Therapeutic interventions

After 100 years of AD discovery the absence of treatment with a major impact is quite disappointing. The drugs approved are mainly for symptomatic treatments, and this is related to the fact that the pathways that cause AD are still not fully declared. Although multiple drugs have now been approved, their expected benefits are marginal. However, the causes behind AD are being slowly identified and new treatments in the pipeline which are aimed at these mechanisms are being developed.

In this section a short overview of the current approved drugs for AD is given, followed by the new therapeutic interventions under development or in clinical trials.

1.1.10.1 Acetylcholinesterase inhibitors

Post-mortem findings in the early 1970s such as reduced acetylcholine [Ach]

release and presynaptic cholinergic deficits in brains of AD patients led to the development of the cholinergic hypothesis of AD. The ‘cholinergic deficit hypothesis’ was the dominant theory in AD in the early 1980s. This hypothesis states that degeneration of cholinergic neurons in the basal forebrain nuclei causes disturbances in presynaptic cholinergic terminals in the hippocampus and neocortex, which is important for memory disturbances and other cognitive symptoms (Terry, Jr. and Buccafusco 2003). It was anticipated that restoring the cholinergic balance by inhibition of Ach breakdown would improve cognitive functions and retard the progression of AD. The 2 Cholinesterases, namely, acetyl cholinesterase [AchE] and butyryl cholinesterase [BuChE] control the availability of Ach in the synapses.

In 1993, the FDA approved the first drug for the treatment of AD, the cholinesterase inhibitor [ChEI] tacrine, which was soon followed by other ChEIs: donepezil [1996], rivastigmine [2000] and galantamine [2001]. All

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galantamine are selective AchE inhibitors while rivastigmine inhibits AchE and BuChE with similar affinity. Theoretically, this dual action could be valuable because in AD, BuChE levels tend to be higher compared with AchE, which decreases in the course of the disease process (Lane et al. 2006).

In addition to inhibiting AchE, galantamine allosterically modulates presynaptic nicotinic receptors.

The efficiency of these drugs has been studied in more than 30 randomized double-blind clinical trials, most of which indicate the symptomatic treatment influence of AchEI. In a 2006 Cochrane review, it was concluded that the acetyl cholinesterase inhibitors donepezil, rivastigmine, and galantamine are efficacious in mild to moderate AD (Birks 2006). Overall, they are safe drugs, but exhibiting predominant gastrointestinal side-effects including nausea, vomiting, and diarrhea. The incidence of side-effects can usually be reduced by starting treatment with a low dose, which is escalated slowly. However caution should be taken in prescribing AchEI to patients with cardiovascular diseases, GIT problems, or Asthma.

1.1.10.2 Memantine

Memantine, a low to moderate affinity, uncompetitive NMDA [N-methyl-D-aspartate] receptor antagonist, was approved in 2003 for AD treatment.

Glutamatergic dysfunction can lead to an excessive influx of calcium ions through NMDA receptors, leading to neuronal death. Such “excitotoxicity”

has been implicated in AD (Danysz et al. 2000)^. Memantine is thought to block selectively the effects associated with abnormal transmission of the neurotransmitter glutamate, without preventing the physiological transmission associated with normal functioning (Wilcock 2003).

Memantine treatment of patients with moderate-to-severe AD has been shown to confer significant benefits on cognition whether alone or when administered concomitantly with other ChEI(Gauthier et al. 2005;Reisberg et

al. 2003;Tariot et al. 2004)^. The efficacy of memantine in patients with mild-to moderate AD is debatable, and the latest Cochrane review concluded that there are no data to lend support to the notion that memantine has any beneficial effect in mild stages (Areosa and Sherriff 2003). Due to the scarcity of trials, the assessment of memantine as a disease modifying drug is difficult.

However, memantine is well tolerated, with few adverse events, and may be a useful therapeutic adjunct in patients with moderate to severe disease, typically defined as an MMSE less than 15 points (Areosa and Sherriff 2003).

1.1.10.3 Piracetam

N CH₂ CONH₂

O

Figure 1-13

Chemical structure of the compound piracetam

Piracetam [2-oxo-pyrrolidine carboxylic acid] was first synthesized in 1964 at the pharmaceutical company UCB. Piracetam is popularly referred to as a

“smart drug”, or scientifically rephrased a Nootropic [“mind-related”] drug.

This name was first assigned to Piracetam due to its unique pharmacological actions which include facilitating inter-hemispheric transfer and enhancing cerebral resistance to cognitive impairments induced by hypoxia and aging (Giurgea et al. 1983). It is prescribed for the treatment of cognitive impairments, cerebral insufficiencies and cortical myoclonus.

Several clinical trials have shown the efficacy of piracetam for cognitive impairments. In 2001 Tsolaki et al reported that the efficacy of piracetam is comparable with AchE inhibitors (Tsolaki et al. 2001). A meta-analysis

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including 19 trials concluded that piracetam was effective in patients with cognitive impairment (Waegemans et al. 2002).

The mechanisms lying behind the actions of piracetam are not fully elucidated. It has been reported that piracetam can restore changes that occur in brain membrane fluidity during aging, and elevates both muscarinic cholinergic and NMDA receptor density in rodents (Cohen and Muller 1993;Pilch and Muller 1988). Moreover, mitochondrial protective properties have been also described for piracetam (Keil et al. 2006).

1.1.10.4 Ginkgo Biloba extract

An extract of Ginkgo biloba leaves was first registered as a medication by Dr.

Willmar Schwabe GmbH & Co in France under the trademark Tanakan by IPSEN. Several different Ginkgo extracts exist nowadays in the European market as well as in the US as dietary supplement. In Germany it’s a highly prescribed medication and since the early 1990s, Ginkgo biloba leaf extracts are becoming one of the most popularly used supplements for memory enhancement in the US.

The fact that Ginkgo extracts constitute several active compounds such as flavonoids and terpenoids, gives it its unique toti-potent properties. A standardized leaf extract [EGb 761^®] was reported as an oxidant, anti-apoptotic, gene regulator and comprises other mechanisms of action, unlike synthetic drugs, which provide a single target for a single receptor as the mechanism of action.

Concerning its clinical efficacy a vast number of clinical trials and meta-analysis are present, but unfortunately major differences in the experimental parameters makes it quite challenging trying to reach a reasonable conclusion.

In light of the present studies Ginkgo has been reported as a safe drug, and shows potential in enhancing cognition and function in patients with dementia [for further details on Ginkgo extract refer to section 1.2].