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PubMed2001

Galantamine for Alzheimer's disease.

BACKGROUND: Galantamine (also called galanthamine, marketed as Reminyl (Janssen)) can be isolated from several plants, including daffodil bulbs, and now synthesized. Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. It is also an allosteric modulator at nicotinic cholinergic receptor sites potentiating cholinergic nicotinic neurotransmission. A small number of early studies showed mild cognitive and global benefits for patients with Alzheimer's disease, and recently several multicentre clinical trials have been published with positive findings. Galantamine has received regulatory approval in Sweden, is available in Austria, and awaits marketing approval in the United States, Europe, and other countries. OBJECTIVES: The objective of this review is to assess the clinical effects of galantamine in patients with probable Alzheimer's disease, and to investigate potential moderators of an effect. SEARCH STRATEGY: The Cochrane Dementia Group specialized register of clinical trials was searched using the terms 'galantamine,' and 'galanthamine' (15 February 2000) as was the Cochrane Controlled Trials Register (2000, Issue 2). These terms were also used to search the following databases: EMBASE, MEDLINE, PsychLit; Combined Health Information Database, NRR (National Research Register), ADEAR (Alzheimer's Disease Education and Referral Centre clinical database, BIOMED (Biomedicine and Health), Glaxo-Wellcome Clinical Trials Register, National Institutes of Health Clinical Trials Databases, Current Controlled Trials, Dissertation Abstracts (mainly North American dissertations) 1961-1994, Index to UK Theses (British dissertations) 1970-1994. Published reviews were inspected for further sources. Additional information was collected from an unpublished investigational brochure for galantamine. SELECTION CRITERIA: Trials selected were randomized, double-blind, parallel-group, and unconfounded comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in people with Alzheimer's disease. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. The pooled odds ratios (95%CI) or the average differences (95%CI) were estimated. Intention-to-treat and observed cases data were both reported, if the data were available to be reported. -Outcomes of interest include the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). - Potential moderating variables of a treatment effect included trial duration and dose. MAIN RESULTS: Seven trials were identified that met criteria for entry, with 6 being Phase II or III industry-sponsored multicentre trials. One was of 12 weeks duration; one of 5 months; one of 29 weeks; and the rest of 6 months duration. Trials of 5 months or more were aggregated in the analyses as '6 months'. Overall, galantamine showed significant treatment effects at daily doses of 16-32 mg/d for trials of 3- to 6-months duration. For global ratings, trials of 3 months duration with doses of 24-32mg/d (Odds Ratio (OR) 2.2; 95%CI 1.4 to 3.7) and 36mg/d (OR 3.3; 95%CI 1.2 to 9.3) were statistically significant in favour of treatment. For trials of 6 months duration (5-months to 29 weeks), only doses of 8mg/d failed to be statistically significant (24mg: OR 2.0; 95%CI 1.5 to2.5; 32mg: OR 1.9; 95%CI 1.4 to 2.5). For cognitive function over 6 months duration: at a 24mg/d, improvements measured -3.5 points (k=3; 95%CI -4.3 to -2.8) on weighted mean difference on the ADAS-Cog scale, and -4.0 points at 32mg/d (k=2; 95%CI -5.0 to -3.0). Both observed cases (WMD 3.8; 95%CI 0.3 to 7.3) and intention to treat analyses using the Disability Assessment of Dementia gave statistically significant results in favour of treatment for daily doses of 32mg for 6 months duration. The small number of trials available for analysis, however, limited the power of analyses to detect differences. Galantamine consistently failed to show statistically significant treatment effects at doses of 8mg/day. Galantamine's adverse effects appear similar to those of other cholinesterase inhibitors, in that it tends to produce gastrointestinal effects acutely and with dosage increases. Overall, people treated with galantamine at doses of 24-32 mg/d were more likely to discontinue participation in most trials than were people treated with lower doses or placebo, but in the one trial with a slower rate of titration the discontinuation rate was not significantly greater than placebo for the 16 mg/day dose. (ABSTRACT TRUNCATED)

Alzheimer Disease↗

PubMed2000

Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group.

BACKGROUND: Galantamine is a reversible, competitive cholinesterase inhibitor that also allosterically modulates nicotinic acetylcholine receptors. These mechanisms of action provided the rationale for a therapeutic trial of galantamine in AD. METHODS: A 6-month, multicenter, double-blind trial was undertaken in 636 patients with mild to moderate AD. Patients were randomly assigned to placebo or galantamine and escalated to maintenance doses of 24 or 32 mg/d. Eligible patients then entered a 6-month, open-label study of the 24 mg/d dose. Primary efficacy measures were the 11-item AD Assessment Scale cognitive subscale (ADAS-cog/11) and the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus). The Disability Assessment for Dementia (DAD) scale was a secondary efficacy variable. RESULTS: Galantamine significantly improved cognitive function relative to placebo; the treatment effects were 3.9 points (lower dose) and 3.8 points (higher dose) on the ADAS-cog/11 scale at month 6 (p < 0.001 in both cases). Both doses of galantamine produced a better outcome on CIBIC-plus than placebo (p < 0.05). Therapeutic response to galantamine was not affected by APOE genotype. At 12 months, mean ADAS-cog/11 and DAD scores had not significantly changed from baseline for patients who received galantamine 24 mg/d throughout the 12 months. The most common adverse events, which were predominantly gastrointestinal, decreased in frequency during long-term treatment. There was no evidence of hepatotoxicity. CONCLUSIONS: Galantamine is effective and safe in AD. At 6 months, galantamine significantly improved cognition and global function. Moreover, cognitive and daily function were maintained for 12 months with the 24 mg/d dose.

Aged↗

PubMed2000

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial. Galantamine International-1 Study Group.

OBJECTIVE: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimer's disease. DESIGN: Randomised, double blind, parallel group, placebo controlled trial. SETTING: 86 outpatient clinics in Europe and Canada. PARTICIPANTS: 653 patients with mild to moderate Alzheimer's disease. INTERVENTION: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. MAIN OUTCOME MEASURES: Scores on the 11 item cognitive subscale of the Alzheimer's disease assessment scale, the clinician's interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. RESULTS: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer's disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P<0.001 for both doses). Galantamine was more effective than placebo on the clinician's interview based impression of change plus caregiver input (P<0.05 for both doses v placebo). At six months, patients in the higher dose galantamine group had significantly better scores on the disability assessment for dementia scale than patients in the placebo group (mean treatment effect 3.4 points, P<0.05). Apolipoprotein E genotype had no effect on the efficacy of galantamine. 80% (525) of patients completed the study. CONCLUSION: Galantamine is effective and well tolerated in Alzheimer's disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

Aged↗

PubMed2000

A 5-month, randomized, placebo-controlled trial of galantamine in AD. The Galantamine USA-10 Study Group.

OBJECTIVE: To investigate the efficacy and tolerability of galantamine, using a slow dose escalation schedule of up to 8 weeks, in 978 patients with mild to moderate AD. METHODS: A 5-month multicenter, placebo-controlled, double-blind trial. Following a 4-week placebo run-in, patients were randomized to one of four treatment arms: placebo or galantamine escalated to final maintenance doses of 8, 16, or 24 mg/day. Outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog), the Clinician's Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus), the AD Cooperative Study Activities of Daily Living inventory, and the Neuropsychiatric Inventory. Standard safety evaluations and adverse event monitoring were carried out. RESULTS: After 5 months, the galantamine-placebo differences on ADAS-cog were 3.3 points for the 16 mg/day group and 3.6 points for the 24 mg/day group (p < 0.001 versus placebo, both doses). Compared with placebo, the galantamine 16- and 24-mg/day groups also had a significantly better outcome on CIBIC-plus, activities of daily living, and behavioral symptoms. Treatment discontinuations due to adverse events were low in all galantamine groups (6 to 10%) and comparable with the discontinuation rate in the placebo group (7%). The incidence of adverse events in the galantamine groups, notably gastrointestinal symptoms, was low and most adverse events were mild. CONCLUSIONS: Galantamine 16 and 24 mg/day significantly benefits the cognitive, functional, and behavioral symptoms of AD as compared with placebo. Slow dose escalation appears to enhance the tolerability of galantamine, minimizing the incidence and severity of adverse events.

Activities of Daily Living↗

PubMed2004

Pharmacokinetics and tissue distribution of galantamine and galantamine-related radioactivity after single intravenous and oral administration in the rat.

The plasma kinetics and tissue distribution of galantamine hydrobromide [4aS-(4a alpha,6beta,8aR*)]-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro-[3a,3,2-ef] [2benzazepin-6-ol hydrobromide, CAS-1953-04-4], a reversible acetylcholinesterase inhibitor, were studied in male and female non-pregnant and pregnant SPF Wistar rats and in male Fisher x Copenhagen pigmented rats. Most studies were performed using 3H-labelled galantamine hydrobromide, measuring unchanged drug (UD) and non-volatile radioactivity (NVR) in plasma and tissues by high-performance liquid chromatography (HPLC), liquid scintillation counting and quantitative whole-body autoradiography (QWBA). Plasma levels after single intravenous administration of UD (1.25-2.5 mg/kg) declined bi- or triphasically, with an elimination half-life of 3.5 h in male, and 5.1 h in female rats. The plasma clearance (Cl) averaged 1.9 l/kg/h (male rats) and 0.9 l/kg/h (female rats), and the volume of distribution (VdSS) was about 5 l/kg for both male and female rats. Following oral administration (2.5-10 mg/kg), galantamine was rapidly absorbed in both sexes, with an absolute oral bioavailability of 77%. Distribution studies after oral administration of 3H-galantamine showed an almost immediate equilibrium between plasma and tissues, with highest tissue levels of NVR and UD in liver, kidney, salivary glands, adrenal glands and, for the female rat, spleen, and lowest in white fat. To most tissues and especially to brain, the distribution of UD was more pronounced than that of its metabolites. Tissue concentrations of UD and NVR declined at a similar rate as plasma, showing no undue retention. QWBA in the pigmented rat showed the same distribution and elimination pattern of NVR. Only in hair follicles and choroid some retention of NVR was seen, but the calculated half-life was less than one day. In the female pregnant SPF Wistar rat, maternal tissue distribution of NVR was similar to that of the non-pregnant rat. NVR tissue levels in the foetus were similar to those found in maternal blood during the whole experiment, indicating a rapid equilibrium without accumulation.

Administration, Oral↗

PubMed2004

Effects of galantamine on attention and memory in Alzheimer's disease measured by computerized neuropsychological tests: results of the Brazilian Multi-Center Galantamine Study (GAL-BRA-01).

OBJECTIVE: To investigate the effects of galantamine on the performance of patients with mild to moderate Alzheimer's disease (AD) in a computerized neuropsychological test battery (CNTB). METHOD: Thirty-three patients with probable AD were treated with galantamine for three months and evaluated in a prospective, open-label, multi-center study. The CNTB and the ADAS-Cog were administered at baseline and after 12 weeks. The CNTB includes reaction time tests to evaluate attention, implicit and episodic memory for faces and words. Statistical comparisons were performed between the results in week 12 versus baseline. Patients who did not reach the therapeutic doses were excluded from the efficacy analysis. RESULTS: Four patients (12.1%) were excluded from the analysis either because of treatment discontinuation (n=3) or because a therapeutic dose was not reached (n=1). The remaining 29 patients were treated with doses of 24 mg/day (n=22) and 16 mg/day (n=7). After 12 weeks, significant reductions in reaction time were seen in the test of episodic memory for faces (p=0.023) and in the test of two-choice reaction time (p=0.039) of the CNTB. CONCLUSION: Treatment with galantamine produced improvement in computerized tests of attention and episodic memory after 12 weeks, leading to statistically significant reduction in the reaction times.

Aged↗

PubMed2006

Galantamine for Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. OBJECTIVES: To assess the clinical effects of galantamine in patients with mild cognitive impairment (MCI), probable or possible Alzheimer's disease (AD), and potential moderators of effect. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25 April 2005 using the terms galanthamin*, galantamin* and Reminyl. Published reviews were inspected for further sources. Additional information was collected from unpublished clinical research reports for galantamine obtained from Janssen and from http://www.clinicalstudyresults.org/. SELECTION CRITERIA: Trials selected were randomised, double-blind, parallel-group comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with MCI or AD. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. Outcomes of interest include the clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of treatment effect assessed included trial duration, dose, and diagnosis of possible versus probable Alzheimer's disease. MAIN RESULTS: Ten trials with a total 6805 subjects were included in the analysis. Treatment with galantamine led to a significantly greater proportion of subjects with improved or unchanged global rating scale rating (k = 8 studies), at all dosing levels except for 8 mg/d . Confidence intervals for the ORs overlapped across the dose range of 16 mg to 36 mg per day, with point estimates of 1.6 - 1.8 when analysed with the intention-to-treat sample. Treatment with galantamine also led to significantly greater reduction in ADAS-cog score at all dosing levels (k = 8), with greater effect over six months compared to three months. Confidence intervals again overlapped. Point estimate of effect was lower for 8 mg/d but similar for 16 mg to 36 mg per day. For example, treatment effect for 24 mg/d over six months was 3.1 point reduction in ADAS-cog (95%CI 2.6-3.7, k = 4, ITT).ADCS-ADL, DAD and NPI were reported only in a small proportion of trials: all showed significant treatment effect in some individual trials at least. Confidence interval of treatment effect for the one trial recruiting patients with possible AD overlapped with the other seven recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related. Prolong release / once daily formulation of galantamine at 16 - 24mg/d was found to have similar efficacy and side-effect profile as the equivalent twice-daily regime. Data from the two MCI trials suggest marginal clinical benefit, but a yet unexplained excess in death rate. AUTHORS' CONCLUSIONS: Subjects in these trials were similar to those seen in earlier anti dementia AD trials, consisting primarily of mildly to moderately impaired outpatients. Galantamine's effect on more severely impaired subjects has not yet been assessed.Nevertheless, this review shows consistent positive effects for galantamine for trials of three to six months' duration. Although there was not a statistically significant dose-response effect, doses above 8 mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile in AD is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over a four week period, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially. Longer term use of galantamine has not been assessed in a controlled fashion. Galantamine use in MCI is not recommended due to its association with an excess death rate.

Alzheimer Disease↗

PubMed2002

Pharmacokinetics and safety of galantamine in subjects with hepatic impairment and healthy volunteers.

The objective of this study was to compare the pharmacokinetics and safety of galantamine in subjects with hepatic impairment with those in healthy subjects. This was an open-label study in which a single oral 4-mg dose of galantamine was administered to volunteers with mild (Child-Pugh score of 5-6, n = 8), moderate (Child-Pugh score of 7-9, n = 8), or severe hepatic impairment (Child-Pugh score of 10-15, n = 1) and to healthy, matched control subjects (n = 8). Galantamine pharmacokinetics and safety (adverse events, laboratory test results, electrocardiograms, vital signs, and cardiac events) were assessed over 6 days after administration of galantamine. The pharmacokinetic parameters of galantamine were similar in subjects with mild hepatic impairment compared with healthy controls. Compared with the healthy control group, subjects with moderate hepatic impairment showed relative increases in the area under the plasma-concentration curve from zero to infinity (AUC0-infinity) (+33%) and terminal half-life (t1/2) (+30%) (p = 0.051 and p = 0.003, respectively), a 23% relative decrease in total plasma clearance (p = 0.061), and a small but significant relative increase in the fraction of free plasma galantamine (p = 0.009). Galantamine was well tolerated by all subjects. There were no serious adverse events (AEs) or premature withdrawals from the study because of AEs. Reported AEs were headache (three cases), nausea (one case), and paresthesia (one case). There were no clinically relevant changes in clinical laboratory findings, vital signs, and electrocardiograms. Low patient recruitment (n = 1) precluded statistical analysis of galantamine pharmacokinetics and safety in severe hepatic impairment. It was concluded that the pharmacokinetics of galantamine in subjects with mild hepatic impairment was similarto those in healthy subjects. In subjects with moderate hepatic impairment, galantamine clearance was decreased by approximately 23% compared with normal volunteers. Galantamine was also well tolerated and appeared to be safe in subjects with mild ormoderate hepatic impairment. Based on the study results, it appears that it would not be necessary to adjust doses of galantamine during administration to subjects with mild hepatic impairment. In subjects with moderately impaired hepatic function, dose titration should proceed cautiously. Unfortunately, difficulties with patient recruitment did not allow adequate assessment of the safety of galantamine in subjects with severe hepatic impairment in this study. Therefore, the use of galantamine in subjects with severe hepatic impairment is not recommended.

Adolescent↗

PubMed2003

Pharmacokinetics of galantamine, a cholinesterase inhibitor, in several animal species.

In this publication, single and repeated dose experiments in rats, mice, rabbits and dogs are reported to assess the pharmacokinetics of galantamine (CAS-1953-04-4), a tertiary alkaloid with reversible cholinesterase inhibiting and nicotinic receptor modulatory properties developed for the treatment of Alzheimer's disease in humans. Rats received single i.v. and single and repeated oral administrations of various doses, up to 160 mg/kg/day. In mice, only repeated oral administration of galantamine was investigated, up to 40 mg/kg/day. Galantamine single and repeated oral doses up to 32 mg/kg/day were administered to female pregnant rabbits. Beagle dogs received single i.v. and single and repeated oral administrations of doses up to 8 mg/kg/day. Generally, oral absorption was rapid, with maximal plasma levels reached within 2 h in all species. Absolute oral bioavailability of a gavage dose was high in rat (77%) and dog (78%). In mice and rats, the bioavailability of galantamine administered via the food was lower than of galantamine administered by gavage. Elimination half-life of galantamine was relatively large in rat and dog and smaller in mouse and rabbit. In general, galantamine displayed dose-proportional to somewhat more than dose-proportional kinetics. In rats, plasma levels were lower in females than in males, whereas in mice, females showed higher levels than males. No gender differences were observed in dogs. No relevant differences in exposure to galantamine were found in rats and dogs upon oral administration of galantamine obtained as a natural extract or from chemical synthesis. The exposure to the active metabolite norgalantamine in plasma of the different animal species was low, except in the dog where the steady-state norgalantamine exposure was approximately 75% of galantamine exposure. Galantamine plasma levels after single and repeated administration of 10 mg/kg/day in all species investigated except female rat and rabbit were much higher than mean therapeutic plasma levels of galantamine obtained in humans. The pharmacokinetic profile of galantamine after repeated oral administration in rats was most similar to the profile obtained after repeated administration of 12 mg b.i.d. in man.

Administration, Oral↗

PubMed2000

Galantamine: a review of its use in Alzheimer's disease.

UNLABELLED: Currently, acetylcholinesterase (AChE) inhibitors are the most promising class of drugs for the treatment of Alzheimer's disease (AD). Galantamine is a reversible, competitive, tertiary alkaloid AChE inhibitor. The drug is selective for AChE rather than butyrylcholinesterase. In addition to inhibition of AChE galantamine interacts allosterically with nicotinic acetylcholine receptors to potentiate the action of agonists at these receptors. Recipients of galantamine 16 or 24 mg/day achieved significant improvements in cognitive and global symptoms relative to placebo recipients in large (n = 285 to 978 patients with mild to moderate AD) well-designed trials of 3 to 6 months' duration. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Moreover, galantamine recipients achieved significantly better outcomes on behavioural symptoms than placebo recipients. In a long term study (12 months), galantamine 24 mg/day slowed the progression of symptoms of the disease and maintained cognitive function and activities of daily living in patients with mild to moderate AD. Galantamine was generally well tolerated with the majority of adverse events being mild to moderate in intensity and transient. Predictably, adverse events were cholinergic in nature and generally related to the gastrointestinal system. These effects were reduced in patients receiving the recommended dose escalation regimen. Galantamine had no clinically relevant effects on vital signs, haematological or biochemical laboratory parameters and, importantly, there were no reports of hepatotoxicity. The incidence of serious adverse events was similar between galantamine (8 to 32 mg/day) and placebo groups (6 to 16% of patients across all treatment groups). CONCLUSIONS: Galantamine is an effective well tolerated symptomatic treatment for AD which improves cognition, function and activities of daily living in the short term (up to 6 months) in patients with mild to moderate AD. In addition, it delays the development of behavioural disturbances and psychiatric symptoms, and reduces caregiver burden (as measured by caregiver time). In the long term (up to 1 year), galantamine maintains cognition and activities of daily living. Adverse events associated with galantamine are mainly cholinergic, usually mild to moderate in intensity and transient. Galantamine has been evaluated in several large well-designed studies and, given the relative lack of established treatment options, it may be considered as one of the first-line pharmacological treatments in patients with mild to moderate AD.

Acetylcholinesterase↗

PubMed2004

Galantamine for Alzheimer's disease.

BACKGROUND: Galantamine is a specific, competitive, and reversible acetylcholinesterase inhibitor. OBJECTIVES: To assess the clinical effects of galantamine in patients with probable or possible Alzheimer's disease (AD), and potential moderators of effect. SEARCH STRATEGY: The trials were identified from a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, last updated on 25 August 2005 using the terms galanthamin*, galantamin* and Reminyl. Published reviews were inspected for further sources. Additional information was collected from unpublished clinical research reports for galantamine obtained from Janssen. SELECTION CRITERIA: Trials selected were randomised, double-blind, parallel-group comparisons of galantamine with placebo for a treatment duration of greater than 4 weeks in subjects with AD. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the reviewers and pooled where appropriate and possible. Outcomes of interest include the clinical global impression of change (CIBIC-plus or CGIC), Alzheimer's Disease Assessment Scale-cognitive sub scale (ADAS-cog), Alzheimer's Disease Cooperative Study/Activities of Daily Living (ADCS-ADL), Disability Assessment for Dementia scale (DAD) and Neuropsychiatric Inventory (NPI). Potential moderating variables of treatment effect assessed included trial duration, dose, and diagnosis of possible vs. probable Alzheimer's disease. MAIN RESULTS: Seven trials with a total 3777 subjects were included in the analysis. Treatment with galantamine led to a significantly greater proportion of subjects with improved or unchanged global rating scale rating (k=7), at all dosing levels except for 8mg/d . Confidence intervals for the ORs overlapped across the dose range of 16mg to 36mg per day, with point estimates of 1.6-2.1 when analysed with the intention-to-treat sample. Treatment with galantamine also led to significantly greater reduction in ADAS-cog score at all dosing levels (k=7), with greater effect over 6 months compared to 3 months. Confidence intervals again overlapped. Point estimate of effect was lower for 8mg/d but similar for 16mg to 36mg per day. For example, treatment effect for 24mg/d over 6 months was 3.1point reduction in ADAS-cog (95%CI 2.6-3.7, k=4, ITT).ADCS-ADL, DAD and NPI were reported only in a small proportion of trials: all showed significant treatment effect in some individual trials at least. Confidence interval of treatment effect for the one trial recruiting patients with possible AD overlapped with the other six recruiting patients with probable AD. Galantamine's adverse effects appeared similar to those of other cholinesterase inhibitors and to be dose related. REVIEWERS' CONCLUSIONS: Subjects in these trials were similar to those seen in earlier anti dementia AD trials, consisting primarily of mildly to moderately impaired outpatients. Galantamine's effect on more severely impaired subjects has not yet been assessed.Nevertheless, this review shows consistent positive effects for galantamine for trials of 3 to 6 months duration. Although there was not a statistically significant dose-response effect, doses above 8mg/d were, for the most part, consistently statistically significant. Galantamine's safety profile is similar to that of other cholinesterase inhibitors with respect to cholinergically mediated gastrointestinal symptoms. It appears that doses of 16 mg/d were best tolerated in the single trial where medication was titrated over a 4 week period, and because this dose showed statistically indistinguishable efficacy with higher doses, it is probably most preferable initially. Longer term use of galantamine has not been assessed in a controlled fashion.

Alzheimer Disease↗

PubMed2000

Galantamine: additional benefits to patients with Alzheimer's disease.

Galantamine, a novel treatment for Alzheimer's disease (AD), has a dual mechanism of action, combining allosteric modulation of nicotinic acetylcholine receptors with reversible, competitive inhibition of acetylcholinesterase. In the Phase III clinical trial programme, over 3,000 patients with mild-to-moderate AD were enrolled in one of five randomized, controlled, double-blind studies. Using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) to assess memory and other cognitive functions, galantamine was found to be significantly superior to placebo in all five studies at doses of 16, 24 and 32 mg/day. In all studies, galantamine-treated patients maintained their cognitive function, whereas the placebo-treated patients experienced a significant deterioration in ADAS-cog scores. The 32-mg/day dose was not associated with any additional cognitive benefit. Pooled data from two 6-month studies (n = 1,269), which were of identical design, show that the therapeutic benefits of galantamine are sustained for the duration of treatment. The treatment effect (galantamine-placebo difference on ADAS-cog) for the pooled data was approximately 4 points. Clinical benefit was seen in all levels of disease severity, with a 7-point advantage over placebo on ADAS-cog for patients with moderately severe disease. Galantamine was well tolerated, with most patients completing the 6-month studies. The long-term effects of galantamine have been evaluated in a 12-month study. Patients who completed one of the pivotal 6-month studies (n = 353) were entered into a 6-month open-label extension. Cognitive and daily function were maintained throughout the 12 months in patients who received galantamine 24 mg/day. This sustained level of benefit may reflect galantamine's dual effect on the cholinergic system. Data from a 5-month, placebo-controlled study have also shown that galantamine produces significant benefits on behavioural symptoms. The persistence and range of therapeutic effects produced by galantamine suggest that it may provide additional benefits for patients with AD.

Alzheimer Disease↗

PubMed2003

Galantamine provides sustained benefits in patients with 'advanced moderate' Alzheimer's disease for at least 12 months.

Galantamine (Reminyl), a novel agent with a dual mode of action, modulates nicotinic acetylcholine receptors and inhibits acetylcholinesterase. Galantamine has consistently demonstrated a broad range of beneficial effects and has shown sustained benefits in cognitive and functional abilities for at least 12 months in patients with mild-to-moderate Alzheimer's disease (AD). As pivotal studies demonstrating the efficacy of cholinergic drugs were designed to exclude patients with severer AD, many patients with the advanced stage of this condition are currently not treated due to the lack of demonstrated efficacy in clinical trials. We aimed to investigate whether there was any evidence for the benefits of galantamine in patients with severer disease, by performing a post hoc analysis using data extracted from the population of the two long-term galantamine studies. We evaluated the efficacy of galantamine in patients with 'advanced moderate' AD. 'Advanced moderate' patients were those with baseline Mini Mental State Examination (MMSE) scores </=14 or Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog) scores >30. These patients were compared with matched controls who received placebo in a different historical study. Cognitive abilities (assessed using the ADAS-cog scale) of 'advanced moderate' AD patients receiving galantamine for 12 months were maintained at baseline levels after 12 months, and significantly improved over those of placebo patients (p < 0.001). Of the 'advanced moderate' patients receiving galantamine, 51% with baseline ADAS-cog of >30 maintained or improved their ADAS-cog scores over baseline values, compared with 13% receiving placebo (p < 0.001). In the subgroup of 'advanced moderate' patients with baseline MMSE </=14, 48% of those receiving galantamine and 4% of those receiving placebo maintained or improved their ADAS-cog scores at 12 months (p = 0.001). In both subgroups, the treatment difference (galantamine vs. historical placebo) amounted to approximately 10 points on the ADAS-cog scale. Functional abilities, as assessed using the Disability Assessment for Dementia scale, remained significantly superior in galantamine-treated patients compared with historical placebo-treated patients at 12 months (p < 0.001). In conclusion, galantamine offered sustained efficacy to patients with 'advanced moderate' AD, confirming the benefits seen in published studies of patients with mild-to-moderate AD. This drug has potential for broader use in clinical practice.

Aged↗

PubMed2005

Pharmacokinetic simulation for switching from galantamine immediate-release to extended-release formulation.

OBJECTIVE: To demonstrate using pharmacokinetic (PK) modeling and simulation, that the PK that the PK parameters for drug exposure with galantamine parameters for drug exposure with galantamine immediate-release (IR) tablet and galantamine extended-release (ER) capsule are comparable in patients with Alzheimer's disease (AD) during in patients with Alzheimer's disease (AD) during the switch from twice-daily IR tablet at steady state to the new once-daily ER capsule, and to support a recommendation that patients receiving the IR tablet at steady state can be successfully switched to the ER capsule at the same daily dosage with no titration period. METHODS: Simulations were performed using a population PK model developed from clinical studies with IR galantamine in the target AD population, in combination with IR and ER absorption parameters obtained from a PK study in healthy volunteers which showed similar results. PK simulations were performed for the switch from IR tablet 8 mg b.i.d. to ER capsule 16 mg q.d. and from IR tablet 12 mg b.i.d. to ER capsule 24 mg q.d. RESULTS: This simulation predicted that patients switched from the IR tablet to the ER capsule, the PK parameters for drug exposure on the first day of ER treatment would be similar to those of IR treatment at steady state. After steady state was achieved with ER galantamine, values for peak concentration and trough concentration were slightly lower (5% and 18%, respectively) than those seen at steady state for IR galantamine; this finding is considered to have no clinical implications. Area under the curve (AUC) with ER galantamine was similar to that seen at steady state with IR galantamine. CONCLUSIONS: These results suggest that no titration period is required in patients receiving stable doses of twice-daily IR galantamine who are switched to once-daily ER galantamine. The once-daily dosage regimen of ER galantamine without a titration period should prove convenient for AD patients and their caregivers and should increase treatment compliance.

Administration, Oral↗

PubMed2005

Galantamine activates muscle-type nicotinic acetylcholine receptors without binding to the acetylcholine-binding site.

Galantamine (Reminyl; Janssen Pharmaceutica, Titusville, NJ) belongs to a class of acetylcholinesterase inhibitors approved for symptomatic treatment of Alzheimer's disease. The drug presumably acts by raising and prolonging the profile of acetylcholine (ACh) via an inhibitory effect on the esterase. However, there is also evidence demonstrating that galantamine can activate the nicotinic ACh receptor or modulate its activation by ACh. In this study, we have examined the ability of galantamine to directly activate the muscle-type nicotinic ACh receptor or to modulate receptor activation by selected nicotinic agonists. Studies of direct activation by galantamine demonstrated that this ligand is a low-efficacy agonist of the muscle-type ACh receptor. Point mutations in the M2-M3 linker (alphaS269I) and the M2 transmembrane domain (epsilonT264P) had similar effects on receptor activation by galantamine and nicotinic agonists, suggesting that the general features of receptor activation by galantamine are similar to that in the presence of ACh. Experiments performed in the simultaneous presence of galantamine and various nicotinic ligands showed that channel activation by the nicotinic ligands studied (ACh, carbachol, and choline) was not affected by the presence of galantamine at concentrations up to 100 microm. In addition, galantamine did not reduce the initial rate of binding for 125I-alpha-bungarotoxin. These results demonstrate that galantamine does not interfere with the occupation of the nicotinic agonist binding site by ACh, carbachol, or choline. We conclude that galantamine activates the muscle-type ACh receptor by interacting with a binding site that is distinct from the site for nicotinic agonists.

Acetylcholine↗

PubMed2002

Galantamine: a pharmacoeconomic review of its use in Alzheimer's disease.

Galantamine is one of several orally administered cholinesterase inhibitors that improve cognition in patients with mild to moderate Alzheimer's disease. Compared with placebo, galantamine 16 or 24 mg/day improved cognition and activities of daily living, delayed emergence of behavioural symptoms and reduced caregiver burden in three pivotal randomised studies of 5 or 6 months' duration. Galantamine may reduce the considerable economic burden of Alzheimer's disease by delaying the need for full-time care (FTC) in patients with mild to moderate Alzheimer's disease. In pharmacoeconomic analyses with a time horizon of 10 years conducted in Canada, Sweden, The Netherlands and the US, data from the pivotal trials were incorporated into a model to examine economic implications associated with galantamine treatment. FTC was defined in the model as the consistent requirement for caregiving and supervision for the greater part of each day regardless of the location of care and the identity of caregiver. When the effect of galantamine 16 or 24 mg/day was analysed from the perspective of a comprehensive healthcare payer, treatment was associated with cost savings (inclusive of drug costs) relative to no treatment, regardless of country for which the model was customised. Cost savings resulted from the delay in the time until FTC was required in patients with mild to moderate disease. In sensitivity analyses, cost savings were most sensitive to the cost of institutional care. In the analyses that considered the effect of galantamine 24 mg/day solely on cognition, galantamine was predicted to reduce the time FTC was required by approximately 10% in patients with mild to moderate Alzheimer's disease compared with no pharmacological treatment. Greater reductions in the time that FTC was required were predicted when the effects of galantamine 16 or 24 mg/day on behavioural symptoms in addition to cognition were considered in the US analysis or in sensitivity analyses in studies in other countries. In conclusion, pharmacoeconomic analyses, which were based on modelling of data from pivotal clinical trials with galantamine and included drug costs, indicate that galantamine treatment may result in cost savings from a healthcare payer perspective. The effects of galantamine on cognition and behavioural symptoms in patients with mild to moderate Alzheimer's disease are predicted to delay the need for FTC, which may result in cost savings. From a societal perspective, the caregiver burden of caring for a patient with Alzheimer's disease in the community may be decreased and the time that patients have without severe disease may be prolonged.

Alzheimer Disease↗

PubMed2003

Galantamine in the treatment of cognitive decline in patients with vascular dementia or Alzheimer's disease with cerebrovascular disease.

INTRODUCTION: Alzheimer's disease and vascular dementia are the two most common types of dementia, with significant overlap of clinical symptoms and pathology. Previous results from a 6-month, double-blind, placebo-controlled, international, multicentre study of the cholinomimetic galantamine in patients with probable vascular dementia or mixed dementia (Alzheimer's disease with cerebrovascular disease) showed significant cognitive, behavioural and functional benefits in these patients. Furthermore, results of a 6-month, open-label extension of this study confirmed that patients with vascular dementia or Alzheimer's disease with cerebrovascular disease may benefit from galantamine therapy for at least 1 year. The objective of the current analysis was to determine if the long-term cognitive benefits of galantamine seen in the above-mentioned study are influenced by dementia type (probable vascular dementia vs Alzheimer's disease with cerebrovascular disease). STUDY DESIGN: A post hoc sub-analysis of a 6-month, multicentre, randomised, double-blind, placebo-controlled study and a subsequent 6-month, open-label extension. PATIENTS AND METHODS: Patients diagnosed with probable vascular dementia or Alzheimer's disease with cerebrovascular disease were treated with galantamine (Reminyl) 24 mg/day for 12 months (6 months double-blind and 6 months open-label) or placebo for 6 months (double-blind) followed by galantamine 24 mg/day for 6 months (open-label). Changes in scores on the 11-item Alzheimer's Disease Assessment Scale cognitive subscale (ADAS-cog/11) were assessed at months 6, 7.5 and 12. Mean changes from baseline were analysed. RESULTS: Patients with probable vascular dementia treated with galantamine for 6 or 12 months showed significant improvements in ADAS-cog/11 scores versus baseline, which were maintained at the end of the 12-month study. Patients who had Alzheimer's disease with cerebrovascular disease continuously treated with galantamine maintained the cognitive abilities seen at baseline for at least 12 months. Additionally, patients who had Alzheimer's disease with cerebrovascular disease who were switched from placebo to open-label galantamine therapy for 6 months demonstrated cognitive benefits, but these benefits were significantly less than those observed in patients treated with galantamine continuously for the 12-month period. Galantamine was well tolerated throughout the entire 12-month study. CONCLUSIONS: These findings suggest that the drug is efficacious for such common forms of dementia as vascular dementia and Alzheimer's disease with cerebrovascular disease. Moreover, some patients benefit from galantamine therapy that is initiated early, soon after diagnosis, and continued for at least 1 year.

Aged↗

PubMed2006

The clinical and cost-effectiveness of donepezil, rivastigmine, galantamine and memantine for Alzheimer's disease.

OBJECTIVES: To provide an update review of the best quality evidence for the clinical effectiveness and cost-effectiveness of donepezil, rivastigmine and galantamine for mild to moderately severe Alzheimer's disease (AD) and of memantine for moderately severe to severe AD. DATA SOURCES: Electronic databases, experts in the field and manufacturer submissions to the National Institute for Health and Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. The quality of included randomised controlled trials (RCTs) was assessed using criteria developed by the NHS Centre for Reviews and Dissemination. An outline assessment of economic evaluations was undertaken using a standard checklist. The clinical and cost-effectiveness data were synthesised through a narrative review with full tabulation of the results of included studies. Where appropriate, meta-analysis of data was undertaken. RESULTS: For mild to moderately severe AD, the results of the study suggested that all three treatments were beneficial when assessed using cognitive outcome measures. Global outcome measures were positive for donepezil and rivastigmine, but mixed for galantamine. Results for measures of function were mixed for donepezil and rivastigmine, but positive for galantamine. Behaviour and mood measures were mixed for donepezil and galantamine, but showed no benefit for rivastigmine. For memantine, two published RCTs were included; in one of these trials the participants were already being treated with donepezil. The results suggest that memantine is beneficial when assessed using functional and global measurements. The effect of memantine on cognitive and behaviour and mood outcomes is, however, less clear. Literature on the cost-effectiveness of donepezil, rivastigmine and galantamine was dominated by industry-sponsored studies, and studies varied in methods and results. Of the three UK studies, two report donepezil as not cost-effective, whereas a third study reports an additional cost (1996 pounds sterling) of between 1200 pounds sterling and 7000 pounds sterling per year in a non-severe AD health state (concerns over these estimates are raised, suggesting that they may underestimate the true cost-effectiveness of donepezil). Cost-effectiveness analysis undertaken in this review suggests that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of 80,000 pounds sterling, with donepezil treatment reducing the mean time spent in full-time care (delays progression of AD) by 1.42-1.59 months (over a 5-year period). From four published cost-effectiveness studies, two UK studies report additional costs associated with rivastigmine treatment. Cost-effectiveness analysis undertaken in the current review suggests that rivastigmine treatment has a cost per QALY in excess of 57,000 pounds sterling, with rivastigmine treatment reducing the mean time spent in full-time care (delays progression) by 1.43-1.63 months (over a 5-year period). From five published cost-effectiveness studies, one UK study reports a cost per QALY of 8693 pounds sterling for 16-mg galantamine treatment and 10,051 pounds sterling for 24-mg galantamine treatment (concerns raised suggest that this may underestimate the true cost-effectiveness of galantamine). Cost-effectiveness analysis undertaken in the present review suggests that galantamine treatment has a cost per QALY in excess of 68,000 pounds sterling, with galantamine reducing the time spent in full-time care (delays progression) by 1.42-1.73 months (over a 5-year period). From two published cost-effectiveness studies, one reports analysis for the UK, finding that memantine treatment results in cost savings and benefits in terms of delaying disease progression (concerns raised suggest that this may underestimate the true cost-effectiveness of memantine). In the current review, the cost-effectiveness of memantine has not been modelled separately, but where alternative parameter inputs on the cost structure and utility values have been used in a reanalysis using the industry model, the cost-effectiveness is reported at between 37,000 pounds sterling and 52,000 pounds sterling per QALY, with this alternative analysis still based on what is regarded as an optimistic or favourable effectiveness profile for memantine. CONCLUSIONS: Although results from the clinical effectiveness review suggest that these treatments may be beneficial, a number of issues need to be considered when assessing the results of the present review, such as the characteristics of the participants included in the individual trials, the outcome measures used, the length of study duration, the effects of attrition and the relationship between statistical significance and clinical significance. Many included trials were sponsored by industry. For donepezil, rivastigmine and galantamine, the cost savings associated with reducing the mean time spent in full-time care do not offset the cost of treatment sufficiently to bring estimated cost-effectiveness to levels generally considered acceptable by NHS policy makers. It is difficult to draw conclusions on the cost-effectiveness of memantine; it is suggested that further amendments to the potentially optimistic industry model (measure of effect) would offer higher cost per QALY estimates. Future research should include: information on the quality of the outcome measures used; development of quality of life instruments for patients and carers; studies assessing the effects of these interventions of durations longer than 12 months; comparisons of benefits between interventions; and research on the prediction of disease progression.

Aged↗