title: Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist.
abstract: OBJECTIVE
  To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist.
  
  
  METHODS
  Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge.
  
  
  RESULTS
  Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency.
  
  
  CONCLUSIONS
  Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluation.
authors.affiliation: Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Carlijn
authors.initials: C
authors.lastname: Holland
authors.forename: Cornelis
authors.initials: C
authors.lastname: van Drunen
authors.forename: Jane
authors.initials: J
authors.lastname: Denyer
authors.forename: Kevin
authors.initials: K
authors.lastname: Smart
authors.forename: Christine
authors.initials: C
authors.lastname: Segboer
authors.forename: Ingrid
authors.initials: I
authors.lastname: Terreehorst
authors.forename: Amy
authors.initials: A
authors.lastname: Newlands
authors.forename: Misba
authors.initials: M
authors.lastname: Beerahee
authors.forename: Wytske
authors.initials: W
authors.lastname: Fokkens
authors.forename: Daphne C
authors.initials: DC
authors.lastname: Tsitoura
mesh_terms: D000293:Adolescent; D000328:Adult; D002211:Capsaicin / Q000037:antagonists & inhibitors*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D012220:Rhinitis / Q000188:drug therapy*; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D064232:Visual Analog Scale
chemical_list: D011759:Pyrrolidines; C512301:SB 705498; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea; D002211:Capsaicin
keywords: TRPV1; capsaicin challenge; intranasal SB-705498; nasal hyper-responsiveness; rhinitis
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