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User:Karenashcruz27/sandbox

Karenashcruz27/sandbox
Clinical data
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Unscheduled (US)
Pharmacokinetic data
Elimination half-life3-5 hours[1] Nefiracetam is usually administered orally. Nefiracetam is an uncharged molecule and is lipid soluble, allowing it to easily pass through the blood brain barrier.10 In a study done in healthy male volunteers, nefiracetam was given in single doses ranging from 10-200mg and in multiple doses with 200mg of the drug given to subjects 3 times a day for seven days. Blood serum concentrations of nefiracetam reach a peak after 2 hours. The half life of the drug is 3-5 hours.
Identifiers
  • N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC14H18N2O2
Molar mass246.305 g/mol g·mol−1
3D model (JSmol)
  • O=C2N(CC(=O)Nc1c(cccc1C)C)CCC2
  • InChI=1S/C14H18N2O2/c1-10-5-3-6-11(2)14(10)15-12(17)9-16-8-4-7-13(16)18/h3,5-6H,4,7-9H2,1-2H3,(H,15,17) checkY
  • Key:NGHTXZCKLWZPGK-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Nefiracetam is a nootropic antidementia drug of the racetam family.[2]

Nefiracetam's cytoprotective actions are mediated by enhancement of GABAergic, cholinergic, and monoaminergic neuronal systems. It has been shown to effectively treat apathy and improve motivation in post-stroke patients. It has been shown to exhibit antiamnesia effects for the Alzheimer's type and cerebrovascular type of dementia.[3][4] In addition, it has also been shown to have antiamnesia effects against a wide variety of memory impairing substances, including: ethanol, chlorodiazepoxide (Librium), scopolamine, bicuculline, picrotoxin, and cycloheximide.[5]

Pharmacokinetics edit

Nefiracetam is usually administered orally. Nefiracetam is an uncharged molecule and is lipid soluble, allowing it to easily pass through the blood brain barrier.[6] In a study done in healthy male volunteers, nefiracetam was given in single doses ranging from 10-200mg and in multiple doses with 200mg of the drug given to subjects 3 times a day for seven days. Blood serum concentrations of nefiracetam reach a peak after 2 hours. The half life of the drug is 3-5 hours.[7]

Pharmacodynamics edit

Action on ACh Receptors edit

The ACh system is affected by memory disorders such as Alzheimer’s disease, and thus nefiracetam has been shown to act via ACh receptors to improve memory. When nefiracetam is administered in submicromolar amounts, short-term depression in ACh dependent currents occurs. The depression is caused by nefiracetam acting on Gs protein-regulated, cAMP-dependent PKA which leads to subsequent ACh receptor phosphorylation.[8] Long term enhancement of ACh currents can be achieved when nefiracetam is applied at micromolar concentrations. This enhancement is caused by nefiracetam acting on calcium dependent PKC which causes subsequent phosphorylation of PKC receptors. However, the specific type of PKC pathway is still unknown.[9]

Action on GABA Receptors edit

Nefiracetam has been shown to bind GABAA receptors and modulate the receptor activity. High concentrations of nefiracetam and low concentrations of GABA evoked strong chloride currents, while high concentrations of GABA in the presence of nefiracetam suppressed these currents. This suggests that nefiracetam acts via a slowly mediated intracellular pathway, of which the exact mechanism is not yet known, and that there exists an optimal level of intracellular nefiracetam that causes increased chloride currents.[10] In the presence of nefiracetam, glutamate decarboxylase activity has been shown to increase, which leads to increased GABA levels[11] and also to enhance GABA uptake.[12]

Action on Voltage-Gated Calcium Channels edit

Research has demonstrated that the memory enhancing properties of nefiracetam functionality are also mediated by voltage-gated calcium channels. The action of nefiracetam on different kinds of calcium channels varies. Nefiracetam causes long lasting currents in voltage-gated calcium channels, however blockage of L-type and N-type calcium channels attenuates the memory enhancing effects of nefiracetam.[13] This suggests that the effects of nefiracetam may be mediated by L and N-type channels, which in turn may be regulated by inhibitory G-proteins and cAMP dependent processes.[14]

Action on NMDA Receptors edit

Since NMDA receptors are implicated in learning and memory, nefiracetam has been thought to act via these receptors in order to enact its memory enhancing properties. Nefiracetam binds to the glycine site of NMDA receptors and acts like an agonist to induce NMDA receptor currents. As long-term potentiation (LTP) is induced through NMDA receptors via activation of CaMKII and PKC pathways, it is thought that nefiracetam also activates these pathways to produce its memory enhancing qualities.[8]

Action on Monoamines edit

Nefiracetam increases levels of enzymes responsible for synthesis of dopamine, serotonin, and norepinephrine. Metabolites for these monoamines (MHPG, DOPAC, and 5-HIAA) were found to be higher in the hippocampus, frontal cortex, hypothalamus, and striatum after chronic nefiracetam administration in mouse models.[15] However, these increases in monoamine levels are not dependent on the dosage of nefiracetam and are region specific.[16]

Treatment edit

Alzheimer's Disease edit

Nefiracetam has been mainly used in the treatment of Alzheimer’s disease. Amyloid-beta peptides are implicated in the formation of senile plaques in Alzheimer’s patients. In rats infused with AB-peptide, nefiracetam was found to increase the rats’ performance on a Y-maze task and water maze task by increasing working memory and spatial reference abilities. Since nefiracetam works to activate voltage gated calcium channels, it is thought that more ACh and dopamine are released through this pathway and therefore ameliorates the effects of AB-peptide plaques in these rats.[17]

Reduction in glutamatergic signaling is also implicated in the learning and memory deficits associated with Alzheimer’s disease. In experiments done in rat hippocampal CA1 slices, bath applications of nefiracetam were shown to induce LTP in NMDA mediated currents, thus showing nefiracetam as a novel treatment for Alzheimer’s. Nefiracetam has been found to act on the glycine binding site of NMDAR’s after no potentiation was seen when 7-CIKN, an NMDAR antagonist that acts at the glycine site, was administered to the bath. LTP induction by nefiracetam causes CaMKII autophosphorylation and phosphorylation of synapsin I (Ser-603) and AMPA-type glutamate receptor subunit 1 (GluA1) (Ser-831). The fact that nefiracetam increases NMDAR activity and CaMKII phosphorylation, which are downregulated in Alzheimer’s patients, suggests that nefiracetam has cognitive enhancing abilities.[18]

Amnesia edit

Research has shown that nefiracetam improves amnesia induced by scopolamine, bicuculline, picrotoxin, ethanol, chlordiazepoxide, and cycloheximide in rat models. Nefiracetam improved learning impairments by increasing acetylcholine release, GABA turnover, and glutamate decarboxylase activity while also activating N and L type calcium channels.[5] Activation of multiple systems results in increased protein synthesis, similar to protein synthesis in LTP, and therefore causes amelioration of induced amnesia and correction of learning impairments.[19]

Side Effects edit

Studies of long term consumption of nefiracetam in humans and primates have shown it to have no toxicity.[20][21] However, animals which metabolize nefiracetam differently from humans and primates are at risk for renal and testicular[22][22] toxicity. Dogs especially are particularly sensitive, which has been shown to be caused by a specific metabolite, M-18.[23] Nefiracetam caused infolding of epithelial cells and and necrotic lesions in the papillary ducts of the dogs, suggesting that papillary epithelial cells are the main target for nefiracetam in the onset of renal papillary necrosis.[24] In another experiment done in male dogs, nefiracetam was observed to lower testosterone levels by impairing the mechanism that converts progesterone to testosterone in Leydig cells. There was also decreased sperm motility and increased instances of malformed sperm observed from semen samples. Examination of the testis showed severe seminiferous atrophy in these dogs, showing that nefiracetam may cause testicular toxicity.[22] Higher doses than those in dogs were needed to cause testicular toxicity in rats, although no toxicity was seen in monkeys. Additionally, there has been no evidence of toxicity during clinical trials.[20][21]


See also edit

References edit

  1. ^ Fujimaki, Y.; Sudo, K.; Hakusui, H.; Tachizawa, H.; Murasaki, M. (1992). "Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers". The Journal of Pharmacy and Pharmacology. 44 (9): 750–4. doi:10.1111/j.2042-7158.1992.tb05513.x. PMID 1360528. S2CID 25913554.
  2. ^ Murphy, Keith J; Foley, Andrew G; O'Connell, Alan W; Regan, Ciaran M (29 June 2005). "Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic Response Identical to that Obtained by Complex Environment Rearing". Neuropsychopharmacology. 31 (1): 90–100. doi:10.1038/sj.npp.1300810. PMID 15988469. S2CID 25669132.
  3. ^ Robinson RG, Jorge RE, Clarence-Smith K, Starkstein S (2009). "Double-blind treatment of apathy in patients with poststroke depression using nefiracetam". The Journal of Neuropsychiatry and Clinical Neurosciences. 21 (2): 144–51. doi:10.1176/appi.neuropsych.21.2.144. PMID 19622685.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ Robinson RG, Jorge RE, Clarence-Smith K (2008). "Double-blind randomized treatment of poststroke depression using nefiracetam". The Journal of Neuropsychiatry and Clinical Neurosciences. 20 (2): 178–84. doi:10.1176/appi.neuropsych.20.2.178. PMID 18451188.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b Hiramatsu, M; Shiotani, T; Kameyama, T; Nabeshima, T (February 1997). "Effects of nefiracetam on amnesia animal models with neuronal dysfunctions". Behavioural Brain Research. 83 (1–2): 107–15. doi:10.1016/s0166-4328(97)86053-6. PMID 9062668. S2CID 4045550.
  6. ^ Fujimaki, Y; Sudo, K; Hakusui, H; Tachizawa, H; Murasaki, M (September 1992). "Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers". The Journal of Pharmacy and Pharmacology. 44 (9): 750–4. doi:10.1111/j.2042-7158.1992.tb05513.x. PMID 1360528. S2CID 25913554.
  7. ^ http://pubchem.ncbi.nlm.nih.gov/compound/Nefiracetam. {{cite web}}: Missing or empty |title= (help)
  8. ^ a b Narahashi, T; Moriguchi, S; Zhao, X; Marszalec, W; Yeh, JZ (November 2004). "Mechanisms of action of cognitive enhancers on neuroreceptors". Biological & Pharmaceutical Bulletin. 27 (11): 1701–6. doi:10.1248/bpb.27.1701. PMID 15516710.
  9. ^ Nishizaki, T; Matsuoka, T; Nomura, T; Sumikawa, K; Shiotani, T; Watabe, S; Yoshii, M (January 1998). "Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways". Molecular Pharmacology. 53 (1): 1–5. doi:10.1124/mol.53.1.1. PMID 9443926.
  10. ^ Huang, CS; Ma, JY; Marszalec, W; Narahashi, T (1996). "Effects of the nootropic drug nefiracetam on the GABAA receptor-channel complex in dorsal root ganglion neurons". Neuropharmacology. 35 (9–10): 1251–61. doi:10.1016/s0028-3908(96)00074-3. PMID 9014140. S2CID 1464068.
  11. ^ Fukatsu, T; Miyake-Takagi, K; Nagakura, A; Omino, K; Okuyama, N; Ando, T; Takagi, N; Furuya, Y; Takeo, S (18 October 2002). "Effects of nefiracetam on spatial memory function and acetylcholine and GABA metabolism in microsphere-embolized rats". European Journal of Pharmacology. 453 (1): 59–67. doi:10.1016/s0014-2999(02)02360-9. PMID 12393060.
  12. ^ Watabe, S; Yamaguchi, H; Ashida, S (20 July 1993). "DM-9384, a new cognition-enhancing agent, increases the turnover of components of the GABAergic system in the rat cerebral cortex". European Journal of Pharmacology. 238 (2–3): 303–9. doi:10.1016/0014-2999(93)90861-b. PMID 8405098.
  13. ^ Yamada, K; Nakayama, S; Shiotani, T; Hasegawa, T; Nabeshima, T (September 1994). "Possible involvement of the activation of voltage-sensitive calcium channels in the ameliorating effects of nefiracetam on scopolamine-induced impairment of performance in a passive avoidance task". The Journal of Pharmacology and Experimental Therapeutics. 270 (3): 881–92. PMID 7932200.
  14. ^ Yoshii, M; Watabe, S (11 April 1994). "Enhancement of neuronal calcium channel currents by the nootropic agent, nefiracetam (DM-9384), in NG108-15 cells". Brain Research. 642 (1–2): 123–31. doi:10.1016/0006-8993(94)90913-x. PMID 8032872. S2CID 42132519.
  15. ^ Abe, E; Murai, S; Saito, H; Masuda, Y; Itoh, T (1992). "Effects of nefiracetam, a novel pyrrolidone derivative, on brain monoamine metabolisms in mice". Journal of Neural Transmission. General Section. 90 (2): 125–36. doi:10.1007/BF01250794. PMID 1463592. S2CID 43867610.
  16. ^ Luthman, J; Lindqvist, E; Kojima, H; Shiotani, T; Tanaka, M; Tachizawa, H; Olson, L (1994). "Effects of nefiracetam (DM-9384), a pyrrolidone derivative, on brain monoamine systems". Archives Internationales de Pharmacodynamie et de Therapie. 328 (2): 125–44. PMID 7535993.
  17. ^ Yamada, K; Tanaka, T; Mamiya, T; Shiotani, T; Kameyama, T; Nabeshima, T (January 1999). "Improvement by nefiracetam of beta-amyloid-(1-42)-induced learning and memory impairments in rats". British Journal of Pharmacology. 126 (1): 235–44. doi:10.1038/sj.bjp.0702309. PMC 1565810. PMID 10051141.
  18. ^ Moriguchi, S (2011). "Pharmacological study on Alzheimer's drugs targeting calcium/calmodulin-dependent protein kinase II". Journal of Pharmacological Sciences. 117 (1): 6–11. doi:10.1254/jphs.11r06cp. PMID 21821968.
  19. ^ Nabeshima, T; Tohyama, K; Murase, K; Ishihara, S; Kameyama, T; Yamasaki, T; Hatanaka, S; Kojima, H; Sakurai, T; Takasu, Y (April 1991). "Effects of DM-9384, a cyclic derivative of GABA, on amnesia and decreases in GABAA and muscarinic receptors induced by cycloheximide". The Journal of Pharmacology and Experimental Therapeutics. 257 (1): 271–5. PMID 1850466.
  20. ^ a b M Murasaki, M Inami, J Ishigooka, H Watanabe, M Utsumi, T Matsumoto; et al. (1994). "Phase I study on DM-9384 (nefiracetam)". Jpn. Pharmacol. Ther. 22: 3539–3587. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  21. ^ a b E Otomo, K Kogure, S Hirai, F Goto, K Hasegawa, Y Tazaki; et al. (1994). "Clinical evaluation of DM-9384 in the treatment of cerebrovascular disorders: early phase II study". Jpn. Pharmacol. Ther. (22): 3589–3624. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  22. ^ a b c Shimada, M; Shikanai, Y; Shimomura, K; Harada, S; Watanabe, G; Taya, K; Kato, M; Furuhama, K (2003). "Investigation of testicular toxicity of nefiracetam, a neurotransmission enhancer, in rats". Toxicology Letters. 143 (3): 307–15. doi:10.1016/s0378-4274(03)00197-8. PMID 12849691. Cite error: The named reference "Shimomura" was defined multiple times with different content (see the help page).
  23. ^ Goto, Koichi; Ishii, Yoshikazu; Jindo, Toshimasa; Furuhama, Kazuhisa (3 March 2003). "Effect of Nefiracetam, a Neurotransmission Enhancer, on Primary Uroepithelial Cells of the Canine Urinary Bladder". Toxicological Sciences. 1 (72): 164–70. doi:10.1093/toxsci/kfg010. PMID 12604846.
  24. ^ Tsuchiya, Y; Yabe, K; Takada, S; Ishii, Y; Jindo, T; Furuhama, K; Suzuki, KT (2005). "Early pathophysiological features in canine renal papillary necrosis induced by nefiracetam". Toxicologic Pathology. 33 (5): 561–9. doi:10.1080/01926230500222593. PMID 16105799. S2CID 7719891.


Category:Racetams Category:Pyrrolidones Category:Acetanilides Category:Nootropics


 

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