The histamine H₄ receptor antagonist, JNJ 39758979, is effective in reducing histamine-induced pruritus in a randomized clinical study in healthy subjects.

The histamine H4 receptor (H4R) is a promising target for the treatment of pruritus. A clinical study was conducted to evaluate the safety and efficacy of the H4R antagonist, JNJ 39758979 [(R)-4-(3-amino-pyrrolidin-1-yl)-6-isopropyl-pyrimidin-2-ylamine], on histamine-induced pruritus in healthy subjects. A single oral dose of 600 mg JNJ 39758979, 10 mg cetirizine, or placebo was administered in a randomized, three-period, double-blind, crossover study. Treatment periods were separated by 22-day washout periods. A histamine challenge was administered on day -1 and at 2 and 6 hours postdose on day 1 of each treatment period. The primary efficacy endpoint was the area under the curve (AUC) of pruritus score 0-10 minutes after the histamine challenge. Secondary efficacy endpoints included wheal and flare areas assessed 10 minutes after the histamine challenge. Safety was assessed for all subjects. Of the 24 enrolled subjects, 23 individuals completed the study. One subject withdrew after completing two treatment periods. Due to a carryover effect of JNJ 39758979, only treatment period 1 was used for pruritus-related evaluations. Compared with placebo, the reduction of the AUC of pruritus score was significant for JNJ 39758979 at 2 hours (P = 0.0248) and 6 hours (P = 0.0060), and for cetirizine at 6 hours (P = 0.0417). In all treatment periods, JNJ 39758979 did not demonstrate a significant decrease in wheal or flare at either time point, although a significant reduction was achieved with cetirizine at 2 and 6 hours (P < 0.0001). Adverse eventss reported in >1 patient with JNJ 39758979 were headache (9%) and nausea (13%). In conclusion, JNJ 39758979 was effective in inhibiting histamine-induced pruritus in healthy subjects.
AuthorsAlexa Kollmeier, Klaus Francke, Bin Chen, Paul J Dunford, Andrew J Greenspan, Yichuan Xia, Xie L Xu, Bei Zhou, Robin L Thurmond
JournalThe Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 350 Issue 1 Pg. 181-7 (Jul 2014) ISSN: 1521-0103 [Electronic] United States
PMID24817035 (Publication Type: Clinical Trial, Phase I, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics.
Chemical References
  • 4-(3-aminopyrrolidin-1-yl)-6-isopropylpyrimidin-2-ylamine
  • HRH4 protein, human
  • Histamine Antagonists
  • Pyrimidines
  • Pyrrolidines
  • Receptors, G-Protein-Coupled
  • Receptors, Histamine
  • Histamine
  • Cetirizine
  • Adolescent
  • Adult
  • Cetirizine (therapeutic use)
  • Cross-Over Studies
  • Double-Blind Method
  • Healthy Volunteers
  • Histamine (adverse effects)
  • Histamine Antagonists (adverse effects, therapeutic use)
  • Humans
  • Male
  • Middle Aged
  • Pruritus (chemically induced, drug therapy)
  • Pyrimidines (adverse effects, therapeutic use)
  • Pyrrolidines (adverse effects, therapeutic use)
  • Receptors, G-Protein-Coupled (antagonists & inhibitors)
  • Receptors, Histamine
  • Young Adult

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