Clinical Autonomic Research

, Volume 11, Issue 4, pp 235–242 | Cite as

l-threo-dihydroxyphenylserine (l-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: A multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure

  • Christopher J. Mathias
  • Jean-Michel Senard
  • Stefan Braune
  • Laura Watson
  • Atsushi Aragishi
  • Joelle E. A. Keeling
  • Michael D. Taylor
Research Article


This study was designed to determine the efficacy and tolerability of increasing doses ofl-threo-dihydroxyphenylserine (l-threo-DOPS) in treating symptomatic orthostatic hypotension associated with multiple system atrophy (MSA) and pure autonomic failure (PAF). Following a one-week run-in, patients (26 MSA; 6 PAF) with symptomatic orthostatic hypotension received increasing doses ofl-threo-DOPS (100, 200 and 300 mg, twice daily) in an open, dose-ranging study. Incremental dose adjustment (after weeks two and four of outpatient treatment) was based on clinical need until blood pressure (BP), and symptoms improved. Final dosage was maintained for six weeks. Withl-threo-DOPS, systolic BP decrease was reduced during orthostatic challenge (−22±28 mm Hg reduction from a baseline decrease of 54.3±27.7 mm Hg, p=0.0001, n=32; supine systolic BP at final visit was 118.9±28.2 mm Hg). By the end of the study, 25 patients (78%) improved, and in 14 patients (44%) orthostatic hypotension was no longer observed. Decreased orthostatic systolic BP decrease occurred in 22% (7/32), 24% (6/25) and 61% (11/18) of patients treated with 100, 200, and 300 mgl-threo-DOPS twice daily, respectively. An improvement occurred in symptoms associated with orthostatic hypotension, such as light-headedness, dizziness (p=0.0125), and blurred vision (p=0.0290).l-threo-DOPS was well tolerated, with the 2 serious adverse events reported being a possible complication of the disease under study, and with no reports of supine hypertension. I conclusion,l-threo-DOPS (100, 200, and 300 mg, twice daily) was well tolerated. The dosage of 300 mg twice dailyl-threo-DOPS seemed to offer the most effective control of symptomatic orthostatic hypotension in MSA and PAF.

Key words

l-threo-DOPS neurogenic orthostatic hypotension multiple system atrophy (MSA, Shy-Drager syndrome) pure autonomic failure (PAF) 


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  1. 1.
    Mathias CJ. Disorders of the autonomic nervous system. In:Neurology in clinical practice. 3rd ed. Bradley WG, Daroff RB, Fenichel GM, et al., eds. Boston: Butterworth Heinemann; 2000. pp. 2131–2165.Google Scholar
  2. 2.
    Luukinen H, Herala M, Koski K, et al. Rapid increase of fall-related severe head injuries with age among older people: a population-based study.J Am Geriatr Soc 1999; 47(12):1451–1452.PubMedGoogle Scholar
  3. 3.
    Mathias CJ, Kimber JR. Postural hypotension: causes, clinical features, investigation and management.Annu Rev Med 1999; 50:317–336.PubMedGoogle Scholar
  4. 4.
    Kaufmann H. Could treatment with DOPS do for autonomic failure what DOPA did for Parkinson's disease?Neurology 1996; 47:1370–1371.PubMedGoogle Scholar
  5. 5.
    Mathias CJ and Bannister R. Dopamine beta-hydroxylase deficiency. InAutonomic failure. A textbook of clinical disorders of the autonomic nervous system, 4th ed. Mathias CJ, Bannister R, eds. Oxford and New York: Oxford University Press; 1999. pp. 387–401.Google Scholar
  6. 6.
    Suzuki T, Azuma T, Araki S, et al. Treatment of autonomic dysfunction with L-threo-3-4-dihydroxyphenylserine (L-DOPS) in patients with familial amyloidotic polyneuropathy: A multicentre study. In:Amyloid and amyloidosis. Isobe T, Araki S, Uchino F, et al., eds. New York and London: Plenum Press; 1988. pp. 851–856.Google Scholar
  7. 7.
    Carvalho MJ, van den Meiracker AH, Boomsma F, et al. Improved orthostatic tolerance in familial amyloidotic polyneuropathy with unnatural noradrenaline precursor L-threo-3,4-dihydrophenylserine.J Auton Nerv Syst 1997; 62:63–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Sobue I, Senda Y, Hirayama K, et al. Clinical pharmacological evaluation of L-threo-3-4-dihydroxyphenylserine (L-DOPS) in Shy-Drager's syndrome and its related diseases. A nation-wide double-blind comparative study.Jpn J Clin Exp Med 1987; 141:353–378.Google Scholar
  9. 9.
    Freeman R, Landsberg L, Young J. The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine: a randomised, placebo-controlled, crossover trial.Neurology 1999; 53(9):2151–2157.PubMedGoogle Scholar
  10. 10.
    Narabayashi H, Nakanishi T. Therapeutic effects of L-DOPS in Parkinson's disease, double-blind comparative study against placebo as control in patients with long-term levodopa therapy.Clin Eval 1987; 15:423–457.Google Scholar
  11. 11.
    May CN, Ham IW, Heslop K, et al. Intravenous morphine causes hypertension, hyperglycaemia and increases sympatho-adrenal activity in the conscious rabbit.Clin Sci 1988; 75:71–77.PubMedGoogle Scholar
  12. 12.
    Suzuki T, Higa S, Sakoda S, et al. Pharmacokinetic studies of oral L-threo-3,4-dihydroxyphenylserine in normal subjects and patients with familial amyloid polyneuropathy.Eur J Clin Pharmacol 1982; 23:463–468.CrossRefPubMedGoogle Scholar
  13. 13.
    Committee for Proprietary Medicinal Products. Points to consider on missing data.CPMP/EWP/1776/99 draft. London, January 25, 2001.Google Scholar
  14. 14.
    Mathias CJ, Mallipeddi R, Bleasdale-Barr K. Symptoms associated with orthostatic hypotension in pure autonomic failure and multiple system atrophy.J Neurol 1999; 246(10):893–898.CrossRefPubMedGoogle Scholar
  15. 15.
    Kachi T, Iwase S, Mano T, et al. Effect of L-threo-3,4-dihydroxyphenylserine on muscle sympathetic nerve activity in Shy-Drager syndrome.Neurology 1988; 38:1091–1094.PubMedGoogle Scholar
  16. 16.
    Mathias CJ. Autonomic disorders and their recognition.N Engl J Med 1997; 10:721–724.Google Scholar
  17. 17.
    Low PA, Gilden JL, Freeman R, et al. for the Midodrine Study Group. Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension.JAMA 1997; 277(13):1046–51.CrossRefPubMedGoogle Scholar

Copyright information

© Lippincott Williams & Wilkins 2001

Authors and Affiliations

  • Christopher J. Mathias
    • 1
    • 5
  • Jean-Michel Senard
    • 3
  • Stefan Braune
    • 4
  • Laura Watson
    • 1
  • Atsushi Aragishi
    • 2
  • Joelle E. A. Keeling
    • 2
  • Michael D. Taylor
    • 2
  1. 1.Neurovascular Medicine Unit, Division of NeuroScience and Psychological MedicineImperial College of Science, Technology and Medicine at St Mary'sLondonU.K.
  2. 2.Autonomic Unit National Hospital of Neurology and Neurosurgery, Institute of NeurologyUniversity CollegeLondonU.K.
  3. 3.Laboratoire de Pharmacologie Medicale et Clinique, INSERM U 317Faculté de MédecineToulouseFrance
  4. 4.Department of NeurologyUniversity of FreiburgFreiburgGermany
  5. 5.(Clinical Research) Sumitomo Pharmaceuticals UKLondonU.K.

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