Levodopa therapy for Parkinson disease

Although levodopa is widely recognized as the most effective therapy for Parkinson disease (PD), its introduction 5 decades ago was preceded by several years of uncertainty and equivocal clinical results. The translation of basic neuroscience research by Arvid Carlsson and Oleh Hornykiewicz provided a logical pathway for treating PD with levodopa. Yet the pioneering clinicians who transformed PD therapeutics with this drug—among them Walther Birkmayer, Isamu Sano, Patrick McGeer, George Cotzias, Melvin Yahr, and others—faced many challenges in determining whether the concept and the method for replenishing deficient striatal dopamine was correct. This article reviews highlights in the early development of levodopa therapy. In addition, it provides an overview of emerging drug delivery strategies that show promise for improving levodopa's pharmacologic limitations.

[1]  S. Fahn.  The history of dopamine and levodopa in the treatment of Parkinson's disease , 2008, Movement disorders : official journal of the Movement Disorder Society.

[2]  W Birkmayer,et al.  The effect of l-3,4-dihydroxyphenylalanine (=DOPA) on akinesia in parkinsonism. , 1998, Parkinsonism & related disorders.

[3]  A. Carlsson,et al.  Treatment of Parkinson's with L-DOPA. The early discovery phase, and a comment on current problems , 2002, Journal of Neural Transmission.

[4]  C. Markham,et al.  Parkinson's disease and levodopa. A five-year follow-up and review. , 1974, The Western journal of medicine.

[5]  Stanley Friedman,et al.  DOPAMINE-β-HYDROXYLASE , 1965 .

[6]  L. Verhagen Metman,et al.  Gastroretentive carbidopa/levodopa, DM‐1992, for the treatment of advanced Parkinson's disease , 2015, Movement disorders : official journal of the Movement Disorder Society.

[7]  B. Boshes.  Sinemet and the treatment of Parkinsonism. , 1981, Annals of internal medicine.

[8]  A. Carlsson.  Monoamine-depleting drugs. , 1975, Pharmacology & therapeutics. Part B: General & systematic pharmacology.

[9]  A. Espay,et al.  Norepinephrine deficiency in Parkinson's disease: The case for noradrenergic enhancement , 2014, Movement disorders : official journal of the Movement Disorder Society.

[10]  F. Mcdowell,et al.  Five years' treatment of Parkinson's disease with levodopa. Therapeutic results and survival of 100 patients. , 1975, Annals of internal medicine.

[11]  M. Hely,et al.  Sydney multicenter study of Parkinson's disease: Non‐L‐dopa–responsive problems dominate at 15 years , 2005, Movement disorders : official journal of the Movement Disorder Society.

[12]  M. Guggenheim.  Dioxyphenylalanin, eine neue Aminosäure aus Vicia faba. , 2022 .

[13]  N. Hillarp,et al.  Release of adenosine triphosphate along with adrenaline and noradrenaline following stimulation of the adrenal medulla. , 1956, Acta physiologica Scandinavica.

[14]  C. Fehling.  TREATMENT OF PARKINSON'S SYNDROME WITH L‐DOPA A DOUBLE BLIND STUDY , 1966 .

[15]  P. Lewitt,et al.  Levodopa therapy for Parkinson's disease: Pharmacokinetics and pharmacodynamics , 2015, Movement disorders : official journal of the Movement Disorder Society.

[16]  P. Holtz,et al.  Über das sympathicomimetische pressorische Prinzip des Harns („Urosympathin“) , 2004, Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie.

[17]  W H Oldendorf,et al.  Kinetic analysis of blood-brain barrier transport of amino acids. , 1975, Biochimica et biophysica acta.

[18]  R. Capildeo,et al.  Research progress in Parkinson's disease , 1981 .

[19]  F. Mcdowell,et al.  Levodopa therapy in athetoid cerebral palsy , 1972, Neurology.

[20]  J. Nutt,et al.  The long-duration response to levodopa: phenomenology, potential mechanisms and clinical implications. , 2011, Parkinsonism & related disorders.

[21]  L. Hansson,et al.  Long‐term intraduodenal infusion of a water based levodopa‐carbidopa dispersion in very advanced Parkinson's disease , 1998, Acta neurologica Scandinavica.

[22]  W. Umbach,et al.  Die Wirksamkeit von L-Dopa bei Parkinson-Patienten mit und ohne stereotaktischen Hirneingriff , 1964, Archiv für Psychiatrie und Nervenkrankheiten.

[23]  S. Fahn,et al.  Mental effects of high-dosage levodopa. , 1971, Archives of general psychiatry.

[24]  O. Hornykiewicz,et al.  Weitere experimentelle Untersuchungen über L-DOPA beim Parkinson-Syndrom und Reserpin-Parkinsonismus , 1964, Archiv für Psychiatrie und Nervenkrankheiten.

[25]  Å. Bertler,et al.  Occurrence and distribution of catechol amines in brain. , 1959, Acta physiologica Scandinavica.

[26]  S. Udenfriend,et al.  TYROSINE HYDROXYLASE. THE INITIAL STEP IN NOREPINEPHRINE BIOSYNTHESIS. , 1964, The Journal of biological chemistry.

[27]  C. Marsden,et al.  SUCCESS AND PROBLEMS OF LONG-TERM LEVODOPA THERAPY IN PARKINSON'S DISEASE , 1977, The Lancet.

[28]  C. Charlton,et al.  L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease. , 2011, Life sciences.

[29]  D. Jennings,et al.  Pharmacokinetic‐pharmacodynamic crossover comparison of two levodopa extension strategies , 2009, Movement disorders : official journal of the Movement Disorder Society.

[30]  S. Fahn,et al.  Levodopa in the treatment of Parkinson's disease: A consensus meeting viewpoint , 1999, Movement disorders : official journal of the Movement Disorder Society.

[31]  J. Hirschmann,et al.  Zur Beeinflussung der Akinese und anderer extrapyramidal-motorischer Störungen mit L-Dopa (L-Dihydroxyphenylalanin) , 1964 .

[32]  M. Sandler.  Catecholamine Synthesis and Metabolism in Man: Clinical Implications (With Special Reference to Parkinsonism) , 1972 .

[33]  C. Markham,et al.  Recent advances in Parkinson's disease. , 1971, Contemporary neurology series.

[34]  O. Hornykiewicz.  Dopamine miracle: From brain homogenate to dopamine replacement , 2002, Movement Disorders.

[35]  T. Sourkes,et al.  Excretion of Dopamine in Diseases of Basal Ganglia , 1961, Science.

[36]  Current Concepts in the Treatment of Parkinsonism. , 1961, Canadian Medical Association journal.

[37]  O. Hornykiewicz,et al.  [Distribution of noradrenaline and dopamine (3-hydroxytyramine) in the human brain and their behavior in diseases of the extrapyramidal system]. , 1998, Klinische Wochenschrift.

[38]  A. Carlsson,et al.  3,4-Dihydroxyphenylalanine and 5-Hydroxytryptophan as Reserpine Antagonists , 1957, Nature.

[39]  R. Duvoisin,et al.  Treatment of parkinsonism with levodopa. , 1969, Archives of neurology.

[40]  M. Yahr.  Drugs Five Years Later: Levodopa , 1975 .

[41]  O. Hornykiewicz,et al.  [The L-3,4-dioxyphenylalanine (DOPA)-effect in Parkinson-akinesia]. , 1961, Wiener klinische Wochenschrift.

[42]  R. Wilkins,et al.  The use of Rauwolfia serpentina in hypertensive patients. , 1953, The New England journal of medicine.

[43]  F. Mcdowell,et al.  L-Dopa and Parkinsonism , 1970 .

[44]  M. Yahr.  Treatment of Parkinsonism : the role of dopa decarboxylase inhibitors , 1973 .

[45]  O. Hornykiewicz.  [The tropical localization and content of noradrenalin and dopamine (3-hydroxytyramine) in the substantia nigra of normal persons and patients with Parkinson's disease]. , 1963, Wiener klinische Wochenschrift.

[46]  A. Carlsson,et al.  The occurrence, distribution and physiological role of catecholamines in the nervous system. , 1959, Pharmacological reviews.

[47]  O. Hornykiewicz,et al.  [ADDITIONAL EXPERIMENTAL STUDIES ON L-DOPA IN PARKINSON'S SYNDROME AND RESERPINE PARKINSONISM]. , 1964, Archiv fur Psychiatrie und Nervenkrankheiten.

[48]  K. Fuxe,et al.  DEMONSTRATION AND MAPPING OUT OF NIGRO-NEOSTRIATAL DOPAMINE NEURONS. , 1964, Life sciences.

[49]  Y. Kakimoto,et al.  Distribution of catechol compounds in human brain. , 1959, Biochimica et biophysica acta.

[50]  M. Stacy,et al.  Extended-release carbidopa-levodopa (IPX066) compared with immediate-release carbidopa-levodopa in patients with Parkinson's disease and motor fluctuations: a phase 3 randomised, double-blind trial , 2013, The Lancet Neurology.

[51]  J. Ahlskog.  Drugs for the Treatment of Parkinson's Disease (Handbook of Experimental Pharmacology, Vol 88) , 1990 .

[52]  K J Zilkha.  The Clinical Uses of Levodopa , 1976 .

[53]  P. LeWitt.  The Pharmacology of Levodopa in Treatment of Parkinson’s Disease: An Update , 1989 .

[54]  E. Tobach,et al.  Dihydroxyphenylalanine in extrapyramidal disease. , 1963, JAMA.

[55]  N. Mercuri,et al.  Dual effects of l-DOPA on nigral dopaminergic neurons , 2013, Experimental Neurology.

[56]  R. Hassler,et al.  Parkinson-Specific Motor and Mental Disorders: Role of the Pallidum : Pathophysiological, Biochemical, and Therapeutic Aspects , 1983 .

[57]  G C Cotzias,et al.  Modification of Parkinsonism--chronic treatment with L-dopa. , 1969, The New England journal of medicine.

[58]  Å. Bertler,et al.  Occurrence and distribution of dopamine in brain and other tissues , 1959, Experientia.

[59]  Prosody and levodopa in Parkinson's disease. , 2013, Arquivos de neuro-psiquiatria.

[60]  S. Fahn,et al.  Newer medical treatment in parkinsonism. , 1970, The Medical clinics of North America.

[61]  P. Riederer,et al.  Parkinson’s Disease: Biochemistry, Clinical Pathology, and Treatment , 1983 .

[62]  Hassler Rg.  Chairman's introduction: role of the pallidum and its transmitters in the therapy of parkinsonian rigidity and akinesia. , 1984, Advances in neurology.

[63]  K. Oster,et al.  Effects of Intravenous Injections of L-Dopa upon Blood Pressure.∗ , 1942 .

[64]  F. Gerstenbrand,et al.  Erfahrungen mit L-Dopa in der Therapie des Parkinsonismus , 1963 .

[65]  L. Schiffer,et al.  Aromatic amino acids and modification of parkinsonism. , 1967, The New England journal of medicine.

[66]  P. Mcgeer,et al.  ADMINISTRATION OF DIHYDROXYPHENYLALANINE TO PARKINSONIAN PATIENTS. , 1964, Canadian Medical Association journal.

[67]  G. Stern,et al.  Angiography in Cerebro-Arterial Occlusive Diseases , 1980 .

[68]  R. Frowein,et al.  Über die Wirkungen des L-Dopa beim Menschen und deren Beeinflussung durch Reserpin, Chlorpromazin, Iproniazid und Vitamin B6 , 1960, Klinische Wochenschrift.

[69]  S. Illarioshkin,et al.  Pharmacokinetics of Levodopa/Carbidopa Delivered From Gastric‐Retentive Extended‐Release Formulations in Patients With Parkinson's Disease , 2012, Journal of clinical pharmacology.

[70]  P. LeWitt.  New levodopa therapeutic strategies. , 2016, Parkinsonism & related disorders.

[71]  R. N. Brogden,et al.  Levodopa: A Review of its Pharmacological Properties and Therapeutic Uses with Particular Reference to Parkinsonism , 2012, Drugs.

[72]  S. Fahn.  The medical treatment of Parkinson disease from James Parkinson to George Cotzias , 2015, Movement disorders : official journal of the Movement Disorder Society.

[73]  A. Lees,et al.  The impact of treatment with levodopa on Parkinson's disease. , 1980, The Quarterly journal of medicine.

[74]  P. Mcgeer,et al.  Drug-induced extrapyramidal reactions. Treatment with diphenhydramine hydrochloride and dihydroxyphenylalanine. , 1961, JAMA.

[75]  J. Presthus,et al.  APPRAISAL OF LONG‐TERM LEVODOPA TREATMENT OF PARKINSONISM WITH SPECIAL REFERENCE TO THERAPY LIMITING FACTORS , 1974, Acta neurologica Scandinavica.

[76]  C. Tanner,et al.  Levodopa and the progression of Parkinson's disease. , 2004, The New England journal of medicine.

[77]  F. Mcdowell,et al.  Second Canadian-American conference on Parkinson's Disease , 1974 .

[78]  U. Rinne,et al.  A Double Blind Study of l-Dopa Treatment in Parkinson's Disease , 1968 .

[79]  R. Hauser,et al.  Double‐blind study of the actively transported levodopa prodrug XP21279 in Parkinson's disease , 2014, Movement disorders : official journal of the Movement Disorder Society.

[80]  K. Aebert.  Was leistet L-Dopa bei der Behandlung der Parkinson-Akinese?* , 1967 .

[81]  G. Linazasoro,et al.  Dopaminergic agonists in Parkinson's disease. , 2014, Neurologia.

[82]  P. Rosenberg,et al.  Iron‐Mediated Oxidation of 3,4‐Dihydroxyphenylalanine to an Excitotoxin , 1995, Journal of neurochemistry.

[83]  D. Calne.  Progress in the treatment of Parkinsonism , 1973 .

[84]  M. Greer,et al.  Dopamine metabolism in Parkinson's disease , 1963, Neurology.

[85]  Susan H Fox,et al.  Clinical spectrum of levodopa‐induced complications , 2015, Movement disorders : official journal of the Movement Disorder Society.

[86]  E. Tolosa,et al.  Four pioneers of L‐dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr , 2015, Movement disorders : official journal of the Movement Disorder Society.