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Respiratory Medicine Jun 2023Amantadine has been proposed as a treatment for COVID-19 because it shows anti-SARS-CoV-2 activity in vitro. However, to date, no controlled study has assessed the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Amantadine has been proposed as a treatment for COVID-19 because it shows anti-SARS-CoV-2 activity in vitro. However, to date, no controlled study has assessed the safety and efficacy of amantadine in COVID-19.
RESEARCH QUESTION
Whether amantadine is effective and safe among patients with different COVID-19 severity classifications.
STUDY DESIGN
and Methods: This was multi-centre, randomised, placebo-controlled study.Patients with oxygen saturation ≤94% and no need for high-flow oxygen or ventilatory support were randomly allocated to receive oral amantadine or placebo (1:1) for 10 days in addition to standard care. The primary endpoint was time to recovery assessed over 28 days since randomisation, defined as discharge from hospital or no need for supplemental oxygen.
RESULTS
The study was terminated early due to a lack of efficacy after an interim analysis. Final data from 95 patients who received amantadine (mean age, 60.2 years; 65% male; 66% with comorbidities) and 91 patients who received placebo (mean age, 55.8 years; 60% male; 68% with comorbidities) were obtained. The median (95% CI) time to recovery was 10 days both in the amantadine (9-11) and placebo arms (8-11; subhazard ratio = 0.94 [95%CI 0.7-1.3]). The percentage of deaths and percentage of patients who required intensive care at 14 and 28 days did not significantly differ between the amantadine and placebo groups.
INTERPRETATION
Adding amantadine to standard care in patients hospitalised with COVID-19 did not increase the likelihood of recovery.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov; No.: NCT04952519; www.
CLINICALTRIALS
gov.
Topics: Humans; Male; Middle Aged; Female; COVID-19; SARS-CoV-2; Double-Blind Method; Patients; Amantadine; Treatment Outcome
PubMed: 36931576
DOI: 10.1016/j.rmed.2023.107198 -
Proceedings (Baylor University. Medical... Sep 2021This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were...
This retrospective study examined clinical parameters associated with amantadine treatment of psychiatric symptoms in children. A total of 297 pediatric patients were prescribed amantadine and met study criteria to assess clinical responses and medication outcomes. More than 62% of patients experienced clinically significant symptom control and 83% achieved at least maintenance symptom control, while 11% discontinued amantadine for nonresponse and 6% stopped amantadine because of side effects. Among patients previously receiving other psychotropic medication, 42% and 28% of patients fully discontinued second- or third-generation antipsychotics or antidepressants, respectively. Patients responsive to amantadine who discontinued or reduced antipsychotic dose experienced a significant reduction in body mass index. Amantadine appears be an efficacious and safe alternative for treatment of a broad set of psychiatric symptoms in children and adolescents. Specifically, it may serve as an effective adjunct to stimulants for attention deficit/hyperactivity disorder-related symptoms and appears to be a safer alternative to second- or third-generation antipsychotics.
PubMed: 34456474
DOI: 10.1080/08998280.2021.1925827 -
Pharmaceuticals (Basel, Switzerland) Jul 2022The present article reviewed the pharmacologic therapies of traumatic brain injury (TBI), including current and potential treatments. Pharmacologic therapies are an... (Review)
Review
The present article reviewed the pharmacologic therapies of traumatic brain injury (TBI), including current and potential treatments. Pharmacologic therapies are an essential part of TBI care, and several agents have well-established effects in TBI care. In the acute phase, tranexamic acid, antiepileptics, hyperosmolar agents, and anesthetics are the mainstay of pharmacotherapy, which have proven efficacies. In the post-acute phase, SSRIs, SNRIs, antipsychotics, zolpidem and amantadine, as well as other drugs, have been used to manage neuropsychological problems, while muscle relaxants and botulinum toxin have been used to manage spasticity. In addition, increasing numbers of pre-clinical and clinical studies of pharmaceutical agents, including potential neuroprotective nutrients and natural therapies, are being carried out. In the present article, we classify the treatments into established and potential agents based on the level of clinical evidence and standard of practice. It is expected that many of the potential medicines under investigation will eventually be accepted as standard practice in the care of TBI patients.
PubMed: 35890136
DOI: 10.3390/ph15070838 -
International Journal of Molecular... Jun 2023Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in...
Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2-4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug.
Topics: Mice; Animals; Rivastigmine; Memantine; tau Proteins; Mice, Transgenic; Cholinesterase Inhibitors; Alzheimer Disease; Mitochondria
PubMed: 37445987
DOI: 10.3390/ijms241310810 -
Neurobiology of Disease Jun 2023Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain...
Epilepsy is considered to result from an imbalance between excitation and inhibition of the central nervous system. Pathogenic mutations in the methyl-CpG binding domain protein 5 gene (MBD5) are known to cause epilepsy. However, the function and mechanism of MBD5 in epilepsy remain elusive. Here, we found that MBD5 was mainly localized in the pyramidal cells and granular cells of mouse hippocampus, and its expression was increased in the brain tissues of mouse models of epilepsy. Exogenous overexpression of MBD5 inhibited the transcription of the signal transducer and activator of transcription 1 gene (Stat1), resulting in increased expression of N-methyl-d-aspartate receptor (NMDAR) subunit 1 (GluN1), 2A (GluN2A) and 2B (GluN2B), leading to aggravation of the epileptic behaviour phenotype in mice. The epileptic behavioural phenotype was alleviated by overexpression of STAT1 which reduced the expression of NMDARs, and by the NMDAR antagonist memantine. These results indicate that MBD5 accumulation affects seizures through STAT1-mediated inhibition of NMDAR expression in mice. Collectively, our findings suggest that the MBD5-STAT1-NMDAR pathway may be a new pathway that regulates the epileptic behavioural phenotype and may represent a new treatment target.
Topics: Animals; Mice; Epilepsy; Memantine; Receptors, N-Methyl-D-Aspartate; Seizures; Signal Transduction; STAT1 Transcription Factor
PubMed: 36997128
DOI: 10.1016/j.nbd.2023.106103 -
Parkinsonism & Related Disorders Mar 2022Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation... (Randomized Controlled Trial)
Randomized Controlled Trial
Immediate-release/extended-release amantadine (OS320) to treat Parkinson's disease with levodopa-induced dyskinesia: Analysis of the randomized, controlled ALLAY-LID studies.
BACKGROUND
Immediate-release (IR) amantadine has been used for treatment of levodopa induced dyskinesia (LID). The immediate-release/extended-release (IR/ER) amantadine formulation OS320 (OSMOLEX ER®) contains an IR outer layer and ER core for once-daily dosing.
OBJECTIVE
Report individual and pooled results for the similarly designed double-blind, placebo-controlled ALLAY-LID I and II trials, assessing IR/ER-amantadine for LID.
METHODS
PD patients with LID were randomized to IR/ER-amantadine 193 mg, 258 mg, or placebo. Primary endpoint was Unified Dyskinesia Rating Scale (UDysRS) score change from baseline to Day 98. Secondary outcome was ON time without troublesome dyskinesia based on diaries. Exploratory outcomes were other diary states (including OFF), MDS-UPDRS Parts II + III and Fatigue Severity Scale.
RESULTS
Overall, 222 individuals enrolled (N = 87 ALLAY-LID I, N = 135 ALLAY-LID II); both trials terminated early for sponsor's decision. While ALLAY-LID I did not meet its primary endpoint, a significant reduction in UDysRS scores versus placebo was observed in ALLAY-LID II for both 193 mg and 258 mg doses. In the pooled analysis, placebo-adjusted UDysRS score differences were -5.5 [-9.8, -1.2], p = 0.012 and -5.2 [-9.5, -0.9], p = 0.017, respectively. IR/ER-amantadine 258 mg significantly increased time spent ON without troublesome dyskinesia in ALLAY-LID II and pooled analysis. Reductions in ON time with dyskinesia supported the primary outcome. There was no effect on OFF time or other outcomes. Overall, 13.3% (193 mg), 18.7% (258 mg) and 11.1% (placebo) discontinued for adverse events, most commonly hallucinations (4.0%, 10.7%, and 1.4%, respectively).
CONCLUSIONS
IR/ER-amantadine significantly reduced LID in ALLAY-LID II but not in ALLAY-LID I; post-hoc pooled data also indicated a positive treatment effect on LID.
Topics: Amantadine; Antiparkinson Agents; Double-Blind Method; Dyskinesia, Drug-Induced; Humans; Levodopa; Parkinson Disease; Treatment Outcome
PubMed: 35227940
DOI: 10.1016/j.parkreldis.2022.01.022 -
Therapeutic Advances in Rare Disease 2022The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature... (Review)
Review
OBJECTIVES
The rare inherited autosomal recessive disease Friedreich ataxia (FA) causes progressive neurodegenerative changes and disability in patients. A systematic literature review (SLR) was carried out to understand and summarize the published efficacy and safety of therapeutic interventions in this disease.
METHODS
Database searches were carried out in MEDLINE, Embase, and Cochrane by two independent reviewers. In addition, trial registries and conference proceedings were hand-searched.
RESULTS
Thirty-two publications were deemed eligible according to PICOS criteria. Twenty-four publications detail randomized controlled trials. The most frequently identified therapeutic intervention was idebenone ( = 11), followed by recombinant erythropoietin ( = 6), omaveloxolone ( = 3), and amantadine hydrochloride ( = 2). Other therapeutic interventions were investigated in one publication: A0001, CoQ10, creatine, deferiprone, interferon-γ-1b, the L-carnitine levorotatory form of 5-hydroxytryptophan, luvadaxistat, resveratrol, RT001, and vatiquinone (EPI-743). These studies included patients from 8 to 73 years old, and disease duration varied from 4.7 to 19 years. Disease severity as per the mean GAA1 and GAA2 allele repeat length ranged from 350 to 930 and 620 to 987 nucleotides, respectively. Most frequently reported efficacy outcomes were the International Cooperative Ataxia Rating Scale (ICARS, = 10), the Friedreich Ataxia Rating Scale (modified FARS and FARS-neuro, = 12), the Scale for Assessment and Rating of Ataxia (SARA, = 7), and the Activities of Daily Living scale (ADL, = 8). Each of these assesses the severity of disability in FA patients. In many studies, patients with FA deteriorated according to these severity scales regardless of treatment, or inconclusive results were found. Generally, these therapeutic interventions were well-tolerated and safe. Serious adverse events were atrial fibrillation ( = 1), craniocerebral injury ( = 1), and ventricular tachycardia ( = 1).
CONCLUSION
Identified literature showed a considerable unmet need for therapeutic interventions that halt or slow the deteriorating nature of FA. Novel efficacious drugs should be investigated that aim to improve symptoms or slow disease progression.
PubMed: 37180421
DOI: 10.1177/26330040221139872 -
ACS Omega Feb 2022A simple and economical process for producing amantadine hydrochloride () on a 250 g scale, an antiviral and anti-Parkinson drug, has been developed. Several methods for...
A simple and economical process for producing amantadine hydrochloride () on a 250 g scale, an antiviral and anti-Parkinson drug, has been developed. Several methods for the preparation of through intermediate -(1-adamantyl)-acetamide () in four or three steps were reported. These procedures started with adamantine () or 1-bromoadamantane (), acetonitrile, and sulfuric acid by using the Ritter-type reaction to obtain -(1-adamantyl)-acetamide, which was deacetylated to afford 1-amino-adamantane () and then the salt formed with anhydrous HCl gives with the overall yield of being 50-58%. In this article, a two-step procedure for the synthesis of from 1-bromadamantane () and formamide via -(1-adamantyl)-formamide () in two steps with an overall yield of 88% was reported. In this procedure, the preparation of from is a key step with a yield of 94%, followed by the hydrolysis of with an aq. solution of HCl to give in high yield (93%). The procedure was also carried out under optimal conditions established to reduce the use of toxic reagents or solvents and was carried out in one pot to make it more environmentally friendly. The procedure can be considered as more suitable for the large-scale production of . The structures of product and intermediate were confirmed by IR, MS, H NMR, C NMR.
PubMed: 35187298
DOI: 10.1021/acsomega.1c04652 -
The Journal of Clinical Psychiatry Dec 2019Patients with obsessive-compulsive disorder (OCD) who do not respond adequately to serotonin reuptake inhibitor (SRI) therapy and cognitive behavioral therapy commonly... (Meta-Analysis)
Meta-Analysis Review
Patients with obsessive-compulsive disorder (OCD) who do not respond adequately to serotonin reuptake inhibitor (SRI) therapy and cognitive behavioral therapy commonly receive SRI augmentation in the form of an atypical antipsychotic drug. Memantine is another augmentation strategy that has been trialed. A recent systematic review and meta-analysis found very large improvements associated with memantine augmentation in OCD. Specifically, in 4 randomized controlled trials (RCTs), the response rate was 81% in 67 memantine-treated patients vs only 19% in 68 placebo-treated patients. The weighted mean difference between memantine and placebo groups was nearly 8 points on the Yale-Brown Obsessive Compulsive Scale. Such striking differences for intervention vs placebo in a difficult-to-treat disorder demand scrutiny. An examination of the RCTs on which the meta-analysis was based showed that all 4 RCTs emerged from the same geographical area, limiting the generalizability of the findings. Of greater concern, all 4 RCTs presented what were effectively completer analyses of data, compromising the scientific validity of the findings. There were several other concerns about the individual studies and about the meta-analysis, itself. Therefore, a reasonable conclusion is that, when the internal and external validity of studies in a meta-analysis are compromised, the findings and conclusions of the meta-analysis cannot be considered sound. It is concluded that, despite the very large benefits reportedly associated with memantine augmentation, the routine use of memantine as an augmentation agent for OCD cannot as yet be recommended.
Topics: Cognitive Behavioral Therapy; Combined Modality Therapy; Drug Therapy, Combination; Humans; Memantine; Obsessive-Compulsive Disorder; Randomized Controlled Trials as Topic; Selective Serotonin Reuptake Inhibitors
PubMed: 31846244
DOI: 10.4088/JCP.19f13163 -
European Review For Medical and... Oct 2022Amantadine is known to have a neuroprotective effect in many neurological diseases. This study aims at investigating the neuroprotective effect of amantadine in rats...
OBJECTIVE
Amantadine is known to have a neuroprotective effect in many neurological diseases. This study aims at investigating the neuroprotective effect of amantadine in rats exposed to carbon monoxide (CO) poisoning.
MATERIALS AND METHODS
Rats were maintained under standard experimental laboratory conditions and randomized into 4 different groups of 7 each namely control, amantadine only, CO exposure, and amantadine + CO exposure. For immunohistochemical analysis, tissues taken from the prefrontal and hippocampal regions were taken into formalin and kept for at least one day. Afterward, the tissue was followed and blocked for paraffin blocking. N-Methyl D-Aspartate (NMDA) levels in homogenates were studied by the Enzyme-Linked Immunosorbent Assay (ELISA) method. Superoxide dismutase (SOD) and catalase (CAT) activities in the supernatants were studied with commercial kits. Nitric oxide (NO) and Asymmetric Dimethyl Arginine (ADMA) levels were studied by the ELISA method. Enzyme activity values were calculated by dividing the protein values in the supernatants and normalizing them.
RESULTS
CAT, SOD, NMDA, ADMA, and NO levels were statistically significantly different between the groups (p < 0.05). According to post-hoc pairwise comparison test results, the values of the control and amantadine groups for CAT, SOD, NMDA, ADMA, and NO parameters were significantly higher than that of CO group. Similarly, values in the control and amantadine groups were considerably higher than values for the amantadine + CO group. NMDA values were significantly lower in group amantadine + CO than in CO group (p: 0.049).
CONCLUSIONS
Apoptosis and endothelial damage after CO poisoning is a complex process, and amantadine administration has a limited contribution in preventing this process.
Topics: Animals; Rats; Amantadine; Antioxidants; Arginine; Carbon Monoxide; Carbon Monoxide Poisoning; Catalase; D-Aspartic Acid; Formaldehyde; N-Methylaspartate; Neuroprotective Agents; Nitric Oxide; Paraffin; Receptors, N-Methyl-D-Aspartate; Superoxide Dismutase
PubMed: 36263571
DOI: 10.26355/eurrev_202210_29872