Oscillatory measurements,blood gas analysis and clinical observations after intravenous clenbuterol administration in healthy and acutely pneumonic calves

The effects of clenbuterol (Ventipulmin, Boehringer Ingelheim) on respiratory functions were investigated in 6 calves aged 4–6 weeks prior to and after experimental infection withPasteurella haemolytica A1. On days 1–3 (prior to infection) and on days 7–9 (after infection), blood gas analysis, monofrequency forced oscillation techniques and clinical examinations (heart rate, respiratory rate) were conducted for 135 min after the intravenous administration of clenbuterol (0.8 µg/kg body weight). In healthy calves prior toPasteurella infection, intravenous administration of clenbuterol induced a mild tachycardia and a reduction in the mean oscillatory respiratory resistance. Using the same dose of clenbuterol in diseased calves after infection, the statistically significant reduction in oscillatory respiratory resistance was more impressive and it was accompanied by a significant increase in the oxygen pressure of the arterialized blood. Heart rate and respiratory rate did not change significantly after the administration of clenbuterol in infected calves.Abbreviations HR heart rate - IV intravenous - MFOT monofrequency forced oscillation technique - PaO₂ arterial oxygen pressure - R_os oscillatory resistance - RR respiratory rate     

Clenbuterol plasma concentrations after repeated oral administration and its effects on cardio-respiratory and blood lactate responses to exercise in healthy Standardbred horses

To evaluate the effects of clenbuterol on cardio-respiratory parameters and blood lactate relation to exercise tolerance, experimental horses performed standardized exercise tests on a high-speed treadmill before and after administration of the drug. Clenbuterol was administered in feed to six healthy Standardbreds at a dose rate of 0.8 micrograms/kg b.wt twice daily for 5.5 days. Each horse was tested twice, without and with a respiratory mask, during two consecutive days. One week elapsed between the baseline tests without drug and the tests with clenbuterol treatment (each horse served as its own control). The results show an unchanged heart rate response to exercise 2 h after the last clenbuterol administration. The blood lactate response and the arterial oxygen tension during exercise did not differ before and after drug treatment. The oxygen uptake as well as pulmonary ventilation relative to the work load performed was essentially unaffected. The arterial pH during exercise was significantly increased (P less than 0.05) following clenbuterol treatment. Plasma levels of clenbuterol were maximal 2 h post-administration with values between 0.45 and 0.75 ng/ml. The plasma half-life of elimination was 10.4 h (+/- 2.25 SD). In conclusion, clenbuterol did not cause any major effects on the cardio-respiratory and blood lactate parameters studied in healthy horses performing submaximal exercise tolerance tests.     

Cardiovascular and haemodynamic effects of intramuscular doses of xylazine in conscious sheep

OBJECTIVE: To determine if a commonly used analgesic dose of xylazine has detrimental cardiovascular or haemodynamic effects in sheep. DESIGN: A physiological study following intramuscular administration of xylazine. PROCEDURE: Xylazine (50 micrograms/kg) was injected intramuscularly into six healthy Merino ewes. For 60 min heart rate, mean arterial blood pressure and cardiac output were recorded; arterial blood samples for the measurement of blood gas tensions were also collected. RESULTS: There were no significant changes in heart rate, mean arterial blood pressure, cardiac output or arterial carbon dioxide tension. A slight degree of arterial hypoxaemia was noted with a 10% reduction in arterial oxygen tension values at 30 min. CONCLUSION: The minimal changes to cardiovascular and respiratory values in this study verify the safety of previously suggested analgesic dosing regimens for sheep. Previously reported hypoxaemic effects in sheep as a result of intravenous xylazine administration appear to be reduced as a result of intramuscular administration.     

Responses of calves to treadmill exercise during beta-adrenergic agonist administration.

Calves perorally administered the beta-adrenergic agonist (beta-A) clenbuterol for 28 d were studied before, during, and after a 12-min treadmill exercise. During exercise on d 1 of clenbuterol administration, respiratory rate, respiratory minute volume, and heart rate and blood glucose, lactate, and insulin concentrations increased more in beta-A-treated calves than in controls. Oxygen extraction rate and growth hormone concentrations were lower in clenbuterol-treated calves, whereas oxygen consumption, carbon dioxide production, and blood cortisol concentration increased similarly in the absence and presence of the beta-A. After 2 wk of daily clenbuterol administration, respiratory rate and respiratory minute volume during exercise were still higher and oxygen extraction was still lower, whereas all other measures were similar to those in controls. The increased heart rate in response to isoproterenol after 3 wk of clenbuterol administration was reduced markedly in resting but only slightly in exercising animals, whereas heart rate reduction by propranolol during exercise was similar to that in controls. Seven days after withdrawal of clenbuterol, newly administered clenbuterol evoked the same effects as on d 1. In conclusion, there were marked reactions to the first clenbuterol treatment that were in part enhanced during treadmill exercise. After 2 wk of beta-A administration, animals responded much less to the beta-A and changes were not different from those in controls. Resensitization to the beta-A was observed 7 d after its withdrawal.     

Acute changes in blood flow in pigs infused with beta-adrenergic agonists

Previous results indicate that clenbuterol decreases carcass adipose tissue accretion when administered to pigs but does not appear to stimulate the adipose tissue beta-adrenergic receptor. Clenbuterol increases plasma free fatty acid concentration when acutely infused in vivo, suggesting an indirect affect. One possible indirect effect is that clenbuterol could change blood flow to adipose tissue. Blood flow was measured with radiolabeled microspheres in tissues from pigs before and after infusion of a beta-adrenergic agonist for 30 min. High probability levels (up to P less than .2) were used to indicate trends due to extreme variability. Infusion of isoproterenol increased heart rate, plasma free fatty acid concentration and blood flow at many adipose tissue sites and at a few skeletal muscle sites. Infusion of isoproterenol decreased blood pressure. Infusion of clenbuterol increased heart rate and tended to increase blood flow to several skin and adipose tissue sites slightly. The results suggest that increased adipose tissue blood flow may contribute to the accelerated release of free fatty acids when clenbuterol is infused acutely in vivo.     

Cardiovascular, respiratory, and body temperature responses of sheep to the ergopeptides ergotamine and ergovaline

OBJECTIVE: To compare the effects of the ergot alkaloid ergovaline with effects of ergotamine on blood pressure, heart rate, respiratory rate, and body temperature in conscious sheep. ANIMALS: 3 sheep with indwelling arterial catheters. PROCEDURE: Ergotamine and ergovaline were injected IV (20 nmol/kg), and their effects on arterial blood pressure, heart rate, respiratory rate and pattern, body temperature, and skeletal muscle electromyographic activity were compared with control values obtained following injections of saline (0.9% NaCI) solution or acetone. RESULTS: Both ergopeptides caused immediate and significant increases in blood pressure (50 to 75 mm Hg) without concomitant increases in heart rate. Ergovaline but not ergotamine significantly increased pulse pressure (35 mm Hg). Both ergopeptides resulted in decreased respiratory rate and increased respiratory depth within the first hour of administration. Body temperature was decreased slightly upon ergopeptide administration but continued to increase thereafter, with greater increases developing with ergovaline than with ergotamine. Increased body temperatures of 3.0 to 3.5 C were maintained for at least 10 hours. Respiratory rate was increased to rates as high as 210 to 220 breaths/min in association with hyperthermia. Ergopeptides had no effect on skeletal muscle electromyographic activity. CONCLUSIONS AND CLINICAL RELEVANCE: In sheep, ergovaline has similar effects to ergotamine on cardiovascular and pulmonary function and body temperature but is more potent. These effects are consistent with clinical signs observed in the toxicoses developed when ruminants ingest grass with high concentrations of ergopeptides.     

Clenbuterol administration does not attenuate the exercise-induced pulmonary arterial, capillary or venous hypertension in strenuously exercising Thoroughbred horses

The present study was carried out to ascertain whether beta2-adrenergic receptor stimulation with clenbuterol would attenuate the pulmonary arterial, capillary and venous hypertension in horses performing high-intensity exercise and, in turn, modify the occurrence of exercise-induced pulmonary haemorrhage (EIPH). Experiments were carried out on 6 healthy, sound, exercise-trained Thoroughbred horses. All horses were studied in the control (no medications) and the clenbuterol (0.8 pg/kg bwt, i.v.) treatments. The sequence of these treatments was randomised for every horse, and 7 days were allowed between them. Using catheter-tip-transducers whose in-vivo signals were referenced at the point of the left shoulder, right heart/pulmonary vascular pressures were determined at rest, sub-maximal exercise and during galloping at 14.2 m/s on a 3.5% uphill grade--a workload that elicited maximal heart rate and induced EIPH in all horses. In the control experiments, incremental exercise resulted in progressive significant increments in right atrial as well as pulmonary arterial, capillary and venous (wedge) pressures and all horses experienced EIPH. Clenbuterol administration to standing horses caused tachycardia, but significant changes in mean right atrial or pulmonary vascular pressures were not observed. During exercise performed after clenbuterol administration, heart rate as well as right atrial and pulmonary arterial, capillary and wedge pressures also increased progressively with increasing work intensity. However, these values were not found to be statistically significantly different from corresponding data in the control study and the incidence of EIPH remained unaffected. Since clenbuterol administration also does not affect the transpulmonary pressure during exercise, it is unlikely that the transmural force exerted onto the blood-gas barrier of exercising horses is altered following i.v. clenbuterol administration at the recommended dosage.     

Cardiopulmonary effects of medetomidine in sheep and in ponies

Medetomidine was administered intravenously to six sheep at 5, 10 and 20 μg kg⁻¹ and to one horse and four ponies at 5 and 10 μg kg⁻¹. In both species medetomidine resulted in significant decreases in heart rate and cardiac output and, initially, in an increase in arterial blood pressure. In the ponies this increase in blood pressure was followed by a significant and prolonged decrease, but in the sheep the secondary decrease in blood pressure was not statistically significant. In the sheep, the three doses of medetomidine resulted in profound and significant decreases in arterial oxygen tensions, which were significantly dose related, but in the ponies the arterial blood oxygen tensions were not significantly decreased. In both species medetomidine caused a small but significant increase in arterial blood carbon dioxide tensions.     

盐酸克伦特罗在羊主要脏器中残留量消除规律的研究

本试验对盐酸克伦特罗在休药期肉羊眼睛、心脏、肾脏、肺脏、脾脏等组织中的残留规律进行了研究。选择24头体重为(30±5)kg健康肉羊进行试验,在饲料中添加50 μg/kg盐酸克伦特罗,连续饲喂35 d后休药,通过液相色谱—质谱联用/质谱检测休药期肉羊组织中克伦特罗含量,研究其残留量消除规律。试验结果表明,肉羊眼睛中有高浓度的盐酸克伦特罗残留且其在肝脏中消除较慢;停药第14天眼睛中盐酸克伦特罗的浓度仍为42.42～63.48 μg/kg,脾脏中盐酸克伦特罗消除速度是最快的;停药3 d时,检测不到盐酸克伦特罗的残留量(低于检出限0.07 μg/kg),故眼睛可用作检测盐酸克伦特罗在肉羊生产上非法使用的靶标。     

Changes in blood pressure following escalating doses of phenylpropanolamine and a suggested protocol for monitoring

This prospective, cross-over, blinded study evaluated the effect of various doses of phenylpropanolamine (PPA) on blood pressure in dogs. Dogs were randomized to receive a placebo or 1 of 3 dosages of immediate release PPA, q12h for 7 days [1 mg/kg body weight (BW), 2 mg/kg BW, or 4 mg/kg BW] in a cross-over design. Blood pressure was recorded every 2 h, for 12 h, on days 1 and 7. There were significant increases in systolic, diastolic, and mean blood pressure following administration of PPA at 2 mg/kg BW and 4 mg/kg BW. A significant decrease in heart rate was also noted at all PPA dosages, but not in the placebo. Administration of PPA was associated with a dose response increase in blood pressure. Dosages of up to 2 mg/kg BW should be considered safe in healthy dogs.     

Hemodynamic effects of orally administered carvedilol in healthy conscious dogs

OBJECTIVE: To evaluate the hemodynamic effects of orally administered carvedilol in healthy dogs with doses that might be used to initiate treatment in dogs with congestive heart failure. ANIMALS: 24 healthy dogs. PROCEDURE: Dogs were randomly allocated to receive carvedilol PO at a dose of 1.56, 3.125, or 12.5 mg, twice daily for 7 to 10 days; 6 dogs served as controls. Investigators were blinded to group assignment. Hemodynamic variables were recorded prior to administration of the drug on day 1 and then 2, 4, and 6 hours after the morning dose on day 1 and days 7 to 10. Change in heart rate after IV administration of 1microg of isoproterenol/kg and change in systemic arterial blood pressure after IV administration of 8 microg of phenylephrine/kg were recorded 2 and 6 hours after administration of carvedilol. RESULTS: Administration of carvedilol did not significantly affect resting hemodynamic variables or response to phenylephrine. The interaction of day and carvedilol dose had a significant effect on resting heart rate, but a significant main effect of carvedilol dose on resting heart rate was not detected. Increasing carvedilol dose resulted in a significant linear decrease in heart rate response to isoproterenol. CONCLUSIONS AND CLINICAL RELEVANCE: In healthy conscious dogs, orally administered carvedilol at mean doses from 0.08 to 0.54 mg/kg given twice daily did not affect resting hemodynamics. Over the dose range evaluated, there was a dose-dependent attenuation of the response to isoproterenol, which provided evidence of beta-adrenergic receptor antagonism.     

Alteration in the arrhythmogenic dose of epinephrine (ADE) following xylazine administration to halothane-anesthetized dogs

The arrhythmogenic dose of epinephrine (ADE) was determined in six dogs during halothane (1.35%) anesthesia before and after xylazine administration (1.1 mg/kg, i.v. bolus; 1.1 mg/kg/hr, i.v. infusion). The arrhythmogenic dose was determined by constant infusion of freshly mixed epinephrine (100 microgram/ml). The ADE was defined as the total dose of epinephrine which produced four or more intermittent or continuous premature ventricular contractions within a 15-sec period. Total dose was calculated as a function of infusion rate and time to arrhythmia. Following xylazine administration, ADE significantly decreased from 6.28 +/- 0.522 to 4.17 +/- 0.679 micrograms/kg. At the end of i.v. xylazine bolus administration, heart rate significantly decreased (115 +/- 4 to 99 +/- 4.9 b.p.m.), and mean arterial pressure significantly increased (83 +/- 4.0 to 122 +/- 3.4 mm Hg). Heart rate measured immediately prior to epinephrine-induced arrhythmia formation was significantly increased following xylazine administration (177 +/- 8 vs 78 +/- 3 b.p.m.). Mean arterial blood pressure was unchanged. Apparently, xylazine, a mixed alpha agonist, potentiated halothane-induced myocardial sensitization to ventricular arrhythmogenesis and was associated with a significant increase in heart rate, but not blood pressure, during subsequent epinephrine infusions.     

Acute and Subacute Metabolic and Endocrine Effects of Clenbuterol in Female Pigs

The aim of the study was to assess the relationship between acute and subacute metabolic and endocrine effects after intravenous administration of the ₂-adrenergic agonist clenbuterol in a growth-promoting dose to female pigs. Acute metabolic and endocrine effects were assessed by measuring the blood glucose, serum insulin and nonesterified fatty acid (NEFA) concentrations during 300 min after a single administration of clenbuterol. Significantly higher serum insulin and NEFA concentrations (19.90±2.50 U/ml, p<0.01, and 0.69±0.04 mmol/L, p<0.001, respectively) were measured 30 min after the preprandial administration of clenbuterol in female pigs. Over the same period, the levels of blood glucose (4.42±0.30 mmol/L) showed no difference from those of control pigs. The postprandial serum NEFA concentration decreased moderately during 210 min after feeding. Postprandial blood glucose and insulin concentrations increased and reached maximal levels 120 min after clenbuterol administration (10.91±0.60 mmol/L and 85.22±7.24 U/ml, respectively), and returned to basal levels at 300 min (4.20±0.21 mmol/L and 7.75±1.60 U/ml, respectively) after the administration of clenbuterol. Subacute metabolic and endocrine effects were assessed by measuring the blood glucose, serum insulin and NEFA concentrations for 21 days after the repeated doses of clenbuterol. In addition, the influence of clenbuterol administration on the endocrine regulation of the onset of the next expected oestrus in female pigs was assessed by measuring their serum 17-oestradiol and progesterone concentrations. Blood glucose, serum insulin and NEFA concentrations after the last administration of clenbuterol did not differ significantly from those in control animals. The onset of the next expected oestrus occurred regularly without any significant difference in serum 17-oestradiol or progesterone concentrations between the treated (9.83±2.60 pg/ml and 0.15±0.03 ng/ml) and control pigs (8.52±2.70 pg/ml and 0.25±0.06 ng/ml). The study results suggest the duration of intravenous administration of clenbuterol in a growth-promoting dose necessary to influence the metabolic and endocrine activities in female pigs.     

Clenbuterol administration does not enhance the efficacy of furosemide in attenuating the exercise-induced pulmonary capillary hypertension in Thoroughbred horses

The stimulation of pulmonary beta2-adrenergic receptors causes a decrease in vascular resistance. Thus, the present study was carried out to examine whether concomitant administration of clenbuterol-a beta2-adrenergic receptor agonist, to horses premedicated with furosemide would attenuate the exercise-induced pulmonary capillary hypertension to a greater extent than furosemide alone, and in turn, affect the occurrence of exercise-induced pulmonary hemorrhage (EIPH). Experiments were carried out on six healthy, sound, exercise-trained Thoroughbred horses. All horses were studied in the control (no medications), furosemide (250 mg i.v., 4 h pre-exercise)-control, and furosemide (250 mg i.v., 4 h pre-exercise)+clenbuterol (0.8 microg/kg i.v., 11 min pre-exercise) experiments. The sequence of these treatments was randomized for every horse, and 7 days were allowed between them. Using catheter-tip-transducers whose in-vivo signals were referenced at the point of the left shoulder, pulmonary vascular pressures were determined at rest, sub-maximal exercise, and during galloping at 14.2 m/s on a 3.5% uphill grade--a workload that elicited maximal heart rate. In the control study, incremental exercise resulted in progressive significant (P<0.05) increments in heart rate, right atrial as well as pulmonary arterial, capillary and venous (wedge) pressures, and all horses experienced EIPH. Furosemide administration caused a significant (P<0.05) reduction in mean right atrial as well as pulmonary capillary and venous pressures of standing horses. Although exercise in the furosemide-control experiments also caused right atrial and pulmonary vascular pressures to increase significantly (P<0.05), the increment in mean pulmonary capillary and wedge pressures was significantly (P<0.05) attenuated in comparison with the control study, but all horses experienced EIPH. Clenbuterol administration to standing horses premedicated with furosemide caused tachycardia, but significant changes in right atrial or pulmonary vascular pressures were not discerned at rest. During exercise in the furosemide+clenbuterol experiments, heart rate, mean right atrial as well as pulmonary arterial, capillary and wedge pressures increased significantly (P<0.05), but these data were not different from the furosemide-control experiments, and all horses experienced EIPH as well. Thus, it was concluded that clenbuterol administration is ineffective in modifying the pulmonary hemodynamic effects of furosemide in standing or exercising horses. Because the intravascular force exerted onto the blood-gas barrier of horses premedicated with furosemide remained unaffected by clenbuterol administration, it is believed that concomitant clenbuterol administration is unlikely to offer additional benefit to healthy horses experiencing EIPH.     

Cardiopulmonary effects of clenbuterol in the horse

Clenbuterol, a bronchospasmolytic agent (β₂ agonist) was studied in terms of its hemodynamic and airflow response in eight, healthy horses. Four animals were instrumented to record intrapleural pressure and air flow, these were used to compute pulmonary resistance, peak flow rates, and tidal volumes. Four animals were instrumented to record pulmonary arterial pressure, carotid arterial pressure, cardiac output, and arterial gas tensions. After control values were recorded, clenbuterol (0.8 μg/kg) was intravenously administered to each horse in each experiment group.
Following clenbuterol administration, non-elastic resistance of the lung or pulmonary resistance significantly decreased, 33.6% reduction at 10 min post-clenbuterol. Pulmonary resistance remained lowered during the entire procedure and showed no tendency of returning toward control values by 3 h post-clenbuterol. Within 30 sec following clenbuterol injection carotid arterial pressure decreased (mean pressure decrease 28.2%). Accompanying the change in arterial pressure, the heart rate drastically increased, 99.0%. Both changes were transient and returned to control ranges within 2 min.
Clenbuterol appears to be effective in reducing non-elastic resistance of the lung, however intravenous administration to an animal with pre-existing cardiovascular or cardiopulmonary disease should be avoided.     

Influence of infused beta-adrenergic agonists on porcine blood metabolites and catecholamines

Anesthetized pigs were infused sequentially with increased concentrations of beta-adrenergic agonists. At selected times during infusion, blood pressure, heart rate and plasma concentrations of free fatty acids (FFA), glycerol, glucose, lactate, norepinephrine, epinephrine and dopamine were measured. Azaperone, a drug used to calm the pigs before anesthesia, caused hypotension and bradycardia but did not affect plasma metabolites. Infusion of norepinephrine, epinephrine, isoproterenol or clenbuterol produced changes in plasma metabolites and plasma catecholamines. These changes during norepinephrine infusion were attributed to the infused agonist, whereas those during epinephrine infusion might have resulted to some extent from release of norepinephrine. Plasma isoproterenol was not quantified because it interfered with the assay of epinephrine and dopamine so that it was not possible to distinguish between infused isoproterenol and release of endogenous epinephrine and dopamine. Infusion of clenbuterol caused a small increase in plasma norepinephrine so that some of the increase in plasma FFA, glycerol and lactate during clenbuterol infusion may result from release of endogenous norepinephrine.     

Effects of adrenergic agonists and antagonists on the blood pressure and heart rate of the pig fetus

The effects of adrenergic agonists and antagonists on blood pressure and heart rate were investigated in 18 chronically catheterised pig fetuses aged between 102 and 109 days of gestation (term is 114 days). One fetus had been decapitated in utero at 42 days of gestation. The alpha adrenergic agonist methoxamine produced a small but dose dependent hypertension and a dose related slowing in heart rate. The beta adrenergic agonist isoprenaline decreased mean arterial pressure in a dose related manner and produced tachycardia. Propranolol, a beta adrenergic blocker, increased mean arterial pressure and decreased heart rate. The response to subsequent alpha adrenergic blockade with phentolamine was hypotension and a slight bradycardia. Decapitation at 42 days of gestation did not seem to change the fetal responsiveness to adrenergic agonists but removed the blood pressure response to beta blockade. These observations indicate that the heart and circulation of the pig fetus are under adrenergic vasomotor control during late gestation.     

Clenbuterol in the horse: urinary concentrations determined by ELISA and GC/MS after clinical doses

Clenbuterol is a beta2 agonist/antagonist bronchodilator marketed as Ventipulmin and is the only member of this group of drugs approved by the US Food and Drug Administration (FDA) for use in horses. Clenbuterol is a class 3 drug in the Association of Racing Commissioners International (ARCI) classification system; therefore, its identification in postrace samples may lead to sanctions. Recently, the sensitivity of postrace testing for clenbuterol has been substantially increased. The objective of this study was to determine the 'detection times' for clenbuterol after administration of an oral clinical dose (0.8 g/kg, b.i.d.) of Ventipulmin syrup. Five horses received oral clenbuterol (0.8 g/kg, b.i.d.) for 10 days, and urine concentrations of clenbuterol were determined by an enhanced enzyme-linked immunoabsorbent assay (ELISA) test and gas chromatography/mass spectrometric (GC/MS) analysis by two different methods for 30 days after administration. Twenty-four hours after the last administration, urine concentrations of apparent clenbuterol, as measured by ELISA, averaged about 500 ng/mL, dropping to about 1 ng/mL by day 5 posttreatment. However, there was a later transient increase in the mean concentrations of apparent clenbuterol in urine, peaking at 7 ng/mL on day 10 postadministration. The urine samples were also analysed using mass spectral quantification of both the trimethylsilyl (TMS) and methane boronic acid (MBA) derivatives of clenbuterol. Analysis using the TMS method showed that, at 24 h after the last administration, the mean concentration of recovered clenbuterol was about 22 ng/mL. Thereafter, clenbuterol concentrations fell below the limit of detection of the TMS-method by day 5 after administration but became transiently detectable again at day 10, with a mean concentration of about 1 ng/mL. Derivatization with MBA offers significant advantages over TMS for the mass spectral detection of clenbuterol, primarily because MBA derivatization yields a high molecular weight base peak of 243 m/z, which is ideal for quantitative purposes. Therefore, mass spectral analyses of selected urine samples, including the transient peak on day 10, were repeated using MBA derivatization, and comparable results were obtained. The results show that clenbuterol was undetectable in horse urine by day 5 after administration. However, an unexpected secondary peak of clenbuterol was observed at day 10 after administration that averaged approximately 1 ng/mL. Because of this secondary peak, the detection time for clenbuterol (0.8 g/kg, b.i.d. x 10 days) is at least 11 days if the threshold for detection is set at 1 ng/mL.     

Pharmacokinetics of selenium administered parenterally at toxic doses in sheep

Pharmacokinetics of Se were evaluated in 24 female crossbred sheep, 8 to 14 months of age, after toxic doses of Se were administered. Five groups of 4 sheep each were given 0.4, 0.6, 0.7, 0.8, or 1 mg of Se/kg of body weight, IM. Nine of these sheep died within 36 hours after Se administration. Blood Se disappearance curves were triphasic for the 11 sheep that lived for at least 36 hours after Se administration and were biphasic for the 9 sheep that died within 36 hours. The lambda 2 rate constants of Se disposition after IM administration indicated a dose dependency. Sheep given 0.4, 0.6, 0.7, or 0.8 mg of Se/kg had lambda 2 rate constants of 0.110, 0.079, 0.046, and 0.034 hour-1, respectively (r2 = 0.97). The respective half-lives of the 2nd distributive phase after IM administration were 6.3, 8.8, 15.1, and 20.4 hours. In the 11 sheep that had triphasic pharmacokinetics, the mean lambda 3 elimination rate was 0.0011 hour-1. Four additional sheep were given 0.7 mg of Se/kg, IV. These sheep survived and had blood Se disappearance curves that were triphasic. In the 4 sheep given Se IV, the mean lambda 3 elimination rate was 0.0020 hour-1, which represented a biological half-life of 354 hours or 14.7 days.     

Effects of low dose rates of sporidesmin given orally to sheep

AIM: To examine clinical and subclinical effects of sporidesmin administered orally to sheep at very low daily dose rates for periods of 3 to 48 days. METHODS: Two experiments were conducted. In Experiment A, sporidesmin-A was administered orally to groups of 16 sheep at daily dose rates of approximately 0.0042, 0.0083 and 0.0167 mg/kg bodyweight for 48 days. In Experiment B, the highest of these doses was administered orally for 3, 6, 12, 24 or 48 consecutive days. Parameters of production, clinical findings, organ weights and pathological findings were recorded. RESULTS: In Experiment A, severe liver lesions and photosensitisation were evident as early as 18 days after commencement of daily low-dose administration of sporidesmin, and were associated with significant bodyweight loss. Significant bodyweight loss also occurred in non-photosensitised sporidesmin-treated sheep. Bodyweight reductions were associated with reduced carcass weights and skin weights in treated animals. Sporidesmin administration was also associated with reduced bodyweight gains and pathological changes of the liver, kidney, hepatic lymph nodes, thymus, adrenal gland, heart and spleen. In Experiment B, only moderate changes occurred in a few sheep in the groups dosed with sporidesmin at 0.0167 mg/kg for 3 or 6 days, but major changes were frequently recorded in animals dosed at this rate for 12 days or longer. These comprised changes in the liver and other organs, and photosensitisation typical of the disease, facial eczema. Results are discussed in relation to animal welfare and economic issues associated with this disease. CONCLUSIONS: Sporidesmin caused significant clinical and sub-clinical disease and reduced animal production at relatively low daily dose rates. The effects of repeated daily low-dose administration of sporidesmin appear to be cumulative. There was considerable variation in susceptibility between individual animals. These results emphasise the considerable production losses and animal welfare effects associated with sporidesmin toxicity in sheep.