Effects of galantamine in patients with mild Alzheimer's disease

BACKGROUND: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer's disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD. METHODS: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21-24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer's Disease Assessment Scale-cognitive subset (ADAS-cog), Clinician's Interview-Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared. RESULTS: Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 +/- 1.1, mean age 74 +/- 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was -1.5 (95% confidence interval -2.2, -0.8, p < 0.001) for GAL and +0.2 (-0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant (p = 0.001). Significantly more patients receiving galantamine were classified as 'improved' using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea. CONCLUSIONS: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.     

Effects of galantamine in patients with mild Alzheimer's disease

SUMMARY

Background: Galantamine is an acetylcholinesterase inhibitor that modulates nicotinic receptors. It is effective in mild to moderate Alzheimer’s disease (AD) but no trial has focused exclusively on mild AD. We performed a post-hoc sub-set analysis using data from four randomised trials to explore the efficacy of galantamine versus placebo in mild AD.

Methods: Participants in all studies met NINCDS-ADRDA criteria for probable AD. We examined data from patients with baseline Mini Mental State Examination (MMSE) 21–24 who received galantamine 24 mg/day (GAL) or placebo (PLAC). Scores for the Alzheimer’s Disease Assessment Scale-cognitive subset (ADAS–cog), Clinician’s Interview–Based Impression of Change (CIBIC), Disability Assessment for Dementia (DAD), and ACDS-ADL scales were compared.

Results:Of the 694 patients (362 GAL, 332 PLAC, mean baseline MMSE 22.4 ± 1.1, mean age 74 ± 7.9 years), 65% completed 6 months treatment (223 GAL, 229 PLAC). Mean change in ADAS-cog at 6 months was –1.5 (95% confidence interval –2.2, –0.8, p < 0.001) for GAL and + 0.2 (–0.6, 0.9, p = 0.72) for PLAC. This difference was statistically significant ( p = 0.001).

Significantly more patients receiving galantamine were classified as ‘improved’ using the CIBIC (26.9% GAL vs 14.3% PLAC, p < 0.001). Galantamine was generally well tolerated; most common adverse events were nausea, vomiting and diarrhoea.

Conclusion: Pooled data from four randomised trials of patients with mild AD indicate that patients who received galantamine 24 mg/day for 6 months improved cognition more often than those who received placebo and that a higher proportion receiving galantamine were globally improved. This suggests that patients with mild AD benefit from galantamine treatment.     

Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease

INTRODUCTION: Exploratory pilot studies and knowledge of its mode of action suggested that galantamine, a cholinesterase inhibitor and modulator of nicotinic receptors, can improve attention. This study was designed to test the effects of galantamine on attention in patients with mild-to-moderate Alzheimer's disease (AD) and to see how changes in attention affected their caregivers. METHODS: This was an open-label, multicentre study. Patients received galantamine (up to 24 mg/day) for 12 weeks. Attention was assessed after 1, 4, 8 and 12 weeks using computerized tests including Choice Reaction Time (CRT), and caregiver, physician and patient ratings. RESULTS: Data were available from 373 patients (mean age 75 years, mean baseline MMSE score 21). Attention as measured by CRT improved significantly from baseline to study endpoint (p < 0.001), improvements were observed after 1 week and statistical significance was maintained from 8 weeks. Physicians rated 67% of patients as globally improved and 5% as worsened. Caregivers reported improved attention in 57% of patients and worsening in 6%; 62% of patients considered they had improved and 3% considered themselves to be worse. Caregiver stress, time spent caring for patients and patients' interactions with others all improved from baseline to endpoint. Galantamine was generally well tolerated; the most common adverse events were gastrointestinal. CONCLUSION: Previous controlled trials have demonstrated that galantamine has a positive effect on cognition, activities of daily living, behaviour and global condition, but this is the first study to suggest that galantamine may specifically improve attention (according to both objective and subjective measures) in patients with AD. These effects may be a consequence of galantamine's potentiating action at nicotinic receptors.     

加兰他敏治疗阿尔茨海默症的研究进展

加兰他敏是从雪片莲中提取的一种生物碱,具有可逆性胆碱酯酶抑制活性.它不仅用于脊髓灰质炎和相关的肌无力、局部麻痹的治疗,更因为它良好的中枢胆碱活性而应用于改善阿尔茨海默病人的思维和记忆功能.现对加兰他敏的作用机制和药效等作一综述,以增进对其治疗阿尔茨海默病及相关疾病的重视.     

Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease

ABSTRACT

Introduction: Exploratory pilot studies and knowledge of its mode of action suggested that galantamine, a cholinesterase inhibitor and modulator of nicotinic receptors, can improve attention. This study was designed to test the effects of galantamine on attention in patients with mild-to-moderate Alzheimer's disease (AD) and to see how changes in attention affected their caregivers.

Methods: This was an open-label, multicentre study. Patients received galantamine (up to 24?mg/day) for 12 weeks. Attention was assessed after 1, 4, 8 and 12 weeks using computerized tests including Choice Reaction Time (CRT), and caregiver, physician and patient ratings.

Results: Data were available from 373 patients (mean age 75 years, mean baseline MMSE score 21). Attention as measured by CRT improved significantly from baseline to study endpoint (?p < 0.001), improvements were observed after 1 week and statistical significance was maintained from 8 weeks. Physicians rated 67% of patients as globally improved and 5% as worsened. Caregivers reported improved attention in 57% of patients and worsening in 6%; 62% of patients considered they had improved and 3% considered themselves to be worse. Caregiver stress, time spent caring for patients and patients’ interactions with others all improved from baseline to endpoint. Galantamine was generally well tolerated; the most common adverse events were gastrointestinal.

Conclusion: Previous controlled trials have demonstrated that galantamine has a positive effect on cognition, activities of daily living, behaviour and global condition, but this is the first study to suggest that galantamine may specifically improve attention (according to both objective and subjective measures) in patients with AD. These effects may be a consequence of galantamine's potentiating action at nicotinic receptors.     

Current status and new developments with galantamine in the treatment of Alzheimer's disease

Galantamine is a newly available cholinergic drug that offsets reductions in central cholinergic neurotransmission in Alzheimer's disease (AD) by specifically and reversibly inhibiting acetylcholinesterase (AChE) and by allosterically modulating nicotinic cholinergic receptors. The clinical impact of this latter mechanism of action has not been fully elucidated. Galantamine has favourable pharmacokinetic features including linear elimination kinetics, a relatively short half-life and high oral bioavailability. The efficacy of galantamine has been studied in an extensive clinical development program. During randomised, double-blind, placebo-controlled trials of up to 6 months' duration, galantamine 16 and 24 mg/day consistently produced a broad spectrum of beneficial effects on cognitive and non-cognitive AD symptoms. Patients' cognition, global function and abilities to perform both instrumental and basic activities of daily living were maintained, the emergence of behavioural symptoms was postponed and apparent reductions in caregiver burden were seen. In long-term studies (> or = 12 months), galantamine maintained cognitive and functional abilities at or near baseline levels for at least 12 months. Again, these benefits were associated with decreases in caregiver burden. The incidence of adverse events, which are typically mild or moderate in severity, is generally low with galantamine. Cholinergically mediated adverse events affecting mainly the gastrointestinal system can be minimised using the recommended slow dose-escalation regimen. Galantamine may therefore help reduce the overall burden and cost involved in caring for AD patients. Being approved for the treatment of mild-to-moderately severe AD in both the US and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine ranks as a first-line therapy for dementia.     

A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease

OBJECTIVE: To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer's disease. PATIENTS AND STUDY DESIGN: This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer's disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks. MAIN OUTCOME MEASURES: The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed. RESULTS: BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients' scores on the MMSE at week 52 did not differ significantly from baseline (-0.52 +/- 0.39, p < 0.5 vs baseline), whereas donepezil patients' scores deteriorated significantly from baseline (-1.58 +/- 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < or = 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12-18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 +/- 0.80 versus baseline, compared with an increase of 4.08 +/- 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p < or = 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments.Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials. CONCLUSIONS: Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.     

Effects of galantamine on behavioural and psychological disturbances and caregiver burden in patients with Alzheimer's disease

BACKGROUND: Behavioural and psychological disturbances occur in up to 90% of patients with Alzheimer's disease (AD), have a substantial impact on both patients and caregivers, and are often associated with the decision to institutionalise patients. Galantamine (Reminyl) is a dual-acting cholinergic treatment that improves cognitive and functional performance, delays the onset of behavioural symptoms and decreases behaviour-associated caregiver distress. OBJECTIVE: To assess the impact of galantamine on behavioural disturbances and associated caregiver burden in non-institutionalised patients with AD. METHODS: This was a 3-month, open-label, multicentre study in Switzerland. Patients with mild-to-moderate AD received galantamine (escalated from 8 to 24 mg/day over 8 weeks). The primary outcome was the Neuropsychiatric Inventory (NPI) for patients who completed 3 months treatment (observed cases, OC). Secondary outcomes included the Nurses' Observation Scale for Geriatric patients (NOSGER), and the Clinical Global Impression (CGI) of change. RESULTS: 124 patients (mean age 75.2 years, 55.6% women) received galantamine and were included in the intention-to-treat (ITT) safety analysis. Significant improvements in NPI scores versus baseline were seen in the OC analysis (p < 0.05, N = 91); mean total NPI scores (+/- SE) were reduced from 14.9 +/- 1.2 at baseline to 11.3 +/- 1.2 at month 3. Eleven out of 12 NPI domains were improved. Anxiety, aberrant motor behaviour, delusions, euphoria and night-time-behaviour all improved by > 30%. Symptoms with the highest baseline frequency and severity improved by 19-27%. A significant reduction in total NPI caregiver burden was observed at month 3 (p < 0.05). Despite this short assessment period the NOSGER evaluation and physicians' CGI also showed improvement. Adverse events (AEs) were mostly gastrointestinal. CONCLUSION: Galantamine significantly reduced behavioural disturbances after 3 months in this population and this had a positive impact on behaviour-related caregiver burden. Galantamine showed the expected safety profile and was well tolerated.     

Effects of galantamine on behavioural and psychological disturbances and caregiver burden in patients with Alzheimer's disease

SUMMARY

Background: Behavioural and psychological disturbances occur in up to 90% of patients with Alzheimer's disease (AD), have a substantial impact on both patients and caregivers, and are often associated with the decision to institutionalise patients. Galantamine (Reminyl?) is a dual-acting cholinergic treatment that improves cognitive and functional performance, delays the onset of behavioural symptoms and decreases behaviour-associated caregiver distress.

Objective: To assess the impact of galantamine on behavioural disturbances and associated caregiver burden in non-institutionalised patients with AD.

Methods: This was a 3-month, open-label, multicentre study in Switzerland. Patients with mild-to-moderate AD received galantamine (escalated from 8 to 24?mg/day over 8?weeks). The primary outcome was the Neuropsychiatric Inventory (NPI) for patients who completed 3?months treatment (observed cases, OC). Secondary outcomes included the Nurses’ Observation Scale for Geriatric patients (NOSGER), and the Clinical Global Impression (CGI) of change.

Results: 124 patients (mean age 75.2?years, 55.6% women) received galantamine and were included in the intention-to-treat (ITT) safety analysis. Significant improvements in NPI scores versus baseline were seen in the OC analysis (?p < 0.05, N = 91); mean total NPI scores (± SE) were reduced from 14.9 ± 1.2 at baseline to 11.3 ± 1.2 at month 3. Eleven out of 12 NPI domains were improved. Anxiety, aberrant motor behaviour, delusions, euphoria and night-time-behaviour all improved by > 30%. Symptoms with the highest baseline frequency and severity improved by 19–27%. A significant reduction in total NPI caregiver burden was observed at month 3 (?p < 0.05). Despite this short assessment period the NOSGER evaluation and physicians’ CGI also showed improvement. Adverse events (AEs) were mostly gastrointestinal.

Conclusion: Galantamine significantly reduced behavioural disturbances after 3?months in this population and this had a positive impact on behaviour-related caregiver burden. Galantamine showed the expected safety profile and was well tolerated.     

Effects of statins on cognitive function in patients with Alzheimer's disease in galantamine clinical trials

BACKGROUND AND OBJECTIVE: A number of reports have been published on the possible involvement of changes in brain cholesterol metabolism in the origin of Alzheimer's disease (AD) and the potential for influencing these changes by administration of HMG-CoA reductase inhibitors ('statins'). The aim of this study was to evaluate a potential association between use of statins and maintenance of cognitive function in patients with AD in galantamine clinical trials. METHOD: A post hoc analysis was conducted on data pooled from three double-blind, placebo-controlled, clinical trials of galantamine in patients with AD. Patients were divided into four treatment groups: statin plus galantamine (n = 42), statin alone (n = 50), galantamine alone (n = 614) or neither galantamine nor statin (n = 619). RESULTS: Galantamine was associated with a significant beneficial effect on cognitive status (p < 0.001). The association of use of statins with changes in cognitive status was not significant (p = 0.083). There was no significant interaction between the effects on cognition of statins and galantamine (p = 0.183) and no statistically significant changes in adverse effect rates were observed. CONCLUSION: These findings suggest the need for larger long-term trials to confirm or refute possible effects of statins on cognitive function and the potential interaction of statins with acetylcholinesterase inhibitors in the treatment of AD.     

Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer's disease: focus on galantamine

ABSTRACT

Objective and scope: This review article used data from an extensive literature search (including MEDLINE database searches) to explore the relationships between sleep, memory and Alzheimer's disease (AD). The importance of taking into account circadian rhythmicity and acetylcholine (ACh) levels when considering acetylcholinesterase inhibitors, galantamine in particular, in the treatment of patients with AD is discussed.

Review findings: Moderate changes of circadian rhythms may occur as part of the normal ageing process, but patients with AD exhibit circadian rhythm disturbances extending beyond those observed in non-demented elderly and this may lead to severe disruption of the sleep–wake cycle. Indeed, ACh plays an active role in maintaining a normal sleep pattern, which is important for memory consolidation. Low levels of ACh during slow-wave sleep compared with wakefulness have been shown to be critical for the consolidation of declarative memory. This suggests the existence of a circadian rhythm in central cholinergic transmission which modulates memory processes, with high ACh levels during wakefulness and reduced levels during slow-wave sleep. When using cholinesterase inhibitors to stimulate central cholinergic transmission in AD, respecting the natural circadian fluctuations of central cholinergic transmission may therefore be an important factor for patient improvement. Interfering with nocturnal cholinergic activity can add to memory problems and induce sleep disorders. Available data suggest that the type of cholinesterase inhibitor used and the time of administration may be critical with regard to the possible development of such disturbances. Plasma levels of galantamine, for example, are high during the waking day and lower at night, supporting a cholinergic stimulation that mirrors the physiological circadian rhythm of cholinergic activity. This may have beneficial implications with regard to sleep and memory.

Conclusions: The pharmacokinetic properties of cholinesterase inhibitors may need to be taken into account to avoid interference with sleep architecture and to achieve optimum benefits from treatment on cognitive processes.     

Pharmacotherapy of a patient with Alzheimer's disease: interactions with the antidementive galantamine

Based on a case-report, drug-related problems of the therapy of a female patient with Alzheimer's disease are discussed. According to the SOAP scheme options for optimizing the pharmacotherapy are discussed.     

A comparison of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease: a meta-analysis

This review was conducted in order to determine the efficacy of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease, and also to determine whether galantamine was a superior pharmacological intervention. Meta-analytic methods were used to analyse the data from eight empirical studies which met the inclusion criteria specified. By finding the mean effect sizes of the treatment on the outcome measures of cognition, it was determined that neither drug was greatly efficacious. However, this result does not necessarily diminish the practical value of the drug. It was also found that galantamine was no better than donepezil at treating cognitive decline in AD.     

老年痴呆患者早期护理干预的研究

目的 评价早期护理干预对老年痴呆患者的效果.方法 对42例轻度老年痴呆患者进行早期护理干预,为期2年,其中干预组21例,非干预组21例,应用简易精神状态检查量表(MMSE),日常生活能力量表(ADL)评定干预效果.结果 干预组老年痴呆患者认知功能及日常生活活动能力相对保存,干预后,MMSE评分和ADL评分分别为17.6±1.9和40.0±4.1,与非干预组比较(15.6±2.4和44.5±5.7),差异有统计学意义(P＜0.01).结论 早期护理干预有助于延缓轻度老年痴呆患者的病情进展.     

吡拉西坦与加兰他敏合用治疗阿尔茨海默病的作用探讨

目的:探讨复方吡拉西坦对痴呆大鼠的作用并比较与吡拉西坦、加兰他敏的疗效。方法:70只Wistar大鼠随机分为假手术组,模型组,复方高、中、低剂量组,单方加兰他敏、单方吡拉西坦7个实验组,每组10只。配制吡拉西坦与加兰他敏的高、中、低3种浓度的复方制剂及其两个单方制剂,术后第2天开始,除伪手术组和模型组灌服等容积的纯化水外,其他实验组分别灌服不同剂量的药物,并于术后第9天行跳台实验,连续记录5d成绩,第14天处死大鼠,测定脑组织中乙酰胆碱和乙酰胆碱酯酶的含量,并制作光镜标本观察海马区组织学变化。结果:与模型组和单方组比较,复方高、中剂量组可显著改善痴呆大鼠组的学习成绩,疗效优于单方给药组(P<0.01);提高脑组织乙酰胆碱的含量(P<0.05);海马区颗粒细胞排列整齐,未见明显异常。结论:复方吡拉西坦对阿尔茨海默病的治疗效果明显优于单方用药,为两药临床合用提供实验基础。     

Alternatives in the treatment of memory loss in patients with Alzheimer's disease

The pathophysiology, symptomatology, and treatment of memory loss in patients with Alzheimer's disease are described. Alzheimer's disease is characterized by cerebral cortical atrophy, neuronal loss, neurofibrillary tangles, and neuritic plaques. The primary neuropharmacologic defect involves reduced activity of the enzyme choline acetyltransferase, causing reduced synthesis of acetylcholine (ACh). Other neurotransmitters known to be compromised in patients with Alzheimer's disease include norepinephrine, serotonin, dopamine, and somatostatin. Initially components of short-term memory and immediate recall are lost. Eventually, memory loss is so severe that patients lose the ability to care for themselves. A definite diagnosis of Alzheimer's disease can be made only at autopsy. Three pharmacologic approaches to enhancing cholinergic function include increasing ACh production by increasing the availability of ACh precursors (lecithin, choline); inhibiting ACh degradation by inhibiting acetylcholinesterase (physostigmine, tacrine hydrochloride); and directly stimulating cholinergic receptors by using cholinomimetic agents (arecoline, RS-86). However, results of studies involving these agents are conflicting: no consistent benefit has been shown in patients with Alzheimer's disease. Although therapy with tacrine hydrochloride has been beneficial in some patients, it has not been effective in all cases and has the potential to cause serious adverse effects. Despite the research in patients with Alzheimer's disease, no agent has yet been found that produces consistent improvement in the memory loss associated with this disease.     

Long-term treatment of patients with Alzheimer's disease in primary and secondary care: results from an international survey

Abstract

Objective:

The International Outcomes Survey in Dementia (IOSID) was initiated to observe the effects of current standard of care for Alzheimer’s disease (AD) on patient outcomes and caregiver burden in a real-life setting.