Recent Advances in Anti-Infective Drug Discovery - Volume 18, Issue 3, 2023

Background: Since leprosy bacilli cannot grow in vitro, testing for antimicrobial resistance against Mycobacterium leprae or assessing the anti-leprosy activity of new drugs remains hard. Furthermore, developing a new leprosy drug through the traditional drug development process is not economically captivating for pharmaceutical companies. As a result, repurposing existing drugs/approved medications or their derivatives to test their anti-leprotic potency is a promising alternative. It is an accelerated method to uncover different medicinal and therapeutic properties in approved drug molecules. Aims: The study aims to explore the binding potential of anti-viral drugs such as Tenofovir, Emtricitabine, and Lamivudine (TEL) against Mycobacterium leprae using molecular docking. Methods: The current study evaluated and confirmed the possibility of repurposing antiviral drugs such as TEL (Tenofovir, Emtricitabine, and Lamivudine) by transferring the graphical window of the BIOVIA DS2017 with the Crystal Structure of a phosphoglycerate mutase gpm1 from Mycobacterium leprae (PDB ID: 4EO9). Utilizing the smart minimizer algorithm, the protein's energy was reduced in order to achieve a stable local minima conformation. Results: The protein and molecule energy minimization protocol generated stable configuration energy molecules. The protein 4EO9 energy was reduced from 14264.5 kcal/mol to -17588.1 kcal/mol. Conclusion: The CHARMm algorithm-based CDOCKER run docked all three molecules (TEL) inside the 4EO9 protein binding pocket (Mycobacterium leprae). The interaction analysis revealed that tenofovir had a better binding molecule with a score of - 37.7297 kcal/mol than the other molecules.

Background: Yoga plays a beneficial adjunctive role in various disorders due to its physiological and psychological benefits. COVID-19 pandemic led to a paradigm shift in delivery of health interventions from on-site to online/ tele-intervention mode. Focus shifted to tele-yoga as a reasonable and feasible alternative to in-person yoga. Studies have evaluated its effect among patients suffering from various disorders, their care givers, healthcare workers, and the general public. We have assessed the effect of tele- Yoga, including its appropriateness, acceptability, and benefits, via this narrative review. Methods: We searched PubMed data base using predefined keywords. Inclusion criteria included controlled trials and Randomized Controlled Trials (RCTs) which are completed and published in English language up to February 2022 with tele-yoga/online yoga as part of intervention. Exclusion criteria included articles in other language or articles whose full text is unavailable. Results: After removing duplications and reviewing articles based on title, abstracts, and available full texts, seven studies with 391 participants were included. Majority of the trials took place in United States, with United Kingdom, Canada, and India following closely behind. Yoga can be safely administered via various online /tele interventions in both diseased and healthy individuls. Tele yoga or modules incorporating tele-yoga has been shown to improve symptoms like dyspnea, psychiatric/psychological burden including stress, anxiety and depression levels and may promote positive effects like spirituality. Conclusion: Tele-yoga is feasible and beneficial in healthy and diseased individuals. Larger well-designed RCTs comparing in-person yoga with tele-yoga are needed to ascertain their full benefits.

Background: Convalescent plasma has been used to provide passive immunotherapy to patients with COVID-19 with a high level of safety. Very few efficacy studies were available, and due to COVID being a relatively new disease, its exact therapeutic role was unclear. This observational study on the impact of COVID convalescent plasma (CCP) on clinical outcomes attempts to evaluate the effectiveness of convalescent COVID-19 plasma therapy in the treatment of COVID-19 patients at the tertiary care center in the Uttarakhand state of India. Methods: CCP was collected by plasmapheresis/whole blood from willing COVIDrecovered donors who underwent pre-donation testing including ABO and RhD grouping, mandatory blood screening tests for HIV, HBV, HCV, syphilis and Malaria, Haemoglobin estimation and COVID IgG assay. Hospitalized patients with severe COVID-19 pneumonia who received these CCP units were followed up and the outcome (Recovery/death) was observed. Results: A total of 63 patients who received CCP were included in the study. Out of the total, 13 (20.7%) were females and 50 (79.3%) were males and their ages ranged from 24 to 80 years with a median age of 53 years. The period between the start of symptoms and hospitalization ranged from 1 to 14 days with an average duration of 4.7 days. Symptoms on presentation included Fever 53/63 (84.1%), Tachypnoea 60/63 (95.2%) and Cough 42/63 (66.7%). Among these patients, 22/63 (34.9%) were on non-invasive ventilation (NIV), 6/63 (9.5%) on non-rebreather mask (NRBM) and 32/63 (50.8%) were on Ventilator support. The infused convalescent plasma had a Mean IgG value of 57.3 AU with a range of (10-142 AU). A total of 37 (58.7%) patients were lost to COVID-19 infection and 26 (41.3%) were discharged from the hospital in a healthy state. Conclusion: The use of convalescent plasma in addition to standard treatment in our study on patients with severe pneumonia due to COVID-19 did not demonstrate reduced mortality of COVID-19 patients amidst numerous variables. The results showed that the use of convalescent plasma as a treatment option in the present conditions needs a serious re-evaluation. Studies on a strictly defined recipient group and transfusion of CCP units, with adequate antibody titer and/or neutralization activity, must be analyzed for future works.

Introduction: COVID-19 causes significant pulmonary microthrombi in some individuals, leading to ARDS and death. Thrombolysis could be an effective approach in some patients with severe ARDS. We describe our experience with the usage of thrombolytic agents in critically ill COVID-19 patients who were in worsening respiratory failure. Methods: Retrospective chart analysis was done in patients who were thrombolysed between May 2020-Sept 2020. Analysis was done to find out factors associated with improvement in oxygenation and survival. Results: Twenty-seven patients with severe ARDS [all had respiratory rate >30, FiO2 >0.6 (on NIV/HFNC) and PiO2/FiO2 ratio <120] were thrombolysed in our ICU for COVID19 causes. C.T. Pulmonary Angiography could not be done in any of the 27 patients due to poor general condition, but 2D echo was normal in most (5 had dilated RA, RV), and none of the patients was in shock. So, there was no conventional indication of thrombolysis in these patients, yet after thrombolysis, we observed dramatic changes in oxygenation (defined by a decrease in FiO2 by ≥0.2) in twenty patients. Five patients had a major bleed. Eleven patients survived (survival rate of 40.7%) and the survival rate was high {66% (8/12)} in patients who were thrombolysed within 2 days of oxygen requirement. Conclusion: In this unprecedented pandemic with high mortality rates, efficacy of early thrombolysis needs to be further explored in randomised controlled trials.

Background: Considering the role of calcium in the replication and morphogenesis of rotaviruses, it is hypothesized that decreased cytosolic calcium levels by using calcium channel blockers can subsequently interfere with rotavirus replication. Objective: The present study investigated the effects of two calcium ion channel blockers, amlodipine and diltiazem, against human rotavirus infection. Methods: Cytotoxic effects of the drugs on MA-104 cells were evaluated using the neutral red assay. The effects of amlodipine and diltiazem at non-toxic concentrations on human rotavirus were examined using cytopathic effect inhibition, TCID50, and real-time PCR assays. Results: The highest inhibitory effect was obtained at concentrations of 0.5 μg/ml of amlodipine and 3 μg/ml of diltiazem, leading to 4.6 and 5.5 logarithmic reductions in infectious rotavirus titer and four- and a five-fold increase in the Ct values compared to the virus control, respectively (p-value < 0.001). Conversely, infectious rotavirus titers were significantly elevated compared to the virus control at concentrations above 0.9 μg/ml of amlodipine and above 25 μg/ml of diltiazem. Conclusion: Our study suggests that in addition to cardiovascular diseases, calcium channel blockers at their optimal doses may also be used to treat gastroenteritis caused by rotavirus infection.

Background: The goal of the study was to investigate the burden of transfusion- transmitted infections (TTIs) hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), syphilis, and malarial parasite (MP) in ABO Blood Groups and Rh Type System among voluntarily blood donors in Khyber Pakhtunkhwa (KPK), Pakistan. It is a retrospective single center cross sectional study. This study was conducted from June 2020 to September 2021 (16 months) at the frontier foundation thalassemia center Peshawar KPK. Donors were physically healthy and fit for donation. Donors with physical disabilities and/or having co-morbid conditions were excluded from the report. Methods: All the samples were screened for anti-HIV, anti-HCV, HBsAg, Syphilis, and Malarial Parasite via ELISA kit and Immune Chromatographic Technique (ICT), respectively. A total of 6311 blood donations were evaluated. The majority of the donations (92%) were from (VNRBD) voluntary non-remunerated blood donation, while only 8% came from replacement donors. Results: Amongst 6311 blood donations, 1.50 % (n = 95) were infected at least with one pathogen, HBV positive cases were 0.855 % (n = 54), HCV positive cases were 0.316% (n = 20), syphilis positive were 0.30% (n = 19) and MP positive cases were only 0.031% (n = 2). HBV, HCV, syphilis and malaria infections rates were found to be low as compared to the previous data published, while no case was reported for HIV. The study also revealed the distribution pattern of the aforementioned pathogens in blood groups and the Rh type system of the reactive samples. Conclusion: The lower reported in our study indicates the awareness among the people of Peshawar about TTIs and their precautions. The prevalence rate that we are reporting is less than previously published articles in the same domain.

Background: Tuberculosis (TB) is still a major cause of death worldwide, despite possibly curable therapies. Neurotoxicity, optic neuritis, and severe liver damage are side effects of isoniazid, a powerful first-line anti-TB drug. Objective: We investigated the use of PCL-PEG copolymer to sustain the release of isoniazid to reduce its adverse effects. Methods: In the present work, PCL-PEG copolymer was synthesized and characterized. Isoniazid-loaded nanoparticles (Inp) were prepared using a PCL-PEG copolymer. Furthermore, a 2³ half factorial design was employed for the optimization of drug and emulsifier concentration in Inp. Full characterization of the nanoparticles was performed in terms of drug loading, entrapment efficiency, particle size, zeta potential, and in vitro drug release. The morphology, FTIR, DSC, and PXRD evaluation of the optimized Batch Inp F13 were studied. Stability was evaluated by storing the freeze-dried Inp F13 at various temperatures. Results: The entrapment efficiency and drug loading of nanoparticles prepared by double emulsion solvent evaporation were found to be the highest. The release study revealed that all batches of nanoparticles exhibited sustained drug release (60.26 - 88.59%) for 5 days. The cytotoxicity study conducted on Mycobacterium tuberculosis revealed a gradual release of isoniazid from Inp, reaching the maximum (on the 15^th day) compared to plain isoniazid (on the 4^th day). At 0.8 μg/mL concentration, the inhibitory activity of Inp F13 was maintained for 15 days, indicating sustained release of isoniazid. Conclusion: The nanoparticles having PCL:PEG in a 95:5 ratio, with 0.5% PVA and initial drug loading of 3 mg, produced the optimum batch. Isoniazid-loaded PCL-PEG nanoparticles allowed controlled (sustained) release of isoniazid.

Background: High-performance thin-layer chromatography (HPTLC) was developed and validated for the determination of aloe-emodin in accordance with ICH guidelines. In addition, a novel RP-UHPLC method was developed, and both methods were used to analyse the herbal extract and herbal formulation. Methods: Separation was carried out on a silica gel 60 F254 HPTLC plate using the mobile phase Toluene: Methanol (9:1). The linearity was good across the 800-4000 ng/spot range. Validation results are within acceptable limits. The percent RSD for accuracy was 0.58-1.77, and precision was 1.10-1.97 and 1.45-1.94 for intraday and interday, respectively. The percentage of aloe-emodin found in the herbal extract and aloe vera capsule was 99.83 ± 1.19 and 99.53 ± 1.29, respectively, using this method. Results: Quantification of aloe-emodin in herbal extract and herbal formulation were done using a novel UHPLC method with chromatographic conditions of orthophosphoric acid Methanol (0.1 percent OPA): Water (65:35, v/v) and pH 3, a flow rate of 1.2 ml/min, and elute detection at 254 nm. At 6.32 minutes, a sharp and symmetric peak was observed. The method developed was validated in accordance with ICH guidelines. The percent RSD numerical value of accuracy was 0.304-0.576, and the inter-day and intraday precision were 0.32-3.08 and 0.51-2.78, respectively. Herbal extract and aloe vera capsule were analysed using the new UHPLC method. Aloe-emodin percentages were reported as 100.3 ± 0.89 and 99.53 ± 1.29, respectively. Conclusion: The antimicrobial and anti-oxidant activities of an aloe-vera herbal formulation were studied, and the results were positive.