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Wikipedia

Vincristine

October 10, 2023

Not to be confused with vinblastine.

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.[5] This includes acute lymphocytic leukemia, acute myeloid leukemia, Hodgkin's disease, neuroblastoma, and small cell lung cancer among others.[5] It is given intravenously.[5]

Vincristine
Clinical data
Pronunciation/ˈvɪnˈkrɪstiːn/ ⓘ[1]
Trade namesOncovin, Vincasar, Marqibo, others[2]
Other namesleurocristine ki
AHFS/Drugs.comMonograph
MedlinePlusa682822
License data
Pregnancy
category
  • AU: D
Routes of
administration		intravenous
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailabilityn/a (not reliably absorbed by the GI tract)[3]
Protein binding~44%[4]
MetabolismLiver, mostly via CYP3A4 and CYP3A5[3]
Elimination half-life19 to 155 hours (mean: 85 hours)[3]
ExcretionFaeces (70–80%), urine (10–20%)[3]
Identifiers
  • (3aR,3a1R,4R,5S,5aR,10bR)-Methyl 4-acetoxy-3a-ethyl-9-((5S,7S,9S)-5-ethyl-5-hydroxy-9-(methoxycarbonyl)-2,4,5,6,7,8,9,10-octahydro-1H-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-1H-indolizino[8,1-cd]carbazole-5-carboxylate
CAS Number
  • 57-22-7 Y
PubChem CID
  • 5978
IUPHAR/BPS
  • 6785
DrugBank
  • DB00541 Y
ChemSpider
  • 5758 Y
UNII
  • 5J49Q6B70F
KEGG
  • D08679 Y
ChEBI
  • CHEBI:28445 Y
ChEMBL
  • ChEMBL303560 N
CompTox Dashboard (EPA)
  • DTXSID1032278
ECHA InfoCard100.000.289
Chemical and physical data
FormulaC46H56N4O10
Molar mass824.958 g·mol−1
3D model (JSmol)
  • Interactive image
  • 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
  • InChI=1S/C46H56N4O10/c1-7-42(55)22-28-23-45(40(53)58-5,36-30(14-18-48(24-28) N
  • Key:OGWKCGZFUXNPDA-XQKSVPLYSA-N Y
 NY (what is this?)  (verify)

Most people experience some side effects from vincristine treatment.[5] Commonly it causes a change in sensation, hair loss, constipation, difficulty walking, and headaches.[5] Serious side effects may include neuropathic pain, lung damage, or low white blood cells which increases the risk of infection.[5] Use during pregnancy may result in birth defects.[5] It works by stopping cells from dividing properly.[5] It is vital that it not be given intrathecally, as this may kill.[6]

Vincristine was first isolated in 1961.[7] It is on the World Health Organization's List of Essential Medicines.[8][9] It is a vinca alkaloid that can be obtained from the Madagascar periwinkle Catharanthus roseus.[7]

Medical uses Edit

Vincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens.[3] Its main uses are in non-Hodgkin's lymphoma as part of the chemotherapy regimen 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.[3] It is also used to induce remission in ALL with dexamethasone and L-asparaginase, and in combination with prednisone to treat childhood leukemia.[3] Vincristine is occasionally used as an immunosuppressant, for example, in treating thrombotic thrombocytopenic purpura (TTP) or chronic idiopathic thrombocytopenic purpura (ITP).[3]

Side effects Edit

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

Vincristine-induced neuropathy is the main dose-limiting side effect.[10] 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.[11] 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.[12] A 2021 study has suggested that Anakinra can reduce the neuropathy.[13][14]

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.[15] 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.[16] 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.[17]

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.[18]

Mechanism of action Edit

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 chromosomes during the metaphase.[19] The cell then undergoes apoptosis.[20] The vincristine molecule inhibits leukocyte production and maturation.[21] 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.[22]

Chemistry Edit

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.[23] Vincristine is created through the semi-synthesis coupling of indole alkaloids vindoline and catharanthine in the vinca plant.[24] 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.[23]

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.[25]

History Edit

 
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 for being anti-tumor, anti-mutagenic are well documented in ancient system of medicine of Ayurveda and folk culture of Madagascar and Southern Africa.[26] Although it was not found to be anti-diabetic in double blinded controlled studies.[27] 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 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, trichloromethane, benz-dichloromethane, and separation by pH to yield vincristine.[28]

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 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.[29]

Production of vincristine required one ton of dried periwinkle leaves to produce one ounce of vincristine. Periwinkle was grown on a ranch in Texas.[30]

Society and culture Edit

Suppliers Edit

Until recently, two generic drug makers were suppliers of vincristine in the United States: Teva and Pfizer. In 2019 Teva stopped producing vincristine, leaving Pfizer as the only company in production.[citation needed] Teva has said that they will restart production, and expect it to be available in 2020.[31]

Shortage Edit

In October 2019 an impending shortage was reported; no adequate substitute is known for treating childhood-cancers.[32] By 2022, the shortage of vincristine continued.[33]

Controversy Edit

Pharmaceutical bioprospecting Edit

Vincristine's origins are debated as an example of pharmaceutical bioprospecting in the fields of ethnobotany and ethnomedicine. Some consider the Catharanthus roseus plant from which vincristine is derived, and its folk remedies to be endemic to Madagascar, and that Madagascar was denied royalties from vincristine sales.[34] 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.[35]

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.[36]

Vincristine and confusion with other drugs in administration Edit

Vincristine has been involved in a number of medical errors. If given into the spine (intrathecal) it causes paralysis and usually death. Multiple instances of vincristine being given wrongly, having been confused with other drugs, have occurred.[37]

Research Edit

In 2012, the FDA approved a liposomal formulation of vincristine branded as Marqibo.[38][39][40] Marqibo was voluntarily withdrawn from the US market in November, 2021.[41]

A nano-particle bound version of vincristine was under development as of 2014.[42]

In 1995 and 2006 Malagasy agronomists and American political ecologists studied the production of Catharanthus roseus around Fort Dauphin and 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.[43][44][45]

References Edit

  1. ^ "Vincristine". Dictionary.com. Random House, Inc. from the original on 9 November 2014. Retrieved 9 November 2014.
  2. ^ "NCI Drug Dictionary". NCI. 2011-02-02. from the original on 8 December 2015. Retrieved 28 November 2015.
  3. ^ a b c d e f g h Brayfield A, ed. (13 December 2013). . Martindale: The Complete Drug Reference. Pharmaceutical Press. Archived from the original on 8 April 2020. Retrieved 15 April 2014.
  4. ^ "Oncovin, Vincasar PFS (vincristine) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. from the original on 16 April 2014. Retrieved 16 April 2014.
  5. ^ a b c d e f g h "Vincristine Sulfate". The American Society of Health-System Pharmacists. from the original on 2015-01-02. Retrieved Jan 2, 2015.
  6. ^ Chotsampancharoen T, Sripornsawan P, Wongchanchailert M (5 December 2015). "Two Fatal Cases of Accidental Intrathecal Vincristine Administration: Learning from Death Events". Chemotherapy. 61 (2): 108–110. doi:10.1159/000441380. eISSN 1421-9794. PMID 26636546. S2CID 22376877.
  7. ^ a b Ravina E (2011). The evolution of drug discovery : from traditional medicines to modern drugs (1. Aufl. ed.). Weinheim: Wiley-VCH. pp. 157–159. ISBN 9783527326693. from the original on 2017-08-01.
  8. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  9. ^ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  10. ^ van de Velde ME, Kaspers GL, Abbink FC, Wilhelm AJ, Ket JC, van den Berg MH (June 2017). "Vincristine-induced peripheral neuropathy in children with cancer: A systematic review". Critical Reviews in Oncology/Hematology. 114: 114–130. doi:10.1016/j.critrevonc.2017.04.004. PMID 28477739.
  11. ^ del Pino BM (Feb 23, 2010). . NCI Cancer Bulletin. 7 (4): 6. Archived from the original on 2011-12-11.
  12. ^ Graf WD, Chance PF, Lensch MW, Eng LJ, Lipe HP, Bird TD (April 1996). "Severe vincristine neuropathy in Charcot-Marie-Tooth disease type 1A". Cancer. 77 (7): 1356–1362. doi:10.1002/(SICI)1097-0142(19960401)77:7<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515. S2CID 196362723.
  13. ^ Starobova H, Monteleone M, Adolphe C, Batoon L, Sandrock CJ, Tay B, et al. (May 2021). "Vincristine-induced peripheral neuropathy is driven by canonical NLRP3 activation and IL-1β release". The Journal of Experimental Medicine. 218 (5): e20201452. doi:10.1084/jem.20201452. PMC 7933984. PMID 33656514.
  14. ^ "Chemotherapy with fewer side effects may be on the way". University of Queensland. 15 March 2021. Retrieved 15 March 2021.
  15. ^ Qweider M, Gilsbach JM, Rohde V (March 2007). "Inadvertent intrathecal vincristine administration: a neurosurgical emergency. Case report". Journal of Neurosurgery. Spine. 6 (3): 280–3. doi:10.3171/spi.2007.6.3.280. PMID 17355029.
  16. ^ Zaragoza MR, Ritchey ML, Walter A (January 1995). "Neurourologic consequences of accidental intrathecal vincristine: a case report". Medical and Pediatric Oncology. 24 (1): 61–2. doi:10.1002/mpo.2950240114. PMID 7968797.
  17. ^ Hooker J, Bogdanich W (January 31, 2008). "Tainted Drugs Tied to Maker of Abortion Pill". New York Times. from the original on March 26, 2017.
  18. ^ Sears JE, Boger DL (March 2015). "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". Accounts of Chemical Research. 48 (3): 653–62. doi:10.1021/ar500400w. PMC 4363169. PMID 25586069.
  19. ^ Anticancer Drugs Targeting Tubulin and Microtubules. Elsevier. 2015-01-01. ISBN 9780444626493.
  20. ^ Jordan MA (January 2002). "Mechanism of action of antitumor drugs that interact with microtubules and tubulin". Current Medicinal Chemistry. Anti-Cancer Agents. 2 (1): 1–17. doi:10.2174/1568011023354290. PMID 12678749.
  21. ^ Silverman JA, Deitcher SR (March 2013). "Marqibo (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine". Cancer Chemotherapy and Pharmacology. 71 (3): 555–64. doi:10.1007/s00280-012-2042-4. PMC 3579462. PMID 23212117.
  22. ^ Morris PG, Fornier MN (November 2008). "Microtubule active agents: beyond the taxane frontier". Clinical Cancer Research. 14 (22): 7167–72. doi:10.1158/1078-0432.ccr-08-0169. PMID 19010832.
  23. ^ a b Kuboyama T, Yokoshima S, Tokuyama H, Fukuyama T (August 2004). "Stereocontrolled total synthesis of (+)-vincristine". Proceedings of the National Academy of Sciences of the United States of America. 101 (33): 11966–70. doi:10.1073/pnas.0401323101. PMC 514417. PMID 15141084.
  24. ^ "Pharmacognosy of Vinca Alkaloids". January 2012. from the original on 2012-01-06.
  25. ^ Waterhouse DN, Madden TD, Cullis PR, Bally MB, Mayer LD, Webb MS (2005). "Preparation, characterization, and biological analysis of liposomal formulations of vincristine". Liposomes. Methods in Enzymology. Vol. 391. pp. 40–57. doi:10.1016/s0076-6879(05)91002-1. ISBN 9780121827960. PMID 15721373.
  26. ^ Mishra JN, Verma NK (March 2017). "A brief study on Catharanthus Roseus: A review" (PDF). International Journal of Research in Pharmacy and Pharmaceutical Sciences. 2 (2). ISSN 2455-698X – via ResearchGate.
  27. ^ "Africa's gift to the world". Education in Chemistry. Retrieved 2018-11-13.
  28. ^ Johnson IS, Armstrong JG, Gorman M, Burnett JP (September 1963). "The Vinca Alkaloids: A New Class of Oncolytic Agents" (PDF). Cancer Research. 23 (8 Part 1): 1390–427. PMID 14070392.
  29. ^ Johnson IS, Armstrong JG, Gorman M, Burnett JP (September 1963). "The Vinca Alkaloids: A New Class of Oncolytic Agents" (PDF). Cancer Research. 23 (8 Part 1): 1421. PMID 14070392.
  30. ^ "Eli Lilly engineers developed a life-saving drug from the leaves of the periwinkle plant. – Treating Diabetes". Treating Diabetes. from the original on 8 September 2017. Retrieved 18 June 2017.
  31. ^ Teva Pharmaceuticals (2019-11-13). "pic.twitter.com/gTY8Jga1kv". @TevaUSA. Retrieved 2019-12-14.
  32. ^ Rabin RC (14 October 2019). "Faced With a Drug Shortfall, Doctors Scramble to Treat Children With Cancer". The New York Times. Retrieved 15 October 2019.
  33. ^ "Medical Middlemen: Broken system making it harder for hospitals and patients to get some life-saving drugs". CBS News.
  34. ^ Plotkin M (1993). Tales of a Shaman's Apprentice: An Ethnobotanist Searches for New Medicines in the Amazon Rain Forest. New York: Penguin Books. pp. 15–16.
  35. ^ Johnson IS, Armstrong JG, Gorman M, Burnett JP (September 1963). "The Vinca Alkaloids: A New Class of Oncolytic Agents" (PDF). Cancer Research. 23 (8 Part 1): 1391. PMID 14070392.
  36. ^ Brown M (2003). Who Owns Native Culture. Cambridge: Harvard University Press. pp. 136–38.
  37. ^ Gilbar PJ (March 2020). "Inadvertent intrathecal administration of vincristine: Time to finally abolish the syringe". Journal of Oncology Pharmacy Practice. 26 (2): 263–266. doi:10.1177/1078155219880600. PMID 31707923. S2CID 207953764.
  38. ^ FDA press release Aug 9, 2012 2014-11-09 at the Wayback Machine
  39. ^ "Marqibo- vincristine sulfate kit". DailyMed. 17 January 2020. Retrieved 9 June 2020.
  40. ^ "Drug Approval Package: Marqibo (vincristine sulfate) NDA #202497". U.S. Food and Drug Administration (FDA). 3 September 2013. Retrieved 9 June 2020.
  41. ^ "Acrotech Biopharma LLC; Withdrawal of Approval of New Drug Application for MARQIBO (VinCRIStine Sulfate LIPOSOME Injection), 5 milligrams/5 milliliters". Federal Register. 2 May 2022. Retrieved 19 June 2022.
  42. ^ Bind Therapeutics conference call of Nov 6, 2014 2016-03-03 at the Wayback Machine
  43. ^ Andriamanalintsoa, Jean Joseph (1995). 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 (PhD Dissertation) (in French). Antananarivo, Madagascar: Universityersité d'Antananarivo, Ecole Superieur des Sciences Agronomiques.
  44. ^ Neimark, Benjamin (2009). "At the "Pharm" gate: The case study of the rosy periwinkle (Catharanthus roseus)". Industrial Heartlands of Nature: The Political Economy of Biological Prospecting in Madagascar (PhD Dissertation). New Brunswick: Rutgers, The State University of New Jersey. p. 70-112. doi:10.7282/T3WD40Q7.
  45. ^ Neimark, Ben (2012). "Green grabbing at the 'pharm' gate: rosy periwinkle production in southern Madagascar". The Journal of Peasant Studies. 39 (2): 423-445. doi:10.1080/03066150.2012.666975. Retrieved 14 July 2023.

External links Edit

  • "Vincristine". Drug Information Portal. U.S. National Library of Medicine.
  • Vincristine and vinblastine
  • The Boger Route to (−)-Vindoline

October 10, 2023
vincristine, confused, with, vinblastine, also, known, leurocristine, marketed, under, brand, name, oncovin, among, others, chemotherapy, medication, used, treat, number, types, cancer, this, includes, acute, lymphocytic, leukemia, acute, myeloid, leukemia, ho. Not to be confused with vinblastine 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 5 This includes acute lymphocytic leukemia acute myeloid leukemia Hodgkin s disease neuroblastoma and small cell lung cancer among others 5 It is given intravenously 5 VincristineClinical dataPronunciation ˈ v ɪ n ˈ k r ɪ s t iː n 1 Trade namesOncovin Vincasar Marqibo others 2 Other namesleurocristine kiAHFS Drugs comMonographMedlinePlusa682822License dataUS DailyMed VincristinePregnancycategoryAU DRoutes ofadministrationintravenousATC codeL01CA02 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US onlyPharmacokinetic dataBioavailabilityn a not reliably absorbed by the GI tract 3 Protein binding 44 4 MetabolismLiver mostly via CYP3A4 and CYP3A5 3 Elimination half life19 to 155 hours mean 85 hours 3 ExcretionFaeces 70 80 urine 10 20 3 IdentifiersIUPAC name 3aR 3a1R 4R 5S 5aR 10bR Methyl 4 acetoxy 3a ethyl 9 5S 7S 9S 5 ethyl 5 hydroxy 9 methoxycarbonyl 2 4 5 6 7 8 9 10 octahydro 1H 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 1H indolizino 8 1 cd carbazole 5 carboxylateCAS Number57 22 7 YPubChem CID5978IUPHAR BPS6785DrugBankDB00541 YChemSpider5758 YUNII5J49Q6B70FKEGGD08679 YChEBICHEBI 28445 YChEMBLChEMBL303560 NCompTox Dashboard EPA DTXSID1032278ECHA InfoCard100 000 289Chemical and physical dataFormulaC 46H 56N 4O 10Molar mass824 958 g mol 13D model JSmol Interactive imageSMILES 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 OInChI InChI 1S C46H56N4O10 c1 7 42 55 22 28 23 45 40 53 58 5 36 30 14 18 48 24 28 NKey OGWKCGZFUXNPDA XQKSVPLYSA N Y N Y what is this verify Most people experience some side effects from vincristine treatment 5 Commonly it causes a change in sensation hair loss constipation difficulty walking and headaches 5 Serious side effects may include neuropathic pain lung damage or low white blood cells which increases the risk of infection 5 Use during pregnancy may result in birth defects 5 It works by stopping cells from dividing properly 5 It is vital that it not be given intrathecally as this may kill 6 Vincristine was first isolated in 1961 7 It is on the World Health Organization s List of Essential Medicines 8 9 It is a vinca alkaloid that can be obtained from the Madagascar periwinkle Catharanthus roseus 7 Contents 1 Medical uses 2 Side effects 3 Mechanism of action 4 Chemistry 5 History 6 Society and culture 6 1 Suppliers 6 2 Shortage 7 Controversy 7 1 Pharmaceutical bioprospecting 8 Vincristine and confusion with other drugs in administration 9 Research 10 References 11 External linksMedical uses EditVincristine is delivered via intravenous infusion for use in various types of chemotherapy regimens 3 Its main uses are in non Hodgkin s lymphoma as part of the chemotherapy regimen 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 3 It is also used to induce remission in ALL with dexamethasone and L asparaginase and in combination with prednisone to treat childhood leukemia 3 Vincristine is occasionally used as an immunosuppressant for example in treating thrombotic thrombocytopenic purpura TTP or chronic idiopathic thrombocytopenic purpura ITP 3 Side effects EditThe main side effects of vincristine are chemotherapy induced peripheral neuropathy hyponatremia constipation and hair loss Vincristine induced neuropathy is the main dose limiting side effect 10 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 11 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 12 A 2021 study has suggested that Anakinra can reduce the neuropathy 13 14 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 15 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 16 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 17 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 18 Mechanism of action EditVincristine 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 chromosomes during the metaphase 19 The cell then undergoes apoptosis 20 The vincristine molecule inhibits leukocyte production and maturation 21 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 22 Chemistry EditThe 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 23 Vincristine is created through the semi synthesis coupling of indole alkaloids vindoline and catharanthine in the vinca plant 24 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 23 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 25 History Edit nbsp Some members of Eli Lilly s vincristine research teamHaving 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 for being anti tumor anti mutagenic are well documented in ancient system of medicine of Ayurveda and folk culture of Madagascar and Southern Africa 26 Although it was not found to be anti diabetic in double blinded controlled studies 27 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 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 trichloromethane benz dichloromethane and separation by pH to yield vincristine 28 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 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 29 Production of vincristine required one ton of dried periwinkle leaves to produce one ounce of vincristine Periwinkle was grown on a ranch in Texas 30 Society and culture EditSuppliers Edit Until recently two generic drug makers were suppliers of vincristine in the United States Teva and Pfizer In 2019 Teva stopped producing vincristine leaving Pfizer as the only company in production citation needed Teva has said that they will restart production and expect it to be available in 2020 31 Shortage Edit In October 2019 an impending shortage was reported no adequate substitute is known for treating childhood cancers 32 By 2022 the shortage of vincristine continued 33 Controversy EditPharmaceutical bioprospecting Edit Vincristine s origins are debated as an example of pharmaceutical bioprospecting in the fields of ethnobotany and ethnomedicine Some consider the Catharanthus roseus plant from which vincristine is derived and its folk remedies to be endemic to Madagascar and that Madagascar was denied royalties from vincristine sales 34 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 35 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 36 Vincristine and confusion with other drugs in administration EditVincristine has been involved in a number of medical errors If given into the spine intrathecal it causes paralysis and usually death Multiple instances of vincristine being given wrongly having been confused with other drugs have occurred 37 Research EditIn 2012 the FDA approved a liposomal formulation of vincristine branded as Marqibo 38 39 40 Marqibo was voluntarily withdrawn from the US market in November 2021 41 A nano particle bound version of vincristine was under development as of 2014 42 In 1995 and 2006 Malagasy agronomists and American political ecologists studied the production of Catharanthus roseus around Fort Dauphin and 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 43 44 45 References Edit Vincristine Dictionary com Random House Inc Archived from the original on 9 November 2014 Retrieved 9 November 2014 NCI Drug Dictionary NCI 2011 02 02 Archived from the original on 8 December 2015 Retrieved 28 November 2015 a b c d e f g h Brayfield A ed 13 December 2013 Vincristine Martindale The Complete Drug Reference Pharmaceutical Press Archived from the original on 8 April 2020 Retrieved 15 April 2014 Oncovin Vincasar PFS vincristine dosing indications interactions adverse effects and more Medscape Reference WebMD Archived from the original on 16 April 2014 Retrieved 16 April 2014 a b c d e f g h Vincristine Sulfate The American Society of Health System Pharmacists Archived from the original on 2015 01 02 Retrieved Jan 2 2015 Chotsampancharoen T Sripornsawan P Wongchanchailert M 5 December 2015 Two Fatal Cases of Accidental Intrathecal Vincristine Administration Learning from Death Events Chemotherapy 61 2 108 110 doi 10 1159 000441380 eISSN 1421 9794 PMID 26636546 S2CID 22376877 a b Ravina E 2011 The evolution of drug discovery from traditional medicines to modern drugs 1 Aufl ed Weinheim Wiley VCH pp 157 159 ISBN 9783527326693 Archived from the original on 2017 08 01 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO World Health Organization 2021 World Health Organization model list of essential medicines 22nd list 2021 Geneva World Health Organization hdl 10665 345533 WHO MHP HPS EML 2021 02 van de Velde ME Kaspers GL Abbink FC Wilhelm AJ Ket JC van den Berg MH June 2017 Vincristine induced peripheral neuropathy in children with cancer A systematic review Critical Reviews in Oncology Hematology 114 114 130 doi 10 1016 j critrevonc 2017 04 004 PMID 28477739 del Pino BM Feb 23 2010 Chemotherapy induced Peripheral Neuropathy NCI Cancer Bulletin 7 4 6 Archived from the original on 2011 12 11 Graf WD Chance PF Lensch MW Eng LJ Lipe HP Bird TD April 1996 Severe vincristine neuropathy in Charcot Marie Tooth disease type 1A Cancer 77 7 1356 1362 doi 10 1002 SICI 1097 0142 19960401 77 7 lt 1356 AID CNCR20 gt 3 0 CO 2 PMID 8608515 S2CID 196362723 Starobova H Monteleone M Adolphe C Batoon L Sandrock CJ Tay B et al May 2021 Vincristine induced peripheral neuropathy is driven by canonical NLRP3 activation and IL 1b release The Journal of Experimental Medicine 218 5 e20201452 doi 10 1084 jem 20201452 PMC 7933984 PMID 33656514 Chemotherapy with fewer side effects may be on the way University of Queensland 15 March 2021 Retrieved 15 March 2021 Qweider M Gilsbach JM Rohde V March 2007 Inadvertent intrathecal vincristine administration a neurosurgical emergency Case report Journal of Neurosurgery Spine 6 3 280 3 doi 10 3171 spi 2007 6 3 280 PMID 17355029 Zaragoza MR Ritchey ML Walter A January 1995 Neurourologic consequences of accidental intrathecal vincristine a case report Medical and Pediatric Oncology 24 1 61 2 doi 10 1002 mpo 2950240114 PMID 7968797 Hooker J Bogdanich W January 31 2008 Tainted Drugs Tied to Maker of Abortion Pill New York Times Archived from the original on March 26 2017 Sears JE Boger DL March 2015 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 Accounts of Chemical Research 48 3 653 62 doi 10 1021 ar500400w PMC 4363169 PMID 25586069 Anticancer Drugs Targeting Tubulin and Microtubules Elsevier 2015 01 01 ISBN 9780444626493 Jordan MA January 2002 Mechanism of action of antitumor drugs that interact with microtubules and tubulin Current Medicinal Chemistry Anti Cancer Agents 2 1 1 17 doi 10 2174 1568011023354290 PMID 12678749 Silverman JA Deitcher SR March 2013 Marqibo vincristine sulfate liposome injection improves the pharmacokinetics and pharmacodynamics of vincristine Cancer Chemotherapy and Pharmacology 71 3 555 64 doi 10 1007 s00280 012 2042 4 PMC 3579462 PMID 23212117 Morris PG Fornier MN November 2008 Microtubule active agents beyond the taxane frontier Clinical Cancer Research 14 22 7167 72 doi 10 1158 1078 0432 ccr 08 0169 PMID 19010832 a b Kuboyama T Yokoshima S Tokuyama H Fukuyama T August 2004 Stereocontrolled total synthesis of vincristine Proceedings of the National Academy of Sciences of the United States of America 101 33 11966 70 doi 10 1073 pnas 0401323101 PMC 514417 PMID 15141084 Pharmacognosy of Vinca Alkaloids January 2012 Archived from the original on 2012 01 06 Waterhouse DN Madden TD Cullis PR Bally MB Mayer LD Webb MS 2005 Preparation characterization and biological analysis of liposomal formulations of vincristine Liposomes Methods in Enzymology Vol 391 pp 40 57 doi 10 1016 s0076 6879 05 91002 1 ISBN 9780121827960 PMID 15721373 Mishra JN Verma NK March 2017 A brief study on Catharanthus Roseus A review PDF International Journal of Research in Pharmacy and Pharmaceutical Sciences 2 2 ISSN 2455 698X via ResearchGate Africa s gift to the world Education in Chemistry Retrieved 2018 11 13 Johnson IS Armstrong JG Gorman M Burnett JP September 1963 The Vinca Alkaloids A New Class of Oncolytic Agents PDF Cancer Research 23 8 Part 1 1390 427 PMID 14070392 Johnson IS Armstrong JG Gorman M Burnett JP September 1963 The Vinca Alkaloids A New Class of Oncolytic Agents PDF Cancer Research 23 8 Part 1 1421 PMID 14070392 Eli Lilly engineers developed a life saving drug from the leaves of the periwinkle plant Treating Diabetes Treating Diabetes Archived from the original on 8 September 2017 Retrieved 18 June 2017 Teva Pharmaceuticals 2019 11 13 pic twitter com gTY8Jga1kv TevaUSA Retrieved 2019 12 14 Rabin RC 14 October 2019 Faced With a Drug Shortfall Doctors Scramble to Treat Children With Cancer The New York Times Retrieved 15 October 2019 Medical Middlemen Broken system making it harder for hospitals and patients to get some life saving drugs CBS News Plotkin M 1993 Tales of a Shaman s Apprentice An Ethnobotanist Searches for New Medicines in the Amazon Rain Forest New York Penguin Books pp 15 16 Johnson IS Armstrong JG Gorman M Burnett JP September 1963 The Vinca Alkaloids A New Class of Oncolytic Agents PDF Cancer Research 23 8 Part 1 1391 PMID 14070392 Brown M 2003 Who Owns Native Culture Cambridge Harvard University Press pp 136 38 Gilbar PJ March 2020 Inadvertent intrathecal administration of vincristine Time to finally abolish the syringe Journal of Oncology Pharmacy Practice 26 2 263 266 doi 10 1177 1078155219880600 PMID 31707923 S2CID 207953764 FDA press release Aug 9 2012 Archived 2014 11 09 at the Wayback Machine Marqibo vincristine sulfate kit DailyMed 17 January 2020 Retrieved 9 June 2020 Drug Approval Package Marqibo vincristine sulfate NDA 202497 U S Food and Drug Administration FDA 3 September 2013 Retrieved 9 June 2020 Acrotech Biopharma LLC Withdrawal of Approval of New Drug Application for MARQIBO VinCRIStine Sulfate LIPOSOME Injection 5 milligrams 5 milliliters Federal Register 2 May 2022 Retrieved 19 June 2022 Bind Therapeutics conference call of Nov 6 2014 Archived 2016 03 03 at the Wayback Machine Andriamanalintsoa Jean Joseph 1995 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 PhD Dissertation in French Antananarivo Madagascar Universityersite d Antananarivo Ecole Superieur des Sciences Agronomiques Neimark Benjamin 2009 At the Pharm gate The case study of the rosy periwinkle Catharanthus roseus Industrial Heartlands of Nature The Political Economy of Biological Prospecting in Madagascar PhD Dissertation New Brunswick Rutgers The State University of New Jersey p 70 112 doi 10 7282 T3WD40Q7 Neimark Ben 2012 Green grabbing at the pharm gate rosy periwinkle production in southern Madagascar The Journal of Peasant Studies 39 2 423 445 doi 10 1080 03066150 2012 666975 Retrieved 14 July 2023 External links Edit Vincristine Drug Information Portal U S National Library of Medicine Vincristine and vinblastine Description and Natural History of the Periwinkle The Boger Route to Vindoline Portal nbsp Medicine Retrieved from https en wikipedia org w index php title Vincristine amp oldid 1178960571, wikipedia, wiki, book, books, library,

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