Modern aspects of COVID-19 in HIV-positive patients (literature review)

The article is devoted to the global problems of modern medicine - HIV infection and the COVID-19 pandemic. The review of the literature highlights current ideas about the pathogenesis and course of COVID-19 in patients with HIV infection, and also touches upon the problems of concomitant pathology and mental health of patients with HIV in the setting of the COVID-19 pandemic. It has been shown that HIV-positive patients are a risk group for the severe course of COVID-19, in particular, individuals with severe immunodeficiency (CD4+ T lymphocytes 200 cells/l) due to the development of synergetic lung damage by SARS-CoV-2 and secondary infectious agents such as cytomegalovirus and Pneumocystis carinii. It has been proven that one of the targets of the SARS-CoV-2 virus is CD4+ T cells, which in COVID-19 leads to a more rapid progression of immunodeficiency in patients with HIV infection and, thus, significantly increases the risk of secondary diseases and death. Particular attention should be paid to middle-aged and elderly people living with HIV, who, compared with HIV-negative patients, are more likely to have concomitant pathology - arterial hypertension, cardiomyopathy and diabetes mellitus, which are the risk factors for severe COVID-19. The results of studies on the effect of antiretroviral drugs on the course of COVID-19 showed that HIV-infected patients receiving tenofovir + emtricitabine have a lower risk of severe COVID-19 and associated hospitalization than patients receiving other HIV treatment regimens. Clinical and preclinical data support the potential use of tenofovir in the treatment of novel coronavirus infection.

A descriptive analytical study to assess the efficacy of combination of various drugs in the treatment of COVID-19 infections

Purpose and Background: The purpose of this study is to examine the efficacy of several medications that are administered for the treatment of patients who have mild, moderate and severe case.

Data Mining and Network Pharmacology on Tibetan Medicine Prescriptions for the Prevention and Treatment of COVID-19

In this paper, the compatibility rules and drug combinations of Tibetan medicine prescriptions are explored, and the possible anti-epidemic mechanism is analyzed from the perspectives of biological network and signaling pathway, so as to provide reference for scientifically elaborating the potential value of ancient Tibetan medicine in preventing epidemic diseases. Association rules and clustering analysis are used for Tibetan drug mining. A total of 18 prescriptions involving 113 Tibetan medicinal materials were included, and 26 high-frequency Tibetan medicinal materials with the statistical frequency ≥3 are included, most of which are medicinal materials for clearing heat, detoxicating, eliminating plague. Thirteen potential drug combinations are obtained through association rule analysis. The KMean clustering and hierarchical clustering were used for clustering analysis to obtain five drug clusters, and the "Bamusaeconcretiosilicea - Carthami Flos"combination was selected for network pharmacology research by comparing the two methods. After drug target and pathway analysis, "Bamusaeconcretiosilicea - Carthami Flos"through MAPK cascade, response to oxygen level, reactive oxygen species metabolism process, PI3K-Akt signaling pathway, NF- κ B signaling pathway, cytokine-cytokine Receptor interaction and calcium signaling pathways have certain feasibility for the treatment of immune disease fever in three aspects: immune response, inflammatory response, and oxidative stress. © 2022 IEEE.

Combinations of Host- and Virus-Targeting Antiviral Drugs Confer Synergistic Suppression of SARS-CoV-2.

Three directly acting antivirals (DAAs) demonstrated substantial reduction in COVID-19 hospitalizations and deaths in clinical trials. However, these agents did not completely prevent severe illness and are associated with cases of rebound illness and viral shedding. Combination regimens can enhance antiviral potency, reduce the emergence of drug-resistant variants, and lower the dose of each component in the combination. Concurrently targeting virus entry and virus replication offers opportunities to discover synergistic drug combinations. While combination antiviral drug treatments are standard for chronic RNA virus infections, no antiviral combination therapy has been approved for SARS-CoV-2. Here, we demonstrate that combining host-targeting antivirals (HTAs) that target TMPRSS2 and hence SARS-CoV-2 entry, with the DAA molnupiravir, which targets SARS-CoV-2 replication, synergistically suppresses SARS-CoV-2 infection in Calu-3 lung epithelial cells. Strong synergy was observed when molnupiravir, an oral drug, was combined with three TMPRSS2 (HTA) oral or inhaled inhibitors: camostat, avoralstat, or nafamostat. The combination of camostat plus molnupiravir was also effective against the beta and delta variants of concern. The pyrimidine biosynthesis inhibitor brequinar combined with molnupiravir also conferred robust synergistic inhibition. These HTA+DAA combinations had similar potency to the synergistic all-DAA combination of molnupiravir plus nirmatrelvir, the protease inhibitor found in paxlovid. Pharmacodynamic modeling allowed estimates of antiviral potency at all possible concentrations of each agent within plausible therapeutic ranges, suggesting possible in vivo efficacy. The triple combination of camostat, brequinar, and molnupiravir further increased antiviral potency. These findings support the development of HTA+DAA combinations for pandemic response and preparedness. IMPORTANCE Imagine a future viral pandemic where if you test positive for the new virus, you can quickly take some medicines at home for a few days so that you do not get too sick. To date, only single drugs have been approved for outpatient use against SARS-CoV-2, and we are learning that these have some limitations and may succumb to drug resistance. Here, we show that combinations of two oral drugs are better than the single ones in blocking SARS-CoV-2, and we use mathematical modeling to show that these drug combinations are likely to work in people. We also show that a combination of three oral drugs works even better at eradicating the virus. Our findings therefore bode well for the development of oral drug cocktails for at home use at the first sign of an infection by a coronavirus or other emerging viral pathogens.

Clinical analysis of drug-induced liver dysfunction in COVID-19 patients in the third hospital of Wuhan in 2020

Objective: To investigate the general rules and characteristics of drug-induced liver dysfunction during the treatment of COVID-19, and to provide references for safe clinical use.

Medication Errors

Paxlovid drug interaction... Eprontia oral solution concentration conversion... Different concentrations of oral liquid Baclofen

Clinical characteristics and factors influencing development of a pulmonary fungal infection in patients with severe respiratory diseases

Objectives: To examine the clinical characteristics, drug resistance, and factors influencing development of a pulmonary fungal infection in patients with severe respiratory diseases in order to provide a reference for clinical treatment.

IDentif.AI-Omicron: Harnessing an AI-Derived and Disease-Agnostic Platform to Pinpoint Combinatorial Therapies for Clinically Actionable Anti-SARS-CoV-2 Intervention.

Nanomedicine-based and unmodified drug interventions to address COVID-19 have evolved over the course of the pandemic as more information is gleaned and virus variants continue to emerge. For example, some early therapies (e.g., antibodies) have experienced markedly decreased efficacy. Due to a growing concern of future drug resistant variants, current drug development strategies are seeking to find effective drug combinations. In this study, we used IDentif.AI, an artificial intelligence-derived platform, to investigate the drug-drug and drug-dose interaction space of six promising experimental or currently deployed therapies at various concentrations: EIDD-1931, YH-53, nirmatrelvir, AT-511, favipiravir, and auranofin. The drugs were tested in vitro against a live B.1.1.529 (Omicron) virus first in monotherapy and then in 50 strategic combinations designed to interrogate the interaction space of 729 possible combinations. Key findings and interactions were then further explored and validated in an additional experimental round using an expanded concentration range. Overall, we found that few of the tested drugs showed moderate efficacy as monotherapies in the actionable concentration range, but combinatorial drug testing revealed significant dose-dependent drug-drug interactions, specifically between EIDD-1931 and YH-53, as well as nirmatrelvir and YH-53. Checkerboard validation analysis confirmed these synergistic interactions and also identified an interaction between EIDD-1931 and favipiravir in an expanded range. Based on the platform nature of IDentif.AI, these findings may support further explorations of the dose-dependent drug interactions between different drug classes in further pre-clinical and clinical trials as possible combinatorial therapies consisting of unmodified and nanomedicine-enabled drugs, to combat current and future COVID-19 strains and other emerging pathogens.

Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology.

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a "magic bullet" drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.

Effectiveness of anti-TB medicines in treating patients experiencing COVID-19 symptoms

Introduction: COVID-19, the life-threatening disease caused by the pathogenic SARS-CoV-2 virus, has limited treatment or measures for curing the infected persons. However, many antibiotics have been tried with varied results.

Pre-Clinical Tools for Predicting Drug Efficacy in Treatment of Tuberculosis.

Combination therapy has, to some extent, been successful in limiting the emergence of drug-resistant tuberculosis. Drug combinations achieve this advantage by simultaneously acting on different targets and metabolic pathways. Additionally, drug combination therapies are shown to shorten the duration of therapy for tuberculosis. As new drugs are being developed, to overcome the challenge of finding new and effective drug combinations, systems biology commonly uses approaches that analyse mycobacterial cellular processes. These approaches identify the regulatory networks, metabolic pathways, and signaling programs associated with M. tuberculosis infection and survival. Different preclinical models that assess anti-tuberculosis drug activity are available, but the combination of models that is most predictive of clinical treatment efficacy remains unclear. In this structured literature review, we appraise the options to accelerate the TB drug development pipeline through the evaluation of preclinical testing assays of drug combinations.

Efficacy of Sofosbuvir and Daclatasvir on the prognosis of kidney transplantation recipients with SARS-CoV-2 infection;a single-center study in Shariati Hospital

Introduction. The novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory coronavirus 2 (SARS-COV-2), was reported in Wuhan, China, in early December 2019 and spread rapidly worldwide. In the COVID-19 era, Kidney transplantation recipients (KTRs) are at high risk due to using immunosuppressive drugs. Therefore, finding an efficient treatment for the management of COVID-19 in KTR patients is crucial due to its poor prognosis. Despite the use of various antiviral and anti-inflammatory drugs, there is yet no definitive cure for Covid-19. Repurposing existing pharmaceuticals is a way to find an immediate medication. Thus, we assessed the antiviral treatment efficacy of Sofosbuvir combined with Daclatasvir on KTRs with SARS-COV-2 infection. Methods. We conducted a single-center retrospective cross-sectional study of all adult kidney transplant recipients with COVID-19, admitted to Shariati Hospital, Tehran, Iran, from October to December 2020. All the patients received a once-daily combination pill of SOF and DAC at a dose of 400/60 mg for 10 days. The study protocol was approved by the Ethical Committee of the Tehran University of Medical Sciences under ID: IR. TUMS. DDRI. REC.1399.028. Statistical analysis was performed using IBM SPSS version 26.0. A P value less than 0.05 was considered statistically significant for all tests. Results. From October to December 2020, 12 adult KTR patients were recruited;four patients (33.3%) died and eight patients survived (66.7%). The dead patients were older than those who survived. However, it was not statistical significance (53.67 .. 3.786 vs. 47.63 .. 11.868, P = 0.422). Acute kidney injury (AKI) due to COVID-19 infection was seen in 11 patients of the study population (91.7%) and all four dead KTRs. Also, three patients underwent dialysis, which two died (50%). The most common comorbidities were hypertension (6 patients, 50%) and diabetes mellitus (4 patients, 33.3%), while no significant correlation was seen between comorbidities and mortality (P > 0.05). About the immunosuppressive drugs, of four dead patients, three (75%) used Mycophenolate, and all of them used Prednisolone. The laboratory results showed that the mean level of each parameter WBC, INR, CRP, Ferritin, D-Dimer on the last day of hospital stay was significantly different between two groups of survived and dead patients at a 95% confidence level (P < 0.05). Conclusion. Sofosbuvir combined with Daclatasvir for treatment of KTRs with SARS-COV-2 infection showed efficacy by reducing the mortality rate. Also, the medication was safe. Patients tolerated it well, and no serious adverse effects were observed. Larger studies are needed to validate these results.

Drugs repurposed for COVID-19 by virtual screening of 6,218 drugs and cell-based assay.

The COVID-19 pandemic caused by SARS-CoV-2 is an unprecedentedly significant health threat, prompting the need for rapidly developing antiviral drugs for the treatment. Drug repurposing is currently one of the most tangible options for rapidly developing drugs for emerging and reemerging viruses. In general, drug repurposing starts with virtual screening of approved drugs employing various computational methods. However, the actual hit rate of virtual screening is very low, and most of the predicted compounds are false positives. Here, we developed a strategy for virtual screening with much reduced false positives through incorporating predocking filtering based on shape similarity and postdocking filtering based on interaction similarity. We applied this advanced virtual screening approach to repurpose 6,218 approved and clinical trial drugs for COVID-19. All 6,218 compounds were screened against main protease and RNA-dependent RNA polymerase of SARS-CoV-2, resulting in 15 and 23 potential repurposed drugs, respectively. Among them, seven compounds can inhibit SARS-CoV-2 replication in Vero cells. Three of these drugs, emodin, omipalisib, and tipifarnib, show anti-SARS-CoV-2 activities in human lung cells, Calu-3. Notably, the activity of omipalisib is 200-fold higher than that of remdesivir in Calu-3. Furthermore, three drug combinations, omipalisib/remdesivir, tipifarnib/omipalisib, and tipifarnib/remdesivir, show strong synergistic effects in inhibiting SARS-CoV-2. Such drug combination therapy improves antiviral efficacy in SARS-CoV-2 infection and reduces the risk of each drug's toxicity. The drug repurposing strategy reported here will be useful for rapidly developing drugs for treating COVID-19 and other viruses.

Corilagin inhibits SARS-CoV-2 replication by targeting viral RNA-dependent RNA polymerase.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become one major threat to human population health. The RNA-dependent RNA polymerase (RdRp) presents an ideal target of antivirals, whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus. Herein, we report that corilagin (RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp, binds directly to RdRp, effectively inhibits the polymerase activity in both cell-free and cell-based assays, fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration (EC50) value of 0.13 µmol/L. Computation modeling predicts that RAI-S-37 lands at the palm domain of RdRp and prevents conformational changes required for nucleotide incorporation by RdRp. In addition, combination of RAI-S-37 with remdesivir exhibits additive activity against anti-SARS-CoV-2 RdRp. Together with the current data available on the safety and pharmacokinetics of corilagin as a medicinal herbal agent, these results demonstrate the potential of being developed into one of the much-needed SARS-CoV-2 therapeutics.

Synergistic and Antagonistic Drug Combinations against SARS-CoV-2.

Antiviral drug development for coronavirus disease 2019 (COVID-19) is occurring at an unprecedented pace, yet there are still limited therapeutic options for treating this disease. We hypothesized that combining drugs with independent mechanisms of action could result in synergy against SARS-CoV-2, thus generating better antiviral efficacy. Using in silico approaches, we prioritized 73 combinations of 32 drugs with potential activity against SARS-CoV-2 and then tested them in vitro. Sixteen synergistic and eight antagonistic combinations were identified; among 16 synergistic cases, combinations of the US Food and Drug Administration (FDA)-approved drug nitazoxanide with remdesivir, amodiaquine, or umifenovir were most notable, all exhibiting significant synergy against SARS-CoV-2 in a cell model. However, the combination of remdesivir and lysosomotropic drugs, such as hydroxychloroquine, demonstrated strong antagonism. Overall, these results highlight the utility of drug repurposing and preclinical testing of drug combinations for discovering potential therapies to treat COVID-19.

Potential Antiviral Options against SARS-CoV-2 Infection.

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.