In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

Nakagawa, Naoki; Obata, Takaaki; Kobayashi, Tadamasa; Okada, Yutaka; Nambu, Fumio; Terawaki, Tamiya; Aishita, Hideki

doi:10.1254/jjp.60.217

Cited by 83 publications

(32 citation statements)

References 26 publications

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“…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.…”

Section: Discussioncontrasting

confidence: 83%

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

et al. 2007

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Abstract. To elucidate the mechanisms underlying nasal symptoms in patients with aspirin hypersensitivity, we evaluated the effects of orally administered non-steroidal anti-inflammatory drugs (NSAIDs) on the nasal patency of guinea pigs with cedar pollen-induced chronic allergic rhinitis. Indomethacin (10 mg / kg) administered 1 h before a pollen challenge amplified the antigen-induced nasal blockage. More interestingly, even in the absence of the pollen challenge, indomethacin induced nasal blockage at 30 min at 4 h after administration. However, indomethacin-induced nasal blockage was not provoked in non-sensitized animals. Another NSAID, diclofenac (30 mg / kg), also evoked nasal blockage, but unexpectedly, aspirin (500 mg / kg) did not affect nasal patency. Indomethacin-induced nasal blockage was unaffected by a cysteinyl leukotriene receptor (CysLT 1 receptor) antagonist, pranlukast (30 mg / kg, p.o.), or by prostaglandin E 2 (10 −3 M, intranasal), suggesting that the nasal blockage may not be due to hyperproduction of cysteinyl leukotrienes or inhibition of prostaglandin E 2 production. These results indicate that the indomethacin-induced nasal blockage may not be an identical phenomena to airway symptoms in aspirin hypersensitivity patients. However, because chronic nasal inflammation is indispensable for the development of nasal blockage, indomethacin-induced nasal blockage may become a clue to elucidate new mechanisms underlying hypersensitivity to NSAIDs.

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Section: Discussioncontrasting

confidence: 83%

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

et al. 2007

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“…Pranlukast (30 mg/ kg, p.o. ), a CysLT1-receptor antagonist, was administered at a dose that specifically inhibits bronchoconstrictive responses induced by CysLTs, but not those by other agonists in guinea pigs in vivo (26), and was found to strongly inhibit the response. Consequently, the dilatation of nasal blood vessels induced by LTD 4 is solely mediated by CysLT1-receptor activation.…”

Section: Discussionmentioning

confidence: 99%

Markedly Increased Nasal Blockage by Intranasal Leukotriene D4 in an Experimental Allergic Rhinitis Model: Contribution of Dilated Mucosal Blood Vessels

Mizutani

Nabe

Imai

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-We examined whether nasal hyperresponsiveness to leukotriene (LT) D4 is seen in our allergic rhinitis model, which showed sneezing and biphasic nasal blockage by repeated antigen inhalation challenge, and whether a dilatation of mucosal blood vessels contributes to this hyperresponsiveness. Nasal blockage [increase of specific airway resistance (sRaw)] was indexed as nasal (hyper)responsiveness. The sensitized -challenged guinea pig showed a remarkable dose-dependent increase in sRaw by intranasal instillation of LTD 4 (10 m l /nostril) at 10 -10 to 10 -6 M 10 h and 2 days but not 7 days after the challenge. The increase in sRaw induced by LTD4 was largely blocked by pranlukast or naphazoline, and this was dosedependently suppressed by N M -nitro-L-arginine methyl ester. Sodium nitroprusside induced an elevation of sRaw in the sensitized -challenged animal in the hyperresponsiveness state, but the degree did not differ from that in the non-sensitized -non-challenged group. The amount of NO2-and NO3 -in nasal cavity lavage fluid after LTD4 instillation in the sensitized -challenged animal in the hyperresponsiveness state was significantly greater than that before the instillation. These results demonstrate that the hyperresponsiveness to LTD4 acquired by repeated antigen challenge is mainly due to dilatation of nasal blood vessels, which can be related to hyperproduction of nitric oxide through cysteinyl LT1-receptor activation.Keywords: Hyperresponsiveness, Allergic rhinitis, Leukotriene D4, Nasal blockage, Nitric oxide Cysteinyl leukotrienes (CysLTs: LTC4, LTD4 and LTE4) are a family of potent inflammatory mediators that appear to contribute to the pathophysiologic features of allergic rhinitis. It has been reported that CysLTs were detected in the nasal washings following antigen challenge of subjects with allergic rhinitis (1, 2) and that treatment with a 5-lipoxygenase inhibitor and a CysLT1-receptor antagonist modified allergen-induced nasal mucosa swelling via dilatation of nasal capacitance blood vessel and increases in nasal capillary permeability (3 -5), suggesting that CysLTs act as significant inflammatory mediators in allergic rhinitis and that allergen-induced vascular changes are predominantly induced by CysLTs.To date, clinical examinations revealed that allergic rhinitis patients show obviously increased nasal blockage in response to topical LTD4, a phenomenon known as nasal hyperresponsiveness (6 -8). On the other hand, although very high doses of topical LTD 4 have been reported to increase either nasal blockage or nasal vascular permeability in non-sensitized animals (9, 10), it has not been determined whether a higher response to the agonist occurs in the allergic rhinitis model. Due to the limitation of clinical research and insufficient information obtained from normal animals, the mechanism of nasal hyperresponsiveness to LTD4 in allergic rhinitis patients remains unclear. The use of an experimental allergic rhinitis model that closely resembles the human case indispensably resolv...

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“…[1][2][3] Pranlukast is a selective cysLTs receptor antagonist, and a 225 mg twice-daily dose has been used to treat bronchial asthma and allergic rhinitis in Japan.The absorption fraction of pranlukast in human is approximately 20%, based on the excretion ratio of the unchanged form in the feces following oral administration (the absolute bioavailability has not been reported). The terminal elimination half-life of pranlukast in plasma is approximately 2 h. Pranlukast is minimally excreted in the urine.…”

mentioning

confidence: 99%

“…[1][2][3] Pranlukast is a selective cysLTs receptor antagonist, and a 225 mg twice-daily dose has been used to treat bronchial asthma and allergic rhinitis in Japan.…”

mentioning

confidence: 99%

In Vitro Metabolism and Inhibitory Effects of Pranlukast in Human Liver Microsomes

Yoneda

Matsumoto

Sutoh

et al. 2009

Biological & Pharmaceutical Bulletin

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Cysteinyl leukotrienes (cysLTs) are 5-lipoxygenase pathway products of arachidonate that induce bronchoconstriction, vascular hyperpermeability, mucosal edema accumulation, and mucus secretion. [1][2][3] Pranlukast is a selective cysLTs receptor antagonist, and a 225 mg twice-daily dose has been used to treat bronchial asthma and allergic rhinitis in Japan.The absorption fraction of pranlukast in human is approximately 20%, based on the excretion ratio of the unchanged form in the feces following oral administration (the absolute bioavailability has not been reported). The terminal elimination half-life of pranlukast in plasma is approximately 2 h. Pranlukast is minimally excreted in the urine. The major metabolic pathway of pranlukast is shown in Fig. 1. The plasma-binding of pranlukast is more than 99%, and the major binding protein is albumin.To date, it has been very difficult to predict drug-drug interactions with pranlukast in the clinical setting due to a lack of information. Therefore, we conducted in vitro experiments using human liver microsomes to allow us to evaluate the potential for drug-drug interactions, based on the metabolism and the inhibitory effects of pranlukast. MATERIALS AND METHODS MaterialsPranlukast and 6-methyl-4-oxo-8-[4-(4-phenylbutoxy)benzoylamino]-2-(tetrazol-5-yl)-4H-1-benzopyran (ONO-RS-425, an internal standard for pranlukast), were synthesized at Ono Pharmaceutical Co., Ltd. (Osaka, Japan). a-Naphthoflavone, quinideine, 4-hydroxybenzoic acid n-butyl ester and 4-hydroxybenzoic acid n-amyl ester were purchased from Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan). Tranylcypromine, terfenadine, metoprolol, tolbutamide, erythromycin and roxithromycin were pur- We investigated the metabolism of pranlukast, a selective leukotriene agonist, and the potential for drugdrug interactions. Although cytochrome P450 (CYP) 3A4 appeared to be the major cytochrome P450 isoform involved in the metabolism of pranlukast, the results suggested that pranlukast metabolism was inhibited less than 50% by ketoconazole, a reversible CYP3A4 inhibitor, or by anti-CYP3A4 antibodies. Irreversible macrolide CYP3A4 inhibitors, clarithromycin, erythromycin and roxithromycin, exhibited little effect on pranlukast metabolism. On the other hand, pranlukast reversibly inhibited CYP2C8 and/or 2C9, and CYP3A4, with K i values of 3.9 and 4.1 m mmol/l, respectively. The [I] in,max,u /K i ratios were 0.004 and 0.003, respectively. The K i values were about 300-fold greater than the [I] in,max,u , therefore it is suggested that, at clinical doses, pranlukast will not affect the pharmacokinetics of concomitantly administered drugs that are primarily metabolized by CYP2C8 and/or 2C9 or CYP3A4.

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In Vivo Pharmacologic Profile of ONO-1078: A Potent, Selective and Orally Active Peptide Leukotriene (LT) Antagonist.

Cited by 83 publications

References 26 publications

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

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

Markedly Increased Nasal Blockage by Intranasal Leukotriene D4 in an Experimental Allergic Rhinitis Model: Contribution of Dilated Mucosal Blood Vessels

In Vitro Metabolism and Inhibitory Effects of Pranlukast in Human Liver Microsomes

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