New and facile one-pot approach for the syntheses of 12 derivatives of 3,5-disubstituted furane-2(5H)-one (4a-l) from easily available starting materials. The suitable synthetic procedures for selective synthesis of diverse furane-2(5H)-one derivatives were achieved via multi-component condensation of 1,3-diphenyl-1H-pyrazole-4-carbaldehyde (1), pyruvic acid and different aromatic amines 3a-l in good to high yields and short reaction time by refluxing in acetic acid as well as obtained by another method (method B) when unsaturated arylidene pyruvic acid 6 was refluxed with different aromatic amines in acetic acid but in smaller yield than method A. Structures of the prepared compounds were elucidated by elemental analysis and spectral data as mass, IR, 1H-NMR and 13C-NMR spectroscopy. The antiviral efficacy of compounds 4a-l against SARS-CoV-2 was evaluated using the MTT assay. It was demonstrated that synthetic compounds 4c-e and 4h-j have a potent and selective inhibitory effect on SARS-CoV-2, a strain obtained from Egyptian patients. We utilized density-functional theory (DFT) analyses to deduce the molecular structures and topologies of the more energetic molecules. Molecular docking studies were performed against the SARS-CoV-2 main protease (PDB ID: 6Y84) and the SARS-CoV-2 Nsp9 RNA binding protein (PDB ID: 6W4B) to study the binding mechanism, non-bonding interactions, and binding affinity. Lastly, a hypothetical pharmacophore model was constructed by applying the Molecular Operating Environment (MOE) tool and eleven pharmaceuticals with proven antiviral activity.

A sentiment analysis of 5051 Twitter posts from January 2022 found that 53.4% of them expressed positive views on ivermectin as a COVID-19 treatment, 35.6% of them were neutral, and 11% of them were negative, highlighting the polarized public perception and the need for careful interpretation of social media data in health communication.

The global impact of emerging and re-emerging viral agents during epidemics and pandemics leads to serious health and economic burdens. Among the major emerging or re-emerging viruses include SARS-CoV-2, Ebola virus (EBOV), Monkeypox virus (Mpox), Hepatitis viruses, Zika virus, Avian flu, Influenza virus, Chikungunya virus (CHIKV), Dengue fever virus (DENV), West Nile virus, Rhabdovirus, Sandfly fever virus, Crimean-Congo hemorrhagic fever (CCHF) virus, and Rift Valley fever virus (RVFV). A comprehensive literature search was performed to identify existing studies, clinical trials, and reviews that discuss drug repositioning strategies for the treatment of emerging and re-emerging viral infections using databases, such as PubMed, Scholar Google, Scopus, and Web of Science. By utilizing drug repositioning, pharmaceutical companies can take advantage of a cost-effective, accelerated, and effective strategy, which in turn leads to the discovery of innovative treatment options for patients. In light of antiviral drug resistance and the high costs of developing novel antivirals, drug repositioning holds great promise for more rapid substitution of approved drugs. Main repositioned drugs have included chloroquine, ivermectin, dexamethasone, Baricitinib, tocilizumab, Mab114 (Ebanga™), ZMapp (pharming), Artesunate, imiquimod, saquinavir, capmatinib, naldemedine, Trametinib, statins, celecoxib, naproxen, metformin, ruxolitinib, nitazoxanide, gemcitabine, Dorzolamide, Midodrine, Diltiazem, zinc acetate, suramin, 5-fluorouracil, quinine, minocycline, trifluoperazine, paracetamol, berbamine, Nifedipine, and chlorpromazine. This succinct review will delve into the topic of repositioned drugs that have been utilized to combat emerging and re-emerging viral pathogens.

The rapid spread and mutation of SARS-CoV-2, the virus responsible for COVID-19, has set the foundation for extensive research into next-generation therapeutic strategies. A critical component of SARS-CoV-2 is the trimeric Spike (S) glycoprotein, which facilitates viral entry into host cells by interacting with the receptor-binding domain (RBD). To inhibit and block viral entry, we designed and developed molecularly imprinted synthetic nanogel antibodies (MIP-SNAs) that cap the Spike S1 RBD. This aims to provide a versatile, biosecure, and effective therapeutic tool for the prevention and treatment of SARS-CoV-2 infection. Herein, we employed reverse miniemulsion polymerization to synthesize MIP-SNAs using poly(ethylene glycol) diacrylate (PEGDA), a nontoxic, nonimmunogenic and FDA-approved polymer, able to interact noncovalently with the functional groups of template Spike S1 RBD. In addition, the formulation of MIP-SNAs was based on a preliminary investigation of protein conformation by circular dichroism. Characterization of the SNAs was conducted using several techniques to investigate the chemical structure, thermal stability, size, and morphology. Under optimal conditions, the MIP-SNAs exhibited high specificity, with rebinding capacities up to 6-fold higher compared to the control nonimprinted synthetic nanogel antibodies. MIP-SNAs also demonstrated notable selectivity toward the SARS-CoV-2 Spike S1 RBD protein compared to the structural resembling Spike proteins of Bat-CoV, while cytocompatibility assays confirmed the biocompatible character of the SNAs. Given the excellent features of the recently developed MIP-SNAs, we are one step closer to finding efficient but also patient-friendly prevention and treatment solutions for SARS-CoV-2 infection. Beyond immediate applications, this technology offers the potential for broader diagnostic and therapeutic uses against related viral pathogens.

Antiviral therapeutics have made a critical contribution in mitigating the symptoms and clinical outcomes of the coronavirus disease of 2019 (COVID-19), in which a single-stranded RNA viral pathogen, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causes multi-organ injuries. Several antivirals were widely prescribed to treat COVID-19, either through the emergency use authorization (EUA) by the governmental regulatory agencies (i.e., remdesivir, paxlovid, molnupiravir, and the SARS-CoV-2-targeted monoclonal antibodies - tixagevimab and cilgavimab), as well as the repurposed use of the existing antiviral or antimalarial drugs (e.g., hydroxychloroquine, chloroquine, and ivermectin). Despite their efficacy in ameliorating COVID-19 symptoms, some adverse side-effects of the antivirals were also reported during the COVID-19 pandemic. Our current review has aimed to gather and extrapolate the recently published information concerning cardiovascular adverse effects caused by each of the antivirals. We also provide further discussion on the potential cellular mechanisms underlying the cardiovascular adverse effects of the selected antiviral drugs, which should be carefully considered when evaluating risk factors in managing patients with COVID-19 or similar infectious diseases. It is foreseeable that future antiviral drug development assisted with the newest artificial intelligence platform may improve the accuracy to predict the structures of biomolecules of antivirals and therefore to mitigate their associated cardiovascular adversities.

Halogenated Schiff base derivatives are gaining more popularity in supramolecular chemistry due to the synergistic effect of hydrogen and halogen-based noncovalent interactions, which helps to design novel therapeutic materials. In this work, we have examined the nature of molecular interactions to investigate the structure-functional relationship of a halogen-based derivative. The FTIR, HRMS and NMR spectroscopic techniques confirmed the formation of the desired novel Schiff base compound. Further, crystal structure studies showed an infinite 1D supramolecular chain formed by type-I halogen…halogen interaction. The Hirshfeld surface and enrichment ratio analyses were performed to visualize and assess the role of diverse interactions involved in crystal packing. The QTAIM, NCI, LOL and ELF studies were conducted extensively to comprehend the strength of interaction constructed based on electron density distribution. The global and local reactive indices were determined using DFT studies to analyze the molecular properties of the compound. Antibacterial activity against MRSA bacteria was performed and showed a good zone of inhibition. The docking analysis was performed for 1mwt protein and validated. The in silico molecular docking studies of the halogenated Schiff base structure with the penicillin-binding protein showed a good docking affinity of -7.5 kcal/mol and supported by in vitro studies. The ligand binding stability within the protein's active site was further demonstrated by molecular dynamics (MD) simulation studies for the Schiff base molecule.

SARS-CoV-2, the virus responsible for the COVID-19 pandemic, predominantly affects the respiratory tract, underscoring the need to develop antiviral agents in an inhalable formulation that can be delivered as prophylactic and/or therapeutic drugs directly to the infection site. Since the beginning of the pandemic, our group has been exploring the possibility of developing combinations of antiviral drugs that can be delivered as inhalable therapy, including combinations of remdesivir and ebselen or remdesivir and disulfiram prepared using a spray-drying technique. In this study, we used a similar spray-drying technique to develop inhalable dry powders combining the controversial drugs ivermectin and niclosamide, which have been reported to exhibit synergistic activity against SARS-CoV-2 in vitro. The combined dry powders were within the size range of 1-5 μm, amorphous in nature and displayed characteristic morphology after spray drying. The emitted dose (ED) of the spray-dried powders ranged from 68 to 83 %, whereas the fine particle fraction (FPF) ranged between 50 and 74 %. All the prepared dry powders remained stable under different humidity conditions (<15 % RH and 53 % RH). Interestingly, the optimized combinational dry powder of ivermectin and niclosamide showed an improved cytotoxic profile (CC50 value of 45.99 µM) and enhanced anti-SARS-CoV-2 activity in vitro (EC50 of 2.67 µM) compared to the single dry powders of ivermectin (CC50 = 20.25 µM and EC50 = 8.61 µM) and niclosamide (CC50 = 21.36 µM and EC50 = 5.28 µM). In summary, we developed a stable and inhalable combinational dry powder containing ivermectin and niclosamide, capable of inhibiting SARS-CoV-2 replication in vitro, demonstrating the potential to prepare dry powders that could be developed and delivered as inhalable antiviral drugs to prevent and/or treat SARS-CoV-2 or similar respiratory viruses.

In this study, the aim was to comparatively examine the perception of risk for developing severe illness or complications due to COVID-19 among the general population and socially vulnerable populations in Brazil, focusing on uncovering the associated factors that disproportionately impacted people experiencing homelessness and slum dwellers. This study is part of the project "Social Thermometer-COVID-19 in Brazil", which employed a hybrid approach, combining a national online survey with field research in state capitals and the Federal District. Data collection took place from August 2020 to October 2023, and the data were analyzed using descriptive statistics and logistic regression. A total of 5094 participants were included in this study, with 2363 from the general population and 2731 from the socially vulnerable population. Among the general population, the majority of participants were women, white individuals, those with higher incomes, formal employment, and higher education levels. Concerning the vulnerable population, most were men, Black individuals, those with lower incomes, unemployment, and lower education levels. It was observed that 87% of the general population perceived a risk of severe COVID-19, compared to 74% of the vulnerable population. Slum dwellers who received emergency aid (ORa = 1.39; 95% CI: 1.02-1.91), adhered to mask-wearing practices (ORa = 1.93; 95% CI: 1.39-2.66), used COVID-19-related medications (ORa = 2.13; 95% CI: 1.31-3. 64), and those with pre-existing conditions, such as high blood pressure (ORa = 1.86; 95% CI: 1.20-2.98), demonstrated a heightened perception of risk for severe COVID-19 complications. Among the homeless population, individuals who wore masks (ORa = 1.67; 95% CI: 1.26-2.20 and had been vaccinated (ORa = 1.44; 95% CI: 1.04-1.98) were also more likely to perceive a high risk. In conclusion, in this study, significant disparities are revealed in the perception of COVID-19 risk between the general and socially vulnerable populations in Brazil. Factors such as receiving emergency aid, adherence to mask-wearing, use of COVID-19-related medications, and pre-existing health conditions were associated with increased risk perception. Despite facing greater socioeconomic challenges, vulnerable groups, particularly those experiencing homelessness and slum dwellers, showed a lower perception of the risk for severe COVID-19 complications.

Ivermectin has been widely used for antiparasitic drug, and has recently shown a broad-spectrum antiviral activity, including anti-Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the pharmacokinetic property of ivermectin has not been fully investigated yet. During the plasma preparation, ~32-46% of ivermectin was found in the precipitation. An Liquid Chromatograph-Mass Spectrometer (LC-MS/MS) method for ivermectin in the whole blood samples from beagle dogs was developed and validated. The specificity, accuracy, precision (intra-day and inter-day), matrix effect, recovery and stability of analyte reported here are satisfied with the criteria of Food and Drug Administration (FDA)-Bioanalysis guideline. The oral administrations pharmacokinetics of ivermectin in beagle dogs under fasting and after high-fat meal were studied, and the following parameters were obtained: fasting Cmax, 104 ± 35 μg·L-1; area under the concentration-time curve (AUC0-∞), 2,555 ± 941 h·μg·L-1; and high-fat meal Cmax, 147 ± 35 μg·L-1; AUC0-∞, 4,198 ± 1,279 h·μg·L-1. When the P-gp inhibitor curcumin was also coadministrated orally, Cmax and AUC0-∞ were found to be 177 ± 57 and 4,213 ± 948 h·μg·L-1, respectively. With the comparison to fasting treatment, coadministration of P-gp inhibitor curcumin resulted in increase of the exposure of ivermectin by 1.6-fold, while the exposure after the high-fat diet versus fasting was increased approximately in 1.4-fold, indicating that alternative absorption might play an important role for increasing the exposure of ivermectin for future clinic applications.

Human parvovirus B19 (B19V) is a major human pathogen in which the ssDNA genome is replicated within the nucleus of infected human erythroid progenitor cells (EPCs) through a process involving both cellular and viral proteins, including the non-structural protein (NS)1. We previously characterized the interaction between NS1 classical nuclear localization signal (cNLS: GACHAKKPRIT-182) and host cell importin (IMP)α and proposed it as a potential target for antiviral drug development. Here, we further extend on such findings. First, we demonstrate that NS1 nuclear localization is required for viral production since introducing the K177T substitution in a cloned, infectious viral genome resulted in a non-viable virus. Secondly, we demonstrate that the antiparasitic drug ivermectin (IVM), known to inhibit the IMPα/β dependent nuclear import pathway, could impair the NS1-NLS:IMPα interaction and suppress viral replication in UT7/EpoS1 cells in a dose-dependent manner. We also show that a panel of structurally related avermectins (AVMs) can dissociate the NS1-NLS:IMPα complex with half-maximal inhibitory concentrations in the nanomolar range. Among them, Eprinomectin emerged as the most selective inhibitor of B19V replication, with a selectivity index of c. 5.0. However, when tested in EPCs generated from peripheral blood mononuclear cells, which constitute a cellular population close to the natural target cells in bone marrow, the inhibitory effect of IVM and Eprinomectin was demonstrated to a lesser extent, and both compounds exhibited high toxicity, thus highlighting the need for more specific inhibitors of the NS1-NLS:IMPα interaction.

The COVID-19 pandemic, resulting in approximately seven million deaths globally, underscores the urgency for effective treatments. Ivermectin, among several repurposed drugs, garnered interest due to its antiviral properties. However, conflicting evidence from observational studies and randomized controlled trials raised questions about its efficacy and safety.

This systematic review and meta-analysis followed MOOSE and PRISMA guidelines. Comprehensive searches were conducted in databases including Scopus, Embase, PubMed, and Web of Science up to April 2024. Data were extracted independently by two reviewers and analyzed using Comprehensive Meta-Analysis V3 software.

Across 33 studies encompassing 15,376 participants, ivermectin showed no significant impact on critical outcomes such as mortality [risk ratio (RR) 0.911, 95% confidence intervals (CI) 0.732-1.135], mechanical ventilation (RR 0.727, 95% CI 0.521-1.016), polymerase chain reaction conversion (RR 1.024, 95% CI 0.936-1.120), ICU admissions (RR 0.712, 95% CI 0.274-1.850), or hospitalization rates (RR 0.735, 95% CI 0.464-1.165) compared to controls. However, it significantly reduced time to symptom alleviation (standardized mean difference -0.302, 95% CI -0.587 to -0.018) and sustained symptom relief (RR 0.897, 95% CI 0.873-0.921). Adverse event (AE) rates were similar between the ivermectin and control groups (RR 0.896, 95% CI 0.797-1.007). Meta-regression indicated older age and diabetes as predictors of AEs.

Despite its observed benefits in symptom management, ivermectin did not significantly influence critical clinical outcomes in COVID-19 patients. These findings highlight the importance of continued research to identify effective treatments for COVID-19, emphasizing the need for high-quality studies with robust methodology to inform clinical practice and public health policy effectively.

Background: Infectious bronchitis virus (IBV) causes a significant illness in birds, making it a leading source of financial loss in the poultry business. The objective of this study was to assess the effectiveness of proliposomes (PLs) containing ivermectin (IVM) against IBV using embryonated chicken eggs (ECEs). Methods: A three-factor, two-level (23) full factorial design was employed; carrier/lipid phase ratio (A), stearyl glycyrrhetinate amount (B), and phospholipid type (C) were studied as independent variables, while product yield (PY), entrapment efficiency (EE), particle size (PS), polydispersity index (PDI), zeta potential (ZP), and cumulative percentage of drug released after 6 h (Q6h) were characterized. The selected formulations (PL2 and PL6) were subjected to further characterizations, including IVM toxicity and anti-viral activity. Results: The PY% ranged from 88.6 ± 2.19% to 98.8 ± 0.45%, EE% was from 71.8 ± 2.01% to 96.1 ± 0.51%, PS was from 330.1 ± 55.65 nm to 1801.6 ± 45.61 nm, PDI was from 0.205 ± 0.06 to 0.603 ± 0.03, ZP was from -18.2 ± 0.60 mV to -50.1 ± 1.80 mV, and Q6h was from 80.95 ± 1.36% to 88.79 ± 2.03%. IVM-loaded PLs had lower toxicity in ECEs than pure IVM; the mortality rate was substantially reduced in IBV-infected ECEs injected with PL2 rather than pure IVM. As further evidence of IVM's anti-viral action against IBV, quantitative real-time polymerase chain reaction (qRT-PCR) revealed that the PL2-treated group exhibited further reduction in IBV's copies in comparison with the pure IVM-treated group. Conclusions: PLs loaded with IVM are an innovative and potentially effective way to inhibit IBV.

Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) caused an outbreak in 2002-2003, spreading to 29 countries with a mortality rate of about 10%. Strict quarantine and infection control methods quickly stopped the spread of the disease. Later research showed that SARS-CoV came from animals (zoonosis) and stressed the possibility of a similar spread from host to human, which was clearly shown by the COVID-19 outbreak. The COVID-19 pandemic, instigated by SARS-CoV-2, has affected 776 million confirmed cases and more than seven million deaths globally as of Sept 15, 2024. The existence of animal reservoirs of coronaviruses continues to pose a risk of re-emergence with improved fitness and virulence. Given the high death rate (up to 70 percent) and the high rate of severe sickness (up to 68.7 percent in long-COVID patients), it is even more critical to identify new therapies as soon as possible. This study combines research on antivirals that target SARS coronaviruses that have been conducted over the course of more than twenty years. It is a beneficial resource that might be useful in directing future studies.

Diabetes mellitus (DM) is recognized and classified as a group of conditions marked by persistent high blood glucose levels. It is also an inflammatory condition that may influence concurrent disease states, including Coronavirus Disease 2019 (COVID-19). Currently, no effective drug has been found to treat COVID-19, especially in DM patients. Many herbal medicines, such as the well-known Andrographis paniculata, have been explored as drugs and complementary therapies due to their antidiabetic, antibacterial, antiviral, anti-inflammatory, and immunomodulatory effects. This study aimed to examine the potential of herbal medicines as complementary therapy in DM patients with COVID-19 complications, drawing from in-vitro and in-vivo investigations. This study analyzed articles published within the last 15 years using keywords including "herbal medicines", "COVID-19", "Diabetes Mellitus", "antidiabetics", "antiviral", and "anti-inflammatory". The results showed that several herbal medicines could serve as complementary therapy for DM patients with COVID-19 complications. These include Andrographis paniculata, Ageratum conyzoides, Artocarpus altilis, Centella asiatica, Momordica charantia, Persea gratissima, Phyllanthus urinaria, Physalis angulata, Tinospora cordifolia, and Zingiber zerumbet. Herbal medicines may serve as a complementary therapy for DM patients with COVID-19, but these claims need experimental validation in infection models and among affected patients.

Flaviviruses are a diverse group of viruses primarily transmitted through hematophagous insects like mosquitoes and ticks. Significant expansion in the geographic range, prevalence, and vectors of flavivirus over the last 50 years has led to a dramatic increase in infections that can manifest as hemorrhagic fever or encephalitis, leading to prolonged morbidity and mortality. Millions of infections every year pose a serious threat to worldwide public health, encouraging scientists to develop a better understanding of the pathophysiology and immune evasion mechanisms of these viruses for vaccine development and antiviral therapy. Extensive research has been conducted in developing effective antivirals for flavivirus. Various approaches have been extensively utilized in clinical trials for antiviral development, targeting virus entry, replication, polyprotein synthesis and processing, and egress pathways exploiting virus as well as host proteins. However, to date, no licensed antiviral drug exists to treat the diseases caused by these viruses. Understanding the mechanisms of host-pathogen interaction, host immunity, viral immune evasion, and disease pathogenesis is highly warranted to foster the development of antivirals. This review provides an extensively detailed summary of the most recent advances in the development of antiviral drugs to combat diseases.

Signal-dependent transport into and out of the nucleus mediated by members of the importin (IMP) superfamily is crucial for eukaryotic function, with inhibitors targeting IMPα being of key interest as anti-infectious agents, including against the apicomplexan Plasmodium species and Toxoplasma gondii, causative agents of malaria and toxoplasmosis, respectively. We recently showed that the FDA-approved macrocyclic lactone ivermectin, as well as several other different small molecule inhibitors, can specifically bind to and inhibit P. falciparum and T. gondii IMPα functions, as well as limit parasite growth. Here we focus on the FDA-approved antiparasitic moxidectin, a structural analogue of ivermectin, for its IMPα-targeting and anti-apicomplexan properties for the first time. We use circular dichroism and intrinsic tryptophan fluorescence measurements to show that moxidectin can bind directly to apicomplexan IMPαs, thereby inhibiting their key binding functions at low μM concentrations, as well as possessing anti-parasitic activity against P. falciparum in culture. The results imply a class effect in terms of IMPα's ability to be targeted by macrocyclic lactone compounds. Importantly, in the face of rising global emergence of resistance to approved anti-parasitic agents, the findings highlight the potential of moxidectin and possibly other macrocyclic lactone compounds as antimalarial agents.

The objective of this systematic review and meta-analysis is to assess the efficacy and safety of Ivermectin compared to placebo or standard of care for the treatment and prevention of COVID-19 disease. Literature search was carried out in PubMed, Scopus, and google scholar. Clinical trial registries (clinical trail.gov) and preprint servers (Medrxiv) were also searched for registered and preprint data respectively. Mortality, Clinical recovery, Clinical worsening, duration of hospital stay, and adverse events were considered as primary outcomes while viral clearance is considered as a secondary outcome. Revised Cochrane risk of bias assessment tool was used to assess the risk of bias. Random effect meta-analysis was carried out for all the outcomes. GRADE was used to rate the certainty of evidence. A total of 19 RCTs with 1111 patients were included in the analysis. Ivermectin use did was not associated with a reduction in the incidence of mortality, duration of hospitalization, clinical worsening, and incidence of adverse events nor it was associated with an increase in clinical improvement compared to either placebo or standard of care. Ivermectin also did not show any reduction in viral clearance compared to both placebo or standard of care and this was associated with substantial inconsistency. The overall certainty of the evidence was very low to low. Based on the very low to low certainty of the evidence, we consider Ivermectin ineffective in the management of COVID-19 disease, both as treatment and prophylaxis.

The COVID-19 pandemic, driven by the rapid evolution of the SARS-CoV-2 virus, presents ongoing challenges to global public health. SARS-CoV-2 is characterized by rapidly evolving mutations, especially in (but not limited to) the spike protein, complicating predictions about its evolutionary trajectory. These mutations have significantly affected transmissibility, immune evasion, and vaccine efficacy, leading to multiple pandemic waves with over half a billion cases and seven million deaths globally. Despite several strategies, from rapid vaccine development and administration to the design and availability of antivirals, including monoclonal antibodies, already having been employed, the persistent circulation of the virus and the emergence of new variants continue to result in high case numbers and fatalities. In the past four years, immense research efforts have contributed much to our understanding of the viral pathogenesis mechanism, the COVID-19 syndrome, and the host-microbe interactions, leading to the development of effective vaccines, diagnostic tools, and treatments. The focus of this review is to provide a comprehensive analysis of the functional impact of mutations on diagnosis, treatments, and vaccine effectiveness. We further discuss vaccine safety in pregnancy and the implications of hybrid immunity on long-term protection against infection, as well as the latest developments on a pan-coronavirus vaccine and nasal formulations, emphasizing the need for continued surveillance, research, and adaptive public health strategies in response to the ongoing SARS-CoV-2 evolution race.

Flaviviruses, which include globally impactful pathogens, such as West Nile virus, yellow fever virus, Zika virus, Japanese encephalitis virus, and dengue virus, contribute significantly to human infections. Despite the ongoing emergence and resurgence of flavivirus-mediated pathogenesis, the absence of specific therapeutic options remains a challenge in the prevention and treatment of flaviviral infections. Through the intricate processes of fusion, transcription, replication, and maturation, the complex interplay of viral and host metabolic interactions affects pathophysiology. Crucial interactions involve metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, each playing a pivotal role in the replication and maturation of flaviviruses. These viral-host metabolic molecular interactions hijack and modulate the molecular mechanisms of host metabolism. A comprehensive understanding of these intricate metabolic pathways offers valuable insights, potentially unveiling novel targets for therapeutic interventions against flaviviral pathogenesis. This review emphasizes promising avenues for the development of therapeutic agents that target specific metabolic molecules, such as amino acids, glucose, fatty acids, and nucleotides, which interact with flavivirus replication and are closely linked to the modulation of host metabolism. The clinical limitations of current drugs have prompted the development of new inhibitory strategies for flaviviruses based on an understanding of the molecular interactions between the virus and the host.

The restriction of access to health services during the COVID-19 pandemic has led to an increase in self-medication. This study aims to examine mothers' use of nutrient supplements with over-the-counter (OTC) medications for their children, including instances of self-medication for themselves. The study also explores maternal characteristics associated with this behavior, the specific medications used, and the reasons for use.

In this descriptive study, 450 mothers with children aged 2 to 6 years in Türkiye were recruited through social media platforms. Questions focused on whether mothers used supplements for themselves and their children, types of products, frequency, and reasons for use. Multivariable binary logistic regression was conducted to examine the factors associated with OTC medication use for children.

Nearly half of the mothers reported administering OTC medications to their children. Factors associated with this practice included the child's age (specifically 48-72 months), attendance at nursery, perceived underweight status, and regular health visits with a pediatrician. Additionally, mothers who frequently used medications without a doctor's recommendation were 5.8 times more likely to give OTC drugs to their children. Maternal self-medication was significantly associated with an increased likelihood of OTC medication use for children (OR = 12.1). The most commonly used supplements included vitamin D, fish oil, multivitamins, vitamin C, immune boosters, zinc, probiotics, herbal teas, oral/nasal sprays, throat lozenges, and aspirin, with the primary purposes being prevention and treatment.

The administration of OTC medications in young children, who rely heavily on maternal care should be more closely monitored to ensure their safety and well-being, especially during epidemics.

Boosting the immune system has become a crucial aspect in the global battle against the COVID-19 pandemic and other similar infections to protect oneself against symptoms, especially in the prevention of viral infections of the lower respiratory tract. The importance of conducting more studies to create successful herbal formulations as infection prevention measures is emphasized in this review, which looks at the function of immune-boosting nutrients, medicinal plants, and herbal treatments. We reviewed and analyzed 207 studies published from 1946 to the present using reputable databases like Google Scholar, PubMed, and NCBI. The review examined 115 plant species in total and identified 12 key nutrients, including vitamins A, D, C, omega-3 fatty acids, iron, and zinc, while noting that four plant families, Rosaceae, Asteraceae, Amaryllidaceae, and Acanthaceae, show potential against respiratory infections like influenza, RSV, and SARS-CoV. To lower the risk of infection, it is recommended to consume nutritious meals that have immune-modulating qualities. Information on the bioactive components of medicinal herbs, spices, and plants that have been effective in treating respiratory viral infections and related conditions is compiled in this review, which highlights phytoactive substances with antibacterial and antiviral activity as effective modulators to lower the risk of infections. Furthermore, it is highlighted that ancient knowledge systems, like Ayurveda and Naturopathy, should be integrated to help develop new herbal formulations. To improve immunity and lessen vulnerability to serious respiratory infections, the results highlight the need for including immune-modulating foods and plant-based medicines into everyday routines.

There have been differential mortality rates from COVID-19 in different parts of the world. It is not clear whether the clinical presentation does also differ, thus the need for this study in a sub-Saharan African setting. The aim of this study was to describe the clinical manifestations and outcomes of patients diagnosed with COVID-19 in selected tertiary hospitals in Tanzania.

This was a retrospective analysis of hospitalised adults confirmed SAR-COV-2 infection in five tertiary-level hospitals in Tanzania. Data collected and analysed included sociodemographic, radiological and clinical characteristics of the patients as well as the outcome of the admission (discharge vs death).

Out of 1387 COVID-19 patients, 52% were males. The median age was 60 years ((IQR)=(19-102)). The most common symptoms were dyspnoea (943,68%), cough (889, 64%), fever (597,43%) and fatigue (570, 41%). In-hospital mortality was (476, 34%). Mortality significantly increased with increasing age, being the most in age >90 years (aHR (95% CI)=4.4 (2.52 to 28.82), p=0.02). Other predictors of mortality were not possessing a health insurance, (aHR (95% CI)=3.7 (1.09 to 14.25), p=0.04); chest pain, (aHR (95% CI)=2.27 (1.36 to 4.13), p=0.03); HIV positivity, (aHR (95% CI)=3.9 (1.46 to 8.15), p=0.03); neutrophilia, (aHR (95% CI)=1.12 (1.01 to 2.65), p=0.03); no use of ivermectin, (aHR (95% CI)=1.21 (1.04 to 1.57), p=0.04) and non-use of steroids, (aHR (95% CI)=1.36 (1.18 to 2.78), p=0.04). The retrospective nature of this study which based on documented patients' records, with a large number of patients left out of the analysis due to missed data, this might in a way affect the results of the present study.

In-hospital mortality was 34%. The independent predictors of mortality were advanced age, HIV infection, no possession of a health insurance, chest pain, neutrophilia and no use of steroids or ivermectin.

Most studies on the docking of ivermectin on the spike protein of SARS-CoV-2 concern the receptor binding domain (RBD) and, more precisely, the RBD interface recognized by the ACE2 receptor. The N-terminal domain (NTD), which controls the initial attachment of the virus to lipid raft gangliosides, has not received the attention it deserves. In this study, we combined molecular modeling and physicochemical approaches to analyze the mode of interaction of ivermectin with the interface of the NTD-facing lipid rafts of the host cell membrane. We characterize a binding area that presents point mutations and deletions in successive SARS-CoV-2 variants from the initial strain to omicron KP.3 circulating in many countries in 2024. We show that ivermectin has exceptional flexibility, allowing the drug to bind to the spike protein of all variants tested. The energy of interaction is specific to each variant, allowing a classification according to their affinity for ivermectin in the following ascending order: Omicron KP.3 < Delta < Omicron BA.5 < Alpha < Wuhan (B.1) < Omicron BA.1. The binding site of ivermectin is subject to important variations of the NTD, including the Y144 deletion. It overlaps with the ganglioside binding domain of the NTD, as demonstrated by docking and physicochemical studies. These results suggest a new mechanism of antiviral action for ivermectin based on competitive inhibition for initial virus attachment to lipid rafts. The current KP.3 variant is still recognized by ivermectin, although with an affinity slightly lower than the Wuhan strain.

Background/Objectives: Ivermectin gained widespread attention as the "miracle drug" during the coronavirus disease 2019 (COVID-19) pandemic. Its inclusion in the 21st World Health Organization (WHO) List of Essential Medicines is attributed to its targeted anti-helminthic response, high efficacy, cost-effectiveness and favorable safety profile. Since the late 2000s, this bio-inspired active pharmaceutical ingredient (API) gained renewed interest for its diverse therapeutic capabilities. However, producing ivermectin formulations does remain challenging due to its poor water solubility, resulting in low bioavailability after oral administration. Therefore, the transdermal drug delivery of ivermectin was considered to overcome these challenges, which are observed after oral administration. Methods: Ivermectin was incorporated in a nano-emulsion, nano-emulgel and a colloidal suspension as ivermectin-loaded nanoparticles. The nano-drug delivery vehicles were optimized, characterized and evaluated through in vitro membrane release studies, ex vivo skin diffusion studies and tape-stripping to determine whether ivermectin was successfully released from its vehicle and delivered transdermally and/or topically throughout the skin. This study concluded with cytotoxicity tests using the methyl thiazolyl tetrazolium (MTT) and neutral red (NR) assays on both human immortalized epidermal keratinocytes (HaCaT) and human immortalized dermal fibroblasts (BJ-5ta). Results: Ivermectin was successfully released from each vehicle, delivered transdermally and topically throughout the skin and demonstrated little to no cytotoxicity at concentrations that diffused through the skin. Conclusions: The type of nano-drug delivery vehicle used to incorporate ivermectin influences its delivery both topically and transdermally, highlighting the dynamic equilibrium between the vehicle, the API and the skin.

The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug-drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug-drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4's role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide's regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug-drug interactions and hinder the hepatic metabolism of ivermectin.

Substandard and falsified medical products for treating COVID-19 have spread worldwide. These medicines have entered Japan through personal importation of products purchased via the Internet. In this study, we investigated the circulation of 19 COVID-19-related medicines on the Internet in Japan and evaluated the pharmaceutical quality and authenticity of 2 medicines (dexamethasone tablets and ivermectin tablets) obtained online. We purchased 23 samples of 0.5-mg dexamethasone tablets and 13 samples of 3-mg ivermectin tablets from the Internet in December 2020 and July 2022. We investigated the quality and authenticity of the obtained samples through visual observation and tested their authenticity. We conducted pharmacopoeia compliance testing (quantitative assay, content uniformity tests, and dissolution tests) using the high-performance liquid chromatography-photodiode array detector method. No prescription was ever required at the time of purchase. Visual observation revealed that most samples lacked a package insert and some samples had packaging deficiencies. In terms of authenticity, eight ivermectin samples were genuine; the authenticity of the other samples remained uncertain. Four dexamethasone samples and three ivermectin samples failed quality testing based on pharmacopeia validation standards. Our findings illustrate that dexamethasone and ivermectin tablets of poor quality are available online. It is important to increase consumer awareness and provide information about these medicines to prevent the purchase of substandard medicines via the Internet.

The most destructive period the world has experienced seems to be behind us. Not a single nation was spared by this disease, and many continue to struggle today. Even after recovering from COVID, patient may continue to experience some post-COVID effects, such as heart irregularities or a decline in lung vitality. In the past three years (2019-2022), the world has witnessed the power of a small entity, a single peculiar virus. Science initially appeared to be helpless in this regard, but due to the emergence of disease, pharmaceutics (the development of anti-covid drugs), immunology (the rapid antigen test), microbiology (the isolation of viruses from infected people), biotechnology (the development of recombinant vaccines), biochemistry (the blood profile, the D-dimer test), and biochemistry (blood profile, D-dimer test), biophysics (PCR, RT-PCR, CT Scan, MRI) had worked together to fight the disease. The results of these efforts are the development of new diagnostic techniques, possible treatment and finally the availability of vaccines against COVID-19. However, it is not proven that the treatment through the traditional medical system is directly active on SARS-CoV-2 but is instead indirectly acting on SARS-CoV-2 effects by improving symptoms derived from the viral disease. In India, the traditional system of medicine and tradition knowledge together worked in the pandemic and proved effective strategies in prevention and treatment of SARS-CoV-2. The use of effective masks, PPE kits, plasma therapy, yoga, lockdowns and social seclusion, use of modern antiviral drugs, monoclonal antibodies, herbal remedies, homoeopathy, hygienic practice, as well as the willpower of people, are all contributing to the fight against COVID. Which methods or practices will be effective against COVID nobody is aware since medical professionals who wear PPE kits do not live longer, and some people in India who remained unprotected and roamed freely were not susceptible to infection. The focus of this review is on the mode of transmission, diagnosis, preventive measures, vaccines currently under development, modern medicine developed against SARS-CoV-2, ayurvedic medicine used during pandemic, homoeopathic medicine used during pandemic, and specific yoga poses that can be used to lessen COVID-related symptoms.

Background and objective The use of ivermectin and nitazoxanide in the treatment of coronavirus disease 2019 (COVID-19) has been a subject of controversy. In this study, we aimed to describe our clinical experience in treating COVID-19 patients with these drugs in Mexico. Material and methods The study involved out- and inpatient clinical assessments of COVID-19 patients conducted in Mexico City from September 2020 to November 2021. Outpatients were treated with either ivermectin, nitazoxanide, or both drugs, while all inpatients received both. Clinical and laboratory analyses were used to assess the results. Results Of the 228 subjects in the outpatient group, 26.8% received ivermectin, 25.4% nitazoxanide, and 47.8% both. The proportion of negative polymerase chain reaction (PCR) was highest in patients treated late with ivermectin (≥5 days after symptom onset; p=0.004), followed by those receiving late treatment with nitazoxanide, and those with the combination at any time. The inpatient group had 179 subjects. A significant increase was seen in neutrophil, lymphocyte, monocyte, ferritin, and D-dimer levels, while an opposite trend was observed for C-reactive protein (CRP) and fibrinogen levels. Mechanical ventilation requirement was 15.5%, and 5% died during hospitalization. Conclusions Despite the limitations of our study, based on its findings, ivermectin and nitazoxanide could be useful in reducing the viral load, the requirement for mechanical ventilation, proinflammatory and procoagulant parameters, and the fatality rate in COVID-19 patients. Controlled clinical trials evaluating this combination should be carried out to determine its true usefulness and safety profile.

The COVID-19 epidemic has become a major international health emergency. Millions of people have died as a result of this phenomenon since it began. Has there been any successful pharmacological treatment for COVID-19 since the initial report on the virus? How many searches are undertaken to address the impact of the infection? What is the number of drugs that have undergone investigation? What are the mechanisms of action and adverse effects associated with the investigated pharmaceuticals used to treat COVID-19? Has the Food and Drug Administration (FDA) approved any medication to treat COVID-19? To date, our understanding is based on a restricted corpus of published investigations into the treatment of COVID-19. It is important to note that no single study comprehensively encompasses all pharmacological interventions for COVID-19. This paper provides an introductory summary of a bibliometric analysis conducted on the data about COVID-19, sourced explicitly from two platforms, namely PubMed and ScienceDirect. The analysis encompasses the period spanning from 2019 to 2022. Furthermore, this study examines the published literature about the pharmacological interventions for the novel coronavirus disease 2019 (COVID-19), explicitly focusing on the safety and effectiveness of different medications such as Remdesivir (marketed as Veklury®), Lopinavir/Ritonavir (commercially known as Kaletra® or Aluvia®), Ribavirin, Favipiravir (marketed as Avigan®), Ivermectin, Casirivimab and Imdevimab (branded as Ronapreve®), Sotrovimab (marketed as Xevudy®), Anakinra, Molnupiravir, Nirmatrelvir/Ritonavir (marketed as Paxlovid®), and Galidesivir. Findings indicate that while Remdesivir and Nirmatrelvir/Ritonavir show significant efficacy in reducing hospitalization and severe outcomes, drugs like Lopinavir/Ritonavir and Ivermectin have inconsistent results. Our insights suggest a multifaceted approach incorporating these therapies can significantly improve patient outcomes. Repurposing drugs has been critical in rapidly responding to COVID-19, allowing existing medications to be used in new ways to combat the virus. Combination therapies and further research are essential to optimize treatment strategies.

Giardia lamblia is a flagellated protozoan parasite causing giardiasis, a common intestinal infection characterized by diarrhea, abdominal cramps, and nausea. Treatments employed to combat this parasitic infection have remained unchanged for the past 40 years, leading to the emergence of resistant strains and prompting the search for new therapeutic agents.

This study investigated the cytotoxic effects of ivermectin (IVM) on G. lamblia trophozoites. We conducted dose-response experiments to assess IVM-induced cytotoxicity. We utilized various biochemical and ultrastructural analyses to explore the underlying mechanisms of cell death, including reactive oxygen species (ROS) production, DNA fragmentation, cell cycle arrest, and apoptosis markers.

Our findings demonstrate that IVM induces dose-dependent cytotoxicity and triggers cell death pathways. We found that IVM treatment generates elevated levels of reactive oxygen species (ROS), DNA fragmentation, and arrests of trophozoites in the cell cycle's S phase. Additionally, ultrastructural analysis reveals morphological alterations consistent with apoptosis, such as cytoplasmic vacuolization, chromatin condensation, and tubulin distribution.

The insights gained from this study may contribute to developing new therapeutic strategies against giardiasis, addressing the challenge posed by drug-resistant strains.

Monkeypox (mpox) is a zoonotic illness caused by the monkeypox virus (MPXV), with higher health concerns among people who are pregnant, children, and persons who are immunocompromised, including people with untreated and advanced HIV disease. Significant progress has been made in developing vaccines against mpox, yet critical challenges and limitations persist in ensuring their effectiveness, safety, and accessibility. The pertinence of this review is highlighted by the World Health Organization's declaration of a global health emergency on August 14, 2024, due to the recent mpox outbreak, underscoring the critical necessity for effective vaccine solutions in the face of a rapidly evolving virus. Here, we comprehensively analyze various vaccine platforms utilized in mpox prevention, including attenuated and non-replicating virus vaccines, viral vector-based vaccines, recombinant protein vaccines, and DNA and mRNA vaccines. We evaluate the advantages and limitations of each platform, highlighting the urgent need for ongoing research and innovation to enhance vaccine efficacy and safety. Recent advancements, such as incorporating immunostimulatory sequences, improved delivery systems, and developing polyvalent vaccines, are explored for their potential to offer broader protection against diverse orthopoxvirus strains. This work underscores the need to optimize currently available vaccines and investigate novel vaccination strategies to address future public health emergencies effectively. By focusing on these advanced methodologies, we aim to contribute to the development of robust and adaptable vaccine solutions for mpox and other related viral threats.

Osteosarcoma is the most common malignant bone tumor in children and adolescents. Conventional chemotherapy remains unsatisfactory due to drug toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatments for advanced osteosarcoma. In the current study, we focused on evaluating the anticancer efficacy of avermectin B1, a novel avermectin analog, against osteosarcoma cells.

The half-inhibitory concentration of avermectin B1 was calculated in three osteosarcoma cell lines. Then, functional experiments were conducted to evaluate the effects of avermectin B1 on cell proliferation, the cell cycle, apoptosis and autophagy. Moreover, the AMPK/ULK1 signaling pathway was detected by Western blot assay. Finally, the in vivo effect of avermectin B1 on tumor growth and metastasis was investigated using the xenograft mouse model. To examine the role of the AMPK/ULK1 pathway, an AMPK-specific inhibitor (dorsomorphin) was used in combination with avermectin B1.

Avermectin B1 inhibited the proliferation of osteosarcoma cells in a dose-dependent manner based on CCK8 and colony formation assays. Then, it was found to inhibit migration and invasion by wound healing assay and cell migration and invasion assay. In addition, avermectin B1 induced osteosarcoma cell apoptosis and autophagy. In vivo, avermectin B1 effectively inhibited osteosarcoma cell growth and pulmonary metastasis. Mechanistically, avermectin B1 activated the AMPK/ULK1 pathway to exert antitumor activity in vitro and in vivo. Dorsomorphin significantly attenuated the Avermectin B1-induced antitumor activities.

Our study suggests that avermectin B1 is a potential agent to treat osteosarcoma cells through the AMPK/ULK1 signaling pathway.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) has emerged as the causative agent behind the global pandemic of Coronavirus Disease 2019 (COVID-19). As the scientific community strives to comprehend the intricate workings of this virus, a fundamental aspect lies in deciphering the myriad proteins it expresses. This knowledge is pivotal in unraveling the complexities of the viral machinery and devising targeted therapeutic interventions. The proteomic landscape of SARS-CoV2 encompasses structural, non-structural, and open-reading frame proteins, each playing crucial roles in viral replication, host interactions, and the pathogenesis of COVID-19. This comprehensive review aims to provide an updated and detailed examination of the structural and functional attributes of SARS-CoV2 proteins. By exploring the intricate molecular architecture, we have highlighted the significance of these proteins in viral biology. Insights into their roles and interplay contribute to a deeper understanding of the virus's mechanisms, thereby paving the way for the development of effective therapeutic strategies. As the global scientific community strives to combat the ongoing pandemic, this synthesis of knowledge on SARS-CoV2 proteins serves as a valuable resource, fostering informed approaches toward mitigating the impact of COVID-19 and advancing the frontier of antiviral research.

Background: During the coronavirus disease (COVID)-19 pandemic several drugs were used to manage the patients mainly those with a severe phenotype. Potential drugs were used off-label and major concerns arose from their applicability to managing the health crisis highlighting the importance of clinical trials. In this context, we described the mechanisms of the three repurposed drugs [Ivermectin-antiparasitic drug, Chloroquine/Hydroxychloroquine-antimalarial drugs, and Azithromycin-antimicrobial drug]; and, based on this description, the study evaluated the clinical efficacy of those drugs published in clinical trials. The use of these drugs reflects the period of uncertainty that marked the beginning of the COVID-19 pandemic, which made them a possible treatment for COVID-19. Methods: In our review, we evaluated phase III randomized controlled clinical trials (RCTs) that analyzed the efficacy of these drugs published from the COVID-19 pandemic onset to 2023. We included eight RCTs published for Ivermectin, 11 RCTs for Chloroquine/Hydroxychloroquine, and three RCTs for Azithromycin. The research question (PICOT) accounted for P-hospitalized patients with confirmed or suspected COVID-19; I-use of oral or intravenous Ivermectin OR Chloroquine/Hydroxychloroquine OR Azithromycin; C-placebo or no placebo (standard of care); O-mortality OR hospitalization OR viral clearance OR need for mechanical ventilation OR clinical improvement; and T-phase III RCTs. Results: While studying these drugs' respective mechanisms of action, the reasons for which they were thought to be useful became apparent and are as follows: Ivermectin binds to insulin-like growth factor and prevents nuclear transportation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), therefore preventing cell entrance, induces apoptosis, and osmotic cell death and disrupts viral replication. Chloroquine/Hydroxychloroquine blocks the movement of SARS-CoV-2 from early endosomes to lysosomes inside the cell, also, this drug blocks the binding between SARS-CoV-2 and Angiotensin-Converting Enzyme (ACE)-2 inhibiting the interaction between the virus spike proteins and the cell membrane and this drug can also inhibit SARS-CoV-2 viral replication causing, ultimately, the reduction in viral infection as well as the potential to progression for a higher severity phenotype culminating with a higher chance of death. Azithromycin exerts a down-regulating effect on the inflammatory cascade, attenuating the excessive production of cytokines and inducing phagocytic activity, and acts interfering with the viral replication cycle. Ivermectin, when compared to standard care or placebo, did not reduce the disease severity, need for mechanical ventilation, need for intensive care unit, or in-hospital mortality. Only one study demonstrated that Ivermectin may improve viral clearance compared to placebo. Individuals who received Chloroquine/Hydroxychloroquine did not present a lower incidence of death, improved clinical status, or higher chance of respiratory deterioration compared to those who received usual care or placebo. Also, some studies demonstrated that Chloroquine/Hydroxychloroquine resulted in worse outcomes and side-effects included severe ones. Adding Azithromycin to a standard of care did not result in clinical improvement in hospitalized COVID-19 participants. In brief, COVID-19 was one of the deadliest pandemics in modern human history. Due to the potential health catastrophe caused by SARS-CoV-2, a global effort was made to evaluate treatments for COVID-19 to attenuate its impact on the human species. Unfortunately, several countries prematurely justified the emergency use of drugs that showed only in vitro effects against SARS-CoV-2, with a dearth of evidence supporting efficacy in humans. In this context, we reviewed the mechanisms of several drugs proposed to treat COVID-19, including Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin, as well as the phase III clinical trials that evaluated the efficacy of these drugs for treating patients with this respiratory disease. Conclusions: As the main finding, although Ivermectin, Chloroquine/Hydroxychloroquine, and Azithromycin might have mechanistic effects against SARS-CoV-2 infection, most phase III clinical trials observed no treatment benefit in patients with COVID-19, underscoring the need for robust phase III clinical trials.

Angiotensin-converting enzyme-2 (ACE2) downregulation represents a detrimental factor in people with a baseline ACE2 deficiency associated with older age, hypertension, diabetes, and cardiovascular diseases. Human coronaviruses, including HCoV-NL63, SARS-CoV-1, and SARS CoV-2 infect target cells via binding of viral spike (S) glycoprotein to the ACE2, resulting in ACE2 downregulation through yet unidentified mechanisms. This downregulation disrupts the enzymatic activity of ACE2, essential in protecting against organ injury by cleaving and disposing of Angiotensin-II (Ang II), leading to the formation of Ang 1-7, thereby exacerbating the accumulation of Ang II. This accumulation activates the Angiotensin II type 1 receptor (AT1R) receptor, leading to leukocyte recruitment and increased proinflammatory cytokines, contributing to organ injury. The biological impacts and underlying mechanisms of ACE2 downregulation during SARS-CoV-2 infection have not been well defined. Therefore, there is an urgent need to establish a solid theoretical and experimental understanding of the mechanisms of ACE2 downregulation during SARS-CoV-2 entry and replication in the host cells. This review aims to discuss the physiological impact of ACE2 downregulation during coronavirus infection, the relationship between ACE2 decline and virus pathogenicity, and the possible mechanisms of ACE2 degradation, along with the therapeutic approaches.

One of the most significant threats to global public health in the 21st century is the novel coronavirus disease (COVID-19) caused by SARS-CoV-2. It rapidly turned into a global pandemic after it was identified in late 2019, and the World Health Organization announced the end of the pandemic on May 5, 2023. Current strategies for managing this disease include vaccination and repurposing antimalarial and antibiotic medications to alleviate symptoms like fever and throat pain, which are associated with acute respiratory distress syndrome (ARDS). Antiviral drugs such as chloroquine, hydroxychloroquine, azithromycin, remdesivir, and favipiravir have been repurposed for the treatment of COVID-19. They were previously recommended for treating SARS-CoV and MERS-CoV. However, the inefficacy and adverse side effects of these repurposed drugs led to a decrease in their widespread use in treating COVID-19 patients. The lack of approved drugs for combating this coronavirus and its unpredictable variants remains a significant challenge.

In 2019, a global viral pandemic, due to the SARS-CoV-2 virus, broke out. Soon after, the search for a vaccine and/or antiviral medicine began. One of the candidate antiviral medicines tested was ivermectin. Although several health authorities warned the public against the use of this medicine outside clinical trials, the drug was widely used at the end of 2020 and in 2021. Simultaneously, several reports started to emerge demonstrating serious adverse effects after self-medicating with ivermectin. It stands to reason that the self-administration of substandard or falsified (SF) medicines bearing harmful quality deficiencies have contributed to this phenomenon. In order to have a better view on the nature of these harmful quality deficiencies, SF ivermectin samples, intercepted in large quantities by the Belgian regulatory agencies during the period 2021-2022, were analyzed in our official medicines control laboratory. None of the samples (n = 19) were compliant to the quality criteria applicable to medicinal products. These SF products either suffered from a systematic underdosing of the active pharmaceutical ingredient or were severely contaminated with bacteria, two of which were contaminated with known pathogens that cause gastrointestinal illness upon oral intake. In addition to the direct risks of self-medicating with such a product, the improper usage and dosage of ivermectin medication might also facilitate ivermectin tolerance or resistance in parasites. This may have detrimental consequences on a global scale, certainly as the number of newly developed active pharmaceutical ingredients that can safely be used to combat parasites is rather scarce.

The original COVID-19 vaccines, developed against SARS-CoV-2, initially mitigated hospitalizations. Bivalent vaccine boosters were used widely during 2022-23, but the outbreaks persisted. Despite this, hospitalizations, mortality, and outbreaks involving dominant mutants like Alpha and Delta increased during winters when the population's vitamin D levels were at their lowest. Notably, 75 % of human immune cell/system functions, including post-vaccination adaptive immunity, rely on adequate circulatory vitamin D levels. Consequently, hypovitaminosis compromises innate and adaptive immune responses, heightening susceptibility to infections and complications. COVID-19 vaccines primarily target SARS-CoV-2 Spike proteins, thus offering only a limited protection through antibodies. mRNA vaccines, such as those for COVID-19, fail to generate secretory/mucosal immunity-like IgG responses, rendering them ineffective in halting viral spread. Additionally, mutations in the SARS-CoV-2 binding domain reduce immune recognition by vaccine-derived antibodies, leading to immune evasion by mutant viruses like Omicron variants. Meanwhile, the repeated administration of bivalent boosters intended to enhance efficacy resulted in the immunoparesis of recipients. As a result, relying solely on vaccines for outbreak prevention, it became less effective. Dominant variants exhibit increased affinity to angiotensin-converting enzyme receptor-2, enhancing infectivity but reducing virulence. Meanwhile, spike protein-related viral mutations do not impact the potency of widely available, repurposed early therapies, like vitamin D and ivermectin. With the re-emergence of COVID-19 and impending coronaviral pandemics, regulators and health organizations should proactively consider approval and strategic use of cost-effective adjunct therapies mentioned above to counter the loss of vaccine efficacy against emerging variants and novel coronaviruses and eliminate vaccine- and anti-viral agents-related serious adverse effects. Timely implementation of these strategies could reduce morbidity, mortality, and healthcare costs and provide a rational approach to address future epidemics and pandemics. This perspective critically reviews relevant literature, providing insights, justifications, and viewpoints into how the scientific community and health authorities can leverage this knowledge cost-effectively.

Ivermectin, a broad-spectrum anti-parasitic drug, has been proposed as a novel vector control tool to reduce malaria transmission by mass drug administration. Ivermectin and some metabolites have mosquito-lethal effect, reducing Anopheles mosquito survival. Ivermectin inhibits liver stage development in a rodent malaria model, but no inhibition was observed in a primate malaria model or in a human malaria challenge trial. In the liver, cytochrome P450 3A4 and 3A5 enzymes metabolize ivermectin, which may impact drug efficacy. Thus, understanding ivermectin metabolism and assessing this impact on Plasmodium liver stage development is critical. Using primary human hepatocytes (PHHs), we characterized ivermectin metabolism and evaluated the efficacy of ivermectin and its primary metabolites M1 (3″-O-demethyl ivermectin) and M3 (4-hydroxymethyl ivermectin) against Plasmodium falciparum liver stages. Two different modes of ivermectin exposure were evaluated: prophylactic mode (days 0-3 post-infection) and curative mode (days 3-5 post-infection). We used two different PHH donors and modes to determine the inhibitory concentration (IC50) of ivermectin, M1, M3, and the known anti-malarial drug pyrimethamine, with IC50 values ranging from 1.391 to 14.44, 9.95-23.71, 4.767-8.384, and 0.9073-5.416 µM, respectively. In our PHH model, ivermectin and metabolites M1 and M3 demonstrated inhibitory activity against P. falciparum liver stages in curative treatment mode (days 3-5) and marginal activity in prophylactic treatment mode (days 0-3). Ivermectin had improved efficacy when co-administered with ketoconazole, a specific inhibitor of cytochrome P450 3A4 enzyme. Further studies should be performed to examine ivermectin liver stage efficacy when co-administered with CYP3A4 inhibitors and anti-malarial drugs to understand the pharmacokinetic and pharmacodynamic drug-drug interactions that enhance efficacy against human malaria parasites in vitro.

This study aimed to assess and compare diverse formulations of ivermectin-loaded liposomes, employing lipid film hydration and ethanol injection methods. Three lipids (DOPC, SPC, and DSPC) were used in predetermined molar ratios. A total of 18 formulations were created, and a factorial design determined the optimal formulation based on particle size, polydispersity index (PDI), zeta potential, and encapsulation efficiency. The average mean particle size, PDI and zeta potential of the selected formulations (F1, F2, F7, F9, and F11) was, respectively, 196.40 ± 44.60 nm, 0.39 ± 0.09, and -40.24 ± 9.17. The encapsulation efficiency exceeded 80%, with a mean loading capacity of 4.00 ± 1.70%. In vitro studies included transmission electron microscopy, Fourier transform infrared spectroscopy, drug release, and antiviral activity assessments against SARS-CoV-2. The liposomal formulations demonstrated superior antiviral activity compared to free ivermectin, as indicated by lower IC50 values. The results of this study emphasize the effectiveness of ivermectin-loaded liposomes in inhibiting viral activity, highlighting their potential as promising candidates for antiviral therapy. The findings suggest that the strategic use of liposomes as drug carriers can significantly modulate and improve the antiviral properties of ivermectin, offering a novel approach to harnessing its full therapeutic potential. Collectively, these results provide a robust foundation for further exploration of ivermectin as a viral protection tool and optimization of its delivery mechanisms.

SARS-CoV-2 spread rapidly across the globe, contributing to the death of millions of individuals from 2019 to 2023, and has continued to be a major cause of morbidity and mortality after the pandemic. At the start of the pandemic, no vaccines or anti-viral treatments were available to reduce the burden of disease associated with this virus, as it was a novel SARS coronavirus. Because of the tremendous need, the development of vaccines to protect against COVID-19 was critically important. The flexibility and ease of manufacture of nucleic acid-based vaccines, specifically mRNA-based products, allowed the accelerated development of COVID-19 vaccines. Although mRNA-based vaccines and therapeutics had been in clinical trials for over a decade, there were no licensed mRNA vaccines on the market at the start of the pandemic. The rapid development of mRNA-based COVID-19 vaccines reduced serious complications and death from the virus but also engendered significant public concerns, which continue now, years after emergency-use authorization and subsequent licensure of these vaccines. This article summarizes and addresses some of the safety concerns that continue to be expressed about these vaccines and their underlying technology.