Search Results (86)

The significant burden of polypharmacy in clinical settings contrasts sharply with the narrow research focus on drug–drug interactions (DDIs), revealing an important gap in understanding the complexity of real-world multi-drug regimens. The present study addresses this gap by conducting a high-resolution, multidimensional bibliometric and network analysis of 19,151 DDI publications indexed in the Web of Science Core Collection (1975–2025). Using advanced tools, including VOSviewer version 1.6.20, Bibliometrix 5.0.0, and AI-enhanced terminology normalization, global research trajectories, knowledge clusters, and collaborative dynamics were systematically mapped. The analysis revealed an exponential growth in publication volume (from 55 in 1990 to 1194 in 2024), with output led by the United States and a marked acceleration in Chinese contributions after 2015. Key pharmacological agents frequently implicated in DDI research included CYP450-dependent drugs such as statins, antiretrovirals, and central nervous system drugs. Thematic clusters evolved from mechanistic toxicity assessments to complex frameworks involving clinical risk management, oncology co-therapies, and pharmacokinetic modeling. The citation impact peaked at 3.93 per year in 2019, reflecting the increasing integration of DDI research into mainstream areas of pharmaceutical science. The findings highlight a shift toward addressing polypharmacy risks in aging populations, supported by novel computational methodologies. This comprehensive assessment offers insights for researchers and academics aiming to navigate the evolving scientific landscape of DDIs and underlines the need for more nuanced system-level approaches to interaction risk assessment. Future studies should aim to incorporate patient-level real-world data, expand bibliometric coverage to underrepresented regions and non-English literature, and integrate pharmacogenomic and time-dependent variables to enhance predictive models of interaction risk. Cross-validation of AI-based approaches against clinical outcomes and prospective cohort data are also needed to bridge the translational gap and support precision dosing in complex therapeutic regimens. Full article

Background: Administration of PARP inhibitors against breast and ovarian cancers with BRCA1 and BRCA2 mutations has shown clinical benefits in patients. However, these agents are also toxic and have a narrow therapeutic index. Objectives: In this work, we aimed to identify membrane proteins that are specifically upregulated in these cancers. Methods: We interrogated public datasets to analyze genes upregulated or downregulated when these mutations were present, compared with wild-type cancers. Surface protein expression and functional annotation analyses were also performed. Results: In breast cancer, we identified 11 upregulated and 44 downregulated transcripts in BRCA1-mut, while 10 upregulated and 57 downregulated transcripts were identified in BRCA2-mut cancers. In ovarian cancer, 79 transcripts were upregulated and 123 were downregulated in BRCA1-mut cancers, while five were upregulated and seven were downregulated in BRCA2-mut tumors. Regarding the biological function related to these genes, in BRCA1-mutated ovarian cancers, the main functions of upregulated genes included MHC assembly or regulation of the interferon gamma pathway; in BRCA2-mut ovarian cancers, regulation of phosphorylation and signaling; in BRCA1-mut breast cancers, cell damage repair and angiogenesis; and finally, in BRCA2-mut breast cancers, cytokine production and T-cell migration. Genes expressed in the surface membrane or extracellular matrix and related to patient outcomes included B3GNT7 and CTSV in BRCA2-mut breast cancers, exhibiting detrimental prognoses. CD6, CXCL9, and CXCL13 were associated with favorable outcomes in BRCA1-mutant ovarian cancers. The last three genes were also correlated with the infiltration of effector T cells and dendritic cells in ovarian tumors. Conclusions: In summary, we identified deregulated candidate genes that could be used as therapeutic targets. Full article

Propolis is a natural resinous substance produced by honeybees that has many biological activities. For thousands of years, it has been widely used as a dietary supplement and traditional medicine to treat a variety of ailments due to its antimicrobial, anti-inflammatory, antioxidant, immunomodulatory, and wound-healing properties. Nutritional supplements and foods may interact with drugs both pharmacodynamically and pharmacokinetically, which could raise clinical concerns. Background/Objectives: This study aimed to investigate the effect of propolis on the plasma disposition of enrofloxacin and to assess the potential pharmacokinetic interaction in rabbits. Methods: In this study, enrofloxacin was applied per os (20 mg/kg) and IM (10 mg/kg) and with propolis (100 mg resin/kg) administration in four groups of rabbits (each of six individuals). Heparinized blood samples were collected at 0, 0.1, 0.3, 0.5, 1, 2, 4, 8, 12, and 24 h post-administration. HPLC-FL was used to analyze the plasma concentrations of enrofloxacin and its active metabolite ciprofloxacin following liquid–liquid phase extraction, i.e., protein precipitation with acetonitrile and partitioning with sodium sulfate. Results: The results revealed that propolis coadministration significantly affected the plasma disposition of enrofloxacin and its active metabolite after both per os and intramuscular administration routes. Significantly greater AUC (48.91 ± 11.53 vs. 26.11 ± 12.44 µg.h/mL), as well as longer T_1/2λz (11.75 ± 3.20 vs. 5.93 ± 2.51 h) and MRT (17.26 ± 4.55 vs. 8.96 ± 3.82 h) values of enrofloxacin and its metabolite ciprofloxacin, were observed after the coadministration of propolis compared to enrofloxacin alone following both per os and IM routes in rabbits. Conclusions: The concurrent use of propolis and prescription medications may prolong the half-life (T_1/2λz) and increase the systemic availability of chronically used drugs with narrow therapeutic indices. The repeated use of drugs such as antibiotics, heart medications, and antidepressants, or drugs with a narrow therapeutic index such as antineoplastic and anticoagulant agents, can cause toxic effects by raising blood plasma levels. Considering the varied metabolism of rabbits and humans, further validation of this study may require thorough clinical trials in humans. Full article

CYP2C9 and CYP2C19 are major CYP450 enzymes that heavily influence the hepatic metabolism and bioactivation of many medications, including over-the-counter and narrow therapeutic index drugs. Compared to the wild-type alleles, genetic variants in either gene could potentially alter the pharmacokinetics of widely used medications, affect the desired therapeutic outcomes of a drug therapy, or increase the risk of undesired adverse events. The frequency of genetic polymorphisms associated with CYP450 enzymes can widely differ across and between racial and ethnic groups. This narrative review highlights the differences in CYP2C9 and CYP2C19 allele frequencies among European and Asian population subgroups, using published literature. Identifying the substantial differences across European and Asian populations, as well as within Asian subgroups, indicates the need to further scrutinize general population data. Clinical scientists and healthcare providers should advocate for more inclusive clinical pharmacogenomic data and racially and ethnically diverse pharmacogenomic databases. Clinical trials of limited racial and geographical diversity may not necessarily have strong external generalizability for all populations. Furthermore, clinical trials that designate an all-inclusive Asian population consisting of multiple ethnicities may not be adequate due to the perceived genetic differences among Asian subgroups. Gravitating towards a more comprehensive approach to utilizing pharmacogenomic data necessitates granular population-level genetic information which can be leveraged to improve how drug therapies are prescribed, achieve health equity, and advance the future of precision medicine. Full article

Lithium is used as a medication in the treatment of bipolar disorder. Lithium has a narrow therapeutic index, and fatal intoxications have been described. The therapeutic drug monitoring of lithium is routinely performed in serum. Serum is commonly unavailable in forensic postmortem analysis, where whole blood is the matrix of choice. In this study, an inductively coupled plasma mass spectrometry (ICP-MS) method was developed and validated for the quantification of lithium in postmortem whole blood. Sample preparation consisted of a 100-fold dilution with acid and required only 40 µL of blood. Carry-over was deemed appropriately reduced with a rinse solution containing 5% hydrochloric acid. A nebulizer gas flow rate of 1.15 L/min showed a sufficient improvement of lithium sensitivity while simultaneously minimizing the background. Germanium was determined to be the most optimal internal standard. The method was validated in terms of linearity, accuracy, precision, and lower limit of quantification. Linearity was demonstrated within the analytical measurement range of 0.10–1.5 mmol/L. The method showed acceptable precision and accuracy, with a total coefficient of a variation ≤2.3% and accuracies ranging from 105 to 108% at all concentrations in the quality control samples. The final method was applied to postmortem blood from 103 consecutive autopsy cases and demonstrated robustness by low intermediate precision and high and consistent recovery of the internal standard. Full article

Background: Tacrolimus (TAC) is the cornerstone of immunosuppression after liver transplantation (LT). TAC has a narrow therapeutic index and high inter- and intra-individual pharmacokinetic (PK) variability, requiring dose individualization. This variability is more noticeable in the early post-LT period. Objectives: This study aimed to compare the PK of different TAC formulations in the early post-LT period and describe the main PK characteristics and plasma levels obtained with each TAC formulation used. Methods: The search was conducted in MEDLINE (PubMed) and EMBASE in accordance with PRISMA-ScR guidelines. The main inclusion criteria were clinical trials and observational studies focusing on the PK parameters of TAC in LT recipients during the first month post-transplant. Results: A total of 2169 articles were identified, of which 23 met the inclusion criteria. Various PK parameters were analyzed after LT for the different TAC formulations: intravenous (iv) and oral forms, such as immediate-release (IRT), prolonged-release (PRT), and extended-release (LCPT) formulations. PK variability was higher in the initial days after LT, with different TAC exposure between formulations. IV TAC allows the rapid attainment of therapeutic levels, but it has fallen into disuse. Regarding oral formulations, IRT reaches target levels faster than PRT and LCPT. PRT and LCPT exposure seem more stable during the first month post-LT than when using IRT. Conclusions: TAC formulations exhibit relevant differences in their PK profile in the early post-LT period. PK differences might influence the dose regimen and the time to achieve PK targets. Given these variations, therapeutic drug monitoring (TDM) is essential for optimizing treatment. Full article

Background/Objectives: Lumbosacral spinal stenosis (LSS) is a degenerative condition characterized by narrowing of the spinal canal and associated neuropathic pain. While mechanical compression is well-characterized, the molecular mechanisms contributing to symptom severity remain poorly understood. Neurturin (NRTN), a member of the glial cell line-derived neurotrophic factor family, has emerged as a potential mediator of neural plasticity and nociception, but its role in spinal stenosis is largely unexplored. Methods: We analyzed NRTN mRNA and protein expression in ligamentum flavum samples from 96 patients undergoing surgery for LSS and 85 non-degenerative postmortem controls. Quantification was performed using real-time quantitative polymerase chain reaction (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), Western blotting, and immunohistochemistry. Pain severity Visual Analog Scale (VAS), body mass index (BMI), diabetes, smoking, and alcohol use were assessed as modulators of NRTN expression. Results: NRTN expression was significantly elevated in LSS patients versus controls at both transcript and protein levels (p < 0.05). NRTN levels positively correlated with pain intensity (VAS; ANOVA p = 0.032 for mRNA, p = 0.041 for protein). Multivariate regression identified BMI (β = 0.50, p = 0.015) and diabetes (β = 0.39, p = 0.017) as independent predictors of increased NRTN expression. Alcohol use also showed a positive association (p = 0.046), while smoking showed no significant independent effect. Conclusions: Neurturin is upregulated in ligamentum flavum tissue from LSS patients and correlates with pain severity and metabolic risk factors. These findings suggest NRTN as a potential biomarker and therapeutic target in degenerative spine disease. Further longitudinal and mechanistic studies are warranted to elucidate its role in chronic pain and neuroinflammation. Full article

Background: Although recent advancements in ischemic stroke management have reduced associated mortality rates, there remains a pressing need for more reliable, efficacious, and well-tolerated therapeutic approaches due to the narrow therapeutic window of current treatment approaches. The current meta-analysis sought to evaluate the safety and efficacy of stem cell-based therapeutic options for patients with ischemic stroke. Methods: PubMed, Web of Science, and Cochrane library databases were searched to retrieve randomized controlled trials (RCTs) evaluating the efficacy and safety of stem cell therapy (SCT) in ischemic stroke patients. Key outcomes included the National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), Barthel Index (BI), Fugl–Meyer Assessment (FMA), infarct size, and safety profile. The random effects model with the continuous method was used to calculate the pooled effect size in Review Manager 5.4.1, and subgroup analyses were performed based on demographics, stroke duration, and SCT delivery protocols. Results: A total of 18 RCTs involving 1026 patients were analyzed, with 538 in the treatment group and 488 in the control group. The mean change in NIHSS score was comparable between groups [MD = −0.80; 95% CI: −2.25, 0.65, p < 0.0001]. However, SCT showed better outcomes in mRS [MD = −0.56; 95% CI: −0.76, −0.35, p = 0.30] and BI scores [MD = 12.00; 95% CI: 4.00, 20.00, p = 0.007]. Additionally, the mean change in FMA score was significantly greater with SCT [MD = 18.16; 95% CI: 6.58, 29.75, p = 0.03]. The mean change in infarct volume also favored stem cell therapy [MD = 8.89; 95% CI: −5.34, 23.12, p = 0.08]. The safety profile was favorable, with adverse event rates comparable to or lower than controls. Conclusions: SCT offers a safe and effective approach to improving functional outcomes in stroke patients, particularly with early intervention. These findings highlight the potential of SCT in ischemic stroke rehabilitation while underscoring the need for standardized protocols and long-term safety evaluation. Full article

Background/Objectives: Degenerative lumbo-sacral spinal stenosis is characterized by spinal canal narrowing, often linked to ligamentum flavum hypertrophy. This study evaluated the elemental composition of ligamentum flavum tissue in DLSS patients compared to healthy controls. Methods: This study involved 180 patients diagnosed with degenerative lumbo-sacral spinal stenosis and 102 healthy controls. Ligamentum flavum samples were analyzed for concentrations of magnesium (Mg), calcium (Ca), phosphorus (P), zinc (Zn), copper (Cu), iron (Fe), sodium (Na), potassium (K), manganese (Mn), and lead (Pb) using inductively coupled plasma optical emission spectrometry (ICP-OES). Statistical analyses were conducted using Student’s t-test, ANOVA, and Pearson’s correlation, with a significance threshold of p < 0.05. Results: The study group exhibited significantly elevated levels of Mg (p < 0.001), Ca (p = 0.014), and P (p = 0.006), along with reduced concentrations of Zn (p = 0.021) and Cu (p = 0.038) compared to controls. No statistically significant differences were observed for Na, K, Mn, or Fe (p > 0.05). Elemental imbalances were more pronounced in individuals with higher body mass index (BMI) and varied by gender. Pain intensity demonstrated a significant correlation with Zn (p = 0.012) and Na (p = 0.045), but no consistent associations with Mg, Ca, or P. Conclusions: Altered Mg, Ca, P, and Zn levels in ligamentum flavum suggest their involvement in degenerative lumbo-sacral spinal stenosis pathophysiology. These elements may serve as potential biomarkers and therapeutic targets for mitigating spinal canal narrowing. Full article

Therapeutic drug monitoring (TDM) is pivotal for optimizing drug dosage regimens in individual patients, particularly for drugs with a narrow therapeutic index. Surface-enhanced Raman spectroscopy (SERS) has shown great potential in TDM due to high sensitivity, non-destructive analysis, specific fingerprint spectrum, low sample consumption, simple operation, and low ongoing costs. Due to the rapid development of SERS for TDM, a review focusing on the analytical method is presented to better understand the trends. This review examines the latest advancements in SERS substrates and their applications in TDM, highlighting the innovations in substrate design that enhance detection sensitivity and selectivity. We discuss the challenges faced by SERS for TDM, such as substrate signal reproducibility and matrix interference from complex biological samples, and explore solutions like digital colloid-enhanced Raman spectroscopy, enrichment detection strategies, microfluidic SERS, tandem instrument technologies, and machine learning-enabled SERS. These advancements address the limitations of traditional SERS applications and improve analytical efficiency in TDM. Finally, conclusions and perspectives on future research directions are presented. The integration of SERS with emerging technologies presents a transformative approach to TDM, with the potential to significantly enhance personalized medicine and improve patient outcomes. Full article

Background: Tacrolimus is widely used as a first-line immunosuppressant in transplant immunology; however, its clinical application is constrained by the narrow therapeutic index and considerable interindividual variability. In this study, we identified the potential regulatory role of a novel PPP3R1 promoter polymorphism, rs4519508 C > T, in the tacrolimus pharmacodynamic pathway. Methods: Dual-luciferase reporter assays and bioinformatic analysis were applied to assess the impact of allelic variation. Electrophoretic mobility shift assays (EMSA) validated the altered binding of transcription factors. Quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA) and Western blots were used to determine the immunosuppressive effect of tacrolimus. Results: Assays revealed that rs4519508 C > T markedly enhanced PPP3R1 promoter activity. EMSA assays validated the binding of E2F6 to rs4519508 C (wild-type) and the binding was significantly weaker to the rs4519508 T (mutant-type). The overexpression of E2F6 significantly reduced the transcriptional activity and expression of PPP3R1 when the rs4519508 site presented as major C allele, an effect that was not observed with the rs4519508 T allele. Furthermore, the downregulation of E2F6 raises the level of downstream immune cytokines inhibited by TAC. Conclusions: This study proposed that E2F6 suppresses the expression of PPP3R1, while rs4519508 C > T impairs the binding of E2F6, and thus elevates the level of PPP3R1, so that the inhibition of the downstream immune cytokines by TAC is attenuated. Our findings reported the potential regulatory role of a novel polymorphism, PPP3R1 rs4519508 C > T, which may serve as pharmacodynamic-associated pharmacogenetic biomarker indicating individual response variability of tacrolimus, and thus aid the clinical management of transplant immunology. Full article

Background: Morphine is a commonly prescribed opioid analgesic used to treat chronic pain. Morphine undergoes glucuronidation by UDP-glucuronosyltransferase (UGT) 2B7 to form morphine-3-glucuronide and morphine-6-glucuronide. Morphine is the gold standard for chronic pain management and has a narrow therapeutic index. Reports have shown that chronic pain patients have increasingly used other supplements to treat their chronic pain, including cannabidiol (CBD). Up to 50% of chronic pain patients report that they co-use cannabis with their prescribed opioid for pain management, including morphine. Previous work has shown that cannabidiol is a potent inhibitor of UGT2B7, including morphine-mediated metabolism. Co-use of morphine and CBD may result in unwanted drug–drug interactions (DDIs). Methods: Using available physiochemical and clinical parameters, morphine and CBD physiologically based pharmacokinetic (PBPK) models were developed and validated in both healthy and cirrhotic populations. Models for the two populations were then combined to predict the severity and clinical relevance of the potential DDIs during coadministration of both morphine and CBD in both healthy and hepatic-impaired virtual populations. Results: The predictive DDI model suggests that a ~5% increase in morphine exposure is to be expected in healthy populations. A similar increase in exposure of morphine is predicted in severe hepatic-impaired populations with an increase of ~10. Conclusions: While these predicted increases in morphine exposure are below the Food and Drug Administration’s cutoff (1.25-fold increase), morphine has a narrow therapeutic index and a 5–10% increase in exposure may be clinically relevant. Future clinical studies are needed to fully characterize the clinical relevance of morphine-related DDIs. Full article

Fucoxanthin (FN), a carotenoid derived from brown seaweed and algae, offers significant health benefits. However, its unique structure leads to challenges in stability and bioavailability. To overcome these issues, we successfully encapsulated fucoxanthin in solid lipid nanoparticles (SLNs) utilizing health-safe materials, achieving remarkable results. SLNs exhibited a nanoscale size of 248.98 ± 4.0 nm, along with an impressive encapsulation efficiency of 98.30% ± 0.26% and a loading capacity of 5.48% ± 0.82% in lipid. The polydispersity index (PDI) was measured at 0.161 ± 0.03, indicating a narrow size distribution, while the high negative zeta potential of −32.93 ± 1.2 mV suggests excellent stability. Pharmacokinetic studies conducted in Sprague–Dawley rats revealed an exceptional oral bioavailability of 2723.16% compared to fucoxanthin crystals, likely attributed to the enhanced stability and improved cellular uptake of the SLNs. To further improve bioavailability, we creatively applied enteric coatings to the freeze-dried SLNs, effectively protecting fucoxanthin from gastric degradation, which is supported by in vitro digestion results. These findings underscore the potential of SLNs as a superior delivery system for fucoxanthin, significantly enhancing its therapeutic efficacy and broadening its application in the food and pharmaceutical industries. Full article

ADCs have emerged as a promising class of therapeutics, combining the targeting specificity of monoclonal antibodies with the cytotoxic potency of small-molecule drugs. Although the majority of approved ADCs are still based on microtubule binder payloads, the recent success of topoisomerase I inhibitors has revitalized interest in the identification of novel agents overcoming present limitations in the field including narrow therapeutic window and chemoresistance. The success of DNA binders as payload for ADCs has been very limited, up to now, due, among other factors, to high hydrophobicity and planar chemical structures resulting in most cases in ADCs with a strong tendency to aggregate, poor plasma stability, and limited therapeutic index. Some of these molecules, however, continue to be of interest due to their favorable properties in terms of cytotoxic potency even in chemoresistant settings, bystander and immunogenic cell death effects, and known combinability with approved drugs. We critically evaluated several clinically tested ADCs containing DNA binders, focusing on payload physicochemical properties, cytotoxic potency, and obtained clinical results. Our analysis suggests that further exploration of certain chemical classes, specifically anthracyclines and duocarmycins, based on the optimization of physicochemical parameters, reduction of cytotoxic potency, and careful design of targeting molecules is warranted. This approach will possibly result in a novel generation of payloads overcoming the limitations of clinically validated ADCs. Full article

Helicobacter pylori infection constitutes a silent pandemic of global concern. In the last decades, the alarming increase in multidrug resistance evolved by this pathogen has led to a marked drop in the eradication rates of traditional therapies worldwide. By using a high-throughput screening strategy, in combination with in vitro DNA binding assays and antibacterial activity testing, we identified a battery of novel drug-like HsrA inhibitors with MIC values ranging from 0.031 to 4 mg/L against several antibiotic-resistant strains of H. pylori, and minor effects against both Gram-negative and Gram-positive species of human microbiota. The most potent anti-H. pylori candidate demonstrated a high therapeutic index, an additive effect in combination with metronidazole and clarithromycin as well as a strong antimicrobial action against Campylobacter jejuni, another clinically relevant pathogen of phylum Campylobacterota. Transcriptomic analysis suggests that the in vivo inhibition of HsrA triggers lethal global disturbances in H. pylori physiology including the arrest of protein biosynthesis, malfunction of respiratory chain, detriment in ATP generation, and oxidative stress. The novel drug-like HsrA inhibitors described here constitute valuable candidates to a new family of narrow-spectrum antibiotics that allow overcoming the current resistome, protecting from dysbiosis, and increasing therapeutic options for novel personalized treatments against H. pylori. Full article