Efficacy and tolerability of rupatadine at four times the recommended dose against histamine- and platelet-activating factor-induced flare responses and ex vivo platelet aggregation in healthy males.
BACKGROUND
European guidelines recommend increasing H1-antihistamine doses up to fourfold in poorly responding patients with urticaria.


OBJECTIVE
To assess the efficacy and tolerability of high-dose rupatadine (40 mg) against platelet-activating factor (PAF)- and histamine-induced flare responses in human skin and to verify its anti-PAF activity by assessing its inhibition of PAF-induced platelet aggregation in the blood of subjects receiving rupatadine 40 mg.


METHODS
In the flare study, six male volunteers received a single dose of rupatadine 40 mg. Flares were induced before dosing and up to 96 h afterwards by intradermal PAF and histamine. In the ex vivo study, four male volunteers received an oral dose of rupatadine 40 mg and blood samples were taken 4 h afterwards. Platelet aggregation was assessed in platelet-rich plasma by incubation for 5 min with PAF.


RESULTS
Rupatadine 40 mg reached maximal plasma levels of 15·1 ± 4·4 ng mL⁻¹)1 at 1 h and its metabolite, desloratadine, 5·2 ± 0·9 ng mL⁻¹)1 at 2 h. Neither was detectable at 12 h. Inhibition of histamine- and PAF-induced flares was significant within 2 h, maximal at 6 h (87·8 ± 3·1% and 87·1 ± 2·5% inhibition, respectively, P < 0·0001) and still statistically significant at 72 h. Rupatadine 40 mg inhibited PAF-induced platelet aggregation ex vivo by 82 ± 9% (P = 0·023). A single oral dose of rupatadine 40 mg was well tolerated with mild transient somnolence being reported.


CONCLUSIONS
A single dose of rupatadine at four times the recommended dose is well tolerated, highly effective for up to 72 h against PAF- and histamine-induced dermal flares and has demonstrable PAF-receptor antagonism ex vivo.
Church
M K
MK
Department of Dermatology and Allergy, Allergy Centre Charité, Charité-Universitätsmedizin Berlin, Berlin, Germany. mkc@southampton.ac.uk
D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D003533:Cyproheptadine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007271:Injections, Intradermal; D008297:Male; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011537:Pruritus / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012867:Skin / Q000187:drug effects; D055815:Young Adult
D006634:Histamine H1 Antagonists; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; C103639:rupatadine; D003533:Cyproheptadine; D006632:Histamine