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1.
Molecules ; 26(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805419

RESUMO

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.


Assuntos
Antivirais/farmacocinética , Reposicionamento de Medicamentos/métodos , Hipertensão Pulmonar/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/farmacocinética , Antivirais/sangue , Medicamentos Biossimilares , Bloqueadores dos Canais de Cálcio/farmacocinética , Simulação por Computador , Bases de Dados de Produtos Farmacêuticos , Desenvolvimento de Medicamentos/métodos , Humanos , Hipertensão Pulmonar/virologia , Distribuição Tecidual
2.
Artigo em Inglês | MEDLINE | ID: mdl-33756448

RESUMO

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.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Monitoramento de Medicamentos/métodos , Espectrometria de Massas em Tandem/métodos , Monofosfato de Adenosina/sangue , Alanina/sangue , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/métodos , Monitoramento de Medicamentos/economia , Feminino , Humanos , Limite de Detecção , Masculino , Espectrometria de Massas em Tandem/economia
3.
J Pharm Biomed Anal ; 196: 113935, 2021 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-33548872

RESUMO

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.


Assuntos
Antivirais/sangue , Antivirais/uso terapêutico , /tratamento farmacológico , Isótopos/química , /efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/sangue , Alanina/análogos & derivados , Alanina/sangue , Amidas/sangue , Azitromicina/sangue , Cloroquina/sangue , Cromatografia Líquida/métodos , Furanos/sangue , Humanos , Hidroxicloroquina/sangue , Lopinavir/sangue , Pandemias/prevenção & controle , Pirazinas/sangue , Pirróis/sangue , Ritonavir/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue
5.
Anal Biochem ; 617: 114118, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33508271

RESUMO

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.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Monitoramento de Medicamentos/métodos , Furanos/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Monofosfato de Adenosina/sangue , Alanina/sangue , Cromatografia Líquida de Alta Pressão/métodos , Humanos , Limite de Detecção
6.
Free Radic Biol Med ; 163: 153-162, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33347987

RESUMO

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.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Pulmão/efeitos dos fármacos , Óxido Nítrico/uso terapêutico , Administração por Inalação , Anti-Inflamatórios/sangue , Anticoagulantes/sangue , Antivirais/sangue , /patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Inflamação , Pulmão/irrigação sanguínea , Pulmão/virologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/virologia , Óxido Nítrico/sangue , /patogenicidade , Índice de Gravidade de Doença , Vasodilatação/efeitos dos fármacos
7.
Spectrochim Acta A Mol Biomol Spectrosc ; 249: 119241, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33333412

RESUMO

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.


Assuntos
Amidas/sangue , Antivirais/sangue , /tratamento farmacológico , Pirazinas/sangue , Espectrometria de Fluorescência/métodos , Amidas/análise , Amidas/uso terapêutico , Antivirais/análise , Antivirais/uso terapêutico , Análise Química do Sangue/métodos , Análise Química do Sangue/estatística & dados numéricos , Humanos , Limite de Detecção , Pirazinas/análise , Pirazinas/uso terapêutico , Sensibilidade e Especificidade , Espectrometria de Fluorescência/estatística & dados numéricos
8.
Circ Arrhythm Electrophysiol ; 13(10): e008686, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32907357

RESUMO

BACKGROUND: Based on inhibition of viral replication and limited reports on clinical efficacy, hydroxychloroquine is being considered as prophylaxis and treatment of coronavirus disease-19 (COVID-19). Although hydroxychloroquine is generally considered safe during pregnancy based on studies in patients with systemic lupus erythematosus and other rheumatic conditions, there may still be reluctance to institute this antimalarial during pregnancy for the sole purpose of antiviral therapy. METHODS: To provide data regarding any potential fetal/neonatal cardiotoxicity, we leveraged a unique opportunity in which neonatal ECGs and hydroxychloroquine blood levels were available in a recently completed study evaluating the efficacy of hydroxychloroquine 400 mg daily to prevent the recurrence of congenital heart block associated with anti-SSA/Ro (anti-Sjögren's Syndrome A/Ro) antibodies. RESULTS: Forty-five ECGs were available for corrected QT interval (QTc) measurement, and levels of hydroxychloroquine were assessed during each trimester of pregnancy and in the cord blood, providing unambiguous assurance of drug exposure. Overall, there was no correlation between cord blood levels of hydroxychloroquine and the neonatal QTc (R=0.02, P=0.86) or the mean of hydroxychloroquine values obtained throughout each individual pregnancy and the QTc (R=0.04, P=0.80). In total 5 (11% [95% CI, 4%-24%]) neonates had prolongation of the QTc >2 SD above historical healthy controls (2 markedly and 3 marginally) but ECGs were otherwise normal. CONCLUSIONS: In aggregate, these data provide reassurances that the maternal use of hydroxychloroquine is associated with a low incidence of infant QTc prolongation. However, if included in clinical COVID-19 studies, early postnatal ECGs should be considered. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01379573.


Assuntos
Antivirais/administração & dosagem , Eletrocardiografia , Coração Fetal/efeitos dos fármacos , Bloqueio Cardíaco/congênito , Frequência Cardíaca/efeitos dos fármacos , Hidroxicloroquina/administração & dosagem , Antivirais/efeitos adversos , Antivirais/sangue , Cardiotoxicidade , Esquema de Medicação , Monitoramento de Medicamentos , Feminino , Sangue Fetal/metabolismo , Coração Fetal/fisiopatologia , Idade Gestacional , Bloqueio Cardíaco/diagnóstico , Bloqueio Cardíaco/fisiopatologia , Bloqueio Cardíaco/prevenção & controle , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/sangue , Lactente , Recém-Nascido , Masculino , Valor Preditivo dos Testes , Gravidez , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento
9.
Virology ; 550: 61-69, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32882638

RESUMO

The world is in the midst of a pandemic caused by a novel coronavirus and is desperately searching for possible treatments. The antiviral remdesivir has shown some effectiveness against SARS-CoV-2 in vitro and in a recent animal study. We use data from a study of remdesivir in rhesus macaques to fit a viral kinetics model in an effort to determine the most appropriate mathematical descripton of the effect of remdesivir. We find statistically significant differences in the viral decay rate and use this to inform a possible mathematical formulation of the effect of remdesivir. Unfortunately, this model formulation suggests that the application of remdesivir will lengthen SARS-CoV-2 infections, putting into question its potential clinical benefit.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Modelos Estatísticos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Animais , Antivirais/sangue , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/patogenicidade , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Esquema de Medicação , Humanos , Inflamação , Macaca mulatta , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Carga Viral , Replicação Viral
10.
J Pharm Sci ; 109(12): 3574-3578, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32891630

RESUMO

SARS-CoV-2 utilizes the IMPα/ß1 heterodimer to enter host cell nuclei after gaining cellular access through the ACE2 receptor. Ivermectin has shown antiviral activity by inhibiting the formation of the importin-α (IMPα) and IMPß1 subunits as well as dissociating the IMPα/ß1 heterodimer and has in vitro efficacy against SARS-CoV-2. Plasma and lung ivermectin concentrations vs. time profiles in cattle were used to determine the apparent plasma to lung tissue partition coefficient of ivermectin. This coefficient, together with a simulated geometric mean plasma profile of ivermectin from a published population pharmacokinetic model, was utilized to develop a minimal physiologically-based pharmacokinetic (mPBPK) model. The mPBPK model accurately described the simulated ivermectin plasma concentration profile in humans. The mPBPK model was also used to simulate human lung exposure to ivermectin after 12, 30, and 120 mg oral doses. The simulated ivermectin lung exposures reached a maximum concentration of 772 ng/mL, far less than the estimated 1750 ng/mL IC50 reported for ivermectin against SARS-CoV-2 in vitro. Further studies of ivermectin either reformulated for inhaled delivery or in combination with other antivirals with differing mechanisms of action is needed to assess its therapeutic potential.


Assuntos
Antivirais/farmacocinética , Infecções por Coronavirus/tratamento farmacológico , Ivermectina/farmacocinética , Pulmão/metabolismo , Pneumonia Viral/tratamento farmacológico , Administração Oral , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Bovinos , Simulação por Computador , Infecções por Coronavirus/metabolismo , Reposicionamento de Medicamentos , Humanos , Ivermectina/administração & dosagem , Ivermectina/sangue , Ivermectina/farmacologia , Modelos Biológicos , Pandemias , Pneumonia Viral/metabolismo
12.
Antiviral Res ; 181: 104866, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32659293

RESUMO

In the context of the COVID-19 pandemic, several drugs have been repurposed as potential candidates for the treatment of COVID-19 infection. While preliminary choices were essentially based on in vitro potency, clinical translation into effective therapies may be challenging due to unfavorable in vivo pharmacokinetic properties at the doses chosen for this new indication of COVID-19 infection. However, available pharmacokinetic and pharmacokinetic-pharmacodynamic studies suffer from severe limitations leading to unreliable conclusions, especially in term of dosing optimization. In this paper we propose to highlight these limitations and to identify some of the major requirements that need to be addressed in designing PK and PK-PD studies in this era of COVID. A special attention should be paid to pre-analytical and analytical requirements and to the proper collection of covariates affecting dose-exposure relationships (co-medications, use of specific organ support techniques and other clinical and para-clinical data). We also promote the development of population PK and PK-PD models specifically dedicated to COVID-19 patients since those previously developed for other diseases (SEL, malaria, HIV) and clinical situations (steady-state, non-ICU patients) are not representative of severe patients. Therefore, implementation of well-designed PK and PD studies targeted to COVID-19 patients is urgently needed. For that purpose we call for multi-institutional collaborative work and involvement of clinical pharmacologists in multidisciplinary research consortia.


Assuntos
Antivirais/farmacologia , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Antivirais/administração & dosagem , Antivirais/sangue , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Coleta de Dados , Relação Dose-Resposta a Droga , Interações Medicamentosas , Humanos , Modelos Biológicos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia
13.
Artigo em Inglês | MEDLINE | ID: mdl-32641296

RESUMO

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 µg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.


Assuntos
Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Hidroxicloroquina/farmacocinética , Lopinavir/farmacocinética , Pneumonia Viral/tratamento farmacológico , Ritonavir/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/sangue , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hospitais Universitários , Humanos , Hidroxicloroquina/sangue , Hidroxicloroquina/farmacologia , Tempo de Internação/estatística & dados numéricos , Lopinavir/sangue , Lopinavir/farmacologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Retrospectivos , Ritonavir/sangue , Ritonavir/farmacologia , Índice de Gravidade de Doença , Análise de Sobrevida
14.
Clin Chem Lab Med ; 58(9): 1461-1468, 2020 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-32573468

RESUMO

Objectives: A method based on liquid chromatography coupled to triple quadrupole mass spectrometry detection using 50 µL of plasma was developed and fully validated for quantification of remdesivir and its active metabolites GS-441524. Methods: A simple protein precipitation was carried out using 75 µL of methanol containing the internal standard (IS) remdesivir-13C6 and 5 µL ZnSO4 1 M. After separation on Kinetex® 2.6 µm Polar C18 100A LC column (100 × 2.1 mm i.d.), both compounds were detected by a mass spectrometer with electrospray ionization in positive mode. The ion transitions used were m/z 603.3 â†’ m/z 200.0 and m/z 229.0 for remdesivir, m/z 292.2 â†’ m/z 173.1 and m/z 147.1 for GS-441524 and m/z 609.3 â†’ m/z 206.0 for remdesivir-13C6. Results: Calibration curves were linear in the 1-5000 µg/L range for remdesivir and 5-2500 for GS-441524, with limit of detection set at 0.5 and 2 µg/L and limit of quantification at 1 and 5 µg/L, respectively. Precisions evaluated at 2.5, 400 and 4000 µg/L for remdesivir and 12.5, 125, 2000 µg/L for GS-441524 were lower than 14.7% and accuracy was in the [89.6-110.2%] range. A slight matrix effect was observed, compensated by IS. Higher stability of remdesivir and metabolite was observed on NaF-plasma. After 200 mg IV single administration, remdesivir concentration decrease rapidly with a half-life less than 1 h while GS-441524 appeared rapidly and decreased slowly until H24 with a half-life around 12 h. Conclusions: This method would be useful for therapeutic drug monitoring of these compounds in Covid-19 pandemic.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/sangue , Betacoronavirus , Cromatografia Líquida/métodos , Infecções por Coronavirus/sangue , Monitoramento de Medicamentos/métodos , Furanos/sangue , Pneumonia Viral/sangue , Pirróis/sangue , Espectrometria de Massas em Tandem/métodos , Triazinas/sangue , Monofosfato de Adenosina/sangue , Monofosfato de Adenosina/farmacocinética , Alanina/sangue , Alanina/farmacocinética , Antivirais/farmacocinética , Estabilidade de Medicamentos , Feminino , Furanos/farmacocinética , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Pandemias , Pirróis/farmacocinética , Reprodutibilidade dos Testes , Triazinas/farmacocinética
15.
Clin Pharmacol Ther ; 108(4): 775-790, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32438446

RESUMO

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.


Assuntos
Antivirais/administração & dosagem , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Antivirais/sangue , Infecções por Coronavirus/sangue , Humanos , Pandemias , Pneumonia Viral/sangue
16.
Travel Med Infect Dis ; 35: 101735, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32387694

RESUMO

The rapidly spreading Coronavirus Disease (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus (SARS-CoV-2), represents an unprecedented serious challenge to the global public health community. The extremely rapid international spread of the disease with significant morbidity and mortality made finding possible therapeutic interventions a global priority. While approved specific antiviral drugs against SARS-CoV-2 are still lacking, a large number of existing drugs are being explored as a possible treatment for COVID-19 infected patients. Recent publications have re-examined the use of Chloroquine (CQ) and/or Hydroxychloroquine (HCQ) as a potential therapeutic option for these patients. In an attempt to explore the evidence that supports their use in COVID-19 patients, we comprehensively reviewed the previous studies which used CQ or HCQ as an antiviral treatment. Both CQ and HCQ demonstrated promising in vitro results, however, such data have not yet been translated into meaningful in vivo studies. While few clinical trials have suggested some beneficial effects of CQ and HCQ in COVID-19 patients, most of the reported data are still preliminary. Given the current uncertainty, it is worth being mindful of the potential risks and strictly rationalise the use of these drugs in COVID-19 patients until further high quality randomized clinical trials are available to clarify their role in the treatment or prevention of COVID-19.


Assuntos
Antimaláricos/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/tratamento farmacológico , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Animais , Antimaláricos/efeitos adversos , Antimaláricos/sangue , Antimaláricos/farmacocinética , Antivirais/sangue , Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Disponibilidade Biológica , Infecções por Coronavirus/virologia , Meia-Vida , Humanos , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/sangue , Hidroxicloroquina/farmacocinética , Pandemias , Pneumonia Viral/virologia , Resultado do Tratamento , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
ACS Infect Dis ; 6(7): 1558-1562, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32463221

RESUMO

Higher rates of serious illness and death from coronavirus SARS-CoV-2 (COVID-19) infection among older people and those who have comorbidities suggest that age- and disease-related biological processes make such individuals more sensitive to environmental stress factors including infectious agents like coronavirus SARS-CoV-2. Specifically, impaired redox homeostasis and associated oxidative stress appear to be important biological processes that may account for increased individual susceptibility to diverse environmental insults. The aim of this Viewpoint is to justify (1) the crucial roles of glutathione in determining individual responsiveness to COVID-19 infection and disease pathogenesis and (2) the feasibility of using glutathione as a means for the treatment and prevention of COVID-19 illness. The hypothesis that glutathione deficiency is the most plausible explanation for serious manifestation and death in COVID-19 patients was proposed on the basis of an exhaustive literature analysis and observations. The hypothesis unravels the mysteries of epidemiological data on the risk factors determining serious manifestations of COVID-19 infection and the high risk of death and opens real opportunities for effective treatment and prevention of the disease.


Assuntos
Anti-Inflamatórios/farmacologia , Anticoagulantes/farmacologia , Antioxidantes/farmacologia , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/patologia , Glutationa/deficiência , Glutationa/farmacologia , Pneumonia Viral/mortalidade , Pneumonia Viral/patologia , Adulto , Anti-Inflamatórios/sangue , Anticoagulantes/sangue , Antivirais/sangue , Betacoronavirus/fisiologia , Infecções por Coronavirus/sangue , Infecções por Coronavirus/virologia , Suscetibilidade a Doenças , Estudos de Viabilidade , Feminino , Glutationa/sangue , Humanos , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/virologia , Prognóstico , Espécies Reativas de Oxigênio/sangue , Fatores de Risco , Índice de Gravidade de Doença , Replicação Viral/efeitos dos fármacos , Deficiência de Vitamina D/complicações
20.
Clin Pharmacol Ther ; 108(2): 242-247, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32246834

RESUMO

An outbreak of 2019-nCoV infection has spread across the world. No specific antiviral drugs have been approved for the treatment of COVID-2019. In addition to the recommended antiviral drugs, such as interferon-ɑ, lopinavir/ritonavir, ribavirin, and chloroquine phosphate, some clinical trials focusing on virus RNA-dependent RNA polymerase (RdRp) inhibitors have been registered and initiated. Favipiravir, a purine nucleic acid analog and potent RdRp inhibitor approved for use in influenza, is also considered in several clinical trials. Herein, we summarized the pharmacokinetic characteristics of favipiravir and possible drug-drug interactions from the view of drug metabolism. We hope this will be helpful for the design of clinical trials for favipiravir in COVID-2019, as data regarding in vitro virus inhibition and efficacy in preclinical animal studies are still not available.


Assuntos
Amidas/farmacocinética , Antivirais/farmacocinética , Pirazinas/farmacocinética , Acetaminofen/farmacocinética , Amidas/administração & dosagem , Amidas/sangue , Animais , Antivirais/administração & dosagem , Antivirais/sangue , Ensaios Clínicos como Assunto , Infecções por Coronavirus/tratamento farmacológico , Interações Medicamentosas , Humanos , Pirazinas/administração & dosagem , Pirazinas/sangue
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