Experiences of adult epilepsy patients with COVID-19 infections and vaccinations

Objective: To assess the course of COVID-19 infections and the tolerability of the mRNA vaccines of Moderna and Pfizer/BioNTech and the viral vector vaccines from Astra Zeneca and Johnson & Johnson in adult patients with epilepsy (PWE). Method(s): From July 2020 to July 2021, we consecutively included adult outpatients with confirmed epilepsy. These PWE were interviewed about COVID-19 infections and vaccinations. Results of follow-up visits were added until the cut-off date (December 31, 2021). The data of COVID-19-infected without vaccinations or fully vaccinated PWE without COVID-19 infections were analyzed. Full vaccination was defined as a double vaccination with the Pfizer/BionTech, Moderna, or Astra Zeneca vaccines or a single Johnson & Johnson vaccination. Result(s): At cut-off, 612 of 1152 PWE fulfilled the inclusion criteria: 51 PWE had been infected without vaccination and 561 had full vaccination without infection. Among the infected PWE, 76.5% presented with symptoms;9.8% had a severe course (one death). The leading symptoms were influenza-like disorders (48.7% of infected PWE with symptoms), anosmia (28.2%), and ageusia (20.5%). Seizure increases or relapses after sustained seizure freedom occurred in 7.8%. Adverse events (AEs) were reported by 113 vaccinated PWE (20.1% of all vaccinated PWE). The leading AEs were fatigue, fever, and headache. The AE rate per vaccine was 14.0% for Pfizer/BionTech, 32.7% for Moderna, 25.8% for Astra Zeneca, and 46.2% for Johnson & Johnson. Of the AEs, 93.3% lasted <=1 week. Seizure increase or relapse occurred in 1.4% and was significantly less frequent than in the infected group (p= 0.0016). Conclusion(s): The course of COVID-19 infections and the tolerability of the vaccines were similar as in the general population, yet, seizure worsening occurred more often after the infection than after the vaccination.Copyright © 2023, The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, part of Springer Nature.

Drug Repositioning in Response to COVID-19 and other Challenging Diseases

Coronavirus disease is a highly contagious infection that is majorly associated with upper respiratory tract illnesses. The World Health Organization (WHO) label the novel coronavirus disease COVID-19 after an epidemic of the disease in Wuhan, Hubei province (China). Over 90 clinical trials, including drug repositioning, have been initiated to get COVID-19 treatment/management. Antibiotic resistance, drug tolerance, mutation, and adverse drug effects possess a lot of setbacks during therapy, especially with emerging infectious diseases. This necessitates the need for research into getting newer drugs or repositioning the available ones to meet up with the treatment of both infectious and non-infectious diseases affecting humanity. Drug repositioning is a stepwise process that aids in discovering new indications and therapeutic targets of drugs and it usually takes 3-12 years on average to be completed whereas, in drug discovery, an average of 10-17 years is needed for the whole process. This is because, in repositioning, the research process goes straight to preclinical and clinical trials since both the toxicological and pharmacological profiles of the drug to be repositioned are known, thus reducing time, risk, and costs. Based on 2009 statistics, 30% of all drugs sold in that year are products of repositioning while only one out of one million potential drug candidates have the possibility of entry into clinical studies with a tendency of significant failures. Hence the need to discover additional uses for already established drugs, especially with the emergence of COVID-19. Drug repositioning is therefore considered an alternative way to new drug development as it entails the discovery of newer therapeutic uses of established drugs. Copyright © 2022 Hyellavala Joseph Fomnya, Saidu Ibrahim Ngulde, Sarah Malgwi Gana, Garleya Bilbonga, Kazabu Ahmed Amshi, Chahari Alfred Midala and Kabiru Alhaji Garba.

Immunological Potency, Efficacy, and Tolerance of “Gam-COVID-Vac” Vaccine among Students: Prospective Study

Background. Students, as the most active and mobile part of population, often unite into educational and informal groups, move to other regions or countries, and present a specific risk group for the spread of new coronavirus infection. Thus, they require preventive vaccination. objective. the aim of the study is to study the immunological potency, tolerance, and efficacy of GamCOVID-Vac vaccine among students of Krasnodar. methods. 119 seronegative students (18–30 years old) were examined. SARSCoV-2 IgG (ELISA method) was determined 1, 3, and 6 months after two completed rounds of vaccination. Post-vaccination adverse events and COVID-19 cases were evaluated in the study. results. SARS-CoV-2 IgG level 1 month after vaccination ranged from 6.15 to 19.38 and was to 16.39 (AU/mL) ± 1,12. Immunological potency values ranged from 4.407 to 21.5 (AU/mL) (14.74 ± 2.93) 3 months after. IgG titers were in the range of 4.14 to 17.71 (AU/mL) (10.97 ± 4.69) 6 months after. Adverse events after vaccination were revealed in 34 respondents (28.6%). Among them, local (hyperemia, pain, edema) — 21 (17.6%): slight — 90.4%, major — 9.6%;general (fever, weakness, algor, headache, arthralgia, myalgia) — 13 (10.9%): slight — 69.2%, major — 30.8%. The increase in vaccination coverage in students from 30.3 to 79.1% reduced the COVID-19 morbidity from 3.81 to 1.57%. conclusion. Gam-COVID-Vac vaccine induced stable humoral response, demonstrated sufficient safety, and reduced morbidity 2.4-fold.

Central carbon metabolism remodeling as a mechanism to develop drug tolerance and drug resistance in Mycobacterium tuberculosis.

Suboptimal efficacy of the current antibiotic regimens and frequent emergence of antibiotic-resistant Mycobacterium tuberculosis (Mtb), an etiological agent of tuberculosis (TB), render TB the world's deadliest infectious disease before the COVID-19 outbreak. Our outdated TB treatment method is designed to eradicate actively replicating populations of Mtb. Unfortunately, accumulating evidence suggests that a small population of Mtb can survive antimycobacterial pressure of antibiotics by entering a "persister" state (slowly replicating or non-replicating and lacking a stably heritable antibiotic resistance, termed drug tolerance). The formation of drug-tolerant Mtb persisters is associated with TB treatment failure and is thought to be an adaptive strategy for eventual development of permanent genetic mutation-mediated drug resistance. Thus, the molecular mechanisms behind persister formation and drug tolerance acquisition are a source of new antibiotic targets to eradicate both Mtb persisters and drug-resistant Mtb. As Mtb persisters are genetically identical to antibiotic susceptible populations, metabolomics has emerged as a vital biochemical tool to differentiate these populations by determining phenotypic shifts and metabolic reprogramming. Metabolomics, which provides detailed insights into the molecular basis of drug tolerance and resistance in Mtb, has unique advantages over other techniques by its ability to identify specific metabolic differences between the two genetically identical populations. This review summarizes the recent advances in our understanding of the metabolic adaptations used by Mtb persisters to achieve intrinsic drug tolerance and facilitate the emergence of drug resistance. These findings present metabolomics as a powerful tool to identify previously unexplored antibiotic targets and improved combinations of drug regimens against drug-resistant TB infection.

Targeted design of drug binding sites in the main protease of SARS-CoV-2 reveals potential signatures of adaptation.

Several existing drugs are currently being tested worldwide to treat COVID-19 patients. Recent data indicate that SARS-CoV-2 is rapidly evolving into more transmissible variants. It is therefore highly possible that SARS-CoV-2 can accumulate adaptive mutations modulating drug susceptibility and hampering viral antigenicity. Thus, it is vital to predict potential non-synonymous mutation sites and predict the evolution of protein structural modifications leading to drug tolerance. As two FDA-approved anti-hepatitis C virus (HCV) drugs, boceprevir, and telaprevir, have been shown to effectively inhibit SARS-CoV-2 by targeting the main protease (Mpro), here we used a high-throughput interface-based protein design strategy to identify mutational hotspots and potential signatures of adaptation in these drug binding sites of Mpro. Several mutants exhibited reduced binding affinity to these drugs, out of which hotspot residues having a strong tendency to undergo positive selection were identified. The data further indicated that these anti-HCV drugs have larger footprints in the mutational landscape of Mpro and hence encompass the highest potential for positive selection and adaptation. These findings are crucial in understanding the potential structural modifications in the drug binding sites of Mpro and thus its signatures of adaptation. Furthermore, the data could provide systemic strategies for robust antiviral design and discovery against COVID-19 in the future.