Computational investigation in inhibitory effects of amantadine on classical swine fever virus p7 ion channel activity.

Classical swine fever virus (CSFV) p7 viroporin plays crucial roles in cellular ion balance and permeabilization. The antiviral drug amantadine effectively inhibits viral replication by blocking the activity of CSFV p7 viroporin. However, little information is available for the binding mode of amantadine with CSFV p7 viroporin, due to the lack of a known polymer structure for CSFV p7. In this study, we employed AlphaFold2 to predict CSFV p7 structures. Subsequently, we conducted a docking study to investigate the binding sites of amantadine to CSFV p7. Computational analysis showed that CSFV p7 forms a pore channel in a hexameric structure. Furthermore, molecular dynamics (MD) simulations and mutant analyses further suggest that CSFV p7 likely exists as a hexamer. Docking studies and MD simulations showed that amantadine interacts with the hydrophibic regions of tetramer and pentamer, as well as with the hydrophobic pore channel of the hexamer. Considering the potential hexameric assembly of CSFV p7, along with docking results, MD simulations, and the characteristics of the gated ion channels, we propose a model of CSFV p7 ion channel based on its hexameric configuration. In this model, residues E21, Y25, and R34 are suggested to selectively recruit and dehydrate ions, while residues L28 and L31 likely act as hydrophobic constrictors, thereby restricting the free movement of water. The binding of amantadine to residues I20, E21, V24 and Y25 effectively blocks ion transport. However, this proposed molecular model requires experimental validation. Our findings give a structural insight into the models of CSFV p7 as an ion channel and provide a molecular explanation for the inhibition effects of amantadine on CSFV p7-mediated ion channel conductance.

Informing future randomized controlled trials of amantadine hydrochloride in neurocritical care and post-neurocritical care stroke patients through a retrospective study.

BACKGROUND: Amantadine hydrochloride has been increasingly prescribed as a neurostimulant for neurocritical care stroke patients to promote wakefulness during inpatient recovery. However, a lack of guidelines makes it difficult to decide who may benefit from this pharmacotherapy and when amantadine should be initiated during the hospital stay. This study aims to determine some factors that may be associated with favorable response to amantadine to inform future randomized controlled trials of amantadine in critical care or post-critical care stroke patients. METHODS: Retrospective chart review for this study included neurocritical care and post-neurocritical care patients with acute ischemic or hemorrhagic stroke who were started on amantadine (N = 34) in the years 2016-2019. Patients were labeled as either responders or nonresponders of amantadine within 9 days of initiation using novel amantadine scoring criteria utilized and published in Neurocritical Care in the year 2021, which included spontaneous wakefulness and Glasgow Coma Scale (GCS). Amantadine response status and predictive variables were analyzed using nonparametric tests and adjusted multivariable regression models. RESULTS: There were large but nonsignificant variations in the median total milligrams of amantadine received in the first 9 days (IQR = 700-1,450 mg, p = 0.727). GCS on the day before amantadine initiation was significantly higher for responders (median = 12, IQR = 9-14) than nonresponders (median = 9, IQR = 8-10, p = 0.009). Favorable responder status was significantly associated with initiation in the critical care unit versus the step-down unit or the general medical/surgical floor [𝛃=1.02, 95% CI (0.10, 1.93), p = 0.031], but there was no significant associations with hospital day number started [𝛃=-0.003, 95% CI (-0.02, 0.02), p = 0.772]. CONCLUSIONS: Future randomized controlled trials of amantadine in hospitalized stroke patients should possibly consider examining dose-dependent relationships to establish stroke-specific dosing guidelines, minimum GCS threshold for which amantadine is efficacious, and the impact of patients' determined level of acuity on clinical outcomes instead of solely examining the impact of earlier amantadine initiation by hospital day number. Future research with larger sample sizes is needed to further examine these relationships and inform future clinical trials.

N-methyl-d-aspartate (NMDA) receptor antagonists for treatment of catatonia in adults: Narrative review.

OBJECTIVE: While the majority of patients with catatonia fully respond to benzodiazepines or ECT, some have a partial or no response. Benzodiazepines may be contraindicated such as when delirium co-exists. This review discusses the utility of NMDA receptor antagonists as alternatives to benzodiazepines in the treatment of catatonia in adults. METHODS: A PubMed search adhering to PRISMA guidelines was conducted for articles on NMDA receptor antagonists in catatonia treatment. RESULTS: Thirty-seven articles, including case reports and case series were identified. Amantadine (27 cases in 13 articles) and memantine (20 cases in 14 articles) were the most commonly reported agents. Amantadine, typically used as monotherapy or adjunctive therapy with benzodiazepines, showed quick responses. Memantine, used alone or with lorazepam, demonstrated rapid responses. A small number of cases (5 cases in 4 articles) reported successful use of ketamine and esketamine, highlighting their potential role in catatonia treatment. CONCLUSION: Despite limitations, NMDA receptor antagonists may be viable options when the patient is partially or not responsive to benzodiazepine, ECT is not available or may not be well tolerated, there is a concern for co-morbid delirium where benzodiazepines may be contraindicated. Further research is needed.

Development of Highly Sensitive Immunochromatography Using Time-Resolved Fluorescence Microspheres for Amantadine Detection.

Amantadine (AMA), commonly used to treat viral infections in livestock and poultry, has been banned owing to its potential hazards to human well-being. To detect unauthorized AMA usage in livestock, we developed a polyclonal antibody with a high affinity for the specific recognition of AMA through a rational design based on a structure similar to AMA and revealed the availability of the hapten design by computational chemistry analysis. Using this antibody, we established a highly responsive time-resolved fluorescence immunochromatographic assay (TRFICA). The visual detection limit of the assay is 0.6 µg/kg, and the quantitative detection limit is 0.05 µg/kg. The TRFICA also showed good recovery rates ranging from 94.5 to 109.9%, with variability coefficients not exceeding 10%. The outcomes of undisclosed sample examinations aligned with those of HPLC-MS/MS analyses, indicating that this approach can function as an ideal screening and monitoring tool for detecting illegal AMA in chicken muscle.

Precision Dopaminergic Treatment in a Cohort of Parkinson's Disease Patients Carrying Autosomal Recessive Gene Variants: Clinical Cohort Data and a Mini Review.

INTRODUCTION: Parkinson's disease (PD) patients harboring recessive gene variants exhibit a distinct clinical phenotype with an early disease onset and relatively mild symptoms. Data concerning individualized therapy for autosomal recessive PD forms are still scarce. METHODS: Demographic and treatment data of a cohort of PD carriers of recessive genes (nine homozygous or compound heterozygous PRKN carriers, four heterozygous PRKN carriers, and three biallelic PINK1 carriers) were evaluated. RESULTS: The average levodopa equivalent daily dose (LEDD) was 806.8 ± 453.5 (range 152-1810) in PRKN carriers and 765 ± 96.6 (range 660-850) in PINK1 carriers. The majority responded to low/moderate doses of levodopa. The response to dopamine agonists (DAs) was often favorable both as initial and longitudinal therapy. In total, 8/13 PRKN and 1/3 PINK1 carriers were treated with amantadine successfully, and this also applied to patients who could not tolerate levodopa or DAs. CONCLUSIONS: In the era of personalized treatment, the therapeutic approach in recessive PD gene carriers might differ as compared to idiopathic PD. Lower LEDD doses were efficient even in patients with a very long disease duration, while a few patients were doing well without any levodopa treatment decades after disease initiation. DAs or amantadine could be used as a first and main line treatment regimen if well tolerated. Literature data on therapeutic strategies in carriers of pathogenic mutations in recessive PD genes, including device-aided treatments, will be further discussed.

Untargeted metabolomics reveals the mechanism of amantadine toxicity on Laminaria japonica.

The antiviral agent amantadine is frequently detected in seawater and marine organisms. Because of increasing concentrations, amantadine has become a contaminant of emerging concern. This compound has toxic effects on the brown algae Laminaria japonica. The effects of amantadine on the biological processes of L. japonica and the corresponding toxic mechanisms remain unclear. In this study, amantadine toxicity on L. japonica was investigated using histopathological and physiological characteristics combined with metabolomics analysis. Changes in metabolites were determined by untargeted metabolomics after exposure to 107 ng/L amantadine for 72 h. The catalase activity in the exposure group slightly increased, whereas the superoxide dismutase activity greatly decreased. An increase in the malondialdehyde concentration was observed after amantadine exposure, which suggested that lipid peroxidation and cell damage occurred. Metabolomics analysis showed that there were 406 differentially expressed metabolites after amantadine exposure. These were mainly phospholipids, amino acids, purines, and their derivatives. Inhibition of the glycerophospholipid metabolism affected the lipid bilayer and cell structure, which was aligned with changes in histological observation. Changes in amino acids led to perturbation of protein synthesis and induced oxidative stress through interference with glutathione metabolism and tyrosine metabolism. Amantadine also interfered with energy metabolism in L. japonica by disturbing the tricarboxylic acid cycle and purine metabolism. The results of this study provide new insights into the mechanism of amantadine toxicity on L. japonica.

NMDA antagonist agents for the treatment of symptoms in autism spectrum disorder: a systematic review and meta-analysis.

Aims: This systematic review and meta-analysis aimed to assess the efficacy of NMDA antagonists in ASD (Autism Spectrum Disorder) on the core (communication and social interaction, repetitive behavior) and associated symptoms (irritability) of ASD, as well as their safety. Methods: PubMed, CENTRAL, CINHAL, EMBASE, and PsycINFO databases were searched until November 2023. Two authors independently selected the studies and extracted data. Randomized controlled trials assessing the efficacy of NMDA receptor antagonists in participants with ASD aged <18 years were included. The quality of the studies was assessed using the Risk of Bias-2 tool. A random-effect meta-analysis model was used to calculate standardized mean differences (SMD) or odds ratios (OR) using meta package in R. Results: This systematic review included ten studies (588 participants). Most studies did not report scales assessing core symptoms of ASD. Meta-analysis of efficacy on ASD core symptoms included three studies (248 participants). NMDA antagonists were not superior to placebo [SMD = 0.29; CI 95% (-1,94; 1.35); I2 = 0%]. NMDA antagonists was not superior to placebo concerning response (four studies, 189 participants) [OR = 2.4; CI 95% (0.69; 8.38); I2 = 35%]. Meta-analysis of efficacy on irritability included three studies (186 participants); NMDA antagonists were not superior to placebo [MD irritability = -1.94; CI 95% (-4.66; 0.77); I2 = 0%]. Compared with placebo, significantly more participants in the NMDA antagonist group reported at least one adverse event (five studies, 310 participants) [OR = 2.04; CI 95% (1.17; 3.57); I2 = 0%]. Conclusion: Current evidence does not support the effectiveness of NMDA antagonists in the treatment of ASD symptoms or irritability. Further research is needed due to the limited and low quality data available. Systematic Review Registration: PROSPERO CRD42018110399.

Evaluation of the Therapeutic Potential of Amantadine in a Vincristine-Induced Peripheral Neuropathy Model in Rats.

This study aimed to evaluate the therapeutic potential of amantadine in a vincristine-induced peripheral neuropathy model in rats. Forty-eight male Wistar rats were used. The treated groups received oral amantadine at doses of 2, 5, 12, 25 and 50 mg/kg, with daily applications for 14 days. The mechanical paw withdrawal threshold was measured using a digital analgesimeter. Immunohistochemical analysis of IL-6, TNFα, MIP1α, IL-10, CX3CR1, CXCR4, SOD, CAT and GPx, and enzymatic activity analysis of CAT, SOD and GPx were performed, in addition to quantitative PCR of Grp78, Chop, Ho1, Perk, Bax, Bcl-xL, Casp 3, Casp 9, IL-6, IL-10, IL-18 and IL-1ß. The results showed an increase in nociceptive thresholds in animals that received 25 mg/kg and 50 mg/kg amantadine. Immunohistochemistry showed a decrease in the immunostaining of IL-6, TNFα, MIP1α and CX3CR1, and an increase in IL-10. CAT and SOD showed an increase in both immunochemistry and enzymatic analysis. qPCR revealed a reduced expression of genes related to endoplasmic reticulum stress and regulation in the expression of immunological and apoptotic markers. Amantadine demonstrated antinociceptive, anti-inflammatory and antioxidant effects in the vincristine-induced peripheral neuropathy model in rats, suggesting that amantadine may be considered an alternative approach for the treatment of vincristine-induced peripheral neuropathic pain.

Amantadine for Traumatic Brain Injury-Supporting Evidence and Mode of Action.

Traumatic brain injury (TBI) is an important global clinical issue, requiring not only prevention but also effective treatment. Following TBI, diverse parallel and intertwined pathological mechanisms affecting biochemical, neurochemical, and inflammatory pathways can have a severe impact on the patient's quality of life. The current review summarizes the evidence for the utility of amantadine in TBI in connection to its mechanism of action. Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients. Indeed, the use of amantadine in TBI has been encouraged by several clinical practice guidelines/recommendations. Amantadine is also available as an infusion, which may be of particular benefit in unconscious patients with TBI due to immediate delivery to the central nervous system and the possibility of precise dosing. In other situations, orally administered amantadine may be used. There are several questions that remain to be addressed: can amantadine be effective in disorders of consciousness requiring long-term treatment and in combination with drugs approved for the treatment of TBI? Do the observed beneficial effects of amantadine extend to disorders of consciousness due to factors other than TBI? Well-controlled clinical studies are warranted to ultimately confirm its utility in the TBI and provide answers to these questions.

Development and validation of rapid screening of 192 veterinary drug residues in aquatic products using HPLC-HRMS coupled with QuEChERS.

The presence of veterinary drug residues in aquatic products represents a significant challenge to food safety. The current detection methods, limited in both scope and sensitivity, underscore the urgent need for more advanced techniques. This research introduces a swift and potent screening technique using high-performance liquid chromatography-high-resolution mass spectrometry (HPLC-HRMS) and a refined QuEChERS protocol, allowing simultaneous qualitative and semi-quantitative analysis of 192 residues. A comprehensive database, employing full scan mode and data-dependent secondary mass spectroscopy, enhances screening accuracy. The method involves efficient extraction using 90% acetonitrile, dehydration with Na2SO4, and acetic acid, followed by cleanup using dispersive solid-phase extract sorbent primary secondary amine. It is suitable for samples with varying fat content, offering detection limits ranging from 0.5 to 10 µg/kg, high recovery rates (60-120%), and low relative standard deviations (<20%). Practical application has validated its effectiveness for multi-residue screening, marking a significant advancement in food safety evaluation.

Amantadine as an Aid to Extubation in Severe Acute Brain Injury: A Case Series.

For a subset of patients with severe acute brain injury (SABI) undergoing invasive mechanical ventilation, the primary barrier to successful extubation is depressed mental status. Amantadine is a neurostimulant that has been demonstrated to increase arousal and improve functional outcomes in patients with SABI. In this case series, we describe 5 patients with SABI and invasive mechanical ventilation who received amantadine as an agent to improve mental status to allow extubation. The primary barrier to extubation for all patients was depressed mental status. Median age was 77 (range 32 to 82). Primary diagnoses were ischemic stroke (n = 1), subdural hemorrhage (n = 2), intracerebral hemorrhage (n = 1), and traumatic brain injury (n = 1). Median Glasgow Coma Score was 7T prior to administration of amantadine and 10T on the day after amantadine was initiated, with improvements in eye-opening and motor response. Four patients displayed improvement in arousal and attention and were successfully extubated 1 to 4 days after initiation of amantadine (median 2 days). The fifth patient only displayed marginal improvement in mental status after starting amantadine, but was ultimately able to be extubated 7 days later. Amantadine may improve the likelihood of or reduce the time to successful extubation in patients with SABI.

Central Nervous System Adverse Reactions to Amantadine Intoxication: A Case Report and Analysis of JADER.

BACKGROUND/AIM: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. PATIENTS AND METHODS: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. RESULTS: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. CONCLUSION: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.

Ultrasensitive SERS aptasensor using Au@Ag bimetallic nanorod SERS tags for the selective detection of amantadine in foods.

Herein, a novel surface enhanced Raman spectroscopy (SERS) aptasensor was developed for amantadine (AMD) detection, based on magnetite nanoparticles coated with polyethylenimine, silver nanoclusters and aptamers (Fe3O4@PEI@AgNC-apt) as the capture probe and complementary DNA-modified gold nanorods (AuNRs@4-MPBA@Ag-c-DNA containing 4-mercaptophenylboric acid molecules) as the reporter probe. In the presence of AMD, the AMD and the reporter probe competed for the aptamer on the surface of the capture probe, resulting in the reporter probe detaching from the capture probe leading to a decrease in intensity of the SERS signal at 1067 cm-1 for 4-MPBA. Under optimal conditions, a good linear relationship was established between the SERS intensity at 1067 cm-1 and the logarithm of the AMD concentration over the range 10-6-102 mg L-1, with a LOD of 0.50 × 10-6 mg L-1. The AMD levels in spiked samples were evaluated using the SERS aptasensor, with good recoveries ranging from 90.57% to 113.49% being obtained.

Amantadine interactions with phase separated lipid membranes.

Amantadine, a small amphilphic organic compound that consists of an adamantane backbone and an amino group, was first recognized as an antiviral in 1963 and received approval for prophylaxis against the type A influenza virus in 1976. Since then, it has also been used to treat Parkinson's disease-related dyskinesia and is being considered as a treatment for corona viruses. Since amantadine usually targets membrane-bound proteins, its interactions with the membrane are also thought to be important. Biological membranes are now widely understood to be laterally heterogeneous and certain proteins are known to preferentially co-localize within specific lipid domains. Does amantadine, therefore, preferentially localize in certain lipid composition domains? To address this question, we studied amantadine's interactions with phase separating membranes composed of cholesterol, DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoyl-glycero-3-phosphocholine), and DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine), as well as single-phase DPhPC (1,2-diphytanoyl-sn-glycero-3-phos-phocholine) membranes. From Langmuir trough and differential scanning calorimetry (DSC) measurements, we determined, respectively, that amantadine preferentially binds to disordered lipids, such as POPC, and lowers the phase transition temperature of POPC/DSPC/cholesterol mixtures, implying that amantadine increases membrane disorder. Further, using droplet interface bilayers (DIBs), we observed that amantadine disrupts DPhPC membranes, consistent with its disordering properties. Finally, we carried out molecular dynamics (MD) simulations on POPC/DSPC/cholesterol membranes with varying amounts of amantadine. Consistent with experiment, MD simulations showed that amantadine prefers to associate with disordered POPC-rich domains, domain boundaries, and lipid glycerol backbones. Since different proteins co-localize with different lipid domains, our results have possible implications as to which classes of proteins may be better targets for amantadine.

Neuropathic pain in cats: Mechanisms and multimodal management.

PRACTICAL RELEVANCE: Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care.Clinical approach:Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways.Aim:This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions.Evidence base:The review draws on current literature, where available, along with the author's extensive experience and research.

The effect of anticholinergic drugs on cognition of patients with Parkinson's disease: a cohort study from the Egyptian population.

BACKGROUND: Cognitive dysfunction is a non-motor manifestation of Parkinson's disease (PD). We aimed to determine the frequency and patterns of cognitive dysfunction in treated patients with PD and their predictors. RESEARCH DESIGN AND METHODS: This study included 80 patients (male = 48; female = 32) and 30 healthy individuals. They underwent neuropsychiatric evaluations. Measurements included Beck's depression inventory - II (BDI-II), mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA). RESULTS: Patients had mean age of 55.56 ± 9.06 yrs, duration of PD of 4.86 ± 2.71 yrs and Hoehn and Yahr Scoring of 2.19 ± 0.89. They were on levodopa/carbidopa therapy and adjuvant therapy with benztropine mesylate, an anticholinergic drug, (n = 51) or amantadine sulfate, a dopaminergic drug, (n = 29). Sixteen (20%) had moderate depressive symptoms. Mild and moderate cognitive impairments were reported in 38.8% and 28.8% (by MMSE) and 46.3% and 31.3% (by MoCA). Patients had lower global cognitive scoring (p = 0.0001) and scorings of different cognitive functions (naming, attention, language, abstraction, memory and orientation) than controls. Patients treated with benztropine had lower cognition than with amantadine. Correlation analyses showed that lower cognition was only associated with chronic PD and its treatment (p = 0.0001). CONCLUSIONS: Cognitive dysfunction is common with PD (77.5%) particularly with anticholinergic drugs. De-prescription of anticholinergics is recommended for patients with PD.

Amantadine use in the French prospective NS-Park cohort.

OBJECTIVE: To assess amantadine use and associated factors in the patients with Parkinson's disease (PD). BACKGROUND: Immediate-release amantadine is approved for the treatment of PD and is largely used in clinical practice to treat "levodopa-induced dyskinesia (LIDs). Its use varies according to countries and PD stages. The prospective NS-Park cohort collects features of PD patients followed by 26 French PD Expert Centres. METHODS: Variables used for the analyses included demographics, motor and non-motor PD symptoms and motor complications [motor fluctuations (MFs), LIDs)], antiparkinsonian pharmacological classes and levodopa equivalent daily dose (LEDD). We evaluated: (i) prevalence of amantadine use and compared clinical features of amantadine users vs. non-users (cross-sectional analysis); (ii) factors associated with amantadine initiation (longitudinal analysis); (iii) amantadine effect on LIDs, MFs, apathy, impulse control disorders and freezing of gait (Fog) (longitudinal analysis). RESULTS: Amantadine use prevalence was 12.6% (1,585/12,542, median dose = 200 mg). Amantadine users were significantly younger, with longer and more severe PD symptoms, greater LEDD and more frequent use of device-aided/surgical treatment. Factors independently associated with amantadine initiation were younger age, longer PD duration, more frequent LIDs, MFs and FoG, higher LEDD and better cognitive function. 9 of the 658 patients on amantadine had stopped it at the following visit, after 12-18 months (1.3%). New users of amantadine presented a higher improvement in LIDs and MF compared to amantadine never users. CONCLUSIONS: About 12% of PD patients within the French NS-Park cohort used amantadine, mostly those with younger age and more severe PD. Amantadine initiation was associated with a subsequent reduction in LIDs and MFs.

Extended-release amantadine for OFF-related dystonia in Parkinson's disease.

INTRODUCTION: Dystonia is a painful OFF-related complication in Parkinson's disease (PD) with limited treatment options. METHODS: Post-hoc analysis using pooled data from two extended-release amantadine pivotal trials and follow-on open-label extension. Dystonia was assessed using the Unified Dyskinesia Rating Scale (UDysRS) Part 2 and the Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) item 4.6. RESULTS: Of 196 participants, 119 (60.7%) reported OFF-related dystonia at baseline per UDysRS. Twelve-week treatment with extended-release amantadine improved OFF dystonia (treatment differences vs placebo: UDysRS Part 2, -1.0 [-1.9,-0.1]; p = 0.03 and MDS-UPDRS Item 4.6, -0.3 [-0.6,-0.05]; p = 0.02). There was no correlation between changes in OFF time and changes in OFF dystonia. Double-blind improvements in OFF dystonia were sustained throughout the 2-year follow-up. CONCLUSIONS: Extended-release amantadine yielded a sustained reduction in OFF-related dystonia in PD patients that was independent from a reduction in OFF time. A randomized controlled trial is warranted to confirm these findings.

Amantadine for functional improvement in patients with traumatic brain injury: A systematic review with meta-analysis and trial sequential analysis.

Introduction: TBIs contribute in over one-third of injury-related deaths with mortality rates as high as 50% in trauma centers serving the most severe TBI. The effect of TBI on mortality is about 10% across all ages. Amantadine hydrochloride is one of the most commonly prescribed medications for patients undergoing inpatient neurorehabilitation who have disorders of consciousness.6 It is a dopamine (DA) receptor agonist and a N-Methyl-D-aspartate (NMDA) receptor antagonist via dopamine release and dopamine reuptake inhibition. The current study will synthesize the current available evidence and show the effect of Amantadine in functional improvement after TBI. Research question: Does Amantadine have an effect on functional improvement of TBI patients? Material and methods: This systematic review included all randomized placebo-controlled trials that compare the use of Amantadine versus placebo for functional improvement of patients after TBI. Outcome measures included DRS, GCS and/or GOS scores. Results: Three studies with a total of 281 patients were included in the quantitative analyses. GRADE assessments show that there was a high certainty of evidence for functional improvement in terms of DRS scores. Discussion and conclusion: Evidence of this review show that the use of Amantadine may have a beneficial effect on functional outcome in moderate to severe traumatic brain injuries among adult patients. Given the still-limited body of knowledge, more relevant studies must be made exploring the impact of Amantadine therapies on promoting functional recovery within the brain injury rehabilitation care continuum, with the goals of achieving larger sample sizes and establishing the early- or later-treatment beneficial effects.