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WASHINGTON, DC—Clinical studies have yet to show that nondopaminergic drugs improve motor disability in Parkinson’s disease to the same degree that dopaminergic drugs do. Nondopaminergic agents may reduce motor complications, however, if administered as add-ons to subtherapeutic doses of levodopa, according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.
Reducing peak-dose levodopa-induced dyskinesia (LID) remains an important area of research, but adverse effects in advanced Parkinson’s disease stemming from nonselective targeting, the lack of drugs with sufficient bioavailability, and the large placebo effect that masks clinical benefit continue to pose challenges, said Susan H. Fox, MBChB, PhD, Associate Professor of Neurology at the University of Toronto. Looking at nondopaminergic targets in the prevention of LID in combination with low-dose levodopa in early Parkinson’s disease may be a better therapeutic strategy, and preclinical studies demonstrated that it provides some benefit, she added.
“So far, no nondopaminergic agent has yet had benefit as a monotherapy in clinical trials,” said Dr. Fox. “There are several targets in development for motor fluctuations [as adjunct therapy] for wearing off.”
Researchers have identified several nondopaminergic targets for LID, and drugs that address them have various degrees of efficacy. The lack of clinically available subtype-selective ligands entails a lack of preclinical studies that can be translated into clinical trials. But neurologists historically use drugs off label to alleviate some symptoms of Parkinson’s disease. For example, clozapine, an antipsychotic, may reduce severe Parkinson’s disease tremor and dyskinesia, said Dr. Fox.
The Basal Ganglia Motor Circuit
The pathologic processes underlying Parkinson’s disease involve several nondopaminergic systems, including glutamergic, noradrenergic, serotonergic, histaminergic, opioid, cannabinoid, and cholinergic systems within cortical, brainstem, and basal ganglia regions of the brain. Many of these neurotransmitter–neuromodulator systems have been implicated in motor and nonmotor symptoms in Parkinson’s disease. Several drugs that target nondopaminergic pathways are available, said Dr. Fox, and they can be used as symptomatic therapy in early Parkinson’s disease, adjunct therapy for wearing off, therapies for reducing LID, and therapies for levodopa-resistant symptoms such as gait difficulty and tremor.
Much research during the past 25 years has focused on the basal ganglia motor circuit, which has two main pathways involved in the propagation and inhibition of movement. “The direct pathway is controlled by dopamine D1 receptors, and then there’s an indirect pathway from the striatum … to the pallidum via the subthalamic nucleus,” said Dr. Fox. The relative balance of these two pathways can lead to a reduction in movement commonly observed in Parkinson’s disease or to the excessive movement observed in dyskinesia.
Targeting the Adenosine A2A Receptor
One potential nondopaminergic therapeutic approach for symptomatic treatment is reducing the activity of the dopamine D2-mediated, indirect GABAergic pathway by targeting the adenosine A2A receptor. Researchers hypothesize that A2A antagonists reduce overactivity of the indirect pathway, thus resulting in an antiparkinsonian action without activating the D1-direct pathway and inducing dyskinesia. Preclinical studies in an MPTP primate model of Parkinson’s disease have lent support to this theory.
“Clinical trials using adenosine A2A antagonist as monotherapy unfortunately didn’t show any good clinical benefit,” even though the drug had improved symptoms of Parkinson’s disease in rodent and primate models, said Dr. Fox. Two clinical trials in patients with early Parkinson’s disease were negative.
Adenosine A2A antagonists also are being investigated as a treatment for motor fluctuations in Parkinson’s disease. Many preclinical studies have suggested that several of these agents enhance the antiparkinsonian action of low doses of levodopa and dopamine agonists, thus improving symptoms without inducing dyskinesia. Dr. Fox cited a 2014 study by Uchida et al that examined istradefylline in MPTP-treated common marmosets. “If you use a low dose of levodopa combined with istradefylline, you don’t get as much dyskinesia as you do if you … treat the animal with a high dose of levodopa,” she said. “The key here is the low dose of levodopa.”
A clinical study published more than 10 years earlier by Bara-Jimenez et al showed similar results. Istradefylline potentiated the anti-Parkinson’s disease action of low-dose levodopa and produced 45% less dyskinesia than an optimal dose of levodopa did. Citing a meta-analysis by Chen et al that included studies evaluating istradefylline for wearing off in Parkinson’s disease, Dr. Fox highlighted the challenges in translating results from animal models to clinical studies.
“The problem with clinical trials is that we always recruit patients who are optimized on levodopa,” she said. “This is probably where some of the side-effect profile of these agents has been a problem…. [Istradefylline] certainly improves the off time, but if you look at the adverse events, dyskinesia is often increased…. This [result] suggests that the preclinical data are really telling us what we should be doing in the clinic, but we’re not actually doing it as yet.”
The Promise of Safinamide
Among other therapies evaluated for Parkinson’s disease motor symptoms, perhaps the most promising is safinamide, a novel drug with dopaminergic and nondopaminergic mechanisms of action. In phase III randomized controlled trials in patients with Parkinson’s disease-related motor fluctuations, safinamide had positive benefits on wearing off and appeared to reduce dyskinesia. The drug also improved motor function when given as an add-on to dopamine-agonist therapy in early Parkinson’s disease.
The preponderance of research into nondopaminergic drugs has focused on finding therapies for LID. A potential approach to treating LID is to reduce the overactivity of the dopamine D1-mediated direct GABAergic striatopallidal pathway. Researchers are studying glutamate NMDA, AMPA, and mGluR antagonists; Mu opioid antagonists; and alpha2A adrenergic antagonists as means to achieve this end. Investigators also are evaluating whether serotonin, 5HT1A agonists, histamine H2-antagonists, or nicotinic agonists can reduce abnormal dopamine release or transmission, another potential means of treating LID. Other studies are designed to show whether 5HT2A/2C antagonists or cannabinoids can enhance inhibitory outputs from the internal globus pallidus to motor and premotor cortical regions.
The overarching clinical aim of the research is to “maintain the levodopa for our patients, because we know this is the best drug for improving the motor symptoms, but to try to reduce the dyskinesia,” said Dr. Fox.
As for levodopa-resistant symptoms, few preclinical studies have evaluated nondopaminergic agents for gait and balance in Parkinson’s disease because animal models are inadequate for assessing bipedal gait. Several small trials involving clinically available drugs have resulted in negative outcomes or minimal benefit. Clinical observations have reported that mirtazapine and low-dose clozapine reduce rest tremor in Parkinson’s disease, Dr. Fox noted.
—Fred Balzac
Suggested Reading
Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293-296.
Black KJ, Koller JM, Campbell MC, et al. Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci. 2010;30(48):16284-16292.
Chen W, Wang H, Wei H, et al. Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson’s disease: a meta-analysis. J Neurol Sci. 2013;324(1-2)21-28.
Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16-20.
Kandadai RM, Jabeen SA, Kanikannan MA, Borgohain R. Safinamide for the treatment of Parkinson’s disease. Expert Rev Clin Pharmacol. 2014;7(6):747-759.
Uchida S, Tashiro T, Kawai-Uchida M, et al. The adenosine A2A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci. 2014;124(4):480-485.
WASHINGTON, DC—Clinical studies have yet to show that nondopaminergic drugs improve motor disability in Parkinson’s disease to the same degree that dopaminergic drugs do. Nondopaminergic agents may reduce motor complications, however, if administered as add-ons to subtherapeutic doses of levodopa, according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.
Reducing peak-dose levodopa-induced dyskinesia (LID) remains an important area of research, but adverse effects in advanced Parkinson’s disease stemming from nonselective targeting, the lack of drugs with sufficient bioavailability, and the large placebo effect that masks clinical benefit continue to pose challenges, said Susan H. Fox, MBChB, PhD, Associate Professor of Neurology at the University of Toronto. Looking at nondopaminergic targets in the prevention of LID in combination with low-dose levodopa in early Parkinson’s disease may be a better therapeutic strategy, and preclinical studies demonstrated that it provides some benefit, she added.
“So far, no nondopaminergic agent has yet had benefit as a monotherapy in clinical trials,” said Dr. Fox. “There are several targets in development for motor fluctuations [as adjunct therapy] for wearing off.”
Researchers have identified several nondopaminergic targets for LID, and drugs that address them have various degrees of efficacy. The lack of clinically available subtype-selective ligands entails a lack of preclinical studies that can be translated into clinical trials. But neurologists historically use drugs off label to alleviate some symptoms of Parkinson’s disease. For example, clozapine, an antipsychotic, may reduce severe Parkinson’s disease tremor and dyskinesia, said Dr. Fox.
The Basal Ganglia Motor Circuit
The pathologic processes underlying Parkinson’s disease involve several nondopaminergic systems, including glutamergic, noradrenergic, serotonergic, histaminergic, opioid, cannabinoid, and cholinergic systems within cortical, brainstem, and basal ganglia regions of the brain. Many of these neurotransmitter–neuromodulator systems have been implicated in motor and nonmotor symptoms in Parkinson’s disease. Several drugs that target nondopaminergic pathways are available, said Dr. Fox, and they can be used as symptomatic therapy in early Parkinson’s disease, adjunct therapy for wearing off, therapies for reducing LID, and therapies for levodopa-resistant symptoms such as gait difficulty and tremor.
Much research during the past 25 years has focused on the basal ganglia motor circuit, which has two main pathways involved in the propagation and inhibition of movement. “The direct pathway is controlled by dopamine D1 receptors, and then there’s an indirect pathway from the striatum … to the pallidum via the subthalamic nucleus,” said Dr. Fox. The relative balance of these two pathways can lead to a reduction in movement commonly observed in Parkinson’s disease or to the excessive movement observed in dyskinesia.
Targeting the Adenosine A2A Receptor
One potential nondopaminergic therapeutic approach for symptomatic treatment is reducing the activity of the dopamine D2-mediated, indirect GABAergic pathway by targeting the adenosine A2A receptor. Researchers hypothesize that A2A antagonists reduce overactivity of the indirect pathway, thus resulting in an antiparkinsonian action without activating the D1-direct pathway and inducing dyskinesia. Preclinical studies in an MPTP primate model of Parkinson’s disease have lent support to this theory.
“Clinical trials using adenosine A2A antagonist as monotherapy unfortunately didn’t show any good clinical benefit,” even though the drug had improved symptoms of Parkinson’s disease in rodent and primate models, said Dr. Fox. Two clinical trials in patients with early Parkinson’s disease were negative.
Adenosine A2A antagonists also are being investigated as a treatment for motor fluctuations in Parkinson’s disease. Many preclinical studies have suggested that several of these agents enhance the antiparkinsonian action of low doses of levodopa and dopamine agonists, thus improving symptoms without inducing dyskinesia. Dr. Fox cited a 2014 study by Uchida et al that examined istradefylline in MPTP-treated common marmosets. “If you use a low dose of levodopa combined with istradefylline, you don’t get as much dyskinesia as you do if you … treat the animal with a high dose of levodopa,” she said. “The key here is the low dose of levodopa.”
A clinical study published more than 10 years earlier by Bara-Jimenez et al showed similar results. Istradefylline potentiated the anti-Parkinson’s disease action of low-dose levodopa and produced 45% less dyskinesia than an optimal dose of levodopa did. Citing a meta-analysis by Chen et al that included studies evaluating istradefylline for wearing off in Parkinson’s disease, Dr. Fox highlighted the challenges in translating results from animal models to clinical studies.
“The problem with clinical trials is that we always recruit patients who are optimized on levodopa,” she said. “This is probably where some of the side-effect profile of these agents has been a problem…. [Istradefylline] certainly improves the off time, but if you look at the adverse events, dyskinesia is often increased…. This [result] suggests that the preclinical data are really telling us what we should be doing in the clinic, but we’re not actually doing it as yet.”
The Promise of Safinamide
Among other therapies evaluated for Parkinson’s disease motor symptoms, perhaps the most promising is safinamide, a novel drug with dopaminergic and nondopaminergic mechanisms of action. In phase III randomized controlled trials in patients with Parkinson’s disease-related motor fluctuations, safinamide had positive benefits on wearing off and appeared to reduce dyskinesia. The drug also improved motor function when given as an add-on to dopamine-agonist therapy in early Parkinson’s disease.
The preponderance of research into nondopaminergic drugs has focused on finding therapies for LID. A potential approach to treating LID is to reduce the overactivity of the dopamine D1-mediated direct GABAergic striatopallidal pathway. Researchers are studying glutamate NMDA, AMPA, and mGluR antagonists; Mu opioid antagonists; and alpha2A adrenergic antagonists as means to achieve this end. Investigators also are evaluating whether serotonin, 5HT1A agonists, histamine H2-antagonists, or nicotinic agonists can reduce abnormal dopamine release or transmission, another potential means of treating LID. Other studies are designed to show whether 5HT2A/2C antagonists or cannabinoids can enhance inhibitory outputs from the internal globus pallidus to motor and premotor cortical regions.
The overarching clinical aim of the research is to “maintain the levodopa for our patients, because we know this is the best drug for improving the motor symptoms, but to try to reduce the dyskinesia,” said Dr. Fox.
As for levodopa-resistant symptoms, few preclinical studies have evaluated nondopaminergic agents for gait and balance in Parkinson’s disease because animal models are inadequate for assessing bipedal gait. Several small trials involving clinically available drugs have resulted in negative outcomes or minimal benefit. Clinical observations have reported that mirtazapine and low-dose clozapine reduce rest tremor in Parkinson’s disease, Dr. Fox noted.
—Fred Balzac
WASHINGTON, DC—Clinical studies have yet to show that nondopaminergic drugs improve motor disability in Parkinson’s disease to the same degree that dopaminergic drugs do. Nondopaminergic agents may reduce motor complications, however, if administered as add-ons to subtherapeutic doses of levodopa, according to a presentation at the 67th Annual Meeting of the American Academy of Neurology.
Reducing peak-dose levodopa-induced dyskinesia (LID) remains an important area of research, but adverse effects in advanced Parkinson’s disease stemming from nonselective targeting, the lack of drugs with sufficient bioavailability, and the large placebo effect that masks clinical benefit continue to pose challenges, said Susan H. Fox, MBChB, PhD, Associate Professor of Neurology at the University of Toronto. Looking at nondopaminergic targets in the prevention of LID in combination with low-dose levodopa in early Parkinson’s disease may be a better therapeutic strategy, and preclinical studies demonstrated that it provides some benefit, she added.
“So far, no nondopaminergic agent has yet had benefit as a monotherapy in clinical trials,” said Dr. Fox. “There are several targets in development for motor fluctuations [as adjunct therapy] for wearing off.”
Researchers have identified several nondopaminergic targets for LID, and drugs that address them have various degrees of efficacy. The lack of clinically available subtype-selective ligands entails a lack of preclinical studies that can be translated into clinical trials. But neurologists historically use drugs off label to alleviate some symptoms of Parkinson’s disease. For example, clozapine, an antipsychotic, may reduce severe Parkinson’s disease tremor and dyskinesia, said Dr. Fox.
The Basal Ganglia Motor Circuit
The pathologic processes underlying Parkinson’s disease involve several nondopaminergic systems, including glutamergic, noradrenergic, serotonergic, histaminergic, opioid, cannabinoid, and cholinergic systems within cortical, brainstem, and basal ganglia regions of the brain. Many of these neurotransmitter–neuromodulator systems have been implicated in motor and nonmotor symptoms in Parkinson’s disease. Several drugs that target nondopaminergic pathways are available, said Dr. Fox, and they can be used as symptomatic therapy in early Parkinson’s disease, adjunct therapy for wearing off, therapies for reducing LID, and therapies for levodopa-resistant symptoms such as gait difficulty and tremor.
Much research during the past 25 years has focused on the basal ganglia motor circuit, which has two main pathways involved in the propagation and inhibition of movement. “The direct pathway is controlled by dopamine D1 receptors, and then there’s an indirect pathway from the striatum … to the pallidum via the subthalamic nucleus,” said Dr. Fox. The relative balance of these two pathways can lead to a reduction in movement commonly observed in Parkinson’s disease or to the excessive movement observed in dyskinesia.
Targeting the Adenosine A2A Receptor
One potential nondopaminergic therapeutic approach for symptomatic treatment is reducing the activity of the dopamine D2-mediated, indirect GABAergic pathway by targeting the adenosine A2A receptor. Researchers hypothesize that A2A antagonists reduce overactivity of the indirect pathway, thus resulting in an antiparkinsonian action without activating the D1-direct pathway and inducing dyskinesia. Preclinical studies in an MPTP primate model of Parkinson’s disease have lent support to this theory.
“Clinical trials using adenosine A2A antagonist as monotherapy unfortunately didn’t show any good clinical benefit,” even though the drug had improved symptoms of Parkinson’s disease in rodent and primate models, said Dr. Fox. Two clinical trials in patients with early Parkinson’s disease were negative.
Adenosine A2A antagonists also are being investigated as a treatment for motor fluctuations in Parkinson’s disease. Many preclinical studies have suggested that several of these agents enhance the antiparkinsonian action of low doses of levodopa and dopamine agonists, thus improving symptoms without inducing dyskinesia. Dr. Fox cited a 2014 study by Uchida et al that examined istradefylline in MPTP-treated common marmosets. “If you use a low dose of levodopa combined with istradefylline, you don’t get as much dyskinesia as you do if you … treat the animal with a high dose of levodopa,” she said. “The key here is the low dose of levodopa.”
A clinical study published more than 10 years earlier by Bara-Jimenez et al showed similar results. Istradefylline potentiated the anti-Parkinson’s disease action of low-dose levodopa and produced 45% less dyskinesia than an optimal dose of levodopa did. Citing a meta-analysis by Chen et al that included studies evaluating istradefylline for wearing off in Parkinson’s disease, Dr. Fox highlighted the challenges in translating results from animal models to clinical studies.
“The problem with clinical trials is that we always recruit patients who are optimized on levodopa,” she said. “This is probably where some of the side-effect profile of these agents has been a problem…. [Istradefylline] certainly improves the off time, but if you look at the adverse events, dyskinesia is often increased…. This [result] suggests that the preclinical data are really telling us what we should be doing in the clinic, but we’re not actually doing it as yet.”
The Promise of Safinamide
Among other therapies evaluated for Parkinson’s disease motor symptoms, perhaps the most promising is safinamide, a novel drug with dopaminergic and nondopaminergic mechanisms of action. In phase III randomized controlled trials in patients with Parkinson’s disease-related motor fluctuations, safinamide had positive benefits on wearing off and appeared to reduce dyskinesia. The drug also improved motor function when given as an add-on to dopamine-agonist therapy in early Parkinson’s disease.
The preponderance of research into nondopaminergic drugs has focused on finding therapies for LID. A potential approach to treating LID is to reduce the overactivity of the dopamine D1-mediated direct GABAergic striatopallidal pathway. Researchers are studying glutamate NMDA, AMPA, and mGluR antagonists; Mu opioid antagonists; and alpha2A adrenergic antagonists as means to achieve this end. Investigators also are evaluating whether serotonin, 5HT1A agonists, histamine H2-antagonists, or nicotinic agonists can reduce abnormal dopamine release or transmission, another potential means of treating LID. Other studies are designed to show whether 5HT2A/2C antagonists or cannabinoids can enhance inhibitory outputs from the internal globus pallidus to motor and premotor cortical regions.
The overarching clinical aim of the research is to “maintain the levodopa for our patients, because we know this is the best drug for improving the motor symptoms, but to try to reduce the dyskinesia,” said Dr. Fox.
As for levodopa-resistant symptoms, few preclinical studies have evaluated nondopaminergic agents for gait and balance in Parkinson’s disease because animal models are inadequate for assessing bipedal gait. Several small trials involving clinically available drugs have resulted in negative outcomes or minimal benefit. Clinical observations have reported that mirtazapine and low-dose clozapine reduce rest tremor in Parkinson’s disease, Dr. Fox noted.
—Fred Balzac
Suggested Reading
Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293-296.
Black KJ, Koller JM, Campbell MC, et al. Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci. 2010;30(48):16284-16292.
Chen W, Wang H, Wei H, et al. Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson’s disease: a meta-analysis. J Neurol Sci. 2013;324(1-2)21-28.
Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16-20.
Kandadai RM, Jabeen SA, Kanikannan MA, Borgohain R. Safinamide for the treatment of Parkinson’s disease. Expert Rev Clin Pharmacol. 2014;7(6):747-759.
Uchida S, Tashiro T, Kawai-Uchida M, et al. The adenosine A2A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci. 2014;124(4):480-485.
Suggested Reading
Bara-Jimenez W, Sherzai A, Dimitrova T, et al. Adenosine A(2A) receptor antagonist treatment of Parkinson’s disease. Neurology. 2003;61(3):293-296.
Black KJ, Koller JM, Campbell MC, et al. Quantification of indirect pathway inhibition by the adenosine A2a antagonist SYN115 in Parkinson disease. J Neurosci. 2010;30(48):16284-16292.
Chen W, Wang H, Wei H, et al. Istradefylline, an adenosine A2A receptor antagonist, for patients with Parkinson’s disease: a meta-analysis. J Neurol Sci. 2013;324(1-2)21-28.
Fernandez HH, Greeley DR, Zweig RM, et al. Istradefylline as monotherapy for Parkinson disease: results of the 6002-US-051 trial. Parkinsonism Relat Disord. 2010;16(1):16-20.
Kandadai RM, Jabeen SA, Kanikannan MA, Borgohain R. Safinamide for the treatment of Parkinson’s disease. Expert Rev Clin Pharmacol. 2014;7(6):747-759.
Uchida S, Tashiro T, Kawai-Uchida M, et al. The adenosine A2A-receptor antagonist istradefylline enhances the motor response of L-DOPA without worsening dyskinesia in MPTP-treated common marmosets. J Pharmacol Sci. 2014;124(4):480-485.
