Parkinson's and the pharmaceutical industry

How medicines for Parkinson’s work

Brain structure and pathology in Parkinson’s

Parkinson’s was the first brain disorder to be linked with a specific chemical deficiency – dopamine. Studies of brain structure showed degeneration in the substantia nigra, a bean-sized structure deep in the brain. There was also marked reduction in dopamine in other areas such as the caudate nucleus, the globus pallidus, and the putamen. These areas all work together, are interconnected by nerve fibres and all are involved in the control and initiation of movement: degeneration in them accounts for many of the symptoms of Parkinson’s.

Improving the usefulness of levodopa

The brain is probably the most controlled and regulated organ of the body. Small specialised blood vessels called capillaries act both as a physical barrier to blood-borne chemicals and as a filter, and only substances able to utilise special carrier systems in these capillaries can leave the blood and enter the brain. This control system, the blood-brain barrier, provides essential protection for the brain, but also makes it difficult to develop medicines for many disorders of the central nervous system.

Because dopamine does not cross the blood-brain barrier, attention turned to levodopa, which does. Levodopa is converted into dopamine in the brain by an enzyme, dopa decarboxylase (DDC), so the aim was to prevent its breakdown and prolong the life of dopamine in the brain.

Further complications arose when biochemical studies showed that breakdown in the body also arose from the activity of catechol-O-methyl transferase (COMT), and monoamine oxidase (MAO). If breakdown by all these routes could be prevented, then dopamine would reach higher levels in the brain and survive longer – with enhanced therapeutic effect. Pharmaceutical research has resulted in the successful development of three separate classes of compounds to block this breakdown, namely:

• dopa decarboxylase (DDC) inhibitors (carbidopa and benserazide)
• monoamine oxidase (MAO) inhibitors (selegiline)
• catechol-O-methyl transferase (COMT) inhibitors (tolcapone and entacapone)

Today people with Parkinson’s usually receive levodopa in combination with either carbidopa, from Du Pont, or benserazide, from Roche. In these combinations, increased levels of levodopa enter the brain, where it is converted into dopamine to combat the symptoms of Parkinson’s.

Using tolcapone or entacapone to inhibit COMT, the amount of levodopa reaching the brain can be increased even more, with a further improvement in patient movement responses. Hence these medicines are ‘added-on’ to the combinations of levodopa plus carbidopa, or levodopa plus benserazide.

The final enzyme involved in dopamine breakdown, MAO-B, occurs mostly in the brain. Selegiline inhibits MAO-B and prolongs the action of levodopa, and can delay the need to commence levodopa therapy by up to two years. It can also reduce the dose of levodopa plus carbidopa or levodopa plus benserazide by 20 to 25 per cent when added to the treatment, and can improve quality of life.

The inhibition of MAO by selegiline also opens up the possibility that, if given in the early stage of Parkinson’s, it may slow the progression of the illness. There have been hints from studies that this is so, but definitive clinical proof is still lacking. Research will continue in this area.

Medicines mimicking dopamine – the dopamine agonists

Electrical nerve impulses travel from the nerve cell body, down a long extension called the axon, to the nerve end. Between the end of one nerve and the next is a gap called the synapse. The nerve impulse is carried across the synapse by the release of a chemical from the nerve end which attaches to receptors on the surface of the next nerve – rather like the baton exchanged between runners in a relay race. There are many different chemicals (neurotransmitters) which can do this and each has a different receptor, a different function and often a different location in the brain.

A number of compounds with anti-Parkinson’s activity has been shown to work because they bind to the dopamine receptor and stimulate it. Earlier compounds of this type, bromocriptine (Novartis), lysuride (Cambridge Pharmaceuticals) and pergolide (Lilly) are very useful in people with mild to moderate movement symptoms. Some, such as pergolide, are used in combination with other medicines. However, they are often used later, frequently only after years of illness.

More recently, two classes of dopamine receptor have been recognised, called D1 and D2. The possibility arose that the stimulation of one or the other (or both) may provide the ideal medicine for anti-Parkinson’s activity. Ropinirole (SmithKline Beecham) and cabergoline (Pharmacia & Upjohn) bind mainly to D2 receptors. Clinical trials of the former support its early use, either alone or in combination with levodopa. Used alone, it can often provide effective relief from symptoms and delay the need for levodopa by several years. Cabergoline also has very high preference for D2 binding, coupled with a long survival time in the body. This helps smooth out ‘on-off’ fluctuations and permits the convenience of once-a-day dosing. At present, it is licensed for use as an addition to medicines containing levodopa, where it can permit a significant reduction in levodopa usage. The launch of these two D2-specific agonists will provide an interesting clinical comparison with apomorphine and especially pergolide, which stimulates both D1 and D2 receptors, but the latter much more strongly.