Cinalukast

Complexation study of cinalukast and montelukast with cyclodextrines.[Pubmed:17118608]

J Pharm Biomed Anal. 2007 Feb 19;43(3):1025-32.

A fluorimetric study on the spectral characteristics of two antileukotrienes, Cinalukast and montelukast, has been performed. Ionization constants of both of them have been photometrically calculated. Cinalukast pK(a) in ethanol:water 50:50 (v/v) medium resulted to be 2.2+/-0.1. Because the spectral characteristics of montelukast are widely affected by the solvent nature, pK(a) was estimated in two different ethanol:water media, 70:30 (v/v) and 10:90 (v/v) and the values calculated were pK(a)=2.9+/-0.1, and pK(a1)=2.0+/-0.1 and pK(a2)=6.5+/-0.1, respectively. It has been proven that the fluorescence of both, Cinalukast and montelukast, is significantly intensified in the presence of cyclodextrins (CyDs). The host-guest complexation processes between Cinalukast and alpha-CyD or heptakis-(2,6-di-O-methyl)-beta-cyclodextrin (DIMEB) and between montelukast and DIMEB have been investigated by fluorescence spectroscopy. A 1:1 stoichiometric ratio was established for the three studied inclusion complexes. The changes produced on the fluorescence of Cinalukast or montelukast, when they are included on the hydrophobic CyD cavity are used to calculate their association constants by a non-linear regression method. Semiempirical MO calculations using AM1 method were performed in order to characterize the studied inclusion complexes. A new method for Cinalukast determination in human serum, based on the fluorescence of the complex Cinalukast-DIMEB exhibiting limit of detection of 7.95 ng mL(-1) has been proposed with satisfactory results. Adequate recovery values between 95 and 103% were calculated at five different concentration levels.

Prolonged protection against exercise-induced bronchoconstriction by the leukotriene D4-receptor antagonist cinalukast.[Pubmed:9042047]

J Allergy Clin Immunol. 1997 Feb;99(2):210-5.

OBJECTIVES: The degree and duration of protection against exercise-induced bronchoconstriction afforded by three doses of a specific leukotriene D4 receptor antagonist, Cinalukast, were assessed after an initial dosing and after 1 week of therapy. METHODS: A placebo-controlled crossover study was performed in eight male patients who had mild, stable asthma and exercise-induced bronchoconstriction. Treatment consisted of four 7-day periods of placebo and three dose levels of the drug (10, 50, and 200 mg administered orally). Exercise challenge was performed at 2 hours and 8 hours after treatment on the first and seventh treatment days. The response was measured as the area under the FEV1-time effect curve (AUEC). RESULTS: On the first day of treatment, the mean (+/- SEM) AUEC at 2 hours was 24.2 +/- 3.3 L.min after placebo and was 5.5 +/- 2.2 L.min, 6.3 +/- 2.7 L.min, 3.3 +/- 3.8 L.min after 10 mg, 50 mg, and 200 mg, respectively (p < 0.05 for all values compared with placebo). The AUEC at 8 hours on the first day was 25.1 +/- 4.4 L.min after placebo and was 6.8 +/- 4.1 L.min, 11.2 +/- 2.5 L.min, and 5.0 +/- 2.8 L.min after 10 mg, 50 mg, and 200 mg, respectively (p < 0.05 for all values compared with placebo). The protection afforded by 10 mg of cinaluicast was lost after 7 days of treatment but persisted with 50 mg and 200 mg doses. CONCLUSION: Orally administered Cinalukast provides at least 8 hours of protection against exercise-induced bronchoconstriction. This protection is lost with regular treatment for 1 week for the lowest dose studied.

Pharmacologic actions of Ro 24-5913, a novel antagonist of leukotriene D4.[Pubmed:1658310]

J Pharmacol Exp Ther. 1991 Nov;259(2):751-8.

Ro 24-5913, (E)-4-[3-[2-(4-cyclobutyl-2- thiazolyl)ethenyl]phenylamino]-2,2-diethyl-4-oxobutanoic acid, has been identified as a chemically unique, potent and selective LTD4 antagonist. In vitro, Ro 24-5913 competes with [3H]LTD4 for its binding site on guinea pig lung membranes with an IC50 of 6.4 +/- 2.2 nM. In isolated guinea pig tracheal smooth muscle, Ro 24-5913 produces concentration-dependent rightward shifts of LTD4-induced contraction curves (pA2 value of 9.6 +/- 0.2). The slope of the Schild plot is not significantly different from 1, indicating that the antagonism is of a competitive nature. In the human bronchus, Ro 24-5913 is an effective antagonist of LTD4-induced contractions (pKB of 9.3 +/- 0.1). In vivo, Ro 24-5913 dose-dependently inhibits LTD4-induced bronchoconstriction in guinea pigs by the i.v. (ID50 0.13 mg/kg), oral (ID50 0.12 mg/kg) and aerosol (IC50 0.008%) routes of administration. This in vivo activity is specific as evidenced by the inability of Ro 24-5913 to inhibit bronchoconstriction induced by LTB4, PAF or histamine. In comparison with other LTD4 antagonists evaluated in this guinea pig model, Ro 24-5913 is markedly superior in terms of oral potency, bioavailability and oral duration of action. Ro 24-5913 also blocks allergic bronchospasm mediated by endogenously generated leukotrienes in guinea pigs; the potency and duration of action is nearly equivalent to that seen as an antagonist of bronchoconstrictions produced by exogenous LTD4. In summary, Ro 24-5913 is representative of a novel chemical class of LTD4 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)