Wikipedia:WikiProject Chemicals/Chembox validation/VerifiedDataSandbox and Vincristine: Difference between pages

{{Short description|Chemical compound; chemotherapy medication}}

{{distinguish|vinblastine}}

| verifiedrevid = 461759697

| IUPAC_name = (3a''R'',3a1''R'',4''R'',5''S'',5a''R'',10b''R'')-Methyl 4-acetoxy-3a-ethyl-9-((5''S'',7''S'',9''S'')-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1''H''-3,7-methano[1]azacycloundecino[5,4-''b'']indol-9-yl)-6-formyl-5-hydroxy-8-methoxy-3a,3a1,4,5,5a,6,11,12-octahydro-1''H''-indolizino[8,1-cd]carbazole-5-carboxylate

| width = 240

| image2 = Vincristine3DanBS.gif

| width2 = 200

| pronounce = {{IPAc-en|audio=En-us-Vincristine.ogg|ˈ|v|ɪ|n|ˈ|k|r|ɪ|s|t|iː|n|}}<ref name=DictionaryVincristine>{{cite web|title=Vincristine|url=http://dictionary.reference.com/browse/Vincristine|website=Dictionary.com|publisher=Random House, Inc|access-date=9 November 2014|url-status=live|archive-url=https://web.archive.org/web/20141109210217/http://dictionary.reference.com/browse/Vincristine|archive-date=9 November 2014}}</ref>

| tradename = Oncovin, Vincasar, Marqibo, others<ref>{{cite web|title=NCI Drug Dictionary|url=http://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=42251|website=NCI|access-date=28 November 2015|url-status=live|archive-url=https://web.archive.org/web/20151208154505/http://www.cancer.gov/publications/dictionaries/cancer-drug?CdrID=42251|archive-date=8 December 2015|date = 2011-02-02}}</ref>

| DailyMedID = Vincristine

| legal_AU = S4

| legal_CA = Rx-only

| legal_UK = POM

| legal_US = Rx-only

| routes_of_administration = [[Intravenous therapy|intravenous]]

| bioavailability = n/a (not reliably absorbed by the [[Gastrointestinal tract|GI tract]])<ref name = MD/>

| protein_bound = ~44%<ref name=MSR>{{cite web|title=Oncovin, Vincasar PFS (vincristine) dosing, indications, interactions, adverse effects, and more|work=Medscape Reference|publisher=WebMD|access-date=16 April 2014|url=http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#showall|url-status=live|archive-url=https://web.archive.org/web/20140416181543/http://reference.medscape.com/drug/oncovin-vincasar-pfs-vincristine-342097#showall|archive-date=16 April 2014}}</ref>

| metabolism = Liver, mostly via [[CYP3A4]] and [[CYP3A5]]<ref name = MD/>

| elimination_half-life = 19 to 155 hours (mean: 85 hours)<ref name = MD/>

| excretion = Faeces (70–80%), urine (10–20%)<ref name = MD>{{cite web|title=Vincristine|work=Martindale: The Complete Drug Reference|publisher=Pharmaceutical Press|date=13 December 2013|access-date=15 April 2014| veditors = Brayfield A |url=http://www.medicinescomplete.com/mc/martindale/current/1879-p.htm|archive-url=https://web.archive.org/web/20200408110229/https://about.medicinescomplete.com/|archive-date=8 April 2020|url-status=dead}}</ref>

| IUPHAR_ligand = 6785

| ATC_supplemental =

| DrugBank = DB00541

| UNII_Ref = {{fdacite|correct|FDA}}

| KEGG_Ref = {{keggcite|correct|kegg}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 303560

| synonyms = leurocristine ki

<!--Chemical data-->

| C=46 | H=56 | N=4 | O=10

| smiles = CC[C@@]1(C[C@@H]2C[C@@](C3=C(CCN(C2)C1)C4=CC=CC=C4N3)(C5=C(C=C6C(=C5)[C@]78CCN9[C@H]7[C@@](C=CC9)([C@H]([C@@]([C@@H]8N6C=O)(C(=O)OC)O)OC(=O)C)CC)OC)C(=O)OC)O

| StdInChI = 1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28)

<!-- Definition and medical uses -->

'''Vincristine''', also known as '''leurocristine''' and marketed under the brand name '''Oncovin''' among others, is a [[chemotherapy]] medication used to treat a number of types of [[cancer]].<ref name=AHFS2015>{{cite web|title=Vincristine Sulfate|url=https://www.drugs.com/monograph/vincristine-sulfate.html|publisher=The American Society of Health-System Pharmacists|access-date=Jan 2, 2015|url-status=live|archive-url=https://web.archive.org/web/20150102141205/http://www.drugs.com/monograph/vincristine-sulfate.html|archive-date=2015-01-02}}</ref> This includes [[acute lymphocytic leukemia]], [[acute myeloid leukemia]], [[Hodgkin's disease]], [[neuroblastoma]], and [[small cell lung cancer]] among others.<ref name=AHFS2015/> It is given intravenously.<ref name=AHFS2015/>

<!-- Side effects and mechanism -->

Most people experience some side effects from vincristine treatment.<ref name=AHFS2015/> Commonly it causes a change in sensation, hair loss, constipation, difficulty walking, and headaches.<ref name=AHFS2015/> Serious side effects may include [[neuropathic pain]], lung damage, or [[leukopenia|low white blood cells]] which increases the risk of infection.<ref name=AHFS2015/> Use during [[pregnancy]] may result in [[birth defects]].<ref name=AHFS2015/> It works by [[mitotic inhibitor|stopping cells from dividing properly]].<ref name=AHFS2015/> It is vital that it not be given [[intrathecal administration|intrathecally]], as this may kill.<ref name="ChotsampancharoenSripornsawanWongchanchailert2015">{{cite journal | vauthors = Chotsampancharoen T, Sripornsawan P, Wongchanchailert M | title = Two Fatal Cases of Accidental Intrathecal Vincristine Administration: Learning from Death Events | journal = Chemotherapy | volume = 61 | issue = 2 | pages = 108–110 | date = 5 December 2015 | pmid = 26636546 | doi = 10.1159/000441380 | s2cid = 22376877 | eissn = 1421-9794 }}</ref>

<!-- History, society and culture -->

Vincristine was first isolated in 1961.<ref name=Rav2011>{{cite book| vauthors = Ravina E |title=The evolution of drug discovery : from traditional medicines to modern drugs|date=2011|publisher=Wiley-VCH|location=Weinheim|isbn=9783527326693|pages=157–159|edition=1. Aufl.|url=https://books.google.com/books?id=iDNy0XxGqT8C&pg=PA157|url-status=live|archive-url=https://web.archive.org/web/20170801200844/https://books.google.ca/books?id=iDNy0XxGqT8C&pg=PA157|archive-date=2017-08-01}}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref><ref name="WHO22nd">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 22nd list (2021) | year = 2021 | hdl = 10665/345533 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free }}</ref> It is a [[vinca alkaloid]] that can be obtained from the Madagascar periwinkle ''[[Catharanthus roseus]]''.<ref name=Rav2011/>

==Medical uses==

Vincristine is delivered via [[intravenous]] [[route of administration|infusion]] for use in various types of [[chemotherapy regimens]].<ref name = MD/> Its main uses are in non-Hodgkin's [[lymphoma]] as part of the chemotherapy regimen [[CHOP (chemotherapy)|CHOP]] R-CVP, [[Hodgkin's lymphoma]] as part of MOPP, COPP, BEACOPP, or the less popular [[Stanford V]] chemotherapy regimen in [[acute lymphoblastic leukemia]] (ALL), and in treatment for [[nephroblastoma]].<ref name = MD/> It is also used to induce remission in ALL with [[dexamethasone]] and L-[[asparaginase]], and in combination with [[prednisone]] to treat childhood leukemia.<ref name = MD/> Vincristine is occasionally used as an [[immunosuppressant]], for example, in treating [[thrombotic thrombocytopenic purpura]] (TTP) or chronic [[idiopathic thrombocytopenic purpura]] (ITP).<ref name = MD/>

==Side effects==

The main side effects of vincristine are [[chemotherapy-induced peripheral neuropathy]], [[hyponatremia]], [[constipation]], and [[alopecia|hair loss]].

Vincristine-induced neuropathy is the main dose-limiting side effect.<ref>{{cite journal | vauthors = van de Velde ME, Kaspers GL, Abbink FC, Wilhelm AJ, Ket JC, van den Berg MH | title = Vincristine-induced peripheral neuropathy in children with cancer: A systematic review | journal = Critical Reviews in Oncology/Hematology | volume = 114 | pages = 114–130 | date = June 2017 | pmid = 28477739 | doi = 10.1016/j.critrevonc.2017.04.004 | doi-access = free }}</ref> Chemotherapy-induced peripheral neuropathy can be severe, and may be a reason to reduce or avoid using vincristine. The symptoms are progressive and enduring tingling numbness, pain and hypersensitivity to cold, beginning in the hands and feet and sometimes affecting the arms and legs.<ref name=NCI>{{cite journal | vauthors = del Pino BM | date = Feb 23, 2010 | journal = NCI Cancer Bulletin | volume = 7 | issue = 4 | page = 6 | title = Chemotherapy-induced Peripheral Neuropathy | url = http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2010/022310/page6 | url-status = dead| archive-url = https://web.archive.org/web/20111211105234/http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2010/022310/page6 | archive-date = 2011-12-11 }}</ref> One of the first symptoms of peripheral neuropathy is [[foot drop]]: A person with a family history of foot drop and/or [[Charcot-Marie-Tooth disease]] (CMT) should avoid vincristine.<ref>{{cite journal | vauthors = Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD | title = Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A | journal = Cancer | volume = 77 | issue = 7 | pages = 1356–1362 | date = April 1996 | pmid = 8608515 | doi = 10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-# | s2cid = 196362723 }}</ref> A 2021 study has suggested that [[anakinra]] can reduce the neuropathy.<ref name="starabova">{{cite journal | vauthors = Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, Deuis JR, Smith AV, Mueller A, Nadar EI, Lawrence GP, Mayor A, Tolson E, Levesque JP, Pettit AR, Wainwright BJ, Schroder K, Vetter I | display-authors = 6 | title = Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release | journal = The Journal of Experimental Medicine | volume = 218 | issue = 5 | pages = e20201452 | date = May 2021 | pmid = 33656514 | pmc = 7933984 | doi = 10.1084/jem.20201452 }}</ref><ref name="queensland">{{cite web |title=Chemotherapy with fewer side effects may be on the way |url=https://www.uq.edu.au/news/article/2021/02/chemotherapy-fewer-side-effects-may-be-way-0 |publisher=University of Queensland |access-date=15 March 2021 |date=15 March 2021}}</ref>

Accidental injection of vinca alkaloids into the spinal canal ([[intrathecal]] administration) is highly dangerous, with a mortality rate approaching 100 percent. The medical literature documents cases of ascending [[paralysis]] due to massive [[encephalopathy]] and spinal nerve [[demyelination]], accompanied by intractable pain, almost uniformly leading to death. Several patients have survived after aggressive and immediate intervention. Rescue treatments consist of washout of the [[cerebrospinal fluid]] and administration of protective medications.<ref>{{cite journal | vauthors = Qweider M, Gilsbach JM, Rohde V | title = Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report | journal = Journal of Neurosurgery. Spine | volume = 6 | issue = 3 | pages = 280–3 | date = March 2007 | pmid = 17355029 | doi = 10.3171/spi.2007.6.3.280 }}</ref> Children may do better following this injury. One child, who was aggressively treated at the time of the injection, recovered almost completely with only mild neurological deficits.<ref>{{cite journal | vauthors = Zaragoza MR, Ritchey ML, Walter A | title = Neurourologic consequences of accidental intrathecal vincristine: a case report | journal = Medical and Pediatric Oncology | volume = 24 | issue = 1 | pages = 61–2 | date = January 1995 | pmid = 7968797 | doi = 10.1002/mpo.2950240114 }}</ref> A significant series of inadvertent intrathecal vincristine administration occurred in [[China]] in 2007 when batches of [[cytarabine]] and [[methotrexate]] (both often used intrathecally) manufactured by the company Shanghai Hualian were found to be contaminated with vincristine.<ref>{{ cite news | url = https://www.nytimes.com/2008/01/31/world/asia/31pharma.html | title = Tainted Drugs Tied to Maker of Abortion Pill | vauthors = Hooker J, Bogdanich W | author-link1 = Jake Hooker (journalist) | author-link2 = Walt Bogdanich | newspaper = New York Times | date = January 31, 2008 | url-status = live | archive-url = https://web.archive.org/web/20170326140321/http://www.nytimes.com/2008/01/31/world/asia/31pharma.html?_r=1&ref=health | archive-date = March 26, 2017 }}</ref>

The overuse of vincristine may also lead to [[drug resistance]] by overexpression of the [[p-glycoprotein]] pump (Pgp). There is an attempt to overcome resistance by the addition of derivatives and substituents to the vincristine molecule.<ref>{{cite journal | vauthors = Sears JE, Boger DL | title = Total synthesis of vinblastine, related natural products, and key analogues and development of inspired methodology suitable for the systematic study of their structure-function properties | journal = Accounts of Chemical Research | volume = 48 | issue = 3 | pages = 653–62 | date = March 2015 | pmid = 25586069 | pmc = 4363169 | doi = 10.1021/ar500400w }}</ref>

==Mechanism of action==

Vincristine works partly by binding to the [[tubulin]] protein, stopping the tubulin dimers from polymerizing to form microtubules, causing the cell to be unable to separate its [[chromosome]]s during the [[metaphase]].<ref name="Elsevier">{{Cite book|title=Anticancer Drugs Targeting Tubulin and Microtubules|date=2015-01-01|publisher=Elsevier|isbn=9780444626493|language=en}}</ref> The cell then undergoes [[apoptosis]].<ref>{{cite journal | vauthors = Jordan MA | title = Mechanism of action of antitumor drugs that interact with microtubules and tubulin | journal = Current Medicinal Chemistry. Anti-Cancer Agents | volume = 2 | issue = 1 | pages = 1–17 | date = January 2002 | pmid = 12678749 | doi = 10.2174/1568011023354290 }}</ref> The vincristine molecule inhibits [[leukocyte]] production and maturation.<ref>{{cite journal | vauthors = Silverman JA, Deitcher SR | title = Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine | journal = Cancer Chemotherapy and Pharmacology | volume = 71 | issue = 3 | pages = 555–64 | date = March 2013 | pmid = 23212117 | pmc = 3579462 | doi = 10.1007/s00280-012-2042-4 }}</ref> A downside, however, to vincristine is that it does not only affect the division of cancer cells. It affects all rapidly dividing cell types, making it necessary for the very specific administration of the drug.<ref>{{cite journal | vauthors = Morris PG, Fornier MN | title = Microtubule active agents: beyond the taxane frontier | journal = Clinical Cancer Research | volume = 14 | issue = 22 | pages = 7167–72 | date = November 2008 | pmid = 19010832 | doi = 10.1158/1078-0432.ccr-08-0169 | s2cid = 2129170 | doi-access = }}</ref>

==Chemistry==

The natural extraction of vincristine from ''Catharanthus roseus'' is produced at a percent yield of less than 0.0003%. For this reason, alternate methods to produce synthetic vincristine are being used.<ref name="Stereocontrolled total synthesis of">{{cite journal | vauthors = Kuboyama T, Yokoshima S, Tokuyama H, Fukuyama T | title = Stereocontrolled total synthesis of (+)-vincristine | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 33 | pages = 11966–70 | date = August 2004 | pmid = 15141084 | pmc = 514417 | doi = 10.1073/pnas.0401323101 | doi-access = free }}</ref> Vincristine is created through the semi-synthesis coupling of indole alkaloids [[vindoline]] and [[catharanthine]] in the vinca plant.<ref>{{ cite web | url = http://pharmaxchange.info/press/2012/01/pharmacognosy-of-vinca-alkaloids-periwinkle/ | title = Pharmacognosy of Vinca Alkaloids | url-status = live | archive-url = https://web.archive.org/web/20120106234053/http://pharmaxchange.info/press/2012/01/pharmacognosy-of-vinca-alkaloids-periwinkle/ | archive-date = 2012-01-06 | date = January 2012 }}</ref> It can also now be synthesized through a stereocontrolled total synthesis technique which retains the correct stereochemistry at C18' and C2'. The absolute stereochemistry at these carbons is responsible for vincristine's anticancer activity.<ref name="Stereocontrolled total synthesis of"/>

The [[liposome]] encapsulation of vincristine enhances the efficacy of the vincristine drug while simultaneously decreasing the [[neurotoxicity]] associated with it. Liposome encapsulation increases vincristine's plasma concentration and circulation lifetime in the body, and allows the drug to enter cells more easily.<ref>{{cite book | vauthors = Waterhouse DN, Madden TD, Cullis PR, Bally MB, Mayer LD, Webb MS | chapter = Preparation, Characterization, and Biological Analysis of Liposomal Formulations of Vincristine | title = Liposomes | series = Methods in Enzymology | volume = 391 | pages = [https://archive.org/details/liposomes0387unse/page/40 40–57] | date = 2005 | pmid = 15721373 | doi = 10.1016/s0076-6879(05)91002-1 | isbn = 9780121827960 | chapter-url = https://archive.org/details/liposomes0387unse/page/40 }}</ref>

==History==

[[File:Some Members of Eli Lilly's Vincristine Research Team.jpg|thumb|Some members of Eli Lilly's vincristine research team]]

Having been used as a folk remedy for centuries, studies in the 1950s revealed that the rosy periwinkle ''[[Catharanthus roseus]]'' contained over 120 alkaloids, many of which are biologically active, the two most significant being vincristine and [[vinblastine]]. Its use as an anti-tumor, anti-mutagenic agent is well documented in the ancient [[Ayurveda]] system of medicine and in the folk culture of [[Madagascar]] and [[Southern Africa]].<ref>{{Cite journal | vauthors = Mishra JN, Verma NK |date=March 2017 |title=A brief study on Catharanthus Roseus: A review |url=https://www.researchgate.net/publication/319007421 |format=PDF |journal=International Journal of Research in Pharmacy and Pharmaceutical Sciences |language=en |volume=2 |issue=2 |issn=2455-698X |via=ResearchGate}}</ref> It was not found to be anti-diabetic in double blinded controlled studies.<ref>{{Cite news|url=https://eic.rsc.org/feature/africas-gift-to-the-world/2000064.article|title=Africa's gift to the world|work=Education in Chemistry|access-date=2018-11-13|language=en}}</ref> While initial studies for its use in [[diabetes mellitus]] were disappointing, the discovery that it caused [[myelosuppression]] (decreased activity of the bone marrow) led to its study in mice with [[leukemia]], whose lifespan was prolonged by the use of a vinca preparation. Treatment of the ground plant with [[Hexane|Skellysolve-B]] defatting agent and an acid benzene extract led to a fraction termed "fraction A". This fraction was further treated with [[aluminium oxide]], [[chromatography]], [[Chloroform|trichloromethane]], benz-dichloromethane, and separation by pH to yield vincristine.<ref>{{cite journal | vauthors = Johnson IS, Armstrong JG, Gorman M, Burnett JP | journal = Cancer Research | volume = 23 | issue = 8 Part 1 | date = September 1963 | pmid = 14070392 | url = http://cancerres.aacrjournals.org/content/23/8_Part_1/1390.full.pdf | title = The Vinca Alkaloids: A New Class of Oncolytic Agents | pages = 1390–427 }}</ref>

Vincristine was approved by the US [[Food and Drug Administration]] (FDA) in July 1963 under the trade name Oncovin and was marketed by [[Eli Lilly and Company]]. The drug was initially developed by a team at Lilly Research Laboratories in [[Indianapolis]] where it was demonstrated that vincristine cured artificially induced leukemia in mice and remission of acute leukemias of childhood.<ref>{{cite journal | vauthors = Johnson IS, Armstrong JG, Gorman M, Burnett JP | journal = Cancer Research | volume = 23 | issue = 8 Part 1 | page = 1421 | date = September 1963 | pmid = 14070392 | url = http://cancerres.aacrjournals.org/content/23/8_Part_1/1390.full.pdf | title = The Vinca Alkaloids: A New Class of Oncolytic Agents }}</ref>

Production of vincristine required one ton of dried periwinkle leaves to produce one ounce of vincristine. The periwinkle was grown on a ranch in Texas.<ref>{{cite web|title=Eli Lilly engineers developed a life-saving drug from the leaves of the periwinkle plant. – Treating Diabetes|url=https://tacomed.com/chapter-12-recombinant-dna-production-of-insulin/eli-lilly-engineers-developed-a-life-saving-drug-from-the-leaves-of-the-periwinkle-plant/|website=Treating Diabetes|access-date=18 June 2017|url-status=live|archive-url=https://web.archive.org/web/20170908170135/https://tacomed.com/chapter-12-recombinant-dna-production-of-insulin/eli-lilly-engineers-developed-a-life-saving-drug-from-the-leaves-of-the-periwinkle-plant/|archive-date=8 September 2017}}</ref>

==Society and culture==

=== Suppliers ===

Until recently, two [[generic drug]] makers were suppliers of vincristine in the United States: [[Teva Pharmaceuticals|Teva]] and [[Pfizer]]. In 2019 Teva stopped producing vincristine, leaving Pfizer as the only company in production.{{citation needed|date=October 2019}} Teva has said that they will restart production, and expect it to be available in 2020.<ref>{{Cite web|url=https://twitter.com/TevaUSA/status/1194665187321757696|title=pic.twitter.com/gTY8Jga1kv| author = Teva Pharmaceuticals | date=2019-11-13|website=@TevaUSA|access-date=2019-12-14}}</ref>

=== Shortage ===

In October 2019 an impending shortage was reported; no adequate substitute is known for treating childhood-cancers.<ref>{{cite news | vauthors = Rabin RC |title= Faced With a Drug Shortfall, Doctors Scramble to Treat Children With Cancer |url=https://www.nytimes.com/2019/10/14/health/cancer-drug-shortage.html |access-date=15 October 2019 |work=The New York Times |date=14 October 2019}}</ref> By 2022, the shortage of vincristine continued.<ref>{{cite web | url=https://www.cbsnews.com/news/generic-drugs-pharmaceutical-companies-60-minutes-2022-05-22/ | title=Medical Middlemen: Broken system making it harder for hospitals and patients to get some life-saving drugs | website=[[CBS News]] | date=22 May 2022 }}</ref>

==Controversy==

===Pharmaceutical bioprospecting===

Vincristine's origins are debated as an example of [[bioprospecting|pharmaceutical bioprospecting]] in the fields of [[ethnobotany]] and [[ethnomedicine]]. Some consider the ''[[Catharanthus roseus]]'' plant from which vincristine is derived, and its [[folk medicine|folk remedies]] to be endemic to Madagascar, and that Madagascar was denied royalties from vincristine sales.<ref>{{cite book | vauthors = Plotkin M |title=Tales of a Shaman's Apprentice: An Ethnobotanist Searches for New Medicines in the Amazon Rain Forest |date=1993 |publisher=Penguin Books |location=New York |pages=15–16}}</ref> However, ''Catharanthus roseus'' has a documented history in folk medicine treatments in other locations. In 1963, Lilly researchers acknowledged that the plant was used in Brazil to treat hemorrhage, scurvy, toothaches, and chronic wounds; in the British West Indies to treat diabetic ulcers; and in the Philippines and South Africa as an oral hypoglycemic agent – but not as a treatment for cancer.<ref>{{cite journal | vauthors = Johnson IS, Armstrong JG, Gorman M, Burnett JP | journal = Cancer Research | volume = 23 | issue = 8 Part 1 | page = 1391 | date = September 1963 | pmid = 14070392 | url = http://cancerres.aacrjournals.org/content/23/8_Part_1/1390.full.pdf | title = The Vinca Alkaloids: A New Class of Oncolytic Agents }}</ref>

''Catharanthus roseus'' has been a cosmopolitan species since before the [[Industrial Revolution]] and the plant's use in folk remedies suggested general bioactivity for diabetes treatment, not cancer. In the mid-eighteenth century, botanist Judith Sumner recorded the arrival of ''Catharanthus roseus'' at London's [[Chelsea Physic Garden]] from the [[Jardin des plantes]] in Paris. It's unclear how the plant first arrived in Paris and the details of its origins in Madagascar beyond reports of its transport from Madagascar by early European explorers. Vincristine was initially distributed at cost to increase accessibility, though later switched to a for-profit model to recover the costs of production and development. According to Michael Brown, vincristine may not be a tidy example of pharmaceutical bioprospecting, but it demonstrates how pharmaceuticals with a history of use in folk medicine have intellectual property claims which are difficult to untangle.<ref>{{cite book | vauthors = Brown M |title=Who Owns Native Culture |date=2003 |publisher=Harvard University Press |location=Cambridge |pages=136–38}}</ref>

== Vincristine and confusion with other drugs in administration ==

Vincristine has been involved in a number of medical errors. Multiple instances of vincristine having been administered improperly, after having been confused with other drugs, have occurred. If delivered into the spine (intrathecal) it causes paralysis and usually death.

In 2003 two Australian oncology pharmacists recommended a solution. The suggested procedure is to prepare and administer vincristine in a small volume mini-bag rather than a syringe thus physically preventing the vincristine syringe being accidentally attached to a spinal needle. Acceptance of this safer procedure has been slow.<ref>{{cite journal |vauthors=Gilbar PJ |date=March 2020 |title=Inadvertent intrathecal administration of vincristine: Time to finally abolish the syringe |journal=Journal of Oncology Pharmacy Practice |volume=26 |issue=2 |pages=263–266 |doi=10.1177/1078155219880600 |pmid=31707923 |s2cid=207953764 |doi-access=free}}</ref>

== Research ==

In 2012, the FDA approved a liposomal formulation of vincristine branded as Marqibo.<ref>[https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315027.htm FDA press release Aug 9, 2012] {{webarchive|url=https://web.archive.org/web/20141109042728/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm315027.htm |date=2014-11-09 }}</ref><ref>{{cite web | title=Marqibo- vincristine sulfate kit | website=DailyMed | date=17 January 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27dcad60-3a01-48e8-9cf6-46ed03d20bf7 | access-date=9 June 2020}}</ref><ref>{{cite web | title=Drug Approval Package: Marqibo (vincristine sulfate) NDA #202497 | website=U.S. [[Food and Drug Administration]] (FDA) | date=3 September 2013 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2012/202497_marqibo_toc.cfm | access-date=9 June 2020}}</ref> Marqibo was voluntarily withdrawn from the US market in November, 2021.<ref>{{cite web | title=Acrotech Biopharma LLC; Withdrawal of Approval of New Drug Application for MARQIBO (VinCRIStine Sulfate LIPOSOME Injection), 5 milligrams/5 milliliters | website=[[Federal Register]] | date=2 May 2022 | url=https://www.federalregister.gov/documents/2022/05/02/2022-09235/acrotech-biopharma-llc-withdrawal-of-approval-of-new-drug-application-for-marqibo-vincristine | access-date=19 June 2022}}</ref>

A nano-particle bound version of vincristine was under development as of 2014.<ref>[http://seekingalpha.com/article/2658685-bind-therapeutics-bind-ceo-scott-minick-on-q3-2014-results-earnings-call-transcript?part=single Bind Therapeutics conference call of Nov 6, 2014] {{webarchive|url=https://web.archive.org/web/20160303230202/http://seekingalpha.com/article/2658685-bind-therapeutics-bind-ceo-scott-minick-on-q3-2014-results-earnings-call-transcript?part=single |date=2016-03-03 }}</ref>

In 1995 and 2006 Malagasy [[agronomists]] and American [[political ecologists]] studied the production of ''Catharanthus roseus'' around [[Fort Dauphin_(Madagascar)|Fort Dauphin]] and [[Ambovombe-Androy|Ambovombe]] and its export as a natural source of the alkaloids used to make vincristine, vinblastine and other [[vinca alkaloid]] cancer drugs. Their research focused on the wild collection of periwinkle roots and leaves from roadsides and fields and its industrial cultivation on large farms.<ref>{{cite book |last1=Andriamanalintsoa |first1=Jean Joseph |title=Contribution a l'etude de la producition de la pervenche de Madagascar ou Catharanthus roseus, Cas d' Ambovombe, d'Amboasary-sud, de Beloha et Tsihombe |date=1995 |publisher=Universityersité d'Antananarivo, Ecole Superieur des Sciences Agronomiques |location=Antananarivo, Madagascar |language=French |format=PhD Dissertation| url=http://madadoc.irenala.edu.mg/documents/v4312_MEM%2012099.pdf}}</ref><ref>{{cite book |last1=Neimark |first1=Benjamin |title=Industrial Heartlands of Nature: The Political Economy of Biological Prospecting in Madagascar |date=2009 |publisher=Rutgers, The State University of New Jersey |location=New Brunswick |page=70-112 |url=https://doi.org/doi:10.7282/T3WD40Q7 |language=English |format=PhD Dissertation |chapter=At the "Pharm" gate: The case study of the rosy periwinkle (Catharanthus roseus)|doi=10.7282/T3WD40Q7 }}</ref><ref>{{cite journal |last1=Neimark |first1=Ben |title=Green grabbing at the 'pharm' gate: rosy periwinkle production in southern Madagascar |journal=The Journal of Peasant Studies |date=2012 |volume=39 |issue=2 |page=423-445 |doi=10.1080/03066150.2012.666975 |s2cid=153584071 |url=https://www.tandfonline.com/doi/citedby/10.1080/03066150.2012.666975?scroll=top&needAccess=true&role=tab |access-date=14 July 2023}}</ref>

== References ==

{{Reflist}}

== External links ==

* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/vincristine | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Vincristine }}

* [http://www.chm.bris.ac.uk/webprojects2002/jjones/Content/vincristine.htm Vincristine and vinblastine]

* [https://web.archive.org/web/20070915032627/http://biotech.icmb.utexas.edu/botany/perihist.html Description and Natural History of the Periwinkle]

* [https://www.organic-chemistry.org/Highlights/2006/05June.shtm The Boger Route to (−)-Vindoline]

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[[Category:Vinca alkaloids]]

[[Category:Commercialization of traditional medicines]]

[[Category:Drugs developed by Eli Lilly and Company]]

[[Category:Mitotic inhibitors]]

[[Category:Acetate esters]]

[[Category:Wikipedia medicine articles ready to translate]]

[[Category:World Health Organization essential medicines]]

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