Pharmaceutics. 2025 May 9;17(5):631. doi: 10.3390/pharmaceutics17050631.

ABSTRACT

Background/Objectives: Nanocarrier particle design for treating chronic pulmonary diseases presents several challenges, including anatomical and physiological barriers. Drug-repurposing technology using monodispersed spherical silica is one of the innovative ways to deliver drugs. In the present study, the anticancer potential of combinational cisplatin/ribavirin was explored for targeted lung cancer therapeutics. Methods: Monodispersed spherical silica (80 nm) capable of diffusing into the tracheal mucus region was chosen and doped with 10 wt% superparamagnetic iron oxide nanoparticles (SPIONs). Subsequently, it was wrapped with chitosan (Chi, 0.6 wt/vol%), functionalized with 5% wt/wt cisplatin (Cp)/ribavarin (Rib) and angiotensin-converting enzyme 2 (ACE-2) (1.0 μL/mL). Formulations are based on monodispersed spherical silica or halloysite and are termed as (S/MSSiO2/Chi/Cp/Rib) or (S/Hal/Chi/Cp/Rib), respectively. Results: X-ray diffraction (XRD) and diffuse reflectance UV-visible spectroscopy (DRS-UV-vis) analysis of S/MSSiO2/Chi/Cp/Rib confirmed the presence of SPION nanoclusters on the silica surface (45% coverage). The wrapping of chitosan on the silica was confirmed with a Fourier transformed infrared (FTIR) stretching band at 670 cm-1 and ascribed to the amide group of the polymer. The surface charge by zetasizer and saturation magnetization by vibrating sample magnetometer (VSM) were found to be -15.3 mV and 8.4 emu/g. The dialysis membrane technique was used to study the Cp and Rib release between the tumor microenvironment and normal pH ranges from 5.5 to 7.4. S/MSSiO2/Chi formulation demonstrated pH-responsive Cp and Rib at acidic pH (5.6) and normal pH (7.4). Cp and Rib showed release of ~27% and ~17% at pH 5.6, which decreases to ~14% and ~3.2% at pH 7.4, respectively. To assess the compatibility and cytotoxic effect of our nanocomposites, the cell viability assay (MTT) was conducted on cancer lung cells A549 and normal HEK293 cells. Conclusions: The study shows that the designed nanoformulations with multifunctional capabilities are able to diffuse into the lung cells bound with dual drugs and the ACE-2 receptor.

PMID:40430922 | DOI:10.3390/pharmaceutics17050631

Pharmaceutics. 2025 Apr 24;17(5):558. doi: 10.3390/pharmaceutics17050558.

ABSTRACT

Numerous anti-diabetic medications, including metformin, have been explored for their anticancer effects because of the substantial correlation between diabetes and cancer incidence. Metformin has recently gained interest for its anticancer effects against malignancies such as breast cancer, one of the leading causes of death among women worldwide. The cancer-related characteristics of cell proliferation, invasion, migration, and apoptosis are all targeted by metformin. Among breast cancer patients, triple-negative breast cancer (TNBC) is linked to an increased risk of early recurrence and metastases and has poor prognosis. In addition, TNBC has fewer treatment options compared to other breast cancer subtypes because it lacks hormone receptors and human epidermal growth factor receptor 2 (HER2), and it often develops resistance to available treatment options. The current review highlights the recent updates on the mechanistic insights and the efficacy of metformin and metformin-based approaches for the treatment of TNBC. We logically discuss the experimental evidence from the in vitro and in vivo studies exploring metformin's effects on metabolic pathways, and then its combination with other therapeutic agents, targeting cell signaling pathways, and approaches to enhance metformin's effects. We also present clinical studies that underscore the beneficial outcomes of metformin or its combination with other agents in TNBC patients.

PMID:40430851 | DOI:10.3390/pharmaceutics17050558

Pharmaceuticals (Basel). 2025 May 9;18(5):700. doi: 10.3390/ph18050700.

ABSTRACT

Neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's disease, due to their multifaced and complicated nature, remain uncurable and impose substantial financial and human burdens on society. Therefore, developing new innovative therapeutic strategies is vital. In this context, drug repurposing has emerged as a promising avenue to expedite the development of treatments for these challenging conditions. One particularly compelling target in this regard is the chaperone protein sigma-1 receptor (S1R), which has garnered significant attention for its neuroprotective properties. Interestingly, several medications, including fluvoxamine (an antidepressant), dextromethorphan (a cough suppressant), and amantadine (an antiviral), which were initially developed for unrelated indications, have shown encouraging results in neurodegenerative therapy through S1R activation. These findings suggest that existing drugs in pharmacopeias can play an essential role in alleviating neurodegenerative symptoms by modulating S1R, thereby offering a faster route and cost-effective path to clinical applications compared to the de novo development of entirely new compounds. Furthermore, as a synergistic benefit, combining S1R-targeting drugs with other therapeutic agents may also improve treatment efficacy. In this review, we highlight key repurposed drugs targeting S1R and explore their mechanisms of action, shedding light on their emerging therapeutic potential in the fight against neurodegeneration.

PMID:40430519 | DOI:10.3390/ph18050700

Pharmaceuticals (Basel). 2025 May 1;18(5):669. doi: 10.3390/ph18050669.

ABSTRACT

Background/Objectives: α-carbonic anhydrase (α-TcCA) has emerged as a promising drug target in T. cruzi, the causative agent of Chagas disease in the Americas. Sulfonamides, known inhibitors of CAs, bind to the zinc ion on the enzyme's active site. This study proposes the repositioning of sulfonamide-based drugs to identify new trypanocidal agents. Method: Ligand-based virtual screening and molecular docking analysis were performed on FDA-approved drugs targeting α-TcCA. These compounds were evaluated in vitro and ex vivo against the A1 and NINOA strains, followed by enzymatic assays. Results: Four sulfonylureas were selected: glimepiride (Glim), acetohexamide (Ace), gliclazide (Glic), and tolbutamide (Tol). Ace and Tol had half-maximal inhibitory concentration (IC50) values similar or better than reference drugs against the NINOA strain in the epimastigote and trypomastigote stages, while Glic and Glim had the highest activity against the A1 strain (epimastigotes and amastigotes). Notably, Ace had the highest trypanocidal activity against all stages in NINOA, with IC50 values of 6.5, 46.5, and 46 μM for epimastigotes, trypomastigotes, and amastigotes, respectively. Additionally, Ace inhibited α-TcCA with KI = 5.6 μM, suggesting that its trypanocidal effect is associated to the enzyme inhibition. Conclusions: This study supports the repositioning of FDA-approved sulfonamide-based hypoglycaemic agents as trypanocidal compounds. Future studies should focus on structural modifications to improve selectivity. Integrating docking, parasitological, and enzymatic data is crucial for optimizing drug candidates for Chagas disease.

PMID:40430488 | DOI:10.3390/ph18050669

Pharmaceuticals (Basel). 2025 Apr 23;18(5):613. doi: 10.3390/ph18050613.

ABSTRACT

Background: Oropouche virus (OROV), part of the Peribunyaviridae family, is an emerging pathogen causing Oropouche fever, a febrile illness endemic in South and Central America. Transmitted primarily through midge bites (Culicoides paraensis), OROV has no specific antiviral treatment or vaccine. This study aims to identify host-targeted therapeutics against OROV using computational approaches, offering a potential strategy for sustainable antiviral drug discovery. Methods: Virus-associated host targets were identified using the OMIM and GeneCards databases. The Enrichr and DSigDB platforms were used for drug prediction, filtering compounds based on Lipinski's rule for drug likeness. A protein-protein interaction (PPI) network analysis was conducted using the STRING database and Cytoscape 3.10.3 software. Four key host targets-IL10, FASLG, PTPRC, and FCGR3A-were prioritized based on their roles in immune modulation and OROV pathogenesis. Molecular docking simulations were performed using the PyRx software to evaluate the binding affinities of selected small-molecule inhibitors-Acetohexamide, Deptropine, Methotrexate, Retinoic Acid, and 3-Azido-3-deoxythymidine-against the identified targets. Results: The PPI network analysis highlighted immune-mediated pathways such as Fc-gamma receptor signaling, cytokine control, and T-cell receptor signaling as critical intervention points. Molecular docking revealed strong binding affinities between the selected compounds and the prioritized targets, suggesting their potential efficacy as host-targeting antiviral candidates. Acetohexamide and Deptropine showed strong binding to multiple targets, indicating broad-spectrum antiviral potential. Further in vitro and in vivo validations are needed to confirm these findings and translate them into clinically relevant treatments. Conclusions: This study highlights the potential of using computational approaches to identify host-targeted therapeutics for Oropouche virus (OROV). By targeting key host proteins involved in immune modulation-IL10, FASLG, PTPRC, and FCGR3A-the selected compounds, Acetohexamide and Deptropine, demonstrate strong binding affinities, suggesting their potential as broad-spectrum antiviral candidates. Further experimental validation is needed to confirm their efficacy and potential for clinical application, offering a promising strategy for sustainable antiviral drug discovery.

PMID:40430433 | DOI:10.3390/ph18050613

Int J Mol Sci. 2025 May 14;26(10):4701. doi: 10.3390/ijms26104701.

ABSTRACT

P-glycoprotein (P-gp), a transmembrane efflux pump encoded by the ABCB1/MDR1 gene, is a major contributor to multidrug resistance in hematological malignancies. These malignancies, arising from hematopoietic precursors at various differentiation stages, can manifest in the bone marrow, circulate in the bloodstream, or infiltrate tissues. P-gp overexpression in malignant cells reduces the efficacy of chemotherapeutic agents by actively expelling them, decreasing intracellular drug concentrations, and promoting multidrug resistance, a significant obstacle to successful treatment. This review examines recent advances in combating P-gp-mediated resistance, including the development of novel P-gp inhibitors, innovative drug delivery systems (e.g., nanoparticle-based delivery), and strategies to modulate P-gp expression or activity. These modulation strategies encompass targeting relevant signaling pathways (e.g., NF-κB, PI3K/Akt) and exploring drug repurposing. While progress has been made, overcoming P-gp-mediated resistance remains crucial for improving patient outcomes. Future research directions should prioritize the development of potent, selective, and safe P-gp inhibitors with minimal off-target effects, alongside exploring synergistic combination therapies with existing chemotherapeutics or novel agents to effectively circumvent multidrug resistance in hematological malignancies.

PMID:40429842 | DOI:10.3390/ijms26104701

Int J Mol Sci. 2025 May 9;26(10):4546. doi: 10.3390/ijms26104546.

ABSTRACT

Lung cancer is among the most common malignancies globally, is frequently associated with a poor prognosis, and is the second leading cause of cancer-related mortality in both genders. Resistance to treatment, heterogeneity, and invasiveness make lung cancer one of the most challenging tumors to combat. Drug repurposing is considered an advantageous strategy for expediting and economizing drug discovery, as it involves rebranding an existing drug for a new therapeutic use. Since depression is a prevalent psychiatric illness among individuals diagnosed with lung cancer, various selective serotonin reuptake inhibitors (SSRIs) used for the treatment of depression were examined for their possible use in lung cancer treatment as repurposed drugs. Herein, we evaluated the efficacy of SSRIs, both alone and in combination with various anticancer agents, in the treatment of lung cancer along with their mechanisms of action. The innovative approach of repurposing SSRIs offers hope by simplifying the drug discovery process and potentially revealing new therapeutic options for lung cancer. Exploring SSRIs' effects on lung cancer treatment may unlock unexpected avenues for combating this aggressive disease.

PMID:40429689 | DOI:10.3390/ijms26104546

Int J Mol Sci. 2025 May 8;26(10):4497. doi: 10.3390/ijms26104497.

ABSTRACT

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds-vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine-showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of -18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.

PMID:40429641 | DOI:10.3390/ijms26104497

Genes (Basel). 2025 Apr 29;16(5):522. doi: 10.3390/genes16050522.

ABSTRACT

BACKGROUND/OBJECTIVES: Genodermatoses are genetic conditions with clinical symptoms manifesting in the skin and adjoining tissues, individually rare but comprising a large and heterogeneous group of disorders that represents 15% of genetic diseases. This article discusses the results of individuals with genodermatoses from a reference center for rare diseases studied through whole genome sequencing conducted by the Brazilian Rare Genomes Project between 2021 and 2023.

METHODS: A retrospective case series with data comprising sex, age at first assessment in the hospital, family history, clinical findings, and molecular results.

RESULTS: Excluding neurofibromatosis type 1, Ehlers-Danlos syndrome and RASopathies are discussed elsewhere. Diagnoses in this work comprised ectodermal dysplasias (n = 6), ichthyosis (n = 4), albinism (n = 4), tuberous sclerosis complex (n = 4), and incontinentia pigmenti (n = 3), in addition to 11 others with individual rare conditions. The sex ratio was 17:16 (M:F), consanguinity was present in 6/33 (18%), and the age at the first evaluation ranged from neonatal to 26 years (median 13.65 years). Negative results were 3/33 (9%), novel variants were 17/41 (41.4%), and 7/30 (23%) presented initially with a double molecular diagnosis, three confirming composed phenotypes.

CONCLUSIONS: Besides reporting 17 novel variants in 14 genes (BLM, CACNA1B, EDA, ELN, ENG, ERC6, EVC2, PNPLA1, PITCH1, PORCN, SIN3A, TP63, TYR, and WNT10B), the study also identified three atypical clinical presentations due to dual diagnoses, and the c.454C>T variant in the SDR9C7 gene, previously reported only in dogs, was, for the first time, confirmed as causative for ichthyosis in humans.

PMID:40428344 | DOI:10.3390/genes16050522

Genes (Basel). 2025 Apr 25;16(5):490. doi: 10.3390/genes16050490.

ABSTRACT

Background: Dyggve-Melchior-Clausen syndrome (DMC) is a rare autosomal recessive skeletal dysplasia characterized by dwarfism, coarse facial features, and intellectual disability. Caused by loss-of-function variants in the DYM gene, which encodes dymeclin, DMC is predominantly reported in consanguineous populations but remains poorly studied in South America. Methods: We report a 21-year-old Ecuadorian male with clinical features suggestive of DMC. Comprehensive clinical, radiological, and genetic evaluations were conducted, including clinical exome sequencing and Sanger sequencing, followed by an in silico analysis to assess the structural and functional consequences of the identified variant. Results: Exome sequencing identified a homozygous c.1878delA (p.Lys626fs) frameshift variant in the DYM gene, which was confirmed by Sanger sequencing as inherited from heterozygous parents. Variants of uncertain significance were detected in other skeletal dysplasia-related genes but did not correlate with the phenotype. A comprehensive review of reported DYM variants was also conducted. Conclusions: This report documents the first case of DMC in Ecuador and the second in South America, expanding the global understanding of DMC's genetic diversity. It underscores the value of next-generation sequencing in rare disease diagnostics and highlights the critical need for inclusive genomic research in underrepresented populations to improve the understanding of genetic heterogeneity and rare disease epidemiology.

PMID:40428312 | DOI:10.3390/genes16050490

Orphanet J Rare Dis. 2025 May 27;20(1):256. doi: 10.1186/s13023-025-03740-1.

ABSTRACT

Mechanistic target of rapamycin (mTOR) is a highly conserved serine/threonine kinase that regulates key cellular processes including cell growth, autophagy and metabolism. Hyperactivation of the mTOR pathway causes a group of rare and ultrarare genetic diseases. mTOR pathway diseases have diverse clinical manifestations that are managed by distinct medical disciplines but share a common underlying molecular basis. There is a now a deep understanding of the molecular underpinning that regulates the mTOR pathway but effective treatments for most mTOR pathway diseases are lacking. Translating scientific knowledge into clinical applications to benefit the unmet clinical needs of patients is a major challenge common to many rare diseases. In this article we expound how mTOR pathway diseases provide an opportunity to coordinate basic and translational disease research across the group, together with industry, medical research foundations, charities and patient groups, by pooling expertise and driving progress to benefit patients. We outline the germline and somatic mutations in the mTOR pathway that cause rare diseases and summarise the prevalence, genetic basis, clinical manifestations, pathophysiology and current treatments for each disease in this group. We describe the challenges and opportunities for progress in elucidating the underlying mechanisms, improving diagnosis and prognosis, as well as the development and approval of new therapies for mTOR pathway diseases. We illustrate the crucial role of patient public involvement and engagement in rare disease and mTOR pathway disease research. Finally, we explain how the mTOR Pathway Diseases node, part of the Research Disease Research UK Platform, will address these challenges to improve the understanding, diagnosis and treatment of mTOR pathway diseases.

PMID:40426219 | DOI:10.1186/s13023-025-03740-1

Brain Sci. 2025 May 18;15(5):515. doi: 10.3390/brainsci15050515.

ABSTRACT

Background/Objectives: Autobiographical memory (AM) is typically viewed in terms of comprising episodic (EAM) and semantic (SAM) components. Despite the emergence of numerous meta-analyses, the literature on these constructs remains fragmented. We aimed to summarize neural activations and to discuss the relations between constructs based on theory and experimentation, while evaluating the consistency between literature sources and discussing the critical issues and challenges of current research. Methods: We conducted a scoping meta-review on AM, EAM, and SAM based on meta-analytic studies in five scientific databases (PubMed, Web of Science, Scopus, PsychInfo, and PsychArticles). No temporal or language limits were applied. Results: We included twelve meta-analyses on AM, EAM and SAM in healthy populations. The meta-analyses of AM and EAM actually investigated the same construct, leading to misinterpretation. The two available meta-analyses on SAM used two different operationalizations of the construct. Neural data about EAM were analyzed via mean rank classification, finding the most relevant areas in the posterior cingulate cortex, hippocampus, precuneus, temporo-parietal junction, angular gyrus, and medial prefrontal cortex. SAM was linked to the posterior and anterior cingulate cortexes, middle and inferior frontal gyri, thalamus, middle and superior temporal gyri, inferior frontal and fusiform gyri, and parahippocampal cortex. Conclusions: Variability in reported activation patterns persists, reflecting differences in methodology and assumptions. We propose the homogenization the notations of EAM and AM based on experimental practice. In this notation, AM does not have a separate experimental task nor activation pattern and may not indicate a separate construct but an array of its components.

PMID:40426686 | DOI:10.3390/brainsci15050515

Iran J Med Sci. 2025 May 1;50(5):351-358. doi: 10.30476/ijms.2024.102645.3570. eCollection 2025 May.

ABSTRACT

BACKGROUND: The cytochrome P450 (P450s or CYPs) enzyme family, particularly CYP2D6, significantly influences drug metabolism, handling approximately 20-25% of prescribed medications. Understanding genetic polymorphisms is crucial for personalized medicine and optimizing drug therapy in specific geographic and racial contexts. Given the complex nature of studying CYP2D6 genotypes, this study aimed to assess the prevalence of rare CYP2D6 star alleles, including rs267608319 (CYP2D6*31), rs1931013246 (CYP2D6*55), rs569439709 (CYP2D6*113), and rs747089665 (CYP2D6*135), within the Iranian population.

METHODS: Blood samples were obtained from 389 individuals across several ethnic groups in Tehran, Iran, from May to December 2022. PCR was used to amplify the region containing the desired variant. Genotyping was performed using the Sanger sequencing method.

RESULTS: Our analysis revealed a high frequency of normal alleles for all four studied variants, indicating the absence of the risk allele in the Iranian population. These findings suggest that the studied alleles have no apparent effect on various ethnic groups in Iran.

CONCLUSION: The Iranian population has a typical genetic makeup for CYP2D6 variations, impacting medication prescribing. Understanding genetic differences is crucial for personalized drug therapies. Further research into Iranian genetic variations is essential for advancing personalized medicine.

PMID:40433186 | PMC:PMC12104541 | DOI:10.30476/ijms.2024.102645.3570

Front Psychiatry. 2025 May 13;16:1570436. doi: 10.3389/fpsyt.2025.1570436. eCollection 2025.

ABSTRACT

BACKGROUND: Behavioral regressions in low verbal patients with severe autism constitute a dramatic challenge for clinicians. A physical comorbidity burden is often involved but difficult to evidence.

AIM: We present five cases of patients under 30 years old (three men and two women), recently hospitalized in a specialized multidisciplinary inpatient unit, settled in Lausanne University Hospital, and for which at some point, a urinary retention contributed to the constitution of a complex behavioral picture.

METHODS: For each patient, we report the individual risk factors, clinical presentation and the conditions for making the diagnosis.

RESULTS: As the usual guidelines for screening, management, and follow-up of urinary retentions are irrelevant in this population, we provide and discuss some recommendations: limitation of anticholinergic burden, strict application of the protocol for going to the toilet with training protocol, regularization of intestinal transit, daily bladder-scan control, and eventually use of Tamsulosin hydrochloride. These recommendations significantly improved the urinary status of our patients.

CONCLUSION: We conclude that chronic urinary retention is probably a recurrent and unrecognized feature in many young adults with autism and challenging behaviors, reflecting the long-term impact of iatrogenic medication and requiring a specific attention.

PMID:40433175 | PMC:PMC12106420 | DOI:10.3389/fpsyt.2025.1570436

Front Pharmacol. 2025 May 13;16:1592134. doi: 10.3389/fphar.2025.1592134. eCollection 2025.

ABSTRACT

Tacrolimus, a calcineurin inhibitor, is widely used to prevent allograft rejection in kidney transplant recipients. Its metabolism is predominantly mediated by the cytochrome P450 3A5 (CYP3A5) enzyme, and single nucleotide variants (SNVs) within intron 3 of the CYP3A5 gene are strongly associated with interindividual variability in enzyme expression and activity. These SNVs can generate a cryptic splice site, resulting in either preserved enzymatic function classified as expressers (CYP3A5 *1/*1 and *1/*3) or loss of function, classified as non-expressers (CYP3A5 *3/*3). Differential expression of CYP3A5 contributes to variability in tacrolimus pharmacokinetics and clinical outcomes, including graft rejection and therapeutic efficacy. In this study, we evaluated three pharmacokinetic parameters: trough concentration (TAC-C0), weight-adjusted daily dose (TAC-D, mg/kg), and dose-normalized trough concentration (TAC-C0/D). One-way ANOVA was used to assess differences in these parameters between CYP3A5 expressers and non-expressers. Additionally, Poisson regression was performed to examine associations between clinical/genetic variables and the incidence rate of acute rejection events. Genotyping was conducted in 45 pediatric kidney transplant recipients. The CYP3A5 *3/*3 genotype was most prevalent (66.7%), followed by *1/*3 (26.7%) and *1/*1 (6.7%). During the 6-month post-transplant period, CYP3A5 expressers required significantly higher tacrolimus doses to achieve target trough levels. Increased drug exposure was associated with a higher incidence of rejection events, whereas CYP3A5 expression correlated with a reduced rate of rejection. These findings underscore the clinical utility of CYP3A5 genotyping for optimizing tacrolimus dosing strategies. Carriers of functional CYP3A5 alleles (*1/*3 or *1/*1) benefit from individualized dose adjustments to achieve therapeutic concentrations and reduce the risk of graft rejection.

PMID:40432883 | PMC:PMC12107630 | DOI:10.3389/fphar.2025.1592134

Nutrients. 2025 May 16;17(10):1694. doi: 10.3390/nu17101694.

ABSTRACT

Background: Nutritional biomarkers are essential for assessing the impact of dietary interventions on health. Amino Acids (AA) serve as potential biomarkers due to their role in metabolic pathways, although the influence of combining macronutrients on AA metabolism remains unclear. Objective: This study aims to evaluate the effects of combining macronutrients (fat, protein, and fiber) on AA metabolism. Methods: A dietary intervention was conducted with 41 participants who were assigned to two groups: the Protein Fat (PF) group and the Protein Fat and Fiber (PFF) group. AA concentration was measured using LC-MS/MS. Results: Our findings indicated that combining macronutrients reduced plasma levels of AA with statistically significant differences between the two diets (p < 0.05 for EAA and BCAA; p < 0,01 for NEAA and AAA). Metabolic profile analysis showed differences between the groups, especially at 55 days (55 D) (R2X: 0.749; R2Y: 0.589; Q2: 0.582, p < 0.001) and 98 days (98 D) (R2X: 0.886; R2Y: 0.7; Q2: 0.605, p < 0.001). Five metabolites (leucine, asparagine, alanine, cysteine, and creatine) were the most influential factors in group differentiation (VIP score), with values ranging between 1.04 and 1.75. Conclusions: The combination of macronutrients led to a significant reduction in plasma amino acids and amines in the PFF group, with recovery post-intervention. These findings highlight the possibility that these metabolites are related to different health statuses.

PMID:40431435 | DOI:10.3390/nu17101694

Pharmaceutics. 2025 May 8;17(5):624. doi: 10.3390/pharmaceutics17050624.

ABSTRACT

Background/Objectives: Carbamazepine is widely used as a first-line treatment for pediatric patients with benign epilepsy. However, most commercial formulations have doses of 100 mg or higher, limiting their suitability for pediatric use. The aim of this study was to develop mini orally disintegrating tablets (ODTs) containing 50 mg of carbamazepine, utilizing direct compression technology, specifically tailored to meet the unique needs of pediatric patients. Methods: The development was carried out following a Quality by Design (QbD) approach, beginning with preformulation studies using the SeDeM expert system. Various co-processed excipients (PROSOLV® ODT and PARTECK® ODT) and non-co-processed excipients (L-HPC LH11 and L-HPC NBD-022) were evaluated. Additionally, modifications to the radius parameter of the SeDeM expert system were investigated to improve formulation design. Results: Optimized Formulations 13 and 14 achieved disintegration times below 1 min, hardness values between 25 and 60 N, and friability under 1%, fulfilling the predefined Critical Quality Attributes (CQAs). Tablets were successfully produced with a diameter of 5 mm and a weight below 100 mg. Moreover, reducing the SeDeM incidence radius from 5.0 to values between 4.0 and 3.5 proved viable, enabling the inclusion of excipients previously considered unsuitable and broadening formulation options without compromising quality. Conclusions: This study demonstrates the feasibility of producing small, fast-disintegrating, and mechanically robust 50 mg carbamazepine ODTs tailored for pediatric patients. It also validates the adjustment of SeDeM parameters as an effective strategy to expand excipient selection and enhance formulation flexibility in pediatric drug development.

PMID:40430915 | DOI:10.3390/pharmaceutics17050624

Pharmaceutics. 2025 Apr 29;17(5):585. doi: 10.3390/pharmaceutics17050585.

ABSTRACT

Background: Childhood cancers represent a heterogeneous group of malignancies and remain one of the leading causes of mortality among children under 14 years of age, ranking second only to accidental injuries, and fourth among individuals aged 15 to 19 years. Despite notable improvements in cure rates, a substantial proportion of patients experience acute or long-term toxicities associated with treatment. Methotrexate (MTX), a chemotherapeutic agent, has been employed effectively for over six decades in the management of pediatric malignancies. High-dose methotrexate constitutes a cornerstone of pediatric cancer therapy; however, its clinical utility is frequently constrained by dose-limiting toxicities. Objectives: This study investigates the impact of genetic polymorphisms in genes involved in nucleotide metabolism, as well as methotrexate and folate metabolic pathways, on treatment-related toxicity in childhood cancer. Methods: Using real-time polymerase chain reaction, 14 polymorphisms across 12 genes were analyzed in a cohort of 107 patients. Toxicity was assessed according to the Common Terminology Criteria for Adverse Events v. 5.0. Results: Multivariate logistic regression analysis revealed that the male sex (p = 0.3) and the AA genotype of MTHFD1 rs2236225 were associated with grade III-IV gastrointestinal toxicity (p = 0.03), while the A allele of MTHFR rs1801133 and the AA genotype of GSTP1 rs1695 were associated with grade I-IV hematologic toxicity (p < 0.01 and p = 0.02, respectively). Conclusions: High-dose methotrexate (HDMTX) is a critical agent in the treatment of childhood cancers. Our findings suggest that genetic polymorphisms within methotrexate and folate metabolic pathways may serve as potential predictive biomarkers of treatment-related toxicity.

PMID:40430876 | DOI:10.3390/pharmaceutics17050585

Pharmaceutics. 2025 Apr 24;17(5):555. doi: 10.3390/pharmaceutics17050555.

ABSTRACT

Background: Advancements in pharmacogenomics, artificial intelligence (AI), and CRISPR gene-editing technology are revolutionizing precision medicine by enabling highly individualized therapeutic strategies. Artificial intelligence-driven computational techniques improve biomarker discovery and drug optimization while pharmacogenomics helps to identify genetic polymorphisms affecting medicine metabolism, efficacy, and toxicity. Genetically editing based on CRISPR presents a precise method for changing gene expression and repairing damaging mutations. This review explores the convergence of these three fields to enhance improved precision medicine. Method: A methodical study of the current literature was performed on the effects of pharmacogenomics on drug response variability, artificial intelligence, and CRISPR in predictive modeling and gene-editing applications. Results: Driven by artificial intelligence, pharmacogenomics allows clinicians to classify patients and select the appropriate medications depending on their DNA profiles. This reduces the side effect risk and increases the therapeutic efficacy. Precision genetic modifications made feasible by CRISPR technology improve therapy outcomes in oncology, metabolic illnesses, neurological diseases, and other fields. The integration of artificial intelligence streamlines genome-editing applications, lowers off-target effects, and increases CRISPR specificity. Notwithstanding these advances, issues including computational biases, moral dilemmas, and legal constraints still arise. Conclusions: The synergy of artificial intelligence, pharmacogenomics, and CRISPR alters precision medicine by letting customized therapeutic interventions. Clinically translating, however, hinges on resolving data privacy concerns, assuring equitable access, and strengthening legal systems. Future research should focus on refining CRISPR gene-editing technologies, enhancing AI-driven pharmacogenomics, and developing moral guidelines for applying these tools in individualized medicine going forward.

PMID:40430848 | DOI:10.3390/pharmaceutics17050555

Pharmaceutics. 2025 Apr 22;17(5):542. doi: 10.3390/pharmaceutics17050542.

ABSTRACT

Background/Objectives: Irinotecan is used in monotherapy or combined with other drugs for treating different cancer streams. SN-38, the active metabolite of irinotecan, is 70% inactivated by the uridine diphosphate (UDP) glucuronosyltransferase family 1 member A1 (UGT1A1) enzyme. The UGT1A1*6 (rs4148323) and *28 (rs3064744) alleles in the gene encoding the enzyme lead to decreased enzyme expression and increased severe irinotecan toxicity. Carrying one or two copies of these alleles results in a UGT1A1 intermediate or poor metabolizer status (IM, PM). The Food and Drug Administration (FDA)-approved drug labels and European Medicines Agency (EMA) European Public Assessment Report (EPAR) for irinotecan recommend dose adjustments based on UGT1A1 genotypes, but only for UGT1A1 PM patients. However, available pharmacogenetic (PGx) dosing guidelines for the UGT1A1-irinotecan interaction lack a consensus about considered genetic variants, genotype-translated phenotypes, and therapeutic recommendations. We aimed to describe evidence regarding the impact of the UGT1A1 genotype in irinotecan toxicity to inform irinotecan-dosing recommendations based on possible UGT1A1 genotypes. Methods: A systematic review was performed to find all the Phase I clinical trials looking for the maximum tolerated dose (MTD) or dose-limiting toxicities (DLTs) of irinotecan depending on the UGT1A1 genotype. Results: Toxicity-related events and the MTD of irinotecan differ among UGT1A1 normal metabolizers (NM), IM, and PM patients considering the UGT1A1*28 and/or *6 variants. Conclusions: Dose adjustments might also be recommended for UGT1A1 IM patients (*1/*28 or *1/*6 genotypes), with a 15% dose reduction considered.

PMID:40430836 | DOI:10.3390/pharmaceutics17050542