| Revision as of 12:47, 31 October 2011 editBeetstra (talk | contribs)Edit filter managers, Administrators172,081 edits Script assisted update of identifiers for the Chem/Drugbox validation project (updated: 'CAS_number').← Previous edit |
Latest revision as of 19:13, 31 August 2024 edit undoGettinglit (talk | contribs)Extended confirmed users1,005 edits Per cited M18 isn't formed in humans |
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{{Short description|Chemical compound}} |
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{{Drugbox |
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{{Drugbox |
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| verifiedrevid = 415860422 |
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| verifiedrevid = 458287215 |
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| IUPAC_name = ''N-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide '' |
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| IUPAC_name = ''N''-(2,6-dimethylphenyl)-2-(2-oxopyrrolidin-1-yl)acetamide |
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| image = Nefiracetam.svg |
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| image = Nefiracetam.svg |
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| width = 150px |
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| width = 150px |
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<!--Clinical data--> |
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<!--Clinical data--> |
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| tradename = |
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| tradename = |
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| pregnancy_category = |
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| pregnancy_category = |
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| legal_AU = S4 |
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| legal_status = Unscheduled (US) |
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| legal_US = Unscheduled |
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| routes_of_administration = Oral |
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| routes_of_administration = Oral |
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<!--Pharmacokinetic data--> |
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<!--Pharmacokinetic data--> |
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| bioavailability = |
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| bioavailability = |
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| metabolism = |
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| metabolism = |
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| excretion = |
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| excretion = |
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| elimination_half-life = 3-5 hours<ref>{{cite journal | vauthors = Fujimaki Y, Sudo K, Hakusui H, Tachizawa H, Murasaki M | title = Single- and multiple-dose pharmacokinetics of nefiracetam, a new nootropic agent, in healthy volunteers | journal = The Journal of Pharmacy and Pharmacology | volume = 44 | issue = 9 | pages = 750–754 | date = September 1992 | pmid = 1360528 | doi = 10.1111/j.2042-7158.1992.tb05513.x | s2cid = 25913554 }}</ref> |
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<!--Identifiers--> |
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<!--Identifiers--> |
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| CAS_number_Ref = {{cascite|correct|??}} |
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| CAS_number_Ref = {{cascite|changed|??}} |
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| CAS_number = <!-- blanked - oldvalue: 77191-36-7 --> |
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| CAS_number = 77191-36-7 |
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| ATC_prefix = none |
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| ATC_prefix = none |
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| PubChem = 71157 |
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| PubChem = 71157 |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} |
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| ChemSpiderID = 64299 |
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| ChemSpiderID = 64299 |
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| UNII_Ref = {{fdacite|changed|FDA}} |
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| UNII_Ref = {{fdacite|correct|FDA}} |
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| UNII = 1JK12GX30N |
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| UNII = 1JK12GX30N |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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| ChEMBL_Ref = {{ebicite|correct|EBI}} |
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<!--Chemical data--> |
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<!--Chemical data--> |
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| C=14 | H=18 | N=2 | O=2 |
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| C=14 | H=18 | N=2 | O=2 |
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| SMILES = O=C2N(CC(=O)Nc1c(cccc1C)C)CCC2 |
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| molecular_weight = 246.305 g/mol |
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| ⚫ |
| smiles = O=C2N(CC(=O)Nc1c(cccc1C)C)CCC2 |
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| InChI = 1/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) |
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| InChIKey = NGHTXZCKLWZPGK-UHFFFAOYAF |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI_Ref = {{stdinchicite|correct|chemspider}} |
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| StdInChI = 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) |
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| StdInChI = 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) |
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| StdInChIKey = NGHTXZCKLWZPGK-UHFFFAOYSA-N |
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| StdInChIKey = NGHTXZCKLWZPGK-UHFFFAOYSA-N |
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}} |
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}} |
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'''Nefiracetam''' is a ] ] drug of the ] family.<ref name=NPP2005>{{Cite journal|first=Keith |last=Murphy |date=22 July 2004 |url=http://relentlessimprovement.com/included/docs/memorypersistance.pdf |title=Chronic Exposure of Rats to Cognition Enhancing Drugs Produces a Neuroplastic response |journal=Neuropsychopharmacology |accessdate=1 September 2010}}</ref> |
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'''Nefiracetam''' is a ] drug of the ] family. Preliminary research suggests that it may possess certain ] properties in rats.<ref name=NPP2005>{{cite journal | vauthors = Murphy KJ, Foley AG, O'connell AW, Regan CM | title = Chronic exposure of rats to cognition enhancing drugs produces a neuroplastic response identical to that obtained by complex environment rearing | journal = Neuropsychopharmacology | volume = 31 | issue = 1 | pages = 90–100 | date = January 2006 | pmid = 15988469 | doi = 10.1038/sj.npp.1300810 | doi-access = free }}</ref> |
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Nefiracetam's cytoprotective actions are mediated by enhancement of ], ], and ] neuronal systems that give antiamnesia effects to the Alzheimer's type and cerebrovascular type of dementia.<ref>{{cite journal |author=Robinson RG, Jorge RE, Clarence-Smith K, Starkstein S |title=Double-blind treatment of apathy in patients with poststroke depression using nefiracetam |journal=The Journal of Neuropsychiatry and Clinical Neurosciences |volume=21 |issue=2 |pages=144–51 |year=2009 |pmid=19622685 |doi=10.1176/appi.neuropsych.21.2.144}}</ref><ref>{{cite journal |author=Robinson RG, Jorge RE, Clarence-Smith K |title=Double-blind randomized treatment of poststroke depression using nefiracetam |journal=The Journal of Neuropsychiatry and Clinical Neurosciences |volume=20 |issue=2 |pages=178–84 |year=2008 |pmid=18451188 |doi=10.1176/appi.neuropsych.20.2.178}}</ref> |
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==Effects== |
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Nefiracetam has reduced testicular testosterone in both rats and dogs. |
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Nefiracetam's cytoprotective actions are mediated by enhancement of ], ], and ] neuronal systems.{{Citation needed|date=July 2018}} Preliminary studies suggest that it improves apathy and motivation in post-stroke patients. It may also exhibit antiamnesia effects for the Alzheimer's type and cerebrovascular type of dementia.<ref>{{cite journal | vauthors = Robinson RG, Jorge RE, Clarence-Smith K, Starkstein S | title = Double-blind treatment of apathy in patients with poststroke depression using nefiracetam | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 21 | issue = 2 | pages = 144–151 | year = 2009 | pmid = 19622685 | doi = 10.1176/appi.neuropsych.21.2.144 }}</ref><ref>{{cite journal | vauthors = Robinson RG, Jorge RE, Clarence-Smith K | title = Double-blind randomized treatment of poststroke depression using nefiracetam | journal = The Journal of Neuropsychiatry and Clinical Neurosciences | volume = 20 | issue = 2 | pages = 178–184 | year = 2008 | pmid = 18451188 | doi = 10.1176/appi.neuropsych.20.2.178 }}</ref> In addition, research in animal models suggests antiamnesic effects against a number of memory impairing substances, including: ethanol, chlorodiazepoxide, scopolamine, bicuculline, picrotoxin, and cycloheximide.<ref name="Effects of nefiracetam on amnesia animal models with neuronal dysfunctions">{{cite journal | vauthors = Hiramatsu M, Shiotani T, Kameyama T, Nabeshima T | title = Effects of nefiracetam on amnesia animal models with neuronal dysfunctions | journal = Behavioural Brain Research | volume = 83 | issue = 1–2 | pages = 107–115 | date = February 1997 | pmid = 9062668 | doi = 10.1016/s0166-4328(97)86053-6 | s2cid = 4045550 }}</ref> |
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To investigate mechanisms of the testicular toxicity of nefiracetam and to find sensitive parameters to predict the toxicity, male beagle dogs were orally administered 180 or 300mg/kg per day of the drug once and for 1 and 4 weeks. Time-course changes in serum and/or testicular hormone levels and semen parameters, and testicular morphology were examined. The testicular testosterone level was decreased 4h after single administration of nefiracetam at 300mg/kg per day, but the progesterone level showed no change at that time. The serum testosterone level was decreased after single, 1-week or 2-week treatment. In contrast, the serum estradiol level was increased from 1- to 4-week treatment. No changes in serum LH, FSH and inhibin B levels were observed throughout the experimental period. Decreased sperm motility and increased number of malformed sperms were first observed in semen after 4-week treatment. Histopathological examination of the testis revealed moderate and severe seminiferous atrophy with multinucleated giant cell formation at 180 and 300mg/kg per day, respectively, after 4-week treatment, but not 1-week treatment. These results show that nefiracetam decreases testicular testosterone level in dogs following single oral administration of a high dose, and induces severe morphologic changes after 4-week treatment. This reduction is shown to be a sensitive parameter to detect the toxicity, and is suggested to be induced by the impaired conversion of progesterone to testosterone in Leydig cells of rats <ref>{{cite journal|pmid=12849691|year=2003|last1=Shimada|first1=M|last2=Shikanai|first2=Y|last3=Shimomura|first3=K|last4=Harada|first4=S|last5=Watanabe|first5=G|last6=Taya|first6=K|last7=Kato|first7=M|last8=Furuhama|first8=K|title=Investigation of testicular toxicity of nefiracetam, a neurotransmission enhancer, in rats|volume=143|issue=3|pages=307–15|journal=Toxicology letters}}</ref> and dogs.<ref>{{cite journal|pmid=15082078|year=2004|last1=Shimomura|first1=K|last2=Shimada|first2=M|last3=Hagiwara|first3=M|last4=Harada|first4=S|last5=Kato|first5=M|last6=Furuhama|first6=K|title=Testicular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancer|volume=18|issue=3|pages=423–30|doi=10.1016/j.reprotox.2004.01.008|journal=Reproductive toxicology (Elmsford, N.Y.)}}</ref> Although the dosages used in the studies were 1500 mg/kg and 300 mg/kg, respectively. |
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==See also== |
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==Pharmacology== |
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Unlike other racetams, nefiracetam shows high ] for the ] (]) = 8.5 nM), where it is presumed to be an ].<ref name="pmid8061686">{{cite journal | vauthors = Gouliaev AH, Senning A | title = Piracetam and other structurally related nootropics | journal = Brain Research. Brain Research Reviews | volume = 19 | issue = 2 | pages = 180–222 | date = May 1994 | pmid = 8061686 | doi = 10.1016/0165-0173(94)90011-6 | s2cid = 18122566 }}</ref><ref name="pmid2328758">{{cite journal | vauthors = Nabeshima T, Noda Y, Tohyama K, Itoh J, Kameyama T | title = Effects of DM-9384 in a model of amnesia based on animals with GABAergic neuronal dysfunctions | journal = European Journal of Pharmacology | volume = 178 | issue = 2 | pages = 143–149 | date = March 1990 | pmid = 2328758 | doi = 10.1016/0014-2999(90)90469-m }}</ref> It was able to potently inhibit 80% of ] binding to the GABA<sub>A</sub> receptor, although it failed to displace the remaining 20% of specific muscimol binding.<ref name="pmid8061686" /><ref name="pmid2328758" /> Nefiracetam is able to reverse the ] caused by the GABA<sub>A</sub> receptor antagonists ] and ] in mice, although it failed to prevent ]s induced by these drugs.<ref name="pmid2328758" /> |
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==Concerns== |
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Studies of long-term consumption of nefiracetam in humans and primates have shown it to have no toxicity.<ref name="Murasaki_1994">{{cite journal| vauthors = Murasaki M, Inami M, Ishigooka J, Watanabe H, Utsumi M, Matsumoto T |title=Phase I study on DM-9384 (nefiracetam)|journal=Jpn. Pharmacol. Ther.|year=1994|volume=22|pages=3539–3587|display-authors=etal}}</ref><ref name="Otomo_1994_2">{{cite journal| vauthors = Otomo E, Kogure K, Hirai S, Goto F, Hasegawa K, Tazaki Y, etal |title=Clinical evaluation of DM-9384 in the treatment of cerebrovascular disorders: early phase II study|journal=Jpn. Pharmacol. Ther.|year=1994|issue=22|pages=3589–3624 }}</ref> However, animals which metabolize nefiracetam differently from humans and primates are at risk for renal and testicular<ref>{{cite journal | vauthors = Shimada M, Shikanai Y, Shimomura K, Harada S, Watanabe G, Taya K, Kato M, Furuhama K | display-authors = 6 | title = Investigation of testicular toxicity of nefiracetam, a neurotransmission enhancer, in rats | journal = Toxicology Letters | volume = 143 | issue = 3 | pages = 307–315 | date = August 2003 | pmid = 12849691 | doi = 10.1016/s0378-4274(03)00197-8 }}</ref><ref name=Shimomura>{{cite journal | vauthors = Shimomura K, Shimada M, Hagiwara M, Harada S, Kato M, Furuhama K | title = Testicular toxicity induced in dogs by nefiracetam, a neutrotransmission enhancer | journal = Reproductive Toxicology | volume = 18 | issue = 3 | pages = 423–430 | date = May 2004 | pmid = 15082078 | doi = 10.1016/j.reprotox.2004.01.008 }}</ref> toxicity. Dogs especially are particularly sensitive, which has been shown to be caused by a specific metabolite, M-18 which isn't formed in humans.<ref name="Goto">{{cite journal | vauthors = Goto K, Ishii Y, Jindo T, Furuhama K | title = Effect of nefiracetam, a neurotransmission enhancer, on primary uroepithelial cells of the canine urinary bladder | journal = Toxicological Sciences | volume = 72 | issue = 1 | pages = 164–170 | date = March 2003 | pmid = 12604846 | doi = 10.1093/toxsci/kfg010 | doi-access = free }}</ref> 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.<ref name="Murasaki_1994"/><ref name="Otomo_1994_2"/> |
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== See also == |
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==References== |
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== References == |
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{{Reflist}} |
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{{GABAA receptor modulators}} |
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{{nervous-system-drug-stub}} |
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