Noscapine

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Noscapine
Narkotin - Narcotine.svg
Systematic (IUPAC) name
(3S)- 6,7-Dimethoxy-3-[(5R)-5,6,7,8-tetrahydro- 4-methoxy- 6-methyl- 1,3-dioxolo (4,5-g)isoquinolin-5-yl]- 1(3H)-isobenzofuranone
Clinical data
AHFS/Drugs.com International Drug Names
Pregnancy cat.
  • Contraindicated
Legal status
  • rx only
Pharmacokinetic data
Bioavailability ~30%
Half-life 1.5 to 4h (mean 2.5)
Identifiers
CAS number 128-62-1 YesY
ATC code R05DA07
PubChem CID 275196
ChemSpider 242139 YesY
UNII 8V32U4AOQU YesY
KEGG D01036 YesY
ChEBI CHEBI:73237 N
ChEMBL CHEMBL364713 YesY
Synonyms Narcotine
Chemical data
Formula C22H23NO7 
Mol. mass 413.421
 N (what is this?)  (verify)

Noscapine (also known as Narcotine, Nectodon, Nospen, Anarcotine and (archaic) Opiane) is a benzylisoquinoline alkaloid from plants of the Papaveraceae family, without painkilling properties. This agent is primarily used for its antitussive (cough-suppressing) effects.

History[edit]

Noscapine was first isolated and characterized in chemical breakdown and properties in 1817 under the denomination of "Narcotine"[1] by Pierre Robiquet, a French chemist in Paris. Robiquet conducted over 20 years between 1815 and 1835 a series of studies in the enhancement of methods for the isolation of morphine, and also isolated in 1832 another very important component of raw opium, that he called codeine, one of today's most widely used opium-originating components.

Structure analysis[edit]

The lactone ring is unstable and opens in basic media. The opposite reaction is presented in acidic media. The bond C1-C3' is also unstable. This is the bond connecting the two optically active carbon atoms. In aqueous solution of sulfuric acid and heating it dissociates into cotarnine (4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinoline) and opic acid (6-formyl-2,3-dimethoxybenzoic acid). When noscapine is reduced with zinc/HCl, the bond C1-C3' saturates and the molecule dissociates into hydrocotarnine (2-hydroxycotarnine) and meconine (6,7-dimethoxyisobenzofuran-1(3H)-one).

Mechanism of action[edit]

Noscapine's antitussive effects appear to be primarily mediated by its σ–receptor agonist activity. Evidence for this mechanism is suggested by experimental evidence in rats. Pretreatment with rimcazole, a σ- specific antagonist, causes a dose-dependent reduction in antitussive activity of noscapine.[2]

Dosage[edit]

The recommended dose for over-the-counter cough treatment varies from country to country; for example, in The Netherlands, 15–30 mg per 8 hours is recommended for adults,[3] whereas in Sweden it is 50 mg per 8 hours.[4]

Potential Treatment of Hereditary Spastic Paraplegia (HSP)[edit]

Mutations in spastin are a common cause of HSP. Noscapine has been shown to counteract the effects of these mutations in patient-derived stem cells [5]

Cancer and stroke treatment[edit]

Noscapine is currently under investigation for use in the treatment of several cancers and hypoxic ischemia in stroke patients. In cancer treatment, noscapine appears to interfere with microtubule function, and thus the division of cancer cells in a way similar to the taxanes. Early animal studies in treatment of prostate cancer are promising.[6] Typical doses in cancer treatment are about 100-fold those in cough treatment.[7]

In stroke patients, noscapine blocks the bradykinine b-2 receptors. A 2003 study in Iran showed a dramatic decrease in mortality in ten acute ischemic stroke patients treated with noscapine.[8]

Noscapine is non-addictive, widely available, has a low side-effect incidence, and is easily administered orally, thus it has been used as an off-label therapy for some cancers. Conceptual studies find great promise for noscapine as a treatment in drug-resistant glioblastoma multiforme. Other medical researchers have evaluated novel noscapine derivatives as active tubulin-binding antineoplastic agents.[9]

Abuse[edit]

There are anecdotal reports of over-the-counter drug abuse in several countries, being readily available from local pharmacies without a prescription. The effects, beginning around 45 to 120 mins after consumption, are similar to dextromethorphan and alcohol intoxication. Unlike dextromethorphan, noscapine is not an NMDA receptor antagonist.[10]

Noscapine in heroin[edit]

Noscapine can survive the manufacturing processes of heroin and can be found in street heroin. This is useful for law enforcement agencies, as the amounts of contaminants can identify the source of seized drugs. In 2005 in Liège, Belgium, the average noscapine concentration was around 8%.[11]

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine.[12] Since the diamorphine in street heroin is the same as the pharmaceutical diamorphine, examination of the contaminants is the only way to test whether street heroin has been used. Other contaminants used in urine samples alongside noscapine include papaverine and acetylcodeine. Noscapine is metabolised by the body, and is itself rarely found in urine, instead being present as the primary metabolites, cotarnine and meconine. Detection is performed by gas chromatography-mass spectrometry or liquid chromatography-mass spectrometry (LCMS) but can also use a variety of other analytical techniques.

Possible side effects[edit]

The effects shown above are not permanent.

Interactions[edit]

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.[13]

The drug should not be taken with any MAOIs (monoamine oxidase inhibitors), as unknown and potentially fatal effects may occur.[citation needed]

Noscapine should not be taken in conjunction with warfarin as the anticoagulant effects of warfarin may be increased.[14]

See also[edit]

References[edit]

  1. ^ Observations sur le mémoire de M. Sertuerner relatif à l’analyse de l’opium, Robiquet, Annales de Chimie et de Physique , volume 5 (1817), p275–278
  2. ^ Kamei J (1996). "Role of opioidergic and serotonergic mechanisms in cough and antitussives". Pulmonary pharmacology 9 (5–6): 349–356. doi:10.1006/pulp.1996.0046. PMID 9232674. 
  3. ^ IB-tekst noscapinehydrochloride (last update 2008). Exmedica
  4. ^ Bipacksedel McNeil Noskapin 50 mg. FASS.se. Last update 2008.
  5. ^ BiologyOpen:[1]
  6. ^ "Noscapine effective against prostate cancer". Retrieved 2007-07-16. 
  7. ^ MedInsight: Noscapine
  8. ^ "A preliminary report on the application of noscapine in the treatment of stroke". Retrieved 2007-07-16. 
  9. ^ Zhou J, Gupta K, Aggarwal S, Aneja R, Chandra R, Panda D, Joshi HC (2003). "Brominated derivatives of noscapine are potent microtubule-interfering agents that perturb mitosis and inhibit cell proliferation". Mol Pharmacol.63(4):799-807.PMID: 12644580
  10. ^ Church J, Jones MG, Davies SN, Lodge D (June 1989). "Antitussive agents as N-methylaspartate antagonists: further studies". Can. J. Physiol. Pharmacol. 67 (6): 561–7. doi:10.1139/y89-090. PMID 2673498. 
  11. ^ Denooz R, Dubois N, Charlier C (2005). "[Analysis of two year heroin seizures in the Liege area]". Revue médicale de Liège (in French) 60 (9): 724–8. PMID 16265967. 
  12. ^ Paterson S, Lintzeris N, Mitchell TB, Cordero R, Nestor L, Strang J (2005). "Validation of techniques to detect illicit heroin use in patients prescribed pharmaceutical heroin for the management of opioid dependence". Addiction 100 (12): 1832–1839. doi:10.1111/j.1360-0443.2005.01225.x. PMID 16367984. 
  13. ^ Jasek, W, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-181-4. 
  14. ^ Ohlsson, S.; Holm, L.; Myrberg, O.; Sundström, A.; Yue, Q. Y. (2008). "Noscapine may increase the effect of warfarin". British Journal of Clinical Pharmacology 65 (2): 277–278. doi:10.1111/j.1365-2125.2007.03018.x. PMC 2291222. PMID 17875192.  edit