Polymeric microneedle arrays are medical devices composed of micro-scale needles that enhance skin permeation by breaching stratum corneum's integrity and creating microchannels. Morphology as well as dimensional characteristics of these structures, namely height, base width, density of arrays and tip diameter can significantly affect the permeation profile of the active ingredient. Additionally, the force applied during application is also considered a key factor of drug delivery. Therefore, within the concept of personalizing the rate and amount of drug permeated through skin, a screening of the aforementioned factors was performed. Specifically, microneedles of various geometries and dimensions were prepared and evaluated with regards to their dimensional accuracy, insertion depth and drug permeation. For this purpose, Ropinirole Hydrochloride (RopHCl) was utilized as model drug due to its hydrophilic nature. In more detail, ten microneedle morphologies were evaluated in relation to their effect in the drug delivered, while a Definitive Screening Design (DSD) was implemented to screen the effect of the microneedle dimensional characteristics in the arrays' performance. Overall, significant differentiations between the microneedles shapes were observed across the permeation profiles while height, interspacing distance and insertion force were the main factors revealed as significant by the experimental design applied. Regarding base width, although it does not directly influence drug permeation, it affects the mechanical rigidity. It can be thus concluded that drug permeation through skin can be effectively personalized by tuning the microneedle array properties, while keeping a constant microneedle composition.

Restless legs syndrome (RLS) refractory to guideline-directed therapy may require treatment with low-dose opioids. Methadone is an established option for refractory RLS but may be limited by medication intolerance. We present a 52-year-old woman with refractory RLS who failed multiple pharmacologic therapies, including ropinirole, carbidopa/levodopa, gabapentin, and pregabalin. Methadone produced excellent symptom control but was discontinued because of dysphoria, emotional lability, cognitive slowing, and persistent daytime grogginess. Transition to tramadol 50 mg nightly resulted in sustained symptom control without recurrence of these adverse effects, allowing discontinuation of gabapentin and improved daytime functioning. This case highlights the importance of individualized opioid selection in refractory RLS and suggests that tramadol may be an effective alternative for carefully selected patients with methadone intolerance.

Current therapeutics for attention-deficit/hyperactivity disorder (ADHD) have significant limitations, necessitating innovative therapies. This study aimed to investigate the efficacy and safety of ropinirole, a dopamine agonist with anti-inflammatory and neuroprotective properties, as an add-on to methylphenidate for children with ADHD. In this eight-week, randomized, double-blind trial, 66 outpatients aged 6-17 with a diagnosis of ADHD were randomized to receive methylphenidate plus either ropinirole 0.25 mg or a matching placebo twice daily. ADHD-related symptoms were assessed using the ADHD Rating Scale-IV (ADHD-RS-IV) reported by teachers and parents at baseline and weeks 4 and 8. Inattention and hyperactivity-impulsivity subscale scores were also recorded. Additionally, adverse effects were monitored throughout the study. Data from 65 participants were used for analyses. Baseline demographic and clinical characteristics were comparable between the arms. Significant time-by-treatment interaction was observed for the ADHD-RS-IV total scores as rated by teachers ([Formula: see text]= 0.051) and parents ([Formula: see text]= 0.153). The ropinirole group demonstrated significantly greater reductions in ADHD-RS-IV total scores from baseline to the endpoint as reported by teachers (Cohen's d = 0.530) and parents (Cohen's d = 0.504). Also, the ropinirole group achieved higher rates of response to treatment (69.7% versus 34.4%) and robust improvement (60.6% versus 25.0%). The incidence of adverse effects was comparable. In conclusion, methylphenidate + ropinirole was safe and beneficial compared to methylphenidate + placebo for reducing inattentive, hyperactive-impulsive, and total symptoms in children with ADHD. Further studies are required.

This commemorative article reflects on a research journey spanning neural development, stem cell biology, regenerative medicine, and iPSC-based drug discovery. My early work focused on RNA-mediated regulation in the nervous system, including studies on myelin basic protein gene regulation and the identification and functional characterization of the RNA-binding protein Musashi. These studies contributed to the conceptual foundation of neural stem cell biology and helped establish methods for identifying and isolating neural stem/progenitor cells, including those present in the adult human brain. Building on this foundation, my colleagues and I pursued translational research in spinal cord injury, ranging from analyses of injury pathophysiology and molecular interventions to preclinical studies using rodent and non-human primate models. These efforts ultimately led to the first-in-human clinical study of induced pluripotent stem cell-derived neural stem/progenitor cell transplantation for subacute spinal cord injury. In parallel, we developed patient-derived iPSC platforms for neurological disease modeling and drug discovery, particularly for amyotrophic lateral sclerosis, where iPSC-based screening identified Ropinirole as a therapeutic candidate and enabled reverse translational research linking cellular phenotypes with clinical responses. Looking ahead, I argue that the future of regenerative therapy will depend on the continued integration of developmental biology, stem cell science, disease modeling, rehabilitation, and clinical translation to address unmet medical needs in disorders of the central nervous system.

Ischemic stroke (IS) persists as a major contributor of mortality and functional impairment globally, because of limited conventional drug delivery system and restrictive properties of the blood-brain barrier (BBB). In recent years, Ligand-conjugated nanomaterial-based drug delivery systems have emerged as effective techniques to improve brain-targeted therapy through multimodal approach. In this context, the present study proposes an innovative nanotechnology based Transferrin (Tf)-conjugated Nanostructured Lipid carrier (NLC) co-loaded Ropinirole (RP), and Mangiferin (MF) to facilitate targeted and effective delivery across the BBB. The characterization of developed Transferrin-conjugated Ropinirole-Mangiferin-Nanostructured Lipid carrier (Tf-RP-MF-NLC) demonstrated a mean particle size of 163.9 ± 2.97 nm, a polydispersity index (PDI) of 0.31 ± 0.04, zeta potential of -8.589 ± 3.63 mV and spherical morphology as shown by Transmission Electron Microscopy (TEM) Analysis. The entrapment efficiency (EE) of RP and MF was found to be >85%, while Tf conjugation efficiency was estimated to be >60%. The % cumulative drug release was found to be >80% for RP and > 65% for MF over 24 h from Tf-RP-MF-NLC. The antioxidant effect and biocompatibility of the Tf-RP-MF-NLC were confirmed by the DPPH assay and haemolysis testing, respectively. Furthermore, results obtained from gamma scintigraphy study revealed that Tf-RP-MF-NLC had enhanced brain targeting and increased drug accumulation as compared to RP-MF-NLC following intraperitoneal (i.p.) administration. Overall, these findings highlights Tf-RP-MF-NLC as a promising brain targeted nanocarrier system with improved drug delivery, suggesting its potential as an effective therapeutic strategy for improved drug delivery to the brain.

Three converging therapeutic paradigms-iPSC-based drug discovery, cell transplantation, and gene therapy-have substantially expanded the therapeutic pipeline for amyotrophic lateral sclerosis (ALS) between 2020 and 2026. The FDA's accelerated approval of tofersen (Qalsody) in April 2023 marked the first treatment targeting a genetic cause of ALS. iPSC-derived drug candidates, including ropinirole and bosutinib, have completed early-phase clinical trials led by Japanese institutions. Cell therapies targeting neuroinflammation through regulatory T cells are being actively explored as immunomodulatory strategies, although efficacy remains to be established in adequately powered trials. Next-generation gene-silencing approaches-including RNA interference (RNAi) therapeutics and AAV-delivered microRNA-entered first-in-human trials in 2024-2025. The identification of STMN2 as a downstream target of TDP-43 dysfunction has opened a potential TDP-43-downstream nucleic acid therapeutic avenue for sporadic ALS, which constitutes approximately 90% of all cases, with company-reported interim data suggesting target engagement in the ongoing Phase 1/2 ANQUR trial (QRL-201). This review synthesizes the latest evidence across all three therapeutic domains, with attention to the hierarchy of evidence, regulatory milestones, and the pioneering contributions of Japanese research groups.

Given the therapeutic importance of ropinirole in Parkinson's disease and its long-term use, reliable quality control of this drug is required, with particular emphasis on impurity control in the finished pharmaceutical product. A zwitterionic hydrophilic interaction liquid chromatography-electrospray ionization mass spectrometry (HILIC-ESI-MS) method was developed and validated for the determination of ropinirole and three degradation impurities in pharmaceutical tablets. Chromatographic separation was achieved on a ZIC®-HILIC column (150 × 2.1 mm, 3.5 μm particle size, 200 Å) under isocratic elution with a mobile phase of 18.8 mM aqueous ammonium formate solution at pH 6.20 and acetonitrile in an 8:92 (v/v) ratio, delivered at a flow rate of 0.25 mL min[-1]. Detection was performed in positive electrospray ionization mode using selected ion monitoring and the target analytes were determined within 10 min for assay and 16 min for impurity testing. The method was validated for linearity, accuracy, precision, sensitivity, robustness, and selectivity. Calibration curves showed good linearity over the concentration range of 21 to 122 ng mL[-1] with correlation coefficients of at least 0.997. Intra-day precision (% CV) did not exceed 6.7 %, while total precision ranged between 2.5 and 8.8 % for all compounds. The method was successfully applied to the analysis of commercially available ropinirole extended-release tablets. To the best of our knowledge, this is the first reported HILIC-ESI-MS method for the assay of ropinirole and the quantitation of three degradation impurities in pharmaceutical tablets.

Lacosamide is a third-generation antiseizure medication that enhances slow inactivation of voltage-gated sodium channels. Although generally well tolerated, it has been associated with cardiac conduction abnormalities, most commonly in the setting of intravenous administration, overdose, or dose escalation. We report a case of a 79-year-old woman with a history of hypertension (treated with losartan and metoprolol), restless legs syndrome (treated with ropinirole), peripheral neuropathy, and seizure disorder who presented to the emergency department with several days of intermittent confusion and generalized weakness following a recent admission for seizure-like activity, during which lacosamide had been initiated. On arrival, she was afebrile with a heart rate of 74 beats per minute, blood pressure 165/88 mmHg, and oxygen saturation 98% on room air; she was oriented to person and year but not to place, which represented a change from her baseline. Initial laboratory evaluation, including complete blood count, comprehensive metabolic panel with normal renal and hepatic function, B12, and thyroid stimulating hormone, was unremarkable, and her admission electrocardiogram showed normal sinus rhythm with a PR interval of 208 ms. While boarding in the emergency department, she received her scheduled oral lacosamide 150 mg, and approximately two hours later was found unresponsive with a heart rate in the 30s and systolic blood pressure of 50 mmHg. She responded to atropine 1 mg IV and 50μg of epinephrine IV, with improvement of her vital signs and mental status. Six hours later, she received a second scheduled dose of lacosamide 150 mg along with her home medications, including metoprolol tartrate 50 mg, and again two hours later became minimally responsive with a heart rate of 49 beats per minute, blood pressure 64/32 mmHg, and a new first-degree atrioventricular block; she again responded to atropine. The second episode was more pronounced and associated with conduction delay not previously present. No seizure activity was observed during either episode. Lacosamide was discontinued, and the patient had no further bradycardic or hypotensive events. The reproducible temporal relationship between dosing and symptoms, along with resolution after medication cessation, supports a causal association. This case highlights that clinically significant cardiac adverse effects can occur with standard oral dosing of lacosamide, particularly in older adults and in the presence of other medications that affect cardiac conduction. Emergency physicians should maintain a high index of suspicion for medication-induced bradycardia and hypotension in patients receiving lacosamide. This case also underscores how hospital boarding can increase the risk of iatrogenic harm, as patients may receive routine medications in a high-acuity environment where evolving adverse effects can be more difficult to anticipate and detect.

Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD) cause progressive loss of specific neuronal populations and currently lack curative therapies. Animal models and immortalized cell lines incompletely recapitulate human pathology and genetic heterogeneity, limiting drug discovery. Human induced pluripotent stem cells (iPSCs) provide a patient‑specific platform for disease modelling, drug screening and studying individual responses. Translational research (TR) uses iPSC models to identify candidate therapies that are subsequently tested in clinical trials, while reverse translational research (rTR) feeds clinical observations back to the bench by analyzing iPSCs derived from trial participants and integrating molecular data with patient phenotypes. This review summarizes recent advances in iPSC‑based TR and rTR for ALS and extends the discussion to other neurodegenerative diseases. Key clinical trials launched from iPSC screens-ropinirole, retigabine and bosutinib-are reviewed alongside emerging rTR efforts that use patient‑derived iPSCs to identify biomarkers and therapeutic mechanisms. We also survey iPSC models for AD, PD and HD, highlighting applications of three‑dimensional (3D) brain organoids and gene‑editing technologies. Finally, we discuss future directions for precision medicine, multimodal integration and technological challenges, with particular attention to how imaging biomarkers may complement iPSC-based TR/rTR frameworks in neurodegenerative diseases.

Intranasal administration is a promising drug delivery route enabling precise and rapid central nervous system targeting. In our previous work, twelve hybrid colloidal dispersions were developed, consisting of synthetic poly(ethylene-oxide)-b-poly(ε-caprolactone) (PEO-b-PCL) block copolymers with an increasing proportion of the hydrophobic PCL segment, Tween 80 (Tw80) and β-cyclodextrin derivatives (βCD), either methyl-β-CD (MβCD) or hydroxy-propyl-β-CD (HPβCD) for IN delivery of ropinirole hydrochloride (RH). Colloidal dispersions were prepared at different weight ratios (system/RH equal to 10:1 and 10:5), characterized and evaluated in vitro. The aim of this study is to evaluate the ex vivo permeation through rabbit nasal mucosa and determine the pharmacokinetic parameters of RH, when administered intranasally as a colloidal dispersion, compared with oral and intranasal RH solutions in C57BL/6J mice. Ex vivo permeation studies showed that all formulations significantly enhanced RH permeation compared to the pure RH solution (0.5 mg/mL, pH 5.6). Among them, F4 [(PEO-b-PCL1/Tw80/HPβCD)/RH 10:5] was selected for further investigation. Pharmacokinetic analysis showed that F4 significantly enhanced both systemic and brain exposure of RH, achieving higher serum AUC and Cmax values, despite a 3-fold lower administered dose compared to the oral dose. It showed high systemic (Frel(Serum) = 1815%) and brain (Frel(Brain) = 363%) relative bioavailability compared with oral administration, underscoring its potential as an intranasal delivery system for efficient CNS targeting.

Nasal administration has emerged as an effective alternative for drug delivery to central nervous system (CNS), particularly in neurodegenerative diseases. Ropinirole hydrochloride (RH) is used as a monotherapy or as an adjunctive combination with levodopa for the management of Parkinson's disease. However, RH undergoes extensive first-pass metabolism, thereby limiting the amount of drug reaching the CNS. The purpose of the present study was the determination of the pharmacokinetic parameters of RH when administered intranasally as colloidal dispersion [(P407/Tw80/HPβCD)/RH 10:5] and as a powder [(P407/Tw80/HPβCD)/RH 10:5 blended with mannitol/lecithin microparticles (25:75)] for brain targeting. In particular, the pharmacokinetic study was carried out in comparison with oral (per os) and IN administration of pure RH solution in C57BL/6J mice. The brain and serum distribution pharmacokinetics of the drug were studied applying the sparse sampling non-compartmental analysis (NCA). The pharmacokinetic profiles after intranasal and per os administration revealed the efficiency of intranasal administration in rapidly and effectively delivering RH, both to the CNS and bloodstream. The pre-eminence of the nasal formulations is witnessed by higher serum AUC and Cmax values after intranasal administration of formulations compared to the per os administration of RH solution. Notably, the intranasal administration of the RH powder resulted in the highest systemic bioavailability (Frel(Serum) = 1497 %) and brain exposure (Frel(Brain) = 541 %), suggesting a promising role for nasal delivery in targeting the CNS.

ObjectiveDopaminergic medications are commonly prescribed for Parkinson's disease (PD), restless legs syndrome, pituitary and psychotic disorders. Accumulating evidence indicates that dopaminergic treatment triggers impulsive-compulsive behaviors (ICBs), yet systematic synthesis of clinical evidence remains limited.MethodThis scoping review summarizes original research directly clinically relevant to ICBs under dopaminergic treatment, selected through systematic searches of MEDLINE PubMed, Web of Science, Embase and PsycInfo.ResultsOf 349 included studies, most focused on PD, with limited evidence from other populations. Reported ICB prevalences ranged between 15 and 35%. ICBs were associated with impaired daily functioning, depression, anxiety and significant family and financial burden. Younger age, male sex and dopamine agonist treatment, especially with pramipexole and ropinirole, were ICB risk factors. Management mainly involved tapering or discontinuing dopamine agonist treatment.ConclusionICBs in PD patients are well characterized, but under-recognition in health care and limited treatment strategies persist. Iatrogenic ICBs in other patient populations remain poorly studied.