ANNIVERSARY REVIEW: 50 years since the discovery of bromocriptine.

Ergotism is the long-term ergot poisoning by ingestion of rye or other grains infected with the fungus Claviceps purpurea and more recently by excessive intake of ergot drugs. It has either neuropsychiatric or vascular manifestations. In the Middle Ages, the gangrenous poisoning was known as St. Anthony's fire, after the order of the Monks of St. Anthony who were particularly skilled at treating the condition. In 1917, Prof. Arthur Stoll returned home to Switzerland from Germany, to lead the development of a new pharmaceutical department at Sandoz Chemical Company. Stoll, using the special methods of extraction learned from his work with his mentor Willstetter, started his industrial research work with ergot. He succeeded in isolating, from the ergot of rye, ergotamine as an active principle of an old popular remedy for excessive post-partum bleeding. The success of this discovery occurred in 1918 and was translated into a pharmaceutical product in 1921 under the trade name Gynergen. In subsequent work, Stoll and his team were leaders in identifying the structure of the many other alkaloids and amines produced by Claviceps purpurea This was the cultural background and scientific foundation on which bromocriptine was discovered.

The Many Faces of Apomorphine: Lessons from the Past and Challenges for the Future.

Apomorphine is now recognized as the oldest antiparkinsonian drug on the market. Though still underused, it is increasingly prescribed in Europe for patients with advanced Parkinson's disease (PD) with motor fluctuations. However, its history is far from being limited to movement disorders. This paper traces the history of apomorphine, from its earliest empirical use, to its synthesis, pharmacological development, and numerous indications in human and veterinary medicine, in light of its most recent uses and newest challenges. From shamanic rituals in ancient Egypt and Mesoamerica, to the treatment of erectile dysfunction, from being discarded as a pharmacological tool to becoming an essential antiparkinsonian drug, the path of apomorphine in the therapeutic armamentarium has been tortuous and punctuated by setbacks and groundbreaking discoveries. Throughout history, three main clinical indications stood out: emetic (gastric emptying, respiratory disorders, aversive conditioning), sedative (mental disorders, clinical anesthesia, alcoholism), and antiparkinsonian (fluctuations). New indications may arise in the future, both in PD (palliative care, nonmotor symptoms, withdrawal of oral dopaminergic medication), and outside PD, with promising work in neuroprotection or addiction.

200 Years of Parkinson's disease: what have we learnt from James Parkinson?

2017 marks 200 years since James Parkinson's published his 'Essay on the Shaking Palsy'. Although now most famous for describing the condition that came to bear his name, Parkinson had a wide range of interests and his influence spread beyond medicine. In this review, we provide a biography of James Parkinson's remarkable life.Parkinson's paper not only comprehensively described the symptoms of Parkinson's disease (PD), but challenged his peers to better understand the pathophysiology of the PD. Key observation over the next 2 centuries, included the recognition of the link between the substantia nigra and PD and the discoveries of dopamine deficiency in patients with PD. We review the subsequent development of pharmacological and surgical therapies. Despite great progress over the last 200 years, Parkinson's hopes for a 'cure if employed early enough' or that 'some remedial process may ere long be discovered by which at least the progression of the disease may be stopped' remain apposite today and we reflect on the challenges ahead for the next century.

The 200-year journey of Parkinson disease: Reflecting on the past and looking towards the future.

It took almost 100 years before a meaningful advance occurred in any basic science understanding of Parkinson disease (PD) following James Parkinson's description in 1817. The Lewy body was described in 1912, and the substantia nigra was found to be depigmented with neuronal loss and gliosis in 1919. The link between dopamine and PD began in 1957, 140 years after Parkinson's Essay. Arvid Carlsson and Oleh Hornykiewicz were the major pioneers. The revolutionary therapeutic breakthrough was the introduction of high dosage levodopa therapy by George Cotzias in 1967. Following 40 years of the dopa/dopamine era, we have entered the era of alpha-synuclein, the protein present in Lewy bodies. Heiko Braak found that alpha-synuclein accumulates initially in the olfactory system and lower brainstem and then travels in an anatomic pattern to involve other regions of the brain and thereby cause progressive symptoms. Alpha-synuclein was somehow converted to a rogue protein. Where this originates and how it is propagated are under intense investigation. At the same time that the alpha-synuclein era was developing, clinical advances took place by recognizing PD as hosting a wide variety of nonmotor features with eventual cognitive impairment in many. Therapeutics has also evolved. Although the most effective therapy for the motor features remains levodopa, surgical approaches and drugs for nonmotor problems continue to expand our ability to treat people with PD. We can expect therapeutic advances in neuroprotection as the basic science discoveries uncovered in the alpha-synuclein era are translated into effective treatments.

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.

The medical treatment of Parkinson disease from James Parkinson to George Cotzias.

It took exactly 150 years since James Parkinson's description in 1817 of the illness bearing his name until the development of effective therapy for this disorder, namely, the introduction of high-dosage levodopa by George Cotzias in 1967. During the first 50 years, no effective therapy was available, but neurologists reported using different agents, including metals. Then, around 1867, Charcot found solanaceous alkaloids to be somewhat helpful, and these became the accepted and popular therapy for the next 75 years. When basic scientists discovered that these alkaloids had central antimuscarinic activity, pharmaceutical chemists developed synthetic chemical agents that were equally effective, with possibly less adverse effects, and around 1950 these synthetic drugs became the standard medical therapy for Parkinson's disease (PD). The link between dopamine and PD did not take place until 1957, 140 years after Parkinson's Essay. The clue came from research on reserpine, a drug derived from the Rauwolfia plant that caused a sedative effect, now recognized as a drug-induced parkinsonian state. Initial investigations revealed that reserpine caused the release and depletion of serotonin stores in the brain. With that knowledge, Arvid Carlsson, a young pharmacologist in Sweden, decided to explore the possibility that reserpine might also affect brain catecholamines. In his now famous, elegant, and simple experiment, he showed that injecting l-dopa, the precursor of catecholamines, alleviated the reserpine-induced parkinsonian state in animals, whereas the precursor of serotonin failed to do so. Carlsson then developed a highly sensitive assay to measure dopamine, and his lab found that dopamine is selectively present in high concentrations in the striatum and that administered l-dopa could restore the dopamine depleted by reserpine. Carlsson postulated that all these findings implicate dopamine in motor disorders. Oleh Hornykiewicz, a young pharmacologist in Vienna, on being aware of the regional localization of brain dopamine, decided to measure it in the brains of people who had PD and postencephalitic parkinsonism. In 1960, he reported finding markedly depleted dopamine in the striatum in these conditions. Immediately after, Hornykiewicz teamed up with the geriatrician, Walther Birkmayer, to inject small doses of l-dopa intravenously (IV) into PD patients. They found benefit and pursued this treatment, but the gastrointestinal side effects limited the dosage, and many neurologists were doubtful that the effects from l-dopa were any better than those with antimuscarinic agents. A number of neurologists tested such low doses of IV l-dopa and even higher oral dosages, but without showing any dramatic benefit, not better than the antimuscarinics. Some of these studies were small, controlled trials. This general lack of efficacy with l-dopa prevailed, and neurologists were discouraged about l-dopa until 1967, when George C. Cotzias, a neuropharmacologist in New York, reported his results. He thought that PD may be result from the loss of neuromelanin in the substantia nigra, and he decided to try to replenish the depleted neuromelanin. Among the agents he tried was dl-dopa. He wisely began with low oral doses and increased the dosage slowly and steadily, thereby limiting the gastrointestinal complication. He also treated his patients for a long duration, months in a government-supported hospital. In the accompanying videotape of an interview Cotzias gave in 1970, he describes much of his success to be able to observe his patients over months while building up the dosage very slowly and observe for signs of toxicity. When higher doses, usually over 12 g/day, were reached, dramatic antiparkinsonian effects were observed, and a revolutionary new treatment for PD was established.

The role of subcutaneous infusion of apomorphine in Parkinson's disease.

Continuous subcutaneous apomorphine infusion therapy (CSAI) has proved to be effective in advanced Parkinson's Disease patients with motor fluctuations not controlled by oral or transdermal medication. In this clinical setting it competes directly with intrajejunal levodopa and deep brain stimulation (DBS), however randomised controlled comparative studies are lacking. The advantages of CSAI is that it is the least invasive of these three therapeutic options, is reversible, practical to use and has shown significant efficacy for the management of both peak-effect dyskinesias and off-period nonmotor-symptoms. Contraindications to the use of CSAI are severe dementia or neuropsychiatric symptoms and severe biphasic dyskinesias, however unlike DBS, advanced age is not a contraindication. This review summarises the evidence regarding efficacy, safety and tolerability of CSAI, provides guidance on the selection of suitable patients and gives practical instructions on how to initiate CSAI and manage possible adverse events.

Metabotropic glutamate receptor 4 (mGlu4)-positive allosteric modulators for the treatment of Parkinson's disease: historical perspective and review of the patent literature.

INTRODUCTION: Metabotropic glutamate receptor 4 (mGlu(4)) is a group III GPCR and has been demonstrated to play a major role in a number of therapeutic areas within the CNS. As the orthosteric site of all glutamate receptors is highly conserved, modulating mGlu(4) via allosteric modulation has emerged as a very attractive mode-of-action and has been validated preclinically in a number of animal models for Parkinson's disease, anxiety, pain, and neuroinflammation. AREAS COVERED: In this review, the patent literature for mGlu(4)-positive allosteric modulators over the past 4 years will be provided. Patents from all companies are discussed and an overview of the chemical matter and relevant biological properties will be given. EXPERT OPINION: Although there has yet to be an mGlu(4)-positive allosteric modulator progressed into clinical trials, there is a wealth of preclinical data from the primary literature that shows the promise of this emerging target. A number of academic and industry laboratories have recently published exciting patent data covering a multitude of chemical matter. Positive allosteric modulation of mGlu(4) remains one of the more attractive non-dopaminergic therapies for Parkinson's disease, as well as emerging data for other indications such as pain, neuroinflammation, schizophrenia and diabetes, which could potentially make mGlu(4) a significant therapeutic target going forward.

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.

Milestones in Parkinson's disease therapeutics.

In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions.

The history of Parkinson's disease: early clinical descriptions and neurological therapies.

Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.