The most disabling symptoms of Parkinson’s are probably postural instability leading to falls as well as cognitive and psychiatric disorders. Motor fluctuations are not far behind. These are short-duration responses to oral levodopa with “on” and “off” periods which can be unpredictable and sometimes impossible to treat.

Strategies currently available are deep brain stimulation, used for many years, and, more recently, intestinal infusions of levodopa gel. These methods are “invasive” and cumbersome, if not frightening, for many patients.

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There are four new approaches in the pipeline.

The first focuses on sustained release. The “Accordion Pill” slowly releases levodopa. Also in trials is a continuous subcutaneous infusion of levodopa (think insulin). Subcutaneous apomorphine has been available as a “rescue” for off periods for decades and is now in late clinical trials as a continuous infusion (also think insulin).

The second is the rapid treatment of “off states.” Subcutaneous apomorphine does this but patients usually need a caregiver to give the injection. Easier is a levodopa inhalation device which delivers the medication into the lungs (think asthma). It is also in late clinical trials.

The third and the least promising, in my opinion, is to add on a daily oral medication with a different mechanism of action than levodopa to reduce off- time. There are several available now in the US and another drug (istradefylline) is marketed in Japan and is in trials in the US. This approach is limited: “another trial, another hour” of on-time.

The last is the most promising but the least likely to succeed, specifically using “viral vectors” to insert genes directly into the brain to enhance dopamine formation.

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