Pyrimethamine reduced tumour growth in pre-clinical cancer models: a systematic review to identify potential pre-clinical studies for subsequent human clinical trials.

Pyrimethamine (PYR), a STAT3 inhibitor, has been shown to reduce tumour burden in mouse cancer models. It is unclear how much of a reduction occurred or whether the PYR dosages and route of administration used in mice were consistent with the FDA's recommendations for drug repurposing. Search engines such as ScienceDirect, PubMed/MEDLINE, and other databases, including Google Scholar, were thoroughly searched, as was the reference list. The systematic review includes fourteen (14) articles. The risk of bias (RoB) was assessed using SYRCLE's guidelines. Due to the heterogeneity of the data, no meta-analysis was performed. According to the RoB assessment, 13/14 studies fall into the moderate RoB category, with one study classified as high RoB. None adhered to the ARRIVE guideline for transparent research reporting. Oral (FDA-recommended) and non-oral routes of PYR administration were used in mice, with several studies reporting very high PYR dosages that could lead to myelosuppression, while oral PYR dosages of 30 mg/kg or less are considered safe. Direct human equivalent dose translation is probably not the best strategy for comparing whether the used PYR dosages in mice are in line with FDA-approved strength because pharmacokinetic profiles, particularly PYR's half-life (t1/2), between humans (t1/2 = 96 h) and mice (t1/2 = 6 h), must also be considered. Based on the presence of appropriate control and treatment groups, as well as the presence of appropriate clinically proven chemotherapy drug(s) for comparison purposes, only one study (1/14) involving liver cancer can be directed into a clinical trial. Furthermore, oesophageal cancer too can be directed into clinical trials, where the indirect effect of PYR on the NRF2 gene may suppress oesophageal cancer in patients, but this must be done with caution because PYR is an investigational drug for oesophageal cancer, and combining it with proven chemotherapy drug(s) is recommended.

Baricitinib statistically significantly reduced COVID-19-related mortality: a systematic review and meta-analysis of five phase III randomized, blinded and placebo-controlled clinical trials.

Due to high heterogeneity and risk of bias (RoB) found in previously published meta-analysis (MA), a concrete conclusion on the efficacy of baricitinib in reducing mortality in coronavirus disease 2019 (COVID-19) patients was unable to form. Hence, this systematic review and MA were conducted to analyse whether RoB, heterogeneity, and optimal sample size from placebo-controlled randomized controlled trials (RCTs) are still the problems to derive a concrete conclusion. Search engines PubMed/MEDLINE, ScienceDirect, and other sources like preprints and reference lists were searched with appropriate keywords. The RoB and MA were conducted using RevMan 5.4. The grading of the articles was conducted using the GRADEPro Guideline Development Tool. Ten RCTs were included in the current systematic review. Only five low RoB articles are Phase III placebo-controlled RCTs with a high certainty level based on the GRADE grading system. For the MA, based on five low RoB articles, baricitinib statistically significantly reduced mortality where the risk ratio (RR) = 0.68 [95% confidence interval (95% CI) 0.56-0.82; P < 0.0001; I2 = 0%; P = 0.85]. The absolute mortality effect (95% CI) based on the grading system was 35 fewer mortalities per 1000 COVID-19 patients, whereas in the baricitinib and control groups, the mortality was 7.4% and 10.9%, respectively. With the presence of an optimal sample size of 3944 from five low RoB-placebo-controlled RCTs, which represent a minimum of 300 million population of people and with the presence of 0% heterogeneity from MA, the effectiveness of baricitinib in reducing the mortality in COVID-19 patients is concretely proven.

Is It Still Relevant to Discover New ACE Inhibitors from Natural Products? YES, but Only with Comprehensive Approaches to Address the Patients' Real Problems: Chronic Dry Cough and Angioedema.

Despite many publications related to the identification of new angiotensin-I-converting enzyme (ACE) inhibitors, especially peptides from natural products, the actual reason/s for why new ACE inhibitors need to be discovered are yet to be fully understood. New ACE inhibitors are pivotal to address serious side effects caused by commercially available ACE inhibitors in hypertensive patients. Despite the effectiveness of commercial ACE inhibitors, due to these side effects, doctors often prescribe angiotensin receptor blockers (ARBs). Recent evidence has shown the benefits of ACE inhibitors over ARBs in hypertensive patients and hypertensive-diabetes mellitus patients. In order to address these side effects, the somatic ACE's enzyme structures need to be revisited. The peptides isolated from the natural products need to be verified for their stability against ACE and several important gastrointestinal enzymes. The stable peptides sequence with the presence of favourable ACE inhibitory-related amino-acids, such as tryptophan (W), at the C-terminal need to be subjected to molecular docking and dynamics analyses for selecting ACE inhibitory peptide/s with C-domain-specific inhibition instead of both C- and N-domains' inhibition. This strategy will help to reduce the accumulation of bradykinin, the driving factor behind the formation of the side effects.

Epstein Barr Virus Reactivation during COVID-19 Hospitalization Significantly Increased Mortality/Death in SARS-CoV-2(+)/EBV(+) than SARS-CoV-2(+)/EBV(-) Patients: A Comparative Meta-Analysis.

Epstein-Barr virus (EBV) reactivation in acute-phase of COVID-19 disease was recently discovered but it is not clear in terms of degree of mortality caused, and this was the aim of the current study. Six databases and three non-databases were thoroughly searched, independently. The articles related to non-human study (abstract, in vitro, in vivo, in silico, case study, poster, and review articles) were excluded for main analysis. Four articles related to mortality linked to EBV reactivation were systematically identified and included in the qualitative and quantitative analyses. Based on proportional meta-analysis of 4 studies, 34.3% or 0.343 (95% CI: 0.189-0.516; I 2 = 74.6) mortality related to EBV reactivation was identified. To address high heterogeneity, subgroup meta-analysis was carried out. Based on subgroup analysis, 26.6% or 0.266 (95% CI: 0.191-0.348; I 2 = 0) with no heterogeneity was identified. Interestingly, in comparative meta-analysis, EBV(-)/SARS-CoV-2(+) patients had statistically lesser mortality (9.9%) than EBV(+)/SARS-CoV-2(+) patients (23.6%) where RR = 2.31 (95% CI: 1.34-3.99; p = 0.003; I 2 = 6%). This finding is equivalent to the absolute mortality effect of 130 more per 1000 COVID-19 patients (95% CI: 34-296). Furthermore, based on statistical analysis, D-dimer was not statistically significantly different (p > 0.05) between the groups although studies have shown that D-dimer was statistically significantly different (p < 0.05) between these groups. Based on the inclusion and analysis of low risk of bias and high quality of articles graded with Newcastle-Ottawa Scale (NOS), when COVID-19 patients' health state is gradually worsening, EBV reactivation needs to be suspected because EBV reactivation is a possible marker for COVID-19 disease severity.

Does baricitinib reduce mortality and disease progression in SARS-CoV-2 virus infected patients? A systematic review and meta analysis.

BACKGROUND: There are conflicting reports on the results of several of the latest clinical trials related to the use of baricitinib in the management of COVID-19 patients. The aim of the current systematic review and meta-analysis was to evaluate the efficacy of baricitinib in COVID-19 patients. METHODS: Databases like ScienceDirect, PubMed/Medline, Publons, Google Scholar and other sources like ClinicalTrials.gov, Cochrane, medRxiv, Research Square and reference lists were thoroughly searched. RESULTS: Fifteen (15) articles which met the inclusion criteria were qualitatively and quantitatively analysed. Based on Cochrane and Newcastle-Ottawa Scale (NOS) risk of bias (RoB) analyses, 14/15 articles are grouped as high-quality. Meta-analyses revealed that randomised control trials (RCTs) and non-randomised control trials (nRCTs) statistically significantly reduced the mortality rate in COVID-19 patients, with a risk ratio (RR) in the fixed-effect model was RR = 0.64 [95% CI: 0.51 to 0.79; p < 0.0001] and RR = 0.58 [95% CI: 0.45 to 0.73; p < 0.00001], respectively, with insignificant heterogeneity and no publication bias found. For block/reduce disease progression (BDP), baricitinib did not statistically significantly reduce disease progression for RCTs. The RR in the random effect model was RR = 0.80 [95% CI: 0.58 to 1.10: p = 0.17], with significant heterogeneity, where I2 was 60%. On the other hand, baricitinib statistically significantly reduced disease progression in nRCTs, as the RR of the fixed effect model was RR = 0.54 [95% CI: 0.37 to 0.78; p = 0.001] with insignificant heterogeneity. CONCLUSION: The current meta-analyses revealed that baricitinib statistically significantly reduced mortality rate and disease progression in COVID-19 patients. PROSPERO REGISTRATION NUMBER: CRD42021281556.

Baricitinib for the Management of SARS-CoV-2-Infected Patients: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Baricitinib is known to reduce mortality and disease progression in COVID-19 patients; however, the data are inconsistent. Therefore, it needs to be explored to further understand the clinical benefits of this drug in the management of COVID-19 patients. Does baricitinib statistically significantly reduce mortality and disease progression in COVID-19 patients? To answer these questions, three databases known as ScienceDirect, PubMed/MEDLINE, and Scopus and other sources, such as preprint (medRxiv) and reference lists, were thoroughly searched. Four randomised controlled trials (RCTs) were included. Based on the meta-analysis, baricitinib statistically significantly reduced mortality with the risk ratio (RR) of RR = 0.74 [95% CI: 0.58 to 0.94; p = 0.01] and moderately high heterogeneity, where I 2 = 62% and p = 0.05. On the other hand, RR = 0.84 [95% CI: 0.75 to 0.95; p = 0.005] with insignificant heterogeneity of I 2 = 20% and p = 0.28 was found for disease progression. Cochrane risk of bias (RoB) analysis revealed that three out of four articles were ranked as high-quality articles with low RoB. Based on the evidence grading, the overall certainty of evidences was moderate. In conclusion, baricitinib statistically significantly reduced mortality and disease progression in COVID-19 patients when the patients were treated with baricitinib at a dosage of 2 mg or 4 mg for a maximum duration of 14 days.

STRUCTURAL CHARACTERISTICS AND ANTIHYPERTENSIVE EFFECTS OF ANGIOTENSIN-I-CONVERTING ENZYME INHIBITORY PEPTIDES IN THE RENIN-ANGIOTENSIN AND KALLIKREIN KININ SYSTEMS.

BACKGROUND: The commercially available synthetic angiotensin-I-converting enzyme (ACE) inhibitors are known to exert negative side effects which have driven many research groups globally to discover the novel ACE inhibitors. METHOD: Literature search was performed within the PubMed, ScienceDirect.com and Google Scholar. RESULTS: The presence of proline at the C-terminal tripeptide of ACE inhibitor can competitively inhibit the ACE activity. The effects of other amino acids are less studied leading to difficulties in predicting potent peptide sequences. The broad specificity of the enzyme may be due to the dual active sites observed on the somatic ACE. The inhibitors may not necessarily competitively inhibit the enzyme which explains why some reported inhibitors do not have the common ACE inhibitor characteristics. Finally, the in vivo assay has to be carried out before the peptides as the antihypertensive agents can be claimed. The peptides must be absorbed into circulation without being degraded, which will affect their bioavailability and potency. Thus, peptides with strong in vitro IC50 values do not necessarily have the same effect in vivo and vice versa. CONCLUSION: The relationship between peptide amino acid sequence and inhibitory activity, in vivo studies of the active peptides and bioavailability must be studied before the peptides as antihypertensive agents can be claimed.