Co-administration of naproxen or celecoxib with omeprazole and/or low-dose aspirin results in marked exacerbation of small intestinal damage.

<p>In contrast, rats given a naproxen derivative (ATB-346 or NCX 429) did not develop significant intestinal injury when given alone or in combination with omeprazole, low-dose aspirin, or both. *p<0.05, **p<0.01 versus the corresponding group treated with NSAID alone (n≥6 per group). Aspirin and omeprazole, alone or given together, did not elicit significant intestinal damage.</p

Increased naproxen-induced small intestinal damage in obese versus lean rats.

<p>Neither lean nor obese rats developed intestinal damage when given ATB-346. **p<0.01 versus the corresponding vehicle- and ATB-346-treated rats. n = 6 rats per group.</p

Effects of NSAIDs in rats with adjuvant arthritis.

<p>Despite comparable suppression of paw swelling (panel A), gastric prostaglandin synthesis (panel B) and whole blood thromboxane synthesis (panel C), ATB-346 and NCX 429 did not cause significant gastric (panel D) or intestinal (panel E) damage. Celecoxib also did not cause significant GI damage. *p<0.05, **p<0.01 versus the naproxen-treated group. n = 8 per group.</p

Serum and biliary levels of naproxen are significantly reduced in rats given a naproxen derivative (ATB-346 or NCX 429) as compared to the levels observed in rats given an equimolar dose of naproxen itself.

<p>The test drugs were administered twice-daily for 2 days. *p<0.05, **p<0001 versus the naproxen-treated group. n = 4 per group.</p

Older (19 months of age) rats develop extensive gastric damage when given naproxen, but not when given equimolar doses of a hydrogen sulfide-releasing naproxen derivative (ATB-346) or a nitric oxide-releasing naproxen derivative (NCX 429).

<p>***p<0.001 versus the vehicle-treated group. n =  6 rats per group.</p

Drug doses.

<p>Data are mean±SE. Estimates were derived from weekly measurements of body weights and food intake standardized by the number of mice per cage.</p

Summary data showing dose-dependent effects of 1-month HCT 1026 treatment on functional muscle ischemia.

<p>Graded doses of NE (NE 1, NE 2) evoked decreases in femoral vascular conductance in the resting hindlimbs that were similar among the three groups of mice. These vasoconstrictor responses were attenuated only in the contracting hindlimbs of mice fed the 300 ppm HCT 1026 diet. Numbers above the bars are NE doses in ng. AUC, area under the curve in arbitrary units; Contr., contraction. For each group, n = 12. *<i>P</i><0.05 vs. corresponding rest.</p

Treatment with a Nitric Oxide-Donating NSAID Alleviates Functional Muscle Ischemia in the Mouse Model of Duchenne Muscular Dystrophy

<div><p>In patients with Duchenne muscular dystrophy (DMD) and the standard mdx mouse model of DMD, dystrophin deficiency causes loss of neuronal nitric oxide synthase (nNOSμ) from the sarcolemma, producing functional ischemia when the muscles are exercised. We asked if functional muscle ischemia would be eliminated and normal blood flow regulation restored by treatment with an exogenous nitric oxide (NO)-donating drug. Beginning at 8 weeks of age, mdx mice were fed a standard diet supplemented with 1% soybean oil alone or in combination with a low (15 mg/kg) or high (45 mg/kg) dose of HCT 1026, a NO-donating nonsteroidal anti-inflammatory agent which has previously been shown to slow disease progression in the mdx model. After 1 month of treatment, vasoconstrictor responses to intra-arterial norepinephrine (NE) were compared in resting and contracting hindlimbs. In untreated mdx mice, the usual effect of muscle contraction to attenuate NE-mediated vasoconstriction was impaired, resulting in functional ischemia: NE evoked similar decreases in femoral blood flow velocity and femoral vascular conductance (FVC) in the contracting compared to resting hindlimbs (ΔFVC contraction/ΔFVC rest = 0.88±0.03). NE-induced functional ischemia was unaffected by low dose HCT 1026 (ΔFVC ratio = 0.92±0.04; P>0.05 vs untreated), but was alleviated by the high dose of the drug (ΔFVC ratio = 0.22±0.03; P<0.05 vs untreated or low dose). The beneficial effect of high dose HCT 1026 was maintained with treatment up to 3 months. The effect of the NO-donating drug HCT 1026 to normalize blood flow regulation in contracting mdx mouse hindlimb muscles suggests a putative novel treatment for DMD. Further translational research is warranted.</p> </div

Summary data showing effects of 2- or 3-month HCT 1026 treatment on functional muscle ischemia.

<p>(A) In the 2-month treatment groups, the vasoconstrictor responses to graded doses of NE (NE 1, NE 2) were slightly attenuated in the contracting hindlimbs of mice fed the 100 ppm HCT 1026 diet and were greatly attenuated in the contracting hindlimbs of mice fed the 300 ppm HCT 1026 diet. (B) In the 3-month treatment groups, NE-mediated vasoconstriction was only attenuated in the contracting hindlimbs of mice fed the 300 ppm HCT 1026 diet. Numbers above the bars are NE doses in ng. AUC, area under the curve in arbitrary units; Contr., contraction. Untreated, n = 10–11; HCT 100 ppm, n = 8; HCT 300 ppm, n = 5–6. *<i>P</i><0.05 vs. corresponding rest.</p

Hemodynamics and hindlimb force after 1 month of treatment.

<p>Data are mean±SE. For each group, n = 12. *<i>P</i><0.05 vs. untreated; ^†<i>P</i><0.05 vs. rest. MAP, mean arterial pressure; HR, heart rate; Flow, femoral blood flow velocity; Conductance, femoral vascular conductance.</p