-
The Lancet. Neurology Jan 2021Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their...
BACKGROUND
Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.
METHODS
In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.
FINDINGS
Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0-53·6) at baseline, 40·6 (38·2-43·1) with placebo, 41·3 (38·8-43·7) with amantadine, 39·0 (36·6-41·4) with modafinil, and 38·6 (36·2-41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).
INTERPRETATION
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.
FUNDING
Patient-Centered Outcomes Research Institute.
Topics: Adult; Amantadine; Central Nervous System Stimulants; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Drug-Related Side Effects and Adverse Reactions; Fatigue; Female; Humans; Male; Methylphenidate; Middle Aged; Modafinil; Multiple Sclerosis; Outcome Assessment, Health Care; Severity of Illness Index
PubMed: 33242419
DOI: 10.1016/S1474-4422(20)30354-9 -
The New England Journal of Medicine Mar 2012Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Amantadine hydrochloride is one of the most commonly prescribed medications for patients with prolonged disorders of consciousness after traumatic brain injury. Preliminary studies have suggested that amantadine may promote functional recovery.
METHODS
We enrolled 184 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after traumatic brain injury and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive amantadine or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models.
RESULTS
During the 4-week treatment period, recovery was significantly faster in the amantadine group than in the placebo group, as measured by the DRS score (difference in slope, 0.24 points per week; P=0.007), indicating a benefit with respect to the primary outcome measure. In a prespecified subgroup analysis, the treatment effect was similar for patients in a vegetative state and those in a minimally conscious state. The rate of improvement in the amantadine group slowed during the 2 weeks after treatment (weeks 5 and 6) and was significantly slower than the rate in the placebo group (difference in slope, 0.30 points per week; P=0.02). The overall improvement in DRS scores between baseline and week 6 (2 weeks after treatment was discontinued) was similar in the two groups. There were no significant differences in the incidence of serious adverse events.
CONCLUSIONS
Amantadine accelerated the pace of functional recovery during active treatment in patients with post-traumatic disorders of consciousness. (Funded by the National Institute on Disability and Rehabilitation Research; ClinicalTrials.gov number, NCT00970944.).
Topics: Adult; Amantadine; Brain Injuries; Coma, Post-Head Injury; Disability Evaluation; Dopamine Agents; Female; Glasgow Coma Scale; Humans; Male; Persistent Vegetative State; Recovery of Function
PubMed: 22375973
DOI: 10.1056/NEJMoa1102609 -
The Cochrane Database of Systematic... Nov 2014Influenza is an acute respiratory illness caused by influenza A and B viruses. Complications may occur, especially among children and the elderly. (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Influenza is an acute respiratory illness caused by influenza A and B viruses. Complications may occur, especially among children and the elderly.
OBJECTIVES
To assess the effectiveness and safety of amantadine and rimantadine in preventing, treating and shortening the duration of influenza A in children and the elderly.
SEARCH METHODS
We searched CENTRAL (2014, Issue 9), MEDLINE (1966 to September week 4, 2014) and EMBASE (1980 to October 2014).
SELECTION CRITERIA
Randomised controlled trials (RCTs) or quasi-RCTs comparing amantadine and/or rimantadine with no intervention, placebo, other antivirals or different doses or schedules of amantadine or rimantadine in children and the elderly with influenza A.
DATA COLLECTION AND ANALYSIS
Two review authors independently assessed the search results. We extracted and analysed data using the standard Cochrane methodology.
MAIN RESULTS
We identified 12 studies (2494 participants: 1586 children and 908 elderly) comparing amantadine and rimantadine with placebo, paracetamol (one trial: 69 children) or zanamivir (two trials: 545 elderly) to treat influenza A.Amantadine was effective in preventing influenza A in children (773 participants, risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza A in the control group was 10 per 100. The corresponding risk in the rimantadine group was one per 100 (95% CI 0 to 3). Nevertheless, the quality of the evidence was low and the safety of the drug was not well established.For treatment, rimantadine was beneficial in abating fever on day three of treatment in children: one selected study with low risk of bias, moderate evidence quality and 69 participants (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100. The corresponding risk in the rimantadine group was 14 per 100 (95% CI 5 to 34).Rimantadine did not show any prophylactic effect in the elderly. The quality of evidence was very low: 103 participants (RR 0.45; 95% CI 0.14 to 1.41). The assumed risk was 17 per 100. The corresponding risk in the rimantadine group was 7 per 100 (95% CI 2 to 23).There was no evidence of adverse effects caused by treatment with amantadine or rimantadine.We found no studies assessing amantadine in the elderly.
AUTHORS' CONCLUSIONS
The quality of the evidence combined with a lack of knowledge about the safety of amantadine and the limited benefits of rimantadine, do not indicate that amantadine and rimantadine compared to control (placebo or paracetamol) could be useful in preventing, treating and shortening the duration of influenza A in children and the elderly.
Topics: Adolescent; Aged; Amantadine; Antiviral Agents; Child; Humans; Influenza A Virus, H1N1 Subtype; Influenza A virus; Influenza, Human; Randomized Controlled Trials as Topic; Rimantadine; Sex Factors; Young Adult
PubMed: 25415374
DOI: 10.1002/14651858.CD002745.pub4 -
Amantadine and Rimantadine Inhibit Hepatitis A Virus Replication through the Induction of Autophagy.Journal of Virology Sep 2022Hepatitis 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....
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 . 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. 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.
Topics: Amantadine; Antiviral Agents; Autophagy; Cell Line; Hepatitis A; Hepatitis A Antibodies; Hepatitis A virus; Humans; Proteomics; Rimantadine; Virus Replication
PubMed: 36040176
DOI: 10.1128/jvi.00646-22 -
Current Pharmaceutical Design 2014Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with... (Review)
Review
Survivors of severe brain injuries may end up in a state of 'wakeful unresponsiveness' or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes of the patients' neurological status, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents' therapeutic mechanisms on cerebral function. In order to improve our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient's etiology, diagnosis, time since injury and overall condition.
Topics: Amantadine; Apomorphine; Consciousness Disorders; Humans; Pyridines; Zolpidem
PubMed: 24025057
DOI: No ID Found -
Archives of Medical Research Oct 2020
Topics: Amantadine; Betacoronavirus; COVID-19; Coronavirus Infections; Humans; Pandemics; Parkinsonian Disorders; Pneumonia, Viral; SARS-CoV-2
PubMed: 32660794
DOI: 10.1016/j.arcmed.2020.07.001 -
The Cochrane Database of Systematic... Apr 2006Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects.
OBJECTIVES
The objective of this review was to assess the efficacy, effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults.
SEARCH STRATEGY
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to August Week 4, 2005), EMBASE (October 2003 to July 2005) and reference lists of articles.
SELECTION CRITERIA
Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults.
DATA COLLECTION AND ANALYSIS
For prophylaxis (prevention) trials the numbers of participants with clinical influenza (influenza-like-illness or ILI) or with confirmed influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects.
MAIN RESULTS
Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose and the course of asymptomatic influenza.
AUTHORS' CONCLUSIONS
Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Routine use of both drugs should be discouraged and both drugs should only be used when all other measures fail.
Topics: Adult; Aged; Amantadine; Antiviral Agents; Drug Administration Schedule; Emergencies; Humans; Influenza A virus; Influenza, Human; Middle Aged; Randomized Controlled Trials as Topic; Rimantadine; Virus Shedding
PubMed: 16625539
DOI: 10.1002/14651858.CD001169.pub3 -
Canadian Medical Association Journal Nov 1983To document an interaction between amantadine hydrochloride and Dyazide that had apparently produced amantadine toxicity, a patient was given amantadine alone for 1...
To document an interaction between amantadine hydrochloride and Dyazide that had apparently produced amantadine toxicity, a patient was given amantadine alone for 1 week, followed by amantadine plus Dyazide for another week, under controlled conditions. A diuretic effect was observed after Dyazide was added to the regimen, but the urine amantadine excretion fell, and the drug's plasma concentration increased. It was concluded that one or both of the components of Dyazide (hydrochlorothiazide and triamterene) reduce the clearance of amantadine and can produce higher plasma concentrations and toxic effects.
Topics: Amantadine; Ataxia; Creatine; Diuresis; Drug Combinations; Drug Synergism; Edema; Humans; Hydrochlorothiazide; Male; Middle Aged; Parkinson Disease; Time Factors; Triamterene
PubMed: 6671185
DOI: No ID Found -
Ugeskrift For Laeger Jun 2022Viroporins are ion channels found in many viruses, where they contribute to virus life cycle and thereby pathogenesis. Viroporin targeting is a known, yet largely... (Review)
Review
Viroporins are ion channels found in many viruses, where they contribute to virus life cycle and thereby pathogenesis. Viroporin targeting is a known, yet largely unexplored, therapeutic strategy so far only used in Influenza A with the drugs amantadine and rimantadine. In this review, we seek to utilize the inhibition by amantadine of the viroporin Protein E in SARS-CoV-2 in an attempt to treat COVID-19 in its early stages. We are executing a double-blinded placebo-controlled trial based on promising in vivo and in vitro work as a stepping-stone for establishing a therapeutic antiviral regime: blocking of viroporins.
Topics: Amantadine; Antiviral Agents; Humans; SARS-CoV-2; Viroporin Proteins; COVID-19 Drug Treatment
PubMed: 35703076
DOI: No ID Found -
Revista Brasileira de Psiquiatria (Sao... 2018Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an... (Review)
Review
OBJECTIVE
Amantadine blocks N-methyl-D-aspartate (NMDA) receptors and has dopaminergic and noradrenergic action, a neurochemical profile that suggests its potential as an antidepressant drug. We conducted a systematic review of preclinical and clinical studies addressing the effects of amantadine in animal models of depression and in patients with depression.
METHODS
PubMed, Science Direct, and Web of Science were searched up to September 1, 2017 to identify clinical and preclinical studies. The following search terms were used: "amantadine AND depress*"; "amantadine AND mood"; "amantadine AND animal models AND antidepres*"; and "amantadine AND (forced swim, learned helplessness, reserpine, chronic mild stress, anhedonia, sucrose preference)."
RESULTS
Amantadine had antidepressant-like effects in animal models and appeared to potentiate the antidepressant effects of other antidepressants. These preclinical findings have received some support from the results of small open-label clinical trials, suggesting that amantadine can reduce depressive symptomatology and potentiate the antidepressant effects of monoaminergic drugs. In addition to its glutamatergic and dopaminergic effects, the potential antidepressant-like effects of amantadine have been linked to molecular and cellular actions, such as increased expression of neurotrophic factors (e.g., brain-derived neurotrophic factor), activation of σ1 receptors, decreased corticosterone levels, and decreased inflammatory response to stress.
CONCLUSION
Amantadine is an interesting candidate as new antidepressant drug for the treatment of depression.
Topics: Amantadine; Animals; Antidepressive Agents; Biogenic Monoamines; Clinical Trials as Topic; Depressive Disorder; Disease Models, Animal; Drug Evaluation, Preclinical; Humans
PubMed: 29898194
DOI: 10.1590/1516-4446-2017-2393