OBJECTIVE: The execution of effective treatment approaches through further trials investigating a rational combination of agents is necessitude for Alzheimer's disease.
METHODS: For this review, more than 248 relevant scientific papers were considered from a variety of databases (Scopus, Web of Science, Google Scholar, ScienceDirect, and PubMed) using the keywords Alzheimer's disease, amyloid-β, combination therapies, cholinesterase inhibitors, dementia, glutamate regulators, AD hypothesis.
RESULT AND DISCUSSION: The researcher's intent is to either develop a disease-modifying therapeutic means for aiming in the early phases of dementia and/or optimize the available symptomatic treatments principally committed to the more advanced stages of Alzheimer's. Since Alzheimer's possesses multifactorial pathogenesis, designing a multimodal therapeutic intervention for targeting different pathological processes of dementia may appear to be the most practical method to alter the course of disease progression.
CONCLUSION: The combination approach may even allow for providing individual agents in lower doses, with reducible costs and side effects. Numerous studies on combination therapy predicted better clinical efficacy than monotherapy. The literature review highlights the major clinical studies (both symptomatic and disease-modifying) conducted in the past decade on combination therapy to combat cognitive disorder.
OBJECTIVES: To assess the clinical effects, including adverse effects, of galantamine in people with probable or possible Alzheimer's disease or mild cognitive impairment, and to investigate potential moderators of effect.
SEARCH METHODS: We systematically searched the Cochrane Dementia and Cognitive Improvement Group's Specialised Register on 14 December 2022 using the term 'galantamine'. The Register contains records of clinical trials identified from major electronic databases (including CENTRAL, MEDLINE, and Embase), trial registries, grey literature sources, and conference proceedings. We manually searched reference lists and collected information from US Food and Drug Administration documents and unpublished trial reports. We imposed no language restrictions.
SELECTION CRITERIA: We included double-blind, parallel-group, randomised controlled trials comparing oral galantamine with placebo for a treatment duration exceeding four weeks in people with dementia due to Alzheimer's disease or with mild cognitive impairment.
DATA COLLECTION AND ANALYSIS: Working independently, two review authors selected studies for inclusion, assessed their quality, and extracted data. Outcomes of interest included cognitive function, change in global function, activities of daily living, functional disability, behavioural function, and adverse events. We used a fixed-effect model for meta-analytic synthesis, and presented results as Peto odds ratios (OR) or weighted mean differences (MD) with 95% confidence intervals. We used Cochrane's original risk of bias tool (RoB 1) to assess the risk of bias in the included studies.
MAIN RESULTS: We included 21 studies with a total of 10,990 participants. The average age of participants was 74 years, and 37% were male. The studies' durations ranged from eight weeks to two years, with 24 weeks being the most common duration. One newly included study assessed the effects of galantamine at two years, and another newly included study involved participants with severe Alzheimer's disease. Nineteen studies with 10,497 participants contributed data to the meta-analysis. All studies had low to unclear risk of bias for randomisation, allocation concealment, and blinding. We judged four studies to be at high risk of bias due to attrition and two due to selective outcome reporting. Galantamine for dementia due to Alzheimer's disease We summarise only the results for galantamine given at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day), assessed at six months. See the full review for results of other dosing regimens and assessment time points. There is high-certainty evidence that, compared to placebo, galantamine improves: cognitive function, as assessed with the Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) (MD-2.86, 95% CI -3.29 to -2.43; 6 studies, 3049 participants; minimum clinically important effect (MCID) = 2.6- to 4-point change); functional disability, as assessed with the Disability Assessment for Dementia (DAD) scale (MD 2.12, 95% CI 0.75 to 3.49; 3 studies, 1275 participants); and behavioural function, as assessed with the Neuropsychiatric Inventory (NPI) (MD -1.63, 95% CI -3.07 to -0.20; 2 studies, 1043 participants) at six months. Galantamine may improve global function at six months, as assessed with the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) (OR 1.58, 95% CI 1.36 to 1.84; 6 studies, 3002 participants; low-certainty evidence). Participants who received galantamine were more likely than placebo-treated participants to discontinue prematurely (22.7% versus 17.2%) (OR 1.41, 95% CI 1.19 to 1.68; 6 studies, 3336 participants; high-certainty evidence), and experience nausea (20.9% versus 8.4%) (OR 2.89, 95% CI 2.40 to 3.49; 7 studies, 3616 participants; high-certainty evidence) during the studies. Galantamine reduced death rates at six months: 1.3% of participants in the galantamine groups had died compared to 2.3% in the placebo groups (OR 0.56, 95% CI 0.33 to 0.96; 6 studies, 3493 participants; high-certainty evidence). Galantamine for mild cognitive impairment We summarise results, assessed at two years, from two studies that gave participants galantamine at 8 to 12 mg twice daily (total galantamine 16 mg to 24 mg/day). Compared to placebo, galantamine may not improve cognitive function, as assessed with the expanded ADAS-cog for mild cognitive impairment (MD -0.21, 95% CI -0.78 to 0.37; 2 studies, 1901 participants; low-certainty evidence) or activities of daily living, assessed with the Alzheimer's Disease Cooperative Study - Activities of Daily Living scale for mild cognitive impairment (MD 0.30, 95% CI -0.26 to 0.86; 2 studies, 1901 participants; low-certainty evidence). Participants who received galantamine were probably more likely to discontinue prematurely than placebo-treated participants (40.7% versus 28.6%) (OR 1.71, 95% CI 1.42 to 2.05; 2 studies, 2057 participants) and to experience nausea (29.4% versus 10.7%) (OR 3.49, 95% CI 2.75 to 4.44; 2 studies, 2057 participants), both with moderate-certainty evidence. Galantamine may not reduce death rates at 24 months compared to placebo (0.5% versus 0.1%) (OR 5.03, 95% CI 0.87 to 29.10; 2 studies, 2057 participants; low-certainty evidence). Results from subgroup analysis and meta-regression suggest that an imbalance in discontinuation rates between galantamine and placebo groups, together with the use of the 'last observation carried forward' approach to outcome assessment, may potentially bias cognitive outcomes in favour of galantamine.
AUTHORS' CONCLUSIONS: Compared to placebo, galantamine (when given at a total dose of 16 mg to 24 mg/day) slows the decline in cognitive function, functional ability, and behaviour at six months in people with dementia due to Alzheimer's disease. Galantamine probably also slows declines in global function at six months. The changes observed in cognition, assessed with the ADAS-cog scale, were clinically meaningful. Gastrointestinal-related adverse events are the primary concerns associated with galantamine use in people with dementia, which may limit its tolerability. Although death rates were generally low, participants in the galantamine groups had a reduced risk of death compared to those in the placebo groups. There is no evidence to support the use of galantamine in people with mild cognitive impairment.
METHOD: A case series.
RESULTS: We present a case series of juvenile myasthenia gravis in a tertiary centre in Malaysia. Two of the three cases consist of a pair of twins who presented with ptosis of bilateral eyes; the first twin presented 4 months later than the second twin. These two cases were positive for anti-acetylcholine receptor antibodies and had generalized myasthenia gravis, whereas the other case was negative for receptor antibodies and was purely ocular myasthenia gravis.
CONCLUSION: Juvenile myasthenia gravis is relatively rare in toddlers. Early diagnosis and commencement of treatment is important to slow the progression of the disease and avoiding life-threatening events.
THE AIM OF THE STUDY: To investigate the effects of the chronic (28 days) oral administration of CT root extract on CCH-induced cognitive impairment, neuronal damage and cholinergic deficit, and its toxicity profile in the CCH rat model.
MATERIALS AND METHODS: The permanent bilateral occlusion of common carotid arteries (PBOCCA) surgery method was employed to develop a CCH model in male Sprague Dawley (SD) rats. Then, these rats were given oral administration of CT root extract at doses of 100, 200, and 300 mg/kg, respectively for 28 days and subjected to behavioural tests. At the end of the experiment, the brain was harvested for histological analysis and cholinesterase activities. Then, blood samples were collected and organs such as liver, kidney, lung, heart, and spleen were procured for toxicity assessment.
RESULTS: Chronic treatment of CT root extract at doses of 200 and 300 mg/kg, restored memory impairments induced by CCH. CT root extract was also found to diminish CCH-induced neuronal damage in the CA1 region of the hippocampus. High dose (300 mg/kg) of the CT root extract was significantly inhibited the increased acetylcholinesterase (AChE) activity in the frontal cortex and hippocampus of the PBOCCA rats. In toxicity study, repeated doses of CT root extract were found to be safe in PBOCCA rats after 28 days of treatment.
CONCLUSIONS: Our findings provided scientific evidence supporting the therapeutic potential of CT root extract in the treatment of vascular dementia (VaD)-related cholinergic abnormalities and subsequent cognitive decline.
METHODS: A crude methanol extract of the aerial parts of Isodon rugosus (Ir.Cr.) was used for both in vitro and in vivo experiments. The plant extract was tested on isolated rabbit jejunum preparations for possible presence of spasmolytic activity. Moreover, isolated rabbit tracheal and aorta preparations were used to ascertain the relaxant effects of the extract. Acetylcholinesterase and butyrylcholinesterase inhibitory activities of Ir.Cr were also determined as well as its antioxidant activity. The in vivo antiemetic activity of the extract was evaluated by using the chick emesis model, while the analgesic and antipyretic activities were conducted on albino mice.
RESULTS: The application of the crude extract of I. rugosus to isolated rabbit jejunum preparations exhibited relaxant effect (0.01-0.3 mg/ml). The Ir.Cr also relaxed K+(80 m M)-induced spastic contractions in isolated rabbit jejunum preparations and shifted the Ca+2 concentration response curves towards right (0.01-0.3 mg/ml). Similarly, the extract, when applied to the isolated rabbit tracheal preparations relaxed the carbachol (1 μM)--as well as K+ (80 mM)-induced contractions in a concentration range of 0.01-1.0 mg/ml. Moreover, it also relaxed (0.01-3.0 mg/ml) the phenylephrine (1 μM)- and K+ (80 mM)-induced contractions in isolated rabbit aorta preparations. The Ir.Cr (80 mg/kg) demonstrated antipyretic activity on pyrogen-induced pyrexia in rabbits as compared to aspirin as standard drug. The Ir.Cr also exhibited anti-oxidant as well as inhibitory effect on acetyl- and butyryl-cholinesterase and lipoxygenase (0.5 mg/ml).
CONCLUSIONS: The observed relaxant effect on isolated rabbit jejunum, trachea and aorta preparations caused by Ir.Cr is possibly to be mediated through Ca+2 channel blockade and therefore may provided scientific basis to validate the folkloric uses of the plant in the management of gastrointestinal, respiratory and cardiovascular ailments. The observed antioxidant activity as well as the lipoxygenase inhibitory activity may validate its traditional use in pain and inflammations.