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Doping Yesterday_ Today_ Tomorrow

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					            Doping
 Yesterday, Today, Tomorrow


              Roberto Verna MD, PhD
                Professor of Clinical Pathology and
Director, Clinical Research Center, “Sapienza” University of Rome
  President of the Italian Association of Clinical Pathology and
                        Molecular Medicine
                Member of the WASPaLM Bureau
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
DOPING




         Prof. Roberto Verna
What is
doping?
      Prof. Roberto Verna
   Doping according to the Italian Law
                        n°
 December 14th, 2000, n°376 (art. 1) of
                         Health:
         the Ministry of Health:
 “doping is the administration or assumption
         of drugs or biologically and
pharmacologically active substances and the
    use of medical acts without any need
justified by pathological conditions and able
to modify physical or biological conditions in
order to achieve the best performances by
                    athletes”
                the athletes”

                                 Prof. Roberto Verna
                               doop”,
The term doping comes from “doop”, a mix
of ergogenic substances that Dutch seamen
  used already four centuries ago before
           facing an ocean storm
                            Prof. Roberto Verna
       doop”
From “doop”
the term has
become
“to dope”
and finally
“doping”
that means
a substance
able to modify
the
performance

                 Prof. Roberto Verna
The term doping comes
           oop”
also from “oop”, a mix
   opium,
of opium, tobacco and
narcotics administered
to racehorses in XIXth
century.
century.




                         Prof. Roberto Verna
“Dope” is also an ancient South African term
     indicating an alcoholic drink used to
                                      dances.
  stimulate during tribal ceremonial dances.
Prof. Roberto Verna
Prof. Roberto Verna
  The use of substances prohibited for
                       drug-
    doping means being drug-addicts
• In fact, doping substances
  are often drugs such as
  Alcohol, Marijuana,
  Cocaine.
• These substances are
  always purchased and used
  secretly,
• Because who uses doping
  substances is aware of
  cheating
                               Prof. Roberto Verna
  Types of doping related to the
different moments of the agonistic
            activity I

1. Before the match, during the training, to
   try to increase muscular mass and
   physical   strength     or    resistance
  (steroids- EPO )

2. After the match, to recover strength
   rapidly.


                                 Prof. Roberto Verna
  Types of doping related to the
different moments of the agonistic
           activity II
                      to:
 3. During the match, to:

             fatigue,
  • Decrease fatigue,
  • Stimulate CNS,
           anxiety,         sports,
  • Reduce anxiety, in some sports,
    cannabinoids,      blockers, etc)
   (cannabinoids, beta blockers, etc)
  • Try to increase oxygen transport and
                   hemotransfusion)
   reduce fatigue (hemotransfusion)
                                Prof. Roberto Verna
History of
 DOPING



        Prof. Roberto Verna
  Doping is an
ancient problem



           Prof. Roberto Verna
      From the Greeks…
Doping is not a recent
discovery, but it was
already common among
antique Greek wrestlers
             b.C.)
(III century b.C.) who
       mushroom-
used a mushroom-
derived drug to enhance
their aggressiveness.


                          Prof. Roberto Verna
                                    Prof. Roberto Verna




Zeus sanctuary in Olympia




                       Callipateira of Rhodes
  …to the Romans
  During their games,
  Roman athletes
  used different
  qualities of meat
  mixed with
  stimulating
  substances
Prof. Roberto Verna
  Goat meat for the jumper
  Antelope meat for the runner
  Bull meat for the wrestler

  …with bread and wine


                      Milone di Crotone
Prof. Roberto Verna
The soldier of Marathon announces the victory, Jean-Pierre CORTOT, 1822-1834
                                                     Prof. Roberto Verna
The soldier of Marathon, Luc-Olivier Merson, 1869

                                         Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Marathon in 1907

                   Prof. Roberto Verna
                                         Prof. Roberto Verna




Leonida alle Termopili, Jacques-Louis David, 1814
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
   Emperor Teodosio
   and Holy Ambrose
     Anton van Dick, 1620




Prof. Roberto Verna
             XIXth Century
An English bicycler,
Arthur Linton, wins the
Parigi-
Parigi-Bordeaux
in 1896 dying after the
race because of the use
of exciting substances
(ether-
(ether-cocaine)
                 XXth Century




                Hicks,
In 1904 Thomas Hicks, after winning the Olympic marathon
    Athens,
 in Athens, was seriously taken ill by the use of stricnine
                 sulfate during the race
        Again XXth century




                                       arrival,
   Dorando Petri on his marathon race arrival,
               worn-
(London 1908) worn-out by fatigue ‘cause of the
         intake of stricnine with cognac
Prof. Roberto Verna
   DOPING IN
SECRET SOCIETIES




            Prof. Roberto Verna
Prof. Roberto Verna
                              Messerschmitt 110
    Stimulating
  substances were
already used during
       WWII

      Messerschmitt 109




                                  to increase the
                                 reaction rate and
                                   decrease fear

      LuftWaffe fighters flying in British skies
                                         Prof. Roberto Verna
 Behind the strategic operations and the most hazardous
  interventions the use of stimulating drugs was able to
enhance every decision and action thus making simpler the
                                die.
                      choice to die.




Soldiers landed from ships in front of Normandy shores
                   heroism,
  pushed by their heroism, but many with the aid of
                                            armies.
    chemicals used several times by various armies.
                                         Prof. Roberto Verna
          IRAQ – AFGHANISTAN
       New frontiers of Military Doping
                 DEXTROAMPHETAMINE
                 is a drug able to sponge
                       fatigue,
                  out fatigue, useful for
                     soldiers in mission

Its use has widely spread non only in infantrymen but also
        pilots,
 among pilots, with enhancement of clearness and quicker
                                        manoeuvres.
       reflexes in the most hazardous manoeuvres.




                                            Prof. Roberto Verna
   In the post war period there was a widespread use of
                                activity.
 stimulating drugs during sport activity. Heavy upset arose
 for the deaths of the cyclists Alfredo Falzini (sympamine
       steanamine)                                Milano-
   and steanamine) in ’49 at the end of the race Milano-
  Rapallo,               amphetamines)
  Rapallo, Knud Jensen (amphetamines) Oympic games ’60,
               amphetamines)
Tom Simpson (amphetamines) in ’67 Tour de France and of
                                        amphetamines)
the French soccer player Luis Quadri (amphetamines) in ‘68




                 Simpson’s
                  death on
                Mont Ventoux


                                          Prof. Roberto Verna
    The powerful Nations
For a long time the
powerful Nations used
doping as a State weapon
to sorpass enemy
countries:
countries:
During the Sixties and
the Seventies DDR,
URSS, USA pushed their
athletes to win at any
cost
                           Prof. Roberto Verna
    Former
 international
efforts against
    doping


       Prof. Roberto Verna
             Prof. Roberto Verna




First cases of
hematic doping
Ben Johnson lasts as
Olympic champion for less
than 24hs. He was
suspended for the use of
anabolyzing steroids




                        Prof. Roberto Verna

     Following the dequalification,
     the Olympic gold has been
     attributed to Carl Lewis,
     example of honesty (15 years
     of career without doping).
Olympic Games at Atlanta have
   been named “GH GAMES”


                     Prof. Roberto Verna
  SYDNEY 2000
Cathy Freeman, Australian
sprinter, reads the new
         oath:
Olympic oath:

      She promises to
      play with loyalty
      without the use of
      doping to improve
      her performance.

                Prof. Roberto Verna
Raducan,
Raducan, a Romanian
athlete awarded with
the gold medal in
gymnastics is
suspended for doping
   ephedryne,
by ephedryne, used
           flu.
to cure a flu.
Ephedryne modifies
the sense of
equilibrium and is
hazardous in
gymnastic.
gymnastic. Prof. Roberto Verna
Three Bulgarian
athletes found
positive make all
    weight-
the weight-lifters
team to be
suspended.
suspended.
     Romanians,
The Romanians, in
          condition,
the same condition,
paid a fine and
      forgiven”
were “forgiven”
         Prof. Roberto Verna
                Winter
                Olympic
                 games
• First appearance of
         (Darbopoetine),
  NESP (Darbopoetine), a
  new molecule substituting
  EPO                         Lazutina              Danilova



                 games:
• Salt Lake City games:
 Lazutina, Danilova,
 Lazutina, Danilova,
            darbopoetine)
 Muehlegg (darbopoetine)
                                         Prof. Roberto Verna
 World championship Paris 2003 – cases of doping
by Modafinil, a stimulating molecule not included in
   Modafinil,
                        substances;
 the list of prohibited substances; it was included
                 since Athens 2004




   Kelli White had to give    Calvin Harrison gold on
              medals,
  back 2 gold medals, 100 e           4x400m
            200m
                                        Prof. Roberto Verna
2003. New cases of positivity to Tetraidrogestrinone (THG)




    Regina Jacobs       Dwain Chambers       Kewin Toht
       1500m            100m European         shot put
      champion             champion
 The TGH was produced by BALCO laboratories headed
       by nutritionist Victor Conte (KMA Club)
                                          Prof. Roberto Verna
                         ATHENS 2004
                Identified a significant number of doping cases that
                have also led to the return of 7 illegally won medals



                                      Williams
   Robert Fazekas




                                                     Irina Korzhanenko


Irina Korzhanenko       Stanozololo)
                       (Stanozololo)               gold medal
Robert Fazekas                  adulteration)
                       (Control adulteration)      gold medal
Luisa Calle Williams    Eptaminolo)
                       (Eptaminolo)                bronze medal
Olena Olefirenko        Etamivan)
                       (Etamivan)                  bronze medal
                                                   Prof. Roberto Verna
                  ATHENS 2004
       Leonidas Sabanis
                            The anti-doping controls will
                            have a retroactive effect and the
                            IOC reserves until 2012 to
                            withdraw the medals won in this
                            edition of the Games
                                        Adrian Annus




Leonidas Sabanis          (Testosterone)                bronze medal
Adrian Annus              (Refusal of the controls)     gold medal
Ferenc Gyurkovics         (Stanozolol)                  silver medal

                                                       Prof. Roberto Verna
ATHENS 2004
 Paralympics
  Doping also affects the Paralympics
  in Athens: two Azerbaijani
  weightlifters were expelled from the
  Games because positive to two
  different substances. Sara Abbasov,
  28 y.o., and Gundula Ismaylov, 31
  y.o. have fallen into the clutches of
  the controls after a test conducted on
  September 18th. The two tested
  positive for nandrolone (the woman)
  and stanozolol (the man).
                        Prof. Roberto Verna
OPERATION “QUADRIFOGLIO”




      CARABINIERI FOR
       HEALTH (NAS)


                    Prof. Roberto Verna
               JUNE 6th 2001
     STARTING OF OPERATION QUADRIFOGLIO
    PERQUISITIONS AT HOTELS IN SANREMO AND
             NEIGHBOURING TOWNS

-184 soldiers involved

-507 packs of prohibited medicines seized: (stimulants,
anabolic steroids, steroids, diuretics, synthetic hemoglobin,
blood products)
Sequestration of large amounts of medical material
(syringes, needle-cannulas, etc.) and anonymous substances
for laboratory analysis

-105 people reported to the Judicial Authority
In January 2003 as part of the “Hercules” operation,
         the Guardia di Finanza of Como
         seized a huge load of human GH
        from Lithuania intended for gyms
   Imperia: thirty thousand
pills and eleven thousand vials
    seized (anabolic drugs)
February 2004
Operation
"HERCULES"
Conducted by the NAS
Carabinieri in Ancona

                        Seizure of medicines of
                        anabolic action
                        Source:
                        - Italy
                        - Greece
                        - Tunisia
                        - Spain
                        - Romania
  LIST OF THE DRUGS FOUND DURING “HERCULES”
           CONFISCATION OPERATION
ALDACTONE            LASIX                RESTANDOL
ANAPOLON TABLET      HOMEOCUR TESTERSET   SAIZEN
OKSIMETOLON          HUMOLIN              SCHERING
ANDRIOL              JINTROPIN            SYNFLEX
BENADON              KADIUR               SOMATOSTATINA
CLOMIPHENE CITRATE   KRIPTOCUR            SPASMOBRONCAL
DECA-DURABOLIN
DECA-                ISOPURAMIN           SPIROPENT
DIANABOL             LIPOSTABIL           SUSTENON
DEPO MEDROL          MASTERON             TAD 600
EFEDRINA LEVEL       METADIENON           TIOSIDE
EPARGRISEOVIT        METANABOL            TI-
                                          TI-TRE LIOTIRONINA
ESICLENE             MONORES              TESTEX ELMU
ESTRUMATE            NAPOPSIN             PROLONGATUM
EUTIROX              NEOTON               TESTOSTERONE CYPIONATE
EXTRABOLINE          NESPO 60             TESTOVIRON
FELDENE              NOVALDEXTAMOXIFEN    TESTOVIS
FINAJECT             PARABOLAN            TRANSMETIL
FINASTERIDE          PLACENTEX            VENTIPULMIN CITRATE
GANABOL              PRIMOBOLAN           VIRORMONE TESTOSTERONE
GENOTROPIN           PROFASI HP           PROPINATE
GH UMATROPE          PROCAR FINASTERIDE   WINSTROL
GLOBUREN             PROVIRON


     APPROXIMATE AMOUNT   : EURO 8.970.000,00
                                            Prof. Roberto Verna
                           drugs,
Jargon words used to order drugs, recorded during tapping
 (COMANDO CARABINIERI PER LA SANITA' - N.A.S.)


EFEDRINA             Mau-
                     Mau-Wang
WINSTROL             double U - dresses - STROMBA
GANABOL                              use)
                     (for veterinary use)
DECA                                            cap"
                     “the ones with the yellow cap" -
                     masterized
ANDRIOL              the moto
DECADURABOLIN        the cars
NANDROLONE DECAONATO lat extension
PROVIRON             trousers
OXANDROLONE          lat machine
HASHISH              smoke - chocolate
GH                             one"
                     “the cold one" – the ice – frozen proteins
                     – chewing gums
PRIMOBOLAN           P - decaffeinated
PROVIRON             PRO
TESTOVIS             “those with the blue box”
                                              Prof. Roberto Verna
        Marion
        Jones




Every Sport Authority is bound to:
• Protect athletes’ health
• Enforce medical and sports ethics
• Maintain the same opportunities for all the
  athletes during a competition
                                      Prof. Roberto Verna
      WORLD ANTIDOPING ORGANISATION

                             WADA, Governments and
                               Sport Organisations


              World Antidoping Code
           List of the Banned Drugs and
                      Methods
            Laboratory Accreditation
                 Random Controls


               Intergovernative           International   CIO Olympic
                  Institutions             federations      Games


                                                                         National
                                            National
          Governments                                                    Olympic
                                           Federations
                                                                        Committees

                                             National
Commission for the                                                      Commissions of the
                                            Antidoping
Vigilance of Doping                                                     Sport Federations
                                           Laboratories
 The “medicalness” of the
athlete and of the sportsman




                    Prof. Roberto Verna
WHY DO ATHLETES AND SPORTSMEN USE
             DRUGS?
•   To improve athletic performance
       • drugs prohibited and not for doping
       • creatine
       • linear and ramified aminoacids


•For a faster athletic recovery in case of strong
athletic involvement
       •   Ergogenic Aids

• To recover losses due to the intense physical effort
       • Vitamins
       • Mineral Salts

• To protect from oxydative damage
       • Vitamins
       • Antioxydants
                                               Prof. Roberto Verna
Drugs used by athletes and NOT
      banned for doping


• Legal drugs

• Health products (supplements)

• Herbal products

• Homeopathic preparations

                                  Prof. Roberto Verna
 Athletes subject to doping controls
  who reported taking medication



       65-          athletes)
     = 65-70% (8000 athletes)

           Types of drugs reported

Non-steroidal anti-inflammatory drugs       35%
Supplements (salt, amino acids, etc.).      20%
Vitamin supplements                         17%
Herbals / homeopathic products              1,5%

                                         Prof. Roberto Verna
For a medication, adverse effects are allowed
only if the ratio risk / benefit of the treatment
                  is favourable.

       A health benefit does NOT exist
         in a subject who is not sick




      Unreasonable risk of ADR occurrence


                                     Prof. Roberto Verna
What are the factors that
 favour the spread of
       doping?


                   Prof. Roberto Verna
          The differences in performance
           among athletes are minimal
• Fractions of seconds in speed trials
• Few seconds in endurance events

                   Consequence

        Exasperated search of the smallest
      improvement through the use of drugs
      believed to be capable of increasing the
                   performance
                                         Prof. Roberto Verna
    The obligation of results




Entire football teams are known taking energetic
        substances to complete the season
                                    Prof. Roberto Verna
The economic benefits and
reputation




                             Anna
                             Kournikova

 The sponsors pay sports champions very
well, but only as long as the champions win
                                Prof. Roberto Verna
The increase in training
loads
               In some sports the
               workload to stay at
               the top can be
               sustained only by
               resorting to drug aid
    Nadia
    Comaneci
                           Prof. Roberto Verna
                     Michael Johnson


The effect of
stress and lack of
psychological
preparation for
sport

                              Prof. Roberto Verna
The pressure of parents...

               Often parents demand from
               children a sporting career
               as champions, even
               accepting the use of doping
               to achieve their dreams




                              Prof. Roberto Verna
  ...Or their lack of interest

• OTHER TIMES THE
  YOUNG RESORT TO
  DOPING WITHOUT
  ANYONE AROUND
  HIM KNOWS IT




                        Prof. Roberto Verna
  The use of prohibited
substances is an admission
         of fear
     Jenny Gale




                  Prof. Roberto Verna
  Not to accept the
duel,      defeat,
duel, the defeat, the
        victoryProf. Roberto Verna
                                     drugs,
Cases of positivity to some “social” drugs, such as
cannabis and cocaine in the English Premier League




        Former Chelsea                 Lee Bowyer today at
    Goalkeeper Mark Bosnich          Newcastle United positive
       positive to cocaine                to Marijuhana
                        Prof. Roberto Verna
     The “medicalization” of sports
              facilities

• Some gyms are a mix
  between spatial structures
  and back-room
  pharmacies.
  You can find anything
  and almost nothing is safe



                               Prof. Roberto Verna
To combat doping it is
 necessary to know
    the effects and
  damage of banned
      substances
                Prof. Roberto Verna
        Classes of substances
    prohibited in-competition only

•   STIMULANTS
•   NARCOTICS
•   CANNABINOIDS
•   GLUCOCORTICOSTEROIDS




                           Prof. Roberto Verna
Classes of substances prohibited in
      and out of competition
 ANABOLIC AGENTS
 DIURETICS AND MASKING AGENTS
 PEPTIDE HORMONES
 BETA-2 AGONISTS
 ANTIESTROGENIC AGENTS




                                Prof. Roberto Verna
      Classes of substances
    prohibited only in certain
             sports
ALCOHOL                  BETABLOCKERS
Aeronautics
                    Aeronautics   Football
Archery
                    Archery       Gymnastics
Motoring
                    Motoring      Modern Pentathlon
Billiards
                    Billiards     Motorcycling
Bowls
                    Bobsleigh     Bowling 9 Pins
Football
                    Bowls         Sailing
Gymnastics
                    Bridge        Shooting
Karate
                    Chess         Ski
Modern Pentathlon
                    Curling       Swimming
Motorcycling
                                  Wrestling
Skating
Ski
Triathlon
Wrestling

                                    Prof. Roberto Verna
 Methods prohibited in and out competition
               ENHANCEMENT OF OXYGEN TRANSFER
   Blood doping: use of autologous, homologous or heterologous red blood cell
          products of any origin, outside of legitimate medical treatment
   Use of products that enhance the uptake, transport or delivery of oxygen (eg
        erythropoietin), hemoglobin products, including but not limited to
       hemoglobin-based blood substitutes, microencapsulated hemoglobin
             products, perfluorochemicals, and efaproxiral (RSR13)


       DRUG, CHEMICAL AND PHYSICAL HANDLING
 Is the use of substances and methods that can alter the integrity
and validity of specimens collected in doping controls (intravenous
            infusion, catheter and replacement of urine)
                           GENE DOPING
 And the non-therapeutic use of genes, genetic elements and / or cells
        that have the capacity to enhance athletic performance

                                                          Prof. Roberto Verna
It has recently been applied a mark on the packaging of pharmaceutical
        products that contain substances prohibited for DOPING:

         The mark is accompanied by the following warning:

                 “For those who play sports:
         the use of the drug without therapeutic need
                  may result in positive test”

    BE FAIR AND TAKE CARE OF YOUR
               HEALTH!



                                                   Prof. Roberto Verna
        HEMATOCHEMICAL MARKERS OF THE
       PHYSICAL CONDITION OF THE ATHLETE

                        • Evaluation of the
• Testosterone
                          agonistic stress and
• Dihydrotestosterone     involvement
• ACTH
• Cortisol
• DHEAs
• delta-4-
  androstenedione
• GH


                                    Prof. Roberto Verna
    HEMATOCHEMICAL MARKERS OF THE
   PHYSICAL CONDITION OF THE ATHLETE

• LDH               • Study of the
• CPK                 muscular
                      characteristics of an
                      athlete




                                Prof. Roberto Verna
     MOUNTAIN SPORTS


•   Complete Blood Count
•   Iron
•   Transferrin
•   Ferritin
•   Hb dissociation curve
•   Diphosphoglycerate




                            Prof. Roberto Verna
       INDICATORS OF THE USE OF PROHIBITED SUBSTANCES AND METHODS

Prohibited substances Prohibited methods
•   Stimulants
                                 • Administration of blood,
•   Narcotics                      RBCs and/or similar
•   Anabolizing Agents             products)
•   Diuretics
•   Peptide Hormones,            • Administration of
    mimicking substances           artificial oxygen
•   Local Anestetics               transporters or plasma
•   Alcohol                        substitutes
•   Cannabis sativa and
    indica
•   Glucocorticosteroids
•   Beta-blockers
                       STIMULATING AGENTS
                    Amphetamine, Ephedrine, Cocaine …

       EFFECTS                                                             ADVERSE EFFECTS

                           Reduced fatigue, euphoria   Ictus                Central Nervous System
Marked effect on                                                            Tremors, Agitation,
stimulating the central
                                                         Heatstroke         Aggressiveness
                                                                            Loss of Critical Sense
nervous system                Increased                    Excitement,
                              heart rate
                                                                            Headache
(increases the                                             restlessness,
                                                                            Insomnia
                                                            insomnia,
competitiveness of                                        aggressiveness    Vomiting, Anorexia
attention, sense of well                                                    Hyperthermia (Heat Stroke)
being, euphoria)                                           Dependence       Seizures
                                                            Addiction       Deep depression, Psychosis
Decreased fatigue
Increased heart rate                                                        Cardiovascular System
Increased blood glucose                                    Dispnea          Vasoconstriction
                                                                            Hypertension
and free fatty acids
                                                               Vomiting
                                                                            Tachycardia
Reduced sense of hunger        Stimulation
                                                                            Rhythm Disturbances
                               of energetic
(anorectic effect)             metabolism                                   Myocardial Infarction



                                                                             Prof. Roberto Verna
               STIMULANTS
               Prohibited only in competition


• Amphetamines are a class
  of stimulants used in many
  sports for their ability to
  increase alertness,
  competitiveness, reduce
  fatigue, give a sense of
  euphoria by stimulating the
  energy metabolism

                                                Prof. Roberto Verna
dental injury by ecstasy
                                      Amphetamines damage:
                                      Excitement
                                      Restlessness
                                      Insomnia
                                      Aggressiveness




Addiction
Psychosis
Convulsions
Depression
Anorexia
                Prof. Roberto Verna
Effect of ecstasy on the spider’s ability to
             weave the cloth




       baseline              after ecstasy

                                 Prof. Roberto Verna
        Side Effects




BRAIN HEMORRHAGE FROM COCAINE
                         Prof. Roberto Verna
          Stimulants – blood parameters
          ECSTASY - MDMA – Methilenedioxymethamphetamine
                                              studies in rats
  5-HIAA 5-hydroxyindoleacetic acid - a breakdown product of
  serotonin.
   5-HT
(levels lower in CSF during the intervals between administration)


  Norepinephrine
   Epinephrine
   Dopamine
Suppression of IFN gamma and IL-10 production in coltures
Neuronal toxicity of the molecule induces serotonin depletion
           Stimulants - Ephedrine
    Short-term adverse effects




Nausea, Vomiting
Increased sweating
Thirst
Restlessness, Insomnia
Tachicardy, Hypertension, Arrhythmias.


                                 Prof. Roberto Verna
                                        NARCOTICS
                    Heroin, Methadone and Morphine…

     EFFECTS                                                     ADVERSE EFFECTS

                                             Mood disorders
                         Increased

Interference in the      tolerance to                                Bronchospasm
                         pain
central nervous system                        Depression of          Depression of
                                              respiratory function
with increased                                                       respiratory function
tolerance of pain                                                    Nausea, vomiting
                                                     Nausea
                                                    Vomiting
                                                                     Constipation
                                                                     Decreased urine flow
                                                 Bronchospasm        Increased sweating
                                                                     Drooling
                                                                     Changing mood
                                                  Constipation
                                                                     Addiction




                                                                     Prof. Roberto Verna
          NARCOTICS
       Prohibited only in competition


 Are taken to reduce pain perception

          Pain is a warning sign
Its removal may lead the athlete to "overdo"




                   The risks are:
           worsening of existing injuries
            causing permanent damage.


                                        Prof. Roberto Verna
                                       NARCOTICS
                  ADVERSE EFFECTS

• Constipation;              Prohibited only in competition

• Nausea and vomiting;
• Insomnia and depression;
• Decreased ability to concentrate;
• Loss of balance and coordination;
• Addiction;
• Reduced heart rate;
• Bradypnea
                                 CANNABINOIDS
                                Hashish, Marijuhana …

      EFFECTS                                                   ADVERSE EFFECTS



Increased sense                               Reduced ability
                                               to coordinate     Anxiety
of wellbeing                                                     Euphoria
                                                                 Drowsiness
Euphoria                                         Altered
                                                perception       Apathy
It is hypothesized                                of time
                                                                 Tachycardia
                                                                 Orthostatic Hypotension
a decrease in emotional
                                                                 Dependence
tension before the race   Euphoria and                           Memory deficits
                           wellbeing
                                                                 Psychosis
                                                  Personality
                                                    changes      Schizophrenia
                                                                 Teratogenic to the foetus
                                                                 Carcinogen (because it is
                                                   Balance       smoked)
                                                   disorders



                                                                  Prof. Roberto Verna
           CANNABINOIDS
              Prohibited only in competition

Marijuana and hashish
distort perceptions and do
not allow proper risk
assessment.
The athlete perform actions
(stunts) that would not do
under normal conditions.



                                               Prof. Roberto Verna
                                     CANNABINOIDS
A decrease of emotional tension before a race is postulated.

               SPECIFIC ADVERSE EFFECTS

Increased heart rate, blood pressure;
Balance and coordination disorders;
Short-term memory loss;
Loss of concentration, hallucinations, psychosis;
Subnormal body temperature;

Abnormal spermatogenesis and ovulation.

                                            Prof. Roberto Verna
                       GLUCOCORTICOSTEROIDS
                 prohibited per oral, rectal, im. or iv. assumption
              medical certification is required for other administration

      EFFECTS                                                         ADVERSE EFFECTS
                                               Alteration of
                             Euphoria         the electrolyte
                                                  balance
Powerful anti-                                                        Alteration of
inflammatory action                          Hypertension
                                                                      Electrolyte Balance
                        Increased
Euphoria                ability to resist                             Hypertension
Increased ability to    to noxious                     Osteoporosis
                                                                      Hyperglycemia
                        stimuli
resist to noxious                                                     Hyperlipidemia
stimuli                                                               Hyperuricemia
                                                      Peptic
                                                      Ulcer           Increased Susceptibility
                                                                      to Infections
                                                                      Peptic Ulcer
                                                     Increased        Osteoporosis
                  Anti-inflammatory
                         action
                                                   Susceptibility     Insomnia
                                                    to Infections
                                                                      Cataract

                                                     Hyperglycemia

                                                                      Prof. Roberto Verna
    GLUCOCORTICOSTEROIDS
              Prohibited only in competition


• Treatment of acute
  pain
• Anti-inflammatory
• Euphorizing effect
• Reducing the
  perception of fatigue



                                               Prof. Roberto Verna
     GLUCOCORTICOSTEROIDS
                     adverse effects
                 Prohibited only in competition


•   Electrolyte Disorders
•   Heart Failure
•   Osteoporosis
•   Immunosuppression
•   Renal Failure
•   Amenorrhea


                                                  Prof. Roberto Verna
        GLUCOCORTICOIDS
   ADVERSE EFFECTS



Insomnia;
Hypertension;
Cataracts;
Diabetes Mellitus;
Osteoporosis;
Immunosuppression



                     Prof. Roberto Verna
   Tests to reveal the use Tests to reveal the use
   of Corticosteroids      of Narcotics and
                           Analgesics

 • Blood Glucose (I)       •   LH
                           •   ADH
                           •   GH
 • Blood Potassium (L)     •   Prolactin
                           •   Testosterone

 • Blood pH (I)


Prof. Roberto Verna
           ANABOLIC DRUGS
                               in-
                   Prohibited “in-out” competion
                                 Lenda Murray   Ms. Olympia
    Ronald Coleman Mr. Olympia




  Are steroid hormones (testosterone,
nandrolone and so on) that strengthen the
        muscles and reduce fat.
                                                    Prof. Roberto Verna
          ANABOLIC DRUGS
              Prohibited “in-out” competion

On the other hand,
they are carcinogenic
to the liver, addictive,
cause changes in sexual
characteristics
producing feminization
in boys and vice versa.



                                              Prof. Roberto Verna
     ANABOLIC DRUGS
         Prohibited “in-out” competion


Disciplines more exposed to their use:


                         Weightlifting
                         Shot put
                         Discus Throw
                         Bodybuilding
                         Football
                         Wrestling

                                         Prof. Roberto Verna
        ANABOLIC DRUGS
               Prohibited “in-out” competion

      Drugs often used in combination

• Human chorionic gonadotropin (HCG):

                •     the synthesis of testosterone
                    contrast to the testicular atrophy

• Diuretics:

         •      water retention
             dilute the urine for drug tests
                                               Prof. Roberto Verna
    ANABOLIC DRUGS
           Prohibited “in-out” competion

     Drugs often used in combination

  Antiestrogens:
• Antiestrogens:
      • prevent gynecomastia in males



• ACTH:
       •      endogenous steroids production
           can provoke a feeling of euphoria



                                           Prof. Roberto Verna
                               ANABOLIC AGENTS
                   Testosterone, Nandrolone, Stanzolol…

      EFFECTS                                                      Adverse effects

                                                                 In males (pre-puberal)
                                                Acne             Early epiphyseal cartilage
                               Increased                         welding (block long bone
Increased muscle mass         synthesis of
                             red blood cells    Long bone        growth)
Decreased fat mass                             growth block      Inhibition of spermatogenesis
Increased fatigue                                                In males (adults)
Decreased catabolic                                              Oligospermia / azoospermia
action of                                       Liver damage     testicular atrophy
glucocorticoids                                                  Prostatic hypertrophy
Increased synthesis of                            Impaired
                                                                 Abnormal liver function with
red blood cells
                          Increased             reproductive     the possibility of tumors
                         bone density              function      Increased plasma lipid
Increased bone
                                                                 In women
density                                                          Suppression of ovarian function
                                               Increase of       Atrophy of the mammary gland
                                               TG and Chol
                            Muscle mass                          Virilization
                              Fat mass
                                                                 Abnormal liver function with
                                                                 the possibility of tumors
                                                 Tendon injury

                                                                    Prof. Roberto Verna
           ANABOLIC DRUGS
                          in-
              Prohibited “in-out” competion

                                Ben Johnson
Testosterone increases
muscle mass and
changes the behavior
with manifestations of
irritability,
aggressiveness and
violence.

                                              Prof. Roberto Verna
  Precursors of
   nandrolone
The story of the players
Guardiola, Stam, de Boer,
Monaco, Couto, Davids,
Bucchi, (tested positive for
nandrolone for taking
supplements made ​in the
USA polluted with
precursors of nandrolone) is
well known.
                               Prof. Roberto Verna
    Other and more recent cases of
        nandrolone in soccer




                 Emanuele Blasi   Saadi Gheddafi
Mohamed Kallon


                                   Prof. Roberto Verna
   NANDROLONE LANDS IN TENNIS




          2003                             2004
Bohdan Ulirach             McEnroe admits that he
                           discovered he had taken
                           substances used in horse
                                   racing

                 Greg Rusedski in 2004, one of the 47
                 positive players among the top 120 of
                 the ATP ranking
                                      Prof. Roberto Verna
       ANABOLIC STEROIDS
                                      Jennifer
                                      Capriati




Can transform an athlete
in less than two years
                           Prof. Roberto Verna
      The use of steroid
  hormones is so effective...
                       Heidi Krieger


...that they can
transform a woman
directly into a man,
as Heidi Krieger.


                                  Prof. Roberto Verna
Heidi Krieger gold
medal in putting the
shot at European        Corriere della sera 4 maggio 2003
games in 1986 when Andreas Krieger (39)
she was 21           today with his wife Ute
                                       Winter
                 Prof. Roberto Verna
                          Anabolic Agents
                 (testosterone, nandrolone, stanzolol…)

muscle mass
body fat
stamina
aggressiveness
catabolic action of glucocorticoids
synthesis of red blood cells
bone density
            ANABOLIC AGENTS
                   Prohibited “in-out” competition

                                      Mental Damage:
                                       Dysphoria
                                       Psychosis
Long lasting use                       Dependence
                                       Severe Depression




 Liver Damage:                        Cardiovascular Damage:
  Cholestasis                          Cardiomyopathy
  Hepatitis                            Acute Myocardial Infarction
  Benign and Malignant Tumors          Cerebrovascular Accident
                                       Pulmonary Embolism


                                                     Prof. Roberto Verna
                             Anabolic Agents
Adverse effects of using anabolic agents depend on
the age and sex of the subject, the duration of
treatment, the dose and type of steroid used


Adverse effects can be divided into
• generic
• specific to men
• specific to women
                          Anabolic Agents
          General adverse effects


Acne;
Damage to the Reproductive System and Sterility;
Hypertension;
Increased Risk of Cardiovascular Disease;
Abnormalities and Renal and Liver Dysfunction;
Aggressive and Violent Behaviour;
Tendon Injury and/or Bone Microfractures
                       Anabolic Agents
    Adverse effects specific to men


Gynecomasty;
Reduced Production of Male Hormones;
Testicular Atrophy and Oligo/azoospermia;
Infertility, Impotence;
Alopecia;
Increased Risk of Prostate Cancer.
                     Anabolic Agents
 Adverse effects specific to women


Hirsutism and Hair Loss;
Menstrual Irregularities and Amenorrhea;
Atrophy of the Mammary Glands;
Voice Change;
Clitoris-megalia
                     Anabolic Agents
      General Haematochemical Alterations


Haematocrit
Platelets
Levels of FSH and LH
Testosterone levels
HDL-cholesterol and total cholesterol
Glycemia, Insulinemia
Liver enzymes and indices of cholestasis
                                           Prof. Roberto Verna
    Analytes specific for anabolyzing substances
•   FSH              ↓   •   Testosteron   ↓
•   LH               ↓   •   Estradiol     ↓
•   PT               ↓   •   Estrone       ↓
•   PTT              ↓   •   LDL Chol      ↑
•   Tot. Chol.       ↓   •   C- Prot
•   HDL Chol         ↓   •   S-Prot
•   GH                   •   D-Dimer
•   CPK              ↑   •   PAI-1
•   AST - ALT        ↑   •   ATIII
•   LDH              ↑   •   APO A             ↓
•   Total Proteins
                             MASKING AGENTS
                     Diuretics, Epitestosterone, Probenecid,
                 Plasma expanders (dextran, hydroxyethyl-starch)
                                                               ADVERSE EFFECTS
        EFFECTS
                            Alterated                            Alteration of the hydro-
                            hormonal         Alterated
                            haematological   hydro-saline        saline equilibrium
Decreased excretion of      parameters       balance             Dehydration, collapse
other prohibited                                                 muscle cramps
substances in the urine,                       Dehydration       Fatigue
                                                Collapse
masking the presence                                             Alteration of the
Alteration of the                                                metabolism of sugars
hormonal and                                         Renal
                                                     lesions     and fats
hematological                                                    Increased uric acid
parameters                                                       Formation of kidney
Removal of fluid                                                 stones, Kidney damage
resulting in loss of body   Increased
                                                                 Hypersensitivity reactions
                            urine
weight (sport weight        excretion
                                                  Muscle cramps and
category)                                         fatigue




                                                                  Prof. Roberto Verna
               MASKING AGENTS
               Prohibited “in-out” competition




They have the ability to                               Zhang Yi
• alter the excretion of
prohibited substances,
• mask their presence in urine
or other samples used in
doping control,
• or modify the hematological
parameters



                                                 Prof. Roberto Verna
             MASKING AGENTS
              Prohibited “in-out” competition

Useful to decrease weight in the orders divided
by classes
           Ivan Ivanov

                             • Dehydration
                             • Amenorrea
                             • Anemia
                             • Electrolyte
                               Dysequilibrium
                             • Osteoporosis
                             • Hypotension
                                                Prof. Roberto Verna
    Tests able to detect the use of diuretics
                          •   Uric acid
• Na
                          •   Glucose
• K
                          •   Urinary aldosterone
• Cholesterol
                          •   Na, K Pump
• Ht
                          •   Na, K Cotransport
• Plasma and
  Urine electrolytes
• 17-OH corticosteroids
• Urine pH (or blood)



Prof. Roberto Verna
       PEPTIDE HORMONES
              Prohibited “in-out” competition

• Small protein molecules
  made by
  biotechnology:
• GH
• GONADOTROPINS
• ERYTHROPOIETIN
• INSULIN


THE DARKER SAMPLE CONTAINS BLOOD SO DENSE THAT IT
DOES NOT COME DOWN ON TURNING THE TUBE UPSIDE
DOWN
                                                Prof. Roberto Verna
     PEPTIDE HORMONES
                      in-
          Prohibited “in-out” competition


GH and gonadotropins
have the same effects as
testosterone: they are
anabolizing agents but
block growth of long
bones, generate
gynecomasty, depression,
testicular atrophy and
hepatic tumors.
                                            Prof. Roberto Verna
                     PEPTIDE HORMONES
Chorionic gonadotropin (HCG) and synthetic pituitary hormone (LH)

     EFFECTS                                                   ADVERSE EFFECTS

                                         Euphoria               In pre-puberal
                                         Depression             Early epiphyseal cartilage
                                                                welding (block long bone growth)
•In males promote the                     Long bone             Inhibition of spermatogenesis
 production of                           growth block           in adulthood
 testosterone by the                                            Oligospermia / azoospermia
                                                                Testicular atrophy
 testis                                                         Prostatic hypertrophy
                                                 Liver          Abnormal liver function with the
                                                damage
                                                                possibility of tumors
                                                                Increased plasma lipid
                                                 Damage         States of euphoria and depression
                                             to reproductive    Gynecomastia
                                                 function
                    Stimulation of                              Precocious puberty in adolescents
               testosterone production

                                           Increased
                                          triglyceride
                                         and cholesterol



                                                                     Prof. Roberto Verna
                                 PEPTIDE HORMONES
                                  Corticotropin (ACTH)

      EFFECTS                                               ADVERSE EFFECTS


                                                                Hypertrophy of the adrenal
                                              Dizziness         cortex
Increases the ability to                      Euphoria
                                              Headache
                                                                Osteoporosis
withstand stress                              Insomnia          Myopathies
Anti-inflammatory                                               Damage to the gastro-
action                                          Gastritis       intestinal Peptic ulcer
                                                 Ulcer          Shiny skin
                     Increased                                  Headache
                  stress tolerance                              Reduced tolerance to
                                               Hypertrophy
                                                   of the       carbohydrates
                                               adrenal cortex   Dizziness
                                                                Euphoria, insomnia
                                                Tendency
                                                to diabetes
                                                                Obesity

                    Anti-inflammatory
                           action
                                                 Muscular and bone fragility



                                                                Prof. Roberto Verna
                       PEPTIDE HORMONES
              Growth hormone (GH) growth factor (IGF-1)

     EFFECTS                                                       ADVERSE EFFECTS


                       Increased protein
                           synthesis
                                                                      Acromegaly in adults
                                                   Cardiopathy
Increased protein                                  Hypertension
                                                                      Fluid retention and edema
synthesis                                                             (generalized and
Increased muscle                                                      peripheral)
tissue growth                                          Diabetes       Arthritis, carpal tunnel
Increased height          Stimolated bone growth                      syndrome
growth in the young                                                   Cardiomyopathy
                                                      Increased
(gigantism)                                            volume of      Hypertension
Increased lipolysis                                     organs        Hyperglycemia Diabetes
Increased blood
glucose
                                                        Muscular and joint damage

                      Increased release
                        of circulating                      Increased hands and feet size
                        energy intake


                                                                       Prof. Roberto Verna
        Tests able to detect the use of GH

•   GH                     •   IGF-1
•   LH                     •   IGF- BP2
•   FSH                    •   IGF – BP3
•   Cholesterol            •   NEFA
•   TG                     •   Insulin
•   Creatinine Clearance
•   BUN
•   Glucose


                                           Prof. Roberto Verna
       Death for doping
“Flo Jo” Griffith (1959-1998)
caught an infectious disease
because of the abuse of
growth hormone extracted
from corpses.

She said:
“when you always get second,
you can accept it or try to
become the number one”.


                                Prof. Roberto Verna
                             PEPTIDE HORMONES
                                            Insulin

     EFFECTS                                                         ADVERSE EFFECTS



                           Stimulates
•Enhances glucose       protein synthesis                             •Hypoglycemic crisis
                                                                       (Arrhythmias,
 uptake by the tissues                                Hypoglycemia
                                                                       Cardiomiopathy,
 (mainly muscle,                                                       Coma, Death)
 adipocytes and liver)
                                                                      •Inhibition of
•Stimulates protein                                                    endogenous
 synthesis                                                             production
•Hypoglycemia                                                         •Hepatic damage
 induces GH release                               Endogenous synthesis
                                                        inhibition
                      Increases tissue
                      uptake of glucose




                                                                       Prof. Roberto Verna
                                   PEPTIDE HORMONES
                                    Erythropoietin (EPO)

      EFFECTS                                                   ADVERSE EFFECTS




                                                                    • Polyglobulia
•Stimulus to
 erythropoiesis                                                     • Increase of blood viscosity
                                                    Poliglobulia    • Myocardial Infarction
•Increases oxygen                                  Thrombosis
 transport capacity                               Cardiac failure   • Thrombosis
                                                                    • Ictus
                                                                    • Pulmonary embolism
                   Stimulates
                  erythropoiesis                                    • Seizures




                                                                    Prof. Roberto Verna
Prof. Roberto Verna
       PEPTIDE HORMONES
              Prohibited “in-out” competition


EPO increases erythrocyte
production thus oxygen
transport.
On the other hand, EPO makes
blood dense like marmalade:
the risk of death by thrombosis
increases by 400%



                                                Prof. Roberto Verna
Tests revealing the use of EPO and analogues
• Peripheral blood examination
  including RBC indices
• Reticulocytes           ↑
• Transferrin
• Ferritin
• Folic Acid
• Vitamin B12
• Iron
• CD 71
• Glycophorin A
• Bilirubin
• CFU-E
• BFU-E
                                 Prof. Roberto Verna
                                       Beta 2 agonists
                         Stimulating and Anabolic Action

        EFFECTS                                                    ADVERSE EFFECTS

                          Cardiostimulating
                               action
                                                  Agitation            Tremors, Agitation,
Bronchodilation                                   Irritability
                                                  Insomnia             Irritability and Insomnia
Increasing the efficiency       Broncodilation                         Hyperhidrosis
of Myocardial Contractility
                                                                       Drooling
Lipolytic Action                                   Heart rhythm
                                                   disorders           Urinary Retention
(Increase of Free Fatty
                                                                       Anorexia
Acids)                        Lipolytic
                                action                                 Hypokalemia
Hypertrophy                                            Hyper           Alterations in Blood Pressure
of Type II Muscle Fibers                               hidrosis
                                                                       Tachycardia and
                                                                       Rhythm Disturbances
                                                                       Dyspnea
                                                   Urinary retention
                              Type II muscle
                              fiber hypertrophy




                                                                       Prof. Roberto Verna
           BETA-
           BETA-2 AGONISTS
                                in-
                    Prohibited “in-out” competion


               THESE DRUGS HAVE AN EFFECTIVE
               ACTION ON THE MUSCLE MASS WITHOUT
               DETERMINING THE MANY SIDE EFFECTS
               RELATED TO THE USE OF STEROIDS.
               They are also used to prevent asthma triggered by
               exercise
                                              Growth in mass and
                                              increased muscle strength
Clenbuterol produces a specific
protein anabolism in both normal
muscle and in the catabolic phase
through the activation of beta-2
adrenergic receptors present in
skeletal muscles themselves
                                                    Prof. Roberto Verna
         BETA-
         BETA-2 AGONISTS
                            in-
                Prohibited “in-out” competion

Therapeutic dose range:
20-80 micrograms per day

Doses in doping:
100-140 micrograms per day



      SIDE EFFECTS: Tremor (very marked), and
 cardiovascular effects such as tachycardia, palpitations,
arrhythmias, hypertension. Anxiety, dizziness, headache,
    insomnia and muscle spasms were also observed.
                                                Prof. Roberto Verna
         AGENTS WITH ANTIESTROGEN ACTIVITY
          Aromatase inhibitors, clomiphene, cyclophenil

   EFFECTS                                     ADVERSE EFFECTS



                                    Alopecia           Nausea and vomiting
Indirect                                               Headache and dizziness
anabolyzing                                            Leukopenia
                                     Liver anomalies
                                                       Thrombocytopenia
capacity       Indirect                                Severe skin reactions
              anabolyzing
                capacity                               Alopecia
                                                       Liver impairment
                                        Nausea and
                                         Vomiting




                                     Leucopenia
                                  Thrombocytopenia


                                                       Prof. Roberto Verna
            ANTIESTROGEN AGENTS
                     Prohibited in and out competition

Prohibited in and out competition,
exclusively for men

Clomiphen
Cyclophenil
Raloxifen
Tamoxifen
Toremifen
Aromatase inhibitors (Aminoglutethimide, Anastrozole, Exemestane,

Letrozole, Fludrocortisone and Desossicortone)

                                                         Prof. Roberto Verna
                               ALCOHOL

    EFFECTS                                    ADVERSE EFFECTS



                                     Depression of
                                    reflex activities
Taken in small doses
it reduces anxiety and
nervous tension                                   Depression of the
                                                  nervous system
                                                  Impaired coordination
Increased self    Reduced
                                                  Liver damage
confidence       anxiety and
                   nervous
                   tension
                                            Altered
                                          coordination




                                                         Prof. Roberto Verna
               ALCOHOL
            Prohibited in particular sports


Alcohol activates the
ventral area of the
brain and releases
dopamine by
changing all the
positive feelings

                                              Prof. Roberto Verna
              ALCOHOL
           Prohibited in particular sports


Damage from alcohol
include severe liver
disease and risk for
infants of drinker
mothers: the foetal
alcohol syndrome



                                             Prof. Roberto Verna
                                  BETABLOCKERS

      EFFECTS                                             ADVERSE EFFECTS

                                               Lightheadedness
                           Anxiety decrease

Reduction in blood                                                    Negative effect on
pressure                                       Increased fatigue      aerobic performance
Decreased heart rate                                                  Increased perceived
Reduced contractility of                                              exertion
the heart                                                             Bronchospasm in
Reduction of oxygen                                    Reduced        patients with asthma
                                                       aerobic
consumption                                          performance      Bradycardia
Reduction of tremor                                                   Hypotension
Reducing anxiety                                                      Insomnia
                      Reduced cardiovascular                          Impotence
                             activity
                                                   Possibility of
                                                   cardiac arrest
                                                   of bronchospasm
                                                   and hypoglycemia


                                                                   Prof. Roberto Verna
        BETABLOCKERS
          Prohibited in particular sports

Beta-blockers reduce tremor with great
effectiveness, and are used in shooting
competitions




                                            Prof. Roberto Verna
            BETABLOCKERS
              Prohibited in particular sports


• On the other hand, beta
  blockers may cause heart
  failure, bronchospasm
  and even death.

• Depression,
  hallucinations, seizures
  and alopecia are also
  reported
                                                Prof. Roberto Verna
    Tests to detect the use of beta-blockers
                                   Prof. Roberto Verna
•   TSH        • Insulin
•   fT3        • Renin
•   fT4        • Emogas analysis
•   HDL-Chol
•   TG
•   NEFA
•   Glucose
 SPORTS YES, DOPING NO




DOPING IN SPORT IS A CRIME
AND MAY SERIOUSLY HARM
      YOUR HEALTH
                   Prof. Roberto Verna
Prof. Roberto Verna
              Genetic Doping
                                    genome

                                                  cell

                                 chromosomes
                                          genes

                                                         genes contain
                                                         instructions for
                DNA                                      protein production




                      proteins



The proteins act alone or
in many cellular
functions in order to
explain complex




                                                          Prof. Roberto Verna
 Genetical manipulation.
Which should the limit be?




                             Prof. Roberto Verna
         Genetic Doping
• Based on the manipulation of genes.

• Using the results obtained in gene
  therapy.

• Is it a future threat for athletes?



                                    Prof. Roberto Verna
              Gene Therapy
• Artificial insertion of genes into the body of the patient.

Purpose:
• Kill or weaken cancer cells.
• Making the body able to reproduce on its own
  substances now available only on administration.

• Replace defective genes with healthy copies.
  Problems: lack of control on the expression of artificial
  gene.

                                              Prof. Roberto Verna
  The structure of a Gene
Control region
                 coding region
                                        DNA



                                        RNA




                                    Protein

                            Prof. Roberto Verna
    How is an artificial gene
         introduced ?
1. Direct injection of DNA into muscle structures

2. By inserting genetically modified cells

3. Introduction of the gene in the organism using a virus
as a vector




                                             Prof. Roberto Verna
Direct injection of DNA into a
            muscle




                       Prof. Roberto Verna
Direct injection of DNA into a
            muscle




                       Prof. Roberto Verna
   Direct injection of DNA into a
               muscle

  Quadriceps mouse
muscle after a single
injection of a plasmid
  containing a gene,
evidenced by the blue
           (lacZ)
     color (lacZ)

                         Danko et al. Human Molecular Genetics (1997) 6:1435-1443



                                                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Inserting genetically modified
             cells




                      Prof. Roberto Verna
Using a virus as a vector




                     Prof. Roberto Verna
Using a virus as a vector




                     Prof. Roberto Verna
     The prospect of gene
           doping
• An alternative to the administration of drugs
  that the body can produce itself
• Changing the natural regulation of genes
• Enhancement of proteins in the body




                                    Prof. Roberto Verna
Examples of the potential of
      gene doping
• Increase in hematocrit by EPO
• Increased muscle strength by IGF-1
• Increased muscle mass by the removal of
  myostatin
• Increased blood flow through VEGF



                                   Prof. Roberto Verna
    Gene therapy using EPO


Monkeys


                     EMATOCRITO
inoculated with a
virus carrying the
gene for EPO

                                  WEEKS AFTER INOCULATION

                     Zhou et al. Gene Therapy (1998) 5:665-670

                                             Prof. Roberto Verna
Gene therapy using IGF-I
Mice inoculated with a
virus carrying the gene
for IGF-I




                Barton-Davis et al. Proc.Natl.Acad.Sci. (1998) 95:15603-15607


                                                              Prof. Roberto Verna
   Removing the gene that controls the
   growth of muscle mass (myostatin)


Foreleg of a                                                       Foreleg of a
normal mouse                                                       mouse lacking
                                                                   the myostatin
                                                                   gene




               Lee et al. Curr. Opin. Gen. Dev. (1999) 9:604-607

                                                           Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
Prof. Roberto Verna
        VEGF gene therapy on
             humans

Blood vessels of a patient
who received the
inoculation of a virus
carrying the gene for
VEGF

                               Before                        After
                             Baumgartner et al. Circulation (1998) 97:1114-1123


                                                       Prof. Roberto Verna
            Can we discover
            genetic doping?
• The protein produced is equal to the endogenous
  protein
• The artificial DNA is present only locally after an
  injection with pure DNA or genetically modified
  cells
• You should know the sequence of artificial DNA
  to be able to detect it




                                          Prof. Roberto Verna
  POSSIBLE COUNTERMEASURES
• Making the gene doping illicit
• Establish close contacts with companies that
  produce gene therapies
• Developing DNA tests that can detect artificial
  genes used in gene therapy
• Developing indirect methods to detect gene doping,
  if possible




                                        Prof. Roberto Verna
               WHEN?
• Gene doping is already present and it
  constitutes a serious risk to the athlete

• It will be easier when gene therapy
  becomes a standard procedure
  (in 10-20 years)



                                    Prof. Roberto Verna
THANK YOU FOR YOUR
    ATTENTION
THE PROBLEM OF FOOD
    SUPPLEMENTS
The world of sport, professional or not, looks for a
"magic" and harmless ingredient that can improve
  physical performance and increase the level of
                  competitiveness


  Companies promote the spread of specialized
    products designed specifically for sports


         These substances are not always safe

                                        Prof. Roberto Verna
Recently, the European Directive on food supplements
(46/2002/EC of June 10th, 2002) has been transposed
                       in Italy

          FOOD SUPPLEMENTS

           products capable of performing


 nutritional effects      physiological effects


                                     Prof. Roberto Verna
          FOOD SUPPLEMENTS:
                    6-10-
        (46/2002/CE 6-10-2002)
         capsules, tablets, bars, vials, bags


in particular, but not limited to, vitamins, minerals,
 amino acids, fatty acids, fibers and herbal extracts




                                        Prof. Roberto Verna
       Guidelines on foods intended to meet
 intense muscular effort, especially for sportsmen


Products aimed at energy integration
Products with minerals designed to restore salt and
water losses (...)
Products for the integration of proteins
Products for the integration of amino acids and
derivatives (creatine)
Other products with nutritional value, adapted to an
intensive muscular effort
Combination of the above products
                                        Prof. Roberto Verna
VITAMINS AND MINERAL SUPPLEMENTS

Minerals replenish salt and water losses resulting from
                   physical activity


Supplementation of vitamins in the diet, in most cases, is
            incongruous and unnecessary


    Sportsmen seldom have a vitamin deficiency


    Moreover, if vitamins are “good”, it doesn’t
     mean they can’t become “bad” if abused

                                             Prof. Roberto Verna
             HERBAL PRODUCTS
     Even among sportsmen the culture of “natural
      supplement” is becoming more widespread

The erroneous belief that, being natural, must necessarily be
harmless
The effect of word of mouth propagation, especially in clubs
and gyms
Advertising campaigns not subject to controls
The wide availability on parallel sales channels (internet)



          self-medication w/out supervision
                                               Prof. Roberto Verna
Is the use of supplements “safe”?
A scientific demonstration of effectiveness
Correct information of the action on the body and
on the performance
Certainty of the content of products

           ARE MISSING


        - Health risks
        - Commercial fraud
        - Positivity to antidoping tests
                                       Prof. Roberto Verna
                   Incongruous / Hazardous
           use of supplements and health products

   Raw materials and production processes are not
                 always controlled.
Extreme vagueness in the indication of the dosages.
Belief that the dosages are not critical as for medicines.
Lack of references to age, sex, body weight, in place to
pathological situations (hypertension)


There isn’t any real assessment of the effectiveness and toxicity
                        of such products
                                                  Prof. Roberto Verna
         Incongruous / dangerous use of
        supplements and health products

  Presence of pharmacologically active
  molecules that have names quite often
               misleading:
  ma-huang, guarana, pullulan, etc. ...

 Different composition versus the one
          shown on the label
(contamination, whether deliberate or accidental)
                                    Prof. Roberto Verna
       Incongruous/hazardous use of
     supplements and health products.


          “ETERNAL LIFE” (slimming)
Dictamnus dasycarpus plant contains numerous toxins
           3 cases of liver failure, 1 death


        “JIN BU HUAN ” (sedative, analgesic)
         Lycopodium serratum plant containing
                a morphin-like alkaloid
     7 cases of hepatotoxicity and acute liver failure



                                          Prof. Roberto Verna
            Potential risk of
            positive drug test
Different composition from the one declared on
the label (contamination, whether deliberate or
accidental, with doping substances or their
precursors)
Active ingredients contained in herbal products
marked with an “unusual” name (eg, ephedrine
/ ma huang-...)
Unknown interactions with other drugs /
metabolites and / or endogenous substances
                                   Prof. Roberto Verna
Potential risks of a positive doping
        test: an example...
  Product based on a mixture of herbs, free for
sale

 Declared ingredients: Cola nut, Passiflora, Ma-
huang, Siberian Ginseng, Chinese Dandelion,
Ginger, Seaweed, Pullulan, Gymnema sylvestre

  The analysis showed the presence of ephedrine
(ephedrine, methylephedrine).
                                    Prof. Roberto Verna
Potential risks of a positive doping test:
           a further example...
  The presence of anabolic steroids was found in
       some packages of food supplements

                in individual packages, NOT all
                the capsules were contaminated
           Contaminated capsules contained steroids
        in amount ranging from 0.3 to 500 micrograms
 The contaminated products are often of U.S. production, almost
always not available over the counter, but on safe parallel channels
                       particularly Internet
                                                  Prof. Roberto Verna
    Supplements and herbal products
     should be considered as drugs?

  YES, according to WHO

 Editorial in JAMA, March 26th, 2003: supplements
should be considered in all respects and consequently
medication should be adequate evidence available on
                   their validity.



                                         Prof. Roberto Verna
It has been proposed the use of a mark
             (Green Seal?)
    to be applied to these products,
         with the indication of:
    ABSENCE OF SUBSTANCES
    PROHIBITED FOR DOPING




                             Prof. Roberto Verna
  The administration of medications,
   including supplements, to people
   without disease, as in the case of
 athletes, is always dangerous because
there is no therapeutic need, that is the
     main purpose of a medication.




                               Prof. Roberto Verna
     The excessive "medicalization",
represents a serious danger for the athlete,

NOT ONLY FOR THE POSSIBILITY OF A
  POSITIVITY TO DOPING TESTS,
           BUT ALSO

FOR THE POSSIBLE OCCURRENCE OF
              ADRs

      ADR:     Adverse Drug Reaction

                                 Prof. Roberto Verna
The ADRs in the U.S. (JAMA 1998; 279: 1200-05)
are, incidentally, the fourth leading cause of death
 after cardiovascular diseases, cancer and stroke:



          more than 100,000 deaths / year.
   The data comes from a meta-analysis of 39 prospective
              studies in hospitalized patients:

  2.216.000 patients with serious non-fatal ADRs
          106.000 patients with fatal ADRs

                                            Prof. Roberto Verna
   Doubts of Sport Medicine
Can the sports physician, motivated by the need for prevention
 (no disease) administer drugs without violating the law and
                     professional ethics?


           TUE: Therapeutical Use Exemption


The physician of professional societies should make a note of
          the use of supplements/health products



                                             Prof. Roberto Verna

				
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