A new approach to treating Parkinson's disease?

Summarized by Robert W. Griffith, MD
January 30, 2001 (Reviewed: February 18, 2003)

Introduction

It's been known for some time that dopamine-containing neurones in the substantia nigra have angiotensin type 1 receptors overlying their bodies and their synaptical endings. In Parkinson's disease, there is a reduction in these receptors, along with the accustomed nigrostriatal degeneration. Animal studies have shown that angiotensin II facilitates dopamine release in the striatum, and administration of an angiotensin converting enzyme (ACE) inhibitor that crosses the blood-brain barrier, perindopril, increases striatal dopamine synthesis and release. It was a logical step to study the effect of this ACE inhibitor in patients with Parkinson's disease, and the results of this trial have recently been reported.

Method

Seven patients with moderately severe Parkinson's disease (Hoen and Yahr scale 3, six women and one man) entered a double blind, placebo-controlled crossover study. Ages ranged from 44 to 70, and the duration of Parkinson's disease from 7 to 14 years. They had to have a predictable response to a standard dose of L-dopa, and be free of renal disease, postural hypotension, or allergy to ACE inhibitors.

The subjects received either 4 weeks of placebo or perindopril (2 mg daily for 1 week, then 4 mg daily for 3 weeks). They then underwent a 4-week 'washout' period, followed by 4 weeks of the alternate treatment (perindopril or placebo). Assessments made at the beginning and the end of each 4-week treatment period included:

• Clinical response to a test dose of L-dopa, using Webster scoring for motor function
• Latency of motor response, area over the curve, and peak motor response on the Webster score
• Latency of motor response, severity, area under the curve and peak score on the dyskinesia scale
• Unified Parkinson's Disease Rating Scale (UPDRS) II scores for 'on' and 'off', and Scale IV scores for motor fluctuations

Patients received optimal doses of L-dopa throughout the study, with the doses adjusted as necessary. Adjunct therapy was allowed, but the dose could not be altered during the study period.

Results

Six subjects completed the study - one withdrew with nausea, malaise, and increasing 'off' periods while taking perindopril. After 4 weeks on the ACE inhibitor, 5 of the 6 had a significant increase in the area over the curve for their Webster scores, indicating an increased motor response to their standardized dose of L-dopa. There was a faster onset, and a reduction in 'on' phase peak dyskinesia.

The UPDRS II scores showed that perindopril was associated with improved functional ability in 'off' phases. The patient diaries revealed a modest but significant increase in 'on' periods during ACE inhibitor treatment, which was maximal in the 3rd and 4th weeks on the drug.

While peak dyskinesia scores were reduced, four of six patients had an increase in dyskinesia during the waking day with perindopril. This was probably a reflection of their increased total 'on' times.

There were no perindopril-related adverse effects on blood pressure, postural hypotension, or renal function.

Comment

This study confirmed the concept that an ACE inhibitor can improve the motor response to L-dopa in patients with Parkinson's disease. The drug also increased the proportion of the day spent in the 'on' state, as well as showing an improvement in the functional disability scale used.

Most effective agents in Parkinson's disease induce dyskinesia; perindopril, on the other hand, produced a greater amplitude of motor response to L-dopa with a reduction in peak dyskinesia, i.e. it seems to have an effect beyond simply increasing dopamine release.

The authors of the study point out that the benefits of perindopril were "modest, and not of the magnitude of L-dopa itself". However, the dose was relatively small, and treatment duration was short. As tolerance as good, there is every reason to conduct further studies with higher doses, for longer treatment periods.

Trandolopril, spiropril and perindopril are ACE inhibitors that can penetrate the blood-brain barrier, while enalapril cannot. It might be of interest to study losartan, an angiotensin ATI receptor antagonist that also crosses the blood-brain barrier, in Parkinson's disease. The clinical profile suggested by perindopril in the present study offers promise for the development of new approaches to treating the disease.

Source

• The angiotensin converting enzyme (ACE) inhibitor, perindopril, modifies the clinical features of Parkinson's disease. KA. Reardon, SY. Chai, FAO. Mendelsohn, MK. Horne, Aust NZ J Med, 2000, vol. 30, pp. 48--53

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