title: Effect of combined histamine H1 and H3 receptor blockade on cutaneous microvascular permeability elicited by compound 48/80.
abstract: The pharmacological consequences of combining a histamine H1 receptor antagonist with a H3 antagonist on cutaneous microvascular permeability due to intradermal (i.d.) injections of compound 48/80, a mast cell liberator of histamine, was studied in the anesthetized guinea pig. Compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) induced permeability responses were attenuated, as determined by Evans blue extravasation, in animals pretreated with the H1 antagonist, chlorpheniramine (CTM; 1.0 mg/kg, i.v.) by 17 +/- 4, 31 +/- 4, 32 +/- 4 and 37 +/- 4%, respectively. Combination treatment with an H1 and H3 antagonist displayed greater inhibitory efficacy against the effects elicited by compound 48/80. Specifically, combined treatment with CTM (1.0 mg/kg, i.v.) and the H3 antagonist, thioperamide (THIO 1.0 mg/kg,i.v.) inhibited the skin responses of i.d. compound 48/80 (0.0003, 0.001, 0.003 and 0.01%) by 36 +/- 4, 45 +/- 4, 49 +/- 4 and 54 +/- 4%. A second H3 antagonist, clobenpropit (CLOB; 0.3 mg/kg, i.v.) plus CTM (1.0 mg/kg, i.v.) also inhibited Evans blue extravasation. Treatment with THIO (1.0 mg/kg, i.v.) and CLOB (0.3 mg/kg, i.v.) administered alone had no effect on compound 48/80-induced skin responses. We conclude that combination administration of a H1 and a H3 histamine receptor antagonist produces greater inhibitory effect on cutaneous microvascular permeability produced by released mast cell-derived histamine than either a H1 or H3 antagonist administered separately. In addition, the antiallergy activity of combining a H3 antihistamine with a H3 antagonist activity might provide a novel approach for the treatment of allergic skin diseases such as urticaria.
authors.affiliation: Schering-Plough Research Institute, Allergy, 2015 Galloping Hill Road, Kenilworth, NJ 07033-0539, USA. robbie.mcleod@spcorp.com
authors.forename: Robbie L
authors.initials: RL
authors.lastname: McLeod
authors.forename: Garfield G
authors.initials: GG
authors.lastname: Mingo
authors.forename: William
authors.initials: W
authors.lastname: Kreutner
authors.forename: John A
authors.initials: JA
authors.lastname: Hey
mesh_terms: D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D002744:Chlorpheniramine / Q000008:administration & dosage / Q000494:pharmacology; D004357:Drug Synergism; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects*; D007271:Injections, Intradermal; D007275:Injections, Intravenous; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D003189:p-Methoxy-N-methylphenethylamine / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D006633:Histamine Antagonists; D006634:Histamine H1 Antagonists; D010880:Piperidines; D011969:Receptors, Histamine H1; D018100:Receptors, Histamine H3; D002744:Chlorpheniramine; D003189:p-Methoxy-N-methylphenethylamine; C052075:thioperamide