Piracetam

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Piracetam
Piracetam.svg
Piracetam ball-and-stick.png
Clinical data
Trade namesBreinox, Dinagen, Lucetam, Nootropil, Nootropyl, Oikamid, Piracetam and many others
AHFS/Drugs.comInternational Drug Names
Routes of
administration
By mouth, parenteral, or vaporized
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: Unscheduled
  • UK: POM (Prescription only)
  • US: Not permitted as drug or supplement
Pharmacokinetic data
Bioavailability~100%
Onset of actionSwiftly following administration. Food delays time to peak concentration by 1.5 hrs approximately to 2-3 hrs since dosing. [1]
Elimination half-life4–5 hr
ExcretionUrinary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.028.466 Edit this at Wikidata
Chemical and physical data
FormulaC6H10N2O2
Molar mass142.158 g·mol−1
3D model (JSmol)
Melting point152 °C (306 °F)
  (verify)

Piracetam (sold under many brand names) is a medication in the racetams group, with chemical name 2-oxo-1-pyrrolidine acetamide. It is approved in the United Kingdom[2] but is not approved in the United States.[3][4] In the UK, piracetam is prescribed mainly for myoclonus,[5] but is used off-label for other conditions. Evidence to support its use for many conditions is unclear, although it is marketed as a nootropic (cognitive enhancer). Studies of piracetam's cognitive effects have had equivocal results, sometimes showing modest benefits in specific populations and sometimes showing minimal or no benefit.[6]

It shares the same 2-oxo-pyrrolidone base structure with pyroglutamic acid. Piracetam is a cyclic derivative of GABA (gamma-Aminobutyric acid). Related drugs include the anticonvulsants levetiracetam and brivaracetam, and the putative nootropics aniracetam and phenylpiracetam.

Medical uses[edit]

Dementia[edit]

A 2001 Cochrane review concluded that there was not enough evidence to support piracetam for dementia or cognitive problems.[7] A 2002 review and 2005 review concluded that piracetam had some positive effects in older patients with these problems.[8][9] In 2008, a working group of the British Academy of Medical Sciences noted that many of the trials of piracetam for dementia were flawed.[10][11]

Depression and anxiety[edit]

Some sources suggest that piracetam's overall effect on lowering depression and anxiety is higher than on improving memory.[12] However, depression is reported to be an occasional adverse effect of piracetam.[13]

Other[edit]

Piracetam may facilitate the deformability of erythrocytes in capillary. [14][15]

Peripheral vascular effects of piracetam have suggested its use potential for vertigo, dyslexia, Raynaud's phenomenon and sickle cell anemia.[9][15] There is no evidence to support piracetam's use in sickle cell crisis prevention[16] or for fetal distress during childbirth.[17][needs update] There is no evidence for benefit of piracetam with acute ischemic stroke,[18] though there is debate as to its utility during stroke rehabilitation.[19][20]

Anti-vasospasm[edit]

Piracetam has been found to diminish erythrocyte adhesion to vascular wall endothelium, making any vasospasm in the capillary less severe. This contributes to its efficacy in promoting microcirculation, including to the brain and kidneys.[14][15]

Side effects[edit]

Piracetam has been found to have very few side effects, and those it has are typically "few, mild, and transient."[21] A large-scale, 12-week trial of high-dose piracetam found no adverse effects occurred in the group taking piracetam as compared to the placebo group.[22] Many other studies have likewise found piracetam to be well tolerated.[21][23][24]

Symptoms of general excitability, including anxiety, insomnia, irritability, headache, agitation, nervousness, tremor, and hyperkinesia, are occasionally reported.[13][25][26] Other reported side effects include somnolence, weight gain, clinical depression, weakness, increased libido, and hypersexuality.[13]

Piracetam reduces platelet aggregation as well as fibrinogen concentration, and thus is contraindicated to patients suffering from cerebral hemorrhage. [14][15] Nonetheless, excessive platelet aggregation is involved in pathophysiologies of microangiopathic hemolytic anemia, disseminated intravascular coagulation, and thrombotic thrombocytopenic purpura.[27][28][29] (See: schistocyte.)

Toxicity[edit]

Piracetam does not appear to be acutely toxic at the doses used in human studies.[7][21][23] The LD50 for oral consumption in humans has not been determined.[30] The LD50 is 5.6 g/kg for rats and 20 g/kg for mice, indicating extremely low acute toxicity.[31] For comparison, in rats the LD50 of vitamin C is 12 g/kg and the LD50 of table salt is 3 g/kg.

Mechanisms of action[edit]

Piracetam's mechanism of action, as with racetams in general, is not fully understood. The drug influences neuronal and vascular functions and influences cognitive function without acting as a sedative or stimulant.[9] Piracetam is a positive allosteric modulator of the AMPA receptor, although this action is very weak and its clinical effects may not necessarily be mediated by this action.[32] It is hypothesized to act on ion channels or ion carriers, thus leading to increased neuron excitability.[30] GABA brain metabolism and GABA receptors are not affected by piracetam [33]

It has been found to increase blood flow and oxygen consumption in parts of the brain, but this may be a side effect of increased brain activity rather than a primary effect or mechanism of action for the drug.[34]

Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors[citation needed], which are implicated in memory processes.[35] Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability.[35][36] Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+).[30] It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains.[37][38] Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5,[39] which is a part of the electron transport mechanism in mitochondria. But in the brain, it also increases the permeability of some intermediates of the Krebs cycle through the mitochondrial outer membrane.[37]

History[edit]

Piracetam was first made some time between the 1950s and 1964 by Corneliu E. Giurgea.[40] There are reports of it being used for epilepsy in the 1950s.[41]

Approval[edit]

Piracetam is primarily used in Europe, Asia, and South America.[citation needed] In the United States, it is not approved by the US Food and Drug Administration for any medical use and it is not permitted to be sold as a dietary supplement. Piracetam is legal to import into the United Kingdom for personal use with or without prescription.[citation needed] Piracetam has no DIN in Canada, and thus cannot be sold but can be imported for personal use in Canada.[42] It has become popular as a cognitive enhancement drug among students.[43]

Availability[edit]

Piracetam 800 mg tablets

Piracetam is sold under a wide variety of brand names worldwide. Popular trade names for piracetam in Europe are Nootropil and Lucetam, among many others. In Argentina, it is made by GlaxoSmithKline S.A. laboratories and sold under the trade name of Noostan (800 mg or 1200 mg). In Venezuela and Ecuador, piracetam is produced by Laboratorios Farma S.A. and sold under the brand name Breinox. In Mexico it is produced by UCB de Mexico, and sold under the brand name of Nootropil. Other names include Nootropil in the United States, Europe, Brazil, Hong Kong, India, and Mexico; Lucetam, Oikamid, Smart, Geratam, and Biotropil in Europe and Brazil; Neurobasal in Colombia; Breinox in Ecuador and Venezuela; Cerecetam in India; Stimulan in Egypt; and Nocetan in Latin America.

See also[edit]

  • AMPA receptor positive allosteric modulator
  • Aniracetam
  • Brivaracetam — an analogue of piracetam with the same additional side chain as levetiracetam and a three–carbon chain. It exhibits greater antiepileptic properties than levetiracetam in animal models, but with a somewhat smaller, although still high, therapeutic range.
  • Hydergine
  • Levetiracetam — an analogue of piracetam bearing an additional CH3–CH2– sidechain and bearing antiepileptic pharmacological properties through a poorly understood mechanism probably related to its affinity for the vesicle protein SV2A.
  • Oxiracetam
  • Phenylpiracetam — a phenylated analog of the drug piracetam which was developed in 1983 in Russia where it is available as a prescription drug.
  • Pramiracetam

Notes[edit]

  1. ^ Leaflet of Piracetam
  2. ^ Pubchem. "Piracetam". pubchem.ncbi.nlm.nih.gov. Retrieved 20 November 2018.
  3. ^ Inspections, Compliance, Enforcement, and Criminal Investigations
  4. ^ Enforcement Report - Week of 20 March 2013
  5. ^ "Nootropil". NetDoctor.co.uk. 8 July 2004. Retrieved 21 September 2009.
  6. ^ Winblad B (2005). "Piracetam: a review of pharmacological properties and clinical uses". CNS Drug Reviews. 11 (2): 169–82. doi:10.1111/j.1527-3458.2005.tb00268.x. PMID 16007238.
  7. ^ a b Flicker L, Grimley Evans G (2001). "Piracetam for dementia or cognitive impairment". The Cochrane Database of Systematic Reviews (2): CD001011. doi:10.1002/14651858.CD001011. PMID 11405971.
  8. ^ Waegemans T, Wilsher CR, Danniau A, Ferris SH, Kurz A, Winblad B (2002). "Clinical efficacy of piracetam in cognitive impairment: a meta-analysis". Dementia and Geriatric Cognitive Disorders. 13 (4): 217–24. doi:10.1159/000057700. PMID 12006732.
  9. ^ a b c Winblad B (2005). "Piracetam: a review of pharmacological properties and clinical uses". CNS Drug Reviews. 11 (2): 169–82. doi:10.1111/j.1527-3458.2005.tb00268.x. PMID 16007238.
  10. ^ Horne G, et al. (May 2008). Brain science, addiction and drugs (PDF) (Report). Academy of Medical Sciences. p. 145. ISBN 1-903401-18-6.
  11. ^ Talbot M (27 April 2009). "Brain Gain: The underground world of 'neuroenhancing' drugs". The New Yorker. Retrieved 21 September 2009.
  12. ^ Malykh AG, Sadaie MR (February 2010). "Piracetam and piracetam-like drugs: from basic science to novel clinical applications to CNS disorders". Drugs. 70 (3): 287–312. doi:10.2165/11319230-000000000-00000. PMID 20166767.
  13. ^ a b c Nootropil®. Arzneimittel-Kompendium der Schweiz. 2013-09-12. Retrieved 2013-10-27.
  14. ^ a b c Winblad B (14 April 2019). "Piracetam: a review of pharmacological properties and clinical uses". CNS Drug Reviews. 11 (2): 169–82. doi:10.1111/j.1527-3458.2005.tb00268.x. PMID 16007238.
  15. ^ a b c d "Nootropil Tablets 1200 mg - Summary of Product Characteristics (SmPC)". (eMC). 15 February 2017. Retrieved 14 April 2019.
  16. ^ Al Hajeri A, Fedorowicz Z (February 2016). "Piracetam for reducing the incidence of painful sickle cell disease crises". The Cochrane Database of Systematic Reviews. 2: CD006111. doi:10.1002/14651858.CD006111.pub3. PMID 26869149.
  17. ^ Hofmeyr GJ, Kulier R (2002). "Piracetam for fetal distress in labour". The Cochrane Database of Systematic Reviews (1): CD001064. doi:10.1002/14651858.CD001064. PMID 11869588.
  18. ^ Ricci S, Celani MG, Cantisani TA, Righetti E (September 2012). "Piracetam for acute ischaemic stroke". The Cochrane Database of Systematic Reviews (9): CD000419. doi:10.1002/14651858.CD000419.pub3. PMID 22972044.
  19. ^ Zhang J, Wei R, Chen Z, Luo B (July 2016). "Piracetam for Aphasia in Post-stroke Patients: A Systematic Review and Meta-analysis of Randomized Controlled Trials". CNS Drugs. 30 (7): 575–87. doi:10.1007/s40263-016-0348-1. PMID 27236454.
  20. ^ Yeo SH, Lim ZI, Mao J, Yau WP (October 2017). "Effects of Central Nervous System Drugs on Recovery After Stroke: A Systematic Review and Meta-Analysis of Randomized Controlled Trials". Clinical Drug Investigation. 37 (10): 901–928. doi:10.1007/s40261-017-0558-4. PMID 28756557.
  21. ^ a b c Koskiniemi M, Van Vleymen B, Hakamies L, Lamusuo S, Taalas J (March 1998). "Piracetam relieves symptoms in progressive myoclonus epilepsy: a multicentre, randomised, double blind, crossover study comparing the efficacy and safety of three dosages of oral piracetam with placebo". Journal of Neurology, Neurosurgery, and Psychiatry. 64 (3): 344–8. doi:10.1136/jnnp.64.3.344. PMC 2169975. PMID 9527146.
  22. ^ De Reuck J, Van Vleymen B (March 1999). "The clinical safety of high-dose piracetam--its use in the treatment of acute stroke". Pharmacopsychiatry. 32 Suppl 1: 33–7. doi:10.1055/s-2007-979234. PMID 10338106.
  23. ^ a b Fedi M, Reutens D, Dubeau F, Andermann E, D'Agostino D, Andermann F (May 2001). "Long-term efficacy and safety of piracetam in the treatment of progressive myoclonus epilepsy". Archives of Neurology. 58 (5): 781–6. doi:10.1001/archneur.58.5.781. PMID 11346373.
  24. ^ Giurgea C, Salama M (1977). "Nootropic drugs". Prog Neuropsychopharmacol. 1 (3–4): 235–247. doi:10.1016/0364-7722(77)90046-7.
  25. ^ Chouinard G, Annable L, Ross-Chouinard A, Olivier M, Fontaine F (1983). "Piracetam in elderly psychiatric patients with mild diffuse cerebral impairment". Psychopharmacology. 81 (2): 100–6. doi:10.1007/BF00429000. PMID 6415738.
  26. ^ Hakkarainen H, Hakamies L (1978). "Piracetam in the treatment of post-concussional syndrome. A double-blind study". European Neurology. 17 (1): 50–5. doi:10.1159/000114922. PMID 342247.
  27. ^ Palta S, Saroa R, Palta A (September 2014). "Overview of the coagulation system". Indian Journal of Anaesthesia. 58 (5): 515–23. doi:10.4103/0019-5049.144643. PMC 4260295. PMID 25535411.
  28. ^ Zini G, d'Onofrio G, Briggs C, Erber W, Jou JM, Lee SH, McFadden S, Vives-Corrons JL, Yutaka N, Lesesve JF (April 2012). "ICSH recommendations for identification, diagnostic value, and quantitation of schistocytes". International Journal of Laboratory Hematology. Wiley. 34 (2): 107–16. doi:10.1111/j.1751-553x.2011.01380.x. PMID 22081912.
  29. ^ Harris P (2014). Mosby's dictionary of medicine, nursing & health professions. Sydney: Mosby Elsevier. ISBN 978-0-7295-8138-7. OCLC 946877066. . ... anaemia (MAHA) /mi'krö. anjê opath'ik/, a disorder in which there is a fibrin mesh formed in small blood vessels due to activation of coagulation by ...
  30. ^ a b c Gouliaev AH, Senning A (May 1994). "Piracetam and other structurally related nootropics". Brain Research. Brain Research Reviews. 19 (2): 180–222. doi:10.1016/0165-0173(94)90011-6. PMID 8061686.
  31. ^ "Piracetam Material Safety Sheet" (PDF). Spectrum.
  32. ^ Ahmed AH, Oswald RE (March 2010). "Piracetam defines a new binding site for allosteric modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors". Journal of Medicinal Chemistry. 53 (5): 2197–203. doi:10.1021/jm901905j. PMC 2872987. PMID 20163115.
  33. ^ Giurgea CE (January 1982). "The nootropic concept and its prospective implications". Drug Development Research. 2 (5): 441–446. doi:10.1002/ddr.430020505. ISSN 1098-2299.
  34. ^ Jordaan B, Oliver DW, Dormehl IC, Hugo N (September 1996). "Cerebral blood flow effects of piracetam, pentifylline, and nicotinic acid in the baboon model compared with the known effect of acetazolamide". Arzneimittel-Forschung. 46 (9): 844–7. PMID 8876930.
  35. ^ a b Winnicka K, Tomasiak M, Bielawska A (2005). "Piracetam--an old drug with novel properties?". Acta Poloniae Pharmaceutica. 62 (5): 405–9. PMID 16459490.
  36. ^ Müller WE, Eckert GP, Eckert A (March 1999). "Piracetam: novelty in a unique mode of action". Pharmacopsychiatry. 32 Suppl 1: 2–9. doi:10.1055/s-2007-979230. PMID 10338102.
  37. ^ a b Grau M, Montero JL, Balasch J (1987). "Effect of Piracetam on electrocorticogram and local cerebral glucose utilization in the rat". General Pharmacology. 18 (2): 205–11. doi:10.1016/0306-3623(87)90252-7. PMID 3569848.
  38. ^ Nickolson VJ, Wolthuis OL (October 1976). "Effect of the acquisition-enhancing drug piracetam on rat cerebral energy metabolism. Comparison with naftidrofuryl and methamphetamine". Biochemical Pharmacology. 25 (20): 2241–4. doi:10.1016/0006-2952(76)90004-6. PMID 985556.
  39. ^ Tacconi MT, Wurtman RJ (1986). "Piracetam: physiological disposition and mechanism of action". Advances in Neurology. 43: 675–85. PMID 3946121.
  40. ^ Li JJ, Corey EJ (2013). Drug Discovery: Practices, Processes, and Perspectives. John Wiley & Sons. p. 276. ISBN 9781118354469.
  41. ^ Schmidt D, Shorvon S (2016). The End of Epilepsy?: A History of the Modern Era of Epilepsy Research 1860-2010. Oxford University Press. p. 69. ISBN 9780198725909.
  42. ^ #2, Government of Canada, Health Canada, Health Products and Food Branch, HPFB Inspectorate, Inspectorate Ottawa, Compliance, Enforcement and Coordination Division (June 2010). "Guidance Document on the Import Requirements for Health Products under the Food and Drugs Act and its Regulations (GUI-0084) [Health Canada, 2010]". www.hc-sc.gc.ca. Retrieved 6 March 2016.
  43. ^ Medew J (1 October 2009). "Call for testing on 'smart drugs'". Fairfax Media. Retrieved 29 May 2014.

References[edit]

External links[edit]