Nortriptyline, a tricyclic antidepressant widely used for the treatment of neuropathic pain, produces antinociceptive effects that cannot be fully accounted for by monoamine reuptake inhibition alone. Increasing evidence indicates that tricyclic antidepressants directly influence neuronal excitability and synaptic transmission within central nociceptive pathways; their actions on inhibitory neurotransmission in the trigeminal system remain incompletely characterized. In the present study, we investigated the effects of nortriptyline on inhibitory synaptic transmission in substantia gelatinosa neurons of the trigeminal subnucleus caudalis using whole-cell patch-clamp recordings in mouse brainstem slices. Nortriptyline produced a concentration-dependent increase in the frequency of spontaneous inhibitory postsynaptic currents without altering event amplitude and in an action potential-independent manner, consistent with a presynaptic mechanism. This facilitation reflected enhanced release of both GABA and glycine from presynaptic terminals. Importantly, the nortriptyline-induced enhancement of inhibitory synaptic activity persisted under Ca[2][+]-free extracellular conditions, indicating that extracellular Ca[2][+] influx is not required. Collectively, these findings demonstrate that nortriptyline enhances inhibitory synaptic transmission in trigeminal substantia gelatinosa neurons primarily through presynaptic mechanisms, likely involving intracellular Ca[2][+] mobilization, and provide a cellular framework for its modulatory effects on orofacial nociceptive processing.

Background: Autonomic side effects are a major determinant of tolerability for many psychotherapeutic drugs. While often attributed to receptor-mediated mechanisms, the potential contribution of direct modulation of smooth muscle excitability remains poorly characterized at a comparative pharmacological level. Methods: A systematic comparative pharmacological profiling of a broad panel of psychotherapeutic drugs (antidepressants, antipsychotics, and anxiolytics) was conducted using a standardized ex vivo model. Potassium chloride (KCl, 105 mM) was used to induce depolarization-dependent contraction in three isolated smooth muscle preparations (rat uterus, rat vas deferens, and guinea-pig ileum). Inhibitory potency (IC50), dose-dependency, and tissue consistency were integrated to define functional inhibitory profiles. Results: Psychotherapeutic drugs exhibited marked heterogeneity in their ability to inhibit K[+]-induced smooth muscle contraction. Integrative analysis stratified compounds into four distinct functional profiles: (i) High Inhibitory Liability (e.g., nortriptyline, paroxetine), characterized by low micromolar IC50 values and dose-dependent inhibition across multiple tissues; (ii) Non-Selective Inhibition (e.g., flunarizine, cinnarizine), showing consistent but dose-independent inhibition; (iii) Tissue-Dependent Inhibition (e.g., risperidone, reboxetine); and (iv) Minimal Inhibition (e.g., moclobemide). Agents classified within the High Inhibitory Liability profile correspond to drugs known to carry a higher clinical burden of autonomic adverse effects. Conclusions: This study reveals a previously underrecognized pharmacodynamic dimension of psychotherapeutic drugs and establishes a comparative functional taxonomy based on their direct, non-receptor-mediated inhibition of smooth muscle excitability. The identified profiles provide a mechanism-informed framework for contextualizing autonomic side-effect liability and may support improved safety evaluation in psychotherapeutic drug development.

Kratom and kratom products are increasingly used in Western countries for pain management, mood disorders, and opioid withdrawal. Despite perceptions of safety, kratom can cause hepatotoxicity and clinically relevant herb-drug interactions, particularly with medications metabolized by cytochrome P450 (CYP) enzymes. We report a 45-year-old male with stable psychiatric conditions on nortriptyline and lisdexamfetamine, who developed mild, reversible liver enzyme elevations and supratherapeutic nortriptyline levels during chronic kratom use (raw, dry leaf, two tablespoons daily for five to six years). Initial labs showed aspartate aminotransferase (AST) 33 U/L, alanine aminotransferase (ALT) 70 U/L, alkaline phosphatase (ALP) 136 U/L, gamma-glutamyl transferase (GGT) 141 U/L, and nortriptyline 350 mcg/L. Dose reduction of nortriptyline partially corrected serum levels, but liver enzyme elevations persisted. Kratom discontinuation led to normalization of both liver function tests and nortriptyline levels within three weeks. This case illustrates two clinically important considerations: kratom-induced liver injury (KILI) and a CYP-mediated herb-drug interaction. The patient's use of raw leaf contrasts with commercial products, which may include concentrated extracts, 7-hydroxymitragynine (7OHMG)-enriched formulations, or ethanol-based preparations, potentially increasing hepatotoxicity and interaction risk. Even mild liver enzyme elevations in patients using kratom warrant evaluation, particularly with concurrent CYP-metabolized medications. Clinicians should educate patients about product variability, monitor liver function and drug levels, and consider temporary kratom discontinuation to assess causality. This case reinforces the growing evidence of kratom's hepatotoxic potential and the importance of integrating pharmacokinetic considerations into patient care.

In this study, we investigated the impact of cationic amphiphilic drugs (CADs) on in vitro and in vivo protein expression following administration of mRNA lipoplexes. The mRNA lipoplexes were formulated using a modified ethanol injection method and applied to human hepatoma HuH-7 cells, human prostate cancer PC-3 cells, and DC2.4 mouse dendritic cells in the presence of various CADs: ebastine (EBS), loperamide (LPM), carvedilol (CVD), nortriptyline (NRT), desloratadine (DSL), and chloroquine (CQ). In vitro, high luciferase (Luc) expression was induced by Luc mRNA lipoplexes in the presence of EBS, LPM, or CVD, whereas similar effects were not observed with NRT, DSL, or CQ. This enhanced expression was attributed to inhibition of lysosomal acidification rather than changes in cellular uptake or mRNA translation efficiency. Intravenous administration of Luc mRNA lipoplexes into the tail vein of mice increased Luc activity in the lungs and spleen; co-administration with EBS or CVD further increased protein expression in the lungs without affecting expression in the spleen. Furthermore, induction of ovalbumin (OVA)-specific antibodies by OVA mRNA lipoplex administration was suppressed by EBS, attributed to reduced TNF-α production in the spleen, whereas CVD did not elicit similar effects. These findings suggest that EBS and CVD promote mRNA lipoplex-mediated protein expression in cultured cells and mouse lung tissue. However, EBS also diminishes antibody responses triggered by mRNA lipoplexes. Accordingly, caution is warranted when administering lipid-based mRNA vaccines to patients taking CADs, as these drugs may influence vaccine efficacy and safety.

The triticeal cartilage is a small cartilage found within the thyrohyoid membrane present in approximately 33%-53% of individuals. Rarely, calcification/ossification of this cartilage can occur, leading to symptoms of dysphagia, odynophagia, or globus sensation. Despite its clinical relevance, symptomatic triticeal cartilage calcification remains poorly characterized in the literature, with only isolated case reports and no established diagnostic or management framework. We present a case of a 44-year-old woman who presented with seven months of atypical throat and neck pain and globus sensation in the setting of prior esophagogastroduodenoscopy with dilation. Medical management, including nortriptyline and hyoscyamine provided no benefit. Physical examination and flexible laryngoscopy were unremarkable, except for focal left-sided neck tenderness. Contrast-enhanced computed tomography of the neck demonstrated a nonspecific 0.3 x 0.3 x 1.0 cm submucosal calcification at the thyrohyoid membrane, suspicious for retained foreign body. The patient underwent left neck exploration which revealed a calcified cartilaginous structure embedded within the pharyngeal constrictors and immediately adjacent to a pharyngeal plexus branch. Final pathology confirmed fibrous tissue and cartilage. The patient reported immediate, complete symptom resolution and remained symptom-free at 13-month follow-up. This case highlights calcified triticeal cartilage as a rare, often overlooked cause of persistent throat symptoms. Recognition of this pathology may prevent misdiagnosis and allow for timely, definitive treatment.

The worldwide consumption of traditional herbal preparations has risen markedly in recent years, raising increasing toxicological concern regarding drug-drug interactions. A major mechanistic basis for these interactions is the ability of specific phytochemicals to inhibit cytochrome P450 enzymes, thereby altering xenobiotic metabolism at the molecular and enzymatic levels. Anwuligan (ANL), a bioactive compound isolated from nutmeg and Schisandra chinensis, has attracted considerable pharmacological interest, yet its inhibitory potential toward P450 enzymes remains poorly defined. In this study, we systematically investigated the effects of ANL on CYP2C19 and evaluated its pharmacokinetic interaction with amitriptyline. Enzyme kinetics revealed that ANL is a mechanism-based inhibitor of CYP2C19, and NAC trapping assays indicated that an o-quinone intermediate generated during its metabolism is the key species responsible for irreversible enzyme inactivation. In vivo pharmacokinetic studies in rats showed that ANL pretreatment increased amitriptyline exposure, with Cmax and AUC0-∞ increased by 1.4-fold and ∼30%, respectively, and CLz/F reduced by 24%. In contrast, nortriptyline exposure decreased, with reductions in Cmax (39%) and AUC (29-34%). These results demonstrate CYP2C19 inhibition by ANL and its potential to cause clinically relevant drug-drug interactions.

Primary Immune Thrombocytopenia (ITP) is an autoimmune disease characterized by thrombocytopenia and bleeding tendency. Exosomes mediate abnormal crosstalk between immune cells and megakaryocytes in ITP, suggesting that exosome-related genes may serve as potential candidates for understanding disease pathogenesis. ITP transcriptome data and exosome-related genes (ERGs) were retrieved from public databases. Potential candidate genes were preliminarily identified by intersecting ITP's differentially expressed genes (DEGs) with exosome-related key module genes, followed by exploratory screening via machine learning and the construction of a preliminary predictive model. Multi-dimensional analyses (enrichment, immune infiltration [subsequently removed due to methodological concerns], drug prediction) and RT-qPCR validation were performed. Four candidate genes (GABARAPL1, SLC39A14, HIBADH, GSR) were identified through bioinformatic analysis, involved in spliceosome and other pathways (P < 0.05, |NES| > 1). GABARAPL1, SLC39A14, and HIBADH showed exploratory correlations with specific functional T-cell subsets (|cor| > 0.3, P < 0.05). Molecular docking simulations suggested potential binding feasibility between SLC39A14/nortriptyline and GSR/oxiglutatione (binding free energy < -5 kcal/mol). RT-qPCR confirmed the significant downregulation of GABARAPL1, SLC39A14, and GSR in ITP patients (P < 0.05), while HIBADH did not show statistically significant changes (P > 0.05). In this exploratory study, GABARAPL1, SLC39A14, and GSR were identified as potential candidate biomarkers with experimental support from clinical samples. HIBADH, while predicted by bioinformatic analysis, requires further investigation to determine its clinical relevance. These findings provide exploratory insights and a preliminary basis for future hypothesis-driven research on the role of exosome-related genes in ITP.

Glucocorticosteroids (GCS) are often the medication of choice for chronic inflammation. Since not all patients are equally sensitive to GCS, certain efforts are undertaken to increase sensitivity and complement glucocorticosteroid therapy with other nonsteroidal medications that can enhance the anti-inflammatory effect of GCS. The tricyclic antidepressant nortriptyline has demonstrated anti-inflammatory properties in several experimental studies, as well as the ability to complement the action of GCS. The aim of this study was to investigate the effects of nortriptyline, as well as its combination with mometasone, on blood mononuclear cells (MNCs) under conditions of stimulated immune responses (IR) of types 1, 2, and 17. In isolated MNCs from six healthy donors, IR type I, type 2, or type 17 were stimulated in the presence of nortriptyline, mometasone, or their combination by adding recombinant activator proteins (IL-2, IL-25, IL-33, thymic stromal lymphopoietin (TSLP), IL-12, IL-1β, IL-23). After three days, the concentration of IL-6 and IL-8 was determined in the supernatants by enzyme-linked immunosorbent assay. In the presence of nortriptyline at a final concentration of 10-5 M, IR type 2 and type 17 were accompanied by a decrease in IL-6 concentration. Addition of a combination of mometasone and nortriptyline to the MNC culture medium under conditions of IR type II activation had a potentiating effect. This was evidenced by a decrease in IL-6 and IL-8 secretion compared to the use of mometasone alone. The study demonstrates the ability of nortriptyline to suppress the secretion of proinflammatory cytokines by blood cells, which is selective and dependent on the type of immune response.

The emergence of drug-resistant bacterial infection and persistent biofilm colonization pose a rigorous challenge to effective wound healing and regeneration, necessitating the innovative therapeutic strategies to combat these pressing clinical crises. Herein, nortriptyline, a novel United States Food and Drug Administration (FDA)-approved tricyclic antidepressant was uncovered to effectively potentiate bactericidal activities of β-lactam antibiotics against methicillin-resistant Staphylococcus aureus (MRSA). Mechanistically, nortriptyline functions by disrupting the microbial iron homeostasis and potentiation of Fenton chemistry-mediated oxidative stress, concomitant with metabolic reprogramming via tricarboxylic acid (TCA) cycle dysregulation and membrane destabilization. To enhance combination therapy-mediated therapeutic potential in wound management, the dual-loaded self-healing hydrogel OHA-PLL@AN was engineered to exhibit excellent biocompatibility and antibacterial potentials through molecular cross-linking of oxidized hyaluronic acid (OHA) and ε-polylysine (PPL). The therapeutic efficacy of OHA-PLL@AN was further validated in a murine model with MRSA-infected cutaneous wounds. OHA-PLL@AN therapy significantly attenuated the inflammatory response, concurrently promoting angiogenesis and accelerating the cutaneous wounds healing. Collectively, these findings underscore the dual drug-loaded self-healing hydrogel OHA-PLL@AN with anti-infection and anti-inflammatory properties as a novel therapeutic strategy for drug-resistant bacterial infected wounds therapy.

The Dutch Pharmacogenetic Working Group (DPWG) aims to integrate pharmacogenetics into clinical practice by creating evidence-based guidelines to optimize pharmacotherapy based on genetic tests. The current guideline describes the gene-drug interactions between CYP2D6 and CYP2C19 and various tricyclic antidepressants (TCAs). For CYP2D6 poor metabolisers (PM), dose reductions are advised for amitriptyline (reduction to 60% of the normal dose), clomipramine (reduction to 50% of the normal dose for the indication depression or in case of side effects at the normal dose for the other indications), doxepin (reduction to 40% of normal dose), imipramine (30% of the normal dose), and nortriptyline (40%). For CYP2D6 intermediate metabolisers (IM) reduced dose is also recommended for amitriptyline (75%), clomipramine (70%), doxepin (80%), imipramine (70%), and nortriptyline (60%). Also, CYP2D6 ultra-rapid metabolisers (UM) require tailored dose adjustments: amitriptyline (1.6 times the normal dose), clomipramine (1.5 times), doxepin (2 times), imipramine (1.7 times), and nortriptyline (1.7 times). Additionally, alternative drugs may be needed for CYP2D6 UM due to potential safety concerns. For CYP2C19 PM, a 70% dose reduction is advised for imipramine. For CYP2C19 IM, no action is required for TCAs. For CYP2C19 UM, an alternative medication is recommended for clomipramine prescribed for anxiety and obsessive-compulsive disorder (OCD). The DPWG classifies CYP2D6 genotyping for all five TCAs and CYP2C19 genotyping for clomipramine in patients with anxiety disorders or OCD, and for imipramine as being "potentially beneficial". Genotyping prior to treatment can be considered on an individual patient basis.