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1.
Comput Biol Med ; 145: 105523, 2022 06.
Article in English | MEDLINE | ID: covidwho-1814279

ABSTRACT

Starting three decades ago and spreading rapidly around the world, acquired immunodeficiency syndrome (AIDS) is an infectious disease distinct from other contagious diseases by its unique ways of transmission. Over the past few decades, research into new drug compounds has been accompanied by extensive advances, and the design and manufacture of drugs that inhibit virus enzymes is one way to combat the AIDS virus. Since blocking enzyme activity can kill a pathogen or correct a metabolic imbalance, the design and use of enzyme inhibitors is a new approach against viruses. We carried out an in-depth analysis of the efficacy of atazanavir and its newly designed analogs as human immunodeficiency virus (HIV) protease inhibitors using molecular docking. The best-designed analogs were then compared with atazanavir by the molecular dynamics simulation. The most promising results were ultimately found based on the docking analysis for HIV protease. Several exhibited an estimated free binding energy lower than -9.45 kcal/mol, indicating better prediction results than the atazanavir. ATV7 inhibitor with antiviral action may be more beneficial for infected patients with HIV. Molecular dynamics analysis and binding energy also showed that the ATV7 drug had more inhibitory ability than the atazanavir drug.


Subject(s)
Atazanavir Sulfate , HIV Protease Inhibitors , Atazanavir Sulfate/pharmacology , Atazanavir Sulfate/therapeutic use , HIV Protease/chemistry , HIV Protease/metabolism , HIV Protease/therapeutic use , HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/metabolism , HIV Protease Inhibitors/pharmacology , Molecular Docking Simulation
2.
J Med Virol ; 93(12): 6557-6565, 2021 12.
Article in English | MEDLINE | ID: covidwho-1544300

ABSTRACT

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/pathology , Drug Combinations , Drug Therapy, Combination , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Oxazines/administration & dosage , Piperazines/administration & dosage , Pyridones/administration & dosage , Ritonavir/administration & dosage , Treatment Outcome
3.
Trials ; 22(1): 831, 2021 Nov 23.
Article in English | MEDLINE | ID: covidwho-1529943

ABSTRACT

BACKGROUND: Remdesivir is a novel broad-spectrum antiviral therapeutic with activity against several viruses that cause emerging infectious diseases. The purpose of this study is to explore how commonly utilized antiretroviral therapy (tenofovir disoproxil fumarate/lamivudine [TDF/3TC] and atazanavir/ritonavir [ATV/r]) influence plasma and intracellular concentrations of remdesivir. METHODS: This is an open-label, randomized, fixed sequence single intravenous dosing study to assess pharmacokinetic interactions between remdesivir and TDF/3TC (Study A, crossover design) or TDF/3TC plus ATV/r (Study B). Healthy volunteers satisfying study entry criteria will be enrolled in the study and randomized to either Study A; N=16 (Sequence 1 or Sequence 2) or Study B; N=8. Participants will receive standard adult doses of antiretroviral therapy for 7 days and a single 200mg remdesivir infusion administered over 60 min. Pharmacokinetic blood sampling will be performed relative to the start of remdesivir infusion; predose (before the start of remdesivir infusion) and 30 min after the start of remdesivir infusion. Additional blood samples will be taken at 2, 4, 6, 12, and 24 h after the end of remdesivir infusion. DISCUSSION: This study will characterize the pharmacokinetics of remdesivir from a typical African population in whom clinical use is anticipated. Furthermore, this study will deliver pharmacokinetic datasets for remdesivir drug concentrations and demographic characteristics which could support pharmacometric approaches for simulation of remdesivir treatment regimens in patients concurrently using tenofovir/lamivudine and/or atazanavir/ritonavir. TRIAL REGISTRATION: ClinicalTrials.gov NCT04385719 . Registered 13 May 2020.


Subject(s)
Anti-HIV Agents , Lamivudine , Adenosine Monophosphate/analogs & derivatives , Adult , Alanine/analogs & derivatives , Atazanavir Sulfate , Healthy Volunteers , Humans , Oligopeptides , Pyridines , Ritonavir , Tenofovir , Uganda
5.
Int Immunopharmacol ; 101(Pt B): 108241, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1466416

ABSTRACT

BACKGROUND: IFNßs are known as one of the most promising drugs used for COVID-19 treatment. This study aimed to investigate the effects of treatment with INF-ß 1-a (interferon beta-1a) and IFN-ß 1-b (interferon beta-1b) on COVID-19 inpatients. METHODS: In this study, we retrospectively evaluated the clinical treatment outcomes of 100 patients with COVID-19 who received IFN-ß 1-a and IFN-ß 1-b during their hospitalization period. The rate of discharge from the hospital was considered equal to the clinical improvement and then evaluated as a primary outcome. Moreover, mortality, ICU admission and length of ICU stay, frequency of intubation and use of mechanical ventilation, duration of hospitalization, laboratory factors, and medications were assessed as secondary outcomes. RESULTS: The median discharge time of IFN-ß 1a recipients was approximately equal to that of IFN-ß 1-b recipients as 9 (5-10) days and 7 (5-11) days, respectively (HR = 2.43, P = 0.75). Mortality rate was also estimated as 10% among IFN-ß 1-a recipients and 14% among IFN-ß 1-b recipients, which was not statistically significant (p = 0.190). ICU hospitalization rate for the IFN-ß 1-a recipients and IFN-ß 1-b recipients was 26% and 36%, respectively. In addition, no significant difference was found between these two intervention groups in terms of ICU length of stay (1 (0-2) vs. 1 (0-4.25(, respectively,) P = 0.357). There was no significant difference between the two study groups in terms of frequency of mechanical ventilation and length of hospital stay. CONCLUSION: There was no significant difference between the two groups in terms of shortening the disease time, clinical improvements and other outcomes.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Interferon beta-1a/therapeutic use , Interferon beta-1b/therapeutic use , SARS-CoV-2 , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Aged , Alanine/analogs & derivatives , Alanine/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/therapy , Dexamethasone/therapeutic use , Female , Humans , Immunization, Passive , Inpatients , Intensive Care Units , Male , Middle Aged , Patient Discharge , Respiration, Artificial , Retrospective Studies , Treatment Outcome
6.
J Comput Aided Mol Des ; 35(9): 963-971, 2021 09.
Article in English | MEDLINE | ID: covidwho-1406168

ABSTRACT

The COVID-19 pandemic has led to unprecedented efforts to identify drugs that can reduce its associated morbidity/mortality rate. Computational chemistry approaches hold the potential for triaging potential candidates far more quickly than their experimental counterparts. These methods have been widely used to search for small molecules that can inhibit critical proteins involved in the SARS-CoV-2 replication cycle. An important target is the SARS-CoV-2 main protease Mpro, an enzyme that cleaves the viral polyproteins into individual proteins required for viral replication and transcription. Unfortunately, standard computational screening methods face difficulties in ranking diverse ligands to a receptor due to disparate ligand scaffolds and varying charge states. Here, we describe full density functional quantum mechanical (DFT) simulations of Mpro in complex with various ligands to obtain absolute ligand binding energies. Our calculations are enabled by a new cloud-native parallel DFT implementation running on computational resources from Amazon Web Services (AWS). The results we obtain are promising: the approach is quite capable of scoring a very diverse set of existing drug compounds for their affinities to M pro and suggest the DFT approach is potentially more broadly applicable to repurpose screening against this target. In addition, each DFT simulation required only ~ 1 h (wall clock time) per ligand. The fast turnaround time raises the practical possibility of a broad application of large-scale quantum mechanics in the drug discovery pipeline at stages where ligand diversity is essential.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Antiviral Agents/metabolism , Atazanavir Sulfate/chemistry , Atazanavir Sulfate/metabolism , Binding Sites , Cloud Computing , Density Functional Theory , Hydrogen Bonding , Ligands , Molecular Docking Simulation , Protein Conformation , Quantum Theory
8.
Medicine (Baltimore) ; 100(31): e26787, 2021 Aug 06.
Article in English | MEDLINE | ID: covidwho-1354339

ABSTRACT

BACKGROUND: Lopinavir, ritonavir, atazanavir, and saquinavir had been reportedly used or suggested for coronavirus disease 2019 (COVID-19) treatment. They may cause electrocardiography changes. We aim to evaluate risk of PR prolongation, QRS widening, and QT prolongation from lopinavir, ritonavir, atazanavir, and saquinavir. METHODS: In accordance with preferred reporting items for systematic reviews and meta-analyses guidelines, our search was conducted in PubMed Central, PubMed, EBSCOhost, and ProQuest from inception to June 25, 2020. Titles and abstracts were reviewed for relevance. Cochrane Risk of Bias Tool 2.0 and Downs and Black criteria was used to evaluate quality of studies. RESULTS: We retrieved 9 articles. Most randomized controlled trials have low risk of biases while all quasi-experimental studies have a positive rating. Four studies reporting PR prolongation however only 2 studies with PR interval >200 ms. One of which, reported its association after treatment with ritonavir-boosted saquinavir treatment while another, during treatment with ritonavir-boosted atazanavir. No study reported QRS widening >120 ms with treatment. Four studies reporting QT prolongation, with only one study reaching QT interval >450 ms after ritonavir-boosted saquinavir treatment on healthy patients. There is only one study on COVID-19 patients reporting QT prolongation in 1 out of 95 patients after ritonavir-boosted lopinavir treatment. CONCLUSION: Limited evidence suggests that lopinavir, ritonavir, atazanavir, and saquinavir could cause PR prolongation, QRS widening, and QT prolongation. Further trials with closer monitoring and assessment of electrocardiography are needed to ascertain usage safety of antivirals in COVID-19 era.


Subject(s)
Atazanavir Sulfate/adverse effects , Long QT Syndrome/etiology , Lopinavir/adverse effects , Ritonavir/adverse effects , Saquinavir/adverse effects , Adult , Atazanavir Sulfate/therapeutic use , Cytochrome P-450 CYP3A Inhibitors/adverse effects , Drug Therapy, Combination/methods , Drug Therapy, Combination/standards , Electrocardiography/methods , Humans , Lopinavir/therapeutic use , Ritonavir/therapeutic use , Saquinavir/therapeutic use
10.
J Med Virol ; 93(12): 6557-6565, 2021 12.
Article in English | MEDLINE | ID: covidwho-1306657

ABSTRACT

The purpose of this study was to compare the effectiveness of Atazanavir/Ritonavir/Dolutegravir/Hydroxychloroquine and Lopinavir/Ritonavir/Hydroxychloroquine treatment regimens in COVID-19 patients based on clinical and laboratory parameters. We prospectively evaluated the clinical and laboratory outcomes of 62 moderate to severe COVID-19 patients during a 10-day treatment plan. Patients were randomly assigned to either KH (receiving Lopinavir/Ritonavir [Kaletra] plus Hydroxychloroquine) or ADH (receiving Atazanavir/Ritonavir, Dolutegravir, and Hydroxychloroquine) groups. During this period, clinical and laboratory parameters and outcomes such as intensive care unit (ICU) admission or mortality rate were recorded. Compared to the KH group, after the treatment period, patients in the ADH group had higher activated partial thromboplastin time (aPTT) (12, [95% confidence interval [CI]: 6.97, 17.06), p = <0.01), international normalized ratio (INR) (0.17, [95% CI: 0.07, 0.27), p = <0.01) and lower C-reactive protein (CRP) (-14.29, (95% CI: -26.87, -1.71), p = 0.03) and potassium (-0.53, (95% CI: -1.03, -0.03), p = 0.04) values. Moreover, a higher number of patients in the KH group needed invasive ventilation (6 (20%) vs. 1 (3.1%), p = 0.05) and antibiotic administration (27 (90%) vs. 21(65.6), p = 0.02) during hospitalization while patients in the ADH group needed more corticosteroid administration (9 (28.1%) vs. 2 (6.7%), p = 0.03). There was no difference in mortality rate, ICU admission rate, and hospitalization period between the study groups. Our results suggest that the Atazanavir/Dolutegravir treatment regimen may result in a less severe disease course compared to the Lopinavir/Ritonavir treatment regimen and can be considered as an alternative treatment option beside standard care. However, to confirm our results, larger-scale studies are recommended.


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , Heterocyclic Compounds, 3-Ring/therapeutic use , Hydroxychloroquine/therapeutic use , Lopinavir/therapeutic use , Oxazines/therapeutic use , Piperazines/therapeutic use , Pyridones/therapeutic use , Ritonavir/therapeutic use , Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/pathology , Drug Combinations , Drug Therapy, Combination , Female , Heterocyclic Compounds, 3-Ring/administration & dosage , Humans , Hydroxychloroquine/administration & dosage , Lopinavir/administration & dosage , Male , Middle Aged , Oxazines/administration & dosage , Piperazines/administration & dosage , Pyridones/administration & dosage , Ritonavir/administration & dosage , Treatment Outcome
11.
Curr HIV Res ; 19(4): 377-382, 2021.
Article in English | MEDLINE | ID: covidwho-1204159

ABSTRACT

BACKGROUND: The World Health Organization (WHO) announced the SARS-COV-2 disease pandemic on March 9, 2020. With the advent of this disease, another health burden was added to about 37.9 million people in the world who are infected with HIV and are suffering from various diseases. These people may be at serious risk of COVID-19. Information about the effects of COVID-19 on people living with HIV, is limited. CASE PRESENTATION: We reported a 61-year-old man who was a known case of HIV from 6 years ago that was being treated with HAART (highly active antiretroviral therapy). He also had a history of Hodgkin's lymphoma from 4 years ago who underwent autologous bone marrow transplantation (BMT) 2 weeks before given referral to our hospital. He complained of weakness, anorexia, and fever. RT-PCR for SARS-COV-2-RNA was positive in his nasopharyngeal and oropharyngeal swab. He was diagnosed with COVID-19 infection and treated with atazanavir. After one week, the patient discharged in a good general state. CONCLUSION: To the best of our knowledge, it is the first report of COVID-19 infection in an HIV positive patient after BMT in Iran. Despite his immunodeficiency, COVID-19 disease had mild manifestations and he had a good prognosis. We hope that our report and that of others can remain promising to doctors and HIV patients cross fingers for COVID-19 recovery.


Subject(s)
Atazanavir Sulfate/therapeutic use , Bone Marrow Transplantation , COVID-19/drug therapy , Comorbidity , HIV Infections/drug therapy , HIV Protease Inhibitors/therapeutic use , Hodgkin Disease/surgery , Humans , Iran , Male , Middle Aged , SARS-CoV-2 , Treatment Outcome
12.
Eur Rev Med Pharmacol Sci ; 25(5): 2435-2448, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1145761

ABSTRACT

OBJECTIVE: Since no effective therapy exists, we aimed to test existing HIV antivirals for combination treatment of Coronavirus disease 19 (COVID-19). MATERIALS AND METHODS: The crystal structures of SARS-CoV-2 main protein (Mpro) (PDB ID: 6Y2F) and SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) (PDB ID: 7BV2) both available from Protein Data Bank were used in the study. Automated Docking by using blind and standard method both on Mpro and RdRp bound to the modified template-primer RNA was performed with AutoDock 4.2.6 program suite. Lamarckian genetic algorithm (LGA) was used for structures docking. All inhibitors were docked with all bonds completely free to rotate. RESULTS: Our molecular docking findings suggest that lopinavir, ritonavir, darunavir, and atazanavir activated interactions with the key binding sites of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) protease with a better inhibition constant (Ki) for lopinavir, ritonavir, and darunavir. Furthermore, we evidenced the ability of remdesivir, tenofovir, emtricitabine, and lamivudine to be incorporated in SARS-CoV-2 RdRp in the same protein pocket where poses the corresponding natural nucleoside substrates with comparable Ki and activating similar interactions. In principle, the four antiviral nucleotides might be used effectively against SARS-CoV-2. CONCLUSIONS: The combination of a protease inhibitor and two nucleoside analogues, drugs widely used to treat HIV infection, could be evaluated in clinical trials for the treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , Drug Therapy, Combination/methods , Nucleosides/therapeutic use , Protease Inhibitors/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Atazanavir Sulfate , Darunavir , Drug Combinations , Early Medical Intervention , Emtricitabine , Humans , Lamivudine , Lopinavir , Molecular Docking Simulation , Ritonavir , SARS-CoV-2
13.
Trials ; 22(1): 3, 2021 Jan 04.
Article in English | MEDLINE | ID: covidwho-1007149

ABSTRACT

OBJECTIVES: To investigate the efficacy and safety of repurposed antiprotozoal and antiretroviral drugs, nitazoxanide and atazanavir/ritonavir, in shortening the time to clinical improvement and achievement of SARS-CoV-2 polymerase chain reaction (PCR) negativity in patients diagnosed with moderate to severe COVID-19. TRIAL DESIGN: This is a pilot phase 2, multicentre 2-arm (1:1 ratio) open-label randomised controlled trial. PARTICIPANTS: Patients with confirmed COVID-19 diagnosis (defined as SARS-CoV-2 PCR positive nasopharyngeal swab) will be recruited from four participating isolation and treatment centres in Nigeria: two secondary care facilities (Infectious Diseases Hospital, Olodo, Ibadan, Oyo State and Specialist State Hospital, Asubiaro, Osogbo, Osun State) and two tertiary care facilities (Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Osun State and Olabisi Onabanjo University Teaching Hospital, Sagamu, Ogun State). These facilities have a combined capacity of 146-bed COVID-19 isolation and treatment ward. INCLUSION CRITERIA: Confirmation of SARS-CoV-2 infection by PCR test within two days before randomisation and initiation of treatment, age bracket of 18 and 75 years, symptomatic, able to understand study information and willingness to participate. Exclusion criteria include the inability to take orally administered medication or food, known hypersensitivity to any of the study drugs, pregnant or lactating, current or recent (within 24 hours of enrolment) treatment with agents with actual or likely antiviral activity against SARS-CoV-2, concurrent use of agents with known or suspected interaction with study drugs, and requiring mechanical ventilation at screening. INTERVENTION AND COMPARATOR: Participants in the intervention group will receive 1000 mg of nitazoxanide twice daily orally and 300/100 mg of atazanvir/ritonavir once daily orally in addition to standard of care while participants in the control group will receive only standard of care. Standard of care will be determined by the physician at the treatment centre in line with the current guidelines for clinical management of COVID-19 in Nigeria. MAIN OUTCOME MEASURES: Main outcome measures are: (1) Time to clinical improvement (defined as time from randomisation to either an improvement of two points on a 10-category ordinal scale (developed by the WHO Working Group on the Clinical Characterisation and Management of COVID-19 infection) or discharge from the hospital, whichever came first); (2) Proportion of participants with SARS-CoV-2 polymerase chain reaction (PCR) negative result at days 2, 4, 6, 7, 14 and 28; (3) Temporal patterns of SARS-CoV-2 viral load on days 2, 4, 6, 7, 14 and 28 quantified by RT-PCR from saliva of patients receiving standard of care alone versus standard of care plus study drugs. RANDOMISATION: Allocation of participants to study arm is randomised within each site with a ratio 1:1 based on randomisation sequences generated centrally at Obafemi Awolowo University. The model was implemented in REDCap and includes stratification by age, gender, viral load at diagnosis and presence of relevant comorbidities. BLINDING: None, this is an open-label trial. NUMBER TO BE RANDOMISED (SAMPLE SIZE): 98 patients (49 per arm). TRIAL STATUS: Regulatory approval was issued by the National Agency for Food and Drug Administration and Control on 06 October 2020 (protocol version number is 2.1 dated 06 August 2020). Recruitment started on 9 October 2020 and is anticipated to end before April 2021. TRIAL REGISTRATION: The trial has been registered on ClinicalTrials.gov (July 7, 2020), with identifier number NCT04459286 and on Pan African Clinical Trials Registry (August 13, 2020), with identifier number PACTR202008855701534 . FULL PROTOCOL: The full protocol is attached as an additional file which will be made available on the trial website. In the interest of expediting dissemination of this material, the traditional formatting has been eliminated, and this letter serves as a summary of the key elements in the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Subject(s)
Antiviral Agents/administration & dosage , Atazanavir Sulfate/administration & dosage , COVID-19/drug therapy , Ritonavir/administration & dosage , Thiazoles/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Antiviral Agents/adverse effects , Atazanavir Sulfate/adverse effects , COVID-19/diagnosis , COVID-19/virology , COVID-19 Nucleic Acid Testing , Clinical Trials, Phase II as Topic , Drug Administration Schedule , Drug Combinations , Drug Repositioning , Drug Therapy, Combination/adverse effects , Drug Therapy, Combination/methods , Female , Humans , Male , Middle Aged , Multicenter Studies as Topic , Nigeria , Nitro Compounds , Pilot Projects , RNA, Viral/isolation & purification , Randomized Controlled Trials as Topic , Ritonavir/adverse effects , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Standard of Care , Thiazoles/adverse effects , Treatment Outcome , Viral Load/drug effects , Young Adult
14.
Sci Rep ; 10(1): 21508, 2020 12 09.
Article in English | MEDLINE | ID: covidwho-965423

ABSTRACT

To increase the success in Covid 19 treatment, many drug suggestions are presented, and some clinical studies are shared in the literature. There have been some attempts to use some of these drugs in combination. However, using more than one drug together may cause serious side effects on patients. Therefore, detecting drug-drug interactions of the drugs used will be of great importance in the treatment of Covid 19. In this study, the interactions of 8 drugs used for Covid 19 treatment with 645 different drugs and possible side effects estimates have been produced using Graph Convolutional Networks. As a result of the experiments, it has been found that the hematopoietic system and the cardiovascular system are exposed to more side effects than other organs. Among the focused drugs, Heparin and Atazanavir appear to cause more adverse reactions than other drugs. In addition, as it is known that some of these 8 drugs are used together in Covid-19 treatment, the side effects caused by using these drugs together are shared. With the experimental results obtained, it is aimed to facilitate the selection of the drugs and increase the success of Covid 19 treatment according to the targeted patient.


Subject(s)
Atazanavir Sulfate/therapeutic use , COVID-19/drug therapy , COVID-19/metabolism , Heparin/therapeutic use , SARS-CoV-2/metabolism , Atazanavir Sulfate/adverse effects , COVID-19/pathology , Drug Interactions , Heparin/adverse effects , Humans
15.
Antimicrob Agents Chemother ; 64(10)2020 09 21.
Article in English | MEDLINE | ID: covidwho-810756

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.


Subject(s)
Antiviral Agents/pharmacology , Atazanavir Sulfate/pharmacology , Betacoronavirus/drug effects , Cytokines/metabolism , Ritonavir/pharmacology , Animals , Atazanavir Sulfate/chemistry , Betacoronavirus/pathogenicity , Betacoronavirus/physiology , COVID-19 , Cell Death/drug effects , Chlorocebus aethiops , Coronavirus 3C Proteases , Coronavirus Infections/drug therapy , Coronavirus Infections/metabolism , Coronavirus Infections/pathology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Therapy, Combination , Humans , Inflammation/metabolism , Inflammation/virology , Lopinavir/pharmacology , Molecular Docking Simulation , Monocytes/virology , Pandemics , Pneumonia, Viral/drug therapy , Pneumonia, Viral/metabolism , Pneumonia, Viral/pathology , Protease Inhibitors/pharmacology , SARS-CoV-2 , Vero Cells , Viral Nonstructural Proteins/antagonists & inhibitors , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
16.
Daru ; 28(2): 625-634, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-734042

ABSTRACT

BACKGROUND: The role of the antiviral therapy in treatment of COVID-19 is still a matter to be investigated. Also efficacy and safety of antiviral regimens were not compared according severity of the disease. In this study the efficacy and safety of hydroxychloroquine plus atazanavir/ritonavir was compared in patients with moderate and severe COVID-19. METHODS: We prospectively evaluated the clinical outcomes of 213 patients with COVID-19 during the hospitalization course and up to 56 days after the hospital discharge. The disease was categorized to moderate and severe based on the severity of pneumonia and peripheral oxygen saturation (SpO2). The patients received the national treatment protocol containing hydroxychloroquine (400 mg BD in first day and then 200 mg BD) plus atazanavir/ritonavir (300/100 mg daily) for 7 days. Main outcomes included discharge rates at day 7, 14 and 28, 28-day mortality, rate of intensive care unit (ICU) admission and intubation, length of hospital and ICU stay and incidence of adverse events. RESULTS: The mean (SD) age of patients was 60(14) years and 53% were male. According to WHO definition, 51.64% and 48.36% of the patients had moderate (SpO2 ≥ 90%) and severe disease (SpO2 < 90%) at baseline, respectively. The discharge rate of the moderate group was significantly higher than the severe group at day 7, 14 and 28 (HR = 0.49; 95% CI: 0.35-0.69, p = < 0.001 at day 7, HR = 0.48; 95% CI: 0.35-0.66, p = < 0.001 at day 14 and HR = 0.49; 95% CI: 0.36-0.67, p = < 0.001at day 28). The 28-day mortality of the severe group was six times higher than the moderate group (HR = 6.00; 95% CI: 2.50-14.44), p = < 0.001). The need of admission in ICU for the severe group and the moderate group was 37.86% and 18.18% of the patients. Length of hospital stay was significantly shorter in the moderate group in comparison with the severe group (5 ± 4 vs. 8 ± 6 days, p < 0.001). Patients in the moderate group experienced the serious adverse events and complications less than the severe group. The discharged patients were followed up to 56 days after discharge. Some of the patients complained of symptoms such as exertional dyspnea, weakness and new-onset hair loss. CONCLUSION: Our study did not support the use of hydroxychloroquine plus atazanavir/ritonavir in patients who had SpO2 < 90% at the time of hospital admission. SpO2 was the only predictor of clinical outcomes (duration of hospital stay, discharge from the hospital and mortality) in patients treated with hydroxychloroquine plus atazanavir/ritonavir.


Subject(s)
Atazanavir Sulfate/administration & dosage , COVID-19/drug therapy , Hydroxychloroquine/administration & dosage , Ritonavir/administration & dosage , Adult , Aged , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Atazanavir Sulfate/adverse effects , COVID-19/mortality , COVID-19/virology , Drug Therapy, Combination , Female , Hospitalization/statistics & numerical data , Humans , Hydroxychloroquine/adverse effects , Intensive Care Units/statistics & numerical data , Length of Stay , Male , Middle Aged , Prospective Studies , Ritonavir/adverse effects , Severity of Illness Index , Time Factors , Treatment Outcome
17.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-663333

ABSTRACT

To the best of our knowledge, there is no published study on the use of interferon ß-1a (IFN ß-1a) in the treatment of severe COVID-19. In this randomized clinical trial, the efficacy and safety of IFN ß-1a were evaluated in patients with severe COVID-19. Forty-two patients in the interferon group received IFN ß-1a in addition to the national protocol medications (hydroxychloroquine plus lopinavir-ritonavir or atazanavir-ritonavir). Each 44-µg/ml (12 million IU/ml) dose of interferon ß-1a was subcutaneously injected three times weekly for two consecutive weeks. The control group consisted of 39 patients who received only the national protocol medications. The primary outcome of the study was time to reach clinical response. Secondary outcomes were duration of hospital stay, length of intensive care unit stay, 28-day mortality, effect of early or late administration of IFN on mortality, adverse effects, and complications during the hospitalization. Between 29 February and 3 April 2020, 92 patients were recruited, and a total of 42 patients in the IFN group and 39 patients in the control group completed the study. As the primary outcome, time to the clinical response was not significantly different between the IFN and the control groups (9.7 ± 5.8 versus 8.3 ± 4.9 days, respectively, P = 0.95). On day 14, 66.7% versus 43.6% of patients in the IFN group and the control group, respectively, were discharged (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.05 to 6.37). The 28-day overall mortality was significantly lower in the IFN than the control group (19% versus 43.6%, respectively, P = 0.015). Early administration significantly reduced mortality (OR, 13.5; 95% CI, 1.5 to 118). Although IFN did not change the time to reach the clinical response, adding it to the national protocol significantly increased discharge rate on day 14 and decreased 28-day mortality. (This study is in the Iranian Registry of Clinical Trials under identifier IRCT20100228003449N28.).


Subject(s)
Antiviral Agents/therapeutic use , Atazanavir Sulfate/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Interferon beta-1a/therapeutic use , Lopinavir/therapeutic use , Pneumonia, Viral/drug therapy , Ritonavir/therapeutic use , Adult , Aged , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , COVID-19 , Cardiovascular Diseases/drug therapy , Cardiovascular Diseases/immunology , Cardiovascular Diseases/mortality , Cardiovascular Diseases/virology , Comorbidity , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Diabetes Mellitus/drug therapy , Diabetes Mellitus/immunology , Diabetes Mellitus/mortality , Diabetes Mellitus/virology , Drug Administration Schedule , Drug Combinations , Drug Therapy, Combination , Dyslipidemias/drug therapy , Dyslipidemias/immunology , Dyslipidemias/mortality , Dyslipidemias/virology , Female , Humans , Hydroxychloroquine/therapeutic use , Intensive Care Units , Length of Stay , Male , Middle Aged , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/mortality , Neoplasms/virology , Pandemics , Patient Safety , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , SARS-CoV-2 , Survival Analysis , Treatment Outcome
19.
Mult Scler Relat Disord ; 43: 102216, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-419863

ABSTRACT

The new severe acute respiratory syndrome- coronavirus 2 is reported to affect the nervous system. Among the reports of the various neurological manifestations, there are a few documented specific processes to explain the neurological signs. We report a para-infectious encephalitis patient with clinical, laboratory, and imaging findings during evolution and convalescence phase of coronavirus infection. This comprehensive overview can illuminate the natural history of similar cases. As the two previously reported cases of encephalitis associated with this virus were not widely discussed regarding the treatment, we share our successful approach and add some recommendations about this new and scarce entity.


Subject(s)
Consciousness Disorders/physiopathology , Coronavirus Infections/physiopathology , Encephalitis/physiopathology , Glucocorticoids/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Immunologic Factors/therapeutic use , Methylprednisolone/therapeutic use , Pneumonia, Viral/physiopathology , Seizures/physiopathology , Adult , Anti-Bacterial Agents/therapeutic use , Anticonvulsants/therapeutic use , Atazanavir Sulfate/therapeutic use , Betacoronavirus , Brain/diagnostic imaging , COVID-19 , Consciousness Disorders/diagnostic imaging , Consciousness Disorders/etiology , Consciousness Disorders/therapy , Coronavirus Infections/complications , Coronavirus Infections/diagnostic imaging , Coronavirus Infections/therapy , Diffusion Magnetic Resonance Imaging , Disease Progression , Encephalitis/diagnostic imaging , Encephalitis/etiology , Encephalitis/therapy , Female , HIV Protease Inhibitors/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Intensive Care Units , Levetiracetam/therapeutic use , Lung/diagnostic imaging , Magnetic Resonance Imaging , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/diagnostic imaging , Pneumonia, Viral/therapy , Pons/diagnostic imaging , Respiration, Artificial , SARS-CoV-2 , Seizures/drug therapy , Seizures/etiology , Temporal Lobe/diagnostic imaging , Thalamus/diagnostic imaging , Tomography, X-Ray Computed
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