Float like a butterfly, sting like a bee

One evening in 1965, a small group of people sat down around a kitchen table in Toronto, determined to correct an injustice. They were concerned –appalled, in fact –that people with Parkinson’s disease were sometimes picked up on the street and thrown in to the drunk tank because a policeman had seen them fall, walk with an odd gait or their slurred speech.

Thus the Parkinson’s Foundation of Canada was born, with a view to educating the public and helping people with the progressive neurological disease live fuller, richer lives.

As a result, the lives of Parkinsonians have improved. Thanks in part to the Foundation, such high-profile individuals as Muhammed Ali, Janet Reno and Johnny Cash have gone public about having Parkinson’s and have elevated public interest. At the same time, clinicians and researchers have made advances in the treatment and management of the condition. Since levodopa?the first ‘breakthrough’ medication for people with Parkinson’s was released in the ’60?s, new and effective compounds have been brought to market, with more poised for release. The ‘shaking palsy’, first identified by English physician James Parkinson in 1817, is a chronic, degenerate neurological condition that worsens over time. Characterized by tremor, stiffness and slowness, Parkinson’s (PD) erodes a person’s ability to walk, talk, sleep – in severe cases, even breathe. Its cause is unknown, though the risk is higher if you have a close relative with PD. So far there is no cure.

Parkinson’s affects more than 100,000 Canadians. The average age is around 60, though about one in five develops ‘young-onset Parkinson’s’ defined as occurring before 50: It’s not just a ‘disease of the elderly,’ as many people assume.

Nor is it a minor economic burden: Parkinson’s costs us $2 billion-plus annually, according to 1993 Health Canada data, more than diabetes, and more than all female cancers combined?without including the costs of PD?s secondary impacts, such as incontinence, sleep disturbances and depression.

The degree to which people are disabled by PD is highly individual. Any patient may experience ‘on-off’ fluctuations, at one moment mobile and controlled, the next completely incapacitated. It?s one of the most frustrating aspects of the disease.

The key action in Parkinson’s is the degeneration of specific cells in the basal ganglia region of the brain that produce dopamine, a neurotransmitter, or chemical messenger, that controls movement coordination. Dopamine deficiency results in the many symptoms of the disease. Effective PD management involves a variety of elements; it may require a multidisciplinary health team, including a physiotherapist (PT) and/or occupational therapist (0T), a pharmacist, nurse and sometimes a speech therapist, psychiatrist or social worker.

A PT, for example, can devise a program of regular exercise to keep muscles flexible and strong; an OT can offer advice about assistive devices; a speech therapist can suggest techniques to deal with slurred speech; and a psychiatrist or social worker can provide counselling for depression.

Surgical techniques are employed, though not often, and primarily in advanced cases: In a pallidotomy, a long thin probe is used to destroy overactive brain cells causing rigidity and slowed movement; and, in deep brain, or thalamic, stimulation, a wire electrode is inserted into the same region to stimulate the deep brain to relieve symptoms.

The most effective and widely used treatment for Parkinson’s, however, is medication to redress dopamine deficiency, an area of rapid advances in recent years. The oldest and most common medication is levodopa, the ’60?s ‘gold standard’ which is converted into dopamine in patients? brains. Because dopamine is naturally inhibited by the blood enzymes DDC (dopa-decarboxylase) and catechol-O-methyltransferase (COMT), levodopa is generally combined with a enzyme inhibitor. The first of these were DDC-inhibitors, including benserazide (Prolopa) and carbidopa (Sinemet).

Most patients respond well initially to levodopa, but, as they begin to develop tolerance, they need larger doses to achieve the same effect and begin to suffer an increased prevalence of side effects, such as nausea, and sleep disturbances, plus severe fluctuations in overall symptom control.

Derek Curwin, 56, is typical. He was diagnosed with Parkinson’s four years ago and prescribed slow-release levodopa. At first, the effects lasted six to eight hours; he could take two tablets a day and live ‘a pretty normal life.’ It wasn’t long before the medication began to lose its punch; Curwin began receiving no more than three and a half hours symptom relief per dose and suffering increasing side effects; "The peaks became higher and the side effects were just horrendous," he says. "I know people who can’t sit on a chair, literally, they fall over on the floor. They have no control over these side effects, (yet) they take tremendous overdoses, because there was nothing else."

Curwin got a boost from the first of a new class of drugs, COMT-inhibitors, when tolcapone (Tasmar) was released last year. Tolcapone blocks the enzyme that breaks down levodopa in the body and ‘smooths out’ the delivery of levodopa to the brain — levelling the up-and-down symptomatic fluctuations.

For Curwin, tolcapone was "amazing." It took time to find the right dosage, but there was no adverse side effects, and he was able to reduce his levodopa dosage.

Such developments, Curwin says "are great for all Parkinsonians." His only hope is that "the drug companies keep it up. This last two or three years it’s been amazing, the number of things coming through."

And the boom isn’t over: A number of medications have either been released this year or are on the brink. Among them, ReQuip (ropinrole) and the newest, Mirapex (pramipexole). Both can be used with levodopa to improve symptom control and tolerability in advanced Parkinson’s or used without levodopa as ‘monotherapy’ to control symptoms in newly diagnosed patients.

Dr. Mark Guttman is a neurologist and co-director of the National Parkinson Foundation Centre of Excellence at the University of Toronto.

Dopamine agonists have often been used late in the course of the condition, he says, "after five to seven years, where the standard Sinemet therapy started to fail." Studies Guttman’s done with pramipexole show that "it’s good in that situation. The Sinemet fails when (patients) develop ‘response fluctuation.’ Instead of a consistent response to the medication, they have a roller coaster of ups and downs.

"By adding Mirapex to the more standard medication, Sinemet, we can often straighten out that curve and have more of a consistent response." In addition, Guttman says "studies have shown that both Mirapex and another dopamine agonist released a few months before, repinerol or ReQuip, can be effective in early Parkinson’s."

And it doesn’t stop there: Yet another drug in development, tacapone — together with tolcapone, or Tasmar — will create "two more avenues to help get a better response to Sinemet," Guttman says, "and both ReQuip and Mirapex can be used in addition to Sinemet. "It’s an exciting time," Guttman says. "There’s lots of research going on internationally. All the therapies now provide symptom control, but we really need is something to slow or stop the condition. That’s the next and final breakthrough."