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Journal of Neural Transmission (Vienna,... Feb 2021The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use... (Review)
Review
The aim of the current review was to provide a new, in-depth insight into possible pharmacological targets of amantadine to pave the way to extending its therapeutic use to further indications beyond Parkinson's disease symptoms and viral infections. Considering amantadine's affinities in vitro and the expected concentration at targets at therapeutic doses in humans, the following primary targets seem to be most plausible: aromatic amino acids decarboxylase, glial-cell derived neurotrophic factor, sigma-1 receptors, phosphodiesterases, and nicotinic receptors. Further three targets could play a role to a lesser extent: NMDA receptors, 5-HT3 receptors, and potassium channels. Based on published clinical studies, traumatic brain injury, fatigue [e.g., in multiple sclerosis (MS)], and chorea in Huntington's disease should be regarded potential, encouraging indications. Preclinical investigations suggest amantadine's therapeutic potential in several further indications such as: depression, recovery after spinal cord injury, neuroprotection in MS, and cutaneous pain. Query in the database http://www.clinicaltrials.gov reveals research interest in several further indications: cancer, autism, cocaine abuse, MS, diabetes, attention deficit-hyperactivity disorder, obesity, and schizophrenia.
Topics: Amantadine; Diamond; Humans; Huntington Disease; Parkinson Disease; Receptors, N-Methyl-D-Aspartate
PubMed: 33624170
DOI: 10.1007/s00702-021-02306-2 -
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 -
Science Advances Dec 2023Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor...
Cortical spreading depolarization (CSD) is a promising target for neuroprotective therapy in traumatic brain injury (TBI). We explored the effect of NMDA receptor antagonism on electrically triggered CSDs in healthy and brain-injured animals. Rats received either one moderate or four daily repetitive mild closed head impacts (rmTBI). Ninety-three animals underwent craniectomy with electrocorticographic (ECoG) and local blood flow monitoring. In brain-injured animals, ketamine or memantine inhibited CSDs in 44 to 88% and 50 to 67% of cases, respectively. Near-DC/AC-ECoG amplitude was reduced by 44 to 75% and 52 to 67%, and duration by 39 to 87% and 61 to 78%, respectively. Daily memantine significantly reduced spreading depression and oligemia following CSD. Animals ( = 31) were randomized to either memantine (10 mg/kg) or saline with daily neurobehavioral testing. Memantine-treated animals had higher neurological scores. We demonstrate that memantine improved neurovascular function following CSD in sham and brain-injured animals. Memantine also prevented neurological decline in a blinded, preclinical randomized rmTBI trial.
Topics: Rats; Animals; Memantine; Brain Injuries, Traumatic; Brain; Electrocorticography; Receptors, N-Methyl-D-Aspartate
PubMed: 38091390
DOI: 10.1126/sciadv.adj2417 -
Tremor and Other Hyperkinetic Movements... 2023There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin... (Review)
Review
BACKGROUND
There are several well-known treatments for Restless Legs Syndrome (RLS), including dopamine agonists (pramipexole, ropinirole, rotigotine), anticonvulsants (gabapentin and its analogs, pregabalin), oral or intravenous iron, opioids and benzodiazepines. However, in clinical practice, treatment is sometimes limited due to incomplete response or side effects and it is necessary to be aware of other treatment options for RLS, which is the purpose of this review.
METHODS
We performed a narrative review detailing all of the lesser known pharmacological treatment literature on RLS. The review purposefully excludes well-established, well-known treatments for RLS which are widely accepted as treatments for RLS in evidence-based reviews. We also have emphasized the pathogenetic implications for RLS of the successful use of these lesser known agents.
RESULTS
Alternative pharmacological agents include clonidine which reduces adrenergic transmission, adenosinergic agents such as dipyridamole, glutamate AMPA receptor blocking agents such as perampanel, glutamate NMDA receptor blocking agents such as amantadine and ketamine, various anticonvulsants (carbamazepine/oxcarbazepine, lamotrigine, topiramate, valproic acid, levetiracetam), anti-inflammatory agents such as steroids, as well as cannabis. Bupropion is also a good choice for the treatment of co-existent depression in RLS because of its pro-dopaminergic properties.
DISCUSSION
Clinicians should first follow evidence-based review recommendations for the treatment of RLS but when the clinical response is either incomplete or side effects are intolerable other options can be considered. We neither recommend nor discourage the use of these options, but leave it up to the clinician to make their own choices based upon the benefit and side effect profiles of each medication.
Topics: Humans; Anticonvulsants; Restless Legs Syndrome; Carbamazepine; Gabapentin; Glutamates
PubMed: 36873914
DOI: 10.5334/tohm.739 -
Toxics Feb 2023Amantadine exposure can alter biological processes in sea cucumbers, which are an economically important seafood in China. In this study, amantadine toxicity in was...
Amantadine exposure can alter biological processes in sea cucumbers, which are an economically important seafood in China. In this study, amantadine toxicity in was analyzed by oxidative stress and histopathological methods. Quantitative tandem mass tag labeling was used to examine changes in protein contents and metabolic pathways in intestinal tissues after exposure to 100 µg/L amantadine for 96 h. Catalase activity significantly increased from days 1 to 3 of exposure, but it decreased on day 4. Superoxide dismutase and glutathione activities were inhibited throughout the exposure period. Malondialdehyde contents increased on days 1 and 4 but decreased on days 2 and 3. Proteomics analysis revealed 111 differentially expressed proteins in the intestines of after amantadine exposure compared with the control group. An analysis of the involved metabolic pathways showed that the glycolytic and glycogenic pathways may have increased energy production and conversion in after amantadine exposure. The NF-κB, TNF, and IL-17 pathways were likely induced by amantadine exposure, thereby activating NF-κB and triggering intestinal inflammation and apoptosis. Amino acid metabolism analysis showed that the leucine and isoleucine degradation pathways and the phenylalanine metabolic pathway inhibited protein synthesis and growth in This study investigated the regulatory response mechanisms in intestinal tissues after exposure to amantadine, providing a theoretical basis for further research on amantadine toxicity.
PubMed: 36976991
DOI: 10.3390/toxics11030226 -
COVID Nov 2022Coronavirus disease 2019 (COVID-19) has had devastating effects worldwide, with particularly high morbidity and mortality in outbreaks on residential care facilities....
Coronavirus disease 2019 (COVID-19) has had devastating effects worldwide, with particularly high morbidity and mortality in outbreaks on residential care facilities. Amantadine, originally licensed as an antiviral agent for therapy and prophylaxis against influenza A virus, has beneficial effects on patients with Parkinson's disease and is used for treatment of Parkinson's disease, multiple sclerosis, acquired brain injury, and various other neurological disorders. Recent observational data suggest an inverse relationship between the use of amantadine and COVID-19. Adamantanes, including amantadine and rimantadine, are reported to have in vitro activity against severe acute respiratory syndrome coronavirus (SARS-CoV) and, more recently, SARS-CoV-2. We hypothesized that adamantanes have antiviral activity against SARS-CoV-2, including variant strains. To assess the activity of adamantanes against SARS-CoV-2, we used in vitro and in vivo models of infection. We established that amantadine, rimantadine, and tromantadine inhibit the growth of SARS-CoV-2 in vitro in cultured human epithelial cells. While neither rimantadine nor amantadine reduces lung viral titers in mice infected with mouse-adapted SARS-CoV-2, rimantadine significantly reduces viral titers in the lungs in golden Syrian hamsters infected with SARS-CoV-2. In summary, rimantadine has antiviral activity against SARS-CoV-2 in human alveolar epithelial cells and in the hamster model of SARS-CoV-2 lung infection. The evaluation of amantadine or rimantadine in human randomized controlled trials can definitively address applications for the treatment or prevention of COVID-19.
PubMed: 37274537
DOI: 10.3390/covid2110111 -
The Cochrane Database of Systematic... Nov 2022Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Review)
Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 12, 2014.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adults treated with cranial irradiation.
SEARCH METHODS
For this review update we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE via Ovid, Embase via Ovid, and PsycInfo via Ovid to 12 September 2022.
SELECTION CRITERIA
We included randomised controlled (RCTs) trials that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (MK, JD) independently extracted data from selected studies and carried out a risk of bias assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Eight studies met the inclusion criteria and were included in this updated review. Six were from the original version of the review, and two more were added when the search was updated. Nineteen further studies were assessed as part of this update but did not fulfil the inclusion criteria. Of the eight included studies, four studies investigated "prevention" of cognitive problems (during radiotherapy and follow-up) and four studies investigated "amelioration" (interventions to treat cognitive impairment as a late complication of radiotherapy). There were five pharmacological studies (two studies on prevention and three in amelioration) and three non-pharmacological studies (two on prevention and one in amelioration). Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Studies in early radiotherapy treatment phase (five studies) Pharmacological studies in the "early radiotherapy treatment phase" were designed to prevent or ameliorate cognitive deficits and included drugs used in dementia (memantine) and fatigue (d-threo-methylphenidate hydrochloride). Non-pharmacological studies in the "early radiotherapy treatment phase" included a ketogenic diet and a two-week cognitive rehabilitation and problem-solving programme. In the memantine study, the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The d-threo-methylphenidate hydrochloride study found no statistically significant difference between arms, with few adverse events. The study of a calorie-restricted ketogenic diet found no effect, although a lower than expected calorie intake in the control group complicates interpretation of the results. The study investigating the utility of a rehabilitation program did not carry out a statistical comparison of cognitive performance between groups. Studies in delayed radiation or late effect phase (four studies) The "amelioration" pharmacological studies to treat cognitive complications of radiotherapy included drugs used in dementia (donepezil) or psychostimulants (methylphenidate and modafinil). Non-pharmacological measures included cognitive rehabilitation and problem solving (Goal Management Training). These studies included patients with cognitive problems at entry who had "stable" brain cancer. The donepezil study did not find an improvement in the primary cognitive outcome of overall cognitive performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. A study comparing methylphenidate with modafinil found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. Another study comparing two different doses of modafinil combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The Goal Management Training study suggested a benefit of the intervention, a behavioural intervention that combined mindfulness and strategy training, on executive function and processing speed. There were a number of limitations across studies and few were without high risks of bias.
AUTHORS' CONCLUSIONS
In this update, limited additional evidence was found for the treatment or amelioration of cognitive deficits in adults treated with cranial irradiation. As concluded in the original review, there is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil, methylphenidate and modafinil may have a role in treating cognitive deficits in adults with brain tumours who have been treated with cranial irradiation; patient withdrawal affected the statistical power of these studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher certainty of evidence. There is evidence from only a single small study to support non-pharmacological interventions in the amelioration of cognitive deficits. Further research is required.
Topics: Adult; Humans; Modafinil; Donepezil; Memantine; Quality of Life; Cognitive Dysfunction; Cranial Irradiation; Cognition; Methylphenidate; Brain Neoplasms; Fatigue; Dementia
PubMed: 36427235
DOI: 10.1002/14651858.CD011335.pub3 -
Medicine Apr 2024Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Dementia severity was assessed mainly through cognitive function, psychobehavioral symptoms, and daily living ability. Currently, there are not many drugs that can be selected to treat mild to moderate AD, and the value of drugs remains controversial.
OBJECTIVE
The aim of this study is to quantitatively evaluate the efficacy and safety of cholinesterase inhibitors (ChEIs), memantine, and sodium oligomannate (GV-971) in the treatment of patients with AD. Additionally, molecular docking analysis will be used to investigate the binding affinities of donepezil, galantamine, rivastigmine, and memantine with key receptor proteins associated with AD, including beta-amyloid (Abeta), microtubule-associated protein (MAP), apolipoprotein E4 (APOE4), and Mitofusin-2 (MFN2), to further validate the results of the meta-analysis.
METHODS
We obtained clinical trials characterized by randomization, placebo control, and double-blinded methodologies concerning ChEIs, memantine, and GV-971. Statistical analysis was performed using Review Manager Version 5.4 software. Molecular docking was also conducted to evaluate the results.
RESULTS
All drugs improved the cognitive function, with the effect value ranging from -1.23 (95% CI -2.17 to -0.30) for 20 mg memantine to -3.29 (95% CI -4.14 to -2.45) for 32 mg galantamine. Although 32 mg galanthamine and GV-971 did not improve the clinicians' Global Impression of Change scale, other drugs showed significant results compared with placebo. On NPI, only 10 mg of donepezil and 24 mg of galantamine had improvement effects. On ADCS/ADL, only 20 mg memantine and 900 mg GV-971 had no significant difference from the placebo. Donepezil 5 mg and GV-971 900 mg did not increase the drug withdrawal rates due to various reasons or adverse reactions when compared to the placebo. Donepezil demonstrated superior binding to the protein and exhibited greater efficacy compared to other drugs.
CONCLUSION
ChEIs, memantine, and GV-971 all can slow the progression of AD but have different effects on respective assessments. Donepezil and GV-971 were relatively well tolerated.
Topics: Humans; Alzheimer Disease; Donepezil; Galantamine; Memantine; Molecular Docking Simulation; Cholinesterase Inhibitors; Rivastigmine
PubMed: 38640313
DOI: 10.1097/MD.0000000000037799 -
Journal of Feline Medicine and Surgery May 2024Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a... (Review)
Review
Chronic pain is a significant welfare concern in cats, and neuropathic pain, which arises from aberrant processing of sensory signals within the nervous system, is a subcategory of this type of pain. To comprehend this condition and how multimodal pharmacotherapy plays a central role in alleviating discomfort, it is crucial to delve into the anatomy of nociception and pain perception. In addition, there is an intricate interplay between emotional health and chronic pain in cats, and understanding and addressing the emotional factors that contribute to pain perception, and vice versa, is essential for comprehensive care.Clinical approach:Neuropathic pain is suspected if there is abnormal sensation in the area of the distribution of pain, together with a positive response to trial treatment with drugs effective for neuropathic pain. Ideally, this clinical suspicion would be supported by confirmation of a lesion at this neurolocalisation using diagnostic modalities such as MRI and neuroelectrophysiology. Alternatively, there may be a history of known trauma at that site. A variety of therapies, including analgesic, anti-inflammatory and adjuvant drugs, and neuromodulation (eg, TENS or acupuncture), can be employed to address different facets of pain pathways.Aim:This review article, aimed at primary care/ general practitioners, focuses on the identification and management of neuropathic pain in cats. Three case vignettes are included and a structured treatment algorithm is presented to guide veterinarians in tailoring interventions.Evidence base:The review draws on current literature, where available, along with the author's extensive experience and research.
Topics: Cats; Animals; Neuralgia; Cat Diseases; Pain Management; Analgesics; Combined Modality Therapy
PubMed: 38710218
DOI: 10.1177/1098612X241246518 -
Advances in Clinical and Experimental... Oct 2021Ischemia-reperfusion models are used to evaluate treatment options that may minimize cellular damage after ischemia.
BACKGROUND
Ischemia-reperfusion models are used to evaluate treatment options that may minimize cellular damage after ischemia.
OBJECTIVES
To investigate the effects of amantadine and topiramate on apoptosis and cellular oxidative damage.
MATERIAL AND METHODS
This experiment was performed using 30 male Wistar albino rats. The right internal carotid artery was identified and clamped with an aneurysm clip under general anesthesia, except for animals in the control group. After 10 min of occlusion, the aneurysm clip was removed, allowing reperfusion. After reperfusion and a waiting period of 12 h, the test and control groups were intraperitoneally administered the following solutions: the sham group received 10 mg/kg of isotonic solution, the amantadine group received 20 mg/kg of amantadine, the topiramate group received 40 mg/kg of topiramate, and the amantadine-topiramate group received 20 mg/kg of amantadine and 40 mg/kg of topiramate. After 24 h, the rats were euthanized.
RESULTS
Apoptosis was evaluated using the TUNEL method. Total antioxidant status (TAS), total oxidant status (TOS), total thiol, and ischemia-modified albumin (IMA) levels were measured in both brain tissue and serum samples. The rate of apoptosis in the sham and amantadine groups increased significantly compared to the control group and the non-ischemic counter hemisphere. In the amantadine-topiramate group, both serum TAS and tissue thiol levels decreased. Tissue TOS levels were significantly higher in the topiramate group compared to all other test groups. Tissue TAS levels were significantly higher in the amantadine group compared to all other test groups.
CONCLUSIONS
This experimental ischemia-reperfusion model revealed that topiramate reduces apoptosis in the early period after ischemia and that its combination with amantadine does not provide additional benefits against cell death. However, topiramate did not have an inhibitory effect on the oxidative stress biomarkers used in our study (TAS, TOS, IMA, and thiol). Studies that reveal the neuroprotective mechanism of action and long-term effects of topiramate are needed to complement this study.
Topics: Amantadine; Animals; Antioxidants; Biomarkers; Brain Ischemia; Male; Oxidative Stress; Rats; Rats, Wistar; Reperfusion; Reperfusion Injury; Serum Albumin; Topiramate
PubMed: 34510842
DOI: 10.17219/acem/138327