Clinical Effects of Short-Term Oral Budesonide on the Hypothalamic-Pituitary-Adrenal Axis in Dogs With Inflammatory Bowel Disease
Six dogs were entered into a 30-day, prospective, nonrandomized, uncontrolled clinical trial evaluating the effects of an oral preparation of budesonide on the hypothalamic-pituitary-adrenal (HPA) axis during therapeutic management of active inflammatory bowel disease. Oral budesonide, at a dose of 3 mg/m2, was administered once daily. Upon entry and completion of the trial, serum basal cortisol, adrenocorticotropic (ACTH)-stimulated cortisol, endogenous ACTH concentration, serum alkaline phosphatase (SAP) activity, and urine specific gravity were evaluated, as well as owner assessment of glucocorticoid-associated side effects. Significant suppression of the HPA axis occurred. No significant differences in SAP activity, urine specific gravity, or owner-subjective assessments were detected.
Introduction
Inflammatory bowel disease (IBD) refers to a group of chronic gastrointestinal disorders characterized by infiltration of the gastrointestinal tract with inflammatory cells. This condition is a common disorder in dogs and can be associated with chronic vomiting, diarrhea, weight loss, or a combination of these signs. Since first recognized as a clinical syndrome in dogs, little progress has been made in defining the underlying cause, the effects of intestinal dysfunction, optimal therapy, and long-term prognosis associated with IBD. To date, it has been suggested that glucocorticoids (GCs) are the drugs of choice for the treatment of canine patients with IBD.1 Unfortunately, their use is often limited by the side effects of iatrogenic hyperadrenocorticism. Recently, new GC analogues have been developed that have potent topical anti-inflammatory activity but low systemic activity owing to their strong affinity for GC receptors and rapid hepatic conversion to metabolites with minimal biological activity.2
Budesonide is a GC analogue that is metabolized to forms with minimal or no steroidal activity. Up to 90% of the drug is metabolized during its first pass through the liver in humans.3 In humans, this drug has potent topical anti-inflammatory activity within the intestinal lumen and considerably less systemic activity than conventional GCs. Oral budesonide has demonstrated similar efficacy compared to oral prednisolone in the treatment of humans with active Crohn’s disease, and it has produced fewer GC-associated side effects and less suppression of the hypothalamic-pituitary-adrenal (HPA) axis.2–8 To date, information describing the effects of oral budesonide on the HPA axis in dogs is lacking in the literature. The purpose of this study was to evaluate the effects of an oral preparation of budesonide on the HPA axis during therapeutic management of active canine IBD.
Materials and Methods
Study Design
The study was a 30-day, prospective, nonrandomized, noncontrolled clinical trial. Oral budesonide, at a dose of 3 mg/m2 (to the closest mg), was administered once daily for the extent of the trial. This research was reviewed and approved by the Review Committee of the Caspary Research Institute at the Animal Medical Center.
Study Population
Six client-owned dogs were enrolled in the study. Dogs of any age and either sex with a biopsy diagnosis of idiopathic IBD were eligible for enrollment. Immunosuppressive drugs were not allowed prior to enrollment, and those animals receiving either oral or topical GCs within 4 weeks of enrollment were excluded. All owners were informed of the nature of the study and gave written, informed consent prior to enrollment.
Therapeutic Agent
The budesonidea utilized for the study was formulated from pure powder-based budesonide and placed in gelatin capsules composed of lactose and ethylcellulose. The capsules were acquired through a prescription drug compounding service.
Objective Evaluation
The following parameters were measured at the time of entry and upon completion of the trial in each animal: serum basal and adrenocorticotropic hormone (ACTH)-stimulated cortisol concentrations, endogenous plasma ACTH concentrations, serum alkaline phosphatase (SAP) activity, and urine specific gravity (USG). Urine specific gravity was measured as a marker for polyuria (PU) to provide possible evidence of antidiuretic (ADH) resistance secondary to exogenous GC administration.
Subjective Evaluation
Owners were provided with a questionnaire that contained criteria to assess the frequency of clinical signs that may have indicated the presence of GC-related side effects. Each owner subjectively quantified water intake, micturition frequency, and appetite prior to initiation and upon completion of the trial. Utilizing a numerical scoring system, each variable was assessed and scored. Water and food intake were scored separately but with the same scoring system; 0 indicated complete refusal, 1 indicated one-fourth normal intake, 2 indicated half normal intake, 3 indicated normal intake, and 4 indicated greater-than-normal intake. Micturition frequency, defined as the average number of urinations observed per day, was scored as either one to five occurrences or six and greater. The data was used to identify potential GC-related side effects associated with administration of budesonide.
Statistical Analysis
For all objective variables assessed, two-sided, paired, student’s t-tests were used to compare results measured before and after treatment with budesonide. Using the Wilcoxon’s signed rank test, owner survey assessment results at the time of entrance were compared to results observed following treatment. A P value of ≤0.05 was considered statistically significant.
Results
Mean (±standard deviation [SD]) basal serum cortisol concentration was 3.3 μg/dL (±1.9 μg/dL) pretreatment and 0.8 μg/dL (±0.7 μg/dL) postbudesonide treatment (reference range, 5.5 to 20.0 μg/dL), demonstrating a significant decrease after the 30-day trial (P=0.0276) [Figure 1]. Mean pretreatment and posttreatment ACTH-stimulated serum cortisol concentrations were 12.6 μg/dL (±2.7 μg/dL) and 3.0 μg/dL (±2.5 μg/dL), respectively (reference range, 5.5 to 20.0 μg/dL), denoting a significant decrease after the 30-day trial (P=0.0006) [Figure 2]. Mean serum endogenous ACTH concentration prior to therapy was 75.0 pg/mL (±23.3 pg/mL) and was 52.3 pg/mL (±22.6 pg/mL) upon completion of the trial (reference range, 20.0 to 80.0 pg/mL), also indicating a significant decrease (P=0.0397) [Figure 3]. No significant change (P=0.402) in mean SAP activity was noted before (110 U/L [±97 U/L]) and after (304 U/L [±581 U/L]) treatment (reference range, 5 to 131 U/L). Mean USG was 1.034 before the study and 1.036 upon completion, so no significant change of this parameter occurred during the trial (P=0.6993).
No significant change (P=1.000) in mean water consumption was noted before (3.2 [±0.4]) and after (3.3 [±0.5]) treatment. Mean micturition frequency was 3.5 (±0.6) before and 4.2 (±0.8) after treatment (no significant change, P=0.250). Mean appetite was not significantly different before (2.8 [±0.8]) and after (3.0 [±0.6]) budesonide treatment (P=1.000).
Discussion
Although glucocorticoids currently represent the primary treatment for canine IBD, their therapeutic value is sometimes outweighed by severe systemic side effects, especially with their long-term use. Prolonged usage is associated with the development of iatrogenic hyperadrenocorticism and suppression of the HPA axis. Commonly seen side effects may include PU, polydipsia (PD), polyphagia, hyperventilation, urinary tract infection, and steroid hepatopathy. Severe side effects are often associated with reduced owner compliance with medication administration, resulting in a reduced therapeutic effect.
Newer GCs with low systemic bioavailability have recently been developed in an attempt to overcome the systemic side effects of steroid therapy while maintaining the therapeutic benefits. These newer drugs are characterized by a high affinity for the local GC receptors and an increased hepatic first-pass effect, resulting in metabolic products with a high topical efficacy at the target organ and decreased frequency of unwanted systemic side effects.9 These drugs are particularly suitable for treating local inflammation at mucosal surfaces. In an inflamed intestinal tract, the enhanced hepatic first-pass effect is key in reducing systemic GC effects after leaving the target organ.10
Budesonide is a new GC analogue with high topical potency and lower systemic activity than conventional GCs. Budesonide has been found to be effective in inducing short-term remission of Crohn’s disease in people.2–5 Budesonide has been used successfully to maintain remission and reduce GC-related side effects in people with IBD, especially when compared to patients managed with more traditional GC therapy.711 Despite reported hepatic first-pass metabolism of up to 90%, side effects such as adrenal insufficiency have occurred with budesonide administration in people.6 Up to 50% of Crohn’s disease patients demonstrated impaired adrenal function following administration of budesonide at 9 mg per day, as measured by the ACTH-stimulation test.5 The incidence of side effects attributed to adrenal insufficiency associated with budesonide administration in humans has not yet been elucidated. Information regarding the effects of oral budesonide on the HPA axis and associated side effects in dogs has yet to be reported.
This study demonstrated that oral budesonide significantly suppresses the HPA axis in treated dogs. Measurement of basal plasma cortisol concentrations has limitations as an indicator of pituitary-adrenal function,12 so results of ACTH-stimulation tests were evaluated instead. The ACTH-stimulation test is considered more accurate in identifying suppression of the HPA axis. Results of this study indicate that after a 1-month treatment period, a significant proportion of dogs exhibited suppression of adrenal function, as indicated by a significant decrease in ACTH-stimulated serum cortisol concentrations. This suppression is further supported by a significant decrease in endogenous ACTH concentrations following completion of the trial.
The clinical importance of biochemical suppression of the HPA axis after short-term therapy is controversial, because tests of pituitary-adrenal function do not consistently correlate with responses to stress.13 Mild suppression of the HPA axis may not result in clinical manifestations of adrenal insufficiency. The functional recovery of the pituitary-adrenal axis in dogs treated with more traditional corticosteroids for long periods is slow, and adrenal insufficiency may occur during the recovery period. The extent to which long-term therapy with budesonide may cause pituitary-adrenal suppression is not known.
Although this study demonstrated suppression of the HPA axis after budesonide administration, the proportion of dogs with GC-associated side effects was not significantly different between the pre- and posttrial populations. This finding may be attributed to the nearly complete hepatic first-pass effect resulting in a very low systemic bioavailability after oral administration. The development of PU/PD associated with traditional GC therapy is not commonly seen in humans, yet it is commonly observed in dogs and may be a result of a combination of mineralocorticoid and glucocorticoid effects. These effects may include interference with the action of ADH at the level of the renal collecting tubules, an increase in glomerular filtration rate initiating diuresis, direct depression of renal tubular permeability to water, and cortisol-induced interference with ADH release from neurosecretory cells.1415 Mean USG remained unchanged after budesonide therapy. This may reflect a lower systemic bioavailability or a reduced affinity for GC receptors at the level of the renal tubule.
Although mean SAP activity did not change significantly after treatment, a trend toward higher values did occur [Figure 4]. The corticosteroid-induced isoenzyme of SAP is unique to the dog.16 Assessment of this specific isoenzyme upon initiation and completion of the trial may have been useful in determining the effect of budesonide on the corticosteroid-induced isoenzyme of SAP. Minimal elevation after therapy may be a significant finding. The corticosteroid-induced isoenzyme is thought to be localized on the bile canalicular membrane of hepatocytes. The trend toward elevation may indicate a systemic bioavailability high enough to result in induction of the isoenzyme associated with exogenous GC administration. Further assessment after long-term therapy may clarify this matter.
Limitations of this study include the absence of a control population of dogs, as well as assessment of the HPA axis only after a short-term, 30-day treatment period. The extent to which long-term therapy with budesonide may affect the HPA axis and cause GC-related side effects remains unclear.
Conclusion
The results of this study demonstrate that oral budesonide, at a dosage of 3 mg/m2, significantly suppresses the HPA axis in dogs. No evidence of ADH resistance secondary to exogenous GC administration was noted during the trial. The clinical importance of biochemical suppression of the HPA axis through use of oral budesonide does not necessarily correlate with significant clinical symptoms of GC excess. Future studies comparing the efficacy and safety of oral budesonide with traditional GC therapy for management of canine IBD are warranted. If reduced GC-associated side effects and comparable efficacy can be demonstrated with oral budesonide therapy, then budesonide may prove to be an important advancement in the management of IBD.
Creative Compounding Center, Inc.; Lapeer, MI
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400120
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400120
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400120
Citation: Journal of the American Animal Hospital Association 40, 2; 10.5326/0400120
Mean basal serum cortisol concentrations prior to and upon completion of trial.
Mean adrenocorticotropic hormone (ACTH)-stimulated serum cortisol concentrations prior to and upon completion of trial.
Mean serum endogenous adrenocorticotropic (ACTH) concentrations prior to and upon completion of trial.
Mean serum alkaline phosphatase (SAP) activity prior to and upon completion of trial.
