Effects of a Specific Cysteinyl Leukotriene Antagonist, Pranlukast, on Antigen-Induced Cysteinyl Leukotriene-Mediated Rhinitis in Guinea Pigs

Abstract

ABSTRACT-To examine the effects of a specific cysteinyl leukotriene (cysLT) antagonist, pranlukast, on allergic rhinitis, antigen-induced rhinitis in guinea pigs was modified by pretreatment with an cyclo oxygenase inhibitor (indomethacin) followed by an H1-blocker (pyrilamine). Intranasal ovalbumin (OVA) administration in actively sensitized guinea pigs resulted in concentration-dependent increases in nasal permeability and nasal airway resistance (NAR). Although pyrilamine (1 mg/kg, i.v.) abolished these antigen-induced changes, pretreatment with indomethacin (5 mg/kg, i.v.) followed by pyrilamine enhanced these responses to a degree similar to that observed with OVA challenge alone. Analyses of nasal perfusate in indomethacin/pyrilamine-pretreated animals showed that cysLTs increased by 270.8%, whereas throm boxane B2 decreased by 88.3% as compared with those on challenged with OVA alone. Oral administration of pranlukast (1-10 mg/kg) dose-dependently prevented increases in nasal permeability and NAR of indo methacin/pyrilamine-pretreated animals. However, an anti-allergic agent, azelastine, did not affect these responses. These results indicate that pranlukast suppresses antigen-induced cysLT-mediated responses of allergic rhinitis in actively sensitized guinea pigs. A cysLT antagonist, pranlukast, may thus prevent cysLT-mediated symptoms of allergic rhinitis.Keywords: Pranlukast, Rhinitis, Leukotriene, Allergic, Ovalbumin Nasal symptoms of allergic rhinitis often display a biphasic pattern after antigen provocation.While the early-phase symptoms (up to 1 hr after antigen provoca tion) such as sneezing and rhinorrhea are transient, the late-phase symptom (4 8 hr after antigen provocation) characterized by nasal congestion is persistent (1). Media tors that have been suggested to participate in these symp toms include histamine, cyclooxygenase metabolites of arachidonic acid and cysteinyl leukotrienes (cysLTs) such as leukotriene C4, D4 and E4 (LTC4, LTD4 and LTE4), main components of the slow-reacting substance of anaphylaxis (SRS-A) (2). Among these mediators, cysLTs are of particular interest as they have been suggested to play a role in nasal congestion (3, 4), a symptom which is resistant to many therapeutic agents including current anti-histaminergics (5). Thus, agents that may antagonize or inhibit the action of cysLTs (anti-cysLTs) may be use ful in the treatment of allergic rhinitis.Although interest has focused on the therapeutic effects of anti-cysLTs against allergic rhinitis, current findings remain inconsistent. Clinical studies to evaluate the effects of anti-cysLTs on allergic rhinitis have produced controversial results (6, 7), and there is lack of an ap propriate animal model for allergic rhinitis to evaluate relevant effects of anti-cysLTs. This study was designed to examine the effects of a specific cysLT antagonist, pranlukast, which has previously been demonstrated to be a useful agent for treatment of bronchial asthma (8) with a novel model of antigen-induced rhinitis in guinea pigs. We...

Nasal Blockage Induced by Oral Administration of Non-steroidal Anti-inflammatory Drugs in a Guinea-Pig Model of Allergic Rhinitis

“…It has been reported by researchers in the laboratories of the manufacturer of pranlukast that 10 -30 mg/ kg pranlukast caused potent inhibition in in vivo experiments of CysLT-mediated allergic reactions (21,22). The present result is different from clinical findings, in which not only the CysLT antagonist montelukast (18,19), but also the 5-lipoxygenase inhibitor zileuton (23) improved nasal function after aspirin administration in aspirin-sensitive asthmatics.…”

“…On the other hand, regarding the allergic rhinitis model of guinea pigs, there is only one study evaluating effects of indomethacin on nasal allergy (21). Fujita et al (21) showed that indomethacin enhanced antigen-induced increase in nasal airway resistance, and the amplified response was inhibited by a treatment with pranlukast (10 mg / kg). However, there is no report that showed Fig.…”

Effects of Fexofenadine Hydrochloride in a Guinea Pig Model of Antigen-Induced Rhinitis

“…It has also been reported that histamine, leukotrienes, and thromboxane, are involved in the mechanism of development of allergic rhinitis in guinea pigs [6,9,10,[12][13][14][15][16][17][18] .…”

“…After the waiting period, warm air was again blown into the nasal cavity and the antigen solution was eliminated from the nasal cavity. The nasal airway resistance was measured for 45 min after the antigen challenge, because (1) usually it has been determined for about 30 min in studies in the acute allergic rhinitis model [11,12,14,15] ; (2) such studies suggest that the resistance is still increased at 45 min, and (3) it is diffi cult to anesthetize guinea pigs with pentobarbital for a longer time. At the end of the assessment of the nasal airway resistance, the animal was euthanized by injection of an excessive amount of pentobarbital.…”

“…That is, the experimental animals also exhibit sneezing [6][7][8][9][10] , nasal secretion [9] and nasal obstruction [6][7][8][9][10][11][12][13][14][15][16][17] . It has been demonstrated that histamine [10,12,14,16] , leukotrienes [9,10,12,13,16] , and thromboxane [6,10,12,14,15,17,18] are involved in the mechanism of development of the pathology in these models. Accordingly, these guinea pig models have come to be widely used for evaluation of the pharmacological effects of drugs being developed for the treatment of allergic rhinitis.…”