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L-Dopa and piribedil alter different components of attentional behavior dependent on dose.

L-Dopa (3, 10, 30, 100 mg/kg) given SC after carbidopa, and piribedil (10, 30, 100, 300 mg/kg) had biphasic effects on investigation of a novel cup. Gerbils given a low dose of L-Dopa (10 mg/kg) or piribedil (10 or 30 mg/kg) investigated the cup more than did vehicle-injected gerbils, whereas those gerbils given a high dose of L-Dopa (100 mg/kg) or piribedil (300 mg/kg) investigated it less. L-Dopa, but not piribedil, also had biphasic effects on investigation of conspecific odors. The increase in duration with no increase in frequency of investigation suggested an inability to shift attention normally. High-dose attenuation of investigation is considered nonspecific, as many other drugs have the same effect. Locomotor activity scores showed no concomitant increase following low doses, but only a dose-dependent decrease. In addition, L-Dopa (100 mg/kg), but not piribedil at any dose tested, prevented the normal decrement in response to the cup 24 h after injection. As a high response is normally only shown when the stimulus is novel, the data suggest that L-Dopa at the high dose, but not piribedil, interfered with selective attention. Thus, the different dopamine agonists affected different aspects of attention. The data are discussed in relation to neural effects of the drugs as reported in the literature.

Animals↗

Parkinson's disease: pathological mechanisms and actions of piribedil.

The cause of the degeneration of dopamine-containing cells in the zona compacta of the substantia nigra in Parkinson's disease remains unknown. The ability of the selective nigral toxin 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) (via its metabolite MPP+) to destroy nigral dopamine cells selectively by inhibiting complex I of the mitochondrial energy chain may provide a clue. Indeed, recent studies of post-mortem brain tissue have suggested the presence of an on-going toxic process in the substantia nigra in Parkinson's disease leading to excess lipid peroxidation. This appears also to involve a disruption of mitochondrial function since mitochondrial superoxide dismutase activity is increased and there is impairment of complex I. These changes may in turn relate to a selective increase in the total iron content of substantia nigra coupled to a generalised decrease in brain ferritin content. Piribedil is used in the symptomatic treatment of Parkinson's disease and is particularly effective against tremor. Piribedil (and its metabolites) acts as a dopamine D-2 receptor agonist. However, in our studies in contrast to other dopamine agonists, in vivo piribedil interacts with dopamine receptors in the substantia nigra and nucleus accumbens but not those in the striatum. In patients with Parkinson's disease the beneficial effects of piribedil may be limited by nausea and drowsiness. Indeed, in MPTP-treated primates piribedil reverses motor deficits but marked side-effects occur. However, pre-treatment with the peripheral dopamine receptor antagonist domperidone prevents the unwanted effects and piribedil produces a profound and longer-lasting reversal of all components of the motor syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

Formulation and in vitro-in vivo evaluation of piribedil solid lipid micro- and nanoparticles.

Modification of the dissolution rate and, thus, the enhancement of the bioavailability of a dopaminergic drug, piribedil, which has a low aqueous solubility and short elimination half-life have been the aim in this study. Preparations of micron and submicron particles using solid lipid carriers have been performed for this purpose. For the avoidance of solvent residues resulting from the preparation technique, cold and hot homogenization methods have been used to prepare solid lipid particles. After obtaining an appropriate particle size, piribedil loading and preparation yield by the use of those two methods, various formulations have been prepared with different lipid, drug and surfactant materials. The factors mentioned were found to affect properties of the particles, and the release rate was found to be the fastest in acidic medium. Suspensions of pure piribedil and a formulation, selected according to the results obtained from in vitro dissolution and particle size experiments, were compared using tremor tests in mice. The same suspensions were applied perorally to rabbits and bioavailability of the solid lipid particle was found to be higher than the pure piribedil. After an in vitro-in vivo evaluation of piribedil solid lipid particles developed for Parkinson's disease therapy, it has been determined that release rate could be controlled and piribedil bioavailability could be improved.

Animals↗

Cognitive skill learning in healthy older adults after 2 months of double-blind treatment with piribedil.

RATIONALE: Cognitive skill learning, as assessed by repeated testing on the Tower of Toronto (TT) task, has been found to be impaired in normal aging. There is evidence that this impairment might be accounted for by the well-documented, age-dependent decline of dopamine D2-like receptor availability. OBJECTIVES: This study was an investigation of whether the D2/D3 dopaminergic agonist piribedil improves cognitive skill learning in older adults. METHODS: Healthy elderly volunteers were assessed using the TT paradigm. Subjects were evaluated at baseline, and after 2 months of a placebo or piribedil (50 mg daily) treatment in a double-blind, crossover design. Two components of cognitive skill learning were considered--the ability to learn to solve the puzzle and the acquisition of a problem-solving routine. RESULTS: Piribedil showed a beneficial effect on the acquisition of a problem-solving routine, depending on the age of subjects, as revealed by solution reliability indexes measures. The effect of piribedil on the ability to learn to solve the puzzle was found to be dependent on the subject's working memory capacities. CONCLUSIONS: The present results suggest that piribedil is likely to enhance cognitive skill learning in healthy older adults and give further evidence that age-related dopamine decline plays an important role in cognitive impairment occurring in normal aging.

Aged↗

The influence of piribedil (ET495) on components of locomotor activity.

Recent evidence suggests piribedil affects both cerebral NA neurones and DA neurones and receptors since it increases brain MOPEG-SO4, an observation confirmed presently. In the reserpinised mouse piribedil and apomorphine caused a reversal of akinesia, which was significantly enhanced by concurrent administration of clonidine. However, piribedil neither reduced nor increased the motor effects of apomorphine or L-DOPA in the reserpinised mouse, but slightly enhanced that of amphetamine. Phenoxybenzamine reduced the motor action of L-DOPA but had no effect on that of apomorphine or amphetamine. These results suggest piribedil has no significant NA receptor blocking or stimulating action in the reserpinised animal. They confirm the view that piribedil increases cerebral NA turnover due to a presynaptic action on NA neurones.

Amphetamine↗

In vitro affinity of piribedil for dopamine D3 receptor subtypes, an autoradiographic study.

Receptor binding autoradiography, using the selective ligand [3H]7-OH-(R)DPAT (R(+)-2-dipropylamino-7-hydroxy 1,2,3,4-tetrahydronaphthalene), showed that piribedil is a potent inhibitor at dopamine D3 receptors in limbic regions (island of Calleja), with affinity (IC50) between 30 and 60 nM. The in vitro IC50 of piribedil for inhibition of [3H]spiperone binding to receptors of the dopamine D2-like family (D2, D3 and D4), ranged between 10(-7) and 10(-6) M in different brain regions (medial and lateral caudate putamen, olfactory tubercles, and nucleus accumbens). At the highest concentration tested (10(-5 M) piribedil inhibited dopamine D1 receptor binding by < 50%. It is concluded that piribedil has 20 times higher affinity for dopamine D3 than for dopamine D2-like receptors, and very low affinity for the dopamine D1 receptor subtype in rat brain. How this pattern of receptor affinity is related to the pharmacological profile of piribedil deserves further investigation.

Animals↗

Different effects of dopamine and piribedil (a dopamine D2 agonist) on frog monocular optokinetic nystagmus asymmetry.

Frog monocular optokinetic nystagmus (OKN) displays a directional asymmetry, reacting only to stimulations in the temporal-nasal (T-N) direction. The nasal-temporal (N-T) component is almost absent. The systemic or intrapretectal injection of Piribedil, a D2 dopamine agonist, provokes the appearance of a N-T component suppressing the monocular OKN asymmetry. Conversely, dopamine or haloperidol (a dopamine antagonist, acting mainly on D2 receptors) have no effect upon the monocular OKN unidirectionality. The monocular OKN N-T component still appears after administration of Piribedil even if this injection is preceded by administration of haloperidol which blocks the dopaminergic D2 receptors. Moreover administration of atropine (a cholinergic muscarinic antagonist) following that of Piribedil suppresses the N-T component; when injected before Piribedil, atropine prevents the appearance of the N-T component. These results suggest that in our experiments, Piribedil binds with muscarinic receptors.

Animals↗

Effects of a D1 and a D2 dopamine antagonist on the self-administration of cocaine and piribedil by rhesus monkeys.

Rhesus monkeys were surgically prepared with chronic intravenous catheters and allowed to self-administer the indirect dopamine (DA) agonist cocaine (0.03 or 0.1 mg/kg/inj) or the direct D2 agonist piribedil (0.1 or 0.2 mg/kg/inj) on a fixed-ratio 10 schedule of drug delivery during daily 2 hour experimental sessions. When responding was stable, they were injected IV with SCH 23390, a selective D1 antagonist (0.003-0.3 mg/kg, 30 min pre-session) or pimozide, a selective D2 antagonist (0.003-0.3 mg/kg, 2 hours pre-session). Intermediate doses of pimozide generally increased self-administration of cocaine or piribedil, though increases in piribedil self-administration were more reliable. In contrast, intermediate doses of SCH 23390 either did not affect or decreased cocaine and piribedil self-administration. High doses of each antagonist decreased the rate of self-administration of each compound and produced catalepsy. The selective increase in responding maintained by cocaine or piribedil following pimozide pretreatment suggests a role for a D2-like receptor in psychomotor stimulant self-administration.

Animals↗

Effects of piribedil and of d-amphetamine on locomotor activity in immature rats.

The effects of piribedil, a direct dopamine (DA) agonist, and of d-amphetamine, an indirect DA agonist, on locomotor activity in 28-day old rats have been investigated. d-Amphetamine (1,2 and 4 mg/kg) increased activity in a dose dependent manner whereas only a 40 mg/kg dose of piribedil significantly increased activity; low doses of piribedil (1.25-10.0 mg/kg) had no effect on activity. Since hyperactivity induced by a direct DA agonist, such as piribedil, is thought to reflect post-synaptic DA receptor activation, the results appear to indicate that post-synaptic DA receptor mechanisms are fully developed in 28-day old rats. In contrast, as low doses of piribedil which cause sedation in adult animals failed to decrease locomotor activity under the present experimental conditions, it seems that DA autoreceptors may not be well developed in 28-day old rats.

Aging↗

Presynaptic actions of piribedil on the cardiovascular system of the pithed rat.

The influence of piribedil on cardiovascular sympathetic responses has been studied in the pithed rat. Piribedil (0.3-1 mg kg-1) inhibited the increases of diastolic blood pressure induced by spinal cord electrical stimulation at the level Th5-L4. This effect was reversed by sulpiride (0.3 mg kg-1) but not by yohimbine (0.3 mg kg-1). The cardiovascular responses induced by noradrenaline were unaffected by piribedil (0.3-1 mg kg-1). However piribedil (0.3-1 mg kg-1) did not modify the heart rate increase induced by spinal cord electrical stimulation at the C7-Th1 level. These results suggest that piribedil inhibits the vascular sympathetic transmission in the pithed rat via stimulation of presynaptic dopamine receptors.

Animals↗

Piribedil enhances frontocortical and hippocampal release of acetylcholine in freely moving rats by blockade of alpha 2A-adrenoceptors: a dialysis comparison to talipexole and quinelorane in the absence of acetylcholinesterase inhibitors.

In a dialysis procedure not requiring perfusate addition of acetylcholinesterase inhibitors to "boost" basal levels of acetylcholine (ACh), the influence of the antiparkinson agent piribedil upon levels of ACh in frontal cortex and dorsal hippocampus of freely moving rats was compared with those of other antiparkinson drugs and selective ligands at alpha(2)-adrenoceptors (ARs). Suggesting a tonic, inhibitory influence of alpha(2A)-ARs upon cholinergic transmission, the alpha(2)-AR agonist 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline tartrate (UK14,304), and the preferential alpha(2A)-AR agonist guanabenz reduced levels of ACh. They were elevated by the antagonists 2(2-methoxy-1,4 benzodioxan-2-yl)-2-imidazoline HCl (RX821002) and atipamezole and by the preferential alpha(2A)-AR antagonist 2-(2H-(1-methyl-1,3-dihydroisoindole)methyl)-4,5-dihydroimidazole (BRL44008). In contrast, trans-2,3,9,13b-tetrahydro-1,2-dimethyl-1H-dibenz[c,f]imidazo[1,5-a]azepine (BRL41992) and prazosin, preferential alpha(2B/2C)-AR antagonists, were inactive. The dopaminergic agonist and antiparkinson agent piribedil, which behaves as an antagonist at alpha(2)-ARs, dose dependently increased extracellular levels of ACh. This action was absent upon pretreatment with a maximally effective dose of RX821002. On the other hand, a further dopaminergic agonist and antiparkinson agent, talipexole, which possesses agonist properties at alpha(2)-ARs, dose dependently reduced levels of ACh. This action was also blocked by RX821002. In contrast to piribedil and talipexole, quinelorane, which interacts with dopaminergic receptors but not alpha(2)-ARs, failed to affect ACh levels. Finally, in analogy to the frontal cortex, piribedil likewise elicited a dose-dependent increase in extracellular levels of ACh in the dorsal hippocampus. In conclusion, in distinction to talipexole and quinelorane, and reflecting its antagonist properties at alpha(2A)-ARs, piribedil reinforces cholinergic transmission in the frontal cortex and dorsal hippocampus of freely moving rats. These actions may be related to its facilitatory influence upon cognitive function.

Acetylcholine↗

Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment.

OBJECTIVE: Age-related decrease in dopamine D(2) receptors is associated with cognitive decline in healthy elderly individuals. This study was an investigation of whether the dopamine receptor agonist piribedil improves global cognitive function in patients with mild cognitive impairment. METHOD: In a 90-day randomized double-blind study, treatment with piribedil was compared to placebo in 60 patients with clinically diagnosed mild cognitive impairment and a Mini-Mental State Examination (MMSE) score of 21 to 25. The primary outcome was change in MMSE score. RESULTS: Of the 30 patients randomly assigned to each treatment group, 19 (63.3%) of those taking piribedil and eight (26.7%) of those treated with placebo had increases in MMSE scores, to 26 or more. The response rate and the mean increase in MMSE scores were significantly greater with piribedil. CONCLUSIONS: Patients with mild cognitive impairment had improvement in global cognitive function when treated with the dopamine receptor agonist piribedil. The results support the role of age-related dopamine decline in cognitive impairment of the elderly.

Aged↗

Differential effects of a dopaminergic drug (piribedil) on pituitary hormone release in normal men and women.

Six normal women, in the follicular phase of their menstrual cycle, and 6 normal men received orally 40, 60 and 100 mg doses of piribedil, a dopamine receptor agonist, or placebo. The effects of piribedil on anterior pituitary hormone release was evaluated. In normal women a dose-related decrease in Prl levels was observed, while in men the Prl decrement was not related to the dose employed. In women an increase in serum hGH occurred after administration of the lowest (40 mg) dose of piribedil. In normal men, on the contrary, a modest hGH stimulation was present after administration of all doses of the drug. No consistent changes in serum TSH, LH and FSH concentrations were observed and no side effects were reported. The results from this study indicate that piribedil can exert differential effects on hypophyseal trophic hormone release and that these effects are sex-related. It is possible that the differences observed in men and women after the administration of piribedil are due to a different endogenous dopaminergic tone, induced by the different sexual steroid environment.

Adolescent↗

[The effectiveness and tolerance of piribedil as adjunct therapy to levodopa in patients with Parkinson's disease: a nine month follow up].

INTRODUCTION: Piribedil is a D2 D3 dopamine agonist, which has been shown to be well tolerated and to improve Parkinsonian symptoms, particularly tremor. However, few studies have been published about this Dopamine Agonist as an adjunct to levodopa therapy in patients with Parkinson's disease (PD). This placebo controlled, parallel group study was undertaken to investigate the effects of piribedil in PD patients insufficiently controlled with levodopa in a nine months follow up. PATIENTS AND METHODS: We included 62 PD patients insufficiently controlled with levodopa and needed an increase in dopamine stimulation. Patients were randomized in two similar groups, one of them taking Piribedil and levodopa and the other group taking a placebo and levodopa. The primary efficacy measures were the items II and III of the UPDRS. The patients were evaluated prior to the start of therapy, and 3, 6 and 9 months after the start of the study. RESULTS: Patients taking Piribedil showed an average of improvement of 37,8% (p < 0.01) in the part II and 63,2% (p < 0.01) in the part III of the UPDRS at the end of the study. At 9 month evaluation, tremor at rest showed an average improvement of 68,6%, rigidity, fingers taps and legs agility improved substantially in their respective items of the UPDRS at the end of the study. CONCLUSIONS: We concluded that PD patients with functional worsening while on stable levodopa doses exhibit a steady improvement of the UPDRS part II and III with the adjunction of Piribedil 150 mg mean daily dose for 9 months.

Antiparkinson Agents↗

Efficacy and safety of piribedil in early combination with L-dopa in the treatment of Parkinson's disease: a 6-month open study.

BACKGROUND: Piribedil is a non-ergot D2/D3 dopamine agonist with antagonistic effect on alpha2-adrenoceptors and lack of agonist properties at 5-HT2A/2C receptors. Previous studies indicated its efficacy in monotherapy as well as in combinatio' s disease in L-dopa-treated parkinsonian patients. PATIENTS AND METHOD: A 6-month, open-labeled, multicenter study was conducted in Thai Parkinsonian patients who were insufficiently controlled by L-dopa (< or = 600 mg/day). Piribedil 50 mg in retard form was titrated upward to 150 mg/day (50 mg tid) by the 5th week and up to 6 months as an add-on treatment. L-dopa daily dose was kept stable until the 3rd month and could be adjusted afterwards. The main efficacy parameter was the change in UPDRS part III score versus baseline over Full Analysis Set, score variation, and percentage of responders defined by at least 30% decrease from baseline of total UPDRS part III score. The secondary efficacy criteria were changes in L-dopa dose between the third month and the end of the study, UPDRS part II score variation, Hoehn and Yahr stage variation and Schwab and England Activities of Daily Living Scale variation. The acceptability of piribedil was assessed by physical examination, weight, blood pressure and heart rate as well as the reported adverse events. RESULTS: Twenty-nine patients (55.2% male) with the mean age of 64.0 +/- 7.2 years and mean duration of disease of 18.3 +/- 8.2 months were recruited The mean UPDRS part III score at baseline was 19.8 +/- 11.4. After 6-month treatment with piribedil, mean UPDRS part III score significantly decreased to 6.6 +/- 4.7 (p < 0.0001) with mean score variation of 13.3 +/- 10.3. Twenty-seven patients (93.1%) were responders. Mean UPDRS part II score was significantly decreased from 7.2 +/- 5.4 at baseline to 2.7 +/- 2.1 at the end of 6 months (p < 0.0001). Hoehn and Yahr stage and Schwab and England Activities of Daily Living Scale were also significantly improved Reported adverse events were mainly gastrointestinal symptoms. Blood pressure and heart rate were not significantly changed during the study period. Peak dose dyskinesia was reported only in one patient. Two patients (6.9%) were withdrawn because of adverse events. CONCLUSION: Piribedil was effective on motor symptoms during a 6-month treatment in early parkinsonian patients insufficiently controlled by L-dopa and it was well tolerated.

Adult↗

A randomized, double-blind study of a skin patch of a dopaminergic agonist, piribedil, in Parkinson's disease.

This randomized, double-blind trial was designed to evaluate the efficacy of a transdermal system of piribedil on the motor symptoms of Parkinson's disease during 3 weeks of treatment administered to three different groups: placebo, one piribedil patch (1 PP), and two (2 PP) piribedil patches. Twenty-seven patients with idiopathic Parkinson's disease, treated with L-dopa but not sufficiently controlled, were included in this trial. The test treatment did not demonstrate any clinical efficacy on either the main end point (Unified Parkinson's Disease Rating Scale motor score) or the secondary end points (rigidity, bradykinesia, postural, and resting tremor scores). The main adverse events were nausea (11%), vomiting (7.4%), and malaise (7.4%) mainly observed in the placebo group (four of seven patients). The local acceptability of the transdermal system was good. Plasma piribedil concentrations at the end of treatment were 6.74+/-1.10 and 9.31+/-3.33 ng/mL in the 1 PP and 2 PP groups, respectively. These plasma levels could account for the lack of clinical efficacy, because a previous pharmacokinetics-PD study conducted in parkinsonian patients and treated with the intravenous route demonstrated that the critical limits of activity on tremor were between 10 and 30 ng/mL.

Administration, Cutaneous↗

Yawning elicited by systemic and intrastriatal injection of piribedil and apomorphine in the rat.

The behavioural effects of systemic and intrastriatal injections of the dopamine agonists piribedil and apomorphine in male rats were examined. Bilateral application of piribedil (50 and 100 micrograms) or apomorphine (5, 10 and 20 micrograms) to the striatum produced yawning and chewing mouth movements accompanied by intermittent stretching and sexual arousal. Low doses of piribedil (1.25 and 2.5 mg/kg) and apomorphine (0.1 and 0.2 mg/kg) injected SC produced an identical yawning syndrome. Previous work has suggested that yawning elicited by systemic dopamine agonist treatment is a consequence of dopamine autoreceptor stimulation. Similarly, the most likely explanation of the present data is that yawning elicited by systemic and central dopamine agonist treatment was due to activation of dopamine autoreceptors. Systemic injection of haloperidol and scopolamine abolished yawning induced by intrastriatal piribedil and these data provide tentative support for the proposal that a dopamine-acetylcholine link may be involved in the expression of yawning.

Animals↗

Effects of apomorphine and piribedil on pentylenetetrazol-induced seizures in mice.

Based on previous work examining the effects of dextroamphetamine on pentylenetetrazol (PTZ)-induced clonic seizure threshold, the objective of the present study was to determine the effects of two other dopamine agonists, apomorphine (AP) and piribedil, on PTZ seizures. TD50 and LD50 values for CD-1 mice were determined initially for the two drugs. Subsequently, dose- and time-response analyses established that AP decreased PTZ seizure threshold 15 min after administraton, but increased the threshold at 60 min. Piribedil elevated the seizure threshold, but like AP, did not exhibit a clear dose-response relationship. Subsequent blocker studies with phentolamine, (-)sotalol, pimozide, and atropine suggested the possible neurotransmitter systems involved in the modulation of the PTZ-induced seizures by AP and piribedil. Pimozide blocked the changes in seizure threshold induced by both drugs. Atropine also decreased the AP-induced increase in threshold at 60 min. The pattern of inhibition of seizure threshold changes induced by the neurotransmitter blockers suggested that piribedil blocked seizures by means of indirect actions on several neurotransmitters.

Animals↗