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1.
Viruses ; 13(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-34071034

RESUMO

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Agonistas de Receptores de GABA-A/uso terapêutico , Vírus da Hepatite Murina/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Animais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Camundongos , Vírus da Hepatite Murina/patogenicidade , Pneumonia/mortalidade , Pneumonia/virologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêutico
2.
Viruses ; 13(6)2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073401

RESUMO

OBJECTIVE: This study was designed to determine the efficacy of ivermectin, an FDA-approved drug, in producing clinical benefits and decreasing the viral load of SARS-CoV-2 among asymptomatic subjects that tested positive for this virus in Lebanon. METHODS: A randomized controlled trial was conducted in 100 asymptomatic Lebanese subjects that have tested positive for SARS-CoV2. Fifty patients received standard preventive treatment, mainly supplements, and the experimental group received a single dose (according to body weight) of ivermectin, in addition to the same supplements the control group received. RESULTS: There was no significant difference (p = 0.06) between Ct-values of the two groups before the regimen was started (day zero), indicating that subjects in both groups had similar viral loads. At 72 h after the regimen started, the increase in Ct-values was dramatically higher in the ivermectin than in the control group. In the ivermectin group, Ct increased from 15.13 ± 2.07 (day zero) to 30.14 ± 6.22 (day three; mean ± SD), compared to the control group, where the Ct values increased only from 14.20 ± 2.48 (day zero) to 18.96 ± 3.26 (day three; mean ± SD). Moreover, more subjects in the control group developed clinical symptoms. Three individuals (6%) required hospitalization, compared to the ivermectin group (0%). CONCLUSION: Ivermectin appears to be efficacious in providing clinical benefits in a randomized treatment of asymptomatic SARS-CoV-2-positive subjects, effectively resulting in fewer symptoms, lower viral load and reduced hospital admissions. However, larger-scale trials are warranted for this conclusion to be further cemented.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ivermectina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Adulto , Infecções Assintomáticas , COVID-19/diagnóstico , COVID-19/virologia , Feminino , Humanos , Líbano/epidemiologia , Masculino , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
3.
Viruses ; 13(6)2021 05 26.
Artigo em Inglês | MEDLINE | ID: covidwho-1244149

RESUMO

OBJECTIVE: This study was designed to determine the efficacy of ivermectin, an FDA-approved drug, in producing clinical benefits and decreasing the viral load of SARS-CoV-2 among asymptomatic subjects that tested positive for this virus in Lebanon. METHODS: A randomized controlled trial was conducted in 100 asymptomatic Lebanese subjects that have tested positive for SARS-CoV2. Fifty patients received standard preventive treatment, mainly supplements, and the experimental group received a single dose (according to body weight) of ivermectin, in addition to the same supplements the control group received. RESULTS: There was no significant difference (p = 0.06) between Ct-values of the two groups before the regimen was started (day zero), indicating that subjects in both groups had similar viral loads. At 72 h after the regimen started, the increase in Ct-values was dramatically higher in the ivermectin than in the control group. In the ivermectin group, Ct increased from 15.13 ± 2.07 (day zero) to 30.14 ± 6.22 (day three; mean ± SD), compared to the control group, where the Ct values increased only from 14.20 ± 2.48 (day zero) to 18.96 ± 3.26 (day three; mean ± SD). Moreover, more subjects in the control group developed clinical symptoms. Three individuals (6%) required hospitalization, compared to the ivermectin group (0%). CONCLUSION: Ivermectin appears to be efficacious in providing clinical benefits in a randomized treatment of asymptomatic SARS-CoV-2-positive subjects, effectively resulting in fewer symptoms, lower viral load and reduced hospital admissions. However, larger-scale trials are warranted for this conclusion to be further cemented.


Assuntos
Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Ivermectina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , Adulto , Infecções Assintomáticas , COVID-19/diagnóstico , COVID-19/virologia , Feminino , Humanos , Líbano/epidemiologia , Masculino , SARS-CoV-2/isolamento & purificação , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
4.
Viruses ; 13(6)2021 05 23.
Artigo em Inglês | MEDLINE | ID: covidwho-1242675

RESUMO

There is an urgent need for new approaches to limit the severity of coronavirus infections. Many cells of the immune system express receptors for the neurotransmitter γ-aminobutyric acid (GABA), and GABA-receptor (GABA-R) agonists have anti-inflammatory effects. Lung epithelial cells also express GABA-Rs, and GABA-R modulators have been shown to limit acute lung injuries. There is currently, however, no information on whether GABA-R agonists might impact the course of a viral infection. Here, we assessed whether clinically applicable GABA-R agonists could be repurposed for the treatment of a lethal coronavirus (murine hepatitis virus 1, MHV-1) infection in mice. We found that oral GABA administration before, or after the appearance of symptoms, very effectively limited MHV-1-induced pneumonitis, severe illness, and death. GABA treatment also reduced viral load in the lungs, suggesting that GABA-Rs may provide a new druggable target to limit coronavirus replication. Treatment with the GABAA-R-specific agonist homotaurine, but not the GABAB-R-specific agonist baclofen, significantly reduced the severity of pneumonitis and death rates in MHV-1-infected mice, indicating that the therapeutic effects were mediated primarily through GABAA-Rs. Since GABA and homotaurine are safe for human consumption, they are promising candidates to help treat coronavirus infections.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Agonistas de Receptores de GABA-A/uso terapêutico , Vírus da Hepatite Murina/efeitos dos fármacos , Pneumonia/tratamento farmacológico , Animais , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Camundongos , Vírus da Hepatite Murina/patogenicidade , Pneumonia/mortalidade , Pneumonia/virologia , Índice de Gravidade de Doença , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Perda de Peso/efeitos dos fármacos , Ácido gama-Aminobutírico/uso terapêutico
5.
PLoS One ; 16(6): e0252302, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34143818

RESUMO

A potent therapy for the infectious coronavirus disease COVID-19 is urgently required with, at the time of writing, research in this area still ongoing. This study aims to evaluate the in vitro anti-viral activities of combinations of certain commercially available drugs that have recently formed part of COVID-19 therapy. Dual combinatory drugs, namely; Lopinavir-Ritonavir (LOPIRITO)-Clarithromycin (CLA), LOPIRITO-Azithromycin (AZI), LOPIRITO-Doxycycline (DOXY), Hydroxychloroquine (HCQ)-AZI, HCQ-DOXY, Favipiravir (FAVI)-AZI, HCQ-FAVI, and HCQ-LOPIRITO, were prepared. These drugs were mixed at specific ratios and evaluated for their safe use based on the cytotoxicity concentration (CC50) values of human umbilical cord mesenchymal stem cells. The anti-viral efficacy of these combinations in relation to Vero cells infected with SARS-CoV-2 virus isolated from a patient in Universitas Airlangga hospital, Surabaya, Indonesia and evaluated for IC50 24, 48, and 72 hours after viral inoculation was subsequently determined. Observation of the viral load in qRT-PCR was undertaken, the results of which indicated the absence of high levels of cytotoxicity in any samples and that dual combinatory drugs produced lower cytotoxicity than single drugs. In addition, these combinations demonstrated considerable effectiveness in reducing the copy number of the virus at 48 and 72 hours, while even at 24 hours, post-drug incubation resulted in low IC50 values. Most combination drugs reduced pro-inflammatory markers, i.e. IL-6 and TNF-α, while increasing the anti-inflammatory response of IL-10. According to these results, the descending order of effective dual combinatory drugs is one of LOPIRITO-AZI>LOPIRITO-DOXY>HCQ-AZI>HCQ-FAVI>LOPIRITO-CLA>HCQ-DOX. It can be suggested that dual combinatory drugs, e.g. LOPIRITO-AZI, can potentially be used in the treatment of COVID-19 infectious diseases.


Assuntos
Antibacterianos/farmacologia , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Hidroxicloroquina/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Chlorocebus aethiops , Combinação de Medicamentos , Hospitalização , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Hidroxicloroquina/uso terapêutico , Indonésia , Concentração Inibidora 50 , Pacientes Internados , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , SARS-CoV-2/fisiologia , Fatores de Tempo , Células Vero , Carga Viral/efeitos dos fármacos
6.
Int J Mol Sci ; 22(10)2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34069929

RESUMO

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008-2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.


Assuntos
Farmacorresistência Viral/genética , Infecções por HIV/genética , Adenina/uso terapêutico , Adulto , Idoso , Fármacos Anti-HIV/farmacologia , Brasil/epidemiologia , Farmacorresistência Viral/fisiologia , Feminino , Infecções por HIV/tratamento farmacológico , Transcriptase Reversa do HIV/genética , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-1/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Tenofovir/uso terapêutico , Falha de Tratamento , Carga Viral/efeitos dos fármacos , Zidovudina/uso terapêutico
7.
BMC Infect Dis ; 21(1): 610, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34174833

RESUMO

BACKGROUND: Current clinical guidelines recommend treating chronic hepatitis B virus (HBV) infection in a minority of cases, but there are relatively scarce data on evolution or progression of liver inflammation and fibrosis in cases of chronic HBV (CHB) that do not meet treatment criteria. We aimed to assess the impact of TDF on liver disease, and the risk of renal impairment in treated CHB patients in comparison to untreated patients. METHODS: We studied a longitudinal ethnically diverse CHB cohort in the UK attending out-patient clinics between 2005 and 2018. We examined TDF treatment (vs. untreated) as the main exposure, with HBV DNA viral load (VL), ALT, elastography scores and eGFR as the main outcomes, using paired tests and mixed effects model for longitudinal measurements. Additionally, decline of eGFR during follow-up was quantified within individuals by thresholds based on clinical guidelines. Baseline was defined as treatment initiation for TDF group and the beginning of clinical follow-up for untreated group respectively. RESULTS: We included 206 adults (60 on TDF, 146 untreated), with a median ± IQR follow-up duration of 3.3 ± 2.8 years. The TDF group was significantly older (median age 39 vs. 35 years, p = 0.004) and more likely to be male (63% vs. 47%, p = 0.04) compared to the untreated group. Baseline difference between TDF and untreated groups reflected treatment eligibility criteria. As expected, VL and ALT declined significantly over time in TDF-treated patients. Elastography scores normalised during treatment in the TDF group reflecting regression of inflammation and/or fibrosis. However, 6/81 (7.4%) of untreated patients had a progression of fibrosis stage from F0-F1 to F2 or F3. There was no evidence of difference in rates or incidence of renal impairment during follow-up in the TDF vs. untreated group. CONCLUSIONS: Risk of liver inflammation and fibrosis may be raised in untreated patients compared to those receiving TDF, and TDF may benefit a larger percentage of the CHB population.


Assuntos
Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Rim/fisiologia , Fígado/fisiologia , Tenofovir/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antivirais/uso terapêutico , Estudos de Coortes , Técnicas de Imagem por Elasticidade , Feminino , Hepatite B/tratamento farmacológico , Hepatite B/fisiopatologia , Hepatite B/virologia , Antígenos E da Hepatite B , Vírus da Hepatite B/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/isolamento & purificação , Hepatite B Crônica/fisiopatologia , Humanos , Rim/efeitos dos fármacos , Rim/virologia , Fígado/efeitos dos fármacos , Fígado/virologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Reino Unido/epidemiologia , Carga Viral/efeitos dos fármacos , Carga Viral/fisiologia , Adulto Jovem
8.
Sci Rep ; 11(1): 11022, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: covidwho-1246394

RESUMO

The novel coronavirus outbreak began in late December 2019 and rapidly spread worldwide, critically impacting public health systems. A number of already approved and marketed drugs are being tested for repurposing, including Favipiravir. We aim to investigate the efficacy and safety of Favipiravir in treatment of COVID-19 patients through a systematic review and meta-analysis. This systematic review and meta-analysis were reported in accordance with the PRISMA statement. We registered the protocol in the PROSPERO (CRD42020180032). All clinical trials which addressed the safety and efficacy of Favipiravir in comparison to other control groups for treatment of patients with confirmed infection with SARS-CoV2 were included. We searched electronic databases including LitCovid/PubMed, Scopus, Web of Sciences, Cochrane, and Scientific Information Database up to 31 December 2020. We assessed the risk of bias of the included studies using Cochrane Collaboration criteria. All analyses were performed using the Comprehensive Meta-Analysis software version 2, and the risk ratio index was calculated. Egger and Begg test was used for assessing publication bias. Nine studies were included in our meta-analysis. The results of the meta-analysis revealed a significant clinical improvement in the Favipiravir group versus the control group during seven days after hospitalization (RR = 1.24, 95% CI: 1.09-1.41; P = 0.001). Viral clearance was more in 14 days after hospitalization in Favipiravir group than control group, but this finding marginally not significant (RR = 1.11, 95% CI: 0.98-1.25; P = 0.094). Requiring supplemental oxygen therapy in the Favipiravir group was 7% less than the control group, (RR = 0.93, 95% CI: 0.67-1.28; P = 0.664). Transferred to ICU and adverse events were not statistically different between two groups. The mortality rate in the Favipiravir group was approximately 30% less than the control group, but this finding not statistically significant. Favipiravir possibly exerted no significant beneficial effect in the term of mortality in the general group of patients with mild to moderate COVID-19. We should consider that perhaps the use of antiviral once the patient has symptoms is too late and this would explain their low efficacy in the clinical setting.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pirazinas/uso terapêutico , SARS-CoV-2/fisiologia , COVID-19/mortalidade , Ensaios Clínicos como Assunto , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Unidades de Terapia Intensiva , Análise de Sobrevida , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
9.
BMC Infect Dis ; 21(1): 489, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: covidwho-1244908

RESUMO

BACKGROUND: Favipiravir possesses high utility for treating patients with COVID-19. However, research examining the efficacy and safety of favipiravir for patients with COVID-19 is limited. METHODS: We conducted a systematic review of published studies reporting the efficacy of favipiravir against COVID-19. Two investigators independently searched PubMed, the Cochrane Database of Systematic Reviews, MedRxiv, and ClinicalTrials.gov (inception to September 2020) to identify eligible studies. A meta-analysis was performed to measure viral clearance and clinical improvement as the primary outcomes. RESULTS: Among 11 eligible studies, 5 included a comparator group. Comparing to the comparator group, the favipiravir group exhibited significantly better viral clearance on day 7 after the initiation of treatment (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.19-5.22), whereas no difference was noted on day 14 (OR = 2.19, 95% CI = 0.69-6.95). Although clinical improvement was significantly better in the favipiravir group on both days 7 and 14, the improvement was better on day 14 (OR = 3.03, 95% CI = 1.17-7.80) than on day 7 (OR = 1.60, 95% CI = 1.03-2.49). The estimated proportions of patients with viral clearance in the favipiravir arm on days 7 and 14 were 65.42 and 88.9%, respectively, versus 43.42 and 78.79%, respectively, in the comparator group. The estimated proportions of patients with clinical improvement on days 7 and 14 in the favipiravir group were 54.33 and 84.63%, respectively, compared with 34.40 and 65.77%, respectively, in the comparator group. CONCLUSIONS: Favipiravir induces viral clearance by 7 days and contributes to clinical improvement within 14 days. The results indicated that favipiravir has strong possibility for treating COVID-19, especially in patients with mild-to-moderate illness. Additional well-designed studies, including examinations of the dose and duration of treatment, are crucial for reaching definitive conclusions.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pirazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidas/efeitos adversos , Antivirais/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , SARS-CoV-2 , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
10.
Sci Adv ; 7(22)2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1247309

RESUMO

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals' weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Anticorpos de Domínio Único/administração & dosagem , Administração por Inalação , Aerossóis/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Masculino , Mesocricetus , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Carga Viral/efeitos dos fármacos
11.
PLoS Pathog ; 17(5): e1009229, 2021 05.
Artigo em Inglês | MEDLINE | ID: covidwho-1239922

RESUMO

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.


Assuntos
Camelídeos Americanos , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Interferons/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Camelídeos Americanos/imunologia , Camelídeos Americanos/metabolismo , Camelídeos Americanos/virologia , Chlorocebus aethiops , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Reservatórios de Doenças/veterinária , Resistência à Doença/efeitos dos fármacos , Resistência à Doença/genética , Resistência à Doença/imunologia , Regulação da Expressão Gênica , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/veterinária , Inflamação/virologia , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/virologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
12.
Sci Rep ; 11(1): 11022, 2021 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-34040117

RESUMO

The novel coronavirus outbreak began in late December 2019 and rapidly spread worldwide, critically impacting public health systems. A number of already approved and marketed drugs are being tested for repurposing, including Favipiravir. We aim to investigate the efficacy and safety of Favipiravir in treatment of COVID-19 patients through a systematic review and meta-analysis. This systematic review and meta-analysis were reported in accordance with the PRISMA statement. We registered the protocol in the PROSPERO (CRD42020180032). All clinical trials which addressed the safety and efficacy of Favipiravir in comparison to other control groups for treatment of patients with confirmed infection with SARS-CoV2 were included. We searched electronic databases including LitCovid/PubMed, Scopus, Web of Sciences, Cochrane, and Scientific Information Database up to 31 December 2020. We assessed the risk of bias of the included studies using Cochrane Collaboration criteria. All analyses were performed using the Comprehensive Meta-Analysis software version 2, and the risk ratio index was calculated. Egger and Begg test was used for assessing publication bias. Nine studies were included in our meta-analysis. The results of the meta-analysis revealed a significant clinical improvement in the Favipiravir group versus the control group during seven days after hospitalization (RR = 1.24, 95% CI: 1.09-1.41; P = 0.001). Viral clearance was more in 14 days after hospitalization in Favipiravir group than control group, but this finding marginally not significant (RR = 1.11, 95% CI: 0.98-1.25; P = 0.094). Requiring supplemental oxygen therapy in the Favipiravir group was 7% less than the control group, (RR = 0.93, 95% CI: 0.67-1.28; P = 0.664). Transferred to ICU and adverse events were not statistically different between two groups. The mortality rate in the Favipiravir group was approximately 30% less than the control group, but this finding not statistically significant. Favipiravir possibly exerted no significant beneficial effect in the term of mortality in the general group of patients with mild to moderate COVID-19. We should consider that perhaps the use of antiviral once the patient has symptoms is too late and this would explain their low efficacy in the clinical setting.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pirazinas/uso terapêutico , SARS-CoV-2/fisiologia , COVID-19/mortalidade , Ensaios Clínicos como Assunto , Progressão da Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Unidades de Terapia Intensiva , Análise de Sobrevida , Resultado do Tratamento , Carga Viral/efeitos dos fármacos
13.
BMC Infect Dis ; 21(1): 489, 2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34044777

RESUMO

BACKGROUND: Favipiravir possesses high utility for treating patients with COVID-19. However, research examining the efficacy and safety of favipiravir for patients with COVID-19 is limited. METHODS: We conducted a systematic review of published studies reporting the efficacy of favipiravir against COVID-19. Two investigators independently searched PubMed, the Cochrane Database of Systematic Reviews, MedRxiv, and ClinicalTrials.gov (inception to September 2020) to identify eligible studies. A meta-analysis was performed to measure viral clearance and clinical improvement as the primary outcomes. RESULTS: Among 11 eligible studies, 5 included a comparator group. Comparing to the comparator group, the favipiravir group exhibited significantly better viral clearance on day 7 after the initiation of treatment (odds ratio [OR] = 2.49, 95% confidence interval [CI] = 1.19-5.22), whereas no difference was noted on day 14 (OR = 2.19, 95% CI = 0.69-6.95). Although clinical improvement was significantly better in the favipiravir group on both days 7 and 14, the improvement was better on day 14 (OR = 3.03, 95% CI = 1.17-7.80) than on day 7 (OR = 1.60, 95% CI = 1.03-2.49). The estimated proportions of patients with viral clearance in the favipiravir arm on days 7 and 14 were 65.42 and 88.9%, respectively, versus 43.42 and 78.79%, respectively, in the comparator group. The estimated proportions of patients with clinical improvement on days 7 and 14 in the favipiravir group were 54.33 and 84.63%, respectively, compared with 34.40 and 65.77%, respectively, in the comparator group. CONCLUSIONS: Favipiravir induces viral clearance by 7 days and contributes to clinical improvement within 14 days. The results indicated that favipiravir has strong possibility for treating COVID-19, especially in patients with mild-to-moderate illness. Additional well-designed studies, including examinations of the dose and duration of treatment, are crucial for reaching definitive conclusions.


Assuntos
Amidas/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pirazinas/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidas/efeitos adversos , Antivirais/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pirazinas/efeitos adversos , SARS-CoV-2 , Resultado do Tratamento , Carga Viral/efeitos dos fármacos , Adulto Jovem
14.
Sci Adv ; 7(22)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34039613

RESUMO

Globally, there is an urgency to develop effective, low-cost therapeutic interventions for coronavirus disease 2019 (COVID-19). We previously generated the stable and ultrapotent homotrimeric Pittsburgh inhalable Nanobody 21 (PiN-21). Using Syrian hamsters that model moderate to severe COVID-19 disease, we demonstrate the high efficacy of PiN-21 to prevent and treat SARS-CoV-2 infection. Intranasal delivery of PiN-21 at 0.6 mg/kg protects infected animals from weight loss and substantially reduces viral burdens in both lower and upper airways compared to control. Aerosol delivery of PiN-21 facilitates deposition throughout the respiratory tract and dose minimization to 0.2 mg/kg. Inhalation treatment quickly reverses animals' weight loss after infection, decreases lung viral titers by 6 logs leading to drastically mitigated lung pathology, and prevents viral pneumonia. Combined with the marked stability and low production cost, this innovative therapy may provide a convenient and cost-effective option to mitigate the ongoing pandemic.


Assuntos
COVID-19/tratamento farmacológico , COVID-19/prevenção & controle , SARS-CoV-2/efeitos dos fármacos , Anticorpos de Domínio Único/administração & dosagem , Administração por Inalação , Aerossóis/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Masculino , Mesocricetus , Pandemias/prevenção & controle , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/prevenção & controle , Carga Viral/efeitos dos fármacos
15.
PLoS Pathog ; 17(5): e1009229, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-34029358

RESUMO

While MERS-CoV (Middle East respiratory syndrome Coronavirus) provokes a lethal disease in humans, camelids, the main virus reservoir, are asymptomatic carriers, suggesting a crucial role for innate immune responses in controlling the infection. Experimentally infected camelids clear infectious virus within one week and mount an effective adaptive immune response. Here, transcription of immune response genes was monitored in the respiratory tract of MERS-CoV infected alpacas. Concomitant to the peak of infection, occurring at 2 days post inoculation (dpi), type I and III interferons (IFNs) were maximally transcribed only in the nasal mucosa of alpacas, while interferon stimulated genes (ISGs) were induced along the whole respiratory tract. Simultaneous to mild focal infiltration of leukocytes in nasal mucosa and submucosa, upregulation of the anti-inflammatory cytokine IL10 and dampened transcription of pro-inflammatory genes under NF-κB control were observed. In the lung, early (1 dpi) transcription of chemokines (CCL2 and CCL3) correlated with a transient accumulation of mainly mononuclear leukocytes. A tight regulation of IFNs in lungs with expression of ISGs and controlled inflammatory responses, might contribute to virus clearance without causing tissue damage. Thus, the nasal mucosa, the main target of MERS-CoV in camelids, seems central in driving an efficient innate immune response based on triggering ISGs as well as the dual anti-inflammatory effects of type III IFNs and IL10.


Assuntos
Camelídeos Americanos , Infecções por Coronavirus/imunologia , Interferon Tipo I/metabolismo , Interferons/metabolismo , Coronavírus da Síndrome Respiratória do Oriente Médio/imunologia , Animais , Antivirais/metabolismo , Antivirais/farmacologia , Camelídeos Americanos/imunologia , Camelídeos Americanos/metabolismo , Camelídeos Americanos/virologia , Chlorocebus aethiops , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/veterinária , Reservatórios de Doenças/veterinária , Resistência à Doença/efeitos dos fármacos , Resistência à Doença/genética , Resistência à Doença/imunologia , Regulação da Expressão Gênica , Imunidade Inata/fisiologia , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/veterinária , Inflamação/virologia , Interferon Tipo I/genética , Interferon Tipo I/farmacologia , Interferons/genética , Interferons/farmacologia , Coronavírus da Síndrome Respiratória do Oriente Médio/efeitos dos fármacos , Coronavírus da Síndrome Respiratória do Oriente Médio/fisiologia , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/virologia , Sistema Respiratório/efeitos dos fármacos , Sistema Respiratório/imunologia , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Células Vero , Carga Viral/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Nat Commun ; 12(1): 2866, 2021 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-34001890

RESUMO

Unlike HIV infection, which progresses to AIDS absent suppressive anti-retroviral therapy, nonpathogenic infections in natural hosts, such African green monkeys, are characterized by a lack of gut microbial translocation and robust secondary lymphoid natural killer cell responses resulting in an absence of chronic inflammation and limited SIV dissemination in lymph node B-cell follicles. Here we report, using the pathogenic model of antiretroviral therapy-treated, SIV-infected rhesus macaques that sequential interleukin-21 and interferon alpha therapy generate terminally differentiated blood natural killer cells (NKG2a/clowCD16+) with potent human leukocyte antigen-E-restricted activity in response to SIV envelope peptides. This is in contrast to control macaques, where less differentiated, interferon gamma-producing natural killer cells predominate. The frequency and activity of terminally differentiated NKG2a/clowCD16+ natural killer cells correlates with a reduction of replication-competent SIV in lymph node during antiretroviral therapy and time to viral rebound following analytical treatment interruption. These data demonstrate that African green monkey-like natural killer cell differentiation profiles can be rescued in rhesus macaques to promote viral clearance in tissues.


Assuntos
Antirretrovirais/farmacologia , Interferon gama/farmacologia , Interleucinas/farmacologia , Células Matadoras Naturais/efeitos dos fármacos , Síndrome de Imunodeficiência Adquirida dos Símios/tratamento farmacológico , Vírus da Imunodeficiência Símia/efeitos dos fármacos , Animais , Antivirais/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/virologia , Feminino , Células Matadoras Naturais/virologia , Ativação Linfocitária/efeitos dos fármacos , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Carga Viral/efeitos dos fármacos , Viremia/sangue , Viremia/tratamento farmacológico
17.
Sci Rep ; 11(1): 8761, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888840

RESUMO

The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 µg or 5 µg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Hidróxido de Alumínio/administração & dosagem , COVID-19/prevenção & controle , Oligodesoxirribonucleotídeos/administração & dosagem , Glicoproteína da Espícula de Coronavírus/imunologia , Hidróxido de Alumínio/imunologia , Animais , Anticorpos Neutralizantes/metabolismo , COVID-19/imunologia , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/imunologia , Linhagem Celular , Cricetinae , Feminino , Humanos , Imunização , Injeções Intramusculares , Oligodesoxirribonucleotídeos/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/fisiologia , Carga Viral/efeitos dos fármacos
18.
Drug Res (Stuttg) ; 71(6): 348-350, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33890267

RESUMO

During the next few months or years, vaccination against SARS-CoV-2 infection will significantly reduce the morbidity and mortality of COVID-19. However, additional measures are needed to protect those who are still not immunized. This is even more important in view of new viral mutations that result in increased transmission rates. We propose that the use of long-standing medicinal solutions based on hypochloric acid (HOCl) and intended for application on wounds may be effective as a gargling solution or nasal irrigation in blocking transmission of the virus. Here, we propose the use of HOCl-containing solutions for blocking the transmission of SARS-CoV-2 in combination with other prevention measures. This may constitute another important cornerstone in the fight against the COVID-19 pandemic.


Assuntos
Anti-Infecciosos Locais/administração & dosagem , COVID-19/prevenção & controle , Ácido Hipocloroso/administração & dosagem , SARS-CoV-2/efeitos dos fármacos , Carga Viral/efeitos dos fármacos , Administração Oral , COVID-19/epidemiologia , COVID-19/transmissão , COVID-19/virologia , Humanos , Mucosa Bucal/virologia , Lavagem Nasal , Mucosa Nasal/virologia , Sprays Nasais , Pandemias/prevenção & controle , SARS-CoV-2/isolamento & purificação
19.
Lancet HIV ; 8(5): e266-e273, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33891877

RESUMO

BACKGROUND: There are few data on life expectancy gains among people living with HIV in low-income and middle-income settings where antiretroviral therapy (ART) is increasingly available. We aimed to analyse life expectancy trends from 2003 to 2017 among people with HIV beginning treatment with ART within the Caribbean, central America, and South America. METHODS: We did a multisite retrospective cohort study and included people with HIV who had started treatment with ART and were aged 16 years or older between Jan 1, 2003, and Dec 31, 2017, from Caribbean, Central and South America network for HIV epidemiology (CCASAnet) sites in Argentina, Brazil, Chile, Haiti, Honduras, Mexico, and Peru, who contributed person-time data from the age of 20 years until date of death, last contact, database closure, or Dec 31, 2017. We used the Chiang method of abridged life tables to estimate life expectancy at age 20 years for three eras (2003-08, 2009-12, and 2013-17) overall and by demographic and clinical characteristics at ART initiation. We used Poisson regression models to weight mortality rates to account for informative censoring. FINDINGS: 30 688 people with HIV were included in the study; 17 491 (57·0%) were from the Haiti site and 13 197 (43·0%) were from all other sites. There were 2637 deaths during the study period: 1470 in Haiti and 1167 in other sites. Crude and weighted mortality rates decreased among all age groups over calendar eras. From 2003-08 to 2013-17, overall life expectancy for people with HIV at age 20 years increased from 13·9 years (95% CI 12·5-15·2) to 61·2 years (59·0-63·4) in Haiti and from 31·0 years (29·3-32·8) to 69·5 years (67·2-71·8) in other sites. Life expectancies at the end of the study period were within 10 years of those of the general population (69·9 years in Haiti and 78·0 years in all other sites in 2018). Disparities in life expectancy among people with HIV by sex or HIV transmission risk factor, CD4 cell count, level of education, and history of tuberculosis at or before ART initiation persisted across calendar eras. INTERPRETATION: Life expectancy among people with HIV receiving ART has significantly improved in Latin America and the Caribbean. Persistent disparities in life expectancy among people with HIV by demographic and clinical factors at ART initiation highlight vulnerable populations in the region. FUNDING: National Institutes of Health. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Expectativa de Vida/tendências , RNA Viral/antagonistas & inibidores , Adolescente , Adulto , Idoso , Terapia Antirretroviral de Alta Atividade , Região do Caribe/epidemiologia , Feminino , Infecções por HIV/mortalidade , Infecções por HIV/transmissão , HIV-1/efeitos dos fármacos , HIV-1/crescimento & desenvolvimento , HIV-1/patogenicidade , Humanos , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , RNA Viral/genética , Estudos Retrospectivos , Risco , Análise de Sobrevida , Carga Viral/efeitos dos fármacos
20.
J Gen Virol ; 102(4)2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33913803

RESUMO

Infectious SARS-CoV-2 can be recovered from the oral cavities and saliva of COVID-19 patients with potential implications for disease transmission. Reducing viral load in patient saliva using antiviral mouthwashes may therefore have a role as a control measure in limiting virus spread, particularly in dental settings. Here, the efficacy of SARS-CoV-2 inactivation by seven commercially available mouthwashes with a range of active ingredients were evaluated in vitro. We demonstrate ≥4.1 to ≥5.5 log10 reduction in SARS-CoV-2 titre following a 1 min treatment with commercially available mouthwashes containing 0.01-0.02 % stabilised hypochlorous acid or 0.58 % povidone iodine, and non-specialist mouthwashes with both alcohol-based and alcohol-free formulations designed for home use. In contrast, products containing 1.5 % hydrogen peroxide or 0.2 % chlorhexidine gluconate were ineffective against SARS-CoV-2 in these tests. This study contributes to the growing body of evidence surrounding virucidal efficacy of mouthwashes/oral rinses against SARS-CoV-2, and has important applications in reducing risk associated with aerosol generating procedures in dentistry and potentially for infection control more widely.


Assuntos
Antivirais/farmacologia , Antissépticos Bucais/farmacologia , SARS-CoV-2/efeitos dos fármacos , Inativação de Vírus/efeitos dos fármacos , COVID-19/prevenção & controle , COVID-19/transmissão , Sobrevivência Celular/efeitos dos fármacos , Humanos , Boca/virologia , Carga Viral/efeitos dos fármacos
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