CNS Drugs

, Volume 1, Issue 3, pp 232–240 | Cite as

Velnacrine in Alzheimer’s Disease

An Initial Appraisal of its Clinical Potential
  • Karen L. Goa
  • Andrew Fitton
Drug Evaluation

Summary

Velnacrine is an hydroxylated derivative of the acetylcholinesterase inhibitor tacrine. The ability of velnacrine to increase cholinergic neurotransmission in vitro provides the rationale for its investigation as a potential treatment in patients with Alzheimer’s disease, who are known to have reduced acetylcholine levels in the central nervous system. Single doses of velnacrine (100 or 150mg) attenuated cognitive impairment induced by central cholinergic blockade in healthy volunteers, and memory improved significantly in a small number of patients with Alzheimer’s disease administered a 75mg dose.

Evidence of efficacy for velnacrine is limited to results of briefly reported placebo-controlled studies. When administered in dosages of up to 225 mg/day for 6 weeks, velnacrine appeared to confer modest benefit in about one-third of 423 patients with Alzheimer’s disease enrolled in a US dose-finding trial. Velnacrine 150 mg/day for 10 days was also considered superior to placebo in a small European trial involving 35 patients, notably in its effects on language, praxis and memory. Fuller results are anticipated from a 6-month investigation demonstrating efficacy for velnacrine 150 or 225 mg/day at 12-week interim analysis. Of interest is the finding from this trial that caregiver time assessed at 24 weeks was shorter for velnacrine compared with placebo recipients.

The development of elevated plasma hepatic enzyme levels leading to treatment discontinuation in 27% of participants in the US trial, combined with the appearance of neutropenia in a few patients, has cast doubt over the tolerability profile of velnacrine. Ongoing investigations are endeavouring to identify the mechanism of the hepatotoxic effect, to establish whether a dose-response relationship exists, and to define possible subpopulations that may respond to velnacrine and those who may be at particular risk of developing hepatotoxicity. Other reported adverse events severe enough to cause treatment withdrawal have included rash, nausea, diarrhoea, headache and dizziness/fainting.

In summary, questions surrounding the tolerability and efficacy of velnacrine must be resolved before its early promise as a treatment in Alzheimer’s disease can be realised. Nonetheless, given the limited therapeutic options presently, available, the drug may yet prove to be of value in at least some patients with Alzheimer’s disease.

Keywords

Adis International Limited Tacrine Caregiver Time Velnacrine Elevated Hepatic Enzyme Level 

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References

  1. 1.
    Jaen JC, Davis RE. Cholinergic therapies for Alzheimer’s disease: acetylcholinesterase inhibitors of current clinical interest. Curr Opin Invest Drugs 1993; 2: 363–77Google Scholar
  2. 2.
    Winblad B, Messamore E, O’Neill C, et al. Biochemical pathology and treatment strategies in Alzheimer’s disease: emphasis on the cholinergic system. Acta Neurol Scand 1993; Suppl.149: 4–6Google Scholar
  3. 3.
    Davies P, Maloney AJE. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 1976; 2: 1403PubMedCrossRefGoogle Scholar
  4. 4.
    Bartus RT, Dean RL, Beer B, et al. The cholinergic hypothesis of geriatric memory dysfunction. Science 1982; 217: 404–14CrossRefGoogle Scholar
  5. 5.
    Shutske GM, Pierrat FA, Cornfeldt ML, et al. (±)-9-Amino- 1,2,3,4-tetrahydroacridin-l-01. A potential Alzheimer’s disease therapeutic of low toxicity. J Med Chern 1988; 31: 1278–9CrossRefGoogle Scholar
  6. 6.
    Braga MFM, Harvey AL, Rowan EG. Effects of tacrine, velnacrine (HP 029), suronacrine (HP 128), and 3,4- diaminopyridine on skeletal neuromuscular transmission in vitro. Br J Pharmacol 1991; 102: 909–15PubMedCrossRefGoogle Scholar
  7. 7.
    Shutske GM, Pierrat FA, Kapples KJ, et al. 9-Amino-l,2,3,4- tetrahydroacridin-l-ols: synthesis and evaluation as a potential Alzheimer’s disease therapeutics. J Med Chern 1989; 32: 1805–13CrossRefGoogle Scholar
  8. 8.
    Bosch F, Morales M, Badia A, et al. Effects of velnacrine, tacrine and physostigmine on tetanic twitch responses at the rat neuromuscular junction. Eur J Pharmacol 1992; 222: 163–6PubMedCrossRefGoogle Scholar
  9. 9.
    Wagstaff AI, McTavish D. Tacrine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in Alzheimer’s disease. Drugs & amp;Aging 1994; 4, In pressGoogle Scholar
  10. 10.
    Siegfried KR. Pharmacodynamic and early clinical studies with velnacrine. Acta Neurol Scand 1993; Suppl.149: 26–8Google Scholar
  11. 11.
    Wesnes KA, Simpson PM, White L, et al. Cholinesterase inhibition in the scopolamine model of dementia. Ann N Y Acad Sci 1991; 640: 268–71PubMedGoogle Scholar
  12. 12.
    Ebmeier KP, Hunter R, Curran SM, et al. Effects of a single dose of the acetylcholinesterase inhibitor velnacrine on recognition memory and regional cerebral blood flow in Alzheimer’s disease. Psychopharmacology 1992; 108: 103–9PubMedCrossRefGoogle Scholar
  13. 13.
    Arai H, Kosaka K, Iizuka R. Changes of biogenic amines and their metabolites in postmortem brains from patients with Alzheimer type dementia. J Neurochem 1984; 43: 388–93PubMedCrossRefGoogle Scholar
  14. 14.
    Butterfield DA, Hensley K, Hall N, et al. Interaction oftacrine and velnacrine with neocortical synaptosomal membranes: relevance to Alzheimer’s disease. Neurochem Res 1993; 18: 989–94PubMedCrossRefGoogle Scholar
  15. 15.
    Butterfield DA, Rangachari A. Membrane-altering effects of velnacrine and N-methylacridinium: relevance to tacrine and Alzheimer’s disease. Biochem Biophys Res Commun 1992; 185: 596–603PubMedCrossRefGoogle Scholar
  16. 16.
    Khatoon S, Campbell SR, Haley BE, et al. Aberrant guanosine triphosphate-beta-tubulin interaction in Alzheimer’s disease. Ann Neurol 1989; 26: 210–5PubMedCrossRefGoogle Scholar
  17. 17.
    Puri SK, Hsu R, Ho I, et al. Single-dose safety, tolerance, and pharmacokinetics of HP 029 in elderly men: a potential Alzheimer agent. Curr Ther Res 1988; 44: 766–80Google Scholar
  18. 18.
    Puri SK, Ho I, Hsu R, et al. Multiple dose pharmacokinetics, safety, and tolerance of velnacrine (HP 029) in healthy elderly subjects: a potential therapeutic agent for Alzheimer’s disease. J Clin Pharmacol 1990; 30: 948–55PubMedGoogle Scholar
  19. 19.
    Cutler NR, Murphy MF, Nash RI, et al. Clinical safety, tolerance and plasma levels of the oral anticholinesterase 1,2,3,4- tetrahydro-9-aminoacridin-l-01-maleate (HP 029) in Alzheimer’s disease: preliminary findings. J Clin Pharmacol 1990; 30: 556–61PubMedGoogle Scholar
  20. 20.
    Puri SK, Hsu R, Ho I, et al. The effect of food on the bioavailability of velnacrine (HP 029) in healthy elderly men: a potential Alzheimer agent. J Clin Pharmacol 1989a; 29: 956–60PubMedGoogle Scholar
  21. 21.
    McNally WP, DeHart P, Pool W, et al. A comparison of in vivo distribution of radioactivity in rat brain following oral administration of tacrine or its I-hydroxymetabolite [abstract). Soc Neurosci Abst 1991; 17: 701Google Scholar
  22. 22.
    Pool WF, Bjorge SM, Windsor B, et al. Comparison of brain to plasma metabolic distributions of tacrine and I-hydroxytacrine in rat [abstract). Soc Neurosci Abst 1991; 17: 700Google Scholar
  23. 23.
    Turcan RG, Hillbeck D, Hartley TE, et al. Disposition of [14C]velnacrine maleate in rats, dogs and humans. Drug Metab Dis 1993; 21: 1037–47Google Scholar
  24. 24.
    Puri SK, Hsu R, Ho I, et al. Single dose safety, tolerance and pharmacokinetics of HP 029 in healthy young men: a potential Alzheimer agent. J Clin Pharmacol 1989b; 29: 278–84PubMedGoogle Scholar
  25. 25.
    Murphy MF, Hardiman ST, Nash RI, et al. Evaluation of HP 029 (velnacrine maleate) in Alzheimer’s disease. Ann N Y Acad Sci 1991; 640: 253–62PubMedGoogle Scholar
  26. 26.
    Siegfried K. A placebo-controlled crossover study of velnacrine in patients with Alzheimer’s disease [abstract). Neurology 1992; 42 Suppl.3: 141Google Scholar
  27. 27.
    Anonymous. Scrip 1992a; No. 1769 Nov 10: 22–3Google Scholar
  28. 28.
    Anonymous. F-D-C Reports 1992b; 54 Nov 09: 5–7Google Scholar
  29. 29.
    Moore MJ, Clipp EC. Alzheimer’s disease and caregiver time. Lancet 1994; 343: 239–40PubMedCrossRefGoogle Scholar
  30. 30.
    Pomara N, Deptula D, Singh R. Pretreatment postural blood pressure drop as a possible predictor of response to the cholinesterase inhibitor velnacrine (HP 029) in Alzheimer’s disease. Psychopharmacol Bull 1991; 27: 301–7PubMedGoogle Scholar
  31. 31.
    Horn R, Kasper S, Eichert V, et al. Mapping of EEG and P300 in patients with dementia of Alzheimer type and treatment with velnacrine (HP-029) [abstract). Pharmacopsychiatry 1992; 25: 105Google Scholar
  32. 32.
    Hardiman S, Miller K, Murphy M. Clinical trials with velnacrine: (PROPP) The physician reference of predicted probabilities—a statistical model for the estimation ofhepatoxicity risk with velnacrine maleate. Acta Neurol Scand 1993; Suppl. 149: 46–52Google Scholar
  33. 33.
    Hofman A, Rocca WA, Brayne C, et al. The prevalence of dementia in Europe: a collaborative study of 1980-1990 findings. Int J Epidemiol 1991; 20: 736–48PubMedCrossRefGoogle Scholar
  34. 34.
    Evans DA, Funkenstein H, Albert NS, et al. Prevalence of Alzheimer’s disease in a community population of older persons. Higherthan previously reported. JAMA 1989; 262: 2551–6PubMedCrossRefGoogle Scholar
  35. 35.
    Cutler NR, Sramek JJ, Murphy MF, et al. Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer’s disease. Ann Pharmacotherapy 1992; 26: 1118–22Google Scholar
  36. 36.
    Robertson A. The politics of Alzheimer’s disease: a case study in apocalyptic demography. Int J Health Serv 1990; 20: 429–42PubMedCrossRefGoogle Scholar
  37. 37.
    Henderson AS. Alzheimer’s disease in its epidemiological context. Acta Neurol Scand 1993; Suppl.149: 1–3Google Scholar
  38. 38.
    Scarle MA. Velnacrine: a tacrine analogue for senile dementia. P & T 1992; 17: 1786–8Google Scholar
  39. 39.
    Hermann C, Stern RG, Losonczy MF, et al. Diagnostic and pharmacological approaches in Alzheimer’s disease. Drugs & Aging 1991; 1: 144–62CrossRefGoogle Scholar
  40. 40.
    Moos WH, Hershenson FM. Potential therapeutic strategies for senile cognitive disorders. Drug News Perspect 1989; 2: 397–409Google Scholar
  41. 41.
    Miller SW, Mahoney JM, Jann MW. Therapeutic frontiers in Alzheimer’s disease. Pharmacotherapy 1992; 12: 217–31PubMedGoogle Scholar
  42. 42.
    Lamy PP. The role of cholinesterase inhibitors in Alzheimer’s disease. CNS Drugs 1994; 1: 146–65CrossRefGoogle Scholar
  43. 43.
    Viau CJ, Curren RD, Wallace K. Cytotoxicity of tacrine and velnacrine metabolites in cultured rat, dog and human hepatocytes. Drug Chern Toxicol 1993; 16: 227–39CrossRefGoogle Scholar
  44. 44.
    Cutler NR, Sramek JJ, Seifert RD, et al. The target population in Phase I clinical trials of acetylcholinesterase inhibitors in dementia: the role of the ‘bridging study’. In: Corain B, et al., editors. Alzheimer’s disease: advances in clinical and basic research. John Wiley & Sons Ltd, 1993: 559–62Google Scholar

Copyright information

© Adis International Limited 1994

Authors and Affiliations

  • Karen L. Goa
    • 1
  • Andrew Fitton
    • 1
  1. 1.Adis International LimitedMairangi Bay, Auckland 10New Zealand

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