The Propionic Acids. Gastrointestinal Toxicity in Various Species

Abstract

A s s~~c rThe propionic acids represent the largest chemical class of nonsteroidal anti-inflammatory agents (NSAID). Several of them are widely used, both in the United States and internationally. This paper discusses observations made on fenoprofen, flurbiprofen, ibuprofen and naproxen. Of these compounds, three are racemates; the fourth, naproxen, is an enantiomer. As a group, the propionic acids, along with most members of the other classes of NSAID, produce gastrointestinal damage in most species. These lesions vary from erythema, hemorrhage and erosion to ulceration and peritonitis. As might be expected, the degree of gastrointestinal intolerance depends on many factors: the individual compound, the dose-level, the duration of the period of drug administration, and the pharmacokinetics and metabolism in a given species. For example, in our experience the rat is less tolerant of NSAID than is the monkey, and the dog is less tolerant than the rat. Gastrointestinal lesions have been seen following both parenteral and oral administration; these findings suggest that factors other than local irritation play a role in the development of lesions. Most NSAID inhibit prostaglandin cyclo-oxygenase activity, which results in a prostaglandin deficiency at the tissue level. The administration of relevant exogenous prostaglandins, such as 16,16-dimethyl PGE,, has been shown to inhibit the gastrointestinal toxicity accompanying the administration of several NSAID, including some of the propionic acids.

Acute and 26-Week Repeated Oral Dose Toxicity Study of UP446, a Combination of <i>Scutellaria</i> Extract and <i>Acacia</i> Extract in Rats

“…treatment related or statistically significant changes in coagulation parameters in each treatment group for both males and females, when compared to the control group. Adverse effects of traditional NSAIDs causing gastrointestinal lesions dosed with as little ibuprofen as 2 mg/kg/ day, equivalent to approximately 140 mg/day in humans has been demonstrated in rats [23,28]. The current study substantiate this findings in that after 26-week of repeated oral treatment of UP466 doses equivalent to as high as 22.68 g/day for average human showed no gastric mucosal or duodenal microscopic changes.…”

Pathophysiology of Cyclooxygenase Inhibition in Animal Models

“…For example, susceptibility of cats, dogs, and horses to the adverse effects of ns-NSAIDs is greater than that of humans (Mahmud et al 1996). Dogs are less tolerant to ns-NSAIDs than rats or humans and more at risk for ns-NSAID-induced gastropathy (Elliott et al 1988;Forsyth et al 1998). However, dogs tolerate ns-NSAIDs better than cats.…”

Effect of Use of NSAID- Ibuprofen in Prolonged Therapeutic Doses on Mucosa of Lower Respiratory Tract of Mice- A Histological Study

“…Rainsford and Menozzi et al have also given oral NSAIDs in their experimentation. [14,15] Elliott et al, [16] have used oral, intra-peritoneal as well as intravenous route of NSAID drug administration in different animals. Whenever the prolonged therapeutic treatment is needed, the physicians prefer to prescribe NSAIDs by oral route.…”

“…Researchers have administered different dosages of NSAIDs for different duration for different purposes. [6,9,11] Elliott et al, [16] in their experimentation administered ibuprofen as a single dose of 1600mg and 1000mg/kg in two groups of mice. In other experimentation they used 135, 270 and 530 mg/kg single doses by intravenous route.…”