ladostigil hemitartrate (TV-3326) / Avraham - LARVOL DELTA

Therapeutic agents for Alzheimer's disease: a critical appraisal. (PubMed, Front Aging Neurosci) - "Rosiglitazone is used to treat diabetes, a risk factor for AD, but failed in a clinical trial because it was given to subjects that already had dementia. Chronic oral administration to aging rats prevented the decline in memory and suppressed overexpression of genes adversely affecting synaptic function in relevant brain regions. In a phase 2 trial, ladostigil reduced the decline in short-term memory and in whole brain and hippocampal volumes in human subjects with mild cognitive impairment and had no more adverse effects than placebo."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Diabetes • Metabolic Disorders

Ladostigil Reduces the Adenoside Triphosphate/Lipopolysaccharide-Induced Secretion of Pro-Inflammatory Cytokines from Microglia and Modulate-Immune Regulators, TNFAIP3, and EGR1. (PubMed, Biomolecules) - "Ladostigil significantly decreased Egr1 gene expression and levels of the protein in the nucleus and increased TNF alpha-induced protein 3 (TNFaIP3), which suppresses cytokine release, in the microglial cytoplasm. Restoration of the aberrant signaling of these proteins in ATP/LPS-activated microglia in vivo might explain the prevention by ladostigil of the morphological and inflammatory changes in the brain of aging rats."

Journal • CNS Disorders • EGR1 • IL1B • IL6 • TNFA • TNFAIP3

Donepezil-indolyl hybrids as multipotent cholinesterase/monoamine oxidase inhibitors for the potential treatment of Alzheimer’s disease (AAIC 2023) - "Thus, drugs used to inhibit activated MAO, including rasagiline, ladostigil and selegiline, may provide neuroprotection against AD by improving cognitive impairment, modulating the proteolytic cleavage of APP and decreasing levels of Aβ protein fragments that accumulate in the brain. The pharmacological profile of compound 11, as well as the fact that it is a readily available compound in a short synthetic sequence, in good chemical yields, prompts us to select it as a lead-compound for further optimization in our current research programme targeted to the preparation of new molecules for the potential treatment of AD."

Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Pain

Oxidative Stress and Its Modulation by Ladostigil Alter the Expression of Abundant Long Non-Coding RNAs in SH-SY5Y Cells. (PubMed, Noncoding RNA) - "We found that the induction of abundant lncRNAs, such as MALAT1, NEAT-1, MIAT, and SHNG12, by the Sin1 oxidative stress paradigm specifies only the undifferentiated cell state. We conclude that a global alteration in the lncRNA profiles upon stress in SH-SY5Y may shift cell homeostasis and is an attractive in vitro system to characterize drugs that impact the redox state of the cells and their viability."

Journal • CNS Disorders • CNS Tumor • Immunology • Inflammation • Neuroblastoma • Oncology • Solid Tumor • Vascular Neurology • HAND2-AS1 • MALAT1 • MIAT

"Submitting ladostigil for accelerated approval then?!" (@MadhavThambiset)

Ladostigil Attenuates Induced Oxidative Stress in Human Neuroblast-like SH-SY5Y Cells. (PubMed, Biomedicines) - "We postulate that ladostigil alleviated cell damage induced by oxidation. Therefore, under conditions of chronic stress that are observed in the aging brain, ladostigil may block oxidative stress processes and consequently reduce neurotoxicity."

Journal • Alzheimer's Disease • CNS Disorders • Immunology • Inflammation • CDK1

Alzheimer's disease treatment: The share of herbal medicines. (PubMed, Iran J Basic Med Sci) - "Numerous synthetic medicines such as tacrine, donepezil, galantamine, rivastigmine, memantine, glutathione, ascorbic acid, ubiquinone, ibuprofen, and ladostigil are routinely used for reduction of the symptoms and prevention of disease progression. Lavandula angustifolia, Ginkgo biloba, Melissa officinalis, Crocus sativus, Ginseng, Salvia miltiorrhiza, and Magnolia officinalis have been widely used for relief of symptoms of some neurological disorders. This paper reviews the therapeutic effects of phytomedicines with prominent effects against various factors implicated in the emergence and progression of AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia

First Synthesis of Racemic Trans Propargylamino-Donepezil, a Pleiotrope Agent Able to Both Inhibit AChE and MAO-B, with Potential Interest against Alzheimer's Disease. (PubMed, Molecules) - "Among the numerous targets which are today validated against AD, acetylcholinesterase (ACh) and Monoamine Oxidase-B (MAO-B) appear as particularly convincing, especially if displayed by a sole agent such as ladostigil, currently in clinical trial in AD. Considering these results, we wanted to take benefit of the structural analogy lying in donepezil (DPZ) and rasagiline, two indane derivatives marketed as AChE and MAO-B inhibitors, respectively, and to propose the synthesis and the preliminary in vitro biological characterization of a structural compromise between these two compounds, we called propargylaminodonepezil (PADPZ). The synthesis of racemic trans PADPZ was achieved and its biological evaluation established its inhibitory activities towards both (h)AChE (IC = 0.4 µM) and (h)MAO-B (IC = 6.4 µM)."

Journal • Alzheimer's Disease • CNS Disorders • Pain

Rasagiline derivatives combined with histamine H receptor properties. (PubMed, Bioorg Med Chem Lett) - "Surprisingly, the 5-substituted 3-piperidinopropyloxy rasagiline derivative 1 was more potent on both targets than its 6-substituted isomer. It showed nanomolar affinities at the desired targets (MAO B IC = 256 nM; hHR K = 2.6 nM) with a high preference over monoamine oxidase A (MAO A) and negligible affinity at histamine H, H, dopamine D, D receptors or acetyl-/butyrylcholinesterases."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Age-Induced Spatial Memory Deficits in Rats Are Correlated with Specific Brain Region Alterations in Microglial Morphology and Gene Expression. (PubMed, J Neuroimmune Pharmacol) - "The data show brain region-specific relations induced by age in spatial learning, microglial morphology and associated genes and their response to ladostigil treatment. Graphical Abstract."

Journal

Effect of ladostigil treatment of aging rats on gene expression in four brain areas associated with regulation of memory. (PubMed, Neuropharmacology) - "Ladostigil also decreased the expression of axonal growth inhibitors and those impairing mitochondrial function. Together, these actions could explain the protection by ladostigil against age-related memory decline."

Journal

Avraham Pharmaceuticals (ILSI 2012) - Avraham announced commencement of a P2 clinical trial to evaluate the safety and efficacy of ladostigil in patients diagnosed with mild cognitive impairment (NCT01429623); Avraham has also completed enrollment of 200 patients in P2 trial of ladostigil; In January 2012, company performed an interim analysis of this P2 trial, which indicated showed a positive trend in the drug's efficacy and found no safety issues; Results are expected in Q4 2012

Anticipated P2 data • Enrollment completion • Interim analysis • P2 initiation • Alzheimer's Disease

Exploring the Multifunctional Neuroprotective Promise of Rasagiline Derivatives for Multi-Dysfunctional Alzheimer's Disease. (PubMed, Curr Pharm Des) - "TV-3326 combines the neurorestorative/neuroprotective actions of the cholinesterase (ChE) inhibitory activity of rivastigmine with rasagiline (a selective monoamine oxidase-B inhibitor and novel antiparkinsonian agent) in a single molecule. It has been revealed that both the compounds possess anti-AD effects and therefore, the clinical development is directed to the treatment of this type of neurodegenerative diseases (NDs). In this article, we have reviewed the neuroprotective molecular mechanisms and multimodal actions of TV-3326 and M-30."

Journal

TV 3326 for Alzheimer's dementia: a novel multimodal ChE and MAO inhibitors to mitigate Alzheimer's-like neuropathology. (PubMed, J Pharm Pharmacol) - "TV 3326 can avert oxidative-nitrative stress and gliosis. It has also been confirmed that TV 3326 contains neuroprotective and anti-apoptotic properties. Therefore, this distinctive combined inhibition of ChE and MAO along with its neuroprotective property makes TV 3326 a useful drug in the treatment of AD."

Journal • Review

Low-dose ladostigil for mild cognitive impairment: A phase 2 placebo-controlled clinical trial. (PubMed, Neurology) - P2; "Ladostigil was safe and well tolerated but did not delay progression to dementia. Its association with reduced brain and hippocampus volume loss suggests a potential effect on atrophy."

Biomarker • Clinical • Journal • P2 data

Propargylamine-derived multi-target directed ligands for Alzheimer's disease therapy. (PubMed, Bioorg Med Chem Lett) - "Current options for the treatment of Alzheimeŕs disease have been restricted to prescription of acetylcholinesterase inhibitors or N-methyl-d-aspartate receptor antagonist, memantine. Propargylamine-derived multi-target directed ligands, such as ladostigil, M30, ASS234 and contilisant, involve different pathways. Apart from acting as inhibitors of both cholinesterases and monoamine oxidases, they show improvement of cognitive impairment, antioxidant activities, enhancement of iron-chelating activities, protect against tau hyperphosphorylation, block metal-associated oxidative stress, regulate APP and Aβ expression processing by the non-amyloidogenic α-secretase pathway, suppress mitochondrial permeability transition pore opening, and coordinate protein kinase C signaling and Bcl-2 family proteins. Other hybrid propargylamine derivatives are also reported."

IO Biomarker • Journal • Review • BCL2