Conference Coverage
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