A Medication for Alzheimer’s Disease is Withdrawn-Metrifonate-Part VII

Bayer, the pharmaceutical company, which applied for FDA approval of the drug Metrifonate, has suspended application for approval. Early research studies had shown positive results in improving cognition and behavioral symptoms in mild/moderate Alzheimer’s disease with "weak indications" of adverse effects. Recent placebo-control studies reported a number of cases involving respiratory paralysis and problems in neuromuscular transmission that could be tragic. Metrifonate now joins a list of drugs that are no longer in development. This is a not an uncommon event in the drug development process.

The Food and Drug Administration originally had approved Metrifonate (ProMed), a 4th medication for the treatment of some of the symptoms of Alzheimer’s disease. It should reach United States markets by the spring of 2000 and is manufactured by Bayer Pharmaceutical. (See Alzheimer’s Disease Part II where we first mentioned this medication in Dec. 1997)

Metrifonate is another cholinesterase enzyme inhibitor, joining Cognex (Tacrine), Donepezil (Aricept) and Ena (Exelop) as the armentarium available to deal with the crippling effects of Alzheimer’s disease. It is converted non-enzymatically in the body to the active chemical known as DDVP which stands for dichlorovinyl dimethyl phosphate, putting it in the class of chemicals known as organophosphates.

A look at the studies done on this drugs safety indicates that the most common side effects relate to problems in the gastrointestinal tract and include diarrhea, vomiting and intestinal discomfort. The studies report a 10% drop out rate due to side effects with low dose of metrifonate (30-60 mg) and a lower drop-out rate (6%) at higher doses (60-80 mg). Leg cramps were less frequently reported as a side effect. There do not seem to be any reports so far of blood count or serum chemistry abnormalities as seen in Tacrine i.e. agranulocytosis. There are no long-term studies on the safety of taking this medication for extended periods of time. However there are some indications that it may be associated with muscular weakness and myasthenia. There are no reports of interactions with other drugs.

A large study done by Cummings et al showed significant improvement in controlling hallucinations and decreasing apathy, less depression, dysphoria, agitation, aggression and aberrant behavior. If this proves true in clinical practice, Metrifonate will prove a valuable addition in dealing with a disease that not only is economically costly to our society but also has such a draining effect on the caretakers of people who have AD. Below are some figures for our readers to ponder when thinking about the magnitude of this problem.

For further information on Alzheimer’s disease see the other parts of this series.

References for this article include:

  1. Crimson M. Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer’s disease. Pharmacotherapy 1998; 18(2pt2): 47s-54s.
  2. Becker R, Colliver J, Markwell S et al. Effects of Metrifonate on cognitive decline in Alzheimer’s disease: A double blind, placebo-controlled 6 months study. Alzh Dis Assoc Dis 1998; 12:54-57. (While this study showed some favorable effects, the results were not statistically significant and when caregivers in the placebo and experimental group were asked about changes in behavior, no difference was noted.)
  3. Cummings J, Cyrus P, Ruzicka B, Gulanski B. The efficacy of Metrifonate in improving the behavioral disturbance of Alzheimer’s disease patients. Neurology 1998; 50:A251. (This study showed many of the behavioral changes noted above.)


The Alzheimer’s Explosion

Americans with Alzheimer’s ………………………………...4 million

Cases projected by 2050………………………………………………...14 million

Percentage of people over 65 with Alzheimer’s …………………..10%

Percentage of people over 85 with Alzheimer’s…………………….50%

Number of new 85 year olds each year………………………………..100,000 to 120,000

Average life span after onset of dementia………………………………8 years

Nursing home residents with Alzheimer’s or other cognitive disorders……50%

Average annual cost of nursing home care per capita………………...$41,000

Total nursing home beds, 1996……………………………………………...1.8 million

Total nursing home beds, 1986……………………………………………...1.7 million

Projected growth of nursing home care expenditures, 1998-2007...70% 

Is it any wonder that we need to press researchers to find a way to deal with this disease?

Supplement to Metrifonate Article

A (1999) by a French group headed by Dubois looked at the efficacy, tolerability and safety of two doses of metrifonate. The study involved 71 independent centers with a total of 594 patients, mean age 72 years, who were followed over a 26 week period of time with different dosages of metrifonate (40/50 mg and 60/70 mg). The researchers looked at the effect of the medication of cognition, activities of daily living and global functioning, and psychiatric and behavioral disturbances.

The conclusion was that "Metrifonate significantly improved a wide range of symptoms across all four clinical domains of Alzheimer's disease in a dose-dependent manner, and was safe and well-tolerated at both doses studied." They felt that the results of the medication "translated to over one year avoidance of disease progress", and that the higher dose, equivalent to 1.0 mg/kg/day, was an effective dosage. To obtain this complete study, send an email to <>.

Ref: Dubois B, McKeith J, Orgogozo JM, Owens C, Didier M, on behalf of the MALT Study Group. A multicentered, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer's disease: The MALT Study.Int J Psychiatry 1999; 14:973-982.

A recent issue of Alzheimer’s Disease and Associated Disease Journal (2000; 14(1): 39-45) reported on a placebo-controlled 6-week study, by Blass et al, for the Metrifonate Study Group, of the safety and tolerability of Metrifonate. The study showed that if you inhibit the production of about 80% of acetylcholinesterase (AChE), using a dosage of Metrifonate dependent upon body weight, you could slow the process of cognitive decline as well as show less adverse reactions to the drug than other medications presently being used. The starting dose for this study varied from 125-225 mg based on weight, followed by a once-daily maintenance dose of 50-90 mg based on weight. On the average, an 87.6% inhibition of acetylcholinesterase was achieved after two weeks of this 6-week study. No liver problems were noted, unlike the possible side effect of Tacrine.

The theoretical foundation of this study relies on the assumption that acetylcholinesterase is partially involved in cognitive decline. By inhibiting its formation, you retard the further deterioration of nerve cells involved in the cognitive process.

It still remains to be seen whether Metrifonate will prove effective. This was only a six-week study. Clinical application over a long period may show a different side-effect profile and not achieve the results in a more heterogeneous clinical group. In the meantime, it may have a place in the treatment of a highly debilitating disease, given the limited available treatments.

(This article is for information purposes and is not intended as medical advice. This should come from a treating physician.)

See: Alzheimer's Disease Part I-Medications for Alzheimer's.
See: Alzheimer’s Disease Part II- Selegiline and AD.
See: Alzheimer's Disease Part III- Use of Gingko Biloba in memory problems of Alzheimer patients.
See: Alzheimer's Disease PartIV-Alternative Treatment.
See: Alzheimer's Disease Part V-Possible New Drugs for Alzheimer's Disease Treatment.
See: Alzheimer's Part VI Early Diagnosis.
See: Alzheimer's Part VIII Implications of Longer Life Expectancies
See: Alzheimer's Part IX-Ethical Care Principles
See: Alzheimer's Disease Part X-Estrogen and Alzheimer's Disease
See: Alzheimer's Disease Part XI-Pocket Smell Test (PST)
See: Alzheimer's Disease Part XII-MAO-B
See: Alzheimer's Disease Part XIII-Critical Flicker Fusion Threshold Test
See: Alzheimer's Disease Part XIV-Donepezil
See: Alzheimer's Disease Part XV-Cerebrolysin
See: Alzheimer's Disease Part XVI-MCI
See: Alzheimer's Disease Part XVII-Summary
See: Alzheimer's Disease Part XVIII-NO Releasing NSAIDs
See: Alzheimer's Disease Part XIX-Vitamin E
See: Alzheimer's Disease-Part XX-Clinical Trials
See: Alzheimer's Disease Part XXI-The Brain
See Dementia with Lewy Bodies- Part XXII by Gourete Broderick
See: Alzheimer's Disease-Part XXIII-HMG
See: Alzheimer's Disease-Part XXIV-A Prequel
See: Alzheimer's Disease-Part XXV-Psychosis
See: Alzheimer's Disease-Part XXVI-Amyloid-beta Hypothesis Controversy 
See: Alzheimer's Disease-Part XXVII- AD and Diabetes
See: Alzhemeir's Disease-Part XXVIII - Insulin and AD



By Harold Rubin, MS, ABD, CRC, Guest Lecturer
November 14, 1999

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