Future Pharmacol., Volume 6, Issue 1 (March 2026) – 16 articles

Background: Bacopa procumbens is a plant species with medicinal properties. Although several of these properties have already been validated, its use for treating pain remains untested. Objective: the objective was therefore to test the antinociceptive effect of two extracts (n-hexane and hydroalcoholic) and two fractions (aqueous and organic) from the most active extract, as well as to determine the chemical profile of Bacopa procumbens. Methods: analgesic activity was determined by antinociceptive activity using the formalin model in mice. Compounds were identified by high-performance liquid chromatography and gas chromatography coupled with mass spectrometry. Compared to the vehicle treatment (3% Tween 20), licking time was 22.8 s and 141.6 s lower when treated with the hexane extract (200 mg/kg); 43.4 s and 152.5 s with the hydroalcoholic extract (200 mg/kg); 27.2 s and 169 s with the organic fraction; and 5.4 s and 32 s difference with the positive control, in phases 1 and 2, respectively. Phytochemical analysis of the hexane extract allowed us to identify 2-pentadecanone, 6,10,14-trimetil- (11.70%), 6,10,14-trimethyl-, dibutyl phthalate (34.71%), and hexane-dioic acid bis(2-ethylhexyl) ester (45.15%). Conclusions: We identified arbutin (1), 5-(p-hydroxybenzoyl) shikimic acid (2), and procumgastrodin A (3) in the BpFo fraction. In conclusion, we demonstrated that the BpH extract and the BpFo fraction have anti-nociceptive properties that may be associated with compounds 2 and 3. Full article

Background/Objectives: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly toxic environmental contaminant whose adverse biological effects are primarily mediated through activation of the aryl hydrocarbon receptor (AhR). Upon ligand binding, AhR undergoes conformational changes that initiate nuclear translocation and transcriptional activation of xenobiotic-responsive genes, contributing to toxicity, carcinogenesis, and dysregulated immune and metabolic responses. Understanding the molecular basis of AhR activation by TCDD is therefore critical for the rational development of targeted therapeutic strategies. Methods: In this study, molecular docking simulations were employed to characterize the interaction of TCDD and selected AhR antagonists (CH223191, BAY 2416964, GNF-351) with the ligand-binding domain of AhR, with particular emphasis on the canonical PAS-B domain. Results: Docking analyses identified the PAS-B cavity (pocket C1) as the most biologically relevant binding site for high-affinity ligands, consistent with experimental evidence. Comparative docking of known AhR antagonists revealed stable binding poses characterized by hydrophobic packing, π–π interactions, and hydrogen-bonding networks that competitively block agonist access and prevent receptor activation. These findings support a competitive antagonism mechanism as a viable approach to counteract TCDD-induced AhR signaling. Conclusions: Collectively, this in silico study provides mechanistic insight into TCDD toxicity at the molecular level and highlights AhR antagonism as a promising strategy for the development of targeted therapies against dioxin-related pathologies. Full article

Antimicrobial resistance is a significant problem that has been studied in recent years. Viral diseases have generated high levels of morbidity and mortality, and recently, the world population faced a highly contagious viral disease (SARS-CoV-2), which caused millions of deaths without an effective drug capable of controlling the infectious process. As a result, various therapeutic alternatives to antimicrobials have emerged that target microorganisms, support the immune system, and reduce inflammation. Lactoferrin is a ultifunctional glycoprotein of the mammalian innate immune system that has shown various benefits, notably its antimicrobial and, primarily, its antiviral effects. No resistance or toxicity to this protein has been reported, which is why it is called a “miracle protein”. This is the first review to focus on the antiviral effects of lactoferrin in clinical trials. In addition, in vitro and in vivo studies evaluating lactoferrin against various viral etiologies are also discussed. Full article

Background/Objectives: The identification of peripheral nerves is critical for their preservation during surgery, as accidental transection or injury can lead to significant patient morbidity. Current methods for identifying nerves typically rely on qualitative white-light visualization of anatomy, texture, and color. To improve nerve identification during surgical procedures, we developed a novel nerve imaging agent, “bevonescein,” a derivative of the peptide–dye conjugate FAM-HNP401. Methods: Variants of FAM-HNP401 were designed to be synthesized completely on solid phase to enable the efficient generation of GMP (Good Manufacturing Practice)-qualified bevonescein. We determined the nerve binding affinity for each variant, CPC-17, CPC-18, CPC-19 (bevonescein), and CPC-20, using mean fluorescent intensity measurements after binding the agents to human sural nerve sections. Results: Bevonescein (CPC-19) demonstrated significantly superior nerve binding compared to other variants and controls. Bevonescein-labeled nerves exhibited a mean fluorescent intensity of 562 ± 34.7, compared to 252 ± 41.7 for CPC-17, 344 ± 34.7 for CPC-18, and 270 ± 41.7 for CPC-20. The dye-alone control, 5-carboxyfluorescein, showed a fluorescent intensity of 168 ± 41.4. Conclusions: Bevonescein represents a first-in-class molecule that can improve the visualization of peripheral nerves during surgery, potentially reducing nerve injury and associated morbidity. It has been successfully tested in a Phase 1/2 clinical trial demonstrating safety and efficacy at a 500 mg dose and is currently in Phase 3 clinical testing. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumours, driven by late diagnosis, early metastatic dissemination, and profound resistance to systemic therapies. Increasing evidence indicates that these hallmarks are not solely tumour cell intrinsic but are critically orchestrated by a complex and highly dynamic tumour microenvironment (TME) composed of pancreatic stellate cells (PSCs), cancer-associated fibroblast (CAF) subtypes, immune cells, endothelial and neuronal elements, and a dense extracellular matrix (ECM). This review provides an integrated overview of the cellular and acellular components of the PDAC TME and delineates how their reciprocal crosstalk drives desmoplasia, immune suppression, metabolic reprogramming, epithelial–mesenchymal transition (EMT), pre-metastatic niche formation, and metastatic outgrowth. Particular emphasis is placed on the context-dependent roles of stromal and immune niches in modulating drug delivery, chemoresistance, and failure of immunotherapy, highlighting why indiscriminate stromal depletion has yielded paradoxical outcomes. Building on these mechanistic insights, the review critically examines emerging therapeutic strategies targeting PSCs, CAF subsets, ECM components, myeloid and lymphoid populations, and key signalling pathways, including approaches that normalize stroma, reprogram immunity, or exploit nanocarrier-based delivery systems. Finally, a structured framework is proposed for rational TME-targeted combination regimens that integrate cytotoxic, targeted, and immunotherapeutic agents to overcome current therapeutic barriers in PDAC. Full article

The overdose mortality landscape has shifted from predominantly opioid exposures to a polysubstance epidemic increasingly driven by illicit fentanyl and fentanyl analogs combined with other centrally active agents. Among the co-intoxicants, veterinary α₂-adrenoceptor (α₂AR) agonists such as xylazine have emerged as clinically confounding adulterants. Recent reports from forensic toxicology, medical examiners, and border/interdiction agencies indicate that medetomidine, a veterinary sedative racemate with the highly selective α₂AR agonist enantiomer dexmedetomidine, is increasingly being detected together with fentanyl and its analogs in seized materials and postmortem assays. Prior reviews have covered these aspects. The current review synthesizes current evidence and clinical experience relevant to fentanyl + medetomidine co-exposure-induced respiratory depression—a primary cause of death. We focus on convergent µ-opioid receptor (MOR) and α₂AR signaling within key physiological substrates, including respiratory rhythm-generating networks, ascending arousal pathways, chemosensory reflex control of ventilation, and autonomic cardiovascular regulation, integrating mechanistic pharmacology, respiratory and cardiovascular toxicology, emergency-room treatment, and emerging public-health implications. Available evidence supports a model in which combined MOR and α₂AR activation produces additive-to-synergistic suppression of ventilation and consciousness, attenuation of hypoxic ventilatory drive and CO₂ responsiveness, with marked sympatholysis manifested as bradycardia and hypotension, all of which can persist beyond presumptive opioid reversal with a MOR antagonist. We discuss the implications for prehospital and emergency care. In sum, the increasing detection of medetomidine in the illicit fentanyl supply represents an emerging and potentially high-risk co-exposure pattern that may be only partially naloxone-responsive. Lastly, we highlight potential future pharmacologic countermeasures for polysubstance overdose, such as the BK-channel antagonist ENA-001, which may address naloxone-insensitive ventilatory suppression in opioid-dominant polysubstance overdose. Full article

Background/Objectives: This study aimed to investigate whether therapy with perampanel is associated with the development of psychosis or psychosis-like symptoms in patients with epilepsy. Methods: We conducted systematic electronic searches in PubMed, Google Scholar, ScienceDirect, and Scindex databases. We included articles published as case reports/case series, as well as conference abstracts and letters from the editor, if they contained enough data for analysis and quality assessment. The main inclusion criteria relate to patients who experienced psychosis or psychosis-like symptoms described by the authors during perampanel therapy or during its recent use. Results: Publications (n = 17) describing a total of 33 patients who met the inclusion criteria were included. Patient ages ranged from 11 to 70 years, and the majority of them were female (66.67%). A confirmed personal psychiatric history was identified in 60.61% of patients. The time interval between the initiation of perampanel and the onset of adverse events varied significantly across cases. The most frequently reported symptom was aggression (75.75%), followed by irritability (30.30%), while delusions or hallucinations were observed in 8 patients (24.24%). Conclusions: Clinicians should be aware that psychosis or psychosis-like symptoms may represent dose-dependent adverse effects of perampanel with a satisfactory prognosis. Identified risk factors for these developments were positive personal psychiatric history, antiseizure polytherapy at high doses, women’s gender, and focal epilepsies with secondary generalization, mainly manifested as tonic–clonic seizures. Early recognition of symptoms, followed by drug discontinuation, dose reduction, symptomatic treatment, or a combination of the mentioned strategies, is crucial for achieving better outcomes. Full article

Background/Objectives: Galleria mellonella (G. mellonella) larvae have emerged as a valuable in vivo model for antifungal drug screening. This study aimed to determine the optimal inoculum concentrations of Candida albicans (C. albicans) in G. mellonella, as well as the appropriate fluconazole concentrations, in order to standardize a preliminary screening method for compounds with antifungal activity. Methods: Larvae were infected with four C. albicans strains, including two reference strains (ATCC^® 10231 and ATCC^® 90028) and two oral isolates (A1 and A2). Fluconazole toxicity was evaluated at doses of 20, 40, and 80 mg/kg over a 72 h period. In the treatment assays, larvae were infected via the left pro-leg and treated with fluconazole, administered as a single or two doses, one hour after infection. Larval viability was monitored over five days based on movement, cocoon formation, and melanization, and survival data were analyzed using Kaplan–Meier curves and the log-rank test. Results: Fluconazole showed no toxicity at the tested concentrations. Infection with up to 2 × 10⁷ cells/mL was non-lethal for most strains, except for A2, which exhibited 50% mortality within 48 h but it was effectively controlled with a single 20 mg/kg dose of fluconazole. Infection with 2 × 10⁸ cells/mL resulted in complete mortality within 48 h; however, a single 80 mg/kg dose significantly improved survival. Conclusions: The G. mellonella model proved to be a suitable and reproducible in vivo system for the preliminary screening of antifungal compounds. The standardized experimental conditions established in this study support its applicability for evaluating antifungal activity in early research stages. Future studies should expand this approach to different fungal species and antifungal agents, as well as explore its applicability in combination therapies. Full article

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Because current therapeutics have limited efficacy once PD is fully developed, it is crucial to start disease-modifying interventions during the prodromal stage of PD. In the present study, we aimed to evaluate whether intranasally delivered human umbilical cord mesenchymal stem cells (hUC-MSCs) have an efficacy in the rotenone-induced prodromal PD-like phenotype mouse model. Methods: To produce the prodromal PD mouse model, C57BL/6 mice were treated with intraperitoneal (i.p.) rotenone for 1 or 2 weeks. hUC-MSCs or PBS were delivered intranasally for 1 or 2 weeks with rotenone injection. We subsequently performed behavioral assessments to evaluate motor and non-motor features, followed by pathological analyses of the mouse brains. Results: Intranasal administration of hUC-MSCs restored motor performance and protected dopaminergic neurons in the SN of mice treated with rotenone for 2 weeks. In the 1-week rotenone mice, hUC-MSCs treatment ameliorated depressive-like behaviors and attenuated olfactory dysfunction. Furthermore, intranasal hUC-MSC treatment suppressed the accumulation of protein aggregates in the brains of mice, which is associated with enhanced autophagic function, as indicated by increased LC3B and normalization of LAMP2A protein expression. Conclusions: Our data demonstrate that intranasal administration of hUC-MSCs improves non-motor symptoms at early time points and attenuates progression to nigrostriatal loss and motor deficits in the rotenone-induced PD mouse model. These findings support the potential of a non-invasive, prodromal-stage intervention to modulate early pathological progression in PD. Full article

Older adults with multiple diseases are likely to be prescribed multiple medications including anticholinergic agents, which are frequently prescribed to manage conditions such as overactive bladder and chronic obstructive pulmonary disease and Parkinson’s disease. Overactive bladder (OAB) has been the subject of increased disease awareness and is a common and significant cause of reduced quality of life, particularly in the elderly. The selective β₃ adrenoceptor agonist, mirabegron was developed for the pharmacological treatment of OAB. Mirabegron has been shown to exert off-target effects on various functional proteins such as muscarinic receptors in rat tissues. This agent may relax the detrusor muscle by activating β₃ adrenoceptors and also antagonizing muscarinic receptors. Mirabegron and antimuscarinics exerted additive effects on muscarinic receptor binding and relaxant responses of cholinergic contractions of the detrusor muscle. Mirabegron excreted in human urine appears to directly attenuate muscarinic receptor-mediated functions in the bladder. Combination therapy of mirabegron and solifenacin in patients with OAB may enhance not only their therapeutic effects on OAB, but also increase the risk of anticholinergic adverse effects. Therefore, the safety of concomitant use of mirabegron and other drugs such as antimuscarinics for elderly patients needs to be carefully considered. Full article

Since their discovery in the 1960s, liposomes have become a versatile platform for drug delivery in cancer research, capable of carrying both hydrophilic and hydrophobic drugs. Throughout the past decades, liposomes have evolved to improve stability, blood circulation time, and targeting ability, overcoming many disadvantages of early formulations. Lipid–polymer hybrid liposomes (LPHLs), a third-generation nanoparticle model, are vesicles where polymers are incorporated in or around the lipid bilayer to increase their stability, to control drug release, and to provide multifunctional capabilities. More recently, cell membrane-coated (CMC) liposomes, which consist of “core” liposomes (preformed liposomes) cloaked in natural cell membranes, have emerged as an even more innovative approach, offering superior immune evasion and highly selective targeting, which are both particularly promising for cancer therapy. Preclinical studies in cancer models demonstrate that these advanced liposomal systems improve pharmacokinetics and therapeutic outcomes. They hold significant potential for developing next-generation, personalized nanomedicines for cancer and other complex diseases. However, challenges related to large-scale production, long-term stability, and safety evaluation remain. Full article

Background/Objectives: Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental condition, and pharmacogenetic studies aim to clarify interindividual variability in treatment responses and adverse effects. Despite increasing research, the field remains fragmented. This review provides a bibliometric analysis of ADHD pharmacogenetics (2005–2025), identifying its intellectual foundations, thematic structure, and global distribution. Methods: A bibliometric search was conducted in Scopus and Web of Science, retrieving 711 documents published between 2005 and July 2025. Data were analyzed with the Bibliometrix R package and Biblioshiny interface, applying bibliometric mapping, Bradford’s Law, co-word analysis, and thematic mapping. Only peer-reviewed journal articles, books, and book chapters were included to ensure scientific rigor. Results: The dataset shows a modest annual growth rate but strong impact, with an average of 29.6 citations per article. Highly cited works converge into four domains: (i) clinical guidelines and pharmacological treatments; (ii) cognitive heterogeneity and subtypes; (iii) neurodevelopmental and genetic mechanisms; (iv) environmental and health-related influences. Geographically, the United States leads with 24.8% of publications, followed by Brazil, China, and European countries. Keyword analysis reveals two main clusters: a clinical–therapeutic pole (methylphenidate, atomoxetine, child) and a genetic–molecular pole (dopamine transporter, SNPs, genotype). Conclusions: ADHD pharmacogenetics shows consolidation with strong clinical and genetic cores but limited integration of comorbidity, adult populations, and non-stimulant treatments. Future research should prioritize multi-center cohorts, multi-omic designs, and stronger international collaboration to advance precision medicine in ADHD. Full article

Background: Staphylococcus aureus is a clinically relevant pathogen with a strong ability to form biofilms on a wide range of surfaces, which markedly reduces the effectiveness of antimicrobial treatments and contributes to therapeutic failure. Although essential oils (EOs) represent effective and economical antimicrobial alternatives, their clinical application is limited by rapid oxidation, volatility, and potential cytotoxicity. In this context, nanoencapsulation emerges as a promising strategy to improve EO stability, control release, and reduce toxicity. In this study, Tetradenia riparia essential oil was encapsulated into poly(lactide) (PLA) nanoparticles (NP) using the nanoprecipitation method. Methods: The physicochemical properties of the nanoparticles were characterized, and their antibacterial, antibiofilm, and cytotoxic activities were evaluated. Antibiofilm and antibacterial effects against S. aureus were assessed by the broth microdilution method, while cytotoxicity was determined using a VERO cell line. Results: The nanoparticles exhibited nanometric size, spherical morphology, and homogeneous structure. Both free EO and EO-loaded nanoparticles demonstrated antibacterial and antibiofilm activity against S. aureus. Importantly, EO-loaded nanoparticles were significantly less cytotoxic than free EO. Nanoencapsulation effectively prevented rapid EO evaporation and degradation, thereby enhancing stability. The nanoparticles exhibited a zeta potential of approximately −23.1 mV, indicating adequate colloidal stability. Differential scanning calorimetry revealed a reduction in melting enthalpy from 429.63 J/g (blank nanoparticles) to 115.83 J/g for EO-loaded nanoparticles, indicating decreased polymer crystallinity and a system favorable for controlled EO release. Conclusions: Overall, these findings demonstrate that nanoencapsulation of T. riparia essential oil into PLA nanoparticles preserves antimicrobial efficacy, reduces cytotoxicity, and improves physicochemical stability, supporting the potential of this nanostructured system as a promising strategy for the treatment of S. aureus biofilm-associated infections. Full article

Background: Neuroblastoma is the most common extracranial solid malignancy in infants and children. High-risk neuroblastoma patients are commonly treated with temozolomide (TMZ), which typically exhibits a poor therapeutic response. Serotonin, also known as 5-hydroxytryptamine (5-HT), plays various essential functions in the human body. In the central nervous system, it serves as a neurotransmitter. Beyond its physiological roles, 5-HT has recently been identified as a potential growth factor for several human tumors, including gliomas and carcinoid tumors. Recent literature has demonstrated that 5-HT receptor antagonists can inhibit the growth of cancer cells. Furthermore, both 5-HT receptors and their antagonists have been identified as potential anticancer agents, suggesting their significance in the development of new treatment strategies. Objectives: The primary aim of this study was to examine the effects of 5-HT and 5-HT antagonists on tumor (neuroblastoma (SH-SY5Y)) and healthy cells (microglia (HMC3)) and determine the impact of their interaction with the anticancer agent TMZ on cell proliferation/viability and migration. Methods: The study explored the interaction between 5-HT, the 5-HT antagonist granisetron (GRN), the anticancer agent TMZ, and their combinations, specifically assessing their influence on cell proliferation, viability, and migration. Results: As a result, the single and combined applications of 5-HT, TMZ, and GRN, a 5-HT antagonist, inhibited cell growth and proliferation in SH-SY5Y, causing decreased cell viability. Additionally, the combination of 5-HT and GRN increased the efficacy of TMZ. Conclusions: The study findings revealed that 5-HT and 5-HT antagonists may have therapeutic effects by exhibiting antiproliferative effects in SH-SY5Y cells at high concentrations. Full article

The treatment of diabetes in the modern era, with its growing patient population, represents a significant challenge due to the wide range of adverse effects associated with medications that target complex biochemical processes. Consequently, researchers are investigating the hypoglycemic potential of existing drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to treat pain, fever, and various inflammatory conditions. Recent studies have shown that NSAIDs, particularly salicylates, can influence glycemia through multiple mechanisms, including inhibition of gastrointestinal enzymes, blockade of K_ATP channels, activation of AMP-activated protein kinase (AMPK), and inhibition of NF-κB signaling, among others. Accordingly, this review explores the hypoglycemic potential of NSAIDs as well as their derivatives, and the diverse mechanisms through which these molecules may influence glucose homeostasis. Full article

Background/Objectives: Leishmaniasis is a neglected parasitic disease with significant global impact and limited therapeutic options due to the toxicity and cost of current treatments. Antimicrobial peptides (AMPs) derived from amphibians, such as Ocellatin-PT4 and Ocellatin-PT6, have emerged as promising bioactive molecules due to their antimicrobial properties and low toxicity to mammalian cells. This study evaluated the leishmanicidal and immunomodulatory effects of Ocellatin-PT4 and Ocellatin-PT6 against Leishmania amazonensis amastigotes. Methods: Peptides were tested on axenic amastigotes and macrophages infected with amastigotes. Cytotoxicity was assessed using MTT (0.4–197 µM for Ocellatin-PT4 and 0.3–152.1 µM for Ocellatin-PT6) and vital dye exclusion assays. Reactive oxygen species (ROS), nitric oxide (NO), and lipid droplet (LD) production were quantified to assess immunomodulatory responses. Results: Ocellatin-PT4 and Ocellatin-PT6 significantly reduced the viability of free and intracellular amastigotes at concentrations ≥ 24.7 µM and ≥19 µM, respectively, without affecting J774 macrophage viability. Infected macrophages treated with the peptides showed reduced parasite load and decreased infection index (≥12.3 µM for Ocellatin-PT4 and ≥2.4 µM for Ocellatin-PT6). Both peptides modulated the oxidative stress response: they reduced ROS levels in infected macrophages while only slightly increasing NO production at higher concentrations. Additionally, lipid droplet accumulation, which was increased during infection, was downregulated by both peptides—particularly by Ocellatin-PT6. Conclusions: Ocellatin-PT4 and Ocellatin-PT6 exert leishmanicidal effects and modulate key macrophage functions without cytotoxicity. These peptides represent promising candidates for the development of novel therapies against cutaneous leishmaniasis. Full article