Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 18 de 18
Filter
1.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-654170

ABSTRACT

Previously, ivermectin (1 to 10 mg/kg of body weight) was shown to inhibit the liver-stage development of Plasmodium berghei in orally dosed mice. Here, ivermectin showed inhibition of the in vitro development of Plasmodium cynomolgi schizonts (50% inhibitory concentration [IC50], 10.42 µM) and hypnozoites (IC50, 29.24 µM) in primary macaque hepatocytes when administered as a high dose prophylactically but not when administered in radical cure mode. The safety, pharmacokinetics, and efficacy of oral ivermectin (0.3, 0.6, and 1.2 mg/kg) with and without chloroquine (10 mg/kg) administered for 7 consecutive days were evaluated for prophylaxis or radical cure of P. cynomolgi liver stages in rhesus macaques. No inhibition or delay to blood-stage P. cynomolgi parasitemia was observed at any ivermectin dose (0.3, 0.6, and 1.2 mg/kg). Ivermectin (0.6 and 1.2 mg/kg) and chloroquine (10 mg/kg) in combination were well-tolerated with no adverse events and no significant pharmacokinetic drug-drug interactions observed. Repeated daily ivermectin administration for 7 days did not inhibit ivermectin bioavailability. It was recently demonstrated that both ivermectin and chloroquine inhibit replication of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in vitro Further ivermectin and chloroquine trials in humans are warranted to evaluate their role in Plasmodium vivax control and as adjunctive therapies against COVID-19 infections.


Subject(s)
Antimalarials/pharmacology , Chloroquine/pharmacology , Ivermectin/pharmacology , Liver/drug effects , Malaria/drug therapy , Plasmodium cynomolgi/drug effects , Animals , Antimalarials/blood , Antimalarials/pharmacokinetics , Biological Availability , Chloroquine/blood , Chloroquine/pharmacokinetics , Drug Administration Schedule , Drug Combinations , Drug Synergism , Female , Hepatocytes/drug effects , Hepatocytes/parasitology , Ivermectin/blood , Ivermectin/pharmacokinetics , Liver/parasitology , Macaca mulatta , Malaria/parasitology , Male , Parasitemia/drug therapy , Plasmodium cynomolgi/growth & development , Plasmodium cynomolgi/pathogenicity , Primary Cell Culture , Schizonts/drug effects , Schizonts/growth & development
3.
Antiviral Res ; 181: 104878, 2020 09.
Article in English | MEDLINE | ID: covidwho-645295

ABSTRACT

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 µM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pandemics , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Berberine/pharmacology , Chlorocebus aethiops , Chloroquine/pharmacology , Coronavirus Infections/virology , Cyclosporine/pharmacology , Drug Antagonism , Drug Combinations , Drug Synergism , Humans , Indoles/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/virology , Vero Cells
4.
Front Immunol ; 11: 1451, 2020.
Article in English | MEDLINE | ID: covidwho-637661

ABSTRACT

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) represents an emergent global threat which is straining worldwide healthcare capacity. As of May 27th, the disease caused by SARS-CoV-2 (COVID-19) has resulted in more than 340,000 deaths worldwide, with 100,000 deaths in the US alone. It is imperative to study and develop pharmacological treatments suitable for the prevention and treatment of COVID-19. Ascorbic acid is a crucial vitamin necessary for the correct functioning of the immune system. It plays a role in stress response and has shown promising results when administered to the critically ill. Quercetin is a well-known flavonoid whose antiviral properties have been investigated in numerous studies. There is evidence that vitamin C and quercetin co-administration exerts a synergistic antiviral action due to overlapping antiviral and immunomodulatory properties and the capacity of ascorbate to recycle quercetin, increasing its efficacy. Safe, cheap interventions which have a sound biological rationale should be prioritized for experimental use in the current context of a global health pandemic. We present the current evidence for the use of vitamin C and quercetin both for prophylaxis in high-risk populations and for the treatment of COVID-19 patients as an adjunct to promising pharmacological agents such as Remdesivir or convalescent plasma.


Subject(s)
Antiviral Agents/therapeutic use , Ascorbic Acid/therapeutic use , Betacoronavirus/physiology , Coronavirus Infections/prevention & control , Immunologic Factors/therapeutic use , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Pre-Exposure Prophylaxis/methods , Quercetin/therapeutic use , Animals , Antiviral Agents/adverse effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Synergism , Drug Therapy, Combination , Humans , Mice , Pneumonia, Viral/virology , Quercetin/adverse effects , Quercetin/chemistry , Quercetin/pharmacokinetics , Virus Replication/drug effects
5.
Plant Cell Rep ; 39(9): 1109-1114, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-607291

ABSTRACT

The exponential spread of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emphasizes the immediate need for effective antiviral drugs and vaccines that could control and prevent the spread of this pandemic. Several new and repurposed drugs are being tested for their effectiveness in the treatment regime, and the development of vaccines is underway. The availability of genome sequence information of the virus and the identification of potential targets to neutralize and eradicate the infection have enabled the search for novel as well as existing molecules to perform the desired function. However, the application of plants in the development of potential biomolecules, such as antibiotics and vaccines, is limited. Traditional medicines involving plant-based formulations have proven successful in boosting immunity and providing tolerance to virus infections. Still, in-depth studies are not available to explore the bioactive compounds of plant origin and their mechanism of action. Given this, the current opinion article conveys our thoughts and perspectives on the promising usage of plant-based biomolecules in circumventing SARS-CoV-2, and how these molecules can work synergistically with other potential drugs for treating SARS-CoV-2.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Phytochemicals/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Antiviral Agents/therapeutic use , Coronavirus Infections/immunology , Drug Combinations , Drug Synergism , Herb-Drug Interactions , Humans , Immunity , Pandemics , Phytochemicals/therapeutic use , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Pneumonia, Viral/immunology
6.
AAPS J ; 22(4): 86, 2020 06 12.
Article in English | MEDLINE | ID: covidwho-596013

ABSTRACT

The co-administration of hydroxychloroquine with azithromycin is proposed in COVID-19 therapy. We hypothesize a new mechanism supporting the synergistic interaction between these drugs. Azithromycin is a substrate of ABCB1 (P-glycoprotein) which is localized in endosomes and lysosomes with a polarized substrate transport from the cell cytosol into the vesicle interior. SARS-CoV-2 and drugs meet in these acidic organelles and both basic drugs, which are potent lysosomotropic compounds, will become protonated and trapped within these vesicles. Consequently, their intra-vesicular concentrations can attain low micromolar effective cytotoxic concentrations on SARS-CoV-2 while concomitantly increase the intra-vesicular pH up to around neutrality. This last effect inhibits lysosomal enzyme activities responsible in virus entry and replication cycle. Based on these considerations, we hypothesize that ABCB1 could be a possible enhancer by confining azithromycin more extensively than expected when the trapping is solely dependent on the passive diffusion. This additional mechanism may therefore explain the synergistic effect when azithromycin is added to hydroxychloroquine, leading to apparently more rapid virus clearance and better clinical benefit, when compared to monotherapy with hydroxychloroquine alone.


Subject(s)
Anti-Infective Agents/pharmacology , Azithromycin/pharmacology , Coronavirus Infections/drug therapy , Hydroxychloroquine/pharmacology , Pneumonia, Viral/drug therapy , ATP Binding Cassette Transporter, Subfamily B/agonists , Anti-Infective Agents/therapeutic use , Azithromycin/therapeutic use , Drug Synergism , Drug Therapy, Combination , Humans , Hydroxychloroquine/therapeutic use , Pandemics
7.
In Vivo ; 34(3 Suppl): 1567-1588, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-532631

ABSTRACT

BACKGROUND: On March 11, 2020, the World Health Organization (WHO) declared the outbreak of coronavirus disease (COVID-19) a pandemic. Since then, thousands of people have suffered and died, making the need for a treatment of severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) more crucial than ever. MATERIALS AND METHODS: The authors carried out a search in PubMed, ClinicalTrials.gov and New England Journal of Medicine (NEJM) for COVID-19 to provide information on the most promising treatments against SARS-CoV-2. RESULTS: Possible COVID-19 agents with promising efficacy and favorable safety profile were identified. The results support the combination of copper, N-acetylcysteine (NAC), colchicine and nitric oxide (NO) with candidate antiviral agents, remdesivir or EIDD-2801, as a treatment for patients positive for SARS-CoV-2. CONCLUSION: The authors propose to study the effects of the combination of copper, NAC, colchicine, NO and currently used experimental antiviral agents, remdesivir or EIDD-2801, as a potential treatment scheme for SARS-COV-2.


Subject(s)
Acetylcysteine/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , Colchicine/therapeutic use , Copper/therapeutic use , Coronavirus Infections/drug therapy , Nitric Oxide/therapeutic use , Pneumonia, Viral/drug therapy , Ribonucleosides/therapeutic use , Acetylcysteine/administration & dosage , Acetylcysteine/pharmacology , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , Alanine/administration & dosage , Alanine/pharmacology , Alanine/therapeutic use , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Autophagy/drug effects , Betacoronavirus/drug effects , Betacoronavirus/physiology , Colchicine/administration & dosage , Colchicine/pharmacology , Copper/administration & dosage , Coronavirus Infections/immunology , Coronavirus Infections/physiopathology , Drug Synergism , Drug Therapy, Combination , Humans , Inflammation , Nitric Oxide/administration & dosage , Nitric Oxide/pharmacology , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/physiopathology , Prodrugs/administration & dosage , Prodrugs/therapeutic use , Ribonucleosides/administration & dosage , Ribonucleosides/pharmacology , Virus Internalization/drug effects , Virus Replication/drug effects
8.
In Vivo ; 34(3 Suppl): 1597-1602, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-531971

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2), initially termed 2019-new CoV (2019-nCoV), is a novel coronavirus responsible for the severe respiratory illness currently ongoing worldwide from the beginning of December 2019. This beta gene virus, very close to bat coronaviruses (bat-CoV-RaTG13) and bat-SL-CoVZC45, causes a severe disease, similar to those caused by Middle East respiratory syndrome (MERS)-CoV and SARS-CoV viruses, featured by low to moderate mortality rate. Unfortunately, the antiviral drugs commonly used in clinical practice to treat viral infections, are not applicable to SARS-Cov-2 and no vaccine is available. Thus, it is extremely necessary to identify new drugs suitable for the treatment of the 2019-nCoV outbreak. Different preclinical studies conducted on other coronaviruses suggested that promising clinical outcomes for 2019-nCoV should be obtained by using alpha-interferon, chloroquine phosphate, arabinol, remdesivir, lopinavir/ritonavir, and anti-inflammatory drugs. Moreover, clinical trials with these suitable drugs should be performed on patients affected by SARS-Cov-2 to prove their efficacy and safety. Finally, a very promising therapeutic drug, tocilizumab, is discussed; it is currently used to treat patients presenting COVID-19 pneumonia. Herein, we recapitulate these experimental studies to highlight the use of antiviral drugs for the treatment of SARS-Cov-2 disease.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus Infections/drug therapy , Pandemics , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Animals , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Chloroquine/analogs & derivatives , Chloroquine/therapeutic use , Clinical Trials as Topic , Coronavirus Infections/complications , Coronavirus Infections/epidemiology , Coronavirus Infections/veterinary , Drug Combinations , Drug Evaluation, Preclinical , Drug Synergism , Drug Therapy, Combination , Drugs, Investigational/therapeutic use , Humans , Indoles/therapeutic use , Lopinavir/therapeutic use , Multicenter Studies as Topic , Neuraminidase/antagonists & inhibitors , Pneumonia, Viral/complications , Pneumonia, Viral/epidemiology , Primates , Ribavirin/therapeutic use , Ritonavir/therapeutic use , Treatment Outcome
9.
J Med Microbiol ; 69(6): 864-873, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-436403

ABSTRACT

Introduction. The emergence of SARS-CoV-2 has taken humanity off guard. Following an outbreak of SARS-CoV in 2002, and MERS-CoV about 10 years later, SARS-CoV-2 is the third coronavirus in less than 20 years to cross the species barrier and start spreading by human-to-human transmission. It is the most infectious of the three, currently causing the COVID-19 pandemic. No treatment has been approved for COVID-19. We previously proposed targets that can serve as binding sites for antiviral drugs for multiple coronaviruses, and here we set out to find current drugs that can be repurposed as COVID-19 therapeutics.Aim. To identify drugs against COVID-19, we performed an in silico virtual screen with the US Food and Drug Administration (FDA)-approved drugs targeting the RNA-dependent RNA polymerase (RdRP), a critical enzyme for coronavirus replication.Methodology. Initially, no RdRP structure of SARS-CoV-2 was available. We performed basic sequence and structural analysis to determine if RdRP from SARS-CoV was a suitable replacement. We performed molecular dynamics simulations to generate multiple starting conformations that were used for the in silico virtual screen. During this work, a structure of RdRP from SARS-CoV-2 became available and was also included in the in silico virtual screen.Results. The virtual screen identified several drugs predicted to bind in the conserved RNA tunnel of RdRP, where many of the proposed targets were located. Among these candidates, quinupristin is particularly interesting because it is expected to bind across the RNA tunnel, blocking access from both sides and suggesting that it has the potential to arrest viral replication by preventing viral RNA synthesis. Quinupristin is an antibiotic that has been in clinical use for two decades and is known to cause relatively minor side effects.Conclusion. Quinupristin represents a potential anti-SARS-CoV-2 therapeutic. At present, we have no evidence that this drug is effective against SARS-CoV-2 but expect that the biomedical community will expeditiously follow up on our in silico findings.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , RNA Replicase/antagonists & inhibitors , Animals , Antiviral Agents/therapeutic use , Betacoronavirus/enzymology , Betacoronavirus/genetics , Betacoronavirus/physiology , Coronavirus Infections/virology , Drug Evaluation, Preclinical/methods , Drug Synergism , Humans , Molecular Conformation , Pandemics , Phylogeny , Pneumonia, Viral/virology , RNA Replicase/drug effects , Rifampin/pharmacology , Sequence Alignment , Sequence Analysis, Protein , Virginiamycin/analogs & derivatives , Virginiamycin/pharmacology , Virus Replication/drug effects
10.
Life Sci ; 255: 117842, 2020 Aug 15.
Article in English | MEDLINE | ID: covidwho-403331

ABSTRACT

The outbreak of COVID-19 caused by 2019-nCov/SARS-CoV-2 has become a pandemic with an urgent need for understanding the mechanisms and identifying a treatment. Viral infections including SARS-CoV are associated with increased levels of reactive oxygen species, disturbances of Ca++ caused by unfolded protein response (UPR) mediated by endoplasmic reticulum (ER) stress and is due to the exploitation of virus's own protein i.e., viroporins into the host cells. Several clinical trials are on-going including testing Remdesivir (anti-viral), Chloroquine and Hydroxychloroquine derivatives (anti-malarial drugs) etc. Unfortunately, each drug has specific limitations. Herein, we review the viral protein involvement to activate ER stress transducers (IRE-1, PERK, ATF-6) and their downstream signals; and evaluate combination therapies for COVID-19 mediated ER stress alterations. Melatonin is an immunoregulator, anti-pyretic, antioxidant, anti-inflammatory and ER stress modulator during viral infections. It enhances protective mechanisms for respiratory tract disorders. Andrographolide, isolated from Andrographis paniculata, has versatile biological activities including immunomodulation and determining SARS-CoV-2 binding site. Considering the properties of both compounds in terms of anti-inflammatory, antioxidant, anti-pyrogenic, anti-viral and ER stress modulation and computational approaches revealing andrographolide docks with the SARS-CoV2 binding site, we predict that this combination therapy may have potential utility against COVID-19.


Subject(s)
Betacoronavirus/metabolism , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Diterpenes/pharmacology , Endoplasmic Reticulum Stress/drug effects , Melatonin/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Activating Transcription Factor 6/metabolism , Antiviral Agents/pharmacology , Drug Synergism , Endoplasmic Reticulum Stress/physiology , Endoribonucleases/metabolism , Humans , Molecular Targeted Therapy , Pandemics , Protein-Serine-Threonine Kinases/metabolism , Unfolded Protein Response/drug effects , eIF-2 Kinase/metabolism
11.
Int J Antimicrob Agents ; 56(2): 106020, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-378805

ABSTRACT

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.


Subject(s)
Antiviral Agents/pharmacology , Azithromycin/pharmacology , Betacoronavirus/drug effects , G(M1) Ganglioside/chemistry , Hydroxychloroquine/pharmacology , Peptidyl-Dipeptidase A/chemistry , Spike Glycoprotein, Coronavirus/chemistry , Amino Acid Sequence , Antiviral Agents/chemistry , Azithromycin/chemistry , Betacoronavirus/growth & development , Betacoronavirus/metabolism , Binding Sites , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Drug Synergism , G(M1) Ganglioside/antagonists & inhibitors , G(M1) Ganglioside/metabolism , Gene Expression , Host-Pathogen Interactions/drug effects , Host-Pathogen Interactions/genetics , Host-Pathogen Interactions/immunology , Humans , Hydroxychloroquine/chemistry , Kinetics , Molecular Docking Simulation , Molecular Dynamics Simulation , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Sequence Alignment , Sequence Homology, Amino Acid , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Virus Attachment/drug effects
12.
Emerg Microbes Infect ; 9(1): 1170-1173, 2020 Dec.
Article in English | MEDLINE | ID: covidwho-324574

ABSTRACT

The emerging SARS-CoV-2 infection associated with the outbreak of viral pneumonia in China is ongoing worldwide. There are no approved antiviral therapies to treat this viral disease. Here we examined the antiviral abilities of three broad-spectrum antiviral compounds gemcitabine, lycorine and oxysophoridine against SARS-CoV-2 in cell culture. We found that all three tested compounds inhibited viral replication in Vero-E6 cells at noncytotoxic concentrations. The antiviral effect of gemcitabine was suppressed efficiently by the cytidine nucleosides. Additionally, combination of gemcitabine with oxysophoridine had an additive antiviral effect against SARS-CoV-2. Our results demonstrate that broad-spectrum antiviral compounds may have a priority for the screening of antiviral compounds against newly emerging viruses to control viral infection.


Subject(s)
Alkaloids/pharmacology , Amaryllidaceae Alkaloids/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Deoxycytidine/analogs & derivatives , Phenanthridines/pharmacology , Virus Replication/drug effects , Animals , Betacoronavirus/growth & development , Betacoronavirus/metabolism , Cell Survival/drug effects , Chlorocebus aethiops , Chloroquine/pharmacology , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Drug Combinations , Drug Synergism , Vero Cells
13.
Med Hypotheses ; 142: 109815, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-186565

ABSTRACT

Currently, drug repurposing is an alternative to novel drug development for the treatment of COVID-19 patients. The antimalarial drug chloroquine (CQ) and its metabolite hydroxychloroquine (HCQ) are currently being tested in several clinical studies as potential candidates to limit SARS-CoV-2-mediated morbidity and mortality. CQ and HCQ (CQ/HCQ) inhibit pH-dependent steps of SARS-CoV-2 replication by increasing pH in intracellular vesicles and interfere with virus particle delivery into host cells. Besides direct antiviral effects, CQ/HCQ specifically target extracellular zinc to intracellular lysosomes where it interferes with RNA-dependent RNA polymerase activity and coronavirus replication. As zinc deficiency frequently occurs in elderly patients and in those with cardiovascular disease, chronic pulmonary disease, or diabetes, we hypothesize that CQ/HCQ plus zinc supplementation may be more effective in reducing COVID-19 morbidity and mortality than CQ or HCQ in monotherapy. Therefore, CQ/HCQ in combination with zinc should be considered as additional study arm for COVID-19 clinical trials.


Subject(s)
Chloroquine/administration & dosage , Coronavirus Infections/drug therapy , Dietary Supplements , Hydroxychloroquine/administration & dosage , Pneumonia, Viral/drug therapy , Zinc/administration & dosage , Aged , Betacoronavirus , Drug Synergism , Female , Humans , Hydrogen-Ion Concentration , Length of Stay , Lysosomes/drug effects , Lysosomes/metabolism , Male , Models, Theoretical , Pandemics , Patient Safety , Zinc/pharmacology
15.
Infez Med ; 28(2): 198-211, 2020.
Article in English | MEDLINE | ID: covidwho-131580

ABSTRACT

The COVID-19 pandemic represents the greatest global public health crisis since the pandemic influenza outbreak of 1918. We are facing a new virus, so several antiviral agents previously used to treat other coronavirus infections such as SARS and MERS are being considered as the first potential candidates to treat COVID-19. Thus, several agents have been used by the beginning of the current outbreak in China first and all over the word successively, as reported in several different guidelines and therapeutic recommendations. At the same time, a great number of clinical trials have been launched to investigate the potential efficacy therapies for COVID-19 highlighting the urgent need to get as quickly as possible high-quality evidence. Through PubMed, we explored the relevant articles published on treatment of COVID-19 and on trials ongoing up to April 15, 2020.


Subject(s)
Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Betacoronavirus , Chloroquine/therapeutic use , Clinical Trials as Topic , Drug Synergism , Humans , Hydroxychloroquine/therapeutic use , Pandemics , Zinc/therapeutic use
16.
Infez Med ; 28(2): 192-197, 2020.
Article in English | MEDLINE | ID: covidwho-127699

ABSTRACT

The recent outbreak of coronavirus disease 2019 (COVID-19), is now officially declared as a pandemic by the World Health Organization. As of now, there is no known effective pharmaceutical agent against the SARS-CoV-2 virus. However, several precautionary measures have been prescribed to prevent further spread of the virus, which include avoidance of social gatherings, proper handwashing, frequently disinfecting of used items and surfaces and so on. More recent studies have highlighted the possibility of treating patients infected with the novel SARS-CoV-2 virus with chloroquine and hydroxychloroquine, of which mechanism of action is not completely understood. We seek to draw the attention of the scientific community to the possibility of drastically reducing the effects of the virus on the affected patients and improving clinical trials outcome through the synergistic action of zinc and chloroquine in patients suffering from the coronavirus disease.


Subject(s)
Chloroquine/therapeutic use , Coronavirus Infections/drug therapy , Hydroxychloroquine/therapeutic use , Pneumonia, Viral/drug therapy , Zinc/therapeutic use , Betacoronavirus , Clinical Trials as Topic , Drug Synergism , Humans , Pandemics
17.
Microb Pathog ; 145: 104228, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-116929

ABSTRACT

Human coronaviruses SARS-CoV-2 appeared at the end of 2019 and led to a pandemic with high morbidity and mortality. As there are currently no effective drugs targeting this virus, drug repurposing represents a short-term strategy to treat millions of infected patients at low costs. Hydroxychloroquine showed an antiviral effect in vitro. In vivo it showed efficacy, especially when combined with azithromycin in a preliminary clinical trial. Here we demonstrate that the combination of hydroxychloroquine and azithromycin has a synergistic effect in vitro on SARS-CoV-2 at concentrations compatible with that obtained in human lung.


Subject(s)
Antiviral Agents/pharmacology , Azithromycin/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Hydroxychloroquine/pharmacology , Pneumonia, Viral/drug therapy , Animals , Cell Line , Chlorocebus aethiops , Drug Repositioning , Drug Synergism , Drug Therapy, Combination/methods , Humans , Pandemics , Vero Cells , Virus Replication/drug effects
18.
Med Hypotheses ; 142: 109754, 2020 Sep.
Article in English | MEDLINE | ID: covidwho-102391

ABSTRACT

The recent global pandemic created by the Coronavirus SARS-CoV-2, started in Wuhan, China in December 2019, has generated panic, both in term of human death (4-5% of infected patients identified through testing) and the global economy. Human sufferings seem to be continuing, and it is not clear how long this will continue and how much more destruction it is going to cause until complete control is achieved. One of the most disturbing issues is Covid-19 treatment; although a large number of medications, previously used successfully with other viruses (including Chinese herbal medicines and anti-malaria drugs), are under consideration, there remain questions as to whether they can play a satisfactory role for this disease. Global attempts are ongoing to find the drugs for the treatment of this virus but none of the antiviral drugs used for treatment of other human viral infection is working and hence attempts to find new drugs are continuing. Here the author is proposing that 5-Fluorouracil (5-FU) which when used on its own is failing as an antiviral agent due to the removal of this compound by proof reading ability exceptionally found in Coronaviruses. The author here is proposing to test 5-FU in combination with a number of deoxynucleosides on animal models infected with this Covid-19. Should encouraging results ensue, therapies could then be tried on patients.


Subject(s)
Coronavirus Infections/drug therapy , Deoxyribonucleosides/administration & dosage , Deoxyribose/administration & dosage , Fluorouracil/administration & dosage , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/analogs & derivatives , Alanine/administration & dosage , Alanine/analogs & derivatives , Betacoronavirus , Chloroquine/administration & dosage , Chloroquine/analogs & derivatives , Clinical Trials as Topic , Drug Administration Schedule , Drug Synergism , Humans , Inflammation/drug therapy , Models, Theoretical , Pandemics
SELECTION OF CITATIONS
SEARCH DETAIL