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.
Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Cambridge and Harlow, UK. boris.a.chizh@gsk.com
Boris A
BA
Chizh
Mary B
MB
O'Donnell
Antonella
A
Napolitano
Jie
J
Wang
Allison C
AC
Brooke
Mike C
MC
Aylott
Jonathan N
JN
Bullman
Emily J
EJ
Gray
Robert Y
RY
Lai
Pauline M
PM
Williams
Jonathan M
JM
Appleby
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000700:Analgesics / Q000008:administration & dosage; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006358:Hot Temperature; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy* / Q000503:physiopathology*; D007249:Inflammation / Q000188:drug therapy / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement / Q000187:drug effects*; D015990:Placebo Effect; D011759:Pyrrolidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016896:Treatment Outcome; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives*
D000700:Analgesics; D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C494484:TRPV1 receptor; D014508:Urea