AHR-14310C: a potent, long-acting, nonsedating H1-antihistamine that prevents antigen-induced mucus formation in sensitive rats.
AHR-14310C(5-[2-[4-[bis(4-fluorophenyl)hydroxymethyl- 1-piperidinyl]ethyl]-3-methyl]-2-oxazolidinone ethanedioate, hydrochloride salt) displays potent and long-acting antihistaminic activity in guinea pigs and in dog and guinea pig models of immediate hypersensitivity. Given orally 1, 5 or 24 hr before an i.v. histamine challenge, AHR-14310C produced ED50 values of 0.76, 0.22 and 0.58 mg/kg, respectively, in protecting naive guinea pigs from the lethal effects of the histamine challenge. AHR-14310C was also effective when the histamine was administered as an aerosol (1-, 5- and 24-hr ED50 values = 0.69, 0.38 and 1.08 mg/kg, respectively). AHR-14310C also attenuated the anaphylactic responses to aerosolized antigen in sensitive guinea pigs and the skin response to antigen in naturally sensitive dogs. AHR-14310C, at doses in vastly excess of those required to block histamine-induced hypotension, did not alter the electroencephalogram of cats, as did the sedating antihistamine, diphenhydramine. AHR-14310C did not affect the autonomic responses to acetylcholine, isoproterenol, epinephrine or 1,1-dimethyl-4-phenylpiperazinium chloride in dogs. At low doses (0.316-1.0 mg/kg p.o.), AHR-14310C blocked antigen-induced tracheal mucous changes in sensitive rats. AHR-14310C has therapeutic potential in allergic individuals, particularly in asthmatics, where bronchorrhea or mucus plugging is a problem.
Nolan
J C
JC
Department of Pharmacology, A. H. Robins Research Laboratories, Richmond, Virginia.
Foxwell
M H
MH
Whitman
L L
LL
Yanni
J M
JM
Walsh
D A
DA
Kilpatrick
B F
BF
Johnson
D N
DN
Proakis
A G
AG
D000109:Acetylcholine / Q000037:antagonists & inhibitors; D000818:Animals; D002415:Cats; D004285:Dogs; D004342:Drug Hypersensitivity / Q000188:drug therapy; D005260:Female; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects; D010080:Oxazoles / Q000378:metabolism / Q000494:pharmacology*; D023303:Oxazolidinones; D010880:Piperidines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012882:Skin Tests; D012890:Sleep / Q000187:drug effects
D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D010080:Oxazoles; D023303:Oxazolidinones; D010880:Piperidines; C064631:AHR 14310C; D000109:Acetylcholine