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Clinical Pharmacokinetics of Drugs for Alzheimer’s Disease

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  • Drug Disposition
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Summary

Pharmacological treatment of patients with Alzheimer’s disease is becoming more important, as evidenced by the number of drugs being developed in different countries. It has been shown in the majority of clinical trials that cholinesterase inhibitors, such as tacrine (tetrahydroaminoacridine), are able to induce beneficial effects in cognition and memory.

Tacrine, like most of the other oral antidementia agents, is rapidly absorbed from the gastrointestinal tract. It is excreted mainly through the kidney, with a terminal elimination half-life of about 3 hours. Tacrine has nonlinear pharmacokinetics and there are large interindividual differences in pharmacokinetic parameters after oral, intravenous and rectal administration. A positive relationship between cognitive changes and plasma tacrine concentrations has been recently described. Similarly, velnacrine exhibits evidence of nonlinearity in some pharmacokinetic parameters, but renal excretion is a minor route of elimination for this drug. Pharmacokinetic data pertaining to eptastigmine, a third cholinesterase inhibitor, is more limited. However, the drug is rapidly distributed to the tissues after oral administration and readily enters the central nervous system, where it can be expected to effectively inhibit acetylcholinesterase in the brain for a prolonged period.

Pharmacokinetic data for the nootropic agents are more limited. However, of the 3 agents reviewed only pramiracetam penetrates the central nervous system (CNS) poorly. Indeed, oxiracetam crosses the blood-brain barrier and persists for longer in the CNS than in the serum.

Selegiline (deprenyl), a neuroprotective agent, is readily absorbed from gastrointestinal tract. It is metabolised mainly in the liver, and to a minimal extent in the lung or kidneys. The steady-state concentrations of metabolites inthe cerebrospinal fluid (CSF) and serum are very similar, reflecting their easy penetration into the CNS. Idebenone, another neuroprotective agent, likewise is rapidly absorbed and achieves peak concentrations in the brain comparable to those in plasma. Similarly, CSF concentrations of metabolites of ST 200 (acetyl-L-carnitine) parallel those in plasma, suggesting that they easily cross the blood-brain-barrier.

Gangliosides (GM1) can be given intramuscularly or subcutaneously, but the latter route of administration provides a concentration 50% higher both in the serum and the ganglioside fraction. However, because of its longer elimination, the intramuscular route is the best form of administration when the brain is the target organ for the treatment.

Absorption of nimodipine is quite rapid. The pharmacokinetics of nimodipine during multiple-dose treatment have not been studied extensively; however, the drug does not appear to accumulate during repeated administration of standard doses. Nimodipine has linear pharmacokinetics and is subject to interindividual variability. It is primarily excreted in the urine, but 32% of the dose is excreted in the faeces, possibly as a consequence of biliary excretion.

To achieve adequate drug concentrations in the brain, different methods have been devised, both invasive (implantable drug infusion pumps and polymer drug-delivery systems, neural transplantation, etc.) and noninvasive (prodrugs microencapsulated within biocompatible polymers that can protect the drug from degradation, etc.) methods. These methods may provide more effective drug delivery into the CNS, and pharmacokinetic data should be determined when these methods of drug delivery are being assessed in clinical trials.

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References

  1. Bowen DM, Smith CB, White P, et al. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other abiotrophies. Brain 1976; 99: 459–96

    PubMed  CAS  Google Scholar 

  2. Bowen DM, Steele JE, Lowe SL, et al. Tacrine in relation to aminoacid transmitters in Alzheimer’s disease. In: Wurtman RJ, editor. Advances in neurology. Vol. 51. Alzheimer’s disease. New York: Raven Press, 1990; 91–6

    Google Scholar 

  3. Davies P, Maloney AJ. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet II: 1976; 1403

    Google Scholar 

  4. Brodie DC, Way EL, Lowenhaupt E. Studies on 9-aminoacridine antagonism of morphine and related drugs. Arch Int Pharmacodynam 1952; 89: 2–9

    Google Scholar 

  5. Summers WK, Viesselman JO, Marsh GM, et al. Use of THA in the treatment of Alzheimer-like dementia: pilot study in twelve patients. Biol Psychiatr 1981; 16: 145–53

    CAS  Google Scholar 

  6. Summers WK, Majovski LV, Marsh GM, et al. Oral tetrahydroaminoacridine in long-term treatment of senile dementia, Alzheimer type. New Engl J Med 1986; 315: 1241–5

    PubMed  CAS  Google Scholar 

  7. Gauthier S, Masson H, Gauthier L, et al. Tetrahydroaminoacridine and lecithin in Alzheimer’s disease. In: Giacobini E, Becker R, editors. Current research in Alzheimer therapy. New York: Taylor & Francis, 1988; 237–46

    Google Scholar 

  8. Forsyth DR, Surmon DJ, Morgan RA, et al. Clinical experience with and side-effects of tacrine hydrochloride in Alzheimer’s disease: a pilot study. Age Ageing 1989; 18: 223–9

    PubMed  CAS  Google Scholar 

  9. Fitten LJ, Perryman KM, Gross PL, et al. Treatment of Alzheimer’s disease with short- and long-term oral THA and lecithin: a double-blind study. Am J Psychiatr 1990; 147: 239–42

    PubMed  CAS  Google Scholar 

  10. Åhlin A, Nybäck H, Junthé T, et al. Tetrahydroaminoacridine in Alzheimer’s dementia: clinical and biochemical results of a double-blind crossover trial. Human Psychopharmacol 1991; 6: 109–8

    Google Scholar 

  11. Eagger SA, Levy R, Sahakian BJ. Tacrine in Alzheimer’s disease. Lancet 337: 1991; 989–92

    PubMed  CAS  Google Scholar 

  12. Davis KL, Thal LJ, Gamzu ER, et al. A double-blind, placebo-controlled multicenter study of tacrine for Alzheimer’s disease. New Engl J Med 1992; 237: 1253–9

    Google Scholar 

  13. Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer’s disease. JAMA 1992; 68: 2523–9

    Google Scholar 

  14. Wilcock GK, Surmon DJ, Scott M, et al. An evaluation of the efficacy and safety of tetrahydroaminoacridine (THA) without lecithin in the treatment of Alzheimer’s disease. Age Ageing 1993;22:316–324

    PubMed  CAS  Google Scholar 

  15. Wilcock GK, Scott H, Pearsall T. Long-term use of tacrine. Lancet 1994; 343: 294

    PubMed  CAS  Google Scholar 

  16. 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; 271: 985–91

    PubMed  CAS  Google Scholar 

  17. Davies B, Andrewes D, Stargatt R, et al. Tacrine in Alzheimer’s disease. Lancet II: 1989; 163–4

    Google Scholar 

  18. Chatellier G, Lacomblez L. Tacrine (tetrahydroaminoacridine;THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. BMJ 1990; 300: 495–9

    PubMed  CAS  Google Scholar 

  19. Gauthier S, Bouchard R, Lamontagne A, et al. Tetrahydroamino-acridine-lecithin combination treatment in patients with intermediate-stage Alzheimer’s disease. Results of a Canadian double-blind, crossover, multicentre study. New Engl J Med 1990; 322: 1272–6

    PubMed  CAS  Google Scholar 

  20. Molloy WD, Guyatt GH, Wilson DB, et al. Effect of tetrahydroaminoacridine on cognition, function and behavior in Alzheimer’s disease. Can Med Assoc J 1991; 144: 29–34

    CAS  Google Scholar 

  21. Maltby N, Broe GA, Creasey H, et al. Efficacy of tacrine and lecithin in mild to moderate Alzheimer’s disease: double blind trial. BMJ 1994; 308: 879–83

    PubMed  CAS  Google Scholar 

  22. Ford JM, Truman CA, Wilcock GK, et al. Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer’s disease. Clin Pharmacol Therapeut 1993; 53: 691–5

    CAS  Google Scholar 

  23. Summers WK, Tachiki KH, Kling A. Tacrine in the treatment of Alzheimer’s disease: a clinical update and recent pharmacologic studies. Eur Neurol 1989; 29: 28–32

    PubMed  Google Scholar 

  24. Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994; 271: 992–8

    PubMed  CAS  Google Scholar 

  25. McNally W, Roth M, Young R, et al. Quantitative whole-body autoradiographic determination of tacrine tissue distribution in rats following intravenous or oral dose. Pharmaceut Res 1989; 6: 924–30

    CAS  Google Scholar 

  26. Nybäck H, Nyman H, Öhman G, et al. Preliminary experiences and results with THA for the amelioration of symptoms of Alzheimer’s disease. In: Giacobini E, Becker R, editors. Current research in Alzheimer therapy. New York: Taylor & Francis, 1988; 231–6

    Google Scholar 

  27. Forsyth DR, Wilcock GK, Morgan RA, et al. Pharmacokinetics of tacrine hydrochloride in Alzheimer’s disease. Clin Pharmacol Therapeut 1989; 46: 634–41

    CAS  Google Scholar 

  28. Hartvig P, Askmark H, Aquilonius SM, et al. Clinical pharmacokinetis of intravenous and oral 9-amino-l,2,3,4-tetrahydroaminoacridine tacrine. Eur J Clin Pharmacol 1990; 38: 259–63

    PubMed  CAS  Google Scholar 

  29. Cutler NR, Sedman AJ, Prior P, et al. Steady-state pharmacokinetics of tacrine in patients with Alzheimer’s disease. Psychopharmacol Bull 1990; 26: 231–4

    PubMed  CAS  Google Scholar 

  30. Åhlin A, Adem A, Junthé T, et al. Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer patients. Int Clin Psychopharmacol 1992; 7: 29–36

    PubMed  Google Scholar 

  31. 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: 948–55

    PubMed  CAS  Google Scholar 

  32. Murphy MF, Hardiman ST, Nash RJ, et al. Evaluation of HP 029 (velnacrine maleate) in Alzheimer’s disease. Ann NY Acad Sci 1991; 253–62

    Google Scholar 

  33. Brufani M, Marta M, Pomponi M. Anticholinesterase activity of a new carbamate, heptylphysostigmine, in view of its use in patients with Alzheimer-type dementia. Eur J Biochem 1986; 157: 115–20

    PubMed  CAS  Google Scholar 

  34. Brufani M, Castellano C, Marta M, et al. A long-lasting cholinesterase inhibitor affecting neural and behavioral processes. Pharmacol Biochem Behav 1987; 26: 625–9

    PubMed  CAS  Google Scholar 

  35. De Sarno P, Pomponi M, Gacobini E, et al. The effect of heptylphysostigmine, a new cholinesterase inhibitor, on the central cholinergic system of the rat. Neurochem Res 1989; 14:971–7

    PubMed  Google Scholar 

  36. Marta M, Castellano C, Oliverio A, et al. New analogs of physostigmine: alternative drugs for Alzheimer’s disease? Life Sci 1988; 43: 1921–8

    PubMed  CAS  Google Scholar 

  37. Unni LK, Hutt V, Imbimbo BP, et al. Kinetics of cholinesterase inhibition of eptastigmine in man. Eur J Clin Pharmacol 1991; 41: 83–4

    PubMed  CAS  Google Scholar 

  38. Segre G, Cerretani D, Baldi A, et al. Pharmacokinetics of heptastigmine in rats. Pharmacol Res 1992; 25: 139–46

    PubMed  CAS  Google Scholar 

  39. Auteri A, Mosca A, Lattuada N, et al. Pharmacodynamics and pharmacokinetics of eptastigmine in elderly subjects. Eur J Clin Pharmacol 1993; 45: 373–6

    PubMed  CAS  Google Scholar 

  40. Becker RE, Colliver J, Elble R, et al. Effects of metrifonate, along-acting cholinesterase inhibitor in Alzheimer disease: report of an open trial. Drug Develop Res 1990; 19: 425–34

    Google Scholar 

  41. Trovanelli G, Gaiti A, De Medio GE, et al. Biochemical studies on the nootropic drug, oxirocetam, in brain. Clin Neuropharmacol 1986; 9Suppl. 3: 56–64

    Google Scholar 

  42. Spignoli G, Pedata F, Giovannelli L, et al. Effect of oxiracetam and piracetam on central cholinergic mechanisms and active-avoidance acquisition. Clin Neuropharmacol 1986; 9Suppl. 3: 39–47

    Google Scholar 

  43. Pugliese AM, Corradetti R, Ballerini L, et al. Effect of the nootropic drug oxiracetam on field potentials of rat hippocampal slices. Br J Pharmacol 1990; 99: 189–93

    PubMed  CAS  Google Scholar 

  44. Ponzio F, Pozzi O, Banfi S, et al. Brain entry and direct central pharmacological effects of the nootropic drug oxiracetam. Pharmacopsychiatry 1989; 22Suppl. 2: 11–5

    Google Scholar 

  45. Itil TM, Menon GN, Songar A, et al. CNS pharmacology and clinical therapeutic effects of oxiracetam. Clin Neuropharmacol 1984; 9Suppl. 3: 70–2

    Google Scholar 

  46. Saletu B, Linzmayer L, Grunberger J, et al. Double-blind, placebo-controlled, clinical, psychometric and neurophysiological investigations with oxiracetam in the Organic Brain Syndrome of late life. Neuropsychobiology 1985; 13: 44–52

    PubMed  CAS  Google Scholar 

  47. Villardita C, Parini J, Quattropani M, et al. Clinical and neuropsychological study with oxiracetam versus placebo in patients with mild to moderate dementia. J Neural Transm Suppl 1987; 24: 293–8

    PubMed  CAS  Google Scholar 

  48. Parnetti L, Mecocci P, Petrini A, et al. Neuropsychological results of long-term therapy with oxiracetam in DAT/MID patients in comparison to a control group. Neuropsychobiology 1989; 22: 97–100

    PubMed  CAS  Google Scholar 

  49. Perucca E, Albrici A, Gatti G, et al. Pharmacokinetics of oxiracetam following intravenous and oral administration in healthy volunteers. Eur J Drug Metab Pharmacokinet 1984; 3: 267–74

    Google Scholar 

  50. Parnetti L, Mecocci P, Gaiti A, et al. Comparative kinetics of oxiracetam in serum and CSF of patients with dementia of Alzheimer type. Eur J Drug Metab Pharmacokinet 1990; 15: 75–8

    PubMed  CAS  Google Scholar 

  51. Poschel BPH, Marriott JG, Gluckman MI. Phrmacology of the cognition activator pramiracetam (CI-879). Drug Exp Clin Res 1983; 9: 853–71

    CAS  Google Scholar 

  52. Pugsley TA, Shih YH, Coughenour L, et al. Some neurochemical properties of pramiracetam (CI-879), a new cognition-enhancing agent. Drug Develop Res 1983; 3: 407–20

    CAS  Google Scholar 

  53. Funk KF, Schmidt J. Zur cholinergen Wirkung von Nootropika. Biomed Biochim Acta 1988; 47: 417–21

    PubMed  CAS  Google Scholar 

  54. Claus JJ, Ludwig C, Mohr E, et al. Nootropic drugs in Alzheimer’s disease: symptomatic treatment with pramiracetam. Neurology 1991; 41: 570–4

    PubMed  CAS  Google Scholar 

  55. Martin JR, Haefely WE. Pharmacology of aniracetam: a novel pyrrolidinone derivative with cognition enhancing activity. Drug Invest 1993; 5Suppl. 1: 4–49

    Google Scholar 

  56. Lee CR, Benfield P. Aniracetam: an overwiew of its pharmacodynamic and pharmacokinetic properties, and a review of its therapeutic potential in senile cognitive disorders. Drugs Aging 1994; 4: 1–15

    Google Scholar 

  57. Amakusa T, Lizuka R, Kuruma I, et al. Transfer to cerebrospinal fluid of aniracetam in cerebrovascular disease. J Clin Therapeut Med 1987;3:381–92

    Google Scholar 

  58. Mayersohn M, Roncari G, Wendt G. Disposition pharmacokinetics and metabolism of aniracetam in animals. Drug Invest 1993; 5Suppl. 1:73–95

    Google Scholar 

  59. Heinonen EH, Rinne UK. Selegiline in the treatment of Parkinson’s disease. Acta Neurol Scand 1989; 126: 103–11

    CAS  Google Scholar 

  60. Knoll J. The possible mechanism of action of (–)-deprenyl in Parkinson’s disease. J Neural Transmission 1978; 43: 177–98

    CAS  Google Scholar 

  61. Cohen G. Monoamine oxidase and oxidative stress at dopaminergic synapses. J Neural Transm Suppl 1990; 32: 229–38

    PubMed  CAS  Google Scholar 

  62. Magyar K, Tothfalusi L. Pharmacokinetic aspects of deprenyl effects. Pol J Pharmacol Pharm 1984; 36: 373–84

    PubMed  CAS  Google Scholar 

  63. Benakis A. Pharmacokinetic study in man of l4C Jumex. Study report. Data on file, Farmos Group Ltd Research Center, 1981

    Google Scholar 

  64. Reynolds GP, Elsworth JD, Blau K, et al. Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978; 6: 542–4

    PubMed  CAS  Google Scholar 

  65. 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; 17: 129–36

    Google Scholar 

  66. Heinonen EH, Myllylä V, Sotaniemi K, et al. Pharmacokinetics and metabolism of selegiline. Acta Neurol Scand 1989; 126: 93–9

    CAS  Google Scholar 

  67. Reynolds GP, Riederer P, Sandler M. 2-Phenylethylamine and amphetamine in human brain: effects of l-deprenyl in Parkinson’s disease. Biochem Soc Trans 1979; 7: 143–5

    PubMed  CAS  Google Scholar 

  68. Hosein EA, Booth SJ, Gasoi I, et al. Neuromuscular blocking activity and other pharmacological properties of various carnitine derivates. J Pharmacol Exp Therapeut 1967; 156: 565–72

    CAS  Google Scholar 

  69. Hiersemenzel R, Dietrich B, Hermann WM. Therapeutic and EEG-effects of acetyl-L-carnitine in elderly outpatients with mild to moderate cognitive decline. Results of two double-blind placebo-controlled studies. In: Agnoli A, Cahn J, Lassen N, et al. editors. Senile dementias: 2nd International Symposium: 1988 Nov 2–4; Rome. Paris: John Libbey Eurotext, 1988; 427–31

    Google Scholar 

  70. Cucinotta D, Passeri M, Ventura S, et al. Multicenter clinical placebo-controlled study with acetyl-L-carnitine in the treatment of mildly demented elderly patients. Drug Develop Res 1988; 14: 213–6

    Google Scholar 

  71. Fritz JB. Carnitine and its role in fatty acids metabolism. Adv Lipid Res 1963; 1:285–334

    PubMed  CAS  Google Scholar 

  72. Falchetto S, Kato G, Provini L. The action of carnitines in cortical eurons. Can J Physiol Pharmacol 1971; 49: 1–7

    PubMed  CAS  Google Scholar 

  73. Onofri M, Bodis-Wollner I, Pola P, et al. Central cholinergic effects of levo-acetylcarnitine. Drugs Exp Clin Res 1983; 9: 161–9

    Google Scholar 

  74. Perez Polo JR, Werrbach-Perez K, Ramacci et al. Role of nerve growth factors in neurological disease. In: Agnoli A, Cahn J, Lassen N, et al., editors. Senile dementias: 2nd International Symposium: 1988 Nov 2–4; Rome. Paris: John Libbey Eurotext, 1988; 15–25

    Google Scholar 

  75. Angelucci L, Ramacci AT, Amenta F. Acetyl-L-carnitine in the rat’s hippocampus aging: morphological, endocrine and behavioural correlates. In: Gorio A, Perez Polo JR, De Velis J, et al., editor. Neural development and regeneration. NATO ASI Series. Vol. H22. Berlin: Springer, 1988; 57–66

    Google Scholar 

  76. Parnetti L, Gaiti A, Mecocci P, et al. Effect of acetyl-L-carnitine on serum levels of Cortisol and adrenocorticotropic hormone and its clinical effect in patients with senile dementia of Alzheimer type. Dementia 1990; 1: 165–8

    Google Scholar 

  77. Nappi G, Martignoni E, Sinforiani E, et al. Systemic acetyl-L-carnitine normalizes pituitary-adrenocortical hyperactivity in pathological ageing brain. Med Sci Res 1988; 16: 291–2

    CAS  Google Scholar 

  78. Calvani M, Carta A. Clues to the mechanism of action of acetyl-L-carnitine in the central nervous system. Dementia 1991; 2: 1–6

    Google Scholar 

  79. Marzo A, Arrigoni Martelli E, Cardace G, et al. Pharmacokinetics of acetyl-L-carnitine after i.v. administration in healthy volunteers and dogs. Trois J Mediterran Pharmacinet Cap D’Adge: 1988; 19–21

    Google Scholar 

  80. Marzo A, Arrigoni Martelli E, Urso R, et al. Metabolism and disposition of intravenously administered acetyl-L-carnitine in healthy volunteers. Eur J Clin Pharmacol 1989; 37: 59–63

    PubMed  CAS  Google Scholar 

  81. Kelly JG, Hunt S, Doyle GD, et al. Pharmacokinetics of oral acetyl-L-carnitine in renal impairment. Eur J Clin Pharmacol 1990; 38: 309–12

    PubMed  CAS  Google Scholar 

  82. Parnetti L, Gaiti A, Cadini D, et al. Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type. Eur J Clin Pharmacol 1992; 42: 89–93

    PubMed  CAS  Google Scholar 

  83. Fishman PH, Brady RO. Distribution and function of gangliosides. Science 1976; 194: 906–15

    PubMed  CAS  Google Scholar 

  84. Ledeen RW. Biology of gangliosides: neuritogenic and neuronotrophic properties. J Neurosci Res 1984; 12: 147–59

    PubMed  CAS  Google Scholar 

  85. Toffano G, Agnati LF, Fuxe KC. The effect of the ganglioside GM1 on neuronal plasticity: gangliosides as modulators of neurotrophic interactions. Int J Development Neurosci 1986; 4: 97–101

    CAS  Google Scholar 

  86. Toffano G, Savoini G, Moron F, et al. GM1 ganglioside stimulates the regeneration of dopaminergic neurons in the central norvous system. Brain Res 1983; 261: 163–6

    PubMed  CAS  Google Scholar 

  87. Karpiak SE, Li YS, Aceto P, et al. Acute effects of gangliosides on CNS injury. In: Tettamanti G, et al. editors. Gangliosides and neuronal plasticity. Padua: Liviana Press, 1986; 407–14

    Google Scholar 

  88. Oderfeld-Novak B, Gradkowska M, Zaremba M, et al. In: Ledeen RW, Hogan EL, Tellamanti G, et al., editors. New trends in ganglioside research: neurochemical and neuroregenerative aspects. Fidia Research Series, Vol. 14. Padua: Liviana Press, 1988; 567–77

  89. Gottfries GC, Adolfsson R, Aquilonius S-M, et al. Biochemical changes in dementia disorders of Alzheimer type (AD/SDAT). Neurobiol Aging 1983; 4: 261–71

    PubMed  CAS  Google Scholar 

  90. Svennerholm L. Ganglioside loss is a primary event in Alzheimer disease type I. Prog Brain Res 1994; 101: 391–404

    PubMed  CAS  Google Scholar 

  91. Tettamanti G, Venerando B, Roberti S, et al. The fate of exogenously administered brain gangliosides. In: Rapport MM, Gorio A, editors. Gangliosides and neuromuscular function, development and repair. New York: Raven Press, 1981; 225–40

    Google Scholar 

  92. Lang W. Pharmacokinetic sudies with 3H-labelled exogenous gangliosides injected intramuscularly into rats. In: Rapport MM, Gorio A, editors. Gangliosides and neuromuscular function, development and repair. New York: Raven Press, 1981; 241–51

    Google Scholar 

  93. Svennerholm L, Gottfries CG, Blennow K, et al. Parenteral administration of GM1 ganglioside to presenile Alzheimer patients. Acta Neurol Scand 1990; 81: 48–53

    PubMed  CAS  Google Scholar 

  94. Schwarzmann G. A simple and novel method for tritium labelling of gangliosides and other sphingolipids. Biochim Biophys Acta 1978; 529: 106–14

    PubMed  CAS  Google Scholar 

  95. Nagaoka A, Suno M, Shibota M, et al. Effects of idebenone on neurological deficits, local cerebral blood flow and energy metabolism in rats with experimental cerebral ischemia. Arch Gerontol Geriatr 1989; 8: 193–202

    PubMed  CAS  Google Scholar 

  96. Nagai Y, Yoshida K, Narumi S, et al. Brain distribution of idebenone and its effect on local cerebral glucose utilization in rats. Arch Gerontol Geriatr 1989; 8: 257–72

    PubMed  CAS  Google Scholar 

  97. Zs.-Nagy I. Chemistry, toxicology, pharmacology and pharmacokinetics of idebenone: a review. Arch Gerontol Geriatr 1990; 11: 177–86

    PubMed  CAS  Google Scholar 

  98. Boni J, Maugeri A, Zingali G, et al. Steady-state pharmacokinetics of idebenone in healthy volunteers. Arch Gerontol Geriatr 1992; 15: 197–206

    PubMed  CAS  Google Scholar 

  99. Rämsch K-D, Graefe K-H, Scherling D, et al. Pharmacokinetics and metabolism of calcium-blocking agents nifedipine, nitrendipine and nimodipine. Am J Nephrol 1986; 6: 73–80

    PubMed  Google Scholar 

  100. Kirch W, Rämsch K-D, Dührsen U, et al. Clinical pharmacokinetics of nimodipine in normal and impaired renal function. Int J Clin Pharmaceut Res 1984; 4: 381–4

    CAS  Google Scholar 

  101. Rämsch K-D, Ahr G, Tettenborn D, et al. Overview on pharmacokinetics of nimodipine in healthy volunteers and in patients with subarachnoid hemorrhage. Neurochirurgia 1985; 28: 74–8

    PubMed  Google Scholar 

  102. Rämsch K-D, Lücker PW, Wetzelsburger N. Pharmacokinetics of intravenously and orally administered nimodipine. Clin Pharmacol Therapeut 1987; 41: 216

    Google Scholar 

  103. Saltiel E, Ellrodt AG, Monk JO, et al. Feldopine. a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension. Drugs 1988; 36: 387–428

    PubMed  CAS  Google Scholar 

  104. Kamath B, Lettieri J, Krol G, et al. Pharmacokinetics and metabolism of radiolabeled nimodipine. Pharmacol Res 1987; 4Suppl. 2: 607

    Google Scholar 

  105. Suwelack D, Weber H. Assessment of enterohepatic circulation of radioactivity following a single dose of 14C nimodipine in the rat. Eur J Drug Metab Pharmacokinet 1985; 10: 231–9

    PubMed  CAS  Google Scholar 

  106. Harbaugh RE. Novel CNS-directed drug delivery systems in Alzheimer’s disease and other neurological disorders. Neurobiol Aging 1989; 10: 623–9

    PubMed  CAS  Google Scholar 

  107. Harbaugh RE. Intracerebroventricular cholinergic drug administration in Alzheimer’s disease: preliminary results of a double-blind study. J Neural Transmission 1987; 24 Suppl.: 271–7

    CAS  Google Scholar 

  108. Pardridge WM. Strategies for drug delivery through the blood-brain barrier. Neurobiol Aging 1989; 10: 636–7

    PubMed  CAS  Google Scholar 

  109. Brewter ME. Noninvasive drug delivery to the brain. Neurobiol Aging 1989; 10: 638–9

    Google Scholar 

  110. Peterson GM. Sustained and controlled release of neuroactive substances in the CNS by encapsulation into implantable polymers. Neurobiol Aging 1989; 10: 639–40

    PubMed  CAS  Google Scholar 

  111. Langer R, Brem H, Langer LF. New directions in CNS drug delivery. Neurobiol Aging 1989; 10: 642–4

    PubMed  CAS  Google Scholar 

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  1. Section of Gerontology and Geriatrics, Department of Clinical Medicine, Pathology and Pharmacology, University of Perugia, Via Eugubina 42, 06122, Perugia, Italy

    Lucilla Parnetti

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Parnetti, L. Clinical Pharmacokinetics of Drugs for Alzheimer’s Disease. Clin. Pharmacokinet. 29, 110–129 (1995). https://doi.org/10.2165/00003088-199529020-00005

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