Nonsteroidal anti-inflammatory drugs are commonly used to treat pain and inflammation in horses. Although NSAIDs are generally regarded as safe when used as directed, systemic administration is associated with several serious and potentially life-threatening adverse events, such as injectionsite infections,1 gastrointestinal ulceration and hypoalbuminemia,2–4 and renal papillary necrosis.5–7 The use of NSAIDs in neonatal foals may be further complicated by their increased inherent risk of gastric ulcers,8 compared with the risk in older horses, and increased risk of renal damage with concurrent use of nephrotoxic drugs.9
Neonatal foals may have focal pain and inflammation as a result of pathological conditions, such as trauma, omphalitis, septic physitis, septic arthritis, and tendon contracture or following surgical procedures such as omphalectomy or arthroscopy. Topical administration of NSAIDs represents a novel approach to pain management in equine neonates, targeting the affected area while minimizing the amount of drug in circulation and, consequently, reducing the risk of adverse events.
Diclofenac, a phenylacetic acid derivative, non-selective cyclooxygenase- and lipoxygenase-inhibiting NSAID used in human medicine, is available in various formulations, including topical,10 and has been approved by the US FDA for topical use in adult horses for the management of pain due to chronic osteoarthritis.11 In adult horses, studies have revealed clinical efficacy in reducing signs of lameness caused by naturally occurring and experimentally induced osteoarthritis,11,12 reducing inflammation in horses with experimentally induced inflammation,13 and reducing tissue swelling following IV regional limb perfusion,14 but uncertain efficacy in horses with experimentally induced acute synovitis.15 Diclofenac has been used systemically in human neonates with good efficacy and minimal adverse events,16 but information on its topical use in human or equine neonates is lacking. The purpose of the study reported here was to evaluate the safety of a selected dose of topical 1% diclofenac sodium cream in healthy neonatal foals and determine plasma diclofenac concentrations after application.
Materials and Methods
Animals
Twelve healthy university-owned Arabian and Arabian-pony cross foals (5 males and 7 females) between the ages of 2 and 14 days were used in the study. The foals had been born over a 2-month period in a single foaling season and enrolled in the study on the basis of unremarkable findings of physical examination and CBC, with a plasma IgG concentrationa > 800 mg/dL at 24 hours of age. On enrollment, mean age was 3 days (range, 2 to 7 days) and mean body weight was 37.5 kg (range, 26 to 54 kg). Foals were housed with their dams throughout the study in box stalls on day 1 and on pasture as a small group thereafter. The study protocol was approved by the Washington State University Institutional Animal Care and Use Committee.
Procedures
Foals were randomly assigned to a treatment (n = 6) or control (6) group by means of a web-based random-number generator.b For each foal in the treatment group, a 1.27-cm strip of 1% diclofenac sodium cream containing 7.3 mg of diclofenacc was applied to a clipped 5-cm square over the left tarsometatarsal region, every 12 hours for 7 days. This corresponded to a systemic dose of 0.13 to 0.28 mg/kg/application. For each foal in the control group, an equivalent volume of placebo creamd was applied in an identical manner. The creams were repackaged in clear plastic syringes to maintain blinding of observers and capped to prevent evaporation of product. Latex gloves were worn for application, with the cream massaged into the skin until it was no longer evident, in accordance with the label instructions for the diclofenac cream.
Physiologic data
To evaluate general wellness of the foals, physiologic data, including heart rate, respiratory rate, and rectal temperature, were recorded for each foal daily throughout the study. Foals were observed daily for attitude, nursing activity, presence and character of manure and urine, and abnormalities at the site of topical application. Body weight was measured daily with an electronic scale.
Laboratory data
A jugular venous blood sample was collected via a 20-gauge needle from each foal daily for evaluation of PCV (via microhematocrit tube centrifugation) and plasma protein concentration (via handheld refractometer). A urine sample was collected from each foal on multiple days throughout the study for measurement of urine specific gravity with a handheld refractometer. On days 0 (day immediately preceding the first day of cream application) and 7 of the study, a jugular venous blood sample was collected for CBC and serum biochemical analysis and a free-catch urine sample was obtained for urinalysis, which included measurement of urine GGT-to-creatinine ratio.
Endoscopy
Gastric endoscopy was performed on days 0 and 7 of the study, with horses manually restrained. Foals were muzzled for 1 hour prior to the procedure to allow clearance of gastric contents. Endoscopic examinations were performed by one of the authors (SEB), who used a 1-m pediatric endoscope. Video recordings were obtained and randomizedb for evaluation by 3 blinded observers (KKS, DCS, and SEB) after completion of the study. A scoring system was used as reported elsewhere17 to characterize the degree of gastric ulcer severity, and the mean of the 3 observers’ scores was calculated for each examination. Briefly, grade 0 indicated that the epithelium was intact with no hyperemia or hyperkeratosis; grade 1 indicated intact mucosa with areas of hyperemia or hyperkeratosis; grade 2 indicated the presence of small, single, or multifocal lesions; grade 3 indicated the presence of large, single, or multifocal lesions or extensive superficial lesions; and grade 4 indicated the presence of extensive lesions with areas of apparent deep ulceration.
Ultrasonographic examination
Ultrasonographic examination of the kidneys and right dorsal colon was performed on days 0 and 7 of the study, with horses manually restrained. Evaluations were performed by a board-certified radiologist and resident in radiology as previously described.18 Two measurements were made of the thickness of the wall of the right dorsal colon, and the mean value was calculated for analysis. Subjective evaluations of renal architecture were recorded for each examination. Individuals performing ultrasonography were unaware of the groups to which foals had been assigned.
Diclofenac assay
To allow collection of blood samples for measurement of plasma diclofenac concentration, a catheter was placed aseptically in the left or right jugular of each horse. On day 1, blood samples (6 mL each) were collected into EDTA tubes via the catheter immediately before (0 hours) and 1, 2, 4, 6, 8, and 12 hours following the first application of cream. The catheter was removed after the 12-hour collection point, and blood samples (6 mL each) were collected via 20-gauge needle from a jugular or cephalic vein immediately prior to the morning application of cream at 24, 48, 72, 96, 120, 144, 156, and 168 hours after the first application. Plasma was separated by centrifugation of blood samples within 1 hour after collection and stored at −80°C until analysis.
Plasma diclofenac concentration was measured by tandem LC-MS analysis of protein-precipitated plasma samples. Diclofenac working solutions were prepared by dilution of the stock solutione with methanol to yield concentrations of 10, 1, 0.1, 0.01, and 0.001 ng/mL. Calibrators were prepared by dilution of the working solutions with drug-free equine plasma to yield concentrations of 0.01, 0.02, 0.05, 0.1, 0.5, 1.0, 2.0, 5.0, 7.5, and 10 ng/mL. Calibration curves and negative control samples were prepared fresh for each quantitative assay. In addition, quality control samples (6 replicates of equine plasma fortified with diclofenac at 2 concentrations within the standard curve) were included as an additional check of accuracy.
Prior to LC-MS analysis, 400 μL of plasma was diluted with 500 μL of a combination of acetonitrile and 1M acetic acid (ratio of 9:1 [vol:vol]) containing the internal standard flufenamic acide (10 ng/mL) to precipitate proteins. For calibrators and samples, water was added to bring the final volume to 1,050 μL. The samples were vortexed for 2 minutes to mix, refrigerated at 4°C for 30 minutes, vortexed for an additional minute, and centrifuged (3,102 × g) for 10 minutes at 4°C. Then, 50 μL of sample was injected into the LC-MS system.
Quantitative analyses were by use of a triple quadrupole MS devicef coupled with an LC system.g Chromatography involved use of a C18 columnh and a linear gradient of acetonitrile in water, with a constant flow rate of 0.2% formic acid at 0.35 mL/min. The acetonitrile concentration was held at 10% for 0.3 minutes and subsequently ramped up to 95% over a 5.0-minute period and re-equilibrated for 3.5 minutes at initial conditions.
Detection and quantification involved full-scan LC-MS-MS transitions of initial product ions for diclofenac (m/z, 296). The response for the major product ion for diclofenac (m/z, 214 + 179) was plotted, and peaks at the proper retention time were integrated by use of quantitative data-reviewing software.i The concentration of diclofenac in each sample (calibrators, quality control samples, and unknowns) was determined by an internal-standard method by use of the peak-area ratio and linear regression analysis.
The response for diclofenac was linear and yielded a coefficient of determination (R2) of ≥ 0.99. The technique was optimized to provide a limit of quantitation of 0.05 ng/mL. The interday, intraday, and interanalyst precision and accuracy of the assay were determined by assaying quality control samples in replicates (n = 6) for diclofenac. Precision was calculated as percentage of the relative SD and accuracy as percentage of nominal concentration. Intraday accuracy was 93% for diclofenac concentrations of 0.6 ng/mL and 106% for 4.0 ng/mL. Interday accuracy was 98% for 0.6 ng/mL and 102% for 4.0 ng/mL. Intraday precision was 14% for 0.6 ng/mL and 13% for 4.0 ng/mL. Interday precision was 11% for 0.6 ng/mL and 11% for 4.0 ng/mL.
Statistical analysis
Statistical analyses were performed with the aid of statistical software.j,k Values of continuous variables are reported as mean ± SD. Initial ages and body weights of foals in the control and treatment groups were compared with the 2-tailed t test. Daily values of physiologic and laboratory variables (ie, rectal temperature, heart rate, respiratory rate, urine specific gravity, PCV, plasma protein concentration, and body weight) were compared between and within treatment groups by use of 2-way repeated measures ANOVA with the Bonferroni t test for multiple post hoc comparisons when appropriate. Clinical laboratory data, equine gastric ulceration scores, and right dorsal colon thicknesses were similarly compared by use of a similar approach. Categorical data related to incidence of skin abnormalities and diarrhea in foals were compared between treatment groups by use of the Fisher exact test. For all analyses, values of P < 0.05 were considered significant.
Results
Animals
One foal in the control group developed a fever and signs of lethargy on day 5 of the study. This foal was removed from the study, and flunixin meglumine was administered IV. The cause of illness was subsequently identified via PCR analysis of a nasal swab specimen obtained during the febrile period as the N752 strain of equine herpesvirus type 1, and the foal responded well to supportive care. Consequently, data from this foal were not included in the final analysis and another foal was assigned to the control group to maintain a sufficient sample size. The substitute foal received the full control treatment (from days 0 to 7).
All included foals fully completed the study. On day 1 of the study (first day of cream application), mean ± SD age of the 6 foals in the control group to which the placebo cream was topically applied (3.0 ± 2.0 days; range, 2 to 7 days) was similar (P = 0.60) to that of the 6 foals in the treatment group to which the 1% diclofenac sodium cream was similarly applied (3.5 ± 1.0 days; range, 2 to 5 days). Mean body weight in the control group (36.1 ± 10.0 kg; range, 27.7 to 51.8 kg) was also similar (P = 0.64) to that in the treatment group (39.0 ± 10.4 kg; range, 25.9 to 54.1 kg). Although mean body weight of foals in both groups increased significantly between days 1 and 7, no significant difference in weight gain was identified between the groups.
Physiologic and clinical laboratory data
No significant differences were identified in physiologic data (heart rate, respiratory rate, and rectal temperature) or daily laboratory data (urine specific gravity, PCV, and plasma protein concentration) within the treatment and control groups over time or between the groups. The potential adverse effects of treatment on foals were evaluated by comparison of laboratory test results (CBC and serum biochemical analysis) obtained on days 1 and 7 of cream application for foals within the control and treatment groups. Values that increased significantly with time in both groups included total WBC, neutrophil, lymphocyte, and platelet counts; serum GGT and aspartate aminotransferase activities; and urine pH. Values that decreased significantly over time in both groups included serum creatinine and glucose concentrations. There was no significant effect of group (control or treatment) on these variables.
A significant difference was identified between control and treatment groups on day 1 for blood monocyte count, serum alkaline phosphatase activity, and serum bilirubin concentration. On day 1, foals in the control group had a significantly lower mean monocyte count and serum calcium concentration and higher mean serum alkaline phosphatase activity and bilirubin concentration than did foals in the treatment group.
Potential adverse renal effects of diclofenac were investigated by comparisons between control and treatment groups of serum creatinine concentrations, BUN concentrations, urine GGT-to-creatinine ratios, urinalysis results, and renal ultrasonography results (Table 1). No significant interactions between group and assessment time were detected for any of the measured renal variables, and no foals had any detectable abnormalities on renal ultrasonography. Two foals (1/group) had a high GGT-to-creatinine ratio for urine samples collected after the final cream application. In both situations, the increase was associated with an increase in the GGT portion of the ratio.
Mean ± SD values of renal variables for neonatal foals to which 1% diclofenac sodium cream* (n = 6; treatment group) or an equivalent amount of placebo cream (6; control group) was applied topically to shaved skin over the anterolateral aspect of the left tarsometatarsal region every 12 hours for 7 days, beginning on day 1.
| Control group | Treatment group | ||||||
|---|---|---|---|---|---|---|---|
| Variable | Day 1 | Day 7 | Day 1 | Day 7 | P value for group effect | P value for time effect | P value for group-by-time interaction |
| BUN (mg/dL) | 11.3 ± 4.1 | 8.7 ± 5.3 | 8.2 ± 2.7 | 6.8 ± 1.3 | 0.17 | 0.15 | 0.62 |
| Serum creatinine (mg/dL) | 1.0 ± 0.3 | 0.7 ± 0.1 | 0.9 ± 0.2 | 0.7 ± 0.2 | 0.54 | 0.006 | 0.18 |
| Urine GGT-to-creatinine ratio | 0.618 ± 0.213 | 0.925 ± 1.396 | 0.816 ± 0.294 | 1.226 ± 1.997 | 0.65 | 0.46 | 0.92 |
| Urine specific gravity | 1.004 ± 0.001 | 1.007 ± 0.005 | 1.004 ± 0.002 | 1.004 ± 0.003 | 0.41 | 0.25 | 0.37 |
| Urine pH | 5.9 ± 0.8 | 7.2 ± 0.5 | 6.4 ± 0.9 | 7.5 ± 0.7 | 0.38 | 0.004 | 0.47 |
A 1.27-cm strip of cream containing 7.3 mg of diclofenac sodium was applied.
Potential adverse gastrointestinal and hepatic effects of diclofenac were investigated by comparisons between control and treatment groups of serum total protein, total bilirubin, and albumin concentrations; serum GGT and sorbitol dehydrogenase activities; gastric endoscopy scores; and thicknesses of the wall of the right dorsal colon (Table 2). No significant interactions between group and assessment time were detected for any of the measured variables, except for a decrease in serum total bilirubin concentration over time in the control group. No foals had detectable abnormalities on ultrasonography of the right dorsal colon. For 3 foals in the treatment group and 2 foals in the control group, > 1 incident of watery feces was observed during the study period; no difference in proportions of foals with diarrhea was identified between groups. No foals required treatment for diarrhea.
Values of gastrointestinal and hepatic function variables for the foals in Table 1.
| Control group | Treatment group | ||||||
|---|---|---|---|---|---|---|---|
| Variable | Day 1 | Day 7 | Day 1 | Day 7 | P value for group effect | P value for time effect | P value for group-by-time interaction |
| Serum albumin (g/dL) | 3.3 ± 0.3 | 3.7 ± 0.3 | 3.3 ± 0.2 | 3.3 ± 0.1 | 0.65 | 0.83 | 0.29 |
| Serum GGT (U/L) | 26.3 ± 6.0 | 43.0 ± 17.7 | 46.7 ± 29.3 | 54.5 ± 27.1 | 0.21 | 0.03 | 0.38 |
| Serum sorbitol dehydrogenase (U/L) | 4.8 ± 1.3 | 7.2 ± 7.3 | 7.2 ± 6.8 | 6.0 ± 3.1 | 0.82 | 0.73 | 0.31 |
| Serum total bilirubin (mg/dL) | 2.6 ± 0.8 | 1.5 ± 0.3 | 1.9 ± 0.9 | 1.5 ± 0.5 | 0.36 | < 0.001 | 0.04† |
| Gastric ulceration score* | 2 | 1 | 2 | 0.5 | 1.00 | 0.01 | 0.07 |
| Right dorsal colon thickness (mm) | 1.7 ± 0.3 | 1.7 ± 0.5 | 1.7 ± 0.3 | 1.8 ± 0.1 | 0.89 | 0.28 | 0.38 |
Gastric ulceration scores17 (0 = intact epithelium with no hyperemia or hyperkeratosis; 1 = intact mucosa with areas of hyperemia or hyperkeratosis; 2 = small, single or multifocal lesions; 3 = large, single, or multifocal lesions or extensive superficial ulcerations; 4 = extensive lesions with areas of apparent deep ulceration) are reported as median values; all other variables are reported as mean ± SD.
Mean serum total bilirubin concentration changed significantly (P < 0.05) over time in the control group but not in the treatment group.
Three foals in the treatment group developed mild skin exfoliation at the treated area during the study period. Four foals in the control group developed similar lesions. Lesions in all foals were mild and specific treatment was not required.
Diclofenac assay
Transdermal absorption of diclofenac in the treatment group of foals was rapid, with peak plasma concentrations reached within 2 hours after first application (Figure 1). With twice daily application of the 1% diclofenac sodium cream, the amount of diclofenac appeared to accumulate in plasma over the study period, with a rapid decline in plasma concentrations following discontinuation of treatment. Maximum diclofenac concentration remained < 1 ng/mL at all assessment times in all foals.
Mean plasma concentrations of diclofenac in 6 neonatal foals at various times after first topical application (0 hours) of a 1.27-cm strip of cream containing 7.3 mg of diclofenac sodium to shaved skin over the anterolateral aspect of the left tarsometatarsal region every 12 hours for 7 days. Error bars represent SD.
Citation: American Journal of Veterinary Research 78, 4; 10.2460/ajvr.78.4.405
Mean plasma concentrations of diclofenac in 6 neonatal foals at various times after first topical application (0 hours) of a 1.27-cm strip of cream containing 7.3 mg of diclofenac sodium to shaved skin over the anterolateral aspect of the left tarsometatarsal region every 12 hours for 7 days. Error bars represent SD.
Citation: American Journal of Veterinary Research 78, 4; 10.2460/ajvr.78.4.405
Mean plasma concentrations of diclofenac in 6 neonatal foals at various times after first topical application (0 hours) of a 1.27-cm strip of cream containing 7.3 mg of diclofenac sodium to shaved skin over the anterolateral aspect of the left tarsometatarsal region every 12 hours for 7 days. Error bars represent SD.
Citation: American Journal of Veterinary Research 78, 4; 10.2460/ajvr.78.4.405
Discussion
The goal of the study reported here was to determine whether topical application of a 1% diclofenac sodium cream to neonatal foals every 12 hours for 7 days was associated with adverse events. All foals remained apparently healthy and gained weight as expected. Although the treatment group contained a higher proportion of foals with diarrhea than did the control group, the difference between groups was not significant, and the diarrhea was not associated with other expected signs of right dorsal colitis secondary to toxic effects of NSAID administration, such as hypoalbuminemia and thickening of the wall of the right dorsal colon. The diarrhea was also transient, self-limiting, and not associated with dehydration in any foal. Because of the young age of the foals in the study, so-called foal heat diarrhea was considered the likely nature of this ailment, although various viral or bacterial agents may have contributed.
No abnormalities of the topical application sites were identified that could be attributed to the diclofenac cream. In adult horses, this medication may be applied on top of the skin without clipping of hair. On the other hand, clinical use in neonates is likely to occur in conjunction with surgery or ultrasonography of inflamed sites, situations in which hair is likely to be clipped. The clipping process may have caused scratches on the study foals or left the clipped areas exposed to rubbing and irritation from the environment. In all foals, identified abnormalities at the application site were mild and focal, and did not require discontinuation of treatment, and all foals had a usual amount of hair growth and an unremarkable skin appearance 2 to 6 months after the study concluded. The study was not designed to evaluate whether any increase in irritation could be expected when the cream is applied to inflamed skin or to skin covered by a bandage (as may occur at surgical sites).
No significant differences were identified between treatment and control groups in values of variables indicating renal health. After the final cream application, 1 foal in each group had a high urine GGT-to-creatinine ratio, which was attributed to the GGT component of the ratio. Urinary GGT is produced by renal tubular epithelial cells, and urine GGT activity increases in conditions that cause damage to these cells, such as the toxic effects caused by aminoglycoside or NSAID administration, although doubling of urine GGT activity in 1 report19 was not associated with other clinical signs of NSAID-induced toxic effects. After the final assessment time, the foals had no other indicators of tubular damage such as urine casts, and results of urinalysis indicated they were appropriately hyposthenuric, with no evidence of dehydration that may be associated with a prerenal insult and increase in urine GGT activity.20 Both posttreatment urine samples contained a small amount of blood; the importance of this in contributing to high urinary GGT activity in horses is unreported, although GGT activity in erythrocytes is reported to be quite low.21
Toxic effects of NSAID administration have been linked to glandular and nonglandular gastric ulcers postulated to result from impairment of mucosal blood flow and protective mechanisms in the glandular portion of the stomach. Neonates may have delayed maturation of these mechanisms, compared with maturation in older horses, placing them at high risk of gastric ulcers.22 No difference in gastric ulceration scores was identified between treatment and control groups. Many foals had evidence of nonglandular ulceration at the beginning of the study with no associated clinical signs, such as colic, bruxism, or inappetence, consistent with previous reports.8,22 Over the study period, ulceration scores decreased in both groups without specific treatment.
Ultrasonographic evidence of increased mural thickness of the right dorsal colon23 and of renal corticomedullary hyperechogenicity6,7 has been identified in horses and foals with toxic effects of NSAID administration. Although the entire right dorsal colon cannot be visually examined ultrasonographically, other clinicopathologic findings such as hypoproteinemia secondary to hypoalbuminemia can accompany development of right dorsal colitis, and such findings were not identified in the study foals. Additionally, renal ultrasonographic abnormalities may exist in the absence of clinicopathologic indicators of renal dysfunction,6 so these ultrasonographic findings combined with clinicopathologic findings provide a more complete picture when evaluating these body systems.
The dose of diclofenac administered to foals in the present study was easily applied to the clipped 5-cm square test area, but up to 1 minute of massaging was required for the cream to appear completely absorbed. Foals appeared to tolerate the procedure well with light manual restraint. Because effective concentrations of diclofenac at the tissue level are unknown in horses, and there appears to be no direct correlation among systemic concentrations, tissue concentrations, and analgesic efficacy, the study dose was extrapolated from that reported for the treatment of osteoarthritis in adult horses, which appears effective in managing pain and inflammation in clinical trials.11,12,14
The label dose for an adult 500-kg horse is a 12.7-cm strip of 1% diclofenac sodium cream containing 73 mg of diclofenac applied twice daily for up to 10 days. Because a typical foal may be expected to weigh 50 kg, 10% of the adult dose was used in the present study (1.27-cm strip estimated to contain 7.3 mg of diclofenac). Body size of foals was not directly correlated with plasma diclofenac concentrations (data not shown). Many of the study foals weighed < 50 kg, but no toxic effects were identified even in the smallest foals, and the maximum plasma concentration of drug achieved in any foal was 0.98 ng/mL. The toxic concentration of diclofenac in horses has not been reported to the authors’ knowledge, but serum concentrations in adult horses of up to 10 ng/mL reportedly can be attained without adverse systemic effects.24
Peak plasma concentrations of diclofenac in neonatal foals in the present study were less than reported peak serum concentrations in adult horses in previous studies.15,24 Systemic concentrations are influenced by absorption, distribution, metabolism, and elimination. In humans, diclofenac may concentrate in the skin after topical application,10 and differences in skin thickness could affect systemic concentrations. The skin of neonatal foals is thinner than that of adult horses, and more rapid absorption, possibly with higher systemic concentration, could therefore be expected in foals, but this was not observed in the foals of the present study.
Foals differ from adult horses in many physiologic processes that may affect drug metabolism and excretion. They have lower plasma protein concentrations and therefore lower degrees of protein-binding of drugs and can have immature metabolic and excretory pathways for some drugs.25 The higher total body water percentage of foals may also account for apparently lower systemic drug concentrations than in adult horses.
A limitation of the study reported here was lack of determination of the analgesic efficacy of diclofenac when applied topically. Efficacy may be associated with local tissue or systemic drug concentrations, but the effective diclofenac concentration is unknown in foals or adult horses. Most research to date has involved evaluation of the efficacy of diclofenac on the basis of improvement in lameness scores or markers of inflammation, which cannot be done in a healthy animal without experimental intervention. Determination of effective local or systemic concentrations of diclofenac in neonatal and adult horses remains a goal for further research and would assist in optimizing treatment regimens involving this medication.
In the study reported here, 1% diclofenac sodium cream applied topically to shaved skin over the tarsometatarsal region every 12 hours for 7 days in healthy neonatal foals appeared safe and plasma concentrations of diclofenac were quite low, suggesting minimal systemic absorption. Although analgesic efficacy of diclofenac has not been demonstrated, practitioners may consider using this cream in managing focal sources of pain and inflammation in neonatal foals.
Acknowledgments
Dr. Sellon has served on the Research Award Selection Committee for Boehringer Ingelheim Vetmedica since May 2015.
Presented in part as a poster at the Annual Forum of the American College of Veterinary Internal Medicine, New Orleans, May-June 2012.
The authors thank Drs. Bob Mealey and Dana Neelis for technical assistance
ABBREVIATIONS
| GGT | γ-glutamyltransferase |
| LC | Liquid chromatography |
| MS | Mass spectrometry |
Footnotes
SNAP foal IgG, Idexx Laboratories, Westbrook, Me.
RANDOM.ORG, Randomness and Integrity Services Ltd, Dublin, Ireland. Available at: www.random.org. Accessed Apr 3, 2011.
Surpass, Boehringer Ingelheim, St. Joseph, Mo.
Cetaphil moisturizing lotion, Galderma Laboratories LP, Fort Worth, Tex.
Sigma Aldrich, St Louis, Mo.
TSQ Quantum Ultra, Thermo Scientific, San Jose, Calif.
Agilent Technologies, Palo Alto, Calif.
Discovery C18, 50 × 2.1 mm, 3-μm column, Supelco, State College, Pa.
Quan Browser, LCQuan software, Thermo Scientific, San Jose, Calif.
GraphPad Prism, version 5.01, GraphPad Software, San Diego, Calif.
Sigma Stat, version 3.5, Jandel Scientific, San Jose, Calif.
References
1. Mitten LA, Hinchcliff KW, Holcombe SJ, et al. Mechanical ventilation and management of botulism secondary to an injection abscess in an adult horse. Equine Vet J 1994; 26: 420–423.
2. Lees P, Creed RF, Gerring EE, et al. Biochemical and haematological effects of phenylbutazone in horses. Equine Vet J 1983; 15: 158–167.
3. MacAllister CG, Morgan SJ, Borne AT, et al. Comparison of adverse effects of phenylbutazone, flunixin meglumine, and ketoprofen in horses. J Am Vet Med Assoc 1993; 202: 71–77.
4. McConnico RS, Morgan TW, Williams CC, et al. Pathophysiologic effects of phenylbutazone on the right dorsal colon in horses. Am J Vet Res 2008; 69: 1496–1505.
5. Gunson DE, Soma LR. Renal papillary necrosis in horses after phenylbutazone and water deprivation. Vet Pathol 1983; 20: 603–610.
6. Léveillé R, Miyabayashi T, Weisbrode SE, et al. Ultrasonographic renal changes associated with phenylbutazone administration in three foals. Can Vet J 1996; 37: 235–236.
7. Read WK. Renal medullary crest necrosis associated with phenylbutazone therapy in horses. Vet Pathol 1983; 20: 662–669.
8. Murray MJ, Murray CM, Sweeney HJ, et al. Prevalence of gastric lesions in foals without signs of gastric disease: an endoscopic survey. Equine Vet J 1990; 22: 6–8.
9. Riviere JE, Coppoc GL, Hinsman EJ, et al. Species dependent gentamicin pharmacokinetics and nephrotoxicity in the young horse. Fundam Appl Toxicol 1983; 3: 448–457.
10. Kienzler JL, Gold M, Nollevaux F. Systemic bioavailability of topical diclofenac sodium gel 1% versus oral diclofenac sodium in healthy volunteers. J Clin Pharmacol 2010; 50: 50–61.
11. Lynn RC, Hepler DI, Kelch WJ, et al. Double-blinded placebo-controlled clinical field trial to evaluate the safety and efficacy of topically applied 1% diclofenac liposomal cream for the relief of lameness in horses. Vet Ther 2004; 5: 128–138.
12. Frisbie DD, McIlwraith CW, Kawcak CE, et al. Evaluation of topically administered diclofenac liposomal cream for treatment of horses with experimentally induced osteoarthritis. Am J Vet Res 2009; 70: 210–215.
13. Caldwell FJ, Mueller PO, Lynn RC, et al. Effect of topical application of diclofenac liposomal suspension on experimentally induced subcutaneous inflammation in horses. Am J Vet Res 2004; 65: 271–276.
14. Levine DG, Epstein KL, Neelis DA, et al. Effect of topical application of 1% diclofenac sodium liposomal cream on inflammation in healthy horses undergoing intravenous regional limb perfusion with amikacin sulfate. Am J Vet Res 2009; 70: 1323–1325.
15. Schleining JA, McClure SR, Evans RB, et al. Liposome-based diclofenac for the treatment of inflammation in an acute synovitis model in horses. J Vet Pharmacol Ther 2008; 31: 554–561.
16. Standing JF, Ooi K, Keady S, et al. Prospective observational study of adverse drug reactions to diclofenac in children. Br J Clin Pharmacol 2009; 68: 243–251.
17. Council EGU. Recommendations for the diagnosis and treatment of equine gastric ulcer syndrome (EGUS). Equine Vet Educ 1999; 11: 262–272.
18. Reef VB. Recent advances in equine abdominal ultrasonography of the foal, in Proceedings. 8th Cong Equine Med Surg 2003.
19. Breuhaus BA, DeGraves FJ, Honore EK, et al. Pharmacokinetics of ibuprofen after intravenous and oral administration and assessment of safety of administration to healthy foals. Am J Vet Res 1999; 60: 1066–1073.
20. Nejat M, Pickering JW, Devarajan P, et al. Some biomarkers of acute kidney injury are increased in pre-renal acute injury. Kidney Int 2012; 81: 1254–1262.
21. Braun JP, Benard P, Burgat V, et al. Gamma glutamyl transferase in domestic animals. Vet Res Commun 1983; 6: 77–90.
22. Andrews FM, Nadeau JA. Clinical syndromes of gastric ulceration in foals and mature horses. Equine Vet J Suppl 1999; 29: 30–33.
23. Jones SL, Davis J, Rowlingson K. Ultrasonographic findings in horses with right dorsal colitis: five cases (2000–2001). J Am Vet Med Assoc 2003; 222: 1248–1251.
24. Anderson D, Kollias-Baker C, Colahan P, et al. Urinary and serum concentrations of diclofenac after topical application to horses. Vet Ther 2005; 6: 57–66.
25. Baggot JD, Short CR. Drug disposition in the neonatal animal, with particular reference to the foal. Equine Vet J 1984; 16: 364–367.
