Selective and nonselective cyclooxygenase-2 inhibitors and experimental fracture-healing. Reversibility of effects after short-term treatment.

BACKGROUND: Cyclooxygenase-2-specific anti-inflammatory drugs (coxibs) and nonspecific nonsteroidal anti-inflammatory drugs have been shown to inhibit experimental fracture-healing. The present study tested the hypothesis that these effects are reversible after short-term treatment. METHODS: With use of a standard model of fracture-healing, identical ED50 dosages of either a nonsteroidal anti-inflammatory drug (ketorolac), a coxib (valdecoxib), or vehicle (control) were orally administered to rats for either seven or twenty-one days and fracture-healing was assessed with biomechanical, histological, and biochemical analyses. RESULTS: When healing was assessed at twenty-one days, the seven-day treatment produced only a trend for a higher rate of nonunion in valdecoxib and ketorolac-treated animals as compared with controls. No differences were observed at thirty-five days. The twenty-one-day treatment produced significantly more nonunions in valdecoxib-treated animals as compared with either ketorolac-treated or control animals (p < 0.05), but these differences disappeared by thirty-five days. The dose-specific inhibition of these drugs on prostaglandin E2 levels and the reversibility of the effects after drug withdrawal were assessed in fracture calluses and showed that ketorolac treatment led to twofold to threefold lower levels of prostaglandin E2 than did valdecoxib. Withdrawal of either drug after six days led to a twofold rebound in these levels by fourteen days. Histological analysis showed delayed remodeling of calcified cartilage and reduced bone formation in association with valdecoxib treatment. CONCLUSIONS: Cyclooxygenase-2-specific drugs inhibit fracture-healing more than nonspecific nonsteroidal anti-inflammatory drugs, and the magnitude of the effect is related to the duration of treatment. However, after the discontinuation of treatment, prostaglandin E2 levels are gradually restored and the regain of strength returns to levels similar to control.

Preparation, characterization, and biological evaluation of technetium(V) and rhenium(V) complexes of novel heterocyclic tetradentate N3S ligands.

Various tetradentate N3S ligands which contain pyridyl, morpholino, or imidazolyl moieties were prepared and labeled with technetium and rhenium. Metal complexation of the ligands occurred efficiently over the pH range from 2 to 11. Ligands possessing the S-THP (tetrahydropyranyl)-protected mercapto group labeled efficiently even under alkaline conditions, and among the three types of heterocyclic metal complexes, a marked difference in stability was observed; rhenium complexes decomposed to ReO4 whereas technetium complexes decomposed to TcO2/TcO4. In general, imidazolyl complexes of both technetium and rhenium were very stable in saline; less than 10% decomposition after 24 h. The technetium histidyl complex and technetium pyridyl complex were quite stable even under cysteine challenge; less than 10% decomposition after 24 h. The rhenium and technetium morpholino complexes were very unstable; greater than 10% decomposition after only 1 h in saline and greater than 25% decomposition in 1 h under cysteine challenge. Profound pharmacokinetic differences among these metal complexes were also observed in rat biodistribution studies. The neutral pyridyl complexes exhibited high blood and liver uptake and slow clearance from these tissues. The replacement of a hydroxyl group by a carboxyl group, which resulted in an anionic complex at physiological pH, resulted in a dramatic decrease in blood and liver uptake. The neutral imidazolyl complex exhibited marked reduction in blood uptake and much faster clearance from blood and liver compared to the neutral pyridyl complex. Finally, the anionic histidyl complex, which contains both the imidazolyl and carboxyl groups, had the most favorable pharmacokinetic properties in that it exhibited very low blood, liver, and kidney uptakes and a rapid clearance from the body via the renal system. The combination of the high stability and favorable pharmacokinetic properties of the imidazolyl complexes should render them useful for targeted delivery of the medically important isotopes.