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Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.
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BACKGROUND: Diabetes is a health problem that has an enormous and intolerable public health burden on the individual, family, and community. Diabetes affects nearly one-fifth of adults in Saudi Arabia and is expected to double by 2030. AIM OF THE STUDY: The study aims to evaluate the impact of switching patients from conventional basal insulin analogues to insulin degludec during a 90-day follow-up period. METHODS: This was a retrospective observational pretest-posttest cohort study conducted at King Abdulaziz University Hospital between June 2019 and August 2020. Adult patients with diabetes who switched their basal insulin to insulin degludec were included and evaluated for its impact on insulin doses, hemoglobin A1c (HbA1c), hypoglycemic events, and/or body weight changes during a 90-day follow-up period. RESULTS: Out of 718 patients, 107 patients were included in the study, with 60.7% being females and their mean (± SD) age was 62.2 ± 14.6 years. There was a significant decrease in the mean baseline of HbA1c from 9.2% to 8.7% after 90 days of follow-up (P<0.001). A statistically significant reduction was noted in the total insulin requirements from a baseline of 71.70 (± 42.4) units to 46.5 (± 29) units, P=0.001, after switching to insulin degludec. However, there were no statistically significant differences in the body weight from the baseline mean (± SD) of 80.5 kg (± 19.4) to 79.9 kg (± 19.9), P=0.68, after switching to insulin degludec. Lastly, there were no statistically significant differences in the reported hypoglycemic episodes from a baseline of 48.7% vs 37.3% after 90 days of follow-up (P = 0.166). CONCLUSION: Switching to the novel insulin degludec conferred better blood glucose control and dose reduction. There was no increase in the frequency of hypoglycemic episodes or body weight.
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OBJECTIVE: Following the recently conducted local studies on the growing misuse of pregabalin, Pregabalin misuse has received national attention. These studies have led to the authorities restricting the availability of pregabalin to hospital pharmacies alone. While the recent epidemiological studies and case reports found gabapentin to be misused worldwide, it was previously presumed to be free of any abuse potential. This study assesses the likelihood of there being a diversion to Gabapentin abuse following the Pregabalin restriction in Jeddah, KSA. METHODS: A cross sectional observational study was conducted between November 2017 and December 2017 using a self-constructed online survey via Twitter and WhatsApp. The survey items included participants' demographics, additional history, Gabapentin for non-medical use (frequency, concurrent use with other drugs, and motivators), and how the participants knew about the Gabapentin misuse. The data was subjected to a descriptive analysis via the utilization of frequencies and percentages. The analysis was carried out by using SPSS V21. RESULTS: Data of the 370 respondents who took the surveys were collected. Most of the respondents were women (n = 289; 78.1%) and below the age of 30 years (n = 300; 81.1%). A total of 72 respondents (19.5%) had a history of psychoactive drug abuse. Ten of the respondents reported Gabapentin misuse (2.7%). Half of the participants reported prior Pregabalin misuse, and were un-employed. Most of the misusers (n = 8; 80%) came to know about the psychotropic effects of Gabapentin from friends. The most common motives for using it were to 'have fun' and 'peer pressure' (n = 6; 60%). Half of the misusers used Gabapentin on a weekly basis. CONCLUSION: The findings of our study suggest a potential diversion from Pregabalin to Gabapentin misuse. Regulations and periodic reviews of the psychoactive prescription medications available in the community pharmacies are essential.
RESUMEN
Chemical investigation of the ethyl acetate extract of Penicillium chrysogenum strain S003, a fungus isolated from Red Sea deep sediment, led to the isolation of a cerebroside molecular species LAMA (1) along with three other known compounds, ergosterol (2), epidioxyergosterol (3), and kojic acid (4). The structures of the isolated compounds were elucidated by interpretation of spectral data, including detailed 1D and 2D NMR (One and two dimensional Nuclear Magnetic Resonance) and mass spectrometry. The cytotoxic activities of isolated compounds 1-4 against five human carcinoma cells were evaluated using sulforhodamine B (SRB) assay. Compounds 2 and 3 displayed promising cytotoxic profiles against lung cancer (A-549), prostate (DU-145), breast adenocarcinoma (MCF-7), and hepatocellular (HepG2) cell lines, with IC50 values of 21.26, 19.3; 1.50, 6.10; 16.95, 13.6; and 2.89, 3.07 µM, respectively, while they were inactive against HeLa cells. Compounds 1 and 4 showed weak cytotoxic profiles against all cell lines under investigation.
