เอกสารกํากับยาภาษาอังกฤษ VAXIGRIP Suspension for injection 2010 strains INFLUENZA VACCINE (SPLIT VIRION, INACTIVATED) Read all of this leaflet carefully before you or your child is vaccinated. - Keep this leaflet. You may need to read it again. If you have any further questions, ask your doctor or pharmacist. This medicine
Advantag of ingestion administration way is its easiness even when applied at home. But with their help necessary treatment concentration in blood cannot be always quickly achieve buy antibiotics online transaction is carried out on anonymity and mutual profit principles, and in addition customers will be positively surprised with quality and speed of service.
Clenbuterol and the horseClenbuterol 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 Pharmacological Activity
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- Ventipulminா Syrup
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 1997;20:216 –219.
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 1998;21:388 –392.
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 1992;53:1908 –1916.
sponses to exercise in healthy Standardbred horses.
14. Robinson NE, Olszewski MA, Boehler D, et al.
Pharmacol Ther 1991;14:243–249.
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 Tiera¨rztl Umschau 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 1995;5:231–236.
Equine Vet J 1994;26:331–336.
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 Exper Physiol 1991;76:301–304.
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 1996;80:795– 801.
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 1999;31:339 –341.
22. Harkins JD, Robinson NE, Jackson CA, et al.
Br J Nutr 1986;56:249 –258.
13. Traub-Dargatz JL, McKinnon AO, Thrall MA, et al.
J Vet Pharmacol Ther submitted 1999.
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.
ﬁle:///The Cas e Agains t Nuclear PowerTHE CASE AGAINST NUCLEAR POWERGORDON TAYLOR2011-06-06The critical issue for nuclear power is the consequences of a major radioactive release. These were predicted in theSandia CRAC-2 study as 42,000 to 100,000 early deaths. They were confirmed empirically by Chernobyl, whichcontaminated huge areas of the Ukraine, Belarus and Russia as well as 40% of Europ