Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion.
We studied the pharmacological actions of combined histamine H1/H3 receptor blockade on the increase in nasal airway resistance (NAR) and decrease in nasal cavity volume produced by nasal exposure to compound 48/80, a mast cell degranulator. In the anesthetized cat compound 48/80 (1%) produced a maximum increase in NAR of 9.1 +/- 0.7 cmH20.L/minute. The increase in NAR in animals pretreated with a combination of the H1 antagonist, chlorpheniramine (CTM; 0.8 mg/kg i.v.) and increasing doses of the H3 antagonist, thioperamide (THIO; 1.0, 3.0, and 10.0 mg/kg i.v.) were 6.1 +/- 2.1, 4.2 +/- 1.0 and 2.2 +/- 0.7 cmH20.L/minute, respectively. A second H3 antagonist, clobenpropit (CLOB; 0.03, 0.3, and 1.0 mg/kg i.v.) combined with CTM (0.8 mg/kg i.v.) also inhibited the nasal effects of compound 48/80. When the nonsedating H1 antihistamine, loratadine (3.0 mg/kg i.v.), was substituted for CTM, it also reduced nasal congestion when given in combination with THIO (10 mg/kg i.v.). In contrast, treatment with CTM (1.0 mg/kg i.v.) and the H2 antagonist, ranitidine (RAN; 1.0 mg/kg i.v.) were without activity. Loratadine, CTM, CLOB, RAN, or THIO administered alone were inactive. The alpha-adrenergic agonist, phenylpropanolamine (PPA; 1.0 mg/kg i.v.) demonstrated decongestant effects, but in contrast to H1/H3 blockade, PPA produced a significant hypertensive effect. Using acoustic rhinometry (AcR) we found that combined i.v. CTM (1.0 mg/kg) and THIO (10 mg/kg) and combined oral CTM (10 mg/kg) and THIO (30 mg/kg) blocked the decrease in nasal cavity volume produced by intranasal compound 48/80 (1%, 50 microL). We conclude that combined H1/H3 histamine receptor blockade enhances the efficacy of an H1 antagonist by conferring decongestant activity to the H1 antihistamine. We propose that the decongestant activity of combined H1/H3 blockade may provide a novel approach for the treatment of allergic nasal congestion without the hypertensive liability of current therapies.
McLeod
R L
RL
Allergy Department, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Mingo
G G
GG
Herczku
C
C
DeGennaro-Culver
F
F
Kreutner
W
W
Egan
R W
RW
Hey
J A
JA
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D002415:Cats; D002744:Chlorpheniramine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D006633:Histamine Antagonists / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000627:therapeutic use*; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D009296:Nasal Cavity / Q000187:drug effects / Q000473:pathology; D014663:Nasal Decongestants / Q000627:therapeutic use*; D015508:Nasal Obstruction / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D009666:Nose / Q000187:drug effects / Q000503:physiopathology; D010880:Piperidines / Q000627:therapeutic use*; D003189:p-Methoxy-N-methylphenethylamine
D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D014663:Nasal Decongestants; D010880:Piperidines; D002744:Chlorpheniramine; D003189:p-Methoxy-N-methylphenethylamine; C052075:thioperamide