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Trade names | Dimebon |
Routes of administration | Oral |
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ECHA InfoCard | 100.119.053 |
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Formula | C21H25N3 |
Molar mass | 319.452 g·mol−1 |
Latrepirdine (INN, also known as dimebolin and sold as Dimebon) is an antihistamine drug which has been used clinically in Russia since 1983. [1]
Research was conducted in both Russia and western nations into potential applications as a neuroprotective drug to treat Alzheimer's disease and, possibly, as a nootropic, as well. [2] After a major phase III clinical trial for Alzheimer's disease (AD) treatment failed to show any benefit, three other AD trials continued. [3] Major industry-based development in this indication essentially stopped after another Phase III trial suffered the same fate in 2012. [4] Latrepirdine failed in the phase III trial for Huntington disease. [5]
Latrepirdine is an orally active, small molecule compound that has been shown to inhibit brain cell death in animal models of Alzheimer's disease and Huntington's disease. Research suggests it may also have cognition-enhancing effects in healthy individuals, in the absence of neurodegenerative disease pathology. [6] However, because of negative results in human clinical trials, the drug remains unlicensed for any neurodegenerative condition. [3] [5]
Latrepirdine attracted renewed interest in 2009 after being shown in small preclinical trials to have positive effects on persons suffering from Alzheimer's disease. Animal studies showing potential beneficial effects on Alzheimer's disease models were shown in Russian research in 2000. [7] Preliminary results from human trials have also been promising. In an initial six-month phase II trial, results have shown significant improvement over placebo at 12 months. [8] Latrepirdine showed promising results in a phase III-equivalent, double-blind trial in Russia with mild–moderate stage patients. [9] [10] In April 2009, Pfizer and Medivation initiated a phase III trial (CONCERT study) aiming for FDA approval. [11] In March 2010, Pfizer announced that this clinical trial failed to show any benefit for the treatment of Alzheimer's disease patients. [3]
Numerous phase III trials for AD were recruiting in 2009. [12] [13] [14] [15]
In July 2009, Pfizer and Medivation announced that "latrepirdine" was to be the proposed international nonproprietary name for latrepirdine for the treatment of Alzheimer's.[ citation needed ]
In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease. [16]
With CONCERT, the remaining Pfizer and Medivation Phase III trial for latrepirdine in Alzheimer's disease failed in 2012, effectively ending the development in this indication. [4]
A Cochrane meta-analysis of the three pivotal phase III efficacy trials found no significant effect of latrepirdine on cognition and function in mild-to-moderate Alzheimer's patients, though there appears to be a modest benefit for overall behavior disturbances. [17]
In April 2011, latrepirdine failed in a phase III clinical trial of patients affected with Huntington's disease. [5] The trial was sponsored by Medivation Inc. and Pfizer.
Latrepirdine appears to operate through multiple mechanisms of action, both blocking the action of neurotoxic beta-amyloid proteins and inhibiting L-type calcium channels, [18] modulating the action of AMPA and NMDA glutamate receptors, [19] and may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores, [20] which are believed to play a role in the cell death that is associated with neurodegenerative diseases and the aging process. [21] It also blocks a number of other receptors, including α-adrenergic, 5-HT2C, 5-HT5A, and 5-HT6. [22] Notably, latrepirdine lacks any anticholinergic effects. [23]
Donepezil, sold under the brand name Aricept among others, is a medication used to treat dementia of the Alzheimer's type. It appears to result in a small benefit in mental function and ability to function. Use, however, has not been shown to change the progression of the disease. Treatment should be stopped if no benefit is seen. It is taken by mouth or via a transdermal patch.
Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation. It is a widely explored treatment option for many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, spinal cord injury, and acute management of neurotoxin consumption. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration are the same. Common mechanisms of neuronal injury include decreased delivery of oxygen and glucose to the brain, energy failure, increased levels in oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and protein aggregation. Of these mechanisms, neuroprotective treatments often target oxidative stress and excitotoxicity—both of which are highly associated with CNS disorders. Not only can oxidative stress and excitotoxicity trigger neuron cell death but when combined they have synergistic effects that cause even more degradation than on their own. Thus limiting excitotoxicity and oxidative stress is a very important aspect of neuroprotection. Common neuroprotective treatments are glutamate antagonists and antioxidants, which aim to limit excitotoxicity and oxidative stress respectively.
A neurodegenerative disease is caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic. Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.
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Xaliproden is a drug which acts as a 5HT1A agonist. It has neurotrophic and neuroprotective effects in vitro, and has been proposed for use in the treatment of several neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and Alzheimer's disease.
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Solanezumab is a monoclonal antibody being investigated by Eli Lilly as a neuroprotector for patients with Alzheimer's disease. The drug originally attracted extensive media coverage proclaiming it a breakthrough, but it has failed to show promise in Phase III trials.
P7C3 (pool 7, compound 3) is a drug related to latrepirdine (dimebon) which has neuroprotective and proneurogenic effects and may be potentially useful for the treatment of Alzheimer's disease and similar neurodegenerative disorders. The pharmacological effects of P7C3 in vitro resemble those of endogenous proneurogenic peptides such as fibroblast growth factor 1 (FGF-1), and the proneurogenic activity of P7C3 was around thirty times that of latrepirdine when they were compared in mice. P7C3 was chosen for further animal studies on the basis of favorable pharmacokinetic factors, such as its high oral bioavailability and long duration of action, but several other related compounds showed similar activity such as the more potent fluorinated analogue P7C3A20 which is up to ten times stronger again, and the methoxy analogue P7C3-OMe, for which it was determined that the (R) enantiomer is the active form.
PBT2 is a safe-for-human-use Zinc ionophore and an experimental drug candidate. It is a second-generation 8-hydroxyquinoline analog intended to be a successor to clioquinol and a potential treatment of Alzheimer's disease and Huntington's disease.
Crenezumab is a fully humanized monoclonal antibody against human 1-40 and 1-42 beta amyloid, which is being investigated as a treatment of Alzheimer's disease. Crenezumab is highly homologous to solanezumab, another monoclonal antibody targeting amyloid-β peptides. In June 2022, the US National Institutes of Health announced that the drug failed as a medication for early-onset Alzheimer's disease following the results of a decade-long clinical trial.
Brilaroxazine, also known as oxaripiprazole, is an investigational atypical antipsychotic which is under development by Reviva Pharmaceuticals for the treatment of neuropsychiatric and inflammatory disorders. It has currently completed the first of two phase III clinical trials for schizophrenia. Reviva Pharmaceuticals also intends to investigate brilaroxazine for the treatment of bipolar disorder, major depressive disorder, attention deficit hyperactivity disorder (ADD/ADHD), psychosis/agitation associated with Alzheimer's disease, Parkinson's disease psychosis, as well as the inflammatory disorders pulmonary arterial hypertension (PAH), idiopathic pulmonary fibrosis (IPF), and psoriasis. The FDA granted brilaroxazine orphan drug designation for the treatment of PAH and IPF.
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Lecanemab, sold under the brand name Leqembi, is a monoclonal antibody medication used for the treatment of Alzheimer's disease. Lecanemab is an amyloid beta-directed antibody. It is given via intravenous infusion. The most common side effects of lecanemab include headache, infusion-related reactions, and amyloid-related imaging abnormalities, a side effect known to occur with the class of antibodies targeting amyloid.
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