What is the Alzheimer’s Disease?
Over a hundred years ago, a German neurologist named Alois Alzheimer (1864-1915) found previously unseen brain lesions in a patient. He detailed an instance of dementia caused by reduced brain function in an article from 1907. Atrophied neurons in various regions of the brain, which was filled with plaques and intertwined fibers, were the root of the problem. This type of deposit has since been known by several names, including senile plaques and neurofibrillary tangles, and is an indicator of Alzheimer’s disease (AD). Neurones die as a result of the harmful effects of these plaques. Dementia, a gradual decline in cognitive abilities primarily impacting memory, reasoning, and attention, develops as a result of neuronal death. Other brain processes, including as movement, are impacted as symptoms intensify. People with AD have amyloid plaques on the exterior of their neurons, which are the result of beta-amyloid peptide building up and aggregating. When tau proteins build up in the cytoplasm of neurons, another symptom of the condition is neurofibrillary tangles. The neuronal cytoskeleton’s microtubules are stabilized by this protein. Neurofibrillary tangles, formed by structurally changed tau proteins, are accumulated inside neurons and induce neuronal death in AD.
The current global dementia (AD) prevalence is at 50 million, with projections showing that figure rising to 66 million in 2030 and 115 million in 2050.
FDA-approved drugs for Alzheimer’s disease
Donepezil: In 1996, the FDA authorized the use of donepezil, the first reversible, second-generation non-competitive acetylcholinesterase (AChE) inhibitor, for the treatment of mild, moderate, and severe Alzheimer’s disease dementia. Additionally, it ranks high on the list of medications given to AD patients. It improves cholinergic neurotransmission by lowering synaptic ACh hydrolysis through a reversible binding with AChE. Donepezil improves oligodendrocyte differentiation and stimulates the phosphatidylinositol-3-kinase/Akt pathway, which in turn decreases toxicity caused by Aβ. In addition to protecting against Aβ toxicity, it stimulates the sigma1 receptor and controls calcium signaling, cellular defense, and neurotransmitter release. Donepezil reaches peak plasma concentrations in three to four hours and has an 86.8% systemic bioavailability. With a half-life of 70 hours, it’s safe to take once day. Cognitive performance in Alzheimer’s disease patients has been shown to improve, serum Aβ levels to drop, hippocampal atrophy to decrease, and tau-protein expression to decrease when 5 mg and 10 mg were taken once day, according to studies. The Food and Drug Administration has also authorized a higher-dose formulation (23 mg) for the treatment of moderate to severe AD. An immediate-release (1996), an orally disintegrating (2004), a sustained-release (2010), and a transdermal patch (2022) formulation is currently approved by the FDA. Less systemic side effects are associated with the 5 mg daily medication delivery via the transdermal once-weekly patch.
Donepezil molecules at BOC Sciences
Rivastigmine: In 2000, the FDA authorized rivastigmine, a cholinesterase inhibitor, for the treatment of AD and Parkinson’s disease. It selectively inhibits the G1 isoform of acetylcholinesterase and butyrylcholinesterase, and it is a delayed reversible dual inhibitor. Cognitive processes like remembering and reasoning are boosted by this mechanism, which increases cholinergic activity. Hepatic metabolism is not seen. It is possible that rivastigmine’s effectiveness decreases as the disease advances and a smaller percentage of functionally intact cholinergic neurons are left. A dose-response relationship is shown with rivastigmine, wherein the drug’s effectiveness is increased with increasing dosages. Both oral and transdermal patch administration are possible. Oral rivastigmine has effective symptomatic effects in mild to severe PDD and all phases of Alzheimer’s disease, according to clinical trials. When taken orally, the bioavailability drops to around 35% due to extensive and saturable first-pass metabolism. However, rivastigmine patch pharmacokinetic investigations have shown that transdermal delivery of the medicine minimizes the volatility of plasma drug concentrations, lowers Cmax, and prolongs tmax compared to oral treatment. The medication undergoes full metabolism and is mostly eliminated by the kidneys. Resveratrol, the active metabolite of rivastigmine, is at least 10 times less effective against AChE than the parent medication. Renal clearance rates range from 2.1 to 2.8 L/h, and rivastigmine has a 1.5-hour half-life. Concurrent treatment of digoxin, a routinely recommended antiarrhythmic and anti-failure medication in elderly individuals, has not been shown in single-dose pharmacokinetic trials to substantially alter the drug’s metabolism. Two capsules per day are recommended, and they come in dosages of 1.5 mg, 3 mg, 4.5 mg, and 6 mg. The transdermal patch is available in four distinct sizes, each with its own dosage and duration of action: 4.6 mg, 9.5 mg, 13.3 mg, and 17.4 mg over 24 hours, respectively. Side effects, such as nausea and vomiting, are less common while using the daily-replaceable patch.
Rivastigmine molecules at BOC Sciences
| Catalog | Product Name | CAS Number |
| B0084-082595 | Rivastigmine | 123441-03-2 |
| (R)-Rivastigmine tartrate | ||
| Rivastigmine-d6 Hydrogen Tartrate | ||
| Rivastigmine Hydrogen Tartrate | ||
| Rivastigmine Impurity E HCl | ||
| Rivastigmine Ether Impurity HCl | ||
| N-Methyl Rivastigmine Chloride | ||
| Rivastigmine Impurity 1 | ||
| Rivastigmine Impurity 2 | ||
| 1070660-34-2 | N-Desmethyl Rivastigmine | 1070660-34-2 |
| 1133229-21-6 | Rivastigmine-d3 | 1133229-21-6 |
| 1133229-22-7 | Rivastigmine-d5 | 1133229-22-7 |
| 129101-54-8 | Rivastigmine tartrate | 129101-54-8 |
| 1346242-31-6 | Rivastigmine Carbamate Impurity | 1346242-31-6 |
| 139306-10-8 | NAP226-90 (Rivastigmine EP Impurity A) | 139306-10-8 |
| 194930-00-2 | Rivastigmine-[d6] Tartrate | 194930-00-2 |
| 25081-93-0 | N-Dimethyl Rivastigmine (Rivastigmine EP Impurity B) | 25081-93-0 |
| 415973-05-6 | (R)-Rivastigmine | 415973-05-6 |
| B2694-479199 | Rivastigmine Impurity F | 889443-69-0 |
| B2694-479202 | Rivastigmine USP Related Compound F | 1346602-84-3 |
| 1049692-05-8 | 4-(1-(dimethylamino)ethyl)phenol hydrochloride | 1049692-05-8 |
| 1219798-58-9 | 3-Methoxyacetophenone-[2,4,5,6-d4] | 1219798-58-9 |
Galantamine: For the treatment of mild to severe AD, the FDA approved galantamine in 2001. Patients with mild to moderate AD should expect to see improvements in function, cognition, and ADLs in as little as six months, and it has a reputation for being well-tolerated throughout that period. This medication helps to postpone BPSDs and reduces the strain on caregivers. The medicine induces an increase in brain ACh levels because it is a reversible competitive inhibitor of AChE. Additionally, it enhances the effects of ACh on nicotinic receptors, leading to a general rise in cholinergic neurotransmission in the brain and making therapy easier. Results from short-term, double-blind, placebo-controlled trials show that galantamine can improve mild to severe AD symptoms on cognitive tests. The tertiary alkaloid galantamine was isolated from the plant Galanthus nivalis in the early 1950s. A synthetic formulation is what’s now on the market. At the recommended maintenance dosages of 16 and 24 mg/day, galantamine exhibits predictable linear elimination kinetics and a relatively short half-life of around 7 hours. Two tablets taken twice day and one extended-release capsule taken first thing in the morning make up the recommended dosage. In large multicentric studies, a dose of 24 mg/day was consistently found to be helpful compared to a placebo for the functional, cognitive, and behavioral symptoms associated with AD. Furthermore, its bioavailability is really high. There is minimal potential for drugs to interact with each other clinically since the medicine undergoes significant metabolism in the liver via many routes including the cytochrome P450 enzymes CYP2D6 and CYP3A4.
Galantamine molecules at BOC Sciences
| Catalog | Product Name | CAS Number |
| Galantamine-O-D-glucuronide | ||
| Galantamine-Beta-D-Glucuronide | ||
| Galantamine Impurity D HCl | ||
| Galantamine O-D3 HBr | ||
| Galantamine-d3 HCl | ||
| 134332-50-6 | Galantamine N-Oxide | 134332-50-6 |
| 1668-85-5 | Epi-Galantamine | 1668-85-5 |
| 2140262-53-7 | Galantamine-[d3] hydrobromide | 2140262-53-7 |
| 366485-18-9 | Epi-Galantamine N-Oxide | 366485-18-9 |
| 60384-53-4 | Ent-Galantamine | 60384-53-4 |
| 60755-80-8 | O-desmethyl Galantamine | 60755-80-8 |
| 664995-65-7 | Anhydro Galantamine | 664995-65-7 |
| B0084-062115 | Galantamine hydrobromide | 1953-04-4 |
| β-D-Glucopyranosiduronic Acid Propyl Methyl Ester, 2,3,4-Triacetate | 1373360-92-9 | |
| 21133-52-8 | Lycoramine | 21133-52-8 |
| 224169-27-1 | Memogain | 224169-27-1 |
| 41303-74-6 | N-Desmethyl Galanthamine | 41303-74-6 |
| B1370-343377 | Galanthamine | 357-70-0 |
Memantine: For the treatment of moderate to severe AD, memantine was approved by the FDA in 2003. It is a main aliphatic amine produced from adamantine hydride. The main way that memantine works is by preventing the glutamate-induced influx of calcium into cells and blocking current flow through the channels of the glutamatergic NMDA receptors. Along with its functions as an antidepressant, antiparkinsonian, neuroprotective, and NMDA receptor antagonist, it also acts as a dopaminergic agent. The learning and memory processes that are based on synaptic plasticity are inhibited by high dosages of memantine. At therapeutically relevant doses, it is possible to improve memory and shield the brain from excitotoxicity by increasing synaptic plasticity. Taking memantine orally increases its absorption rate. In 3-7 hours, the medication concentration reaches its peak. When given at the recommended therapeutic dosage, its pharmacokinetics are linear. The absorption of drugs is unaffected by food. The kidneys mostly remove it by active tubular secretion, with 48% of the dosage being unaltered and 52% being converted to 6-hydroxy memantine, 1-nitroso-deaminated memantine, and the marginally active N-glucuronide conjugate. Tubular reabsorption, which is sensitive to pH, acts as a buffer, reducing the clearance. It is appropriate for once-daily dosage and has a half-life of 60-70 hours. Oral formulations with quick release and sustained release are both available. It binds predominantly to cation channels that are regulated by NMDA receptors and is an uncompetitive NMDA receptor antagonist with low to moderate affinity.
Memantine molecules at BOC Sciences
References
- Nunes D., et al., Drug delivery systems as a strategy to improve the efficacy of FDA-approved Alzheimer’s drugs, Pharmaceutics, 2022, 14(11): 2296.
- Carvalho K M., et al., Analysis of technological developments in the treatment of Alzheimer’s disease through patent documents, Intelligent Information Management, 2015, 7(5): 268-281.
- Varadharajan A., et al., Guidelines for pharmacotherapy in Alzheimer’s disease–A primer on FDA-approved drugs, Journal of neurosciences in rural practice, 2023, 14(4): 566.