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Keywords:

  • Carbon;
  • Diarrhea;
  • IBD ;
  • Therapy

Abstract

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

Background

Chronic idiopathic enteropathies (CIE) in dogs are complex diseases of unknown origin. AST-120 is a spherical carbon adsorbent preparation with a high adsorption ability for low molecular substances.

Objectives

Evaluation of the clinical efficacy of AST-120 in dogs with CIE.

Animals

Ten client-owned dogs with mild (n = 7) to moderate (n = 3) CIE.

Methods

Explorative, prospective, randomized, placebo-controlled, double-blinded pilot study. Dogs with chronic diarrhea and no or insufficient response to an elimination diet were included. The dogs received either AST-120 (n = 5) or placebo (n = 5) for a duration of 21 days. The canine inflammatory bowel disease activity index (CIBDAI) was used to assess disease severity at baseline and clinical outcome after 3 weeks of treatment. Furthermore, changes in body weight and the parameters stool consistency and frequency were compared within and between groups.

Results

The mean CIBDAI score decreased from 5.6 (SD 1.5) to 2.0 (SD 1.2) in the AST-120 group (P = .125) and from 4.8 (SD .8) to 3.6 (SD 2.3) in the placebo group (P = .688). Compared with baseline, posttreatment CIBDAI scores decreased more than 60% in 4/5 dogs treated with AST-120 and in 1/5 dogs treated with placebo (P = .206). Changes in CIBDAI scores, body weights, stool consistency, and frequency within and between groups did not achieve statistical significance after 3 weeks of treatment. No adverse effects of AST-120 were noted.

Conclusions and Clinical Importance

This study investigated potential efficacy of AST-120 as an alternative therapy in dogs with mild-to-moderate CIE.

Abbreviations
BW

body weight

CIBDAI

canine inflammatory bowel disease activity index

CIE

chronic idiopathic enteropathy

IBD

inflammatory bowel disease

SC

stool consistency

SF

stool frequency

Chronic diarrhea is a common clinical sign in dogs and chronic idiopathic enteropathies (CIE) such as inflammatory bowel diseases (IBD) and antibiotic-responsive enteropathies have to be considered as underlying causes.[1] Therapy of CIE in dogs is for the most part empirical and current treatment protocols include dietary modification in combination with either antibacterial or immunosuppressive therapy or a combination of both.[1, 2] AST-120 is a spherical carbon adsorbent with a very high specific surface area and an inherent sustained binding profile optimized to adsorb low molecular weight proinflammatory mediators (eg, serotonin, histamine, toll-like receptor ligands, N-formyl-methionyl-leucyl-phenylalanine, nitric oxide and bile acids) present in the gastrointestinal tract.[3-5] AST-120 prevents progression of renal failure in humans and is useful for the control of intractable anal fistulas in Crohn's disease.[6, 7]

The objective of this study was to evaluate the efficacy of AST-120 in dogs with CIE when treated orally with 2 g per 10 kg body weight (BW) daily for 3 weeks.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

The study was conducted at the Clinic of Small Animals, Freie Universitaet Berlin, from September 2009 to January 2011. All procedures were performed in accordance with German animal-welfare legislation and the dog's owner had to sign an owner consent form. Dogs suffering from CIE (chronic diarrhea of at least 3 weeks duration) and no or insufficient response to an elimination diet of 3 weeks' duration (hypoallergenic1 or novel protein diet2) were included. A comprehensive diagnostic work-up (hematology, plasma biochemistry profile, serum trypsin-like immunoreactivity, cortisol, cobalamin, folate, fecal parasitology and bacteriological culture, abdominal radiographs and ultrasound) was conducted to eliminate underlying causes. Anthelmintic treatment3 was administered if dogs had not been dewormed within the last 2 months. Endoscopy of the gastrointestinal tract with histopathologic analysis of intestinal biopsies was recommended, but was not mandatory. The canine inflammatory bowel disease activity index (CIBDAI) was assessed based on the parameters attitude/activity, appetite, vomiting, stool consistency (SC), stool frequency (SF) and weight loss and only dogs with a composite CIBDAI score ≥4 were included in the study.[8] The explorative study was conducted as a double-blinded, placebo-controlled, randomized pilot study with a parallel group design. Study day (S) 1 was defined as the day of inclusion: the dogs were given a consecutive case number and were assigned randomly to receive either study medication A (AST-120) or B (placebo: nonactivated spherical carbon beads without the ability to adsorb compounds), according to a randomization list at a ratio of 1 : 1 in the order of inclusion. Treatment was administered by the owner by mixing either AST-120 or placebo (daily dosage 2 g/10 kg BW) with the dog's feed. Subcutaneous injections of cobalamin (500 μg per 5–15 kg BW; 800–1,200 μg in dogs >15 kg BW) were given to all dogs at S-1 and at a weekly (serum cobalamin ≤300 pg/dL) or biweekly interval (serum cobalamin ≤400 pg/dL). If necessary concomitant treatment (omeprazole 1 mg/kg, PO, twice daily; metoclopramide .2–.3 mg/kg, PO, 1–3 times daily; novamine sulfone 20 mg/kg, PO, 1–3 times daily) was allowed and had to be administered at least 30 minutes before treatment with AST-120 or placebo.[9] Pre- (S-1) and posttreatment (S-21) dogs were weighed, SC and SF and the composite CIBDAI score were assessed. Statistical analyses were performed using SPSS (IBM SPSS statistics campus, Ehningen, Germany; version 20). Exploratory P values with respect to within and between treatment group comparisons were computed for the efficacy parameters BW, SC, SF, and CIBDAI score. Changes from baseline (S-1) within each treatment group were analyzed by the Wilcoxon signed-rank test for paired samples and changes from baseline between the 2 treatment groups were analyzed by the Mann–Whitney U-test for two independent samples. Within and between treatment group comparisons, the Fisher's exact test was used to analyze the proportions of dogs with improvement of both SC and SF after 3 weeks of treatment. The Mann–Whitney U-test for 2 independent samples was furthermore used to compare the 2 groups at baseline (age, BW, CIBDAI, plasma albumin and serum cobalamin concentrations). Statistical significance was set at P < .05.

Results

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

In total, 13 dogs were enrolled in the study. Three dogs had to be excluded from the efficacy analysis: in 1 case (placebo), for welfare reasons, and in another case (AST-120) because of an antibiotic treatment of cystitis. Furthermore, in 1 dog of the placebo group, test item application was stopped prematurely after 8 days because of a worsening condition and the dog was subjected to a crossover to the other study medication (data not shown). Thus, 10 dogs (3 German Shepherd Dog, 6 different pure-bred and 1 mixed-breed) were included in the efficacy analysis: demographics and baseline characteristics are summarized in Table 1. The average duration and severity of the disease were similar in both treatment groups and clinical signs were predominantly located in both the small and large intestine. Endoscopy was performed in 5 dogs (2/5 AST-120 group, 3/5 placebo group), and histology revealed a similar distribution of inflammatory cells but only in dogs of the AST-120 group inflammatory infiltrates were detected in the large intestinal mucosa. Serum cobalamin and plasma albumin concentrations did not differ significantly between both groups at baseline (Table 1). In all dogs, the serum cobalamin concentration was below 400 pg/mL.

Table 1. Baseline characteristics of 10 dogs with chronic idiopathic enteropathies treated either with AST-120 or placebo.
 Total (n = 10)AST-120 (n = 5)Placebo (n = 5)P valuea
Demographic variables, anthelmintic treatment and disease severity
Sex (n): male/female4/63/21/4 
Age (mean and SD in years)4.8 (2.9)2.4 (1.6)7.2 (1.5).016
Body weight (mean and SD in kg)27.7 (14.4)30.7 (15.8)24.7 (13.9).587
Anthelmintic treatment before inclusion (n): 2 weeks before/within past 2 months3/71/42/3 
CIBDAI (mean and SD)5.2 (1.2)5.6 (1.5)4.8 (.8).532
Blood parametersReference rangeMean (SD)
Plasma albumin2.8–3.6 g/dL2.8 (.3)2.8 (.2)2.9 (.4).460
Serum cobalamin300–800 pg/mL250 (86)276 (75)224 (96).421
  1. SD, standard deviation; CIBDAI, canine inflammatory bowel disease activity index.

  2. a

    P values based on Mann–Whitney U-test for 2 independent samples, P < .05.

Number of dogs affected
Plasma albumin concentration <2.8 g/dL (n)431 
Serum cobalamin concentration <300 pg/mL (n)734 
Albumin and cobalamin concentration lowered (n)321 
Dietary treatment
Hill's prescription diet z/d Ultra (n)422 
Self-cooked novel protein diet (n)22 
Self-cooked diet combined with z/d Ultra (n)413 

All dogs received either AST-120 (n = 5) or placebo (n = 5) orally mixed into the diet for a duration of 3 weeks (Table 1). Owners split the daily amount of 2 g/10 kg BW into equal parts and administered it across 2 feeding times. The mean CIBDAI scores were 5.6 before treatment and 2.0 after treatment (P = .125) in the AST-120 group and, 4.8 and 3.6 (P = .688) in the placebo group (comparison between groups: P = .198; Fig 1, Table 2). In the AST-120 group, both SC and SF improved in 4/5 dogs (P = .200) compared to 2/5 dogs (P = .400) treated with placebo (comparison between groups: P = .524; Fig 2). Changes in CIBDAI scores, SC, SF, and BW within and between groups did not achieve statistical significance at S-21 (Table 2).

Table 2. Efficacy analyses of clinical parameters in 10 dogs with chronic idiopathic enteropathies treated either with AST-120 or placebo.
Parameter (scoring)AST-120 (n = 5)Placebo (n = 5)P value**
S-1S-21P value*S-1S-21P value*
M (SD)M(SD)M (SD)M (SD)
  1. CIBDAI, canine inflammatory bowel disease activity index; M, mean; S, Study day; SD, standard deviation. P values based on Wilcoxon signed-rank test for paired samples (*) or Mann–Whitney U-test for two independent samples (**). Statistical significance P < .05.

CIBDAI (0–18)5.6 (1.5)2.0 (1.2).1254.8 (0.8)3.6 (2.3).688.198
Stool consistency (0–3)2.0 (1.0)0.6 (.6).1252.0 (0.7)1.8 (1.3)1.000.246
Stool frequency (0–3)2.6 (.9)1.2 (1.1).1252.0 (0.7)1.4 (0.9).500.333
Body weight in kg30.7 (15.8)31.7 (16.8).06324.7 (13.9)24.5 (13.8).375.079
image

Figure 1. Comparison of pretreatment and posttreatment canine inflammatory bowel disease activity index (CIBDAI) of dogs with chronic idiopathic enteropathies treated either with AST-120 (n = 5) or placebo (n = 5). Dot plots with trend lines represent individual CIBDAI scores and posttreatment changes. S, study day.

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image

Figure 2. Comparison of pretreatment and posttreatment stool consistency (A) and stool frequency (B) of dogs with chronic idiopathic enteropathies treated either with AST-120 (n = 5) or placebo (n = 5). Bracketed numbers represent the scores in the assessment of the canine inflammatory bowel disease activity index. S, study day.

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Both AST-120 and placebo were accepted well according to the owners. There were no adverse events attributed to the administration of AST-120 or placebo in any dog of this study nor did AST-120 or placebo have any detrimental effect on safety parameters (ie, hematology, plasma biochemistry; data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

AST-120 is a spherical carbon adsorbent and recent publications have pointed to a reduction in clinical signs in human patients with fistulizing Crohn's disease and nonconstipating irritable bowel syndrome.[7, 10] The objective of this pilot study was to evaluate the efficacy of AST-120 in dogs with CIE when treated orally with 2 g per 10 kg BW daily for 3 weeks. With respect to the CIBDAI score and the single parameters, SC and SF, short-term treatment with AST-120 improved in 4/5 dogs, whereas improvement occurred in 2/5 placebo-treated dogs (P = .524). Compared with baseline, posttreatment CIBDAI scores decreased more than 60% in 4/5 dogs treated with AST-120 and in 1/5 dog treated with placebo (P = .206). In these dogs, no lag time between initiation of treatment and onset of clinical improvement was noticed. Most dogs responded within the first 7 days after starting treatment. There were no adverse events attributed to the administration of AST-120 in any dogs, which coincides with previous studies in humans.[6, 7, 10]

AST-120 is nonadsorbed and has significantly reduced binding affinity to higher molecular weight proteins (eg, digestive enzymes), allowing patients to maintain nutritional status.[5] After treatment with AST-120, BW increased in all 5 dogs compared to 1/5 dog treated with placebo.

There are several limitations inherent in this study. The statistical analyses were exploratory in nature as the study was not powered to address any predefined hypothesis. A formal sample size calculation as for confirmatory studies was not done. Therefore, all resulting P values had to be interpreted in the exploratory sense only. Subset analysis was limited because of the small sample size.

Dogs treated with AST-120 were significantly younger than dogs of the placebo group assuming that the age might have influenced the results. Variable dietary treatment and concomitant administration of omeprazole, metoclopramide, novamine sulfone, or both have to be considered as confounding factors that might have influenced the clinical progression. Concomitant treatment might preclude the evaluation of AST-120 efficacy regarding the assessment of parameters, such as abdominal pain and the CIBDAI-specific parameters attitude/activity, appetite, and vomiting. However, as the type and frequency of concomitant medication were similar in both treatment groups, it was assumed that the treatment groups were impacted at the same rate. In addition to the composite CIBDAI scoring, the influence on the parameters SC and SF was separately determined. In a previous study in humans, it was shown that concomitant administration of AST-120 with ciprofloxacin or azathioprine had no impact on the pharmacokinetics or bioavailability of these compounds and that AST-120 can be used in addition to medications commonly used in the treatment of IBD.[9] Clinical efficacy of AST-120 supplementary to medications commonly used in the treatment of CIE in dogs and potential drug–drug interactions need to be further analyzed. This study was an early phase trial and treatment was restricted to a period of 21 days. In comparison, in humans with CIE, the double-blinded treatment phases were restricted to a period of 8 weeks.[7, 10] However, it was shown that in patients with irritable bowel syndrome, clinical signs increased when AST-120 was replaced by placebo and decreased once AST-120 treatment was started again for another treatment period of 8 weeks.[10] Long-term therapy or long-term follow-up was not intended in this study, respectively. The mechanism for the response to AST-120 supplementation was not investigated in this study and remains unknown. Although the underlying cause of CIE is still unknown, accumulating evidence suggests that intestinal inflammation results from altered interaction between gut microbes and the mucosal immune system in a susceptible host.[11] Therefore, it is suggested that AST-120 stabilizes intestinal immune responses as well as intestinal microbiota because of binding of low molecular weight pro-inflammatory mediators in the gut.

Conclusion

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

In conclusion, this study investigated the potential efficacy of AST-120 as an alternative therapy in dogs with mild-to-moderate CIE. However, in light of the limitations and the explorative nature of this study, definitive conclusions should be drawn with caution and further more definitive studies are needed including optimized design, larger study populations, and more dogs with moderate and severe disease.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References

This study was performed at the Clinic of Small Animals, Freie Universitaet Berlin, Germany. The study was supported by Bayer Animal Health GmbH, Germany.

Conflicts of interest: Two of the authors, Drs Beddies and Wirtherle, are employed by Bayer Animal Health.

Footnotes
  1. 1

    Hill's Prescription Diet z/d Canine ULTRA Allergen-Free

  2. 2

    Self-cooked (proportion of protein to carbohydrate 1 : 2; eg, turkey or horse and potato)

  3. 3

    Drontal flavor Plus (1 tablet per 10 kg BW) or Drontal Plus XL (1 tablet per 35 kg BW)

References

  1. Top of page
  2. Abstract
  3. Materials and Methods
  4. Results
  5. Discussion
  6. Conclusion
  7. Acknowledgments
  8. References
  • 1
    Fogle JE, Bissett SA. Mucosal immunity and chronic idiopathic enteropathies in dogs. Compend Contin Educ Vet 2007;29:290302.
  • 2
    Craven M, Simpson JW, Ridyard AE, et al. Canine inflammatory bowel disease: Retrospective analysis of diagnosis and outcome in 80 cases (1995–2002). J Small Anim Pract 2004;45:336342.
  • 3
    Araki Y, Tsujikawa T, Andoh A, et al. Therapeutic effects of an oral adsorbent on acute dextran sulphate sodium-induced colitis and its recovery phase in rats, especially effects of elimination of bile acids in gut lumen. Dig Liver Dis 2000;32:691698.
  • 4
    Anderson K, Fischer L. Prevention of GI absorption of bacterial toxins: An in vitro evaluation of the potential for prophylactic use of a novel oral adsorbent. Gastroenterology 2008;134:A675.
  • 5
    Anderson K, Tomiyana S, Nitta T. AST-120: A novel, engineered carbon microsphere product for use in chronic inflammatory bowel disease and liver dysfunction. Gastroenterology 2008;134:A675.
  • 6
    Ueda H, Shibahara N, Takagi S, et al. AST-120, an oral adsorbent, delays the initiation of dialysis in patients with chronic kidney diseases. Ther Apher Dial 2007;11:189195.
  • 7
    Fukuda Y, Takazoe M, Sugita A, et al. Oral spherical adsorptive carbon for the treatment of intractable anal fistulas in Crohn's disease: A multicenter, randomized, double-blind, placebo-controlled trial. Am J Gastroenterol 2008;103:17211729.
  • 8
    Jergens AE, Schreiner CA, Frank DE, et al. A scoring index for disease activity in canine inflammatory bowel disease. J Vet Intern Med 2003;17:291297.
  • 9
    Willmer J, Anderson K, Proksch S, et al. Absence of pharmacokinetic drug-drug interactions in healthy volunteers between AST-120, a novel oral adsorbent and concomitant medications: CiproXR (CFXR) and azathioprine (AZA). Gut 2008;57(Suppl 2):A374.
  • 10
    Tack JF, Miner PB Jr, Fischer L, et al. Randomised clinical trial: The safety and efficacy of AST-120 in non-constipating irritable bowel syndrome – A double-blind, placebo-controlled study. Aliment Pharmacol Ther 2011;34:868877.
  • 11
    Packey CD, Sartor RB. Interplay of commensal and pathogenic bacteria, genetic mutations, and immunoregulatory defects in the pathogenesis of inflammatory bowel diseases. J Intern Med 2008;263:597606.