Efficacy of oral amantadine among patients hospitalised with COVID-19: A randomised, double-blind, placebo-controlled, multicentre study.

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.

Aminoadamantanes: from treatment of Parkinson's and Alzheimer's disease to symptom amelioration of long COVID-19 syndrome?

INTRODUCTION: The aminoadamantanes amantadine and memantine are well known. They mainly act as N-methyl-D-aspartate antagonists. AREAS COVERED: The antiviral drug amantadine moderately ameliorates impaired motor behavior in patients with Parkinson's disease. Memantine provides beneficial effects on memory function in patients with advanced Alzheimer's disease already treated with acetylcholine esterase inhibitors. Both compounds counteract impaired monoamine neurotransmission with associated symptoms, such as depression. They improve vigilance, lack of attention and concentration, fatigue syndromes according to clinical findings in patients with chronic neurodegenerative processes. Their extrasynaptic N-methyl-D-Aspartate receptor blockade weakens a prolonged influx of Ca2+ ions as the main responsible components of neuronal excitotoxicity. This causes neuronal dying and associated functional deficits. EXPERT OPINION: We suggest aminoadamantanes as future therapies for amelioration of short- and long-term consequences of a COVID 19 infection. Particularly the extended-release amantadine formulations will be suitable. They showed better clinical efficacy compared with the conventional available compounds. Amantadine may particularly be suitable for amelioration of fatigue or chronic exhaustion, memantine for improvement of cognitive deficits. Clinical research in patients, who are affected by the short- and long-term consequences of a COVID 19 infection, is warranted to confirm these still hypothetical putative beneficial effects of aminoadamantanes.

The drugs amantadine and memantine are known as aminoadamantanes. Amantadine improves motor skills in patients with Parkinson's disease. It also reduces fatigue in individuals suffering from multiple sclerosis. Memantine improves memory dysfunction linked to Alzheimer's disease. Aminoadamantanes affect communication between nerve cells by supporting neurotransmission of monoamines. Clinical studies have found that these drugs benefit patients with chronic neurodegenerative diseases, who have depression, fatigue, loss of attention or concentration deficits. These brain function problems may also appear to some extent due to COVID-19 infection. We suggest that aminoadamantanes could improve these problems in COVID-19 patients in both the short and long term. Clinical research is needed to confirm this hypothesis.

Morbidity and severity of COVID-19 in patients with Parkinson's disease treated with amantadine - A multicenter, retrospective, observational study.

BACKGROUND: After more than 2 years of the pandemic, effective treatment for COVID-19 is still under research. In recent months, publications hypothesized amantadine's potential beneficial effect on SARS-CoV-2 infection. OBJECTIVE: To compare the groups of Parkinson's Disease (PD) patients who were administered amantadine chronically and those who did not take this medication in the context of the incidence and severity of COVID-19 infection. METHODS: An observational, retrospective, multicenter cohort study was conducted among consecutive patients with idiopathic PD. The structured questionnaires were completed during the patient's follow-up visits at the Outpatient Clinic or during hospitalization. The questionnaire included the following informations: patient's age, duration of PD, Hoehn-Yahr (H-Y) stage, comorbidities, medications, COVID-19 confirmed by reverse transcription polymerase chain reaction (RT-PCR) swab test for SARS-CoV-2 with specified symptoms and their severity (home or hospital treatment). The vaccination status was verified as well. RESULTS: Five hundred fifty-two (n = 552) patients participated in the study - 329 men (60%). The mean H-Y stage was 2.44 (range: 1-4) and the mean duration of PD was 9.6 years (range: 1-34). One hundred four subjects (19%) had confirmed COVID-19 infection. Subjects over 50 years of age had a significantly lower incidence of COVID-19 (17% vs 38%, p = 0.0001) with difference also in mean H-Y stage (2.27 vs 2.49; p = 0.011) and disease duration (8.4 vs 9.9 years, p = 0.007). There were no differences between patients with and without co-morbidities. In the whole analyzed group 219 (40%) subjects were treated with amantadine. Comparing COVID-19 positive and negative patients, amantadine was used by 48/104 (46%) and 171/448 (38%) respectively. 22% of patients on amantadine vs. 17% of patients without amantadine developed COVID-19. These differences were not significant. There were no differences in morbidity and severity of COVID-19 between amantadine users and non-users as well. CONCLUSIONS: COVID-19 was less common in older (>50) with longer duration and more advanced patients. Amantadine did not affect the risk of developing COVID-19 or the severity of infection.

Psychotic Disorders in the Course of SARS-CoV-2 Infection or Uncomplicated Amantadine Treatment?-Case Report.

The mental health impact of SARS-CoV-2 infection is currently the subject of intense research. Mental disorders in the course of coronavirus infection are non-specific. They most often have a sudden onset and short-term course and resolve spontaneously or after the administration of low doses of antipsychotic drugs. At the same time, attempts have been made to develop recommendations for COVID-19 therapy. Single reports suggest the effectiveness of amantadine in the treatment. The mechanism of action of the drug in this case is not known; it is expected that amantadine, by reducing the expression of the cathepsin L gene, may interfere with SARS-CoV-2 replication. In addition, this drug stimulates dopaminergic transmission, which may result in numerous side effects, often of a neuropsychological nature, the most common of which are visual hallucinations. Therefore, it is extremely difficult to unequivocally diagnose the cause of mental disorders among patients with SARS-CoV-2 infection who took amatatide for off-label treatment. A clear assessment of whether the psychological symptoms in this group of patients are the primary or secondary clinical manifestation of the infection or a complication of amantadine treatment is difficult. In this context, we attempted to describe a case of a patient with psychotic symptoms who was confirmed with SARS-CoV-2 infection and treated with amantadine.

Improved survival in intensive care unit in severe COVID-19 associated with amantadine use - retrospective study.

OBJECTIVES: Possible immunomodulatory effect of amantadine in patients treated in intensive care unit (ICU), mostly among patients with brain injuries or vascular diseases was observed in several studies. The potential antiviral effect of amantadine against SARS-CoV-2 was discarded in clinical trials; however, immunomodulatory potential was not studied. The aim of the study was to investigate the effect of immunomodulatory amantadine therapy on mortality in patients with respiratory insufficiency due to COVID-19 requiring mechanical ventilation in ICU. METHODS: Retrospective analysis of 241 cases of 141 (58.5%) receiving intravenous amantadine sulfate vs 100 (41.5%) controls on standard of care only was performed. RESULTS: Overall mortality was 72.6%, being notably lower among amantadine treated patients (59.5%, n = 84) compared with controls (91%, n = 91), P-value = 0.001. In multivariate models administration of amantadine was independently associated with lower mortality rate (hazard ratio: 0.220, CI: 0.146-0.333 P-value = 0.001). Furthermore, survival was improved in patients who received amantadine; late administration of amantadine after 5th day was independently associated with lower mortality (hazard ratio: 0.560, CI: 0.313-0.999, P-value = 0.050). CONCLUSION: In patients treated in ICU with severe respiratory failure, administration of amantadine is associated with lower mortality, which may be associated with the potential anti-inflammatory and immunomodulatory effects of this agent.

Fluvoxamine and Amantadine: Central Nervous System Acting Drugs Repositioned for COVID-19 as Early Intervention.

BACKGROUND: As the World faces unprecedented pandemic caused by SARS-CoV-2 virus, repositioning of existing drugs to treatment of COVID-19 disease is urgently awaited, provided that high quality scientific evidence supporting safety and efficacy in this new indication is gathered. Efforts concerning drugs repositioning to COVID-19 were mostly focused on antiviral drugs, or drugs targeting the late phase of the disease. METHODS: Based on published research, the pharmacological activities of fluvoxamine and amantadine, two well-known drugs widely used in clinical practice for psychiatric and neurological diseases, respectively, have been reviewed, with a focus on their potential therapeutic importance in the treatment of COVID-19. RESULTS: Several preclinical and clinical reports were identified suggesting that these two drugs might exert protective effects in the early phases of COVID-19. CONCLUSION: Preclinical and early clinical evidence are presented indicating that these drugs hold promise to prevent COVID-19 progression when administered early during the course of infection.

The use of amantadine in the prevention of progression and treatment of COVID-19 symptoms in patients infected with the SARS-CoV-2 virus (COV-PREVENT): Study rationale and design.

BACKGROUND: COVID-19, a disease caused by infection with the SARS-CoV-2 virus, is asymptomatic or mildly symptomatic in most cases. Some patients, usually burdened with risk factors develop acute respiratory failure and other organ dysfunction. In such cases, the mortality rate is very high despite the use of intensive therapy. Amantadine has complex activity including antiviral, antiinflammatory and dopaminergic effects. This clinical trial will assess the efficacy and safety of amantadine in the prevention of COVID-19 progression toward acute respiratory failure and neurological complications. METHODS AND RESULTS: The trial will enroll 200 patients who are positive for SARS-CoV-2 infection and have one or more risk factors for worsening the disease. These patients will be included as hospitalized or ambulatory subjects for early treatment of illness. The recruitment will take place in 8 centers covering different regions of Poland. For 14 days they will be given either 200 mg of amantadine a day or placebo. Our hypothesis is a considerable reduction in the number of patients with progression toward respiratory insufficiency or neurological complications thanks to the treatment of amantadine. CONCLUSIONS: Demonstrating the efficacy and safety of amantadine treatment in improving the clinical condition of patients diagnosed with COVID-19 is of great importance in combating the effects of the pandemic. It has potential to influence on the severity and course of neurological complications, which are very common and persist long after the infection as long-COVID syndrome. CLINICAL TRIAL REGISTRATION: www. CLINICALTRIALS: gov identification no. NCT04854759; Eudra CT number: 2021-001144-98 (dated 27 February 2021).

SARS-CoV-2 infection in patients with serious mental illness and possible benefits of prophylaxis with Memantine and Amantadine.

Patients with serious mental illness are a high-risk category of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Patients with schizophrenia are not participatory and have increased mortality and morbidity, patients with dementia cannot be cared for while depression, anxiety, bipolar tubing are associated with low immune status. Social stress is amplified by social isolation, amplifying depression and the mechanisms of decreased immunity. Hygiene measures and prophylactic behavior are impossible to put into practice in conditions of chronic mental illness. In coronavirus disease 2019 (COVID-19), the risk for severe development is associated with the presence of comorbidities and immune system deficiency. Prothrombotic status, cytokine storm and alveolar destruction are mechanisms that aggravate the evolution of patients, especially in the context in which they have dysfunction of the autonomic system. The activity of proinflammatory cytokines is accentuated by hyperglutamatergia, which potentiates oxidative stress and triggers the mechanisms of neural apoptosis by stimulating microglial activation. Activation of M1-type microglia has an important role in pathogenesis of major psychiatric disorders, such as major depression, schizophrenia or bipolar disorder, and may associate hippocampal atrophy and disconnection of cognitive structures. Memantine and Amantadine, N-methyl-D-aspartate (NMDA) glutamate receptor inhibitors, have demonstrated, through their pharmacological profile, psychotropic effects but also antiviral properties. In the conditions of the COVID-19 pandemic, based on these arguments, we suggest that they can be associated with the therapy with the basic psychotropics, Memantine or Amantadine, for the control of neuropsychiatric symptoms but also as adjuvants with antiviral action.

[Amantadine in the treatment of Parkinson's disease. New opportunities in the context of COVID-19]. / Amantadiny v lechenii bolezni Parkinsona. Novye vozmozhnosti v usloviyakh COVID-19.

The article presents data from recent studies on the mechanisms of action and clinical efficacy of amantadines, and also describes a possible protective effect against COVID-19.

Novel Pulmonary Delivery of Antiviral Drugs for Treating COVID-19 in Patients with Parkinson's Disease.

The COVID-19 pandemic has caused a significant burden on public health worldwide. Currently, there are limited medications for the treatment of COVID-19 in patients with Parkinson's disorder (PD). Several antiviral drugs and other pharmacotherapies have shown promising results and are used by various delivery methods. Among the antiviral drugs, amantadine alone was reported to provide therapeutic benefit against COVID-19 in patients with PD. Here, we propose novel strategies for pulmonary drug delivery technology of antiviral drug, amantadine. As such pulmonary delivery of this drug or in combination with the additional antiviral drugs could be a more effective strategy for the treatment of COVID-19-related complications in patients with PD. Furthermore, the important benefits and limitations of this novel delivery technology will be discussed.

Amantadine in the prevention of clinical symptoms caused by SARS-CoV-2.

BACKGROUND: Amantadine is a drug that can help in the prevention of SARS-CoV-2 symptomatology, as has been demonstrated in observational clinical studies. METHODS: We searched in the PubMed database Clinical Studies of coronavirus-infected patients who have been treated with amantadine in a preventive manner as well as patients with Parkinson's disease. RESULTS: Four clinical studies were found in which relatives of patients with COVID-19 had been prescribed the use of amantadine in a preventive manner to avoid the symptoms caused by the coronavirus. CONCLUSION: Amantadine is a drug that can be prescribed as a prophylactic that prevents symptomatology caused by SARS-CoV-2 coronavirus.

Amantadine Treatment for People with COVID-19.

SARS-Cov-2, whose symptoms include difficulty swallowing, coughing, diarrhea, and breathing failure, has caused the loss of many lives around the world. In the absence of a vaccine or medication to help prevent or decrease the effects of the disease, we suggest that amantadine may reduce the effects of COVID-19.

Cathepsin L in COVID-19: From Pharmacological Evidences to Genetics.

The coronavirus disease 2019 (COVID-19) pandemics is a challenge without precedent for the modern science. Acute Respiratory Discomfort Syndrome (ARDS) is the most common immunopathological event in SARS-CoV-2, SARS-CoV, and MERS-CoV infections. Fast lung deterioration results of cytokine storm determined by a robust immunological response leading to ARDS and multiple organ failure. Here, we show cysteine protease Cathepsin L (CatL) involvement with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 from different points of view. CatL is a lysosomal enzyme that participates in numerous physiological processes, including apoptosis, antigen processing, and extracellular matrix remodeling. CatL is implicated in pathological conditions like invasion and metastasis of tumors, inflammatory status, atherosclerosis, renal disease, diabetes, bone diseases, viral infection, and other diseases. CatL expression is up-regulated during chronic inflammation and is involved in degrading extracellular matrix, an important process for SARS-CoV-2 to enter host cells. In addition, CatL is probably involved in processing SARS-CoV-2 spike protein. As its inhibition is detrimental to SARS-CoV-2 infection and possibly exit from cells during late stages of infection, CatL could have been considered a valuable therapeutic target. Therefore, we describe here some drugs already in the market with potential CatL inhibiting capacity that could be used to treat COVID-19 patients. In addition, we discuss the possible role of host genetics in the etiology and spreading of the disease.

Observational study of people infected with SARS-Cov-2, treated with amantadine.

BACKGROUND: We conducted an observational study of 15 patients from a Southeastern area of Mexico with symptoms compatible with SARS-Cov-2, which were treated with the antiviral amantadine. METHODOLOGY: In this study, data were collected from 15 individuals with clinical symptoms of COVID-19 infection, which were treated on an ambulatory basis with 100 mg of amantadine for a period of 14 days. RESULTS: This drug demonstrated its effectiveness, as patients recovered successfully with this treatment without the necessity of attending a hospital to use mechanical ventilation. All patients developed IgG antibodies to SARS-Cov-2. CONCLUSION: Amantadine can be used as a viable and cost-effective alternative for treating people with severe acute respiratory syndrome (SARS-Cov-2) on an ambulatory basis, while the vaccine is not available.