CNS Drugs

, Volume 4, Issue 3, pp 230–246 | Cite as

Selegiline

A Review of its Clinical Efficacy in Parkinson’s Disease and its Clinical Potential in Alzheimer’s Disease
  • Lynda R. Wiseman
  • Donna McTavish
Drug Evaluation

Abstract

Summary

Synopsis

Selegiline (deprenyl) increases nigrostriatal dopamine levels by several mechanisms, including selective and irreversible inhibition of cerebral monoamine oxidase type-B. Through this mechanism it may also protect neurons against damage by free radicals and possibly exogenous neurotoxins.

When used alone in patients with early Parkinson s disease, oral selegiline 5mg twice daily initially reduces symptom severity compared with placebo. During prolonged therapy, selegiline slows the rate of symptom progression and delays the need for levodopa therapy by 6 to 9 months.

The benefits of coadministration of selegiline with levodopa as de novo therapy in early Parkinson s disease compared with levodopa monotherapy remain unclear. Studies have shown either similar disease progression in both treatment groups after 3 years or significantly slowed disease progression and reduced levodopa requirement after 14 to 54 months in patients treated with both drugs compared with levodopa monotherapy.

In patients with more advanced disease who have mild levodopa response fluctuations, concomitant selegiline allows a reduction in levodopa dosage. Improvements in overall disability and ‘end-of-dose’ fluctuations are observed, although benefits are rarely maintainedfor longer than a year.

Improvements in cognitive function, behaviour and activities of daily living have been observed in patients with Alzheimer s disease following administration of selegiline IO mg/day for up to 15 months, and the drug appeared to be more effective in this regard than 1-acetylcarnitine, oxiracetam and phosphatidylserine in single-blind studies. In addition, preliminary findings suggest that selegiline may have an additive effect when coadministered with cholinergic therapy.

At the dosage recommended for Parkinson s disease and Alzheime~ s disease, selegiline is not associated with the tyramine (‘cheese’) reaction.

Thus, selegiline is a valuable treatment optionfor de novo therapy of patients with early Parkinson s disease, improving symptoms and postponing the needfor levodopa therapy. Whether it also offers clinically significant neuroprotection remains unclear. Selegiline is a useful adjunct to long term levodopa therapy in patients with more advanced disease experiencing response fluctuations, and recent findings suggest that it may offer some clinical benefit to patients with Alzheimer s disease.

Overview of Pharmacological Properties

Selegiline increases cerebral dopamine levels through selective irreversible inhibition of monoamine oxidase type-B (MAO-B), an enzyme involved in central dopamine metabolism.

The drug has proven to be an effective treatment for the symptoms of Parkinson’s disease, a disorder that results from a progressive loss of dopaminergic cells in the substantia nigra and consequent depletion of the neurotransmitter dopamine. While opinion remains divided as to whether selegiline is also neuroprotective in patients with early Parkinson’s disease, several mechanisms of action have been identified which may account for a neuroprotective effect of the drug. Inhibition of MAO-B by selegiline may reduce the free radical formation and oxidative stress associated with dopamine metabolism, which can cause neuronal damage and cell death. In addition, selegiline-mediated inhibition of MAO-B may prevent the conversion of environmental agents [such as 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP)] to their active toxic forms which are capable of inducing Parkinson-like symptoms in humans. In animal studies, selegiline inhibited neurotoxin uptake into neurons and protected dopaminergic neurons against damage from neurotoxins by inhibiting MAO-B activity. Selegiline also rescued damaged neurons through a trophic-like effect independent of MAO-B inhibition. Other activities of selegiline supporting a neuroprotective effect have also been identified in in vitro and animal studies; however, no direct pathological evidence supporting a neuroprotective effect of selegiline in humans is available.

While prolonged selegiline administration increased the lifespan of aged rodents, data on such an effect in humans with Parkinson’s disease are conflicting.

Findings that patients with Alzheimer’s disease have reduced brain dopamine levels and increased MAO-B activity indicate that selegiline may be of some clinical benefit in the treatment of this disease.

The bioavailability, mean peak plasma concentration (Cmax) and time to reach Cmax following an oral IOmg dose of selegiline are, respectively, about 10%,2 µg/L and 0.6 hours. Selegiline is subjected to extensive and rapid hepatic metabolism, the main metabolites being l-methamphetamine, l-amphetamine and demethyl-selegiline. While demethyl-selegiline has some MAO-B inhibitory activity, l-methamphetamine and l-amphetamine may contribute to neuroprotective effects of the drug. The apparent volume of distribution of selegiline is 500L, although the drug is 94% bound to plasma proteins. Renal elimination is the predominant route of excretion, with 86% of an oral dose recovered in the urine, principally as l-methamphetamine (59%) and l-amphetamine (26%).

Clinical Efficacy

Improvements in symptom severity have been observed in previously untreated patients with early Parkinson’s disease during the first 3 months of monotherapy with oral selegiline 5mg twice daily. In particular, initial improvements in the Unified Parkinson’s Disease Rating Scale (UPDRS) scores for motor function and mental state were observed. During prolonged therapy (1 to 3 years), selegiline monotherapy significantly slowed symptom progression compared with placebo. Scores for overall disability were lower in selegiline recipients after 1 to 3 years of therapy, and the need for levodopa to control symptoms was delayed by 6 to 9 months. Subsequent coadministration of selegiline with levodopa reduced the dosage of levodopa required to maintain an adequate response by up to 80% after 5 years’ combined treatment.

A single comparative study found that while levodopa monotherapy was associated with a higher incidence of motor fluctuations than selegiline, lisuride or bromocriptine monotherapy in patients with early Parkinson’s disease, fewer patients treated with levodopa required add-on therapy compared with the other treatment groups after a mean follow-up of 20 months.

Coadministration of selegiline with levodopa as de novo therapy in patients with early Parkinson’s disease significantly improved disability scores compared with levodopa monotherapy over treatment periods of 14 to 54 months in 3 recent double-blind studies. In addition, the need to increase the levodopa dose to compensate for disease progression was less common in patients who received selegiline. In contrast to these findings, a large nonblind randomised study found no clinical benefit of adding selegiline to levodopa therapy over a 3-year period.

Concomitant administration of selegiline to patients experiencing response fluctuations during long term levodopa therapy generally improved motor function, reduced disability rating scores, improved ‘end-of-dose’ fluctuations and reduced levodopa dosage requirements (by 10 to 30%). However, long term studies indicate that the benefits of adding selegiline to long term levodopa therapy are maintained in the majority of patients for only 7 to 8 months.

Double-blind placebo-controlled trials indicate that selegiline is of some clinical benefit in patients with Alzheimer’s disease. In the majority of studies, selegiline therapy was associated with greater improvements in rating scores for cognitive function, behaviour and activities of daily living compared with placebo, or the neuropsychotherapeutic agents l-acetylcarnitine (ST-200), oxiracetam and phosphatidylserine. Preliminary findings suggest that selegiline may have an additive effect when coadministered with cholinesterase inhibitors (such as tacrine or physostigmine salicylate), although this requires further investigation.

Pharmacoeconomic Considerations

Studies evaluating the pharmacoeconomic value of selegiline in the treatment of Parkinson’s disease are unavailable at present. However, clinical studies indicate that the drug is likely to improve patient quality of life and have a favourable cost-effectiveness ratio as monotherapy in patients with early disease and when used as adjunctive therapy in patients with response fluctuations receiving long term levodopa therapy. Selegiline therapy has the potential to reduce direct costs including hospitalisation, medical care and physician fees, and indirect costs associated with the significant impairment in quality of life in patients with Parkinson’s disease. The greatest economic benefit of selegiline is anticipated to result from a delay in the onset of disability in patients with early Parkinson’s disease. It has been estimated that an agent which slowed progression of disability by around 10% would realise savings (through reduction in both direct and indirect costs) in the order of $US330 million per annum in the US. While the available evidence indicates that selegiline delays symptom progression by up to 9 months, further study is required to determine the true pharmacoeconomic value of the drug to society.

Tolerability

Selegiline, at the dosage used for treatment of Parkinson’s and Alzheimer’s diseases, is a selective and irreversible MAO-B inhibitor which is not associated with the tyramine (‘cheese’) reaction. Peak concentration dyskinesias may be exacerbated when selegiline is added to the levodopa treatment regimen, and mood elevation, insomnia, hallucinations and confusion have been reported during coadministration of both drugs. Insomnia and euphoria may occur during selegiline monotherapy, as well as gastrointestinal symptoms (mainly nausea) and orthostatic hypotension.

Dosage and Administration

Selegiline 5mg twice daily (with breakfast and at midday), administered orally either as monotherapy or in combination with levodopa, is recommended for the treatment of patients with Parkinson’s disease. Clinical trials to date indicate that the same dosage of selegiline may be of clinical benefit in patients with Alzheimer’s disease.

The concurrent use of selegiline with pethidine (meperidine) is contraindicated, and administration of selegiline with selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors or tricyclic antidepressants should be avoided.

Keywords

Levodopa MPTP Selegiline Deprenyl Levodopa Therapy 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Chrisp P, Mammen GJ, Sorkin EM. Selegiline: a review of its pharmacology, symptomatic benefits and protective potential in Parkinson’s disease. Drugs Aging 1991 May-Jun; 1: 228–48PubMedCrossRefGoogle Scholar
  2. 2.
    Heinonen EH, Lammintausta R. A review of the pharmacology of selegiline. Acta Neurol Scand 1991; 84 Suppl.136: 44–59CrossRefGoogle Scholar
  3. 3.
    Knoll J. The pharmacological basis of the beneficial effects of (-)deprenyl (selegiline) in Parkinson’s and Alzheimer’s diseases. J Neural Transm Gen Sect 1993; 40 Suppl.: 69–91Google Scholar
  4. 4.
    Elsworth JD, Roth RH. Deprenyl: pharmacological aspects of its clinical effects. Biog Amines 1993; 9 (5/6): 381–94Google Scholar
  5. 5.
    Gerlach M, Riederer P, Youdim MBH. The molecular pharmacology of L-deprenyl. Eur J Pharmacol Mol Pharmacol 1992 Jun 5; 226: 97–108CrossRefGoogle Scholar
  6. 6.
    Golbe LI, Langston JW, Shoulson I. Selegiline and Parkinson’s disease: protective and symptomatic considerations. Drugs 1990; 39: 646–51PubMedCrossRefGoogle Scholar
  7. 7.
    Halliwell B. Oxidants and the central nervous system: some fundamental questions. Acta Neurol Scand 1989; 126 Suppl.80: 23–33CrossRefGoogle Scholar
  8. 8.
    Sonsalla PK, Golbe L. Deprenyl as prophylaxis against Parkinson’s disease? Clin Neuropharmacol 1988; 11: 500–11PubMedCrossRefGoogle Scholar
  9. 9.
    Youdim MBH, Ben-Shachar D, Riederer P. Is Parkinson’s disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration? Acta Neurol Scand 1989; 126 Suppl.: 47–54CrossRefGoogle Scholar
  10. 10.
    Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonism due to l-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP): seven cases. Neurology 1985; 35: 949–56PubMedCrossRefGoogle Scholar
  11. 11.
    Davis GC, Williams AC, Markey SP, et al. Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1979; 1: 249–54PubMedCrossRefGoogle Scholar
  12. 12.
    Langston JW, Ballard P, Tetrud JW, et al. Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 1983; 219: 979–80PubMedCrossRefGoogle Scholar
  13. 13.
    Cohen G, Pasik P, Cohen B, et al. Pargyline and selegiline prevent the neurotoxicity of l-methyl-4-phenyl-I,2,3,6-tetrahydropyridine (MPTP) in monkeys. Eur J Pharmacol 1984; 106: 209–10PubMedCrossRefGoogle Scholar
  14. 14.
    Fuller MA, Hemrick-Luecke SK. A high dose of MPTP overcomes the protective effect of selegiline against dopaminergic neurotoxicity. J Pharm Pharmacol 1989; 41: 492–3PubMedCrossRefGoogle Scholar
  15. 15.
    Heikkila RE, Manzino L, Cabbat FS, et al. Protection against the dopaminergic neurotoxicity of l-methyl-4-phenyl-I,2,5,6- tetrahydropyridine by monoamine oxidase inhibitors. Nature 1984; 311: 467–9PubMedCrossRefGoogle Scholar
  16. 16.
    Sziniki I, Kardos V, Patthy M, et al. Amphetamine-metabolites of deprenyl involved in protection against neurotoxicity induced by MPTP and 2-methyl-MPTP. J Neural Transm Gen Sect 1994; 41 Suppl.: 207–19Google Scholar
  17. 17.
    Heinonen E. Selegiline in the treatment of Parkinson’s disease: pharmacokinetic and clinical studies. Research Reports from the Department of Neurology University of Turku 1995; No.33 (Y)Google Scholar
  18. 18.
    Tatton WG, Greenwood CE. Rescue of dying neurons: a new action for deprenyl in MPTP parkinsonism. J Neurosci Res 1991 Dec; 30: 666–72PubMedCrossRefGoogle Scholar
  19. 19.
    Wu R-M, Chiueh CC, Pert A, et al. Apparent antioxidant effect of I-deprenyl on hydroxyl radical formation and nigral injury elicited by MPP+ in vivo. Eur J Pharmacol 1993 Oct 26; 243: 241–7PubMedCrossRefGoogle Scholar
  20. 20.
    Salo PT, Tatton WG. Deprenyl reduces the death of motoneurons caused by axotomy. J Neurosci Res 1992 Feb; 31: 394–400PubMedCrossRefGoogle Scholar
  21. 21.
    Koutsilieri E, O’Callaghan JFX, Chen T-S, et al. Selegiline enhances survival and neutrite outgrowth of MPP+-treated dopaminergic neurons. Eur J Pharmacol 1994; 269: R3–4CrossRefGoogle Scholar
  22. 22.
    Tatton W, Wadia J, Ju W, et al. (-)Deprenyl prevents mitochondrial depolarization and reduces programmed cell death in trophically-deprived cells [abstract]. New Trends Clin Neuropharmacol 1994; 7 (1): 34–5Google Scholar
  23. 23.
    Tatton WG, Seniuk NA. ‘Trophic-like’ actions of (-)deprenyl on neurons and astroglia. In: Racagni G, Brunello N, Langer SZ, editors. Recent advances in the treatment of neurodegenerative disorders and cognitive dysfunction. Vol.7. Basel, Karger: Int Acad Biomed Drug Res, 1994: 238–48Google Scholar
  24. 24.
    Seniuk NA, Henderson JT, Tatton WG, et al. Increased CNTF gene expression in process-bearing astrocytes following injury is augmented by R( -)-deprenyl. J Neurosci Res 1994 Feb 1; 37: 278–86PubMedCrossRefGoogle Scholar
  25. 25.
    Carrillo MC, Kitani K, Kanai S, et al. The effect of a long term (6 months) treatment with (-)deprenyl on antioxidant enzyme activities in selective brain regions in old female Fischer 344 rats. Biochem Pharmacol 1994 Apr 20; 47: 1333–8PubMedCrossRefGoogle Scholar
  26. 26.
    Tatton WG, Ju WYL, Holland DP, et al. (-)Deprenyl reduces PC 12 cell apoptosis by inducing new protein synthesis. J Neurochern 1994; 63: 1572–5CrossRefGoogle Scholar
  27. 27.
    Knoll J. (-)Deprenyl-medication: a strategy to modulate the age-related decline of the striatal dopaminergic system. J Am Geriatr Soc 1992 Aug; 40: 839–47PubMedGoogle Scholar
  28. 28.
    Cohen G, Spina MB. Deprenyl suppresses the oxidant stress associated with increased dopamine turnover. Ann Neurol 1989; 26: 689–90PubMedCrossRefGoogle Scholar
  29. 29.
    Rinne JO, Royttli M, Paljlirvi L, et al. Selegiline (deprenyl) treatment and death of nigral neurons in Parkinson’s disease. Neurology 1991 Jun; 41: 859–61PubMedCrossRefGoogle Scholar
  30. 30.
    Knoll J, Dallo J, Yen IT. Striatal dopamine, sexual activity and lifespan. Longevity of rats treated with (-)deprenyl. Life Sci 1989; 45: 525–31PubMedCrossRefGoogle Scholar
  31. 31.
    Milgram NW, Racine RJ, Nellis P, et al. Maintenance on Ldeprenyl prolongs life in aged male rats. Life Sci 1990; 47: 415–20PubMedCrossRefGoogle Scholar
  32. 32.
    Freisleben H-J, Lehr F, Fuchs J. Lifespan of immunosuppressed NMRI-mice is increased by deprenyl. J Neural Transm Gen Sect 1994; 41 Suppl.: 231–6Google Scholar
  33. 33.
    Birkmayer W, Knoll J, Riederer P, et al. Increased life expectancy resulting from addition of I-deprenyl to Madopar treatment in Parkinson’s disease: a long term study. J Neural Transm Gen Sect 1985; 65: 113–27CrossRefGoogle Scholar
  34. 34.
    Elizan TS, Yahr MD, Moros DA, et al. Selegiline as an adjunct to conventionallevodopa therapy in Parkinson’s disease. Experience with this type B monoamine oxidase inhibitor in 200 patients. Arch Neurol 1989; 46: 1280–3PubMedCrossRefGoogle Scholar
  35. 35.
    Oreland L, Gottfries C-G. Brain and platelet monoamine oxidase in aging and in dementia of the Alzheimer type. Prog Neuropsych Bioi Psychiatry 1986; 10: 533–40CrossRefGoogle Scholar
  36. 36.
    Riederer P, Jellinger K. Neurochemical insights into monoamine oxidase inhibitors, with specific reference to deprenyl (selegiline). Acta Neurol Scand 1983; 68 Suppl: 43–55CrossRefGoogle Scholar
  37. 37.
    Fowler CJ, Wiberg A, Oreland L, et al. The effect of age on the activity and molecular properties of human brain monoamine oxidase. J Neural Transm Gen Sect 1980; 49: 1–20CrossRefGoogle Scholar
  38. 38.
    Amenta F, Bograni S, Cadel S, et al. Microanatomical changes in the frontal cortex of aged rats: effect of I-deprenyl treatment. Brain Res Bull 1994; 34 (2): 125–31PubMedCrossRefGoogle Scholar
  39. 39.
    Stoll S, Hafner U, Pohl D, et al. Age-related memory decline and longevity under treatment with selegiline. Life Sci 1994; 55 (25/26): 2155–63PubMedCrossRefGoogle Scholar
  40. 40.
    Heinonen EH, Antilla M, Karnani AM, et al. Pharmacokinetics of selegiline after oral dosing [abstract no.P248]. Mov Disord 1994; 9 Suppl.1: 57Google Scholar
  41. 41.
    Reynolds GP, Elsworth JD, Blau K, et al. Deprenyl is metabolised to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978; 6: 542–4PubMedCrossRefGoogle Scholar
  42. 42.
    Yoshida T, Yamada Y, Yamamoto T, et al. Metabolism of deprenyl, a selective monoamine oxidase (MAO)B inhibitor in rat: relationship of metabolism to MAO-B inhibitory potency. Xenobiotica 1986; 16: 129–36PubMedCrossRefGoogle Scholar
  43. 43.
    Heinonen EH. Myllylä V, Sotaniemi K, et al. Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 1989; 126 Suppl.80: 93–9Google Scholar
  44. 44.
    Fowler JS, MacGregor RR, Wolf AP, et al. Mapping human brain monoamine oxidase A and B with II C-Iabelled suicide inactivators and PET Science 1987; 235: 481–5PubMedCrossRefGoogle Scholar
  45. 45.
    Heinonen EH, Anttila MI, Lammintausta RAS. Pharmacokinetic aspects of I-deprenyl (selegiline) and its metabolites. Clin Pharmacol Ther 1994; 56: 742–9PubMedCrossRefGoogle Scholar
  46. 46.
    Heinonen EH, Anttila M, Nyman L, et al. Desmethylseiegiline, a metabolite of selegiline, is an irreversible inhibitor of MAOB in human subjects [abstract]. Neurology 1993 Apr; 43Supp. 2: A156Google Scholar
  47. 47.
    Gmil J, Szekacs G, Szebeni G, et al. Neurotoxicity of DSP-4 on pigs and prevention of its neurotoxicity by deprenyl. In: 6th Amine Oxidase and 5th Trace Amine Conference, 1994; B-09Google Scholar
  48. 48.
    Magyar K, Gaal J, Lengyel J. Neuroprotective effect of (-)deprenyl against DSP-4 toxicity [abstract]. J Neurochem 1994; 63 Suppl. 1: S44Google Scholar
  49. 49.
    Fahn S, Elton RL, Members of the UPDRS Development Committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Caine DB, et al., editors. Recent developments in Parkinson’s disease. Vol. 2. Florham Park, New Jersey: MacMillan Healthcare Information, 1987: 153–63Google Scholar
  50. 50.
    Hoehn MM, Yahr MD. Parkinsonism: onset, progression and mortality. Neurology 1967; 17: 427–42PubMedCrossRefGoogle Scholar
  51. 51.
    Canter GJ, de La Torre R, Mier M. A method for evaluating disability in patients with Parkinson’s disease. J Nerv Ment Dis 1961; 133: 143–7PubMedCrossRefGoogle Scholar
  52. 52.
    Webster DD. Critical analysis of the disability in Parkinson’s disease. Mod Treat 1968; 5: 257–82PubMedGoogle Scholar
  53. 53.
    Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960; 23: 56–62PubMedCrossRefGoogle Scholar
  54. 54.
    Allain H, Pollak P, Neukirch HC, et al. Symptomatic effect of selegiline in de novo parkinsonian patients. Mov Disord 1993; 8 Suppl.I: 36–40CrossRefGoogle Scholar
  55. 55.
    Myllylii VV, Sotaniemi KA, Vuorinen JA, et al. Selegiline as initial treatment in de novo parkinsonian patients. Neurology 1992 Feb; 42: 339–43CrossRefGoogle Scholar
  56. 56.
    Effects of tocopherol and deprenyl on the progression of disability in early Parkinson’s disease. The Parkinson Study Group. N Engl J Med 1993 Jan 21; 328: 176–83CrossRefGoogle Scholar
  57. 57.
    Tetrud JW, Langston Jw. The effect of deprenyl (selegiline) on the natural history of Parkinson’s disease. Science 1989; 245: 519–22PubMedCrossRefGoogle Scholar
  58. 58.
    Myllylii VV, Sotaniemi KA, Vuorinen JA, et al. Selegiline in de novo Parkinsonian patients: the Finnish study. Mov Disord 1993; 8 Suppl.I: 41–4CrossRefGoogle Scholar
  59. 59.
    Musicco M, Caraceni T, Beghi E, et al. Dopamine agonists, deprenyl and levodopa in de novo patients with Parkinson’s disease: a multicenter randomized trial [abstract]. Neurology 1993 Apr; 43 Suppl.2: A333Google Scholar
  60. 60.
    Olanow CW, Koller W, Hauser R, et al. A prospective longitudinal controlled study of deprenyl in Parkinson’s disease [abstract]. Neurology 1994; 44 Suppl.: A258Google Scholar
  61. 61.
    Larsen JP. Effect of selegiline in Parkinson’s disease [abstract]. Satellite Symposium to the 5th Meeting of the European Neurological Society; 1995 June 19; Munich, Germany.Google Scholar
  62. 62.
    Comparisons of therapeutic, levodopa and selegiline, and bromocriptine in, mild Parkinson’s disease: three year interim report. Parkinson’s Disease Research Group in the United Kingdom. Parkinson’s Disease Research Group in the United Kingdom. BMJ 1993 Aug 21; 307: 469–72CrossRefGoogle Scholar
  63. 63.
    Brannan T, Yahr MD. Comparative study of selegiline plus 1- dopa-carbidopa versus I-dopa-carbidopa alone in the treatment of Parkinson’s disease. Ann Neurol 1995; 37: 95–8PubMedCrossRefGoogle Scholar
  64. 64.
    Myllylii W, Heinonen EH, Vuorinen JA, et al. Early selegiline therapy reduces levodopa dose requirement in Parkinson’s disease. Acta Neurol Scand 1995; 91: 177–82CrossRefGoogle Scholar
  65. 65.
    Giovannini P, Martignoni E, Piccolo I, et al. (-)Deprenyl in Parkinson’s disease: a two-year study in the different evolutive stages. J Neural Transm 1986; 22 Suppl.: 235–46Google Scholar
  66. 66.
    Lieberman A. Long-term experience with selegiline and levodopa in Parkinson’s disease. Neurology 1992 Apr; 42 Suppl.4: 32–6PubMedGoogle Scholar
  67. 67.
    Yahr MD, Elizan TS, Moros D. Selegiline in the treatment of Parkinson’s disease: long term experience. Acta Neurol Scand 1989; 126: 157–61CrossRefGoogle Scholar
  68. 68.
    Adem A. Putative mechanisms of action of tacrine in Alzheimer’s disease. Acta Neurol Scand 1992; 85 Suppl.1.39: 69–74CrossRefGoogle Scholar
  69. 69.
    Wagstaff AJ, McTavish D. Tacrine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in Alzheimer’s disease. Drugs Aging 1994; 4 (6): 510–40PubMedCrossRefGoogle Scholar
  70. 70.
    Agnoli A, Fabbrini G, Fioravanti M. CBF and cognitive evaluation of Alzheimer type patients before and after IMAO-B treatment: a pilot study. Eur Neuropsychopharmacol 1992 Mar; 2: 31–5PubMedCrossRefGoogle Scholar
  71. 71.
    Burke WJ, Roccaforte WH, Wengel SP, et al. L-deprenyl in the treatment of mild dementia of the Alzheimer type: results of a 15-month trial. J Am Geriatr Soc 1993 Nov; 41: 1219–25PubMedGoogle Scholar
  72. 72.
    Finali G, Piccirilli M, Oliani C, et al. Alzheimer-type dementia and verbal memory performances: influence of selegiline therapy. Ital J Neurol Sci 1992 Mar; 13: 141–8PubMedCrossRefGoogle Scholar
  73. 73.
    Mangoni A, Grassi MP, Frattola L, et al. Effects of a MAO-B inhibitor in the treatment of Alzheimer’s disease. Eur Neurol 1991 Mar-Apr; 31: 100–7PubMedCrossRefGoogle Scholar
  74. 74.
    Piccinin GL, Finali G, Piccirilli M. Neuropsychological effects of I-deprenyl in Alzheimer’s type dementia. Clin Neuropharmacol 1990; 13 (2): 147–63PubMedCrossRefGoogle Scholar
  75. 75.
    Tariot PN, Sunderland T, Weingartner H, et al. Cognitive effects of I-deprenyl in Alzheimer’s disease. Psychopharmacology 1987; 91: 489–95PubMedCrossRefGoogle Scholar
  76. 76.
    Campi N, Todeschini GP, Scarzella L. Selegiline versus I-acetylcarnitine in the treatment of Alzheimer-type dementia. Clin Ther 1990; 12 (4): 306–14PubMedGoogle Scholar
  77. 77.
    Falsaperla A, Preti PAM, Oliani C. Selegiline versus oxiracetam in patients with Alzheimer-type dementia. Clin Ther 1990 Sep-Oct; 12: 376–84PubMedGoogle Scholar
  78. 78.
    Monteverde A, Gnemmi P, Rossi F, et al. Selegiline in the treatment of mild to moderate Alzheimer-type dementia. Clin Ther 1990; 12 (4): 315–22PubMedGoogle Scholar
  79. 79.
    Riekkinen P, Koivisto K, Helkala EL, et al. Effect of selegiline in Alzheimer’s disease. Selegiline — Expanding Horizons. Satellite Symposium to the 5th Meeting of the European Neurological Society; 1995 June 19, Munich, Germany.Google Scholar
  80. 80.
    Burke WJ, Ranno AE, Roccaforte WH, et al. L-Deprenyl in the treatment of mild dementia of the Alzheimer type: preliminary results. J Am Geriatr Soc 1993 Apr; 41: 367–70PubMedGoogle Scholar
  81. 81.
    Schneider LS, Olin JT, Pawluczyk S. A double-blind crossover pilot study of I-deprenyl (selegiline) combined with cholinesterase inhibitor in Alzheimer’s disease. Am J Psychiatry 1993 Feb; 150: 321–3PubMedGoogle Scholar
  82. 82.
    Sunderland T, Molchan S, Lawlor B, et al. A strategy of “combination chemotherapy” in Alzheimer’s disease: rationale and preliminary results with physostigmine plus deprenyl. Int Psychogeriatr 1992; 4Suppl2: 291–309PubMedGoogle Scholar
  83. 83.
    Ahlskog IE. Parkinson’s disease: update on pharmacologic options to slow progression and treat symptoms. Hosp Formul 1992; 27: 146–63Google Scholar
  84. 84.
    Marttila RJ, Rinne UK. Epidemiology of Parkinson’s disease: an overview. J Neural Transm Park Dis Dement Sect 1981; 51: 135–48CrossRefGoogle Scholar
  85. 85.
    Bryson HM, Milne RJ, Chrisp P. Selegiline: an appraisal of the basis of its pharmacoeconomic and quality-of-life benefits in Parkinson’s disease. PharmacoEconomics 1992 Aug; 2: 118–36PubMedCrossRefGoogle Scholar
  86. 86.
    Jurian R, Clark S, Shoulson I, et al. Economic impact of protective therapy for early Parkinson’s disease. Ann Neurol 1988; 24 (1): 153Google Scholar
  87. 87.
    Ward CD. Does selegiline delay progression of Parkinson’s disease? A critical re-evaluation of the DATATOP study. J Neurol Neurosurg Psychiatry 1994 Feb; 57: 217–20PubMedCrossRefGoogle Scholar
  88. 88.
    Zornberg GL, Bodkin JA, Cohen BM. Severe adverse interaction between pethidine and selegiline. Lancet 1991 Jan 26; 337: 246PubMedCrossRefGoogle Scholar
  89. 89.
    Suchowersky D, deVries JD. Interaction of fluoxetine and selegiline. Can J Psychiatry 1990; 35: 571–2PubMedGoogle Scholar
  90. 90.
    Jermain DM, Hughes PL, Follender AB. Potential fluoxetinese1egiline interaction. Ann Phannacother 1992 Oct; 26: 1300Google Scholar
  91. 91.
    Dingemanse J. An update of recent moclobemide interaction data. Int Clin Psychopharmacol 1993 Jan; 7: 167–80PubMedCrossRefGoogle Scholar
  92. 92.
    West R, editor. Parkinson’s Disease. London: Office of Health Economics, 1991Google Scholar
  93. 93.
    Paulson Gw. Management of the patient with newly-diagnosed Parkinson’s disease. Geriatrics 1993 Feb; 48: 30–40PubMedGoogle Scholar
  94. 94.
    Agid Y. Parkinson’s disease: pathophysiology. Lancet 1991; 337: 1321–4PubMedCrossRefGoogle Scholar
  95. 95.
    Langtry HD, Clissold SP. Pergolide: a review of its pharmacological properties and therapeutic potential in Parkinson’s disease. Drugs 1990; 39: 491–506PubMedCrossRefGoogle Scholar
  96. 96.
    Marsden CD. Parkinson’s disease. Lancet 1990; 335: 948–52PubMedCrossRefGoogle Scholar
  97. 97.
    Mizuno Y, Mori H, Kondo T. Practical guidelines for the drug treatment of Parkinson’s disease. CNS Drugs 1994; 1 (6): 410–26CrossRefGoogle Scholar
  98. 98.
    The market for Alzheimer drugs. Scrip Mag 1992 Nov; 22Google Scholar
  99. 99.
    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: 2551–6PubMedCrossRefGoogle Scholar
  100. 100.
    Lamy PP. The role of cholinesterase inhibitors in Alzheimer’s disease. CNS Drugs 1994; 1 (2): 146–65CrossRefGoogle Scholar
  101. 101.
    Balson R, Gibson P, Ames D, et al. Tacrine-induced hepatotoxicity: tolerability and management. CNS Drugs 1995; 4 (3): 168–81CrossRefGoogle Scholar

Copyright information

© Adis International Limited 1995

Authors and Affiliations

  • Lynda R. Wiseman
    • 1
  • Donna McTavish
    • 1
  1. 1.Adis International LimitedMairangi BayNew Zealand

Personalised recommendations