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Chizh, B.A. et al.

Boris A. Chizh, Mary B. O'Donnell, Antonella Napolitano, Jie Wang, Allison C. Brooke, Mike C. Aylott, Jonathan N. Bullman, Emily J. Gray, Robert Y. Lai, Pauline M. Williams, Jonathan M. Appleby,

The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans.

TRPV1 is a cation channel activated by a range of noxious stimuli and highly expressed in nociceptive fibres. TRPV1 receptors are involved in pain and sensitisation associated with tissue injury and inflammation; hence, TRPV1 antagonists are potentially useful for the treatment of such pain states. SB-705498 is a potent, selective and orally bioavailable TRPV1 antagonist with demonstrated efficacy in a number of preclinical pain models. In this first-time-into-human study, we have investigated the pharmacodynamic and antihyperalgesic activity of SB-705498. The compound was safe and well tolerated at single oral doses up to 400mg. In a cohort of 19 healthy volunteers, we used a randomised placebo-controlled single-blind cross-over design to assess the effects of SB-705498 (400mg) on heat-evoked pain and skin sensitisation induced by capsaicin or UVB irradiation. Compared with placebo, SB-705498 reduced the area of capsaicin-evoked flare (P=0.0047). The heat pain threshold on non-sensitised skin was elevated following SB-705498 (estimated difference from placebo [95% confidence intervals]: 1.3 degrees C [0.07,2.53], P=0.019). Following capsaicin sensitisation, the heat pain threshold and tolerance were similar between SB-705498 and placebo. However, SB-705498 increased heat pain tolerance at the site of UVB-evoked inflammation (estimated difference from placebo: 0.93 degrees C [0.25,1.6], P=0.0054). The magnitude of the pharmacodynamic effects of SB-705498 appeared to be related to plasma concentration. These results indicate that SB-705498, at a clinically safe and well-tolerated dose, has target-specific pharmacodynamic activity in humans. These data provide the first clinical evidence that a TRPV1 antagonist may alleviate pain and hyperalgesia associated with inflammation and tissue injury.[1]

References

The effects of the TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity and inflammatory hyperalgesia in humans. Chizh, B.A., O'Donnell, M.B., Napolitano, A., Wang, J., Brooke, A.C., Aylott, M.C., Bullman, J.N., Gray, E.J., Lai, R.Y., Williams, P.M., Appleby, J.M. Pain (2007) [Pubmed]

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