Current Reviews in Clinical and Experimental Pharmacology最新文献

Pain is a protective mechanism of the body that is intensified during inflammatory processes through the sensitization of nociceptive neurons. Although current drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, and opioids, are effective, their side effects reinforce the search for safer alternatives. In this context, studies investigating the analgesic effects of specialized pro-resolving mediators (SPMs), derived from polyunsaturated fatty acids, stand out. Resolvin D1 (RvD1), derived from the omega-3 fatty acid docosahexaenoic acid, acts in a multimodal manner to modulate pain and inflammation by regulating immunological, neuronal, and glial responses. Thus, RvD1 is a promising molecule for resolving inflammatory and painful processes. Herein, we address the main analgesic mechanisms of RvD1 in different preclinical models.

Introduction: Model-informed drug development (MIDD) is a regulatory-endorsed approach that streamlines drug discovery, development, and approval. Actively promoted by the U.S. Food and Drug Administration (FDA), it integrates quantitative modelling to support decision-making across drugs, generics, and biologics.

Objectives: This study aims to highlight the applications, benefits, and future perspectives of MIDD in optimizing clinical trial design, supporting regulatory review, advancing biopharmaceutics, and enabling innovation in emerging therapeutic areas.

Methods: Current applications of MIDD were evaluated, focusing on its role in new drug development, generic drug approval, biopharmaceutics, and early exploration in cell and gene therapy. The study emphasizes computational modelling, dose optimization, clinical trial refinement, and postapproval lifecycle management strategies.

Results: MIDD has demonstrated considerable impact in optimizing dose selection, refining trial design, and addressing regulatory concerns regarding efficacy and safety. In the field of biopharmaceutics, computational modelling has guided formulation development and facilitated subsequent in vivo studies. In genetics, mathematical modelling has enabled efficient development and approval of complex formulations, reducing both time and cost. MIDD shows strong potential for quantitatively analysing biological activity, pharmacodynamics, transgene expression, immune responses, safety, and therapeutic effectiveness.

Conclusion: MIDD is a transformative approach in drug development, offering robust tools for decision- making and regulatory assessment. Its broader implications across therapeutic domains are expected to enhance innovation, improve patient outcomes, and reduce development costs. Future advancements, particularly in cell and gene therapy, will further expand its role as a cornerstone of drug development.

Background: Anemia is a prevalent complication in chronic kidney disease (CKD) that remains challenging to manage effectively. Daprodustat was recently approved for anemia in CKD. This meta-analysis aims to provide evidence-based insights for the clinical use of daprodustat in CKD-related anemia.

Method: A systematic review and meta-analysis were conducted in accordance with the PRISMA 2020 guidelines, with searches conducted in databases such as PubMed and ClinicalTrials.gov, encompassing studies published up to August 30, 2024. Data from 12 randomized controlled trials involving 9,278 CKD patients (both dialysis-dependent (DD) and non-dialysis-dependent (NDD)) were analyzed.

Results: Daprodustat significantly increased hemoglobin (Hb) levels compared to placebo in both NDD (MD = 1.92, 95% CI [0.67, 3.02], p = 0.001) and DD (MD = 1.72, 95% CI [0.34, 3.65], p = 0.01) patients. However, no significant difference in Hb levels was observed between daprodustat and recombinant human erythropoietin (rhEPO) (MD = 0.05, 95% CI [-0.10, 0.21], p = 0.50). Daprodustat improved iron metabolism by significantly lowering hepcidin and increasing total ironbinding capacity (TIBC) compared to rhEPO. Cardiovascular safety analysis showed no significant difference in major adverse cardiovascular events (MACE) between daprodustat and rhEPO (RR = 1.02, 95% CI [0.92, 1.14], p = 0.83), though a significant reduction in MACE incidence was observed in DD patients (RR = 0.98, 95% CI [0.87, 1.15], p = 0.02). Serious adverse events were significantly lower with daprodustat compared to rhEPO (RR = 0.82, 95% CI [0.66, 0.84], p = 0.02 in DD; RR = 0.61, 95% CI [0.48, 0.78], p = 0.008 in NDD patients).

Conclusion: Daprodustat offers a promising alternative to traditional anemia treatments in CKD, with efficacy comparable to rhEPO and a favorable cardiovascular safety profile, which marks its potential as a valuable therapeutic option.

Introduction: Antimicrobial Resistance (AMR) poses a significant global health threat, leading to increased morbidity, mortality, and healthcare costs. Intensive Care Units (ICUs) are particularly susceptible to AMR due to frequent invasive procedures, extended hospital stays, and the selective pressure exerted by broad-spectrum antibiotics. This review aims to shed light on the current landscape of antibiotic resistance within ICUs of Saudi hospitals. It also explores molecular patterns of bacterial resistance and identifies potential strategies to address this issue. Additionally, it discusses the challenges in implementing these strategies within the Saudi healthcare system.

Methods: We conducted a literature search across electronic databases, including Web of Science, PubMed, EMBASE, Scopus, and Google Scholar, until September 30th, 2024, to identify relevant studies. Selected studies were analyzed to extract insights into prevailing bacterial resistance trends in Saudi ICUs and the molecular mechanisms responsible.

Results: Our findings provide an overview of the current state of AMR in Saudi ICUs, including the emergence and prevalence of specific molecular patterns of bacterial resistance. Moreover, it presents potential strategies to combat antibiotic resistance, including antimicrobial stewardship programs, infection control measures, and the development of new antibiotics. It also highlights the inherent challenges in implementing these strategies within the unique healthcare landscape of Saudi Arabia.

Discussion: The increasing emergence and spread of MDR bacteria in Saudi Arabia are attributed to the unoptimized antibiotic use, over-the-counter antibiotics without prescription, a high volume of international travellers, and challenges in adherence to infection control practices. Addressing the challenges and implementing effective prevention strategies are critical to maintaining antibiotic efficacy and combating AMR. Several strategies have been employed by the National AMR Committee, in partnership with WHO, to address antibiotic resistance in intensive care units.

Conclusion: AMR in Saudi ICUs is a pressing concern requiring immediate attention. A multifaceted approach combining surveillance, education, and policy interventions is essential to overcome this issue. Addressing AMR is crucial for global efforts to preserve the efficacy of antibiotics and maintain the effectiveness of critical healthcare interventions.

Introduction: Treatment-Resistant Depression (TRD) is a complex clinical condition characterized by inadequate response to conventional antidepressant treatments. There is growing evidence that microRNAs (miRNAs) play a role in the underlying pathophysiology of TRD and may offer new avenues for diagnostics and therapy.

Methods: A structured literature review of peer-reviewed publications indexed in PubMed, Scopus, and Web of Science was conducted. The search strategy included combinations of keywords such as "treatment- resistant depression," "microRNAs," "biomarkers," and "miRNA-based interventions." Articles were selected based on relevance to miRNA expression patterns in TRD, therapeutic modulation, and their clinical potential.

Results: Dysregulation of several miRNAs-including miR-135a, miR-34a, and miR-155-was consistently observed in patients with TRD. These miRNAs were linked to impaired synaptic plasticity and persistent neuroinflammation. Therapeutic approaches using miRNA mimics or inhibitors showed potential in restoring neurobiological balance and enhancing response to traditional antidepressants. However, delivery system limitations and blood-brain barrier penetration remain significant challenges.

Discussion: miRNAs appear to play a dual role in TRD, serving both as biomarkers for diagnosis and as targets for novel therapies. Integrating miRNA profiling into clinical workflows could enhance diagnostic precision and guide individualized treatment strategies. Translational barriers, such as delivery specificity and standardization of detection protocols, must be addressed before the widespread clinical application of this technology.

Conclusion: This review highlights miRNAs as promising diagnostic and therapeutic tools in TRD. Continued advancements in delivery systems and validation of biomarker panels may pave the way for their clinical implementation in personalized psychiatry.

Introduction: Obesity is a condition that affects a large part of the global population, and especially in the Western world, leading to a significant systemic inflammatory response in the body, characterized by modification of the secretory inflammatory cytokines and adipokines. The combination of fat accumulation and inflammation can lead to concomitant conditions, such as Insulin Resistance (IR) and increased production and release of fatty acids, ultimately enhancing the occurrence of conditions like metabolic and cardiovascular disorders, with inflammation and oxidative stress being implicated in these phenomena and appearing as important interconnecting factors. In this review, an attempt is made to analyze, in terms of their full scope of action, the pharmaceutical approaches against obesity, which affect fats, sugars, adipokines, and also the central nervous system.

Methods: Using data from experimental animal procedures and clinical trials, the involvement of anti-obesity drugs against systemic chronic inflammation and oxidative stress, as well as in obesityrelated cardiometabolic disorders, is analyzed.

Results: Anti-obesity treatments targeting more than one factor at the mechanistic level and limiting the body's inflammatory responses could contribute in multiple ways to improving metabolic and cardiovascular conditions and derangements. However, they carry a high risk of adverse effects, which may be reduced with the combination of such treatments, leading to a more favorable activity- to-hazard ratio and elucidation of the complete mechanistic properties of these treatments.

Discussion: Until now, many gaps in the literature remain concerning one or more of these aspects for all these treatments. Through the prism of the multi-functional nature of these compounds, an attempt is made to clarify the multi-level nature of action of these substances against obesity, potentially allowing limiting the multi-drug treatment of these conditions, leading to the limitation of interactions, and the multiple side effects related to the drug combination.

Conclusion: In order to achieve the above-mentioned objectives, in addition to investigating the full range of action of these anti-obesity drug treatments, the full history of their dose-dependent side effects and contraindications is required, through further clinical studies and analyses. These findings will shed light on the complete anti-inflammatory, antioxidant, and metabolic changes that anti-obesity treatments could offer, and the clinical manipulation of conditions associated with obesity, since the current misalignment and, in some cases, the mixed results between the already existing research groups lead to less definite conclusions.

Introduction: Small fiber neuropathy (SFN) affects pain and autonomic function, and there is increasing evidence that immune pathways are linked to its pathology. Intravenous immunoglobulin (IVIG) has been proposed as a treatment option for patients with painful SFN but has yielded mixed results. This review evaluates the effectiveness of IVIGs in the treatment of painful SFN.

Methods: According to PRISMA guidelines, a thorough literature search was conducted using five major electronic databases (PubMed, Google Scholar, Scopus, EMBASE, and Web of Science) up to August 17, 2023. Data extraction was performed independently by two reviewers, and quality assessments were performed using Joanna Briggs Institute tools. The PRISMA guidelines ensured the transparency of the review.

Results: This systematic review included seven studies to evaluate the effectiveness of IVIG for the treatment of SFN. The review included 458 patients from various studies conducted between 2005 and 2023, covering various neuropathy subtypes such as idiopathic SFN, sarcoidosis-associated SFN, etc. Both double-blind RCTs reported no significant differences between IVIG and placebo in neuropathy severity or pain reduction. Retrospective cohort studies varied in quality and produced mixed results. Of note, some studies showed significant pain reduction with IVIG, while others did not. The effectiveness of IVIG on neuropathy severity and intraepidermal nerve fiber density was similarly variable, with some studies reporting efficacy and others indicate no significant changes. Overall, IVIG showed potential benefits, but the results were inconsistent across studies.

Discussion: IVIG shows potential efficacy in select SFN subtypes, particularly autoimmuneassociated forms (e.g., TS-HDS/FGFR-3 positive), with some retrospective studies reporting pain and functional improvements. However, two high-quality RCTs found no significant benefit over placebo. Marked heterogeneity in study design, IVIG protocols, diagnostic criteria, and outcome measures limits comparability and generalizability. Adverse events, including infusion reactions were common. These findings highlight IVIG's possible role in immunologically mediated SFN but underscore the need for standardized protocols, biomarker-based patient selection, and large, wellcontrolled trials to establish definitive efficacy.

Conclusion: Some evidence suggests the potential benefit of IVIG therapy for certain subgroups of patients with SFN. However, the overall effectiveness is still unclear, and further studies are needed.

Cis-diamminedichloroplatinum (II) (cisplatin, CDDP) is one of the main anticancer drugs, used for the treatment of various malignancies. However, clinical application of this drug is associated with various side effects, prominently nephrotoxicity. One of the promising tools to decrease the side effects of the drug and simultaneously improve its therapeutic effects is the loading the drug into nanoparticles (NPs). This literature review focuses on the efficacy of various types of NPs, such as liposome, micelle, dendrimer, poly (lactic-co-glycolic acid), chitosan, alginate, curcumin (CUR), and metallic NPs to improve the therapeutic effects of CDDP and to decrease the nephrotoxicity. The results of these studies demonstrated that the reviewed NPs are able to decrease the nephrotoxic effects of CDDP in one of four different ways, including as a conjugating agent, encapsulating agent, antioxidant agent, or nanocarrier. Finally, among these reviewed NPs, liposomal NPs and the co-treatment with CUR as an antioxidant agent have more promising effects in reducing the toxicity of CDDP. Overall, the wide use of nanoliposomes in drug delivery systems due to their high stability, biocompatibility, drug loading capacity, and high bioavailability prompts the authors to propose liposomal CDDP delivery as a potent candidate for future studies. Moreover, because of the synergistic effects of CUR and CDDP on cancerous cells, the antioxidative properties of CUR in mitigating CDDP-induced nephrotoxicity, and the radiosensitizing influence of CUR, there is potential for the co-delivery of CDDP and CUR via liposomes to the tumor region.