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55-557: By December 2000, all nine Festina riders had confessed to using erythropoietin (EPO) and other substances during the 1998 Tour de France, and suspended sentences ranging from 5–12 months were handed out to Festina soigneur Willy Voet , Festina manager Bruno Roussel, La Française des Jeux soigneur Jef d'Hont , former Festina soigneur Jean Dalibot, and Festina communication officer Joel Chabiron. The two accused pharmacists, Éric Paranier and Christine Paranier, along with Team ONCE physician Nicolás Terrados , were only given fines, while

110-412: A n/a n/a n/a n/a n/a Erythropoietin ( / ɪ ˌ r ɪ θ r oʊ ˈ p ɔɪ . ɪ t ɪ n , - r ə -, - p ɔɪ ˈ ɛ t ɪ n , - ˈ iː t ɪ n / ; EPO ), 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

165-498: A performance-enhancing drug , EPO has been banned since the early 1990s, but a first test was not available until the 2000 Summer Olympics . Before this test was available, some athletes were sanctioned after confessing to having used EPO, for example in the Festina affair , when a car with doping products for the Festina cycling team was found. The first doping test in cycling was used in

220-464: A positive feedback loop . Erythropoietins available for use as therapeutic agents are produced by recombinant DNA technology in cell culture , and include Epogen/Procrit ( epoetin alfa ) and Aranesp ( darbepoetin alfa ); they are used in treating anemia resulting from chronic kidney disease , chemotherapy induced anemia in patients with cancer, inflammatory bowel disease ( Crohn's disease and ulcerative colitis ) and myelodysplasia from

275-422: A 30,000 francs fine (4,573 euros). Her husband Éric received a fine of 10,000 francs (around 1,500 euros). Jef d'Hont received a nine-month suspended sentence and a fine of 20,000 francs (around 3,000 euros). Jean Dalibot and Joel Chabiron received a five-month suspended sentence. Dr. Terrados was given a 30,000 francs fine. The case against Eric Rijckaert was dropped due to his deteriorating health; he died of cancer

330-567: A 4-year suspension by the International Tennis Integrity Agency for two separate violations, one concerning the level of EPO in a blood sample collected in August 2022; Halep maintained her innocence, and indicated she would appeal the ban. Halep was later cleared to return following a successful appeal, due to findings that a contaminated supplement most likely contributed to the positive tests. TVM (cycling team) TVM

385-409: A common substance used by the cyclists. A 2007 study showed that EPO has a significant effect on exercise performance. A 2017 study showed at submaximal exertion the effects of EPO were not distinguishable from a placebo. Stating "[At] Submaximal [exertion]...[mean power] did not differ between groups." Nevertheless, at "maximal [exertion power output was] higher in the rHuEPO group compared with

440-529: A feedback mechanism measuring blood oxygenation and iron availability. Constitutively synthesized transcription factors for EPO, known as hypoxia-inducible factors , are hydroxylated and proteosomally digested in the presence of oxygen and iron. During normoxia GATA2 inhibits the promoter region for EPO. GATA2 levels decrease during hypoxia and allow the promotion of EPO production. Erythropoietin production can be induced by HIF-2α as well as by PGC-1α . Erythropoietin also activates these factors, resulting in

495-468: A functional EPO receptor is not detected in those tissues. In the bloodstream, red cells themselves do not express erythropoietin receptor, so cannot respond to EPO. However, indirect dependence of red cell longevity in the blood on plasma erythropoietin levels has been reported, a process termed neocytolysis. In addition, there is conclusive evidence that EPO receptor expression is upregulated in brain injury. Erythropoietin levels in blood are quite low in

550-424: A hemotropic factor called hemopoietin. Eva Bonsdorff and Eeva Jalavisto called the hemopoietic substance 'erythropoietin'. K.R. Reissman and Allan J. Erslev demonstrated that a certain substance, circulated in the blood, is able to stimulate red blood cell production and increase hematocrit . This substance was purified and confirmed as erythropoietin. In 1977, Goldwasser and Kung purified EPO. Pure EPO allowed

605-484: A hospital and made to undergo extensive tests and give blood, hair and urine samples. Upon release the following day, five Festina riders (Zülle, Dufaux, Moreau, Brochard and Meier) admitted to doping while Virenque and Hervé maintained their innocence. Zülle claimed that he needed to engage in doping to satisfy Festina's corporate sponsors, while Dufaux stated that he confessed due to overwhelming evidence collected by police. In custody, Voet and Roussel explained how doping

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660-592: A month later. December 30, 2000: Swiss cycling federation gave a nine-month ban to Virenque and a 4,000 Swiss franc fine. Many books have been written about the Festina affair. In the French judicial system, the TVM affair treated as an independent court case, though it is often referred to as part of the Festina affair since French police executed the TVM raid, interrogated six TVM riders, held several TVM key staff in custody, and performed additional advanced doping tests during

715-504: A suitcase and a rubbish bin in TVM's hotel rooms in Toulouse and Metz . An investigation into TVM was launched on July 24. On July 28, the TVM team was met by police in Albertville . Six TVM riders, including Jeroen Blijlevens , Bart Voskamp , Servais Knaven and Steven de Jongh , were taken in the night to a hospital where they gave blood, hair, and urine samples; TVM soigneur Jan Moors

770-519: A vehicle belonging to the TVM team during a routine customs check close to Reims in northeast France. On the same day as the Festina arrests, French police raided TVM's hotel in Pamiers , resulting in the arrest and detainment of TVM manager Cees Priem and TVM doctor Andrei Michailov. Four other TVM officials, including directeur sportif Hendrik Redant , were interrogated and released. Police found drug evidence in

825-443: Is an essential hormone for red blood cell production. Without it, definitive erythropoiesis does not take place. Under hypoxic conditions, the kidney will produce and secrete erythropoietin to increase the production of red blood cells by targeting CFU-E , pro erythroblast and basophilic erythroblast subsets in the differentiation. Erythropoietin has its primary effect on red blood cell progenitors and precursors (which are found in

880-445: Is controversial with numerous studies showing no effect. It is also inconsistent with the low levels of EPO receptors on those cells. Clinical trials in humans with ischemic heart, neural and renal tissues have not demonstrated the same benefits seen in animals. In addition some research studies have shown its neuroprotective effect on diabetic neuropathy, however these data were not confirmed in clinical trials that have been conducted on

935-472: Is taken into police custody and imprisoned for 11 days. September 23, 1998: Voet accuses Virenque of doping in the French newspaper Le Parisien . Voet said to the newspaper that only three Festina riders were drug free. These were Christophe Bassons , Patrice Halgand and Laurent Lefèvre . October 15, 1998: There is a confrontation between Virenque, Voet and Rijckaert where Virenque calls himself an innocent victim. November 28, 1998: The results of

990-400: The 2001 La Flèche Wallonne . The first rider to test positive in that race was Bo Hamburger , although he was later acquitted because his B-sample was not conclusive. The U.S. Postal Service Pro Cycling Team , under the leadership of Lance Armstrong and Johan Bruyneel , ran a sophisticated doping program that lasted for many years during the late 1990s and early 2000s. Erythropoietin was

1045-490: The French Cycling Federation for six months and cannot ride until April 30, 1999. December 17, 1998: Team doctor of Team ONCE Nicolas Terrados is charged in relation to the import of banned substances. January 26, 1999: Joel Chabiron, Festina communications director, is charged. March 23, 1999: Jean Marie Dalibot, the soigneur of Festina, is charged. March 26, 1999: Virenque is charged with inciting

1100-585: The Union Cycliste Internationale (UCI), but Virenque, Dufaux and Brochard called a press conference and stated that the Festina team would not withdraw from the race. However, Tour de France race directeur Jean-Marie Leblanc expelled Festina from the Tour after Roussel confessed to systematic doping on the team. The following day, Virenque left the Tour in tears. Nine riders and three officials from Festina were taken into police custody on July 23; of

1155-408: The bone marrow . Low levels of EPO (around 10  mU /mL) 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 (up to 10 000 mU/mL) include any anemia , and hypoxemia due to chronic lung disease and mouth disease. Erythropoietin is produced by interstitial fibroblasts in

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1210-533: The 19th stage and returned to the Netherlands on July 31. Massi questioned by an investigating magistrate as suspicions mounted that he was involved in Festina's doping network. At this stage there are fewer than one hundred riders in the race compared to the 189 riders that started the race. On August 1, Massi was charged with inciting and facilitating the use of doping. In Reims, TVM riders submitted to several hours of questioning, after which team masseur Johannes Moors

1265-600: The EPO gene and its oxygen-dependent regulation. Along with William Kaelin Jr. , they were awarded the 2019 Nobel Prize in Physiology or Medicine for their discovery of hypoxia-inducible factor (HIF), which regulates the EPO gene, as well as other genes, in response to hypoxia. In December 2007, Retacrit and Silapo (both epoetin zeta ) were approved for use in the European Union. As

1320-469: The Festina investigation. After the public prosecutor in Reims had prepared the case, the court arbitration was conducted during 28–31 May 2001, with Cees Priem (TVM manager), Andrei Mikhailov (TVM doctor) and Jan Moors (TVM soigneur) being charged for import, transport and possession of doping/drugs on French soil. Main events: TVM trial: Erythropoietin n/a n/a n/a n/a n

1375-491: The Française des Jeux team, Jef d'Hont, was the one providing him with EPO and treating him with a glucose-infusion one hour ahead of a UCI hematocrit test in the 1997 edition of Paris–Nice, in a vain attempt to lower his hematocrit value below the 50%-limit. He also stated that his team manager Marc Madiot had been fully aware of his EPO use in 1997. October 23, 2000: On the first day of the trial, Voet stated that he never let

1430-650: The Tour peloton conducted an industrial action by cycling slowly. Team ONCE, led by French champion Laurent Jalabert , pulled out first while the Banesto and Riso Scotti teams left at the feeding zone. The peloton stopped a second time and threatened a mass withdrawal, leading the stage to be cancelled. That afternoon, raids were conducted on Team ONCE, Team Polti , La Française des Jeux , Lotto and Casino . Team managers Marc Madiot (La Française des Jeux) and Vincent Lavenu (Casino) and rider Rodolfo Massi (Casino) were arrested. Kelme and Vitalicio Seguros pulled out of

1485-411: The Tour de France announce the teams of the 1999 Tour de France where they take the unprecedented step of banning teams, team officials and individual riders. In the aftermath of the Festina affair, Virenque was banned together with his former teammate Hervé. Manolo Saiz , manager of ONCE–Deutsche Bank , Dr Nicolas Terrados team doctor of Team ONCE and the entire TVM–Farm Frites were also banned. This

1540-404: The absence of anemia, at around 10 mU/mL. However, in hypoxic stress, EPO production may increase up to 1000-fold, reaching 10 000 mU/mL of blood. In adults, EPO is synthesized mainly by interstitial cells in the peritubular capillary bed of the renal cortex , with additional amounts being produced in the liver, and the pericytes in the brain . Regulation is believed to rely on

1595-485: The amino acid sequence to be partially identified and the gene to be isolated. Synthetic EPO was first successfully used to correct anemia in 1987. In 1985, Lin et al isolated the human erythropoietin gene from a genomic phage library and used it to produce EPO. In 1989, the US Food and Drug Administration (FDA) approved the hormone Epogen for use in certain anemias. Gregg L. Semenza and Peter J. Ratcliffe studied

1650-434: The analysis of the samples taken from the nine Festina riders are known and are subsequently released and revealed evidence of Human Growth Hormone , amphetamines , steroids , corticoids and Erythropoietin (EPO) . In eight of the nine riders test positive for synthetic EPO. The results of the ninth rider ( Christophe Moreau ) were indeterminate but Moreau had already admitted use of EPO. Traces of amphetamines were found in

1705-505: The bone marrow in humans) by promoting their survival through protecting these cells from apoptosis , or cell death. Erythropoietin is the primary erythropoietic factor that cooperates with various other growth factors (e.g., IL-3 , IL-6 , glucocorticoids , and SCF ) involved in the development of erythroid lineage from multipotent progenitors . The burst-forming unit-erythroid ( BFU-E ) cells start erythropoietin receptor expression and are sensitive to erythropoietin. Subsequent stage,

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1760-477: The case against Festina doctor Eric Rijckaert was dropped because of his deteriorating health. On July 8, 1998, Festina soigneur Willy Voet was stopped by customs officers at the French-Belgian border close to Neuville-en-Ferrain , near the city of Lille . Officers discovered several hundred grams and capsules of anabolic steroids , erythropoietin (EPO), syringes , and other doping products. Voet

1815-631: The colony-forming unit-erythroid ( CFU-E ), expresses maximal erythropoietin receptor density and is completely dependent on erythropoietin for further differentiation. Precursors of red cells, the proerythroblasts and basophilic erythroblasts also express erythropoietin receptor and are therefore affected by it. Erythropoietin was reported to have a range of actions beyond stimulation of erythropoiesis including vasoconstriction -dependent hypertension , stimulating angiogenesis , and promoting cell survival via activation of EPO receptors resulting in anti-apoptotic effects on ischemic tissues. However this proposal

1870-464: The deep peroneal, superficial peroneal, tibial and sural nerves. Erythropoietin has been shown to exert its effects by binding to the erythropoietin receptor (EpoR). EPO binds to the erythropoietin receptor on the red cell progenitor surface and activates a JAK2 signalling cascade. This initiates the STAT5 , PIK3 and Ras MAPK pathways. This results in differentiation, survival and proliferation of

1925-461: The endogenous protein; for example, in features of posttranslational modification . EPO is highly glycosylated (40% of total molecular weight), with half-life in blood around 5 h. EPO's half-life may vary between endogenous and various recombinant versions. Additional glycosylation or other alterations of EPO via recombinant technology have led to the increase of EPO's stability in blood (thus requiring less frequent injections). Erythropoietin

1980-514: The entire team, only Christophe Bassons was not arrested nor implicated in doping. Eric van de Sijpe, a Belgian judge, ordered a search of Rijckaert's office, whereby the police obtained computer files proving the riders were using EPO. Virenque, Dufaux, Pascal Hervé , Didier Rous , Alex Zülle, and Armin Meier were questioned in Lyon and held in police custody. All nine of the implicated riders were escorted to

2035-479: The erythroid cell. SOCS1, SOCS3 and CIS are also expressed which act as negative regulators of the cytokine signal. High level erythropoietin receptor expression is localized to erythroid progenitor cells. While there are reports that EPO receptors are found in a number of other tissues, such as heart, muscle, kidney and peripheral/central nervous tissue, those results are confounded by nonspecificity of reagents such as anti-EpoR antibodies. In controlled experiments,

2090-407: The hematocrit level of the riders exceed 54% whereas other teams were letting it go as high as 64%. This was under the order of team doctor Eric Rijckaert. October 24, 2000: Virenque admitted to doping. October 25, 2000: Pascal Hervé , Virenque's friend and the only other Festina rider to deny doping, admitted to doping. October 27, 2000: Former rider Thomas Davy testified at the trial that

2145-488: The key figure in the Operación Puerto doping scandal. December 22, 2000: Virenque was cleared from the criminal charge of "inciting the administration of doping and masking products to others and complicity in the importation of drugs". Voet was given a 10-month suspended sentence and a 30,000 franc fine. Bruno Roussel was given a suspended sentence of one year and a fine of 50,000 francs. Christine Paranier received

2200-584: The kidney in close association with the peritubular capillary and proximal convoluted tubule . It is also produced in perisinusoidal cells in the liver . Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood. It is homologous with thrombopoietin . Exogenous erythropoietin, recombinant human erythropoietin (rhEPO), is produced by recombinant DNA technology in cell culture and are collectively called erythropoiesis-stimulating agents (ESA): two examples are epoetin alfa and epoetin beta . ESAs are used in

2255-553: The person supplying him with EPO while he was riding for Française des Jeux in 1997. November 1, 2000: On the stand UCI President Hein Verbruggen admitted that organised doping may exist. The following day several doctors of Spanish cycling teams refuted this statement. Jesús Hoyos (Banesto), Kepa Celaya (ONCE) and Eufemiano Fuentes (Kelme doctor) spoke to the Spanish daily paper As to refute this statement. Fuentes would later emerge as

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2310-536: The placebo group." So, even though there was no difference at lower levels of exertion at maximal exertion the EPO group still performed better than the placebo group. In March 2019, American mixed martial artist and former UFC Bantamweight Champion T.J. Dillashaw tested positive for EPO in a drug test administered by USADA , and was stripped of the UFC bantamweight title and suspended for 2 years. In September 2023 two-time tennis major champion Simona Halep received

2365-456: The race the following day. Blijlevens pulled out near the border with Switzerland. Massi, leader of the Mountains classification , was not able to start the stage as he was still being held in police custody. The Casino team truck was seized by police, while the Festina riders reportedly implicated La Française des Jeux, Casino and Big Mat in the team's doping scheme. The TVM team who did not start

2420-574: The route of the Tour ;– by farmers or by police in the hotels used by teams – for example a hotel in Voreppe used by GAN, Casino, Saeco and Kelme. August 10, 1998: Cantina Tollo and La Française des Jeux vehicles are searched by French customs officials. September 13, 1998: Two pharmacists Christine and Eric Paranier are questioned in respect to supplying illegal doping products to Voet. September 18, 1998: Française des Jeux soigneur Jef d'Hont

2475-557: The samples of Moreau, Pascal Hervé , Laurent Brochard and Didier Rous . Four riders had hematocrit levels below the legal limit of 50%, establish in February 1997. These included Virenque, Armin Meier, Moreau who had a level of 49.3 and Laurent Dufaux who had a level of 47.2%. Five riders were above the limit. Brochard had 50.3%, Neil Stephens 50.3%, Hervé 52.6%, Rous 51% and Alex Zülle 52.3%. December 15, 1998: Laurent Brochard , Christophe Moreau and Didier Rous are suspended by

2530-514: The team's riders. As the Tour de France began in Dublin , it was announced that the Festina riders Richard Virenque , Alex Zülle and Laurent Dufaux would face questioning when they returned to France. On July 15, Roussel and Festina team doctor Eric Rijckaert were arrested in Cholet , and the team's hotel was searched by eight gendarmes . Roussel lost his licence as a manager of a cycling team from

2585-595: The teams Castorama , Banesto , Team Telekom and La Française des Jeux had been running organized systematic doping programs, similar to the one revealed at the Festina Team. He knew that from riding at Castorama (1992–94), Banesto (1995–96) and Française des Jeux (1997). His use of EPO started in 1995, and continued until the end of his career, after the 1997 season. When asked if Miguel Induráin at Banesto had also used EPO, he said "I don't know. I didn't go into every room, but I think he did". He stated that Jef d'Hont as

2640-493: The treatment of anemia in chronic kidney disease , anemia in myelodysplasia , and in anemia from cancer chemotherapy . Risks of therapy include death, myocardial infarction , stroke , venous thromboembolism , and tumor recurrence. Risk increases when EPO treatment raises hemoglobin levels over 11 g/dL to 12 g/dL: this is to be avoided. rhEPO has been used illicitly as a performance-enhancing drug . It can often be detected in blood, due to slight differences from

2695-614: The treatment of cancer ( chemotherapy and radiation ). The package inserts include boxed warnings of increased risk of death, myocardial infarction , stroke , venous thromboembolism , and tumor recurrence, particularly when used to increase the hemoglobin levels to more than 11 g/dL to 12 g/dL. In 1905, Paul Carnot proposed the idea that a hormone regulates the production of red blood cells. After conducting experiments on rabbits subject to bloodletting , Carnot and his graduate student Clotilde-Camille Deflandre attributed an increase in red blood cells in rabbit subjects to

2750-640: The use and administration of doping products to others. April 1, 1999: Jean-Marie Leblanc is taken into police custody and questioned. April 4, 1999: French Federation Cycling vice president Roger Legacy and President Baal are charged with violation of the anti-doping law of 1989. (These charges would be subsequently dropped). June, 1999: In an interview with L'Équipe , Roussel alleged that when he told Virenque of Voet being arrested, Virenque replied mes produits, comment Je vais faire maintenant? which could be translated as my products/stuff – what am I going to do now? June 17, 1999: The organisers of

2805-525: Was arrested. Police also took three cases, a sports bag and a dustbin from the TVM team. Afterwards, the rest of the team were taken into custody and escorted to the hospital for extensive drug tests. Other cycling teams on the Tour expressed support for the embattled riders, and objected to their treatment as criminals. Banesto and Team ONCE expressed support for a statement by International Olympic Committee president Juan Antonio Samaranch that performance-enhancing drugs should be legalized. On July 29,

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2860-409: Was in relation to the actions and behaviour of these teams and riders during the 1998 Tour. October 23, 2000: Start of the Festina trial with ten people charged, including: Witnesses included: October 23, 2000: Erwann Menthéour's book, Secret Defonce: Ma vérité sur le dopage (February 1999) describes how he used EPO while riding for Française des Jeux in 1997, and stated that the soigneur of

2915-428: Was jailed for suspicion of possessing drugs and breaches of French customs laws. Police soon found banned substances in the hotel of Team ONCE, which Terrados claimed were used by support staff. August 4, 1998: Jean-Marie Leblanc acknowledges that the increasing speed of the peloton in the Tour was due to the increasing use of doping in the peloton. August 5, 1998: The media contains many reports of drug finds along

2970-420: Was organised on the Festina team, and claimed that the other cycling teams are involved in smuggling banned substances. On July 27, Festina rider Neil Stephens admitted taking performance-enhancing drugs but claimed that he thought the EPO injections were legal supplements. On July 19, 1998, the day after Festina left the Tour, the French daily Aujourd’hui reported that police had found 104 ampules of EPO in

3025-561: Was taken into police custody. Festina offices were searched in Lyon and seized other suspect products, including perfluorocarbon . Two days after the arrest, Bruno Roussel, directeur sportif of Festina, denied any involvement with the uncovered drugs. However, the following day, French police announced that on top of the contraband items found in Voet's car, a document was discovered at Festina's headquarters which detailed systematic drug programmes for

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