Anti-Inflammatory Drugs in Equine Neonatal Medicine. Part I

Journal of Equine Veterinary Science 35 (2015) 475–480

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Journal of Equine Veterinary Science

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Review Article Anti-inﬂammatory Drugs in Equine Neonatal Medicine. Part I: Nonsteroidal Anti-inﬂammatory Drugs

Carolina Castagnetti, Jole Mariella*

Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, Bologna, Italy article info abstract

Article history: Nonsteroidal anti-inflammatory drugs (NSAIDs) are the class of drugs most commonly Received 18 November 2014 used in equine medicine. This article reviews the literature on the different NSAIDs used in Received in revised form 6 February 2015 equine neonatology: flunixin meglumine, phenylbutazone, ibuprofen, ketoprofen, melox- Accepted 20 February 2015 icam, and firocoxib. These drugs are routinely used in equine adults, but in neonatal foals, Available online 25 February 2015 the risk of side effects should be carefully evaluated. Many of the studies on NSAID pharmacokinetics in neonatal foals have been performed on healthy animals, and more Keywords: information is needed to determine the appropriate dosage in the compromised equine Foal fi NSAID neonate. The review highlights the lack of speci c NSAID dosages for compromised foals Side effect and emphasizes the risk of side effects in the neonate. Dosage Ó 2015 Elsevier Inc. All rights reserved.

1. Introduction and chelating iron [4,6]. Common NSAID characteristics are rapid gastrointestinal absorption because food does not Nonsteroidal anti-inflammatory drugs (NSAIDs) are a change their bioavailability, high protein binding, usually chemically heterogeneous group of compounds able to with albumin, and renal excretion, although some NSAIDs inhibit the cyclooxygenases (COX), enzymes occurring in and their metabolites undergo enterohepatic circulation two isoenzymatic forms (COX-1 and COX-2), and conse- [2]. The side effects associated with the use of NSAIDs are quently the conversion of arachidonic acid into prosta- related to COX-1 inhibition, the most common being gastric glandins, thromboxane, and prostacyclin [1]. Blocking the ulcers and renal failure. Gastric ulceration is related to production of prostaglandins has anti-inflammatory, anal- depressed mucosal production of PGE2, the prostaglan- gesic, antipyretic, antiendotoxic, and antithrombotic ef- din responsible for inhibiting acid secretion, enhancing fects. The anti-inflammatory effect of NSAIDs is usually the mucosal blood flow, and promoting the secretion of gastric result of COX-2 inhibition, whereas the unwanted effects of mucus. In 1996, Appleyard et al [7] found tumor necrosis these drugs are primarily due to COX-1 inhibition. Melox- factor a (TNF-a) was released into plasma within 30 mi- icam and the newest NSAIDs (coxibs) exhibit selectivity for nutes of NSAID administration in rats and implicated TNF-a COX-2 and have fewer adverse effects than the other mol- in the pathogenesis of NSAID-induced gastric injury. Pre- ecules [2]. Irrespective of prostaglandin synthesis, NSAIDs vious studies had revealed a direct adverse effect of TNF-a have additional mechanisms of actions such as decreasing on the gastrointestinal mucosa, whereas TNF-a infusion in oxidants [3,4], scavenging oxygen-derived free radicals [5], rats caused significant gastric and small intestinal mucosal injury at necropsy [8,9]. A study on the mucosal messenger RNA cytokine profile of the gastric wall in neonatal foals found that foals with evidence of gastritis or gastric ulcer- * Corresponding author at: Jole Mariella, Department of Veterinary a a Medical Sciences, University of Bologna, Via Tolara di Sopra 50, 40064 ation were more likely to express TNF- and that TNF- was Ozzano dell’Emilia, Bologna, Italy. not expressed in foals without evidence of gastritis or E-mail address: [email protected] (J. Mariella). gastric ulceration [10].

0737-0806/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jevs.2015.02.008 476 C. Castagnetti, J. Mariella / Journal of Equine Veterinary Science 35 (2015) 475–480

Acute renal failure during NSAID therapy develops after the saline-treated control group of this study had the same inhibition of renal PGE2 biosynthesis, resulting in renal lesions. The authors concluded that the treatment of vasoconstriction and increased water reabsorption [2].In healthy neonatal foals with the recommended dosage of the kidney, COX-1 functions mainly in the control of renal FXM caused no clinical, clinicopathologic, or pathologic hemodynamics and the glomerular filtration rate (GFR), differences compared with treatment with physiological whereas COX-2 primarily affects salt and water excretion saline, but treatment with 6.6 mg/kg/d increased total [11]. Blockade of either or both of these enzymes will gastrointestinal ulceration, gastric ulceration, and cecal therefore have different effects on renal function such as petechiation. an increase in serum creatinine, hyperkalemia, interstitial In 1993, Semrad et al [21] studied FXM pharmacoki- nephritis, proteinuria, and acute renal dysfunction. Non- netics in foals during the first month of life, finding that steroidal anti-inflammatory drugs reduce the production of drug disposition was longer and its clearance was lower at PGE2 and PGI2, involved in renal blood circulation, thereby 24–28 hours of life than at 10–11 days or 27–28 days. decreasing the GFR. This is particularly detrimental in pa- Crisman et al studied FXM pharmacokinetics in foals less tients with impaired renal function, which results in water than 24 hours old, reporting that clearance was lower than retention [12]. that determined for older foals and adult horses and vol- Based on structure, NSAIDs can be divided into two ume of distribution was larger than in adults. Mean plasma different classes: carboxylic acid and enolic acid deri- half-life was 8.5 hours [22]. On the basis of these studies vatives. The main subgroups of enolic acids are the [21,22], FXM should be administered differently to foals pyrazolones (phenylbutazone [PBZ]) and the oxicams <24 hours old compared with adults. Doses in foals should (meloxicam and piroxicam). The carboxylic acid subgroup be increased by as much as 1.5 times to induce comparable includes salicylates (aspirin), propionic acids (ibuprofen, therapeutic concentrations, but longer dose intervals naproxen, carprofen, ketoprofen, and vedaprofen), an- would be necessary to avoid drug toxicity. The PO route of thranilic acids (tolfenamic and meclofenamic acids), phe- administration studied in adults [31] has not been evalu- nylacetic acids (acetaminophen), and aminonicotinic acids ated in foals, but if ascertained by new studies, this route (flunixin). The newest coxib class of selective COX-2 could be a good option, particularly when the treatment inhibitors studied in adult horses includes deracoxib [13], has to be administered by the owners. celecoxib [14], etoricoxib [15], firocoxib [16,17], and robenacoxib [18]. To date, only six NSAIDs have been specifically 3. Phenylbutazone evaluated in neonate and older foals: flunixin meglumine (FXM) [19–22], PBZ [23,24], ketoprofen [25], ibuprofen In 1982, Traub et al [23] studied the effects of a clinical [26], meloxicam [27], and firocoxib [28]. therapeutic dosage of PBZ (10 mg/kg daily) on the gastric The aim of this review was to highlight the lack of mucosa of 15 foals between 3 and 10 months of age for specific NSAID dosages for compromised foals and to 12–42 days. The dose was divided into two treatments per emphasize the risk of side effects in the neonate. For every day and was administered PO. Phenylbutazone treatment drug, studies performed on adult horses or on older foals resulted in oral and gastric ulceration, decreased total pro- will be presented first, focusing on the few studies per- tein, increase in blood urea nitrogen, inappetence, weight formed on neonatal foals at the end of each section. loss, and diarrhea. Some of these toxic effects, oral ulceration and diarrhea, occurred as early as treatment days 3–6. Geor 2. Flunixin Meglumine et al [32] reported that ranitidine and sucralfate provided partial protection against the clinicopathologic manifesta- Flunixin meglumine is widely used as an analgesic, tions of PBZ toxicity in neonatal foals and that sucralfate antipyretic, anti-inflammatory, and antiendotoxic agent appeared superior to ranitidine. The foals receiving sucral- [29,30]. Few studies have addressed the side effects of FXM fate did not develop diarrhea, and their gastric ulcers in older foals. In 1988, Traub-Dargatz et al [19] studied the appeared less active with normal mucus [32]. effects on gastric mucosa of a therapeutic dose of FXM In 1993, the study by Wilcke et al [24] suggested that (1.1 mg/kg) administered for 30 days to thirteen 4- to there was a larger volume distribution, a longer serum half- 6-month-old foals. PO administration resulted in oral and life, and a lower total clearance of PBZ in 5- to 17-hour-old gastric ulceration and erosions of the glandular stomach foals than in adult horses. Léveillé et al [33] reported that mucosa, whereas intramuscular administration resulted in PBZ administration at a dosage of 5 mg/kg body weight, PO, erosions of the glandular stomach mucosa. No renal lesions every l2 hours for 7 days caused morphologic renal changes were observed. in two of the three 7- to 10-day-old foals included. Ultra- In neonatal foals, Carrick et al [20] reported the effects of sound evaluation showed a diffuse hyperechoic zone daily IV administration of FXM at dosages of 0.55, 1.1, 2.2, within the medulla near the corticomedullary junction. At and 6.6 mg/kg for 5 days. The major clinical abnormality necropsy, the kidney appeared grossly normal, but histo- was diarrhea, but the incidence was not dose related. All logically, there were multiple foci of mineralization in the foals were euthanized after 6 days, necropsied, and exam- collecting tubules of the medullary region, corresponding ined for lesions. The primary gross pathologic lesions to the hyperechoic zones. consisted of ulceration of the glandular stomach, pete- Phenylbutazone plasma concentration was also studied chiation or congestion of the cecum, and petechiation, in neonate foals suckling mares receiving 4.4 mg/kg every congestion, or edema of the colon. The most common site 12 hours for 7 days after parturition. Neither PBZ nor its of cecal petechiation was the cecocolic junction. The foals in active metabolite, oxyphenbutazone (OPBZ), was found in C. Castagnetti, J. Mariella / Journal of Equine Veterinary Science 35 (2015) 475–480 477 foal plasma [34]. Another study found that PBZ given to evidence of drug accumulation in plasma. Side effects pregnant mares can cross the placental barrier because observed in adult horses at higher doses were not observed both PBZ and OPBZ were detected in substantial concen- in 2- to 3-day-old foals given 1.8 mg/kg twice daily for 7 trations in neonatal foals. In that study, two mares received days. Firocoxib has a high selectively for COX-2 and has oral dosing of PBZ paste at 4.4 mg/kg twice a day until been well studied in adult horses [17] in which it is used to parturition for approximately 20 days and PBZ appeared in mediate pain and inflammation associated with degener- the fetal circulation. Phenylbutazone and OPBZ appear to ative joint disease. The pharmacokinetics of firocoxib was be eliminated more slowly from neonatal foals than from studied in 36-hour-old foals receiving the standard adult adult horses [35]. therapeutic dose (0.1 mg/kg every 24 hours PO) for 9 days. Suxibuzone, a PBZ-derived NSAID, was designed to Firocoxib appears to be cleared faster and has a shorter produce less gastric irritation, and its clinical effectiveness half-life in foals compared with adult animals. However, its was similar to that of PBZ. Suxibuzone was studied in adult bioavailability in foals is lower than that reported for adult horses, and Monreal et al [36] reported that suxibuzone horses resulting in more frequent or higher dosages. It also had a markedly lower gastrointestinal toxicity than PBZ appears that firocoxib did not cause any oral or gastric when a high dosage is administered PO. Suxibuzone has ulceration or side effects in the foals included in the study never been studied in foals. [27]. Currently, firocoxib has not been studied in compromised foals, and further work is required to determine the 4. Ketoprofen and Ibuprofen effective therapeutic dose.

Ketoprofen and ibuprofen are two propionic acid 6. Indications derivatives. They are nonselective COX inhibitors with therapeutic and side effects common to other NSAIDs. Ibuprofen 6.1. Pain administration was first studied in healthy foals aged 5–8 weeks [25]. Foals included in the study had evidence of Given its analgesic effect, FXM is often used in foals to impaired renal function because there was a significant in- treat abdominal pain (1.1 mg/kg twice or once a day IV or crease in blood urea nitrogen, creatinine, and urine gamma intramuscular), but other drugs such as butorphanol glutamyl transferase values. Moreover, five of seven foals in tartrate (0.01–0.04 mg/kg IV) or N-butylscopolammonium the study had gastric ulcers at necroscopy without manifest- bromide (0.3 mg/kg slowly IV) are often more effective with ing clinical signs. The authors claimed that these side effects fewer side effects [45]. Judicious use of analgesics is may become clinically relevant in foals with renal function required to balance the need for pain relief and appropriate compromised by sepsis or the use of nephrotoxic drugs. assessment of the patient’s progress [46]. Foals are partic- Wilcke et al [26] studied the pharmacokinetics of ularly susceptible to the formation of peritoneal adhesions, ketoprofen administered at a dosage of 2.2 mg/kg/body and small intestinal ischemia and luminal distension have weight IV in foals less than 24 hours old. The study showed been shown to produce bowel-to-bowel adhesions [47].In that clearance was lower and volume of distribution was an experimental study, four 6-week-old foals subjected to larger than those determined for adult horses. So foals complete ischemia followed by reperfusion received <24 hours old should receive a 1.5 times higher dosage to 1.1 mg/kg FXM divided four times a day. Ten days after the produce comparable therapeutic concentrations, with a experiment, treated foals had no bowel-to-bowel adhe- longer dose interval. This is because neonates have sions [48]. Flunixin meglumine may help minimize syno- increased total body water and extracellular fluid volume vial inflammation and subsequent articular cartilage compared with adults [37]. This means that the serum damage during septic arthritis. However, pain relief may concentration of hydrosoluble drugs such as NSAIDs is bias the clinical evaluation of the patient’s response to lower in neonates because of a large volume of distribution. other aspects of the therapy such as antibiotic treatment On the other hand, Brewer et al [38] demonstrated that 2- and joint lavage. Meijer et al [49] treated foals with PBZ for day-old foals had a GFR and effective renal plasma flow at least the first 4 days after joint lavage, whereas others comparable with adults. [50,51] reported that foals were treated with FXM at 1.1 mg/kg IV once before or during surgery and that 5. Meloxicam and Firocoxib continued use of NSAIDs was not routine. Conditions such as luxation and fracture were more often treated with PBZ Meloxicam is a potent anti-inflammatory drug of the [52–54], although it significantly decreased mineral appo- oxicam class with a more selective COX-2 inhibition activity sition rate in cortical bone [55]. in vitro [39,40]. Its anti-inflammatory and analgesic effects after PO administration to adult horses have been demonstrated in several studies [41–44]. Raidal et al [27] 6.2. Fever found that plasma concentrations after a single oral dose of meloxicam (0.6 mg/kg) and time to maximum plasma Pyrexia is a common clinical sign in foals and is related concentration were similar in adult horses and in foals of to many conditions, namely localized infections (such as 2–23 days of life. Drug clearance was more rapid in foals pneumonia, arthritis and osteomyelitis, omphalitis) but (elimination half-life, 2.48 Æ 0.25 hours). Administration also neonatal isoerythrolysis. Hyperthermia can also have of 0.6 mg/kg meloxicam every 12 hours for up to 3 weeks severe side effects on the foal, and temperatures more than was well tolerated by foals of 17–33 days of life, with no 40C can cause convulsions and coma. Flunixin meglumine 478 C. Castagnetti, J. Mariella / Journal of Equine Veterinary Science 35 (2015) 475–480 is one of the drugs most commonly used to reduce tem- Table 1 perature in foals. Take home messages. Many of the NSAID studies on pharmacokinetics in neonatal foals 6.3. Ophthalmology have been performed on healthy animals, and more information is needed to determine the appropriate dosage in the compromised equine neonate. In adults, FXM is effective in reducing uveal exudation Flunixin meglumine and ketoprofen had a larger volume of and relieving ocular discomfort and is considered the most distribution and faster clearance in foals than in adult horses. efficacious NSAID for systemic treatment of iridocyclitis Phenylbutazone had major toxic effects in neonatal foals. [56]. Because a recent study detected ophthalmic lesions, Suxibuzone has never been studied in neonatal or older foals, but such as entropion, uveitis, ulcerative keratitis, and retinal it may be a good alternative to phenylbutazone. Meloxicam and firocoxib appeared to be safe in a group of neonatal hemorrhage in 55.7% of neonatal foals with systemic dis- foals (less than 1 wk) also at high dosage. ease [57], in the authors’ opinion, systemic NSAIDs could Abbreviation: NSAID, nonsteroidal anti-inflammatory drug. also be a good option in neonates.

6.4. Patency of the Ductus Arteriosus encephalopathy). Because hypovolemia and dehydration could increase the risk of side effects, such as gastrointes- It has been well known since the 1950s that the ductus tinal tract ulceration, hypoproteinemia, and papillary ne- arteriosus remains patent for some time after birth in the crosis, it is imperative not to administer FXM before following mammalian orders: primates (man), carnivores restoring plasma volume and correcting severe dehydra- ’ (dog), artiodactyls (sheep and cow), and perissodactyls tion. Moreover, the foal s mare could have received NSAIDs (horse). The blood flows from the aorta to the pulmonary for a prolonged period during gestation, or there could be a trunk may cause a continuous murmur from the ductus. concurrent administration of potentially nephrotoxic The benefit of augmented pulmonary blood flow can be agents such as aminoglycoside antibiotics. considerable if the lungs are not uniformly efficient as in the newborn. Failure of the ductus to close may impose a 7. Discussion and Conclusions severe strain on the left heart, and inadequate ventilation of the lungs may raise pulmonary vascular resistance suf- Although many years have passed because of the ficiently to reverse the direction of blood flow through the development of the equine neonatology, few medications ductus [58]. Because prostaglandins have also been impli- have been tested in neonatal clinical trials. Little is known cated in the maintenance of patent ductus arteriosus, about the pharmacology of NSAIDs and their adverse NSAIDs, particularly indomethacin or ibuprofen, have been effects in premature or compromised foals. As also occurs used in neonates to close the inappropriately patent ductus in human neonatology, extrapolation of benefits and safety [59,60]. The patency of the ductus arteriosus has been from adult studies is common. Developmental character- recognized in foals [61], but no specific study on this aspect istics and most of the neonatal diseases can profoundly has been performed in foals. affect the efficacy, disposition, and safety of NSAIDs. Body composition significantly affects the distribution of drugs 6.5. Endotoxemia in the body: neonates have a high proportion of total body water and a low proportion of fat, so the volume of distri- Flunixin is the NSAID most commonly used to treat bution can be increased for water-soluble compounds and and prevent endotoxemia in adult horses and foals. Pre- decreased for fat-soluble compounds. Moreover, protein treatment of adult horses with low-dose FXM (0.25 mg/kg binding is diminished, and drug clearance can be prolonged vs. 1.1 mg/kg) before endotoxin challenge significantly due to immature hepatic metabolism and renal excretion. reduced plasma eicosanoid generation, elevated blood In addition to these maturational factors, some pathologic lactate, and clinical signs of endotoxemia in a dose- conditions, such as hypothermia and hypotension, can dependent fashion [62,63]. Although similar studies are affect the pharmacodynamics and pharmacokinetics of the lacking in neonatal foals because the equine neonate is drugs used in neonates. more prone to the toxic effect of NSAIDs, a low-dose pro- In the authors’ opinion, when the risk of side effects is tocol administered two to three times daily is anecdotally high, the decision to administer NSAIDs should be taken considered appropriate for the management of endo- with caution especially during the transitional period and toxemia in septic neonates. No controlled trials have in the most compromised foals (Table 1). Suxibuzone has addressed the effect of such therapy in the neonate, so never been studied in older or neonatal foals, but it may be whether this approach is beneficial or not remains to be a good alternative to the use of PBZ. Moreover, because established. More recent studies on endotoxemia in foals fewer side effects have been reported for the newer coxib have focused on other drugs, such as polymyxin B, which class of selective COX-2 inhibitors, the latest drugs should lowered the two important mediators of endotoxemia: also be studied in the equine neonate and young foals. TNF-a and thromboxane B2, in 3- to 5-day-old neonatal foals with experimental endotoxemia [64,65]. In the authors’ opinion, it is noteworthy that foals at References risk of developing endotoxemia are very often severely ill, [1] Dowling P. Non steroidal antiinflammatory drugs. In: Reed SM, hypovolemic and/or dehydrated, and sometimes affected Bayly WM, Sellon DC, editors. Equine internal medicine. St. Louis: by other conditions (prematurity and neonatal Saunders; 2004. p. 220–8. C. Castagnetti, J. Mariella / Journal of Equine Veterinary Science 35 (2015) 475–480 479

[2] Abukhalaf IK, von Deutsch DA, Bayorh MA, Socci RR. Non steroidal [28] Hovanessian N, Davis JL, McKenzie HC, Hodgson JL, Hodgson DR, antiinflammatory drugs. In: Mozayani A, Raymon LP, editors. Crisman MV. Pharmacokinetics and safety of firocoxib after oral Handbook of drug interactions. A clinical and forensis guide. Totowa administration of repeated consecutive doses to neonatal foals. J Vet (NJ): Humana Press inc; 2004. p. 337–76. Pharmacol Ther 2014;37:243–51. [3] Demling RH, LaLonde C. Early postburn lipid peroxidation: effect of [29] Sanchez LC, Robertson SA. Pain control in horses: what do we really ibuprofen and allopurinol. Surgery 1990;107:85–93. know? Equine Vet J 2014;46:517–23. [4] Aruoma OI, Halliwell B. The iron-binding and hydroxyl radical [30] Lefebvre D, Pirie RS, Handel IG, Tremaine WH, Hudson NP. Clinical scavenging action of anti-inflammatory drugs. Xenobiotica 1988;18: features and management of equine post operative ileus: survey of 459–70. diplomates of the European Colleges of Equine Internal Medicine [5] Baltazar MT, Dinis-Oliveira RJ, Duarte JA, Bastos ML, Carvalho F. (ECEIM) and Veterinary Surgeons (ECVS). Equine Vet J 2014. http:// Antioxidant properties and associated mechanisms of salicylates. dx.doi.org/10.1111/evj.12355 [Epub ahead of print]. Curr Med Chem 2011;18:3252–64. [31] Pellegrini-Masini A, Poppenga RH, Sweeney RW. Disposition of [6] Peterson DA, Gerrard JM, Rao GH, White JG. Inhibition of ferrous flunixin meglumine injectable preparation administered orally to iron induced oxidation of arachidonic acid by indomethacin. Pros- healthy horses. J Vet Pharmacol Ther 2004;27:183–6. taglandins Med 1979;2:97–108. [32] Geor RJ, Petrie L, Papich MG, Rousseaux C. The protective effects of [7] Appleyard CB, McCafferty DM, Tigley AW, Swain MG, Wallace JL. sucralfate and ranitidine in foals experimentally intoxicated with Tumor necrosis factor mediation of NSAID-induced gastric damage: phenylbutazone. Can J Vet Res 1989;53:231–8. role of leukocyte adherence. Am J Physiol 1996;270:42–8. [33] Léveillé R, Miyabayashi T, Weisbrode SE, Biller DS, Takiguchi M, [8] Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Williams JF. Ultrasonographic renal changes associated with phen- et al. Shock and tissue injury induced by recombinant human ylbutazone administration in three foals. Can Vet J 1996;37:235–6. cachectin. Science 1986;234:470–4. [34] Crisman MV, Sams RA, Irby MH. The disposition of phenylbutazone [9] Kahky MP, Daniel CO, Cruz AB, Gaskill 3rd HV. Portal infusion of in lactating mares and its effect on nursing foals. Proc Annu Meet tumor necrosis factor increases mortality in rats. J Surg Res 1990;49: Am Assoc Equine Pract 1989;35:127–31. 138–45. [35] Crisman MV, Wilcke JR, Sams RA, Gerken DF. Concentrations of [10] Mariella J, Castagnetti C, Peli A, Morini M, Sorteni C, Bettini G, et al. phenylbutazone and oxyphenbutazone in post-parturient mares Mucosal mRNA cytokines profile of gastric wall in neonatal foals: and their neonatal foals. J Vet Pharmacol Ther 1991;14:330–4. comparison with endoscopy and histology. J Equine Vet Sci 2013; [36] Monreal L, Sabaté D, Segura D, Mayós I, Homedes J. Lower gastric 33:977–83. ulcerogenic effect of suxibuzone compared to phenylbutazone [11] Weir MR. Renal effects of nonselective NSAIDs and coxibs. Cleve Clin when administered orally to horses. Res Vet Sci 2004;76:145–9. J Med 2002;69(Suppl 1):53–8. [37] Fielding CL, Magdesian KG, Edman JE. Determination of body water [12] Süleyman H, Demircan B, Karagöz Y. Anti-inflammatory and side ef- compartments in neonatal foals by use of indicator dilution tech- fects of cyclooxygenase inhibitors. Pharmacol Rep 2007;59:247–58. niques and multifrequency bioelectrical impedance analysis. Am J [13] Tomlinson JE, Blikslager AT. Effects of cyclooxygenase inhibitors Vet Res 2011;72:1390–6. flunixin and deracoxib on permeability of ischaemic-injured equine [38] Brewer BD, Clement SF, Lotz WS, Gronwall R. Renal clearance, uri- jejunum. Equine Vet J 2005;37:75–80. nary excretion of endogenous substances, and urinary diagnostic [14] Menozzi A, Pozzoli C, Poli E, Dacasto M, Giantin M, Lopparelli RM, indices in healthy neonatal foals. J Vet Intern Med 1990;5:28–33. et al. Effects of nonselective and selective cyclooxygenase in- [39] Beretta C, Garavaglia G, Cavalli M. COX-1 and COX-2 inhibition in hibitors on small intestinal motility in the horse. Res Vet Sci 2009; horse blood by phenylbutazone, flunixin, carprofen and meloxicam: 86:129–35. an in vitro analysis. Pharmacol Res 2005;52:302–6. [15] Subhahar M. Pharmacokinetics and pharmacodynamics of some [40] Moses VS, Hardy J, Bertone AL, Weisbrode SE. Effects of anti- NSAIDs in horses: a pharmacological, biochemical and forensic inflammatory drugs on lipopolysaccharide-challenged and -un- study (doctoral). Preston, United Kingdom: University of Central challenged equine synovial explants. Am J Vet Res 2001;62:54–60. Lancashire; 2013. [41] Lees P, Sedgwick AD, Higgins AJ, Pugh KE, Busch U. Pharmacody- [16] Cox S, Yarbrough J. Determination of firocoxib in equine plasma namics and pharmacokinetics of meloxicam in the horse. Br Vet J using high performance liquid chromatography. J Chromatogr B 1991;147:97–108. Analyt Technol Biomed Life Sci 2011;879:205–8. [42] Toutain PL, Cester CC. Pharmacokinetic-pharmacodynamic rela- [17] Kvaternick V, Pollmeier M, Fischer J, Hanson PD. Pharmacokinetics tionships and dose response to meloxicam in horses with induced and metabolism of orally administered firocoxib, a novel second arthritis in the right carpal joint. Am J Vet Res 2004;65:1533–41. generation coxib, in horses. J Vet Pharmacol Ther 2007;30:208–17. [43] Little D, Brown SA, Campbell NB, Moeser AJ, Davis JL, Blikslager AT. [18] Marshall JF, Bhatnagar AS, Bowman SG, Howard CM, Morris NN, Effects of the cyclooxygenase inhibitor meloxicam on recovery of Skorich DA, et al. Evaluation of the cyclooxygenase selectivity of ischemia-injured equine jejunum. Am J Vet Res 2007;68:614–24. robenacoxib and its effect on recovery of ischemia-injured jejunal [44] de Grauw JC, van de Lest CHA, Brama PAJ, RAmbags BP, van mucosa in horses. Am J Vet Res 2011;72:226–32. Weeren PR. In vivo effects of meloxicam on inflammatory media- [19] Traub-Dargatz JL, Bertone JJ, Gould DH, Wrigley RH, Weiser MG, tors, MMP activity and cartilage biomarkers in equine joints with Forney SD. Chronic flunixin meglumine therapy in foals. Am J Vet acute synovitis. Equine Vet J 2009;41:693–9. Res 1988;49:7–12. [45] MacKinnon M, Southwood LL, Burke MJ, Palmer JE. Colic in equine [20] Carrick JB, Papich MG, Middleton DM, Naylor JM, Townsend HGG. neonates: 137 cases (2000–2010). J Amvet Med Assoc 2013;243: Clinical and pathological effects of flunixin meglumine administra- 1586–95. tion to neonatal foals. Can J Vet Res 1989;53:195–201. [46] Barton MH. Gastrointestinal disease. In: Paradis MR, editor. [21] Semrad SD, Sams RA, Ashcraft SM. Pharmacokinetics of and serum Equine neonatal medicine. Philadelphia: Elsevier Saunders; 2006. thromboxane suppression by flunixin meglumine in healthy foals p. 191–207. during the first month of life. Am J Vet Res 1993;54:2083–7. [47] Lundin CS, Sullins KE, White NA, Clem MF, Debowes RM, Pfeiffer CA. [22] Crisman MV, Wilcke JR, Sams RA. Pharmacokinetics of flunixin Induction of peritoneal adhesions with small intestinal ischaemia meglumine in healthy foals less than twenty-four hours old. Am J and distention in the foal. Equine Vet J 1989;21:451–8. Vet Res 1996;57:1759–61. [48] Sullins KE, White NA, Lundin CS, Dabareiner R, Gaulin G. Prevention [23] Traub JL, Gallina AM, Grant BD, Reed SM, Gavin PR, Paulsen LM. of ischemia-induced small intestinal adhesion in foals. Equine Vet J Phenylbutazone toxicosis in the foal. Am J Vet Res 1983;44:1410–8. 2004;36:370–5. [24] Wilcke JR, Crisman MV, Sams RA, Gerken DF. Pharmacokinetics of [49] Meijer MC, van Weeren PR, Rijkenhuizen AB. Clinical experiences of phenylbutazone in neonatal foals. Am J Vet Res 1993;54:2064–7. treating septic arthritis in the equine by repeated joint lavage: a [25] Breuhaus BA, DeGraves FJ, Honore EK, Papich MG. Pharmacokinetics series of 39 cases. J Vet Med A Physiol Pathol Clin Med 2000;47: of ibuprofen after intravenous and oral administration and assess- 351–65. ment of safety of administration to healthy foals. Am J Vet Res 1999; [50] Neil KM, Axon JE, Todhunter PG, Adams PL, Caron JP, Adkins AR. 60:1066–73. Septic osteitis of the distal phalanx in foals: 22 cases (1995-2002). [26] Wilcke JR, Crisman MV, Scarratt WK, Sams RA. Pharmacokinetics of J Am Vet Med Assoc 2007;230:1683–90. ketoprofen in healthy foals less than twenty-four hours old. Am J [51] Neil KM, Axon JE, Begg AP, Todhunter PG, Adams PL, Fine AE, et al. Vet Res 1998;59:290–2. Retrospective study of 108 foals with septic osteomyelitis. Aust Vet J [27] Raidal SL, Edwards S, Pippia J, Boston R, Noble GK. Pharmacokinetics 2010;88:4–12. and safety of oral administration of meloxicam to foals. J Vet Intern [52] Rubio-Martínez LM, Vázquez FJ, Romero A, Ormazábal JR. Elbow Med 2013;27:300–7. joint luxation in a 1-month-old foal. Aust Vet J 2008;86:56–9. 480 C. Castagnetti, J. Mariella / Journal of Equine Veterinary Science 35 (2015) 475–480

[53] McCann ME, Hunt RJ. Conservative management of femoral diaph- [60] Sekar KC, Corff KE. Treatment of patent ductus arteriosus: indo- yseal fractures in four foals. Cornell Vet 1993;83:125–32. methacin or ibuprofen. J Perinatol 2008;28:60–2. [54] Hance SR, Bramlage LR, Schneider RK, et al. Retrospective study of [61] Bayly WM, Reed SM, Leathers CW, Brown CM, Traub JL, Paradis MR, 38 cases of femur fracture in horses less than one year of age. et al. Multiple congenital heart anomalies in five Arabian foals. J Am Equine Vet J 1992;24:357–63. Vet Med Assoc 1982;181:684–9. [55] Rohde C, Anderson DE, Bertone AL, Weisbrode SE. Effects of phen- [62] Semrad SD, Hardee GE, Hardee MM, Moore JN. Low dose flunixin ylbutazone on bone activity and formation in horses. Am J Vet Res meglumine: effects on eicosanoid production and clinical signs 2000;61:537–43. induced by experimental endotoxaemia in horses. Equine Vet J [56] Brooks DE. Equine ophthalmology. In: Gelatt KN, editor. Veterinary 1987;19:201–6. ophthalmology. Baltimore, Lippincott: Williams and Wilkins; 1998. [63] Semrad SD, Moore JN. Effects of multiple low doses of flunixin p. 1053–116. meglumine on repeated endotoxin challenge in the horse. Prosta- [57] Labelle AL, Hamor RE, Townsend WM, Mitchell MA, Zarfoss MK, glandins Leukot Med 1987;27:169–81. Breaux CB, et al. Ophthalmic lesions in neonatal foals evaluated for [64] Bentley AP, Barton MH, Lee MD, Norton NA, Moore JN. nonophthalmic disease at referral hospitals. J Am Vet Med Assoc Antimicrobial-induced endotoxin and cytokine activity in an 2011;239:486–92. in vitro model of septicemia in foals. Am J Vet Res 2002;63: [58] Amoroso EC, Dawes GS, Mott JC. Patency of the ductus arteriosus in 660–8. the newborn calf and foal. Br Heart J 1958;20:92–6. [65] Wong DM, Sponseller BA, Alcott CJ, Agbedanu PN, Wang C, Hsu WH. [59] Clyman RI, Hardy P, Waleh N, Chen YQ, Mauray F, Fouran JC, et al. Effects of intravenous administration of polymyxin B in neonatal Cyclooxygenase-2 plays a significant role in regulating the tone of foals with experimental endotoxemia. J Am Vet Med Assoc 2013; the fetal lamb ductus arteriosus. Am J Physiol 1999;276:913–21. 243:874–81.