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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 -
Current Pharmaceutical Design 2020The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to... (Review)
Review
The global burden of neurodegenerative diseases is alarmingly increasing in parallel to the aging of population. Although the molecular mechanisms leading to neurodegeneration are not completely understood, excitotoxicity, defined as the injury and death of neurons due to excessive or prolonged exposure to excitatory amino acids, has been shown to play a pivotal role. The increased release and/or decreased uptake of glutamate results in dysregulation of neuronal calcium homeostasis, leading to oxidative stress, mitochondrial dysfunctions, disturbances in protein turn-over and neuroinflammation. Despite the anti-excitotoxic drug memantine has shown modest beneficial effects in some patients with dementia, to date, there is no effective treatment capable of halting or curing neurodegenerative diseases such as Alzheimer's disease, Parkinson disease, Huntington's disease or amyotrophic lateral sclerosis. This has led to a growing body of research focusing on understanding the mechanisms associated with the excitotoxic insult and on uncovering potential therapeutic strategies targeting these mechanisms. In the present review, we examine the molecular mechanisms related to excitotoxic cell death. Moreover, we provide a comprehensive and updated state of the art of preclinical and clinical investigations targeting excitotoxic- related mechanisms in order to provide an effective treatment against neurodegeneration.
Topics: Alzheimer Disease; Glutamic Acid; Humans; Memantine; Neurons
PubMed: 31931694
DOI: 10.2174/1381612826666200113162641 -
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 -
Journal of Fish Diseases Mar 2022Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is...
Outbreaks of viral encephalopathy and retinopathy (VER) in marine and freshwater species severely devastate the aquaculture worldwide. The causative agent of VER is nervous necrosis virus (NNV), which mainly infects the early developmental stages of fish, limiting the effectiveness of vaccines. To counter this case, the anti-NNV potentials of nine drugs with broad-spectrum antiviral activity were explored using ribavirin as a positive drug. Toxicity of the selected drugs to SSN-1 cells and grouper was firstly evaluated to determine the safety concentrations. For screening in vitro, amantadine and oseltamivir phosphate can relieve the cytopathic effects and inhibit NNV replication with the 90% inhibitory concentrations (IC ) of 38.74 and 106.75 mg/L, respectively. Amantadine has a stronger anti-NNV activity than ribavirin at the with- and post-NNV infection stages, indicating that it is a potential therapeutic agent against VER by acting directly on NNV. Similarly, amantadine also has a strong anti-NNV activity in vivo with the IC of 27.91 mg/L at the 7 days post-infection, while that was 73.25 mg/L for ribavirin. Following exposure to amantadine (40 mg/L) and ribavirin (100 mg/L) for 7 days, the survival rates of NNV-infected grouper were increased to 44% and 39%, respectively. The maximum amantadine content (11.88 mg/Kg) in grouper brain was reached following exposure for 24 hr, and amantadine can be quickly excreted from fish, reducing the risk of drug residue. Results so far indicated that amantadine is a promising therapeutic agent against NNV in aquaculture, providing an effective strategy for VER control at the early developmental stages of fish.
Topics: Amantadine; Animals; Brain Diseases; Fish Diseases; Nodaviridae; RNA Virus Infections; Retinal Diseases
PubMed: 34962648
DOI: 10.1111/jfd.13574 -
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 -
BMJ Case Reports Jan 2024
Topics: Humans; Livedo Reticularis; Amantadine; Parkinson Disease; Antiparkinson Agents
PubMed: 38216170
DOI: 10.1136/bcr-2023-257492 -
Practical Neurology Oct 2023Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat...
Amantadine is an N-methyl-d-aspartate receptor agonist with secondary dopaminergic activity that is used to treat Parkinson's disease-related dyskinesia and to treat fatigue in multiple sclerosis. It is primarily renally excreted and so impaired kidney function prolongs its half-life and may lead to toxicity. We describe a woman with multiple sclerosis taking amantadine who developed acute renal impairment, which triggered florid visual hallucinations that resolved on stopping the medication.
Topics: Female; Humans; Antiparkinson Agents; Levodopa; Amantadine; Hallucinations; Multiple Sclerosis
PubMed: 37419676
DOI: 10.1136/pn-2023-003723 -
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 -
Headache Sep 2021
Topics: Excitatory Amino Acid Antagonists; Humans; Memantine; Migraine Disorders
PubMed: 34510445
DOI: 10.1111/head.14201 -
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