Table 2: Anti-tumor agents for targeting hypoxia-induced CA IX for therapy and diagnosis.

The expression of carbonic anhydrase (CA) IX is up-regulated in many types of solid tumors in humans under hypoxic and acidic microenvironment. Inhibition of CA IX enzymatic activity with selective inhibitors, antibodies or labeled probes has been shown to reverse the acidic environment of solid tumors and reduce the tumor growth establishing the significant role of CA IX in tumorigenesis. Thus, the development of potent antitumor drugs targeting CA IX with minimal toxic effects is important for the target-specific tumor therapy. Recently, several promising antitumor agents against CA IX have been developed to treat certain types of cancers in combination with radiation and chemotherapy. Here we review the inhibition of CA IX by small molecule compounds and monoclonal antibodies. The methods of enzymatic assays, biophysical methods, animal models including zebrafish and Xenopus oocytes, and techniques of diagnostic imaging to detect hypoxic tumors using CA IX-targeted conjugates are discussed with the aim to overview the recent progress related to novel therapeutic agents that target CA IX in hypoxic tumors

Efficacy and safety of single- and repeated-selurampanel dosing for 2 weeks in patients with chronic subjective tinnitus: Results of a randomized, double-blind, placebo-controlled, cross-over, proof-of-concept phase IIa study

To evaluate efficacy and safety of BGG492 (selurampanel; an orally active, competitive AMPA glutamate receptor antagonist) in patients with moderate-to-catastrophic chronic subjective tinnitus. Study (NCT01302873) enrolled patients with subjective tinnitus based on THI severity grade 3, 4 or 5 (moderate, severe or catastrophic), and those with chronic (&gt;6 and &lt;36 months) tinnitus. Primary endpoints were clinical status of tinnitus using TBF-12 and tinnitus loudness using VAS after multiple dose 2-week BGG492 treatment. Safety was assessed by recording all adverse events (AEs). After a single dose of BGG492 VAS scores for tinnitus loudness (P=0.012) and tinnitus annoyance (P=0.004) were significantly reduced vs placebo. After 2 weeks treatment a significantly greater proportion of patients showed improvement of ≥4 points from baseline in TBF-12 (stringent responder definition) with BGG492 vs placebo (26.7% [n=23] vs 14% [n=12], respectively; odds ratio [OR] (90% CI):2.30 (1.10, 4.83); P=0.064), fulfilling proof-of-concept achievement criteria. No notable difference in proportion of responders to BGG492 vs placebo was observed as assessed using VAS (26.7% [n=23] vs 27.6% [n=24], respectively; OR (90% CI):0.94 (0.52, 1.67); P=0.848). Dizziness was the most frequently reported AE in 50% [n=21] and 31.5% [n=17] patients on BGG492 100 and 50mg TID, respectively vs 9.6% [n=9] on placebo. In conclusion, BGG492 showed reduction of both tinnitus loudness and annoyance after a single dose and reduction of tinnitus handicap after 2 weeks of treatment in patients with chronic subjective tinnitus, thereby supporting further clinical investigation of AMPA receptor antagonists with an improved benefit/risk ratio. A dose of 100mg TID BGG492 showed higher efficacy but somewhat lower tolerability compared to 50mg TID.</p