McLeod R L, Mingo G G, Herczku C, DeGennaro-Culver F, Kreutner W, Egan R W, Hey J A
Allergy Department, Schering-Plough Research Institute, Kenilworth, NJ 07033-0539, USA.
Am J Rhinol. 1999 Sep-Oct;13(5):391-9. doi: 10.2500/105065899781367483.
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.
我们研究了组胺H1/H3受体联合阻断对鼻腔暴露于肥大细胞脱颗粒剂化合物48/80所引起的鼻气道阻力(NAR)增加和鼻腔容积减小的药理作用。在麻醉猫中,化合物48/80(1%)使NAR最大增加9.1±0.7 cmH2O·L/分钟。预先用H1拮抗剂氯苯那敏(CTM;0.8 mg/kg静脉注射)和递增剂量的H3拮抗剂硫代哌酰胺(THIO;1.0、3.0和10.0 mg/kg静脉注射)联合处理的动物,NAR的增加分别为6.1±2.1、4.2±1.0和2.2±0.7 cmH2O·L/分钟。另一种H3拮抗剂氯苯丙哌嗪(CLOB;0.03、0.3和1.0 mg/kg静脉注射)与CTM(0.8 mg/kg静脉注射)联合使用也能抑制化合物48/80的鼻效应。当用非镇静性H1抗组胺药氯雷他定(3.0 mg/kg静脉注射)替代CTM时,与THIO(10 mg/kg静脉注射)联合使用也能减轻鼻充血。相比之下,用CTM(1.0 mg/kg静脉注射)和H2拮抗剂雷尼替丁(RAN;1.0 mg/kg静脉注射)处理则无活性。单独给予氯雷他定、CTM、CLOB、RAN或THIO均无活性。α-肾上腺素能激动剂苯丙醇胺(PPA;1.0 mg/kg静脉注射)显示出减充血作用,但与H1/H3阻断不同的是,PPA产生了显著的升压作用。使用鼻声反射仪(AcR),我们发现静脉注射CTM(1.0 mg/kg)和THIO(10 mg/kg)联合以及口服CTM(10 mg/kg)和THIO(30 mg/kg)联合可阻断鼻内给予化合物48/80(1%,50 μL)所引起的鼻腔容积减小。我们得出结论,组胺H1/H3受体联合阻断通过赋予H1抗组胺药减充血活性来增强其疗效。我们提出,H1/H3联合阻断的减充血活性可能为治疗过敏性鼻充血提供一种新方法,而不会产生现有疗法的高血压副作用。