An update on the safety of current therapies for Alzheimer’s disease: focus on rivastigmine

Abstract

Alzheimer's disease (AD) is the most common cause of major neurocognitive disorders worldwide. Despite all research efforts, therapeutic options for AD are still limited to two drug classes: cholinesterase inhibitors (ChEIs) and the NMDA-receptor antagonist memantine. Donepezil, rivastigmine and galantamine are the three ChEIs FDA-approved as first-line treatment for AD. Although they share the same mode of action, they differ in terms of their pharmacologic characteristics and route of administration, which can impact their safety and tolerability profile. Rivastigmine, available in both oral and transdermal patch formulations, is a slowly reversible dual inhibitor of acetyl and butyryl cholinesterase, selective for the G1 isoform of acetylcholinesterase, without hepatic metabolism by the CYP-450 system. Despite its unique features, it has been associated with a higher incidence of adverse events in comparison to other ChEIs. The oral form, approved for the treatment of mild to moderate AD, is associated with a higher incidence of gastrointestinal side effects. The transdermal patch formulation approved for use across all stages of AD has been shown to have a better tolerability profile in comparison to both the oral form and even other ChEIs. One important tolerability concern is adverse dermatologic reactions, which are mostly benign, and can be either preventable or manageable. One important safety concern is the risk of treatment overdose by administering multiple patches at the same time, potentially leading to fatal outcomes. This can be prevented by educating patients and caregivers about the proper use of the patch. The goal for the future would be to optimize the patch formulation to increase both efficacy and safety.

Chitosan-Based Nanocarriers for Nose to Brain Delivery

“…However, its poor bioavailability and limited entry into the brain resulting from its hydrophilic nature requires frequent dosing resulting in side effects such as nausea, anorexia, dyspepsia, severe bradycardia, etc. [52][53][54]. NPs loaded with rivastigmine were prepared by modified ionotropic gelation method to isolate high yields of stable nanoparticles.…”

Empagliflozin reduces vascular damage and cognitive impairment in a mixed murine model of Alzheimer’s disease and type 2 diabetes

“…On the other hand, AD has no successful treatment, and therapeutic efforts have been directed towards classical neuropathological features that include gamma-secretase modulators, BACE1 inhibitors, immunotherapy, or taubased therapies [5][6][7]. However, different limitations have been raised [8] reducing the presently approved treatments to acetylcholinesterase inhibitors and glutamate antagonist memantine [9]. The close relationship between T2D and AD has resulted in studies based on metabolic approaches, such as intranasal insulin administration [10] or antidiabetic agents [11,12].…”

Cholinesterase inhibitors in patients with diabetes mellitus and dementia: an open-cohort study of ~23 000 patients from the Swedish Dementia Registry

“…The lack of association between rivastigmine and mortality in patients with DM is in contrast to studies concluding its benefits in inhibiting both acetyl- and butyrylcholinesterase,40 as well as rivastigmine’s alternative administration method—the transdermal patch—which avoids the cholinergic peaks and improves safety and tolerability 41 42. On the other hand, accidental applications of multiple rivastigmine patches could lead to carbamate-like poisoning and death 43. This could be more pronounced in polymedicated patients and with increased dementia severity (such as patients with DM); however, we could not stratify on rivastigmine’s delivery methods in our study.…”