Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and

piperazine Piperazine () is an organic compound that consists of a six-membered ring containing two nitrogen atoms at opposite positions in the ring. Piperazine exists as small alkaline deliquescent crystals with a saline taste. The piperazines are a broad ...

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...

which acts as a D₂ and D₃ receptor

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

. It also has α₂-adrenergic antagonist properties.

Medical uses

* Treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

(PD), either as

monotherapy Combination therapy or polytherapy is therapy that uses more than one medication or modality. Typically, the term refers to using multiple therapies to treat a ''single'' disease, and often all the therapies are pharmaceutical (although it can also ...

(without

levodopa -DOPA, also known as levodopa and -3,4-dihydroxyphenylalanine, is an amino acid that is made and used as part of the normal biology of some plants and animals, including humans. Humans, as well as a portion of the other animals that utilize -DOPA ...

)) or in combination with L-DOPA therapy, in the early stages of the disease as well as in the advanced ones * Treatment of

pathological Pathology is the study of the causal, causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when us ...

cognitive deficit Cognitive deficit is an inclusive term to describe any characteristic that acts as a barrier to the cognition process. The term may describe * deficits in overall intelligence (as with intellectual disabilities), * specific and restricted defici ...

s in the

elderly Old age refers to ages nearing or surpassing the life expectancy of human beings, and is thus the end of the human life cycle. Terms and euphemisms for people at this age include old people, the elderly (worldwide usage), OAPs (British usage ...

(impaired

attention Attention is the behavioral and cognitive process of selectively concentrating on a discrete aspect of information, whether considered subjective or objective, while ignoring other perceivable information. William James (1890) wrote that "Atte ...

motivation Motivation is the reason for which humans and other animals initiate, continue, or terminate a behavior at a given time. Motivational states are commonly understood as forces acting within the agent that create a disposition to engage in goal-dire ...

memory Memory is the faculty of the mind by which data or information is encoded, stored, and retrieved when needed. It is the retention of information over time for the purpose of influencing future action. If past events could not be remembered, ...

, etc.) * Treatment of

dizziness Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness. Dizziness is a common medical c ...

in the young patients * Treatment of

retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...

ischemic Ischemia or ischaemia is a restriction in blood supply to any tissue, muscle group, or organ of the body, causing a shortage of oxygen that is needed for cellular metabolism (to keep tissue alive). Ischemia is generally caused by problems wi ...

manifestations * Adjunctive treatment of

intermittent claudication Intermittent claudication, also known as vascular claudication, is a symptom that describes muscle pain on mild exertion (ache, cramp, numbness or sense of fatigue), classically in the calf muscle, which occurs during exercise, such as walking, and ...

due to

peripheral vascular disease Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular diseas ...

(PVD) of the

lower limb The human leg, in the general word sense, is the entire lower limb of the human body, including the foot, thigh or sometimes even the hip or gluteal region. However, the definition in human anatomy refers only to the section of the lower limb ext ...

s (stage 2) * Adjunctive treatment of

anhedonia Anhedonia is a diverse array of deficits in hedonic function, including reduced motivation or ability to experience pleasure. While earlier definitions emphasized the inability to experience pleasure, anhedonia is currently used by researchers t ...

and

treatment-resistant depression Treatment-resistant depression is a term used in psychiatry to describe people with major depressive disorder (MDD) who do not respond adequately to a course of appropriate antidepressant medication within a certain time. Definitions of treatment- ...

in unipolar and bipolar depressives (''

off label Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although ...

'') * Treatment of gait disorders associated with Parkinson's disease (no related cause) and other forms of parkinsonism

Other uses

The drug has been shown to enhance working memory capacities in normal aging adults. In age-related memory impairment, it has a positive effect on psychophysiological state of elderly people, improving memory and attention and increasing the velocity of psychomotor reactions and lability of nervous processes. It enhances cognitive skill learning in healthy older adults. It showed a positive effect in

restless legs syndrome Restless legs syndrome (RLS), also known as Willis-Ekbom disease (WED), is generally a long-term disorder that causes a strong urge to move one's legs. There is often an unpleasant feeling in the legs that improves somewhat by moving them. This ...

Dosage

Parkinson's disease

Administration of piribedil should be initiated with one sustained-release tablet (50 mg) daily during the first week. Dosage should then be gradually increased every week until achieving the optimal therapeutic dose: * As monotherapy: three to five tablets in three to five doses daily. * In combination with L-DOPA therapy: one to three tablets daily.

Other indications

One tablet daily at the end of the main meal. In severe cases: two tablets daily in two doses.

Side effects

* Minor

gastrointestinal The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...

upset (

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

vomiting Vomiting (also known as emesis and throwing up) is the involuntary, forceful expulsion of the contents of one's stomach through the mouth and sometimes the Human nose, nose. Vomiting can be the result of ailments like Food-poisoning, foo ...

flatulence Flatulence, in humans, is the expulsion of gas from the intestines via the anus, commonly referred to as farting. "Flatus" is the medical word for gas generated in the stomach or bowels. A proportion of intestinal gas may be swallowed environm ...

, etc.) in predisposed individuals, or when taken between meals: adjust dosage individually, and/or add

domperidone Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the le ...

; *

Orthostatic hypotension Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when standing up or sitting down. Primary orthostatic hypertension is also often referred to as neurogenic orthostatic hyp ...

drowsiness Somnolence (alternatively sleepiness or drowsiness) is a state of strong desire for sleep, or sleeping for unusually long periods (compare hypersomnia). It has distinct meanings and causes. It can refer to the usual state preceding falling asleep ...

may occur, particularly in predisposed individuals (underlying condition or causative illness); * Mild

, confusion and feeling "drunk" also may occur. As with other dopamine agonists (like

pramipexole Pramipexole, sold under the brand Mirapex among others, is medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipex ...

and

ropinirole Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. I ...

), compulsive behavior like

pathological gambling Problem gambling or ludomania is repetitive gambling behavior despite harm and negative consequences. Problem gambling may be diagnosed as a mental disorder according to ''DSM-5'' if certain diagnostic criteria are met. Pathological gambling is ...

, overeating, excessive shopping, increased

libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act up ...

, sexual and/or other intense urges, may develop.TRIVASTAL Retard 50 (piribedil) Prescribing Information, Servier Laboratories, April 2008

Another rare side effect of piribedil is excessive daytime sleepiness and unintended sleep episodes.

Overdose

At very high doses, piribedil has an emetic action on the

chemoreceptor trigger zone The chemoreceptor trigger zone (CTZ) is an area of the medulla oblongata that receives inputs from blood-borne drugs or hormones, and communicates with other structures in the vomiting center to initiate vomiting. The CTZ is located within the area ...

(CTZ). Tablets will thus be rapidly rejected, which explains why no data are currently available concerning the risk of overdosage.

Interactions

Dopamine antagonist A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have fo ...

s reduce the effect of piribedil.

Pharmacology

Pharmacodynamics

Dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...

, selective for subtypes D₂ and D₃. *

antagonist An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

, selective for subtypes D₄. *

Adrenergic receptor The adrenergic receptors or adrenoceptors are a class of G protein-coupled receptors that are targets of many catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) produced by the body, but also many medications like beta ...

, subtypes α_2A and α_2C: could be the reason why piribedil seems to cause less drowsiness than other dopamine agonists. * Lack of affinity to

serotonin receptor 5-HT receptors, 5-hydroxytryptamine receptors, or serotonin receptors, are a group of G protein-coupled receptor and ligand-gated ion channels found in the central and peripheral nervous systems. They mediate both excitatory and inhibitory neur ...

5-HT_2B: theoretically no risk of heart valve impairment.

Synthesis

Parkinson's patent:H Corrodi & K Fuxe, (1973 to Science Union et Cie). Piribedil synthesis

] 2-Chloropyrimidine 722-12-9(1) and 1-Piperonylpiperazine 2231-06-4(2) give Piribedil (3). Alternately, 2-(1-Piperazinyl)pyrimidine 0980-22-7(4) can be reacted with Piperonyl bromide 606-51-1(5).

References

External links

* {{Portal bar , Medicine Alpha-2 blockers Aminopyrimidines Benzodioxoles Dopamine agonists Piperazines