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1.
Expert Rev Anti Infect Ther ; : 1-9, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38703086

RESUMO

OBJECTIVES: This study assessed the clinical effectiveness of the combination of nirmatrelvir and ritonavir (NMV-r) in treating nonhospitalized patients with COVID-19 who have preexisting psychiatric disorders. METHODS: Patients diagnosed with COVID-19 and psychiatric disorders between 1 March 2020, and 1 December 2022, were included using the TriNetX network. The primary outcome was the composite outcome of all-cause emergency department (ED) visits, hospitalization, or death within 30 days. RESULTS: Propensity score matching yielded two cohorts of 20,633 patients each. The composite outcome of all-cause ED visits, hospitalization, or death within 30 days was 3.57% (737 patients) in the NMV-r cohort and 5.69% (1176) in the control cohort, resulting in a reduced risk in the NMV-r cohort (HR: 0.657; 95% confidence interval (CI): 0.599-0.720). The NMV-r cohort exhibited a lower risk of all-cause hospitalization (HR: 0.385; 95% CI: 0.328-0.451) and all-cause death (HR: 0.110; 95% CI: 0.053-0.228) compared with the control group. CONCLUSION: NMV-r could mitigate the risk of adverse outcomes in nonhospitalized patients with COVID-19 and preexisting psychiatric disorders. However, only a limited number of patients in this population received adequate treatment, thus emphasizing the importance of promoting its appropriate use.

2.
AIDS Res Ther ; 21(1): 29, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38724976

RESUMO

BACKGROUND: The COVID-19 pandemic has put the provision of health services globally at risk. In Sub-Saharan Africa, it had a major impact on HIV services. However, there is a lack of data on the post-pandemic period. This study aims to evaluate the resumption of HIV services and retention in care for adolescents and young people in the period following the COVID-19 pandemic. METHODS: A retrospective cohort study was conducted using interrupted time series analysis. Three periods were considered: pre-pandemic (form June 2019 to March 2020), pandemic (form April 2020 to March 2022) post-pandemic (from April 2022 to March 2023). Six outcome measures were considered: number of outpatient visits, HIV tests, HIV positivity ratio, the antiretroviral treatment (ART) non-adherence ratio, recall ratio, and the return ratio for adolescent and young adults on ART. RESULTS: During the study period, 447,515 outpatient visits and 126,096 HIV tests were recorded. After a reduction at the beginning of the pandemic period, both visits and tests increased during the pandemic (p < 0.05) and decreased in the post-pandemic (p < 0.05), recovering the pre-pandemic trends. The HIV positivity ratio slightly decreased from 3.3% to 1.7% during the study period (p < 0.05). The ART non-adherence ratio decreased from 23.4% to 2.4% throughout the study period (p < 0.05), with a drop at the beginning of the post-pandemic period (p < 0.05). The recall ratio increased during the study period (p < 0.05) with a drop at the beginning of the pandemic and post-pandemic periods (p < 0.05). The return ratio decreased at the beginning of the pandemic (p < 0.05) but returned to the pre-pandemic ratio in the post-pandemic period. CONCLUSIONS: The post-pandemic values of the investigated outcomes were comparable to pre-pandemic period, or even improved. Differently from other services, such as the community activities, that have been severely affected by COVID-19 pandemic, the HIV service system has shown resilience following emergency situation.


Assuntos
COVID-19 , Infecções por HIV , Análise de Séries Temporais Interrompida , Humanos , Adolescente , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , COVID-19/epidemiologia , Estudos Retrospectivos , Adulto Jovem , Feminino , Masculino , Adulto , SARS-CoV-2 , Fármacos Anti-HIV/uso terapêutico , Adesão à Medicação/estatística & dados numéricos , Atenção à Saúde , Pandemias
3.
PLoS One ; 19(5): e0299696, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38728335

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the COVID-19 disease, which represents a new life-threatening disaster. Regarding viral infection, many therapeutics have been investigated to alleviate the epidemiology such as vaccines and receptor decoys. However, the continuous mutating coronavirus, especially the variants of Delta and Omicron, are tended to invalidate the therapeutic biological product. Thus, it is necessary to develop molecular entities as broad-spectrum antiviral drugs. Coronavirus replication is controlled by the viral 3-chymotrypsin-like cysteine protease (3CLpro) enzyme, which is required for the virus's life cycle. In the cases of severe acute respiratory syndrome coronavirus (SARS-CoV) and middle east respiratory syndrome coronavirus (MERS-CoV), 3CLpro has been shown to be a promising therapeutic development target. Here we proposed an attention-based deep learning framework for molecular graphs and sequences, training from the BindingDB 3CLpro dataset (114,555 compounds). After construction of such model, we conducted large-scale screening the in vivo/vitro dataset (276,003 compounds) from Zinc Database and visualize the candidate compounds with attention score. geometric-based affinity prediction was employed for validation. Finally, we established a 3CLpro-specific deep learning framework, namely GraphDPI-3CL (AUROC: 0.958) achieved superior performance beyond the existing state of the art model and discovered 10 molecules with a high binding affinity of 3CLpro and superior binding mode.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Aprendizado Profundo , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/metabolismo , SARS-CoV-2/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Humanos , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/antagonistas & inibidores , Ligação Proteica , COVID-19/virologia , Simulação de Acoplamento Molecular
4.
Curr Microbiol ; 81(7): 169, 2024 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-38733424

RESUMO

The rapid spread of the SARS-CoV-2 virus has emphasized the urgent need for effective therapies to combat COVID-19. Investigating the potential targets, inhibitors, and in silico approaches pertinent to COVID-19 are of utmost need to develop novel therapeutic agents and reprofiling of existing FDA-approved drugs. This article reviews the viral enzymes and their counter receptors involved in the entry of SARS-CoV-2 into host cells, replication of genomic RNA, and controlling the host cell physiology. In addition, the study provides an overview of the computational techniques such as docking simulations, molecular dynamics, QSAR modeling, and homology modeling that have been used to find the FDA-approved drugs and other inhibitors against SARS-CoV-2. Furthermore, a comprehensive overview of virus-based and host-based druggable targets from a structural point of view, together with the reported therapeutic compounds against SARS-CoV-2 have also been presented. The current study offers future perspectives for research in the field of network pharmacology investigating the large unexplored molecular libraries. Overall, the present in-depth review aims to expedite the process of identifying and repurposing drugs for researchers involved in the field of COVID-19 drug discovery.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/química , Humanos , Simulação de Acoplamento Molecular , COVID-19/virologia , Reposicionamento de Medicamentos , Internalização do Vírus/efeitos dos fármacos , Simulação de Dinâmica Molecular
5.
Sci Rep ; 14(1): 10696, 2024 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730068

RESUMO

COVID-19, caused by SARS-CoV-2, affects neuronal cells, causing several symptoms such as memory loss, anosmia and brain inflammation. Curcuminoids (Me08 e Me23) and curcumin (CUR) are derived from Curcuma Longa extract (EXT). Many therapeutic actions have been linked to these compounds, including antiviral action. Given the severe implications of COVID-19, especially within the central nervous system, our study aims to shed light on the therapeutic potential of curcuminoids against SARS-CoV-2 infection, particularly in neuronal cells. Here, we investigated the effects of CUR, EXT, Me08 and Me23 in human neuroblastoma SH-SY5Y. We observed that Me23 significantly decreased the expression of plasma membrane-associated transmembrane protease serine 2 (TMPRSS2) and TMPRSS11D, consequently mitigating the elevated ROS levels induced by SARS-CoV-2. Furthermore, Me23 exhibited antioxidative properties by increasing NRF2 gene expression and restoring NQO1 activity following SARS-CoV-2 infection. Both Me08 and Me23 effectively reduced SARS-CoV-2 replication in SH-SY5Y cells overexpressing ACE2 (SH-ACE2). Additionally, all of these compounds demonstrated the ability to decrease proinflammatory cytokines such as IL-6, TNF-α, and IL-17, while Me08 specifically reduced INF-γ levels. Our findings suggest that curcuminoid Me23 could serve as a potential agent for mitigating the impact of COVID-19, particularly within the context of central nervous system involvement.


Assuntos
Anti-Inflamatórios , Antioxidantes , Antivirais , Tratamento Farmacológico da COVID-19 , Curcumina , SARS-CoV-2 , Humanos , Curcumina/farmacologia , Curcumina/análogos & derivados , Antioxidantes/farmacologia , Antivirais/farmacologia , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/fisiologia , Anti-Inflamatórios/farmacologia , Linhagem Celular Tumoral , Curcuma/química , Serina Endopeptidases/metabolismo , COVID-19/virologia , COVID-19/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Extratos Vegetais/farmacologia , Citocinas/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/virologia
6.
BMC Vet Res ; 20(1): 187, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730463

RESUMO

BACKGROUND: Porcine epidemic diarrhea virus (PEDV), a type of coronavirus, is one of the main pathogens that can infect pigs of all ages. It causes diarrhea and acute death of newborn piglets, resulting in massive economic losses to the worldwide swine industry. While vaccination remains the primary approach in combating PEDV, it often fails to address all the challenges posed by the infection, particularly in light of the emergence of evolving mutant strains. Therefore, there is a critical need to identify potent antiviral drugs that can effectively safeguard pigs against PEDV infection. RESULTS: In this study, the antiviral efficacy of SP2509, a specific antagonist of Lysine-specific demethylase 1(LSD1), was evaluated in vitro. The RT-qPCR, Western blot, TCID50, and IFA showed that at a concentration of 1µmol/L, SP2509 significantly inhibited PEDV infection. Additionally, viral life cycle assays showed that SP2509 operates by impeding PEDV internalization and replication rather than attachment and release. Regarding mechanism, in Huh-7 cells, knockdowns LSD1 can suppress PEDV replication. This indicated that the inhibition effect of SP2509 on PEDV largely depends on the activity of its target protein, LSD1. CONCLUSION: Our results in vitro show that SP2509 can inhibit PEDV infection during the internalization and replication stage and revealed a role of LSD1 as a restriction factor for PEDV. These imply that LSD1 might be a target for interfering with the viral infection, and SP2509 could be developed as an effective anti-PEDV agent.


Assuntos
Antivirais , Histona Desmetilases , Vírus da Diarreia Epidêmica Suína , Replicação Viral , Vírus da Diarreia Epidêmica Suína/efeitos dos fármacos , Animais , Antivirais/farmacologia , Replicação Viral/efeitos dos fármacos , Histona Desmetilases/antagonistas & inibidores , Suínos , Chlorocebus aethiops , Doenças dos Suínos/virologia , Doenças dos Suínos/tratamento farmacológico , Infecções por Coronavirus/veterinária , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Células Vero
7.
BMC Pulm Med ; 24(1): 231, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38745298

RESUMO

BACKGROUND: COVID-19 survivors may develop long-term symptoms of fatigue, dyspnea, mental health issues, and functional limitations: a condition termed post-acute sequelae of COVID-19 (PASC). Pulmonary rehabilitation (PR) is a recommended treatment for PASC; however, there is a lack of data regarding PR's effect on multiple health indices and the factors that influence patient outcomes. The aim of our study is to evaluate the impact of pulmonary rehabilitation on functional and psychological parameters in patients diagnosed with Post-Acute Sequelae of SARS-CoV-2 Infection (PASC), thereby offering insights into the efficacy of such interventions in improving the quality of life and clinical outcomes for these individuals. METHODS: We extracted patient demographic, comorbidity, and outcome data from Allegheny Health Network's electronic medical records. Functionality test results were compared before and after PR, including 6-minute walk test (6MWT), chair rise repetitions (CR reps), timed up and go test (TUG), gait speed (Rehab gait), modified medical research council scale (MMRC), shortness of breath questionnaire (SOBQ), hospital anxiety and depression scale (HADS) and chronic obstructive pulmonary disease assessment test (CAT) scores. Multiple regression analysis was done to evaluate the effect of comorbidities and patient factors on patient responses to PR. RESULTS: The 55 patients included in this study had a mean time of 4 months between the initial COVID-19 diagnosis and the subsequent PASC diagnosis. Following pulmonary rehabilitation (PR), significant improvements were observed across various metrics. The distance covered in the 6-minute walk test (6MWT) increased markedly from a pre-rehabilitation average of 895 feet (SD 290) to 1,300 feet (SD 335) post-rehabilitation, with a mean change of 405 feet (95% CI [333, 477]). Chair rise repetitions (CR reps) saw an increase from 9 (SD 3) reps to 13 (SD 3) reps, with a change of 4 reps (95% CI [3.7, 4.9]). The timed up and go test (TUG) time decreased significantly from 13 s (SD 5) to 10 s (SD 2), reflecting a mean reduction of 3 s (95% CI [-4.5, -2.5]). Rehabilitation gait speed improved from 1.0 m/s to 1.3 m/s, changing by 0.3 m/s (95% CI [0.2, 0.3]). The Modified Medical Research Council (MMRC) dyspnea scale showed a notable decrease from a mean of 2 (SD 1) to 1 (SD 1), a change of -1 (95% CI [-1.5, -1]). The Shortness of Breath Questionnaire (SOBQ) scores reduced significantly from 51 (SD 21) to 22 (SD 18), with a change of -29 (95% CI [-34, -23]). The Hospital Anxiety and Depression Scale (HADS) scores decreased from 11 (SD 7) to 8 (SD 7), a reduction of -4 (95% CI [-5, -2]). Lastly, the Chronic Obstructive Pulmonary Disease (COPD) Assessment Test (CAT) scores significantly dropped from 18 (SD 7) to 9 (SD 7), changing by -10 (95% CI [-11, -8]). However, the presence of hypertension, diabetes, chronic lung diseases, outpatient status, and receipt of specific pharmacologic treatments (decadron, decadron + remdesivir, and decadron + remdesivir + tocilizumab) were identified as factors associated with a poor response to PR. CONCLUSION: Our study supports PR as an integrated model of care for PASC patients to improve several physical and mental health indices. The long-term effects of PR on patients' functional status should be investigated in the future.


Assuntos
COVID-19 , Síndrome de COVID-19 Pós-Aguda , Qualidade de Vida , SARS-CoV-2 , Humanos , COVID-19/reabilitação , COVID-19/psicologia , COVID-19/complicações , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Teste de Caminhada , Dispneia/etiologia , Dispneia/reabilitação , Dispneia/psicologia , Dispneia/fisiopatologia , Estudos Retrospectivos
8.
Gene ; : 148553, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38734190

RESUMO

The global mortality rate has been significantly impacted by the COVID-19 pandemic, caused by the SARS CoV-2 virus. Although the pursuit for a potent antiviral is still in progress, experimental therapies based on repurposing of existing drugs is being attempted. One important therapeutic target for COVID-19 is the main protease (Mpro) that cleaves the viral polyprotein in its replication process. Recently minocycline, an antimycobacterium drug, has been successfully implemented for the treatment of COVID-19 patients. But it's mode of action is still far from clear. Furthermore, it remains unresolved whether alternative antimycobacterium drugs can effectively regulate SARS CoV-2 by inhibiting the enzymatic activity of Mpro. To comprehend these facets, eight well-established antimycobacterium drugs were put through molecular docking experiments. Four of the antimycobacterium drugs (minocycline, rifampicin, clofazimine and ofloxacin) were selected by comparing their binding affinities towards Mpro. All of the four drugs interacted with both the catalytic residues of Mpro (His41 and Cys145). Additionally, molecular dynamics experiments demonstrated that the Mpro-minocyline complex has enhanced stability more stable, experiences reduced conformational fluctuations and greater compactness than other three Mpro-antimycobacterium and Mpro-N3/lopinavir complexes. This research furnishes evidences for implementation of minocycline against SARS CoV-2. In addition, our findings also indicate other three antimycobacterium/antituberculosis drugs (rifampicin, clofazimine and ofloxacin) could potentially be evaluated for COVID-19 therapy.

9.
J Infect Dev Ctries ; 18(4): 520-531, 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38728643

RESUMO

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic caused global health, economic, and population loss. Variants of the coronavirus contributed to the severity of the disease and persistent rise in infections. This study aimed to identify potential drug candidates from fifteen approved antiviral drugs against SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike protein (6M0J) using virtual screening and pharmacokinetics to gain insights into COVID-19 therapeutics. METHODOLOGY: We employed drug repurposing approach to analyze binding performance of fifteen clinically approved antiviral drugs against the main protease of SARS-CoV-2 (6LU7), SARS-CoV (5B6O), and SARS-CoV-2 spike proteins bound to ACE-2 receptor (6M0J), to provide an insight into the therapeutics of COVID-19. AutoDock Vina was used for docking studies. The binding affinities were calculated, and 2-3D structures of protein-ligand interactions were drawn. RESULTS: Rutin, hesperidin, and nelfinavir are clinically approved antiviral drugs with high binding affinity to proteins 6LU7, 5B6O, and 6M0J. These ligands have excellent pharmacokinetics, ensuring efficient absorption, metabolism, excretion, and digestibility. Hesperidin showed the most potent interaction with spike protein 6M0J, forming four H-bonds. Nelfinavir had a high human intestinal absorption (HIA) score of 0.93, indicating maximum absorption in the body and promising interactions with 6LU7. CONCLUSIONS: Our results indicated that rutin, hesperidin, and nelfinavir had the highest binding results against the proposed drug targets. The computational approach effectively identified SARS-CoV-2 inhibitors. COVID-19 is still a recurrent threat globally and predictive analysis using natural compounds might serve as a starting point for new drug development against SARS-CoV-2 and related viruses.


Assuntos
Antivirais , COVID-19 , Reposicionamento de Medicamentos , Simulação de Acoplamento Molecular , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , SARS-CoV-2/efeitos dos fármacos , Humanos , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/química , Glicoproteína da Espícula de Coronavírus/metabolismo , COVID-19/virologia , Pandemias , Betacoronavirus/efeitos dos fármacos , Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/metabolismo , Proteases 3C de Coronavírus/química
10.
J Int Med Res ; 52(5): 3000605241247705, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38698526

RESUMO

Nirmatrelvir/ritonavir is a novel drug combination that is authorized by the Food and Drug Administration for the treatment of coronavirus disease 2019 (COVID-19). Ritonavir is a cytochrome P450 3A inhibitor and a P-glycoprotein inhibitor that increases the plasma concentration of tacrolimus and other medications. We describe the cases of two patients treated with nirmatrelvir/ritonavir: a patient who had undergone kidney transplantation and another with a history of hematopoietic stem cell transplantation. Toxic concentrations of tacrolimus were induced in both. This case series highlights the risk associated with the concomitant administration of tacrolimus and nirmatrelvir/ritonavir.


Assuntos
Tratamento Farmacológico da COVID-19 , Interações Medicamentosas , Transplante de Rim , Ritonavir , Tacrolimo , Humanos , Ritonavir/uso terapêutico , Tacrolimo/uso terapêutico , Tacrolimo/efeitos adversos , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/isolamento & purificação , Feminino , Transplante de Células-Tronco Hematopoéticas , Imunossupressores/uso terapêutico , Imunossupressores/efeitos adversos , Inibidores do Citocromo P-450 CYP3A/uso terapêutico , Combinação de Medicamentos , COVID-19/virologia , Idoso , Antivirais/uso terapêutico
11.
Artigo em Inglês | MEDLINE | ID: mdl-38743116

RESUMO

Fracture healing is a process in which many factors interact. In addition to many treatments, physical and biological therapy methods that affect different steps of this process, there are many biological and chemical agents that cause fracture union delay. Although the number of studies on fracture healing is increasing day by day, the mechanism of fracture healing, which is not fully understood, still attracts the attention of all researchers. In this study, we aimed to investigate the effects of favipiravir and hydroxychloroquine used in the treatment of COVID-19. In this study, 48 male Wistar rats weighing 300 ± 50 g were used. Each group was divided into eight subgroups of six rats each to be sacrificed at the 2nd and 4th weeks and evaluated radiologically and histologically. Favipiravir (group 1), hydroxychloroquine (group 2), favipiravir + hydroxychloroquine (group 3), and random control (group 4) were used. A statistically significant difference was observed between the 15th day histological scoring averages of the groups (p < 0.05). Although there was no statistically significant difference between the 15th day radiological score distributions of the groups (p > 0.05), we obtained different results in terms of complete bone union distributions and radiological images of the fracture line. Although favipiravir has a negative effect on fracture union in the early period, favipiravir may have a positive effect on fracture union in the late period. We did not find any effect of hydroxychloroquine on fracture union.

12.
Org Biomol Chem ; 22(19): 3986-3994, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38695061

RESUMO

Algae-based marine carbohydrate drugs are typically decorated with negative ion groups such as carboxylate and sulfate groups. However, the precise synthesis of highly sulfated alginates is challenging, thus impeding their structure-activity relationship studies. Herein we achieve a microwave-assisted synthesis of a range of highly sulfated mannuronate glycans with up to 17 sulfation sites by overcoming the incomplete sulfation due to the electrostatic repulsion of crowded polyanionic groups. Although the partially sulfated tetrasaccharide had the highest affinity for the receptor binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, the fully sulfated octasaccharide showed the most potent interference with the binding of the RBD to angiotensin-converting enzyme 2 (ACE2) and Vero E6 cells, indicating that the sulfated oligosaccharides might inhibit the RBD binding to ACE2 in a length-dependent manner.


Assuntos
Enzima de Conversão de Angiotensina 2 , Antivirais , Micro-Ondas , Polissacarídeos , SARS-CoV-2 , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Antivirais/síntese química , Antivirais/química , Chlorocebus aethiops , Enzima de Conversão de Angiotensina 2/metabolismo , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/química , Células Vero , Polissacarídeos/química , Polissacarídeos/farmacologia , Polissacarídeos/síntese química , Humanos , Animais , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/química , Ácidos Hexurônicos/química , Ácidos Hexurônicos/farmacologia , Ácidos Hexurônicos/síntese química , Sulfatos/química , Sulfatos/farmacologia , Sulfatos/síntese química , Tratamento Farmacológico da COVID-19 , Relação Estrutura-Atividade
13.
Drug Des Devel Ther ; 18: 1547-1571, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38737333

RESUMO

The Coronavirus disease 2019 (COVID-19) pandemic is one of the most considerable health problems across the world. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the major causative agent of COVID-19. The severe symptoms of this deadly disease include shortness of breath, fever, cough, loss of smell, and a broad spectrum of other health issues such as diarrhea, pneumonia, bronchitis, septic shock, and multiple organ failure. Currently, there are no medications available for coronavirus patients, except symptom-relieving drugs. Therefore, SARS-CoV-2 requires the development of effective drugs and specific treatments. Heterocycles are important constituents of more than 85% of the physiologically active pharmaceutical drugs on the market now. Several FDA-approved drugs have been reported including molnupiravir, remdesivir, ritonavir, oseltamivir, favipiravir, chloroquine, and hydroxychloroquine for the cure of COVID-19. In this study, we discuss potent anti-SARS-CoV-2 heterocyclic compounds that have been synthesized over the past few years. These compounds included; indole, piperidine, pyrazine, pyrimidine, pyrrole, piperazine, quinazoline, oxazole, quinoline, isoxazole, thiazole, quinoxaline, pyrazole, azafluorene, imidazole, thiadiazole, triazole, coumarin, chromene, and benzodioxole. Both in vitro and in silico studies were performed to determine the potential of these heterocyclic compounds in the fight against various SARS-CoV-2 proteins.


Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , Compostos Heterocíclicos , SARS-CoV-2 , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/síntese química , Compostos Heterocíclicos/farmacologia , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , COVID-19
14.
J Hazard Mater ; 472: 134462, 2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38718506

RESUMO

The antiviral drugs favipiravir and oseltamivir are widely used to treat viral infections, including coronavirus 2019 (COVID-19), and their levels are expected to increase in the aquatic environment. In this study, the potential toxic and teratogenic effects of these drugs were evaluated using the frog embryo teratogenesis assay Xenopus (FETAX). In addition, glutathione S-transferase (GST), glutathione reductase (GR), catalase, carboxylesterase (CaE), and acetylcholinesterase (AChE) enzyme activities and malondialdehyde levels were measured as biochemical markers in embryos and tadpoles for comparative assessment of the sublethal effects of the test compounds. Prior to embryo exposure, drug concentrations in the exposure medium were measured with high-performance liquid chromatography. The 96-h median lethal concentration (LC50) was 137.9 and 32.3 mg/L for favipiravir and oseltamivir, respectively. The teratogenic index for favipiravir was 4.67. Both favipiravir and oseltamivir inhibited GR, CaE, and AChE activities in embryos, while favipiravir increased the GST and CaE activities in tadpoles. In conclusion, favipiravir, for which teratogenicity data are available in mammalian test organisms and human teratogenicity is controversial, inhibited Xenopus laevis embryo development and was teratogenic. In addition, sublethal concentrations of both drugs altered the biochemical responses in embryos and tadpoles, with differences between the developmental stages.

15.
Kidney Int Rep ; 9(5): 1244-1253, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38707795

RESUMO

Introduction: Even with effective vaccines, patients with CKD have a higher risk of hospitalization and death subsequent to COVID-19 infection than those without CKD. Molnupiravir and nirmatrelvir-ritonavir have been approved for emergency use, but their effectiveness for the CKD population is still unknown. This study was conducted to determine the effectiveness of these drugs in reducing mortality and severe COVID-19 in the CKD population. Methods: This was a target trial emulation study using electronic health databases in Hong Kong. Patients with CKD aged 18 years or older who were hospitalized with COVID-19 were included. The per-protocol average treatment effect among COVID-19 oral antiviral initiators, including all-cause mortality, intensive care unit (ICU) admission, and ventilatory support within 28 days, were compared to noninitiators. Results: Antivirals have been found to lower the risk of all-cause mortality, with Molnupiravir at a hazard ratio (HR) of 0.85 (95% confidence interval [CI], 0.77 to 0.95] and nirmatrelvir-ritonavir at an HR of 0.78 [95% CI, 0.60 to 1.00]. However, they do not significantly reduce the risk of ICU admission (molnupiravir: HR, 0.88 [95% CI, 0.59 to 1.30]; nirmatrelvir-ritonavir: HR, 0.86 [95% CI, 0.56 to 1.32]) or ventilatory support (molnupiravir: HR, 1.00 [95% CI, 0.76 to 1.33]; nirmatrelvir-ritonavir: HR, 1.01 [95% CI, 0.74 to 1.37]). There was a greater risk reduction in males and those with higher Charlson Comorbidity Index (CCI). The nirmatrelvir-ritonavir trial also showed reduced risk for those who had antiviral treatment and received 3 or more vaccine doses. Conclusion: Both molnupiravir and nirmatrelvir-ritonavir reduced mortality rates for hospitalized COVID-19 patients with CKD.

16.
Int J Nanomedicine ; 19: 3907-3917, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38708183

RESUMO

Background: As highlighted by recent pandemic outbreaks, antiviral drugs are crucial resources in the global battle against viral diseases. Unfortunately, most antiviral drugs are characterized by a plethora of side effects and low efficiency/poor bioavailability owing to their insolubility. This also applies to the arylnaphthalide lignin family member, diphyllin (Diph). Diph acts as a vacuolar ATPase inhibitor and has been previously identified as a promising candidate with broad-spectrum antiviral activity. However, its physicochemical properties preclude its efficient administration in vivo, complicating preclinical testing. Methods: We produced human recombinant H- ferritin (HsaFtH) and used it as a delivery vehicle for Diph encapsulation through pH-mediated reversible reassembly of HsaFtH. Diph nanoformulation was subsequently thoroughly characterized and tested for its non-target cytotoxicity and antiviral efficiency using a panel of pathogenic viral strain. Results: We revealed that loading into HsaFtH decreased the undesired cytotoxicity of Diph in mammalian host cells. We also confirmed that encapsulated Diph exhibited slightly lower antiviral activity than free Diph, which may be due to the differential uptake mechanism and kinetics of free Diph and Diph@HsaFtH. Furthermore, we confirmed that the antiviral effect was mediated solely by Diph with no contribution from HsaFtH. Conclusion: It was confirmed that HsaFtH is a suitable vehicle that allows easy loading of Diph and production of highly homogeneous nanoparticles dispersion with promising broad-spectrum antiviral activity.


Assuntos
Antivirais , Lignanas , Proteínas Recombinantes , Humanos , Antivirais/farmacologia , Antivirais/química , Antivirais/farmacocinética , Proteínas Recombinantes/química , ATPases Vacuolares Próton-Translocadoras/antagonistas & inibidores , ATPases Vacuolares Próton-Translocadoras/metabolismo , Interações Hidrofóbicas e Hidrofílicas , Animais , Nanopartículas/química
17.
Lancet Infect Dis ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38710190

RESUMO

BACKGROUND: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong. METHODS: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes. FINDINGS: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis. INTERPRETATION: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae. FUNDING: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund.

18.
Carbohydr Polym ; 337: 122156, 2024 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-38710572

RESUMO

Seaweeds represent a rich source of sulfated polysaccharides with similarity to heparan sulfate, a facilitator of myriad virus host cell attachment. For this reason, attention has been drawn to their antiviral activity, including the potential for anti-SARS-CoV-2 activity. We have identified and structurally characterized several fucoidan extracts, including those from different species of brown macroalga, and a rhamnan sulfate from a green macroalga species. A high molecular weight fucoidan extracted from Saccharina japonica (FSjRPI-27), and a rhamnan sulfate extracted from Monostroma nitidum (RSMn), showed potent competitive inhibition of spike glycoprotein receptor binding to a heparin-coated SPR chip. This inhibition was also observed in cell-based assays using hACE2 HEK-293 T cells infected by pseudotyped SARS-CoV-2 virus with IC50 values <1 µg/mL. Effectiveness was demonstrated in vivo using hACE2-transgenic mice. Intranasal administration of FSjRPI-27 showed protection when dosed 6 h prior to and at infection, and then every 2 days post-infection, with 100 % survival and no toxicity at 104 plaque-forming units per mouse vs. buffer control. At 5-fold higher virus dose, FSjRPI-27 reduced mortality and yielded reduced viral titers in bronchioalveolar fluid and lung homogenates vs. buffer control. These findings suggest the potential application of seaweed-based sulfated polysaccharides as promising anti-SARS-CoV-2 prophylactics.


Assuntos
Antivirais , COVID-19 , Mananas , Polissacarídeos , SARS-CoV-2 , Alga Marinha , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Humanos , SARS-CoV-2/efeitos dos fármacos , Alga Marinha/química , Antivirais/farmacologia , Antivirais/química , Células HEK293 , Camundongos , COVID-19/prevenção & controle , COVID-19/virologia , Tratamento Farmacológico da COVID-19 , Camundongos Transgênicos , Glicoproteína da Espícula de Coronavírus/metabolismo , Desoxiaçúcares/farmacologia , Desoxiaçúcares/química , Enzima de Conversão de Angiotensina 2/metabolismo
19.
Ter Arkh ; 96(3): 205-211, 2024 Apr 16.
Artigo em Russo | MEDLINE | ID: mdl-38713033

RESUMO

The COVID-19 pandemic has highlighted pressing challenges in biomedical research methodology. It has become obvious that the rapid and effective development of treatments for "new" viral infections is impossible without the coordination of interdisciplinary research and in-depth analysis of data obtained within the framework of the post-genomic paradigm. Presents the results of a systematic computer analysis of 290,000 scientific articles on COVID-19, with an emphasis on the results of post-genomic studies of SARS-CoV-2. The futility of the overly simplified approach, which considers only one "most important receptor protein", only one "key virus gene", etc., is shown. It is shown how post-genomic technologies will make it possible to find informative biomarkers of severe coronavirus infection, including those based on complex immune disorders associated with COVID-19.


Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Tratamento Farmacológico da COVID-19 , Genômica/métodos , Antivirais/uso terapêutico , Antivirais/farmacologia
20.
Ter Arkh ; 96(3): 280-285, 2024 Apr 16.
Artigo em Russo | MEDLINE | ID: mdl-38713044

RESUMO

AIM: Evaluation of the efficacy and safety of riamilovir as a drug for the prevention of coronavirus infection (COVID-19) in adults who have constant contact with COVID-19 patients as a result of living together. MATERIALS AND METHODS: The study included 750 adult participants living with patients with confirmed polymerase chain reaction method COVID-19, who had a negative polymerase chain reaction result for the SARS-CoV-2 virus at the initial level, met the criteria for inclusion, non-inclusion and exclusion, and signed a voluntary informed consent to participate in a clinical trial. RESULTS: The efficacy, good tolerability and safety of the drug riamilovir for the prevention of COVID-19 infection among people who have come into contact with COVID-19 patients in a family focus of infection have been established. CONCLUSION: As a result of a multicenter randomized double-blind clinical trial, the effectiveness of the drug riamilovir for the prevention of COVID-19 infection was established. It was shown that the relative risk of disease in the group taking riamilovir for prophylaxis was 88.96% lower than in the control group. Based on the results of a clinical trial, in October 2023 Ministry of Health of the Russian Federation approved the inclusion of a new indication (prophylaxis of COVID-19 infection) in the instructions for the medical use of the drug riamilovir (trade name - Triazavirin®).


Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Humanos , Método Duplo-Cego , Masculino , Feminino , Adulto , COVID-19/prevenção & controle , COVID-19/epidemiologia , Pessoa de Meia-Idade , Antivirais/administração & dosagem , Antivirais/uso terapêutico , SARS-CoV-2 , Resultado do Tratamento , Federação Russa
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