In Parkinson's disease, the presynaptic extremities of dopaminergic neurons situated in the substantia nigra are altered to varying degrees, depending on the severity and history of the lesion. Dopamine, a neurotransmitter synthesized in the presynaptic extremities, is therefore synthesized in smaller quantities and postsynaptic nerve endings (especially cholinergic, but also glutamatergic and GABAergic) are no longer sufficiently stimulated to allow effective neurotransmission. Piribedil, the active substance of TRIVASTAL L.A., crosses the blood-brain barrier to act on the cerebral dopaminergic pathways.
Due to its D₂ dopaminergic action, TRIVASTAL L.A. replaces dopamine and compensates for the insufficiency of this neurotransmitter. It binds to D₂ dopaminergic receptors and consequently restores effective neurotransmission (Figure 1).
New findings have recently demonstrated that TRIVASTAL L.A. is also a noradrenergic enhancer, thanks to a presynaptic α2-adrenoreceptor antagonism. This adrenergic property could lead to innovative therapeutic benefits, especially on symptoms which remain today resistant to levodopa.¹

1. Millan M, Cussac D, Milligan G et al. Antiparkinsonian agent Piribedil displays antagonist properties at native, rat, and cloned, human α2 adrenoceptors : cellular and functional characterization. J Pharmacol Experiment Therapeut. 2001;297:876-887.

Yes, indeed. TRIVASTAL L.A. is effective on all the parkinsonian motor symptoms. Thus, TRIVASTAL L.A. is significantly effective on the cardinal symptoms of Parkinson's disease, tremor, bradykinesia and rigidity, but it is also significantly effective on posture, gait, facial expression, speech, and arm swinging.^1-4

1. Truelle JL, Chanelet J, Bastard J, Six P, Emile J. Etude clinique et électrophysiologique prolongée, chez 54 parkinsoniens, d'un nouvel agoniste dopaminergique. Sem Hôp Paris. (Ther). 1977;(B),53(9):453-456.
   
   
2. Rondot P, Ziegler M. Activité et acceptabilité du piribedil dans la maladie de Parkinson : étude multicentrique. J Neurol. 1993;240(translation of suppl1 to vol 239):S28-S34.
   
   
3. Ziegler M, Castro-Caldas A, Del Signore S, Rascol O. Efficacy of piribedil in akinetic-hypertonic parkinsonian patients 4-month combination treatment with L-dopa. Parkinsonism Rel Dis. 2001;7:S1-S133.
   
   
4. Kwiecinski H, Fedorova N, Takacs A, Ruzicka E, et al. A multicenter trial of piribedil as early adjunct treatment for Parkinson's disease. Piribedil International Study Group (PISG). Paper presented at : American Academy of Neurology. Denver. April 2002.

TRIVASTAL L.A. significantly induces less dyskinesia than L-dopa. These results emphasize the importance of avoiding initial dyskinesia induction through early use of dopamine agonist drugs in monotherapy.¹

7. Jenner P, Smith L, Jackson M et al. Piribedil induces low levels of dyskinesia in MPTP-treated common marmosets. Neurology. 2000;54:A53.

Young parkinsonian patients (<50 years) develop more severe and earlier fluctuations and dyskinesias following the introduction of levodopa therapy than older patients.

The international guidelines¹ recommend delaying the introduction of treatment with L-dopa for as long as possible. Therefore, the choice of treatment depends on the severity of the symptoms:

• in the presence of minor motor disability, it is possible to prescribe a first-line dopamine agonist at the lowest possible effective dose (TRIVASTAL L.A., 1 to 2 tablets daily after dose adaptation);
  
  
• in the presence of marked functional slowing, a higher dose of a dopamine agonist can be prescribed as monotherapy for as long as possible (TRIVASTAL L.A., 1 to 4 tablets daily);
  
  
• when the improvement induced with this treatment is insufficient and incompatible with continuing to work, L-dopa treatment is then indicated. It is prescribed at the lowest dosage possible due to combination with a dopamine agonist (1 tablet of TRIVASTAL L.A. for 250 mg of L-dopa).

1. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology. 2000; 54:P04-P041.

Yes, of course, TRIVASTAL L.A. is indicated in monotherapy. This was clearly demonstrated during the multicenter trial coordinated by Prof Rondot. This trial was conducted in 113 parkinsonian patients presenting a complete, or a trembling form of Parkinson's disease. This patient group consisted of 66 men and 47 women, with a mean age of 63.1 ± 0.6 years, and a mean duration of disease of approximately 2 years. The severity of their lesions was scored between I and III on the Hoehn and Yahr scale.(Table I)

TRIVASTAL L.A. was prescribed according to a progressive dosage, reaching 150 to 200 mg/day at the end of the third month. No other parkinsonian treatment was coprescribed. A 30% to 50% improvement in most signs of the disease was observed in the 90 patients who completed the trial.

In the 32 patients in whom tremor was predominant, the tremor score was improved from 1.7 to 1.2, ie, a 29% reduction (P<0.05). In the 58 patients presenting a complete form of Parkinson's disease, the total score on the Webster scale decreased from 1.8 to 6.9, ie, a 42% reduction (P<0.001) (Table II).

TRIVASTAL L.A., used alone in patients who had never previously received L-dopa, was found to be as active on bradykinesia and rigidity as on parkinsonian tremor. This activity has also been confirmed not only in the trembling forms, but also in complete forms of Parkinson's disease. TRIVASTAL L.A. can, therefore, be proposed as monotherapy at the onset of Parkinson's disease.

Webster's scale: 4-point scale (from 0 to 3) including the following 10 items: bradykinesia, rigidity, posture, swinging of extremities, gait, resting tremor, facial expression, seborrhea, speech, autonomy.

Table II. Scores on the Webster scale in the Rondot and Ziegler study.1

Yes, of course, TRIVASTAL L.A. is also recommended in combination with L-dopa. When parkinsonian patients are insufficiently improved by L-dopa, TRIVASTAL L.A. can be added, as demonstrated in at least two studies:

• Professor Rascol¹³ evaluated the complementary activity provided by TRIVASTAL L.A. (150 mg/day for 6 months) in an international, multicenter, randomized, double-blind, placebo-controlled study,involving 115 parkinsonian patients insufficiently controlled by L-dopa, but without fluctuations.

The primary end point was the Unified Parkinson's Disease Rating Scale (UPDRS). After a 4-month treatment, in intention-to-treat, the percentage of responders was significantly higher in the TRIVASTAL L.A. group (56.4% vs 37.7% ; P=0.04). At month 6, the percentage of responders was still significantly higher in the TRIVASTAL L.A. group (61.8% vs 39.6% ; P=0.02). The decrease in the UPDRS III motor score from baseline was significantly higher in the TRIVASTAL L.A. group (P<0.04) (Figure 1).

Moreover,TRIVASTAL L.A. was well tolerated.

Professor Kwiecinski² has recently confirmed the added value of TRIVASTAL L.A. in adjunct to L-dopa in another international, multicenter, randomized, placebo-controlled study. TRIVASTAL L.A. (150 mg/day) was initiated for a 6-month treatment in 273 parkinsonian patients insufficiently controlled by L-dopa.

The primary end point was the improvement of the UPDRS III from baseline. At 6 months, TRIVASTAL L.A. significantly decreased the UPDRS III score more than placebo in both the full analysis set (P=0.009) and in the per-protocol set (P=0.006) (Table III).

Furthermore, TRIVASTAL L.A. provided significant efficacy on all the motor subscores: tremor, rigidity, bradykinesia, posture, and gait. TRIVASTAL L.A. was safe and well-tolerated.

The addition of TRIVASTAL L.A. in patients insufficiently improved by L-dopa provides a marked supplementary improvement.

Main efficacy criterion: UPDRS III change, expressed as mean (standard error)

1. Ziegler M, Lacomblez L, Rascol O, et al. Efficacy of piribedil in adjunction to L-dopa in a 6-month randomized placebo-controlled study in early Parkinson's disease. Neurology. 2000;5:P04-041.
   
   
2. Kwiecinski H, Fedorova N, Takacs A, Ruzicka E, et al. A multicenter trial of piribedil as early adjunct treatment for Parkinson's disease. Piribedil International Study Group (PISG). Paper presented at: American Academy of Neurology. Denver. April 2002.