Mol Interv
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The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. ⋯ Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.
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Drug interactions and drug specificity are core themes for the pharmacologist. The paper discussed in this Viewpoint exploits the former to attain the latter. ⋯ Capsaicin is a selective activator of the TRPV1 channel, the localization of which is restricted to sensory C-fiber neurons involved in nociception. Because the large pore size of the activated TRPV1 allows passage of large cations such as QX-314, combined treatment with capsaicin and QX-314 puts QX-314 uniquely into that subclass of neurons mediating pain, thereby achieving sensational specificity.
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Voltage-gated sodium channels in nociceptive neurons are attractive targets for novel pain therapeutics. Although drugs that target voltage-gated sodium channels have proven value as pain therapeutics, the drugs that are currently available are non-specific sodium channel inhibitors, which limit their usefulness. Recently, a selective small-molecule inhibitor of Na(v)1.8, a voltage-gated sodium channel isoform that participates in peripheral pain mechanisms, has been developed. This exciting new compound shows efficacy in several animal models of pain and is anticipated to be only the first of many new isoform-specific sodium channel blockers.