関: noscapine hydrochloride

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/07/18 18:02:59」(JST)

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

History

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, today's probably most widely used opium-originating component.

Structure analysis

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

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

Cancer and stroke treatment

Noscapine is currently under investigation for use in the treatment of several cancers and hypoxic ischemia in stroke patients.^{[citation needed]} 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.^[3] Typical doses in cancer treatment are about 100-fold those in cough treatment.^[4]

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.^[5]

Noscapine is non-addictive, widely available, has a low side-effect incidence, and is easily administered orally, thus it has great potential for use, especially in developing countries.

Abuse

Noscapine has a history 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.^[6]

Noscapine in heroin

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%.^[7]

Noscapine has also been used to identify drug users who are taking street heroin at the same time as prescribed diamorphine.^[8] 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

Loss of coordination
Hallucinations (auditory and visual)
Loss of sexual drive
Swelling of prostate
Loss of appetite
Dilated pupils
Increased heart rate
Shaking and muscle spasms
Chest pains
Increased alertness
Loss of any sleepiness
Loss of stereoscopic vision

The effects shown above are not permanent.

Interactions

Noscapine can increase the effects of centrally sedating substances such as alcohol and hypnotics.^[9]

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.^[10]

References

^ 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
^ 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.
^ "Noscapine effective against prostate cancer". http://www.news-medical.net/?id=21951. Retrieved 2007-07-16.
^ MedInsight: Noscapine
^ "A preliminary report on the application of noscapine in the treatment of stroke". http://www.springerlink.com/content/dlp6jd6gvrtgauk3/. Retrieved 2007-07-16.
^ 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.
^ Denooz R, Dubois N, Charlier C (2005). "[Analysis of two year heroin seizures in the Liege area]" (in French). Revue médicale de Liège 60 (9): 724–8. PMID 16265967.
^ 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.
^ Jasek, W, ed. (2007) (in German). Austria-Codex (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-181-4.
^ 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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2291222. edit

UpToDate Contents

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1. 新生児禁断症候群 neonatal abstinence syndrome

English Journal

Noscapine recirculates enterohepatically and induces self-clearance.

Mukkavilli R1, Gundala SR2, Yang C2, Jadhav GR3, Vangala S3, Reid MD4, Aneja R5.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.Eur J Pharm Sci.2015 Sep 18;77:90-9. doi: 10.1016/j.ejps.2015.05.026. Epub 2015 May 28.
Noscapine (Nos), an antitussive benzylisoquinoline opium alkaloid, is a non-toxic tubulin-binding agent currently in Phase II clinical trials for cancer chemotherapy. While preclinical studies have established its tumor-inhibitory properties in various cancers, poor absorptivity and rapid first-pass
PMID 26026989

Biochemical characterization and molecular dynamic simulation of β-sitosterol as a tubulin-binding anticancer agent.

Mahaddalkar T1, Suri C2, Naik PK2, Lopus M3.
European journal of pharmacology.Eur J Pharmacol.2015 Aug 5;760:154-62. doi: 10.1016/j.ejphar.2015.04.014. Epub 2015 Apr 23.
Βeta-sitosterol (β-SITO), a phytosterol present in pomegranate, peanut, corn oil, almond, and avocado, has been recognized to offer health benefits and potential clinical uses. β-SITO is orally bioavailable and, as a constituent of edible natural products, is considered to have no undesired side
PMID 25912799

Wheat germ agglutinin anchored chitosan microspheres of reduced brominated derivative of noscapine ameliorated acute inflammation in experimental colitis.

Kaur K1, Sodhi RK2, Katyal A3, Aneja R4, Jain UK1, Katare OP5, Madan J6.
Colloids and surfaces. B, Biointerfaces.Colloids Surf B Biointerfaces.2015 Aug 1;132:225-35. doi: 10.1016/j.colsurfb.2015.05.022. Epub 2015 May 21.
Reduced brominated derivative of noscapine (Red-Br-Nos, EM012), has potent anti-inflammatory property. However, physicochemical limitations of Red-Br-Nos like low aqueous solubility (0.43×10(-3)g/mL), high lipophilicity (logP∼2.94) and ionization at acidic pH greatly encumber the scale-up of oral
PMID 26047885

Japanese Journal

A NEW TOTAL SYNTHESIS OF (±)-α-NOSCAPINE

Mao Yongjun,Song Shuai,Zhao Dongmei [他]
Heterocycles : an international journal for reviews and communications in heterocyclic chemistry 87(12), 2633-2640, 2013-12-01
NAID 40019893640

Fixed drug eruption caused by noscapine

ISHIGURO Emiko,HATAMOCHI Atsushi,HAYASHI Shujiro,HAMASAKI Yoichiro,YAMAZAKI Soji
Journal of dermatology 38(3), 295-297, 2011-03-01
NAID 10029330857

A Rapid and Reliable Solid-Phase Extraction Method for High-Performance Liquid Chromatographic Analysis of Opium Alkaloids from Papaver Plants

Yoshimatsu Kayo,Kiuchi Fumiyuki,Shimomura Koichiro [他],MAKINO Yukiko
Chemical & pharmaceutical bulletin 53(11), 1446-1450, 2005-11-01
… With this solid-phase extraction method, the recovery of morphine, codeine, oripavine, thebaine, papaverine, noscapine and sanguinarine was from 99.94 to 112.18% when the standard alkaloids were added to the plant samples. …
NAID 10016784457

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リンク元	「ノスカピン」
拡張検索	「noscapine hydrochloride」

「ノスカピン」

Noscapine
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	?
Pharmacokinetic data
Bioavailability	~30%
Half-life	1.5 to 4h (mean 2.5)
Identifiers
CAS number	128-62-1
ATC code	R05DA07
PubChem	CID 275196
ChemSpider	242139
UNII	8V32U4AOQU
KEGG	D01036
ChEMBL	CHEMBL364713
Synonyms	Narcotine
Chemical data
Formula	C22H23NO7
Mol. mass	413.421
	SMILES O=C2O[C@@H](c1ccc(OC)c(OC)c12)[C@@H]5N(C)CCc4c5c(OC)c3OCOc3c4;
	InChI InChI=1S/C22H23NO7/c1-23-8-7-11-9-14-20(29-10-28-14)21(27-4)15(11)17(23)18-12-5-6-13(25-2)19(26-3)16(12)22(24)30-18/h5-6,9,17-18H,7-8,10H2,1-4H3/t17-,18+/m1/s1 ; Key:AKNNEGZIBPJZJG-MSOLQXFVSA-N ;
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　　[★]

英: noscapine
ラ: noscapinum
同: ナルコチン narcotine
化: 塩酸ノスカピン noscapine hydrochloride
商: ナルコチン、ノスカピン
関: アヘンアルカロイド

「noscapine hydrochloride」

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塩酸ノスカピン

関: noscapine

[0] 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

[pmid9232674-1] 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.

[2] "Noscapine effective against prostate cancer". http://www.news-medical.net/?id=21951. Retrieved 2007-07-16.

[3] MedInsight: Noscapine

[4] "A preliminary report on the application of noscapine in the treatment of stroke". http://www.springerlink.com/content/dlp6jd6gvrtgauk3/. Retrieved 2007-07-16.

[5] 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.

[pmid16265967-6] Denooz R, Dubois N, Charlier C (2005). "[Analysis of two year heroin seizures in the Liege area]" (in French). Revue médicale de Liège 60 (9): 724–8. PMID 16265967.

[pmid16367984-7] 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.

[8] Jasek, W, ed. (2007) (in German). Austria-Codex (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-181-4.

[9] 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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2291222. edit

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noscapine