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

Abstract

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.

• Authors: 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
• Journal: Pain (Pain) Vol. 132 Issue 1-2 Pg. 132-41 (Nov 2007) ISSN: 1872-6623 [Electronic] United States
• PMID: 17659837 (Publication Type: Journal Article, Randomized Controlled Trial)

Chemical References

• Analgesics
• Pyrrolidines
• SB 705498
• TRPV Cation Channels
• TRPV1 protein, human
• TRPV1 receptor
• Urea

Topics

• Administration, Oral
• Adolescent
• Adult
• Analgesics (administration & dosage)
• Cohort Studies
• Dose-Response Relationship, Drug
• Female
• Hot Temperature
• Humans
• Hyperalgesia (drug therapy, physiopathology)
• Inflammation (drug therapy, physiopathology)
• Male
• Middle Aged
• Pain Measurement (drug effects)
• Placebo Effect
• Pyrrolidines (administration & dosage)
• Signal Transduction (drug effects)
• TRPV Cation Channels (antagonists & inhibitors, metabolism)
• Treatment Outcome
• Urea (administration & dosage, analogs & derivatives)