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  5. Volume 20, Issue 1, 2025

Current Reviews in Clinical and Experimental Pharmacology - Volume 20, Issue 1, 2025

Volume 20, Issue 1

Volume 20, Issue 1, 2025

  • Pharmacology

      • Targeting SIRT1 by Scopoletin to Inhibit XBB.1.5 COVID-19 Life Cycle

        https://doi.org/10.2174/0127724328281178240225082456

        Natural products have historically driven pharmaceutical discovery, but their reliance has diminished with synthetic drugs. Approximately 35% of medicines originate from natural products. Scopoletin, a natural coumarin compound found in herbs, exhibits antioxidant, hepatoprotective, antiviral, and antimicrobial properties through diverse intracellular signaling mechanisms. Furthermore, it also enhances the activity of antioxidants. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) causes viral pneumonia through cytokine storms and systemic inflammation. Cellular autophagy pathways play a role in coronavirus replication and inflammation. The Silent Information Regulator 1 (SIRT1) pathway, linked to autophagy, protects cells FOXO3, inhibits apoptosis, and modulates SIRT1 in type-II epithelial cells. SIRT1 activation by adenosine monophosphate-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) enhances the autophagy cascade. This pathway holds therapeutic potential for alveolar and pulmonary diseases and is crucial in lung inflammation. Angiotensin-converting enzyme 2 (ACE-2) activation, inhibited by reduced expression, prevents COVID-19 virus entry into type-II epithelial cells. The coronavirus disease 2019 (COVID-19) virus binds ACE-2 to enter into the host cells, and XBB.1.5 COVID-19 displays high ACE-2-binding affinity. ACE-2 expression in pneumocytes is regulated by signal transducers and activators of transcription-3 (STAT3), which can increase COVID-19 virus replication. SIRT1 regulates STAT3, and the SIRT1/STAT3 pathway is involved in lung diseases. Therapeutic regulation of SIRT1 protects the lungs from inflammation caused by viral-mediated oxidative stress. Scopoletin, as a modulator of the SIRT1 cascade, can regulate autophagy and inhibit the entry and life cycle of XBB.1.5 COVID-19 in host cells.

    • Translational Approach using Advanced Therapy Medicinal Products for Huntington's Disease

      https://doi.org/10.2174/0127724328300166240510071548

      Current therapeutic approaches for Huntington's disease (HD) focus on symptomatic treatment. Therefore, the unavailability of efficient disease-modifying medicines is a significant challenge. Regarding the molecular etiology, targeting the mutant gene or advanced translational steps could be considered promising strategies. The evidence in gene therapy suggests various molecular techniques, including knocking down mHTT expression using antisense oligonucleotides and small interfering RNAs and gene editing with zinc finger proteins and CRISPR-Cas9-based techniques. Several post-transcriptional and post-translational modifications have also been proposed. However, the efficacy and long-term side effects of these modalities have yet to be verified. Currently, cell therapy can be employed in combination with conventional treatment and could be used for HD in which the structural and functional restoration of degenerated neurons can occur. Several animal models have been established recently to develop cell-based therapies using renewable cell sources such as embryonic stem cells, induced pluripotent stem cells, mesenchymal stromal cells, and neural stem cells. These models face numerous challenges in translation into clinics. Nevertheless, investigations in Advanced Therapy Medicinal Products (ATMPs) open a promising window for HD research and their clinical application. In this study, the ATMPs entry pathway in HD management was highlighted, and their advantages and disadvantages were discussed.

  • Pharmacology

      • Anatomy, Etiology, Management, and Medico-Legal Implications of Botulinum-induced Blepharoptosis

        https://doi.org/10.2174/0127724328310459240809073519

        Botulinum toxin injections, a popular aesthetic treatment, have over 7.4 million beneficiaries in the U.S. Despite their safety record, these injections pose potential complications. It is essential for aesthetic practitioners to manage these complications with the least impact on the patient. Upper eyelid ptosis, though rare, is a significant side effect of botulinum toxin injections. Through our study, we have identified the etiology, anatomy, and therapeutic management of botulinum-induced blepharoptosis. Hence, the goal of this study was to identify the basic aetiology of blepharoptosis and manage this complication, as well as discuss the basis of medico-legal implications involving this popular drug. The complex medico-legal implications of botulinum toxin-induced blepharoptosis call for continuous discourse, education, and clarity on drug-use legal standards. With evolving global and Italian legislation, practitioners must ensure they meet care standards, weighing treatment benefits against potential legal and ethical outcomes. Blepharoptosis is a rare but significant complication of botulinum-type injections. Etiology and thorough anatomy are crucial for avoiding this complication and handling it with the least impact on the patient. Medico-legal implications are currently not fully established, but the basis of aesthetic treatment standards, as well as continuing medical education, will ensure correct medico-legal coverage of such complications.

    • Efficacy and Safety of Glycopyrrolate in the Management of Organophosphate and Carbamate Poisoning: A Systematic Review

      https://doi.org/10.2174/0127724328290595240509051331
      Objective

      There is a lack of evidence on the effectiveness of antidotes in the management of organophosphate and carbamate (OPC) poisoning. We aimed to review the efficacy and safety of glycopyrrolate in the management of OPC poisoning.

      Methodology

      Databases such as PubMed, Scopus, Embase, and Cochrane Library were extensively searched from inception to November 2022 and updated till October 2023. Interventional, observational, and descriptive studies assessing the efficacy and safety of glycopyrrolate administered in any dose, route, and duration for the management of OPC poisoning published in the English language were considered for this review. The treatment with any other regimen that did not include glycopyrrolate was regarded as the comparator. The survival, intensive care unit (ICU) and ventilatory outcomes were considered efficacy outcomes, and adverse effects were considered safety outcomes. Suitable quality assessment tools were used to assess the risk of bias in the included studies. Two independent reviewers were involved in the study selection, data extraction, and quality assessment and any discrepancies were resolved through mutual discussion or consultation with a third reviewer.

      Results

      A total of 9 studies (2 RCTs, 4 cohorts, 1 case series, and 2 case reports) out of 591 non-duplicate records were considered for this review. Overall, the RCTs were observed to have a moderate quality, and observational studies and descriptive studies were found to have good quality. All the included studies used atropine administration as a standard treatment option along with glycopyrrolate. The OPC patients treated with glycopyrrolate had a fewer hospitalization days with comparable recovery and ventilatory outcomes than those that had not been treated with glycopyrrolate. The occurrence of adverse events and complications was lower in the glycopyrrolate group than in the control group.

      Conclusion

      Currently, there is a lack of comparative studies to recommend the use of glycopyrrolate in OPC poisoning, and further interventional studies are required to make an evidence-based recommendation on this topic.

      PROSPERO Registration Number

      CRD42022380112

    • The Association between use of Renin-Angiotensin-Aldosterone System Inhibitors and the Risk and Mortality of Pancreatic Cancer: A Systematic Review and Meta-Analysis

      https://doi.org/10.2174/0127724328291047240409062436
      Background

      Pancreatic Cancer (PC) is one of the most malignant tumors and highly invasive neoplasms around the world.

      Objective

      This systematic review and meta-analysis aims to study the relationship between the use of renin-angiotensin-aldosterone system inhibitors and the incidence and mortality of PC.

      Methods

      The electronic search was conducted systematically until October 10, 2023. in databases, including Scopus, Web of Science (WOS), PubMed/MEDLINE, Cochrane Library, and Embase. The required data were extracted from the articles and were analyzed by Stata 15 using statistical tests (Chi-square and I2), Forest plots, and publication bias tests (Begg's and Egger's tests).

      Results

      A total of four studies (2011-2019; n=314,856) investigated the relationship between RAS antagonists and PC risk. No significant associations were found between angiotensin receptor blockers (ARBs) (OR=0.94, 95% CI: 0.77-1.14, =0.513), angiotensin-converting enzyme inhibitors (ACEIs) (OR=0.96, 95% CI: 0.84-1.09, =0.505), or combination therapy (ARBs + ACEIs) (OR=0.97, 95% CI: 0.87-1.09, =0.627) and PC risk. Also, nine studies (2010-2023; n=20,483) examined the association between renin-angiotensin-aldosterone system inhibitors and PC mortality. Significant reductions in PC mortality were found for ARBs (OR=0.81, 95% CI: 0.66-0.98, =0.032), ACEIs (OR=0.89, 95% CI: 0.80-0.99, =0.038), and combination therapy (OR=0.83, 95% CI: 0.70-0.97, =0.022). No evidence of publication bias was found in the study results.

      Conclusion

      In summary, while renin-angiotensin-aldosterone system inhibitors did not appear to impact PC risk, their use was associated with lower PC mortality based on this meta-analysis of the current evidence. More rigorous and well-designed studies are required to validate and support these findings.

    • The Effect of Dapagliflozin on Heart Function in Animal Models of Cardiac Ischemia, A Systematic Review and Meta-analysis

      https://doi.org/10.2174/0127724328313815240723044625
      Introduction

      In this study, a meta-analysis was conducted to investigate the therapeutic effect of Dapagliflozin (DAPA) on animals suffering from myocardial ischemia reperfusion compared to the group that did not receive treatment.

      Methods

      According to the inclusion and exclusion criteria two researchers performed the primary and secondary screening based on the title abstract and full text. After data extraction, meta-analysis was performed using STATA software. Standardized mean differences were used to analyze the results of the reported studies. Subgroup analysis and quality control of articles were also conducted.

      Results

      A total of 21 separate experiments showed that DAPA increased mean fractional shortening (%FS) and ejection fraction (%EF) compared to the untreated animals. A significant reduction in the weight and size of the infarcted area and significant increases in dp/dt+, dp/dt-, left ventricular end-systolic internal dimensions (LVIDs), left ventricular end-diastolic internal dimensions (LVIDd), Volume systole and Volume diastole were observed in treated animals.

      Conclusion

      DAPA has the potential to become a candidate for the treatment of post-ischemic heart damage, pending animal and human studies to validate this.

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