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In Silico Models for Anti-COVID-19 Drug Discovery: A Systematic Review
The coronavirus disease 2019 (COVID-19) is a severe worldwide pandemic. Due to the emergence of various SARS-CoV-2 variants and the presence of only one Food and Drug Administration (FDA) approved anti-COVID-19 drug (remdesivir), the disease remains a mindboggling global public health problem. Developing anti-COVID-19 drug candidates that are effective against SARS-CoV-2 and its various variants is a pressing need that should be satisfied. This systematic review assesses the existing literature that used in silico models during the discovery procedure of anti-COVID-19 drugs. Cochrane Library, Science Direct, Google Scholar, and PubMed were used to conduct a literature search to find the relevant articles utilizing the search terms “In silico model,” “COVID-19,” “Anti-COVID-19 drug,” “Drug discovery,” “Computational drug designing,” and “Computer-aided drug design.” Studies published in English between 2019 and December 2022 were included in the systematic review. From the 1120 articles retrieved from the databases and reference lists, only 33 were included in the review after the removal of duplicates, screening, and eligibility assessment. Most of the articles are studies that use SARS-CoV-2 proteins as drug targets. Both ligand-based and structure-based methods were utilized to obtain lead anti-COVID-19 drug candidates. Sixteen articles also assessed absorption, distribution, metabolism, excretion, toxicity (ADMET), and drug-likeness properties. Confirmation of the inhibitory ability of the candidate leads by in vivo or in vitro assays was reported in only five articles. Virtual screening, molecular docking (MD), and molecular dynamics simulation (MDS) emerged as the most commonly utilized in silico models for anti-COVID-19 drug discovery.
Changes in Protease-Activated Receptor and Trypsin-1 Expression Are Involved in the Therapeutic Effect of Mg2+ Supplementation in Type 2 Diabetes-Induced Gastric Injury in Male Adult Rats
Purpose. Gastric inflammation is common and usually severe in patients with type 2 diabetes mellitus (T2DM). Evidence suggests protease-activated receptors (PARs) are a link between inflammation and gastrointestinal dysfunction. Given that magnesium (Mg2+) deficiency is a highly prevalent condition in T2DM patients, we assessed the therapeutic role of Mg2+ on the factors involved in gastric inflammation in T2DM. Methods. A rat model of T2DM gastropathy was established using a long-term high-fat diet + a low dose of streptozocin. Twenty-four rats were divided into control, T2DM , T2DM + insulin (positive control), and T2DM + Mg2+ groups. At the end of 2-month therapies, changes in the expression of gastric trypsin-1, PAR1, PAR2, PAR3, PI3K/Akt, and COX-2 proteins were measured by western blot. Hematoxylin and eosin and Masson’s trichrome staining were used to detect gastric mucosal injury and fibrosis. Results. The expression of trypsin-1, PAR1, PAR2, PAR3, and COX-2 increased in diabetes, and Mg2+/insulin treatment strongly decreased their expression. The PI3K/p-Akt significantly decreased in T2DM, and treatment with Mg2+/insulin improved PI3K in T2DM rats. Staining of the gastric antrum tissue of the insulin/Mg2+-treated T2DM rats showed a significantly minimal mucosal and fibrotic injury compared with those of rats from the T2DM group. Conclusion. Mg2+ supplement, comparable to insulin, via decreasing PARs expression, mitigating COX-2 activity, and decreasing collagen deposition could exert a potent gastroprotective effect against inflammation, ulcer, and fibrotic development in T2DM patients.
Renoprotective Effect of Thai Patients with Type 2 Diabetes Mellitus Treated with SGLT-2 Inhibitors versus DPP-4 Inhibitors: A Real-World Observational Study
Background. Recently, there is a lack of studies comparing the renoprotective effects of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and dipeptidyl peptidase-4 (DPP-4) inhibitors. This study therefore aimed to investigate the renoprotective effects of SGLT-2 inhibitors and DPP-4 inhibitors on Thai patients with type 2 diabetes mellitus. Methods. Patient medication records of all patients who used those two antidiabetic classes at Fort Wachirawut Hospital were reviewed. Renal function tests, blood glucose levels, and other baseline characteristics were collected. Continuous variables were compared within the group using the Wilcoxon signed-rank test and between groups using the Mann–Whitney U test. Results. There were 388 and 691 patients with SGLT-2 inhibitors and DPP-4 inhibitors, respectively. The mean estimated glomerular filtration rate (eGFR) of the SGLT-2 inhibitor group was significantly lower from baseline at 18 months of treatment, as well as the DPP-4 inhibitor group. However, the trend of eGFR reduction in patients with baseline eGFR <60 mL/min/1.73 m2 was smaller than those with baseline eGFR ≥60 mL/min/1.73 m2. In addition, the fasting blood sugar and haemoglobin A1c levels significantly decreased from baseline in both the groups. Conclusions. Both SGLT-2 inhibitors and DPP-4 inhibitors showed the same trends of eGFR reductions from baseline in Thai patients with type 2 diabetes mellitus. However, SGLT-2 inhibitors should be considered in patients with impaired renal function rather than in all T2DM patients.
Stability-Enhanced Ternary Solid Dispersions of Glyburide: Effect of Preparation Method on Physicochemical Properties
Introduction. Limited aqueous solubility and subsequent poor absorption and low bioavailability are the main challenges in oral drug delivery. Solid dispersion is a widely used formulation strategy to overcome this problem. Despite their efficiency, drug crystallization tendency and poor physical stability limited their commercial use. To overcome this defect, ternary solid dispersions of glyburide: sodium lauryl sulfate (SLS) and polyethylene glycol 4000 (PEG), were developed using the fusion (F) and solvent evaporation (SE) techniques and subsequently evaluated and compared. Materials and Methods. Physicochemical and dissolution properties of the prepared ternary solid dispersions were evaluated using differential scanning calorimetry (DSC), infrared spectroscopy (FTIR), and dissolution test. Flow properties were also assessed using Carr’s index and Hausner’s ratio. The physical stability of the formulations was evaluated initially and after 12 months by comparing dissolution properties. Results. Formulations prepared by both methods similarly showed significant improvements in dissolution efficiency and mean dissolution time compared to the pure drug. However, formulations that were prepared by SE showed a greater dissolution rate during the initial phase of dissolution. Also, after a 12-month follow-up, no significant change was observed in the mentioned parameters. The results of the infrared spectroscopy indicated that there was no chemical interaction between the drug and the polymer. The absence of endotherms related to the pure drug from thermograms of the prepared formulations could be indicative of reduced crystallinity or the gradual dissolving of the drug in the molten polymer. Moreover, formulations prepared by the SE technique revealed superior flowability and compressibility in comparison with the pure drug and physical mixture (ANOVA, ). Conclusion. Efficient ternary solid dispersions of glyburide were successfully prepared by F and SE methods. Solid dispersions prepared by SE, in addition to increasing the dissolution properties and the possibility of improving the bioavailability of the drug, showed acceptable long-term physical stability with remarkably improved flowability and compressibility features.
Awareness, Actions, and Predictors of Actions on Adverse Drug Reaction Reporting among Patients Attending a Referral Hospital in Southern Highland Tanzania
Purpose. This study assessed the awareness, actions, and predictors of actions on adverse drug reaction reporting among patients attending a referral hospital in southern highland Tanzania. Methods. A hospital-based cross-sectional study was conducted from January to August 2022 at Mbeya Zonal Referral Hospital (MZRH) in Mbeya, Tanzania. A total of 792 adult patients with chronic conditions attending outpatient clinics at MZRH were recruited consecutively. A semistructured questionnaire was used to collect demographic characteristics, ADR awareness, and actions when encountering ADR. Data were analyzed using the statistical package for social sciences (SPSS) version 23 and results are summarized using frequency and percentages. Binary logistic regression was used to assess the predictors associated with reporting ADR among patients. value ≤0.05 was considered statistically significant. Results. Out of 792, 397 (50.1%) were males and 383 (48.6%) had a primary education level. Only 171 (21.6%) participants previously experienced ADR, and 111 (14.1%) were aware that ADR is an unexpected harm that occurs after medication use. The majority 597 (70.3%) of the participants said will report ADR to healthcare providers, 706 (88.9%) prefer reporting ADR to healthcare providers, and 558 (69.1%) said patients are not aware of the importance of reporting ADR. Patients aged below 65 years of age, unemployed ((AOR (95% CI) = 0.4 (0.18–0.87), self-employed ((AOR (95% CI) = 0.5 (0.32–0.83)), and those who ever encountered ADR ((AOR (95% CI) = 0.1 (0.05–0.11)) were more likely to report the ADR to HCPs compared to the rest. Conclusions. The majority of patients are not aware of what is ADR and the importance of ADR reporting. Most of the patients prefer to report ADR to healthcare providers. We recommend an awareness campaign to raise awareness of the patients on ADR and other methods of ADR reporting.
Antioxidant, Anti-Inflammatory, and Anticarcinogenic Efficacy of an Ayurvedic Formulation: Amritotharanam Kashyam
Amritotharanam Kashyam, a specific Ayurvedic drug, was the focus of the current inquiry to evaluate its efficacy. For liver and digestive-related issues, this medication is suggested. This was obtained from a standard Ayurvedic vendor in Chennai (India), and GC-MS analysis was carried out according to the standard procedure. A few critical biomolecules include benzoic acid, hexadecanoic acid, 6,9-octadecadienoic acid, 9-octadecenoic acid, methyl ester (E)-, heptadecanoic acid, 16-methyl, methyl ester, methyl 18-methylnonadecanoate, tetracosanoic acid, distearin, hexadecanoic acid, and 1-(hydroxymethyl)-1,2-ethanediol ester. The obtained biomolecules exhibited some significant therapeutic functions, including acidification, inhibition of arachidonic acid formation, increase in the aromatic amino acid decarboxylase, suppression of uric acid generation, inhibitors of catechol-O-methyltransferase, urine acidifiers, etc. The anticancer and antiviral potential of these phytocompounds were investigated using molecular docking and dynamics. The phytocompounds pharmacokinetic characteristics were investigated using ADME analysis. Through docking and dynamics simulation, in silico tests demonstrated the phytocompounds' inhibitory efficiency against the target proteins. These functions reasonably relate to the medicinal function of Amritotharanam Kashyam. The MTT assay findings demonstrated this medication’s anticancer effects. The ability to be an effective drug is demonstrated by its antioxidant, anti-inflammatory, and membrane-stabilizing properties.