Background/Objectives: Cholinergic dysfunction plays a central role in memory impairment, yet trihexyphenidyl (THP)-based paradigms remain less explored than scopolamine-based models. This study aimed to characterize a THP-induced cholinergic challenge in a two-trial Y-maze with a 24 h interval and to compare the effects of donepezil and tacrine on recall-phase exploratory allocation. Methods: Male Wistar rats (n = 9/group) were studied in a validation phase including saline, THP 5 mg/kg, and THP 10 mg/kg groups, followed by an intervention phase including control, THP 10 mg/kg, donepezil 1 and 3 mg/kg + THP, and tacrine 3 and 5 mg/kg + THP groups. All treatments were administered intraperitoneally (i.p.). Acquisition- and recall-phase behavior was analyzed. Recall outcomes included arm times, arm entries, the novel-to-familiar arm time ratio (U/K time ratio), the novel-to-familiar arm entry ratio (U/K entry ratio), discrimination indices and time-per-entry indices. Data were analyzed by one-way ANOVA; Tukey's post hoc test was used in the validation experiment, whereas Dunnett's test was used in the intervention experiment for comparisons against THP 10. Results: THP at 10 mg/kg produced a robust recall-phase phenotype, with increased familiar-arm exploration, reduced novel-arm exploration and lower normalized indices. Under THP challenge, donepezil was associated with clearer effects at 3 mg/kg, whereas tacrine displayed a broader dose-dependent profile, with the strongest shift in recall-phase exploratory allocation toward the novel arm observed at 5 mg/kg. Conclusions: THP 10 mg/kg produced a robust recall-phase exploratory phenotype in a 24 h two-trial Y-maze paradigm. Under THP challenge, donepezil and tacrine were associated with shifts in recall-phase exploratory allocation. These findings support the potential utility of THP-based paradigms for studying cholinergic disruption in Y-maze settings, while direct comparison with scopolamine-based models remains to be established.

A man in his 20s presented with rapidly progressive spastic parkinsonism, right-hand focal dystonia, memory impairment, and behavioural changes over eight months, resulting in complete dependence. Examination showed spasticity, rigidity, bradykinesia, ankle clonus, postural instability, slowed saccades, and cognitive deficits (Mini-Mental State Examination 25/30, Montreal Cognitive Assessment 20/30). Brain magnetic resonance imaging revealed mild cerebellar atrophy, claval hypertrophy, and minimal lentiform susceptibility blooming. Whole-exome sequencing identified a heterozygous pathogenic PLA2G6 variant (c.2222G>A; p.Arg741Gln). No family history was present. Symptomatic treatment with levodopa/carbidopa, trihexyphenidyl, and baclofen yielded partial initial benefit but limited sustained response over six months of follow-up. This case expands the adult-onset PLA2G6-associated neurodegeneration phenotype by combining aggressive progression, early cognitive involvement, and rare infantile-like neuroimaging features with minimal iron deposition.

Parkinson's disease (PD) has been associated with some types of food and drugs. Here, we query PubMed for the association of PD with foods and drugs, using a list of 217,776 compounds derived from the Human Metabolome Database (HMDB). To calculate associations, a Python script was developed to query PubMed for co-citations of PD with each compound, and adjust this count for compound abundance. Notably, PD is found to be associated with small-molecule drugs, adjunctive therapies, contraindicated drugs, diagnostic agents, biomarkers, conditional essential molecules, and inducers. Drugs include L-dopa (49%), carbidopa (63%), benserazide (50%), entacapone (74%), tolcapone (56%), rasagiline (76%), selegiline (46%), pargyline (4%), ropinirole (61%), pramipexole (56%), lisuride (27%), cabergoline (16%), bromocriptine (12%), and zonisamide (9%). Adjunctive therapies include droxidopa (33%), trihexyphenidyl (28%), biperiden (17%), amantadine (24%), memantine (7%), rivastigmine (13%), donepezil (6%), galantamine (4%), domperidone (6%), clonazepam (4%), tetrabenazine (16%), mazindol (13%), quetiapine (6%), and clozapine (4%). Contraindicated drugs include haloperidol (4%), sulpiride (3%), and methyldopa (6%). Diagnostic agents include FP-CIT (60%) and beta-CIT (43%). Biomarkers include 3-methoxytyrosine (48%) and homovanillic acid (12%). Endogenous cofactors include tetrahydrobiopterin (4%) and Coenzyme Q10 (4%). Chemical inducers of PD include 6-hydroxydopamine (40%), N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 78%), tetrahydropyridine (77%), probenecid (4%), quinolinic acid (4%), 1,2,3,4-tetrahydroisoquinoline (TIQ, 16%), salsolinol (32%), rotenone (25%), and β-Methylamino-L-alanine (BMAA, 29%). Notably, our study highlights conditional essential endogenous cofactors associated with PD and emphasizes rational directions for investigation in PD.

Adenylyl cyclase 5 (ADCY5)-related movement disorder (ADCY5-RMD) is a rare genetic hyperkinetic movement disorder caused by pathogenic variants in the ADCY5 gene, characterized by childhood-onset chorea, dystonia, myoclonus, and distinctive paroxysmal exacerbations, often with nocturnal worsening. The disorder exhibits marked phenotypic variability, minimal disease progression, and frequently normal neuroimaging, leading to frequent misdiagnosis as dyskinetic cerebral palsy or epilepsy. We report the case of a 60-year-old woman with childhood-onset generalized dystonia, prominent oromandibular and lingual involvement, asymmetric distal choreoathetosis, and recurrent nocturnal ballistic bouts beginning at age 13. Episodes occurred predominantly during sleep-wake transitions and were exacerbated by stress. Neurological examination and brain magnetic resonance imaging (MRI) were unremarkable. Whole-exome sequencing (WES) identified a heterozygous de novo splice-site mutation in ADCY5 (c.2088+1G>A), classified as pathogenic. Symptomatic treatment with trihexyphenidyl, clonazepam, and quetiapine led to a significant reduction in episode frequency and severity. This case expands the phenotypic spectrum of ADCY5-RMD by demonstrating persistence of sleep-related paroxysmal dyskinesia into late adulthood and highlights the importance of considering ADCY5-RMD in long-standing childhood-onset hyperkinetic movement disorders.

In this contribution, an efficient high-performance liquid chromatographic (HPLC) method was developed for the simultaneous determination of four impurities in trihexylphe idyl hydrochloride. The developed HPLC method was based on an octadecylsilane-bonded silica gel column (Agilent TC-C18 250 mm × 4.6 mm, 5 µm) as the stationary phase, and the solvents were sodium hexafluorophosphate 0.05 mol/L and methanol for the gradient elution at a flow rate of 1.0 mL/min, with the injection volume of 20 µL, the ultraviolet (UV) detection at a wavelength of 210 nm, and the column temperature of 30°C. Under the established chromatographic conditions, all four target impurities were completely eluted within 30 min. The proposed method demonstrates good specificity, precision, robustness, and accuracy for the quantification of the four critical impurities in trihexyphenidyl hydrochloride, and was successfully applied for the analysis of trihexyphenidyl hydrochloride in a pharmaceutical preparation.

Dystonia is a predominant and debilitating movement disorder associated with dyskinetic cerebral palsy (DCP). Although trihexyphenidyl (THP) is commonly used as a treatment, its efficacy often exhibits a plateau effect. The combination of dopaminergic and anticholinergic agents represents a rational therapeutic strategy; however, robust evidence for the combination of Madopar (levodopa/benserazide) and THP is lacking.

This study presents the first reported case of a 3-year-old child with EIF2AK2-related dystonia treated with adjunctive luteolin supplementation. EIF2AK2-related dystonia, characterized by exacerbations during infections, is associated with disruptions in the integrated stress response (ISR). The ISR, a cellular signaling pathway activated in response to stress, culminates in the phosphorylation of eIF2α, which modulates protein synthesis and can induce cell death. Pathogenic variants in EIF2AK2 disrupt this pathway, contributing to the development of dystonia. Luteolin, a flavonoid possessing anti-inflammatory and neuroprotective properties, was hypothesized to modulate the ISR, thereby attenuating infection-induced dystonic exacerbations. The patient, exhibiting early-onset dystonia with clinical worsening during febrile episodes, harbored a de novo pathogenic variant in EIF2AK2. Following initial clinical improvement with trihexyphenidyl, adjunctive luteolin therapy was initiated, resulting in further clinical enhancements. Quantitative assessment using dystonia rating scales (UDRS, MSS, DSS) demonstrated sustained improvement, characterized by a reduction in the severity and frequency of infection-triggered relapses. The proposed mechanism of action involves luteolin disrupting the PACT-PKR interaction, a critical step in ISR activation, thus preventing excessive eIF2α phosphorylation and subsequent cellular dysfunction. This mechanism, supported by in vitro studies utilizing relevant disease models, suggests luteolin's potential to stabilize cellular homeostasis under stress. This case report indicates that luteolin may serve as a promising adjunctive therapeutic strategy for patients with infection-sensitive dystonic phenotypes, such as EIF2AK2-related dystonia. Further randomized controlled trials are warranted to validate these findings and establish the optimal dosing regimen and long-term safety profile of luteolin in vivo.

Anticholinergic medications (ACMs) prescribed for the treatment of antipsychotic-associated extrapyramidal symptoms (EPSs) are frequently prescribed for durations that exceed expert guidelines and are associated with significant side-effect burden. Evidence suggests that education with regard to the risks of long-term prescribing of ACMs for resolved EPSs may be lacking in the health care community, and no best practices exist for deprescribing ACMs. This review discusses EPSs and their treatment with two ACMs, benztropine and trihexyphenidyl, and it presents evidence of the risks of chronic ACM prescribing, including serious side effects such as cognitive impairment, dry mouth, blurred vision, and risk for delirium, as well as sequelae of severe constipation and urinary retention. It is pertinent to remember that many psychotropic agents, including several antipsychotics, as well as other commonly prescribed medications have moderate to strong anticholinergic properties. Each ACM, when prescribed with other medications concomitantly, compounds ACM burden and associated side effects. Informed by the authors' extensive experience with quality improvement projects on deprescribing ACMs, this review examines both the benefits and risks of ACM deprescribing, with an emphasis on choosing appropriate patients and engaging in shared decision making while utilizing patient-facing assessments and decision-support tools. ACM tapering schedules are suggested, along with recommendations for closer patient monitoring during the deprescription process. Barriers to deprescription at the patient, prescribing clinician, and system level are then reviewed, along with relevant ethical considerations inherent to any medication changes, including ACM deprescribing.

Drug repositioning accelerates therapeutic discovery by identifying new indications for approved drugs, substantially reducing the time and cost associated with drug development. However, graph collaborative filtering (GCF)-based methods for predicting drug-disease associations are limited by data sparsity and structural noise, impeding the modeling of latent high-order and semantic relationships. We hypothesize that jointly leveraging complementary information from structural and semantic neighborhoods can alleviate data sparsity and improve predictive performance. To this end, we propose a unified framework, Rich-Neighborhood Contrastive Learning for Drug Repositioning (RCL-DR), which integrates both structural and semantic neighborhood modeling into a LightGCN-based collaborative filtering backbone and optimizes semantic prototypes via an Expectation-Maximization (EM) algorithm. Experiments on three public datasets using 10 × 10- fold cross-validation demonstrate that RCL-DR outperforms representative baselines, achieving an area under the receiver operating characteristic curve (AUROC) of 0.9419 and an area under the precision-recall curve (AUPR) of 0.5126, representing absolute improvements of 0.0345 and 0.0138, respectively. Furthermore, RCL-DR identifies promising drug candidates for Alzheimer's disease (e.g., buspirone) and Parkinson's disease (e.g., trihexyphenidyl) by predicting previously unknown drug-disease associations on the Fdataset and validating them against authoritative databases. In summary, RCL-DR provides a unified contrastive learning framework for robust drug repositioning and precision pharmacology.

BACKGROUND Tardive dyskinesia is an iatrogenic syndrome that can include dystonia, akathisia, facial tics, chorea, and other abnormal involuntary movements. Tardive dyskinesia follows antipsychotic medication and results from the antagonism of dopamine receptors. This report describes a 40-year-old woman with schizophrenia treated with the long-acting antipsychotic paliperidone palmitate, with persistent tardive dyskinesia, requiring long-term management. CASE REPORT A 40-year-old woman with schizophrenia was administered long-acting paliperidone palmitate for 1 month in April 2017 and then switched to long-acting paliperidone palmitate for 3 months starting in October 2017. After 3 months of long-acting injection exposure (April 2018), she developed sustained cervical posturing and mask-like facies. Dose reduction to 350 mg was ineffective; the long-acting injection was stopped in June 2019, and aripiprazole 10 mg/day was started. Adjuncts (trihexyphenidyl, amantadine, and intermittent benzodiazepines) provided only limited benefit. Clozapine was started in December 2019 and titrated, with gradual, incomplete improvement. On readmission in May 2024, Neurology diagnosed tardive dyskinesia, particularly tardive dystonia. Over 6 years without vesicular monoamine transporter 2 (VMAT-2) inhibitors, her dystonia lessened but persisted, and she was discharged on clozapine and fluvoxamine. CONCLUSIONS Tardive dystonia can follow exposure to long-acting injectable paliperidone and may be prolonged yet partly reversible despite discontinuation. Given therapeutic limits, variable prognosis, and the 3-month formulation's extended pharmacokinetics, clinicians should maintain high suspicion, minimize dopamine-receptor-blocking exposure, and individualize care, considering timely VMAT-2 inhibitors or clozapine, plus structured long-term motor monitoring and shared decision-making. This report highlights the presentation of tardive dyskinesia as a complication of antipsychotic medication and the approach to management of this iatrogenic syndrome.