Piribedil

Structural formula
General
Non-proprietary name	Piribedil
other names	2- [4- (1,3-Benzodioxol-5-ylmethyl) piperazin-1-yl] pyrimidine ( IUPAC ) ET495 EU4200
Molecular formula	C 16 H 18 N 4 O 2
External identifiers / databases
CAS number 3605-01-4 78213-63-5 ( maleate ) EC number 222-764-6 ECHA InfoCard 100.020.695 PubChem 4850 Wikidata Q413976
Drug information
ATC code	N04 BC08
Drug class	Parkinson's medication
Mechanism of action	Dopamine D 2/3 receptor agonist
properties
Molar mass	298.34 g · mol -1
Melting point	98 ° C (polymorph I) 91 ° C (polymorph II)
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Maleate Caution H and P phrases H: 315-319-335 P: 261-305 + 351 + 338
Toxicological data	1460 mg kg −1 ( LD 50 ,  mouse ,  oral )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Piribedil ( trade name in Germany: Clarium ; manufacturer: Desitin ) is a drug from the group of dopamine agonists that is used in the treatment of Parkinson's disease . Piribedil is a piperazine - derivative and thus belongs to the Non- Ergot -Dopaminagonisten. In addition to the stimulating effect on the dopamine receptors D _2/3 , it inhibits the α2 adrenoreceptor subtypes α _2A and α _2C .

Presentation and extraction

The compound can be prepared in a four-step synthetic sequence. In the first step, the benzodioxole is obtained from catechol and methylene chloride . This is then converted into 5-chloromethylbenzo [1,3] dioxole in a Friedel-Crafts alkylation with formaldehyde in the presence of hydrochloric acid and zinc chloride . The subsequent reaction with piperazine gives 1-benzo [1,3] dioxol-5-ylmethyl-piperazine, which is reacted with 2-chloropyrimidine to form the target compound in the last step .

Clinical information

Application areas (indications)

Piribedil is approved for the treatment of early and advanced Parkinson's disease both in mono and in combination therapy with L-dopa .

Contraindications (contraindications)

Piribedil must not be used

• if you are hypersensitive to Piribedil
• in cardiovascular shock
• in the acute phase of a heart attack
• in combination with neuroleptics (except clozapine )

Drug interactions

The simultaneous use of neuroleptics and piribedil can lead to or worsen psychotic disorders .

Use during pregnancy and breastfeeding

The effects of piribedil when used during pregnancy and breastfeeding are not well known. Therefore, Piribedil should not be used during pregnancy and breastfeeding.

Adverse effects (side effects)

Piribedil's side effects are dose-dependent and usually only occur at the start of treatment and disappear after treatment is discontinued.

• Gastrointestinal tract: slight gastrointestinal complaints (nausea, vomiting, flatulence) occur frequently. They often disappear again after individual dose adjustment.
• Nervous system: absent-mindedness, hallucinations, agitation, or dizziness were commonly observed. You may feel drowsy; Excessive daytime sleepiness and sudden attacks of sleep have been observed in very rare cases. Patients being treated with Piribedil who are drowsy or have sudden attacks of sleep must be informed that they are not allowed to drive or engage in other activities that could cause them or others to be injured or even killed due to impaired alertness to become (e.g. when operating machines).
• Cardiovascular system: very rarely low or unstable blood pressure with syncope or nausea have been observed.
• Psychiatric disorders: Signs of gambling addiction / pathological gambling, increased libido and hypersexuality have been reported.
• Allergy: the excipient Ponceau 4R , which is contained in all piribedil preparations marketed in Germany (as of December 2017), can cause allergic reactions.
• Overdose: high doses of piribedil cause nausea. Therefore, overdoses are very rare. Signs of an overdose include unstable blood pressure or nausea and vomiting.

Other Information

History

The substance was synthesized by the French company Servier in the 1960s and has been used clinically since the early 1970s, first in ophthalmology and soon afterwards also for Parkinson's disease. However, piribedil has been used rarely for a long time because it was believed that its effectiveness would be limited to reducing tremors in Parkinson's disease.

Since the mid-1970s, piribedil has been widely used to treat vascular disease and mild cognitive impairment . For these areas of application, Piribedil has also been on the market in Germany as a Trivastal since 1975 .

Piribedil has now been systematically followed up in Parkinson's disease. The results of the CONTROL and REGAIN studies led to a reassessment of the substance and, in 2007, also to the above. Approval in Germany.

Individual evidence

1. ^ The Merck Index. An Encyclopaedia of Chemicals, Drugs and Biologicals. 14th edition. 2006, ISBN 0-911910-00-X , p. 1292.
2. ↑ ^{a b} M. Kuhnert-Brandstätter, L. Bösch: Polymorphic drugs: amisometradine, bolandioldipripionate, Clominorex, etaphedrine hydrochloride and piribedil. In: Sci. Pharm. 46, 1978, pp. 62-67.
3. ↑ ^{a b} Datasheet Piribedil maleate salt from Sigma-Aldrich , accessed on April 21, 2011 ( PDF ).
4. ↑ M. Laubie, H. Schmitt, JC Le Douarec: Cardiovascular effects of the 1- (2 "pyrimidyl) -5 piperonyl piperazine (ET495). In: Eur J Pharmacol . 6, 1969, pp. 75-82. PMID 4389616 .
5. ↑ Schorygin et al: Chem. Zentralbl. 110 (1939) 2178.
6. ↑ Wilson Cunico, Claudia RB Gomes, Marcele Moreth, Diogo P. Manhanini, Isabela H. Figueiredo, Carmen Penido, Maria GMO Henriques, Fernando P. Varotti, Antoniana U. Krettli: Synthesis and antimalarial activity of hydroxyethylpiperazine derivatives In: Eur J Med Chem . 44, 2009, pp. 1363-1368, doi: 10.1016 / j.ejmech.2008.04.009 .
7. ^ A. Kleemann , J. Engel, B. Kutscher, D. Reichert: Pharmaceutical Substances - Synthesis, Patents, Applications. 4th edition. Thieme-Verlag, Stuttgart 2001, ISBN 1-58890-031-2 .
8. ↑ Technical information on the preparation Clarium 50 mg, Desitin company, as of October 2017.
9. ^ J. Feuillerat, F. Jaubert, J. Vedy, M. Chovet: Le EU 4200 (Piribedil) en pratique ophtalmologique courante. Premier results. In: Med Trop (Mars). 30, 1970, pp. 215-235. PMID 5426024 .
10. ^ RD Sweet, C. Wasterlain, FH McDowell: Piribedil - an oral dopamine agonist for the treatment of Parkinson's disease. In: Trans Am Neurol Assoc. 99, 1974, pp. 258-260. PMID 4463553 .
11. ↑ L. Smith, M. De Salvia, P. Jenner, CD Marsden: An appraisal of the antiparkinsonian activity of piribedil in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated common marmosets. In: Mov Disord. 11, 1996, pp. 125-135. PMID 8684381 .
12. ↑ A. Piccinelli, G. Neri, A. Agnoli: Trattamento medico a lungo termine dei postumi delle cerebrovasculopatie acute (confronto papaverina-piribedil). In: Minerva Med. 65, 1974, pp. 4199-4213. PMID 4610451 .
13. ↑ D. Nagaraja, S. Jayashree: Randomized study of the dopamine receptor agonist piribedil in the treatment of mild cognitive impairment. In: Am J Psychiatry. 158, 2001, pp. 1517-1519. PMID 11532743 .
14. ↑ A. Castro-Caldas, P. Delwaide, W. Jost et al .: The Parkinson-Control study: a 1-year randomized, double-blind trial comparing piribedil (150 mg / day) with bromocriptine (25 mg / day) in early combination with levodopa in Parkinson's disease. In: Mov Disord. 21, 2006, pp. 500-509. PMID 16267842 .
15. ↑ O. Rascol, B. Dubois, AC Caldas et al .: Early piribedil monotherapy of Parkinson's disease: A planned seven-month report of the REGAIN study. In: Mov Disord. 21, 2006, pp. 2110-2115. PMID 17013922 .

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