ArticleLiterature Review

Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review

May 2020
Clinical Microbiology and Infection 26(8)

DOI:10.1016/j.cmi.2020.05.016

Authors:

Chaturaka Rodrigo

UNSW Sydney

Deepika Fernando

University of Colombo

Senaka Rajapakse

University of Colombo

Background Repurposing hydroxychloroquine (HCQ) and chloroquine (CQ) as antiviral agents is a re-emerging topic with new viral epidemics. Objectives To summarize evidence from human clinical studies for using HCQ or CQ as antiviral agents for any viral infection. Data sources PubMed, EMBASE, Scopus, Web of Science for published studies without time or language restrictions. Cochrane Clinical Trial Registry and Chinese Clinical Trials Registry for trials registered after 2015. MedRxiv for pre-prints within the last 12 months. Study eligibility criteria Interventional and prospective observational studies (with or without a control group) Participants Adults and children with a confirmed viral infection. Intervention Use of chloroquine or hydroxychloroquine as antiviral agents in one or more groups of the study. Methods Two authors independently screened abstracts and all authors agreed on eligible studies. A meta-analysis was planned if similar studies were available in terms of participants, intervention, comparator and outcomes. Results Nineteen studies were eligible (HIV: 8, HCV: 2, Dengue: 2, Chikungunya: 1, COVID-19: 6) including two pre-prints. Nine and ten studies assessed CQ and HCQ respectively. Benefits of either drug for viral load suppression in HIV is inconsistent. CQ is ineffective in curing dengue (high certainty evidence) and may have little or no benefit in curing chikungunya (low-certainty evidence). The evidence for COVID-19 infection is rapidly evolving but at this stage we are unsure if CQ or HCQ has any benefit in clearing viraemia (very low certainty evidence). Conclusions Using HCQ or CQ for HIV/HCV infections is clinically irrelevant now as other effective antivirals are available for viral load suppression (HIV) and cure (HCV). There is no benefit of CQ in dengue and the same conclusion is likely for chikungunya infection. More evidence is needed to confirm if HCQ or CQ is beneficial in COVID-19 infection.

-NC-ND license The journey of antimalarial drugs against SARS-CoV-2: Review article

Article

Full-text available

Jan 2021

The recent outbreak of coronavirus pandemic (COVID-19) introduced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has greatly affected the global public health. This pandemic disease became particularly threatening after the start of a new wave. Vaccines of tested efficacy to stop COVID-19 infection are being investigated vigorously worldwide. Currently, some specific drugs have been authorized for COVID-19, but the improvement of antivirals requires time. Hence, a faster way of treatment is done by drug repurposing. Repurposing of drugs is promising for treating and reducing the symptoms of the disease, and it a fast, easy, and safe method to address the crisis, because of their previously known applications. Some antimalarial drugs, especially chloroquine and hydroxychloroquine, have been repurposed, as they exhibited promising results in vitro and in vivo. This article investigates repurposed antimalarial drugs, focusing on their antiviral mechanisms of action, effects in combinations, trial results, and their side effects.

Efficacy of chloroquine and hydroxychloroquine in treating COVID-19 infection: A meta-review of systematic reviews and an updated meta-analysis

Article

Full-text available

Jul 2021
Trav Med Infect Dis

Objective To synthesize findings from systematic reviews and meta-analyses on the efficacy and safety of chloroquine (CQ) and hydroxychloroquine (HCQ) with or without Azithromycin for treating COVID-19, and to update the evidence using a meta-analysis. Methods A comprehensive search was carried out in electronic databases for systematic reviews, meta-analyses and experimental studies which investigated the efficacy and safety of CQ, HCQ with or without Azithromycin to treat COVID-19. Findings from the reviews were synthesised using tables and forest plots and the quality effect model was used for the updated meta-analysis. The main outcomes were mortality, the need for intensive care services, disease exacerbation, viral clearance and occurrence of adverse events. Results Thirteen reviews with 40 primary studies were included. Two meta-analyses reported a high risk of mortality, with ORs of 2.2 and 3.0, and the two others found no association between HCQ and mortality. Findings from two meta-analyses showed that HCQ with Azithromycin increased the risk of mortality, with similar ORs of 2.5. The updated meta-analysis of experimental studies showed that the drugs were not effective in reducing mortality (RR 1.1, 95%CI 1.0–1.3, I² = 0.0%), need for intensive care services (OR 1.1, 95%CI 0.9–1.4, I² = 0.0%), virological cure (OR 1.5, 95%CI 0.5–4.4, I² = 39.6%) or disease exacerbation (OR 1.2, 95%CI 0.3–5.9, I² = 31.9%) but increased the odds of adverse events (OR 12,3, 95%CI 2.5–59.9, I² = 76.6%). Conclusion There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation. Registration PROSPERO: CRD42020191353.

The Journey of Antimalarial Drugs against SARS-CoV-2: Review Article

Article

Full-text available

May 2021

Ahmed A. Al-Karmalawy

Therapeutic interventions for COVID-19: a living overview of reviews

Article

Full-text available

Dec 2020
Ther Adv Respir Dis

Background: Coronavirus disease 2019 (COVID-19) has rapidly spread worldwide, but safe and effective treatment options remain unavailable. Numerous systematic reviews of varying qualities have tried to summarize the evidence on the available therapeutic interventions for COVID-19. This overview of reviews aims to provide a succinct summary of the findings of systematic reviews on different pharmacological and non-pharmacological therapeutic interventions for COVID-19. Methods: We searched PubMed, Embase, Google Scholar, Cochrane Database of Systematic Reviews, and WHO database of publications on COVID-19 from 1 December 2019 through to 11 June 2020 for peer-reviewed systematic review studies that reported on potential pharmacological or non-pharmacological therapies for COVID-19. Quality assessment was completed using A MeaSurement Tool to Assess systematic Reviews-2 (AMSTAR-2) measure. Results: Out of 816 non-duplicate studies, 45 were included in the overview. Antiviral and antibiotic agents, corticosteroids, and anti-malarial agents were the most common drug classes used to treat COVID-19; however, there was no direct or strong evidence to support their efficacy. Oxygen therapy and ventilatory support was the most common non-pharmacological supportive care. The quality of most of the included reviews was rated as low or critically low. Conclusion: This overview of reviews demonstrates that although some therapeutic interventions may be beneficial to specific subgroups of COVID-19 patients, the available data are insufficient to strongly recommend any particular treatment option to be used at a population level. Future systematic reviews on COVID-19 treatments should adhere to the recommended systematic review methodologies and ensure that promptness and comprehensiveness are balanced.

The situation of small molecules targeting key proteins to combat SARS-CoV-2: Synthesis, metabolic pathway, mechanism of action, and potential therapeutic applications

Article

Full-text available

Mar 2021
MINI-REV MED CHEM

Due to the global epidemic and high mortality of 2019 coronavirus disease (COVID-19), there is an immediate need to discover drugs that can help before a vaccine becomes available. Given that the process of producing new drugs is so long, the strategy of repurposing existing drugs is one of the promising options for the urgent treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19 disease. Although FDA has approved Remdesivir for the use in hospitalized adults and pediatric patients suffering from COVID-19, no fully effective and reliable drug has been yet identified worldwide to treat COVID-19 specifically. Thus, scientists are still trying to find antivirals specific to COVID-19. This work reviews the chemical structure, metabolic pathway, mechanism of action of existing drugs with potential therapeutic applications for COVID-19. Further, we summarized the molecular docking stimulation of the medications related to key protein targets. These already drugs could be developed for further clinical trials to supply suitable therapeutic options for patients suffering from COVID-19.

Effect of Hydroxychloroquine in Hospitalized patients with COVID-19

Article

Full-text available

Oct 2020
NEW ENGL J MED

Ashar Ahmed

Effect of Hydroxychloroquine in Hospitalized Patients with COVID-19

The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis and clinical assessment: an updated meta-analysis of randomized trials

Article

Full-text available

May 2024

Background Coronavirus disease 2019 (COVID-19), a disease that affected tens of millions of people, upended the lives of countless individuals around the globe. The chloroquine (CQ) and its analogue hydroxychloroquine (HCQ) were the most frequently cited as potential treatments and preventatives against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The primary aim of this investigation was to scrutinize the effectiveness and safety of HCQ for COVID-19 prevention and to present powerful evidence and reference for clinical practice. Methods PubMed, Ovid and the Cochrane COVID-19 Register of Controlled Trials (CENTRAL) were systematically searched from inception to January 31, 2022. Randomized controlled trials (RCTs) trials that included participants who were SARS-CoV-2 negative at the time of registration were enrolled in this meta-analysis. The intervention group took HCQ or CQ orally. The control group was not blinded by quinine or placebo. Pooled relative risk (RR) of SARS-CoV-2 infection, mortality, hospitalization, adverse events, and compliance were calculated. The software tools utilized for statistical analyses were Stata 14 and Review Manager 5.3. Results A total of 9 studies including 7,825 participants were enrolled. Bias of individual studies were assessed as low risk. The pooled RR for SARS-CoV-2 infection was 0.75 [95% confidence interval (CI): 0.68–0.83] (z=−4.01, P<0.0001; I²=11%). The pooled RR for hospitalization was 0.72 (95% CI: 0.35–1.50) (z=0.87, P=0.39; I²=0.0%). The pooled RR for mortality and adverse events were 3.26 (95% CI: 0.13–79.74) (z=0.72, P=0.47; I²=0.0%) and 1.90 (95% CI: 1.20–3.02) (z=2.73, P=0.0063; I²=94%). Conclusions Results of this meta-analysis indicated significant impact of HCQ on SARS-CoV-2 infection with higher risk of adverse events. These findings must be considered with caution, and further research is necessary to delineate the specific circumstances where HCQ may be effective for COVID-19 prevention.

In Silico identification of dengue NS5 phytochemical inhibitors as potential antiviral drug compounds via molecular docking

Article

Full-text available

Apr 2024

Dengue fever is a viral disease caused by the dengue flavivirus, transmitted through the bites of infected mosquitoes. The endeavor to combat dengue has led many researchers to develop antiviral drugs. Several medicinal plants, containing diverse phytochemicals, exhibit potential for inhibiting pathogenic proteins and are employed in ongoing research and therapeutic advancement. This has piqued researchers’ interest in identifying potential plantderived molecule inhibitors 』of the dengue virus NonStructural Protein 5 (NS5) and analyzing their subsequent interactions. This study employed candidate selection and molecular docking using an in silico approach. We used the Protein Data Bank database and performed National Center for Biotechnology Information (NCBI) blastp analysis to gather and compare the best protein structures of the two NS5 serotypes. In addition, we identified ligand molecules previously reported to exhibit potential inhibitory effects against NS5 by retrieving their 3D structures from NCBI PubChem. Moreover, we utilized PyRx and PyMOL to perform molecular docking. The findings revealed a conspicuous prevalence of interactions between the MTase domain in NS5 and phytochemical compounds, notably Kaempferol and 6-Shogaol. Based on the evidence presented in this study, we propose that investigating the NS5 protein in flavivirus is necessary for dengue fever prevention, as these proteins play a vital role in the replication of the virus. Our findings provide valuable insights beneficial for advancing research into antiviral medication. We suggest further investigation into other medicinal plants that may inhibit dengue and the additional scrutiny of Kaempferol and 6-Shogaol, the compounds that yielded significant results in this study.

Use of aminoquinolines as a prophylactic agent against COVID‑19 in frontline workers‑ A critical review

Article

Aug 2020

FATHMATH RASHMEE

Emerging and reemerging pathogens are global challenges for public health. The infectious disease COVID‑19 caused by SARS‑ CoV‑2, a newly emerged beta coronavirus is spreading throughout the globe. There is currently no specific treatment nor a vaccine available for the disease, though the pandemic continues to grow, the scientific community is searching eagerly to employ a prophylactic drug that could decrease COVID‑19 spread. As chemoprophylaxis is an acceptable approach in mitigating infectious diseases, discovering an efficient chemoprophylactic agent could be one way to potentially control COVID‑19. There have been several existing drugs repurposing for the treatment and prevention of COVID‑19. Most research efforts are focused on the 4‑aminoquinoline derivative compounds hydroxychloroquine (HCQ) and chloroquine (CQ). A literature search was performed using Google Scholar and PUBMED to find articles about the role of CQ/HCQ as a prophylaxis to COVID‑19. In addition, a review of all the clinical trials registered in clinical trials.gov focusing on HCQ and its role as prophylaxis for COVID‑19 in frontline workers is also included in this review. A total of 59 publications are included, of these 24 are ongoing clinical trials, and 35 publications including pre‑clinical and clinical studies as well as systematic reviews, research letters/ correspondence, opinions, and viewpoints have been included, in the intention to outline the current evidence regarding the benefits and harms of using HCQ/CQ as a prophylactic for COVID‑19 in frontline workers, in addition, to provide an overall picture of the use of these drugs around the world, for this purpose. In conclusion, the literature does not yet present well‑designed clinical studies that demonstrate HCQ/COQ effectiveness in COVID‑19, However, we are in a race against time to find effective treatments and preventive measures against the growing pandemic, considering the repositioning drugs like 4‑aminoquinoline derivatives CQ and HCQ, that shows antiviral efficacy against SARS‑CoV‑2 , which are easily available, affordable, and have a good safety profile, in a resource‑poor country, like the Maldives, will benefit the healthcare system and augment the safety of frontline workers against COVID‑19.

Bioremediation of Acetaminophen and Hydroxychloroquine by Kosakonia cowanii JCM 10956(T) with ecotoxicity studies

Preprint

Full-text available

May 2023

Acetaminophen and hydroxychloroquine are widely used drugs during COVID situations. Residual concentrations of acetaminophen and hydroxychloroquine have been detected in pharmaceutical industry wastewater, effluent treatment plants, and surface water. The present study was carried out on the bioremediation of acetaminophen (paracetamol) and hydroxychloroquine by using the bacterial isolate Kosakonia cowanii JCM 10956(T) (GenBank: OQ733302.1). Identification of the isolate was done using the 16S rRNA sequencing technique. The LC50 values for bacteria were determined for acetaminophen and hydroxychloroquine as 2186.70 and 1735.13 ppm, respectively. Isolate was found to degrade acetaminophen (1500 ppm) into hydroquinone after five days of incubation with an 81% biodegradation rate. Hydroxychloroquine (1000 ppm) was found to be degraded into oxalic acid with 7-chloroquinoline-4-amine and 4-aminoquinoline-7-ol as intermediates. After 15 days of incubation, 60% of hydroxychloroquine was found to be degraded. Acetaminophen and hydroxychloroquine biodegradation followed a first-order kinetic model with a rate constant of 0.339 d − 1 and 0.0618 d − 1 , respectively. Half-lives for acetaminophen and hydroxychloroquine were found to be 2.05 and 11.2 days, respectively. Based on the analytical techniques of UV-visible spectra, HPLC, mass spectra, and proton nuclear magnetic spectroscopy (1H NMR) studies, biodegradative metabolites were identified. Ecotoxicological testing of the parent drug and degradative product was done using algal inhibition and shrimp lethality assays. The biodegradative product of acetaminophen, hydroquinone, has more algal toxicity and less toxicity against shrimp as compared to the parent drug. Whereas for the hydroxychloroquine biodegradative product, oxalic acid has less algal toxicity and more toxicity against shrimp compared to the parent drug. Industrial applications of hydroquinone and the metal leaching role of oxalic acid will give new insight into the bioconversion of expired paracetamol and hydroxychloroquine into value-added products.

Electrostatic Surface Potential as a Key Parameter in Virus Transmission and Evolution: How to Manage Future Virus Pandemics in the Post-COVID-19 Era

Article

Full-text available

Jan 2023

Virus-cell interactions involve fundamental parameters that need to be considered in strategies implemented to control viral outbreaks. Among these, the surface electrostatic potential can give valuable information to deal with new epidemics. In this article, we describe the role of this key parameter in the hemagglutination of red blood cells and in the co-evolution of synaptic receptors and neurotransmitters. We then establish the functional link between lipid rafts and the electrostatic potential of viruses, with special emphasis on gangliosides, which are sialic-acid-containing, electronegatively charged plasma membrane components. We describe the common features of ganglioside binding domains, which include a wide variety of structures with little sequence homology but that possess key amino acids controlling ganglioside recognition. We analyze the role of the electrostatic potential in the transmission and intra-individual evolution of HIV-1 infections, including gatekeeper and co-receptor switch mechanisms. We show how to organize the epidemic surveillance of influenza viruses by focusing on mutations affecting the hemagglutinin surface potential. We demonstrate that the electrostatic surface potential, by modulating spike-ganglioside interactions, controls the hemagglutination properties of coronaviruses (SARS-CoV-1, MERS-CoV, and SARS-CoV-2) as well as the structural dynamics of SARS-CoV-2 evolution. We relate the broad-spectrum antiviral activity of repositioned molecules to their ability to disrupt virus-raft interactions, challenging the old concept that an antibiotic or anti-parasitic cannot also be an antiviral. We propose a new concept based on the analysis of the electrostatic surface potential to develop, in real time, therapeutic and vaccine strategies adapted to each new viral epidemic.

Electrochemical Sensing of Favipiravir with an Innovative Water-Dispersible Molecularly Imprinted Polymer Based on the Bimetallic Metal-Organic Framework: Comparison of Morphological Effects

Article

Full-text available

Sep 2022

Molecularly imprinted polymers (MIPs) are widely used as modifiers in electrochemical sensors due to their high sensitivity and promise of inexpensive mass manufacturing. Here, we propose and demonstrate a novel MIP-sensor that can measure the electrochemical activity of favipiravir (FAV) as an antiviral drug, thereby enabling quantification of the concentration of FAV in biological and river water samples and in real-time. MOF nanoparticles’ application with various shapes to determine FAV at nanomolar concentrations was described. Two different MOF nanoparticle shapes (dodecahedron and sheets) were systematically compared to evaluate the electrochemical performance of FAV. After carefully examining two different morphologies of MIP-Co-Ni@MOF, the nanosheet form showed a higher performance and efficiency than the nanododecahedron. When MIP-Co/Ni@MOF-based and NIP-Co/Ni@MOF electrodes (nanosheets) were used instead, the minimum target concentrations detected were 7.5 × 10−11 (MIP-Co-Ni@MOF) and 8.17 × 10−9 M (NIP-Co-Ni@MOF), respectively. This is a significant improvement (>102), which is assigned to the large active surface area and high fraction of surface atoms, increasing the amount of greater analyte adsorption during binding. Therefore, water-dispersible MIP-Co-Ni@MOF nanosheets were successfully applied for trace-level determination of FAV in biological and water samples. Our findings seem to provide useful guidance in the molecularly imprinted polymer design of MOF-based materials to help establish quantitative rules in designing MOF-based sensors for point of care (POC) systems.

Ayurvedic Herbs Advised for COVID-19 Management: Therapeutic Potential and Clinical Relevance

Article

Jun 2022

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide. There is no effective medication for COVID-19 as of now, so it would be good to take preventive measures that not only boost our immunity but also fight against infections in this perilous time. The utilization of traditional Chinese medicine in China to treat COVID-19 patients sets the prototype demonstrating that traditional medicines can contribute to prevention and treatment successfully. In India, the Ministry of AYUSH (Ayurveda, Yoga, Unani, Siddha, Homeopathy) released a self-care advisory during the COVID-19 crisis as a preventive aspect. This review article discusses the therapeutic potential and clinical relevance of some herbs [(Tulsi (Ocimum sanctum), Haridra (Curcuma longa), Tvaka (Cinnamon), Maricha (Piper longum), Shunthi (Zingiber officinale), Munakka (Dried grapes), Lavang (Syzigiumaromaticum), Pudina (Mentha arvensis), and Ajwain (Trachyspermum ammi)] advised by AUYSH to take during COVID-19 infection. They are effective in COVID-19 management, therefore, authors have discussed their detailed traditional uses as therapeutics and spotted scientific insight and clinical significance of the above-mentioned herbs along with their mechanistic viewpoint, adequately, on a single platform. Provided information could be a treasure to open up a new research arena on natural products to manage human health crises effectively, caused not only by COVID-19 but also by other infectious diseases.

Citation: Picaud F and Herlem G. Hydroxychloroquine and Azithromycin Molecular Action against SARS-CoV-2 Viral Protein: A Molecular Dynamic Study Hydroxychloroquine and Azithromycin Molecular Action against SARS-CoV-2 Viral Protein: A Molecular Dynamic Study

Preprint

Full-text available

Jan 2021

Review Article: Utilization of physical and chemical microbial load reduction agents for SARS-CoV-2: Toxicity and development of drug resistance implications

Article

Full-text available

Jan 2022

The novel human coronavirus (CoV) 2019, similar to previous severe acute respiratory syndrome corona virus-1 outbreaks, has posed the unprecedented challenges that have shaped global action on preventive and easy to employ measures and policies, including regular disinfection. There is an indiscriminate use of antimicrobial agents, which may pose toxicity to humans, environmental hazards, and, in some cases, development antiviral drug resistance. This review comprehensively highlights the physical and chemical countermeasures applied to prevent various CoV infections and their potential toxicity on humans and the environment, as well as the danger of developing drug resistance. Literature information was sourced from PubMed, ScienceDirect, Embase, MEDLINE, and China National Knowledge Infrastructure databases using Google Scholars and Free Full PDF as search engines. Articles written in the English language were retrieved and included in the study. Researches covering the literature on physical and chemical severe acute respiratory syndrome corona virus-2 preventive measures, their toxicity, and possible ways of developing drug resistance were also discussed. The literature review reveals that physical inactivation under the influence of temperature, humidity, and light, especially ultraviolet-C radiation, has proven effective in reducing the spread of CoV infections. Similarly, chemical countermeasures such as the use of alcohol-and iodine-based disinfecting agents have demonstrated inhibitory potentials of the viruses on surfaces depending on nature, dose, and exposure time. The inactivation occurs through the interference of these agents with the lipid envelope, thereby disrupting the viral activity. A vast majority of the antimicrobial agents are reported to contain corrosive chemicals that are toxic to humans, especially children, and the environment. The toxicity is due to the unhealthy accumulation and pollution caused by the inappropriate disposal of biomedical waste. This study showed that chemicals might have long-term effects on public health, such as reproductive disorders, chronic obstructive pulmonary disease, cancers, skin damage, and central nervous system impairment. Therefore, further research on long-term preventive alternatives such as the formulation of these agents with natural products as active ingredients is necessary to mitigate the effects of alcohol-and iodine-based chemicals on humans and the environment.

Multipurpose Drugs Active Against Both Plasmodium spp. and Microorganisms: Potential Application for New Drug Development

Article

Full-text available

Dec 2021

Malaria, a disease caused by the protozoan parasites Plasmodium spp., is still causing serious problems in endemic regions in the world. Although the WHO recommends artemisinin combination therapies for the treatment of malaria patients, the emergence of artemisinin-resistant parasites has become a serious issue and underscores the need for the development of new antimalarial drugs. On the other hand, new and re-emergences of infectious diseases, such as the influenza pandemic, Ebola virus disease, and COVID-19, are urging the world to develop effective chemotherapeutic agents against the causative viruses, which are not achieved to the desired level yet. In this review article, we describe existing drugs which are active against both Plasmodium spp. and microorganisms including viruses, bacteria, and fungi. We also focus on the current knowledge about the mechanism of actions of these drugs. Our major aims of this article are to describe examples of drugs that kill both Plasmodium parasites and other microbes and to provide valuable information to help find new ideas for developing novel drugs, rather than merely augmenting already existing drug repurposing efforts.

Molecular Mechanisms of Oxidative stress in Stroke and Cancer

Article

Full-text available

Dec 2021

Oxidative stress is a silent participant in all chronic progressive pathology and degenerative disorders. Neurodegeneration and cognitive impairment are caused by increased imbalanced oxidative stress and down-regulated natural anti-oxidant combat mechanisms. Cancer is the end result of cell malfunction and the activation of tumor-specific genes, which are regulated by specific geneo-molecular pathways. Acute stroke is the pathology of oxidative stress and a decrease in the body's combating defence mechanisms. Oxidative stress, which results from an imbalance between oxidative and antioxidative activities in cells, has been linked to the aetiology of a number of chronic degenerative diseases, including cancer and stroke. The harmful effects of ROS and their role in lesion progression after cancer and ischemic stroke are undeniable; however, the therapeutic usefulness of anti-oxidants in this scenario remains debatable. In this review, we have summarized the potent molecular mechanisms which play a vital role through activation of various pathways and associated advanced targeted therapeutics to combat cancer and stroke like chronic pathologies. Graphical The graphical Illustrious depiction of Oxidative stress mediated cancer and stroke progression. Reactive oxygen species (ROS) generation by endogenous and exogenous sources can lead to oxidative damage and modification of proteins, oxidation of lipids and DNA damage, when antioxidants are impaired, leading to OS. Besides, essential signaling molecules, ROS are imperative mediator for plenty of pathophisologies in plethora of chronic diseases including cancer and stroke. Antioxidants are of majorly endogenous enzymes and exogenous non-enzymatic origins which are chiefly prerequisite to attenuate OS.

Chloroquine/Hydroxychloroquine Use and Suicide Risk: Hypotheses for Confluent Etiopathogenetic Mechanisms?

Article

Full-text available

Nov 2021

Chloroquine (CQ) and hydroxychloroquine (HCQ) are classical anti-malarial and anti-inflammatory treatments, which were used as first-line therapy at the beginning of the 2019 coronavirus disease (COVID-19) pandemic. Besides the emerging data on their lack of efficacy against COVID-19 infection, such treatments have been associated with some severe health concerns, including those of neuropsychiatric nature, such as a possible increase in suicide risk. Here we report a case of a patient with no history of psychiatric illnesses, who abruptly developed depression with melancholic features, severe suicidal ideation (SI), and attempted suicide (SA) shortly after receiving HCQ for his COVID-19 infection. The case was followed by a mini-review of the heterogeneous scientific literature on the hypothetical association between neuropsychiatric symptoms, with a focus on SI and suicidal behavior (SB, including SA and death by suicide), when CQ and HCQ are used in COVID-19, rheumatologic diseases, and malaria settings. Considering the anti-inflammatory properties of CQ and HCQ and the implications for neuroinflammation in suicide pathogenesis, the possible increase in suicide risk caused by these medications appears paradoxical and suggests that other underlying pathological trajectories might account for this eventuality. In this regard, some of these latter mechanistic postulates were proposed. Certainly the role and contribution of psycho-social factors that a COVID-19 patient had to face can neither be minimized nor excluded in the attempt to understand his suffering until the development of SI/SB. However, while this case report represents a rare scenario in clinical practice and no consensus exists in the literature on this topic, a psychiatric screening for suicide risk in patients using of CQ and HCQ could be carefully considered.

Target‐based drug repurposing against Candida albicans—A computational modeling, docking, and molecular dynamic simulations study

Article

Full-text available

Oct 2021

The emergence of multidrug‐resistant strains of Candida albicans has become a global threat mostly due to co‐infection with immune‐compromised patients leading to invasive candidiasis. The life‐threatening form of the disease can be managed quickly and effectively by drug repurposing. Thus, the study used in silico approaches to evaluate Food and Drug Administration (FDA) approved drugs against three drug targets—TRR1, TOM40, and YHB1. The tertiary structures of three drug targets were modeled, refined, and evaluated for their structural integrity based on PROCHECK, ERRAT, and PROSA. High‐throughput virtual screening of FDA‐approved drugs (8815), interaction analysis, and energy profiles had revealed that DB01102 (Arbutamine), DB01611 (Hydroxychloroquine), and DB09319 (Carindacillin) exhibited better binding affinity with TRR1, TOM40, and YHB1, respectively. Notably, the molecular dynamic simulation explored that Gln45, Thr119, and Asp288 of TRR1; Thr107 and Ser121 of TOM40; Arg193, Glu213, and Ser228 of YHB1 are crucial residues for stable drug‐target interaction. Additionally, it also prioritized Arbutamine‐TRR1 as the best drug‐target complex based on MM‐PBSA (−52.72 kcal/mol), RMSD (2.43 Å), and radius of gyration (−21.49 Å) analysis. In‐depth, PCA results supported the findings of molecular dynamic simulations. Interestingly, the conserved region (>70%) among the TRR1 sequences from pathogenic Candida species indicated the effectiveness of Arbutamine against multiple species of Candida as well. Thus, the study dispenses new insight and enriches the understanding of developing an advanced technique to consider potential antifungals against C. albicans. Nonetheless, a detailed experimental validation is needed to investigate the efficacy of Arbutamin against life‐threatening candidiasis.

What is The Case of More Accessible Treatment Options in COVID 19: Comparison of Hydroxychloroquine and Favipiravir Based on Laboratory Values?

Article

Full-text available

Jan 2021

An overview of the anti-SARS-CoV-2 properties of Artemisia annua, its antiviral action, protein-associated mechanisms, and repurposing for COVID-19 treatment

Article

Full-text available

Jul 2021

Andréa Fuzimoto

Artemisia annua and its phytocompounds have a rich history in the research and treatment of malaria, rheumatoid arthritis, systemic lupus erythematosus, and other diseases. Currently, the World Health Organization recommends artemisinin-based combination therapy as the first-line treatment for multi-drug-resistant malaria. Due to the various research articles on the use of antimalarial drugs to treat coronaviruses, a question is raised: do A. annua and its compounds provide anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) properties. PubMed/MEDLINE, Scopus, and Google Scholar were searched for peer-reviewed articles that investigated the antiviral effects and mechanisms of A. annua and its phytochemicals against SARS-CoVs. Particularly, articles that studied the herb’s role in inhibiting the coronavirus-host proteins were favored. Nineteen studies were retrieved. From these, fourteen in silico molecular docking studies demonstrated potential inhibitory properties of artemisinins against coronavirus-host proteins, including 3CLPRO, S protein, N protein, E protein, cathepsin-L, helicase protein, nsp3, nsp10, nsp14, nsp15, and GRP78 receptor. Collectively, A. annua constituents may impede the SARS-CoV-2 attachment, membrane fusion, and internalization into the host cells, and hinder the viral replication and transcription process. This is the first comprehensive overview of the application of compounds from A. annua against SARS-CoV-2/coronavirus disease 2019 (COVID-19) describing all target proteins. A. annua’s biological properties, the signaling pathways implicated in the COVID-19, and the advantages and disadvantages for repurposing of A. annua compounds are discussed. The combination of A. annua’s biological properties, action on different signaling pathways and target proteins, and a multi-drug combined-therapy approach may synergistically inhibit SARS-CoV-2 and assist in the COVID-19 treatment. Also, A. annua may modulate the host immune response to better fight the infection.

Contemporary narrative review of treatment options for COVID‐19

Article

Jul 2021

The coronavirus disease 2019 (COVID‐19) pandemic is ongoing and many drugs have been studied in clinical trials. From a pathophysiological perspective, anti‐viral drugs may be more effective in the early stage while immunomodulators may be more effective in severe patients in later stages of infection. While drugs such as lopinavir‐ritonavir, hydroxychloroquine and azithromycin have proved to be ineffective in randomized controlled trials, corticosteroids, neutralizing monoclonal antibodies, remdesivir, tocilizumab and baricitinib have been reported to benefit certain groups of patients with COVID‐19. In this review, we will present the key clinical evidence and progress in promising COVID‐19 therapeutics, as well as summarize the experience and lessons learned from the development of the current therapeutics.

Antivirals against the Chikungunya Virus

Article

Full-text available

Jul 2021

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

Simple rapid in vitro screening method for SARS-CoV-2 anti-virals that identifies potential cytomorbidity-associated false positives

Article

Full-text available

Dec 2021
VIROL J

Background The international SARS-CoV-2 pandemic has resulted in an urgent need to identify new anti-viral drugs for treatment of COVID-19. The initial step to identifying potential candidates usually involves in vitro screening that includes standard cytotoxicity controls. Under-appreciated is that viable, but stressed or otherwise compromised cells, can also have a reduced capacity to replicate virus. A refinement proposed herein for in vitro drug screening thus includes a simple growth assay to identify drug concentrations that cause cellular stress or “cytomorbidity”, as distinct from cytotoxicity or loss of viability. Methods A simple rapid bioassay is presented for antiviral drug screening using Vero E6 cells and inhibition of SARS-CoV-2 induced cytopathic effects (CPE) measured using crystal violet staining. We use high cell density for cytotoxicity assays, and low cell density for cytomorbidity assays. Results The assay clearly illustrated the anti-viral activity of remdesivir, a drug known to inhibit SARS-CoV-2 replication. In contrast, nitazoxanide, oleuropein, cyclosporine A and ribavirin all showed no ability to inhibit SARS-CoV-2 CPE. Hydroxychloroquine, cyclohexamide, didemnin B, γ-mangostin and linoleic acid were all able to inhibit viral CPE at concentrations that did not induce cytotoxicity. However, these drugs inhibited CPE at concentrations that induced cytomorbidity, indicating non-specific anti-viral activity. Conclusions We describe the methodology for a simple in vitro drug screening assay that identifies potential anti-viral drugs via their ability to inhibit SARS-CoV-2-induced CPE. The additional growth assay illustrated how several drugs display anti-viral activity at concentrations that induce cytomorbidity. For instance, hydroxychloroquine showed anti-viral activity at concentrations that slow cell growth, arguing that its purported in vitro anti-viral activity arises from non-specific impairment of cellular activities. The cytomorbidity assay can therefore rapidly exclude potential false positives.

An Assessment of the Impact of Coronavirus Disease (COVID-19) Pandemic on National Antimicrobial Consumption in Jordan

Article

Full-text available

Jun 2021

Coronavirus disease 2019 (COVID-19) has overlapping clinical characteristics with bacterial respiratory tract infection, leading to the prescription of potentially unnecessary antibiotics. This study aimed at measuring changes and patterns of national antimicrobial use for one year preceding and one year during the COVID-19 pandemic. Annual national antimicrobial consumption for 2019 and 2020 was obtained from the Jordan Food and Drug Administration (JFDA) following the WHO surveillance methods. The WHO Access, Watch, and Reserve (AWaRe) classification was used. Total antibiotic consumption in 2020 (26.8 DDD per 1000 inhabitants per day) decreased by 5.5% compared to 2019 (28.4 DDD per 1000 inhabitants per day). There was an increase in the use of several antibiotics during 2020 compared with 2019 (third generation cephalosporins (19%), carbapenems (52%), macrolides (57%), and lincosamides (106%)). In 2020, there was a marked reduction in amoxicillin use (−53%), while the use of azithromycin increased by 74%. National antimicrobial consumption of the Access group decreased by 18% from 2019 to 2020 (59.1% vs. 48.1% of total consumption). The use of the Watch group increased in 2020 by 26%. The study highlighted an increase in the use of certain antibiotics during the pandemic period that are known to be associated with increasing resistance. Efforts to enhance national antimicrobial stewardship are needed to ensure rational use of antimicrobials.

Scientific rationale of Indian AYUSH Ministry advisory for COVID-19 prevention, prophylaxis, and immunomodulation

Article

Full-text available

Apr 2021

The current outbreak of COVID-19 is caused by the SARS-CoV-2 virus that has affected > 210 countries. Various steps are taken by different countries to tackle the current war-like health situation. In India, the Ministry of AYUSH released a self-care advisory for immunomodulation measures during the COVID-19 and this review article discusses the detailed scientific rationale associated with this advisory. Authors have spotted and presented in-depth insight of advisory in terms of immunomodulatory, antiviral, antibacterial, co-morbidity associated actions, and their probable mechanism of action. Immunomodulatory actions of advised herbs with no significant adverse drug reaction/toxicity strongly support the extension of advisory for COVID-19 prevention, prophylaxis, mitigations, and rehabilitation capacities. This advisory also emphasized Dhyana (meditation) and Yogasanas as a holistic approach in enhancing immunity, mental health, and quality of life. The present review may open-up new meadows for research and can provide better conceptual leads for future researches in immunomodulation, antiviral-development, psychoneuroimmunology, especially for COVID-19.

Effect of Hydroxychloroquine in Hospitalized Patients with Covid-19

Article

Nov 2020

BACKGROUND Hydroxychloroquine and chloroquine have been proposed as treatments for coronavirus disease 2019 (Covid-19) on the basis of in vitro activity and data from uncontrolled studies and small, randomized trials. METHODS In this randomized, controlled, open-label platform trial comparing a range of possible treatments with usual care in patients hospitalized with Covid-19, we randomly assigned 1561 patients to receive hydroxychloroquine and 3155 to receive usual care. The primary outcome was 28-day mortality. RESULTS The enrollment of patients in the hydroxychloroquine group was closed on June 5, 2020, after an interim analysis determined that there was a lack of efficacy. Death within 28 days occurred in 421 patients (27.0%) in the hydroxychloroquine group and in 790 (25.0%) in the usual-care group (rate ratio, 1.09; 95% confidence interval [CI], 0.97 to 1.23; P=0.15). Consistent results were seen in all prespecified subgroups of patients. The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death (30.7% vs. 26.9%; risk ratio, 1.14; 95% CI, 1.03 to 1.27). There was a small numerical excess of cardiac deaths (0.4 percentage points) but no difference in the incidence of new major cardiac arrhythmia among the patients who received hydroxychloroquine. CONCLUSIONS Among patients hospitalized with Covid-19, those who received hydroxychloroquine did not have a lower incidence of death at 28 days than those who received usual care. (Funded by UK Research and Innovation and National Institute for Health Research and others; RECOVERY ISRCTN number, ISRCTN50189673; ClinicalTrials.gov number, NCT04381936.)

The efficacy and safety of hydroxychloroquine (HCQ) in treatment of COVID19 –a systematic review and meta-analysis

Article

Mar 2021
Indian J Med Microbiol

Introduction The treatment of SARS CoV2 (Severe Acute Respiratory Syndrome corona virus 2) also known as COVID-19 (corona virus disease 2019) continues to remain an enigma even after six months of the pandemic. Hydroxychloroquine (HCQ) has been one of the most widely tested drugs for SARS CoV2 on account of its antiviral properties. However the results so far have been far from categorical. The meta-analyses conducted till date are also lacking in precision and appropriateness. This systematic review and meta-analysis addresses the efficacy and safety of HCQ in SARS CoV2 by overcoming the limitations of earlier meta-analysis. Methods A total of 5 prominent medical databases were searched and fourteen studies (n = 12455) were included in the systematic review and meta-analyses. The data on survival, alleviation of symptoms, conversion of RT PCR positivity to negativity, use and efficacy in presence of co-morbidities (Hypertension, diabetes and heart disease) and cardiac and gastrointestinal side effects were extracted. Meta-analysis was applied to calculate the pooled estimates. Fixed-effects model results were chosen since I² was <25%.Meta-analysis was conducted using STATA version 13 (StataCorp LP, College Station, TX, USA). Results The pooled estimates showed that HCQ treatment did not significantly affect survival at 14 and 28 days in COVID-19 patients with respect to the control population (RR: 1.003, 95% CI: 0.983–1.022), alleviation of symptoms at day 10 (RR: 1.044, 95% CI: 0.911 1.196), success in presence of co-morbidities (RR: 1.058, 95% CI: 1.035–1.082) and conversion from RT PCR positive to RT PCR negative on day 6 (RR:1.123, 95% CI: 1.041 1.212). There was higher risk for cardiac side effects (RR: 2.012, 95% CI: 1.428 2.833) and gastrointestinal side effects (RR: 1.318, 95% CI: 0.730 2.380) in HCQ recipients. Conclusion There is no evidence on the safety and efficacy of HCQ either alone or in combination with other drugs in SARS CoV2 infection.

Effects of chloroquine or hydroxychloroquine treatment on non‐SARS‐CoV2 viral infections: A systematic review of clinical studies

Article

Mar 2021

Chloroquine (CQ) and hydroxychloroquine (HCQ) have been used as antiviral agents for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection. We performed a systematic review to examine whether prior clinical studies that compared the effects of CQ and HCQ to a control for the treatment of non‐SARS‐CoV2 infection supported the use of these agents in the present SARS‐CoV2 outbreak. PubMed, EMBASE, Scopus and Web of Science (PROSPERO CRD42020183429) were searched from inception through 2 April 2020 without language restrictions. Of 1766 retrieved reports, 18 studies met our inclusion criteria, including 17 prospective controlled studies and one retrospective study. CQ or HCQ were compared to control for the treatment of infectious mononucleosis (EBV, n = 4), warts (human papillomavirus, n = 2), chronic HIV infection (n = 6), acute chikungunya infection (n = 1), acute dengue virus infection (n = 2), chronic HCV (n = 2), and as preventive measures for influenza infection (n = 1). Survival was not evaluated in any study. For HIV, the virus that was most investigated, while two early studies suggested HCQ reduced viral levels, four subsequent ones did not, and in two of these CQ or HCQ increased viral levels and reduced CD4 counts. Overall, three studies concluded CQ or HCQ were effective; four concluded further research was needed to assess the treatments' effectiveness; and 11 concluded that treatment was ineffective or potentially harmful. Prior controlled clinical trials with CQ and HCQ for non‐SARS‐CoV2 viral infections do not support these agents' use for the SARS‐CoV2 outbreak.

The efficacy and safety of hydroxychloroquine for COVID-19 prophylaxis: A systematic review and meta-analysis of randomized trials

Article

Full-text available

Jan 2021
PLOS ONE

Background Populations such as healthcare workers (HCW) that are unable to practice physical distancing are at high risk of acquiring Coronavirus disease-2019 (COVID-19). In these cases pharmacological prophylaxis would be a solution to reduce severe acute respiratory syndrome coronavirus-2 (SARS CoV-2) transmission. Hydroxychloroquine has in vitro antiviral properties against SARS CoV-2. We therefore sought to determine the efficacy and safety of hydroxychloroquine as prophylaxis for COVID-19. Methods and findings We electronically searched EMBASE, MEDLINE, the Cochrane COVID-19 Register of Controlled Trials, Epistemonikos COVID-19, clinicaltrials.gov, and the World Health Organization International Clinical Trials Registry Platform up to September 28th, 2020 for randomized controlled trials (RCTs). We calculated pooled relative risks (RRs) for dichotomous outcomes with the corresponding 95% confidence intervals (CIs) using a random-effect model. We identified four RCTs (n = 4921) that met our eligibility criteria. The use of hydroxychloroquine, compared to placebo, did not reduce the risks of developing COVID-19 (RR 0.82, 95% CI 0.65 to 1.04, moderate certainty), hospitalization (RR 0.72, 95% CI 0.34 to 1.50, moderate certainty), or mortality (RR 3.26, 95% CI 0.13 to 79.74, low certainty), however, hydroxychloroquine use increased the risk of adverse events (RR 2.76, 95% CI 1.38 to 5.55, moderate certainty). Conclusion Although pharmacologic prophylaxis is an attractive preventive strategy against COVID-19, the current body of evidence failed to show clinical benefit for prophylactic hydroxychloroquine and showed a higher risk of adverse events when compared to placebo or no prophylaxis.

Dexamethasone in Hospitalized Patients with Covid-19 — Preliminary Report

Article

Jul 2020

Pilar Rivera Ortega

Background Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Here, we report the preliminary results of this comparison. Results A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.91 to 1.55). Conclusions In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. (Funded by the Medical Research Council and National Institute for Health Research and others; RECOVERY ClinicalTrials.gov number, NCT04381936; ISRCTN number, 50189673.)

COVID-19 in patients with Systemic Lupus Erythematosus: Lessons learned from the inflammatory disease

Article

Full-text available

Dec 2020
TRANSL RES

As the world navigates the Coronavirus disease 2019 (COVID-19) pandemic, there is a growing need to assess its impact in patients with autoimmune rheumatic diseases, such as systemic lupus erythematosus (SLE). Patients with SLE are a unique population when considering the risk of contracting COVID-19 and infection outcomes. The use of systemic glucocorticoids and immunosuppressants, and underlying organ damage from SLE are potential susceptibility factors. Most patients with SLE have evidence of high type I IFN activity, which may theoretically act as an antiviral line of defense or contribute to the development of a deleterious hyperinflammatory response in COVID-19. Other immunopathogenic mechanisms of SLE may overlap with those described in COVID-19, and thus studies in SLE could provide some insight into immune responses occurring in severe cases of the viral infection. We reviewed the literature to date on COVID-19 in patients with SLE and provide an in-depth review of current research in the area, including immune pathway activation, epidemiology, clinical features, outcomes, and the psychosocial impact of the pandemic in those with autoimmune disease.

Dengue prevention and treatment: a scoping review

Article

Dec 2024

Background and objectives: Dengue is an arbovirus with significant socioeconomic impact worldwide and in Brazil. This scenario led the Brazilian Ministry of Health to launch a preventive manual in 2009, and a treatment manual in 2016 to deal with this disease. Between the year of these publications and today, numerous therapeutic options emerged and were discussed in the literature. So, this independent research aims to investigate dengue treatment methods presented in the literature. Methods: A scoping review was forged following the Problem, Concept, and Context (PCC) strategy, following the guiding questions: “What methods for preventing dengue have been presented in scientific literature in the last 14 years?” “What methods for treating dengue have been presented in scientific literature in the last 8 years? The literature search was performed in PubMed, LILACS, Cochrane, and Scielo using the descriptors "Dengue AND Prevention" and "Dengue AND treatment". Results: Almost 18 thousand studies were evaluated. Of these, 7474 discussed dengue preventive measures, as only 17 were included in the final text. In parallel, 10.462 were focused on dengue treatment, as only 28 articles were included in the final text. Interpretation and conclusions: Numerous preventive and therapeutic measures have emerged in recent years; however, further comprehensive studies are imperative to substantiate their effectiveness on a large scale and assess their viability for widespread implementation. In this sense, vaccines and supportive measures, such as fluid therapy, remain primary interventions in dengue prevention and treatment, serving as cornerstones in mitigating the impact of this disease. KEY WORDS: Dengue; arboviroses; prevention; treatment; epidemiology.

Sensitive detection of chloroquine phosphate using a carbon paste electrode: Formation and stability of inclusion complexes with β-cyclodextrin

Article

Apr 2025

A Narrative Overview of Coronavirus Infection: Clinical Signs and Symptoms, Viral Entry and Replication, Treatment Modalities, and Management

Article

Apr 2024
CURR TOP MED CHEM

The global pandemic known as coronavirus disease (COVID-19) is causing morbidity and mortality on a daily basis. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV- -2) virus has been around since December 2019 and has infected a high number of patients due to its idiopathic pathophysiology and rapid transmission. COVID-19 is now deemed a newly identified “syndrome” condition since it causes a variety of unpleasant symptoms and systemic side effects following the pandemic. Simultaneously, it always becomes potentially hazardous when new variants develop during evolution. Its random viral etiology prevents accurate and suitable therapy. Despite the fact that multiple preclinical and research studies have been conducted to combat this lethal virus, and various therapeutic targets have been identified, the precise course of therapy remains uncertain. However, just a few drugs have shown efficacy in treating this viral infection in its early stages. Currently, several medicines and vaccinations have been licensed following clinical trial research, and many countries are competing to find the most potent and effective immunizations against this highly transmissible illness. For this narrative review, we used PubMed, Google Scholar, and Scopus to obtain epidemiological data, pre-clinical and clinical trial outcomes, and recent therapeutic alternatives for treating COVID-19 viral infection. In this study, we discussed the disease's origin, etiology, transmission, current advances in clinical diagnostic technologies, different new therapeutic targets, pathophysiology, and future therapy options for this devastating virus. Finally, this review delves further into the hype surrounding the SARS-CoV-2 illness, as well as present and potential COVID-19 therapies. Keywords: Viral infection, severe acute respiratory illness, Coronavirus-2, COVID-19, SARS-CoV variations, Remdesivir, immunization, and vaccine resistance

New methods for resolution of hydroxychloroquine by forming diastereomeric salt and adding chiral mobile phase agent on RP-HPLC

Article

May 2024
CHIRALITY

Hydroxychloroquine (HCQ), 2‐([4‐([7‐Chloro‐4‐quinolyl]amino)pentyl]ethylamino)ethanol, exhibited significant biological activity, while its side effects cannot be overlooked. The RP‐HPLC enantio‐separation was investigated for cost‐effective and convenient optical purity analysis of HCQ. The thermodynamic resolution of Rac‐HCQ, driven by enthalpy and entropy, was achieved on the C18 column using Carboxymethyl‐β‐cyclodextrin (CM‐β‐CD) as the chiral mobile phase agent (CMPA). The effects of C CM‐β‐CD , pH, and triethylamine (TEA) V% on the enantio‐separation process were explored. Under the optimum conditions at 24°C, the retention times for the two enantiomers were and , resulting in . The resolution via diastereomeric salt formation of Rac‐HCQ was developed to obtain the active pharmaceutical ingredient of single enantiomer S‐HCQ. Di‐p‐Anisoyl‐L‐Tartaric Acid (L‐DATA) was proved effective as the resolution agent for Rac‐HCQ. Surprisingly, it was found that refluxing time was a key fact affecting the resolution efficiency, which meant the kinetic dominate during the process of the resolution. Four factors—solvent volume, refluxing time, filtration temperature, and molar ratio—were optimized using the single‐factor method and the response surface method. Two cubic models were established, and the reliability was subsequently verified. Under the optimal conditions, the less soluble salt of 2L‐DATA:S‐HCQ was obtained with a yield of 96.9% and optical purity of 63.0%. The optical purity of this less soluble salt increases to 99.0% with a yield of 74.2% after three rounds recrystallization.

Mercuric-sulphide based metallopharmaceutical formulation as an alternative therapeutic to combat viral and multidrug-resistant (MDR) bacterial infections

Article

Full-text available

Oct 2023

According to the Global Antimicrobial Resistance and Use Surveillance System (GLASS) data, antibiotic resistance escalates more challenges in treatment against communicable diseases worldwide. Henceforth, the use of combinational antimicrobial therapy and metal-conjugated phytoconstituents composites are considered as alternatives. The present study explored the efficacy of mercuric-sulfide-based metallopharmaceutical, Sivanar Amirtham for anti-bacterial, anti-tuberculosis, anti-HIV therapeutics and toxicity profile by haemolytic assay, first of its kind. The anti-bacterial study was performed against both gram-positive and gram-negative pathogens including Staphylococcus aureus (ATCC 29213), Methicillin-resistant Staphylococcus aureus (MRSA: ATCC 43300), Enterococcus faecalis (ATCC 29212), Pseudomonas aeruginosa (PA14) and Vibrio cholerae (MTCC 3905) by agar well diffusion assay, wherein the highest zone of inhibition was identified for MRSA (20.7 mm) and V. cholerae (34.3 mm) at 25 mg/mL. Furthermore, the anti-tuberculosis activity experimented by microtitre alamar blue assay against M. tuberculosis (ATCC 27294) demonstrated significant activity at the concentration range of 12.5–100 µg/mL. Additionally, the anti-HIV efficacy established by the syncytia inhibition method using C8166 cell lines infected with HIV-1IIIB, showed a significant therapeutic effect. The in-vitro toxicity assay proved Sivanar Amirtham to be non-haemolytic and haemocompatible. The physicochemical characterization studies revealed the nano-sized particles with different functional groups and the distinctive metal–mineral complex could be attributed to the multi-site targeting ability. The rationale evidence and scientific validation for the efficacy of Sivanar Amirtham ensures that it could be proposed as an alternative or adjuvant for both prophylactics and therapeutics to overcome HIV infection and antimicrobial resistance as well as the multi-drug resistance challenges.

Experiencia del uso de cloroquina en pacientes con COVID-19

Article

Full-text available

Oct 2022

Exploring the Link Between Malaria and COVID-19

Chapter

Apr 2023

Orhan E. Arslan

Drug repurposing for SARS-CoV-2 (COVID-19) treatment

Chapter

Jan 2022

Drug repurposing involves the process of investigating already existing drugs with an aim to use them for different therapeutic purposes than the intended one. This approach is relatively faster, less costly, and reliable in terms of safety as the drug under study is already derisked and known for its other chemistry and pharmacokinetic properties. With these benefits in mind, it is a very reliable way to undertake drug development for emerging diseases such as COVID-19 which demand immediate interventions to slow or completely stop its havoc on mankind. One of the biggest challenges that drug repurposing has is the possibility of the occurrence of new mechanisms of action between the drug ligand and some proteins in the human physiology. Drug repurposing appears to have settled in the meantime in drug development, though more studies in the future will be warranted particularly in regards to resistance.

CORONAVIRUS DRUG DISCOVERY

Book

May 2022

Coronavirus Drug Discovery SARS-CoV-2 (COVID-19) Prevention, Diagnosis, and Treatment

The coronavirus global pandemic and its impacts on society

Chapter

May 2022

Various individuals, community organizations and institutions must be involved in planning and developing a cure for the COVID-19 flu pandemic. In addition to governmental organizations, those who need to be involved in the process are responsible for implementing pandemic plans. There should be a balance between centralized national control and regional and local communities through the effective implementation of the guidelines. There is a need to introduce social distancing and to study and isolate cases to contain disease spread. Due to the amendment and tightening of the law "SARS-CoV-2" in many countries, special attention should be paid to respect for citizens, especially national minorities. That is why it is necessary to protect freedom statements and providing access to critical information; make sure that quarantines, locks and travel bans comply with legal standards; persons.

Encefalitis como complicación neurológica por dengue

Article

Full-text available

Feb 2022
REV CHIL INFECTOL

We present the case of a 32-year-old male, previously healthy, with a 5-day history of fever, frontal-occipital headache, retro-ocular pain, rash, petechiae, myalgia, arthralgia, and abdominal pain. Blood tests with leukopenia, severe thrombocytopenia, transaminitis, long clotting times. Severe dengue with associated coagulopathy was diagnosed, indicating transfer to ICU. Presents torpid evolution, altered state of consciousness, psychomotor agitation, and aggressiveness. Structural, ischemic-hemorrhagic alterations, bacterial and fungal infections were ruled out. Finally diagnosing dengue encephalitis, confirmed by DENV PCR in CSF. Support measures are provided with favorable evolution. Encephalitis is the most serious neurological complication after dengue virus infection.

The antimicrobial and immunomodulatory effects of Ionophores for the treatment of human infection

Article

Nov 2021
J INORG BIOCHEM

Ionophores are a diverse class of synthetic and naturally occurring ion transporter compounds which demonstrate both direct and in-direct antimicrobial properties against a broad panel of bacterial, fungal, viral and parasitic pathogens. In addition, ionophores can regulate the host-immune response during communicable and non-communicable disease states. Although the clinical use of ionophores such as Amphotericin B, Bedaquiline and Ivermectin highlight the utility of ionophores in modern medicine, for many other ionophore compounds issues surrounding toxicity, bioavailability or lack of in vivo efficacy studies have hindered clinical development. The antimicrobial and immunomodulating properties of a range of compounds with characteristics of ionophores remain largely unexplored. As such, ionophores remain a latent therapeutic avenue to address both the global burden of antimicrobial resistance, and the unmet clinical need for new antimicrobial therapies. This review will provide an overview of the broad-spectrum antimicrobial and immunomodulatory properties of ionophores, and their potential uses in clinical medicine for combatting infection.

Binding of Chloroquine to Whey Protein Relieves Its Cytotoxicity while Enhancing Its Uptake by Cells

Article

Aug 2021

Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

Article

Full-text available

Jul 2021

A virus outbreak challenges the economic, medical and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure-activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2. This article is protected by copyright. All rights reserved.

Persistent Joint Pain Following Arthropod Virus Infections

Article

Full-text available

Apr 2021
Curr Rheumatol Rep

Purpose of Review Persistent joint pain is a common manifestation of arthropod-borne viral infections and can cause long-term disability. We review the epidemiology, pathophysiology, diagnosis, and management of arthritogenic alphavirus infection. Recent findings The global re-emergence of alphaviral outbreaks has led to an increase in virus-induced arthralgia and arthritis. Alphaviruses, including Chikungunya, O’nyong’nyong, Sindbis, Barmah Forest, Ross River, and Mayaro viruses, are associated with acute and/or chronic rheumatic symptoms. Identification of Mxra8 as a viral entry receptor in the alphaviral replication pathway creates opportunities for treatment and prevention. Recent evidence suggesting virus does not persist in synovial fluid during chronic chikungunya infection indicates that immunomodulators may be given safely. Summary The etiology of persistent joint pain after alphavirus infection is still poorly understood. New diagnostic tools along and evidence-based treatment could significantly improve morbidity and long-term disability.

DRUG REPURPOSING: IN SILICO MODELING OF COVID-19

Article

Full-text available

Mar 2021
RJPBCS

By and by the world is in a battle with the novel Covid and with no prompt medicines accessible the scourge brought about by the SARS-CoV-2 is expanding step by step. A ton of researchers are continuing for the potential medication up-and-comer that could help the medical care framework in this battle. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds that are Remdesivir, Hydroxy-chloroquine, Curcumin, Moroxydine, Artesunate Sulphate, Quercetin, Amantadine, Zanamivir, Umifenovir, Tipranavir, Indinavir with SARS-CoV-2 Mpro Proteins with PDB id's 6LU7, 6WTT, 7BQY. could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

Structural insights into SARS‑CoV‑2 spike protein and its natural mutants found in Mexican population

Article

Full-text available

Feb 2021

The severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a newly emerged coronavirus responsible for coronavirus disease 2019 (COVID‑19); it become a pandemic since March 2020. To date, there have been described three lineages of SARS‑CoV‑2 circulating worldwide, two of them are found among Mexican population, within these, we observed three mutations of spike (S) protein located at amino acids H49Y, D614G, and T573I. To understand if these mutations could affect the structural behavior of S protein of SARS‑CoV‑2, as well as the binding with S protein inhibitors (cepharanthine, nelfinavir, and hydroxychloroquine), molecular dynamic simulations and molecular docking were employed. It was found that these punctual mutations affect considerably the structural behavior of the S protein compared to wild type, which also affect the binding of its inhibitors into their respective binding site. Thus, further experimental studies are needed to explore if these affectations have an impact on drug‑S protein binding and its possible clinical effect

A Meta-Review of Meta-Analyses and an Updated Meta-Analysis on the Efficacy of Chloroquine and Hydroxychloroquine in treating COVID-19 Infection

Conference Paper

Full-text available

Oct 2020

Objective: To synthesize the findings presented in systematic reviews and meta-analyses as well as to update the evidence using a meta-analysis in evaluating the efficacy and safety of CQ and HCQ with or without Azithromycin for the treatment of COVID-19 infection. Methods: The design of this meta-review followed the preferred reporting items for overviews of systematic reviews including harms checklist (PRIO-harms). A comprehensive search included several electronic databases in identifying all systematic reviews and meta-analyses as well as experimental studies which investigated the efficacy and safety of CQ, HCQ with or without antibiotics as COVID-19 treatment. Findings from the systematic reviews and metaanalyses were reported using a structured summary including tables and forest plots. The updated metaanalyses of experimental studies was carried out using the distributional assumption-free quality effects model. Risk of bias was assessed using the assessing the methodological quality of systematic reviews (AMSTAR) tool for reviews and the methodological standard for epidemiological research (MASTER) scale for the experimental studies. The main outcome for both the meta-review and the updated metaanalyses was mortality. Secondary outcomes included transfer to the intensive care unit (ICU) or mechanical ventilation, worsening of illness, viral clearance and the occurrence of adverse events. Results: A total of 13 reviews with 40 primary studies comprising 113,000 participants were included. Most of the primary studies were observational (n=27) and the rest were experimental studies. Two meta-analyses reported a high risk of mortality with similar ORs of 2.5 for HCQ with Azithromycin. However, four other metaanalyses reported contradictory results with two reporting a high risk of mortality and the other two reporting no significant association between HCQ with mortality. Most reviews reported that HCQ with or without Azithromycin had no significant effect on virological cure, disease exacerbation or the risk of transfer to the ICU, need for intubation or mechanical ventilation. After exclusion of studies that did not meet the eligibility criteria, the updated meta-analysis contained eight experimental studies (7 RCTs and 1 quasiexperimental trial), with a total of 5279 participants of whom 1856 were on either CQ/HCQ or combined with Azithromycin. CQ/HCQ with or without Azithromycin was significantly associated with a higher risk of adverse events. HCQ was not effective in reducing mortality transfer to the ICU, intubation or need for mechanical ventilation virological cure (RR 1.0, 95%CI 0.9-1.2, I2 =55%, n=5 studies) nor disease exacerbation (RR 1.2, 95%CI 0.3-5.0, I2 =29%, n=3 studies). Conclusion: There is conclusive evidence that CQ and HCQ, with or without Azithromycin are not effective in treating COVID-19 or its exacerbation.

A pilot study of hydroxychloroquine in treatment of patients with moderate COVID-19

Article

Full-text available

May 2020

Objective: To evaluate the efficacy and safety of hydroxychloroquine (HCQ) in the treatment of patients with moderate coronavirus disease 2019 (COVID-19). Methods: We prospectively enrolled 30 treatment-naïve patients with confirmed COVID-19 after informed consent at Shanghai Public Health Clinical Center. The patients were randomized 1：1 to HCQ group and the control group. Patients in HCQ group were given HCQ 400 mg per day for 5 days plus conventional treatments, while those in the control group were given conventional treatment only. The primary endpoint was negative conversion rate of SARS-CoV-2 nucleic acid in respiratory pharyngeal swab on days 7 after randomization. This study has been approved by the Ethics Committee of Shanghai Public Health Clinical Center and registered online (NCT04261517). Results: One patient in HCQ group developed to severe during the treatment. On day 7, nucleic acid of throat swabs was negative in 13 (86.7%) cases in the HCQ group and 14 (93.3%) cases in the control group (P>0.05). The median duration from hospitalization to virus nucleic acid negative conservation was 4 (1,9) days in HCQ group, which is comparable to that in the control group [2 (1,4) days, Z=1.27, P>0.05]. The median time for body temperature normalization in HCQ group was 1 (0,2) day after hospitalization, which was also comparable to that in the control group [1 (0,3) day]. Radiological progression was shown on CT images in 5 cases (33.3%) of the HCQ group and 7 cases (46.7%) of the control group, and all patients showed improvement in follow-up examinations. Four cases (26.7%) of the HCQ group and 3 cases (20%) of the control group had transient diarrhea and abnormal liver function (P>0.05). Conclusions: The prognosis of COVID-19 moderate patients is good. Larger sample size study are needed to investigate the effects of HCQ in the treatment of COVID-19. Subsequent research should determine better endpoint and fully consider the feasibility of experiments such as sample size.

Effect of High vs Low Doses of Chloroquine Diphosphate as Adjunctive Therapy for Patients Hospitalized With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection A Randomized Clinical Trial

Article

Full-text available

Apr 2020

Importance There is no specific antiviral therapy recommended for coronavirus disease 2019 (COVID-19). In vitro studies indicate that the antiviral effect of chloroquine diphosphate (CQ) requires a high concentration of the drug. Objective To evaluate the safety and efficacy of 2 CQ dosages in patients with severe COVID-19. Design, Setting, and Participants This parallel, double-masked, randomized, phase IIb clinical trial with 81 adult patients who were hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection was conducted from March 23 to April 5, 2020, at a tertiary care facility in Manaus, Brazilian Amazon. Interventions Patients were allocated to receive high-dosage CQ (ie, 600 mg CQ twice daily for 10 days) or low-dosage CQ (ie, 450 mg twice daily on day 1 and once daily for 4 days). Main Outcomes and Measures Primary outcome was reduction in lethality by at least 50% in the high-dosage group compared with the low-dosage group. Data presented here refer primarily to safety and lethality outcomes during treatment on day 13. Secondary end points included participant clinical status, laboratory examinations, and electrocardiogram results. Outcomes will be presented to day 28. Viral respiratory secretion RNA detection was performed on days 0 and 4. Results Out of a predefined sample size of 440 patients, 81 were enrolled (41 [50.6%] to high-dosage group and 40 [49.4%] to low-dosage group). Enrolled patients had a mean (SD) age of 51.1 (13.9) years, and most (60 [75.3%]) were men. Older age (mean [SD] age, 54.7 [13.7] years vs 47.4 [13.3] years) and more heart disease (5 of 28 [17.9%] vs 0) were seen in the high-dose group. Viral RNA was detected in 31 of 40 (77.5%) and 31 of 41 (75.6%) patients in the low-dosage and high-dosage groups, respectively. Lethality until day 13 was 39.0% in the high-dosage group (16 of 41) and 15.0% in the low-dosage group (6 of 40). The high-dosage group presented more instance of QTc interval greater than 500 milliseconds (7 of 37 [18.9%]) compared with the low-dosage group (4 of 36 [11.1%]). Respiratory secretion at day 4 was negative in only 6 of 27 patients (22.2%). Conclusions and Relevance The preliminary findings of this study suggest that the higher CQ dosage should not be recommended for critically ill patients with COVID-19 because of its potential safety hazards, especially when taken concurrently with azithromycin and oseltamivir. These findings cannot be extrapolated to patients with nonsevere COVID-19. Trial Registration ClinicalTrials.gov Identifier: NCT04323527

Treating COVID-19 with Chloroquine

Article

Full-text available

Apr 2020

Hydroxychloroquine Inhibits Zika Virus NS2B-NS3 Protease

Article

Full-text available

Dec 2018

Zika virus is a mosquito-transmitted flavivirus that causes devastating fetal outcomes in the context of maternal infection during pregnancy. An important target for drugs combatting Zika virus pathogenicity is NS2B-NS3 protease, which plays an essential role in hydrolysis and maturation of the flavivirus polyprotein. We identify hydroxychloroquine, a drug that already has approved uses in pregnancy, as a possible inhibitor of NS2B-NS3 protease by using a Food and Drug Administration-approved drug library, molecular docking, and molecular dynamics simulations. Further, to gain insight into its inhibitory potential toward NS2B-NS3 protease, we performed enzyme kinetic studies, which revealed that hydroxychloroquine inhibits protease activity with an inhibition constant (Ki) of 92.34 ± 11.91 μM. Additionally, hydroxychloroquine significantly decreases Zika virus infection in placental cells.

Paradoxical Effect of Chloroquine Treatment in Enhancing Chikungunya Virus Infection

Article

Full-text available

May 2018

Since 2005, Chikungunya virus (CHIKV) re-emerged and caused numerous outbreaks in the world, and finally, was introduced into the Americas in 2013. The lack of CHIKV-specific therapies has led to the use of non-specific drugs. Chloroquine, which is commonly used to treat febrile illnesses in the tropics, has been shown to inhibit CHIKV replication in vitro. To assess the in vivo effect of chloroquine, two complementary studies were performed: (i) a prophylactic study in a non-human primate model (NHP); and (ii) a curative study “CuraChik”, which was performed during the Reunion Island outbreak in 2006 in a human cohort. Clinical, biological, and immunological data were compared between treated and placebo groups. Acute CHIKV infection was exacerbated in NHPs treated with prophylactic administration of chloroquine. These NHPs displayed a higher viremia and slower viral clearance (p < 0.003). Magnitude of viremia was correlated to the type I IFN response (Rho = 0.8, p < 0.001) and severe lymphopenia (Rho = 0.8, p < 0.0001), while treatment led to a delay in both CHIKV-specific cellular and IgM responses (p < 0.02 and p = 0.04, respectively). In humans, chloroquine treatment did not affect viremia or clinical parameters during the acute stage of the disease (D1 to D14), but affected the levels of C-reactive Protein (CRP), IFNα, IL-6, and MCP1 over time (D1 to D16). Importantly, no positive effect could be detected on prevalence of persistent arthralgia at Day 300. Although inhibitory in vitro, chloroquine as a prophylactic treatment in NHPs enhances CHIKV replication and delays cellular and humoral response. In patients, curative chloroquine treatment during the acute phase decreases the levels of key cytokines, and thus may delay adaptive immune responses, as observed in NHPs, without any suppressive effect on peripheral viral load.

Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis

Article

Full-text available

Nov 2017

One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission. Here, we show that interferon signalling-competent SJL mice support chronic ZIKV infection. Infected dams and sires are both able to transmit ZIKV to the offspring, making this an ideal model for in vivo validation of compounds shown to suppress ZIKV in cell culture. Administration of CQ to ZIKV-infected pregnant SJL mice during mid-late gestation significantly attenuated vertical transmission, reducing the ZIKV load in the foetal brain more than 20-fold. Given the limited side effects of CQ, its lack of contraindications in pregnant women, and its worldwide availability and low cost, we suggest that CQ could be considered for the treatment and prophylaxis of ZIKV.

ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions

Article

Full-text available

Oct 2016
Br Med J

Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I ("Risk Of Bias In Non-randomised Studies-of Interventions"), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.

Efficacy of combination DMARD therapy vs. hydroxychloroquine monotherapy in chronic persistent chikungunya arthritis: a 24-week randomized controlled open label study

Article

Full-text available

Oct 2016

In a proportion of patients, chikungunya arthritis (CA) might run into a chronic persistent phase. The treatment for this phase is not very clear. In this randomized parallel group open label study of 24 weeks duration, we evaluated the efficacy of DMARD combination in persistent CA. Consecutive 139 patients with persistent CA (persistent arthritis for >1 year after the chikungunya fever either in 2008 or 2009 fulfilling epidemiological criteria for CA) were screened. Of these patients who were already taking hydroxychloroquine (HCQ) and had active arthritis were randomized to receive either fixed-dose combination therapy (methotrexate 15 mg/day, sulfasalazine 1 g/day, and HCQ 400 mg/day) or continue with HCQ 400 mg/day (dose optimized) monotherapy. Both groups received oral prednisolone up to 6 weeks. Assessments at every 4 weeks were carried out for primary efficacy (disease activity score; DAS ESR 28) and secondary efficacies, HAQ—Indian version and pain VAS100mm. Seventy-two patients were randomized (37 combination therapy, 35 monotherapy). Both groups were well matched in all respects. At 24 weeks, the combination therapy group showed significant improvement in both disease activity (mean ± SD DAS28; 3.39 ± 0.87 vs. 4.74 ± 0.65, p < 0.0001) and disability (mean ± SD HAQ; 1.4 ± 0.31 vs. 1.88 ± 0.47, p < 0.0001). At the study end, pain VAS was significantly less in the combination therapy group (46 ± 6.13 vs. 60.8 ± 11.6, p < 0.0001). Three patients withdrew from the combination group (inefficacy; 2, adverse event; 1) and seven from monotherapy (inefficacy; 7). This study provide evidence that for chronic persistent CA combination DMARD therapy with methotrexate, sulfasalazine and HCQ is superior to monotherapy with HCQ.

Hydroxychloroquine augments early virological response to pegylated interferon plus ribavirin in genotype-4 chronic hepatitis C patients: Early Virological Response to HCQ, IFN, and RBV

Article

Full-text available

May 2016

Introduction: The therapeutic effect of pegylated interferon (peg-IFN) alfa-2a combined with ribavirin (RBV) on chronic hepatitis C Egyptian patients is low and further efforts are required to optimize this therapy for achievement of higher rates of virological response. This study aimed to evaluate the safety and efficacy of hydroxychloroquine (HCQ) in combination with pegylated interferon plus ribavirin on early virological response (EVR) in chronic hepatitis C Egyptian patients. Methods: Naïve 120 Egyptian patients with chronic hepatitis C virus infection were divided into two groups. Group 1 have administered the standard of care therapy (pegylated interferon alfa-2a plus ribavirin) for 12 weeks, (n= 60). Group 2 have administered hydroxychloroquine plus standard of care therapy for 12 weeks, (n = 60). Therapeutics included hydroxychloroquine (200 mg) oral twice daily, peginterferon alfa-2a (160 ug) subcutaneous once weekly and oral weight-based ribavirin (1000-1200 mg/day). Results: Baseline characteristics were similar in the two groups. The percentage of early virological response was significantly more in patients given the triple therapy than in patients given the standard of care [54/60 (90%) vs 43/60 (71.7%); P = 0.011; respectively]. Biochemical response at week 12 was also significantly higher in patients given the triple therapy compared with the standard of care [58/60 (96.7%) vs 42/60 (70%); P <0.001; respectively]. Along the study, the observed adverse events were mild and similar across treatment groups. Conclusions: Addition of hydroxychloroquine to pegylated interferon plus ribavirin improves the rate of early virological and biochemical responses in chronic hepatitis C Egyptian patients without an increase in adverse events. This article is protected by copyright. All rights reserved.

Chloroquine could be used for the treatment of filoviral infections and other viral infections that emerge or emerged from viruses requiring an acidic pH for infectivity

Article

Full-text available

Mar 2016

Hephzibah J E Akpovwa

Viruses from the Filoviridae family, as many other virus families, require an acidic pH for successful infection and are therefore susceptible to the actions of 4‐aminoquinolines, such as chloroquine. Although the mechanisms of action of chloroquine clearly indicate that it might inhibit filoviral infections, several clinical trials that attempted to use chloroquine in the treatment of other acute viral infections – including dengue and influenza A and B – caused by low pH‐dependent viruses, have reported that chloroquine had no clinical efficacy, and these results demoted chloroquine from the potential treatments for other virus families requiring low pH for infectivity. The present review is aimed at investigating whether chloroquine could combat the present Ebola virus epidemic, and also at exploring the main reasons for the reported lack of efficacy. Literature was sourced from PubMed, Scopus, Google Scholar, reference list of articles and textbooks – Fields Virology (Volumes 1and 2), the cytokine handbook, Pharmacology in Medicine: Principles and Practice, and hydroxychloroquine and chloroquine retinopathy. The present analysis concludes that (1) chloroquine might find a place in the treatment of Ebola, either as a monotherapy or in combination therapies; (2) the ineffectiveness of chloroquine, or its analogue, hydroxychloroquine, at treating infections from low pH‐dependent viruses is a result of the failure to attain and sustain a steady state concentration sufficient to increase and keep the pH of the acidic organelles to approximately neutral levels; (3) to successfully treat filoviral infections – or other viral infections that emerge or emerged from low pH‐dependent viruses – a steady state chloroquine plasma concentration of at least 1 µg/mL(~3.125 μM/L) or a whole blood concentration of 16 μM/L must be achieved and be sustained until the patients' viraemia becomes undetectable. These concentrations, however, do not rule out the efficacy of other, higher, steady state concentrations – although such concentrations might be accompanied by severe adverse effects or toxicities. The feasibility of the conclusion in the preceding texts has recently been supported by a subsequent study that shows that amodiaquine, a derivative of CQ, is able to protect humans infected with Ebola from death.

New use of an old drug: chloroquine reduces viral and ALT levels in HCV non-responders (a randomized, triple-blind, placebo-controlled pilot trial)

Article

Full-text available

Jan 2016

Hepatitis C virus (HCV) infection induces autophagy, but the virus assimilates the autophagic response into its own life cycle. Chloroquine (CQ) is an autophagy inhibitor that is clinically used to treat malaria. The aims of this pilot clinical trial were to evaluate the therapeutic potential and short-term safety of CQ in patients with chronic HCV genotype 1, who were unresponsive to a combination of pegylated interferon alpha and ribavirin. Ten non-responders to previous antiviral treatment(s) were randomized to receive either CQ (150 mg daily for 8 weeks) or placebo, and were followed for 4 weeks after CQ therapy. HCV RNA load and plasma alanine transaminase (ALT) levels were measured at baseline, week 4 (initial response), week 8 (end-of-treatment response), and at the end of 12 weeks. A significant decrease in HCV RNA after the treatments (week 8) was observed in all patients in the CQ group (P = 0.04). However, HCV RNA levels increased within 4 weeks after discontinuation of CQ treatment although they were still lower than baseline. In addition, the ALT normalized during treatment in the CQ group. However, this response was also lost after treatment cessation. This study provides preliminary evidence that CQ is possibly a safe treatment option for HCV non-responders.

Antiviral therapies against Ebola and other emerging viral diseases using existing medicines that block virus entry

Article

Full-text available

Jan 2015

Emerging viral diseases pose a threat to the global population as intervention strategies are mainly limited to basic containment due to the lack of efficacious and approved vaccines and antiviral drugs. The former was the only available intervention when the current unprecedented Ebolavirus (EBOV) outbreak in West Africa began. Prior to this, the development of EBOV vaccines and anti-viral therapies required time and resources that were not available. Therefore, focus has turned to re-purposing of existing, licenced medicines that may limit the morbidity and mortality rates of EBOV and could be used immediately. Here we test three such medicines and measure their ability to inhibit pseudotype viruses (PVs) of two EBOV species, Marburg virus (MARV) and avian influenza H5 (FLU-H5). We confirm the ability of chloroquine (CQ) to inhibit viral entry in a pH specific manner. The commonly used proton pump inhibitors, Omeprazole and Esomeprazole were also able to inhibit entry of all PVs tested but at higher drug concentrations than may be achieved . We in vivo propose CQ as a priority candidate to consider for treatment of EBOV.

Chloroquine use improves dengue-related symptoms

Article

Full-text available

Aug 2013

Dengue is the most important arboviral disease in the world. As chloroquine, an antimalarial agent, has shown some antiviral effects, this study evaluated its effect in patients with dengue. A randomised, double-blind study was performed by administering chloroquine or placebo for three days to 129 patients with dengue-related symptoms. Of these patients, 37 were confirmed as having dengue and completed the study; in total, 19 dengue patients received chloroquine and 18 received placebo. There was no significant difference in the duration of the disease or the degree and days of fever. However, 12 patients (63%) with confirmed dengue reported a substantial decrease in pain intensity and a great improvement in their ability to perform daily activities (p = 0.0004) while on the medication and the symptoms returned immediately after these patients stopped taking the medication. The same effect was not observed in patients with diseases other than dengue. Therefore, this study shows that patients with dengue treated with chloroquine had an improvement in their quality of life and were able to resume their daily activities. However, as chloroquine did not alter the duration of the disease or the intensity and days of fever, further studies are necessary to confirm the clinical effects and to assess the side effects of chloroquine in dengue patients.

Reduction of Immune Activation with Chloroquine Therapy during Chronic HIV Infection

Article

Full-text available

Jan 2010
J VIROL

Increased levels of activated T cells are a hallmark of the chronic stage of human immunodeficiency virus (HIV) infection and are highly correlated with HIV disease progression. We evaluated chloroquine (CQ) as a potential therapy to reduce immune activation during HIV infection. We found that the frequency of CD38+ HLA-DR+ CD8 T cells, as well as Ki-67 expression in CD8 and CD4 T cells, was significantly reduced during CQ treatment. Our data indicate that treatment with CQ reduces systemic T-cell immune activation and, thus, that its use may be beneficial for certain groups of HIV-infected individuals.

A Randomized Controlled Trial of Chloroquine for the Treatment of Dengue in Vietnamese Adults

Article

Full-text available

Aug 2010
PLOS NEGLECT TROP D

There is currently no licensed antiviral drug for treatment of dengue. Chloroquine (CQ) inhibits the replication of dengue virus (DENV) in vitro. A double-blind, randomized, placebo-controlled trial of CQ in 307 adults hospitalized for suspected DENV infection was conducted at the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam) between May 2007 and July 2008. Patients with illness histories of 72 hours or less were randomized to a 3-day course of CQ (n = 153) or placebo (n = 154). Laboratory-confirmation of DENV infection was made in 257 (84%) patients. The primary endpoints were time to resolution of DENV viraemia and time to resolution of DENV NS1 antigenaemia. In patients treated with CQ there was a trend toward a longer duration of DENV viraemia (hazard ratio (HR) = 0.80, 95% CI 0.62-1.05), but we did not find any difference for the time to resolution of NS1 antigenaemia (HR = 1.07, 95% CI 0.76-1.51). Interestingly, CQ was associated with a significant reduction in fever clearance time in the intention-to-treat population (HR = 1.37, 95% CI 1.08-1.74) but not in the per-protocol population. There was also a trend towards a lower incidence of dengue hemorrhagic fever (odds ratio = 0.60, PP 95% CI 0.34-1.04) in patients treated with CQ. Differences in levels of T cell activation or pro- or anti-inflammatory plasma cytokine concentrations between CQ- and placebo-treated patients did not explain the trend towards less dengue hemorrhagic fever in the CQ arm. CQ was associated with significantly more adverse events, primarily vomiting. CQ does not reduce the durations of viraemia and NS1 antigenaemia in dengue patients. Further trials, with appropriate endpoints, would be required to determine if CQ treatment has any clinical benefit in dengue. Current Controlled Trials number ISRCTN38002730.

Effects of chloroquine on viral infections: An old drug against today's diseases?

Article

Full-text available

Dec 2003
LANCET INFECT DIS

Chloroquine is a 9-aminoquinoline known since 1934. Apart from its well-known antimalarial effects, the drug has interesting biochemical properties that might be applied against some viral infections. Chloroquine exerts direct antiviral effects, inhibiting pH-dependent steps of the replication of several viruses including members of the flaviviruses, retroviruses, and coronaviruses. Its best-studied effects are those against HIV replication, which are being tested in clinical trials. Moreover, chloroquine has immunomodulatory effects, suppressing the production/release of tumour necrosis factor alpha and interleukin 6, which mediate the inflammatory complications of several viral diseases. We review the available information on the effects of chloroquine on viral infections, raising the question of whether this old drug may experience a revival in the clinical management of viral diseases such as AIDS and severe acute respiratory syndrome, which afflict mankind in the era of globalisation.

Chloroquine is a potent inhibitor of SARS coronavirus infection and spread

Article

Full-text available

Sep 2005
VIROL J

Severe acute respiratory syndrome (SARS) is caused by a newly discovered coronavirus (SARS-CoV). No effective prophylactic or post-exposure therapy is currently available. We report, however, that chloroquine has strong antiviral effects on SARS-CoV infection of primate cells. These inhibitory effects are observed when the cells are treated with the drug either before or after exposure to the virus, suggesting both prophylactic and therapeutic advantage. In addition to the well-known functions of chloroquine such as elevations of endosomal pH, the drug appears to interfere with terminal glycosylation of the cellular receptor, angiotensin-converting enzyme 2. This may negatively influence the virus-receptor binding and abrogate the infection, with further ramifications by the elevation of vesicular pH, resulting in the inhibition of infection and spread of SARS CoV at clinically admissible concentrations. Chloroquine is effective in preventing the spread of SARS CoV in cell culture. Favorable inhibition of virus spread was observed when the cells were either treated with chloroquine prior to or after SARS CoV infection. In addition, the indirect immunofluorescence assay described herein represents a simple and rapid method for screening SARS-CoV antiviral compounds.

New insights into the antiviral effects of Chloroquine

Article

Full-text available

Mar 2006
LANCET INFECT DIS

In a paper published 2 years ago in this journal some of us described the potentially therapeutic benefits of the quinoline antimalarial chloroquine in viral diseases such as HIV-1/AIDS and severe acute respiratory syndrome (SARS). Chloroquine/hydroxychloroquine has since been adopted to treat HIV-1-infected patients in clinical trials and new insights into its antiviral activity have been obtained from in-vitro studies. On the HIV/AIDS front chloroquine (250 mg twice daily) has been administered to HIV-1-infected patients with baseline viral loads over 50 000 copies per mL in combination with lamivudine (150 mg twice daily) and hydroxyurea (500 mg twice daily) in an ongoing clinical trial in India. Ten out of 18 volunteers had an undetectable viral load at week 24.2 The median drop in viral load was more than 2.0 log more than the median 1.5 log drop seen with a nucleoside reverse transcriptase inhibitor (NRTI) and hydroxyurea alone. (excerpt)

Therapeutic potential of chloroquine added to zidovudine plus didanosine for HIV-1 infected children

Article

Full-text available

Sep 2006

To evaluate the efficacy and safety of CHQ in a combination treatment with ZDV/ddI in HIV-1-infected children. Fifty five HIV-infected children were randomly enrolled into 3 treatment groups: (I) ZDV + ddI (n = 25); and (II) ZDV + ddI + CHQ (n = 21); and (III) ZDV + ddI experienced children were non-randomly added CHQ (n = 9). Weight, CD4+ T-lymphocytes and plasma HIV-RNA were measured at weeks 0, 8 and 24. Fifteen, 16 and 8 children from Groups I, II and III were evaluated. No significant improvement in the mean Z-score for weight in groups I and II, but a decrease occurred in group III after 6 months of therapy. In group I, II and III, the respective change in the mean CD4+ T-lymphocyte percentage was +6.7, +4.0 and -0.6. The decrease in the plasma HIV-RNA log was 0.9, 1.1 and 0.7, respectively. There was a trend for more nausea/vomiting in group II/III and more opportunistic infections in group III. 1. The addition of chloroquine in ZDV/ddI regimen provided no significant improvement in clinical, immunological and virological parameters. 2. Chloroquine induced immunosuppression and nausea complicated its use.

GRADE: An emerging consensus on rating quality of evidence and strength of recommendations

Article

Full-text available

May 2008
Br Med J

Guidelines are inconsistent in how they rate the quality of evidence and the strength of recommendations. This article explores the advantages of the GRADE system, which is increasingly being adopted by organisations worldwide Summary points Failure to consider the quality of evidence can lead to misguided recommendations; hormone replacement therapy for post-menopausal women provides an instructive example High quality evidence that an intervention’s desirable effects are clearly greater than its undesirable effects, or are clearly not, warrants a strong recommendationUncertainty about the trade-offs (because of low quality evidence or because the desirable and undesirable effects are closely balanced) warrants a weak recommendationGuidelines should inform clinicians what the quality of the underlying evidence is and whether recommendations are strong or weakThe Grading of Recommendations Assessment, Development and Evaluation (GRADE ) approach provides a system for rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic and is increasingly being adopted by organisations worldwideGuideline developers around the world are inconsistent in how they rate quality of evidence and grade strength of recommendations. As a result, guideline users face challenges in understanding the messages that grading systems try to communicate. Since 2006 the BMJ has requested in its “Instructions to Authors” on bmj.com that authors should preferably use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence when submitting a clinical guidelines article. What was behind this decision?In this first in a series of five articles we will explain why many organisations use formal systems to grade evidence and recommendations and why this is important for clinicians; we will focus on the GRADE approach to recommendations. In the next two articles we will examine how the GRADE system categorises quality of evidence and strength of recommendations. The final two articles will …

Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19

Article

Jun 2020

Background Despite limited and conflicting evidence, hydroxychloroquine, alone or in combination with azithromycin, is widely used in COVID-19 therapy. Methods We performed a retrospective study of electronic health records of patients hospitalized with confirmed SARS-CoV-2 infection in United States Veterans Health Administration medical centers between March 9, 2020 and April 29, 2020. Patients hospitalized within 24 hours of diagnosis were classified based on their exposure to hydroxychloroquine alone (HC) or with azithromycin (HC+AZ) or no HC as treatments. The primary outcomes were mortality and use of mechanical ventilation. Findings A total of 807 patients were evaluated. Compared to the no HC group, after propensity score adjustment for clinical characteristics, the risk of death from any cause was higher in the HC group (adjusted hazard ratio (aHR), 1.83; 95% CI, 1.16 to 2.89; P=0.009) but not in the HC+AZ group (aHR, 1.31; 95% CI, 0.80 to 2.15; P=0.28). Both the propensity score-adjusted risks of mechanical ventilation and death after mechanical ventilation were not significantly different in the HC group (aHR, 1.19; 95% CI, 0.78 to 1.82; P=0.42 and aHR, 2.11; 95% CI, 0.96 to 4.62; P=0.06, respectively) or in the HC+AZ group (aHR, 1.09; 95% CI, 0.72 to 1.66; P=0.69 and aHR, 1.25; 95% CI, 0.59 to 2.68; P=0.56, respectively), compared to the no HC group. Conclusions Among patients hospitalized with COVID-19, this retrospective study did not identify any significant reduction in mortality or in the need for mechanical ventilation with hydroxychloroquine treatment with or without azithromycin. Funding University of Virginia Strategic Investment Fund.

Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

Article

Mar 2020
INT J ANTIMICROB AG

Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.

Antimalarial drugs and their metabolites are potent Zika virus inhibitors: HAN et al.

Article

Feb 2019

Studies aimed at repurposing existing drugs revealed that some antimalarial compounds possess anti‐Zika virus (ZIKV) activity. Here, we further tested fourteen additional antimalarial drugs and their metabolites or analogs for anti‐ZIKV activity using a phenotypic screening approach. We identified four compounds with varying anti‐ZIKV activity, including a metabolite of amodiaquine termed desethylamodiaquine (DAQ) and desethylchloroquine (DECQ), a metabolite of chloroquine, which both exhibited low micromolar effective concentrations against three different ZIKV strains. Two other compounds termed dihydroartemisinin (DHA) and quinidine (QD) exhibited only partial inhibition of ZIKV replication. Characterization of the inhibitory mechanisms of DAQ and DECQ showed that both drugs target the entry step as well as post‐entry events of the viral replication cycle. These hits represent attractive starting points for future optimization of new anti‐ZIKV drug candidates derived from antimalarial drugs and their analogs. This article is protected by copyright. All rights reserved.

Direct antiviral agents (DAAs) - A new age in the treatment of hepatitis C virus infection

Article

Oct 2017
PHARMACOL THERAPEUT

Ulrich Spengler

Hepatitis C virus (HCV) is a global health problem, because infection frequently leads to chronic hepatitis C eventually progressing to liver cirrhosis and liver cancer. Improved insights into the HCV replication cycle and the role of HCV non-structural proteins has recently enabled to identify drugs directly acting on specific HCV target structures. Agents from three drug classes have been developed and approved by the health authorities. Combinations of two or more drugs from different classes achieve high (>90%) HCV clearance rates and are well tolerated. This interferon-free DAA (direct antiviral agent) therapy has revolutionized antiviral therapy in hepatitis C so that successful hepatitis C treatment can be offered to virtually all patients irrespective of their co-morbidity. This review provides an overview over currently approved regimens and outlines their use in clinical practice. In addition potential short-comings of the current therapeutic options such as drug-drug interactions and selection of viral resistance are addressed. DAA combination therapy has the potential to obtain global control over hepatitis C. However, easy access to DAAs, availability of reliable HCV diagnostics, and affordable costs remain still important goals, which must be reached to globally eliminate hepatitis C.

The Cochrane Collaboration's tool for assessing risk of bias in randomized trials

Article

Oct 2011
Br Med J

Effect of chloroquine on some clinical and biochemical parameters in non-response chronic hepatitis C virus infection patients: Pilot clinical trial

Article

May 2016

Background: Hepatitis C virus infection frequently leads to chronic hepatitis C which may progress to cirrhosis and can be ended to hepatocellular carcinoma. This study aimed to investigate the effect of Anthropometric Parameters, Vit D3, Thyroid Function, Ferritin and Biochemistry Parameters in patients chronically infected with HCV with non-response criteria which was treated by chloroquine. Methods: This study was the continuation of our previous investigation with a triple-blind method in a randomized controlled pilot study. After understanding the study procedures, patients signed an informed consent form and were randomized into the treatment (chloroquine 150 mg once daily, for 8 weeks) and control (placebo once daily, for 8 weeks) groups. The inclusion criteria were male, between 18 and 60 years of age, confirmed chronic hepatitis C with non-response criteria, and Genotype 1. Data were analyzed with an intention to treat perspective at the end follow up (12 weeks) considering to variables such as anthropometric parameters, Vit D3, thyroid function, ferritin and biochemistry parameters evaluated. Results: Although there were decreases in total weight (P-value=0.4), mid-arm circumference (P-value=0.05), and body mass index (P-value=0.04) there were increases in total body fat (P-value=0.8) and triceps skin fold thickness (P-value=0.7) in the intervention group compared to the control group. Also, a reduction of AST (P-value=0.30), ALT (P-value=0.10), cholesterol (P-value=0.005), triglyceride (P-value=0.40) and ferritin (P-value=0.030) levels was seen in the intervention group during the follow up period. Our results also showed that serum TSH levels (P-value=0.5) were slightly higher in the chloroquine group than in the placebo group, though the trend was reversed for T3 (P-value=0.05) and T4 (P-value=0.04) levels. however, median of T3 and T4 were similar in both groups. A significant increase in vitamin D levels from 15 to 34 ng/ml was observed in the chloroquine group (P-value=0.04). Conclusions: The results suggest that chloroquine therapy may be very useful for HCV treatment in patients with non-response criteria, and helps to normalize some anthropometric parameters, biochemical, ferritin, and vitamin D status.

The Effect of Chloroquine on Immune Activation and Interferon Signatures Associated with HIV-1

Article

Mar 2016

Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor antagonist properties, could reduce immune activation thought to be driven by Toll-like receptor ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off ART and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = 0.003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p < 0.001). Transcriptional analyses in the off-ART cohort showed decreased expression of interferon-stimulated genes in 5 of 10 chloroquine-treated participants and modest decreases in CD38 and CCR5 RNAs in all chloroquine-treated participants. Chloroquine modestly reduced immune activation in ART-treated HIV-infected participants.

GRADE: An emerging consensus on rating quality of evidence and strength of recommendations

Article

Jan 2009

The Cochrane Collaboration's tool for assessing risk of bias in randomised trials

Article

Jan 2011

Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy

Article

Jul 2012
J Am Med Assoc

Therapies to decrease immune activation might be of benefit in slowing HIV disease progression. To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline. Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL. Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks. The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models. There was no significant difference in CD8 cell activation between the 2 groups (-4.8% and -4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, -0.6%; 95% CI, -4.8% to 3.6%; P = .80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (-85 cells/μL vs -23 cells/μL at week 48; difference, -62 cells/μL; 95% CI, -115 to -8; P = .03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P = .003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P = .03). Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication. isrctn.org Identifier: ISRCTN30019040.

Henipavirus outbreaks to antivirals: The current status of potential therapeutics

Article

Apr 2012

Christopher Broder

The henipaviruses, Hendra virus and Nipah virus, are classic examples of recently emerged viral zoonoses. In a relatively short time since their discoveries in the mid and late 1990s, respectively, a great deal of new information has been accumulated detailing their biology and certain unique characteristics. Their broad species tropism and abilities to cause severe and often fatal respiratory and/or neurologic disease in both animals and humans has sparked considerable interest in developing effective antiviral strategies to prevent or treat henipavirus infection and disease. Here, recent findings on the few most advanced henipavirus countermeasures are summarized and discussed.

Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders

Article

May 2011
BLOOD

Despite optimal suppression of HIV replication, restoration of CD4(+) T cells is not always achieved in antiretroviral therapy-treated individuals. Defective CD4 recovery in immunologic nonresponders is possibly associated with TLR-mediated immune activation driven by alterations of gut permeability. Hydroxychloroquine (HCQ) reduces endosomal TLR signaling; thus, we verified whether HCQ could dampen immune activation and be associated with an increase in CD4(+) T cells. To this end, we enrolled in a prospective study 20 HIV-infected immunologic nonresponders (CD4 count < 200 cells/mL or CD4 increase < 5% in the last 12 months) who received 400 mg/day HCQ for 6 months. HCQ had a notable impact on immune activation as shown by significant modifications of the following parameters: (1) reduced plasma lipopolysaccharide; (2) decreased TLR4-expressing CD14(+) cells, TLR4-mediated signal transduction, and mRNA synthesis; (3) reduced percentages of activated CD4(+) (CD4(+)/Ki67(+)) and CD14(+) (CD14(+)/CD69(+)) cells; (4) increased T-regulatory cells (Tregs), naive Tregs, and TLR4-expressing Tregs; (5) augmented plasmacytoid dendritic cells and reduced IFNα-secreting plasmacytoid dendritic cells; and (6) reduced IL-6 and TNFα production. HCQ-induced immune modulation was associated with increased percentages of circulating CD4(+) T cells and was mostly retained 2 months after therapy interruption. HCQ reduces lipopolysaccharide/TLR-mediated immune activation; this compound could be a useful immunomodulant in HIV-infected patients. This study is registered at EutraCT as 2009-012499-28 with study number HLS01/2009-1-16-03-2009.

Antiviral Treatment of Chikungunya Virus Infection

Article

Apr 2009

Chikungunya virus is a typical emerging virus which has been responsible for several million cases of human infections since 2004. No antiviral treatment is currently available. The antimalarial chloroquine has been used in the past but recent studies suggest that it is not or poorly active in vivo. A number of tracks are currently under investigation (inhibition of viral enzymes, of virus entry or maturation, enhancement of immunological response) and new animal models have been made available, including a mouse model and a non-human primate model. We review here the main perspectives of chikungunya antiviral treatment.

Hydroxychloroquine treatment of patients with human immunodeficiency virus Type 1

Article

Jul 1995
CLIN THER

Hydroxychloroquine (HCQ), an antimalarial agent used to treat patients with autoimmune diseases, has been shown to suppress human immunodeficiency virus type 1 (HIV-1) replication in vitro in T cells and monocytes by inhibiting posttranscriptional modification of the virus. These in vitro observations have been expanded into an in vivo study of HCQ as a potential anti-HIV-1 agent in HIV-1-infected patients. A randomized, double-blind, placebo-controlled clinical trial was conducted in 40 asymptomatic HIV-1-infected patients who had CD4+ counts between 200 and 500 cells/mm3. Patients were randomly assigned to receive either HCQ 800 mg/d or placebo for 8 weeks. Virologic and immunologic parameters, including HIV-1 ribonucleic acid (RNA) via use of polymerase chain reaction, viral culture, antigen and mitogen responses, and proinflammatory cytokine levels were measured at the beginning and end of the study. The amount of recoverable HIV-1 RNA in plasma declined significantly in the HCQ group over the 8-week period (P = 0.022), while it increased in the placebo group. The percentage of CD4+ T cells remained stable in the HCQ-treated group (18.1 +/- 9.2% before treatment vs 18.6 +/- 10.5% after treatment) and fell significantly in the placebo group (21 +/- 7% before treatment vs 19.3 +/- 6.3% after treatment; P = 0.032). However, this was not reflected as a change in absolute CD4+ counts for either group (HCQ, 262.8 +/- 166 cells/mm3 vs 251 +/- 163 cells/mm3; placebo, 312 +/- 121 cells/mm3 vs 321 +/- 124 cells/mm3). Mitogen- and antigen-specific responses remained constant in the HCQ group while T cell proliferative responses to Candida decreased in the placebo group (4.8 +/- 3.6 x 10(3) SI [stimulation index] vs 3.0 +/- 3.0 x 10(3) SI; P = 0.032). Lastly, serum interleukin 6 levels declined in the HCQ group (14.3 +/- 13.5 U/mL vs 12.0 +/- 16.7 U/mL; P = 0.023) but not in the placebo group (11.3 +/- 8.8 U/mL vs 7.0 +/- 11.7 U/mL); this was coincident with a decrease in serum immunoglobulin (Ig)G (2563 +/- 1352 mg/mL vs 2307 +/- 1372 mg/dL; P = 0.032), compared with the placebo group (2733 +/- 1473 mg/dL vs 2709 +/- 1501 mg/dL). No other parameters, including serum p24 and beta-2 microglobulin levels, were altered by HCQ therapy. HCQ thus may be useful in the treatment of patients with HIV-1 infection.

Comparison of hydroxychloroquine with zidovudine in asymptomatic patients infected with HIV-1

Article

Sep 1997
CLIN THER

Hydroxychloroquine, hydroxycarbamide, and didanosine as economic treatment for HIV-1

Article

May 2002

Most people who have HIV-1 and live in less-developed countries cannot afford standard combination antiretroviral therapy, and more economical approaches to treatment are therefore needed. We treated 22 patients who were infected with HIV-1 (viral load < 100000 copies/mL and CD4 count >150 cells/microL) with hydroxychloroquine (200 mg), hydroxycarbamide (hydroxyurea) (500 mg), and didanosine (125-200 mg), taken twice daily. Treatment was well tolerated, with few serious adverse events. Viral load showed a sustained decrease of 1 3 log, and CD4 count was maintained (percentage increase; 2 9%) over 48 weeks in the 16 evaluable patients. This new combination of drugs could be suitable for countries that have restricted resources, but should first be further investigated.

Treatment of viral hepatitis with chloroquine

Article

Apr 1963

A PAREJA-CORONEL

In vitro inhibition of severe acute respiratory syndrome coronavirus by Chloroquine

Article

Nov 2004

We report on chloroquine, a 4-amino-quinoline, as an effective inhibitor of the replication of the severe acute respiratory syndrome coronavirus (SARS-CoV) in vitro. Chloroquine is a clinically approved drug effective against malaria. We tested chloroquine phosphate for its antiviral potential against SARS-CoV-induced cytopathicity in Vero E6 cell culture. Results indicate that the IC50 of chloroquine for antiviral activity (8.8 +/- 1.2 microM) was significantly lower than its cytostatic activity; CC50 (261.3 +/- 14.5 microM), yielding a selectivity index of 30. The IC50 of chloroquine for inhibition of SARS-CoV in vitro approximates the plasma concentrations of chloroquine reached during treatment of acute malaria. Addition of chloroquine to infected cultures could be delayed for up to 5h postinfection, without an important drop in antiviral activity. Chloroquine, an old antimalarial drug, may be considered for immediate use in the prevention and treatment of SARS-CoV infections.

Potential antivirals and antiviral strategies against SARS coronavirus infections

Article

May 2006
EXPERT REV ANTI-INFE

Erik De Clercq

There are a number of antivirals as well as antiviral strategies that could be envisaged to prevent or treat severe acute respiratory syndrome (SARS) (or similar) coronavirus (CoV) infections. Targets for the prophylactic or therapeutic interventions include interaction of the spike (S) glycoprotein (S1 domain) with the host cell receptor, fusion of the S2 domain with the host cell membrane, processing of the replicase polyproteins by the virus-encoded proteases (3C-like cysteine protease [3CLpro] and papain-like cysteine protease) and other virus-encoded enzymes such as the NTPase/helicase and RNA-dependent RNA polymerase. Human monoclonal antibody blocking S1 may play an important role in the immunoprophylaxis of SARS. Fusion inhibitors reminiscent of enfuvirtide in the case of HIV may also be developed for SARS-CoV. Various peptidomimetic and nonpeptidic inhibitors of 3CLpro have been described, the best ones inhibiting SARS-CoV replication with a selectivity index greater than 1000. Human interferons, in particular alpha- and beta-interferon, as well as short interfering RNAs could further be pursued for the control of SARS. Various other compounds, often with an ill-defined mode of action but selectivity indexes up to 100, have been reported to exhibit in vitro activity against SARS-CoV: valinomycin, glycopeptide antibiotics, plant lectins, hesperetin, glycyrrhizin, aurintricarboxylic acid, chloroquine, niclosamide, nelfinavir and calpain inhibitors.

Recycling of chloroquine and its hydroxyl analogue to face bacterial, fungal and viral infections in the 21st century

Article

Nov 2007
INT J ANTIMICROB AG

Chloroquine (CQ) and its hydroxyl analogue hydroxychloroquine (HCQ) are weak bases with a half-century long use as antimalarial agents. Apart from this antimalarial activity, CQ and HCQ have gained interest in the field of other infectious diseases. One of the most interesting mechanisms of action is that CQ leads to alkalinisation of acid vesicles that inhibit the growth of several intracellular bacteria and fungi. The proof of concept of this effect was first used to restore intracellular pH allowing antibiotic efficacy for Coxiella burnetii, the agent of Q fever, and doxycycline plus HCQ is now the reference treatment for chronic Q fever. There is also strong evidence of a similar effect in vitro against Tropheryma whipplei, the agent of Whipple's disease, and a clinical trial is in progress. Other bacteria and fungi multiply in an acidic environment and encouraging in vitro data suggest that this concept may be generalised for all intracellular organisms that multiply in an acidic environment. For viruses, CQ led to inhibition of uncoating and/or alteration of post-translational modifications of newly synthesised proteins, especially inhibition of glycosylation. These effects have been well described in vitro for many viruses, with human immunodeficiency virus (HIV) being the most studied. Preliminary in vivo clinical trials suggest that CQ alone or in combination with antiretroviral drugs might represent an interesting way to treat HIV infection. In conclusion, our review re-emphasises the paradigm that activities mediated by lysosomotropic agents may offer an interesting weapon to face present and future infectious diseases worldwide.

On Chikungunya Acute Infection and Chloroquine Treatment

Article

Jul 2008
VECTOR-BORNE ZOONOT

In recent issues, the efficacy of chloroquine (and the dosage that may be used) in the treatment of acute chikungunya infections was discussed. We have conducted a double-blind placebo-controlled randomized trial on the French Reunion Island (Indian Ocean), in which 27 patients received chloroquine and 27 patients received a placebo treatment. The chloroquine treatment consisted of 600 mg at day 1, 600 mg at days 2 and 3, and 300 mg at days 4 and 5. No significant difference between groups could be identified regarding the duration of febrile arthralgia or the decrease of viremia between day 1 and day 3. However, at day 200, patients who received chloroquine complained more frequently of arthralgia than those who received placebo (p < 0.01). In conclusion, our results suggest that there is currently no justification for the use of chloroquine to treat acute chikungunya infections.

Repurposing of the 329 anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis

Jan 2017
18132-18173

A Kumar
B Liang
M Aarthy
S K Singh
N Garg
I U Mysorekar

Kumar A, Liang B, Aarthy M, Singh SK, Garg N, Mysorekar IU, et al. Hydroxychloroquine 327 Inhibits Zika Virus NS2B-NS3 Protease. ACS Omega. 2018;3(12):18132-41. 328 10. Shiryaev SA, Mesci P, Pinto A, Fernandes I, Sheets N, Shresta S, et al. Repurposing of the 329 anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis. Sci Rep. 2017;7(1).

GRADE: an 342 emerging consensus on rating quality of evidence and strength of recommendations

Jan 2008
924

Jac Sterne
M A Hernán
B C Reeves
J Savović
N D Berkman
M Viswanathan

Sterne JAC, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: 340 a tool for assessing risk of bias in non-randomised studies of interventions. BMJ. 2016;355:i4919. 341 16. Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an 342 emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 343 2008;336(7650):924.

Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial

Jan 2020
42

Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection: A Randomized Clinical Trial. 413 JAMA Network Open. 2020;3(4):e208857-e. 414 42.

Controlled Clinical Trial for Chloroquine Phosphate in the treatment of Novel Coronavirus Pneumonia

Jan 2019

A Single-Blind

A Single-blind, Randomized, Controlled Clinical Trial for Chloroquine Phosphate in the treatment of Novel Coronavirus Pneumonia 2019 (COVID-19)

Collaboration's tool for assessing risk of bias in randomised trials

Jan 2011
15

Collaboration's tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. 339 15.

Multicenter collaboration group of department of science technology of Guangdong Province health commission of Guangdong Province for chloroquine in the treatment of novel coronavirus pneumonia

Jan 2020
185

Zhonghua

Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19

Jan 2020

Magagnoli

Hydroxychloroquine in patients with COVID-19: an open-label, randomized, controlled trial

Jan 2020

Tang

Efficacy of hydroxychloroquine in patients with COVID-19: results of a randomized clinical trial

Jan 2020

Chen

Clinical evidence for repurposing chloroquine and hydroxychloroquine as antiviral agents: a systematic review

Abstract

No full-text available

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