Different toxicological profile of two COMT inhibitors in vivo: the role of uncoupling effects.

The toxicity profiles of entacapone and tolcapone, novel catechol- O-methyl-transferase (COMT) inhibitors, have been reported to differ from each other. It has also been shown that tolcapone, but not entacapone, is a potent uncoupler of oxidative phosphorylation in vitroat low micromolar concentrations. Signs of hepatotoxicity induced by tolcapone treatment have been previously reported in toxicological studies and in clinical use. The present study was designed to investigate the mechanism of hepatotoxicity of tolcapone and its possible relationship to uncoupling of oxidative phosphorylation in vivo. A 15-day oral toxicity study with entacapone or tolcapone (300 and 500 mg/kg/day) was carried out, and 2, 4-dinitrophenol (DNP), a known uncoupling agent of oxidative phosphorylation, served as a positive reference substance (20 mg/kg/day). No treatment related findings were observed in entacapone-treated rats. Clinical chemistry parameters regarding hepatocellular damage were increased in tolcapone and DNP-treated animals. The energy status measured as ATP/ADP ratio from the liver samples and energy charge (EC) in liver cell mitochondria were diminished both in tolcapone- and in DNP-treated rats. These signs together with clinical symptoms consisting of increased respiration, decreased activity and drowsiness, and elevation of the rectal body temperature observed in tolcapone- and DNP-treated animals suggest a relationship between the treatment and uncoupling of oxidative phosphorylation in vivo.

Comparative toxicological study on the hepatic safety of entacapone and tolcapone in the rat.

Entacapone and tolcapone are novel COMT (catechol-O-methyltransferase) inhibitors indicated for the adjunctive treatment of Parkinson's disease (PD) in combination with levodopa. The marketing authorisation of tolcapone was suspended in the European Union (EU) in 1998 mainly due to severe abnormal hepatic reactions. This fact raised concern about the safety of COMT inhibitors in the treatment of parkinsonian patients. In order to investigate whether these COMT inhibitors exhibit different effects on the liver comparative toxicological studies were performed in the rat. Short term toxicological studies in rats at high oral doses of entacapone and tolcapone (200, 400 or 600mg/kg daily) were carried out. Tolcapone (400 mg/kg/day or 600 mg/kg/day) increased mortality after only one week treatment and induced signs of toxicity such as a rise in body temperature, stimulation of respiration and rapid onset of rigor mortis after death. Entacapone did not show any adverse effects at the tested dose levels. In the histopathological examination liver cell necrosis was observed in the tolcapone (400 and 600mg/kg/day) treated rats, but it revealed no treatment related signs of toxicity in entacapone-treated rats. We conclude that the toxicological profile of the two COMT inhibitors, entacapone and tolcapone, differ from each other, tolcapone--unlike entacapone--showed hepatotoxicity.

Selegiline treatment and the extent of degenerative changes in brain tissue of patients with Alzheimer's disease.

BACKGROUND: A beneficial effect of selegiline (L-deprenyl) in Alzheimer's disease (AD) has been reported in several clinical studies. METHODS: The brain tissue from 17 deceased patients, members of a double-blind clinical trial to assess the potential benefit of selegiline in AD, were analysed. FINDINGS: In our study, the decrease in the Mini-Mental State Examination (MMSE) scores during the progress of the disease had been significantly influenced by selegiline treatment. Prior to death, the MMSE scores were significantly higher in those patients receiving selegiline than in those receiving placebo. However, according to our results, none of the lesions critical for AD diagnosis, such as counts of senile/neuritic plaques, neurofibrillary tangles or beta-A4 load, were influenced by the selegiline treatment. INTERPRETATION: In conclusion, according to our study, mechanisms other than neuronal degeneration seen as lesions critical for AD diagnosis are influenced by selegiline treatment, leading to the functional benefit found in AD.

Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis.

INTRODUCTION: The Parkinson's Disease Research Group of the United Kingdom (PDRG-UK) reported increased mortality in PD patients treated with levodopa plus selegiline compared with those treated with levodopa alone. METHODS: We performed a meta-analysis on five long-term, prospective, randomized trials of selegiline in patients with untreated PD. Included in the analysis were four randomized, double-blind, placebo-controlled studies and one randomized, double-blind, placebo-controlled study of 2 years' duration followed by long-term, open follow-up. RESULTS: The mean duration of follow-up was 4.1 +/- 1.8 years. There were 14 deaths in 297 selegiline-treated patients (4.7%) and 17 deaths in 292 non-selegiline-treated patients (5.8%). The hazard ratio for mortality was 1.02 (95% CI 0.44 to 2.37; p = 0.96). An analysis restricted to patients receiving only levodopa with or without selegiline noted 11 deaths in 257 levodopa/selegiline-treated patients (4.3%) and 11 deaths in 254 patients treated with levodopa alone (4.3%). The hazard ratio was 1.06 (95% CI 0.44 to 2.55; p = 0.90). Death rate per 1,000 patient years was 11.4 in the selegiline group and 14.2 in the nonselegiline group. Kaplan-Meier survival curves reflecting pooled survival data showed no significant difference in duration of survival. The hazard ratio was 0.84 (95% CI 0.41 to 1.70; p = 0.63) for selegiline- versus non-selegiline-treated patients and 1.05 (95% CI 0.46 to 2.43; p = 0.91) for selegiline/levodopa- versus levodopa-treated patients. CONCLUSION: These results contrast with those of the PDRG-UK study and demonstrate no increase in mortality associated with selegiline treatment whether or not patients also received levodopa.

Selegiline delays the onset of disability in de novo parkinsonian patients. Swedish Parkinson Study Group.

OBJECTIVE: The objective of this study was to investigate the effect of selegiline first as monotherapy and then in combination with levodopa in the early phase of PD. METHODS: A total of 157 de novo PD patients were randomized to receive either selegiline or placebo in a double-blind study until levodopa therapy became necessary. Thereafter, the drugs were withdrawn for an 8-week washout period to evaluate the possible symptomatic effect of selegiline. RESULTS: Analysis of Kaplan-Meier survival curves for each group showed that selegiline delayed significantly the need for levodopa therapy (p = 0.028). The semiannual rate of disability progression was slowed down significantly in the selegiline group analyzed with the Unified Parkinson's Disease Rating Scale (total and motor scores; p < 0.001). Selegiline had a "wash-in" effect (i.e., an initial symptomatic amelioration of PD at 6 weeks and 3 months). However, after the 8-week washout period, no significant differences in the deterioration of disability between the groups was revealed in any of the scales, suggesting that besides having a slight symptomatic effect, selegiline may also have neuroprotective effects. Similarly, the progression of symptoms from baseline to the end of the washout period was significantly slower (p = 0.033) in the selegiline group when the progression was adjusted by the time to reach the end point. Selegiline was well tolerated. CONCLUSIONS: Selegiline delayed significantly the need to start levodopa in early PD. After a 2-month washout period (before the start of levodopa therapy) no significant symptomatic effect of selegiline was seen in comparison with the placebo group, supporting the concept of neuroprotective properties of the drug.

Safety of selegiline (deprenyl) in the treatment of Parkinson's disease.

Selegiline (deprenyl), a selective, irreversible inhibitor of monoamine oxidase type B (MAO-B) is widely used in the treatment of Parkinson's disease. As the first MAO-B inhibitor approved for the treatment of Parkinson's disease, concerns were raised about the safety of the drug based on the adverse effect profiles of older, nonselective MAO inhibitors. Unlike the nonselective MAO inhibitors, selegiline does not significantly potentiate tyramine-induced hypertension (the 'cheese effect') at the dosages (5 to 10 mg daily) used for the treatment of Parkinson's disease. Selegiline has been well tolerated when given alone. The most frequent adverse events seen during monotherapy have been insomnia, nausea, benign cardiac arrhythmias, dizziness and headache. When combined with levodopa, selegiline can potentiate the typical adverse effects of levodopa, if the dose of levodopa is not reduced sufficiently. Thus, the most common adverse effects associated with this combination are nausea, dizziness, fatigue, constipation and insomnia. At the later stages of Parkinson's disease when fluctuations in disability occur, peak dose dyskinesias, psychiatric complications like hallucinations and insomnia, and orthostatic hypotension are further potentiated by selegiline. Mortality was recently reported to be increased when selegiline and levodopa were given together in comparison with treatment with levodopa alone, but a large meta-analysis of 5 long term studies and 4 separate studies did not support this conclusion. Selegiline seems to be generally well tolerated in combination with other drugs. However, when pethidine (meperidine) has been given to patients who are receiving selegiline therapy, severe adverse effects have been reported. Thus, the concomitant use of these drugs is not recommended. A low tyramine diet is recommended if selegiline is used together with nonselective MAO inhibitors or the selective, reversible MAO-A inhibitor, moclobemide. Several adverse effects have been reported when fluoxetine and selegiline have been used together. A recent survey revealed that the incidence of a true serotonin syndrome is, however, very low with this combination. Concomitant use of selegiline and other selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) like citalopram, which have generally less interactions than fluoxetine, seems to be well tolerated. Nevertheless, caution is advised when combining a SSRI or a tricyclic antidepressant and selegiline.

Deprenyl and desmethylselegiline protect mesencephalic neurons from toxicity induced by glutathione depletion.

Oxidative stress is thought to play an important role in the pathogenesis of Parkinson's disease (PD). Glutathione (GSH), a major cellular antioxidant, is decreased in the substantia nigra pars compacta of PD patients. The aim of the present study was to investigate whether deprenyl and its desmethyl metabolite, putative neuroprotective agents in the treatment of PD, could protect cultured rat mesencephalic neurons from cell death caused by GSH depletion due to treatment with L-buthionine-(S,R)-sulfoximine (BSO). BSO (10 microM) caused extensive cell death after 48 hr, as demonstrated by disruption of cellular integrity and release of lactate dehydrogenase into the culture medium. Both deprenyl and desmethylselegiline, at concentrations of 5 and 50 microM, significantly protected dopaminergic neurons from toxicity without preventing the BSO-induced loss in GSH. Protection was not associated with monoamine oxidase type B inhibition in that pargyline, a potent MAO inhibitor, was ineffective and pretreatment with pargyline did not prevent the protective effects of deprenyl. Protection was not associated with inhibition of dopamine uptake by deprenyl because the dopamine uptake inhibitor mazindol did not diminish BSO toxicity. The antioxidant ascorbic acid (200 microM) also protected against BSO-induced cell death, suggesting that oxidative events were involved. This study demonstrates that deprenyl and its desmethyl metabolite can diminish cell death associated with GSH depletion.

Inhibition of platelet monoamine oxidase type B by selegiline.

Selegiline is an irreversible inhibitor of monoamine oxidase type B (MAO-B). No comparative data are available on the MAO-B inhibition caused by orally and intravenously administered selegiline. This study aimed to clarify this matter and to investigate the dose-response of MAO inhibition caused by orally administered selegiline. Sixteen healthy volunteers were given selegiline as a single intravenous dose (0.5 mg) and in three low oral doses (0.5 mg, 1.0 mg, and 1.5 mg) in an open-label randomized crossover trial. The MAO-B inhibition after the 0.5-mg intravenous dose was 79.6 +/- 15.1%. The dose-response of the three oral doses causing MAO-B inhibition was logistic. To check whether this equation could be applied to higher doses, eight of the volunteers were given 5-mg and 10-mg oral doses. The MAO-B inhibition after these doses (84.9 +/- 11.9% and 95.6 +/- 4.5, respectively) fitted well with the logistic model. With this equation obtained, it was calculated that a 3.4-mg oral dose of selegiline would be needed to obtain the same degree of MAO-B inhibition as after the intravenous dose of 0.5 mg. Therefore, the ratio of MAO-B inhibitory potential of intravenously and orally given selegiline is approximately 7 to 1, which fits well with the low bioavailability of the drug after oral administration.

Desmethylselegiline, a metabolite of selegiline, is an irreversible inhibitor of monoamine oxidase type B in humans.

Selegiline, an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is metabolized into desmethylselegiline, levomethamphetamine, and levoamphetamine. In animal experiments, desmethylselegiline also has been shown to be an irreversible inhibitor of MAO-B. This study investigated the inhibitory potential of MAO-B and the pharmacokinetics of desmethylselegiline in humans. A double-blind, crossover trial was performed to compare the effects of a single dose (10 mg) of selegiline or desmethylselegiline on MAO-B platelet activity. The urinary excretion of phenylethylamine, which is considered to be a parameter of MAO-B inhibition, also was measured. The concentrations of selegiline, desmethylselegiline, and their metabolites were measured in plasma after administration of the two compounds. Ten healthy volunteers participated in the study. There was a clear inhibition of platelet MAO-B by both compounds. Desmethylselegiline caused a 63.7 +/- 12.7% inhibition of platelet MAO-B compared with 96.4 +/- 3.9% caused by selegiline. The maximal inhibition by desmethylselegiline was reached significantly later after desmethylselegiline (time to reach maximal inhibition [tmax], 27 +/- 20 hours) than after selegiline administration (tmax, 1.4 +/- 1.4 hours). The platelet MAO-B activity returned to baseline levels within 2 weeks, thus reflecting the irreversible nature of the inhibition by both compounds. The cumulative 48-hour excretion of phenylethylamine was 33% lower after desmethylselegiline than after selegiline administration. All three major metabolites of selegiline could be detected in plasma after selegiline administration. Levoamphetamine was the only metabolite of desmethylselegiline. The area under the concentration-time curve from time 0 to 24 hours (AUC0-24) of desmethylselegiline was 33 times higher than that of selegiline, suggesting a better bioavailability of desmethylselegiline. Desmethylselegiline is an orally active, irreversible inhibitor of MAO-B and could possibly be used to treat Parkinson's disease in the same way as selegiline.

Selegiline as the primary treatment of Parkinson's disease--a long-term double-blind study.

INTRODUCTION: To assess the therapeutic efficacy of selegiline combined with levodopa in the long-term treatment of Parkinson's disease (PD). MATERIAL AND METHODS: A randomized, prospective, double-blind study on 44 patients with PD needing levodopa therapy after the initial double-blind treatment with placebo or selegiline was carried out. The patients were followed-up for 5 years under combination therapy. RESULTS: Selegiline induced a significant (P < 0.001) slowing in the need to increase the daily levodopa dose in order to compensate for the progression of the disease. After 5 years of combination therapy the mean dose of levodopa was on average 320 mg lower in the selegiline group (405 +/- 59 mg vs 725 +/- 78 mg). The difference in the levodopa doses between the two groups increased along with follow-up time, as also the ratio of the levodopa doses (placebo/selegiline group). The number of daily levodopa doses needed to compensate for the occurrence of motor fluctuations was significantly lower in the selegiline group. The parkinsonian disability did not differ between the two groups because the clinical condition was kept as optimal as possible by adjusting the levodopa dosage. Nine patients in the placebo group needed initiation of additional dopaminergic therapy in comparison to one in the selegiline group (P = 0.004). During the 5-year follow-up period 11 patients were withdrawn from the selegiline group, 7 due to adverse events. There was no difference in mortality between the two groups. CONCLUSIONS: Selegiline therapy offers beneficial long-term effets in the treatment of PD.

Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease.

In an earlier report of our placebo-controlled selegiline trial on de novo parkinsonian patients, we have shown that the need to start additional levodopa therapy is significantly postponed by using selegiline monotherapy. Now we report the two-year interim results of the double-blind continuation of the trial in 44 patients after the introduction of levodopa to the earlier therapy with placebo or selegiline (21 and 23 patients, respectively). The clinical disability was assessed by three rating scales. The daily dose of levodopa needed to maintain an optimal condition had to be increased progressively up to a 52% higher level in the placebo group than in the selegiline group (543 +/- 150 and 358 +/- 117 mg, respectively, p < 0.001). The number of daily doses of levodopa was also statistically significantly higher in the placebo group during the 24 months' observation period (p < 0.01). The ratio of levodopa doses that was expected to stay the same contrarily significantly increased suggesting that selegiline would, besides having the levodopa potentiating effect, also have a beneficial influence on the progression of the basic cerebral dopamine deficiency. The combination of selegiline and levodopa was well tolerated, and the adverse event profiles did not differ from each other. In conclusion, early selegiline therapy allows a significant saving in the subsequent levodopa dosage. This saving seems to become even stronger along with the treatment time.

Pharmacokinetic aspects of l-deprenyl (selegiline) and its metabolites.

l-Deprenyl (selegiline), an irreversible and selective inhibitor of monoamine oxidase type B (MAO-B), is rapidly absorbed from the gastrointestinal tract and distributed into tissues. The reaction between MAO and selegiline takes place in two steps. The initial reversible reaction is followed by an irreversible reaction in which selegiline is bound covalently to the flavin part of the enzyme. Studies with positron emission tomography have shown retention of selegiline in brain areas with high MAO-B activity, including striatal structures, hippocampus, thalamus, and substantia nigra. Inhibition of MAO-B in vivo takes place rapidly; for example, platelet MAO is inhibited almost totally within the first 60 minutes after a single 10 mg oral dose of the drug. The recovery of MAO after inhibition depends on the organ and species in question. In rat brain the half-life of recovery in the brain is approximately 8 to 12 days; in rat liver it is shorter, 1 to 3 days. Selegiline is metabolized into l-(-)-desmethylselegiline, l-(-)-methamphetamine, and l-(-)-amphetamine mainly in the liver through the microsomal P-450 system. The stereoselectivity of the metabolites is maintained; no racemic transformation takes place. All three main metabolites are found in human serum, cerebrospinal fluid, and urine, and l-(-)-methamphetamine accounts for most of the metabolite pool. The metabolites are excreted mainly via urine l-(-)-Desmethylselegiline has been shown to be an irreversible inhibitor of MAO-B in the rat and in humans.

Selegiline in the treatment of narcolepsy.

We treated 17 narcolepsy patients in a placebo-controlled, double-blind, crossover trial with 10-, 20-, 30-, and 40-mg daily doses of selegiline, a monoamine oxidase inhibitor widely used in Parkinson's disease. There was a dose-dependent as well as a statistically and clinically significant improvement in narcoleptic symptoms and polygraphic measures. At 40 mg, there was a 36% reduction in the number of daytime sleep episodes and a 34% reduction in their duration (compared with placebo, mean values). The number of excessive sleepiness episodes decreased by 43%, and the duration decreased by 47%. The number of cataplectic attacks was reduced by 89%. On the multiple sleep latency test, the REM sleep latency increased from 5.0 to 13.3 minutes, and the number of sleep-onset REM periods decreased from 3.1 to 0.6. Sleep (S1) latency was not changed. No intolerable adverse events occurred. The effective dose range was 20 to 40 mg, requiring a low-tyramine diet, which was easy to maintain. In conclusion, selegiline alleviates both main symptoms of narcolepsy--the abnormal sleep tendency and cataplexy. Thus, treatment with selegiline makes it possible to avoid polypharmacy and to use a potent stimulant without known addiction risk.

Selegiline in de novo parkinsonian patients: the Finnish study.

Selegiline (L-deprenyl) has been recommended as an antiparkinsonian drug to be used as an adjunct to therapy with L-dopa, if and when L-dopa starts to lose its effect. However, initial selegiline monotherapy followed by L-dopa may be both effective and safe. A double-blind, placebo-controlled trial was carried out in previously untreated patients with Parkinson's disease randomized to receive selegiline (10 mg/day; 27 patients) or placebo (25 patients) until L-dopa treatment became imperative. Three rating scales were used for assessment. The study design continues to be double-blind even after L-dopa is introduced. L-Dopa was needed after 545 +/- 90 days in the selegiline group. This was significantly later (p = 0.03) than after placebo (372 +/- 28 days). Disability was less severe in the selegiline group, and there were no serious adverse effects. A nearly twofold dose of L-dopa was needed in the placebo group to achieve a sufficient therapeutic effect during long-term treatment. These results show that selegiline is safe and effective as monotherapy in early parkinsonism. It delays the need for L-dopa treatment and reduces the amount of daily L-dopa required. This could be explained by either a symptomatic effect or neuroprotective efficacy or, more likely, a combination of both.

Effects of monoamine oxidase inhibition by selegiline on concentrations of noradrenaline and monoamine metabolites in CSF of patients with Alzheimer's disease.

A double-blind, cross-over trial with 12 patients with Alzheimer's disease (AD) was carried out primarily to test the suitability of this design in the investigation of the clinical effects of selegiline (10 mg/day) in AD. Cerebrospinal fluid (CSF) samples for the determination of concentrations of noradrenaline (NA) and several monoamine metabolites were collected at baseline and at the end of both four-week treatment periods (placebo and selegiline). The severity of dementia was assessed using Ferm's and Gottfries-Bråne-Steen (GBS) dementia scales. The concentrations of the dopamine metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the NA metabolites, 3,4-dihydroxyphenylglycol (DHPG), and 3-methoxy-4-hydroxyphenyl glycol (MHPG) decreased significantly during selegiline treatment. There was a clear trend of reduction in concentrations of homovanillic acid (HVA) during selegiline treatment, whereas the concentrations of NA, 5-hydroxyindoleacetic acid (5-HIAA), and tryptophan did not differ significantly. The study design was not suitable for the analysis of the clinical results as there was a significant carry-over effect in both scales. As only the first period data could be used in the analysis, there were no significant differences in the scores of Ferm's or GBS scales, but clear positive trends could be detected in favour of selegiline.

Comparative bioavailability of carbamazepine from two slow-release preparations.

In order to compare the multiple-dose bioavailability of carbamazepine (CBZ) from 2 slow-release preparations, Neurotol slow and Tegretol Retard, a single-blind, randomized, cross-over study was carried out. 21 adult patients with epilepsy were enrolled in the study. At the end of both 2-week treatment periods, a blood sample series was drawn after the administration of the morning CBZ dose. The serum concentrations of CBZ, CBZ-10,11-epoxide (CBZE) and 10,11-dihydro-10,11-trans-dihydroxy-CBZ (CBZD) were measured using HPLC. The mean bioavailability of CBZ from Neurotol slow was 11% (P = 0.002) higher than from Tegretol Retard. Owing to the better bioavailability, the peak (Cmax), lowest (Cmin) and mean (Css) concentrations of CBZ were also significantly higher during Neurotol slow treatment. Fluctuation of serum CBZ concentrations (Cmax-Cmin/Css, ADCss/AUC0-12h) did not differ significantly between the 2 treatments; neither did tmax. Similar results were obtained with CBZE and CBZD. There were more epileptic seizures on Tegretol Retard than on Neurotol slow, but the difference was not statistically significant. We conclude that there are significant differences in the bioavailability of CBZ from these 2 slow-release preparations.

Selegiline as initial treatment in de novo parkinsonian patients.

To investigate the efficacy and safety of selegiline in the early phase of Parkinson's disease (PD), we carried out a placebo-controlled, double-blind, parallel trial. De novo PD patients were randomized to receive either selegiline (10 mg/d) or matching placebo. We continued selegiline or placebo until levodopa therapy became necessary and assessed the disability using three different rating scales at baseline, after 3 weeks, at 2, 4, 8, and 12 months, and at every 4 months thereafter. Fifty-two patients were eligible for the analysis, 27 in the selegiline group and 25 in the placebo group. The median duration of time before levodopa had to be initiated was 545 +/- 90 days with selegiline and 372 +/- 28 days with placebo (p = 0.03). Disability was significantly less in the selegiline group than in the placebo group up to 12 months. The period of time during which the mean total Columbia University Rating Scale score stayed below the baseline was used to express the initial symptomatic effect of the treatments. The difference in this initial improvement time between the two groups was about 3 months and did not alone explain the difference in the delay of the need to start levodopa therapy. Selegiline was well tolerated and there were no severe side effects. We conclude that selegiline delays the need to start levodopa in de novo PD patients, has symptomatic efficacy, and possibly retards the progression of the disease.

Optoelectronic movement analysis in Parkinson's disease: effect of selegiline on the disability in de novo parkinsonian patients--a pilot study.

New opto-electronic camera systems permit easy quantification of the motor performance during natural acts in freely moving humans. We used a simple test movement (PLM test) to quantify the disturbance in the postural (P), locomotor (L) and manual (M) part of the body movement and the coordination of the different movement phases into a smooth motor act. The test movement time was used to quantify the overall performance. With this technique we have measured the effects of selegiline on the degree of parkinsonism in a double-blind, placebo-controlled pilot study of 5 de novo patients with Parkinson's disease. There was a clear trend that selegiline was superior to placebo in reducing the test movement time.

Selegiline as a primary treatment of Parkinson's disease.

In order to investigate the efficacy of selegiline as a primary treatment in Parkinson's disease (PD), we carried out a placebo controlled, double-blind prospective trial. Fifty-four de novo patients with PD were randomized to receive either selegiline (10 mg/day) or matching placebo. We continued the monotherapy until the initiation of levodopa therapy became necessary. The disability of the patients was evaluated with three different rating scales at baseline, after 3 weeks, 2, 4, 8, and 12 months, and every 4 months thereafter. Fifty-two patients were eligible for the final analysis: 27 in the selegiline group and 25 in the placebo group. The median duration of time without levodopa was 545 +/- 90 days in the selegiline treated patients and 372 +/- 28 days in the placebo treated ones (p = 0.03). The disability of the patients was significantly milder in the selegiline than in the placebo group up to 12 months. More patients showed symptomatic improvement in the selegiline than in the placebo group. However, the symptomatic effect alone did not explain the prolongation of the time without levodopa in the selegiline treated patients. Selegiline was well tolerated and no severe side effects were encountered.