Levodopa Therapy for Parkinson's Disease: History, Current Status and Perspectives.

Parkinson's Disease (PD) is a neurodegenerative disorder characterized by a preferential degeneration of dopaminergic neurons in the substantia nigra pars compacta. This results in a profound decrease of striatal dopamine (DA) levels, which in turn leads to the cardinal motor symptoms of PD; muscle rigidity, hypo- and bradykinesia and resting tremor. Even 50 years after its initial use, the DA precursor levodopa (L-dopa), is still the most effective medical therapy for the symptomatic treatment of PD. Long-term L-dopa treatment is however, unfortunately associated with undesirable side effects such as motor fluctuations and dyskinesias. Furthermore, despite the disease alleviating effects of L-dopa, it is still discussed whether L-dopa has a neurotoxic or neuroprotective effect on dopaminergic neurons. Here we review the history of L-dopa, including its discovery, development and current use in the treatment of PD. We furthermore review current evidence of the L-dopa-induced side effects and perspectives of L-dopa treatment in PD compared to other established treatments such as DA-agonists and the inhibitors of catechol-o-methyltransferase and monoamine oxidase B.

Apomorphine and levodopa in Parkinson's disease: Two revolutionary drugs from the 1950's.

This article reviews the history of apomorphine and levodopa, which were both discovered in the 1950's and have revolutionized treatment paradigms of Parkinson's disease. Although the discovery of levodopa is a prime example of successful translation of basic neuroscience into clinical routine, the history of apomorphine was based on less solid evidence. Despite this, both drugs are, more than 6 decades after the first clinical experiments, still the two most efficacious medications to treat patients with Parkinson's disease. New and promising delivery strategies for both levodopa and apomorphine are currently under investigation to further improve clinical responses.

Harbinger of storm: influence of Oliver Sacks on levodopa therapy in early 1970s.

Most known by his literary ability, the words of the neurologist Oliver Sacks (1933-2015) also had an impact on scientific community about the role of levodopa on parkinsonisms. Different from the most authors and based on his experience described on the book "Awakenings", he had a pessimistic opinion about levodopa, which was related on many articles written by himself and colleagues in early 1970s. We reviewed the scientific contribution of Oliver Sacks associated to levodopa therapy on parkinsonisms, and how he advised caution with its complications before the majority of physicians.

Harbinger of storm: influence of Oliver Sacks on levodopa therapy in early 1970s / Arauto da tempestade: a influência de Oliver Sacks sobre a terapia com levodopa no início da década de 1970

ABSTRACT Most known by his literary ability, the words of the neurologist Oliver Sacks (1933-2015) also had an impact on scientific community about the role of levodopa on parkinsonisms. Different from the most authors and based on his experience described on the book “Awakenings”, he had a pessimistic opinion about levodopa, which was related on many articles written by himself and colleagues in early 1970s. We reviewed the scientific contribution of Oliver Sacks associated to levodopa therapy on parkinsonisms, and how he advised caution with its complications before the majority of physicians.

RESUMO Mais conhecido por sua habilidade literária, as palavras do neurologista Oliver Sacks (1933-2015) também tiveram um impacto sobre a comunidade científica a respeito do uso de levodopa nos parkinsonismos. Diferente da maioria dos autores e baseado em sua experiência única descrita no livro “Tempo de Despertar”, ele tinha uma opinião mais pessimista sobre a levodopa, que ficou relatada em uma série de artigos publicados por ele e colaboradores no início da década de 1970. Revisaremos a contribuição científica de Oliver Sacks referente ao tratamento dos parkinsonismos com levodopa, e como advertiu a cautela com as complicações decorrentes desta medicação antes da maioria dos médicos.

Four pioneers of L-dopa treatment: Arvid Carlsson, Oleh Hornykiewicz, George Cotzias, and Melvin Yahr.

Four individuals stand out as pioneers of the early work that led to levodopa becoming a revolutionary new treatment for Parkinson's disease: Arvid Carlsson, Oleh Hornykiewicz, George C. Cotzias, and Melvin D. Yahr. All four were MDs. The first three had extra training in pharmacology, and in fact did their research in pharmacology. The fourth was a clinical neurologist, the only one in this group with those credentials. The story starts with Carlsson, who became interested in studying the mechanism of reserpine's sedative effect, now recognized as a drug-induced parkinsonian state. A key experiment in 1957 showed that levodopa (l-dopa) could alleviate the immobility induced by reserpine in animals. Carlsson then showed that reserpine depleted brain dopamine, and that l-dopa restored it. Carlsson developed a sensitive fluorescent technique to measure dopamine levels, and his laboratory also showed the distribution of dopamine in animal brain to be highest in the striatum. Within a year, Carlsson postulated that dopamine appears to play a role in motor function. His proposal that dopamine serves as a neurotransmitter in brain was met with much skepticism, but he persisted and continued to study brain dopamine, eventually leading to being awarded the Nobel Prize in Medicine in 2000. Hornykiewicz also went into pharmacology research after graduating from medical school. Fortuitously, his assigned first project was on the blood pressure effects of dopamine, recognized as a precursor of norepinephrine. When he completed his postdoctoral studies, Carlsson's work on the reserpinized animal and on the regional distribution of brain dopamine was published. This inspired Hornykiewicz to determine dopamine levels in patients with Parkinson's disease. He obtained postmortem material, and his 1960 paper showed a marked depletion of dopamine in the striatum in this disorder. He went on in subsequent papers to correlate severity of parkinsonian features with the amount of striatal dopamine depletion. In the meantime, after his discovery of low dopamine in brains of patients with Parkinson's disease, Hornykiewicz persuaded Walther Birkmayer to inject l-dopa into patients. They reported success and continued this treatment, usually combining it with the use of a monoamine oxidase inhibitor. However, the response was limited in duration, and subsequent trials by others were not achieving similar success, and many failed to find any benefit. The fulfilment of the l-dopa story stemmed from the hypothesis held by Cotzias that Parkinson's disease was caused by loss of brain neuromelanin in the substantia nigra. Although Cotzias's research had been in pharmacology, he also headed a clinical pharmacology research group at a federal laboratory on Long Island, New York, USA. He decided to try to restore this pigment in patients, not animals, and one of the three drugs he tried was d,l-dopa. As reported in his 1967 article, d,l-dopa proved to be dramatically successful in reversing the symptoms, but at extremely high dosages and with considerable hematologic adverse effects. Cotzias immediately tested l-dopa and found the same benefit with half the dosage and without the hematologic problems. Yahr was a clinical neurologist who had been treating patients with PD with available therapy and also headed a federally financed research group investigating the disorder. Always on the lookout for potential new treatments, he was initially skeptical about l-dopa when studies with low doses were being reported. Seeing videos of patients presented by Cotzias, however, he realized that the results needed confirmation through a double-blind controlled clinical trial. He proceeded to develop and execute such a trial with l-dopa, duplicating Cotzias's success. Both Cotzias and Yahr had encountered motor fluctuations and dyskinesias, but the amelioration of bradykinesia, rigidity, and tremor was so pronounced that these adverse effects did not prevent regulatory approval of l-dopa, and almost 50 years later l-dopa remains the most effective pharmacologic agent for treating Parkinson's disease. This article relates the personal stories of these four pioneers and how they achieved their success.

Walther Birkmayer, Co-describer of L-Dopa, and his Nazi connections: victim or perpetrator?

Walther Birkmayer, an Austrian neurologist, codiscovered the efficacy of levodopa therapy for Parkinsonism in 1961. However, little has been published regarding Birkmayer's ties to National Socialism. Through documentary review, we have determined that he was an early illegal member of the SS and the Nazi party, taking part in the "de-Jewification" of the Vienna University Clinic of Psychiatry and Neurology. He also was a leader in the Nazi racial policy office and was praised for his dedication and fanaticism despite being forced to later resign from the SS. He sought support from leading Viennese Nazis, and was able to maintain his professional status for the war's remainder. Postwar, he succeeded at reintegration personally and professionally into Austrian society, all but erasing any obvious ties to his Nazi past. His story reflects ethical transgressions regarding professional and personal behavior in response to a tyrannical regime and provides lessons for today's neuroscientists.

Gait disturbances in Parkinson disease. Did freezing of gait exist before levodopa? Historical review.

Gait disturbances occur frequently in advanced Parkinson's disease (PD) including slow gait, postural changes, festination and freezing of gait. We have reviewed descriptions of gait abnormalities in PD from classic predopa-literature and compared them with those found in contemporary references. Several components of gait disturbances associated with shaking palsy were very well known in classic literature. James Parkinson, Charcot, Gowers and Wilson described slowness of gait, postural changes, loss of postural reflexes and festination; according to James Parkinson, festination was a pathognomonic element in shaking palsy. In contrast, freezing of gait was rarely mentioned in historic literature save for anecdotal reports (Buzzard 1888). Freezing of gait was fully noticed after the chronic use of levodopa (Barbeau and Ambani). In this historical review, we analyze the concept, identification and evolution of gait disturbances in PD through the time.

A brief history of levodopa.

This article highlights some landmarks in the history of levodopa, beginning with its isolation in 1910-13 from seedlings of Vicia faba to the demonstration, in 1961, of its "miraculous" effect in patients with Parkinson's disease (PD). Midway between these two time points, in 1938, L: -dopa decarboxylase was discovered, the enzyme that produces dopamine (DA) from levodopa. In 1957, DA was shown to occur in the brain, and in 1959 it was found to be enriched in the basal ganglia. At that time the striatal localization of DA, together with studies done in 1957-58 in naive and reserpine-treated animals regarding DA in the brain and the central effects of levodopa, suggested its possible involvement in "extrapyramidal control" and "reserpine parkinsonism". Following these discoveries, a study of (postmortem) brains of patients with basal ganglia disorders, including PD, was started, demonstrating, in 1960, a severe striatal DA deficit specifically in PD, thus furnishing a rational basis for the concept of "DA replacement therapy" with levodopa. Accordingly, in 1961, the first highly successful clinical trial with i.v. levodopa was carried out. In 1963, the DA deficit in the PD substantia nigra was found, indicative of a nigrostriatal DA pathway in the human brain, subsequently established in animal studies in 1964-65. In 1967, the chronic, high dose oral levodopa regimen was introduced in treatment of PD. Besides the above highlights in the history of levodopa, the article also cites critical opinions of world authorities in brain research of the time, harmful to the cause of DA, levodopa and PD. Today, the concept of DA replacement with levodopa is uncontested, with levodopa being the "gold standard" of modern drug treatment of PD.

Levodopa: past, present, and future.

Levodopa has been the mainstay of treatment for Parkinson's disease (PD) for more than 40 years. During this time, researchers have strived to optimize levodopa formulations to minimize side effects, enhance central nervous system (CNS) bioavailability, and achieve stable therapeutic plasma levels. Current strategies include concomitant treatment with inhibitors of dopa decarboxylase (DDC) and catechol-O-methyltransferase (COMT) to prolong the peripheral levodopa half-life and increase CNS bioavailability. Levodopa combined with DDC inhibition is the current standard method of delivering levodopa for symptomatic treatment of PD. Recent research suggests that continuous dopaminergic stimulation that more closely approximates physiological stimulation may delay or prevent the development of motor fluctuations ('wearing off') and dyskinesias. Strategies currently being used to achieve more continuous dopaminergic stimulation include the combination of an oral levodopa/DDC inhibitor with a COMT inhibitor and the enteral infusion of a levodopa gel formulation. Attempts are underway to develop oral and transdermal very long-acting levodopa preparations.

L-dopa therapy for Parkinson's disease: past, present, and future.

Dopamine (DA) supplementation therapy by l-dopa for Parkinson's disease (PD) was established around 1970. The dose of l-dopa can be reduced by the combined administration of inhibitors of peripheral l-amino acid decarboxylase (AADC), catechol O-methyltransferase (COMT), or monoamine oxidase B (MAO B). DA in the striatum may be produced from exogenously administered l-dopa by various AADC-containing cells, such as serotonin neurons. The long-term administration of l-dopa in PD patients may produce l-dopa-induced dyskinesia (LID), which may be due to chronic overstimulation of supersensitive DA D1 receptors. l-dopa may be used in combination with various new strategies such as gene therapy or transplantation in the future.

The history of dopamine and levodopa in the treatment of Parkinson's disease.

The discoveries of dopamine as a neurotransmitter in the brain, its depletion in patients with Parkinson disease, and its replacement with levodopa therapy were major revolutionary events in the rise to effective therapy for patients with this disorder. This review describes these events and the persons who carried out these accomplishments. Their impact went beyond a single clinical entity of parkinsonism, for it opened up the beginning of a much better understanding of the role of dopamine in other neurologic movement disorders and also in many psychiatric diseases.