INTRODUCTION: Singapore has a rapidly ageing population and an increasing prevalence of Alzheimer's disease (AD). Compliance to AD medications is associated with treatment effectiveness. We investigated compliance to acetylcholinesterase inhibitors (AChEIs) and N-methyl-D-aspartate (NMDA) receptor antagonist and treatment persistence among patients seen at the General Memory Clinic of National University Hospital, Singapore. We also identified the reasons for non-compliance. METHODS: Patients seen at the General Memory Clinic between 1 January 2013 and 31 December 2014, who were prescribed AChEIs and NMDA receptor antagonist, were included in this retrospective cohort study. Non-compliance to medications was indirectly measured by failure to renew prescription within 60 days of the last day of medication supplied by the previous prescription. The reasons for non-compliance were identified. RESULTS: A total of 144 patients were included. At one year, 107 patients were compliant to AD medications, while 37 patients were non-compliant. Around 60% of the non-compliant patients discontinued the use of AD medications within the first six months, and the mean persistent treatment period among this group of patients was 10.3 ± 3.5 months. The main reason for non-compliance was patients' and caregivers' perception that memory loss was of lower priority than other coexisting illnesses. Other reasons for non-compliance included side effects of medications (18.9%), perceived ineffectiveness of treatment (16.2%), inability to attend clinic (5.4%) and high cost of medications (2.7%). CONCLUSION Our findings suggest that the reasons for medication non-compliance can be identified early. Better compliance may be achieved through a multidisciplinary approach to patient education.
Aged ; Aged, 80 and over ; Alzheimer Disease ; drug therapy ; epidemiology ; psychology ; Caregivers ; Cholinesterase Inhibitors ; therapeutic use ; Drug Costs ; Female ; Humans ; Interdisciplinary Communication ; Male ; Medication Adherence ; Middle Aged ; Patient Compliance ; Quality of Life ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Retrospective Studies ; Singapore ; epidemiology ; Treatment Outcome

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the presence of extracellular β-amyloid in the senile plaques, intracellular aggregates of abnormal phosphorylation of tau protein in the neurofibrillary tangles, neuronal loss and cerebrovascular amyloidosis. The manifestations of clinical symptoms include memory impairment, cognitive decline, altered behavior and language deficit. Currently available drugs in AD therapy consist of acetylcholinesterase inhibitors, NMDA receptor antagonists, non-steroidal anti-inflammatory drugs, etc. These drugs can only alleviate the symptoms of AD. Gene therapy is achieved by vector-mediated gene transfer technology, which can delivery DNA or RNA into target cells to promote the expression of a protective or therapeutic protein and silence certain virulence genes.
Alzheimer Disease ; therapy ; Anti-Inflammatory Agents, Non-Steroidal ; therapeutic use ; Cholinesterase Inhibitors ; therapeutic use ; Genetic Therapy ; Humans ; Phosphorylation ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; tau Proteins ; metabolism

Alzheimer's disease (AD) is a complex neurodegenerative disorder which seriously causes the dementia in elderly people and afflicts millions of people worldwide. Drug discovery for Alzheimer's disease therapy has been a hot research area and a big challenge, in which development of acetylcholinesterase (AChE) inhibitors design was the most active and some AChE inhibitors are commercially available for AD medication already. However, practical using of commercial AChE inhibitors showed their limited usefulness and related adverse effects. Thus, it is extremely urgent to find novel AChE inhibitors with higher potency and less adverse effects. Based on the accurate crystallographic studies about AChE, strategies for multi-binding site AChE inhibitors have been formed, followed by design of the multi-target directed ligands. In this review, the structures and binding modes of commercial AChE inhibitors were briefly discussed, together with the development of AChE inhibitor design for AD therapy: from multi-binding site inhibitors to multi-target directed ligands.
Acetylcholinesterase ; chemistry ; metabolism ; Alzheimer Disease ; drug therapy ; Amyloid Precursor Protein Secretases ; antagonists & inhibitors ; Amyloid beta-Peptides ; metabolism ; Animals ; Aspartic Acid Endopeptidases ; antagonists & inhibitors ; Binding Sites ; Butyrylcholinesterase ; chemistry ; metabolism ; Cholinesterase Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; therapeutic use ; Drug Design ; Humans ; Ligands ; Monoamine Oxidase Inhibitors ; chemical synthesis ; chemistry ; Receptors, N-Methyl-D-Aspartate ; antagonists & inhibitors ; Structure-Activity Relationship

Acute Disease ; Adult ; Antidotes ; therapeutic use ; Antiparkinson Agents ; therapeutic use ; Benserazide ; Cholinesterase Inhibitors ; poisoning ; Humans ; Insecticides ; poisoning ; Levodopa ; therapeutic use ; Male ; Organophosphate Poisoning ; Parkinson Disease ; drug therapy ; pathology ; Pralidoxime Compounds ; therapeutic use ; Trihexyphenidyl ; therapeutic use

BACKGROUNDThe nervous system, through the vagus nerve and its neurotransmitter acetylcholine, can down-regulate the systemic inflammation in vivo, and recently, a role of brain cholinergic mechanisms in activating this cholinergic anti-inflammatory pathway has been indicated. Galanthamine is a cholinesterase inhibitor and one of the centrally acting cholinergic agents available in clinic. This study aimed to evaluate the effect of galanthamine on circulating tumor necrosis factor alpha (TNF-alpha) in rats with lipopolysaccharide-induced peritonitis and the possible role of the vagus nerve in the action of galanthamine.

METHODSRat models of lipopolysaccharide-induced peritonitis and bilateral cervical vagotomy were produced. In the experiment 1, the rats were randomly divided into control group, peritonitis group, and peritonitis groups treated with three dosages of galanthamine. In the experiment 2, the rats were randomly divided into sham group, sham plus peritonitis group, sham plus peritonitis group treated with galanthamine, vagotomy plus peritonitis group, and vagotomy plus peritonitis group treated with galanthamine. The levels of plasma TNF-alpha were determined in every group.

RESULTSThe level of circulating TNF-alpha was significantly increased in rats after intraperitoneal injection of endotoxin. Galanthamine treatment decreased the level of circulating TNF-alpha in rats with lipopolysaccharide-induced peritonitis, and there was significant difference compared with rats with lipopolysaccharide-induced peritonitis without treatment. The 3 mg/kg dosage of galanthamine had the most significant inhibition on circulating TNF-alpha level at all the three tested doses. Galanthamine obviously decreased the TNF-alpha level in rats with lipopolysaccharide-induced peritonitis with sham operation, but could not decrease the TNF-alpha level in rats with lipopolysaccharide-induced peritonitis with vagotomy.

CONCLUSIONCholinesterase inhibitor galanthamine has an inhibitory effect on TNF-alpha release in rats with lipopolysaccharide-induced peritonitis, and the vagus nerve plays a role in the process of the action of galanthamine.

Animals ; Cholinesterase Inhibitors ; therapeutic use ; Galantamine ; therapeutic use ; Lipopolysaccharides ; toxicity ; Male ; Peritonitis ; blood ; chemically induced ; drug therapy ; Rats ; Rats, Sprague-Dawley ; Tumor Necrosis Factor-alpha ; blood

Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight = 3.29, RMS = 0.53, total cost-null cost = 62.75, Correl = 0.93, Config = 19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.
Acetylcholinesterase ; chemistry ; metabolism ; Alzheimer Disease ; enzymology ; prevention & control ; Cholinesterase Inhibitors ; chemistry ; classification ; therapeutic use ; Drug Design ; Humans ; Models, Chemical ; Models, Molecular ; Molecular Structure ; Quantitative Structure-Activity Relationship ; Structure-Activity Relationship

OBJECTIVEThe present study investigated the inhibitory effects of Chinese herb component sinapine on activity of acetylcholinesterase (AChE) in cerebral homogenate and blood serum of rats.

METHODAChE was prepared from cerebral homogenate and blood serum of rats, respectively. Acetylcholinesterase activity assay kit and Chromatometry were used to detect the AChE activity.

RESULTSinapine significantly inhibited AChE activity in vitro, with more effective on cerebral homogenate (IC50 3.66 micromol x L(-1)) than blood serum (IC50 22.1 micromol x L(-1)).

CONCLUSIONSinapine could significantly inhibit the cerebral AChE activity and may be a promising drug used for prevention and cure of Alzheimer's disease as a cholinesterase inhibitor.

Acetylcholinesterase ; blood ; metabolism ; Alzheimer Disease ; drug therapy ; prevention & control ; Animals ; Brain ; cytology ; enzymology ; Choline ; analogs & derivatives ; pharmacology ; therapeutic use ; Cholinesterase Inhibitors ; pharmacology ; therapeutic use ; Rats

Activities of Daily Living ; Alzheimer Disease ; diagnosis ; drug therapy ; psychology ; therapy ; Caregivers ; psychology ; Cholinesterase Inhibitors ; therapeutic use ; Clinical Trials as Topic ; Cognition ; Endpoint Determination ; Humans ; Memantine ; therapeutic use ; Neuropsychological Tests ; Patient-Centered Care ; Quality of Life ; Singapore ; Stress, Psychological ; prevention & control ; Treatment Outcome

To evaluate the impact of galantamine treatment on the function, caregiver time, and resource used in the treatment of patients with mild to moderate Alzheimer's disease (AD), costs and outcomes were evaluated during a 52-week prospective, randomized, double-blind, community-controlled trial of galantamine. Patients received either galantamine treatment (n=72) or no treatment (n=66). The analysis was performed from a societal perspective. Galantamine treatment reduced time spent caring for the patients and maintained improved functional capacity, whereas, when no treatments were given, a great increase in caregiver time and progressive functional deteriorations were observed. Saved caregiver time was equivalent to 113 working days per year. After 52 weeks, mean total annual costs per patient were 14,735,000 Korea Won (KRW) (USD 12,315) for patients with galantamine treatment and 25,325,000 KRW (USD 21,166) for patients without treatment. Adjusted annual cost saving of galantamine treatment was 6,428,000 KRW (USD 5,372) when compared to no treatment (p=0.0089). Galantamine had a beneficial effect not only to slow functional decline in patients with mild to moderate AD, but also to save a substantial amount of costs, closely related to reduction in caregiver burden and decrease in caregiver time.
Aged ; Alzheimer Disease/*drug therapy ; Cholinesterase Inhibitors/*therapeutic use ; Cost of Illness ; Double-Blind Method ; Female ; Galantamine/economics/*therapeutic use ; Health Care Costs ; Humans ; Male ; Prospective Studies

Adrenergic alpha-Antagonists ; therapeutic use ; Cholinesterase Inhibitors ; therapeutic use ; Diagnosis, Differential ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; therapeutic use ; Glomerulonephritis, IGA ; diagnosis ; drug therapy ; Humans ; Medicine, Chinese Traditional ; Phytotherapy