Preclinical toxicity evaluation of tepoxalin, a dual inhibitor of cyclooxygenase and 5-lipoxygenase, in Sprague-Dawley rats and beagle dogs.

Tepoxalin [5- (4-chlorophenyl)-N-hydroxy-1-(4-methoxyphenyl)-N-methyl-1H-pyrazole -3-propanamide] is an orally active anti-inflammatory agent, which inhibits both cyclooxygenase and 5-lipoxygenase activities. The oral toxicity of tepoxalin was evaluated in 1- and 6-month rat (up to 50 mg/kg/day) and dog (up to 150 mg/kg bid) studies. In rats, increased liver weight, centrilobular hypertrophy, and hepatic necrosis were observed at dosages >/=20 mg/kg/day. Renal changes indicative of analgesic nephropathy syndrome (i.e., papillary edema or necrosis, cortical tubular dilatation) were seen at >/=15 mg/kg. In rats treated for 1 month, these hepatic and renal effects were largely reversible after a 1-month recovery period. Gastrointestinal erosions and ulcers were seen in female rats given 40 mg/kg/day for 6 months. Changes in clinical pathology parameters included decreases in red blood cell count, hemoglobin, and hematocrit mean values; elevation in platelet counts; and an increase in prothrombin and activated partial thromboplastin times. Mild increases in alanine aminotransferase, aspartate aminotransferase, and cholesterol were also noted in rats. Decreased erythrocyte parameters, increased leukocyte counts, and decreased total protein, albumin, and/or calcium were noted in some dogs in the 300 mg/kg/day group following 6 months of dosing. Small pyloric ulcerations were seen at 100 and 300 mg/kg/day dosages for up to 6 months. In both rats and dogs, no accumulation of tepoxalin or its carboxylic acid metabolite was detected in plasma following multiple dosing over a range of 5 to 50 mg/kg/day for rats and 20 to 300 mg/kg/day for dogs. Plasma concentrations of the carboxylic acid metabolite were severalfold higher than those of the parent compound. The no-effect dosages in rats (5 mg/kg/day) and dogs (20 mg/kg/day) were approximately one and six times the ED50 (3.5 mg/kg), respectively, for inhibition of inflammatory effects in the adjuvant arthritic rat without gastric mucosal damage. In terms of severity, the relative lack of gastrointestinal side effects, within the estimated therapeutic dose range, distinguishes tepoxalin from most marketed anti-inflammatory drugs.

Effects of systemic aluminum on the resolution of a uremic and dietary phosphorus-dependent model of uremic osteomalacia in rats.

We have developed a model of osteomalacia that is dependent on both uremia and the feeding of a diet low in phosphorus and that can be reversed by subsequent dietary phosphorus repletion. The objectives for this study were to use this model to investigate the role of aluminum (Al) in both the induction and resolution of osteomalacia. Adult male Sprague-Dawley rats were five-sixths nephrectomized and fed either low or normal dietary phosphorus, both with and without intraperitoneal Al injections. Uremic rats fed low phosphorus developed osteomalacia characterized by increased osteoid surface, volume, and thickness and osteoid maturation time and decreased mineralizing surface. Al-treated uremic rats fed low phosphorus were similarly affected, developing increased osteoid volume and thickness and osteoid maturation time and decreased osteoblastic surface, mineralizing surface, and bone formation rate. In addition, they had a significantly increased Al-positive surface. Al-treated uremic rats fed normal phosphorus had only increased osteoid thickness and aluminum-positive surface and decreased osteoblastic surface. Osteomalacic rats continuously treated with Al during the induction and phosphorus repletion stages had increased growth plate thickness, osteoid volume and thickness, and Al-positive surface and decreased osteoblastic and mineralizing surface. Mineralization in these rats was impaired to such a degree that no detectable double labels were present. Osteomalacic rats treated with Al during the induction phase but not during phosphorus repletion had increased osteoid surface and volume and Al-positive surface and decreased osteoblastic and mineralizing surface. Double labels were not detectable in these rats, either.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of the major vitamin D metabolites upon the resolution of osteomalacia in uremic adult rats.

We have previously shown that an osteomalacia dependent upon both a low phosphorus diet and uremia (five-sixth nephrectomy) can be produced rapidly in rats. This is associated with hypophosphatemia and elevated 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). In order to investigate the role of exogenously administered vitamin D metabolites upon the resolution of this osteomalacia, 72 male Sprague Dawley rats weighting 320 +/- 20 g were subjected to a two-step, subtotal nephrectomy and subsequently fed a diet with low (0.03%) phosphorus (LP) for seven days. Groups of six rats each were then either continued on the LP diet, or switched to a nutrient-matched diet with normal (0.3%) phosphorus (NP) for an additional 10 days. During this time, the rats were infused daily with either: 27 ng 1,25(OH)2D3; 81 ng 24,25 dihydroxyvitamin D3 (24,25(OH)2D3); 135 ng 25 hydroxyvitamin D3 (25(OH)D3); both 27 ng 1,25(OH)2D3 and 81 ng 24,25(OH)2D3; or placebo. Dietary phosphorus repletion was found to reverse the osteomalacia by decreasing the growth plate thickness, the osteoid surface and volume, the osteoid maturation time, serum calcium, and plasma 1,25(OH)2D3, and by increasing the mineralizing surface, bone formation rate, and serum phosphorus. The osteomalacia was also reversed in phosphorus-repleted rats treated with 24,25(OH)2D3, with no additional effects attributable to the 24,25(OH)2D3 itself. Osteomalacia in phosphorus-repleted rats treated with 25(OH)D3 or 1,25(OH)2D3 was only partially reversed; healing was interpreted to be impaired by the elevated plasma 1,25(OH)2D3 levels present in these rats.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of uremia and dietary phosphorus on the bone of rats.

In order to evaluate the effects of uremia and low levels of dietary phosphorus on bone, male Sprague-Dawley rats weighing 320 +/- 20 g (12 weeks old) were subjected to either a two-step, subtotal nephrectomy or sham-operation (SO), and then fed a custom diet with either normal calcium (0.5%) and normal phosphorus (0.3%) (NCNP), or normal calcium and low phosphorus (0.03%). When compared to the NCNP SO group after seven days, only uremic rats fed low phosphorus diets developed osteomalacia characterized by an increase in the osteoid thickness, surface and volume, a prolonged osteoid maturation time, and a decreased bone formation rate. No other groups developed these changes. This osteomalacia was also associated with hypophosphatemia, a reduced serum PTH and an elevation in the serum 1,25(OH)2D3. It was concluded that while neither this degree of uremia nor the low phosphorus diets alone had any significant effect, the combination of uremia and low dietary phosphorus resulted in the initiation of osteomalacia. This animal model should prove useful in investigations dealing with the influence of uremia on the mineralization process.