Metrifonate

Abstract

Acetylcholinesterase (AChE) inhibitors are currently the most promising drugs available for the treatment of Alzheimer's disease (AD). Their efficacy is based on the cholinergic hypothesis of AD which links reduced levels of cerebral acetylcholine (ACh) with declining cognitive function in affected individuals. AChE inhibitors are believed to work by increasing the level of ACh in the synaptic cleft by binding to local AChE and preventing the hydrolysis of ACh. Metrifonate differs from other AChE inhibitors in that it is a prodrug which is, non-enzymatically converted in vivo to the active moiety 2,2-dichlorovinyl dimethylphosphate (DDVP). DDVP administered alone has a very short plasma elimination half-life, but small amounts released from metrifonate are sufficient to inhibit AChE activity in vivo. DDVP is an irreversible inhibitor of AChE and activity is maintained for several weeks. Metrifonate has been used as an anthelmintic since 1962 and has been under investigation as a treatment for the symptoms of AD since 1990. Randomised, placebo-controlled clinical trials, using a variety of dose regimens, have demonstrated that metrifonate produces a significant, but modest, improvement in the 3 domains of AD: cognition, behaviour and function. However, it should be noted that with some assessment instruments in some trials, the improvement' was actually a reduction in the rate of worsening of symptoms compared with placebo. Weekly and daily schedules, with and without loading doses, have been evaluated and the research supports a fixed daily dose of 40 to 50mg, administered to supply approximately 0.65 mg/kg. In studies of up to 6 months' duration, metrifonate was well tolerated, and adverse events were mild and predominantly gastrointestinal. In clinical practice it is likely that metrifonate will be administered for several years and long term monitoring of adverse events will be important to further define the drug's tolerability profile. Muscle weakness occurred in a dose-related fashion in 20 of 3000 patients taking part in long term trials, and in some patients respiratory support was required. The mechanism of muscle weakness is not well defined and requires further investigation. Conclusions: Clinical data support the use of metrifonate in patients with AD. However, the improvements noted are modest and to date there is no evidence that metrifonate is more effective than other currently approved AChE inhibitors. The unique pharmacokinetic/pharmacodynamic profile of metrifonate may endow the agent with some advantages over other therapies, but this has yet to be evaluated in comparative trials. Moreover, long term studies evaluating the effects of metrifonate on maintenance of independence are required. While the clinical future of metrifonate is uncertain, it is one of a small group of drugs that have been shown to improve the outlook of patients with AD. Metrifonate is administered orally and after absorption is nonenzymatically converted to the active compound 2,2-dichlorovinyl dimethylphosphate (DDVP), at neutral or alkaline pH. After a short reversible phase, DDVP irreversibly binds to acetylcholinesterase (AChE). With the exception of nicotinic receptors, metrifonate does not bind to neurotransmitter receptors or binding sites associated with ion channels. Therefore, the pharmacological action of metrifonate is through inhibition of AChE and a consequent increase in levels of acetylcholine (ACh).