Levodopa Therapy for Parkinson Disease: a Look Backward and Forward

Henry Ford Health System <a href="/goto?url=https://scholarlycommons.henryford.com/" target="_blank">Henry Ford Health System Scholarly Commons </a><a href="/goto?url=https://scholarlycommons.henryford.com/neurology_articles" target="_blank">Neurology Articles </a>4-5-2016 <a href="/goto?url=https://scholarlycommons.henryford.com/neurology" target="_blank">Neurology </a>Levodopa therapy for Parkinson disease: A look backward and forward Peter A. LeWitt Henry Ford Health System, [email protected] Stanley Fahn Henry Ford Health System Follow this and additional works at: <a href="/goto?url=https://scholarlycommons.henryford.com/neurology_articles?utm_source=scholarlycommons.henryford.com%2Fneurology_articles%2F276&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">https:</a><a href="/goto?url=https://scholarlycommons.henryford.com/neurology_articles?utm_source=scholarlycommons.henryford.com%2Fneurology_articles%2F276&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">/</a><a href="/goto?url=https://scholarlycommons.henryford.com/neurology_articles?utm_source=scholarlycommons.henryford.com%2Fneurology_articles%2F276&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">/</a><a href="/goto?url=https://scholarlycommons.henryford.com/neurology_articles?utm_source=scholarlycommons.henryford.com%2Fneurology_articles%2F276&utm_medium=PDF&utm_campaign=PDFCoverPages" target="_blank">scholarlycommons.henryford.com/neurology_articles </a>Recommended Citation LeWitt PA, and Fahn S. Levodopa therapy for Parkinson disease: A look backward and forward. Neurology 2016; 86(14 Suppl 1):S3-s12. This Article is brought to you for free and open access by the Neurology at Henry Ford Health System Scholarly Commons. It has been accepted for inclusion in Neurology Articles by an authorized administrator of Henry Ford Health System Scholarly Commons. Levodopa therapy for Parkinson disease A look backward and forward Peter A. LeWitt, MD Stanley Fahn, MD ABSTRACT 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. Neurology® 2016;86 (Suppl 1):S3–S12 Correspondence to Dr. LeWitt: <a href="mailto:[email protected]" target="_blank">[email protected] </a>GLOSSARY CNS 5 central nervous system; PD 5 Parkinson disease; TOPA 5 2,4,5-trihydroxyphenylalanine. Among neurodegenerative diseases, Parkinson disease (PD) is unique in having several highly effective medications for suppressing its signs and symptoms. Heading the list of treatment options over the past 5 decades has been a remarkably effective medication: levodopa (3,4- dihydroxy-L-phenylalanine; also known as L-DOPA).1–3 Its worldwide impact on reversing the disabilities of PD and improving quality of life has been enormous, though it arrived on the therapeutics scene amidst skepticism and, initially, unfulfilled promise.4,5 Eventually, after almost a decade of unconvincing clinical trials, levodopa finally proved itself to be a successful therapy.6,7 It provided the first opportunity for clinician and patient alike to recognize how much of the parkinsonian motor syndrome—resting tremor, slowed movement, decreased dexterity, rigidity, postural disturbance, and other impairments—are reversible consequences of striatal dopaminergic deficiency. Levodopa has also been one of the most cost-effective medications ever developed. Although, after nearly a half-century of use, this medication continues to be an enduring treatment for PD, it also behaves, as pioneering researcher Oleh Hornykiewicz recognized early on, as “.far from perfect as a drug.”8 Levodopa’s limitations at treating the full spectrum of parkinsonian signs and symptoms, as well as declining effectiveness, have been recognized in follow-up of PD populations for 10 years and longer.9 How levodopa came to be developed as a therapy is instructive for the modern reader in that it nicely illustrates a dictum of Louis Pasteur that “chance favors the prepared mind.” In fact, several “prepared minds” lent rational and imaginative thinking to the understanding of the distinctive pathology of the PD brain and how its biochemical changes might be reversed. Highlighting these revolutionary events was the development of an animal model (reserpineinduced akinesia), which was actually more of an analogy to parkinsonism than a rigorous recapitulation of all clinical features. A key part of the research leading to levodopa as a therapy From the Department of Neurology (P.A.L.), Henry Ford Hospital; Department of Neurology (P.A.L.), Wayne State University School of Medicine, Detroit, MI; and Department of Neurology (S.F.), Columbia University Medical Center, New York, NY. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. This Neurology® supplement was not peer-reviewed. Information contained in this Neurology supplement represents the opinions of the authors. These opinions are not endorsed by nor do they reflect the views of the American Academy of Neurology, Editor-in-Chief, or Associate Editors of Neurology. © 2016 American Academy of Neurology S3 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. was emerging knowledge about how amino extracted the active ingredient and developed acids could be transferred across the blood–brain its therapeutic use in the 1950s as a powerful barrier (unlike dopamine, which, as a charged antihypertensive agent.15 The attraction of molecule, is excluded). When Carlsson et al.10 reserpine for Carlsson16 was its ability to first found levodopa could reverse the akinesia in deplete brain stores of serotonin. His experireserpinized rabbits, dopamine was regarded as ments with reserpine searched for its effects no more than an intermediate in the catechol- on other neurotransmitters as well. In collaboamine synthesis pathway for norepinephrine and ration with Nils Åke Hillarp, Carlsson found epinephrine. Following that experiment, the that reserpine depleted norepinephrine and epiSwedish neuroscientist and Nobel Prize winner nephrine in the adrenal glands of rabbits.17 Arvid Carlsson11 showed that dopamine was Could this have relevance for neurotransmitters present in the brain, was depleted with reserpine, in the brain? Carlsson endeavored to determine and could be restored with levodopa. Later, as if the tranquilizer effect of reserpine in mice and dopamine’s role in central nervous system rabbits was due to depletion of serotonin or the (CNS) neurotransmission became recognized, catecholamines. In the first of a series of landlevodopa achieved the status of “.the most nat- mark experiments on the brain that explored ural substance.for treating.the striatal dopa- behavioral and neurochemical outcomes, he <ul style="display: flex;"><li style="flex:1">mine deficiency syndrome.”8 </li><li style="flex:1">studied mice and rabbits rendered immobile </li></ul>Like the antituberculosis drug D-cycloserine, by reserpine. Carlsson and colleagues discovanother modified amino acid, levodopa lacks ered that this motor impairment could not be the complexity of many drugs used in modern attributed to depleted serotonin.10,18 Adminismedicine. The Swiss biochemist Marcus Gug- tering 5-hydroxytryptophan, the immediate genheim12 isolated levodopa from a natural precursor of serotonin, had no effect on immosource, the broad bean (Vicia faba), and bility. Carlsson had used 5-hydroxytryptohan in characterized this compound in 1913. With his experiments because he was aware that a curiosity as to its biological roles, he heroically charged molecule like serotonin was unable to self-administered a 2.5-g oral dose.12 This cross the blood–brain barrier. Using similar promptly caused nausea and vomiting,12 side reasoning, he next tested racemic 3,4- effects that even today are sometimes experi- dihydroxyphenylalanine, which, as an amino enced by patients. In the 1940s, D,L-3,4- acid, could be transported across the blood– dihydroxyphenylalanine as a racemic mixture brain barrier by means of a sodium-dependent (levodopa is the proper name for just the levo L-stereospecific uptake mechanism.19 In contrast species) was administered to humans in experi- to the absence of effect conferred by the serotoments that investigated its effects on blood nin precursor, D,L-3,4-dihydroxyphenylalanine pressure13 and its metabolism to form dopa- administration rapidly and almost completely mine.14 Even though levodopa can be found in reversed the animal’s inability to move. This trace amounts in the human brain and else- profound (though transient) effect was enhanced where in the body, no other physiologic func- by pretreating the animals with iproniazid, tions have been determined for it. Levodopa a monoamine oxidase inhibitor, supporting lacks a nucleic acid triplet codon and does not “the assumption that the effect of 3,4- <ul style="display: flex;"><li style="flex:1">find its way into protein formation. </li><li style="flex:1">dihydroxyphenylalanine was due to an amine </li></ul>Although this compound was recognized as formed from it.”10 Carlsson developed a sensitive the starting source of catecholamine synthesis, fluorescent assay for dopamine, and his doctoral interest in levodopa as a potential therapy for students were able to demonstrate in the brains PD was nonexistent until after it was utilized of dogs that regional dopamine concentrations in the animal research experiments mentioned were highest in the caudate and putamen (the above by Arvid Carlsson, who was investigating striatum).20 In this region, concentrations of reserpine’s sedative effect. Reserpine, a naturally norepinephrine were only at trace levels. <ul style="display: flex;"><li style="flex:1">occurring alkaloid compound derived from the </li><li style="flex:1">The identity of dopamine as a major brain </li></ul>snakeroot plant, was originally used in tradi- neurotransmitter and integral to motor functional medicine in India. Swiss chemists tion (and subsequently to behavioral function) S4 Neurology 86 (Suppl 1) April 5, 2016 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. led to the analogy that depleted dopamine ganglia (where the brain’s highest dopamine concentrations might explain the pathophysi- concentrations were found).11,20 <ul style="display: flex;"><li style="flex:1">ology of PD, which in some respects resem- </li><li style="flex:1">Next in the pathway for developing dopa- </li></ul>bled the behavioral deficits of reserpinized minergic therapy of PD were the contribuanimals. At this point, there was no under- tions of Austrian neuropharmacologist Oleh standing of why this might be, especially since Hornykiewicz.26 With an interest in measurnorepinephrine concentrations did not rise ing and understanding the roles of dopamine when levodopa was administered. It required in the striatum, Hornykiewicz wondered another breakthrough, recognition of the reg- whether observations made in reserpinized anulatory step in norepinephrine production imals corresponded to findings in the PD imposed by dopamine-b-hydroxylase in brain. He obtained autopsied brain specimens norepinephrine-synthesizing neurons.21 Once from people who died of PD, postencephalitic this discovery was made, the diversity of cate- parkinsonism, or Huntington disease, and cholamine functions in the brain became bet- without neurologic disease, and measured ter understood as the era of dopaminergic dopamine and norepinephrine in a number therapeutics opened for PD. Ironically, these of brain regions. Ehringer and Hornykiewicz27 developments also ushered in a long period of found a striking loss of dopamine in the parneglect for exploring norepinephrine as a ther- kinsonian brains, in contrast to Huntington <ul style="display: flex;"><li style="flex:1">apeutic target for PD.22 </li><li style="flex:1">disease and control brain; the loss was partic- </li></ul>Offering a functional role to dopamine was ularly striking in the striatum, where the doparevolutionary at the time, especially since the mine content reduction was approximately entire pathway of catecholamine synthesis 90%. Further research determined in the starting from phenylalanine and tyrosine had upper brainstem that a small group of pigyet to be worked out (though much earlier, mented neurons, the substantia nigra, also Hermann Blaschko23 identified the steps used had major loss of dopamine.28 A functional in creating epinephrine from levodopa). Recog- connection between the substantia nigra and nizing the role of dopamine and the simplicity striatum was subsequently recognized by hisby which its function could be restored by levo- tochemical imaging of axonal projections that dopa administration marked a turning point in extend between these regions.29 <ul style="display: flex;"><li style="flex:1">the eventual discoveries that led to harnessing </li><li style="flex:1">The therapeutic dimensions of these discov- </li></ul>this drug for the treatment of PD. The variable eries soon became obvious to Hornykiewicz, and inconclusive initial clinical results, how- who collaborated with Austrian geriatrician ever, led to this idea being largely unaccepted Walther Birkmayer to undertake clinical trials by many neurologists.4,5 A number of scientific with L-3,4-dihydroxyphenylalanine. This was questions remained unsettled. Many neuro- given IV in acute experiments to patients with scientists raised concerns that dopamine did PD and those with parkinsonism due to von not meet established criteria for a neurotrans- Economo encephalitis. These clinical trials, mitter and felt it was merely a precursor for which were initiated in mid-1961, involved a the other catecholamines. Furthermore, high group of 20 patients who received levodopa at dosage of levodopa was suspected to be a pos- doses between 50 and 150 mg.30 In some insible neurotoxin (and responsible for killing stances, there were striking results, with marked some of the animals in some experiments).24 improvements in mobility for some of the paAlthough tyrosine was suspected to be the tients who had long been bedridden or unable endogenous source for levodopa, the enzyme to walk.26 The benefits became evident quickly responsible for this synthesis was not known. following the injections, and for some of the The rate-limiting step, tyrosine hydroxylase, patients, lasted for up to 24 hours. Unknown was finally identified in 1964.25 It was largely to these investigators were similar experiments Carlsson’s work eventually convining neuro- that had been conducted 1 year earlier by a scientists that dopamine behaved as a neuro- research group in Japan led by Isamu Sano. transmitter in brain, subserving many of the Their clinical experiment followed a similar motor activities mediated through the basal logic to the work of Carlsson, Hornykiewicz, Neurology 86 (Suppl 1) April 5, 2016 S5 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. and Birkmayer, in that they capitalized on their some reduction in clinical signs and symptoms own findings that dopamine concentrations in (such as impaired speech or posture), the rethe brain were greatest in several basal ganglia maining 30% were judged not to have experiregions.31 Since they also determined that stri- enced any improvements. <ul style="display: flex;"><li style="flex:1">atal dopamine concentration in an autopsied </li><li style="flex:1">The first to use high oral dosages of D,L-3,4- </li></ul>PD brain was very much diminished, Sano32 dihydroxyphenylalanine in patients with PD went on to conduct a trial of racemic 3,4- were the Canadian neuropharmacologist Patdihydroxyphenylalanine. In this study, the 5 rick McGeer and neurologist Ludmila Zeldopatients who received 200 mg IV demonstrated wicz in 1964.40 Starting with doses of 250 mg/ what the researchers described as minimal im- d, they built up the dose gradually by increprovements of rigidity and tremor. The report ments of 250 mg/d until a daily dosage of 5 g/ of the study did not receive attention outside of d was reached. They treated 10 patients (6 PD, Japan at the time and, presumably because of 3 postencephalitic parkinsonism, and 1 arterithe limited clinical benefits, this research group osclerotic) for several days, and 1 patient <ul style="display: flex;"><li style="flex:1">did not pursue further experimentation. </li><li style="flex:1">received 3 g/d for 3 years. Two of the patients </li></ul>Other research groups, aware of the findings showed some benefit. IV levodopa (250 mg) in reserpinized rodents, also attempted to was also given to 3 of the patients, of whom restore striatal dopamine concentrations and only one of the 3 (a postencephalitic patient) relieve parkinsonian signs and symptoms using had a beneficial response. The authors conthe strategy of precursor therapy. In the 7 years cluded that levodopa had little to offer as a following the publication of Carlsson’s report, therapeutic agent in the treatment of and the work of Birkmayer and Hornykiewicz, parkinsonism.40 <ul style="display: flex;"><li style="flex:1">small-scale clinical investigations were carried </li><li style="flex:1">The results of studies by both Birkmayer </li></ul>out in Germany, Italy, Canada, Sweden, and McGeer were particularly discouraging Finland, and the United States.33–47 For the and might have spelled the end of attempts most part, these studies used IV administration to treat PD with levodopa. Many experts, of either the levo or the racemic forms of 3,4- including Melvin Yahr and Roger Duvoisin dihydroxyphenylalanine and study designs that in the late 1960s, were unimpressed with the were either open-label or placebo-controlled.24 reported results using both D,L-3,4- Overall, the clinical results from these studies dihydroxyphenylalanine and levodopa.49,50 were not impressive for achieving relief of par- From today’s perspective, after decades of kinsonian features. During this period, consid- experience in recognizing the diversity of parerable basic neuroscience progress enhanced kinsonian signs and symptoms, disorders that knowledge about dopamine’s role in parkin- mimic PD, the impact of placebo effect on clinsonism. However, the therapeutic approach of ical trials, the importance of controlled experiadministering a dopamine precursor seemed to ments, and the need for testing long duration of fail and there was considerable skepticism in the treatment, it seems no wonder that the small <ul style="display: flex;"><li style="flex:1">early 1960s. </li><li style="flex:1">doses of administered levodopa or racemic 3,4- </li></ul>Birkmayer and Hornykiewicz, who made use dihydroxyphenylalanine and the insufficient of the levo form of 3,4-dihydroxyphenylalanine trials of higher doses were doomed to fail. <ul style="display: flex;"><li style="flex:1">in their 1961 experiments, attempted to repli- </li><li style="flex:1">Fortunately, another mindset as to the ther- </li></ul>cate their findings in subsequent studies. They apeutic challenge in PD brought renewed reported on 200 patients with parkinsonian interest in levodopa. The American pharmasymptoms who received 25-mg IV injections cologist George Cotzias initiated a series of exof levodopa that were administered once or periments with treatment strategies that twice weekly (together with an inhibitor of differed from an approach to restore striatal monoamine oxidase).48 The results of this dopaminergic neurotransmission. Instead, approach were far less encouraging than what Cotzias51 envisioned that the treatment for they previously reported. They found evidence PD needed to target the absence of neuromelfor improvement in slowed movement for only anin pigment in the substantia nigra. This 20% of the patients. While half of them showed neuropathologic finding, which was also S6 Neurology 86 (Suppl 1) April 5, 2016 ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited. prominent in the parkinsonian and dystonic 200–300 mg every 2–4 days. The uptitration disorder induced in Chilean miners from was discontinued if optimized clinical benefit chronic exposure to manganese, led Cotzias was observed or if adverse effects developed. and colleagues to treat a group of patients with The uppermost dosage was 8 g/d if needed. PD with intramuscular injections of The study was laborious, requiring several melanocyte-stimulating hormone and oral months of in-hospital treatment and evaluaadministration of phenylalanine and 3,4- tion. The results showed at least partial dihydroxyphenylalanine (the latter 2 amino improvement for most of the patients, and acids in racemic forms). Although their treat- 10 of the 28 had “dramatic” improvement, ment hypothesis was not to replenish dopamine with another 10 classified as showing in the brain, their trial with D,L-3,4- “marked” improvement. The investigators dihydroxyphenylalanine showed dramatic effec- classified the remainder is having “moderate” tiveness, in contrast to melanocyte-stimulating or “modest” improvement in parkinsonian hormone and phenylalanine (each of which signs, and every feature of parkinsonism exacerbated tremor).6 Among 16 patients receiv- showed some response, although not uniing D,L-3,4-dihydroxyphenylalanine for treat- formly across all of the patients. To achieve ment periods ranging from 33 to 347 days, 8 these effects, the average optimal dosage was patients showed either complete or marked 5.8 g per day (ranging from 4.2 to 7.5 g/d).7 <ul style="display: flex;"><li style="flex:1">improvement of rigidity and tremor. The </li><li style="flex:1">With the high doses of levodopa used in </li></ul>doses used ranged from 3 to 16 g/d in divided the study came adverse effects not previously doses. An additional 2 patients showed some encountered. Nausea and vomiting were improvements, and no patients worsened. common but could be prevented by the Among the adverse effects were nausea, vom- development of pharmacologic tolerance with iting, and postural lightheadedness. Cotzias the slow titration schedule. One of the paand colleagues6 observed that side effects tients showed psychic changes including seem to be more prominent with rapid irritability, anger, hostility, paranoia, and increase of daily drug intake. They also found sleeplessness. Others showed improvements that 25% of the patients developed a mild, in mental functioning that were described as transient granulocytopenia in correlation to an effect of psychic “awakening” (the topic intake of more than 200 g of the drug. The of an influential book about high-dose levosalient points that differentiated this study dopa therapy of postencephalitic parkinsonfrom previous clinical experience with levo- ism that was published in 1973 by Oliver dopa or D,L-3,4-dihydroxyphenylalanine are Sacks, Awakenings,52 followed by a Hollythe greatly increased daily intake that was wood movie with the same title in 1990, used and the sustained periods of treatment. based on the book). As continued exposure The slow buildup of dosage seems to be the to levodopa was observed by Cotzias et al.,7 critical factor permitting an adequate test for involuntary movements (dyskinesias) became <ul style="display: flex;"><li style="flex:1">investigation of replacement therapy.6 </li><li style="flex:1">evident in half of them (and in some instances </li></ul>The outcome of the initial 1967 clinical took on relatively severe choreic or ballistic study carried out by Cotzias et al.6 at features). During the course of their second Brookhaven National Laboratories led to the study, the L-aromatic amino acid decarboxylconclusion that further studies with levodopa, ase inhibitor carbidopa was developed and instead of the racemic mixture, seemed “highly became available for some participants in warranted.” Two years later, Cotzias et al.7 re- the clinical trial. This compound, blocking ported on a group of 28 parkinsonian patients peripheral conversion of levodopa to dopatreated with levodopa. The patients were first mine, offered a synergistic action, permitting given placebo and then had levodopa intro- lower doses of levodopa to be used. On this duced in a regimen of substituting levodopa basis, the optimized intake of levodopa for placebo gradually in dosing of 3 times per tended to be much lower. <ul style="display: flex;"><li style="flex:1">day. Initially, they received 100 mg. Subse- </li><li style="flex:1">The 1969 publication of clinical trial results </li></ul>quent dosing, as tolerated, was increased by from the Brookhaven National Laboratories

Levodopa Therapy for Parkinson Disease: a Look Backward and Forward

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