Impotentie brengt een constant ongemak met zich mee, net als fysieke en psychologische problemen in uw leven cialis kopen terwijl generieke medicijnen al bewezen en geperfectioneerd zijn
Clenbuterol and the horse
Clenbuterol and the Horse
N. Edward Robinson, B.Vet.Med, PhD, MRCVS
Clenbuterol is a ␤ -agonist bronchodilator and mucokinetic drug. When administered at the recom-
mended dose of 0.8 g/kg q 12 h, it reaches plasma levels that should relax airway smooth muscle.
However, the measurable degree of bronchodilation achieved may not always be clinically obviouseven in horses with heaves.
After a ten-day treatment (0.8 g/kg q 12 h), the half-life of elimination
from plasma is about ten hours and plasma levels are below the pharmacological threshold withinthree days.
Urinary elimination is prolonged and irregular so that control of clenbuterol usage in
racehorses should be based on blood rather than urine levels.
Animal Clinical Sciences, Michigan State University, East Lansing, MI 48824-1314.
leased from sympathetic nerves and the adrenal
In May 1998, the U.S. Food and Drug Administra-
The catecholamines activate several types
tion (FDA) approved the use of Ventipulmin (clen-
of adrenoceptors (␣ , ␣ , ␤ , ␤ , and ␤ ) so that heart
buterol HCl) syrup for the management of horses
rate and contractility increase, blood flow increases
affected with airway obstruction, such as occurs in
to the muscles and is reduced to splanchnic organs,
chronic obstructive pulmonary disease (COPD).
glycogenolysis and lipolysis increase, the pupils di-
In other parts of the world, Ventipulmin had been
late, gastrointestinal motility is decreased, and the
available for many years but, because it was not
available in the U.S., it was frequently used illicitly.
iological actions evoked by activation of specific ad-
As with most things forbidden, a mythology devel-
oped around Ventipulmin and its active ingredient
companies have been able to develop specific drugs
that activate (agonists) or block (antagonists) spe-
what is known about clenbuterol so that practicing
veterinarians and racing regulators can make in-
Clenbuterol is one of a large group of compounds
The active ingredient in Ventipulmin syrup is clen-
that are selective ␤ -adrenergic agonists. Other
drugs in this class include albuterol (salbutamol),
Commissioners International (ARCI) classifies clen-buterol as a Class 3 agent. Identification of clenbuterol
in post-race samples can therefore lead to sanctions.
␤ -adrenoceptor activity is expressed by their ␤ /␤
The ␤ /␤ ratio for clenbuterol is 4.0, the
What is Clenbuterol?
same as that for albuterol but less than pirbuterol,
During the “flight and fright” reaction, catechol-
amines (epinephrine and norepinephrine) are re-
selectivity, clenbuterol at low doses preferentially
activates ␤ -adrenoceptors but at higher doses it
In normal horses, a single intravenous bolus of
begins to activate ␤ -adrenoceptors.
clenbuterol (0.8 g/kg) decreased the pulmonary re-
Clenbuterol is more lipid soluble than other ␤ -
sistance from 0.38 to 0.25 cm H O/l/s within ten
agonists such as albuterol and this endows it with
This very small decrease persisted for at
buterol has been shown to decrease the pulmonary
oral bioavailability of clenbuterol is 80 –90% and
resistance and work of breathing,5 decrease the
change in pleural pressure,6 and improve clinical
brain barrier better than less lipid soluble ␤ -ago-
buterol in the airways is not limited to bronchodila-
also results in accumulation of clenbuterol in tissues
Clenbuterol increases ciliary beat frequency
with a high lipid content such as fat depots and
and therefore improves airway mucociliary clear-
ance rate in horses with and without COPD.8
In the cardiovascular system, administration of a
bolus of clenbuterol (0.8 mg/kg, IV) to normal horses
The most important action of clenbuterol and other
is followed almost immediately by a decrease in
␤ -agonists in the lung is relaxation of airway blood pressure. The blood pressure decrease is fol-
lowed by a reflex increase in heart rate and pulmo-
widely used for relief of bronchospasm in human
asthma and similar diseases in animals.
these drugs bind to ␤ -adrenoceptors, they activate
temic blood pressure is due to vasodilator effects of
adenylyl cyclase, which leads to an increase in the
intracellular concentration of the second messenger
also been demonstrated in the bronchial circulation,
cyclic adenosine monophosphate (cAMP) and activa-
chial tree and in the uterus, ␤ -agonists, cAMP, and
crease release of mediators from mast cells and in-
PKA inhibit smooth muscle contraction by opening
hibit the increase in vascular permeability that
Kϩ channels and by down-regulation of myosin light
have been demonstrated when clenbuterol is admin-
The pharmacological activity of clenbuterol on
istered to rats10 but the clinical significance of such
equine airway smooth muscle has been defined in
Injectable clenbuterol is used in obstetrical prac-
the maximal effect is known as the EC .
tice to prevent uterine contraction in cattle.
for clenbuterol has been reported as 2.1 nM (95%
relaxing uterine muscle, clenbuterol can be used to
confidence interval, 0.9 – 6.8 nM)2 and 5.7 nM.1
delay the onset of labor or to facilitate uterine repair
These concentrations correspond well with the
plasma concentrations (1.6 –2.7 nM) obtained during
The ␤ -agonists facilitate lipolysis and increase
twice-daily oral treatment with 0.8 g/kg of clen-
In vitro, 0.1 nM is the lowest concentra-
tion at which clenbuterol has a measurable effect
tioning agents are fed to growing animals, they fa-
on airway smooth muscle and maximal effect is
vor the formation of muscle over deposition of fat.
Feeding clenbuterol to cattle, sheep, pigs, and poul-
In vivo, the bronchodilator effect of clenbuterol
try results in a carcass that has less fat and more
has been demonstrated by measurements of lung
The doses used for repartitioning are ei-
function and by clinical observations of the effort of
ther much larger than those used for bronchodila-
tion or the treatment periods are long.
ments of lung function are pulmonary resistance,
example, the dose used for repartitioning in steers
dynamic compliance, and change in pleural pres-
was 30 g/kg for 98 days.11 In young growing fe-
male rats, 10 g/kg/day for 15 days increased muscle
degree of obstruction of the air passages and ranges
mass, whereas in male rats, 200 g/kg/day increased
in value from as low as 0.25 cm H O/l/s in a normal
the rate of protein accretion within 4 days.12
horse up to more than 3.0 cm H O/l/s in a horse with
is no published information on the repartitioning
function of peripheral airways and ranges in valuefrom as high as 2.0 l/cm H O in normal horses down
Therapeutic Uses and Effectiveness
In horses, the primary therapeutic use of clenbuterol
pleural pressure indicates how much effort the horse
COPD, is a disease in which bronchospasm is a
a change in pleural pressure of around 10 cm H O
during each breath while heavey horses may de-
ness of clenbuterol has therefore been tested most
velop a pressure of more than 75 cm H O.
administered clenbuterol IV to horses with airway
disease and obtained a decrease in the work of
clenbuterol may provide relief in horses that have
inhaled smoke, have nonspecific airway inflamma-
clenbuterol (0.8 mg/kg, IV) to horses affected with
tion, or are recovering from pneumonia.
COPD and measured the change in pleural pressure
It is important to realize that bronchodilator
creased pleural pressure change (a measure of the
severity of airway obstruction) from 35.5 to 25.2 cm
of the dust load to which the horse is exposed15 in
H O (SEM ϭ 2.9). In practical terms, these horses
combination with use of a potent corticosteroid such
would have moderate signs of heaves before treat-
After treatment, their signs would be some-
A large clinical trial of clenbuterol syrup was con-
ducted in COPD-affected horses by Erichsen et al.7
Ventipulmin syrup is the only form of clenbuterol
These investigators used a score based on clinical
available for horses in the United States and is the
signs of respiratory distress, and administered in-
first ␤ -agonist approved for use in the horse in that
cremental oral doses of clenbuterol from 0.8 to 3.2
g/kg q 12 h. Twenty-five percent of horses re- America, Ventipulmin has been available in many
sponded to the lowest dose and, overall, 75% of 239
horses improved with one of the incremental doses.
Ventipulmin is administered at a dose of 0.8 g/kg q
Improvements persisted throughout the 30-day
It is used as an adjunct to other treatments
In contrast to these observations of the effi-
that will reduce airway inflammation, for example,
cacy of clenbuterol, Traub-Dargatz et al.13 were un-
corticosteroid administration or antigen avoidance
able to show any clinical benefit of the drug (0.4
mg/horse q 12 h) in COPD-affected animals.
States, the FDA required proof of efficacy in the
worth noting that in none of the trials of clenbuterol
efficacy were the investigators blinded as to treat-ment and only in the study of Erichsen et al.7 was
this required a dose greater than 0.8 g/kg.7 Hence
there any attempt to determine a dose response to
the label for Ventipulmin in the USA recommends a
The varying observations about the efficacy of
Even though Ventipulmin syrup can be adminis-
clenbuterol in horses with COPD can be understood
tered at up to 3.2 g/kg, this dose must be ap-
if one considers a) the relationship between lung
function and clinical signs, and b) the pharmacology
will result in side effects of sweating, trembling,
vere airway obstruction, measurable improvements
proached gradually as recommended on the label,
in lung function can occur without a noticeable clin-
tolerance to side effects will develop.
The label states that Ventipulmin syrup is indi-
istered intravenously and its effect was measured
cated for management of horses with airway ob-
shortly thereafter, i.e., when plasma concentrations
were high, the improvement in lung function was
restricted to horses with heaves, but the drug can be
used in any animal in which the veterinarian judges
sure after treatment (25.2 cm H O) would still be
there is airway obstruction as a result of inflamma-
sufficient to be associated with signs of airway ob-
tion, bronchospasm, and mucus accumulation.
flammatory airway disease of racehorses in training
peak concentrations of clenbuterol than is intra-
Untoward effects of Ventipulmin are like those of
therefore expect a lesser improvement in lung func-
other ␤ -agonists. These agents are only selective
tion and even more difficulty in detecting this by
for ␤ -adrenoceptors but, when used in high enough
doses, will activate ␤ -adrenoceptors. Activation of
Traub-Dargatz et al.13 and the need for incremental
doses to obtain a definitive clinical effect.7
-adrenoceptors causes tachycardia, excitement,
There is no doubt that clenbuterol is a bronchodi-
lator and mucokinetic drug, is absorbed from the
agonist overdose, it should be left in a quiet stall
intestinal tract, and achieves blood concentrations3
until signs pass, generally in one to two hours.
in a range that can relax airway smooth muscle.1,2
Subsequent doses should be decreased.
It is therefore logical to use clenbuterol for relief of
the potential tachycardia, Ventipulmin syrup is not
airway obstruction due to bronchospasm and mucus
recommended for use in horses with cardiac disease.
Ventipulmin syrup should not be used in near-term
mares because it prevents uterine contraction and
can occur to varying degrees whenever the airways
Effects of Clenbuterol on Performance
Clearly, the plasma concentration of drug is below
Because it is a bronchodilator and a repartitioning
this level by 72 h after the end of a 10-day oral
agent, there has been great concern about clen-
buterol’s ability to enhance performance.
conclude that clenbuterol has no pharmacological
amount of bronchodilation that occurs in normal
effect on ␤ -adrenoceptors at this time and therefore
the withdrawal time of 72 h used in Canada and
measurable dilation of the airways induced by a
several states has a sound scientific basis.
␤ -agonist is not associated with an improvement
The problem with the regulation of clenbuterol
arises solely from the use of very sensitive detection
horses 30 min before exercising on a treadmill does
ministration, clenbuterol can be detected in urine
not improve oxygen consumption or cardiovascu-
detection, positive urine samples can occur for 13
would be lower, it is even less likely that oral ad-
days21 or longera and horses can shift from negative
ministration would have any effect on oxygen con-
to positive and back again during this period.
such problem occurs with the use of blood samples.
found no effect of 10-day oral treatment with clen-
Intratracheal Injection of Clenbuterol
buterol on lactate accumulation of oxygen tension inStandardbred horses exercising on a treadmill.
The sensitivity of urine tests for clenbuterol was
As stated above, there are no data on the reparti-
increased in part because of anecdotal reports that
tioning effect of clenbuterol in horses.
clenbuterol was being injected directly into the tra-
repartitioning occurred at the therapeutic dose,
We recently studied the effect of such an
there is no evidence that the increased muscle mass
is associated with increased ability to exercise.
the effect of 90 g of clenbuterol or an equivalent
Indeed, in mice treated with clenbuterol, measures
volume of saline injected into the trachea of heaves-
of performance were reduced even though muscle
after the intratracheal injections but there was nodifference between the saline or clenbuterol injec-
Elimination of Clenbuterol from Plasma
Two and four hours after injections, lung
function tended to be worse rather than better after
During twice-daily oral administration of 0.8 g/kg
clenbuterol, plasma concentrations average 350
were unable to demonstrate any effect of intratra-
pg/ml and may reach 750 pg/ml (mean Ϯ 2 SD).
cheal injection on either heart rate or excitement.22
When administration ceases, clenbuterol is cleared
It thus appears that the concern over the effects of
from blood with a half-life of 10.4 h (SD ϭ 2.25).3
intratracheal injection is unfounded especially if it
If a horse is two standard deviations above the
mean, its plasma concentration during administra-
sensitive measurements of serum concentrations of
tion will be 750 pg/ml and its half-life of elimination
clenbuterol make it easy to detect such an injection
hours, the plasma concentration in this horse will be23 pg/ml.
What Do We Need to Know?
borne out by observations in 14 Warmbloods treated
The pharmacokinetics of clenbuterol and its thera-
peutic efficacy have been established at the usual
tions were all below the limit of quantification (50
dose of 0.8 g/kg. It is clear from studies of clen-
pg/ml) by the third day of withdrawal.
buterol elimination that it will be much easier to
obtained using a more sensitive assay showed serum
regulate the use of this drug by use of blood rather
concentrations less than 30 pg/ml at 48 h and below
10 pg/ml at 72 h after cessation of administration.a
be the in vivo pharmacological threshold I have de-rived from in vitro data.
such a threshold will take extensive studies and the
At the time of writing (April 2000), regulations re-
result will most likely be higher than my estimate of
garding clenbuterol in racehorses vary widely from
31 pg/ml that is achieved with a 72-h withdrawal
state to state ranging from three days withdrawal to
zero tolerance for the drug in urine based on a verysensitive detection method.
References and Footnotes
Shows Association and American Quarter Horse As-
1. To¨rneke K, Ingvast Larsson C, Appelgren L-E.
sociation allow a 24-hour withdrawal as long as clen-
of equine tracheal muscle in vitro
by different adrenoceptor
buterol is a declared medication while Federation
J Vet Pharmacol
Equestre Internationale has zero tolerance.
2. To¨rneke K, Ingvast Larsson C, Appelgren L-E.
son between clenbuterol, salbutamol and terbutaline in rela-
The threshold concentration of clenbuterol to have
tion to receptor binding and in vitro
relaxation of equine
any bronchodilator effect is 0.1 nM (31.5 pg/ml).1
J Vet Pharmacol
3. Kallings P, Ingvast-Larsson C, Persson S, et al.
with chronic obstructive pulmonary disease treated with
plasma concentrations after repeated oral administration
prednisone, methyl sulfonmethane, and clenbuterol hydro-
and its effects on cardio-respiratory and blood lactate re-
Am J Vet Res
sponses to exercise in healthy Standardbred horses.
14. Robinson NE, Olszewski MA, Boehler D, et al.
between clinical signs and lung function in horses with re-
4. Shapland JE, Garner HE, Hatfield DG.
current airway obstruction (heaves) during a bronchodilator
effects of clenbuterol in the horse.
Equine Vet J
accepted Oct. 1999.
15. Jackson CA, Robinson NE, Berney C, et al.
Der Einfluß des ␤ -Rezeptoren-stimuli-
it really effective in the treatment of chronic obstructive
erenden Sympathiko-mimetikums Ventipulmins (NAB-365)
auf die Atmungsmechanik des Pferdes.
Am Assoc Equine Practnr 1999;304 –305.
16. Rush BR, Raub ES, Rhoads WS, et al.
Ein Vergleich des Effektes nach einmaliger
in horses with recurrent airway obstruction after aerosol and
parenteraler Gabe von Ventipulmin oder Euphyllin auf die
parenteral administration of beclomethasone dipropionate
1984;39:656 – 662.
7. Erichsen DF, Aviad AD, Schultz RH, et al.
and safety of clenbuterol HCl when administered to effect in
mill running in nonasthmatic highly conditioned athletes.
horses with chronic obstructive pulmonary disease (COPD).
Scand J Med Sci Sports
Equine Vet J
18. Sandsund M, Sue-Chu M, Helgerud J, Reinertsen RE,
Effect of cold exposure (Ϫ15 degrees C) and
ary transport in healthy horses with chronic obstructive pul-
salbutamol treatment on physical performance in eline non-
9. Sanders EA, Gleed RD, Hackett RP, Dobson A.
sympathomimetic drugs on the bronchial circulation of the
in fit Thoroughbred horses during a maximal exercise test.
10. Inagaki N, Kawasaki H, Hiyama H, et al.
anisms of ␤-adrenoceptor agonists for immunoglobulin E--
mediated experimental allergic reactions in rats.
11. Ricks CA, Dalrymple RH, Baker PK, et al.
J Appl Physiol
agonist to alter fat and muscle deposition in steers.
21. Kleemann R, Goossens L, Reder E, Quirke J-F.
kinetics of clenbuterol hydrochloride in competition horses.
12. Reeds PR, Hay SM, Dorwood PM, et al.
Equine Vet J
22. Harkins JD, Robinson NE, Jackson CA, et al.
Br J Nutr
13. Traub-Dargatz JL, McKinnon AO, Thrall MA, et al.
J Vet Pharmacol Ther
ation of clinical signs of disease, bronchoalveolar and trachealwash analysis, and arterial blood gas tensions in 13 horses
aTobin T, (Lexington, KY) personal communication, June 2000.
ª 2011 Adis Data Information BV. All rights reserved. Role of Cannabinoids in Multiple SclerosisJohn P. Zajicek1 and Vicentiu I. Apostu21 Clinical Neurology Research Group, Peninsula College of Medicine and Dentistry, Plymouth, UK2 Clinical Neurology Research Group, Peninsula Medical School, Plymouth, UKAbstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Designation Qualification Experience Research areas of interest Electrode materials for lithium ion batteries, Microstructure Property Correlation List of publications 1. Quantum confinement effects and band gap engineering of SnO2 nanocrystals in a MgO matrix M.B. Sahana, C. Sudakar, A. Dixit, J.S. Thakur, R. Naik, V.M. Naik, Acta Materialia, 60(3) 2012, 1072-1078. 2. N