Active pharmaceutical ingredients (APIs) are present in aquatic environments at concentrations that can impact ecosystems. Their major pathway to the environment is in the discharge of wastewater effluents from centralised wastewater treatment works (WWTWs). However, in most rural areas where houses are not connected to a public sewage network, single households or groups of houses rely on onsite wastewater treatment works (OWTWs), mainly septic tanks (STs). Therefore, STs are reviewed as a pathway for APIs to the aquatic environment. Despite STs being extensively used globally, there is a geographical bias in available data with most studies conducted in the USA. Furthermore, studies focus on a few APIs (e.g., carbamazepine, sulfamethoxazole and paracetamol) and the impact of STs to groundwater. Previous reliance on grab sampling and the heterogenous composition of influent wastewater characterised by the small contributing populations makes assessing ST removal efficiency challenging. Available data suggests little or no removal of APIs in the anaerobic environment of STs. Conducting an intensive monitoring approach (e.g., continuous 24 h composite sampling) for durations several times the ST hydraulic retention time will help benchmark their performance for API removal against other processes. Recent studies show surface waters receiving ST discharges have API concentrations exceeding their predicted no effect concentration (PNEC, the concentration below which no adverse effect is expected). Mean concentrations of 17β-estradiol, ampicillin, ibuprofen, memantine, palmitamid, paracetamol and trihexyphenidyl all exceeded their PNEC by up to 50 times. However, there is a lack of data for several APIs identified to be of possible environmental concern in prioritisation watch lists such as those outlined by the EU (e.g., amoxicillin, clarithromycin, desmethylvenlafaxine and clindamycin). Receiving surface waters can be small ecologically important streams, demanding the need for further monitoring and intervention. Other than adopting secondary treatment (e.g., constructed wetlands where possible) or alternative OWTWs which achieve greater API removal, sustainable medicine use is proposed as a viable means of reducing the environmental impact of ST discharges where risks are identified. Utilising environmentally informed prescribing and other 'upstream' interventions such as return schemes for unused pharmaceuticals, have great potential for success where small populations of people can be specifically targeted.

Hemichorea associated with non-ketotic hyperglycemia (HC-NH) is a rare neurological complication and is also considered a specific complication of diabetes. Its exact pathogenesis remains unclear. We report a case of a 79-year-old female patient with HC-NH. Her primary clinical presentation included involuntary movements in the right limbs that began 3 days prior to admission. These movements worsened during emotional agitation and could be accompanied by insomnia but resolved after falling asleep. Imaging studies revealed no significant intracranial lesions on CT. MRI showed hyperintensity on T1-weighted images (T1WI) in the left globus pallidus and putamen and slightly lower signal intensity on T2-weighted imaging (T2WI). Fingerstick glucose monitoring during hospitalization showed only mild elevation, and urine ketones showed negative results. Treatment included glucose control, tiapride, Trihexyphenidyl, and haloperidol for choreiform movements, along with lorazepam to alleviate anxiety and tension. The patient showed slight improvement, and choreiform movements markedly diminished 3 months after discharge. This case demonstrates that blood glucose levels may not be markedly elevated at the onset of HC-NH, potentially leading to delayed or misdiagnosis. Additionally, symptom control may not achieve optimal results in the short term. Therefore, early diagnosis and treatment are crucial for the prognosis of this condition.

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.