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Erythropoetin:  The Perfect Drug?

Alexander D. Martin

Introduction: 

             Global knowledge is, and has been, increasing at an astonishing rate over the past few decades – to be exact, every 15 years (http://www.aventis-rt.com/it/en/content.asp); and while this is amazing, perhaps the most surprising aspect of it all, is that the rate at which we acquire knowledge is still increasing exponentially.  By 2010, the rate at which we will be doubling our amount of “useful” knowledge will be every hour (http://picoscience.8m.com/).From all of this newfound information come many new medicinal breakthroughs in human development, such as mechanical hearts and radical new surgeries.  But some of the breakthroughs, while possibly beneficial to society, have been considered by the majority to be quite controversial (e.g. human cloning, artificial human growth hormone, the “morning after” pill, etc.).  One such drug, Erythropoetin, or more commonly referred to as EPO, made its appearance in the United States during the late 1980’s when used in the treatment of hemophiliacs.  EPO stimulates the production of red blood cells that are responsible for bringing oxygen to all parts of our bodies; a significant increase in EPO will raise the stamina of an anemia patient, and help pave the way for recovery.  To most people this would sound like a very good, not to mention safe and non-controversial, discovery.  But then again, how does EPO work, and how is it made?  Are there any side effects of Erythropoetin?  It is a naturally occurring substance, but would anything happen to professional sports programs if athletes began taking EPO to influence their performance?  Perhaps physicians and sports psychologists can help explain the pros and cons of this new drug.

            

History of EPO:         

             Erythropoetin was first developed in 1983 soon after the discovery of the EPO gene on chromosome 7, but was not approved for use by the FDA until June of 1989 (http://www.healthanswers.com/Library/library_fset.asp).  EPO is a naturally occurring glycosylated protein (a protein with a carbohydrate as the non-protein component) in our bodies that is produced 90% by the kidneys and 10% by the liver.  EPO production begins in the interstitial cells of the kidney, and in a healthy person, hematocrit levels (red blood cell count) are regulated by renal tubular cells that sense how much oxygen is being carried in the blood, and then determine whether to activate or deactivate more interstitial cells (http://www.healthanswers.com/Library/library_fset.asp).  Once EPO is dispersed into the blood  stream it makes contact with erythroid progenitor cells (the cells responsible for producing RBC’s) in bone marrow throughout our skeletal structure and stimulates the production of almost all of our bodies red blood cells (http://www.rice.edu/~jenky/sports/epo.html).  The process of growing EPO artificially, however, is quite different and very complex.  Dr. Steve Triezenberg explains it best, “the gene that encodes EPO was cloned by scientists at several different companies.  That gene was then joined to a piece of DNA so that the gene could be expressed in cells that could then be grown in laboratories.  The protein is then purified from those cells,” and distributed to a patient; the patients hematocrit levels will then rise, and in turn, raise the amount of oxygen flowing through that patients body

(http://newton.dep.anl.gov/askasci/bio99/bio99063.htm).

            

Side effects of EPO: 

             As it turns out for hemophiliacs, EPO is a lifesaving drug.  But as any other anti-biotic or over the counter medicine, it can cause side effects, such as:

 

Symptoms

•chest pain

•difficulty breathing

•headaches

•high blood pressure

•muscle aches 

•rapid weight gain

•seizures

•skin rash or hives

•swelling of feet or ankles

•unusual weakness

•diarrhea

•fever, chills, flu-like  symptoms

•nausea, vomiting

•redness, stinging, or swelling at the injection site

 

 

EPO Scandals

Italian cyclist Marco Pantani (left), controversial winner of the 1998 Tour de France, follows closely behind fellow country-man Rodolfo Massi (right), in the early stages of the race. Both riders were under close scrutiny by Tour officials concerning possible doping scandals, past and present. The 1998 cycling competition was thought to be one of the dirtiest in years in regards to the use of illegal substances, such as EPO.

 

 However, it is peculiar that there be any side effects at all, for the natural occurring EPO in our bodies is identical to the synthetic forms produced in laboratories. Speculation leads most physicians to believe that this is due to a foreign agent in the bloodstream, or simply because the body is not used to processing such high levels of EPO.  The average person has a hematocrit level of 40 to 45, in which the blood is still relatively thin and easily flows through the body’s circulatory system.  Oxygen transport has been shown to be optimal between the hematocrit levels of 35%-55%, and significantly decreases above and below these levels (http://www.healthanswers.com/Library/library_fset.asp).  But if for some reason the patient responds to the increased levels of EPO in a negative way, their hematocrit levels could sky rocket to better than 55, in which case blood clotting becomes much more likely.  On rare occasions this has caused life-threatening complications among patients, resulting in heart attacks and strokes.  But according to Dr. Benjamin Levine, Senior Director of the Institute for Exercise and Environmental Medicine, “Once you get above 55 or 60 you can sludge blood in your brain or heart…(but) there is not even a hint of a risk until you get above a hematocrit of 55,” (http://cbshealthwatch.medscape.com/cx/viewarticle/222670_1). 

            

Benefits of EPO:

             For most anemia patients, the highs of synthetic EPO far outweigh the lows.  During the initial phases of treatment, EPO has been shown to raise hematocrit levels by as much as 2% a week   (http://www.healthanswers.com/Library/library_fset.asp).  And as a patient’s hematocrit rises, they will experience a drastic improvement in their quality of life.  More oxygen flowing in their bodies means more energy, the ability to freely move around and not worry about premature fatigue, as well as an improvement in their psychological health; the majority of HIV and chemo patients, as well as hemophiliacs, have a very hard time dealing with their physical conditions and when they experience any improvements in their health, they immediately feel better about life and are altogether happier people after treatment.  Although in some instances, even minor improvements may not be evident until six weeks into treatment, but for the most part EPO is  successful in the elevation of a persons RBC count (http://www.healthanswers.com/Library/library_fset.asp).  Athletes, on the other hand, usually increase their dosages for rapid results.

 

Prospective Cohort – RHE In Post Surgical Anemia Patients:

             An in depth study, conducted between December 1989 and February 1991, attempted to reveal whether or not Recombinant Human Erythropoetin (RHE) is effective in raising the hematocrit (Hct) levels of severe post-surgical anemia patients.  The study was conducted at Cooper Hospital on the Robert Wood Johnson Medical School campus, and was headed by Doctor Umur Atabek.  The main goal of the study was to determine the safety of RHE, because if it proved to have no adverse side effects, many problems could be fixed that have previously complicated the treatment of anemic patients.  Namely, avoiding homologous blood transfusions, lowering the blood transfusion trigger point, and using RHE to improve the yield of autologously pre-donated blood (Atabek et al., 1995).

             Methodology:  Prospective patients were thoroughly examined and prepped for the study; however, several candidates were rejected due to histories of hematologic disease, uncontrolled hypertension disorders, and seizures.  Between 1989 and 1991, forty Jehovah’s Witness (JW) patients (all of whom qualified to participate) became severely anemic directly after surgery, and because of their religion refused to accept blood transfusions; this is how Dr. Atabek and his collegues found the subjects for this experiment (Atabek et al., 1995).  All patients received intravenous and oral iron supplementation throughout the study due to  the fact that iron is the main component needed for Erythropoesis and the production of red blood cells.  The cohort was divided into three groups:  Group (C), was composed of six female and fourteen male JW patients who did not receive RHE at any time during the study; group (E), which was divided into two subgroups,  was composed of six female and fourteen male JW patients who received varying levels of RHE throughout the entire study (Atabek et al., 1995).  The first group  contained seven patients, all of who received RHE at 100 u/kg intravenously three times a week; while the second group of thirteen received RHE at 300 u/kg  intravenously three times a week for one week, and then RHE at 150 u/kg three times a week for two additional weeks (Atabek et al., 1995).

             Results & Conclusions:  Every patient recruited for the study suffered radical blood loss during their procedures, which significantly contributed to their depleted hematocrit levels.  Seven patients died during the study, three of which died during the first two weeks.  Starting Hct for group (C) was 12.8, while group (E) was 15.8 (Atabek et al., 1995); a normal hematocrit is in the vicinity of 38-46 for women, and 42-54 for men, as to point out the severity of these patients  conditions (http://www.medicinenet.com/Script/Main/Art.asp?li=MNI&ArticleKey=8060).  After one week of treatment with RHE, group (E) significantly improved their Hct to 19.3, while group (C), which was only given iron supplements, actually dropped to 12.5.  After two weeks of treatment, both groups  improved:  Group (E) reached a Hct of 22.5; and group (C) a Hct of 17.8.  Both groups made notable improvements, but the RHE treated patients ended the study  with a higher Hct, and started to recover more quickly than those entirely treated with supplements.  After analyzing all of the recorded data, Dr. Atabek and his team concluded that treatment of RHE beginning at the time of surgery or immediately post-operatively can accelerate Erythropoesis and the recovery towards a stable Hct.  A prior study revealed that when dispensed in 600 u/kg doses three times a week, to healthy volunteers, RHE can dramatically increase hematocrit levels in just a single week; much more so than the results examined in Dr. Atabek’s study.  RHE has also considerably lessened autologous blood transfusion requirements for anemic and HIV patients, as well as diabetics.

 

Iron Supplementation:

             The body’s need for iron, especially when undergoing EPO treatment, is quite substantial.  Iron is a key component in Erythropoesis and must be taken at the proper dosages in order for the patient to remain healthy; iron deficiency and iron overload are very dangerous situations.  A study done in 1999 showed that in order for iron overloaded patients to see the benefits of rHuEpo treatment, they needed to take doses twice that of what a normal patient would require (Tarng et al., 1999).  The type of iron used for supplementation is extremely important as well.  A study conducted this year examined the potential benefits and weaknesses of Venofer and Ferrlecit (two types of iron used in the supplementation of hemodialysis patients on rHuEpo).  After the completion of the six month study, it was determined that the two supplements are equally effective, however, Venofer is more practible because it is administered once per month at higher dosages; and consequently unneeded visits to the treatment center can be avoided (Kosch et al., 2001).

 

 

Erythropoesis Stimulated By Altitude Training:

             A common belief of athletes and athletic trainers is that altitude training increases Erythropoesis and hematocrit levels, thereby increasing stamina and performance.  However, a recent study has proven otherwise.  A  team of physicians, headed by Dr. JM Vallier, conducted a study in 1996 to determine what the benefits of altitude training actually are, and where they come from.  The study did not in fact take place at a high altitude, but was simulated (at 4000m) in a hypobaric chamber.  Five subjects were chosen for the experiment, every one of which was a tri-athlete on the French national team; three males and 2 females, who, on the average trained 20-30 hours per week, in 2-3 training sessions per day.  The athletes did not, however, train this vigorously in the chamber; they met three times a week for three consecutive weeks and trained at various intensities for one and a half hours in each session.  Extensive tests were performed on the athletes before, during, and after exercise; such as, VO2 Max (maximal oxygen uptake), blood tests (which examined red blood cell count, hemoglobin, reticulocytes, and EPO levels), and a continuous zirconium analyzer that monitored oxygen and CO2 levels based on infrared absorption (Vallier et al., 1996).

             Findings:  At the conclusion of the study, all data clearly showed that altitude training did not stimulate Erythropoesis, despite the fact that performance increased.  Red blood cell count was not significantly changed, nor were hemoglobin and EPO levels affected (Vallier et al., 1996).  Performance gains (which were measured at a simulated altitude of 2000m) showed an increase in the time an athlete could compete before exhaustion, by an average value of 34% (Vallier et al., 1996).  These gains, while proven in the laboratory, also held true in actual competition; all subjects participated in the European long-distance triathlon, which commenced shortly after the completion of this study, and reported shorter cycling times (Vallier et al., 1996).  Dr. Vallier noted that in previous studies, under Terrados et al. and Jansson et al., that these endurance gains could be a result of “muscle adaptation with an enhanced activity of citrate synthesis…increased capillarization and decreased enzymatic glycolytic activity,”  (Vallier et al., 1996).  Vallier also believes that a psychological aspect may play a role, especially since the athletes in this study were required to train under high levels of stress (Vallier et al., 1996).

 

 

 

 

 

Doping Spreads:

             The old saying, “It doesn’t matter if you win or lose, it’s how you play the game” has been replaced with, “Win at any, and all costs.”  And as athletics has become more and more competitive, the use of performance enhancing substances has risen to an all time high.  “Several years ago, 198 athletes were asked if they would take a performance-enhancing drug if they knew they would NOT be caught and they would win, 195 said they would take the drug.  The second question revealed a more frightening scenario.  The athletes were asked if they would take a drug that would ensure they would win every competition for five years and wouldn't get caught, but the side effects would kill them--more than HALF said they would take the drug.”  How can one draw the line between ompetitiveness and these unprecedented extremes? (http://cbshealthwatch.medscape.com/cx/viewarticle/222694_print).

 

Special Video Clip

Marco Pantani’s victory finish, and flashy trophy presentation, of the 1998 Tour de France (CNNSI).

 

Frigo Ejected:  June 6, 2001 -Italian cyclist Dario Frigo (right) was caught doping during a random police raid in San Remo between stages of the 2001 Giro d’Italia.  Director of Fassa Bortolo, Giancarlo Ferretti, immediately fired Frigo from the team after getting word of the scandal. Race director Carmine Castellano comments on Frigo’s dismissal from the tour, "I feel myself, in turn, disappointed, and made bitter. The fact is unpleasant. The worst thing is to me that Frigo seemed to be the new face, the clean face of cycling. Instead not."

 

 

The IOC Fights Back: 

             The International Olympic Committee (IOC) banned the use of EPO in 1990 for just this reason.  Several controversies in the Tour de France between 1987 and 1990 gave the IOC good reason to be very concerned about the effects of EPO on athletes.  Over the course of those three years, and 1991, eighteen Dutch and Belgian cyclists died from coronary failure, allegedly from the use of EPO http://www.maximonline.com/articles/default.asp?article_id=4163).  Despite many warnings from drug abuse organizations, the use of EPO still continued, and in fact escalated.  However, this is not surprising considering the major improvements that EPO can have on an endurance athlete’s particular event.  Studies have shown that when taken regularly, and at the proper dosage, EPO can raise stamina by 5%-15% http://cbshealthwatch.medscape.com/cx/viewarticle/222694_print).  The effects of a 15% increase in the stamina of a marathon runner would be unprecedented; it could easily mean a 15+ minute decrease in their time – feasibly making the number 20 seed in the Olympic finals, the number one seed.  "It's the way a lot of us get involved (using drugs), seeing the cheats win, knowing they got away with it," says Australian discus thrower Werner Reiterer.  Since many banned substances cannot be found in drug tests, honest athletes have started “using” to balance out the playing field.  And as long as athletes have the mind-set of “winning is everything,” it will be very hard to stop the use of banned substances in professional sports, especially if an increasing number of these new drugs are undetectable.  The structure of amino acids in synthetic EPO is identical to that of the natural EPO found in our bodies, and because of this, it was elusive to all known drug tests until just recently.  The minor differences in the sugar chains of synthetic and natural EPO has given us a way of detecting its presence (http://www.coachr.org/epo.htm).  The IOC recently approved two such tests, a French urine test and Australian blood test, which will supposedly be able to determine whether or not an athlete has been “doping” (using synthetic EPO) to up their hematocrit levels; fortunately, this approval came just in time for the Salt Lake Games in 2002.  However, according to Souillard et al. (1996), it is very important that doping tests be conducted during training or sometime before competition, but never at the time of competition, due to the fact that EPO has a very short half life and can only be detected 4-7 days after the final dose is injected. On the contrary, Audran et al. (1999) claims that if a blood sample is taken any time after doping has occurred, and the ratio between serum soluble transferrin receptors (sTfr) and serum protein is larger than 153, there is a greater than 99% chance that doping has taken place.  Perhaps all of these findings will at some point link together and form a test that will prevent future scandals caused by EPO.

            

Closing Thoughts On Doping & EPO Usage:       

             The world is full of brilliant, innovative, and most importantly curious people.  And thanks to these bright young men and women we are creating stupendous new technology that, for the most part, is making the world a better place to live in.  Unfortunately, as long as there are terrorists, corrupt people, and the like, some of these inventions will prove to be very harmful.  As the great physicist Albert Einstein once said, "I made one great mistake in my life... when I signed the letter to President Roosevelt recommending that atom bombs be made.”  Of course at the time, the United States needed a powerful weapon such as the A-bomb to achieve, ironically, world peace.  However, as these difficult times unfold before our eyes, with the collapse of the twin towers, this powerful ally of the past could very well cause a nuclear war, in which case no country would stand victorious.  And on a smaller scale EPO can somewhat relate to this; it was created to help hemophiliacs, and HIV and chemotherapy patients, but was abused by high profile athletes to dramatically improve their performance.  Granted this is not a threat to national security, but it is a trade off that biochemical engineers will have to deal with in the future.  Will the good a new drug brings far outweigh its destructive properties?  To our misfortune, there is no way of predicting what consequences may arise from such an event; as a result, society will simply have to trust our worthy physicians, and leaders in all fields for that matter, to make the decisions that best serve our interests.

 

References:

             Atabek U, Alvarez R, Pello MJ, Alexander JB, Camishion RC, Curry C, Spence RK.  Erythropoetin Accelerates Hematocrit Recovery in Post-surgical Anemia:  American Surgeon, 1995 January; Vol. 61.1, pg. 74-7.

 

             Audran M, Gareau R, Matecki S, Durand F, Chenard C, Sicart MT, Marion B, Bressolle F.  Effects of Erythropoetin Administration in Training Athletes and Possible Indirect Detection in Doping Control:  Medicine And Science In Sports And Exercise, 1999; Vol. 31.5, pg. 639-45.

 

             Bressolle F, Audran M, Gareau R, Pham TN, Gomeni R.  Comparison of a Direct and Indirect Population Pharacodynamic Model:  Application to Recombinant Human Erythropoetin in Athletes:  Journal of Pharmacokinetics and Biopharmaceutics, 1997; Vol. 25.3, pg. 263-75

 

             Kosch M, Bahner U, Bettger H, Matzkies F, Teschner M, Schaefer RM.  A Randomized, Controlled Parallel-group Trial on Efficacy and Safety of Iron Sucrose (Venofer) vs. Iron Gluconate (Ferrlecit) in Haemodialysis Patients Treated With rHuEpo:  Nephrology Dialysis Transplantation, 2001 June; Vol. 16.6, pg. 1239-44.

 

             Souillard A, Audran M, Bressolle F, Gareau R, Duvallet A, Chanal JL.  Pharmacokinetics and Pharmacodynamics of Recombinant Human Erythropoetin   in Athletes; Blood Sampling and Doping Control:  British Journal of Clinical Pharmacology, 1996; Vol. 42.3, pg. 355-64.

 

             Tarng DC, Huang TP, Chen TW, Yang WC.  Erythropoetin Hypo-responsiveness:  From Iron Deficiency to Iron Overload:  Kidney International, 1999; Vol. 55 Suppl. 69, pg. S107-18.

 

             Vallier JM, Chateau P, Guezennec CY.  Effects of Physical Training in a Hypobaric Chamber on the Physical Performance of Competitive Tri-athletes: European Journal of Applied Physiology and Occupational Physiology, 1996; Vol. 73.5, pg. 471-8.

 

 

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