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					                  Lecture 1
Drugs, Ethics and Medicolegal Issues in Sport

           Professor Bruce Lynn
   MSc School of Human Health and Performance
The basic idea
To raise the oxygen carrying capacity of the blood and so
improve performance in events involving aerobic exercise, i.e.
any events lasting more than 1-2 minutes.

This can be done by increasing the haemoglobin (Hb) content in
the blood

•By legal means (altitude training) or

•By illegal means
   •blood doping or “boosting”
   •use of the hormone erythropoietin.
Some facts and figures
We have 3.1013 red blood cells, containing a total of 900g of
haemoglobin. Red cells last on average 120 days, so we need to replace
1/120 every day, i.e. 2.5.1011 cells, or 3 million every second! This
massive production of red cells takes place in the bone marrow.

             Normal ranges of Hb and haematocrit.

                                 Men            Women

              Hb, g/dl           14-16          12.5-15

              Haematocrit        42-50%         38-47%


 Definitions:
 Hb: Amount of this oxygen-carrying protein within red blood cells. Units
 g/decilitre blood (decilitre = 100ml).
 Hematocrit: Proportion of red blood cells to the total blood volume
 (= packed cell volume or PCV).
Blood doping

The direct method of increasing blood haemoglobin content.

Blood, or more usually concentrated red cells, are transfused via an
intravenous catheter.

If blood cells from a donor are used this is heterologous transfusion.

Alternatively the athletes own blood can be collected, stored, then
transfused back – this is autologous transfusion.

Either way careful storage of red cells is necessary.
Blood doping

Blood doping (or boosting) definitely works although estimates of the
extent of improvements in performance vary.

A recent review concludes that endurance performance is typically
improved by 2-3% (Gledhill et al,1999) but other studies have shown
maximal oxygen uptake (V02max) up by 13% (Robinson et al, 1982).

But remember, even a 2% improvement is massive in competitive
endurance events such as athletics. Over 10,000 meters this represents
200 meters, i.e. winning by half a lap!
Blood doping
There are a number of difficulties.
Heterologous transfusion
•   Great care needs to be taken over tissue matching.
•   There is the risk of getting a blood-borne infection such as AIDS or
    hepatitis.

Autologous transfusion
•   Means long periods out of competition as it takes 4-6 weeks to
    recover from a blood donor session (but see later for a possible fix).

For both methods the effects begin to wane within 3-4 weeks, so then
    need a repeat transfusion.

Nevertheless there have been plenty of rumours. It would not be
   surprising if rumours of blood boosting occurred as a significant
   number of people need to be involved in the process of taking blood,
   storing it, re-infusing it and checking haematocrits.
From the BBC Sport web site, 24 November 2006

 Hamilton to ride for Tinkoff team
 Cyclist Tyler Hamilton, whose two-year
 suspension for blood doping ended in
 September, has signed for Italian-based
 Russian team Tinkoff.
                                                        Hamilton was sacked
  The 35-year-old tested positive for a blood           by Phonak after his
  transfusion at the 2004 Tour of Spain, weeks after    positive test
  winning Olympic individual time trial gold.

  Hamilton was allowed to keep his title because his
  B test was destroyed by being deep-frozen.

  "I'm ready to make a comeback," he told the All
  Sport news agency.

  2007 update. Tyler has cycled hardly at all in 2007
  and is now beimg connected to Operacion
  Puerta…see next slide
Operaćion Puerta
May 2006. Police raids in Madrid and Zaragosa as part of
Operation Puerta OP).
Found lots of steroids – but also transfusion gear and 100
packets of blood in clinic of Dr Eufemianos Fuertes.
Possibly the better testing for EPO is driving people back
to transfusions.
Can overcome one of the drawbacks of donating your own
blood for later use by using EPO to speed the recovery to
normal levels apparently the Fuertes method.
OP blood packets were labelled with pseudonyms, but a
number of top cyclists were easily identified.
Operaćion Puerta, cont
The authorities are now trying to match blood from bags to
cyclists through DNA testing.
No cyclists have been successfully prosecuted! But several
who initially protested innocence have confessed (e.g. Ivan
Basso – says he went to Fuertes but never actually used the
blood….).
I think the main case against Dr Fuertes has still to go to
court – at which point we can expect a lot of finger
pointing!
But already the authorities have all the Swiss bank account
details which must make interesting reading.
Blood doping – testing
Heterologous transfusions
The current test looks for 15 different minor antigens and can detect the
    presence of just one unit (about 500 millilitres) of transfused blood

Autologous tranfusions
No current test. But could look for low levels of EPO as neg feedback
    will reduce EPO synthesis following a tranfusion
Or can look for unusual RBC:reticulocyte ratio as again transfusion will
    reduce natural production and so reduce reticulocyte count
Erythropoietin (EPO)

EPO is a hormone that is released from the kidney in response to
tissue hypoxia and travels to the bone marrow.
Erythropoietin is a large peptide (or small protein) comprising 165 amino acids
with a large number of attached carbohydrate residues (it is 30% glycosylated).
Action of EPO

In the bone marrow it stimulates production of pronormoblasts
(immediate red blood cell (erythrocyte) precursors) from CFU-E cells
(committed unipotential colony-forming unit - erythroid).

Pronormoblasts in turn develop into normoblasts.

The normoblasts start to lose their nucleus and become reticulocytes.

The retuculocytes enter the blood system and finally develop into red
blood cells with no nuclear material visible at all.
Recombinant human EPO is used to treat anaemia associated with kidney
failure, e.g. for those on dialysis, and so is widely available, although
pretty expensive.

                                                Mean (±SD) level of
                                                hematocrit (upper panel) and
                                                hemoglobin (lower panel) for
                                                the rhEPO treated subjects
                                                (filled symbols, N = 10) and
                                                control subjects (open
                                                symbols, N = 10) for the
                                                treatment (days 1–30) and
                                                posttreatment period (days
                                                P1–P28). Dashed lines show
                                                prerace limits of the
                                                International Cycling Union
                                                (ICU) for hematocrit
                                                (hematocrit = 50%) and of the
                                                International Skiing
                                                Federation (FIS) for
                                                hemoglobin (hemoglobin =
                                                18.5 g·L-1).
  EPO induced increases in blood Hb appear, like blood doping, to
  increase performance in endurance events (Birkeland et al, 2000).




Mean (±SD) level of maximal oxygen uptake (bars) and time to exhaustion (circles) for
the rhEPO-treated subjects (hatched/filled symbols, N = 10) and control subjects (open
symbols, N = 10) before treatment (day 0) and in the posttreatment period (days P1–
P28).
It is important not to get Hb too high.

Blood viscosity increases with effects on heamodynamics that mean
harder work for the heart, and so an increased risk of heart problems.

Pathologically elevated red cell counts also lead to a higher risk of
clots.

But many people who live at altitude have elevated Hb without any
circulatory or cardiac problems - but maybe have made compensating
adaptations.

A spate of unexplained sudden deaths in cyclists in late 1980s was
attributed to arrival of EPO on the scene. There have also been
problems with side effects in some long- term dialysis patients.
Limiting haematocrit

Some sports (e.g. cycling for a while) set upper limits on haematocrit
(50% for male competitors)

Justified as a ban to competing on health grounds (i.e. risks due to
increased blood viscosity). High haematocrit was not a doping offense.

But 1% of normal population (and 20% of native highlanders) have
haematocrits at or above this level.

It is also claimed that haematocrit tests are subverted by masking with
plasma expanders. If you expand the plasma volume, then the
proportion of red cells (the haematocrit) will fall, even though the total
number of red cells is still much elevated.

Measuring total blood volume is not an easy thing to do, so expanding
plasma volume is a straightforward way to avoid detection in a
heamatocrit test.
Plasma expanders

Cyclists apparently get by the haematocrit test by having saline infusions
shortly before being tested at the start of events. The short term boost to
blood volume may even also aid performance!

Others use high molecular weight expanders.

But these are easily detected over a long period, as almost the entire
Finnish cross-country ski-ing team found to their cost at the world
championships in 2001! (Seiler, 2001)
Detecting EPO use.
It is possible to distinguish recombinant EPO from endogenous EPO, and
this can even be done in urine samples. Unfortunately, EPO has a short
life in the body and is only detectable for 1-2 days. As blood cells last 120
days, single tests at the time of competition are useless.




                                                 Mean (±SD) level of serum EPO
                                                 for the rhEPO-treated subjects
                                                 (filled symbols, N = 10) before
                                                 treatment (day 0) and
                                                 posttreatment period (days P1–
                                                 P28), as well as the baseline
                                                 value for the control subjects
                                                 (open symbols, N = 10).
Detecting EPO use.

In practice, the boost from EPO does not last 120 days.
As can be seen from the earlier figure, it is well down by 20 days
(presumably why the Festina cycling team was toting EPO around in
the 1998 Tour de France, an event that lasts 3 weeks).

And urine testing gets more sensitive all the time.

There is also a blood test that looks at the proportion of immature red
cells that has the ability to detect EPO use up to 14 days after stopping
injections.

So the window of opportunity is narrowing
Urine testing for EPO

Anti-doping urine analysis
demo-nstrating the presence
of recom-binant human
erythropoietin (rHuEPO) in
urine (see lane 4). Lane 1:
rHuEPO standard;
2: positive urine (control);
3: negative urine (control);
4: sample declared positive;
5: darbepoetin alfa (Aranesp
standard).

 Test based on isoelectric focusing patterning and a double
 blotting protocol. Works because the exogenous isoforms of
 rHuEPO are less acidic than the endogenous EPO
 Lasne F, de Ceaurriz J. Nature (2000); 405:635.
NESP

Interestingly, a longer lasting version of EPO is now available for
clinical use, darbepoetin or Aranesp (nesp in the peleton!).

This is effective for longer, so patients (or athletes) need fewer
injections and this is more convenient and cheaper.

It does make it easier to detect, however, and this version of EPO
was in fact successfully detected in competitors in the 2002 Winter
Olympics.

DYNEPO

New kid on the block. rHuEPO made in a human cell line. Has
sialate etc residue profile very similar to natural human EPO.

French anti-doping lab claims it can detect it, and found it in samples
from 10 riders in the 2007 Tour de France. But test not yet approved
by WADA, so these do not count as “positives”
Iron metabolism, ferritin, transferrin

It is also possible to look at iron metabolism.
Hb contains iron and the body has well developed transport and
storage systems for iron so that enough is available to produce the
red cells we need.
If EPO stimulates red cell production then the levels of the iron
storage protein ferritin fall.
At same time the levels of soluble transferrin receptor (needed to get
iron into developing red cells) rise in response to the increased
demand.
So by looking at the ferritin:transferrin ratio you get quite a good
indication of red cell production rates.
Unfortunately you can mask these changes by increasing iron and
folic acid intake in diet.
It may be possible to track transferrin receptor mRNA levels - these
rise up to 40 times with EPO use, but no-one has a test based on this
yet.
Mean (±SD) level of soluble transferrin
receptor concentration (sTfR; upper panel),
ferritin concentration (middle panel), and
sTfR/ferritin ratio (x100; lower panel) for
the rhEPO treated subjects (filled symbols,
N=10) and control subjects (open symbols,
N=10) for the treatment (days 1–30) and
posttreatment period (days P1-P28).
Dashed line in upper panel shows the
mean +2 SD (95% CI) for all subjects at
baseline (= 4.6 mg/L).
With better testing, the problem of EPO abuse may now wane.

Given the dynamics (about 30 days useful boost, but possible
detection up to 14 days), a strategy of random tests in the run up to
major competitions looks like the way to go.

It will be interesting to see how many sports in how many countries
develop such a programme!

In the UK most Olympic sports now have at least some out-of-
competition testing.

Cycling, after the fiasco of last years Tour de France and the loss of
major sponsors, is also getting out-of-competitions testing
organised.

And some team managers claim they are going to test their own
riders.
Time line of EPO abuse
1984 rh-EPO licensed
1988 EPO abuse reported
1998 Festina team car full of EPO in tour de France
2000 First reliable test for EPO
     Chinese rowers withdraw from Sydney Olympics
     No confirmed EPO +ves at Sydney
2001 Yegereva tests +ve, gets off on technicality, goes on to win world 5000m
2002 Winter Olympics. 3 cross-country skiers banned for Darbepoetin use.
2003 David Miller, darling of British cycling, caught using EPO
2007 Iban Mayo banned from Tour de France for EPO +ve
Other actions of EPO

EPO is actually a cytokine, and like many cytokine-like hormones,
is turning out to have many actions

They mostly involve hypoxia or ischaemia

For example the respiratory response to hypoxia is boosted by
EPO, partly by an action on chemoreception in the carotid body.

EPO is also produced in the brain and affects hypoxic responses
centrally. (Note EPO does not cross the blood-brain barrier)

Finally, EPO is tissue protective against stroke and cardiac infarct!
Altitude acclimatisation

Living at altitudes above about 2000m leads to enough tissue anoxia to
stimulate EPO release and red cell production.

For example, a group who spent 30 days at the top of Pikes Peak
(4300m) in Colorado had average increases in Hb from 13.7 on arrival to
16.2 at departure, with parallel increases in haematocrit (from 43-48%).

These are similar to the increases seen with blood doping or EPO use.
Altitude acclimatisation
However, on return to sea level, little if any increase in endurance
performance is found.
The reasons are complex.
Firstly, it is not possible to train at maximum intensity at altitude just
because the atmospheric oxygen level is lower.
Secondly, the adjustments of the circulation to altitude involve more than
just an increased Hb. Hyperventilation, a normal response to the
lowered oxygen level, leads to increased carbon dioxide excretion and
eventually to a reduction in the buffering power of the blood. This may
reduce performance levels as lactic acid produced during high intensity
exercise will not be so well neutralised. There may also be reductions in
blood volume and shifts in the Hb dissociation curve, changes that may
impair performance.
Note, however, that for competitions held at altitude, suitable
acclimatisation is essential.
Live high, train low
To get round some of these problems you live and sleep up the
mountain, but travel down to sea level to train.
This option is now available to those of us who do not live conveniently
close to a suitable mountain – the nitrogen tent or house. Athletes live
in nitrogen tents with the oxygen level reduced to 15-16% (equivalent
to being at 2500m altitude).
These strategies allow you to train in the normal way, but should
provoke a useful boost in blood Hb due to the time spent at simulated
altitude.
There will still be problems with other, disadvantageous, circulatory
adaptations.
Data on the efficacy of this approach are not very extensive.
Preliminary results from the nitrogen house set up by the Australian
Institute of Sport have stimulated interest. They found no increase in
Hb, but claimed there were small increases (<1%) in performance
levels (Hahn & Gore, 2001).
The coaches and athletes certainly
believe altitude training important

Here is Steve Cram writing in the Guardian
Tuesday October 2, 2007, after the Great
North Run this year:
                                                         Kara Goucher,
“For most this still means training in the
mountains but increasingly it involves
                                                         coached by Salazar,
hypoxic tents, where the pressure can be                 beating Paula
adjusted to mimic any altitude and it is                 Radcliffe. 2007 Great
where many sleeping hours are spent.                     North Run
Salazar likes to combine the two. In
preparation for the world championships in
Osaka his group trained at Park City in
Utah at 7,000-8,000ft. In addition he
advises sleeping in the tents at a setting of
anything up to 13,000ft. “
http://sport.guardian.co.uk/athletics/comment/0,,21816
91,00.html
Nitrogen tent




      http://altitudetraining.com/wrap/images/four30_large
Percent change in 5000-m time from baseline performance (at 6 weeks)
in three training groups.




Recalculated and redrawn from data of Levine & Stray-Gundersen, 1997.
The bar labeled likely range of true change is our estimate of the 95%
confidence interval for points other than the baseline.

                http://www.sportsci.org/traintech/altitude/wgh.html
Summary – Blood doping, erythropoietin and
  altitude training
•   Increasing blood haemoglobin levels to the very top
    end of the normal range increases aerobic exercise
    capacity significantly.
•   Such effects are obtained with direct blood transfusions
    or with EPO injections.
•   Both procedures are banned. The current tests look
    adequate to eliminate EPO abuse if applied out of
    competition.
•   Altitude (real or simulated) acclimatization is not the
    same as blood boosting. The overall changes to blood
    and circulation are more complex, and deliver smaller,
    if any, advantages in terms of sea level performance.
References
Overviews
Drugs in sport – blood doping, erythropoeitin and altitude training. A. Narvani et al, Key
Topics in Sports Medicine, pp78-82, 2006.
Blood boosting and sport. Armstrong, DJ. and Reilly, T. Chapt 7 in Drugs in sport, 3rd edn, ed
DR Mottram, 2003.
Papers cited
Birkeland, KI, Stray-Gundersen, J et al (2000) Effect of rhEPO administration on serum
levels of sTfR and cycling performance. Med-Sci-Sports-Exerc. 32(7): 1238-43
Gore, C. J., et al. (2003). Second-generation blood tests to detect erythropoietin abuse by
athletes. Haematologica 88, 333-344.
Gledhill, N, Warburton, D and Jamnik, V. (1999) Can J Appl Physiol, 24, 54-65
Hahn, A. G. & Gore, C. J. (2001). The effect of altitude on cycling performance: a challenge
to traditional concepts. Sports Med. 31, 533-557.
Levine, B.D., & Stray-Gundersen, J. (1997). "Living high-training low": effect of moderate-
altitude acclimatization with low-altitude training on performance. Journal of Applied
Physiology, 83, 102-112.
Robinson, RJ et al, (1982) The effect of induced erythrocythemia on hypoxia tolerance during
exercise. J Appl Physiol. 53, 490.
N Robinson, S Giraud, C Saudan, N Baume, L Avois, P Mangin, M Saugy, Erythropoietin and
blood doping, Br J Sports Med 2006;40(Suppl I):i30–i34.
Seiler, S (2001) Doping Disaster for Finnish Ski Team: a Turning Point for Drug Testing?
Sportscience 5(1), sportsci.org/jour/0101/ss.html
      Stray-Gundersen J, Videman T, Penttilä I, Lereim I., Abnormal hematologic profiles in
      elite cross-country skiers: blood doping or? Clin J Sport Med. 2003 May;13(3):132-
      7.Links

				
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