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.

Amantadine in unvaccinated patients with early, mild to moderate COVID-19: A randomized, placebo-controlled, double-blind trial.

BACKGROUND AND PURPOSE: Adamantanes were listed as an interesting option as an early intervention against COVID-19. We aimed to evaluate the effectiveness of amantadine in preventing the progression of COVID-19 and its neurological sequelae. METHODS: Unvaccinated patients with confirmed SARS-CoV-2 infection within 5 days were enrolled. Subjects were randomized (50:50) to amantadine (AMD; 100 mg twice daily) or placebo (PLB) for 14 days. The Ordinal Scale for Clinical Improvement of the World Health Organization (OSCI-WHO) was the primary measure. Secondary endpoints included assessment for fatigue; depression, disorders of smell and taste, and sleepiness on Days 1 and 15. RESULTS: We enrolled 99 patients (49 AMD and 50 PLB). Disease progression (OSCI-WHO = 4) was observed in 6% (AMD) and 8% (PLB) patients (p > 0.05) with further deterioration (OSCI-WHO〉4) in 0% (AMD) and 8% (PLB) patients (p > 0.05). Complete recovery on Day 15 was 60% higher in the AMD compared with the PLB group (p = 0.025). There was improvement in taste (AMD: p = 0.003; PLB: p = 0.0001) and smell (AMD: p = 0.005; PLB: p = 0.0004) but not in fatigue in both groups. Improvement was observed in the AMD (p = 0.010) but not in the PLB group (p = 0.058) when assessing depression as well as sleepiness (AMD: p = 0.0002; PLB: p = 0.341). There was one death in the PLB group (2.0%) and none in the AMD group (p > 0.05) until Day 210. Overall, the drug was well tolerated. CONCLUSION: The central effects of amantadine on the nervous system with reduction of sleepiness and depression might have had a supportive effect on faster recovery in early COVID-19 patients.

Amantadine and Rimantadine Inhibit Hepatitis A Virus Replication through the Induction of Autophagy.

Hepatitis A virus (HAV) infection is a major cause of acute viral hepatitis worldwide. Furthermore, HAV causes acute liver failure or acute-on-chronic liver failure. However, no potent anti-HAV drugs are currently available in the clinical situations. There have been some reports that amantadine, a broad-spectrum antiviral, suppresses HAV replication in vitro. Therefore, we examined the effects of amantadine and rimantadine, derivates of adamantane, on HAV replication, and investigated the mechanisms of these drugs. In the present study, we evaluated the effects of amantadine and rimantadine on HAV HM175 genotype IB subgenomic replicon replication and HAV HA11-1299 genotype IIIA replication in cell culture infection systems. Amantadine and rimantadine significantly inhibited HAV replication at the post-entry stage in Huh7 cells. HAV infection inhibited autophagy by suppressing the autophagy marker light chain 3 and reducing number of lysosomes. Proteomic analysis on HAV-infected Huh7 cells treated by amantadine and rimantadine revealed the changes of the expression levels in 42 of 373 immune response-related proteins. Amantadine and rimantadine inhibited HAV replication, partially through the enhancement of autophagy. Taken together, our results suggest a novel mechanism by which HAV replicates along with the inhibition of autophagy and that amantadine and rimantadine inhibit HAV replication by enhancing autophagy. IMPORTANCE Amantadine, a nonspecific antiviral medication, also effectively inhibits HAV replication. Autophagy is an important cellular mechanism in several virus-host cell interactions. The results of this study provide evidence indicating that autophagy is involved in HAV replication and plays a role in the HAV life cycle. In addition, amantadine and its derivative rimantadine suppress HAV replication partly by enhancing autophagy at the post-entry phase of HAV infection in human hepatocytes. Amantadine may be useful for the control of acute HAV infection by inhibiting cellular autophagy pathways during HAV infection processes.

Amantadine for NeuroenhaNcement in acutE patients Study - a protocol for a prospective pilot proof of concept phase IIb study in intensive and intermediate care unit patients (ANNES).

BACKGROUND: Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid hemorrhage. Amantadine acts as a nicotinic receptor antagonist, dopamine receptor agonist and non-competitive N-Methyl-D-aspartate receptor antagonist. Amantadine is a long-known drug, originally approved for treatment of influenza A and Parkinson`s Disease. It has been proven effective in improving vigilance after traumatic brain injury. The underlying mechanisms remain largely unknown, albeit anti-glutamatergic and dopaminergic effects might be most relevant. With limited evidence of amantadine efficacy in non-traumatic pathologies, the aim of our study is to assess the effects of amantadine for neuroenhancement in non-traumatic neurointensive patients with persisting coma. METHODS: An investigator-initiated, monocenter, phase IIb proof of concept open-label pilot study will be carried out. Based on the Simon design, 43 adult (neuro)intensive care patients who meet the clinical criteria of persisting coma not otherwise explained and < 8 points on the Glasgow Coma Scale (GCS) will be recruited. Amantadine will be administered intravenously for five days at a dosage of 100 mg bid. The primary endpoint is an improvement of at least 3 points on the GCS. If participants present as non-responders (increase < 3 points or decrease on the GCS) within the first 48 h, the dosage will be doubled from day three to five. Secondary objectives aim to demonstrate that amantadine improves vigilance via alternative scales. Furthermore, the incidence of adverse events will be investigated and electroencephalography (EEG) will be recorded at baseline and end of treatment. DISCUSSION: The results of our study will help to systematically assess the clinical utility of amantadine for treatment of persisting coma in non-traumatic brain injury. We expect that, in the face of only moderate treatment risk, a relevant number of patients will benefit from amantadine medication by improved vigilance (GCS increase of at least 3 points) finally leading to a better rehabilitation potential and improved functional neurological outcome. Further, the EEG data will allow evaluation of brain network states in relation to vigilance and potentially outcome prediction in this study cohort. TRIAL REGISTRATION: NCT05479032.

New Adamantane-Containing Edaravone Conjugates as Potential Neuroprotective Agents for ALS Treatments.

Currently, there are no effective drugs for the treatment of amyotrophic lateral sclerosis (ALS). Only two drugs-edaravone and riluzole-have been approved, but they have very limited efficacy. The aim of this work was to modify the structural core of the Edaravone-phenylpyrazolone moiety and combine it with aminoadamantane pharmacophore in order to expand the spectrum of its action to a number of processes involved in the pathogenesis of ALS. New conjugates of edaravone derivatives with 1-aminoadamantanes combined with alkylene or hydroxypropylene spacers were synthesized, and their biological activity was investigated. Compounds were found that could inhibit lipid peroxidation and calcium-related mitochondrial permeability, block fast sodium currents of CNS neurons, and reduce aggregation of the mutated form of the FUS-protein typical to ALS. So, the proposed modification of the edaravone molecule has allowed the obtaining of new original structures that combine some prospective therapeutic mechanisms against key chains of the pathogenesis of ALS. The identified lead compounds can be used for further optimization and development of new promising drugs on this basis for the treatment of ALS.

Abuse of amantadine in poultry may be associated with higher fatality rate of H5N1 infections in humans.

Amantadine, an antiviral drug, has been widely used in human anti-influenza treatments. However, several highly pathogenic avian influenza viruses show amantadine-resistance mutations in the viral matrix 2 (M2) protein. Here we analyzed global H5N1 sequencing data and calculate possible correlations between frequencies of key mutations in M2 and the mortality rates. We found that the frequency of L26I/V27A mutation in M2 (isolated from both human and avian hosts) is linearly correlated with the mortality rates of human H5N1 infections. The significant correlation between M2 mutations in avians and the mortality rates in humans suggests that the pre-existence of L26I/V27A in birds may determine patient fatalities after transinfections from avian to human hosts. 100% prevalence of L26I/V27A mutation increased the mortality rates from 51% (95% confidence interval [CI] 37%-65%) to 89% (95% CI 88%-90%). Mutations involving Leu26 or Val27 were identified to be the major mutations emerging from drug selection pressure. Thus the emergence of the super H5N1 virus with a fatality of over 90% may be attributed to the abuse of amantadine in poultry, especially in some southeast Asian countries. A more stringent control to antiviral veterinary drugs is imperative.

Amantadine treatment is associated with improved consciousness in patients with non-traumatic brain injury.

OBJECTIVE: This study determined the effect of amantadine treatment on consciousness in patients with non-traumatic brain injury. METHODS: We pooled individual patient data of five single-centre observational studies to determine the effect of amantadine treatment among patients with ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, community-acquired bacterial meningitis and status epilepticus, admitted between January 2012 and December 2015 and ventilated ≥7 days. Patient selection and multivariable regression modelling were used to adjust for differences in intergroup comparison and for parameters associated with consciousness. Improvement of consciousness 5 days after treatment initiation was defined as primary outcome. Secondary outcomes included Glasgow Coma Scale (GCS) at day 5 and GCS at day 10, rate of ICU delirium, epileptic seizures and all-cause mortality at 90 days. RESULTS: Overall, 84 of 294 (28.6%) eligible patients received amantadine. Amantadine treatment was associated with improvement of consciousness at day 5 (amantadine: 86.9% vs control: 54.0%; absolute difference: 32.9 (20.0-44.2); adjusted OR (aOR): 5.71 (2.50-13.05), p<0.001). Secondary outcomes showed differences in GCS 5 days (9 (8-11) vs 6 (3-9), p<0.001) and GCS 10 days (10(8-11) vs 9(6-11),p=0.003) after treatment initiation. There were no significant differences regarding all-cause mortality (aOR: 0.89 (0.44-1.82), p=0.758) and ICU delirium (aOR: 1.39 (0.58-3.31), p=0.462). Rate of epileptic seizures after initiation of amantadine treatment was numerically higher in the amantadine group (amantadine: 10.7% vs control: 3.0%; absolute difference: 7.7 (0.3-16.4); aOR: 3.68 (0.86-15.71), p=0.079). CONCLUSIONS: Amantadine treatment is associated with improved consciousness among patients with different types of non-traumatic brain injury in this observational cohort analysis. Epileptic seizures should be considered as potential side effects and randomised controlled trials are needed to confirm these findings.

Outcome of Guillain-Barré syndrome following intravenous immunoglobulin compared to natural course.

BACKGROUND AND PURPOSE: Intravenous immunoglobulin (IVIg) is recommended in Guillain-Barré syndrome (GBS), but its efficacy may vary in different subtypes. We report the outcomes of patients with GBS following IVIg treatment compared to the natural course (NC). We also compare the effect of IVIg treatment in different subtypes of GBS. METHODS: From a cohort of 528 GBS subjects, we have extracted 189 patients who received IVIg and compared their outcomes with 199 age- and peak disability-matched patients who did not receive IVIg, plasmapheresis, or corticosteroid. Disability was assessed using the 0-6 Guillain-Barré Syndrome Disability Scale (GBSDS). Clinical and neurophysiological subtypes were recorded. The primary outcome was functional disability at 6 months, which was categorized as complete (GBSDS ≤ 1), partial (GBSDS 2-3), or poor (GBSDS > 3). The secondary outcomes were in-hospital death, duration of hospitalization, and mechanical ventilation. RESULTS: In-hospital death (2.6% vs. 2%, p = 0.74) and 3-month poor recovery (20.7% vs. 18%) were similar in the IVIg and NC groups. At 6 months, however, a lesser proportion of patients in the IVIg group had poor recovery (2.2% vs. 8.3%, p = 0.026). The outcomes of IVIg and NC were compared in 72 acute motor axonal neuropathy (AMAN) and 256 acute inflammatory demyelinating polyradiculoneuropathy (AIDP) patients. IVIg therapy did not alter the outcome in AMAN but resulted in a lesser proportion of poor recovery at 6 months in AIDP (0.8% vs. 6.6%, p = 0.03). CONCLUSIONS: IVIg is beneficial in AIDP variants of GBS but not in the AMAN subtype. A customized treatment may be cost-effective until a randomized controlled trial is conducted in AMAN.

Pharmacologic Therapies to Promote Recovery of Consciousness.

Pharmacologic interventions are commonly used to support rehabilitation efforts of patients with disorders of consciousness (DoC). The 2018 practice guidelines recommend amantadine in adults with traumatic DoC to promote functional recovery, though several other stimulants are used off-label in clinical practice and trials, such as methylphenidate, bromocriptine, levodopa, and zolpidem. Differences in the mechanisms of action, adverse effects, pharmacokinetics, and drug-drug interactions should be considered when selecting the best agent for each individual patient. Overall, pharmacologic stimulants may provide a safe and inexpensive pathway to increased functionality and participation in rehabilitation. This article provides a concise summary of scientific evidence supporting the use of pharmacologic therapies to stimulate recovery of consciousness in patients with DoC.

Amantadine therapy for Parkinson's Disease: In Vivo Confocal Microscopy corneal findings, case report and revision of literature.

BACKGROUND: To report a case of a patient showing bilateral corneal opacities after amantadine chronic treatment for Parkinson's Disease (PD) and corneal edema associated with intra-epithelial and -endothelial depositions. After amantadine discontinuation a complete clinical remission with only a partial ultrastructural corneal recovery was reported. CASE PRESENTATION: We describe a 78-year-old man with non-medical-responding bilateral corneal edema in treatment with systemic Amantadine for PD. In vivo confocal Microscopy (IVCM) analysis revealed hyperreflective particles at the epithelial level and expanded hyperreflective keratocyte and a disarrangement of stromal lamellae; endothelial cells showed hyperreflective intracellular inclusions in central and in peripheral areas with central polymegatism and pleomorphism. After 1 and 6 months the amantadine discontinuation, the absence of bilateral corneal edema and opacities were noted at the slit lamp examination, associated with the disappearance of epithelial and stromal abnormalities, but the persistence of endothelial hyperreflective deposits with a pleomorphism and polymegatism worsening at the IVCM exam. CONCLUSION: The evaluation of a patient's cornea 6 months after the discontinuation of systemic amantadine therapy showed a clinical complete remission, with a complete resolution of the bilateral corneal oedema. On the other hand, ultrastructurally, amantadine toxicity is a completely reversible phenomenon at the epithelial level; conversely IVCM showed persistent endothelial degradation.

Prescribing Patterns of Amantadine During Pediatric Inpatient Rehabilitation After Traumatic Brain Injury: A Multicentered Retrospective Review From the Pediatric Brain Injury Consortium.

OBJECTIVES: To describe dosing practices for amantadine hydrochloride and related adverse effects among children and young adults with traumatic brain injury (TBI) admitted to pediatric inpatient rehabilitation units. SETTING: Eight pediatric acute inpatient rehabilitation units located throughout the United States comprising the Pediatric Brain Injury Consortium. PARTICIPANTS: Two-hundred thirty-four children and young adults aged 2 months to 21 years with TBI. DESIGN: Retrospective data revie. MAIN OUTCOME MEASURES: Demographic variables associated with the use of amantadine, amantadine dose, and reported adverse effects. RESULTS: Forty-nine patients (21%) aged 0.9 to 20 years received amantadine during inpatient rehabilitation. Forty-five percent of patients admitted to inpatient rehabilitation with a disorder of consciousness (DoC) were treated with amantadine, while 14% of children admitted with higher levels of functioning received amantadine. Children with DoC who were not treated with amantadine were younger than those with DoC who received amantadine (median 3.0 vs 11.6 years, P = .008). Recorded doses of amantadine ranged from 0.7 to 13.5 mg/kg/d; the highest total daily dose was 400 mg/d. Adverse effects were reported in 8 patients (16%); nausea/abdominal discomfort and agitation were most common, each reported in 3 patients. The highest reported dose without an adverse effect was 10.1 mg/kg/d. CONCLUSION: During pediatric inpatient rehabilitation, amantadine was prescribed to children across a range of ages and injury severity and was most commonly prescribed to older children with DoC. Dosing varied widely, with weight-based dosing for younger/smaller children at both lower and higher doses than what had been previously reported. Prospective studies are needed to characterize the safety and tolerability of higher amantadine doses and optimize amantadine dosing parameters for children with TBI.

A descriptive analysis of pharmacological management of aggression and/or agitation in patients with traumatic brain injury in a Southwest Virginia inpatient population.

WHAT IS KNOWN AND OBJECTIVE: Traumatic brain injury (TBI) is a major cause of disability, and it has been associated with agitation and aggression. In a previous study, we reviewed the literature to identify evidence-based pharmacological agents for treatment of agitation in TBI. Based on the results of our previous study that summarizes the findings of several systematic reviews, the use of haloperidol and benzodiazepines is not supported by the available evidence while the use of amantadine, beta blockers, antiepileptics and methylphenidate is supported by the limited available evidence. In this study, we describe the psycho-pharmacological agents that were administered to patients with agitation and/or aggression in the context of TBI in inpatient facilities of a private, non-profit health care system in southwest Virginia. We will also compare the psycho-pharmacological agents ordered before and after psychiatric consultation. METHODS: Adult patients who were admitted to Carilion Clinic's inpatient facilities from March 30, 2013, to March 30, 2018, had a diagnosis of TBI, and received psychiatric consultation for agitation and/or aggression were enrolled in this study. A retrospective review of electronic medical records was conducted by researchers and data were collected on the following measures: ordered psycho-pharmacological agents, frequency, dosing and duration of orders, whether each administered psycho-pharmacological agent was started before or after psychiatric consultation, and psycho-pharmacological agents prescribed upon discharge. RESULTS AND DISCUSSION: About 68% of patients were started on benzodiazepines and/or typical antipsychotics and 23% of patients were subsequently discharged on these medication categories. Only 23% of patients were ordered to receive medications supported by the evidence such as amantadine, beta blockers or antiepileptics. The percentage of patient-days with an order to receive typical antipsychotics significantly decreased following psychiatric consultation (p = 0.0056), but the percentage of patient-days with an order to receive benzodiazepines significantly increased following psychiatric consultation (p = 0.0001). This finding remained statistically significant after excluding patients with active or unclear alcohol/benzodiazepine withdrawal (p < 0.0001). WHAT IS NEW AND CONCLUSION: This study demonstrates the widespread use of typical antipsychotics and benzodiazepines in the management of agitation in TBI and the importance of multidisciplinary collaboration, research and education of providers to improve patient care.

Amantadine, a promising therapeutic agent against viral encephalopathy and retinopathy.

Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is nervous necrosis virus (NNV), which mainly infects the early developmental stages of fish, limiting the effectiveness of vaccines. To counter this case, the anti-NNV potentials of nine drugs with broad-spectrum antiviral activity were explored using ribavirin as a positive drug. Toxicity of the selected drugs to SSN-1 cells and grouper was firstly evaluated to determine the safety concentrations. For screening in vitro, amantadine and oseltamivir phosphate can relieve the cytopathic effects and inhibit NNV replication with the 90% inhibitory concentrations (IC90 ) of 38.74 and 106.75 mg/L, respectively. Amantadine has a stronger anti-NNV activity than ribavirin at the with- and post-NNV infection stages, indicating that it is a potential therapeutic agent against VER by acting directly on NNV. Similarly, amantadine also has a strong anti-NNV activity in vivo with the IC90 of 27.91 mg/L at the 7 days post-infection, while that was 73.25 mg/L for ribavirin. Following exposure to amantadine (40 mg/L) and ribavirin (100 mg/L) for 7 days, the survival rates of NNV-infected grouper were increased to 44% and 39%, respectively. The maximum amantadine content (11.88 mg/Kg) in grouper brain was reached following exposure for 24 hr, and amantadine can be quickly excreted from fish, reducing the risk of drug residue. Results so far indicated that amantadine is a promising therapeutic agent against NNV in aquaculture, providing an effective strategy for VER control at the early developmental stages of fish.

Anticancer Activity of Amantadine and Evaluation of Its Interactions with Selected Cytostatics in Relation to Human Melanoma Cells.

Patients with Parkinson's disease are prone to a higher incidence of melanoma. Amantadine (an anti-Parkinson drug) possesses the antiproliferative potential that can be favorable when combined with other chemotherapeutics. Cisplatin (CDDP) and mitoxantrone (MTO) are drugs used in melanoma chemotherapy, but they have many side effects. (1) Clinical observations revealed a high incidence of malignant melanoma in patients with Parkinson's disease. Amantadine as an anti-Parkinson drug alleviates symptoms of Parkinson's disease and theoretically, it should have anti-melanoma properties. (2) To characterize the interaction profile for combinations of amantadine with CDDP and MTO in four human melanoma cell lines (A375, SK-MEL 28, FM55P and FM55M2), type I isobolographic analysis was used in the MTT test. (3) Amantadine produces the anti-proliferative effects in various melanoma cell lines. Flow cytometry analysis indicated that amantadine induced apoptosis and G1/S phase cell cycle arrest. Western blotting analysis showed that amantadine markedly decreased cyclin-D1 protein levels and increased p21 levels. Additionally, amantadine significantly increased the Bax/Bcl-2 ratio. The combined application of amantadine with CDDP at the fixed-ratio of 1:1 exerted an additive interaction in the four studied cell lines in the MTT test. In contrast, the combination of amantadine with MTO (ratio of 1:1) produced synergistic interaction in the FM55M2 cell line in the MTT (* p < 0.05). The combination of amantadine with MTO was also additive in the remaining tested cell lines (A375, FM55P and SK-MEL28) in the MTT test. (4) Amantadine combined with MTO exerted the most desirable synergistic interaction, as assessed isobolographically. Additionally, the exposure of melanoma cell lines to amantadine in combination with CDDP or MTO augmented the induction of apoptosis mediated by amantadine alone.

Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials.

The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.

Cortico-subcortical functional connectivity modifications in fatigued multiple sclerosis patients treated with fampridine and amantadine.

BACKGROUND AND PURPOSE: Fatigue in multiple sclerosis (MS) is common and disabling; medication efficacy is still not fully proven. The aim of this study was to investigate 4-week modifications of fatigue severity in 45 relapsing-remitting MS patients after different symptomatic treatments, and changes in concomitant resting state (RS) functional connectivity (FC). METHODS: Patients were randomly, blindly assigned to treatment with fampridine (n = 15), amantadine (n = 15) or placebo (n = 15), and underwent clinical assessment and 3-Tesla RS functional magnetic resonance imaging at baseline (t0) and after 4 weeks (w4) of treatment. Fifteen healthy controls (HCs) were also studied. Changes in modified fatigue impact scale (MFIS) score and network RS FC were assessed. RESULTS: In MS, abnormalities of network RS FC at t0 did not differ between treatment groups and correlated with fatigue severity. At w4, global scores and subscores on the MFIS decreased in all groups, with no time-by-treatment interaction. At w4, all patient groups had changes in RS FC in several networks, with significant time-by-treatment interactions in basal ganglia, sensorimotor and default-mode networks in fampridine-treated patients versus the other groups, and in frontoparietal network in amantadine-treated patients. In the fampridine group, RS FC changes correlated with concurrently decreased MFIS score (r range = -0.75 to 0.74, p range = 0.003-0.05). CONCLUSIONS: Fatigue improved in all MS groups, independently of treatment. Concomitant RS FC modifications were located in sensorimotor, inferior frontal and subcortical regions for fampridine- and amantadine-treated patients, and in associative sensory cortices for placebo-treated patients.

Dual Neurostimulant Therapy May Optimize Acute Neurorecovery for Severe Traumatic Brain Injuries.

BACKGROUND: Neurostimulants (NS) can be used to treat patients with a traumatic brain injury (TBI) with altered levels of consciousness. We sought to determine if amantadine alone (monotherapy) versus amantadine + methylphenidate (dual therapy) would correlate with better neurorecovery (NR) among acutely hospitalized patients with a severe TBI. METHODS: We performed a retrospective review of adult patients admitted to our level I trauma center from 2016-2019 with a severe TBI. NR was calculated by dividing the difference between admission and discharge Glasgow Coma Scale (GCS) scores by 12. Resulting ratios were used to divide the cohort into two groups: excellent NR (1) and non-excellent NR (<1). RESULTS: A total of 76 patients comprised the cohort; 19.7% (n = 15) had excellent NR. The excellent NR group had a larger proportion of patients receiving dual therapy compared to the non-excellent group (86.7% versus 59%, P = 0.04). In monotherapy (n = 27), amantadine was initiated 13 (8-20) d following injury and treatment lasted 7 (2-16) d. In dual therapy (n = 49), amantadine was initiated 12 (6-19) d following injury and continued for 9 (4-25.5) d. Methylphenidate was initiated 15 (7-20.5) d following injury and continued for 5 (2-13.5) d. After adjusting for confounders, dual versus monotherapy predicted excellent NR (OR 5.4, 95% CI 1.2 - 38.9, P = 0.03). CONCLUSIONS: During the acute hospitalization for a severe TBI, dual NS therapy compared to monotherapy is associated with an increased likelihood of excellent NR. Larger prospective trials are warranted to validate these findings.

Early amantadine treatment reduces the risk of death in patients with large hemisphere infarctions:a Chinese hospital-based study.

BACKGROUND: Amantadine hydrochloride is one of the most frequently prescribed drugs for patients with severe traumatic brain injury in restoring consciousness and accelerating the pace of functional recovery. However, there is a paucity of studies on the effectiveness of amantadine in patients with severe stroke especially large hemisphere infarction (LHI). The present study aimed to investigate whether amantadine treatment is associated with better clinical outcomes in conservatively treated LHI patients. METHODS: We retrospectively collected conservatively treated LHI patients according to inclusion/exclusion criteria. The patients were divided into two groups based on the treatment regimen, whether they did receive amantadine hydrochloride in addition to standard therapy (ST) or not. The primary outcomes were in-hospital death, 3-month mortality, and unfavorable outcome (defined as modified Rankin Scale score of 4 to 6). All outcomes were compared between the two groups before and after propensity score matching (PSM). Multivariate logistic regression was performed to identify the association between early amantadine hydrochloride treatment and clinical outcomes in LHI patients. RESULTS: Thirty-one LHI patients treated with amantadine combined with ST and 127 patients treated with ST were enrolled. Amantadine group had a shorter prehospital delay (median: 2 vs. 10 h), a higher baseline NIHSS score (21.71 ± 4.76 vs. 17.49 ± 5.84), and a higher rate of dominant hemisphere involvement (67.74% vs. 45.67%). After PSM, amantadine treatment significantly reduced the risk of in-hospital death (7.41% vs. 31.11%, p=0.019) and 3-month mortality (25.93% vs. 55.56%, p=0.008). Amantadine treatment yielded a significant decrease in death in-hospital (before PSM: OR 0.143, 95% CI 0.034 to 0.605; after PSM: OR 0.113, 95% CI 0.020 to 0.635) and 3-month mortality (before PSM: OR 0.214, 95% CI 0.077 to 0.598; after PSM: OR 0.176, 95% CI 0.053 to 0.586) in unmatched and matched multivariate analyses. CONCLUSION: The results of our study provide initial evidence that early amantadine treatment was associated with a decrease in death in conservatively treated LHI patients. Considering the limitations of observational study, randomized controlled trials with a large sample size may help provide a clearer picture of the utility of amantadine in LHI patients.

Does amantadine maintain function in long-established brain injury? A single case experimental design.

OBJECTIVE: The role of dopamine agonist (DA) in restoring consciousness and cognition in recovery phase following acquired brain injury (ABI) is established (1-5). The role in later recovery is less well defined. We report a single case experimental design (SCED) trial of amantadine demonstrating improvement in function, six years following ABI. METHOD: A scoring system based on established abilities in personal care and interaction was used to identify tasks with component actions, 34 actions in total, each ranked in terms of quality of response to a request or prompt. Actions were scored on maintenance dose amantadine; on withdrawal; and after reintroduction. Daytime sleep duration was also recorded. RESULTS: At 3rd and 5th weeks post withdrawal, deterioration was noted in 27 of 34 graded activities. At 3rd and 5th weeks following reintroduction, all but 3 grades returned to baseline or better. Afternoon sleep duration increased from 35 to 80 minutes during withdrawal period returning towards baseline on amantadine resumption. CONCLUSION: We believe this provides evidence for benefit of amantadine in sustaining function following ABI. The SCED model used provides a template for others to use to identify comparable change in similar trials.

The efficacy of amantadine hydrochloride in the treatment of COVID-19 - a single-center observation study.

Coronavirus disease 19 (COVID-19) rapidly spread worldwide. The search for effective measures to counter the development and effects of the pandemic includes: identifying the disease pathogen, introducing methods of reducing its transmission, building the population immunity, and the search for a cure, both among the new and already-known substances with potential antivirus activity such as amantadine hydrochloride. AIM: The aim of the study was an observational single-center analysis of confirmed COVID-19 cases treated with amantadine in ambulatory settings. MATERIALS AND METHODS: The 55 patients with confirmed COVID-19 diagnosis were treated in ambulatory settings by amantadine with a treatment schema varied from 200 mg to 500 mg per day. A retrospective analysis was based on symptoms, hospitalization, and number of deaths. RESULTS: The mean age of the patients was 55.9 years (SD=15), and most patients were male (60%). Despite the majority of patients 64% (n=35) suffering from comorbidities and 53% (n=29) of patients having been diagnosed with pneumonia, none of them died, and only four had required hospitalization in the course of COVID-19. Clinical stabilization was achieved in 91% (n=50) of patients within 48 hours after the first dose of amantadine with further improvement; additionally, all patients experienced remission of COVID-19. In total, 93% (n=51) of patients did not require hospitalization during the treatment. CONCLUSIONS: The data may suggest that amantadine hydrochloride shows efficacy in preventing hospitalization and deaths in patients with COVID-19. At the same time, it emphasizes that daily monitoring of the patient and regular examination are important in the case of SARS-CoV-2 infection dynamics. It may be justified to carry out a prospective, randomized, and double-blinded clinical study with the postulated amantadine scheme.