Evaluation of the effect of the specific CCR1 antagonist CP-481715 on the clinical and cellular responses observed following epicutaneous nickel challenge in human subjects.
BACKGROUND
The CC-chemokine receptor-1 (CCR1) is thought to be involved in recruitment of inflammatory cells in allergic contact dermatitis (ACD). CP-481715 is a specific antagonist of CCR1.


OBJECTIVE
To determine the inhibitory effects of CP-418 715 in ACD by evaluating the clinical signs and cellular infiltration in skin biopsies following epicutaneous nickel challenge in allergic subjects.


METHODS
In this phase 1/2 study, 40 subjects were randomized to 5 days of treatment in four parallel groups (placebo three times daily (TID), placebo once daily (QD), 1000 mg CP-418 715 TID, and 3000 mg CP-418 715 QD). Twenty-four hours after the first drug administration, nickel sulfate patches were applied on subjects' backs and removed 48 hours later.


RESULTS
Pretreatment with 1000 mg CP-481715 TID resulted in significant reductions in visual scores of the nickel reactions (P = 0.01). Instrumentally measured erythema tended to decrease in the CP-481715 mg TID group (P = 0.06). No differences were noted between the 3000 mg CP-481715 mg QD group and pooled placebo. No significant differences were found for immunohistological cell counts. CP-418 715 was generally safe and well tolerated.


CONCLUSIONS
Blocking of CCR1 only partly inhibited clinical manifestations of ACD. Several chemokine receptors are likely relevant for the cellular influx observed in ACD lesions.
Unit of Clinical Pharmacology, Gentofte Hospital, Niels Andersens Vej 65, 2900 Hellerup, Denmark.
Jeanett
J
Borregaard
Lone
L
Skov
Lisy
L
Wang
Naitee
N
Ting
Cunshan
C
Wang
Lisa A
LA
Beck
Jesper
J
Sonne
Alan
A
Clucas
D017449:Dermatitis, Allergic Contact / Q000175:diagnosis* / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007509:Irritants / Q000008:administration & dosage; D008297:Male; D009532:Nickel / Q000008:administration & dosage; D011810:Quinoxalines / Q000627:therapeutic use*; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors*
C515300:CCR1 protein, human; D007509:Irritants; D011810:Quinoxalines; D054389:Receptors, CCR1; C479133:quinoxaline-2-carboxylic acid (4-carbamoyl-1-(3-fluorobenzyl)-2,7-dihydroxy-7-methyloctyl)amide; C029938:nickel sulfate; D009532:Nickel