Treatment options: The latest evidence with galantamine (Reminyl®)

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Abstract

Vascular dementia (VaD) has a great deal of overlap (in terms of features and symptoms) with Alzheimer's disease (AD). Mixed dementia, or AD with concomitant cerebrovascular disease (AD with CVD), is increasingly being recognized as a distinct clinical condition that occurs with substantial frequency. The robust evidence for the effectiveness of cholinergic treatments such as galantamine (Reminyl®) in AD suggests its potential use in the treatment of dementias related to CVD, and preclinical evidence supports this rationale. Galantamine, which has a unique dual cholinergic mode of action, may be of particular benefit in VaD and AD with CVD. For example, behavioral symptoms, which can be more severe in VaD than in AD and are important determinants of the impact of dementia, may be especially benefited by galantamine. This results from its potential to modulate systems involving other neurotransmitters such as 5-HT (serotonin) and dopamine, which affect mood and emotional balance. The results of a recent landmark clinical trial with galantamine in patients with VaD, or AD with CVD, indicate that galantamine produces benefits across a broad range of symptoms of dementia in both patient populations. Significant cognitive improvements over 6 months, long-term maintenance of cognition for at least 12 months, and global benefits, as well as efficacy in both behavioral and functional symptoms, indicate efficacy with galantamine that is so far unsurpassed by any other drug treatment for dementia. Galantamine therefore has potential to benefit a wide range of patients with dementia in the clinic.

Introduction

Vascular dementia (VaD)—dementia associated with cerebrovascular disease (CVD)—is the second most common cause of dementia after Alzheimer's disease (AD), accounting for 10–50% of all dementia cases [1], [2] (Fig. 1). VaD is a complex disorder characterized by multiple subtypes and a variety of risk factors, pathological features and symptoms, many of which overlap with those of AD. One of the major advances in the differential diagnosis of AD and VaD has been the recognition that a continuum of ‘mixed’ conditions exists, with ‘pure’ VaD and ‘pure’ AD representing the end points of the spectrum [4]. The prevalence of coexisting AD and CVD (‘mixed’ dementia) is thought to be substantial and has probably been underestimated, particularly in the elderly [4], [5].

The heterogeneity of VaD in the past has led to difficulties in establishing diagnostic criteria for VaD and providing effective treatment options. Historically, research on therapies for VaD has focused on preventative measures. Studies with agents that target risk factors for CVD (both cardiovascular and cerebrovascular) have not, to date, yielded robust evidence for effectiveness [1]. Relatively recent findings indicate, however, that agents that enhance cholinergic neurotransmission could provide clinically relevant benefits, not just in AD, but in a variety of dementia types. There is extensive evidence showing that impairment of the cholinergic system has an important role in many of the symptoms observed in patients with AD [6]. Evidence suggesting the presence of important cholinergic deficits in VaD, which can occur concomitantly with other neurochemical deficits such as reduced 5-HT (serotonin) levels, is also accumulating [7], [8], [9], [10], [11], [12]. Until now, however, clinical trials examining the efficacy of cholinergic drugs in VaD have been inconclusive [11], [12].

Galantamine (Reminyl®) is approved for the treatment of AD in Europe and in the USA. Galantamine has a dual mode of action: it allosterically modulates nicotinic acetylcholine receptors (nAChRs) in the brain and reversibly inhibits acetylcholinesterase [6]. It has been suggested that this dual mode of action could produce a beneficial cascade of neurotransmitters, possibly affecting the serotonergic and gamma-aminobutyric acid (GABA)-ergic systems. The efficacy of galantamine on the cognitive, functional and behavioral symptoms of dementia in AD has been demonstrated in several large-scale clinical trials [13], [14], [15]. Like AD, VaD is characterized by cognitive and functional decline, and behavioral changes with a corresponding increase in caregiver burden [16]. Such evidence provides a rationale for the treatment of patients with VaD or mixed dementia with galantamine.

In a landmark multicenter, prospective, double-blind, placebo-controlled study evaluating the efficacy of galantamine in patients with a diagnosis of VaD or AD combined with CVD (GAL-INT-6), encouraging results have been seen across a broad spectrum of parameters measuring efficacy [17]. Here, I will discuss some of the important features of this study in anticipation of the publication of the full study results early in 2003.

Section snippets

Design of the GAL-INT-6 trial

In this multicenter, international study, patients diagnosed with probable VaD or mixed dementia entered a 4-week placebo run-in period, before entering a 6-month, double-blind treatment phase where they were randomized to receive Reminyl 24 mg/day (n=396) or placebo (n=196) for 6 months. At the end of double-blind treatment, patients from both groups were eligible to enter a 6-month, open-label extension phase, during which all patients received Reminyl 24 mg/day (Fig. 2). A summary of the

Diagnosis of VaD and AD

Appropriate identification of CVD-related dementia types is important if treatment effects are to be evaluated correctly. Attempts to define drug efficacy in previous studies of VaD with a variety of agents have been hampered by the lack of a standard approach to classification and outcomes' assessment. For instance, diagnostic parameters that require radiological evidence of CVD are essential for clinical trials involving patients with VaD.

In GAL-INT-6, VaD was defined according to the

Study endpoints

Based on epidemiological studies comparing the natural history of the symptoms of VaD, there appear to be good data to justify the use of the scales used in investigations of AD during studies of VaD [16]. Measures of cognitive, functional, behavioral and global efficacy are all required in VaD clinical trials, and measurements in these domains form part of an optimal assessment battery for VaD clinical trials, as they do in AD [16]. However, it should be recognized that AD-specific assessments

Therapeutic options in VaD

Research into potential treatments for VaD and vascular cognitive impairment has previously focused mainly on preventive measures [1], although the available treatment options for patients with VaD have remained limited. Evidence of therapeutic benefits with primary prevention in VaD (treatment of vascular risk factors such as hypertension, diabetes mellitus and cardiac arrhythmia in the absence of cognitive impairment) is scarce [37], [38]. Similarly, there is little evidence to support

Conclusions

VaD is a complex disorder for which few pharmacological treatment options are available. The overlap in the epidemiology and symptomatology of AD and VaD, the recognition that a spectrum of dementia syndromes exists ranging from pure VaD to pure AD, and evidence that the underlying pathology of VaD involves the nicotinic-cholinergic system provide a rationale for treating VaD and AD combined with CVD (‘mixed’ dementia) using cholinergic anti-dementia agents.

In patients with AD, galantamine has

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