AI for Drug Repurposing in the Pandemic Response

Given the time criticality of finding treatments for the novel COVID-19 pandemic disease, drug repurposing has proved to be a vital strategy as the first response while de novo drug and vaccine developments are underway. Furthermore, Artificial Intelligence (AI) has also accelerated drug development in general. Key desirable features of AI that support a rapid and sustained response along the pandemic timeline include technical flexibility and efficiency (i.e. speed, resource-efficiency, algorithm adaptability), and clinical applicability and acceptability (i.e. scientific rigor, physiological applicability and practical implementation of proposed drugs). This chapter reviews a selection of AI-based applications used in drug development targeting COVID-19, including IDentif.AI-a small data platform for a rapid identification of optimal drug combinations, to illustrate the potential of AI in drug repurposing. The benefits and limitations of using Real-World Data are also discussed. The response to the COVID-19 pandemic has offered multiple learnings which highlight the need to strengthen both short- and long-term strategies in developing AI technologies, scientific and regulatory frameworks as well as worldwide collaborations to enable effective preparedness for future epidemic and pandemic risks. © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2022.

A comprehensive overview on COVID-associated mucormycosis

In recent times, numerous reports of systemic fungal infections have been a major concern. The angioinvasive fungal infection, mucormycosis has surged in patients with COVID-19 due to various factors, mainly uncontrolled diabetes and inappropriate corticosteroid use. The prevalence of this acute and fatal fungal infection caused by Mucorales-related fungal species has been highest in the Indian population. COVID-associated mucormycosis (CAM) has a propensity for contiguous spread, and exhibits high morbidity as well as mortality. Unless promptly detected and treated, it is associated with a poor prognosis. A high index of suspicion, aggressive surgical debridement and use of systemic antifungal agents continue to be the standard of care for CAM. Moreover, there is an imperative need to address this public health issue by increasing public awareness and education. This article provides a comprehensive overview on the emergence of CAM during the pandemic, the current burden, pathophysiology, diagnostic interventions and management of CAM in Indian clinical practice.

Combination Therapy with UV-4B and Molnupiravir Enhances SARS-CoV-2 Suppression.

The host targeting antiviral, UV-4B, and the RNA polymerase inhibitor, molnupiravir, are two orally available, broad-spectrum antivirals that have demonstrated potent activity against SARS-CoV-2 as monotherapy. In this work, we evaluated the effectiveness of UV-4B and EIDD-1931 (molnupiravir's main circulating metabolite) combination regimens against the SARS-CoV-2 beta, delta, and omicron BA.2 variants in a human lung cell line. Infected ACE2 transfected A549 (ACE2-A549) cells were treated with UV-4B and EIDD-1931 both as monotherapy and in combination. Viral supernatant was sampled on day three when viral titers peaked in the no-treatment control arm, and levels of infectious virus were measured by plaque assay. The drug-drug effect interaction between UV-4B and EIDD-1931 was also defined using the Greco Universal Response Surface Approach (URSA) model. Antiviral evaluations demonstrated that treatment with UV-4B plus EIDD-1931 enhanced antiviral activity against all three variants relative to monotherapy. These results were in accordance with those obtained from the Greco model, as these identified the interaction between UV-4B and EIDD-1931 as additive against the beta and omicron variants and synergistic against the delta variant. Our findings highlight the anti-SARS-CoV-2 potential of UV-4B and EIDD-1931 combination regimens, and present combination therapy as a promising therapeutic strategy against SARS-CoV-2.

[Treatment of toxic hepatitis in COVID-19 patients].

BACKGROUND: The article reflects the clinical significance of the early diagnosis of toxic hepatitis in patients who have undergone a new coronavirus infection with the determination of clinical and laboratory predictors of the response to therapy. A dynamic analysis of the effectiveness of toxic hepatitis therapy in patients of three experimental groups and a control group is presented. AIM: The aim of the present study is to increase the effectiveness of the treatment of toxic hepatitis in patients who have undergone COVID-19. MATERIALS AND METHODS: On the basis of the newly created infection centers of the Central Clinical Hospital "RZhD-Medicine" and Vishnevsky 3-rd Central Military Clinical Hospital 996 patients with COVID-19, who had clinical and laboratory signs of toxic liver damage (cytolytic and/or cholestatic syndromes) against the background of COVID-19 therapy. RESULTS: On the 14th day from the start of therapy in group 3, there was a significant decrease in the clinical manifestations of jaundice in 163 (72.8%) patients, on the 21st day of treatment, this symptom was stopped in all patients. In groups 1 and 2, the decrease in clinical manifestations of jaundice was significantly lower - 122 (55.2%) and 134 (58.8%); p<0.05. At the end of therapy, no manifestations of jaundice were observed in all experimental groups, while in the control group, symptom reduction was achieved only in 47 (14.5%) patients. CONCLUSION: The use of drugs with hepatoprotective effect in the form of monotherapy in groups 1 (UDCA) and 2 (ademethionine) showed a low therapeutic effect with positive dynamics of clinical and laboratory indicators of toxic hepatitis activity. The use of combined treatment in group 3 (UDCA and ademethionine) demonstrated the maximum therapeutic effect, pronounced positive dynamics in the form of normalization of clinical and laboratory indicators of toxic hepatitis activity.

Efficacy of Remdesivir and Neutralizing Monoclonal Antibodies in Monotherapy or Combination Therapy in Reducing the Risk of Disease Progression in Elderly or Immunocompromised Hosts Hospitalized for COVID-19: A Single Center Retrospective Study.

INTRODUCTION: Remdesivir (REM) and monoclonal antibodies (mAbs) could alleviate severe COVID-19 in at-risk outpatients. However, data on their use in hospitalized patients, particularly in elderly or immunocompromised hosts, are lacking. METHODS: All consecutive patients hospitalized with COVID-19 at our unit from 1 July 2021 to 15 March 2022 were retrospectively enrolled. The primary outcome was the progression to severe COVID-19 (P/F < 200). Descriptive statistics, a Cox univariate-multivariate model, and an inverse probability treatment-weighted (IPTW) analysis were performed. RESULTS: Overall, 331 subjects were included; their median (q1-q3) age was 71 (51-80) years, and they were males in 52% of the cases. Of them, 78 (23%) developed severe COVID-19. All-cause in-hospital mortality was 14%; it was higher in those with disease progression (36% vs. 7%, p < 0.001). REM and mAbs resulted in a 7% (95%CI = 3-11%) and 14% (95%CI = 3-25%) reduction in the risk of severe COVID-19, respectively, after adjusting the analysis with the IPTW. In addition, by evaluating only immunocompromised hosts, the combination of REM and mAbs was associated with a significantly lower incidence of severe COVID-19 (aHR = 0.06, 95%CI = 0.02-0.77) when compared with monotherapy. CONCLUSIONS: REM and mAbs may reduce the risk of COVID-19 progression in hospitalized patients. Importantly, in immunocompromised hosts, the combination of mAbs and REM may be beneficial.

PCL-based nanoparticles for doxorubicin-ezetimibe co-delivery: A combination therapy for prostate cancer using a drug repurposing strategy.

Introduction: Drug repurposing is an effective strategy for identifying the use of approved drugs for new therapeutic purposes. This strategy has received particular attention in the development of cancer chemotherapy. Considering that a growing body of evidence suggesting the cholesterol-lowering drug ezetimibe (EZ) may prevent the progression of prostate cancer, we investigated the effect of EZ alone and in combination with doxorubicin (DOX) on prostate cancer treatment. Methods: In this study, DOX and EZ were encapsulated within a PCL-based biodegradable nanoparticle. The physicochemical properties of drug containing nanoparticle based on PCL-PEG-PCL triblock copolymer (PCEC) have been exactly determined. The encapsulation efficiency and release behavior of DOX and EZ were also studied at two different pHs and temperatures. Results: The average size of nanoparticles (NPs) observed by field emission scanning electron microscopy (FE-SEM) was around 82±23.80 nm, 59.7±18.7 nm, and 67.6±23.8 nm for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively, which had a spherical morphology. In addition, DLS measurement showed a monomodal size distribution of around 319.9, 166.8, and 203 nm hydrodynamic diameters and negative zeta potential (-30.3, -6.14, and -43.8) mV for EZ@PCEC, DOX@PCEC, and DOX+EZ@PCEC NPs, respectively. The drugs were released from the NPs sustainably in a pH and temperature-dependent manner. Based on the MTT assay results, PCEC copolymer exhibited negligible cytotoxicity on the PC3 cell line. Therefore, PCEC was a biocompatible and suitable nano-vehicle for this study. The cytotoxicity of the DOX-EZ-loaded NPs on the PC3 cell line was higher than that of NPs loaded with single drugs. All the data confirmed the synergistic effect of EZ in combination with DOX as an anticancer drug. Furthermore, fluorescent microscopy and DAPI staining were performed to show the cellular uptake, and morphological changes-induced apoptosis of treated cells. Conclusion: Overall, the data from the experiments represented the successful preparation of the nanocarriers with high encapsulation efficacy. The designed nanocarriers could serve as an ideal candidate for combination therapy of cancer. The results corroborated each other and presented successful EZ and DOX formulations containing PCEC NPs and their efficiency in treating prostate cancer.

Repurposing clinically available drugs and therapies for pathogenic targets to combat SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) pandemic has affected a large portion of the global population, both physically and mentally. Current evidence suggests that the rapidly evolving coronavirus subvariants risk rendering vaccines and antibodies ineffective due to their potential to evade existing immunity, with enhanced transmission activity and higher reinfection rates that could lead to new outbreaks across the globe. The goal of viral management is to disrupt the viral life cycle as well as to relieve severe symptoms such as lung damage, cytokine storm, and organ failure. In the fight against viruses, the combination of viral genome sequencing, elucidation of the structure of viral proteins, and identifying proteins that are highly conserved across multiple coronaviruses has revealed many potential molecular targets. In addition, the time- and cost-effective repurposing of preexisting antiviral drugs or approved/clinical drugs for these targets offers considerable clinical advantages for COVID-19 patients. This review provides a comprehensive overview of various identified pathogenic targets and pathways as well as corresponding repurposed approved/clinical drugs and their potential against COVID-19. These findings provide new insight into the discovery of novel therapeutic strategies that could be applied to the control of disease symptoms emanating from evolving SARS-CoV-2 variants.

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.

Recent nanoengineered diagnostic and therapeutic advancements in management of Sepsis.

COVID-19 acquired symptoms have affected the worldwide population and increased the load of Intensive care unit (ICU) patient admissions. A large number of patients admitted to ICU end with a deadly fate of mortality. A high mortality rate of patients was reported with hospital-acquired septic shock that leads to multiple organ failures and ultimately ends with death. The patients who overcome this septic shock suffer from morbidity that also affects their caretakers. To overcome these situations, scientists are exploring progressive theragnostic techniques with advanced techniques based on biosensors, biomarkers, biozymes, vesicles, and others. These advanced techniques pave the novel way for early detection of sepsis-associated symptoms and timely treatment with appropriate antibiotics and immunomodulators and prevent the undue effect on other parts of the body. There are other techniques like externally modulated electric-based devices working on the principle of piezoelectric mechanism that not only sense the endotoxin levels but also target them with a loaded antibiotic to neutralize the onset of inflammatory response. Recently researchers have developed a lipopolysaccharide (LPS) neutralizing cartridge that not only senses the LPS but also appropriately neutralizes with dual mechanistic insights of antibiotic and anti-inflammatory effects. This review will highlight recent developments in the new nanotechnology-based approaches for the diagnosis and therapeutics of sepsis that is responsible for the high number of deaths of patients suffering from this critical disease.

A Randomized, Controlled Trial of Trifarotene Plus Doxycycline for Severe Acne Vulgaris

OBJECTIVE: We evaluated the efficacy and safety of trifarotene plus oral doxycycline in acne. METHOD(S): This was a randomized (2:1 ratio) 12-week, double-blind study of once-daily trifarotene cream 50microg/g plus enteric-coated doxycycline 120mg (T+D) versus trifarotene vehicle and doxycycline placebo (V+P). Patients were aged 12 years or older with severe facial acne (>=20 inflammatory lesions, 30 to 120 non-inflammatory lesions, and <=4 nodules). Efficacy outcomes included change from baseline in lesion counts and success (score of 0/1 with >=2 grade improvement) on investigator global assessment (IGA). Safety was assessed by adverse events and local tolerability. RESULT(S): The study enrolled 133 subjects in the T+D group and 69 subjects in the V+P group. The population was balanced, with an approximately even ratio of adolescent (12-17 years) and adult (>=18 years) subjects. The absolute change in lesion counts from baseline were: -69.1 T+D versus -48.1 V+P for total lesions, -29.4 T+D versus -19.5 V+P for inflammatory lesions, and -39.5 T+D versus -28.2 for non-inflammatory lesions (P<0.0001 for all). Success was achieved by 31.7 percent of subjects in the T+D group versus 15.8 percent in the V+P group (P=0.0107). The safety and tolerability profiles were comparable between the T+D and V+P arms. CONCLUSION(S): T+D was demonstrated to be safe and efficacious as a treatment option for patients with severe acne.Copyright © 2022 Matrix Medical Communications. All rights reserved.

Gilteritinib: Repurposing of AXL-targeting kinase inhibitors against COVID-19.

The coronavirus disease-19 (COVID-19) is an ongoing infection outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel positive single-stranded, enveloped RNA virus belonging to the genus Betacoronavirus. During the pandemic, the SARS-CoV-2 subvariants evolved rapidly with enhanced transmissibility, and became a global public health threat as its alarmingly rising rate of infection led to excessive mortality. According to the WHO data, COVID-19 caused more than 6 million deaths and affected 215 countries. Although vaccines are beneficial for preventing hospitalization, reducing severe illness and deaths from COVID-19, the constantly mutated Spike protein under high selection pressure leading to off-target or immune evasion which warrants additional therapeutic strategies. Therefore, it is important to identify and test potential therapeutic targets against proteins that are highly conserved among multiple coronaviruses for clinical drug development to combat SARS-COV-2. While research for new therapies continues, the cost-effective and rapid repurposing of existing therapeutics may provide a viable treatment alternative for COVID-19.

The Unusual Architecture of RNA-Dependent RNA Polymerase (RdRp)'s Catalytic Chamber Provides a Potential Strategy for Combination Therapy against COVID-19.

The unusual and interesting architecture of the catalytic chamber of the SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) was recently explored using Cryogenic Electron Microscopy (Cryo-EM), which revealed the presence of two distinctive binding cavities within the catalytic chamber. In this report, first, we mapped out and fully characterized the variations between the two binding sites, BS1 and BS2, for significant differences in their amino acid architecture, size, volume, and hydrophobicity. This was followed by investigating the preferential binding of eight antiviral agents to each of the two binding sites, BS1 and BS2, to understand the fundamental factors that govern the preferential binding of each drug to each binding site. Results showed that, in general, hydrophobic drugs, such as remdesivir and sofosbuvir, bind better to both binding sites than relatively less hydrophobic drugs, such as alovudine, molnupiravir, zidovudine, favilavir, and ribavirin. However, suramin, which is a highly hydrophobic drug, unexpectedly showed overall weaker binding affinities in both binding sites when compared to other drugs. This unexpected observation may be attributed to its high binding solvation energy, which disfavors overall binding of suramin in both binding sites. On the other hand, hydrophobic drugs displayed higher binding affinities towards BS1 due to its higher hydrophobic architecture when compared to BS2, while less hydrophobic drugs did not show a significant difference in binding affinities in both binding sites. Analysis of binding energy contributions revealed that the most favorable components are the ΔEele, ΔEvdw, and ΔGgas, whereas ΔGsol was unfavorable. The ΔEele and ΔGgas for hydrophobic drugs were enough to balance the unfavorable ΔGsol, leaving the ΔEvdw to be the most determining factor of the total binding energy. The information presented in this report will provide guidelines for tailoring SARS-CoV-2 inhibitors with enhanced binding profiles.

Treatment of blast phase chronic myeloid leukaemia: A rare and challenging entity.

Despite the success of BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib in chronic phase (CP) chronic myeloid leukaemia (CML), patients with blast phase (BP)-CML continue to have a dismal outcome with median survival of less than one year from diagnosis. Thus BP-CML remains a critical unmet clinical need in the management of CML. Our understanding of the biology of BP-CML continues to grow; genomic instability leads to acquisition of mutations which drive leukaemic progenitor cells to develop self-renewal properties, resulting in differentiation block and a poor-prognosis acute leukaemia which may be myeloid, lymphoid or bi-phenotypic. Similar advances in therapy are urgently needed to improve patient outcomes; however, this is challenging given the rarity and heterogeneity of BP-CML, leading to difficulty in designing and recruiting to prospective clinical trials. This review will explore the treatment of BP-CML, evaluating the data for TKI therapy alone, combinations with intensive chemotherapy, the role of allogeneic haemopoietic stem cell transplantation, the use of novel agents and clinical trials, as well as discussing the most appropriate methods for diagnosing BP and assessing response to therapy, and factors predicting outcome.

Lung cancer and oncolytic virotherapy--enemy's enemy.

Lung cancer is one of the malignant tumors that seriously threaten human health worldwide, while the covid-19 virus has become people's nightmare after the coronavirus pandemic. There are too many similarities between cancer cells and viruses, one of the most significant is that both of them are our enemies. The strategy to take the advantage of the virus to beat cancer cells is called Oncolytic virotherapy. When immunotherapy represented by immune checkpoint inhibitors has made remarkable breakthroughs in the clinical practice of lung cancer, the induction of antitumor immunity from immune cells gradually becomes a rapidly developing and promising strategy of cancer therapy. Oncolytic virotherapy is based on the same mechanisms that selectively kill tumor cells and induce systemic anti-tumor immunity, but still has a long way to go before it becomes a standard treatment for lung cancer. This article provides a comprehensive review of the latest progress in oncolytic virotherapy for lung cancer, including the specific mechanism of oncolytic virus therapy and the main types of oncolytic viruses, and the combination of oncolytic virotherapy and existing standard treatments. It aims to provide new insights and ideas on oncolytic virotherapy for lung cancer.

Alternatives Therapeutic Approaches to Conventional Antibiotics: Advantages, Limitations and Potential Application in Medicine.

Resistance to antimicrobials and particularly multidrug resistance is one of the greatest challenges in the health system nowadays. The continual increase in the rates of antimicrobial resistance worldwide boosted by the ongoing COVID-19 pandemic poses a major public health threat. Different approaches have been employed to minimize the effect of resistance and control this threat, but the question still lingers as to their safety and efficiency. In this context, new anti-infectious approaches against multidrug resistance are being examined. Use of new antibiotics and their combination with new ß-lactamase inhibitors, phage therapy, antimicrobial peptides, nanoparticles, and antisense antimicrobial therapeutics are considered as one such promising approach for overcoming bacterial resistance. In this review, we provide insights into these emerging alternative therapies that are currently being evaluated and which may be developed in the future to break the progression of antimicrobial resistance. We focus on their advantages and limitations and potential application in medicine. We further highlight the importance of the combination therapy approach, wherein two or more therapies are used in combination in order to more effectively combat infectious disease and increasing access to quality healthcare. These advances could give an alternate solution to overcome antimicrobial drug resistance. We eventually hope to provide useful information for clinicians who are seeking solutions to the problems caused by antimicrobial resistance.

Therapeutic Options for the Single Pill Combination of Lisinopril, Amlodipine and Rosuvastatin: a Systematic Review

Aim. To evaluate the effect of taking a single pill combination of amlodipine, lisinopril and rosuvastatin on blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) in hypertensive patients with or without severe hypercholesterolemia. Material and methods. Articles published in Russian were selected for analysis. Six articles that met the criteria for inclusion in a systematic review were found by searching the eLibrary database for the keyword "equamer". The results of 5 observational clinical studies were presented in these articles. The effectiveness of the fixed combination of amlodipine, lisinopril and rosuvastatin was assessed mainly by changes in the level of systolic and diastolic blood pressure, the concentration of LDL cholesterol. In addition, the effects of fixed-dose amlodipine, lisinopril, and rosuvastatin on central aortic pressure and its increment index, as well as carotid-femoral pulse wave velocity, were studied in part of the studies. The effect of the fixed combination of amlodipine, lisinopril and rosuvastatin on blood pressure and LDL-C concentration, as well as on these additional indicators, in patients who had a coronavirus infection with severe lung damage was studied in one study. Results. Evidence from a systematic review demonstrates the efficacy of single pill combination amlodipine, lisinopril and rosuvastatin in reducing blood pressure and LDL-C in a wide range of patients with different baseline risk of developing cardiovascular complications and different baseline levels of blood pressure and LDL-C. Conclusion. The data obtained confirm the feasibility of more frequent prescription of the single pill combination of amlodipine, lisinopril and rosuvastatin in clinical practice for the treatment of hypertensive patients with high or moderate risk of developing cardiovascular diseases, including patients with concomitant hypercholesterolemia.

Plant Spices as a Source of Antimicrobial Synergic Molecules to Treat Bacterial and Viral Co-Infections.

The COVID-19 pandemic exposed the lack of antiviral agents available for human use, while the complexity of the physiological changes caused by coronavirus (SARS-CoV-2) imposed the prescription of multidrug pharmacotherapy to treat infected patients. In a significant number of cases, it was necessary to add antibiotics to the prescription to decrease the risk of co-infections, preventing the worsening of the patient's condition. However, the precautionary use of antibiotics corroborated to increase bacterial resistance. Since the development of vaccines for COVID-19, the pandemic scenario has changed, but the development of new antiviral drugs is still a major challenge. Research for new drugs with synergistic activity against virus and resistant bacteria can produce drug leads to be used in the treatment of mild cases of COVID-19 and to fight other viruses and new viral diseases. Following the repurposing approach, plant spices have been searched for antiviral lead compounds, since the toxic effects of plants that are traditionally consumed are already known, speeding up the drug discovery process. The need for effective drugs in the context of viral diseases is discussed in this review, with special focus on plant-based spices with antiviral and antibiotic activity. The activity of plants against resistant bacteria, the diversity of the components present in plant extracts and the synergistic interaction of these metabolites and industrialized antibiotics are discussed, with the aim of contributing to the development of antiviral and antibiotic drugs. A literature search was performed in electronic databases such as Science Direct; SciELO (Scientific Electronic Library Online); LILACS (Latin American and Caribbean Literature on Health Sciences); Elsevier, SpringerLink; and Google Scholar, using the descriptors: antiviral plants, antibacterial plants, coronavirus treatment, morbidities and COVID-19, bacterial resistance, resistant antibiotics, hospital-acquired infections, spices of plant origin, coronaviruses and foods, spices with antiviral effect, drug prescriptions and COVID-19, and plant synergism. Articles published in English in the period from 2020 to 2022 and relevant to the topic were used as the main inclusion criteria.

Therapeutic Efficacy and Outcomes of Remdesivir versus Remdesivir with Tocilizumab in Severe SARS-CoV-2 Infection.

The infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated many challenges to find an effective drug combination for hospitalized patients with severe forms of coronavirus disease 2019 (COVID-19) pneumonia. We conducted a retrospective cohort study, including 182 patients with severe COVID-19 pneumonia hospitalized between March and October 2021 in a Pneumology Hospital from Cluj-Napoca, Romania. Among patients treated with standard of care, 100 patients received remdesivir (R group) and 82 patients received the combination of remdesivir plus tocilizumab (RT group). We compared the clinical outcomes, the inflammatory markers, superinfections, oxygen requirement, intensive care unit (ICU) admission and mortality rate before drug administration and 7 days after in R group and RT group. Borg score and oxygen support showed an improvement in the R group (p < 0.005). Neutrophiles, C-reactive protein (CRP) and serum ferritin levels decreased significantly in RT group but with a higher rate of superinfection in this group. ICU admission and death did not differ significantly between groups. The combination of remdesivir plus tocilizumab led to a significantly improvement in the inflammatory markers and a decrease in the oxygen requirement. Although the superinfection rate was higher in RT group than in R group, no significant difference was found in the ICU admission and mortality rate between the groups.

Combination Therapies against COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus disease 2019 (COVID-19), which was announced as a pandemic leading to devastating economic and medical burden worldwide. The virus attacks the organ system across the body by binding to its receptor (for example, angiotensin converting enzyme 2) on the surface of the host cell of various organs. The patients present with a variety of pathological symptoms ranging from fever, cough and cytokine storm to acute respiratory distress syndrome (ARDS). Many combination therapies have been developed to combat the disease, via blocking one or more processes of the viral life cycle and/or relieving host complications simultaneously. In this review, the progress of those combination therapies containing at least one small molecule is updated. We believe it'll provide significant inspiration for further development of treatment strategy against SARS-CoV-2, especially its mutant variants.