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Clinics and Practice Jul 2023The usual adverse events of amantadine are dizziness, dry mouth, and peripheral edema. Postmarketing experience has revealed abnormal movements such as tremors,...
The usual adverse events of amantadine are dizziness, dry mouth, and peripheral edema. Postmarketing experience has revealed abnormal movements such as tremors, involuntary muscle contractions, and gait abnormalities. Herein, we report a case of an elderly male who presented with generalized twitching associated with amantadine. A 64-year-old male presenting with jerking movements within one day of onset was admitted. Sudden and involuntary distal lower and upper limb muscle twitching was observed. The subject presented subsequent brief movements when attempting to stand or hold arms antigravity. He was diagnosed with Parkinson's disease three years ago. Eight days before the presentation to the emergency department, he consulted with his primary care physician, who prescribed amantadine to improve his motor symptoms. On the seventh day, he developed brisk abnormal movements. Laboratory exams, neuroimaging, and electroencephalogram were unremarkable. Amantadine was discontinued. After three days, the patient reported that his jerking movements had fully recovered. To the authors' knowledge, 22 individuals with amantadine-associated myoclonus had already been reported in the literature. The pathophysiology of amantadine-induced myoclonus is probably related to serotoninergic pathways. Myoclonus secondary to amantadine was slightly more common in men. The population affected was elderly, with a mean and median age of 67.7 and 64 years.
PubMed: 37489424
DOI: 10.3390/clinpract13040075 -
Behavioural Neurology 2023Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades....
Alzheimer's disease (AD), as the main cause of dementia, has a progressive and neurodegenerative pattern with number of cases increasing over the next decades. Therefore, discovering an effective treatment with the ability to invert memory impairment and pathophysiological events of AD seems to be required. The present study performed to investigate the probable effects of Edaravone (EDV) in AD-like disorder induced by intracerebroventricular streptozotocin (ICV-STZ) administration in mice. This study also compares the two different methods of ICV-STZ in the memory impairment induction. NMRI male mice were administrated with 3 mg/kg of STZ for two times during 48 hours span, and after 24 hours, animals were treated with EDV (5 and 10 mg/kg), Donepezil, and Memantine for 14 days. After behavioral tests regarding memory and cognitive function, animals were sacrificed, and the hippocampi were utilized for further analyses. Our results demonstrated that administration of STZ induced memory impairment in the Morris water maze (MWM) test and decreased the discriminative factor in novel object recognition (NOR). The biochemical output shows a significant decrease in ferric reducing antioxidant power (FRAP) and glutathione (GSH) levels followed by increase in malondialdehyde (MDA) and protein carbonylation (PCO) levels. The output showed no difference between the patterns of AD-like disorder induction. Following our treatment groups, administration of EDV (5 and 10 mg/kg), Donepezil, and Memantine significantly improved memory performance and discriminatory behavior. Aforementioned treatments managed to improve FRAP and GSH content of hippocampus, while significantly attenuating MDA, PCO, and nitric oxide overproduction. In addition, no significant difference has been observed between the effect of 5 and 10 mg/kg EDV application. It was supposed that EDV managed to ameliorate memory dysfunction, discriminatory behavior, oxidative stress, and cellular antioxidant power in a dose-independent pattern in mice.
Topics: Rats; Male; Mice; Animals; Edaravone; Streptozocin; Antioxidants; Memantine; Rats, Wistar; Donepezil; Oxidative Stress; Memory Disorders; Alzheimer Disease; Inflammation; Maze Learning; Disease Models, Animal
PubMed: 37476485
DOI: 10.1155/2023/9652513 -
Journal of the American Medical... Sep 2023Alzheimer's disease (AD) is a progressive neurological disorder with no specific curative medications. Sophisticated clinical skills are crucial to optimize treatment...
BACKGROUND
Alzheimer's disease (AD) is a progressive neurological disorder with no specific curative medications. Sophisticated clinical skills are crucial to optimize treatment regimens given the multiple coexisting comorbidities in the patient population.
OBJECTIVE
Here, we propose a study to leverage reinforcement learning (RL) to learn the clinicians' decisions for AD patients based on the longitude data from electronic health records.
METHODS
In this study, we selected 1736 patients from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We focused on the two most frequent concomitant diseases-depression, and hypertension, thus creating 5 data cohorts (ie, Whole Data, AD, AD-Hypertension, AD-Depression, and AD-Depression-Hypertension). We modeled the treatment learning into an RL problem by defining states, actions, and rewards. We built a regression model and decision tree to generate multiple states, used six combinations of medications (ie, cholinesterase inhibitors, memantine, memantine-cholinesterase inhibitors, hypertension drugs, supplements, or no drugs) as actions, and Mini-Mental State Exam (MMSE) scores as rewards.
RESULTS
Given the proper dataset, the RL model can generate an optimal policy (regimen plan) that outperforms the clinician's treatment regimen. Optimal policies (ie, policy iteration and Q-learning) had lower rewards than the clinician's policy (mean -3.03 and -2.93 vs. -2.93, respectively) for smaller datasets but had higher rewards for larger datasets (mean -4.68 and -2.82 vs. -4.57, respectively).
CONCLUSIONS
Our results highlight the potential of using RL to generate the optimal treatment based on the patients' longitude records. Our work can lead the path towards developing RL-based decision support systems that could help manage AD with comorbidities.
Topics: Humans; Alzheimer Disease; Memantine; Cholinesterase Inhibitors; Artificial Intelligence; Learning
PubMed: 37463858
DOI: 10.1093/jamia/ocad135 -
Deutsches Arzteblatt International Sep 2023Severe quantitative disorders of consciousness (DoC) due to acute brain injury affect up to 47% of patients upon admission to intensive care and early rehabilitation...
BACKGROUND
Severe quantitative disorders of consciousness (DoC) due to acute brain injury affect up to 47% of patients upon admission to intensive care and early rehabilitation units. Nevertheless, the rehabilitation of this vulnerable group of patients has not yet been addressed in any German-language guidelines and has only been studied in a small number of randomized clinical trials.
METHODS
In an S3 clinical practice guideline project, a systematic literature search was carried out for interventions that could improve consciousness in patients with coma, unresponsive wakefulness syndrome, or minimally conscious state after acute brain injury, and an evidence-based evaluation of these interventions was performed. Recommendations concerning diagnostic methods and medical ethics were issued by consensus.
RESULTS
Misdiagnoses are common in patients with DoC, with minimal consciousness often going unrecognized. Patients with DoC should, therefore, be repeatedly assessed with standardized instruments, particularly the Coma Recovery Scale-Revised. The literature search yielded 54 clinical trials, mostly of low quality; there were two randomized controlled clinical trials providing level 1 evidence. The best available evidence for the improvement of impaired consciousness is for the administration of amantadine (4 studies) and for anodal transcranial direct-current stimulation of the left dorsolateral prefrontal cortex in patients in the minimal conscious state (8 studies, 2 systematic reviews). Further important components of rehabilitation include positioning methods and sensory stimulation techniques such as music therapy.
CONCLUSION
For the first time, evidence-based German-language clinical practice guidelines have now become available for the neurological rehabilitation of patients with DoC.
PubMed: 37434290
DOI: 10.3238/arztebl.m2023.0159 -
Sleep Science (Sao Paulo, Brazil) Jun 2023Amantadine has both anti-glutamatergic and dopaminergic action and may improve restless legs syndrome (RLS). We compared the efficacy and adverse-effect profile of...
Amantadine has both anti-glutamatergic and dopaminergic action and may improve restless legs syndrome (RLS). We compared the efficacy and adverse-effect profile of amantadine and ropinirole in RLS. In this randomized, open-label, 12-week flexible-dose exploratory study, RLS patients with international RLS study group severity scale score (IRLSS) > 10 were randomized to receive either amantadine(100-300mg/day) or ropinirole (0.5-2mg/day). Drug dose was increased until week-6 if IRLSS failed to improve by ≥10% of previous visit score. IRLSS change from baseline at week-12 was the primary outcome. Secondary outcomes included change in RLS-related quality of life (RLS-QOL) and insomnia severity index (ISI), along with clinical-global-impression of change/improvement (CGI-I), and proportion of patients with adverse-effects and resulting discontinuation. Twenty-four patients received amantadine and 22 received ropinirole. Both groups had a significant effect for visit*treatment arm (F (2.19,68.15) =4.35;P = 0.01). With a similar baseline IRLSS, both intention-to-treat (ITT) and per-protocol analyses revealed comparable IRLSS until week-8, with ropinirole appearing superior from week-10 to week-12 (week-12 IRLSS, amantadine vs ropinirole:17.0 5.7 vs 9.0 4.4;P < 0.001). ITT analysis at week-12 showed comparable proportion of responders (≥10% IRLSS reduction) in both groups (P = 0.10). Both drugs improved sleep and QOL, but week-12 scores favoured ropinirole [(ISI:14.4 5.7 vs 9.4 4.5; P = 0.001) ;(RLS-QOL:70.4 17.9 vs 86.5 9.8; P = 0.005)]. CGI-I at week-12 favoured ropinirole (Mann-Whitney U = 35.50, S. E = 23.05;P = 0.01). Four patients in amantadine and two in ropinirole group developed adverse effects, with resulting discontinuation in two patients on amantadine. The present study reports equivalent reduction in RLS symptoms with both amantadine and ropinirole until week-8, with the latter being superior from week-10 onwards. Ropinirole was better tolerated.
PubMed: 37425973
DOI: 10.1055/s-0043-1770810 -
Virology Journal Jul 2023SARS-CoV-2 has caused a worldwide pandemic since December 2019 and the search for pharmaceutical targets against COVID-19 remains an important challenge. Here, we...
BACKGROUND
SARS-CoV-2 has caused a worldwide pandemic since December 2019 and the search for pharmaceutical targets against COVID-19 remains an important challenge. Here, we studied the envelope protein E of SARS-CoV and SARS-CoV-2, a highly conserved 75-76 amino acid viroporin that is crucial for virus assembly and release. E protein channels were recombinantly expressed in HEK293 cells, a membrane-directing signal peptide ensured transfer to the plasma membrane.
METHODS
Viroporin channel activity of both E proteins was investigated using patch-clamp electrophysiology in combination with a cell viability assay. We verified inhibition by classical viroporin inhibitors amantadine, rimantadine and 5-(N,N-hexamethylene)-amiloride, and tested four ivermectin derivatives.
RESULTS
Classical inhibitors showed potent activity in patch-clamp recordings and viability assays. In contrast, ivermectin and milbemycin inhibited the E channel in patch-clamp recordings but displayed only moderate activity on the E protein in the cell viability assay, which is also sensitive to general cytotoxic activity of the tested compounds. Nemadectin and ivermectin aglycon were inactive. All ivermectin derivatives were cytotoxic at concentrations > 5 µM, i.e. below the level required for E protein inhibition.
CONCLUSIONS
This study demonstrates direct inhibition of the SARS-CoV-2 E protein by classical viroporin inhibitors. Ivermectin and milbemycin inhibit the E protein channel but their cytotoxicity argues against clinical application.
Topics: Humans; Viroporin Proteins; SARS-CoV-2; Cell Survival; HEK293 Cells; Ivermectin; COVID-19; Severe acute respiratory syndrome-related coronavirus
PubMed: 37422646
DOI: 10.1186/s12985-023-02095-y -
Molecular Neurodegeneration Jul 2023Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant... (Review)
Review
Stroke and late-onset Alzheimer's disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a "gatekeeper" role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca-mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
Topics: Animals; Receptors, N-Methyl-D-Aspartate; Alzheimer Disease; Ischemic Stroke; Memantine; Stroke
PubMed: 37400870
DOI: 10.1186/s13024-023-00636-1 -
Clinical Microbiology and Infection :... Oct 2023The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if pre-emptive treatment with amantadine... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVES
The COVID-19 pandemic has revealed a severe need for effective antiviral treatment. The objectives of this study were to assess if pre-emptive treatment with amantadine for COVID-19 in non-hospitalized persons ≥40 years or adults with comorbidities was able to prevent disease progression and hospitalization. Primary outcomes were clinical status on day 14.
METHODS
Between 9 June 2021 and 27 January 2022, this randomized, double-blinded, placebo-controlled, single-centre clinical trial included 242 subjects with a follow-up period of 90 days. Subjects were randomly assigned 1:1 to either amantadine 100 mg or placebo twice daily for 5 days. The inclusion criteria were confirmed SARS-CoV-2 infection and at least one of (a) age ≥40 years, age ≥18 years and (b) at least one comorbidity, or (c) body mass index ≥30. The study protocol was published at www.
CLINICALTRIALS
gov (unique protocol #02032021) and at www.clinicaltrialregister.eu (EudraCT-number 2021-001177-22).
RESULTS
With 121 participants in each arm, we found no difference in the primary endpoint with 82 participants in the amantadine arm, and 92 participants in the placebo arm with no limitations to activities, respectively, and 25 and 37 with limitations to activities in the amantadine arm and the placebo arm, respectively. No participants in either group were admitted to hospital or died. The OR of having state severity increased by 1 in the amantadine group versus placebo was 1.8 (CI 1.0-3.3, [p 0.051]). On day 7, one participant was hospitalized in each group; throughout the study, this increased to five and three participants for amantadine versus placebo treatment (p 0.72). Similarly, on day 7, there was no difference in the status of oropharyngeal swabs. Most participants (108 in each group) were SARS-CoV-2 RNA positive (p 0.84).
CONCLUSION
We found no effect of amantadine on disease progression of SARS-CoV-2 infection.
Topics: Adult; Humans; Adolescent; COVID-19; SARS-CoV-2; Pandemics; COVID-19 Drug Treatment; RNA, Viral; Amantadine; Treatment Outcome; Double-Blind Method
PubMed: 37353078
DOI: 10.1016/j.cmi.2023.06.023