Erythropoiesis-stimulating agent | |
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Drug class | |
![]() Structure of erythropoietin | |
Class identifiers | |
Synonyms | Erythropoiesis-stimulating drugs, [1] erythropoietin-type blood factors [2] |
Use | Anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS [3] [2] |
ATC code | B03XA |
Legal status | |
In Wikidata |
Erythropoiesis-stimulating agents (ESA) are medications which stimulate the bone marrow to make red blood cells. [3] They are used to treat anemia due to end stage kidney disease, chemotherapy, major surgery, or certain treatments in HIV/AIDS. [3] [2] In these situations they decrease the need for blood transfusions. [2] The different agents are more or less equivalent. [2] They are given by injection. [2]
Common side effects may include joint pain, rash, vomiting, and headache. [4] Serious side effects may include heart attacks, stroke, increased cancer growth, or pure red cell aplasia. [2] It is unclear if use is safe during pregnancy. [5] [6] They work similar to naturally occurring erythropoietin. [3]
They were first approved for medical use in the United States in 1989. [5] It is on the World Health Organization's List of Essential Medicines. [7] Commercially available agents include epoetin alfa and darbepoetin alfa, and biosimilars. [3] [2] Use among athletes is prohibited by the World Anti-Doping Agency. [5]
ESAs are used to maintain hemoglobin at the lowest level that both minimizes transfusions and best meets a person's needs. [8] 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. [8] [9] In preterm babies ESAs may help reduce the need for red blood cell transfusions. [10]
The 2020 Cochrane Anaesthesia Review Group review of erythropoietin (EPO) plus iron versus control treatment including placebo or iron for preoperative anaemic adults undergoing non‐cardiac surgery [11] demonstrated that patients were much less likely to require red cell transfusion and in those transfused, the volumes were unchanged (mean difference -0.09, 95% CI -0.23 to 0.05). Pre-op hemoglobin (Hb) concentration was increased in those receiving 'high dose' EPO, but not 'low dose'.[ citation needed ]
There is no evidence that one agent is better than another in the setting of CKD. [12]
ESAs may fail to achieve an adequate therapeutic response when one or more of the following is present: [13]
The following types of ESAs are available:[ citation needed ]
Recombinant erythropoietin has a variety of glycosylation patterns giving rise to alpha, beta, delta, and omega forms:
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Darbepoetin alfa, which early literature during its development often termed as novel erythropoiesis-stimulating protein (NESP), is a form created by five substitutions (Asn-30, Thr-32, Val-87, Asn-88 and Thr-90) that create two new N-glycosylation sites. [24] This glycoprotein has a longer terminal half-life, meaning it is possible to administer it less frequently.
Erythropoiesis-stimulating agents have a history of use as blood doping agents in endurance sports, such as horseracing, boxing, [25] 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. [26] 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).[ citation needed ]
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. [27]
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. [28] 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. [29]
Since 2002, EPO tests performed by US sports authorities have consisted of only a urine or "direct" test. From 2000 to 2006, EPO tests at the Olympics were conducted on both blood and urine. [30] [31] 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. [32]
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. [33]
Recombinant EPO is believed to have come into use in cycling about 1990. [34] In theory, EPO use can increase VO2max by a significant amount, [35] 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 transfusions 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". [36]
Dr. Michele Ferrari, a former student and protege of Conconi, [37] 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 would not "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. [38] [39] Ferrari was fired shortly after, but continued to work in the industry with top riders, allegedly including Lance Armstrong. [37] [40] 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. [36]
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. [41] [42] 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". [43] By 1998, EPO use had become widespread, and the Festina affair tarnished the 1998 Tour de France. [34] One manager offered a 270,000-franc-per-month raise to Christophe Bassons if he would use EPO, but Bassons refused. [44]
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. [45] In 2010, Floyd Landis admitted to using performance-enhancing drugs, including EPO, throughout his career as a professional cyclist. [46] 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. [47] In accordance with this decision, Tour organizers removed Armstrong's name and results from the race's history. [48]
Witnesses testified that code words used for EPO included "Edgar", "Poe", [49] "Edgar Allan Poe", and "Zumo" (Spanish for 'juice'). [50]
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.[ citation needed ]
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. [51] [21] 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. [52]
Darbepoetin alfa (INN) is a re-engineered form of erythropoietin containing 5 amino acid changes resulting in the creation of 2 new sites for N-linked carbohydrate addition. It has a 3-fold longer serum half-life compared to epoetin alpha and epoetin beta. It stimulates erythropoiesis by the same mechanism as rHuEpo and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy. Darbepoetin is marketed by Amgen under the trade name Aranesp.
Erythropoietin, also known as erythropoetin, haematopoietin, or haemopoietin, is a glycoprotein cytokine secreted mainly by the kidneys in response to cellular hypoxia; it stimulates red blood cell production (erythropoiesis) in the bone marrow. Low levels of EPO are constantly secreted in sufficient quantities to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO include any anemia, and hypoxemia due to chronic lung disease.
Tyler Hamilton is an American former professional road bicycle racer. He is the only American rider to win one of the five Monuments of cycling, taking Liège–Bastogne–Liège in 2003. Hamilton became a professional cyclist in 1995 with the US Postal Service cycling team. He was a teammate of Lance Armstrong during the 1999, 2000 and 2001 Tours de France, where Armstrong won the general classification. He was a key asset for Armstrong, being a very good climber as well as time-trialist. Hamilton appeared at the 2000 and 2004 Summer Olympics. In 2004, he won a gold medal at the individual time trial. The first doping test after his Olympic victory gave a positive result, but because the backup sample was frozen, no doping offence could be proven. After he failed further doping tests at the 2004 Vuelta a España, Hamilton was suspended for two years from the sport.
Blood doping is a form of doping in which the number of red blood cells in the bloodstream is boosted in order to enhance athletic performance. Because such blood cells carry oxygen from the lungs to the muscles, a higher concentration in the blood can improve an athlete's aerobic capacity (VO2 max) and endurance. Blood doping can be achieved by making the body produce more red blood cells itself using drugs, giving blood transfusions either from another person or back to the same individual, or by using blood substitutes.
Francisco "Frankie" Andreu is an American former professional cyclist whose career highlights include riding as team captain of the U.S. Postal Service cycling team in 1998, 1999 and 2000. During his career, he won a number of race stages and finished fourth in the cycling road race at the 1996 Olympics. His testimony played a key part in the United States Anti-Doping Agency's investigation of fellow U.S. Postal cyclist Lance Armstrong's doping practices.
Epoetin alfa is a human erythropoietin produced in cell culture using recombinant DNA technology. Authorised by the European Medicines Agency on 28 August 2007, it stimulates erythropoiesis and is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy.
Performance-enhancing substances, also known as performance-enhancing drugs (PEDs), are substances that are used to improve any form of activity performance in humans. A well-known example of cheating in sports involves doping in sport, where banned physical performance-enhancing drugs are used by athletes and bodybuilders. Athletic performance-enhancing substances are sometimes referred as ergogenic aids. Cognitive performance-enhancing drugs, commonly called nootropics, are sometimes used by students to improve academic performance. Performance-enhancing substances are also used by military personnel to enhance combat performance.
A biosimilar is a biologic medical product that is almost an identical copy of an original product that is manufactured by a different company. Biosimilars are officially approved versions of original "innovator" products and can be manufactured when the original product's patent expires. Reference to the innovator product is an integral component of the approval.
Epoetin beta (INN), sold under the brand name Neorecormon among others, is a synthetic, recombinant form of erythropoietin, a protein that promotes the production of red blood cells. It is an erythropoiesis-stimulating agent (ESA) that is used to treat anemia, commonly associated with chronic kidney failure and cancer chemotherapy.
Methoxy polyethylene glycol-epoetin beta, sold under the brand name Mircera, is a long-acting erythropoietin receptor activator (CERA) used for the treatment of anaemia associated with chronic kidney disease. It is the first approved, chemically modified erythropoiesis-stimulating agent (ESA).
Carlo Santuccione was an Italian sports doctor who was also known as Ali the Chemist. Santuccione worked with Francesco Conconi at the University of Ferrara in Italy at the Centro Studi Biomedici Applicati allo Sport or Biomedical Research Institute.
Continuous erythropoietin receptor activator (CERA) is the generic term for drugs in a new class of third-generation erythropoiesis-stimulating agents (ESAs). In the media, these agents are commonly referred to as 'EPO', short for erythropoietin. CERAs have an extended half-life and a mechanism of action that promotes increased stimulation of erythropoietin receptors compared with other ESAs.
Donald Hardt Catlin was an American anti-doping scientist and one of the founders of modern drug-testing in professional sports.
Peginesatide, developed by Affymax and Takeda, is an erythropoietic agent, a functional analog of erythropoietin.
At the time of the 1999 Tour de France there was no official test for EPO. In August 2005, 60 remaining antidoping samples from the 1998 Tour and 84 remaining antidoping samples given by riders during the 1999 Tour, were tested retrospectively for recombinant EPO by using three recently developed detection methods. More precisely the laboratory compared the result of test method A: "Autoradiography — visual inspection of light emitted from a strip displaying the isoelectric profile for EPO", with the result of test method B: "Percentage of basic isoforms — using an ultra-sensitive camera that by percentage quantify the light intensity emitted from each of the isoelectric bands". For those samples with enough urine left, these results of test method A+B were finally also compared with the best and latest test method C: "Statistical discriminant analysis — taking account all the band profiles by statistical distinguish calculations for each band".
Roxadustat, sold under the brand name Evrenzo, is an anti-anemia medication. Roxadustat is a HIF prolyl-hydroxylase inhibitor that increases endogenous production of erythropoietin and stimulates production of hemoglobin and red blood cells. It was investigated in clinical trials for the treatment of anemia caused by chronic kidney disease (CKD). It is taken by mouth. The drug was developed by FibroGen, in partnership with AstraZeneca.
Daprodustat, sold under the brand name Duvroq among others, is a medication that is used for the treatment of anemia due to chronic kidney disease. It is a hypoxia-inducible factor prolyl hydroxylase inhibitor. It is taken by mouth.
Epoetin theta, sold under the brand name Biopoin among others, is a copy of the human hormone erythropoietin.
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