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Metrifonate

A Review of its Use in Alzheimer’s Disease

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Summary

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.

Pharmacodynamic Properties

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). Metrifonate also inhibits the activity of CNS butyrylcholinesterase (BChE) and AChE on red blood cells. This latter property has provided a useful marker for inhibition of brain AChE in humans. Metrifonate inhibits both the tetrameric and monomeric forms of AChE.

In healthy human volunteers, inhibition of AChE peaks at ≈1 hour after administration of metrifonate. Recovery of AChE activity is biphasic: most of the AChE activity is recovered after 8 hours, but the return to baseline activity takes several weeks and inhibition persists long after DDVP has been cleared from the blood. This persistence of activity allows consistent inhibition of AChE to be achieved within 7 to 8 days of initiation of metrifonate treatment with a loading dose. Without a loading dose it takes 6 to 8 weeks to establish a consistent AChE inhibition level.

Studies in rats have demonstrated the ability of metrifonate to improve memory in a manner independent of dose. However, a clear relationship between age, loss of cognitive function and metrifonate-induced improvement has not been established.

Pharmacokinetic Properties

Metrifonate is a prodrug, thus the pharmacokinetics of its active metabolite DDVP are also important. In healthy volunteers the pharmacokinetics of a single dose of metrifonate 2.5 to 15 mg/kg were largely independent of dose. After a single oral dose of metrifonate ≈0.66 mg/kg, the blood concentration/time profiles of metrifonate and DDVP were similar, but the area under the blood concentration-time curve (AUC) of DDVP was 2% of that of metrifonate. Renal clearance of unchanged metrifonate and DDVP is negligible, suggesting rapid and complete metabolism. The bioavailability of metrifonate and DDVP were not significantly affected by concomitant food, or by the time of day the drug was administered.

In patients with Alzheimers’s disease (AD) treated with metrifonate 1.5 to 4.0 mg/kg for 6 days there was no marked difference in the AUC and peak blood concentration (Cmax) values for metrifonate or DDVP on days 1 and 6, indicating that there was no accumulation of either compound. However, blood concentrations of both metrifonate and DDVP increased with dose. The time to maximum concentration and elimination half-life values were largely independent of dose for both compounds and unaffected by repeated administration of metrifonate. No pharmacokinetic studies of metrifonate in patients with AD at clinically relevant doses have been carried out.

Very little metrifonate or DDVP is excreted unchanged through the kidneys and the pharmacokinetics of the drug are generally unaffected by the renal status of patients.

Therapeutic Efficacy

Metrifonate has been evaluated in patients with AD in several randomised placebo-controlled trials. The persistence of in vivo AChE inhibition after metrifonate administration suggested that weekly dose schedules might be used, but more frequent administration has been used in phase III trials. The 5 pivotal trials of metrifonate have used daily dose schedules; 3 employed loading doses, 1 compared loading- and no loading-dose schedules and the most recent study did not use a loading dose. These studies used similar inclusion and assessment criteria, allowing intertrial comparisons and an analysis of pooled data to be carried out. Three trials were of 26 weeks’ duration, 1 ran for 12 weeks and 1 for 6 weeks. The pooled analysis confirmed the individual finding of these trials and reported highly significant metrifonate-induced improvements in all 3 domains of AD —cognition, behaviour and function.

All trials reported significant improvements (or in some instances a slowing of deterioration) in one or more of cognition, behaviour and function. In those trials that compared different doses of metrifonate, the changes were found to be dose related. All 5 trials reported a significant improvement in the cognitive subscale of the AD Assessment Scale (ADAS-cog), with the best improvement of 1.3 to 3.24 points versus placebo reported after 26 weeks of treatment using a variety of regimens. The trial which compared a no loading-with a loading-dose regimen suggested that using a loading dose was not advantageous in terms of efficacy, and may be associated with increased adverse events during the loading-dose period.

Tolerability

Most of the adverse events associated with metrifonate are attributable to peripheral cholinergic effects. These are common to all AChE inhibitors and are generally mild and transitory, with gastrointestinal events being the most common. Tolerability data have been collected from all the pivotal clinical trials of metrifonate in patients with AD, and from 1 small study (n = 39) specifically designed to evaluate safety and tolerability. In the latter, a loading dose of 2.5 mg/kg was used for 2 weeks followed by 1.0 mg/kg for 4 weeks. 76 and 80% of metrifonate and placebo recipients, respectively, experienced adverse events. During the loading-dose phase diarrhoea was the only event that occurred in metrifonate-patients at a frequency greater than 10% of that seen in the placebo group. During the entire 6-week study events occurring more frequently in metrifonate-treated than in placebo-treated patients were diarrhoea, nausea, leg cramps and accidental injury (falls). No severe adverse events were reported, but 1 patient discontinued therapy with metrifonate during the loading-dose phase because of adverse events.

Studies of 12 or 26 weeks’ duration reported the same range and severity of cholinergic adverse events. Again, these were generally mild, and in some trials it was not possible to differentiate between placebo and metrifonate recipients on the basis of overall adverse events. Abdominal pain, nausea, flatulence, diarrhoea and leg cramps were the most commonly reported events in disfavour of metrifonate. These occurred in fewer than 20% of patients (where the incidence was reported). In 1 long term noncomparative study (56 weeks) of metrifonate 15 to 17 mg/day (based on bodyweight) diarrhoea and abdominal pain were the only events that occurred at a rate ≥10%.

A pattern of more frequent and severe adverse events during the loading-dose compared with the maintenance-dose phase was seen in all trials which used such regimens. Laboratory indices were unaffected by metrifonate, but most trials reported a reduction in heart rate of 5 to 9 beats/minute. This was not considered clinically important.

Of concern is the report of muscle weakness in ≈20 of 3000 patients taking part in various long term studies of metrifonate in AD. A few of these patients required respiratory support. The cause of this adverse effect is not yet established.

Dosage and Administration

Metrifonate is administered orally in tablet form. Loading- and no loading-dose schedules have been used, but it is likely that protocols based on the latter regimens would be recommended in clinical practice. The long-acting properties of metrifonate allow once daily administration, and dose is usually determined by bodyweight range rather than individual bodyweights. The dose used in the most recent clinical trials was between 40 and 50 mg/day which is ≈0.65 to 0.75 mg/kg/day.

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References

  1. Klysh AO. Alzheimer’s disease update [online]. Available from: URL: http://www.inetce.org/Articles/alzheimers.html [Accessed: 1999 Oct 1]

  2. Small GW, Rabins PV, Barry PP, et al. Diagnosis and treatment of Alzheimer disease and related disorders: consensus statement of the American Association for Geriatric Psychiatry, the Alzheimer’s Association, and the American Geriatrics Society. JAMA 1997 Oct 22–29; 278: 1363–71

    Article  PubMed  CAS  Google Scholar 

  3. Evans DA et al. Estimated prevalence of Alzheimer’s disease in the United States. Milbank Quarterly 1990; 68(2): 267–89

    Article  PubMed  CAS  Google Scholar 

  4. Ernst RL, Hay JW. The U.S. economic and social cost of Alzheimer’s disease revisited. Am J Public Health 1994; 84: 1261–4

    CAS  Google Scholar 

  5. Evans DA, Funkenstein HH, Albert MS, et al. Prevalence of Alzheimer’s disease in a community population of older persons: higher than previously reported. JAMA 1989; 262: 2551–6

    Article  PubMed  CAS  Google Scholar 

  6. Carr DB, Goate PD, Morris JC. Current concepts in the pathogenesis of Alzheimer’s disease. Am J Med 1997; 103(3A): 3S–10S

    Article  PubMed  CAS  Google Scholar 

  7. Stephenson J. Researchers find evidence of a new gene for late-onset Alzheimer disease. JAMA 1997; 277(10): 755

    Article  Google Scholar 

  8. Small GW. Treatment of Alzheimer’s disease: current approaches and promising developments. Am J Med 1998 Apr 27; 104: 32S–8S

    Article  PubMed  CAS  Google Scholar 

  9. Ladner CJ, Lee JM. Pharmacological drug treatment of Alzheimer disease: the cholinergic hypothesis revisited. J Neuropathol Exp Neurol 1998; 57(8): 719–31

    Article  PubMed  CAS  Google Scholar 

  10. Coyle JT, Price DL, DeLong MR. Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 1983; 219: 1184–90

    Article  PubMed  CAS  Google Scholar 

  11. Weinberger DR, Gibson R, Copploa R, et al. The distribution of cerebral muscarine acetylcholine receptors in vivo in patients with dementia. Arch Neurol 1991; 48: 169–76

    Article  PubMed  CAS  Google Scholar 

  12. Andrews JS, Jansen JHM, Linders S, et al. Effects of disrupting the cholinergic system on short-term spatial memory in rats. Psychopharmacology 1994; 114: 485–94

    Article  Google Scholar 

  13. Bymaster FP, Heath I, Hendrix JC, et al. Comparative behavioral and neurochemical activities of cholinergic antagonists in rats. J Pharmacol Exp Ther 1993; 267: 16–24

    PubMed  CAS  Google Scholar 

  14. Ohno M, Yamamoto T, Watanabe S. Blockade of hippocampal M1 muscarine receptors impairs working memory performance of rats. Brain Res 1994; 650: 260–6

    Article  PubMed  CAS  Google Scholar 

  15. Drachman DA, Leavitt J. Human memory and cholinergic system: a relationship to aging. Arch Neurol 1974; 30: 113–21

    Article  PubMed  CAS  Google Scholar 

  16. Ukai M, Shinkai N, Kameyama T. Cholinergic receptor agonists inhibit pirenzepine-induced dysfunction of spontaneous alteration performance in the mouse. Gen Pharmacol 1995; 26(7): 1529–32

    Article  PubMed  CAS  Google Scholar 

  17. Jaen JC, Davis RE. Cholinergic therapies for Alzheimer’s disease: acetylcholinesterase inhibitors of current clinical interest. Curr Opin Invest Drug 1993 Apr; 2: 363–77

    Google Scholar 

  18. Lamy PP. The role of cholinesterase inhibitors in Alzheimer’s disease. CNS Drugs 1994 Feb; 1: 146–65

    Article  Google Scholar 

  19. Little A, Levy R, Chuaqui-Kidd P, et al. A double-blind, placebo controlled trial of high-dose lecithin in Alzheimer’s disease. J Neurol Neurosurg Psychiatry 1985; 48(8): 736–42

    Article  PubMed  CAS  Google Scholar 

  20. Christie JE, Shering A, Ferguson J, et al. Physostigmine and arecoline: effects of intravenouis infusions in Alzheimer presenile dementia. Br J Psychiatry 1981; 138: 46–50

    Article  PubMed  CAS  Google Scholar 

  21. Giacobini E. Invited review. Cholinesterase inhibitors for Alzheimer’s disease therapy: from tacrine to future applications. Neurochem Int 1998; 32(5–6): 413–9

    Article  PubMed  CAS  Google Scholar 

  22. Jann MW. Preclinical pharmacology of metrifonate. Pharmacotherapy 1998 Mar–Apr; 18 (2 Pt 2): 55S–67S

    Google Scholar 

  23. Holmstedt B, Nordgren I, Sandoz M, et al. Metrifonate: summary of toxicological and pharmacological information available. Arch Toxicol 1978 Oct 13; 41: 3–29

    Article  PubMed  CAS  Google Scholar 

  24. Mucke HAM. Metrifonate. Drugs Future 1998 May; 23: 491–7

    Article  CAS  Google Scholar 

  25. Hallak M, Giacobini E. A comparison of the effects of two inhibitors on brain cholinesterase. Neuropharmacology 1987; 26(6): 521–30

    Article  PubMed  CAS  Google Scholar 

  26. Hallak M, Giacobini E. Physostigmine, tacrine and metrifonate: The effect of multiple doses on acetylcholine metabolism in rat brain. Neuropharmacology 1989; 28(3): 199–206

    Article  PubMed  CAS  Google Scholar 

  27. Becker RE, Colliver J, Elble R, et al. Effects of metrifonate, a long-acting cholinesterase inhibitor, in Alzheimer disease: report of an open trial. Drug Dev Res 1990; 19(4): 425–34

    Article  Google Scholar 

  28. Hinz VC, Blokland A, Van der Staay F-J, et al. Receptor interaction profile and CNS general pharmacology of metrifonate and its transformation product dichlorvos in rodents. Drug Dev Res 1996; 38(1): 31–42

    Article  CAS  Google Scholar 

  29. Hinz VC, Grewig S, Schmidt BH. Metrifonate induces cholinesterase inhibition exclusively via slow release of dichlorvos. Neurochem Res 1996 Mar; 21: 331–7

    Article  PubMed  CAS  Google Scholar 

  30. Hofer W. Chemistry of metrifonate and dichlorvos. Acta Pharmacol Toxicol 1981; 49Suppl V: 7–14

    CAS  Google Scholar 

  31. Pacheco G, Palacios-Esquivel R, Moss DE. Cholinesterase inhibitors proposed for treating dementia in Alzheimer’s disease: selectivity toward human brain acetylcholinesterase compared with butyrylcholinesterase. J Pharmacol Exp Ther 1995 Aug; 274: 767–70

    PubMed  CAS  Google Scholar 

  32. Mesulam M-M, Geula C. Cortical cholesterinases in Alzheimer’s disease: anatomical and enzymatic shifts from the normal pattern. In: Becker R, Giacobini E, editors. Cholinergic basis for Alzheimer therapy. Boston (MA): Birkhauser, 1991: 25–30

    Google Scholar 

  33. Rosenberry TL, Roberts WL, Hass R. Glycolipid membrane binding of human erthrocyte acetylcholinesterase. Fed Proc 1986; 45: 2970–5

    PubMed  CAS  Google Scholar 

  34. Moriearty PL, Becker RE. Inhibition of human brain and red blood cell acetylcholinesterase (AChE) by heptylphysostigmine. Methods Find Exp Clin Pharmacol 1992; 14: 615–21

    PubMed  CAS  Google Scholar 

  35. Siek GC, Katz LS, Fishman EB, et al. Molecular forms of acetylcholinesterase in subcortical areas of normal and Alzheimer disease brain. Biol Psychiatry 1990; 27: 573–80

    Article  PubMed  CAS  Google Scholar 

  36. Younkin SG, Goodridge B, Katz J, et al. Molecular forms of acetylcholinesterase in Alzheimer’s disease. Fed Proc 1986; 45: 2982–8

    PubMed  CAS  Google Scholar 

  37. Fishman EB, Siek GC, MacCallum RD, et al. Distribution of the molecular forms of acetylcholinesterase in human brain: alterations in dementia of the Alzheimer type. Ann Neurol 1986; 19: 246–52

    Article  PubMed  CAS  Google Scholar 

  38. Ogane N, Giacobini E, Messamore E. Preferential inhibition of acetylcholinesterase molecular forms in rat brain. Neurochem Res 1992 May; 17: 489–95

    Article  PubMed  CAS  Google Scholar 

  39. Giovannini MG, Scali C, Bartolini L, et al. Effect of subchronic treatment with metrifonate and tacrine on brain cholinergic function in aged F344 rats. Eur J Pharmacol 1998 Jul 31; 354: 17–24

    Article  PubMed  CAS  Google Scholar 

  40. Scali C, Giovannini MG, Bartolini L, et al. Effect of metrifonate on extracellular brain acetylcholine and object recognition in aged rats. Eur J Pharmacol 1997 May 1; 325: 173–80

    Article  PubMed  CAS  Google Scholar 

  41. Mori F, Cuadra G, Giacobini E. Metrifonate effects on acetylcholine and biogenic amines in rat cortex. Neurochem Res 1995 Sep; 20: 1081–8

    Article  PubMed  CAS  Google Scholar 

  42. Heinig R, Versavel M, Breuel HP, et al. Rapid attainment of steady-state acetylcholinesterase inhibition by administration of metrifonate loading and maintenance doses once-daily in elderly volunteers [abstract no. 39-26]. Biol Psychiatry 1997 Jul; 42 Suppl. : 94S

    Article  Google Scholar 

  43. Aden-Abdi Y, Villen T, Ericsson O, et al. Metrifonate in healthy volunteers ≡ interrelationship between pharmacokinetic properties, cholinesterase inhibition and side-effects. Bull World Health Organ 1990; 68(6): 731–6

    PubMed  CAS  Google Scholar 

  44. Pettigrew LC, Bieber F, Lettieri J, et al. Pharmacokinetics, pharmacodynamics, and safety of metrifonate in patients with Alzheimer’s disease. J Clin Pharmacol 1998 Mar; 38: 236–45

    PubMed  CAS  Google Scholar 

  45. Riekkinen Jr P, Schmidt B, Stefanski R, et al. Metrifonate improves spatial navigation and avoidance behavior in scopolamine-treated, medial septum-lesioned and aged rats. Eur J Pharmacol 1996 Aug 8; 309: 121–30

    Article  PubMed  CAS  Google Scholar 

  46. Itoh A, Nitta A, Katono Y, et al. Effects of metrifonate on memory impairment and cholinergic dysfunction in rats. Eur J Pharmacol 1997 Mar 12; 322: 11–9

    Article  PubMed  CAS  Google Scholar 

  47. van der Staay FJ, Hinz VC, Schmidt BH. Effects of metrifonate on escape and avoidance learning in young and aged rats. Behav Pharmacol 1996 Jan; 7: 56–64

    Google Scholar 

  48. van der Staay FJ, Hinz VC, Schmidt BH. Effects of metrifonate, its transformation product dichlorvos, and other organophosphorus and reference cholinesterase inhibitors on Morris water escape behavior in young-adult rats. J Pharmacol Exp Ther 1996 Aug; 278: 697–708

    PubMed  Google Scholar 

  49. Blokland A, Hinz V, Schmidt BH. Effects of metrifonate and tacrine in the spatial Morris task and modified Irwin test: evaluation of the efficacy/safety profile in rats. Drug Dev Res 1995 Dec; 36: 166–79

    Article  CAS  Google Scholar 

  50. Aden-Abdi YA, Villen T. Pharmacokinetics of metrifonate and its rearrangement product dichlorvos in whole blood. Pharmacol Toxicol 1991 Feb; 68: 137–9

    Article  Google Scholar 

  51. Unni LK, Womack C, Hannant ME, et al. Pharmacokinetics and pharmacodynamics of metrifonate in humans. Methods Find Exp Clin Pharmacol 1994 May; 16: 285–9

    PubMed  CAS  Google Scholar 

  52. Dingemanse J, Halabi A, Kleinbloesem CH, et al. Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor metrifonate in patients with renal impairment. Ther Drug Monit 1999 Jun; 21: 310–6

    Article  PubMed  CAS  Google Scholar 

  53. Villén T, Aden Abdi Y, Ericsson Ö, et al. Analysis of metrifonate and diclorvos in whole blood using gas chromatography and gas chromatography mass spectrometry. J Chromatogr 1990; 529(2): 309–17

    PubMed  Google Scholar 

  54. Heinig R, Dietrich H, Halabi A. Pharmacokinetics of metrifonate and its metabolite dichlorvos in healthy volunteers and in patients with renal impairment. Clin Drug Invest 1999 Jul; 18: 35–46

    Article  CAS  Google Scholar 

  55. World Health Organization. Trichlorfon. Environmental Health Criteria 132. World Health Organization, Geneva, 1992

    Google Scholar 

  56. Heinig R, Sachse R. The effect of food and time of administration on the pharmacokinetic and pharmacodynamic profile of metrifonate. Int J Clin Pharmacol Ther 1999; 37(9): 456–64

    PubMed  CAS  Google Scholar 

  57. Becker RE, Colliver JA, Markwell SJ, et al. Double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease. Alz Dis Assoc Disord 1996; 10(3): 124–31

    Article  CAS  Google Scholar 

  58. Becker RE, Colliver JA, Markwell SJ, et al. Effects of metrifonate on cognitive decline in Alzheimer disease: a double-blind, placebo-controlled, 6-month study. Alz Dis Assoc Disord 1998 Mar; 12: 54–7

    Article  CAS  Google Scholar 

  59. Cummings JL, Cyrus PA, Bieber F, et al. Metrifonate treatment of the cognitive deficits of Alzheimer’s disease. Neurology 1998 May; 50: 1214–21

    Article  PubMed  CAS  Google Scholar 

  60. Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer’s disease. Neurology 1998 May; 50: 1222–30

    Article  PubMed  CAS  Google Scholar 

  61. Raskind MA, Cyrus PA, Ruzicka BB, et al. The effects of metrifonate on the cognitive, behavioral, and functional performance of Alzheimer’s disease patients. J Clin Psychiatry 1999 May; 60: 318–25

    Article  PubMed  CAS  Google Scholar 

  62. Dubois B, McKeith, Orgogozo J-M, et al. A multicentre, 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 Geriatr Psychiatry 1999; 14(11): 973–82

    Article  PubMed  CAS  Google Scholar 

  63. Jann MW, Cyrus PA, Eisner LS, et al. Efficacy and safety of a loading-dose regimen versus a no-loading-dose regimen of metrifonate in the symptomatic treatment of Alzheimer’s disease: a randomized, double-masked, placebo-controlled trial. Clin Ther 1999 Jan; 21: 88–102

    Article  PubMed  CAS  Google Scholar 

  64. McKhann G, Drachman D, Folstein M, et al. Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA work group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s disease. Neurology 1984; 34: 939–44

    Article  PubMed  CAS  Google Scholar 

  65. American Psychiatric Association. Diagnosis and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association, 1994

    Google Scholar 

  66. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state” a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98

    Article  PubMed  CAS  Google Scholar 

  67. Rosen WG, Terry RD, Fuld P, et al. Pathological verification of ischemic score in differentiation of dementias. Ann Neurol 1980; 7: 486–8

    Article  PubMed  CAS  Google Scholar 

  68. Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141(11): 1356–64

    PubMed  CAS  Google Scholar 

  69. Knopman DS, Knapp MJ, Gracon SI, et al. The Clinician Interview-Based Impression (CIBI): a clinician’s global change rating scale in Alzheimer’s disease. Am J Psychiatry 1994; 44: 2315–21

    CAS  Google Scholar 

  70. Cummings JL, Mega M, Gray K, et al. The neuropsychiatric inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308–14

    Article  PubMed  CAS  Google Scholar 

  71. Reisberg B, Ferris S, De Leon MJ, et al. The global deterioration scale for assessment of primary degenerative dementia. Am J Psychiatry 1982; 139(9): 1136–9

    PubMed  CAS  Google Scholar 

  72. Gauthier S, Gélinas I, Gauthier L. Functional disability in Alzheimer’s disease. Int Psychogeriatr 1997; 9 Suppl. 1: 163–5

    Article  Google Scholar 

  73. Shikiar R, Shakespeare A, Sagnier P-P, et al. The impact of metrifonate therapy on caregivers of patients with Alzheimer’s disease: results from the MALT clinical trial. J Am Geriatr Soc 2000; 48: 268–74

    PubMed  CAS  Google Scholar 

  74. Farlow MR, Cyrus PA. Metrifonate therapy in Alzheimer’s disease: a pooled analysis of four randomized, double blind, placebo-controlled trials. Dementia Geriatr Cogn Disord 2000. In press

  75. Cyrus P, Camicioli R, Kaye J. Patients with Alzheimer’s disease benefit from metrifonate treatment regardless of their demographic characteristics and previous cholinesterase therapy [abstract]. Neurology 1999 Apr 12; 52 Suppl. 2: A482

    Google Scholar 

  76. Forchetti C, Cyrus P. Metrifonate improves cognitive performance in patients with Alzheimer’s disease despite concurrent mild ischemic damage [abstract]. Neurology 1999 Apr 12; 52 Suppl. 2: A173

    Google Scholar 

  77. Bayer halts trial on new Alzheimer’s drug. Pharm J 1998 Oct 10; 261: 561

  78. Blass JP, Cyrus PA, Bieber F, et al. Arandomized, double blind, placebo-controlled, multi-center study to evaluate the safety and tolerability of metrifonate in patients with probable Alzheimer disease. Alz Dis Assoc Disord 2000; 14(1): 39–41

    Article  CAS  Google Scholar 

  79. Cyrus PA, Ruzicka B, Gulanski B. Metrifonate in the long-term treatment of Alzheimer’s disease [abstract]. J Am Geriatr Soc 1998 Sep; 46: S35

    Google Scholar 

  80. Steinberg M. Pharmacologic treatment of Alzheimer’s disease: an update on approved, unapproved therapies. Formulary 1999 Jan; 34: 32–44

    CAS  Google Scholar 

  81. Becker RE, Giacobini E. Pharmacokinetics and pharmacodynamics of acetylcholinesterase inhibition: can acetylcholine levels in the brain be improved in Alzheimer’s disease? Drug Dev Res 1988; 14(3–4): 235–46

    Article  Google Scholar 

  82. Knapp MJ, Knopman DS, Solomon PR, et al. A 30-week randomized controlled trial of high-dose tacrine in patients with Alzheimer’s disease. JAMA 1994 Apr; 271(13): 985–91

    Article  PubMed  CAS  Google Scholar 

  83. Dooley M, Lamb H. Donepezil: A review of its use in Alzheimers’s disease. Drugs Aging 2000; 16(3): 199–226

    Article  PubMed  CAS  Google Scholar 

  84. Spencer CM, Noble S. Rivastigmine: a review of its use in Alzheimer’s disease. Drugs Aging 1998 Nov; 13: 391–410

    Article  PubMed  CAS  Google Scholar 

  85. Knopman DS. Metrifonate for Alzheimer’s disease. Is the next cholinesterase inhibitor better [abstract]? Neurology 1998 May; 50: 1203–5

    CAS  Google Scholar 

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    Douglas Ormrod & Caroline Spencer

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Various sections of the manuscript reviewed by: J. Blass, Dementia Research Service, Burke Medical Research Institute and Hospital, White Plains, New York, USA; B. Dubois, Hôpital de la Pitié-Salpêtrière, Paris, France; M.R. Farlow, Department of Neurology, Indiana University Medical Center, Indianapolis, Indiana, USA; E. Giacobini, Department of Geriatrics, University Hospitals of Geneva, Geneva, Switzerland; C-G. Gottfries, Department of Psychiatry and Neurochemistry, University of Göteborg, Göteborg, Sweden; G. Pepeu, Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy.

Data Selection Sources: Medical literature published in any language since 1966 on Metrifonate, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug. Search strategy: AdisBase search terms were ‘Metrifonate’ or ‘Trichlorfon’. Medline search terms were ‘Trichlorfon’ or ‘Metrifonate’. EMBASE search terms were ‘Metrifonate’ or ‘Trichlorfon’. Searches were last updated 7 May 2000. Selection: Studies in patients with Alzheimer’s disease who received metrifonate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included. Index terms: Metrifonate, Alzheimer’s disease, pharmacodynamics, pharmacokinetics, therapeutic use.

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Ormrod, D., Spencer, C. Metrifonate. Mol Diag Ther 13, 443–467 (2000). https://doi.org/10.2165/00023210-200013060-00006

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  • DOI: https://doi.org/10.2165/00023210-200013060-00006

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