F. Stocchi

Rasagiline as an adjunct to levodopa in patients with Parkinson's disease and motor fluctuations (LARGO, Lasting effect in Adjunct therapy with Rasagiline Given Once daily, study): a randomised, double-blind, parallel-group trial

BACKGROUND Rasagiline mesylate is a novel drug for Parkinsons disease with selective, irreversible monoamine oxidase B (MAO-B) inhibitor activity, and is effective as monotherapy in early disease. This study investigated rasagiline efficacy and safety in levodopa-treated patients with Parkinsons disease and motor fluctuations. METHODS In an 18-week, double-blind, multicentre (74 hospitals and academic centres in Israel, Argentina, and Europe) trial, 687 outpatients were randomly assigned to oral rasagiline (231 individuals; 1 mg once daily), entacapone (227; 200 mg with every levodopa dose), or placebo (229). Primary outcome was change in total daily off-time (intention-to-treat population). Other measures included the clinical global improvement (CGI) score and unified Parkinsons disease rating scale (UPDRS) scores. Analysis was by intention to treat. FINDINGS 88 (13%) patients who were assigned treatment did not complete the study (23 rasagiline, 30 entacapone, 35 placebo), mainly because of withdrawal of consent (n=34) and adverse events (n=34). Both rasagiline and entacapone reduced mean daily off-time (-1.18 h rasagiline and -1.2 h entacapone vs placebo -0.4 h; p=0.0001, p<0.0001, respectively) and increased daily on-time without troublesome dyskinesia (0.85 h vs placebo 0.03 h; p=0.0005 for both). We recorded significant mean improvements in CGI scores (-0.86 rasagiline and -0.72 entacapone vs -0.37 placebo; p<0.0001, p=0.0002, respectively). Changes in UPDRS scores also significantly improved for activities of daily living during off-time (-1.71 and -1.38 vs placebo; p<0.0001, p=0.0006, respectively) and motor function during on-time (-2.94 and -2.73 vs placebo; both p<0.0001). Frequency of adverse events was similar for all treatments. INTERPRETATION Once-daily rasagiline reduces mean daily off-time and improves symptoms of Parkinsons disease in levodopa-treated patients with motor fluctuations, an effect similar to that of entacapone.

The Bereitschaftspotential preceding simple foot movement and initiation of gait in Parkinson's disease

We compared the Bereitschaftspotential preceding a simple foot movement while sitting and a stepping movement while standing in a group of normal subjects and seven patients with mild to moderate Parkinsons disease (PD) while off medication. None had major difficulties stepping to initiate gait. Electromyographic signals from tibialis anterior triggered the averaging of electroencephalographic signals from the scalp. Bereitschaftspotentials preceding a standing stepping movement were larger than those before a foot movement while sitting in normal subjects, but no difference was observed in patients with PD. The absence of an increase in the Bereitschaftspotential when stepping in PD may reflect an impairment of the preparation and assembly of the complex sequences of movement necessary to initiate walking, even in the early stages of the illness.

Comparison between a fast and a slow release preparation of levodopa and a combination of the two : a clinical and pharmacokinetic study

After overnight drug withdrawal and in the fasting state, 11 patients with Parkinsons disease (PD) and a fluctuating response to chronic levodopa treatment were given, in random sequence on consecutive days, equivalent levodopa doses (with peripheral decarboxylase inhibitor) (a) as levodopa methyl ester (ME), (b) as Sinemet CR, or (c) as half the dose of ME together with a halved tablet of Sinemet CR. All patients turned ON rapidly after treatments a and c, but only half did so after treatment b. On period duration was longest after treatment c, intermediate after treatment a, and shortest after treatment b. Pharmacokinetic analysis in a subset of 6 patients revealed no significant difference between treatments a and c, although there was a trend for t1/2 to be longer after treatment c. We conclude that giving ME with a halved tablet of Sinemet CR provided a useful clinical balance between rapid onset and extended duration of action of at least the first levodopa intake of the day. In view of differing release profiles between whole and halved tablets of Sinemet CR, similar single-dose pharmacokinetic studies, followed by sequential-dose clinical studies, are indicated when Sinemet CR 125 tablets soon become available.

Sympathetic skin response and cardiovascular autonomic function tests in Parkinson's disease and multiple system atrophy with autonomic failure.

The relationship between sympathetic skin response (SSR) and cardiovascular autonomic function tests (CVTs) was investigated in 15 patients with idiopathic Parkinsons disease (PD), 15 patients with clinical evidence of multiple system atrophy (MSA) with autonomic failure, and in 15 healthy control subjects. SSR was elicited by electrical stimulation of the right and left median nerves and simultaneously recorded on the palms of both hands. CVTs included the following sympathetic and parasympathetic tests: orthostatism, head‐up tilt, cold pressor test, deep breathing, Valsalva maneuver, and hyperventilation. The SSR was normal in all patients with PD and control subjects but was abnormal or absent in all patients with MSA. For patients with MSA, SSR latency was significantly longer and amplitude was significantly smaller than that of patients with PD and control subjects. For patients with PD, SSR did not differ from that of control subjects. In these patients, SSR latency was significantly longer and SSR amplitude was smaller when the side with more marked motor symptoms was stimulated, both ipsilaterally and contralaterally to the side of stimulation. A statistically significant difference in SSR latencies and amplitudes was found between patients with PD and control subjects only when motor asymmetries were considered. CVTs showed severe sympathetic and parasympathetic hypofunction in patients with MSA, but not in patients with PD or control subjects. No correlation was found between SSR and CVTs that assess sympathetic function in patients and control subjects. SSR is indicated as an additional test for the evaluation of sympathetic degeneration in patients with MSA.

The clinical efficacy of oral levodopa methyl ester solution in reversing afternoon "off" periods in Parkinson's disease.

SummaryWe compared the efficacy of a single dose of an oral solution of levodopa methyl ester (ME) to that of standard levodopa, in the form of a single dose of Madopar, in reversing afternoon “off” periods in 12 patients with Parkinsons disease (PD). The highly soluble ME solution led to a significantly more rapid reversal of “off” periods. This preparation may therefore convey a clinical advantage in patients experiencing motor fluctuations whilst taking multiple daily dosages of levodopa, particularly in those with long or highly variable latency to the next “on” period.

Antagonist effect of terguride in Parkinson's disease.

The effects of the partial dopamine agonist terguride (9,10 transdihydrolisuride; THDL) on striatal dopamine receptors were studied by its i.v. administration to 13 patients with Parkinsons disease. Patients were maintained in a steadily mobile state with abnormal involuntary movements by a constant i.v. infusion of levodopa. Terguride showed dopamine antagonist properties in nine patients. In two of these nine patients, a decrease in dyskinesia score was observed without a concomitant worsening of parkinsonian symptoms, whereas in the remaining seven, full parkinsonian akinesia followed THDL administration. The subsequent i.v. injection of the dopamine agonist lisuride reversed THDL-induced akinesia in these seven patients. In the remaining four patients, no clinically significant motor effects were observed. These results show dopamine antagonist activity of terguride in patients with Parkinsons disease treated with Levodopa. Further studies using a wider dose titration are required to evaluate the possible role of dopamine partial agonists in the therapy of levodopa-induced dyskinesias.

Differential diagnosis of Parkinson’s disease

Diagnosis of idiopathic Parkinson’s disease (PD) is essentially clinical and is reached by exclusion. An akinetic rigid syndrome frequently means PD, although a number of other neurodegenerative diseases can share bradykinesia, rigidity, postural instability, and sometimes tremor. Parkinsonism can be classified as follows: pure parkinsonism; parkinsonism associated with other neurological and clinical signs; parkinsonism plus dementia; post-intoxication parkinsonism and parkinsonism due to other causes. The diagnostic approach will be discussed.