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  • 1
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    Online Resource
    In vitro antiviral activity of the anti-HCV drugs daclatasvir and sofosbuvir against SARS-CoV-2, the aetiological agent of COVID-19
    Oxford University Press (OUP) ; 2021
    In:  Journal of Antimicrobial Chemotherapy Vol. 76, No. 7 ( 2021-06-18), p. 1874-1885
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 76, No. 7 ( 2021-06-18), p. 1874-1885
    Abstract: Current approaches of drug repurposing against COVID-19 have not proven overwhelmingly successful and the SARS-CoV-2 pandemic continues to cause major global mortality. SARS-CoV-2 nsp12, its RNA polymerase, shares homology in the nucleotide uptake channel with the HCV orthologue enzyme NS5B. Besides, HCV enzyme NS5A has pleiotropic activities, such as RNA binding, that are shared with various SARS-CoV-2 proteins. Thus, anti-HCV NS5B and NS5A inhibitors, like sofosbuvir and daclatasvir, respectively, could be endowed with anti-SARS-CoV-2 activity. Methods SARS-CoV-2-infected Vero cells, HuH-7 cells, Calu-3 cells, neural stem cells and monocytes were used to investigate the effects of daclatasvir and sofosbuvir. In silico and cell-free based assays were performed with SARS-CoV-2 RNA and nsp12 to better comprehend the mechanism of inhibition of the investigated compounds. A physiologically based pharmacokinetic model was generated to estimate daclatasvir’s dose and schedule to maximize the probability of success for COVID-19. Results Daclatasvir inhibited SARS-CoV-2 replication in Vero, HuH-7 and Calu-3 cells, with potencies of 0.8, 0.6 and 1.1 μM, respectively. Although less potent than daclatasvir, sofosbuvir alone and combined with daclatasvir inhibited replication in Calu-3 cells. Sofosbuvir and daclatasvir prevented virus-induced neuronal apoptosis and release of cytokine storm-related inflammatory mediators, respectively. Sofosbuvir inhibited RNA synthesis by chain termination and daclatasvir targeted the folding of secondary RNA structures in the SARS-CoV-2 genome. Concentrations required for partial daclatasvir in vitro activity are achieved in plasma at Cmax after administration of the approved dose to humans. Conclusions Daclatasvir, alone or in combination with sofosbuvir, at higher doses than used against HCV, may be further fostered as an anti-COVID-19 therapy.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkab072
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 1467478-6
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  • 2
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    Atazanavir, Alone or in Combination with Ritonavir, Inhibits SARS-CoV-2 Replication and Proinflammatory Cytokine Production
    American Society for Microbiology ; 2020
    In:  Antimicrobial Agents and Chemotherapy Vol. 64, No. 10 ( 2020-09-21)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 64, No. 10 ( 2020-09-21)
    Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is already responsible for far more deaths than previous pathogenic coronaviruses (CoVs) from 2002 and 2012. The identification of clinically approved drugs to be repurposed to combat 2019 CoV disease (COVID-19) would allow the rapid implementation of potentially life-saving procedures. The major protease (Mpro) of SARS-CoV-2 is considered a promising target, based on previous results from related CoVs with lopinavir (LPV), an HIV protease inhibitor. However, limited evidence exists for other clinically approved antiretroviral protease inhibitors. Extensive use of atazanavir (ATV) as antiretroviral and previous evidence suggesting its bioavailability within the respiratory tract prompted us to study this molecule against SARS-CoV-2. Our results show that ATV docks in the active site of SARS-CoV-2 Mpro with greater strength than LPV, blocking Mpro activity. We confirmed that ATV inhibits SARS-CoV-2 replication, alone or in combination with ritonavir (RTV) in Vero cells and a human pulmonary epithelial cell line. ATV/RTV also impaired virus-induced enhancement of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α) levels. Together, our data strongly suggest that ATV and ATV/RTV should be considered among the candidate repurposed drugs undergoing clinical trials in the fight against COVID-19.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.00825-20
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 1496156-8
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  • 3
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    Beyond Members of the Flaviviridae Family, Sofosbuvir Also Inhibits Chikungunya Virus Replication
    American Society for Microbiology ; 2019
    In:  Antimicrobial Agents and Chemotherapy Vol. 63, No. 2 ( 2019-02)
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 63, No. 2 ( 2019-02)
    Abstract: Chikungunya virus (CHIKV) causes a febrile disease associated with chronic arthralgia, which may progress to neurological impairment. Chikungunya fever (CF) is an ongoing public health problem in tropical and subtropical regions of the world, where control of the CHIKV vector, Aedes mosquitos, has failed. As there is no vaccine or specific treatment for CHIKV, patients receive only palliative care to alleviate pain and arthralgia. Thus, drug repurposing is necessary to identify antivirals against CHIKV. CHIKV RNA polymerase is similar to the orthologue enzyme of other positive-sense RNA viruses, such as members of the Flaviviridae family. Among the Flaviviridae , not only is hepatitis C virus RNA polymerase susceptible to sofosbuvir, a clinically approved nucleotide analogue, but so is dengue, Zika, and yellow fever virus replication. Here, we found that sofosbuvir was three times more selective in inhibiting CHIKV production in human hepatoma cells than ribavirin, a pan-antiviral drug. Although CHIKV replication in human induced pluripotent stem cell-derived astrocytes was less susceptible to sofosbuvir than were hepatoma cells, sofosbuvir nevertheless impaired virus production and cell death in a multiplicity of infection-dependent manner. Sofosbuvir also exhibited antiviral activity in vivo by preventing CHIKV-induced paw edema in adult mice at a dose of 20 mg/kg of body weight/day and prevented mortality in a neonate mouse model at 40- and 80-mg/kg/day doses. Our data demonstrate that a prototypic alphavirus, CHIKV, is also susceptible to sofosbuvir. As sofosbuvir is a clinically approved drug, our findings could pave the way to it becoming a therapeutic option against CF.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.01389-18
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2019
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  • 4
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    Incidence and Determinants of Severe Morbidity among HIV-Infected Patients from Rio De Janeiro, Brazil, 2000–2010
    SAGE Publications ; 2014
    In:  Antiviral Therapy Vol. 19, No. 4 ( 2014-05), p. 387-397
    Details
    In: Antiviral Therapy, SAGE Publications, Vol. 19, No. 4 ( 2014-05), p. 387-397
    Abstract: Reliable information on severe morbidity is essential for identifying priorities for case management and to guide resource allocation within the health sector. Methods This study describes overall, AIDS- and non-AIDS-related severe morbidity as well as mortality and its determinants in an urban cohort of HIV-infected individuals from a public healthcare institution, the Evandro Chagas Research Institute (IPEC) of the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil. Severe morbid events were defined as all clinical diagnoses listed in hospitalization discharge records; all diagnoses were checked and validated. Generalized estimating equation models were used to estimate incidence rates while adjusting for within-subject correlation. Results Between 2000 and 2010, 3,537 patients were followed for a total of 16,960 person-years (PY) of follow-up. Over the years, annual incidence rate of severe morbid events, AIDS-related events, non-AIDS-related events, and deaths significantly decreased from, respectively, 36.6, 12.9, 23.7 and 3.2 per 100 PY in 2000 to 25.3, 7.9, 17.4 and 1.9 per 100 PY in 2010. Patients’ immunological profiles significantly improved with time; 84% of the patients used combination antiretroviral therapy (cART) per year. Immunodeficiency was associated with a higher incidence rate of AIDS- and non-AIDS-related events as well as with the incidence rate of specific non-AIDS events (bacterial infections, toxicities, cardiovascular, renal and respiratory diseases). Conclusions Our results show that in a middle income country with access to cART, non-AIDS-related events represent an important cause of severe morbidity alongside a still high incidence rate of AIDS-related events.
    Type of Medium: Online Resource
    ISSN: 1359-6535 , 2040-2058
    URL: Article
    DOI: 10.3851/IMP2716
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2014
    detail.hit.zdb_id: 2118396-X
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  • 5
    Online Resource
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    Limited-Sampling Strategy Models for Itraconazole and Hydroxy-Itraconazole Based on Data from a Bioequivalence Study
    American Society for Microbiology ; 1999
    In:  Antimicrobial Agents and Chemotherapy Vol. 43, No. 1 ( 1999-01), p. 134-140
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 43, No. 1 ( 1999-01), p. 134-140
    Abstract: The extensive interindividual variability in oral bioavailability of itraconazole prompted an assessment of the bioequivalence of two formulations marketed in Brazil, namely, Sporanox (reference) and Traconal (test). Eighteen healthy volunteers received single 200-mg oral doses of each formulation at 2-week intervals in a randomized, crossover protocol. The concentrations of itraconazole and hydroxy-itraconazole in plasma were measured by high-performance liquid chromatography, and the datum points ( n = 396) were subsequently used to develop limited-sampling strategy models for estimation of the areas under the curve (AUCs) for both compounds. The 90% confidence intervals for individual percent ratios (test/reference formulations) of the maximum concentration of drug in serum, the AUC from 0 to 48 h and the AUC from time zero to infinity (AUC 0–∞ ) for itraconazole and hydoxy-itraconazole were below the range of 80 to 125%, suggesting that these formulations are not bioequivalent. Linear regression analysis of the AUC 0–∞ against time and a “jackknife” validation procedure revealed that models based on three sampling times accurately predict ( R 2 , 〉 0.98; bias, 〈 3%; precision, 3 to 7%) the AUC 0–∞ for each of the four formulation-compound pairs tested. Increasing the number of sampling points to more than three adds little to the accuracy of the estimates of AUC 0–∞ . The three-point models developed for the reference formulation were validated retrospectively and were found to predict within 2% the AUC 0–∞ reported in previous studies performed under similar protocols. In conclusion, the data in this study indicate (i) that the tested formulations are not bioequivalent when single doses are compared and (ii) that limited-sampling strategy models based on three points predict accurately the AUC 0–∞ s for itraconazole and hydroxy-itraconazole and could be a valuable tool in pharmacokinetic and bioequivalence studies of single oral doses of itraconazole.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.43.1.134
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 1999
    detail.hit.zdb_id: 1496156-8
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  • 6
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    Neuroinflammation in Sepsis: Molecular Pathways of Microglia Activation
    MDPI AG ; 2021
    In:  Pharmaceuticals Vol. 14, No. 5 ( 2021-05-01), p. 416-
    Details
    In: Pharmaceuticals, MDPI AG, Vol. 14, No. 5 ( 2021-05-01), p. 416-
    Abstract: Frequently underestimated, encephalopathy or delirium are common neurological manifestations associated with sepsis. Brain dysfunction occurs in up to 80% of cases and is directly associated with increased mortality and long-term neurocognitive consequences. Although the central nervous system (CNS) has been classically viewed as an immune-privileged system, neuroinflammation is emerging as a central mechanism of brain dysfunction in sepsis. Microglial cells are major players in this setting. Here, we aimed to discuss the current knowledge on how the brain is affected by peripheral immune activation in sepsis and the role of microglia in these processes. This review focused on the molecular pathways of microglial activity in sepsis, its regulatory mechanisms, and their interaction with other CNS cells, especially with neuronal cells and circuits.
    Type of Medium: Online Resource
    ISSN: 1424-8247
    URL: Article
    DOI: 10.3390/ph14050416
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 7
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    Table1.DOCX
    Frontiers Media SA ; 2022
    In:  Frontiers in Pharmacology Vol. 13 ( 2022-6-16)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 13 ( 2022-6-16)
    Abstract: Background: The consumption of antibiotics is one of the metrics used to evaluate the impact of antimicrobial stewardship programs (ASP). The aim of this study was to determine the prevalence of antibiotic consumption in Brazilian intensive care units (ICUs) and estimate the deviation of the prescribed daily dose (PDD) from the defined daily dose (DDD). Methods: This is a multicenter, observational, point-prevalence study carried out in adult ICUs of 8 Brazilian hospitals from August 2019, to February 2020. We collected data on the patient’s demographic and clinical characteristics, antibiotic therapy, classification and site of infections. The DU90 (antibiotic accounting for 90% of the volume utilized) was calculated, and the antibiotics were classified by the Anatomical Therapeutic Chemical (ATC) Index and the World Health Organization (WHO) Access, Watch, Reserve (AWaRe) groups. For the most prevalent antibiotics, the deviation of PDD from DDD was determined. Results: Three hundred thirty-two patients from 35 ICUs were analyzed. The prevalence of antibiotic use was 52.4%. The patients in use of antibiotics were predominantly over 60 years of age (81.6%) with pulmonary infections (45.8%). A predominance of empirical regimens was observed (62.6%) among antibiotic therapies. The highest frequencies of prescriptions observed were for piperacillin + tazobactam (16.1%), meropenem (13.3%), amoxicillin + clavulanate (7.2%), azithromycin (7.2%), and teicoplanin (6.1%). The watch (64.2%) and reserve (9.6%) categories of the AWaRe classification accounted for 73.8% of all antibiotics, and they were prescribed alone or in combinations. High variability of doses was observed for the most prescribed antibiotics, and large deviations of PDD from the DDD were observed for meropenem, teicoplanin, and tigecycline. Conclusions: The high prevalence of antibiotic prescription was related to a predominance of empirical regimens and antibiotics belonging to the WHO Watch classification. High variability of doses and large deviations of PDD from DDD for meropenem, teicoplanin, and tigecycline was observed, suggesting that DDD may be insufficient to monitor the consumption of these antibiotics in the ICU population. The variability of doses found for the most prescribed antibiotics suggests the need for monitoring and intervention targets for antibiotic stewardship teams.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2022.913568
    DOI: 10.3389/fphar.2022.913568.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2587355-6
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  • 8
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    Antimicrobial consumption and drug utilization patterns among COVID-19 and non-COVID-19 patients
    Oxford University Press (OUP) ; 2023
    In:  Journal of Antimicrobial Chemotherapy Vol. 78, No. 3 ( 2023-03-02), p. 840-849
    Details
    In: Journal of Antimicrobial Chemotherapy, Oxford University Press (OUP), Vol. 78, No. 3 ( 2023-03-02), p. 840-849
    Abstract: To understand differences in antimicrobial use between COVID-19 and non-COVID-19 patients. To compare two metrics commonly used for antimicrobial use: Defined Daily Dose (DDD) and Days of Therapy (DOT). To analyse the order in which antimicrobials were prescribed to COVID-19 patients using process mining techniques. Methods We analysed data regarding all ICU admissions from 1 January 2018 to 14 September 2020, in 17 Brazilian hospitals. Our main outcome was the antimicrobial use estimated by the DDD and DOT (Days of Therapy). We compared clinical characteristics and antimicrobial consumption between COVID-19 and non-COVID-19 patients. We used process mining to evaluate the order in which the antimicrobial schemes were prescribed to each COVID-19 patient. Results We analysed 68 405 patients admitted before the pandemic, 12 319 non-COVID-19 patients and 3240 COVID-19 patients. Comparing those admitted during the pandemic, the COVID-19 patients required advanced respiratory support more often (42% versus 12%). They also had longer ICU length of stay (6 versus 3 days), higher ICU mortality (18% versus 5.4%) and greater use of antimicrobials (70% versus 39%). Most of the COVID-19 treatments started with penicillins with ß-lactamase inhibitors (30%), third-generation cephalosporins (22%), or macrolides in combination with penicillins (19%). Conclusions Antimicrobial prescription increased in Brazilian ICUs during the COVID-19 pandemic, especially during the first months of the epidemic. We identified greater use of broad-spectrum antimicrobials by COVID-19 patients. Overall, the DDD metric overestimated antimicrobial use compared with the DOT metric.
    Type of Medium: Online Resource
    ISSN: 0305-7453 , 1460-2091
    URL: Article
    DOI: 10.1093/jac/dkad025
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2023
    detail.hit.zdb_id: 1467478-6
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