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1.
Int J Mol Sci ; 23(22)2022 Nov 16.
Article in English | MEDLINE | ID: covidwho-2116063

ABSTRACT

Tyrosine kinase inhibitors (TKI) such as Masitinib were reported to be useful as therapeutic options in malignant disorders and nonmalignant diseases, like coronavirus disease 2019 (COVID-19). Most kinases must be translocated into targeted cells by the action of specific transport proteins, as they are hydrophilic and not able to cross cell membranes freely. Accordingly, the efficacy of TKI in target cells is closely dependent on the expression of their transporters. Specifically, Masitinib is an organic cation and is expected to interact with organic cation transporters (OCT and Multidrug and Toxin Extrusion proteins-MATE-). The aim of this work was to characterize the interaction of Masitinib with different OCTs. Human embryonic kidney 293 cells stably transfected with murine or human OCT were used for the experiments. The interaction of Masitinib with OCTs was investigated using quenching experiments. The intracellular accumulation of this drug was quantified using high performance liquid chromatography. Our results identified interactions of Masitinib with almost all investigated mouse (m) and human (h) OCTs and hMATE1 and indicated OCT1 and hOCT2 to be especially potent Masitinib translocators across cell membranes. Interestingly, some important differences were observed for the interaction with murine and human OCTs. In the future, investigations concerning further in vitro and in vivo properties of Masitinib and its efficacy related to transporter-related uptake mechanisms under pathophysiological conditions should be performed. Clinical trials in humans and other animals with Masitinib have already shown promising results. However, further research is necessary to understand the disease specific transport mechanisms of Masitinib to contribute to a successful and responsible therapy employment.


Subject(s)
COVID-19 , Organic Cation Transport Proteins , Humans , Mice , Animals , Organic Cation Transport Proteins/metabolism , Organic Cation Transporter 2 , Thiazoles
2.
Expert Rev Anti Infect Ther ; 20(12): 1615-1622, 2022 Dec.
Article in English | MEDLINE | ID: covidwho-2097136

ABSTRACT

BACKGROUND: This study investigated the clinical outcomes, virological efficacy and safety of nitazoxanide in the treatment of patients with COVID-19. RESEARCH DESIGN AND METHODS: The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before August 23, 2022. Only randomized controlled trials (RCTs) that assessed the usefulness and safety of nitazoxanide in patients with COVID-19 were included. RESULTS: Five RCTs were included. The overall mortality of COVID-19 patients receiving nitazoxanide (study group) was 1.3% (9/670), which was lower than the control group (1.8%, 12/681), but this difference did not reach statistical significance (risk difference [RD], 0.00; 95% CI: -0.01 to 0.01; P =0.97). However, nitazoxanide was associated with a higher virological eradication rate than placebo or standard care (RD, 0.09; 95% CI: 0.01 to 0.17; P = 0.03). Compared with the placebo or standard care, nitazoxanide were associated with a similar risk of any adverse event (RD, -0.02; 95% CI: -0.07 to 0.03; P = 0.44). CONCLUSIONS: Although nitazoxanide can help virological eradication and is also tolerable, it does not provide additional clinical benefits. Based on these evidences, the use of nitazoxanide in the treatment of patients with COVID-19 is not recommended.


Subject(s)
COVID-19 , Humans , COVID-19/drug therapy , Randomized Controlled Trials as Topic , Nitro Compounds/adverse effects , Thiazoles/adverse effects
3.
Acta Chim Slov ; 69(3): 647-656, 2022 Sep 26.
Article in English | MEDLINE | ID: covidwho-2056608

ABSTRACT

These days, the world is facing the threat of pandemic Coronavirus Disease 2019 (COVID-19). Although a vaccine has been found to combat the pandemic, it is essential to find drugs for an effective treatment method against this disease as soon as possible. In this study, electronic and thermodynamic properties, molecular electrostatic potential (MEP) analysis, and frontier molecular orbitals (FMOs) of nine different covid drugs were studied with Density Functional Theory (DFT). In addition, the relationship between the electronic structures of these drugs and their biological effectiveness was examined. All parameters were computed at the B3LYP/6-311++g(d,p) level. The Solvent effect was evaluated using conductor-like polarizable continuum model (CPCM) as the solvation model. It was observed that electrophilic indexes were important to understand the efficiencies of these drugs in COVID-19 disease. Paxlovid, hydroxyquinone, and nitazoxanide were found as the most thermodynamically stable molecules. Thermodynamic parameters also demonstrated that these drugs were more stable in the aqueous media. Global descriptors and the reactivity of these drugs were found to be related. Nitazoxanide molecule exhibited the highest dipole moment. The high dipole moments of drugs can cause hydrophilic interactions that increase their effectiveness in an aqueous solution.


Subject(s)
COVID-19 , Quantum Theory , COVID-19/drug therapy , Electronics , Humans , Models, Molecular , Nitro Compounds , Solvents/chemistry , Thiazoles , Water/chemistry
4.
Chem Res Toxicol ; 35(9): 1467-1481, 2022 09 19.
Article in English | MEDLINE | ID: covidwho-2008236

ABSTRACT

Masitinib is a small molecule tyrosine kinase inhibitor under investigation for the treatment of amyotrophic lateral sclerosis, mastocytosis, and COVID-19. Hepatotoxicity has been reported in some patients while taking masitinib. The liver injury is thought to involve hepatic metabolism of masitinib by cytochrome P450 (P450) enzymes to form chemically reactive, potentially toxic metabolites. The goal of the current investigation was to determine the P450 enzymes involved in the metabolic activation of masitinib in vitro. In initial studies, masitinib (30 µM) was incubated with pooled human liver microsomes in the presence of NADPH and potassium cyanide to trap reactive iminium ion metabolites as cyano adducts. Masitinib metabolites and cyano adducts were analyzed using reversed-phase liquid chromatography-tandem mass spectrometry. The primary active metabolite, N-desmethyl masitinib (M485), and several oxygenated metabolites were detected along with four reactive metabolite cyano adducts (MCN510, MCN524, MCN526, and MCN538). To determine which P450 enzymes were involved in metabolite formation, reaction phenotyping experiments were conducted by incubation of masitinib (2 µM) with a panel of recombinant human P450 enzymes and by incubation of masitinib with human liver microsomes in the presence of P450-selective chemical inhibitors. In addition, enzyme kinetic assays were conducted to determine the relative kinetic parameters (apparent Km and Vmax) of masitinib metabolism and cyano adduct formation. Integrated analysis of the results from these experiments indicates that masitinib metabolic activation is catalyzed primarily by P450 3A4 and 2C8, with minor contributions from P450 3A5 and 2D6. These findings provide further insight into the pathways involved in the generation of reactive, potentially toxic metabolites of masitinib. Future studies are needed to evaluate the impact of masitinib metabolism on the toxicity of the drug in vivo.


Subject(s)
COVID-19 , Activation, Metabolic , Benzamides , Catalysis , Cytochrome P-450 Enzyme System/metabolism , Humans , Microsomes, Liver/metabolism , NADP/metabolism , Piperidines , Potassium Cyanide , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Pyridines , Thiazoles
5.
Eur J Clin Pharmacol ; 78(11): 1813-1821, 2022 Nov.
Article in English | MEDLINE | ID: covidwho-2007128

ABSTRACT

PURPOSE: Nitazoxanide is a broad-spectrum antiparasitic that has been tested for COVID-19 due to its anti-inflammatory effects and in vitro antiviral activity. This study synthesized the best evidence on the efficacy and safety of nitazoxanide in COVID-19. METHODS: Searches for studies were performed in peer-reviewed and grey-literature from January 1, 2020 to May 23, 2022. The following elements were used to define eligibility criteria: (1) Population: individuals with COVID-19; (2) Intervention: nitazoxanide; (3) Comparison: placebo; (4) Outcomes: primary outcome was death, and secondary outcomes were viral load, positive RT-PCR status, serum biomarkers of inflammation, composite measure of disease progression (ICU admission or invasive mechanical ventilation), and any adverse events; (5) Study type: blinded, placebo-controlled, randomized clinical trials (RCTs). Treatment effects were reported as relative risk (RR) for dichotomous variables and standardized mean difference (SMD) for continuous variables with 95% confidence intervals (CI). RESULTS: Five blinded, placebo-controlled RCTs were included and enrolled individuals with mild or moderate SARS-CoV-2 infection. We found no difference between nitazoxanide and placebo in reducing viral load (SMD = - 0.16; 95% CI - 0.38 to 0.05) and the frequency of positive RTP-PCR results (RR = 0.92; 95% CI 0.81 to 1.06). In addition, there was no decreased risk for disease progression (RR = 0.63; 95% CI 0.38 to 1.04) and death (RR = 0.81; 95% CI 0.36 to 1.78) among patients receiving nitazoxanide. Patients with COVID-19 treated with nitazoxanide had decreased levels of white blood cells (SMD = - 0.15; 95% - 0.29 to - 0.02), lactate dehydrogenase (LDH) (SMD - 0.32; 95% - 0.52 to - 0.13), and D-dimer (SMD - 0.49; 95% CI - 0.68 to - 0.31) compared to placebo, but the magnitude of effect was considered small to moderate. CONCLUSION: This systematic review showed no evidence of clinical benefits of the use of nitazoxanide to treat patients with mild or moderate COVID-19. In addition, we found a reduction in WBC, LDH, and D-dimer levels among nitazoxanide-treated patients, but the effect size was considered small to moderate.


Subject(s)
COVID-19 , Anti-Inflammatory Agents , Antiparasitic Agents , Antiviral Agents/adverse effects , COVID-19/drug therapy , Disease Progression , Humans , Lactate Dehydrogenases , Nitro Compounds , Randomized Controlled Trials as Topic , SARS-CoV-2 , Thiazoles
6.
Water Res ; 223: 119021, 2022 Sep 01.
Article in English | MEDLINE | ID: covidwho-2004603

ABSTRACT

Due to the Covid-19 pandemic, the worldwide biocides application has been increased, which will eventually result in enhanced residuals in treated wastewater. At the same time, chlorine disinfection of secondary effluents and hospital wastewaters has been intensified. With respect to predicted elevated exposure in wastewater, the chlorination kinetics, transformation pathways and toxicity evolution were investigated in this study for two typical isothiazolinone biocides, methyl-isothiazolinone (MIT) and chloro-methyl-isothiazolinone (CMIT). Second-order rate constants of 0.13 M-1·s-1, 1.95 × 105 M-1·s-1 and 5.14 × 105 M-1·s-1 were determined for the reaction of MIT with HOCl, Cl2O and Cl2, respectively, while reactivity of CMIT was around 1-2 orders of magnitude lower. While chlorination of isothiazolinone biocides at pH 7.1 was dominated by Cl2O-oxidation, acidic pH and elevated Cl- concentration favored free active chlorine (FAC) speciation into Cl2 and increased overall isothiazolinone removal. Regardless of the dominant FAC species, the elimination of MIT and CMIT resulted in an immediate loss of acute toxicity under all experimental conditions, which was attributed to a preferential attack at the S-atom resulting in subsequent formation of sulfoxides and sulfones and eventually an S-elimination. However, chlorination of isothiazolinone biocides in secondary effluent only achieved <10% elimination at typical disinfection chlorine exposure 200 mg·L-1·min, but was predicted to be remarkably increased by acidizing solution to pH 5.5. Alternative measures might be needed to minimize the discharge of these toxic chemicals into the aquatic environment.


Subject(s)
COVID-19 , Disinfectants , Water Pollutants, Chemical , Water Purification , Chlorine , Disinfectants/toxicity , Halogenation , Halogens , Humans , Hydrogen-Ion Concentration , Kinetics , Pandemics , Sulfones , Sulfoxides , Thiazoles , Waste Water , Water Pollutants, Chemical/analysis , Water Purification/methods
7.
Molecules ; 27(15)2022 Jul 25.
Article in English | MEDLINE | ID: covidwho-1994112

ABSTRACT

A set of heterocyclic products was synthesized from natural (+)-camphor and semi-synthetic (-)-camphor. Then, 2-Imino-4-thiazolidinones and 2,3-dihydrothiazoles were obtained using a three-step procedure. For the synthesized compounds, their antiviral activity against the vaccinia virus and Marburg virus was studied. New promising agents active against both viruses were found among the tested compounds.


Subject(s)
Antiviral Agents , Camphor , Antiviral Agents/pharmacology , Camphor/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology
8.
J Antimicrob Chemother ; 77(10): 2706-2712, 2022 09 30.
Article in English | MEDLINE | ID: covidwho-1992221

ABSTRACT

BACKGROUND: The COVER trial evaluated whether nitazoxanide or sofosbuvir/daclatasvir could lower the risk of SARS-CoV-2 infection. Nitazoxanide was selected given its favourable pharmacokinetics and in vitro antiviral effects against SARS-CoV-2. Sofosbuvir/daclatasvir had shown favourable results in early clinical trials. METHODS: In this clinical trial in Johannesburg, South Africa, healthcare workers and others at high risk of infection were randomized to 24 weeks of either nitazoxanide or sofosbuvir/daclatasvir as prevention, or standard prevention advice only. Participants were evaluated every 4 weeks for COVID-19 symptoms and had antibody and PCR testing. The primary endpoint was positive SARS-CoV-2 PCR and/or serology ≥7 days after randomization, regardless of symptoms. A Poisson regression model was used to estimate the incidence rate ratios of confirmed SARS-CoV-2 between each experimental arm and control. RESULTS: Between December 2020 and January 2022, 828 participants were enrolled. COVID-19 infections were confirmed in 100 participants on nitazoxanide (2234 per 1000 person-years; 95% CI 1837-2718), 87 on sofosbuvir/daclatasvir (2125 per 1000 person-years; 95% CI 1722-2622) and 111 in the control arm (1849 per 1000 person-years; 95% CI 1535-2227). There were no significant differences in the primary endpoint between the treatment arms, and the results met the criteria for futility. In the safety analysis, the frequency of grade 3 or 4 adverse events was low and similar across arms. CONCLUSIONS: In this randomized trial, nitazoxanide and sofosbuvir/daclatasvir had no significant preventative effect on infection with SARS-CoV-2 among healthcare workers and others at high risk of infection.


Subject(s)
COVID-19 , Antiviral Agents/therapeutic use , COVID-19/prevention & control , Carbamates , Humans , Imidazoles , Nitro Compounds , Pyrrolidines , SARS-CoV-2 , Sofosbuvir/therapeutic use , South Africa , Thiazoles , Treatment Outcome , Valine/analogs & derivatives
9.
EBioMedicine ; 82: 104148, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1991004

ABSTRACT

BACKGROUND: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. METHODS: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. FINDINGS: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. INTERPRETATION: These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19. FUNDING: This work was supported by the Fondation de France "call FLASH COVID-19", project TAMAC, by "Institut national de la santé et de la recherche médicale" through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 ('Activité des molécules antivirales dans le modèle hamster'), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator".


Subject(s)
COVID-19 , SARS-CoV-2 , Animals , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Cricetinae , Humans , Nitro Compounds , Thiazoles
10.
Int J Mol Sci ; 23(14)2022 Jul 12.
Article in English | MEDLINE | ID: covidwho-1964004

ABSTRACT

It is well-known that thiazole derivatives are usually found in lead structures, which demonstrate a wide range of pharmacological effects. The aim of this research was to explore the antiviral, antioxidant, and antibacterial activities of novel, substituted thiazole compounds and to find potential agents that could have biological activities in one single biomolecule. A series of novel aminothiazoles were synthesized, and their biological activity was characterized. The obtained results were compared with those of the standard antiviral, antioxidant, antibacterial and anticancer agents. The compound bearing 4-cianophenyl substituent in the thiazole ring demonstrated the highest cytotoxic properties by decreasing the A549 viability to 87.2%. The compound bearing 4-trifluoromethylphenyl substituent in the thiazole ring showed significant antiviral activity against the PR8 influenza A strain, which was comparable to the oseltamivir and amantadine. Novel compounds with 4-chlorophenyl, 4-trifluoromethylphenyl, phenyl, 4-fluorophenyl, and 4-cianophenyl substituents in the thiazole ring demonstrated antioxidant activity by DPPH, reducing power, FRAP methods, and antibacterial activity against Escherichia coli and Bacillus subtilis bacteria. These data demonstrate that substituted aminothiazole derivatives are promising scaffolds for further optimization and development of new compounds with potential influenza A-targeted antiviral activity. Study results could demonstrate that structure optimization of novel aminothiazole compounds may be useful in the prevention of reactive oxygen species and developing new specifically targeted antioxidant and antibacterial agents.


Subject(s)
Antioxidants , Influenza, Human , Anti-Bacterial Agents/chemistry , Antioxidants/chemistry , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Escherichia coli , Humans , Microbial Sensitivity Tests , Structure-Activity Relationship , Thiazoles/chemistry
11.
Trials ; 23(1): 583, 2022 Jul 22.
Article in English | MEDLINE | ID: covidwho-1957067

ABSTRACT

BACKGROUND: The 2020 pandemic of SARS-CoV-2 causing COVID-19 disease is an unprecedented global emergency. COVID-19 appears to be a disease with an early phase where the virus replicates, coinciding with the first presentation of symptoms, followed by a later 'inflammatory' phase which results in severe disease in some individuals. It is known from other rapidly progressive infections such as sepsis and influenza that early treatment with antimicrobials is associated with a better outcome. The hypothesis is that this holds for COVID-19 and that early antiviral treatment may prevent progression to the later phase of the disease. METHODS: Trial design: Phase IIA randomised, double-blind, 2 × 2 design, placebo-controlled, interventional trial. RANDOMISATION: Participants will be randomised 1:1 by stratification, with the following factors: gender, obesity, symptomatic or asymptomatic, current smoking status presence or absence of comorbidity, and if the participant has or has not been vaccinated. BLINDING: Participants and investigators will both be blinded to treatment allocation (double-blind). DISCUSSION: We propose to conduct a proof-of-principle placebo-controlled clinical trial of favipiravir plus or minus nitazoxanide in health workers, their household members and patients treated at the Mexican Social Security Institute (IMSS) facilities. Participants with or without symptomatic COVID-19 or who tested positive will be assigned to receive favipiravir plus nitazoxanide or favipiravir plus nitazoxanide placebo. The primary outcome will be the difference in the amount of virus ('viral load') in the upper respiratory tract after 5 days of therapy. Secondary outcomes will include hospitalization, major morbidity and mortality, pharmacokinetics, and impact of antiviral therapy on viral genetic mutation rate. If favipiravir with nitazoxanide demonstrates important antiviral effects without significant toxicity, there will be a strong case for a larger trial in people at high risk of hospitalization or intensive care admission, for example older patients and/or those with comorbidities and with early disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT04918927 . Registered on June 9, 2021.


Subject(s)
COVID-19 , Amides , Antiviral Agents/adverse effects , COVID-19/drug therapy , Humans , Nitro Compounds , Pyrazines , SARS-CoV-2 , Secondary Prevention , Thiazoles , Treatment Outcome
12.
Molecules ; 27(10)2022 May 23.
Article in English | MEDLINE | ID: covidwho-1953751

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 is a global burden on human health and economy. The 3-Chymotrypsin-like cysteine protease (3CLpro) becomes an attractive target for SARS-CoV-2 due to its important role in viral replication. We synthesized a series of 8H-indeno[1,2-d]thiazole derivatives and evaluated their biochemical activities against SARS-CoV-2 3CLpro. Among them, the representative compound 7a displayed inhibitory activity with an IC50 of 1.28 ± 0.17 µM against SARS-CoV-2 3CLpro. Molecular docking of 7a against 3CLpro was performed and the binding mode was rationalized. These preliminary results provide a unique prototype for the development of novel inhibitors against SARS-CoV-2 3CLpro.


Subject(s)
COVID-19 , Protease Inhibitors , COVID-19/drug therapy , Cysteine Endopeptidases/chemistry , Humans , Molecular Docking Simulation , Pandemics , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , SARS-CoV-2 , Thiazoles/pharmacology , Viral Proteins/metabolism
13.
Pharmacol Res Perspect ; 9(3): e00800, 2021 05.
Article in English | MEDLINE | ID: covidwho-1898944

ABSTRACT

Antiprotozoal drug nitazoxanide (NTZ) has shown diverse pharmacological properties and has appeared in several clinical trials. Herein we present the synthesis, characterization, in vitro biological investigation, and in silico study of four hetero aryl amide analogs of NTZ. Among the synthesized molecules, compound 2 and compound 4 exhibited promising antibacterial activity against Escherichia coli (E. coli), superior to that displayed by the parent drug nitazoxanide as revealed from the in vitro antibacterial assay. Compound 2 displayed zone of inhibition of 20 mm, twice as large as the parent drug NTZ (10 mm) in their least concentration (12.5 µg/ml). Compound 1 also showed antibacterial effect similar to that of nitazoxanide. The analogs were also tested for in vitro cytotoxic activity by employing cell counting kit-8 (CCK-8) assay technique in HeLa cell line, and compound 2 was identified as a potential anticancer agent having IC50 value of 172 µg which proves it to be more potent than nitazoxanide (IC50  = 428 µg). Furthermore, the compounds were subjected to molecular docking study against various bacterial and cancer signaling proteins. The in vitro test results corroborated with the in silico docking study as compound 2 and compound 4 had comparatively stronger binding affinity against the proteins and showed a higher docking score than nitazoxanide toward human mitogen-activated protein kinase (MAPK9) and fatty acid biosynthesis enzyme (FabH) of E. coli. Moreover, the docking study demonstrated dihydrofolate reductase (DHFR) and thymidylate synthase (TS) as probable new targets for nitazoxanide and its synthetic analogs. Overall, the study suggests that nitazoxanide and its analogs can be a potential lead compound in the drug development.


Subject(s)
Amides , Anti-Bacterial Agents , Antineoplastic Agents , Antiparasitic Agents , Nitro Compounds , Thiazoles , Amides/chemistry , Amides/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Bacterial Proteins/metabolism , Biological Assay , Cell Survival/drug effects , Escherichia coli/drug effects , Escherichia coli/growth & development , HeLa Cells , Humans , Mitogen-Activated Protein Kinase 9/metabolism , Molecular Docking Simulation , Nitro Compounds/chemistry , Nitro Compounds/pharmacology , Tetrahydrofolate Dehydrogenase/metabolism , Thiazoles/chemistry , Thiazoles/pharmacology , Thymidylate Synthase/metabolism
14.
Br J Clin Pharmacol ; 88(5): 2180-2189, 2022 05.
Article in English | MEDLINE | ID: covidwho-1895952

ABSTRACT

AIMS: To explore and describe the adverse reaction signals in the safety reporting for alpelisib. METHODS: We performed a disproportionality analysis of the World Health Organization's VigiBase pharmacovigilance database from 1 January 2019 to 30 June 2021. Disproportionality analysis by information components (ICs) were used to evaluate the potential association between adverse events (AEs) and alpelisib. RESULTS: A total of 33 327 reports were extracted, 5695 of them were chosen with alpelisib as the suspected drug. After combining the same ID, 687 cases remained. The 45-64-years group had the most cases (n = 203, 29.55%). There were 129 Preferred Terms with significant signals. Hyperglycaemia (IC025 = 6.74), breast cancer metastatic (IC025 = 5.85) and metastases to liver (IC025 = 4.70) were the AEs with the strongest signal. AEs with the most cases were hyperglycaemia (n = 595), rash (n = 535) and diarrhoea (n = 475). CONCLUSION: We established a comprehensive list of AEs potentially associated with alpelisib. AEs with the most significant signals were hyperglycaemia, breast cancer metastatic, metastases to liver. The AEs with the most cases were hyperglycaemia, rash, diarrhoea, blood glucose increase and nausea.


Subject(s)
Breast Neoplasms , Drug-Related Side Effects and Adverse Reactions , Exanthema , Hyperglycemia , Adverse Drug Reaction Reporting Systems , Breast Neoplasms/drug therapy , Databases, Factual , Diarrhea , Drug-Related Side Effects and Adverse Reactions/epidemiology , Female , Humans , Hyperglycemia/chemically induced , Hyperglycemia/epidemiology , Pharmacovigilance , Thiazoles , World Health Organization
15.
Arch Pharm (Weinheim) ; 355(9): e2200121, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1858558

ABSTRACT

As an attempt to contribute to the efforts of combating the pandemic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for COVID-19, new analogs of the repurposed drug nitazoxanide which showed promising inhibitory efficacy on a viral protease enzyme were designed, synthesized and evaluated for their inhibitory activity on the main protease of the SARS-CoV-2 virus, using the COV2-3CL protease inhibition assay. The obtained results showed that the N-(substituted-thiazol-2-yl)cinnamamide analogs 19, 20, and 21 were the most active compounds with IC50 values of 22.61, 14.7, 21.99 µM, respectively, against the viral protease compared to the reference drugs, nitazoxanide, and lopinavir. Molecular modeling studies showed binding interactions of 19, 20, and 21 with hydrogen bonds to Gln189 and Glu166, arene-arene interaction between the thiazole moiety and His41, and other hydrophobic interactions between the ethene spacer moiety and Asn142. Moreover, an extra arene-arene interaction between substituted benzo[d]thiazole and His41 was observed regarding compounds 19 and 21. Surface mapping and flexible alignment proved the structural similarity between the new drug candidates and nitazoxanide. Compliance of the new compounds to Lipinski's rule of five was investigated and absorption, distribution, metabolism, excretion, and toxicology data were predicted. The newly synthesized compounds are promising template ligands for further development and optimization.


Subject(s)
COVID-19 , SARS-CoV-2 , COVID-19/drug therapy , Coronavirus 3C Proteases , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptide Hydrolases , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/pharmacology , Viral Nonstructural Proteins
16.
BMJ Open ; 12(4): e048777, 2022 04 27.
Article in English | MEDLINE | ID: covidwho-1854328

ABSTRACT

INTRODUCTION: High adherence to oral anticoagulants is essential for stroke prevention in patients with atrial fibrillation (AF). We developed a smartphone application (app) that pushes alarms for taking medication and measuring blood pressure (BP) and heart rate (HR) at certain times of the day. In addition to drug alarms, the habit of measuring one's BP and HR may reinforce drug adherence by improving self-awareness of the disease. This pilot study aims to test the feasibility and efficacy of the smartphone app-based intervention for improving drug adherence in patients with AF. METHODS AND ANALYSIS: A total of 10 university hospitals in Korea will participate in this randomised control trial. Patients with AF, being treated with edoxaban for stroke prevention will be included in this study. Total of 500 patients will be included and the patients will be randomised to the conventional treatment group (250 patients) and the app conditional feedback group (250 patients). Patients in the app conditional feedback group will use the medication reminder app for medication and BP check alarms. The automatic BP machine will be linked to the smartphone via Bluetooth. The measured BP and HR will be updated automatically on the smartphone app. The primary endpoint is edoxaban adherence by pill count measurement at 3 and 6 months of follow-up. Secondary endpoints are clinical composite endpoints including stroke, systemic embolic event, major bleeding requiring hospitalisation or transfusion, or death during the 6 months. As of 24t November 2021, 80 patients were enrolled. ETHICS AND DISSEMINATION: This study was approved by the Seoul National University Bundang Hospital Institutional Review Board and will be conducted according to the principles of the Declaration of Helsinki. The study results will be published in a reputable journal. TRIAL REGISTRATION NUMBER: KCT0004754.


Subject(s)
Atrial Fibrillation , Mobile Applications , Stroke , Atrial Fibrillation/drug therapy , Humans , Pilot Projects , Pyridines , Randomized Controlled Trials as Topic , Smartphone , Stroke/prevention & control , Thiazoles
17.
Electrophoresis ; 43(15): 1617-1625, 2022 08.
Article in English | MEDLINE | ID: covidwho-1825938

ABSTRACT

The incidence of thrombotic complications in SARS-CoV-2 infections has become a global concern; thus, anticoagulants are an integral part of the treatment. Edoxaban (EDX) is an oral anticoagulant suitable for pharmacologic thromboprophylaxis. Herein, two novel analytical methods for EDX determination in tablets are developed and validated using capillary zone electrophoresis (CZE) and high-performance liquid chromatography (HPLC). Operating conditions such as the electrolyte's concentration and pH value, injection time, volume, and the capillary temperature, were optimized. The methods were successfully validated by establishing the linearity, intra- and inter-day precisions (relative standard deviation [%]), accuracy, and robustness. Adequate separation of excipients and degradation products of EDX generated by stress degradation conditions demonstrated the stability-indicating capability of the methods. The analytical procedures were linear in the range of 25-125 µg/ml (r > 0.999), with the limits of detection and quantification of 3.26 and 10.87 µg/ml for CZE and 0.740 and 2.78 µg/ml for HPLC. Although both methodologies are suitable for determining EDX in tablets, CZE provides a greener alternative due to low-cost analysis using less organic solvents and minimizing waste generation.


Subject(s)
COVID-19 , Venous Thromboembolism , Anticoagulants , Chromatography, High Pressure Liquid/methods , Electrophoresis, Capillary/methods , Humans , Pyridines , Reproducibility of Results , SARS-CoV-2 , Tablets , Thiazoles
18.
Arab J Gastroenterol ; 23(3): 165-171, 2022 Aug.
Article in English | MEDLINE | ID: covidwho-1821101

ABSTRACT

BACKGROUND AND STUDY AIMS: Currently, there is no therapy approved for COVID-19. We evaluated the efficacy and safety of sofosbuvir/ledipasvir and nitazoxanide for the treatment of patients with COVID-19 infection. PATIENTS AND METHODS: A multicenter, open-label randomized controlled trial included one hundred and ninety patients with non-severe COVID-19 infection. Patients were randomized into three groups. All groups received standard care treatment (SCT). In addition, group 1 received sofosbuvir/ledipasvir, and group 2 received nitazoxanide. Follow-up by reverse-transcriptase polymerase chain reaction (RT-PCR) was done at intervals of 5, 8, 11, and 14 days. The primary endpoint was viral clearance. RESULTS: Viral clearance was significantly higher in the sofosbuvir/ledipasvir and nitazoxanide groups compared to the SCT group in all follow-up intervals (p < 0.001). In the sofosbuvir/ledipasvir arm, 36.9% showed early viral clearance by day 5. By day 14, 83.1% of the sofosbuvir/ledipasvir group, 39.7% of the nitazoxanide group, and 19.4% of the SCT group tested negative for SARS-CoV-2. Sofosbuvir/ledipasvir and nitazoxanide treatment were the only significant factors in Cox regression of negative RT-PCR with the highest OR (17.88, 95% CI: 6.66-47.98 and 2.59, 95% CI: 1.11-6.07, respectively). No mortality or serious adverse events were recorded. CONCLUSION: The addition of sofosbuvir/ledipasvir or nitazoxanide to the SCT results in an early and high viral clearance rate in mild and moderate patients with COVID-19. These drugs represent a safe and affordable treatment for COVID-19.


Subject(s)
COVID-19 , Sofosbuvir , Antiviral Agents/therapeutic use , Benzimidazoles , COVID-19/drug therapy , Drug Repositioning , Drug Therapy, Combination , Fluorenes , Genotype , Hepacivirus , Humans , Nitro Compounds , SARS-CoV-2 , Sofosbuvir/therapeutic use , Thiazoles , Treatment Outcome , Viral Load
19.
Bioorg Med Chem Lett ; 58: 128526, 2022 02 15.
Article in English | MEDLINE | ID: covidwho-1814173

ABSTRACT

The COVID-19 pandemic has drastically impacted global economies and public health. Although vaccine development has been successful, it was not sufficient against more infectious mutant strains including the Delta variant indicating a need for alternative treatment strategies such as small molecular compound development. In this work, a series of SARS-CoV-2 main protease (Mpro) inhibitors were designed and tested based on the active compound from high-throughput diverse compound library screens. The most efficacious compound (16b-3) displayed potent SARS-CoV-2 Mpro inhibition with an IC50 value of 116 nM and selectivity against SARS-CoV-2 Mpro when compared to PLpro and RdRp. This new class of compounds could be used as potential leads for further optimization in anti COVID-19 drug discovery.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus 3C Proteases/antagonists & inhibitors , Drug Discovery , Protease Inhibitors/pharmacology , SARS-CoV-2/drug effects , Thiazoles/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , COVID-19/drug therapy , Coronavirus 3C Proteases/metabolism , Humans , Microbial Sensitivity Tests , Molecular Structure , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , SARS-CoV-2/enzymology , Thiazoles/chemical synthesis , Thiazoles/chemistry
20.
Expert Opin Ther Pat ; 32(7): 791-815, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1795496

ABSTRACT

INTRODUCTION: Several viral infections cause life-threatening consequences in humans, making them the most serious public health concerns. Despite the fact that several antiviral medicines are available on the market, there is no full treatment for many important viral infections. To date, antiviral medicines have significantly reduced the spread of epidemics, but their continued use has resulted in the creation of drug-resistant variants throughout time. As a result, the development of new, safe, and efficient antiviral drugs is critical. AREAS COVERED: This review covered reports in the patent literature in the period 2014 to the first quarter of 2021 on the antiviral activities of thiazole derivatives. These molecules were reported to inhibit a wide range of viruses including influenza viruses, coronaviruses, herpes viruses, hepatitis B and C, bovine viral diarrhea virus, chikungunya virus and human immunodeficiency viruses. EXPERT OPINION: The most bioactive molecules can be used as lead structures for the development of new thiazole compounds with potent and selective antiviral activity. In addition, more efforts are needed to better understand the host-virus interactions for the discovery and development of new therapeutic agents and creative treatment strategies that are supposed to improve rates of clinical cure of the serious viruses.


Subject(s)
Thiazoles , Virus Diseases , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Humans , Patents as Topic , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazoles/therapeutic use , Virus Diseases/drug therapy
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