Abstract
Rupatadine (UR-12592, 8-chloro-6,11-dihydro-11-[1-[(5-methyl3-pyridinyl)methyl]-4-piperidinylidene]-5H-benzo[5,6]cyclohepta[1,2b]pyridine) is a novel compound that inhibits both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with specific receptors (K i app values against [3H]WEB-2086 binding to rabbit platelet membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 μM, respectively). Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 = 9.29 ± 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4(LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit platelets (WRP) (pA2= 6.68 ± 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 μM), while not affecting ADP- or arachidonic acid-induced platelet aggregation. Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 μg/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine’s duration of action was long, as assessed by the histamine- and PAF-induced increase in vascular permeability test in dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects. Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadine’s PAF antagonist effects were near those of WEB-2086. Rupatadine is therefore a good candidate for further development in the treatment of allergic and inflammatory conditions in which both PAF and histamine are implicated.
Footnotes
-
Send reprint requests to: Dr. J. Forn, Research Center, J. Uriach & Cı́a, S.A., Degà Bahı́ 59, 08026 Barcelona, Spain.
- Abbreviations:
- PAF
- platelet-activating factor
- PRP
- platelet-rich plasma
- HPRP
- human platelet-rich plasma
- WRP
- washed rabbit platelets
- BSA
- bovine serum albumin
- PBS
- phosphate buffered saline
- LTD4
- leukotriene D4
- Received May 31, 1996.
- Accepted September 13, 1996.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|
