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originally posted 21 may 1997 ---------------------------------------------------- Up And Coming Medical Therapies for PD by Matthias C. Kurth, MD, Ph.D. Medical Director and Advisor for Young Parkinsonians and the US NPR YOPPERS FORUM - --------------------------------------------------- The coming year will bring new and exciting treatment options for Parkinson's disease patients. Four new drugs, all shown to improve patients' symptoms, are expected to be approved by the Federal Drug Administration (FDA). Each drug offers unique advantages that will greatly increase patient and physician choices in developing a therapeutic program to minimize the impact of Parkinson's disease throughout the day. These agents will be particularly useful for young onset patients since two of them may offer some element of neuroprotection and all four agents will enhance patients' well-being by improving symptom control. In preparation for the release of these agents, a review of their properties, mechanisms of action and results of clinical trials is in order. This knowledge will empower patients and physicians to combine the appropriate medications for optimal control of parkinsonian symptoms. ----------------------------------------------------------------------- NEW COMT INHIBITORS ----------------------------------------------------------------------- One new approach to treating Parkinson's disease involves prolonging the action of levodopa by inhibiting the natural enzyme catechol-o-methyltransferase (COMT) which destroys dopamine and levodopa. Inhibition of this enzyme in the body decreases the concentration of a levodopa metabolite, 3-0-methyldopa, which may have a role in inducing or aggravating levodopa response fluctuations. More importantly, blood levels of levodopa are maintained for a longer time and patients experience a smoother, more beneficial effect from each dose of levodopa. Both tolcapone and entacapone are potent COMT inhibitors that prolong the duration of levodopa activity in patients with Parkinson's disease. Differences in the side effect profile, dosing schedule and potency will need to be addressed in comparative studies. Both tolcapone and entacapone will be valuable adjuncts for all patients using levodopa therapy. ----------------------------------------------------------------------- Tolcapone (Tasmar - Hoffman-LaRoche) ----------------------------------------------------------------------- Tolcapone is the most potent COMT inhibitor currently in clinical development. Studies in patients with Parkinson's disease in the United States and Europe are complete and have been submitted to the FDA. Tolcapone prolongs the effects of levodopa thereby decreasing motor response fluctuations in patients and improving quality of life. Patients on levodopa that do not experience motor fluctuations also benefited significantly through improved quality of life and decreased symptoms. Tolcapone is given three times daily in doses from 100 mg to 200 mg in addition to the patient's levodopa medication schedule. Peak effect of tolcapone is reached in about 1 - 2 hours and maintained for the duration of the 6 hour dosing interval. Patients experience better control of their Parkinsonian symptoms while needing lower doses of levodopa. Side effects are few, but include occasional mild headache, nausea, loose stools, change in urine color, and in some patients a transient increase in dyskinesia. Tolcapone is absorbed by the small intestine and metabolized by the liver. Food delays the absorption of tolcapone somewhat, but this does not appear to be clinically significant. The ability of this compound to prolong blood and brain levels of levodopa while reducing the levels of potentially toxic metabolites should be an important development in the treatment of Parkinson's disease. ----------------------------------------------------------------------- Entacapone (no brandname available - Orion/Farmos and Sandoz) ----------------------------------------------------------------------- Entacapone is another new COMT inhibitor. Like tolcapone, this compound improves the effectiveness of levodopa by decreasing fluctuations in medication response through inhibition of COMT. Studies to determine long-term safety and benefits of entacapone as a supplement to levodopa treatment in Parkinson's disease patients with reduced benefits or complications from levodopa have been completed in the United States and Europe. Entacapone enhances the effects of levodopa and is safe. Occasional mild side effects include headache, dizziness. nausea, loose stools, increased dyskinesia and changes in the color of urine. Entacapone is taken with each dose of levodopa. Peak effect is within one hour and its duration of action closely matches that of carbidopa/levodopa. These properties suggest that a combination tablet containing levodopa, carbidopa and entacapone may be feasible and desirable. Current plans include further studies to determine the benefit of entacapone in patients taking levodopa, but not experiencing motor fluctuations. ----------------------------------------------------------------------- NEW DOPAMINE AGONISTS ----------------------------------------------------------------------- As soon as levodopa became available for the treatment of Parkinson's disease, efforts to find medications that could mimic its dramatic effect on the symptoms of Parkinson's disease, but with fewer side effects, were begun. The result of this search yielded the well known dopamine agonists bromocriptine (Parlodel) and pergolide (Permax). Neither met the desired expectation of fully replacing levodopa. Only the nonspecific dopamine agonist, apomorphine, has the spectrum of efficacy needed to fully treat patients in a manner similar tolevodopa. Unfortunately, apomorphine has significant side effects and is difficult to store and administer. In a significant step towards achieving true levodopa replacement, two new agents are currently under review by the FDA for use in patients with early Parkinson's disease. In addition to having sufficient potency to act as first line therapy, these two drugs may also have neuroprotective effects that slow disease progression. ----------------------------------------------------------------------- Pramipexole (Mirapex - Pharmacia & Upjohn) ----------------------------------------------------------------------- Pramipexole is a potent, non-ergot dopamine agonist used alone in treating patients not yet taking levodopa and as an adjunct to levodopa in treating advanced Parkinson's disease patients. While stimulating the dopamine D2-receptor, pramipexole may be effective in either blocking or selectively not stimulating the D1-receptor, thereby preventing dyskinesia. More recently, a specific dopamine D3 receptor activity has been identified and linked to a neurotrophic effect. In tissue culture models of Parkinson's disease, pramipexole protected neurons from specific dopaminergic neurotoxins, while bromocriptine and pergolide had no such effect. Pramipexole may also delay the need for levodopa and the development of dyskinesla. End of dose wearing off is reduced in patients with more advanced disease receiving pramipexole and levodopa. Patients in the United States, Canada and Europe have been treated with pramipexole in doses ranging from 0.1 mg to 5 mg daily. No dose-limiting toxicity was identified. Tolerability and safety were excellent with only occasional dizziness, nausea, vomiting, insomnia or somnolence and visual hallucinations identified as primary side effects. Symptomatic low blood pressure was not a significant side effect. The half-life of pramipexole is about 9-12 hours, easily allowing a three times a day schedule. The drug is excreted by the kidneys so that patients with kidney problems may need to be monitored closely for side effects. ----------------------------------------------------------------------- Ropinirole (ReQuip - Smith, Kline and Beecham) ----------------------------------------------------------------------- Ropinirole is a potent, highly selective, dopamine agonist, not related to pramipexole or the ergot derived drugs, developed for early therapy in Parkinson's disease patients not yet treated with levodopa and as adjunct therapy in treating Parkinson's disease patients not optimally controlled on levodopa. This potent D2-dopamine agonist is active both centrally and peripherally with central nervous system and cardiovascular activity seen. Antidepressant and anxiolytic effects have also been noted in patients with Parkinson's disease. Evidence of a possible neuroprotective effect has been documented. More than 300 patients with Parkinson's disease have completed placebo- controlled studies of ropinirole, taking doses up to 10 mg daily. Typical dopamineric side effects such as nausea, vomiting and orthostatic hypotension may occur at doses above 0.5 mg. Incremental dosage increases minimize these side effects, and the drug is tolerated extremely well by the majority of patients. A three times daily dosing schedule of lower doses given with meals allows for fewer side effects and closer conformance to its half-life of 3.5-5 hours. ----------------------------------------------------------------------- Cabergoline (no brandname available - Pharmacia & Upjohn) ----------------------------------------------------------------------- Cabergoline, an ergoline derivative related to bromocriptine and pergolide, is a D2-specific dopaminergic agonist that is more potent and longer-acting than other dopamine agonists currently used to treat Parkinson's disease. In patients receiving levodopa, it effectively decreases levodopa response fluctuations and allows for lower levodopa doses. Plasma activity peaks between 0.5 and 4 hours with a half-life of about 7.5 hours and a slower elimination of 68-72 hours. Patients in Italy, the United States and Canada have been treated with cabergoline once daily in dosages from 0.5 to 5.0 mg. Side effects are typical for dopaminergic agents and can include dizziness, nausea, dry mouth and orthostatic hypotension. Episodes of visual hallucinations also occurred in a few patients. The once daily schedule and long-acting effects offer greater compliance and provide greater control of motor fluctuations than currently available dopamine agonists. Unfortunately, this drug may not be offered as an anti-parkinsonian agent, but instead may only be marketed as a prolactin suppressing agent to stop lactation. At this time, no efforts to market this drug for Parkinson's disease are underway. ----------------------------------------------------------------------- SUMMARY ----------------------------------------------------------------------- The treatment options for patients diagnosed with Parkinson's disease will be increased significantly with the introduction of these new medications. Combining the right amount and frequency of each medication in an individual will be more complicated in some ways, yet simpler in other ways. One prediction would be that newly diagnosed patients will begin therapy with one of the new dopamine agonists. Later such patients might consider adding one of the older drugs that offers additional hope of neuroprotection, either amandatine or selegiline. Another prediction is that patients already taking levodopa, either in the form of Sinemet (primarily taken by US patients) or Madopar (used mainly in Europe), would want to consider addition of a COMT inhibitor, either tolcapone or entacapone. Significant improvements in symptom control and reduced wearing-off can be expected immediately. Both medications work well with either regular carbidopa/levodopa and the slow- release formulation of Sinemet CR. Patients with a stable response to levodopa should experience improvement without needing significant adjustments in levodopa dosages. Some adjustments might be warranted in patients with significant levodopa induced dyskinesia or other dopaminergic side effects. The introduction of these new medications will make 1997 one of the most exciting years for advancements in the treatment of Parkinson's disease. Patients, family members, caregivers, physicians and health care systems all over the world will benefit, all because of the diligent application of our rapidly growing understanding of the functions of the human central nervous system. Given the pace of progress over the last few years, a true understanding of the cause and ultimate cure for Parkinson's disease should not be too far in the future. ----------------------------------------------------------------------- janet [log in to unmask]