Ulcerogenic effect in rats

The risk of gastrointestinal ulceration, bleeding and even perforation with non-steroidal anti-inflammatory drug therapy is well known (Hawkey 1994 Lanas et al. 2003). The mechanisms by which these drugs cause gastro-intestinal irritation are complex (Rains-ford 1989). Deleterious effects may result from local actions, which cause injuries to the submucosal capillaries with subsequent necrosis and bleeding, or from inhibition of the formation of protective prostaglandins. 

Unfortunately, methods in safety pharmacology and safety toxicology were not able to predict the risk of serious cardiovascular events (myocardial infarction and stroke), which became apparent after treatment of patients for more than 18 months with a selective COX-2 antagonist (VIGOR study group, Bombardier et al. 2000, FDA Drug Information September 30, 2004). The mechanism of action of these effects remains to be clarified, since other long-term studies did not show an increased cardiovascular risk (Silverstein 

Gastric irritation properties of orally administered compounds are evaluated in fasted rats. Following treatment the animals are sacrificed after predetermined time in- 

The number of animals with one or more lesions of the stomach is calculated as a percentage of the animals of the test group. Running various doses, an ED5q value can be calculated. Standard compounds which produce gastric lesions are Acetylsalicylic acid (10-100 mg/kg) naproxene (5-50 mg/kg) in-domethacin (1-10 mg/kg). 

A good correlation between gastro-intestinal side effects in man and the ulcerogenic effects in rats has been found. The anti-inflammatory compounds of the pyrazolone type, like phenylbutazone, are almost devoid of these effects, whereas non-steroidal antiinflammatory compounds of the classical phenyl acetyl type show ulcerogenic properties, which parallel their therapeutic effect. 

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Recently, attention has been paid to chitosan because of its favorable biological properties, such as biodegradabihty, biocompatibility, and nmi-toxicity, as weU as its physiochemical properties [2, 3]. Moreover, it has been reported that chitosan can accelerate gastric ulcer healing [4], that pretreatment with chitosan prevents ulcerogenic effect in rats [5], and that chitosan displays antimicrobial activity [6,7]. 

There is information on intermediate-duration oral exposure in animals. Studies revealed decreased reproductive indices, decreased sperm count and tubular degeneration in rats and mice. Blood cell counts were low in rats and there was evidence of ulcerogenic effects in dogs. Acrylonitrile was also lethal in dogs. Data in animals were sufficient to derive an intermediate-duration oral MRL. Further studies in animals would be useful in defining threshold for these effects. 

Takeuchi K, Ukawa H, Konaka A, Kita-muraM, Sugawa Y. 1998. Effect of nitric oxide-releasing aspirin derivative on gastric functional and ulcerogenic responses in rats comparison with plain aspirin. J. Pharmacol. Exp. Ther. 286 115-21... 

Documented effects Fruits are used as raw material for the preparation Kholosas, which has choleretic activity and is used to treat cholecystitis and hepatitis (Khalmatov et al. 1984). Extracts of the fresh fruits exhibit high anti-ulcerogenic activity in rats (Gurbuz et al. 2003). A galactolipid, which is found in this species, has been shown to possess antitumor-promoting properties, as well as anti-inflammatory effects (Larsen et al. 2003). In a clinical trial, treadnent with a standardized rose-hip powder showed significant reduction of symptoms associated with osteoarthritis (Warholm et al. 2003). 

III. Gastrointestinal Effects Induction of Ulcers in Rats Submitted to Cold Stress Ulcerogenic effects at a gastrointestinal level of the experimental agents were determined after oral administration according to the method of Rainsford (3). Testing results are provided in Table 5. 

Oral Delivery Amphiphilic P-CD nanocapsules loaded with indomethacin have been evaluated in vivo. The nanocapsules have been applied to the rat model. It was reported that the gastrointestinal mucosa of the rat was significantly protected from the ulcerogenic effects of the active ingredient indomethacin in free form. Drug encapsulation yield in the nanocapsules were >98% and the drug content per CD unit was 7.5% w/w [89],... 

El-Monem, A. Foda Said, S. Effect of complexation of indometacin with calcium gliycerophosphate on its bioavailability, ulcerogenicity and antiinflammatory activity in rats. Pharm. Ind. 1991, 55 (1), 94-97. 

Anandan R., Nair P. G., and Mathew S. 2004. Anti-ulcerogenic effect of chitin and chitosan on mucosal antioxidant defence system in HCl-ethanol-induced ulcer in rats. J Pharm Pharmacol 56 265-269. 

Fig.5 Anti-ulcerogenic effect of PGI -Me and its 0-cyclodextrin complex in rats /lOO ng /kg was administered 60, 30, 15, 0 min prior to ulcer provocation.

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