Erythropoiesis-stimulating agent

An erythropoiesis-stimulating agent (abbreviated ESA), also known as an erythropoiesis-stimulating drug (ESD)[1] is a medicine similar to erythropoietin, which stimulates red blood cell production (erythropoeisis). ESAs, structurally and biologically, are similar to naturally occurring protein erythropoietin. They are used in conditions were reduced blood cell production causes anemia, such as advanced chronic kidney disease.

Types

The following types of ESAs are available:

Medical uses

ESAs are used to maintain hemoglobin at the lowest level that both minimizes transfusions and best meets a person's needs.[2] Medical speciality professional organizations do not recommend the use of ESAs in people with chronic kidney disease (CKD) who have hemoglobin levels greater than 10 g/dL and do not have anemia symptoms.[2][3]

There is no evidence that one agent is better than another in the setting of CKD.[4]

Available forms

Recombinant erythropoietin has a variety of glycosylation patterns giving rise to alpha, beta, delta, and omega forms:

  • epoetin zeta (biosimilar forms for epoetin alpha):
    • Silapo (Stada)
    • Retacrit (Hospira)
  • Miscellaneous:
    • Epocept, made by Lupin Pharmaceuticals
    • EPOTrust, made by Panacea Biotec Ltd
    • Erypro Safe, made by Biocon Ltd.
    • Repoitin, made by Serum Institute of India Limited
    • Vintor, made by Emcure Pharmaceuticals
    • Epofit, made by Intas pharma
    • Erykine, made by Intas Biopharmaceutica
    • Wepox, made by Wockhardt Biotech
    • Espogen, made by LG life sciences.
    • ReliPoietin, made by Reliance Life Sciences
    • Shanpoietin, made by Shantha Biotechnics Ltd
    • Zyrop, made by Cadila Healthcare Ltd.
    • EPIAO (rHuEPO), made by Shenyang Sunshine Pharmaceutical Co.. LTD. China
    • Cinnapoietin, made by CinnaGen biopharmaceutical Iran.

Darbepoetin alfa, which early literature during its development often termed as novel erythropoiesis-stimulating protein (NESP), is a form created by five substitutions (Asn-57, Thr-59, Val-114, Asn-115 and Thr-117) that create two new N-glycosylation sites.[7] This glycoprotein has a longer terminal half-life, meaning it is possible to administer it less frequently.

Misuse

Erythropoiesis-stimulating agents have a history of use as blood doping agents in endurance sports, such as horseracing, boxing,[8] cycling, rowing, distance running, race walking, snowshoeing, cross country skiing, biathlon, Mixed Martial Arts and triathlon. The overall oxygen delivery system (blood oxygen levels, as well as heart stroke volume, vascularization, and lung function) is one of the major limiting factors to muscles' ability to perform endurance exercise. Therefore, the primary reason athletes may use ESAs is to improve oxygen delivery to muscles, which directly improves their endurance capacity. With the advent of recombinant erythropoietin in the 1990s, the practice of autologous and homologous blood transfusion has been partially replaced by injecting erythropoietin such that the body naturally produces its own red cells. ESAs increase hematocrit (% of blood volume that is red cell mass) and total red cell mass in the body, providing a good advantage in sports where such practice is banned.[9] In addition to ethical considerations in sports, providing an increased red cell mass beyond the natural levels reduces blood flow due to increased viscosity, and increases the likelihood of thrombosis and stroke. Due to dangers associated with using ESAs, their use should be limited to the clinic where anemic patients are boosted back to normal hemoglobin levels (as opposed to going above the normal levels for performance advantage, leading to an increased risk of death).

Though EPO was believed to be widely used in the 1990s in certain sports, there was no way at the time to directly test for it, until in 2000, when a test developed by scientists at the French national antidoping laboratory (LNDD) and endorsed by the World Anti-Doping Agency (WADA) was introduced to detect pharmaceutical EPO by distinguishing it from the nearly identical natural hormone normally present in an athlete's urine. The first EPO-doping cases were found by the Swiss Laboratory for Doping Analyses.[10]

In 2002, at the Winter Olympic Games in Salt Lake City, Dr. Don Catlin, the founder and then-director of the UCLA Olympic Analytical Lab, reported finding darbepoetin alfa, a form of erythropoietin, in a test sample for the first time in sports.[11] At the 2012 Summer Olympics in London, Alex Schwazer, the gold medalist in the 50-kilometer race walk in the 2008 Summer Olympics in Beijing, tested positive for EPO and was disqualified.[12]

Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From 2000–2006, EPO tests at the Olympics were conducted on both blood and urine.[13][14] However, several compounds have been identified that can be taken orally to stimulate endogenous EPO production. Most of the compounds stabilize the hypoxia-inducible transcription factors which activate the EPO gene. The compounds include oxo-glutarate competitors, but also simple ions such as cobalt(II) chloride.[15]

Inhalation of a xenon/oxygen mixture activates production of the transcription factor HIF-1-alpha, which leads to increased production of erythropoietin and improved performance. It has been used for this purpose in Russia since at least 2004.[16]

Cycling

Synthetic EPO is believed to have come into use in cycling about 1990.[17] In theory, EPO use can increase VO2max by a significant amount,[18] making it useful for endurance sports like cycling. Italian antidoping advocate Sandro Donati has claimed that the history of doping in cycling can be traced to the Italian Dr Francesco Conconi at the University of Ferrara. Conconi had worked on the idea of giving athletes tranfusions of their own blood in the 1980s. Donati felt this work "opened the road to EPO . . . because blood doping was a trial to understand the role of EPO".[19]

Dr Michele Ferrari, a former student and protege of Conconi,[20] had a controversial interview mentioning the drug in 1994, just after his Gewiss-Ballan team had a remarkable performance in the La Flèche Wallonne race. Ferrari told l'Equipe journalist Jean-Michel Rouet that EPO had no "fundamental" effect on performance and that if his riders used it, it wouldn't "scandalize" himself. After the journalist pointed out several riders were suspected of dying from EPO, Ferrari said EPO was not dangerous, and only abuse of it was dangerous, saying, "It's also dangerous to drink 10 liters of orange juice." The 'orange juice' comment has been widely misquoted.[21][22] Ferrari was fired shortly after, but continued to work in the industry with top riders, allegedly including Lance Armstrong.[20][23] That same year, Sandro Donati, working for the Italian National Olympic Committee, presented a report accusing Conconi of being linked to the use of EPO in the sport.[19]

In 1997, the Union Cycliste Internationale (UCI) instituted a new rule that riders testing above 50% haematocrit were not only immediately disqualified, but banned from racing for two weeks.[24][25] Robert Millar, former racer, later wrote for Cycling News that the 50% limit was "an open invitation to dope to that level", pointing out that normally haematocrit levels would start "around 40-42%" and drop during the course of a "grand tour", but after EPO, they were staying at 50% for "weeks at a time".[26] By 1998, EPO use had become widespread, and the Festina affair tarnished the 1998 Tour de France.[17] One manager offered a 270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused.[27]

In the 1998 Tour de France Stuart O'Grady won one stage, held the Tour de France yellow jersey for three days, and came second in the points classification with the assistance of EPO.[28] In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout his career as a professional cyclist.[29] In 2012, the USADA released a report on its investigation into massive doping by the US Postal Service cycling team under the leadership of Lance Armstrong. The report contained affidavits from numerous riders on the team, including Frankie Andreu, Tyler Hamilton, George Hincapie, Floyd Landis, Levi Leipheimer, and others, outlining that they and Armstrong used a cocktail of performance-enhancing substances for the Tour de France, most notably EPO, during Armstrong's seven consecutive Tour wins. It detailed how Armstrong and the Postal manager, Johan Bruyneel, forced other team members to dope as well. It also went to the root of their doping network, targeting the shadowy doctors and back room enablers who helped cyclists procure and administer drugs as well as highly placed executives who helped to avoid doping controls and hide positive test results. Armstrong was subsequently stripped of all of his victories from 1998 onward—including his Tour wins and his performance in the 2000 Summer Olympics. The UCI concurred with the decision. While several of the doping offenses took place outside the normal eight-year statute of limitations for doping offenses, USADA contended the statute of limitations did not apply due to Armstrong's "fraudulent concealment" of his doping. Longstanding precedent in U.S. law holds that the statute of limitations does not apply in cases of fraudulent conduct by a defendant.[30] In accordance with this decision, Tour organizers removed Armstrong's name and results from the race's history.[31]

Witnesses testified that code words used for EPO included "Edgar", "Poe",[32] "Edgar Allan Poe", and "Zumo" (Spanish for 'juice').[33]

Dynepo

Dynepo is the brand name for a form of EPO developed by Shire Pharmaceuticals. The first development steps were performed by HMR and Aventis. Aventis obtained the license in Europe in 2002. The company expected to launch the product in Europe in 2006, although patents held by the American biotechnology company Amgen, Inc. may have precluded its sale in the United States.

Dynepo was made in cultured human cells. It was therefore expected to have an authentic human form of sialic acid and other oligosaccharide residues. It was hoped that this would make a longer-acting product than existing brands. There were concerns that such production would also make Dynepo undetectable in the urine tests for EPO used, at that time, to detect doping by athletes. Dynepo was withdrawn from European markets on 17 February 2009 for commercial reasons.[34] On July 1, 2009, professional cycling team Silence–Lotto announced that Thomas Dekker was tested positive for Dynepo on a test taken on December 24, 2007, while Dekker was riding for Rabobank.[35]

Failure

ESAs may fail to achieve an adequate therapeutic response when one or more of the following is present:[36]

References

  1. ↑ Tanne, Janice Hopkins (2010). "FDA restricts use of erythropoiesis stimulating drugs". BMJ 340. doi:10.1136/bmj.c1050.
  2. 1 2 Aapro, M. S.; Link, H. (2008). "September 2007 Update on EORTC Guidelines and Anemia Management with Erythropoiesis-Stimulating Agents". The Oncologist 13: 33–36. doi:10.1634/theoncologist.13-S3-33. PMID 18458123.
  3. ↑ American Society of Nephrology, "Five Things Physicians and Patients Should Question" (PDF), Choosing Wisely: an initiative of the ABIM Foundation (American Society of Nephrology), retrieved August 17, 2012
  4. ↑ Palmer, SC; Saglimbene, V; Mavridis, D; Salanti, G; Craig, JC; Tonelli, M; Wiebe, N; Strippoli, GF (8 December 2014). "Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis.". The Cochrane database of systematic reviews 12: CD010590. doi:10.1002/14651858.CD010590.pub2. PMID 25486075.
  5. ↑ "Aranesp(darbepoetin alfa)". Amgen.com. Retrieved 2009-04-29.
  6. ↑ "Procrit (Epoetin alfa)". Ortho Biotech Products. Archived from the original on 2009-10-26. Retrieved 2009-04-29.
  7. ↑ Macdougall IC (Jul 2000). "Novel erythropoiesis stimulating protein". Seminars in Nephrology 20 (4): 375–81. PMID 10928340.
  8. ↑ "Boxing Scandals". Bleacher Report. December 2011. Retrieved 2011-12-22.
  9. ↑ Jelkmann W, Lundby C (Sep 2011). "Blood doping and its detection". Blood 118 (9): 2395–404. doi:10.1182/blood-2011-02-303271. PMID 21652677.
  10. ↑ History of the Swiss Laboratory for Doping Analyses, www.doping.chuv.ch (page visited on 11 June 2014).
  11. ↑ Steeg JL (2007-02-28). "Catlin has made a career out of busting juicers - USATODAY.com". USA TODAY. Retrieved 2009-03-31.
  12. ↑ "FDA Reports New Risks Posed by Anemia Drugs" Associated Press story in the Washington Post (August 8, 2012)
  13. ↑ Lasne F, Martin L, Crepin N, de Ceaurriz J (Dec 2002). "Detection of isoelectric profiles of erythropoietin in urine: differentiation of natural and administered recombinant hormones". Analytical Biochemistry 311 (2): 119–26. doi:10.1016/S0003-2697(02)00407-4. PMID 12470670.
  14. ↑ Kohler M, Ayotte C, Desharnais P, Flenker U, Lüdke S, Thevis M, Völker-Schänzer E, Schänzer W (Jan 2008). "Discrimination of recombinant and endogenous urinary erythropoietin by calculating relative mobility values from SDS gels". International Journal of Sports Medicine 29 (1): 1–6. doi:10.1055/s-2007-989369. PMID 18050057.
  15. ↑ Jelkmann W (2012). "The disparate roles of cobalt in erythropoiesis, and doping relevance.". Open Journal of Hematology 3: 3–6. doi:10.13055/ojhmt_3_1_6.121211.
  16. ↑ "Breathe it in". The Economist. 8 February 2014.
  17. 1 2 Lodewijkx HF, Brouwer B (Dec 2011). "Some empirical notes on the epo epidemic in professional cycling". Research Quarterly for Exercise and Sport 82 (4): 740–54. doi:10.5641/027013611X13275192112069. PMID 22276416.
  18. ↑ Lundby C, Robach P, Boushel R, Thomsen JJ, Rasmussen P, Koskolou M, Calbet JA (Aug 2008). "Does recombinant human Epo increase exercise capacity by means other than augmenting oxygen transport?". Journal of Applied Physiology 105 (2): 581–7. doi:10.1152/japplphysiol.90484.2008. PMID 18535134.
  19. 1 2 Harrison C (2003-03-01). "The Man Who Knows Too Much". Sport Monthly. chrisharrisonwriting.
  20. 1 2 Gifford B (Jan–Feb 2006). "Paging Doctor Ferrari". Bicycling: 50–59.
  21. ↑ Maloney T (2003). "An Interview With Dr. Michele Ferrari, part two: That l'Equipe Interview". by Jean-Michel Rouet, from l'Equipe, 1994, reprinted excerpt. Cycling News.
  22. ↑ 10 liters of orange juice: see the article on Water intoxication, for example.
  23. ↑ Juliet Macur: Cycle of Lies: The Fall of Lance Armstrong
  24. ↑ Martin DT, Ashenden M, Parisotto R, Pyne D, Hahn AG (March–April 1997). "Blood testing for professional cyclists: What's a fair hematocrit limit?". Sports Science.
  25. ↑ "Pantani: Future 'in doubt'". BBC. 5 June 1999. Retrieved 30 June 2011.
  26. ↑ Millar R (2003-10-23). "The Bare Minimum". Cycling News.
  27. ↑ Startt J (2012-10-15). "Christophe Bassons Interview: 'People Now See I Wasn't Lying'". This Just In. Bicycling.com.
  28. ↑ "Stuart O'Grady admits to doping at 1998 Tour de France". Theaustralian.com.au. 2013-07-25. Retrieved 2013-07-25.
  29. ↑ "Landis admits to illegal drug use". BBC News. 2010-05-20.
  30. ↑ United States Anti Doping Agency. "Report on proceedings under the world anti-doping code and the usada protocol united states anti-doping agency, claimant, v. lance armstrong, respondent. reasoned decision of the united states anti-doping agency" (PDF). USADA. Retrieved 2012-10-28.
  31. ↑ "A lifetime ban: Does the time fit the crime?" Velo News, 12/16/13
  32. ↑ "U.S. Postal Service Pro Cycling Team Investigation". Statement From USADA CEO Travis T. Tygart Regarding The U.S. Postal Service Pro Cycling Team Doping Conspiracy. USADA. 2012-10-10.
  33. ↑ Chapman M (2012-10-15). "Cycling's Dirty Truth". Sport, Peddlers. BBC Radio 5. Archived from the original on October 16, 2012.
  34. ↑ Wathion, Noël. "Public statement on Dynepo (epoetin delta)" (PDF). European Medicines Agency. Retrieved 31 August 2015.
  35. ↑ Bauer K (2011). Ride a Stage of the Tour De France The Legendary Climbs and How to Ride Them. London: A & C Black. p. 35. ISBN 978-1-4081-3333-0.
  36. ↑ Burtis, C.A.; Ashwood, E.R. and Bruns, D.E. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. 5th Edition. Elsevier. pp 1554
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