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1.
Cell Mol Life Sci ; 79(5): 227, 2022 Apr 07.
Article in English | MEDLINE | ID: covidwho-1777692

ABSTRACT

SARS-CoV-2, the causative agent of COVID-19, has caused an unprecedented global health crisis. The SARS-CoV-2 spike, a surface-anchored trimeric class-I fusion glycoprotein essential for viral entry, represents a key target for developing vaccines and therapeutics capable of blocking virus invasion. The emergence of SARS-CoV-2 spike variants that facilitate virus spread and may affect vaccine efficacy highlights the need to identify novel antiviral strategies for COVID-19 therapy. Here, we demonstrate that nitazoxanide, an antiprotozoal agent with recognized broad-spectrum antiviral activity, interferes with SARS-CoV-2 spike maturation, hampering its terminal glycosylation at an endoglycosidase H-sensitive stage. Engineering multiple SARS-CoV-2 variant-pseudoviruses and utilizing quantitative cell-cell fusion assays, we show that nitazoxanide-induced spike modifications hinder progeny virion infectivity as well as spike-driven pulmonary cell-cell fusion, a critical feature of COVID-19 pathology. Nitazoxanide, being equally effective against the ancestral SARS-CoV-2 Wuhan-spike and different emerging variants, including the Delta variant of concern, may represent a useful tool in the fight against COVID-19 infections.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Nitro Compounds , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics , Thiazoles
3.
Clin Pharmacol Ther ; 111(3): 585-594, 2022 03.
Article in English | MEDLINE | ID: covidwho-1482119

ABSTRACT

Repurposing approved drugs may rapidly establish effective interventions during a public health crisis. This has yielded immunomodulatory treatments for severe coronavirus disease 2019 (COVID-19), but repurposed antivirals have not been successful to date because of redundancy of the target in vivo or suboptimal exposures at studied doses. Nitazoxanide is a US Food and Drug Administration (FDA) approved antiparasitic medicine, that physiologically-based pharmacokinetic (PBPK) modeling has indicated may provide antiviral concentrations across the dosing interval, when repurposed at higher than approved doses. Within the AGILE trial platform (NCT04746183) an open label, adaptive, phase I trial in healthy adult participants was undertaken with high-dose nitazoxanide. Participants received 1,500 mg nitazoxanide orally twice-daily with food for 7 days. Primary outcomes were safety, tolerability, optimum dose, and schedule. Intensive pharmacokinetic (PK) sampling was undertaken day 1 and 5 with minimum concentration (Cmin ) sampling on days 3 and 7. Fourteen healthy participants were enrolled between February 18 and May 11, 2021. All 14 doses were completed by 10 of 14 participants. Nitazoxanide was safe and with no significant adverse events. Moderate gastrointestinal disturbance (loose stools or diarrhea) occurred in 8 participants (57.1%), with urine and sclera discoloration in 12 (85.7%) and 9 (64.3%) participants, respectively, without clinically significant bilirubin elevation. This was self-limiting and resolved upon drug discontinuation. PBPK predictions were confirmed on day 1 but with underprediction at day 5. Median Cmin was above the in vitro target concentration on the first dose and maintained throughout. Nitazoxanide administered at 1,500 mg b.i.d. with food was safe with acceptable tolerability a phase Ib/IIa study is now being initiated in patients with COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , Nitro Compounds/administration & dosage , Nitro Compounds/adverse effects , Nitro Compounds/pharmacokinetics , Thiazoles/administration & dosage , Thiazoles/adverse effects , Thiazoles/pharmacokinetics , Adult , Antiviral Agents/adverse effects , Antiviral Agents/pharmacokinetics , COVID-19/drug therapy , Drug Repositioning , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young Adult
4.
Sci Rep ; 11(1): 19998, 2021 10 07.
Article in English | MEDLINE | ID: covidwho-1462031

ABSTRACT

Understanding the effects of metabolism on the rational design of novel and more effective drugs is still a considerable challenge. To the best of our knowledge, there are no entirely computational strategies that make it possible to predict these effects. From this perspective, the development of such methodologies could contribute to significantly reduce the side effects of medicines, leading to the emergence of more effective and safer drugs. Thereby, in this study, our strategy is based on simulating the electron ionization mass spectrometry (EI-MS) fragmentation of the drug molecules and combined with molecular docking and ADMET models in two different situations. In the first model, the drug is docked without considering the possible metabolic effects. In the second model, each of the intermediates from the EI-MS results is docked, and metabolism occurs before the drug accesses the biological target. As a proof of concept, in this work, we investigate the main antiviral drugs used in clinical research to treat COVID-19. As a result, our strategy made it possible to assess the biological activity and toxicity of all potential by-products. We believed that our findings provide new chemical insights that can benefit the rational development of novel drugs in the future.


Subject(s)
Antiviral Agents/metabolism , COVID-19/drug therapy , Drug Discovery , SARS-CoV-2/drug effects , Adenine/adverse effects , Adenine/analogs & derivatives , Adenine/metabolism , Adenine/pharmacology , Adenosine/adverse effects , Adenosine/analogs & derivatives , Adenosine/metabolism , Adenosine/pharmacology , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/metabolism , Adenosine Monophosphate/pharmacology , Alanine/adverse effects , Alanine/analogs & derivatives , Alanine/metabolism , Alanine/pharmacology , Amides/adverse effects , Amides/metabolism , Amides/pharmacology , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , COVID-19/metabolism , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Chloroquine/metabolism , Chloroquine/pharmacology , Drug Design , Humans , Metabolic Networks and Pathways , Molecular Docking Simulation , Nitro Compounds/adverse effects , Nitro Compounds/metabolism , Nitro Compounds/pharmacology , Pyrazines/adverse effects , Pyrazines/metabolism , Pyrazines/pharmacology , Pyrrolidines/adverse effects , Pyrrolidines/metabolism , Pyrrolidines/pharmacology , Ribavirin/adverse effects , Ribavirin/metabolism , Ribavirin/pharmacology , SARS-CoV-2/metabolism , Thiazoles/adverse effects , Thiazoles/metabolism , Thiazoles/pharmacology
5.
Pharmacotherapy ; 40(5): 416-437, 2020 05.
Article in English | MEDLINE | ID: covidwho-1449937

ABSTRACT

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into an emergent global pandemic. Coronavirus disease 2019 (COVID-19) can manifest on a spectrum of illness from mild disease to severe respiratory failure requiring intensive care unit admission. As the incidence continues to rise at a rapid pace, critical care teams are faced with challenging treatment decisions. There is currently no widely accepted standard of care in the pharmacologic management of patients with COVID-19. Urgent identification of potential treatment strategies is a priority. Therapies include novel agents available in clinical trials or through compassionate use, and other drugs, repurposed antiviral and immunomodulating therapies. Many have demonstrated in vitro or in vivo potential against other viruses that are similar to SARS-CoV-2. Critically ill patients with COVID-19 have additional considerations related to adjustments for organ impairment and renal replacement therapies, complex lists of concurrent medications, limitations with drug administration and compatibility, and unique toxicities that should be evaluated when utilizing these therapies. The purpose of this review is to summarize practical considerations for pharmacotherapy in patients with COVID-19, with the intent of serving as a resource for health care providers at the forefront of clinical care during this pandemic.


Subject(s)
Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Coronavirus Infections/drug therapy , Immunomodulation , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/adverse effects , Adenosine Monophosphate/analogs & derivatives , Adrenal Cortex Hormones , Alanine/administration & dosage , Alanine/adverse effects , Alanine/analogs & derivatives , Antibodies, Monoclonal, Humanized/administration & dosage , Antibodies, Monoclonal, Humanized/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , Betacoronavirus , COVID-19 , Chloroquine/administration & dosage , Chloroquine/adverse effects , Coronavirus Infections/therapy , Drug Combinations , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Immunization, Passive , Interferon-alpha/administration & dosage , Interferon-alpha/adverse effects , Lopinavir/administration & dosage , Lopinavir/adverse effects , Nelfinavir/administration & dosage , Nelfinavir/adverse effects , Nitro Compounds , Pandemics , Purines , Pyrazoles , Ribavirin/administration & dosage , Ribavirin/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , SARS-CoV-2 , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Thiazoles/administration & dosage , Thiazoles/adverse effects
6.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L35-L36, 2020 07 01.
Article in English | MEDLINE | ID: covidwho-1388545
7.
Ann Pharmacother ; 56(3): 309-318, 2022 03.
Article in English | MEDLINE | ID: covidwho-1280556

ABSTRACT

OBJECTIVE: To conduct a systematic review on the effectiveness and safety of pharmacological and nonpharmacological interventions, in the ambulatory setting, aimed at preventing severe disease in patients with COVID-19. DATA SOURCES: Electronic databases (PubMed, EMBASE, and EuropePMC) were searched on January 6, 2021. STUDY SELECTION AND DATA EXTRACTION: A systematic review was conducted, adhering to PRISMA guidelines. The quality of individual trials was assessed using the Cochrane Risk-of-Bias Tool 2, and the certainty of evidence was assessed using GRADE. DATA SYNTHESIS: The collective search retrieved 3818 citations. Eight trials relating to 9 pharmacological interventions were identified. No evidence for nonpharmacological interventions was identified. Low certainty evidence of effectiveness in preventing severe disease was found for fluvoxamine (absolute difference: -8.7%; 95% CI: -1.8% to -16.4%) and bamlanivimab plus etesevimab (absolute difference: -4.9%; 95% CI: -0.8% to -8.9%). Both trials were limited by small sample sizes and short durations of follow-up. In addition, very low certainty evidence of effect was found for ivermectin plus doxycycline and sulodexide. Based on published data, insufficient evidence of effect was found for bamlanivimab (monotherapy), casirivimab plus imdevimab, ivermectin (monotherapy), nitazoxanide, and peginterferon lambda. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: This review assessed all ambulatory treatments for COVID-19 that may improve patient outcomes and reduce hospitalizations. CONCLUSION: Recent trials have shown promising results for a number of pharmacological agents to treat COVID-19 in the ambulatory setting. However, larger, more robust trials are needed to support the routine use of these agents outside of monitored clinical trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 , Ambulatory Care , Antibodies, Neutralizing , COVID-19/therapy , Disease Progression , Humans , Interferons , Ivermectin , Nitro Compounds , Polyethylene Glycols , Thiazoles
8.
Expert Rev Anti Infect Ther ; 20(1): 17-21, 2022 01.
Article in English | MEDLINE | ID: covidwho-1258702

ABSTRACT

INTRODUCTION: Mediators of immunity and inflammation are playing a crucial role in COVID-19 pathogenesis and complications as demonstrated by several genetic and clinical studies. Thus, repurposing of drugs that possess anti-inflammatory and/or immune-modulatory effects for COVID-19 is considered a rational approach. AREAS COVERED: We analyze selected studies that correlated COVID-19 with dysregulated interferon and inflammatory responses while reflecting on our academic and real-life experience using non-steroidal anti-inflammatory drugs, nitazoxanide and azithromycin for management of COVID-19. Moreover, we interpret the results that suggested a potential survival benefit of low-dose aspirin and colchicine when used for COVID-19. EXPERT OPINION: Nitazoxanide/azithromycin combination has been first hypothesized by the author and practiced by him and several researchers to benefit COVID-19 patients due to a potential ability to augment the natural interferon response as well as their positive immunomodulatory effects on several cytokines. Furthermore, NSAIDs, that are unfortunately currently at best of second choice after paracetamol, have been early postulated and clinically practiced by the author to prevent or ameliorate COVID-19 complications and mortality due to their anti-inflammatory and immunomodulatory properties. Finally, we repeat our previous call to adopt our observational study that used these drugs in sufficiently powered double blind randomized clinical trials.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , COVID-19/immunology , Cytokine Release Syndrome/drug therapy , Drug Repositioning , Interleukin-6/antagonists & inhibitors , Nitro Compounds/therapeutic use , Thiazoles/therapeutic use , COVID-19/complications , Cytokine Release Syndrome/complications , Cytokine Release Syndrome/immunology , Humans , Interferons/immunology , Interleukin-6/immunology , Observational Studies as Topic , SARS-CoV-2/pathogenicity
9.
J Med Virol ; 93(5): 3176-3183, 2021 05.
Article in English | MEDLINE | ID: covidwho-1196542

ABSTRACT

This trial compared the rate and time of viral clearance in subjects receiving a combination of nitazoxanide, ribavirin, and ivermectin plus Zinc versus those receiving supportive treatment. This non-randomized controlled trial included 62 patients on the triple combination treatment versus 51 age- and sex-matched patients on routine supportive treatment. all of them confirmed cases by positive reverse-transcription polymerase chain reaction of a nasopharyngeal swab. Trial results showed that the clearance rates were 0% and 58.1% on the 7th day and 13.7% and 73.1% on the 15th day in the supportive treatment and combined antiviral groups, respectively. The cumulative clearance rates on the 15th day are 13.7% and 88.7% in the supportive treatment and combined antiviral groups, respectively. This trial concluded by stating that the combined use of nitazoxanide, ribavirin, and ivermectin plus zinc supplement effectively cleared the SARS-COV2 from the nasopharynx in a shorter time than symptomatic therapy.


Subject(s)
COVID-19/drug therapy , Ivermectin/therapeutic use , Nitro Compounds/therapeutic use , Ribavirin/therapeutic use , SARS-CoV-2 , Thiazoles/therapeutic use , Zinc/therapeutic use , Adult , Antimetabolites/administration & dosage , Antimetabolites/therapeutic use , Antiparasitic Agents/administration & dosage , Antiparasitic Agents/therapeutic use , Female , Humans , Ivermectin/administration & dosage , Male , Nitro Compounds/administration & dosage , Ribavirin/administration & dosage , Thiazoles/administration & dosage , Trace Elements/administration & dosage , Trace Elements/therapeutic use , Zinc/administration & dosage
10.
SLAS Discov ; 26(6): 749-756, 2021 07.
Article in English | MEDLINE | ID: covidwho-1136206

ABSTRACT

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) represents a significant threat to human health. Despite its similarity to related coronaviruses, there are currently no specific treatments for COVID-19 infection, and therefore there is an urgent need to develop therapies for this and future coronavirus outbreaks. Formation of the cap at the 5' end of viral RNA has been shown to help coronaviruses evade host defenses. Nonstructural protein 14 (nsp14) is responsible for N7-methylation of the cap guanosine in coronaviruses. This enzyme is highly conserved among coronaviruses and is a bifunctional protein with both N7-methyltransferase and 3'-5' exonuclease activities that distinguish nsp14 from its human equivalent. Mutational analysis of SARS-CoV nsp14 highlighted its role in viral replication and translation efficiency of the viral genome. In this paper, we describe the characterization and development of a high-throughput assay for nsp14 utilizing RapidFire technology. The assay has been used to screen a library of 1771 Food and Drug Administration (FDA)-approved drugs. From this, we have validated nitazoxanide as a selective inhibitor of the methyltransferase activity of nsp14. Although modestly active, this compound could serve as a starting point for further optimization.


Subject(s)
Antiviral Agents/pharmacology , Exoribonucleases/antagonists & inhibitors , High-Throughput Screening Assays , Nitro Compounds/pharmacology , RNA Caps/antagonists & inhibitors , RNA, Viral/antagonists & inhibitors , SARS-CoV-2/drug effects , Thiazoles/pharmacology , Viral Nonstructural Proteins/antagonists & inhibitors , Antiparasitic Agents/chemistry , Antiparasitic Agents/pharmacology , Antiviral Agents/chemistry , COVID-19/virology , Cloning, Molecular , Drug Repositioning , Enzyme Assays , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Escherichia coli/genetics , Escherichia coli/metabolism , Exoribonucleases/genetics , Exoribonucleases/metabolism , Gene Expression , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Humans , Kinetics , Mass Spectrometry/methods , Methylation , Nitro Compounds/chemistry , Prescription Drugs/chemistry , Prescription Drugs/pharmacology , RNA Caps/genetics , RNA Caps/metabolism , RNA, Viral/genetics , RNA, Viral/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , SARS-CoV-2/enzymology , SARS-CoV-2/genetics , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Thiazoles/chemistry , Viral Nonstructural Proteins/genetics , Viral Nonstructural Proteins/metabolism , Virus Replication/drug effects
11.
ACS Infect Dis ; 7(6): 1317-1331, 2021 06 11.
Article in English | MEDLINE | ID: covidwho-1065792

ABSTRACT

The rapidly growing COVID-19 pandemic is the most serious global health crisis since the "Spanish flu" of 1918. There is currently no proven effective drug treatment or prophylaxis for this coronavirus infection. While developing safe and effective vaccines is one of the key focuses, a number of existing antiviral drugs are being evaluated for their potency and efficiency against SARS-CoV-2 in vitro and in the clinic. Here, we review the significant potential of nitazoxanide (NTZ) as an antiviral agent that can be repurposed as a treatment for COVID-19. Originally, NTZ was developed as an antiparasitic agent especially against Cryptosporidium spp.; it was later shown to possess potent activity against a broad range of both RNA and DNA viruses, including influenza A, hepatitis B and C, and coronaviruses. Recent in vitro assessment of NTZ has confirmed its promising activity against SARS-CoV-2 with an EC50 of 2.12 µM. Here we examine its drug properties, antiviral activity against different viruses, clinical trials outcomes, and mechanisms of antiviral action from the literature in order to highlight the therapeutic potential for the treatment of COVID-19. Furthermore, in preliminary PK/PD analyses using clinical data reported in the literature, comparison of simulated TIZ (active metabolite of NTZ) exposures at two doses with the in vitro potency of NTZ against SARS-CoV-2 gives further support for drug repurposing with potential in combination chemotherapy approaches. The review concludes with details of second generation thiazolides under development that could lead to improved antiviral therapies for future indications.


Subject(s)
COVID-19 , Cryptosporidiosis , Cryptosporidium , Drug Repositioning , Humans , Nitro Compounds , Pandemics , SARS-CoV-2 , Thiazoles
12.
Recenti Prog Med ; 112(1): 15-18, 2021 01.
Article in Italian | MEDLINE | ID: covidwho-1054909

ABSTRACT

It was a very dark year for EBM. One of the side effects of the Covid-19 pandemic is a severe compression of the evidences. Here are some worrying events. May 2020: the saga of hydroxychloroquine. October 2020: the nitazoxanide case. November 2020: Trump Administration Interferes on Expert Opinion. December 2020: the results of the trials on the first two vaccines were announced in press releases, leaving many scientific uncertainties. Peter Piot, head of the London School of Hygiene & Tropical Medicine noted that none of the CoViD-19 vaccines have offered much data to date. «It is frustrating that all of these announcements are delivered via press release, and not give us a chance to review the actual data. We desperately need total transparency on evidence and data¼, says Piot. Better now to relaunch the spread of EBM. In the issue, we have included the best EBM-based readings from the Club for Evidence-Based in Gastroenterology & Hepatology (ebgh.it).


Subject(s)
Access to Information , COVID-19 , Evidence-Based Medicine/trends , Pandemics , SARS-CoV-2 , Antiviral Agents/therapeutic use , Brazil , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19 Vaccines , Clinical Trials as Topic , Disclosure , Humans , Hydroxychloroquine/therapeutic use , Italy , Nitro Compounds , Politics , Propaganda , Thiazoles/therapeutic use , United States
13.
Eur J Pharmacol ; 891: 173748, 2021 Jan 15.
Article in English | MEDLINE | ID: covidwho-1049786

ABSTRACT

The global pandemic of Coronavirus Disease 2019 (COVID-19) has brought the world to a grinding halt. A major cause of concern is the respiratory distress associated mortality attributed to the cytokine storm. Despite myriad rapidly approved clinical trials with repurposed drugs, and time needed to develop a vaccine, accelerated search for repurposed therapeutics is still ongoing. In this review, we present Nitazoxanide a US-FDA approved antiprotozoal drug, as one such promising candidate. Nitazoxanide which is reported to exert broad-spectrum antiviral activity against various viral infections, revealed good in vitro activity against SARS-CoV-2 in cell culture assays, suggesting potential for repurposing in COVID-19. Furthermore, nitazoxanide displays the potential to boost host innate immune responses and thereby tackle the life-threatening cytokine storm. Possibilities of improving lung, as well as multiple organ damage and providing value addition to COVID-19 patients with comorbidities, are other important facets of the drug. The review juxtaposes the role of nitazoxanide in fighting COVID-19 pathogenesis at multiple levels highlighting the great promise the drug exhibits. The in silico data and in vitro efficacy in cell lines confirms the promise of nitazoxanide. Several approved clinical trials world over further substantiate leveraging nitazoxanide for COVID-19 therapy.


Subject(s)
COVID-19 , Drug Repositioning , SARS-CoV-2 , Thiazoles/pharmacology , Antiprotozoal Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Clinical Trials as Topic , Humans , Immunity, Innate/drug effects , Nitro Compounds , SARS-CoV-2/drug effects , SARS-CoV-2/physiology
15.
Ann Palliat Med ; 10(1): 707-720, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1030457

ABSTRACT

The whole world is battling through coronavirus disease 2019 (COVID-19) which is a fatal pandemic. In the early 2020, the World Health Organization (WHO) declared it as a global health emergency without definitive treatments and preventive approaches. In the absence of definitive therapeutic agents, this thorough review summarizes and outlines the potency and safety of all molecules and therapeutics which may have potential antiviral effects. A number of molecules and therapeutics licensed or being tested for some other conditions were found effective in different in vitro studies as well as in many small sample-sized clinical trials and independent case studies. However, in those clinical trials, there were some limitations which need to be overcome to find the most promising antiviral against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In conclusion, many of above-mentioned antivirals seems to have some therapeutic effects but none of them have been shown to have a strong evidence for their proper recommendation and approval in the treatment of COVID-19. Constantly evolving new evidences, exclusive adult data, language barrier, and type of study (observational, retrospective, small-sized clinical trials, or independent case series) resulted to the several limitations of this review. The need for multicentered, large sample-sized, randomized, placebo-controlled trials on COVID-19 patients to reach a proper conclusion on the most promising antiviral agent is warranted.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Azetidines/pharmacology , Azetidines/therapeutic use , Chloroquine/pharmacology , Chloroquine/therapeutic use , Drug Combinations , Humans , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/pharmacology , Indoles/therapeutic use , Interferons/pharmacology , Interferons/therapeutic use , Ivermectin/pharmacology , Ivermectin/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Nitro Compounds , Oseltamivir/pharmacology , Oseltamivir/therapeutic use , Purines/pharmacology , Purines/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , Thiazoles/pharmacology , Thiazoles/therapeutic use
16.
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
17.
Eur Respir J ; 58(1)2021 07.
Article in English | MEDLINE | ID: covidwho-999707

ABSTRACT

BACKGROUND: Nitazoxanide is widely available and exerts broad-spectrum antiviral activity in vitro. However, there is no evidence of its impact on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. METHODS: In a multicentre, randomised, double-blind, placebo-controlled trial, adult patients presenting up to 3 days after onset of coronavirus disease 2019 (COVID-19) symptoms (dry cough, fever and/or fatigue) were enrolled. After confirmation of SARS-CoV-2 infection using reverse transcriptase PCR on a nasopharyngeal swab, patients were randomised 1:1 to receive either nitazoxanide (500 mg) or placebo, three times daily, for 5 days. The primary outcome was complete resolution of symptoms. Secondary outcomes were viral load, laboratory tests, serum biomarkers of inflammation and hospitalisation rate. Adverse events were also assessed. RESULTS: From June 8 to August 20, 2020, 1575 patients were screened. Of these, 392 (198 placebo, 194 nitazoxanide) were analysed. Median (interquartile range) time from symptom onset to first dose of study drug was 5 (4-5) days. At the 5-day study visit, symptom resolution did not differ between the nitazoxanide and placebo arms. Swabs collected were negative for SARS-CoV-2 in 29.9% of patients in the nitazoxanide arm versus 18.2% in the placebo arm (p=0.009). Viral load was reduced after nitazoxanide compared to placebo (p=0.006). The percentage viral load reduction from onset to end of therapy was higher with nitazoxanide (55%) than placebo (45%) (p=0.013). Other secondary outcomes were not significantly different. No serious adverse events were observed. CONCLUSIONS: In patients with mild COVID-19, symptom resolution did not differ between nitazoxanide and placebo groups after 5 days of therapy. However, early nitazoxanide therapy was safe and reduced viral load significantly.


Subject(s)
COVID-19 , Adult , Humans , Nitro Compounds , SARS-CoV-2 , Thiazoles , Treatment Outcome
18.
Eur Rev Med Pharmacol Sci ; 24(23): 12593-12608, 2020 12.
Article in English | MEDLINE | ID: covidwho-995021

ABSTRACT

The coronavirus disease 2019 (COVID-19) is declared as an international emergency in 2020. Its prevalence and fatality rate are rapidly increasing but the medication options are still limited for this perilous disease. The emergent outbreak of COVID-19 triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) keeps propagating globally. The present scenario has emphasized the requirement for therapeutic opportunities to relive and overcome this latest pandemic. Despite the fact, the deteriorating developments of COVID-19, there is no drug certified to have considerable effects in the medical treatment for COVID-19 patients. The COVID-19 pandemic requests for the rapid testing of new treatment approaches. Based on the evidence, hydroxychloroquine is the first medicine opted for the treatment of disease. Umifenovir, remdesivir, and fevipiravir are deemed the most hopeful antiviral agent by improving the health of infected patients. The dexamethasone is a first known steroid medicine that can save the lives of seriously ill patients, and it is shown in a randomized clinical trial by the United Kingdom that it reduced the death rate in COVID-19 patients. The current review recapitulates the existing evidence of possible therapeutic drugs, peptides, humanized antibodies, convulsant plasma, and vaccination that has revealed potential in fighting COVID-19 infections. Many randomized and controlled clinical trials are taking place to further validate these agent's safety and effectiveness in curing COVID-19.


Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/drug therapy , COVID-19/therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Amides/therapeutic use , Anti-Bacterial Agents/therapeutic use , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Neutralizing/therapeutic use , Antiparasitic Agents/therapeutic use , COVID-19/prevention & control , Cannabinoids/therapeutic use , Chloroquine/therapeutic use , Complement Inactivating Agents/therapeutic use , Dexamethasone/therapeutic use , Drug Combinations , Enzyme Inhibitors/therapeutic use , Humans , Hydroxychloroquine/therapeutic use , Immunization, Passive , Indoles/therapeutic use , Interferons/therapeutic use , Ivermectin/therapeutic use , Lopinavir/therapeutic use , Nitro Compounds , Pyrazines/therapeutic use , Ritonavir/therapeutic use , SARS-CoV-2 , Teicoplanin/therapeutic use , Tetracyclines/therapeutic use , Thiazoles/therapeutic use
19.
J Infect Dev Ctries ; 14(9): 982-986, 2020 09 30.
Article in English | MEDLINE | ID: covidwho-963457

ABSTRACT

INTRODUCTION: Nitazoxanide has shown efficacy in vitro against coronavirus infections (MERS, SARS, SARS-CoV-2). The aim of this report is to describe the results of treating COVID-19 positive patients with nitazoxanide in three clinical settings: pregnancy/puerperium, hospitalized patients in an Internal Medicine Service and in an ambulatory setting. METHODOLOGY: This was a prospective follow-up and report of COVID-19 cases in three different situations, pregnant women, hospitalized patients receiving medical attention in an Internal Medicine Service and ambulatory patients residing in Toluca City, and Mexico City. RESULTS: The experience with a first group of 20 women, pregnant (17) or in immediate puerperium (3) was successful in 18 cases with two unfortunate deaths. The five cases treated in an Internal Medicine service showed a positive outcome with two patients weaned from mechanical ventilation. Of the remaining 16 patients treated in an ambulatory setting, all got cured. Nitazoxanide seems to be useful against SARS-CoV-2, not only in an early intervention but also in critical condition as well as in pregnancy without undesired effects for the babies. As an adjunctive therapy budesonide was used that seems to contribute to the clinical improvement. CONCLUSIONS: Nitazoxanide could be useful against COVID-19 as a safe and available regimen to be tested in a massive way immediately.


Subject(s)
Antiviral Agents/therapeutic use , Betacoronavirus , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Thiazoles/therapeutic use , Adult , Ambulatory Care , COVID-19 , Coronavirus Infections/mortality , Female , Follow-Up Studies , Hospitalization , Humans , Male , Mexico/epidemiology , Nitro Compounds , Pandemics , Pneumonia, Viral/mortality , Pregnancy , Pregnancy Complications, Infectious/drug therapy , Pregnancy Complications, Infectious/mortality , Prospective Studies , SARS-CoV-2 , Treatment Outcome
20.
BMC Infect Dis ; 20(1): 862, 2020 Nov 19.
Article in English | MEDLINE | ID: covidwho-934261

ABSTRACT

BACKGROUND: The speed and reach of the COVID-19 pandemic has created special scenarios to be considered, such as those in where patients who meet criteria for hospitalization due to moderate/severe disease cannot be hospitalized due to economic constraints and saturation of national health systems. The aim of this report is to present an unusual case of a severe COVID-19 patient managed at home in a developing country, and to discuss some of the available guidelines and potential therapeutic options for this type of cases. CASE PRESENTATION: A 60-year-old female seeking medical attention through teleconsultation presents with profound dyspnea, oppressive chest pain, fatigue, episodic hallucinations, and difficulty sleeping, for what she originally sought medical attention at an ER but could not be admitted due to saturation of the health system. A positive PCR test for COVID-19, and a CT scan of the chest showing bilateral consolidations with ground-glass opacities confirmed the diagnosis. The patient was managed at home, with corticosteroids, nitazoxanide and a single dose of 40 mg of subcutaneous enoxaparin. Colchicine was added at the third day of treatment. Standard oxygen therapy through nasal cannula was also recommended. Daily follow-ups were established to monitor for signs of clinical improvement. Two weeks later from the initial consultation the patient presents marked improvement in her symptoms, as well as in her CT scan, which prompted in discontinuation of the medications and the oxygen therapy. CONCLUSIONS: There are several limitations in this report regarding the clinical data and the management, but such limitations do also reflect the state of emergency and the chaos that resides in the health care systems of developing nations. For the ambulatory care of COVID-19 patients, several aspects of disease management may differ from current guidelines and basic requirements may represent a huge challenge to cover. Further research is needed to assist physicians in the daily clinical decision making, to optimize patient outcomes, and to reduce the probability of adverse scenarios of patients with COVID-19 managed in the ambulatory setting.


Subject(s)
Ambulatory Care , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , Adrenal Cortex Hormones/therapeutic use , Antiparasitic Agents , Betacoronavirus/genetics , Betacoronavirus/isolation & purification , COVID-19 , Coronavirus Infections/pathology , Coronavirus Infections/therapy , Coronavirus Infections/virology , Enoxaparin/therapeutic use , Female , Humans , Middle Aged , Nitro Compounds , Oxygen Inhalation Therapy , Pandemics , Pneumonia, Viral/pathology , Pneumonia, Viral/therapy , Pneumonia, Viral/virology , RNA, Viral/genetics , RNA, Viral/metabolism , Reverse Transcriptase Polymerase Chain Reaction , SARS-CoV-2 , Severity of Illness Index , Telemedicine , Thiazoles/therapeutic use , Thorax/diagnostic imaging , Tomography, X-Ray Computed
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