and in vivo datasets to accurately simulate systemic therapy disposition and site-of-action penetration of the CCBs and ACEi compounds to tissues implicated in COVID-19 pathogenesis.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning/methods , Hypertension, Pulmonary/drug therapy , Angiotensin-Converting Enzyme Inhibitors/pharmacokinetics , Antiviral Agents/blood , Biosimilar Pharmaceuticals , COVID-19/complications , Calcium Channel Blockers/pharmacokinetics , Computer Simulation , Databases, Pharmaceutical , Drug Development/methods , Humans , Hypertension, Pulmonary/virology , Tissue Distribution
12.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1171: 122641, 2021 May 01.
Article in English | MEDLINE | ID: covidwho-1126911

ABSTRACT

Remdesivir, formerly GS-5734, has recently become the first antiviral drug approved by the U.S. Food and Drug Administration (FDA) to treat COVID-19, the disease caused by SARS-CoV-2. Therapeutic dosing and pharmacokinetic studies require a simple, sensitive, and selective validated assay to quantify drug concentrations in clinical samples. Therefore, we developed a rapid and sensitive LC-MS/MS assay for the quantification of remdesivir in human plasma with its deuterium-labeled analog, remdesivir-2H5, as the internal standard. Chromatographic separation was achieved on a Phenomenex® Synergi™ HPLC Fusion-RP (100 × 2 mm, 4 µm) column by gradient elution. Excellent accuracy and precision (<5.2% within-run variations and. <9.8% between-run variations) were obtained over the range of 0.5-5000 ng/mL. The assay met the FDA Bioanalytical Guidelines for selectivity and specificity, and low inter-matrix lot variability (<2.7%) was observed for extraction efficiency (77%) and matrix effect (123%) studies. Further, stability tests showed that the analyte does not degrade under working conditions, nor during freezing and thawing processes.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , COVID-19/drug therapy , Drug Monitoring/methods , Tandem Mass Spectrometry/methods , Adenosine Monophosphate/blood , Alanine/blood , Chromatography, High Pressure Liquid/economics , Chromatography, High Pressure Liquid/methods , Drug Monitoring/economics , Female , Humans , Limit of Detection , Male , Tandem Mass Spectrometry/economics
13.
Anal Biochem ; 617: 114118, 2021 03 15.
Article in English | MEDLINE | ID: covidwho-1064675

ABSTRACT

Remdesivir (RDV) is a phosphoramidate prodrug designed to have activity against a broad spectrum of viruses. Following IV administration, RDV is rapidly distributed into cells and tissues and simultaneously metabolized into GS-441524 and GS-704277 in plasma. LC-MS/MS methods were validated for determination of the 3 analytes in human plasma that involved two key aspects to guarantee their precision, accuracy and robustness. First, instability issues of the analytes were overcome by diluted formic acid (FA) treatment of the plasma samples. Secondly, a separate injection for each analyte was performed with different ESI modes and organic gradients to achieve sensitivity and minimize carryover. Chromatographic separation was achieved on an Acquity UPLC HSS T3 column (2.1 × 50 mm, 1.8 µm) with a run time of 3.4 min. The calibration ranges were 4-4000, 2-2000, and 2-2000 ng/mL, respectively for RDV, GS-441524 and GS-704277. The intraday and interday precision (%CV) across validation runs at 3 QC levels for all 3 analytes was less than 6.6%, and the accuracy was within ±11.5%. The long-term storage stability in FA-treated plasma was established to be 392, 392 and 257 days at -70 °C, respectively for RDV, GS-441524 and GS-704277. The validated method was successfully applied in COVID-19 related clinical studies.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/blood , Drug Monitoring/methods , Furans/blood , Pyrroles/blood , Tandem Mass Spectrometry/methods , Triazines/blood , Adenosine/analogs & derivatives , Adenosine Monophosphate/blood , Alanine/blood , COVID-19/drug therapy , Chromatography, High Pressure Liquid/methods , Humans , Limit of Detection
14.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119241, 2021 Mar 15.
Article in English | MEDLINE | ID: covidwho-1065570

ABSTRACT

The present work describes development of rapid, robust, sensitive and green spectrofluorimetric method for determination of favipiravir (FAV). Different factors affecting fluorescence were carefully studied and Box Behnken Design was applied to optimize experimental parameters. The proposed method is based on measuring native fluorescence of FAV in 0.2 M borate buffer (pH 8.0) at 432 nm after excitation at 361 nm. There was a linear relationship between FAV concentration and relative fluorescence intensity over the range 40-280 ng/mL with limit of detection of 9.44 ng/mL and quantitation limit of 28.60 ng/mL. The method was successfully implemented for determination of FAV in its pharmaceutical formulation with mean % recovery of 99.26 ± 0.87. Moreover, the high sensitivity of the method allowed determination of FAV in spiked human plasma over a range of 48-192 ng/mL. The proposed spectrofluorimetric method was proved to be eco-friendly according to analytical eco-scale.


Subject(s)
Amides/blood , Antiviral Agents/blood , COVID-19/blood , COVID-19/drug therapy , Pyrazines/blood , Spectrometry, Fluorescence/methods , Amides/analysis , Amides/therapeutic use , Antiviral Agents/analysis , Antiviral Agents/therapeutic use , Blood Chemical Analysis/methods , Blood Chemical Analysis/statistics & numerical data , Humans , Limit of Detection , Pyrazines/analysis , Pyrazines/therapeutic use , SARS-CoV-2 , Sensitivity and Specificity , Spectrometry, Fluorescence/statistics & numerical data
15.
Free Radic Biol Med ; 163: 153-162, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1065088

ABSTRACT

Nitric oxide (NO) is a free radical playing an important pathophysiological role in cardiovascular and immune systems. Recent studies reported that NO levels were significantly lower in patients with COVID-19, which was suggested to be closely related to vascular dysfunction and immune inflammation among them. In this review, we examine the potential role of NO during SARS-CoV-2 infection from the perspective of the unique physical, chemical and biological properties and potential mechanisms of NO in COVID-19, as well as possible therapeutic strategies using inhaled NO. We also discuss the limits of NO treatment, and the future application of this approach in prevention and therapy of COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Anticoagulants/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lung/drug effects , Nitric Oxide/therapeutic use , Administration, Inhalation , Anti-Inflammatory Agents/blood , Anticoagulants/blood , Antiviral Agents/blood , COVID-19/blood , COVID-19/pathology , COVID-19/virology , Endothelial Cells/drug effects , Endothelial Cells/pathology , Endothelial Cells/virology , Humans , Inflammation , Lung/blood supply , Lung/virology , Mitochondria/drug effects , Mitochondria/virology , Nitric Oxide/blood , SARS-CoV-2/drug effects , SARS-CoV-2/pathogenicity , Severity of Illness Index , Vasodilation/drug effects
16.
J Pharm Biomed Anal ; 196: 113935, 2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1051795

ABSTRACT

BACKGROUND: The present COVID-19 pandemic has prompted worldwide repurposing of drugs. The aim of the present work was to develop and validate a two-dimensional isotope-dilution liquid chromatrography tandem mass spectrometry (ID-LC-MS/MS) method for accurate quantification of remdesivir and its active metabolite GS-441524, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in serum; drugs that have gained attention for repurposing in the treatment of COVID-19. METHODS: Following protein precipitation, samples were separated with a two-dimensional ultra-high performance liquid chromatography (2D-UHPLC) setup, consisting of an online solid phase extraction (SPE) coupled to an analytical column. For quantification, stable isotope-labelled analogues were used as internal standards for all analytes. The method was validated on the basis of the European Medicines Agency bioanalytical method validation protocol. RESULTS: Detuning of lopinavir and ritonavir allowed simultaneous quantification of all analytes with different concentration ranges and sensitivity with a uniform injection volume of 5 µL. The method provided robust validation results with inaccuracy and imprecision values of ≤ 9.59 % and ≤ 11.1 % for all quality controls. CONCLUSION: The presented method is suitable for accurate and simultaneous quantification of remdesivir, its metabolite GS-441525, chloroquine, hydroxychloroquine, lopinavir, ritonavir, favipiravir and azithromycin in human serum. The quantitative assay may be an efficient tool for the therapeutic drug monitoring of these potential drug candidates in COVID-19 patients in order to increase treatment efficacy and safety.


Subject(s)
Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/blood , COVID-19/drug therapy , Isotopes/chemistry , SARS-CoV-2/drug effects , Adenosine/analogs & derivatives , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/blood , Alanine/analogs & derivatives , Alanine/blood , Amides/blood , Azithromycin/blood , Chloroquine/blood , Chromatography, Liquid/methods , Furans/blood , Humans , Hydroxychloroquine/blood , Lopinavir/blood , Pandemics/prevention & control , Pyrazines/blood , Pyrroles/blood , Ritonavir/blood , Tandem Mass Spectrometry/methods , Triazines/blood
18.
Ther Drug Monit ; 43(1): 131-135, 2021 02 01.
Article in English | MEDLINE | ID: covidwho-1028266

ABSTRACT

BACKGROUND: Although the efficacy of lopinavir/ritonavir has not been proven, it has been proposed as an off-label treatment for COVID-19. Previously, it has been reported that the plasma concentrations of lopinavir significantly increase in inflammatory settings. As COVID-19 may be associated with major inflammation, assessing the plasma concentrations and safety of lopinavir in COVID-19 patients is essential. METHODS: Real-world COVID-19 data based on a retrospective study. RESULTS: Among the 31 COVID-19 patients treated with lopinavir/ritonavir between March 18, 2020 and April 1, 2020, higher lopinavir plasma concentrations were observed, which increased by 4.6-fold (interquartile range: 3.6-6.2), compared with the average plasma concentrations in HIV. Lopinavir concentrations in all except one patient were above the upper limit of the concentration range of HIV treatment. Approximately one to 5 patients prematurely stopped treatment mainly because of an ADR related to hepatic or gastrointestinal disorders. CONCLUSIONS: Lopinavir plasma concentrations in patients with moderate-to-severe COVID-19 were higher than expected, and they were associated with the occurrence of hepatic or gastrointestinal adverse drug reactions. However, a high plasma concentration may be required for in vivo antiviral activity against SARS-CoV-2, as suggested by previous studies. Therefore, in the absence of adverse drug reaction, lopinavir dosage should not be reduced. Caution is essential because off-label use can be associated with a new drug safety profile.


Subject(s)
Antiviral Agents/blood , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Lopinavir/blood , Lopinavir/therapeutic use , Ritonavir/blood , Ritonavir/therapeutic use , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Comorbidity , Drug Combinations , Female , Humans , Lopinavir/administration & dosage , Lopinavir/adverse effects , Male , Middle Aged , Retrospective Studies , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Severity of Illness Index
19.
Drug Res (Stuttg) ; 71(5): 250-256, 2021 May.
Article in English | MEDLINE | ID: covidwho-997994

ABSTRACT

Despite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1-5 µM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1-5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Hydroxychloroquine/pharmacokinetics , Lung/metabolism , Models, Biological , Administration, Inhalation , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Lung/drug effects , Nebulizers and Vaporizers , Tissue Distribution
20.
Int J Antimicrob Agents ; 57(2): 106247, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-987980

ABSTRACT

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06-0.14) mg/L and 0.07 (0.05-0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10-7.26) mg/L and 1.81 (1.20-7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3-162.7) and 21.2 (18.4-109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.


Subject(s)
Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Hydroxychloroquine/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/blood , Bronchoalveolar Lavage Fluid/chemistry , Critical Illness , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/blood , Intubation, Gastrointestinal , Lung/drug effects , Lung/virology , Male , Middle Aged , Retrospective Studies , Tablets/administration & dosage , Tablets/pharmacokinetics
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