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25 pages, 2882 KiB

Open AccessArticle

The Clinical Pharmacokinetics and Pharmacodynamics of Glimepiride—A Systematic Review and Meta-Analysis

by Mubara Azhar, Mohammed S. Alasmari, Ammara Zamir, Hamid Saeed, Faleh Alqahtani, Tanveer Ahmad and Muhammad Fawad Rasool

Pharmaceuticals 2025, 18(1), 122; https://doi.org/10.3390/ph18010122 - 17 Jan 2025

Viewed by 2108

Abstract

Background/Objectives: Glimepiride (GLM), a commonly used sulphonylurea drug for the management of type 2 diabetes mellitus (T2DM), has been the subject of numerous studies exploring its kinetic behaviors. However, a comprehensive evaluation that synthesizes all available pharmacokinetic (PK) data across diverse populations remains [...] Read more.

Background/Objectives: Glimepiride (GLM), a commonly used sulphonylurea drug for the management of type 2 diabetes mellitus (T2DM), has been the subject of numerous studies exploring its kinetic behaviors. However, a comprehensive evaluation that synthesizes all available pharmacokinetic (PK) data across diverse populations remains limited. This systematic review aims to provide detailed knowledge about the pharmacokinetics (PK), the associated pharmacodynamics (PD), and the drug interactions of GLM, which can be used to assess key parameters and identify factors influencing variability across diverse populations and clinical settings. Methods: A systematic search of the peer-reviewed literature was combined using major databases—Google Scholar, PubMed, Cochrane, and ScienceDirect, to identify studies reporting the PK of GLM. Following the data extraction, a meta-analysis using a random effect (RE) model was performed, where feasible, to quantitatively assess the variability of key PK parameters across different studies to create a more robust PK parameter estimate. Results: The final screening has yielded 40 articles. The area under the curve (AUC_0-∞) and the peak concentration (C_max) rise proportionately with increasing doses, depicting the linear kinetics of GLM. The subjects with genotype CYP2C9 *1/*3 depicted a 4-fold higher (AUC_0-∞) as compared to that of the CYP2C9 *1/*1 population. Preliminary meta-analysis results indicated significant variability in (AUC_0-∞) and C_max values among different studies. Heterogeneity across studies was high, warranting the use of RE models. Conclusions: The findings of this review would be helpful in the development and evaluation of PK models that may aid in suggesting individualized dosing. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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17 pages, 4354 KiB

Open AccessArticle

Peptide-Purified Anti-N-methyl-D-aspartate Receptor (NMDAR) Autoantibodies Have Inhibitory Effect on Long-Term Synaptic Plasticity

by Charlotte Day, John-Paul Silva, Rebecca Munro, Brice Mullier, Véronique Marie André, Christian Wolff, Gary J. Stephens and Angela Bithell

Pharmaceuticals 2024, 17(12), 1643; https://doi.org/10.3390/ph17121643 - 6 Dec 2024

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Abstract

Background/Objectives: Recent studies, typically using patient cerebrospinal fluid (CSF), have suggested that different autoantibodies (Aabs) acting on their respective receptors, may underlie neuropsychiatric disorders. The GluN1 (NR1) subunit of the N-methyl-D-aspartate receptor (NMDAR) has been identified as a target of anti-NMDAR Aabs in [...] Read more.

Background/Objectives: Recent studies, typically using patient cerebrospinal fluid (CSF), have suggested that different autoantibodies (Aabs) acting on their respective receptors, may underlie neuropsychiatric disorders. The GluN1 (NR1) subunit of the N-methyl-D-aspartate receptor (NMDAR) has been identified as a target of anti-NMDAR Aabs in a number of central nervous system (CNS) diseases, including encephalitis and autoimmune epilepsy. However, the role or the nature of Aabs responsible for effects on neuronal excitability and synaptic plasticity is yet to be established fully. Methods: Peptide immunisation was used to generate Aabs against selected specific GluN1 extracellular sequences based on patient-derived anti-NMDAR Aabs that have been shown to bind to specific regions within the GluN1 subunit. ‘Protein A’ purification was used to obtain the total IgG, and further peptide purification was used to obtain a greater percentage of NMDAR-target specific IgG Aabs. The binding and specificity of these anti-NMDAR Aabs were determined using a range of methodologies including enzyme-linked immunosorbent assays, immunocytochemistry and immunoblotting. Functional effects were determined using different in vitro electrophysiology techniques: two-electrode voltage-clamps in Xenopus oocytes and measures of long-term potentiation (LTP) in ex vivo hippocampal brain slices using multi-electrode arrays (MEAs). Results: We show that anti-NMDAR Aabs generated from peptide immunisation had specificity for GluN1 immunisation peptides as well as target-specific binding to the native protein. Anti-NMDAR Aabs had no clear effect on isolated NMDARs in an oocyte expression system. However, peptide-purified anti-NMDAR Aabs prevented the induction of LTP at Schaffer collateral-CA1 synapses in ex vivo brain slices, consistent with causing synaptic NMDAR hypofunction at a network level. Conclusions: This work provides a solid basis to address outstanding questions regarding anti-NMDAR Aab mechanisms of action and, potentially, the development of therapies against CNS diseases. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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11 pages, 2744 KiB

Open AccessArticle

Copper Increases the Cooperative Gating of Rat P2X2a Receptor Channels

by Elias Leiva-Salcedo, Denise Riquelme, Juan Pablo Huidobro-Toro and Claudio Coddou

Pharmaceuticals 2024, 17(12), 1590; https://doi.org/10.3390/ph17121590 - 26 Nov 2024

Viewed by 687

Abstract

Background/Objectives: P2X receptor channels are widely expressed in the CNS, where they have multiple functions in health and disease. The rat P2X2a (rP2X2a) receptor channel is modulated by copper, an essential trace element that plays important roles in synaptic modulation and neurodegenerative disorders. [...] Read more.

Background/Objectives: P2X receptor channels are widely expressed in the CNS, where they have multiple functions in health and disease. The rat P2X2a (rP2X2a) receptor channel is modulated by copper, an essential trace element that plays important roles in synaptic modulation and neurodegenerative disorders. Although essential extracellular amino acids that coordinate copper have been identified, the exact mechanism of copper-induced modulation has not been yet elucidated. Methods: We used HEK293T cells expressing rP2X2a channel(s) and performed outside-out single-channel and whole-cell recordings to explore copper’s effects on rP2X2 currents and determine whether this metal can increase the cooperative gating of rP2X2a channel. Results: In whole-cell recordings and in patches containing 2 or 3 rP2X2a channels, copper enhanced the ATP-induced currents, significantly reducing the ATP EC₅₀ and increasing the Hill coefficient. Moreover, copper increased the apparent P_o in patches containing two or three channels. By contrast, in patches containing only one rP2X2a channel, we did not observe any significant changes in ATP EC₅₀, the Hill coefficient, or P_o. Conclusions: Copper modulates the gating of rP2X2a channels, enhancing interchannel cooperativity without altering single-channel conductance or P_o. This novel regulatory mechanism could be relevant for understanding the role of P2X2 channels in physiological and pathological processes. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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9 pages, 3316 KiB

Open AccessArticle

Lung Toxicity Occurring During Enfortumab Vedotin Treatment: From a Priming Case Report to a Retrospective Analysis

by Grégoire Desimpel, François Zammit, Sarah Lejeune, Guillaume Grisay and Emmanuel Seront

Pharmaceuticals 2024, 17(11), 1547; https://doi.org/10.3390/ph17111547 - 18 Nov 2024

Cited by 2 | Viewed by 1349

Abstract

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination [...] Read more.

Background/Objectives: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) that combines monomethyl auristatin E (MMAE), a potent cytotoxic agent, with a monoclonal antibody targeting Nectin-4. It has emerged as a promising therapy for metastatic urothelial carcinoma (mUC), either as monotherapy or in combination with pembrolizumab, improving significantly the overall survival of these patients. EV is associated with common adverse events, including skin reactions, glucose imbalance, and peripheral neuropathy, which are usually mild in severity and easily manageable. Methods: Following an initial case of pleuro-pneumopathy occurring in a patient treated with EV, we conducted a retrospective analysis of EV effects on pulmonary imaging. Results: In a cohort of 20 all-comers mUC patients, we identified three cases of potentially EV-related lung toxicity, resulting in a pleuro-pneumopathy rate of 15%. Two of these cases appeared highly symptomatic and required high steroid doses, with a rapid resolution of symptoms and normalization of radiological findings. In one patient, rechallenge of EV was associated with reoccurrence of pneumopathy. We described the clinical and radiological features of these cases, as well as their evolution after EV discontinuation and rechallenge. Conclusions: This case series underscores the importance of close pulmonary monitoring during EV treatment. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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15 pages, 2444 KiB

Open AccessArticle

Glucose-Lowering Drugs and Primary Prevention of Chronic Kidney Disease in Type 2 Diabetes Patients: A Real-World Primary Care Study

by Antonio Rodríguez-Miguel, Beatriz Fernández-Fernández, Alberto Ortiz, Miguel Gil, Sara Rodríguez-Martín, Gema Ruiz-Hurtado, Encarnación Fernández-Antón, Luis M. Ruilope and Francisco J. de Abajo

Pharmaceuticals 2024, 17(10), 1299; https://doi.org/10.3390/ph17101299 - 29 Sep 2024

Cited by 1 | Viewed by 2020

Abstract

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: [...] Read more.

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1–326.5) per 10,000 person-years. In the nested case–control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73–0.99 and AOR = 0.89; 95%CI: 0.74–1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56–0.94 and AOR = 0.64; 95%CI: 0.46–0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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23 pages, 8869 KiB

Open AccessArticle

Liposomal Rifabutin—A Promising Antibiotic Repurposing Strategy against Methicillin-Resistant Staphylococcus aureus Infections

by Jacinta O. Pinho, Magda Ferreira, Mariana Coelho, Sandra N. Pinto, Sandra I. Aguiar and Maria Manuela Gaspar

Pharmaceuticals 2024, 17(4), 470; https://doi.org/10.3390/ph17040470 - 8 Apr 2024

Cited by 6 | Viewed by 2289

Abstract

Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes [...] Read more.

Methicillin-resistant Staphylococcus aureus (M RSA) infections, in particular biofilm-organized bacteria, remain a clinical challenge and a serious health problem. Rifabutin (RFB), an antibiotic of the rifamycins class, has shown in previous work excellent anti-staphylococcal activity. Here, we proposed to load RFB in liposomes aiming to promote the accumulation of RFB at infected sites and consequently enhance the therapeutic potency. Two clinical isolates of MRSA, MRSA-C1 and MRSA-C2, were used to test the developed formulations, as well as the positive control, vancomycin (VCM). RFB in free and liposomal forms displayed high antibacterial activity, with similar potency between tested formulations. In MRSA-C1, minimal inhibitory concentrations (MIC) for Free RFB and liposomal RFB were 0.009 and 0.013 μg/mL, respectively. Minimum biofilm inhibitory concentrations able to inhibit 50% biofilm growth (MBIC₅₀) for Free RFB and liposomal RFB against MRSA-C1 were 0.012 and 0.008 μg/mL, respectively. Confocal microscopy studies demonstrated the rapid internalization of unloaded and RFB-loaded liposomes in the bacterial biofilm matrix. In murine models of systemic MRSA-C1 infection, Balb/c mice were treated with RFB formulations and VCM at 20 and 40 mg/kg of body weight, respectively. The in vivo results demonstrated a significant reduction in bacterial burden and growth index in major organs of mice treated with RFB formulations, as compared to Control and VCM (positive control) groups. Furthermore, the VCM therapeutic dose was two fold higher than the one used for RFB formulations, reinforcing the therapeutic potency of the proposed strategy. In addition, RFB formulations were the only formulations associated with 100% survival. Globally, this study emphasizes the potential of RFB nanoformulations as an effective and safe approach against MRSA infections. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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15 pages, 2771 KiB

Open AccessArticle

Aloe-Emodin Derivative, an Anthraquinone Compound, Attenuates Pyroptosis by Targeting NLRP3 Inflammasome in Diabetic Cardiomyopathy

by Yingying Hu, Shuqian Zhang, Han Lou, Monayo Seth Mikaye, Run Xu, Ziyu Meng, Menghan Du, Pingping Tang, Zhouxiu Chen, Yongchao Chen, Xin Liu, Zhimin Du and Yong Zhang

Pharmaceuticals 2023, 16(9), 1275; https://doi.org/10.3390/ph16091275 - 8 Sep 2023

Cited by 5 | Viewed by 2626

Abstract

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and [...] Read more.

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague–Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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Review

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23 pages, 650 KiB

Open AccessReview

Exploring the Protective Effects of Traditional Antidiabetic Medications and Novel Antihyperglycemic Agents in Diabetic Rodent Models

by Cosmin Gabriel Tartau, Ianis Kevyn Stefan Boboc, Liliana Mititelu-Tartau, Maria Bogdan, Beatrice Rozalina Buca, Liliana Lacramioara Pavel and Cornelia Amalinei

Pharmaceuticals 2025, 18(5), 670; https://doi.org/10.3390/ph18050670 - 1 May 2025

Viewed by 270

Abstract

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing [...] Read more.

Type 2 Diabetes (T2D) is a complex metabolic disorder that affects multiple organs, leading to severe complications in the pancreas, kidneys, liver, and heart. Prolonged hyperglycemia, along with oxidative stress and chronic inflammation, plays a crucial role in accelerating tissue damage, significantly increasing the risk of diabetic complications such as nephropathy, hepatopathy, and cardiovascular disease. This review evaluates the protective effects of various antidiabetic treatments on organ tissues affected by T2D, based on findings from experimental animal models. Metformin, a first-line antidiabetic agent, has been widely recognized for its ability to reduce inflammation and oxidative stress, thereby mitigating diabetes-induced organ damage. Its protective role extends beyond glucose regulation, offering benefits such as improved mitochondrial function and reduced fibrosis in affected tissues. In addition to traditional therapies, new classes of antidiabetic drugs, including sodium-glucose co-transporter-2 inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists not only improve glycemic control but also exhibit nephroprotective and cardioprotective properties by reducing glomerular hyperfiltration, oxidative stress, and inflammation. Similarly, GLP-1 receptor agonists have been associated with reduced hepatic steatosis and enhanced cardiovascular function. Preclinical studies suggest that tirzepatide, a dual GLP-1/gastric inhibitory polypeptide receptor agonist may offer superior metabolic benefits compared to conventional GLP-1 agonists by improving β-cell function, enhancing insulin sensitivity, and reducing fatty liver progression. Despite promising preclinical results, differences between animal models and human physiology pose a challenge. Further clinical research is needed to confirm these effects and refine treatment strategies. Future T2D management aims to go beyond glycemic control, emphasizing organ protection and long-term disease prevention. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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34 pages, 1841 KiB

Open AccessReview

Biofilm-Associated Candidiasis: Pathogenesis, Prevalence, Challenges and Therapeutic Options

by Valerie Amann, Ann-Kathrin Kissmann, Carolina Firacative and Frank Rosenau

Pharmaceuticals 2025, 18(4), 460; https://doi.org/10.3390/ph18040460 - 25 Mar 2025

Viewed by 665

Abstract

The rising prevalence of fungal infections, especially those caused by Candida species, presents a major risk to global health. With approximately 1.5 million deaths annually, the urgency for effective treatment options has never been greater. Candida spp. are the leading cause of invasive [...] Read more.

The rising prevalence of fungal infections, especially those caused by Candida species, presents a major risk to global health. With approximately 1.5 million deaths annually, the urgency for effective treatment options has never been greater. Candida spp. are the leading cause of invasive infections, significantly impacting immunocompromised patients and those in healthcare settings. C. albicans, C. parapsilosis and the emerging species C. auris are categorized as highly dangerous species because of their pathogenic potential and increasing drug resistance. This review comparatively describes the formation of microbial biofilms of both bacterial and fungal origin, including major pathogens, thereby creating a novel focus. Biofilms can further complicate treatment, as these structures provide enhanced resistance to antifungal therapies. Traditional antifungal agents, including polyenes, azoles and echinocandins, have shown effectiveness, yet resistance development continues to rise, necessitating the exploration of novel therapeutic approaches. Antimicrobial peptides (AMPs) such as the anti-biofilm peptides Pom-1 and Cm-p5 originally isolated from snails represent promising candidates due to their unique mechanisms of action and neglectable cytotoxicity. This review article discusses the challenges posed by Candida infections, the characteristics of important species, the role of biofilms in virulence and the potential of new therapeutic options like AMPs. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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26 pages, 2086 KiB

Open AccessReview

The Anti-Inflammatory Potential of Tricyclic Antidepressants (TCAs): A Novel Therapeutic Approach to Atherosclerosis Pathophysiology

by Majid Eslami, Marzieh Monemi, Mohammad Ali Nazari, Mohammad Hossein Azami, Parand Shariat Rad, Valentyn Oksenych and Ramtin Naderian

Pharmaceuticals 2025, 18(2), 197; https://doi.org/10.3390/ph18020197 - 31 Jan 2025

Cited by 2 | Viewed by 1363

Abstract

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory [...] Read more.

Atherosclerosis, a chronic inflammatory disease, is driven by complex molecular mechanisms involving inflammatory cytokines and immune pathways. According to recent research, tricyclic antidepressants (TCAs), which are typically prescribed to treat depressive disorders, have strong anti-inflammatory effects. TCAs, including imipramine and amitriptyline, alter inflammatory signaling cascades, which include lowering the levels pro-inflammatory cytokines like TNF-α, IL-1β, and IL-6 and inhibiting NF-κB activation. By inhibiting the NLRP3 inflammasome and suppressing pathways including JAK/STAT, MAPK, and PI3K, these effects are produced, improving endothelial function and reducing oxidative stress. The intricacy of TCAs’ anti-inflammatory actions has demonstrated by the existence of contradictory findings about how they alter IL-6 levels. The dependence of the heterogeneity of the reaction on the use of particular TCAs and experimental settings is shown by the fact that some studies show reduced IL-6 production, while others indicate increases or no changes. This review explores the multifaceted mechanisms through which TCAs modulate inflammatory pathways. TCAs inhibit NF-κB activation, reduce oxidative stress, and suppress the production of key inflammatory mediators, including IL-6 and TNF-α. They also regulate Toll-like receptor (TLR) signaling and NOD-, LRR-, and NLR family pyrin domain-containing protein 3 (NLRP3) inflammasome activation, reducing the release of IL-1β and IL-18, critical drivers of endothelial dysfunction and plaque instability. Given their capacity to target critical inflammatory molecules and pathways, TCAs provide great potential in the therapy of atherosclerosis, particularly for individuals with associated depression and cardiovascular risk factors. Nevertheless, further research is essential to clarify the precise molecular mechanisms, resolve inconsistencies in current findings, and establish the clinical applicability of TCAs as anti-inflammatory agents in atherosclerosis management. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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21 pages, 820 KiB

Open AccessReview

Role of Trimetazidine in Ameliorating Endothelial Dysfunction: A Review

by Yusof Kamisah and Hamat H. Che Hassan

Pharmaceuticals 2024, 17(4), 464; https://doi.org/10.3390/ph17040464 - 5 Apr 2024

Cited by 4 | Viewed by 2589

Abstract

Endothelial dysfunction is a hallmark of cardiovascular diseases, contributing to impaired vasodilation, altered hemodynamics, and atherosclerosis progression. Trimetazidine, traditionally used for angina pectoris, exhibits diverse therapeutic effects on endothelial dysfunction. This review aims to elucidate the mechanisms underlying trimetazidine’s actions and its potential [...] Read more.

Endothelial dysfunction is a hallmark of cardiovascular diseases, contributing to impaired vasodilation, altered hemodynamics, and atherosclerosis progression. Trimetazidine, traditionally used for angina pectoris, exhibits diverse therapeutic effects on endothelial dysfunction. This review aims to elucidate the mechanisms underlying trimetazidine’s actions and its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders. Trimetazidine enhances vasodilation and hemodynamic function by modulating endothelial nitric oxide synthase activity, nitric oxide production, and endothelin-1. It also ameliorates metabolic parameters, including reducing blood glucose, mitigating oxidative stress, and dampening inflammation. Additionally, trimetazidine exerts antiatherosclerotic effects by inhibiting plaque formation and promoting its stability. Moreover, it regulates apoptosis and angiogenesis, fostering endothelial cell survival and neovascularization. Understanding trimetazidine’s multifaceted mechanisms underscores its potential as a therapeutic agent for endothelial dysfunction and associated cardiovascular disorders, warranting further investigation for clinical translation. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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9 pages, 1745 KiB

Open AccessCase Report

Safety of Nintedanib in a Patient with Chronic Pulmonary Fibrosis and Kidney Disease

by Marta Maggisano, Lucrezia Mondini, Maria Chernovsky, Paola Confalonieri, Francesco Salton, Nicolò Reccardini, Metka Kodric, Pietro Geri, Marco Confalonieri, Michael Hughes, Rossella Cifaldi and Barbara Ruaro

Pharmaceuticals 2024, 17(9), 1147; https://doi.org/10.3390/ph17091147 - 30 Aug 2024

Cited by 3 | Viewed by 1823

Abstract

Nintedanib, an intracellular inhibitor that targets multiple tyrosine kinase, is an important drug for the treatment of pulmonary fibrosis. Until now, no studies have been published reporting the nintedanib tolerability or its efficacy in patients with chronic pulmonary lung disease and chronic kidney [...] Read more.

Nintedanib, an intracellular inhibitor that targets multiple tyrosine kinase, is an important drug for the treatment of pulmonary fibrosis. Until now, no studies have been published reporting the nintedanib tolerability or its efficacy in patients with chronic pulmonary lung disease and chronic kidney disease comorbidity. The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) and for this reason it is contraindicated in these patients. We describe a case of use of nintedanib in a patient affected by idiopathic pulmonary fibrosis (IPF) who started, from 2022, nintedanib 150 mg twice a day with careful monitoring of liver and kidney function. Due to the onset of stage 3/4 chronic kidney disease associated with proteinuria, nintedanib was suspended for two months, and the patient received Prednisone at a dose of 12.5 mg/day. During the two months of suspension, the renal function did not improve, unlike the respiratory status worsened. In the past a renal biopsy was performed which showed no correlation with nintedanib use. Nintedanib therapy started again following the decline in lung function and desaturation below 90% in the 6-min walking test (6MWT). Patient showed a good tolerability of nintedanib with sporadic episode of diarrhea and an improvement of pulmonary function leading to a stable state of chronic pulmonary fibrosis disease. For this reason, in mutual agreement with the patient, we decided to maintain nintedanib therapy even when the patient required hemodialysis. No toxic effects appeared. This case report revealed the safety of nintedinab in patient with concomitant kidney failure, but more studies are necessary. Full article

(This article belongs to the Special Issue The 20th Anniversary of Pharmaceuticals—Advances in Pharmacology)

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