| 词条 | Nalmefene |
| 释义 |
| Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 462258343 | IUPAC_name = 17-cyclopropylmethyl-4,5α-epoxy-6-methylenemorphinan-3,14-diol | image = Nalmefene sceletal.svg | width = 240 | tradename =Selincro | Drugs.com = {{drugs.com|monograph|nalmefene-hydrochloride}} | MedlinePlus = a605043 | licence_EU = yes | legal_AU = | legal_CA = | legal_UK = POM | legal_US = | routes_of_administration = By mouth, intravenous | bioavailability = | protein_bound = 45% | metabolism = hepatic | elimination_half-life = 10.8 ± 5.2 hours | excretion = renal | IUPHAR_ligand = 1628 | CAS_number_Ref = {{cascite|changed|??}} | CAS_number = 55096-26-9 | CAS_supplemental = {{CAS|58895-64-0}} (HCl) | ATC_prefix = N07 | ATC_suffix = BB05 | PubChem = 5284594 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 4447642 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = TOV02TDP9I | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 982 | C=21 | H=25 | N=1 | O=3 | molecular_weight = 339.43 g/mol | smiles = OC(C1=C2[C@@]34[C@H]5O1)=CC=C2C[C@@H](N(CC4)CC6CC6)[C@]3(O)CCC5=C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 1S/C21H25NO3/c1-12-6-7-21(24)16-10-14-4-5-15(23)18-17(14)20(21,19(12)25-18)8-9-22(16)11-13-2-3-13/h4-5,13,16,19,23-24H,1-3,6-11H2/t16-,19+,20+,21-/m1/s1 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = WJBLNOPPDWQMCH-MBPVOVBZSA-N }}Nalmefene[1](trade name Selincro), originally known as nalmetrene, is an opioid antagonist used primarily in the management of alcohol dependence. It has also been investigated for the treatment of other addictions such as pathological gambling.[2] Nalmefene is an opiate derivative similar in both structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to naltrexone include longer half-life, greater oral bioavailability and no observed dose-dependent liver toxicity.[3] Like other drugs of this type, nalmefene may precipitate acute withdrawal symptoms in patients who are dependent on opioid drugs, or more rarely when used post-operatively, to counteract the effects of strong opioids used in surgery. Medical usesOpioid overdoseIntravenous doses of nalmefene have been shown effective at counteracting the respiratory depression produced by opioid overdose.[3]This is not the usual application for this drug, for two reasons:
When nalmefene is used to treat an opioid overdose, doses of nalmefene greater than 1.5 mg do not appear to give any greater benefit than doses of only 1.5 mg. Alcohol dependenceNalmefene is used in Europe to reduce alcohol dependence[5] and NICE recommends the use of nalmefene to reduce alcohol consumption in combination with psychological support for people who drink heavily.[6] Based on a meta analysis, the usefulness of nalmefene for alcohol dependence is unclear.[7] Nalmefene, in combination with psychosocial management, may decrease the amount of alcohol drunk by people who are alcohol dependent.[7][10] The medication may also be taken "as needed", when a person feels the urge to consume alcohol.[8] Side effectsThe following adverse effects have been reported with nalmefene: Very Common (≥1⁄10)
Common (≥1⁄100 to <1/10)
The majority of these reactions were mild or moderate, associated with treatment initiation, and of short duration.[9] PharmacologyPharmacodynamicsNalmefene acts as a silent antagonist of the μ-opioid receptor (MOR) (Ki = 0.24 nM) and as a weak partial agonist (Ki = 0.083 nM; Emax = 20–30%) of the κ-opioid receptor (KOR), with similar affinity for these two receptors but a several-fold preference for the KOR.[10] [11][12] In vivo evidence indicative of KOR activation, such as elevation of serum prolactin levels due to dopamine suppression and increased hypothalamic-pituitary-adrenal axis activation via enhanced adrenocorticotropic hormone and cortisol secretion, has been observed in humans and animals.[10][13] Side effects typical of KOR activation such as hallucinations and dissociation have also been observed with nalmefene in human studies.[14] It is thought that the KOR activation of nalmefene might produce dysphoria and anxiety.[15] In addition to MOR and KOR binding, nalmefene also possesses some, albeit far lower affinity for the δ-opioid receptor (DOR) (Ki = 16 nM), where it behaves as an antagonist.[10][12][16]Nalmefene is structurally related to naltrexone and differs from it by substitution of the ketone group at the 6-position of naltrexone with a methylene group (CH2). It binds to the MOR with similar affinity relative to naltrexone, but binds "somewhat more avidly" to the KOR and DOR in comparison.[10][13] PharmacokineticsNalmefene is extensively metabolized in the liver, mainly by conjugation with glucuronic acid and also by N-dealkylation. Less than 5% of the dose is excreted unchanged. The glucuronide metabolite is entirely inactive, while the N-dealkylated metabolite has minimal pharmacological activity.{{citation needed|date=April 2016}} ChemistryNalmefene is a derivative of naltrexone and was first reported in 1975.[17] Society and cultureUnited StatesIn the US, immediate-release injectable nalmefene was approved in 1995 as an antidote for opioid overdose. It was sold under the trade name Revex. The product was discontinued by its manufacturer around 2008.[18][19] Perhaps, due to its price, it never sold well. (See {{section link||Opioid overdose}}, above.) Nalmefene in pill form, which is used to treat alcohol dependence and other addictive behaviors, has never been sold in the United States.[20] EuropeLundbeck has licensed nalmefene from Biotie Therapies and performed clinical trials with nalmefene for treatment of alcohol dependence.[21]In 2011 they submitted an application for their drug termed Selincro to the European Medicines Agency.[22] The drug was approved for use in the EU in March 2013.[23] and in October 2013 Scotland became the first country in the EU to prescribe the drug for alcohol dependence.[24] England followed Scotland by offering the substance as a treatment for problem drinking in October 2014.[25] In November 2014 nalmefene was appraised and approved as a treatment supplied by Britain's National Health Service (NHS) for reducing alcohol consumption in people with alcohol dependence.[26] ResearchNalmefene is a partial agonist of the κ-opioid receptor and may be useful to treat cocaine addiction.[27] See also
References1. ^ US Patent 3814768 6-methylene-6-desoxy dihydro morphine and codeine derivatives and pharmaceutically acceptable salts {{Antiaddictives}}{{Antidotes}}{{Hallucinogens}}{{Opioidergics}}2. ^[https://clinicaltrials.gov/ct2/show/NCT00132119?term=nalmefene&rank=6 NCT00132119] ClinicalTrials.gov 3. ^Label information. U.S. Food and Drug Administration{{cite web |url=http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf |title=Archived copy |accessdate=2014-11-07 |deadurl=bot: unknown |archiveurl=https://web.archive.org/web/20061013033351/http://www.fda.gov/cder/foi/label/2000/20459S2lbl.pdf |archivedate=October 13, 2006 |df= }} 4. ^Based on: {{cite web|last1=Stephens|first1=Everett|title=Opioid Toxicity Medication » Medication Summary|url=https://emedicine.medscape.com/article/815784-medication#1|website=Medscape|publisher=WebMD LLC}} 5. ^{{cite web|title=Selincro 18mg film-coated tablets|url=https://www.medicines.org.uk/emc/medicine/27609|publisher=UK Electronic Medicines Compendium|language=en|date=September 2016}} 6. ^{{cite web|title=Technology appraisal guidance [TA325]: Nalmefene for reducing alcohol consumption in people with alcohol dependence|url=https://www.nice.org.uk/guidance/ta325/chapter/1-Guidance|publisher=NICE|date=26 November 2014}} 7. ^1 {{cite journal|last1=Palpacuer|first1=C|last2=Laviolle|first2=B|last3=Boussageon|first3=R|last4=Reymann|first4=JM|last5=Bellissant|first5=E|last6=Naudet|first6=F|title=Risks and benefits of nalmefene in the treatment of adult alcohol dependence: a systematic literature review and meta-analysis of published and unpublished double-blind randomized controlled trials |journal=PLOS Medicine|date=December 2015|volume=12|issue=12|pages=e1001924|pmid=26694529|doi=10.1371/journal.pmed.1001924|pmc=4687857}} 8. ^1 {{cite journal|first1=François |last1=Paille |first2=Hervé |last2=Martini |title=Nalmefene: a new approach to the treatment of alcohol dependence |journal=Substance Abuse and Rehabilitation|year=2014|volume=5|number=5|pages=87–94|pmid=25187751|doi=10.2147/sar.s45666|pmc=4133028}} 9. ^{{cite web|title=Selincro|url=https://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124|website=European Medicines Agency|accessdate=3 November 2015}} 10. ^1 2 3 {{cite journal|last1=Bart|first1=G|last2=Schluger|first2=JH|last3=Borg|first3=L|last4=Ho|first4=A|last5=Bidlack|first5=JM|last6=Kreek|first6=MJ|title=Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity?|journal=Neuropsychopharmacology |date=December 2005|volume=30|issue=12|pages=2254–62|doi=10.1038/sj.npp.1300811|pmid=15988468}} 11. ^{{cite journal | vauthors = Bart G, Schluger JH, Borg L, Ho A, Bidlack JM, Kreek MJ | title = Nalmefene induced elevation in serum prolactin in normal human volunteers: partial kappa opioid agonist activity? | journal = Neuropsychopharmacology | volume = 30 | issue = 12 | pages = 2254–62 | year = 2005 | pmid = 15988468 | doi = 10.1038/sj.npp.1300811 }} 12. ^1 {{cite book|author=Linda P. Dwoskin|title=Emerging Targets & Therapeutics in the Treatment of Psychostimulant Abuse|url=https://books.google.com/books?id=b3UpAgAAQBAJ&pg=PA398|date=29 January 2014|publisher=Elsevier Science|isbn=978-0-12-420177-4|pages=398–}} 13. ^1 {{cite journal|last1=Niciu|first1=Mark J.|last2=Arias|first2=Albert J.|title=Targeted opioid receptor antagonists in the treatment of alcohol use disorders |journal=CNS Drugs |volume=27|issue=10|year=2013|pages=777–787|issn=1172-7047|doi=10.1007/s40263-013-0096-4|pmid=23881605|pmc=4600601}} 14. ^{{cite journal | vauthors = | title = Nalmefene (new drug) Alcohol dependence: no advance | journal = Prescrire International | volume = 23 | issue = 150 | pages = 150–152 | year = 2014 | pmid = 25121147 | url =http://english.prescrire.org/en/F11B931CD8AA2ECB608882529D799668/Download.aspx }} (subscription required) 15. ^{{cite book |author=Stephen M. Stahl |title=Prescriber's guide: Stahl's essential psychopharmacology |url=https://books.google.com/books?id=qgNeAwAAQBAJ&pg=PA465 |date=15 May 2014 |publisher=Cambridge University Press |isbn=978-1-139-95300-9|pages=465–}} 16. ^{{cite journal | vauthors = Grosshans M, Mutschler J, Kiefer F | title = Treatment of cocaine craving with as-needed nalmefene, a partial κ opioid receptor agonist: first clinical experience | journal = International Clinical Psychopharmacology | volume =30 | issue =4 | pages =237–8 | year = 2015 | pmid = 25647453 | doi = 10.1097/YIC.0000000000000069 }} 17. ^{{cite book|last1=Fulton|first1=Brian S.|title=Drug Discovery for the Treatment of Addiction: Medicinal Chemistry Strategies|date=2014|publisher=John Wiley & Sons|isbn=9781118889572|page=341|url=https://books.google.com/books?id=M5E_BAAAQBAJ&pg=PT341|language=en}} 18. ^See: {{cite web|title=Baxter discontinues Revex injection|url=http://www.empr.com/news/baxter-discontinues-revex-injection/article/122431/|website=Monthly Prescribing Reference website|publisher=Haymarket Media, Inc|accessdate=10 October 2016|date=9 July 2008}} 19. ^{{cite web|title=Drug Shortages|url=http://www.fda.gov/Cder/drug/shortages/default.htm|publisher=FDA Center for Drug Evaluation and Research|archiveurl=https://web.archive.org/web/20081226211459/http://www.fda.gov/Cder/drug/shortages/default.htm|archivedate=26 December 2008}} 20. ^1 See: {{cite web|title=Drug Record: Nalmefene |work=LiverTox |publisher=National Library of Medicine |date=24 March 2016 |url=http://livertox.nih.gov/Nalmefene.htm }} 21. ^{{Cite web | title = Efficacy of nalmefene in patients with alcohol dependence (ESENSE1) | url= http://clinicaltrials.gov/ct2/show/NCT00811720?term=ESENSE1&rank=1}} 22. ^{{Cite news | title = Lundbeck submits Selincro in EU; Novo Nordisk files Degludec in Japan | url = http://www.thepharmaletter.com/file/109811/lundbeck-submits-selincro-in-eu-novo-nordisk-files-degludec-in-japan.html | publisher= The Pharma Letter | date = 22 December 2011}} 23. ^{{cite web|title=Selincro|work=European Medicines Agency|date=13 March 2013|url=http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002583/human_med_001620.jsp&mid=WC0b01ac058001d124}} 24. ^{{cite news |title=Alcohol cravings drug nalmefene granted approval in Scotland|publisher=BBC News |date=7 October 2013 |url=https://www.bbc.com/news/uk-scotland-24431152}} 25. ^{{cite news |title=Nalmefene granted approval in England |work=The Independent |date=3 October 2014 |url=https://www.independent.co.uk/life-style/health-and-families/heavy-drinkers-to-be-offered-lifesaving-pill-that-helps-reduce-alcohol-consumption-9771600.html }} 26. ^{{cite web|title=Alcohol dependence treatment accepted for NHS use|url=http://www.mims.co.uk/alcohol-dependence-treatment-accepted-nhs-use/health-promotion/article/1324040|publisher=MIMS|date=26 November 2014}} 27. ^{{cite book|last1=Bidlack|first1=Jean M |title=Mixed κ/μ partial opioid agonists as potential treatments for cocaine dependence |volume=69 |year=2014 |pages=387–418 |doi=10.1016/B978-0-12-420118-7.00010-X |pmid=24484983 |journal=Adv. Pharmacol.|series=Advances in Pharmacology |isbn=9780124201187 }} 7 : Dissociative drugs|Morphinans|Phenols|Alcohols|Alkene derivatives|Kappa agonists|Opioid antagonists |
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