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Vincristine

From Wikipedia, the free encyclopedia
Not to be confused with vinblastine.
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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.289 Edit this at Wikidata
Chemical and physical data
FormulaC46H56N4O10
Molar mass824.972 g·mol−1
3D model (JSmol)
  • 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 checkY
 ☒NcheckY (what is this?)  (verify)

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]

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] 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 as well as the chemotherapy regimen VDC-IE for Ewing's Sarcoma. [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.[9] 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.[10] 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.[11] A 2021 study has suggested that anakinra can reduce the neuropathy.[12][13]

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.[14] 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.[15] 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.[16]

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.[17]

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.[18] The cell then undergoes apoptosis.[19] The vincristine molecule inhibits leukocyte production and maturation.[20] 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.[21]

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.[22] Vincristine is created through the semi-synthesis coupling of indole alkaloids vindoline and catharanthine in the vinca plant.[23] 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.[22]

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.[24]

History

[edit]

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.[25] It was not found to be anti-diabetic in double blinded controlled studies.[26] 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 (hexane), followed by dilute tartaric acid and benzene extraction, provided an active fraction. This fraction was further chromatographed on deactivated aluminium oxide using trichloromethane and benzene, and separation by pH using extraction with various buffers to yield vincristine.[27]

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.[28]

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.[29]

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.[30]

Shortage

[edit]

In October 2019 an impending shortage was reported; no adequate substitute is known for treating childhood-cancers.[31] By 2022, the shortage of vincristine continued.[32]

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.[33] 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.[34]

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.[35]

Vincristine and confusion with other drugs in administration

[edit]

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.[36]

Research

[edit]

In 2012, the FDA approved a liposomal formulation of vincristine branded as Marqibo.[37][38][39] Marqibo was voluntarily withdrawn from the US market in November, 2021.[40]

A nano-particle bound version of vincristine was under development as of 2014.[41]

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.[42][43][44]

References

[edit]
  1. ^ "Vincristine". Dictionary.com. Random House, Inc. Archived from the original on 9 November 2014. Retrieved 9 November 2014.
  2. ^ "NCI Drug Dictionary". NCI. 2011-02-02. Archived 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). "Vincristine". 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. Archived 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. Archived 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. Archived from the original on 2017-08-01.
  8. ^ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  9. ^ 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.
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  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<1356::AID-CNCR20>3.0.CO;2-#. PMID 8608515. S2CID 196362723.
  12. ^ 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.
  13. ^ "Chemotherapy with fewer side effects may be on the way". University of Queensland. 15 March 2021. Retrieved 15 March 2021.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ 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.
  18. ^ Anticancer Drugs Targeting Tubulin and Microtubules. Elsevier. 2015-01-01. ISBN 9780444626493.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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. S2CID 2129170.
  22. ^ 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.
  23. ^ "Pharmacognosy of Vinca Alkaloids". January 2012. Archived from the original on 2012-01-06.
  24. ^ 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.
  25. ^ 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.
  26. ^ "Africa's gift to the world". Education in Chemistry. Retrieved 2018-11-13.
  27. ^ 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.
  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): 1421. PMID 14070392.
  29. ^ "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.
  30. ^ Teva Pharmaceuticals (2019-11-13). "pic.twitter.com/gTY8Jga1kv". @TevaUSA. Retrieved 2019-12-14.
  31. ^ 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.
  32. ^ "Medical Middlemen: Broken system making it harder for hospitals and patients to get some life-saving drugs". CBS News. 22 May 2022.
  33. ^ 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.
  34. ^ 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.
  35. ^ Brown M (2003). Who Owns Native Culture. Cambridge: Harvard University Press. pp. 136–38.
  36. ^ 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.
  37. ^ FDA press release Aug 9, 2012 Archived 2014-11-09 at the Wayback Machine
  38. ^ "Marqibo- vincristine sulfate kit". DailyMed. 17 January 2020. Retrieved 9 June 2020.
  39. ^ "Drug Approval Package: Marqibo (vincristine sulfate) NDA #202497". U.S. Food and Drug Administration (FDA). 3 September 2013. Retrieved 9 June 2020.
  40. ^ "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.
  41. ^ Bind Therapeutics conference call of Nov 6, 2014 Archived 2016-03-03 at the Wayback Machine
  42. ^ 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.
  43. ^ 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.
  44. ^ 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. S2CID 153584071. Retrieved 14 July 2023.
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