title: Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.
abstract: Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.
authors.affiliation: Division de Pharmacologie et Toxicologie Cliniques, CHU Vaudois, CH-1011 Lausanne, Switzerland. eric.grouzmann@chuv.ch
authors.forename: Eric
authors.initials: E
authors.lastname: Grouzmann
authors.forename: Paul
authors.initials: P
authors.lastname: Bigliardi
authors.forename: Monique
authors.initials: M
authors.lastname: Appenzeller
authors.forename: André
authors.initials: A
authors.lastname: Pannatier
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
mesh_terms: D002211:Capsaicin / Q000008:administration & dosage; D002253:Carbonated Beverages; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000187:drug effects; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D003875:Drug Eruptions / Q000188:drug therapy*; D004487:Edema / Q000139:chemically induced; D004890:Erythema / Q000139:chemically induced; D006801:Humans; D007271:Injections, Intradermal; D008297:Male; D010146:Pain / Q000139:chemically induced; D011719:Pyrazines / Q000008:administration & dosage*; D000068900:Sitagliptin Phosphate; D012867:Skin / Q000187:drug effects*; D013373:Substance P; D014230:Triazoles / Q000008:administration & dosage*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D013373:Substance P; D018819:Dipeptidyl Peptidase 4; D002211:Capsaicin; D000068900:Sitagliptin Phosphate