Neurotransmitters and pharmacology
Mark J. Ashley, David A. Hovda in Traumatic Brain Injury, 2017
Several glutamate receptor antagonists are available for experimental work in animals, and some of these have been described previously for both the AMPA and NMDA receptors. There are only two clinically used drugs that have NMDA antagonist properties that are believed to contribute to their therapeutic effects or side effects in a significant way. These include memantine (Namenda®) and ketamine. However, there are other drugs on the market that have minor glutamate receptor antagonistic action (e.g., felbamate and amantadine) along with other effects. Glutamate receptor antagonists are of interest for treating such disorders as epilepsy, ischemic stroke, and posttraumatic brain injury. Moreover, such drugs are believed to have some potential in various neurodegenerative diseases, such as Huntington’s chorea, Alzheimer’s disease, Fredrick’s ataxia, and others. Indeed, memantine is used to treat Alzheimer’s disease. Thus, the search for new glutamate receptor blockers continues to be active research. One disappointing aspect of this work has been psychotic-like side effects that have accompanied the testing of some NMDA antagonists in humans.
Fibromyalgia
Sahar Swidan, Matthew Bennett in Advanced Therapeutics in Pain Medicine, 2020
Memantine, a NMDAR antagonist typically used to treat dementia in Alzheimer’s disease, was studied in 63 patients with fibromyalgia in a double-blind, parallel randomized placebo controlled trial.148 Memantine was dosed at 20 mg/day after a 1-month titration period, and assessments of pain, global function, clinical impression, depression, anxiety, and quality of life were completed at baseline, post-treatment, and at 3- and 6-month follow-up. Memantine significantly reduced pain and increased pain threshold, and improved all other secondary outcomes with the exception of anxiety at 6 months. Compared with placebo, the absolute risk reduction obtained with memantine was 16.13% (95% confidence interval = 2.0% to 32.6%), and the number needed to treat was 6.2 (95% confidence interval = 3 to 47). Memantine was well-tolerated, with dizziness (eight patients) and headache (four patients) the most common side effects.
Ethical issues in dementia
Gurcharan S Rai, Jeremy Playfer, Marshall B Kapp, Gurdeep S Rai, Iva Blackman in Medical Ethics and the Elderly, 2018
At present there are four drugs available for use in patients with Alzheimer’s disease, namely donepezil (a piperidine-based reversible inhibitor of acetylcholinesterase), rivastigmine (a centrally selective inhibitor of acetylcholinesterase), gallantamine (a competitive acetylcholinesterase inhibitor) and memantine (a voltage-dependent, moderate-affinity non-competitive NMDA-receptor antagonist). Donepezil, rivastigmine and gallantamine are recommended for patients with moderate severity only (MMSE 10–20). Memantine is no longer recommended for patients in the later stages of the disease, except as part of well-designed clinical study. In line with NICE guidelines, only specialists in the care of patients with dementia (i.e. psychiatrists, neurologists and physicians specialising in care of the elderly) are allowed to prescribe with regular review at six months using the Mini-Mental State Examination (MMSE) score, global, functional and behavioural assessments. Of course, MMSE may not be appropriate as a tool for assessment for those from different ethnic groups and patients with disabilities. In these patients it is important to consider using alternative tests such as the Cambridge Cognitive Examination (CAMCOG), Modified Cambridge Examination for Mental Disorders of the Elderly (CAMDEX), Dementia Questionnaire for Mentally Retarded Persons (DMR) or Dementia Scale for Down’s Syndrome (DSS). None of these drugs is curative, and not all patients with Alzheimer’s disease show a response to them.
Emerging drugs in the treatment of chronic cough
Published in Expert Opinion on Emerging Drugs, 2023
Danica Brister, Mustafaa Wahab, Moaaz Rashad, Nermin Diab, Martin Kolb, Imran Satia
N-methyl-d-aspartate receptors (NMDARs) are present throughout the central nervous system (CNS), are the target for the excitatory neurotransmitter glutamate and are thought to be pivotal for the initiation and maintenance of CNS plasticity in neuropathic pain [80,81]. Blocking NMDARs could therefore be a potential therapeutic target in RCC/UCC. Dextromethorphan, a weak antagonist of NMDARs, is used in many over-the-counter antitussive preparations, but compared with placebo, it reduces acute cough by no more than 17% [82]. Memantine is an approved medication for Alzheimer’s disease and is a low-affinity uncompetitive NMDAR antagonist, preferentially targeting already activated receptors. Importantly, memantine has previously been shown to block experimentally evoked coughs by inhalation of citric acid and bradykinin in conscious guinea pigs [83]. A small open-label feasibility and tolerability dose escalation study in 14 patients with RCC/UCC demonstrated that most patients could not tolerate a dose greater than 10 mg, with a median tolerated duration of only 38.5 days [84]. The most common adverse events reported were dizziness, tiredness, and drowsiness. Although this was not an efficacy study, there no significant improvement in awake cough frequency after treatment with memantine.
Cortical projection neurons as a therapeutic target in multiple sclerosis
Published in Expert Opinion on Therapeutic Targets, 2020
Tatjana Beutel, Julia Dzimiera, Hannah Kapell, Maren Engelhardt, Achim Gass, Lucas Schirmer
Another approach in the protection of excitatory neurons could be by pharmacological modulation of glutamate receptors at the postsynaptic membrane. Memantine, which is used in the treatment of Alzheimer’s disease, suppressed severity and duration of EAE [145]. Unfortunately, clinical trials with MS patients diagnosed with cognitive dysfunction treated with memantine had no benefit compared to those in the placebo group [146,147]. This data suggests that neuronal loss was already too substantial and could not be rescued by glutamate modulation or that modulation of glutamate receptors needs to be more specific considering that there are allelic variants of NMDA receptors [148]. Another possibility of preventing excitotoxicity could be by activating genes expressing glutamate transporters in astrocytes. Beta-lactam antibiotics are known for acting as a transcriptional factor inducing glutamate transporter expression [149]. Animal studies have shown that the beta-lactam antibiotic ceftriaxone increased the expression of the glutamate transporter EAAT2/GLT-1 in astocytes, which led to a neuroprotective effect in an ALS mouse model [149].
Mechanistic comparison of current pharmacological treatments and novel phytochemicals to target amyloid peptides in Alzheimer’s and neurodegenerative diseases
Published in Nutritional Neuroscience, 2018
Neelima Ayyalasomayajula, Challa Suresh
Memantine: Memantine is marketed under the brand name Namenda, introduced in 2003 to treat moderate-to-severe AD.Mechanism of action: Memantine can interact with multiple ligand gated ion channels and act as antagonist for Glutaminergic (NMDA receptor), dopaminergic (D2), Cholinergic (ACh), seratonergic (5-HT3), sigmaergic (σ1) systems.82–86 At high concentrations, it inhibits NMDA receptor-dependent excitotoxicity and regulates synaptic plasticity seen in dementia of AD patients.87Side effects: Continuous administration of Memantine has side effects, including nervous system disorders (dizziness, seizures), gastrointestinal problems (vomiting, constipation, pancreatitis), psychiatric disorders (hallucinations and confusion) nausea, diarrhea, headache, fatigue, blurred vision, increased muscle weakness, and difficulty in walking, as reported in a review.88
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