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Picamilon

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Picamilon
Clinical data
Trade namesНПК ЭХО
Other namesnicotinoyl-GABA
Routes of
administration		Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%–88%[2]
Elimination half-life1.5 hours[2]
ExcretionRenal
Identifiers
  • 4-(Pyridine-3-carbonylamino)butanoic acid
CAS Number
PubChem CID
ChemSpider
UNII
CompTox Dashboard (EPA)
ECHA InfoCard100.118.799 Edit this at Wikidata
Chemical and physical data
FormulaC10H12N2O3
Molar mass208.217 g·mol−1
3D model (JSmol)
  • O=C(NCCCC(=O)O)c1cccnc1
  • InChI=1S/C10H12N2O3/c13-9(14)4-2-6-12-10(15)8-3-1-5-11-7-8/h1,3,5,7H,2,4,6H2,(H,12,15)(H,13,14) checkY
  • Key:NAJVRARAUNYNDX-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Picamilon (also known as N-nicotinoyl-GABA, pycamilon, and pikamilon) is a drug formed by a synthetic combination of niacin and γ-aminobutyric acid (GABA). It was developed in the Soviet Union in 1969[3] and further studied in both Russia[4] and Japan as a prodrug of GABA.[5]

In Russia, picamilon is sold as a prescription drug. The rights to the drug belong to the Russian pharmaceutical company NPK ECHO ("НПК ЭХО"). It is not approved for sale in the United States and has been deemed an adulterating agent in dietary supplements,[6] with five American companies required to remove their picamilon products from the market in November 2015.[7] However, as recently as 2020, picamilon has been found in pharmaceutical dosages in over-the-counter supplements in the US.[8]

Regulation

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In the United States, the Food and Drug Administration ruled in 2015 that picamilon does not fit any of the dietary ingredient categories in the Dietary Supplement Health and Education Act of 1994,[7][9] namely that it is not a vitamin; a dietary mineral; an herb or other botanical; an amino acid; a dietary substance for use by humans to supplement the diet by increasing the total dietary intake; or a concentrate, metabolite, constituent, extract, or combination of any ingredient described above that had been marketed in the United States before 1994. Despite the FDA ruling, picamilon remains an ingredient in supplements marketed as nootropics in the US.[8]

Pharmacology

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Picamilon
Picamilon 20 mg from Russia

A Russian study from 1991 showed that picamilon permeated the blood–brain barrier in cats and increased cerebral blood flow.[10] Further work showed it crosses the blood-brain barrier in mice and rats.[11] It is believed that picamilon is hydrolyzed into GABA and niacin, similar to the way tocopheryl nicotinate (vitamin E nicotinate) is hydrolyzed.[12] GABA in the brain would activate GABA receptors, which in theory should have an anxiolytic effect.[13] The second released component, niacin, is a vasodilator.[14][15] A 2023 assay study showed that picamilon itself is inactive against 50 biological targets, including GABA receptors, despite being a GABA analogue.[16]

Pharmacokinetics

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Plasma picamilon concentrations are generally in the 500–3000 μg/L range during the first few hours after single oral doses of 50–200 mg.[2] It exhibits linear pharmacokinetics with a half-life of 1–2 hours.[2] As discussed previously, the drug undergoes hydrolysis to GABA and nicotinic acid. Urinary excretion of parent drug and the two metabolites accounts for up to 79% of a single dose.[2]

See also

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References

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  1. ^ "Picamilon in Dietary Supplements". FDA. November 29, 2017. Retrieved June 9, 2023.
  2. ^ a b c d e Cui W, Chen X, Zhan Y, Zhang Z, Zhang Y, Zhong D (May 2010). "Determination of picamilon concentration in human plasma by liquid chromatography-tandem mass spectrometry". Journal of Chromatography B. 878 (15–16): 1181–4. doi:10.1016/j.jchromb.2010.03.013. PMID 20359966.
  3. ^ Kopelevich VM, Gunar VI (April 1999). "Some approaches to the directed search for new drugs based on nicotinic acid". Pharmaceutical Chemistry Journal. 33 (4): 177–187. doi:10.1007/BF02509934. S2CID 36930437.
  4. ^ Mirzoian RS, Gan'shina TS (1989). "[The new cerebrovascular preparation pikamilon]". Farmakologiia i Toksikologiia (in Russian). 52 (1): 23–6. PMID 2707413.
  5. ^ Matsuyama K, Yamashita C, Noda A, Goto S, Noda H, Ichimaru Y, et al. (October 1984). "Evaluation of isonicotinoyl-gamma-aminobutyric acid (GABA) and nicotinoyl-GABA as pro-drugs of GABA". Chemical & Pharmaceutical Bulletin. 32 (10): 4089–95. doi:10.1248/cpb.32.4089. PMID 6529802.
  6. ^ Avula B, Chittiboyina AG, Sagi S, Wang YH, Wang M, Khan IA, et al. (March 2016). "Identification and quantification of vinpocetine and picamilon in dietary supplements sold in the United States". Drug Testing and Analysis. 8 (3–4): 334–43. doi:10.1002/dta.1853. PMID 26426301.
  7. ^ a b "FDA sends five warning letters over supplements containing picamilon". NutraIngredients-USA.com, William Reed Business Media. 2 December 2015. Retrieved 3 December 2015.
  8. ^ a b Cohen PA, Avula B, Wang YH, Zakharevich I, Khan I (June 2021). "Five Unapproved Drugs Found in Cognitive Enhancement Supplements". Neurology. Clinical Practice. 11 (3): e303 – e307. doi:10.1212/CPJ.0000000000000960. PMC 8382366. PMID 34484905.
  9. ^ Welch C. "Declaration of Dr. Cara Welch" (PDF). Department of Health and Human Services. Retrieved 21 October 2015.
  10. ^ Dorofeev BF, Kholodov LE (1991). "Pikamilon pharmacokinetics in animals". Farmakologiia i Toksikologiia (in Russian). 54 (2): 66–9. PMID 1884802.
  11. ^ Dorofeev BF, Kholodov LE (March 1991). "[Pikamilon pharmacokinetics in animals]". Farmakologiia i Toksikologiia. 54 (2): 66–69. PMID 1884802.
  12. ^ Duncan KR, Suzuki YJ (March 2017). "Vitamin E Nicotinate". Antioxidants. 6 (1): 20. doi:10.3390/antiox6010020. PMC 5384183. PMID 28335380.
  13. ^ Shephard RA (June 1987). "Behavioral effects of GABA agonists in relation to anxiety and benzodiazepine action". Life Sciences. 40 (25): 2429–36. doi:10.1016/0024-3205(87)90758-2. PMID 2884549.
  14. ^ Gille A, Bodor ET, Ahmed K, Offermanns S (2008). "Nicotinic acid: pharmacological effects and mechanisms of action". Annual Review of Pharmacology and Toxicology. 48: 79–106. doi:10.1146/annurev.pharmtox.48.113006.094746. PMID 17705685.
  15. ^ Prousky J, Seely D (January 2005). "The treatment of migraines and tension-type headaches with intravenous and oral niacin (nicotinic acid): systematic review of the literature". Nutrition Journal. 4: 3. doi:10.1186/1475-2891-4-3. PMC 548511. PMID 15673472.
  16. ^ Santillo MF, Sprando RL (April 2023). "Picamilon, a γ-aminobutyric acid (GABA) analogue and marketed nootropic, is inactive against 50 biological targets". Basic & Clinical Pharmacology & Toxicology. 132 (4): 355–358. doi:10.1111/bcpt.13836. PMID 36668678.
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