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.
We fabricated a new light-emitting device that combined a polymer light-emitting diode (PLED) and a vertical-type metal-base organic transistor (MBOT) through a floating electrode. By employing a layered floating electrode of Mg:Ag/Au, the MBOT on the PLED was operated successfully and a current amplification factor of approximately 20 was observed. The PLED luminescence exceeding 100 cd/m2 can be modulated using the MBOT with a low base voltage (2.8 V) and VCC (8 V). The emission contrast (on/off ratio) was improved with insertion of an insulating layer under the base, and the cut-off frequency was estimated to be 8 kHz. This device is expected to be a promising driving system of organic light-emitting diode (OLED), realizing low voltage and high numerical aperture.
ONO-5788 is a novel low molecular weight orally administered molecule with potent and selective agonistic effects at the human SST2 receptor subtype. ONO-5788 could offer the advantages of a more convenient route of administration for patients with acromegaly and other indications and also a preferential safety profile compared to injections. Methods : This First in Human study includes a double-blind, randomized, placebo-controlled, single ascending dose (SAD) part (including an assessment of food effect) in healthy adult male and female volunteers, 18-55 years of age. 34 males and 14 females were enrolled. Subjects were randomised to ONO-5788 or placebo (6:2 ratio) in each cohort with escalating doses of ONO-5788 (0.4, 1.6, 5, 20, 50 or 120mg) assessed. The first 2 dose levels were dosed as an oral liquid solution, the 4 remaining dose levels were dosed as oral API in capsule. Findings : Preliminary blinded data suggested no significant safety issues during administration of single doses of ONO-5788. A low incidence of mild to moderate gastrointestinal adverse events was observed at the higher doses (loose stools n=4; abdominal cramping n=3; abdominal discomfort, abdominal tenderness, discolouration of stools, pale stools, dyspepsia, nausea, all n=2). There were no safety findings for safety labs, ECGs or vital signs and no SAEs were reported. A transient increase in serum glucose was noted at 6 hours post-dose (3 hours post-meal) which followed a dose-response pattern when comparing mean glucose values across all 6 cohorts; all subjects were asymptomatic and no intervention was required. Pharmacokinetics of ONO-5788 and its active metabolite (ONO-ST1-641) were well characterized at the doses tested. Parent drug concentrations were notably higher than the active metabolite (approximately 40-fold greater). A 300-fold dose range was explored (0.4mg to 120mg) but, using arithmetic mean Cmax, AUClast and AUCinf values, ONO-5788 exposure was approximately 59-90 times higher at the highest dose compared to the lowest and ONO-ST1-641 exposure was 139-193 times higher at the highest dose. There were less than dose-proportional increases in exposure observed with both ONO-5788 and ONO-ST1-641 at doses above 20mg. Lower exposure was observed with food at the 20mg dose. The mean half-life of ONO-5788 ranged between 6.4-22 hours and for ONO-ST1-641 between 62-110 hours. Conclusion : ONO-5788 was found to be well tolerated in this SAD study at all doses tested. The pharmacokinetic profiles of ONO-5788 and its active metabolite were well characterised with a half-life suggesting the potential for once-daily dosing. Safety, tolerability, pharmacokinetics and pharmacodynamics will continue to be assessed in healthy volunteers with multiple dosing, dosing of a cohort of elderly subjects and a proof-of-principle study to further characterize ONO-5788 prior to studies in patients.
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