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