Restorative Approaches: Other Agents
The structural and functional disturbances of central catecho-laminergic systems in AD and their important role in brain-related functions provide the rationale for pharmacological enhancement of these systems. The general strategies em-ployed are analogous to those used with cholinergic agents: precursor loading, inhibition of degradative enzymes and use of agonists. Studies of dopamine precursors (e.g., with tyro-sine, l-dopa) and agonists (e.g., clonidine, guanefacine, aman-tadine, bromocriptine) have largely been negative (Schneider and Tariot, 1997).
There have been some positive effects reported with sel-egiline (l-deprenyl, Eldepryl®, Somerset), a monoamine oxidase (MAO) inhibitor that relatively selectively inhibits MAO type B at a 5 to 10 mg daily dose (Tariot et al., 1993). The overall effect of selegiline at this dose may be to increase CNS levels of dopamine and some trace neurotransmitters such as phenylethylamine without affecting norepinephrine levels. Selegiline is currently marketed for the treatment of Parkinson’s disease for which it has demonstrated effects in maintaining motor function (Parkinson Study Group, 1993). However, an adequate efficacy trial has yet to be completed in AD.
Selegiline, 5 mg b.i.d., along with and separately from vitamin E, 1000 IU b.i.d., has been associated with prolonged maintenance of ADLs and survival in the community in moder-ately to severely impaired AD patients but with no improvement in function (Sano et al., 1997).
In view of regional decreases in glucose utilization and ab-normal oxidative metabolism, drugs have been employed with the aim of correcting these abnormalities, including ergot al-kaloids and nootropics. A discussion of the ergot alkaloids, Hydergine®, can be found in a Cochrane systematic review (Olin et al., 2002). Although once one of the most frequently prescribed medications in the world, it is now uncommonly prescribed. Numerous clinical trials in various elderly patient groups have not clarified its efficacy or clinical role. Another ergoloid derivative available in Europe, nicergoline (Sermion, Pharmacia), was associated with significant improvement on some areas such as orientation and attention and has been un-dergoing clinical testing (Fioravanti and Flicker, 2002; Winblad et al., 2001).
Piracetam, oxiracetam, pramiracetam, aniracetam, CI 933, and BMY 21502 are pyrrolidone derivatives of γ-aminobutyric acid (GABA), although they do not appear to have GABA-like ef-fects, and are postulated to have a neuroprotective effect on the CNS against hypoxia, electroconvulsive treatment and drug intoxication. These types of drugs may also enhance the CNS microcirculation by reducing platelet activity and by reducing adherence of red blood cells to vessel walls and may stimulate central cholinergic activity. These diverse effects are termed nootropic to indicate the class of drugs that are structurally related to piracetam and may improve learning and memory (Nicholson, 1990). However, a specific mechanism of action relevant for dementia has not been established. Double-blind, multicenter, controlled studies have shown mixed results with piracetam in the treatment of dementia in the elderly (Flicker and Evans, 2002; Vernon and Sorkin, 1991). Pramiracetam and oxiracetam have been evaluated in large scale multicenter stud-ies with no sufficiently significant clinical effects in demen-tia. Piracetam is undergoing a clinical trial for mild cognitive impairment.
Estrogens may have cholinergic neurotrophic and neuroprotec-tive effects and may enhance cognitive function (Simpkins et al., 1994).
A beneficial role for estrogen in AD, cognitive function, mood and aging is suggested by observations of an inverse re-lationship of ERT (Estrogen Replacement Therapy) dose and duration with dementia diagnoses on death certificates (Paganini-Hill and Henderson, 1994); by preliminary trials suggesting a cognitive enhancing effect of estradiol, estrone, and conjugated estrogens in AD (Asthana et al., 2001; Fillit et al., 1986; Honjo et al., 1989; Ohkura et al., 1994).
Unfortunately, clinical trials of conjugated equine estro-gens (Premarin®) to improve cognition in both hysterectomized and nonhysterectomized women with AD have not led to suc-cess, and indeed women treated with Premarin fared somewhat worse both in cognition and safety including 5% developing deep vein thrombosis (Henderson et al., 2000; Mulnard et al., 2000). Thus currently estrogen replacement cannot be recommended as a treatment for women with Alzheimer’s dementia.