J. vet. Pharmacol. Therap. 31, 150–155, doi: 10.1111/j.1365-2885.2007.00934.x.

Effect of short-term treatment with meloxicam and pimobendan on the renal function in healthy beagle dogs M. FUSELLIER J.-C. DESFONTIS A. LE ROUX S. MADEC F. GAUTIER A. THULEAU & M. GOGNY Unite´ de Physiopathologie Animale et Pharmacologie Fonctionnelle, UPSP 5304, ENV Nantes, Nantes Cedex, France

Fusellier, M., Desfontis, J.-C., Le Roux, A., Madec, S., Gautier, F., Thuleau, A., Gogny, M. Effect of short-term treatment with meloxicam and pimobendan on the renal function in healthy beagle dogs. J. Vet. Pharmacol. Therap. 31, 150–155. The aim of the study was to investigate the renal function in clinically normal dogs receiving meloxicam and pimobendan alone or in combination. Ten adult female beagle dogs were administered the treatment for 7 days in a randomized crossover trial (control ⁄ meloxicam ⁄ pimobendan ⁄ meloxicam and pimobendan). Renal function was assessed by blood urea, creatinine, sodium, potassium and chloride concentrations and by glomerular filtration rate, measured by means of renal scintigraphy [renal uptake of 99mTc-diethylenetriaminepentacetic acid (DTPA)] and plasma clearance of 99mTc-DTPA. As compared with the control group, renal uptake and plasma clearance of 99mTc-DTPA were not significantly modified after a 7-day period of treatment with meloxicam or pimobendan alone, or meloxicam and pimobendan in combination. Furthermore, urea, creatinine, sodium, potassium and chloride levels in the serum of the dogs during the 7-day period treatment were not significantly modified in relation to the treatments. It was therefore concluded that meloxicam and pimobendan alone or in combination did not alter renal function in healthy dogs. (Paper received 19 April 2007; accepted for publication 7 December 2007) J.-C. Desfontis, Unite´ de Physiopathologie Animale et Pharmacologie Fonctionnelle, UPSP 5304, Ecole Nationale Ve´te´rinaire de Nantes, BP 40706, 44307 Nantes Cedex 03, France. E-mail: [email protected]

INTRODUCTION The quantity of fluid that filters through the kidneys’ glomeruli per minute is termed the total glomerular filtration rate (GFR). GFR is influenced by glomerular capillary hydrostatic and osmotic pressure, osmotic pressure in Bowman’s capsule and rate of blood flow through the nephrons. GFR is one of the best indicators of renal function. Changes in arterial blood pressure most frequently cause variations in glomerular capillary hydrostatic pressure. Kidneys are able to regulate glomerular filtration pressure and glomerular blood flow by adjusting afferent and efferent arteriolar vascular resistance in response to changes in mean systemic arterial pressure. This autoregulation maintains a constant GFR by maintaining constant blood flow through the nephrons at arterial blood pressure between 80 and 170 mmHg in dogs. Renal autoregulation is based on vasomotor activity of afferent and efferent glomerular arteries in relation to the sympathetic nervous system, various hormones and local renal mediators such as prostaglandins. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to act by inhibiting cyclooxygenase (COX) activity, thus preventing 150

the synthesis of prostaglandins. As prostaglandins play an important role in homeostatic mechanisms that help to prevent renal damage attributable to hypovolemia, suppression of prostaglandins in anaesthetized surgical patients could adversely affect renal function (Forsyth et al., 2000; Gambaro & Perazella, 2003). It has been proposed that prostaglandins generated by COX-2 participate in the inflammatory process, while those engendered by COX-1 are important in some homeostatic mechanisms, such as preservation of gastric mucosal integrity and maintaining renal blood flow during hypotension and hypovolaemia (Seibert et al., 1994; Smith & DeWitt, 1995; Vane et al., 1998). Although constitutive COX-2 has been shown to be expressed in kidney, COX-2-derived metabolites play a minor role in the control of renal haemodynamic in dogs. However, renal haemodynamic became dependent on COX-2 metabolites when sodium intake is low and was much more sensitive to the prolonged administration of a selective COX-2 inhibitor when endogenous nitric oxide production was reduced (Roig et al., 2002). Apart from the typical NSAIDs, meloxicam preferentially acts through the inhibition of COX-2 activity (Engelhardt et al.,  2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

Meloxicam and pimobendan safety on renal function in dogs 151

1996a,b; Pairet et al., 1998). In vitro, meloxicam inhibited COX2 activity 12 times more effectively than for COX-1 activity (KayMugford et al., 2000). The safety of administering an NSAID in combination with other agents has been poorly evaluated. Renal effects have been investigated for carprofen (Forsyth et al., 2000; Ko et al., 2000; Lobetti & Joubert, 2000; Bostro¨m et al., 2002), ketorolac and ketoprofen (Lobetti & Joubert, 2000) during an anaesthetic procedure. Recently, Crandell et al. (2004) and Bostro¨m et al. (2006) have reported an absence of adverse effects of meloxicam on renal function during anaesthesia. Pimobendan is a benzimidazole derivative with combined inotropic and peripheral vasodilating properties through a combined effect of sensitizing cardiac myofilaments to intracellular calcium, inhibiting phosphodiesterases 3 and 5 and activating potassium channels. Pimobendan and its metabolite UD-CG 212 Cl produced vasodilation in various organs including kidneys (Verdouw et al., 1987). Only one study has investigated the effect of pimobendan on renal function in human (Martin et al., 1992). In eight healthy volunteers, no adverse effects on renal blood flow and GFR have been reported. Renal adverse effects because of pimobendan and NSAID combination have never been evaluated either in healthy dogs or in dogs with congestive heart failure. The purpose of the study reported here was to determine whether a functional renal dysfunction developed in healthy dogs undergoing meloxicam or pimobendan administration alone and in combination.

MATERIALS AND METHODS Animals Ten healthy adult female beagle dogs (3 years old), weighing between 9.5 and 10.5 kg, were included in the study. Dogs were obtained from Harlan (Gannat, France) and were housed and cared in the veterinary school unit facility. Dogs were fed with a standard food (Adult; Royal Canin, Aimargues, France). Before the experiment, renal ultrasonography was performed for each dog in order to assess the absence of morphological abnormalities. Study design The study was performed in a randomized, crossover, blinded manner. Each dog received each of the four treatments per os during a 7-day period [no treatment for control, meloxicam 0.2 mg ⁄ kg at day 0 (D0) in the morning and 0.1 mg ⁄ kg the following days, pimobendan 0.25 mg ⁄ kg in the morning and the end of afternoon, meloxicam and pimobendan same dosing]. Dosages were selected to fit manufacturer’s recommendations. There was, at least, a 2-week washout period between two successive treatments. On the day of the GFR evaluation (day 7), the dogs were not given food, and water was withheld for 2 h prior to induction of anaesthesia. Two intravenous catheters were placed in the cephalic veins. One was used for an infusion of lactated Ringers  2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

solution (5 mL ⁄ kg ⁄ h, Ringer-Lactate; Aguettant, Lyon, France) during the anaesthesia and allowed the administration of anaesthetic as a bolus (propofol 6.5 mg ⁄ kg, Fusellier et al., 2007). A second administration of propofol (1 mg ⁄ kg) was performed, if necessary. The second catheter was only used for the injection of the radiopharmaceutical. Serum biochemical analysis Blood samples were collected on day-1 (D-1), day 3 (D3) and day 7 (D7). Blood urea, creatinine, potassium, sodium and chloride were measured by use of standard reagent kits (Vet’Test 8008 and VetLyte; Idexx Laboratory, Cergy-Pontoise, France). Renal scintigraphy Within 15 min of reaching a stable plane of anaesthesia, renal scintigraphy was performed as described below (Fusellier et al., 2005). Four MBq ⁄ kg body weight of 99mTc-diethylenetriaminepentacetic acid (DTPA) (Cisbio International, Buc, France) was prepared in the injection tubing and counted 30 cm from the centre of the gamma camera (DS7; Sopha Medical, General Electric Medical Systems, Buc, France) fitted with a low-energy all-purpose collimator (predose count). The percentage of 99mTc binding to the DTPA was analysed for each experiment and found to be >95%. The dogs were positioned in supine position with the gamma camera positioned ventrally close to the animal. The intravenous injection of the radiopharmaceutical was performed in the right cephalic vein as a rapid bolus, and the catheter was flushed with saline solution. Using a dedicated image processing computer, 1-sec sequentially acquired dynamic images were recorded into a 64 · 64 matrix for 1 min and, then, 5-sec sequentially acquired dynamic images were recorded for 14 min. Just after this, the depth of each kidney was evaluated by positioning the gamma camera laterally and taking a static image for 30 sec on the right and then on the left. Immediately after the 16-min period, the syringe and tubing were repositioned in a manner similar to that for the predose count, and a postdose count was obtained, and then the dose was measured at the point of injection. Separate regions of interest were drawn manually around each kidney, and a background crescent region of interest was drawn adjacent to the caudal pole of each kidney. Renal activity was corrected for background activity and depth. Uptake of each kidney was determined as the cumulative activity between 1 and 3 min in the kidney divided by the injected dose (predose count minus postdose and point of injection counts, Barthez et al., 1998) and was used to evaluate GFR (Fig. 1). The regions of interest for each procedure were independently drawn by three trained persons to prevent analysis bias and the final values were calculated as an average of the three measurements. Plasma clearance of

99m

Tc-DTPA

Heparinized blood samples were collected, using the intravenous catheter that had not been previously used for the 99mTc-DTPA

152 M. Fusellier et al.

particularly, no episodes of vomiting were observed. The weight of the dogs remained relatively stable during the whole study. Serum biochemical analysis

Fig. 1. Typical scintigraphic acquisition for a dog represented as cumulative activity of 64 · 5-sec sequentially acquired dynamic images 1 min after 99mTc-DTPA intravenous injection.

injection, 5, 10, 15, 20, 25, 30, 45, 60, 75, 90, 105, 120, 150 and 180 min after the injection of the radiopharmaceutical. At the end of the blood collection period, 99mTc-DTPA activity was measured on a 500-lL aliquot of plasma using a well counter (Riastar; Packard Instrument Company, Meriden, CT, USA). Plasma activity was corrected for physical decay and plotted as a function of time. Area under the time–activity curve was calculated by means of the trapezoidal method (Multifit 2.01 for Apple computer; Day Computing, Cambridge, UK). Plasma clearance of 99mTc-DTPA was calculated as the injected dose of 99m Tc-DTPA divided by the area under the time–activity curve. Statistical analysis All results are expressed as mean ± SEM of n experiments, which represents the number of dogs. Data were compared between treatments and across times within each treatment by use of a two-way analysis of variance for repeated measures, and a contrast method analysis (means comparison) has been used as a post hoc test. A value of P < 0.05 was considered to be significant.

Treatment with meloxicam, pimobendan or meloxicam and pimobendan did not significantly change urea, creatinine, sodium, potassium and chloride levels in the serum of the dogs during the 7-day period treatment (Tables 1 & 2). Blood urea and creatinine values were within the range of values considered to be normal whatever the treatment (normal laboratory limits, urea: 0.15–0.57 g ⁄ L, creatinine: 5–18 mg ⁄ L). Sodium, potassium and chloride ion plasma concentration values were within the range of values considered to be normal whatever the treatment (normal laboratory limits, Na+: 144–160 mmol ⁄ L, K+: 3.5–5.8 mmol ⁄ L, Cl): 109–122 mmol ⁄ L), except for one value of sodium plasma concentration below the range (115 mmol ⁄ L) for a dog in the control group, six values for potassium plasma concentration below the range and five values for chloride ion plasma concentration up to 124 mmol ⁄ L all at D7 whatever the treatment. Creatinine, potassium and chloride ion plasma concentrations were significantly modified in all groups including the control in relation to time (P < 0.001, Table 1). A significant decrease in creatinine plasma concentration between D-1 and D7 (7.78 ± 0.23 and 6.71 ± 0.21) and between D3 and D7 (7.43 ± 0.17 and 6.71 ± 0.21) was observed. For potassium plasma concentration, levels significantly increased between D-1 and D3 (4.24 ± 0.07 and 4.46 ± 0.07) and significantly decreased between D-1 and D7 (4.24 ± 0.07 and 3.75 ± 0.06) and between D3 and D7. A significant increase was obtained in chloride ion plasma concentration between D-1 and D7 (116.72 ± 0.37 and 119.50 ± 0.53) and between D3 and D7 (117.25 ± 0.31 and 119.50 ± 0.53). Glomerular filtration rate After the 7-day period of treatment, renal uptake percentage of 99m Tc-DTPA ranged from 7.3% to 8.5% (Fig. 2a, Table 3) and plasma clearance of 99mTc-DTPA ranged from 5.1 to 5.6 mL ⁄ min ⁄ kg (Fig. 2b, Table 3). Differences in renal uptake and plasma clearance of 99mTc-DTPA were not significant between any of the treatment and control. For the control group, the renal uptake percentage of 99mTc-DTPA was 7.3 ± 0.4% and plasma clearance of 99mTc-DTPA was 5.6 ± 0.3 mL ⁄ min ⁄ kg. Table 1. P-values for treatment and time factors in repeated-measures two-way ANOVAs for serum biochemical parameters (urea, creatinine, sodium, potassium and chloride) Effect

RESULTS General status of health During the whole period of the study, the dogs did not present any clinical signs of intolerance to the treatments and,

Urea

Treatment 0.6769 Time 0.0820 Interaction 0.5010 treatment · time

Creatinine Sodium Potassium Chloride 0.8195 0.0030** 0.0521

0.5899 0.2743 0.5894

0.1508 0.8827 0.0001** 0.0001** 0.6192 0.7013

**P < 0.001 significant difference.  2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

Meloxicam and pimobendan safety on renal function in dogs 153 Table 2. Mean ± SEM values for serum biochemical analysis (urea, creatinine, sodium, potassium and chloride) before and during the treatment with meloxicam, pimobendan or control Treatment Control

Meloxicam

Pimobendan

Meloxicam + pimobendan

Day Before  Day 3 Day 7 Before  Day 3 Day 7 Before  Day 3 Day 7 Before  Day 3 Day 7

Urea (g ⁄ L) 0.29 0.31 0.34 0.3 0.32 0.33 0.32 0.29 0.3 0.28 0.32 0.36

± ± ± ± ± ± ± ± ± ± ± ±

0.03 0.02 0.02 0.02 0.02 0.03 0.02 0.02 0.02 0.01 0.01 0.01

Creatinine (mg ⁄ L) 7.53 7.5 7.1 7.19 7.7 6.41 8.66 7.38 6.31 7.76 7.13 7.03

± ± ± ± ± ± ± ± ± ± ± ±

0.25 0.41 0.4 0.36 0.39 0.33 0.62 0.23* 0.36** 0.45 0.32 0.55

Sodium (mmol ⁄ L) 155.75 156.5 151.25 156.25 155.5 155.5 156.63 155.38 154.63 155.38 156.5 156.25

± ± ± ± ± ± ± ± ± ± ± ±

0.45 0.68 5.26 0.53 0.5 0.71 0.94 0.32 1.22 0.75 0.82 0.86

Potassium (mmol ⁄ L) 4.29 4.56 3.78 4.19 4.26 3.79 4.1 4.4 3.69 4.38 4.63 3.75

± ± ± ± ± ± ± ± ± ± ± ±

0.14 0.14 0.07** 0.13 0.11 0.13* 0.12 0.08 0.17** 0.14 0.19 0.12**

Chloride (mmol ⁄ L) 116.38 117.38 119.5 116.75 117.63 119.75 117.38 116 119.25 116.38 118 119.5

± ± ± ± ± ± ± ± ± ± ± ±

0.75 0.32 1.12* 0.7 0.73 0.75* 0.96 0.65 1.31 0.63 0.6 1.2*

*P < 0.05, **P < 0.01, significant difference compared with time ‘before’ in the same treatment, obtained with post hoc test (n = 8).  The day before the treatment.

mL ⁄ min ⁄ kg) or meloxicam and pimobendan in combination (7.9 ± 0.9%, 5.4 ± 0.4 mL ⁄ min ⁄ kg).

99mTc-DTPA

Renal uptake (%)

(a)

99m

Tc-DTPA Plasma clearance (mL/kg/min)

(b)

Fig. 2. Renal uptake of 99mTc-DTPA (a, n = 5–9) and plasma clearance of 99mTc-DTPA (b, n = 10) in dogs after a 7-day oral administration of pimobendan (black), meloxicam (vertical lines) or meloxicam and pimobendan (horizontal lines) once daily or control dogs (white). Mean ± SEM values were not significantly different between any of the treatments and the control.

After the 7-day period of treatment, the values were not significantly modified by meloxicam (8.5 ± 1.1%, 5.3 ± 0.6 mL ⁄ min ⁄ kg), pimobendan (7.4 ± 0.6%, 5.1 ± 0.3  2008 The Authors. Journal compilation  2008 Blackwell Publishing Ltd

DISCUSSION In the present study, we did not show any significant difference in renal glomerular filtration as evaluated by GFR or serum biochemical analysis after treatment with meloxicam and pimobendan alone or in combination. As this study is a first and preliminary step that was conducted in healthy dogs with noninvasive procedures, we did not collect urine from dogs and had no information concerning renal concentration ability and renal tubular function. Moreover, the duration of the study was selected in order to reach a steady state in the effect of each drug. Controversial results have been reported concerning the renal effects of NSAIDs in dogs. Most of the studies have been performed under anaesthesia (Forsyth et al., 2000; Ko et al., 2000; Lobetti & Joubert, 2000; Bostro¨m et al., 2002, 2003, 2006; Fusellier et al., 2005) and were greatly dependent on the anaesthetic regimen effect on systemic and renal arterial pressure. Moreover, different renal effects of anaesthesia have been reported in relation to the anaesthetic regimen applied. Medetomidine significantly decreased renal uptake of 99mTcDTPA and increased time to peak of the time–activity curve, while propofol or a mixture of xylazine, ketamine and halothane did not change GFR in young healthy dogs (Fusellier et al., 2004, 2007). Then, in the present study, propofol was used as the anaesthetic during the scintigraphy acquisitions. In the kidney glomeruli, angiotensin II is well known to preferentially induce vasoconstriction of efferent arterioles, whereas prostaglandin E is more responsible for vasodilatation of afferent arterioles. COX-2-derived metabolites are reported to be involved in the modulation of afferent arteriolar vasoconstriction (Imig & Deichmann, 1997). Indeed, Llinas et al. (2001) showed that renal vasoconstriction elicited by norepinephrine was increased when inhibition of COX-2 was performed, then contributing to a decrease in GFR. It also appeared that

154 M. Fusellier et al.

RU (%) PC (mL ⁄ min ⁄ kg)

Control

Meloxicam

Pimobendan

Meloxicam + pimobendan

7.3 ± 0.4 5.6 ± 0.3

8.5 ± 1.1 5.3 ± 0.6

7.4 ± 0.6 5.1 ± 0.3

7.9 ± 0.9 5.4 ± 0.4

COX-mediated renal vasodilation may mainly be involved in hypotensive or hypovolemic conditions. Nevertheless, COX-2specific inhibitors, such as meloxicam, have not shown any alteration in renal function even in dogs with acepromazineinduced hypotension (Bostro¨m et al., 2006). In the present study, meloxicam and pimobendan alone or in combination failed to impair glomerular filtration in healthy dogs. Meloxicam is a COX-2-specific inhibitor and pimobendan is an inotropic agent with peripheral vasodilating properties. Arteriolar and venous vasodilations because of pimobendan are mediated through the inhibition of phosphodiesterases 3 and 5 (Mathew & Katz, 1998). As little information is available about the extent and target vessels of pimobendan-induced vasodilation according to the species concerned, our results could suggest that renal circulation was not greatly modified by either meloxicam and pimobendan alone or the drugs combination. Small but significant modifications in creatinine, potassium and chloride ion plasma concentration during the time of experiments were noted. As the values were in the normal laboratory limits, we cannot take these variations into consideration as relevant deviations. In a previous study, we have already noted such irrelevant variations in creatinine and urea blood concentrations (Fusellier et al., 2005). Electrolyte measurements obtained with usual reagent kits are performed with a good sensitivity and specificity. So, most tight variations obtained in the measurements can be related to individual or residual variability and not to an experimental factor such as drug treatment. Although the present study did not show any significant change in glomerular filtration rate in healthy dogs, we must not rule out any adverse effects on renal function of meloxicam, pimobendan or their combination as they can be administered for a long time in dogs with pain or inflammation and congestive heart failure. In summary, our results showed that administration of meloxicam and pimobendan alone or in combination for 7 days did not alter GFR in healthy dogs. These findings could be mainly attributed to the huge ability of autoregulation in the healthy kidney, as the absence of systemic hypotension could be valuably hypothesized. Further studies on the adverse effects of meloxicam and ⁄ or pimobendan on renal function should be conducted in dogs with congestive heart failure.

ACKNOWLEDGMENTS The authors thank Boehringer Ingelheim France for funding, Francis Prual, Patrick Guyot for care of the animals and

P-value by ANOVA 0.48 0.65

Table 3. Renal uptake percentage (RU) and plasma clearance (PC) of 99mTc-DTPA

Franc¸oise Coppin (Biochemistry Unit) for radiopharmaceutical titration.

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