Cytisine

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Cytisine
(-)-Cytisine.svg
Cytisine 3D ball.png
Clinical data
Other namesCytisine; Baptitoxine; Sophorine
License data
ATC code
Identifiers
  • (1R,5S)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,3]diazocin-8-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.924 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H14N2O
Molar mass 190.246 g·mol−1
3D model (JSmol)
Melting point 152 °C (306 °F)
Boiling point 218 °C (424 °F)
  • O=C1/C=C\C=C2/N1C[C@@H]3CNC[C@H]2C3
  • InChI=1S/C11H14N2O/c14-11-3-1-2-10-9-4-8(5-12-6-9)7-13(10)11/h1-3,8-9,12H,4-7H2/t8-,9+/m0/s1
  • Key:ANJTVLIZGCUXLD-DTWKUNHWSA-N

Cytisine, also known as baptitoxine, cytisinicline, or sophorine, is an alkaloid that occurs naturally in several plant genera, such as Laburnum and Cytisus of the family Fabaceae. It has been used medically to help with smoking cessation. [1] It has been found effective in several randomized clinical trials, including in the United States and New Zealand, [1] and is being investigated in additional trials in the United States and a non-inferiority trial in Australia in which it is being compared head-to-head with the smoking cessation aid varenicline (sold in the United States as Chantix). [2] It has also been used entheogenically via mescalbeans by some Native American groups, historically in the Rio Grande Valley predating even peyote. [3]

Contents

Sources

Cytisine is extracted from the seeds of Cytisus laburnum L. (Golden Rain acacia), and is found in several genera of the subfamily Faboideae of the family Fabaceae, including Laburnum , Anagyris , Thermopsis , Cytisus , Genista , Retama and Sophora . Cytisine is also present in Gymnocladus of the subfamily Caesalpinioideae.[ citation needed ]

Uses

Smoking cessation

Cytisine has been available in post-Soviet states for more than 40 years as an aid to smoking cessation under the brand name Tabex from the Bulgarian pharmaceutical company Sopharma AD. [4] In 1961, Bulgarian pharmacist Strashimir Ingilizov synthesized Tabex using the alkaloid Cytisine which was derived from the seeds of the yellow acacia (Cytisus laburnum), a European decorative shrub prevalent in Bulgaria and commonly referred to as “golden rain”. [5] It was first marketed in Bulgaria in 1964 and then became widely available in the Soviet Union. [6] In Poland, it is sold under the brand name Desmoxan, and it is also available in Canada under the brand name Cravv. [7] [8]

Its molecular structure has some similarity to that of nicotine, and it has similar pharmacological effects. Like the smoking cessation aid varenicline, cytisine is a partial agonist of nicotinic acetylcholine receptors (nAChRs). [9] Cytisine has a short half-life of 4.8 hours. [10] As a result, the extract provides smokers with satisfaction similar to smoking a cigarette, alleviating the urge to smoke and reducing the severity of nicotine withdrawal symptoms, while also reducing the reward experience of any cigarettes smoked. [11]

In 2011, a randomized controlled trial with 740 patients found cytisine improved 12-month abstinence from nicotine from 2.4% with placebo to 8.4% with cytisine. [12] A 2013 meta-analysis of eight studies demonstrated that cytisine has similar effectiveness to varenicline but with substantially lower side effects. [13] A 2014 systematic review and economic evaluation concluded that cytisine was more likely to be cost-effective for smoking cessation than varenicline. [14]

Recreational

Plants containing cytisine, including the scotch broom and mescalbean, have also been used recreationally. Positive effects are reported to include a nicotine-like intoxication. [12]

Reagent for organic chemistry

(−)-Cytisine extracted from Laburnum anagyroides seeds was used as a starting material for the preparation of "(+)- sparteine surrogate", for the preparation of enantiomerically enriched lithium anions of opposite stereochemistry to those anions obtained from sparteine. [15]

Toxicity

Cytisine has been found to interfere with breathing and cause death in test mice; LD50 i.v. in mice is about 2 mg/kg. [16] Cytisine is also teratogenic. [17]

Māmane ( Sophora chrysophylla ) can contain amounts of cytisine that are lethal to most animals. The palila (Loxioides bailleui, a bird), Uresiphita polygonalis virescens and Cydia species (moths), and possibly sheep and goats are not affected by the toxin for various reasons, and consume māmane, or parts of it, as food. U. p. virescens caterpillars are possibly able to sequester the cytisine to give themselves protection from predation; they have aposematic coloration which would warn off potential predators. [18]

Related Research Articles

<span class="mw-page-title-main">Smoking cessation</span> Process of discontinuing tobacco smoking

Smoking cessation, usually called quitting smoking or stopping smoking, is the process of discontinuing tobacco smoking. Tobacco smoke contains nicotine, which is addictive and can cause dependence. As a result, nicotine withdrawal often makes the process of quitting difficult.

<span class="mw-page-title-main">Nicotine replacement therapy</span> Treatment for tobacco use disorder

Nicotine replacement therapy (NRT) is a medically approved way to treat people with tobacco use disorder by taking nicotine through means other than tobacco. It is used to help with quitting smoking or stopping chewing tobacco. It increases the chance of quitting tobacco smoking by about 55%. Often it is used along with other behavioral techniques. NRT has also been used to treat ulcerative colitis. Types of NRT include the adhesive patch, chewing gum, lozenges, nose spray, and inhaler. The use of multiple types of NRT at a time may increase effectiveness.

<span class="mw-page-title-main">Varenicline</span> Nicotinic receptor agonist

Varenicline, sold under the brand names Chantix and Champix among others, is a medication used for smoking cessation and for the treatment of dry eye syndrome. It is a nicotinic acetylcholine receptor partial agonist. When activated, this receptor releases dopamine in the nucleus accumbens, the brain's reward center, thereby reducing cravings and withdrawal symptoms with smoking cessation, although less pronounced than a full agonist.

NicVAX is an experimental conjugate vaccine intended to reduce or eliminate physical dependence to nicotine. According to the U.S. National Institute of Drug Abuse, NicVAX can potentially be used to inoculate against nicotine addiction. This proprietary vaccine is being developed by Nabi Biopharmaceuticals of Rockville, MD. with the support from the U.S. National Institute on Drug Abuse. NicVAX consists of the hapten 3'-aminomethylnicotine which has been conjugated (attached) to Pseudomonas aeruginosa exotoxin A.

<i>Sophora chrysophylla</i> Species of plant

Sophora chrysophylla, known as māmane in Hawaiian, is a species of flowering plant in the pea and bean family, Fabaceae, that is endemic to Hawaii. It is highly polymorphic, growing as a shrub or tree, and able to reach a height of 15 m (49 ft) in tree form. Yellow flowers are produced in winter and spring.

<span class="mw-page-title-main">Palila</span> Species of bird

The palila is a critically endangered finch-billed species of Hawaiian honeycreeper. It has a golden-yellow head and breast, with a light belly, gray back, and greenish wings and tail. The bird has a close ecological relationship with the māmane tree, and became endangered due to destruction of the trees and accompanying dry forests. The first specimen of the palila was collected in 1876 at the Greenwell Ranch on the Big Island by Pierre Étienne Théodore Ballieu (1828–1885), who was French consul in Hawai‘i from 1869 to 1878. The type specimen is housed at the Muséum national d'histoire naturelle in Paris.

<span class="mw-page-title-main">Nicotine withdrawal</span> Process of withdrawing from nicotine addiction

Nicotine withdrawal is a group of symptoms that occur in the first few weeks after stopping or decreasing use of nicotine. Symptoms include intense cravings for nicotine, anger or irritability, anxiety, depression, impatience, trouble sleeping, restlessness, hunger, weight gain, and difficulty concentrating. Withdrawal symptoms make it harder to quit nicotine products, and most methods for quitting smoking involve reducing nicotine withdrawal. Quit smoking programs can make it easier to quit. Nicotine withdrawal is recognized in both the American Psychiatric Association Diagnostic and Statistical Manual (DSM) and the WHO International Classification of Diseases (ICD).

Tobacco harm reduction (THR) is a public health strategy to lower the health risks to individuals and wider society associated with using tobacco products. It is an example of the concept of harm reduction, a strategy for dealing with the use of drugs. Tobacco smoking is widely acknowledged as a leading cause of illness and death, and reducing smoking is vital to public health.

<span class="mw-page-title-main">Electronic cigarette</span> Device that vaporizes a liquid nicotine solution for inhalation

An electronic cigarette (e-cigarette), or vape, is a device that simulates tobacco smoking. It consists of an atomizer, a power source such as a battery, and a container such as a cartridge or tank. Instead of smoke, the user inhales vapor. As such, using an e-cigarette is often called "vaping". The atomizer is a heating element that vaporizes a liquid solution called e-liquid, which quickly cools into an aerosol of tiny droplets, vapor and air. The vapor mainly comprises propylene glycol and/or glycerin, usually with nicotine and flavoring. Its exact composition varies, and depends on several things including user behavior.

<span class="mw-page-title-main">Nicotine dependence</span> Chronic disease

Nicotine dependence is a state of substance dependence on nicotine. It is a chronic, relapsing disease characterized by a compulsive craving to use the drug despite social consequences, loss of control over drug intake, and the emergence of withdrawal symptoms. Tolerance is another component of drug dependence. Nicotine dependence develops over time as an individual continues to use nicotine. While cigarettes are the most commonly used tobacco product, all forms of tobacco use—including smokeless tobacco and e-cigarette use—can cause dependence. Nicotine dependence is a serious public health problem because it leads to continued tobacco use and the associated negative health effects. Tobacco use is one of the leading preventable causes of death worldwide, causing more than 8 million deaths per year and killing half of its users who do not quit. Current smokers are estimated to die an average of 10 years earlier than non-smokers.

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.

Elbert D. Glover is an American researcher and author in the field of tobacco addiction and smoking cessation. He retired as professor emeritus at the University of Maryland at College Park School of Public Health where he served as Chairperson of the Department of Behavioral and Community Health from 2005 to his retirement in 2015. He was an entrepreneur, editor, publisher, co-founder and principal owner of Health Behavior and Policy Review, and co-founder, owner, editor, and publisher of American Journal of Health Behavior and Tobacco Regulatory Science. Glover was the founder of the American Academy of Health Behavior and served as its first president from 1997 to 2001.

<span class="mw-page-title-main">Dianicline</span> Chemical compound

Dianicline (SSR-591,813) is a drug developed by Sanofi-Aventis which acts as a partial agonist at neural nicotinic acetylcholine receptors. It is subtype-selective, binding primarily to the α4β2 subtype. It is being developed as a medication for the treatment of nicotine dependence to assist in smoking cessation. Dianicline is very similar to the already marketed drug varenicline and it is unclear what advantages it will have over the older drug, although it may have an improved side effect profile. It has been through human trials up to Phase II, although results have not yet been reported. Drug development has been discontinued after reporting of unfavourable results during Phase III trials.

<span class="mw-page-title-main">Hawaiian tropical dry forests</span> Tropical dry forest ecoregion of the Hawaiian Islands

Hawaiian tropical dry forests are a tropical dry broadleaf forest ecoregion in the Hawaiian Islands. They cover an area of 6,600 km2 (2,500 sq mi) on the leeward side of the main islands and the summits of Niʻihau and Kahoʻolawe. These forests are either seasonal or sclerophyllous. Annual rainfall is less than 127 cm (50 in) and may be as low as 25 cm (9.8 in). The rainy season there lasts from November to March.

Schizophrenia and tobacco smoking have been historically associated. Smoking is known to harm the health of people with schizophrenia.

Jed Eugene Rose is an American academic professor, inventor and researcher in the field of nicotine and smoking cessation. Rose is presently the President and CEO of the Rose Research Center, LLC in Raleigh, North Carolina. Additionally, he is the Director of the Duke Center for Smoking Cessation at Duke University Medical Center.

<span class="mw-page-title-main">Quinolizidine alkaloids</span> Class of chemical compounds

Quinolizidine alkaloids are natural products that have a quinolizidine structure; this includes the lupine alkaloids.

Nicotine vaccine is a novel immunological strategy for treating nicotine addiction. Nicotine vaccine uses active immunization as the methodology to create polyclonal antibodies to the antigens, which is then used to treat drug abuse. The immune system is then able to identify nicotine as a foreign substance and initiate an immune reaction targeting the drug. As a result, the quantity of nicotine that enters the brain would decrease after receiving the vaccine. In preclinical studies, nicotine vaccines have demonstrated the ability to combat the negative effects of nicotine abuse, but none of the developed vaccines has been authorized for use in clinical trials as a smoking cessation strategy. Theoretically, the decrease of nicotine's rewarding effects should result in smoking cessation. Some companies have tested candidate vaccines in clinical trials, but evidence failed to show the adequate antibody responses or exhibit superior efficacy to factors concerning placebo.

Natalie K. Walker is a New Zealand academic, and is a Professor of Social and Community Health at the University of Auckland, specialising in the reduction of harm from non-communicable diseases such as cardiovascular disease and cancer. She has an interest in smoking cessation but also researches on alcohol, cannabis and sugar.

References

  1. 1 2 Walker N, Howe C, Glover M, McRobbie H, Barnes J, Nosa V, et al. (December 2014). "Cytisine versus nicotine for smoking cessation". The New England Journal of Medicine. 371 (25): 2353–2362. doi: 10.1056/nejmoa1407764 . PMID   25517706. S2CID   13759117.
  2. ↑ Thomas D, Farrell M, McRobbie H, Tutka P, Petrie D, West R, et al. (May 2019). "The effectiveness, safety and cost-effectiveness of cytisine versus varenicline for smoking cessation in an Australian population: a study protocol for a randomized controlled non-inferiority trial" (PDF). Addiction. 114 (5): 923–933. doi:10.1111/add.14541. PMID   30589984. S2CID   58621453.
  3. ↑ Howard JH (1957). "The Mescal Bean Cult of the Central and Southern Plains: An Ancestor of the Peyote Cult". American Anthropologist. 59 (1): 75–87. doi: 10.1525/aa.1957.59.1.02a00070 . JSTOR   666531.
  4. ↑ Zatonski W, Cedzynska M, Tutka P, West R (December 2006). "An uncontrolled trial of cytisine (Tabex) for smoking cessation". Tobacco Control. 15 (6): 481–484. doi:10.1136/tc.2006.016097. PMC   2563682 . PMID   17130378.
  5. ↑ Gatsov, Nikolai (October 1964). "Ein Mittel Gegen Rauchen". Bulgarien. 1: 39.
  6. ↑ "Old anti-smoking drug passes new test". Reuters. 28 September 2011. Retrieved 11 March 2022.
  7. ↑ Prochaska JJ, Das S, Benowitz NL (August 2013). "Cytisine, the world's oldest smoking cessation aid". BMJ. 347 (aug23 1): f5198. doi:10.1136/bmj.f5198. PMID   23974638. S2CID   31845933.
  8. ↑ Zatoński W, Janik-Koncewicz K, Stępnicka Z, Zatońska K, Połtyn-Zaradna K, Herbeć A (2020). "History of smoking cessation treatment in Poland – the strengthening role of cytisine as the most effective and safe pharmacotherapy". Journal of Health Inequalities. 6 (2): 116–123. doi: 10.5114/jhi.2020.102969 . ISSN   2450-5927. S2CID   234956118.
  9. ↑ Dallanoce C, Frigerio F, Martelli G, Grazioso G, Matera C, Pomè DY, et al. (June 2010). "Novel tricyclic Delta(2)-isoxazoline and 3-oxo-2-methyl-isoxazolidine derivatives: synthesis and binding affinity at neuronal nicotinic acetylcholine receptor subtypes". Bioorganic & Medicinal Chemistry. 18 (12): 4498–4508. doi:10.1016/j.bmc.2010.04.065. PMID   20478710.
  10. ↑ Jeong SH, Newcombe D, Sheridan J, Tingle M (June 2015). "Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose". Drug Testing and Analysis. 7 (6): 475–482. doi:10.1002/dta.1707. PMID   25231024. S2CID   45441989.
  11. ↑ Reinberg S (17 December 2014). "Cheap Natural Compound May Help Smokers Quit. But cytisinicline isn't widely available, study authors note". WebMD . Retrieved 4 June 2021.
  12. 1 2 West R, Zatonski W, Cedzynska M, Lewandowska D, Pazik J, Aveyard P, Stapleton J (September 2011). "Placebo-controlled trial of cytisine for smoking cessation". The New England Journal of Medicine. 365 (13): 1193–1200. doi: 10.1056/NEJMoa1102035 . PMID   21991893.
  13. ↑ Hajek P, McRobbie H, Myers K (November 2013). "Efficacy of cytisine in helping smokers quit: systematic review and meta-analysis". Thorax. 68 (11): 1037–1042. doi: 10.1136/thoraxjnl-2012-203035 . PMID   23404838.
  14. ↑ Leaviss J, Sullivan W, Ren S, Everson-Hock E, Stevenson M, Stevens JW, et al. (May 2014). "What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation". Health Technology Assessment. 18 (33): 1–120. doi:10.3310/hta18330. PMC   4780997 . PMID   24831822.
  15. ↑ "Synthesis of (+)-(1R,@S,9S)-11-Methyl-7,11-Diazatricyclo[7.3.1.02.7]tridecane, a (+)sparteine surrogate". Organic Syntheses. 83: 141. 2006. doi: 10.15227/orgsyn.083.0141 .
  16. ↑ The Merck Index, 10th Ed. (1983) p.402, Rahway: Merck & Co.
  17. ↑ Keeler RF. Handbook of Natural Toxins: Toxicology of Plant and Fungal Compounds. CRC Press. p. 43.
  18. ↑ Banko PC, Cipollini ML, Breton GW, Paulk E, Wink M, Izhaki I (July 2002). "Seed chemistry of Sophora chrysophylla (mamane) in relation to diet of specialist avian seed predator Loxioides bailleui (palila) in Hawaii" (PDF). Journal of Chemical Ecology. 28 (7): 1393–1410. doi:10.1023/A:1016248502927. PMID   12199503. S2CID   7064787. Archived from the original (PDF) on 21 December 2012. Retrieved 4 May 2007.
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