Drugs & Aging

, Volume 14, Issue 3, pp 173–196 | Cite as

Treatment of Amyotrophic Lateral Sclerosis

Disease Management

Abstract

Survival of patients with amyotrophic lateral sclerosis (ALS) is improving. Timely and more frequent implementation of bimodal passive airway pressure (BIPAP) and percutaneous endoscopically placed gastrostomy (PEG) may be the major factors impacting on longer survival. However, several drugs recently subjected to rigorous clinical trials have demonstrated significant results or encouraging trends. ALS is a complex disease in which aging neurons are subjected to a variety of susceptibility genes, most of which remain to be discovered, that interact with equally unrecognised environmental factors. This makes it unlikely that a single therapeutic agent will be of value. The thrust must be on polypharmacy. The ‘cocktail’ that will eventually be of greatest benefit has yet to be formulated. It might contain glutamate N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists, antioxidants or a combination of trophic factors and neuroprotective agents. This statement is made with the understanding that the aetiopathogenesis of ALS is far from clear.

Drug delivery is a problem and better delivery systems are needed. The efficacy of some of the medications that presently only induce modest benefit may be improved by liposomal packaging, use of a patch or inhalation delivery or intraventricular pump reservoirs.

There is a great need to develop an early marker of ALS and sensitive reproducible measures of disease progression. This will curtail the present need for large, lengthy and very expensive clinical trials.

The new millennium will see the advent of targeted therapy using viral vectors which can deliver replacement genes, trophic factors and other drugs to degenerating neurons; transplantation of neural progenitor cells which can become mature functioning neurons; anti-apoptotic agents which will allow neurons to survive longer; and mechanisms that can protect the telomerase maintenance system which is so crucial in the immortalisation of cells.

Keywords

Amyotrophic Lateral Sclerosis Adis International Limited Gabapentin Lamotrigine Amyotrophic Lateral Sclerosis Patient 

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References

  1. 1.
    Eisen A. Amyotrophic lateral sclerosis is a multifactorial disease. Muscle Nerve 1995; 18: 741–52PubMedGoogle Scholar
  2. 2.
    Eisen A, Krieger C. Amyotrophic lateral sclerosis: a synthesis of research and clinical practice. Cambridge: Cambridge University Press, 1998Google Scholar
  3. 3.
    Eisen A, Schulzer M, MacNeil M, et al. Duration of amyotrophic lateral sclerosis is age dependent. Muscle Nerve 1993; 16: 27–32PubMedGoogle Scholar
  4. 4.
    Brooks BR, World Federation of Neurology Sub Committee on Neuromuscular Diseases. El Escorial criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci 1994; 124 Suppl.: 96–107PubMedGoogle Scholar
  5. 5.
    Siddique T, Nijhawan D, Hentati A. Molecular genetic basis of familial ALS. Neurology 1996; 47 Suppl.: S27–35PubMedGoogle Scholar
  6. 6.
    Juneja T, Pericak-Vance A, Laing NG, et al. Prognosis and survival in familial amyotrophic lateral sclerosis: progression and survival in patients with glu100gly and ala4val mutations in Cu,Zn superoxide dismutase. Neurology 1997; 48: 55–7PubMedGoogle Scholar
  7. 7.
    Andersen PM, Forsgren L, Binzer M, et al. Autosomal rescessive adult-onset amyotrophic lateral sclerosis associated with homozygosity for AsP90A1a CuZn-superoxide dismutase mutation: a clinical and genealogical study of 36 patients. Brain 1996; 119: 1153–72PubMedGoogle Scholar
  8. 8.
    Lillienfeld DE, Chan E, Ehland J, et al. Rising mortality from motoneuron disease in the USA, 1982–84. Lancet 1989; I: 710–2Google Scholar
  9. 9.
    Brooks BR. Clinical epidemiology of amyotrophic lateral sclerosis. Neurol Clin 1996; 14: 399–421PubMedGoogle Scholar
  10. 10.
    Bensimon G, Lacombiez L, Meininger V, and the ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330: 585–91PubMedGoogle Scholar
  11. 11.
    Lacomblez L, Bensimon G, Leigh PN, et al. A dose-ranging study of riluzole in amyotrophic lateral sclerosis. Lancet 1996; 347: 1425–31PubMedGoogle Scholar
  12. 12.
    Miller RG, Bouchard JP, Duquette P, et al. Clinical trials of riluzole in patients with ALS. Neurology 1996; 47Suppl. 2: S86–92PubMedGoogle Scholar
  13. 13.
    Zech VL, Telford IR. Negative therapeutic effect of massive doses of vitamin E on amyotrophic lateral sclerosis. Arch Neurol 1943; 50: 190–2Google Scholar
  14. 14.
    Munsat TL. Issues in clinical trial design 1: use of natural history controls. A protagonist view. Neurology 1996; 47 Suppl.: S96–7PubMedGoogle Scholar
  15. 15.
    Munsat TL. Issues in amyotrophic lateral sclerosis clinical trial design. In: Searratrice G, Munsat T, editors. Pathogenesis and therapy of amyotrophic lateral sclerosis, advances in neurology. Vol. 68. Philadelphia: Lippincott-Raven Publishers, 1995: 209–18Google Scholar
  16. 16.
    Andres PL, Finison L, Conlon T. Use of composite scores (megascores) to measure deficit in ALS. Neurology 1988; 38: 405–8PubMedGoogle Scholar
  17. 17.
    Munsat TL, Andres PL, Finison L, et al. The natural history of motoneuron loss in amyotrophic lateral sclerosis. Neurology 1988; 38: 409–13PubMedGoogle Scholar
  18. 18.
    Miller RG, Petajan JH, Bryan WW. A placebo-controlled trial of recombinant human ciliary neurotrophic (rh CNTF) factor in amyotrophic lateral sclerosis. Ann Neurol 1966; 39:256–60Google Scholar
  19. 19.
    Eisen A. Therapeutic opportunities in amyotrophic lateral sclerosis. Neurologist 1996; 2: 85–95Google Scholar
  20. 20.
    Cohen G, Werner P. Free radicals, oxidative stress, and neurodegeneration. In: Calne DB, editor. Neurodegenerative diseaese. Philadelphia: W.B. Saunders Co, 1994: 139–61Google Scholar
  21. 21.
    Olanow CW, Arendash GW. Metals and free radicals in neurodegeneration. Curr Opin Neurol; 1994; 7: 548–58PubMedGoogle Scholar
  22. 22.
    Sardesai VM. Role of antioxidants in health maintenance. Nutr Clin Pract 1995; 10: 19–25PubMedGoogle Scholar
  23. 23.
    Sohal RS, Kua HH, Agarwal S, et al. Oxidative damage, mitochondrial oxidant generation and antioxidant defenses: during aging and in response to food restriction in the mouse. Mech Ageing Dev 1994; 74: 121–33PubMedGoogle Scholar
  24. 24.
    Bowling AC, Schulz JB, Brown RH Jr, et al. Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1993; 61: 2322–5PubMedGoogle Scholar
  25. 25.
    Robberecht W, Sapp P, Kristina M, et al. Cu/Zn superoxide dismutase activity in familial and sporadic amyotrophic lateral sclerosis. J Neurochem 1994; 62: 384–7PubMedGoogle Scholar
  26. 26.
    Duval C, Poelman MC. Scavenger effect of vitamin E and derivatives on free radicals generated by photoirradiated pheomelamin. J Pharm Sci 1995; 84: 107–10PubMedGoogle Scholar
  27. 27.
    Tonstad S. Antiksidanter og hjerte-og karsykdom-epidemiologiske aspekter: bor tilskudd anbefales for hoyrisikopasienter? Tidsskr Nor Laegeforen 1995; 115: 227–9PubMedGoogle Scholar
  28. 28.
    Bellizzi MC, Franklin MF, Duthie GG, et al. Vitamin E and coronary heart disease: the European paradox. Eur J Clin Nutr 1994; 48: 822–31PubMedGoogle Scholar
  29. 29.
    Singh RB, Niaz MA, Bishnoi I, et al. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: the Peerzada Prospective Study. Acta Cardiol 1994; 49: 453–67PubMedGoogle Scholar
  30. 30.
    Vatassery GT. Vitamin E: neurochemistry and implications for neurodegeneration in Parkinson’s disease. Ann N Y Acad Sci 1992; 669: 97–109PubMedGoogle Scholar
  31. 31.
    Reider CR, Paulson GW. Lou Gehrig and amyotrophic lateral sclerosis: is Vitamin E to be revisited? Arch Neurol; 1997; 54: 527–8PubMedGoogle Scholar
  32. 32.
    Hideo T, Takashi A, Mika S, et al. A-tocopherol quinone level is remarkably low in the cerebrospinal fluid of patients with sporadic amyotrophic lateral sclerosis. Neurosci Lett 1996; 207: 5–8Google Scholar
  33. 33.
    Wu RM, Mohanakumar KP, Murphy DL, et al. Antioxidant mechanism and protection of nigral neurons against MPP+ toxicity by deprenyl (selegiline). Ann N Y Acad Sci 1994; 738: 214–21PubMedGoogle Scholar
  34. 34.
    Kitani K, Kanai S, Carrillo MC, et al. (−) Deprenyl increases the life span as well as activities of superoxide dismutase and catalase but not of glutathione peroxidase in selective brain regions in Fischer rats. Ann N Y Acad Sci 1994; 717: 60–71PubMedGoogle Scholar
  35. 35.
    Olanow CW. A rationale for monoamine oxidase inhibition as neuroprotective therapy for Parkinson’s disease. Mov Disord 1993; Suppl. 1: 1–7Google Scholar
  36. 36.
    Aquilonius SM, Jossan SS, Ekblom JG, et al. Increased binding of 3H-L-deprenyl in spinal cords from patients with amyotrophic lateral sclerosis. J Neural Transm 1992; 89: 111–22Google Scholar
  37. 37.
    Josson SS, Ekblom J, Aquilonius SM, et al. Monoamine oxidase-B in motor cortex and spinal cord in amyotrophic lateral sclerosis studied by quantitative autoradiography. J Neural Transm 1994; Suppl. 41: 243–8Google Scholar
  38. 38.
    Iwasaki Y, Ikeda K, Shiojima T, et al. Deprenyl enhances neurite outgrowth in cultured rat spinal ventral horn neurons. J Neurol Sci 1994; 125: 11–3PubMedGoogle Scholar
  39. 39.
    Lange DJ, Murphy PL, Diamond B, et al. Selegiline is ineffective in a collaborative double-blind, placebo-controlled trial for treatment of amyotrophic lateral sclerosis. Arch Neurol 1998; 55(1): 93–6PubMedGoogle Scholar
  40. 40.
    Josson SS, Ekblom J, Gudjonsson O, et al. Double blind crossover trial with deprenyl in amyotrophic lateral sclerosis. J Neural Transm 1994; 41: 237–41Google Scholar
  41. 41.
    Mazzini L, Testa D, Balzarini C, et al. An open-randomized clinical trial of selegiline in amyotrophic lateral sclerosis. J Neurol 1994; 241(4): 223–7PubMedGoogle Scholar
  42. 42.
    Rothstein JD, Bristol LA, Hosier B, et al. Chronic inhibition of superoxide dismutase produces apoptotic death in spinal neurons. Proc Natl Acad Sci U S A 1994; 91: 4155–9PubMedGoogle Scholar
  43. 43.
    Colton CA, Pagan F, Snell J, et al. Protection from oxidation enhances the survival of cultured mesencephalic neurons. Exp Neurol 1995; 132: 54–61PubMedGoogle Scholar
  44. 44.
    Khawli FA, Reid MB. N-acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro. J Appl Physiol 1994; 77: 317–24PubMedGoogle Scholar
  45. 45.
    Reid MB, Stokic DS, Koch SM, et al. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Invest 1994; 94: 2468–74PubMedGoogle Scholar
  46. 46.
    Louwerse ES, Weverling GJ, Bossuyt PMM, et al. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 1995; 52: 559–64PubMedGoogle Scholar
  47. 47.
    Lanthier A, Patwardhan VV. Sex steroids and 5-en-3b-hydroxysteroids in specific regions of the human brain and cranial nerves. J Steroid Biochem 1986; 25: 445–9PubMedGoogle Scholar
  48. 48.
    Beaulieu EE. Neurosteroids: a new function in the brain. Biol Cell 1991; 71: 3–10Google Scholar
  49. 49.
    Mathur C, Prasad VVK, Raju VS, et al. Steroids and their conjugates in the mammalian brain. Biochemistry 1993; 90: 85–8Google Scholar
  50. 50.
    Regelson W, Kalimi M. Dehydroepiandrosterone (DHEA): the multifunctional steroid. In: Pierpaoli W, Regelson W, Fabris N, editors. The aging clock: the pineal gland and other pacemakers in the progression of aging and carcinogenesis. Third Stromboli Conference on Aging and Cancer. Ann N Y Acad Sci 1994; 719: 564–72Google Scholar
  51. 51.
    Bird CE, Murphy J, Boroomand K, et al. Dehydroepiandrosterone: kinetics of metabolism in normal men and women. J Clin Endocrinol Metab 1978; 47: 818–22PubMedGoogle Scholar
  52. 52.
    Birkenhager-Gillesse EG, Derksen J, Lagaay AM. Dehydroepiandrosterone sulphate (DHEAS) in the oldest old aged 85 and over. In: Pierpaoli W, Regelson W, Fabris N, editors. The aging clock: the pineal gland and other pacemakers in the progression of aging and carcinogenesis. Third Stromboli Conference on Aging and Cancer. Ann N Y Acad Sci 1994; 719: 543–51Google Scholar
  53. 53.
    Eisen A, Pearmain J, Stewart H. Dehydroepiandrosterone sulphate (DHEAS) concentrations and amyotrophic lateral sclerosis. Muscle Nerve 1995; 18: 1481–3PubMedGoogle Scholar
  54. 54.
    Kalimi M, Regelson W, editors. The biological role of dehydroepiandrosterone (DHEA). New York: Walter de Gruyter, 1990Google Scholar
  55. 55.
    Friess E, Trachsel L, Guldner J, et al. DHEA administration increases rapid eye movement sleep and EEG power in the sigma frequency range. Am JPhysiol 1995; 268: (1): E107–13Google Scholar
  56. 56.
    Nasman B, Olsson T, Backstrom T, et al. Serum dehydroepiandrosterone sulphate in Alzheimer’s disease and multi-in-farct dementia. Biol Psychiatry 1991; 30: 684–90PubMedGoogle Scholar
  57. 57.
    Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994; 343: 1479–81PubMedGoogle Scholar
  58. 58.
    Flood JF, Smith GE, Roberts E. Dehydroepiandrosterone and its sulfate enhance memory retention in mice. Brain Res 1988; 447: 269–78PubMedGoogle Scholar
  59. 59.
    Mayo W, Delhi F, Robel P, et al. Infusion of neurosteroids into nucleus basalis magnocellularis affects cognitive processes in the rat. Brain Res 1993; 607: 324–8PubMedGoogle Scholar
  60. 60.
    Shaw PJ. Excitatory amino acid receptors, excitotoxicity, and the human nervous system. Curr Opin Neurol Neurosurg 1993; 6: 414–22PubMedGoogle Scholar
  61. 61.
    Zeman S, Lloyd C, Meldrum B, et al. Excitatory amino acids, free radicals and the pathogenesis of motor neuron disease. Neuropathol Appl Neurobiol; 1994; 20: 219–31PubMedGoogle Scholar
  62. 62.
    Leigh PN. Pathogenic mechanisms in amyotrophic lateral sclerosis and other motor neuron disorders. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia: WB Saunders, 1994: 473–88Google Scholar
  63. 63.
    Lipton SA, Rosenberg PA. Excitatory amino acids as a final common pathway for neurologic disorders. N Engl J Med 1994; 330: 613–22PubMedGoogle Scholar
  64. 64.
    Rothstein JD. Excitotoxicity hypothesis. Neurology 1996; 47Suppl. 2: S19–26PubMedGoogle Scholar
  65. 65.
    Rothstein JD, Martin LJ, Kuncl RW. Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 1992; 326: 1464–8PubMedGoogle Scholar
  66. 66.
    Rothstein JD, Martin L, Levey AI, et al. Localization of neuronal and glial glutamate transporters. Neuron 1994; 13: 713–25PubMedGoogle Scholar
  67. 67.
    Rothstein JD, Van Kammen M, Levey AI, et al. Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. Ann Neurol 1995; 38: 73–84PubMedGoogle Scholar
  68. 68.
    Arizza JL, Fairman WA, Wadiche JI, et al. Functional comparisons of three glutamate transporter subtypes cloned from human motor cortex. J Neurosci 1994; 14: 5559–69Google Scholar
  69. 69.
    Chien-Liang GL, Bristol LA, Jin L, et al. Aberrant RNA processing in a neurodegenerative disease: the cause of absent EAAT2, a glutamate transporter, in amyotrophic lateral sclerosis. Neuron 1998; 20: 589–602Google Scholar
  70. 70.
    Plaitakis A, Fesdjian CO, Shashidharan P. Glutamate antagonists in amyotrophic lateral sclerosis: a review of their therapeutic potential. CNS Drugs 1996; 5: 437–56Google Scholar
  71. 71.
    Gurney ME, Cutting FB, Zhai P. Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. Ann Neurol 1996; 39: 147–57PubMedGoogle Scholar
  72. 72.
    Gurney ME, Fleck TJ, Himes CS, et al. Riluzole preserves motor function in a transgenic model of familial amyotrophic lateral sclerosis. Neurology 1998; 50: 62–6PubMedGoogle Scholar
  73. 73.
    Horowski R, Wachtel H, Turski L, et al. Glutamate excitotoxicity as a possible pathogenic mechanism in chronic neurodegeneration. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia: W.B. Saunders Co., 1994; 163–75Google Scholar
  74. 74.
    Brodie MJ. Lamotrigine. Lancet 1992; 339: 1397–400PubMedGoogle Scholar
  75. 75.
    Eisen A, Stewart H, Cameron D, et al. Anti-glutamate therapy in amyotrophic lateral sclerosis using Lamotrigine. Can J Neurol Sci 1993; 20: 297–301PubMedGoogle Scholar
  76. 76.
    Hebert T, Drapeau P, Pradier L, et al. Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol 1994; 45: 1055–60PubMedGoogle Scholar
  77. 77.
    Hubert JP, Delumeau JC, Glowiniski J, et al. Antagonism by riluzole of entry of calcium evoked by NMD A and veratridine in rat cultured granule cells: evidence for dual mechanism of action. Br J Pharmacol 1994; 113: 261–7PubMedGoogle Scholar
  78. 78.
    Mantz J, Laudmbach V, Lecharny JB, et al. Riluzole, a novel antiglutamate, blocks GABA uptake by striatal synaptosomes. Eur J Pharmacol 1994; 257: R7–8PubMedGoogle Scholar
  79. 79.
    Rowland LP. Riluzole for the treatment of amyotrophic lateral sclerosis: too soon to tell? N Engl J Med 1994; 330: 636–7PubMedGoogle Scholar
  80. 80.
    Nakamura R, Kamakura K, Kwak S. Late onset selective damage in the rat spinal cord induced by continuous intrathecal administration of AMPA. Brain Res 1994; 654: 279–85PubMedGoogle Scholar
  81. 81.
    Shaw PJ, Chinnery RM, Ince PG. Non-NMD A receptors in motor neuron disease (MND): a quantitative autoradiographic study in spinal cord and motor cortex using [3H]CNQX and [3H]kainate. Brain Res 1994; 655: 186–94PubMedGoogle Scholar
  82. 82.
    Carriedo SG, Yin HZ, Weiss JH. Motor neurons are selectively vulnerable to AMPA/kainate receptor-mediated injury in vitro. J Neurosci 1996; 16: 4069–79PubMedGoogle Scholar
  83. 83.
    Ornstein PL, Arnold MB, Allen NK, et al. Structure-activity studies of 6-(tetrazolylalkyl)-substituted decahydroisoquinoline-3-carboxylic acid AMPA receptor antagonsits: 1. effects of stereochemistry, chain length, and chain substitution. J Med Chem 1996; 39: 2219–31PubMedGoogle Scholar
  84. 84.
    Yielding KL, Tomkins GM. An effect of L-leucine and other essential amino acids on the structure and activity of glutamic dehydrogenase. Proc Natl Acad Sci U S A 1961; 47: 983–9PubMedGoogle Scholar
  85. 85.
    Erecinska M, Nelson D. Activation of glutamate dehydrogenase by leucine and its non-metabolized analogue in rat brain synaptosomes. J Neurochem 1990; 65: 59–67Google Scholar
  86. 86.
    Plaitakis A, Constantakakis E, Smith J. The neuroexcitotoxic amino acids glutamate and aspartate are altered in the spinal cord and brain in amyotrophic lateral sclerosis. Ann Neurol 1998; 24: 446–9Google Scholar
  87. 87.
    Testa D, Caraceni T, Fetoni V. Branched-chain amino acids in the treatment of amyotrophic lateral sclerosis. J Neurol 1989; 236: 445–7PubMedGoogle Scholar
  88. 88.
    Plaitakis A, Sivak M, Fesdjian CO, et al. Treatment of amyotrophic lateral sclerosis with branched chain amino acids (BCAA): results of a second trial. Neurology 1992; 42Suppl. 3:454Google Scholar
  89. 89.
    Beghi E, the Italian ALS Study Group. Branched-chain amino acids and amyotrophic lateral sclerosis: a treatment failure? Neurology 1993; 43: 2466–70Google Scholar
  90. 90.
    Steiner T. Multinational trial of branched-chain amino acids in amyotrophic lateral sclerosis. Muscle Nerve 1994; Suppl. 1994; 1: S66Google Scholar
  91. 91.
    Tandan R, Bromberg MB, Forshew D, et al. A controlled trial of amino acid therapy in amyotrophic lateral sclerosis: I. clinical, functional, and maximum isometric torque data. Neurology 1996; 47: 1220–6PubMedGoogle Scholar
  92. 92.
    Rosenberg JM, Harrell C, Ristic H, et al. The effect of gabapentin on neuropathic pain. Clin J Pain 1997; 13(3): 251–5PubMedGoogle Scholar
  93. 93.
    Wetzel CH, Connelly JF. Use of gabapentin in pain management. Ann Pharmacother 1997; 31(9): 1082–3PubMedGoogle Scholar
  94. 94.
    Taylor CP. Emerging perspectives on the mechanism of action of gabapentin. Neurology 1994; 44Suppl. 5: S10–16PubMedGoogle Scholar
  95. 95.
    Miller RG, Moore D, Young LA, et al. A placebo-controlled trial of gabapentin in amyotrophic lateral sclerosis. Neurology 1996; 47: 1383–8PubMedGoogle Scholar
  96. 96.
    The Italian ALS Study Group. Ceftriaxone in amyotrophic lateral sclerosis. Eur J Neurol 1996; 3: 295–8Google Scholar
  97. 97.
    Smith LG. Improvement of patients with amyotrophic latreral sclerosis given ceftriaxone [letter]. Lancet 1992; 339: 1417PubMedGoogle Scholar
  98. 98.
    Carod-Artal FJ, Perez-Lopez-Fraile I, Gracia-Najam, et al. Failure of empirical treatment with ceftriaxone in motor neuron disease. Neurologia 1994; 9: 29–31PubMedGoogle Scholar
  99. 99.
    Robberecht W. Lack of improvement with ceftriaxone in motoneuron disease. Lancet 1992; 340: 1096–7PubMedGoogle Scholar
  100. 100.
    Smith LG. Failure of ceftriaxone for amyotrophic latreral sclerosis [letter]. Lancet 1992; 340: 379PubMedGoogle Scholar
  101. 101.
    Church J, Lodge D, Berry SC. Differential effects of dextrorphan and levorphan on the excitation of rat spinal neurons by amino acids. Eur J Pharmacol 1985; 111: 185–90PubMedGoogle Scholar
  102. 102.
    Choi DW, Peters S, Viseskul V. Dextrorphan and levorphanol selectively block N-methyl-D-aspartate receptor mediated neurotoxicity on cortical neurons. J Pharmacol Exp Ther 242: 713–20Google Scholar
  103. 103.
    Askmark H, Aquilonius SM, Gillberg PG, et al. A pilot trial of dextromethorphan in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 1993; 56: 197–200PubMedGoogle Scholar
  104. 104.
    Hollander D, Pradas J, Kaplan R, et al. High-dose dextromethorphan in amyotrophic lateral sclerosis: phase 1 safety and pharmacokinetic studies. Ann Neurol 1994; 36: 920–4PubMedGoogle Scholar
  105. 105.
    Appel SH, Smith RG, Engelhardt JI, et al. Evidence for autoimmunity in amyotrophic lateral sclerosis. J Neurol Sci 1993; 118: 169–74PubMedGoogle Scholar
  106. 106.
    Appel SH, Smith RG, Alexianu MF, et al. Autoimmunity as an etiological factor in sporadic amyotrophic lateral sclerosis. In: Searratrice G, Munsat T, editors. Pathogenesis and therapy of amyotrophic lateral sclerosis: advances in neurology. Vol. 68. Philadelphia: Lippincott-Raven Publishers, 1995: 47–57Google Scholar
  107. 107.
    Drachman DB, Fishman PS, Rothstein JD, et al. Amyotrophic lateral sclerosis: an autoimmune disease? In: Searratrice G, Munsat T, editors. Pathogenesis and therapy of amyotrophic lateral sclerosis: advances in neurology. Vol. 68. Philadelphia: Lippincott-Raven Publishers, 1995; 59–65Google Scholar
  108. 108.
    Drachman DB, Chaudhry V, Cornblath D, et al. Trial of immunosuppression in amyotrophic lateral sclerosis using total lymphoid irradiation. Ann Neurol 1994; 35: 142–50PubMedGoogle Scholar
  109. 109.
    McGeer EG, McGeer PL. Neurodegeneration and the immune system. In: Calne DB, editor. Neurodegenerative diseases. Philadelphia: WB Saunders Co., 1994: 277–99Google Scholar
  110. 110.
    McGeer PL, Rogers J, McGeer EG. Neuroimmune mechanisms in Alzheimer’s disease pathogenesis. Alz Dis Assoc Disord 1994; 8: 149–58Google Scholar
  111. 111.
    Breitner JC, Gau BA, Welsh KA, et al. Inverse association of anti-inflammatory treatments and Alzheimer’s disease: initial results of a co-twin control study. Neurology; 1994; 44: 227–32PubMedGoogle Scholar
  112. 112.
    Rich JB, Rasmusson DX, Carson KA, et al. Nonsteroidal anti-inflammatory drugs in Alzheimer’s disease. Neurology; 1995; 45: 51–5PubMedGoogle Scholar
  113. 113.
    Andersen K, Launer LJ, Ott A, et al. Do nonsteroidal anti-inflammatory drugs decrease the risk for Alzheimer’s disease? The Rotterdam study. Neurology 1995; 45: 1441–5PubMedGoogle Scholar
  114. 114.
    Rogers J, Kirby LC, Hempe SR, et al. Clinical trial of indomethacin in Alzheimer’s disease. Neurology 1993; 43: 1609–11PubMedGoogle Scholar
  115. 115.
    Hefti F. Neurotrophic factor therapy for nervous system degenerative diseases. J Neurobiol 1994; 25: 1418–35PubMedGoogle Scholar
  116. 116.
    Seeburger JL, Springer JE. Experimental rationale for the therapeutic use of neurotrophins in amyotrophic lateral sclerosis. Exp Neurol 1993; 124: 64–72PubMedGoogle Scholar
  117. 117.
    DiStefano PS. Neurotrophic factors in the treatment of motor neuron disease and trauma. Exp Neurol 1993; 124: 56–9PubMedGoogle Scholar
  118. 118.
    Lindholm D. Role of neurotrophins in preventing glutamate induced neuronal cell death. J Neurol 1994; 242Suppl. 1: 16–8Google Scholar
  119. 119.
    Gao W-Q, Dybdal N, Shinsky N, et al. Neurotrophin-3 reverses experimental cisplatin-induced peripheral sensory neuropathy. Ann Neurol 1995; 38: 30–7PubMedGoogle Scholar
  120. 120.
    Ikeda K, Klinkosz B, Greene T, et al. Effects of brain-derived neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann Neurol 1995; 37: 505–11PubMedGoogle Scholar
  121. 121.
    Lai EC, Felice KJ, Festoff BW, The North America ALS/IGF-I Study Group, et al. Effect of recombinant human insulin-like growth factor-1 on progression of ALS: a placebo-controlled study. Neurology 1997; 49(6): 1621–30PubMedGoogle Scholar
  122. 122.
    Borasio GD, de Jong JMBV, Emile J, the European ALS/IGF-I Study Group, et al. Insulin-like growth factor-1 in the treatment of amyotrophic lateral sclerosis: results of the European multicenter, double-blind, placebo-controlled trial. J Neurol Sci 1996; 243Suppl. 2: 26Google Scholar
  123. 123.
    Lotz B, Brooks B, Sanjak M, et al. A double blind placebo-controlled clinical trial of subcutaneous recombinant human ciliary neurotrophic factor (rHCNTF) in amyotrophic lateral sclerosis. Neurology 1996; 46: 1244–9Google Scholar
  124. 124.
    Dittrich F, Thoenen H, Sendtner M. Ciliary neurotrophic factor: pharmacokinetics and acute phase response in rat. Ann Neurol 1994; 35: 151–63PubMedGoogle Scholar
  125. 125.
    Longo FM. Will ciliary neurotrophic factor slow progression of motor neuron disease? Ann Neurol 1994; 36: 125–7PubMedGoogle Scholar
  126. 126.
    Sendtner M, Schmalbruch, Stockli KA, et al. Ciliary neurotrophic factor prevents degeneration of motor neurons in mouse mutant progressive moto-neuronopathy. Nature 1992; 358: 502–4PubMedGoogle Scholar
  127. 127.
    Mitsumoto H, Ikeda K, Holmlund T, et al. The effects of ciliary neurotrophic factor on motor dysfunction in wobbler mouse motor neuron disease. Ann Neurol 1994; 36: 142–8PubMedGoogle Scholar
  128. 128.
    Masu Y, Wolf E, Holtman B, et al. Disruption of the CNTF gene results in motor neuron degeneration. Nature 1993; 365: 27–32PubMedGoogle Scholar
  129. 129.
    Anand P, Cedarbaum J, Lindsay RM, et al. Marked depletion of ciliary neurotrophic factor in ventral horn of spinal cord but not cerebral motor cortex in amyotrophic lateral sclerosis [abstract]. Ann Neurol 1994; 36: 318Google Scholar
  130. 130.
    Carson MJ, Behringer RR, Brinster RL, et al. Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993; 10: 729–40PubMedGoogle Scholar
  131. 131.
    Adem A, Ekblom J, Gillberg PG, et al. Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis. J Neural Transm 1994; 97: 73–84Google Scholar
  132. 132.
    Gimenez-Gallego G, Cuevas P. Fibroblast growth factors, proteins with a broad spectrum of biological activities. Neurol Res 1994; 16: 212–316Google Scholar
  133. 133.
    Dore S, Krieger C, Kar S, et al. Distribution and levels of insulin-like growth factor (IGF-I and IGF-II) and insulin receptor binding sites in the spinal cords of amyotrophic lateral sclerosis (ALS) patients. Mol Brain Res 1996; 41: 128–33PubMedGoogle Scholar
  134. 134.
    Kishino A, Ishige Y, Tatsuno C, et al. BDNF prevents and reverses adult rat motor neuron degeneration and induces axonal outgrowth. Exp Neurol 1997; 144(2): 273–86PubMedGoogle Scholar
  135. 135.
    Fournier J, Steinberg R, Gauthier T, et al. Neuroprotective effects of SR57746A in central and peripheral models in rodents and primates. Neuroscience 1993; 55: 629–41PubMedGoogle Scholar
  136. 136.
    Nishi R. Neurotrophic factors: two are better than one. Science 1994; 265: 1052–3PubMedGoogle Scholar
  137. 137.
    Mitsumoto H, Ikeda K, Klinkosz B, et al. Arrest of motor neuron disease in wobbler mice cotreated with CNTF and BDNF. Science 1994; 265: 1107–10PubMedGoogle Scholar
  138. 138.
    Greenberg DA. Calcium channels and neuromuscular disease. Ann Neurol 1994; 35: 131–2PubMedGoogle Scholar
  139. 139.
    Miller RG, Smith SA, Murphy JR, et al. A clinical trial of verapamil in amyotrophic lateral sclerosis. Muscle Nerve 1996; 19: 511–5PubMedGoogle Scholar
  140. 140.
    Ziv I, Achiron A, Djaldetti R, et al. Can nimodipine affect progression of motor neuron disease? A double blind pilot study. Clin Neuropharmacol 1994; 17: 423–8PubMedGoogle Scholar
  141. 141.
    Miller RG, Shepherd R, Dao H, et al. Controlled trial of nimodipine in amyotrophic lateral sclerosis. Neuromuscular Disord 1996; 6: 101–4Google Scholar
  142. 142.
    Hopkins LC, Tatarian GT, Pianta TF. Management of ALS: respiratory care. Neurology; 1996; 47Suppl. 2: S123–5PubMedGoogle Scholar
  143. 143.
    Renston JP, DiMarco AF, Supinski GS. Respiratory muscle rest using nasal BiPAP ventilation in patients with stable severe COPD. Chest 1994; 105: 1053–60PubMedGoogle Scholar
  144. 144.
    Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospective trial of noninvasive positive pressure ventilation in acute respiratory failure. Am J Respir Crit Care Med 1995; 151: 1799–806PubMedGoogle Scholar
  145. 145.
    Elliott MW, Simonds AK. Nocturnal assisted ventilation using bilevel positive airway pressure: the effect of expiratory positive airway pressure. Eur Respir J 1995; 8: 436–40PubMedGoogle Scholar
  146. 146.
    Kasarskis EJ, Neville HE. Management of ALS: nutritional care. Neurology 1996; 47Suppl. 2: S118–20PubMedGoogle Scholar
  147. 147.
    Aisen ML, Sevilla D, Gibson G, et al. 3,4-Diaminopyridine as a treatment for amyotrophic lateral sclerosis. J Neurol Sci 1995; 129: 21–4PubMedGoogle Scholar
  148. 148.
    McClearn GE. Prospects for quantitative trait locus methodology in gerontology. Exp Gerontol 1997; 32: 49–54PubMedGoogle Scholar
  149. 149.
    Landman J, Kavaler E, Droller, et al. Applications of telomerase in urologic oncology. World J Urol 1997; 15: 120–4PubMedGoogle Scholar
  150. 150.
    Kruk PA, Balajee AS, Rao KS, et al. Telomere reduction and telomerase inactivation during neuronal cell differentiation. Biochem Biophys Res Commun 1996; 224: 487–92PubMedGoogle Scholar
  151. 151.
    Zakian VA. Telomeres: beginning to understand the end. Science 1995; 270: 1601–7PubMedGoogle Scholar
  152. 152.
    Yanagi K, Mochida A, Gotoh E. Telomere DNA and telomerase of lymphoma-derived cell lines: telomere hypothesis for cell growth control. Nippon Rinsho 1997; 55: 328–33PubMedGoogle Scholar
  153. 153.
    Harley CB, Sherwood SW. Telomerase, checkpoints and cancer. Cancer Surv 1997; 29: 263–84PubMedGoogle Scholar
  154. 154.
    Fisher LJ, Ray J. In vivo and ex vivo gene transfer to the brain. Curr Opin Neurobiol 1994; 4: 735–41PubMedGoogle Scholar
  155. 155.
    Kasahara N, Dozy AM, Kan YW. Tissue-specific targeting of retroviral vectors through ligand-receptor interactions. Science 1994; 266: 1373–6PubMedGoogle Scholar
  156. 156.
    Gimenez y Ribotta M, Revah F, Pradier L, et al. Prevention of motoneuron death by adenovirus-mediated neurotrophic factors. J Neurosci Res 1997; 48(3): 281–5PubMedGoogle Scholar
  157. 157.
    Aebischer P, Kato AC. Treatment of amyotrophic lateral sclerosis using gene therapy approach. Eur Neurol 1994; 35: 65–8Google Scholar
  158. 158.
    Aebischer P, Pochon NA, Heyd B, et al. Gene therapy for amyotrophic lateral sclerosis (ALS) using a polymer encapsulated xenogenic cell line engineered to secrete hCNTF. Human Gene Ther 1996; 7(7): 851–60Google Scholar
  159. 159.
    Rosenblad C, Martinez-Serrano A, Bjorklund A. Intrastriatal glial cell line-derived neurotrophic factor promotes sprouting of spared nigrostratal dopaminergic afferents and induces recovery of function in a rat model of Parkinson’s disease. Neuroscience 1998; 82(1): 129–37PubMedGoogle Scholar
  160. 160.
    Kaal EC, Joosten EA, Bar PR. Prevention of apoptotic motoneuron death in vitro by neurotrophins and muscle extract. Neurochem Int 1997; 31: 193–201PubMedGoogle Scholar
  161. 161.
    Thatte U, Dahanukar S. Apoptosis: clinical relevance and pharmacological manipulation. Drugs 1997; 54: 511–32PubMedGoogle Scholar
  162. 162.
    Lo AC, Houenou LJ, Oppenheim RW. Apoptosis in the nervous system: morphological features, methods, pathology, and prevention. Arch Histol Cytol 1995; 58: 139–49PubMedGoogle Scholar
  163. 163.
    Wang E. Regulation of apoptosis resistance and ontogeny of age-dependent diseases. Exp Gerontol 1997; 32: 471–84PubMedGoogle Scholar
  164. 164.
    Murphy AN, Bredesen DE, Cortopassi G, et al. Bcl-2 potentiates the maximal calcium uptake capacity of neural cell mitochondria. Proc Nat Acad Sci U S A 1996; 93: 9893–8Google Scholar
  165. 165.
    Tatton WG, Chalmers-Redman RM, Ju WY. et al. Apoptosis in neurodegenerative disorders: potential for therapy by modifying gene transcription. J Neural Transm 1997; Suppl. 49: 245–68Google Scholar
  166. 166.
    Snyder EY. Grafting immortalized neurons to the CNS. Curr Opin Neurobiol 1994; 4: 742–51PubMedGoogle Scholar
  167. 167.
    Snyder EY, Flax JD. Transplantation of neural progenitor and stem-like cells as a strategy for gene therapy and repair of neurodegenerative diseases. Ment Retard 1995; 1: 27–38Google Scholar
  168. 168.
    Snyder EY, Park KI, Flax JD, et al. Potential of neural ‘stem-like’ cells for gene therapy and repair of the degenerating central nervous system. Adv Neurol 1997; 72: 121–32PubMedGoogle Scholar
  169. 169.
    Martinez-Serrano A, Bjorklund A. Gene transfer to the mammalian brain using neural stem cells: a focus on trophic factors, neurodegeneration, and cholinergic neuron systems. Clin Neurosci 1995–96; 3: 301–9PubMedGoogle Scholar
  170. 170.
    Snyder EY, Macklis JD. Multipotential neural progenitor or stem-like cells may be uniquely suited for therapy for some neurodegenerative conditions. Clin Neurosci 1995–96 3: 310–6PubMedGoogle Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.The Neuromuscular Diseases UnitVancouver General Hospital and The University of British ColumbiaVancouverCanada

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