Alteration of the pharmacokinetics of COL-3, a matrix metalloproteinase inhibitor, due to actue gastrointestinal tosicity of doxorubicin

Purpose Combination of COL-3, a matrix metalloproteinase inhibitor, and doxorubicin (DOX) might be a promising anticancer regimen. The present study was to examine the potential pharmacokinetic interactions and toxicity profile following their coadministration in rats.
Methods Normal rats were treated with single agent or different combinations with oral or intravenous COL-3 and DOX, and the bile-duct cannulated (BDC) rats received oral COL-3 plus DOX. In a separate disposition study, the effects of DOX on the biliary, urinary, and fecal excretion of COL-3 were examined. In addition, the effects of DOX on in vitro protein binding, metabolism, and transport of COL-3 across Caco-2 monolayers were investigated.
Results COL-3 did not affect the pharmacokinetics of DOX in rats. However, treatment with DOX significantly decreased the oral absorption, and prolonged the elimination, of COL-3 in the normal rats, but not in the BDC rats. DOX did not alter the biliary and urinary excretion of COL-3, but significantly decreased the fecal excretion of COL-3. DOX significantly enhanced the basolateral to apical flux of COL-3 across Caco-2 monolayers, but had no apparent effects on the protein binding and metabolism of COL-3. The combination of DOX with oral COL-3 did not significantly (p > 0.05) increase the acute diarrhea score and intestinal damage compared to rats receiving DOX alone.
Conclusions These results indicated that DOX altered the oral absorption and elimination of COL-3, largely resulting from gastrointestinal toxicity caused by biliary excretion of DOX. Further studies are required to explore the efficacy and optimized dosage regimen of this promising combination.

Queer contingencies: bifurcation and the sexuality of schooling

This article critiques the contemporary focus on same-sex attracted youth, “antihomophobia,” and “safe schools,” as well as the ways these foci structure the logics of the prevailing policy approach. The author examines how contemporary antihomophobic reform in education is sustained by a series of false dilemmas: that the political demands and  investments of straights and nonstraights can be easily distinguished one from another; that the expression of homophobia is anathema to queer educative work; and that everything that is at stake in the messy confluence of sexuality, gender, and schooling can be made sense of by figuring the problem as a matter of being safe. Gesturing toward a queer social policy for schooling, this article critiques the “zero-tolerance” approach of antihomophobia education, arguing that it falsely bifurcates the social world of the school into homophobic/antihomophobic iterations, unsafe/safe versions, and straight/homosexual interest.