Effects of Tilmicosin Phosphate Administration on Echocardiographic Parameters in Healthy Donkeys (Equus asinus): An Experimental Study

Journal of Equine Veterinary Science 38 (2016) 24–29

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Original Research

Effects of Tilmicosin Phosphate Administration on Echocardiographic Parameters in Healthy Donkeys (Equus asinus): An Experimental Study Mohamed A. Youssef, Hussam M. Ibrahim, El-Shaimaa M. Farag, Sabry A. El-Khodery* Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt

a r t i c l e i n f o

a b s t r a c t

Article history: Received 20 July 2015 Received in revised form 22 December 2015 Accepted 4 January 2016 Available online 9 January 2016

The aim of this study was to evaluate the effect of tilmicosin on echocardiographic measurements in donkeys. For this purpose, placebo and tilmicosin 30% (10 mg/kg) were administered subcutaneously to clinically healthy donkeys (n ¼ 10) in a randomized prospective crossover study. Cardiac functions were evaluated by echocardiography using a 2.5-MHz curved-linear transducer at 0, 15, 30, 60, and 120 minutes after administration. Examination was carried out at 3 to 5 intercostal spaces, and measurements were obtained at three planes of images. Tilmicosin induced a significant decrease in fractional shortening percentage (FS%) at 30 minutes after treatment (P < .05), but ejection fraction percentage (EF%) and stroke volume (SV) were decreased at 60 minutes after treatment (P < .05). However, left ventricular volume at end-systole (LVESV) was increased when compared to placebo at 30, 60, and 90 minutes after administration (P < .05). Left ventricular volume at end-diastole (LVEDV) was increased at 60 minutes after treatment (P < .05). There was a positive correlation between FS% and EF% (r ¼ 0.89, P < .01), LVESV and left ventricle internal diameter at systole (LVIDs; r ¼ 0.97, P < .01), and SV and LVEDV (r ¼ 0.56, P < .01). However, there was negative correlation between LVESV and EF% (r ¼ 0.41, P < .05), ESV and FS% (r ¼ 0.44, P < .05), LVIDs and EF% (r ¼ 0.43, P < .05), and LVIDs and FS% (r ¼ 0.47, P < .05). The present results indicate that tilmicosin could induce transient and short-lasting changes of cardiac function in donkeys. Ó 2016 Elsevier Inc. All rights reserved.

Keywords: Echocardiography Equine Macrolide Adverse effect Cardiac function

1. Introduction Tilmicosin, a macrolide antibiotic, is usually used in food animals for treatment of respiratory diseases associated with Mannheimia haemolytica and Pasteurella multocida [1–3]. In foals, tilmicosin showed various activity in vitro against most Streptococcus spp., Staphylococcus spp., Actinobacillus spp., and Pasteurella spp., and Rhodococcus equi [4–7]. In addition, tilmicosin exerts an anti-inflammatory effect via modulating

* Corresponding author at: Sabry A. El-Khodery, Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Mansoura 35516, Egypt. E-mail address: [email protected] (S.A. El-Khodery). 0737-0806/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jevs.2016.01.004

the synthesis of many mediators and cytokines involved in the inflammatory process [8]. The use of the injectable tilmicosin product has been associated with acute cardiac toxicity in both human and animals [9–11]. In experimental animals, tilmicosin has been documented to cause cardiac toxicity and collapse [12,13]. In dogs, the adverse cardiovascular was evident with single dose of 5 mg/kg [9]. In cattle, the adverse effect is dose dependent [14], and a dose rate of 50 mg/kg could cause small foci of necrosis in the left ventricular papillary muscle of the heart [15]. Subcutaneous injection of tilmicosin in cattle causes inflammation at the injection site, but the severity of reaction is dose dependent [16]. In horses, tilmicosin at 10 mg/kg caused severe reactions at the injection sites including vascular collapse and transient

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swelling [17]. However, tilmicosin at 50 to 70 mg could increase cardiac muscle–derived enzymes in mice only [18]. The adverse effect of tilmicosin on the heart has been recognized through clinical findings, postmortem findings [19], increased serum level of cardiac muscle–derived enzyme, creatinine kinase [20], and other biochemical alterations [18]. In equines, echocardiography is the most acceptable tool for evaluation of the cardiac anatomy and functions [21–24]. In addition, via echocardiography, determination of the cardiac performance of clinically healthy animals and diagnosis of any cardiac pathologic conditions can be accomplished [25,26]. The donkey suffers from a similar range of respiratory diseases as the horse; however, there are a number of subtle variations, knowledge of which can influence the success of treatment [27]. In donkeys, there are no available data about the use of tilmicosin and the evidence of adverse effect on the cardiac function. Consequently, the objective of the present study was to evaluate the effect of single dose of tilmicosin on cardiac functions in donkeys via echocardiography. 2. Materials and Methods 2.1. Animals Ten, clinically healthy donkeys (Equus asinus) were used in a randomized crossover study. The age of donkeys was 9 to 13 years (mean  standard deviation, 10.8  1.6 years), and their body weight was 120 to 200 kg (mean  standard deviation, 151  25.3 kg). None of those donkeys had cardiovascular disorders or any evidence of systemic diseases based on clinical and echocardiographic examination. Two weeks before starting the study, each donkey was stabled on straw-bedded boxes and fed on 1-kg hay/100 kg and 0.5-kg concentrate twice daily with unlimited access to water. This study was carried out at the Department of Internal Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Mansoura University, Egypt. The study was approved by the Animal welfare and Ethics Committee, Faculty of Veterinary Medicine, Mansoura University. 2.2. Study Design A randomized crossover experimental study incorporated two treatment trials, the placebo (normal saline, NaCl 0.9%; El-Nasr Pharmaceutical Chemicals Co, Egypt) and the tilmicosin (Pneumotac; ADWIA Pharmaceuticals Co S.A.E. 10th of Ramadan City, Egypt). Therapeutic dose of tilmicosin 30% was injected subcutaneously (10 mg/kg). Saline and tilmicosin were administered subcutaneously at the side of the neck with equal volume. According to the pharmacokinetics of tilmicosin in horses [17], the interval between the two treatments was 1 week. Echocardiographic examination and cardiac indices were evaluated for each donkey before treatment and at 15, 30, 60, and 120 minutes after treatment. During the monitoring periods, there was no access to food or water. In addition, the evidence of clinical adverse effects as injection site swelling

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and inflammation, lameness, collapse, anaphylaxis/ anaphylactoid reactions, and death was observed during the monitoring period after the administration of tilmicosin. 2.3. Ultrasonographic Examination First, donkeys were restrained in stocks without any sedation, and the chest was clipped at third to the fifth intercostal spaces just caudal to the triceps muscle mass, and from 3 to 5 cm below the olecranon to 5 to 10 cm above it. This area was cleaned with alcohol, and then, coupling gel was applied to enhance the contact with the probe. Transcutaneous echocardiographic examinations were performed according to standard methods [23,28,29] and the recommendations of the American Society of Echocardiography [30]. Echocardiographic examination was carried out using a 2.5-MHz curved-linear transducer (CHISON Digital Color Doppler Ultrasound system, iVis 60 EXPERT VET; CHISON Medical Imaging Co, Ltd, China). The location, rotation, and angulation of the transducer were considered to obtain the standard images. On echocardiographic examination, three image planes were included: right parasternal long-axis two-dimensional four-chamber view, left parasternal long-axis two-dimensional five-chamber view, and right parasternal short-axis view. Once the optimal imaging plane had been determined, both the cardiac indices were calculated using the Cube method and cardiac function using the Teichholz method. In all echocardiographic examination, the cardiac measurements were obtained by the same person. In addition, heart rate and respiratory rate were counted at each time point for each donkey. 2.4. Cardiac Function The B-mode and guided M-mode measurements were obtained according to the methods described by Amory et al. [29]. Interventricular septal thickness at end-systole (IVSTs), interventricular septal thickness at end-diastole (IVSTd), left ventricular internal diameter at end-systole (LVIDs), left ventricular internal diameter at end-diastole (LVIDd), left ventricular posterior wall thickness at endsystole (LVPWs), and left ventricular posterior wall thickness at end-diastole (LVPWd) were assessed through the Cube method. Meanwhile, the left ventricular volume at end-diastole (LVEDV) and in end-systole (LVESV) was assessed using the Teichholz method according to an established formula [31]: LVEDV ¼ [7.0  (LVIDd)3]/[2.4 þ LVIDd] and LVESV ¼ [7.0  (LVIDs)3]/[2.4 þ LVIDs]. However, stroke volume (SV) was calculated using the formula: SV ¼ LVEDV  LVESV. Finally, fractional shortening (FS) was assessed using the formula: FS% ¼ [(LVIDd  LVIDs)  100]/ LVIDd, and ejection fraction (EF) was assessed using the formula: EF% ¼ [(LVEDV  LVESV)  100]/LVEDV as previously stated [32]. 2.5. Statistical Analysis Data analyses were performed using a commercial statistical software program (SPSS for Windows, version 16.0;

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Table 1 Left ventricular volume at end-systole (mL; mean  standard deviation) after administration of tilmicosin phosphate in donkeys. Groups

B-mode Placebo Tilmicosin M-mode Placebo Tilmicosin

Time After Administration (min) 0

15

30

60

90

120

68.4  7.9 71.8  8.3

74.4  6.6 79.7  6.1

63.3  7.3a 81.8  9.6b

71.2  5.1a 112  10.5b

69.4  5.8a 111.3  18.8b

69.4  6.7 79.2  8.4

63  6.7 61.6  9.2

66  7.1 55.9  8.3

65.4  8.1a 80.1  7.8b

65.7  6.7a 96  7.7b

64  7.9a 125  19.1b

66.1  8.1 70.2  7.9

a,b Means with different superscript letters are significantly different at P < .05. For B-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .01. For M-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05.

SPSS Inc, Chicago, IL). Data were tested for normal distribution using the Kolmogorov–Smirnov normality test. As data were following the Gaussian distribution and hence normally distributed, mean and standard deviation for each variable at each time point were presented. General linear model with repeated-measures analysis of variance was used to assess the changes occurred in the echocardiogrphic parameters with treatment and time. Wilks’ lambda test was selected to assess within-group and evidence of time  treatment interaction. Where Wilks’ lambda test showed a statistically significant difference between groups, a t test was used at each time point to identify which group was statistically different. Correlation between echocardiographic parameters was carried out using Pearson correlation analysis. For all statistical analyses, differences at P < .05 were considered significant. 3. Results Right parasternal long-axis views (four-chamber view) showed the right ventricle, interventricular septum, bicuspid valve, left atrium, left ventricle, mitral valve, and aorta. All donkeys were clinically normal and echocardiogrphic findings revealed no abnormalities. Cardiac measurements and indices before administration of tilmicosin were within the normal ranges of donkeys. The echocardiographic findings of examined donkeys included: IVSTs (2.3  0.7 cm), IVSTd (1.6  0.3 cm), LVIDs (2.9  0.6 cm), LVIDd (5.1  0.9 cm), LVPWs (2.1  0.6 cm), LVPWd (1.5  0.4 cm), LVEDV (214  23.5 mL), LVESV (69.4  7.9 mL), FS% (30.4  3.2), EF% (72.2  7.1), and SV (175.5  20.1 mL).

Tilmicosin induced a significant increase in LVESV when compared to placebo at 30, 60, and 90 minutes after administration. The highest level of LVESV was 111.3  18.8 and 125  19.1 mL for B and M modes, respectively (Table 1). However, a transitory significant increase in LVEDV was observed at 60 minutes after treatment (Table 2). Fractional shortening percentage, EF%, and SV were decreased significantly in donkeys treated with tilmicosin when compared to the placebo. Fractional shortening percentage decreased early at 30 minutes after treatment (Table 3), but EF% and SV decreased later at 60 minutes after treatment (Tables 4 and 5). However, other functions and indices showed nonsignificant variation. There was a positive correlation between FS% and EF% (r ¼ 0.89, P < .01), ESV and LVIDs (r ¼ 0.97, P < .01), and SV and EDV (r ¼ 0.56, P < .01). However, there was a negative correlation between ESV and EF% (r ¼ 0.41, P < .05), ESV and FS% (r ¼ 0.44, P < .05), LVIDs and EF% (r ¼ 0.43, P < .05), LVIDs and FS% (r ¼ 0.47, P < .05). 4. Discussion A safe and effective antimicrobial agent would be useful for the treatment or prevention of pneumonia in equines. Tilmicosin has been approved for the control and treatment of respiratory diseases in food animals [3]. However, adverse clinical signs may be associated with administration of tilmicosin, especially cardiac toxicity [9]. Only biochemical and pathologic investigations have been carried out to recognize the tilmicosin-induced cardiac toxicity in experimental animals [18,20]. Such studies did

Table 2 Left ventricular volume at end-diastole (mL; mean  standard deviation) after administration of tilmicosin phosphate in donkeys. Groups

B-mode Placebo Tilmicosin M-mode Placebo Tilmicosin

Time After Administration (min) 0

15

30

60

90

120

213  24.5 217  21.8

212  19.5 198.1  15.1

211  18.5 211.5  12.8

213  26.3a 241  25.6b

211  29.6 215  21.7

199  15.3 204.3  21.5

222  20.5 227  22.1

212  15.3 199.1  12.1

217  14.1 213.5  13.9

220  26.3 231  25.6

227  30.4 211  27.8

202  16.1 214.3  20.2

a,b Means with different superscript letters are significantly different at P < .05. For B-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05. For M-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05.

M.A. Youssef et al. / Journal of Equine Veterinary Science 38 (2016) 24–29

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Table 3 Fractional shortening percentage (mean  standard deviation) after administration of tilmicosin phosphate in donkeys. Groups

B-mode Placebo Tilmicosin M-mode Placebo Tilmicosin

Time After Administration (min) 0

15

30

60

90

120

30.4  3.2 31.3  4.1

31.6  4.1 38.3  5.1

33.4  5.0a 25.2  3.5b

31.1  3.8a 20.3  5.1b

32.5  2.8a 15.5  4.0b

31  5.2 27.6  6.1

32.6  6.1 34.2  4.7

34.1  5.6 37.2  4.9

32.1  5.1a 24.9  7.0b

34.5  5.1a 22.3  3.7b

31.1  5.3a 15.2  3.4b

33.5  4.2 29.5  5.1

a,b Means with different superscript letters are significantly different at P < .05. For B-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .01. For M-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .01.

not allow proper evaluation of cardiac functions and indices. Although there is a difference between horses and donkeys [27], we used the results of pharmacokinetics of tilmicosin in horses as a guide. The mean residence time of tilmicosin in horses is 1.2 days [17]. Thus, 1-week interval between the two consecutive treatments in donkeys may suggest elimination of the drug. Clinically, tachypnea (23–31 respiratory cycles/min) and tachycardia (45–60 beats/min) were evident in all donkeys at 60 and 90 minutes after administration. These findings may reflect the effect of the drug on the heart. Similar findings were reported in calves [33] and dogs [9,15]. In the present study, donkeys showed no other adverse effects; however, a study in foals showed swelling at the injection site and self-limiting diarrhea [4]. Left ventricular volume at end-systole significantly increased in tilmicosin-treated donkeys early at 30 minutes after administration (Table 1), suggesting a state of systolic failure, which is attributed to impairment of the contractile and/or pumping function of the heart. Therefore, the left ventricular cavity size was increased with an increase in LVESV and reduction in EF. Generally, in animals, systolic myocardial failure is a general reduction in the ability of the heart muscle to contract due to several causes. In systolic failure in animals, there is reduced wall motion during contraction of the ventricles with subsequent reduction of SV [34]. A study on heart disease in humans has shown that large increases in ESV predict adverse cardiovascular outcomes in participants with LV systolic dysfunction [35]. However, administration of tilmicosin at a dose of 0.25, 1.0, 2.5, and 5.0 mg/kg induced dose-dependent adverse effects on heart rate and left ventricular end-diastolic pressure [9].

In the present study, LVEDV significantly increased only at 60 minutes after treatment with tilmicosin. Such increase may be attributed to transitory increase of ventricular compliance. However, we cannot rely on EDV to interpret the effect of tilmicosin because LVEDV can be affected by many mechanisms depending on ventricular compliance and severe disturbance is associated with heart failure. Fractional shortening percentage, EF%, and SV were significantly decreased in the tilmicosin-treated group (Tables 3–5), indicating decreased contractility of the cardiac muscle. In systolic heart failure, the increased wall stress and impaired contractile function are the main functional derangements and are the major mechanisms for a reduced EF [36]. Another supposition is myocardial damage and depression as a result of alterations in the cellular redox state with subsequent negative inotropy after tilmicosin injection. These findings were similar to those reported previously [18,20]. Similarly, in human patients, the decrease of EF% is termed systolic heart failure because patients with diastolic heart failure usually have a normal EF% [37]. Although FS%, EF%, and SV are simple measures of the ventricular performance and hence pump function of the heart, they should not be regarded as accurate measurements, but may be helpful guide, because their accuracy depends on the original measurements and the use of appropriate formulae. Although we used only one dose of tilmicosin (10 mg/ kg), all donkeys showed tachypnea and tachycardia. Previous reports stated that the toxic and potentially fatal doses of tilmicosin depend on animal species and route of administration [20,38]. Tilmicosin at 5 mg /g IV caused death in cattle, 10 mg/kg IM in swine caused convulsions,

Table 4 Ejection fraction percentage (mean  standard deviation) after administration of tilmicosin phosphate in donkeys. Groups

B-mode Placebo Tilmicosin M-mode Placebo Tilmicosin

Time After Administration (min) 0

15

30

60

90

120

72.2  7.1 67.3  8.2

73.4  6.8 77.2  6.4

65.9  6.5 59.1  7.8

67.2  5.4a 48.1  8.2b

64.3  5.7a 37.5  6.9b

67.7  11.1 60.3  9.7

67.5  6.9 70.5  7.3

70.2  7.0 74.5  6.5

70.4  8.1a 55.5  7.1b

71.2  6.2a 53.1  4.6b

69.5  8.2a 38.5  5.9b

70.6  9.8 66.5  6.6

a,b Means with different superscript letters are significantly different at P < .05. For B-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05. For M-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05.

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Table 5 Stroke volume (mL; mean  standard deviation) after administration of tilmicosin phosphate in donkeys. Groups

B-mode Placebo Tilmicosin M-mode Placebo Tilmicosin

Time After Administration (min) 0

15

30

60

90

120

175.5  20.1 168.4  18.4

169.0  11.9 160.8  16.7

166.5  15.62 157.9  14.1

168.2  17.2 156.5  19.1

166.0  13.4a 89.5  15.2b

167.2  19.6 154  21.7

175.5  20.1 165.4  17.6

165.0  12.6 159.8  17.2

168.5  19.6 159.9  14.8

169.2  18.1 160.5  20.3

168.0  19.4a 80.5  11.2b

175.2  20.6a 168  9.9b

a,b Means with different superscript letters are significantly different at P < .05. For B-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05. For M-mode measurements, Wilks’ lambda test for treatment  time interaction, P < .05.

and 30 mg/kg IM in a rhesus monkey caused death [15]. Preexisting circulatory dysfunction, systemic illness, and conditions that directly or indirectly interfere with the normal physiologic responses of the heart and blood vessels are the factors contributing to tilmicosin-induced cardiotoxicity [39]. Previous reports suggest that tilmicosininduced cardiovascular toxicity is represented by tachycardia and decreased cardiac contractility which may be as a result of either stimulation of cardiac beta receptors (negative inotropy) [15,20] or secondary to the direct effect of atrial stretch on the sinoatrial node in response to the increased left ventricular end diastolic pressure [9]. The tilmicosin induces negative inotropic effects on the heart via interference with calcium cycling at the level of the sarcoplasmic reticulum, inhibiting calcium flux across membranes, and depletion of intracellular calcium, resulting in decreased myocardial contractility, decreased SV, and decreased cardiac workload [40]. In dogs, intravenous calcium counteracts tilmicosin-induced tachycardia and negative inotropy, restoring arterial pulse pressure [9]. Negative inotropic effects include also changes of ventricular contraction and therefore the rate of ejection. Other reports found that tilmicosin injection is associated with increased serum cardiac damage markers [18] and decreased cardiac antioxidant enzyme [41]. Unfortunately, in the present study, cardiac damage markers and cardiac antioxidant enzymes have not been evaluated to support these explanations. The limitations of the present study should be acknowledged. We used a single dose of tilmicosin (10 mg/ kg). This dose may not allow documentation of all probable adverse effects on the heart. Lack of pharmacokinetic studies of tilmicosin in donkeys may preclude full interpretation of results. Further investigations are required to get concrete conclusions about tilmicosin-induced cardiac toxicity with full consideration of the shortcomings of previous studies.

5. Conclusions The results of the present investigation indicate that tilmicosin at 10 mg/kg could induce transient and shortlasting changes of cardiac function and indices in donkeys. The results emphasize the role of echocardiography to identify how cardiac functions are affected. Donkeys may be liable to show signs of cardiac toxicity associated with

tilmicosin used as a model for echocardiographic changes associated with tilmicosin in equines and a guide for other animal species. However, further studies are required to assess the dose-dependent adverse effect of tilmicosin on cardiac functions and indices. Acknowledgments The authors of this article have no financial or personal relationship with other people or organizations that could appropriately influence or bias the content of the article. References [1] McClary DG, Loneragan GH, Shryock TR, Carter BL, Guthrie CA, Corbin MJ, et al. Relationship of in vitro minimum inhibitory concentrations of tilmicosin against Mannheimia haemolytica and Pasteurella multocida and in vivo tilmicosin treatment outcome among calves with signs of bovine respiratory disease. J Am Vet Med Assoc 2011;239:129–35. [2] Christodoulopoulos G, Warnick LD, Papaioannou N, Fthenakis GC. Tilmicosin administration to young lambs with respiratory infection: safety and efficacy considerations. J Vet Pharmacol Ther 2002; 25:393–7. [3] de Jong A, Thomas V, Simjee S, Moyaert H, El Garch F, Maher K, et al. Antimicrobial susceptibility monitoring of respiratory tract pathogens isolated from diseased cattle and pigs across Europe: the VetPath study. Vet Microbiol 2014;172:202–15. [4] Womble A, Giguere S, Murthy YV, Cox C, Obare E. Pulmonary disposition of tilmicosin in foals and in vitro activity against Rhodococcus equi and other common equine bacterial pathogens. J Vet Pharmacol Ther 2006;29:561–8. [5] Villarino N, Martin-Jimenez T. Pharmacokinetics of macrolides in foals. J Vet Pharmacol Ther 2013;36:1–13. [6] Jacks SS, Giguère S, Nguyen A. In vitro susceptibilities of Rhodococcus equi and other common equine pathogens to azithromycin, clarithromycin, and 20 other antimicrobials. Antimicrob Agents Chemother 2003;47:1742–5. [7] Fenger CK. Treatment of R. equi pneumonia in two foals with a novel preparation of microcrystalized tilmicosin. Proc 18th Annual Veterinary Medical Forum. USA: American College of Veterinary Internal Medicine; 2000. [8] Cao XY, Dong M, Shen JZ, Wu BB, Wu CM, Du XD, et al. Tilmicosin and tylosin have anti-inflammatory properties via modulation of COX-2 and iNOS gene expression and production of cytokines in LPS-induced macrophages and monocytes. Int J Antimicrob Agents 2006;27:431–8. [9] Main BW, Means JR, Rinkema LE, Smith WC, Sarazan RD. Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs. J Vet Pharmacol Ther 1996;19:225–32. [10] Lust EB, Barthold C, Malesker MA, Wichman TO. Human health hazards of veterinary medications: information for emergency departments. J Emerg Med 2011;40:198–207. [11] Cochrane RL, Thomson TD. Toxicology and pharmacology of tilmicosin following administration of subcutaneous, intravenous and

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