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- Naloxone hydrochloride
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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/13 09:52:11」(JST)
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Not to be confused with naltrexone or naloxazone.
| Systematic (IUPAC) name | |
|---|---|
| (1S,5R,13R,17S)- 10,17-dihydroxy- 4-(prop-2-en-1-yl)- 12-oxa- 4-azapentacyclo [9.6.1.01,13.05,17.07,18] octadeca- 7(18),8,10-trien- 14-one | |
| Clinical data | |
| AHFS/Drugs.com | monograph |
| Pregnancy cat. | B (USA) B1 (Aus) |
| Legal status | Prescription Only (S4) (AU) |
| Routes | IV, IM |
| Pharmacokinetic data | |
| Bioavailability | 2% (Oral, 90% absorption but high first-pass metabolism) |
| Metabolism | Liver |
| Half-life | 1-1.5 h |
| Excretion | Urine, Biliary |
| Identifiers | |
| CAS number | 465-65-6 Y |
| ATC code | V03AB15 |
| PubChem | CID 5284596 |
| IUPHAR ligand | 1638 |
| DrugBank | DB01183 |
| ChemSpider | 4447644 Y |
| UNII | 36B82AMQ7N Y |
| KEGG | D08249 Y |
| ChEBI | CHEBI:7459 N |
| ChEMBL | CHEMBL80 Y |
| Synonyms | 17-allyl- 4,5α-epoxy- 3,14-dihydroxymorphinan- 6-one |
| Chemical data | |
| Formula | C19H21NO4 |
| Mol. mass | 327.37 g/mol |
|
SMILES
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InChI
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| N (what is this?) (verify) |
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Naloxone is an opioid inverse agonist [1] drug developed by Sankyo in the 1960s.[2] Naloxone is a drug used to counter the effects of opiate overdose, for example heroin or morphine overdose. Naloxone is specifically used to counteract life-threatening depression of the central nervous system and respiratory system. Naloxone is also experimentally used in the treatment for congenital insensitivity to pain with anhidrosis (CIPA), an extremely rare disorder (1 in 125 million) that renders one unable to feel pain. It is marketed under various trademarks including Narcan, Nalone, and Narcanti, and has sometimes been mistakenly called "naltrexate." It is not to be confused with naltrexone, an opioid receptor antagonist with qualitatively different effects, used for dependence treatment rather than emergency overdose treatment.
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Pharmacodynamics[edit]
Naloxone has an extremely high affinity for μ-opioid receptors in the central nervous system. Naloxone is a μ-opioid receptor competitive antagonist, and its rapid blockade of those receptors often produces rapid onset of withdrawal symptoms. Naloxone also has an antagonist action, though with a lower affinity, at κ- and δ-opioid receptors.
Chemistry[edit]
Naloxone is synthesized from thebaine. The chemical structure of naloxone resembles that of oxymorphone, the only difference being the substitution of the N-methyl group with an allyl (prop-2-enyl) group. The name naloxone has been derived from N-allyl and oxymorphone.
Administration[edit]
Naloxone is most commonly injected intravenously for fastest action, which usually causes the drug to act within a minute, and last up to 45 minutes. It can also be administered via intramuscular or subcutaneous injection. Finally, a wedge device (nasal atomizer) attached to a syringe may be used to create a mist which delivers the drug to the nasal mucosa,[3] although this solution is more common outside of clinical facilities. Naloxone is used orally along with Oxycontin Controlled Release, and helps in reducing the constipation associated with opioids. Enteral administration of Naloxone blocks opioid action at the intestinal receptor level, but has low systemic bioavailability due to marked hepatic first pass metabolism.[4]
Uses[edit]
| This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (July 2008) |
Counteracting opiate overdose and addiction[edit]
Naloxone has been distributed as part of emergency overdose response kits to heroin and other opioid drug users, and this has been shown to reduce rates of fatal overdose.[5][6][7][8][9][10][11][12][13] Prescribing naloxone should be accompanied by standard education that includes preventing, identifying, and responding to an overdose; rescue breathing; and calling 911.[14] Naloxone should be prescribed if the patient is also prescribed a high dose of opioid (>100 mg of morphine equivalence/day), is prescribed any dose of opioid accompanied by a benzodiazepine, or is a suspected or known to use opioids non-medically. [15] Projects of this type are under way in many US cities, including San Francisco, Philadelphia, Baltimore, Boston, Los Angeles, Milwaukee, and Chicago and the states of New Mexico, New York as well as in Canada in certain cities such as Toronto.[16][17][18] CDC estimates that US programs for drug users and their caregivers prescribing take-home doses of naloxone and training on its utilization are estimated to have reversed 10,000 opioid overdose deaths.[17] Healthcare institution-based naloxone prescription programs have also helped reduce rates of opioid overdose in North Carolina, and have been replicated in the US military.[19][20] Nevertheless, scale-up of healthcare-based opioid overdose interventions is limited by providers' insufficient knowledge and negative attitudes towards prescribing take-home naloxone and by sluggish federal government response.[21][22] Programs training police and fire personnel in opioid overdose response using naloxone have also shown promise in the US and there is increasing effort to integrate opioid fatality prevention in the overall response to the overdose crisis.[23][24][25][26][27]
Pilot projects were also started in Scotland in 2006. Also in the UK, in December 2008 the Welsh Assembly Government announced intention to establish demonstration sites for 'take home' Naloxone.[28] While naloxone is still the standard treatment in emergency reversal of opioid overdose, its clinical use in the long-term treatment of opioid addiction is being increasingly superseded by naltrexone. Naltrexone is structurally similar but has a slightly increased affinity for κ-opioid receptors over naloxone, can be administered orally, and has a longer duration of action.
Enteral naloxone has been successfully used in the reduction of gastritis and esophagitis associated with opioid therapy in mechanically-ventilated acute care patients.
The combination oxycodone/naloxone is used for the prophylaxis of opioid-induced constipation in patients requiring strong opioid therapy under the trade name Targin and in the Netherlands under Targinact.[29]
Beyond treatment for overdose, a variant of Naloxone called (+)-naloxone is showing promise as a way of treating opioid-related addiction.[30] By binding to the body's TLR4 immune receptors, substances like heroin no longer produce the dopamine needed to generate substance addiction yet retains the pain-relieving effect of these drugs. This means that if both morphine and (+)-naloxone are taken simultaneously, a patient will receive the necessary analgesic effect of the morphine but avoid the potential for addiction. Such usage is still awaiting clinical testing.
Preventing opioid abuse[edit]
| This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. Unsourced material may be challenged and removed. (January 2013) |
Naloxone is used as a secondary chemical in the drug Suboxone. Suboxone and Subutex were created to help opiate-addicted patients detox. Suboxone contains four parts buprenorphine and one part naloxone, while Subutex contains only buprenorphine. Naloxone was added to Suboxone in an effort to dissuade patients from injecting the tablets. Supposedly, the naloxone would throw the user into precipated withdrawals, or at the very least, blocking buprenorphine's abusable effects. However, given that buperenorphine has a higher affinity for opioid receptors than naloxone, naloxone is not a hindrance, it neither causes precipated withdrawals nor blocks the user's 'high'. In fact, buprenorphine has a higher affinity for opioid receptors than almost all opioids including heroin.
Oral or sublingual administration affects only the gastrointestinal tract, and has the added benefit of helping to reverse constipation and lowered bowel motility caused by chronic medical use, or abuse, of a variety of opioids. Because of possible side effects of naloxone in some patients, chemical detox can begin with Suboxone's sister drug, Subutex, which does not contain naloxone. It is common for Suboxone film to be used in all cases unless pregnancy is a concern.
Depersonalization disorder[edit]
A 2001 Russian study has shown that naloxone can be used to treat depersonalization disorder. According to the study: "In three of 14 patients, depersonalization symptoms disappeared entirely and seven patients showed a marked improvement. The therapeutic effect of naloxone provides evidence for the role of the endogenous opioid system in the pathogenesis of depersonalization."[31]
Side-effects[edit]
Possible side effects include: change in mood, increased sweating, nausea, nervousness, restlessness, trembling, vomiting, allergic reactions such as rash or swelling, dizziness, fainting, fast or irregular pulse, flushing, headache, heart rhythm changes, seizures, sudden chest pain.[32]
Naloxone has been shown to block the action of pain-lowering endorphins which the body produces naturally. The likely reason for this is that these endorphins operate on the same opioid receptors that naloxone blocks. Naloxone is capable of blocking a placebo pain-lowering response, both in clinical and experimental pain, if the placebo is administered together with a hidden or blind injection of naloxone.[33] Other studies have found that placebo alone can activate the body's μ-opioid endorphin system, delivering pain relief via the same receptor mechanism as morphine.[34]
Legal status[edit]
Patent status[edit]
The patent for naloxone has expired. It is available in generic forms.
Prescription status[edit]
In the US, naloxone is classified as a prescription medication, though it is not a controlled substance.[35] While it is legal to prescribe naloxone in every state, dispensing the drug by medical professionals (including physicians or other licensed prescribers) at the point of service is subject to rules that vary by jurisdiction.[36][37] Naloxone distribution programs utilize licensed prescribers to distribute the drug, sometimes relying on “standing orders” mechanisms[20][38] to increase scale-up.
Shortage and Pricing[edit]
Naloxone has been periodically under FDA shortage designation since 2001 and was recently re-verified as being in shortage due to a manufacturing delay.[39] Twenty-one out of 48 naloxone prescription programs surveyed in 2010 reported they had experienced challenges in obtaining naloxone in the months leading up to the survey, mainly due either to cost increases that outstripped allocated funding or the suppliers’ inability to fill orders.[17] The approximate cost of a 1 ml ampoule of naloxone in the United States is estimated to be significantly higher than in most Western countries; on average, the price for naloxone supply has increased precipitously in recent years.[20]
Identification[edit]
The CAS number of naloxone is 465-65-6; the anhydrous hydrochloride salt has CAS 357-08-4 and the hydrochloride salt with 2 molecules of water, hydrochloride dihydrate, has CAS 51481-60-8.
See also[edit]
- Cyprodime
- Nalmefene
- (+)-Naloxone
- Naloxol
- Naltrexone
References[edit]
- ^ Sirohi, S; Dighe, SV; Madia, PA; Yoburn, BC (August 2009). "The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity". Journal of Pharmacology and Experimental Therapeutics 330 (2): 513–9. doi:10.1124/jpet.109.152678. PMC 2713087. PMID 19435929.
- ^ US Patent 3254088 - Morphine Derivative
- ^ "Journal of Emergency Nursing".
- ^ (PMID 10601678 [PubMed - indexed for MEDLINE])
- ^ Dettmer K, Saunders B, Strang J. (2001 Apr). "Take home naloxone and the prevention of deaths from opiate overdose: two pilot schemes". BMJ 322 (7291): 895–896. PMC PMC30585. PMID 11302902.
- ^ Maxwell S, Bigg D, Stanczykiewicz K, Carlberg-Racich S. (2006). "Prescribing naloxone to actively injecting heroin users: a program to reduce heroin overdose deaths". J Addict Dis 25 (3): 89–96. doi:10.1300/J069v25n03_11. PMID 16956873.
- ^ Seal KH, Thawley R, Gee L, et al. (2005). "Naloxone distribution and cardiopulmonary resuscitation training for injection drug users to prevent heroin overdose death: a pilot intervention study". J Urban Health 82 (2): 303–311. doi:10.1093/jurban/jti053. PMC PMC2570543. PMID 15872192.
- ^ Strang J, Powis B, Best D, et al. (1999). "Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability". Addiction 94 (2): 199–204. doi:10.1046/j.1360-0443.1999.9421993.x. PMID 10396785.
- ^ Galea A, Worthington N, Piper TM, et al. (2006). "Provision of naloxone to injection drug users as an overdose prevention strategy: early evidence from a pilot study in New York City". Addict Behav 31 (5): 907–912. doi:10.1016/j.addbeh.2005.07.020. PMID 16139434.
- ^ Strang J, Best D, Man L, et al. (2000). "Peer-initiated overdose resuscitation: fellow drug users could be mobilised to implement resuscitation". Int J Drug Policy 11 (6): 437–445. PMID 11099924.
- ^ Sherman SG, Gann DS, Tobin KE, et al. (2009). ""The life they save may be mine": diffusion of overdose prevention information from a city sponsored programme". Int J Drug Policy 20 (2): 137–142. doi:10.1016/j.drugpo.2008.02.004. PMID 18502635.
- ^ Tobin KE, Sherman SG, Beilenson P, et al. (2009). "Evaluation of the Staying Alive programme: training injection drug users to properly administer naloxone and save lives". Int J Drug Policy 20 (2): 131–136. doi:10.1016/j.drugpo.2008.03.002. PMID 18434126.
- ^ Pollini RA, McCall L, Mehta Sh, et al. (2006). "Non-fatal overdose and subsequent drug treatment among injection drug users". Drug Alcohol Depend 83 (2): 104–110. doi:10.1016/j.drugalcdep.2005.10.015. PMID 16310322.
- ^ Bowman S, Eisereman J, Beletsky L, Stancliff S, Bruce D. (2013 May). "Reducing the health consequences of opioid addicition in primary care". Am J Med. doi:10.1016/j.amjmed.2012.11.031. PMID 23664112. In press
- ^ Lazarus P. (2007). Project Lazarus, Wilkes County, North Carolina: Policy Briefing Document Prepared for the North Carolina Medical Board in Advance of the Public Hearing Regarding Prescription Naloxone. Raleigh, NC. Unknown parameter
|document=ignored (help) - ^ "OD Prevention Program Locator.". Overdose Prevention Alliance. Retrieved 15 May 2012.
- ^ a b c "Community-Based Opioid Overdose Prevention Programs Providing Naloxone — United States, 2010". Centers for Disease Control and Prevention. 2010 Dec.
- ^ http://www.thestar.com/news/gta/2012/09/09/toronto_naloxone_program_reduces_drug_overdoses_among_addicts.html
- ^ Albert S, Brason FW 2nd, Sanford CK, Dasgupta N, Graham J, Lovette B. (2011 Jun). "Project Lazarus: community-based overdose prevention in rural North Carolina". Pain Medicine. 12 Suppl 2: S77–85. doi:10.1111/j.1526-4637.2011.01128.x. PMID 21668761.
- ^ a b c Beletsky L, Burris S, and Kral AH. (2009 Jul). "Closing Death's Door: Action Steps to Facilitate Emergency Opioid Drug Overdose Reversal in the United States". Center for Health Law, Policy and Practice, Temple University School of Law. Retrieved 2012-05-12.
- ^ Beletsky L, Ruthazer R, Macalino GE, Rich JD, Tan L, Burris S. (2007 Jan). "Physicians' knowledge of and willingness to prescribe naloxone to reverse accidental opiate overdose: challenges and opportunities". Journal of Urban Health 84 (1): 126–36. doi:10.1007/s11524-006-9120-z. PMC 2078257. PMID 17146712.
- ^ Beletsky L, Rich JD, Walley AY. (2012). "Prevention of Fatal Opioid Overdose". JAMA 308 (18): 1863–1864. doi:10.1001/jama.2012.14205. PMC PMC3551246. PMID 23150005.
- ^ Beletsky L, Moroz E. "The Quincy Police Department: Pioneering Naloxone Among First Responders.". Overdose Prevention Alliance. Retrieved 15 May 2012.
- ^ Lavoie D. (2012 April). "Naloxone: Drug-Overdose Antidote Is Put In Addicts' Hands". Huffington Post.
- ^ Davis CS, Beletsky L. (2009). "Bundling occupational safety with harm reduction information as a feasible method for improving police receptiveness to syringe access programs: evidence from three U.S. cities". Harm Reduction Journal.
- ^ Beletsky L, Rich JD, Walley AY. (2012). "Prevention of Fatal Opioid Overdose". JAMA 308 (18): 1863–1864. doi:10.1001/jama.2012.14205. PMC PMC3551246. PMID 23150005.
- ^ 2013 National drug control strategy. 2013. Available at http://www.whitehouse.gov//sites/default/files/ondcp/policy-and-research/ndcs_2013.pdf
- ^ "IHRA 21st International Conference Liverpool, 26th April 2010 - Introducing 'take home' Naloxone in Wales". Retrieved 9 March 2011.
- ^ Simpson K, et al. (2008 Dec). "Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain". Curr Med Res Opin 24 (12): 3503–3512. doi:10.1185/03007990802584454. PMID 19032132. Retrieved 2009-04-09.
- ^ "Scientists Can Now Block Heroin, Morphine Addiction". Retrieved 2012-08-17.
- ^ Nuller YL, Morozova MG, Kushnir ON, Hamper N (June 2001). "Effect of naloxone therapy on depersonalization: a pilot study". J. Psychopharmacol. (Oxford) 15 (2): 93–5. doi:10.1177/026988110101500205. PMID 11448093.
- ^ http://www.drugs.com/sfx/naloxone-side-effects.html
- ^ Sauro, Marie D; Greenberg, Roger P. (Feb 2005), "Endogenous opiates and the placebo effect: A meta-analytic review", Journal of Psychosomatic Research 58 (2): 115–120, PMID 15820838
- ^ http://www.jyi.org/news/nb.php?id=429
- ^ 21 U.S.C.A. §§801-904; see e.g., LA Rev Stat. Ann. §40:964 (specifically excluding Naloxone from the schedule of controlled substances.)
- ^ Burris S, Beletsky L, Castagna CA, Coyle C, Crowe C, McLaughlin JM. (July 2009). "Stopping an Invisible Epidemic: Legal Issues in the Provision of Naloxone to Prevent Opioid Overdose". Center for Health Law, Policy and Practice, Temple University School of Law 201 (2): 122–4. doi:10.1055/s-2008-1045881. PMID 1434381.
- ^ Beletsky L, Ruthazer R, Macalino GE, Rich JD, Tan L, Burris S. (2007 Jan). "Physicians' knowledge of and willingness to prescribe naloxone to reverse accidental opiate overdose: challenges and opportunities". Journal of Urban Health 84 (1): 126–36. doi:10.1007/s11524-006-9120-z. PMC 2078257. PMID 17146712.
- ^ Burris S, Beletsky L, Castagna CA, Coyle C, Crowe C, McLaughlin JM. (2009 Jul). "Stopping an Invisible Epidemic: Legal Issues in the Provision of Naloxone to Prevent Opioid Overdose". Drexel Law Review 1: 273–340. Retrieved 2012-05-12.
- ^ "Current Drug Shortages, US Food and Drug Administration". Retrieved 12 May 2012.
External links[edit]
- Chicago Recovery Alliance's naloxone distribution project
- Report on Naloxone and other opiate antidotes, by the International Programme on Chemical Safety
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