Drug transporters are involved in clinically relevant drug-drug interactions. P-glycoprotein (P-gp) is an efflux transporter that displays genetic polymorphism. Phenotyping permits evaluation of real-time, in vivo P-gp activity and P-gp-mediated drug-drug interactions. Digoxin, fexofenadine, talinolol and quinidine are commonly used probe drugs for P-gp phenotyping. Although current regulatory guidance documents highlight methodologies for evaluating transporter-based drug-drug interactions, whether current probe drugs are suitable for phenotyping has not been established, and validation criteria are lacking. This review proposes validation criteria and evaluates P-gp probes to determine probe suitability. Based on these criteria, digoxin, fexofenadine, talinolol and quinidine have limitations to their use and are not recommended for P-gp phenotyping.
L-chicoric acid (L-CA) is a potent inhibitor of HIV integrase (IN) in vitro. In this report, the effects of a glycine to serine mutation at position 140 (G140S) on HIV IN and its effects on IN inhibitor resistance are described. HIV containing the G140S mutation showed a delay in replication. Using real-time polymerase chain reaction, the delay was secondary to a failure in integration. The mutant protein (IN(G140S)) was attenuated approximately four-fold for catalysis under equilibrium conditions compared to wild-type IN (IN(WT)) and attenuated five-fold in steady-state kinetic analysis of disintegration. Fifty percent inhibitory concentration assays were performed with IN inhibitors against both IN proteins in disintegration and strand transfer reactions. IN(G140S) was resistant to both L-CA and L-731,988, a diketoacid. HIV containing the mutation was resistant to both inhibitors as well. The G140S mutation attenuates IN activity and confers resistance to IN inhibitors, suggesting that diketoacids and L-CA interact with a similar binding site on HIV IN.
Cancer chemotherapy has evolved from a few therapeutic agents in three drug classes to more than 50 drugs in over ten drug classes. With generally cytotoxic mechanisms of action, there is continued research interest in preventing and managing adverse events of chemotherapy. Although treatment-induced symptom management has made significant progress, most therapies lead to intolerable reactions that result in a dose reduction or discontinuation of therapy. Mucositis is a common adverse event that can occur after administration of systemic chemotherapy and/or radiation therapy leading to inflammatory lesions anywhere from the oral cavity to the GI tract. Although pathophysiologically similar, gastrointestinal mucositis and oral mucositis (OM) differ in terms of symptom presentation and offending therapies. The focus of the article will be on OM; gastrointestinal mucositis will be mentioned when therapy efficacy is relevant to OM. OM prophylaxis has been a subject of interest for at least the past 30 years, yet progress has been limited due to a lack of understanding of the condition. With the recent introduction of palifermin (Kepivance™), novel therapies continue to be developed that may significantly reduce the incidence, duration and/or severity of OM. In addition, outcomes including an improvement in patient quality of life, increasing treatment dose intensity or reducing healthcare costs may result from successful management of OM prophylaxis. This article will review currently available OM prophylactic therapies. Agents in preclinical or clinical development and natural supplements will also be discussed.
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