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Frontiers in Psychiatry 2023Antipsychotic-induced catatonia is an iatrogenic and debilitating adverse reaction, but there is a dearth of recent documented cases. This report describes a 35-year-old...
Antipsychotic-induced catatonia is an iatrogenic and debilitating adverse reaction, but there is a dearth of recent documented cases. This report describes a 35-year-old incarcerated Korean-American male with a history of unspecified psychosis who presented for antipsychotic induced catatonia after administration of haloperidol decanoate intramuscular (200 mg across the span of 1 week). Neurologic workup was performed including MRI, lumbar puncture, and electroencephalography. Despite an approximate month long hospitalization, benzodiazepine challenge, benztropine trial, and amantadine adjunct, our patient continued to experience bradykinesia, waxy flexibility, and mask-like facies, and was minimally verbally responsive. Several challenges in the treatment of incarcerated individuals at the hospital are highlighted in this case report, including adverse reaction to medication, difficulty of care coordination, and limited access to health records among providers.
PubMed: 37720901
DOI: 10.3389/fpsyt.2023.1092253 -
PloS One 2023Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug...
A causal inference study: The impact of the combined administration of Donepezil and Memantine on decreasing hospital and emergency department visits of Alzheimer's disease patients.
Alzheimer's disease is the most common type of dementia that currently affects over 6.5 million people in the U.S. Currently there is no cure and the existing drug therapies attempt to delay the mental decline and improve cognitive abilities. Two of the most commonly prescribed such drugs are Donepezil and Memantine. We formally tested and confirmed the presence of a beneficial drug-drug interaction of Donepezil and Memantine using a causal inference analysis. We applied doubly robust estimators to one of the largest and high-quality medical databases to estimate the effect of two commonly prescribed Alzheimer's disease (AD) medications, Donepezil and Memantine, on the average number of hospital or emergency department visits per year among patients diagnosed with AD. Our results show that, compared to the absence of medication scenario, the Memantine monotherapy, and the Donepezil monotherapy, the combined use of Donepezil and Memantine treatment significantly reduces the average number of hospital or emergency department visits per year by 0.078 (13.8%), 0.144 (25.5%), and 0.132 days (23.4%), respectively. The assessed decline in the average number of hospital or emergency department visits per year is consequently associated with a substantial reduction in medical costs. As of 2022, according to the Alzheimer's Disease Association, there were over 6.5 million individuals aged 65 and older living with AD in the US alone. If patients who are currently on no drug treatment or using either Donepezil or Memantine alone were switched to the combined used of Donepezil and Memantine therapy, the average number of hospital or emergency department visits could decrease by over 613 thousand visits per year. This, in turn, would lead to a remarkable reduction in medical expenses associated with hospitalization of AD patients in the US, totaling over 940 million dollars per year.
Topics: Humans; Alzheimer Disease; Donepezil; Memantine; Hospitals; Emergency Service, Hospital
PubMed: 37708117
DOI: 10.1371/journal.pone.0291362 -
Case Reports in Pediatrics 2023. Organophosphates are chemicals that lead to the accumulation of acetylcholine, causing muscarinic symptoms such as salivation and nicotinic manifestations like muscle...
. Organophosphates are chemicals that lead to the accumulation of acetylcholine, causing muscarinic symptoms such as salivation and nicotinic manifestations like muscle weakness and hypertension and rarely leading to basal ganglia impairment, manifesting as extrapyramidal symptoms. Literature reported that the use of amantadine, an amine that has both antiviral and dopaminergic activities, improves extrapyramidal manifestations. Most of the studies exploring the effect of amantadine were conducted on adults and there are extremely limited data in regards to this topic in Saudi Arabia. Thus, the purpose of this case study is to report the outcome of treating a child who developed extrapyramidal symptoms due to organophosphates poisoning with amantadine. . A 6-year-old boy was found by his family drowsy and drooling with an insecticide bottle beside him. He was brought to the ER and arrested on arrival, and he was eventually revived after 5 minutes of CPR. Then, he developed features of extrapyramidal involvement such as delirium, hyperactivity, akathisia, aphonia, and tremors. He was started on oral amantadine 50 mg once daily and then increased to twice daily for two weeks while admitted. During admission, his symptoms were assessed daily, and an improvement was noticed by his family and the medical team. Upon discharge, he was able to form sentences; tremors were almost resolved; and there was no rigidity or agitation. He was followed up postdischarge and showed significant improvement. He continued amantadine for almost 3 months until the full resolution of his symptoms. . This case illustrates the promising benefits of using amantadine in treating extrapyramidal manifestations following organophosphate ingestion.
PubMed: 37700928
DOI: 10.1155/2023/1632052 -
International Journal of Molecular... Aug 2023Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor...
Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate-glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron-astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA.
Topics: Animals; Rats; Rats, Inbred Lew; Encephalomyelitis, Autoimmune, Experimental; Glutamine; Memantine; Brain; Glutamic Acid; gamma-Aminobutyric Acid; Amino Acids; Homeostasis; Antifibrinolytic Agents
PubMed: 37685956
DOI: 10.3390/ijms241713149 -
Cureus Aug 2023In this report, we present a case series involving four pediatric patients who sustained a traumatic brain injury (TBI) and required intensive care unit admission...
In this report, we present a case series involving four pediatric patients who sustained a traumatic brain injury (TBI) and required intensive care unit admission immediately after the injury. In each of the four cases, amantadine was started during the acute care hospital admission to address agitation. Cases were retrieved from the electronic medical record at the Children's Hospital of Philadelphia between July 1, 2020, and October 31, 2022. This case series describes clinical data on TBI presentation, amantadine administration, patient behavior, and hospital course relating to agitation. This is the first publication that reports the effect of amantadine on agitation in the acute phase of recovery in the pediatric TBI population. Improvement in agitation was observed within 48 hours of amantadine initiation in all four cases based on the primary team progress notes, as well as the quantity of pro re nata medications given for agitation. Resolution of agitation was also observed in all cases, though the time scale varied. No adverse events were reported in relation to amantadine use, supporting other reports that the medication may be well tolerated in the pediatric population. More research is needed to determine the optimal dose of amantadine for the pediatric population and whether amantadine hastens agitation resolution compared to the current standard of care.
PubMed: 37664300
DOI: 10.7759/cureus.42892 -
Frontiers in Neurology 2023The withdrawal of life-sustaining therapies is frequently considered for pediatric patients with severe acute brain injuries who are admitted to the intensive care unit....
The withdrawal of life-sustaining therapies is frequently considered for pediatric patients with severe acute brain injuries who are admitted to the intensive care unit. However, it is worth noting that some children with a resultant poor neurological status may ultimately survive and achieve a positive neurological outcome. Evidence suggests that adults with hidden consciousness may have a more favorable prognosis compared to those without it. Currently, no treatable network disorders have been identified in cases of severe acute brain injury, aside from seizures detectable through an electroencephalogram (EEG) and neurostimulation via amantadine. In this report, we present three cases in which multimodal brain network evaluation played a helpful role in patient care. This evaluation encompassed various assessments such as continuous video EEG, visual-evoked potentials, somatosensory-evoked potentials, auditory brainstem-evoked responses, resting-state functional MRI (rs-fMRI), and passive-based and command-based task-based fMRI. It is worth noting that the latter three evaluations are unique as they have not yet been established as part of the standard care protocol for assessing acute brain injuries in children with suppressed consciousness. The first patient underwent serial fMRIs after experiencing a coma induced by trauma. Subsequently, the patient displayed improvement following the administration of antiseizure medication to address abnormal signals. In the second case, a multimodal brain network evaluation uncovered covert consciousness, a previously undetected condition in a pediatric patient with acute brain injury. In both patients, this discovery potentially influenced decisions concerning the withdrawal of life support. Finally, the third patient serves as a comparative control case, demonstrating the absence of detectable networks. Notably, this patient underwent the first fMRI prior to experiencing brain death as a pediatric patient. Consequently, this case series illustrates the clinical feasibility of employing multimodal brain network evaluation in pediatric patients. This approach holds potential for clinical interventions and may significantly enhance prognostic capabilities beyond what can be achieved through standard testing methods alone.
PubMed: 37638177
DOI: 10.3389/fneur.2023.1227195 -
RSC Advances Aug 2023A series of ten novel compounds were synthesized by incorporating a 1,3 thiazole core into amantadine and their structures were validated using different analytical and...
A series of ten novel compounds were synthesized by incorporating a 1,3 thiazole core into amantadine and their structures were validated using different analytical and spectral methods such as FTIR, EI-MS, H NMR, and C NMR. The antibacterial and enzyme inhibitory properties of these newly synthesized compounds were evaluated. Remarkably, the compounds exhibited significant antibacterial activity against and . Additionally, the inhibitory activities of the synthesized compounds, against α-amylase, α-glucosidase, and urease were investigated. Among the tested compounds, compound 6d demonstrated potent and selective inhibition of α-amylase IC = 97.37 ± 1.52 μM, while acarbose was used as positive control and exhibited IC = 5.17 ± 0.25 μM. Compound 6d and 6e exhibited prominent inhibition against α-glucosidase IC = 38.73 ± 0.80 μM and 41.63 ± 0.26 μM respectively. Furthermore, compound 6d inhibited urease with exceptional efficacy IC = 32.76 μM, while positive control thiourea showed more prominent activity having IC = 1.334 μM. Molecular docking studies disclosed the binding mechanism and affinity of these new inhibitors within the binding sites of various amino acids. To investigate the association between molecular structural characteristics and inhibitory actions of synthesized derivatives, preliminary structure-activity relationship (SAR) studies were performed. These findings indicated that compounds 6a, 6c, 6d and 6e are potential candidates for hit-to-lead follow-up in the drug-discovery process for treating diabetes and hyperglycemia.
PubMed: 37614781
DOI: 10.1039/d3ra05330j -
BMC Neurology Aug 2023Persisting coma is a common complication in (neuro)intensive care in neurological disease such as acute ischemic stroke, intracerebral hemorrhage or subarachnoid...
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.
Topics: Adult; Humans; Amantadine; Brain Injuries; Brain Injuries, Traumatic; Clinical Trials, Phase II as Topic; Coma; Ischemic Stroke; Pilot Projects; Prospective Studies; Proof of Concept Study
PubMed: 37608315
DOI: 10.1186/s12883-023-03345-w -
Journal of Virology Aug 2023The influenza A virus (IAV) M2 protein has proton channel activity, which plays a role in virus uncoating and may help to preserve the metastable conformation of the IAV...
The influenza A virus (IAV) M2 protein has proton channel activity, which plays a role in virus uncoating and may help to preserve the metastable conformation of the IAV hemagglutinin (HA). In contrast to the highly conserved M2 proteins of conventional IAV, the primary sequences of bat IAV H17N10 and H18N11 M2 proteins show remarkable divergence, suggesting that these proteins may differ in their biological function. We, therefore, assessed the proton channel activity of bat IAV M2 proteins and investigated its role in virus replication. Here, we show that the M2 proteins of bat IAV did not fully protect acid-sensitive HA of classical IAV from low pH-induced conformational change, indicating low proton channel activity. Interestingly, the N31S substitution not only rendered bat IAV M2 proteins sensitive to inhibition by amantadine but also preserved the metastable conformation of acid-sensitive HA to a greater extent. In contrast, the acid-stable HA of H18N11 did not rely on such support by M2 protein. When mutant M2(N31S) protein was expressed in the context of chimeric H18N11/H5N1(6:2) encoding HA and NA of avian IAV H5N1, amantadine significantly inhibited virus entry, suggesting that ion channel activity supported virus uncoating. Finally, the cytoplasmic domain of the H18N11 M2 protein mediated rapid internalization of the protein from the plasma membrane leading to low-level expression at the cell surface. However, cell surface levels of H18N11 M2 protein were significantly enhanced in cells infected with the chimeric H18N11/H5N1(6:2) virus. The potential role of the N1 sialidase in arresting M2 internalization is discussed. IMPORTANCE Bat IAV M2 proteins not only differ from the homologous proteins of classical IAV by their divergent primary sequence but are also unable to preserve the metastable conformation of acid-sensitive HA, indicating low proton channel activity. This unusual feature may help to avoid M2-mediated cytotoxic effects and inflammation in bats infected with H17N10 or H18N11. Unlike classical M2 proteins, bat IAV M2 proteins with the N31S substitution mediated increased protection of HA from acid-induced conformational change. This remarkable gain of function may help to understand how single point mutations can modulate proton channel activity. In addition, the cytoplasmic domain was found to be responsible for the low cell surface expression level of bat IAV M2 proteins. Given that the M2 cytoplasmic domain of conventional IAV is well known to participate in virus assembly at the plasma membrane, this atypical feature might have consequences for bat IAV budding and egress.
Topics: Animals; Amantadine; Cell Line; Chiroptera; Hemagglutinin Glycoproteins, Influenza Virus; Influenza A virus; Influenza A Virus, H5N1 Subtype; Protons
PubMed: 37540019
DOI: 10.1128/jvi.00388-23 -
Alzheimer's Research & Therapy Aug 2023There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have...
BACKGROUND
There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population.
OBJECTIVE
To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic.
METHODS
Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019.
RESULTS
Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval [CI] 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020.
CONCLUSIONS
The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.
Topics: Humans; Male; Female; Alzheimer Disease; Donepezil; Rivastigmine; Memantine; Cholinesterase Inhibitors; Retrospective Studies; Pandemics; Prevalence; Piperidines; Phenylcarbamates; Indans; COVID-19; Galantamine
PubMed: 37537656
DOI: 10.1186/s13195-023-01271-0