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Evidence for the efficacy of UTP in healing ulcers

Summary of a field trial investigating UTP08 as a treatment for EGUS in racing thoroughbreds

Pearson W1, Moore A2

1 Dept Plant Agriculture, University of Guelph, Guelph ON1 VitaTech Laboratory Services, Mississauga ON2 

 

Introduction

EGUS is recognized as a significant health concern in mature and immature horses.  It is most common among performance horses, with an incidence as high as 100% (Bell et al., 2007).  Clinical presentation of EGUS varies and is dependent on location and severity of ulcers. Signs may include poor body condition, retained hair-coat, reduced appetite, mild colic and compromised athletic performance (Bell et al., 2007). Clinical signs in foals may also include diarrhea, suppressed growth rate, grinding of teeth, a pot-bellied appearance, interrupted nursing and excessive salivation (Borrow 1993).

Bioflavonoids are increasingly recognized as potential preventives or treatments for ulcers in laboratory animals (Jung et al., 2007; Baggio et al., 2007) and humans (Ares and Outt 1998). However, the effectiveness of bioflavonoids in preventing or treating EGUS is not documented. Information on mode of action is substantively incomplete (Campos et al., 2008), and no data are available in the equine model. Information on the utility, safety and mode of action of bioflavonoids on EGUS will allow for evidence-based application of bioflavonoid-rich treatments and effectively reduce the economic and welfare impact of EGUS in performance horses. Furthermore, information on mechanism of action will allow practitioners to make educated predictions about interactions between bioflavonoids and other medications which may be co-administered. 

UTP08 is an aqueous extract of 7 plants (marshmallow, meadowsweet, licorice, fenugreek, yarrow, chamomile, and slippery elm) which was developed as a bioflavonoid-rich supplement to treat EGUS in performance horses. The objectives of the current study were 1) to detect bioflavonoid species which are present in UTP08, and 2) to conduct a pilot investigation on the efficacy of UTP08 in performance horses diagnosed with EGUS. It was hypothesized that UTP08 would reduce ulcer score in horses with spontaneous EGUS. 

Methods

The bioflavonoid profile of UTP08 was determined by LC/MS at the University of Guelph. A sample of UTP08 was extracted using CHCl3 / ACN and a total ion chromatograph was detected by electrospray ionization mass spectroscopy with negative ions measured over the range of 100 – 1000 m/z. Peaks were compared to retention times and molecular mass of pure standards of bioflavonoids known to be present in the constituent herbs. 

Twelve thoroughbreds in active race training with endoscopic evidence of EGUS (score  1; see Table 1), as determined by a qualified veterinary practitioner (AM), received 0.4 mL (0.23 g; n=6) per kg BW UTP08 in their feed twice daily for 28 days in an open-label trial. All horses were campaigning at Woodbine Racetrack in Toronto Ontario Canada. Horses were removed from any/all ulcer medication for a minimum of 7 days prior to entry into the study, and no concurrent anti-ulcer medication was permitted for the 28 days of the trial. At the end of 28 days, all horses were fasted for 12 hours, and EGUS was scored endoscopically by the same veterinarian as conducted the baseline examinations. Ulcer score at the end of the trial was compared to that from the beginning using a paired Student t-test. 

Table 1: Scoring method utilized for quantifying EGUS

Score

 

0

No visible ulceration

0.5

Mild gastritis

1

Mild ulceration – few small ulcers

2

Moderate ulceration - medium size ulcers on a number of sites on squamous epithelium with signs of inflammation; may be bleeding ulcers

3

Severe ulceration - large ulcers covering a large area of the squamous epithelium with severe inflammation +/- bleeding ulcers

 

Results

The bioflavonoids definitively identified in UTP08 were genistein/apigenin, kaempferol, rutin, and isoquercitin. 

Upon recruitment into the field trial, the mean ulcer score of all horses was 1.8  0.29. By the end of the supplementation period this fell to 0.8  0.10 (p<0.001) (Figure 1). 

 

 

 

 

 

 

 

Figure 1: Ulcer score (0 – 3) of 12 racing thoroughbreds which received 0.4 mL/kg BW (0.23 g/kg BW) UTP08 in their feed twice daily for 28 days in an open-label trial. Change in ulcer score from the beginning of the trial (Day 0) to the end (Day 28) was statistically significant (p<0.001).

 

Discussion

This study demonstrates significant benefit of feeding UTP08 to racing thoroughbreds with pre-existing gastric ulceration. In this pilot field study we utilized horses that were actively racing, as these horses are at higher risk for EGUS than their sedentary counterparts due to the influence of exercise on gastric pH coupled with gastric compression (Lorenzo-Figueras and Merritt, 2002). Gastric compression forces gastric contents to the proximal portion of the stomach, where the squamous mucosa is more susceptible to injury.  This may explain the increase in gastric ulceration of the non-glandular stomach that is associated with continual and strenuous exercise. 

Conventional veterinary treatment of EGUS usually involves antacids, histamine H2 receptor antagonists and proton pump inhibitors. Antacids are basic compounds that act to neutralize the acid within the stomach.  Their actions are short-lived, and in many cases it is difficult to administer sufficient quantity of antacid to achieve a satisfactory clinical effect (Murray and Grodinsky 1992).  These drugs may be more effective as a prophylactic rather than as a treatment.  Histamine H2 receptor antagonists work by inhibiting the secretion of gastric acid by the parietal cells of the GI tract.  This action is effected by blocking the interaction of histamine with H2 receptor on the parietal cells (Bruneton 1996).  Drugs in this class that have shown effectiveness in increasing gastric pH in horses include cimetidine and ranitidine (Sangiah et al., 1988).  However, there is currently a lack of research demonstrating efficacy in healing ulcers that are already present (MacAllister et al., 1994), and it is likely that these drugs are also better suited to a prophylactic role. Arguably the most effective and most widely utilized drugs for the treatment and healing of gastric ulceration in horses are proton pump inhibitors.  In particular, omeprazole is effective for healing ulcers (Murray et al., 1997), and is generally considered the gold standard against which other drugs are compared.  However, research has shown that when treatment with omeprazole is discontinued without concurrent removal of the stimulus for ulceration, horses quickly re-develop the ulceration (Andrews et al., 1999), and up to 25% of horses with EGUS do not respond to treatment with omeprazole at all (White et al. 2007).  At approximately $1200 per month per horse, this is a very expensive treatment regimen, and may be cost prohibitive for many horse owners.  

How UTP08 produced the effect seen in the current pilot study is not known, and requires further research. However, a growing body of evidence implicates plant bioflavonoids in the prevention/treatment of gastric ulceration in mammals. A specific flavan (3-methoxy-5,7,3’,4’-tetrahydroxyflavan) is as effective as omeprazole in reducing total gastric secretion, reducing the free and total acids in the gastric secretions, and reducing gastric mucosal histamine (Parmar and Hennings 1984). A related flavan, 5-methoxyflavone, reduced indomethacin-induced gastric damage in rats by up to 99% (Blank et al.1997).  Another naturally-occurring flavone, narigenin, was found to effectively prevent gastric ulceration initiated by absolute ethanol. There were fewer ulcers formed, together with increased production of gastric mucous and increased concentration of total proteins and hexosamines in gastric tissue (Motilva et al. 1994). In addition, the flavonic fraction of Bidens aurea (Martin Calero et al. 1996), Erica andevalensis (Reyes et al. 1996) and Silybum marianum (Alarcon de la Lastra et al. 1995) prevented the development of and/or augmented the healing of rat gastric mucosa after gastric challenge. 

The mechanism of action of bioflavonoids in gastroprotection is not well understood.  Hypotheses include an ability of flavonoids to reduce leukocyte activation (evidenced by reduced myeloperoxidase activity) which reduces their adherence to the endothelial surface (Blank et al. 1997; Kahraman et al. 2003). Increased leukocyte adherence is associated with reduced perfusion of the mucosa, which predisposes to injury. Activation of these cells (by inflammatory mediators such as LTB4) leads to release of oxygen-derived free radicals, which damage the endothelium and mucosa (Martin Calero et al. 1996). Myeloperoxidase is a leukocyte-specific enzyme which is used as a marker for leukocyte infiltration (Berenguer et al., 2007). Additionally, bioflavonoids inhibit the enzyme histidine decarboxylase (Middleton 1988).  Histamine, as liberated from histidine decarboxylase, stimulates gastric acid secretion (Parmar et al. 1984), and is involved with the pathogenesis of ulcers. The suppressive effect of flavonoids on tissue histamine levels has been demonstrated in several studies. Twelve flavonoids were tested for their ability to inhibit the activity of histidine decarboxylase in vitro, and several are reported effective (Wendt et al. 1980). It is also shown that 3-methoxy-5,7,3’,4’-tetrahydroxyflavan is a specific histidine decarboxylase inhibitor and effectively reduces tissue histamine in pylorus-ligated rats (Parmar et al. 1984).

Another possible mechanism of anti-ulcer action is stimulation of gastric PGE2 formation (Choi et al. 2007; Brzozowski et al. 1998). PGE2 stimulates production of mucous by goblet cells to protect cells from acidic injury (Akiba et al. 2000) and by promoting healing of existing ulcers through increased angiogenesis (Hatazawa et al. 2007).

The current study provides rationale for further study into UTP08 as a gastroprotective agent in horses and other performance animals. Future studies should evaluate the longterm safety of UTP08 in the target animal species, mechanistic studies of UTP08 interactions with gastric mucosa, prophylactic effect on occurrence of EGUS, and dose-optimization studies. 

 

Conclusions

This open field study on the efficacy of UTP08 in treating existing EGUS in racehorses demonstrates that the product is effective in reducing gastric ulcer score to a clinically relevant degree. The data provide rationale for further investigating this product in controlled trials to determine whether it can prevent occurrence and/or severity of EGUS in exercising horses.

Acknowledgements

Financial support for this study provided by Selected Bioproducts Ltd. 

 

References


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