THE ANTILEUCOTRIENES / MONTELUKAST ZAFIRLUKAST

EL MONTELUKAST

El Montelukast fue aprobado por la FDA en 1998 para el tratamiento de problemas respiratorios: asma, rinitis alérgica y sinusitis, nombre comercial SINGULAIR.

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****** DATA-MÉDICOS *********

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ANTI-LEUCOTRIENOS

ANTI-LEUKOTRIENES

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***** DERMAGIC-EXPRESS No 7 *********

****** 27 OCTUBRE DE 1.998 *******

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EDITORIAL ESPAÑOL:

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Hola amigos del cyber, DERMAGIC con ustedes de nuevo, hace unos meses en la red a través de las listas americanas recogí el ensayo terapéutico que los colegas Americanos están haciendo con 2 de estos productos, en algunas patologías dermatológicas, EL MONTELUKAST (Singulair) y el ZAFIRLUKAST (accolate), en mi búsqueda conseguí otro 3 más, el PRANLUKAST, el ZILEUTON, y el VERLUKAST los cinco son antagonistas de los leucotrienos y según las experiencias observadas en la bibliografía, son muy buenos en el ASMA. Están siendo probados también en rinitis alérgica, eccema dishidrótico, psoriasis, y dermatitis atópica, por esa conocida asociación asma-atopia-eccema. El ZAFIRLUKAST Y MONTELUKAST ya salieron al mercado, desconozco si los otros ya están disponibles. Estas REFERENCIAS que les traigo no están relacionadas con aspectos dermatológicos, pero nos hablan un poco de las bondades de estos productos.

Montelukast (Singulair) Tabs 10 mgrs (Merck, laboratorio)

Zafirlukast (Accolate) Tabs 20 mgrs (Zeneca Pharmaceuticals)

Pranlukast (SB205312/ONO-1078] )

Verlukast

Zileuton (A-64077)

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DERMAGIC/EXPRESS(9)

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A N T A G O N I S T A S D E L E U C O T R I E N O S

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REFERENCIA 1: zafirlucast

REFERENCIA 2: zafirlucast

REFERENCIA 3: los anti-leucotrienos usos en asma

REFERENCIA 4: pranlukast

REFERENCIA 5: pranlukas

REFERENCIA 6: pranlukast

REFERENCIA 7: pranlukast

REFERENCIA 8: montelukast

REFERENCIA 9: montelukast

REFERENCIA 10: montelukast

REFERENCIA 11: montelukast

REFERENCIA 12: farmacologia inhibidores de leucotrienos

REFERENCIA 13: leucotrienos en patogenesis del asma: zafirlukast, pranlukast, montelukast, zileuton

RFERENCIA 14: antileucotrienos en asma: zairlukast, pranlukast, zileuton, verlukast

REFERENCIA 15: Revision del producto ZAFIRLUKAST (ACCOLATE)

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1.) Determination of zafirlukast, a selective leukotriene antagonist, human plasma by normal-phase high-performance liquid chromatography with fluorescence detection.

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AU: Bui-KH; Kennedy-CM; Azumaya-CT; Birmingham-BK

AD: Drug Disposition and Metabolism Department, ZENECA Pharmaceuticals, Wilmington, DE 19897, USA.

SO: J-Chromatogr-B-Biomed-Sci-Appl. 1997 Aug 15; 696(1): 131-6

PY: 1997

LA: ENGLISH

CP: NETHERLANDS

AB: A high-performance liquid chromatographic (HPLC) method was developed for the determination of zafirlukast, a selective peptide leukotriene receptor antagonist, in human plasma. Zafirlukast and the internal standard, ICI 198 707, were extracted from deproteinated plasma samples using large reservoir C18 solid-phase extraction columns and analyzed by normal-phase liquid chromatography with fluorescence detection. The method had a lower limit of quantitation of 0.75 ng/ml and a linear calibration curve in the range of 0.75 to 200 ng/ml. The absolute recovery of zafirlukast was > 90%, and the within-day and between-day relative standard deviations were < 9%. The utility of the method in the characterization of the plasma concentration-time profiles of zafirlukast in clinical studies was demonstrated.

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2.) TI: The leukotriene receptor antagonist zafirlukast inhibits sulfur dioxide-induced bronchoconstriction in patients with asthma.

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AU: Lazarus-SC; Wong-HH; Watts-MJ; Boushey-HA; Lavins-BJ; Minkwitz-MC

AD: Cardiovascular Research Institute, University of California, San Francisco, California 94143-0111, USA.

SO: Am-J-Respir-Crit-Care-Med. 1997 Dec; 156(6): 1725-30

ISSN: 1073-449X

PY: 1997

LA: ENGLISH

CP: UNITED-STATES

AB: Inhalation of sulfur dioxide (SO2) causes bronchoconstriction in most people with asthma. To examine the role of leukotrienes in this response, the antagonism of SO2-induced bronchoconstriction by a single oral dose of the leukotriene receptor antagonist zafirlukast was assessed in a double-blind, placebo-controlled, two-period crossover trial in 12 subjects with mild-to-moderate asthma. Subjects had bronchial hyperresponsiveness, an FEV1 < or = 70% of predicted, and a positive response to inhaled SO2 (an 8-unit increase in specific airway resistance on inhaling an SO2 concentration of < or = 4 ppm (PC8SRaw). Subjects were treated with zafirlukast (20 mg) or placebo on two treatment days 5 to 14 d apart. Two and 10 hours after treatment, subjects inhaled SO2 (0.25, 0.5, 1.0, 2.0, 4.0, and 8.0 ppm) during eucapnic hyperventilation at 20 L/min. PC8SRaw was determined after each challenge. Blood samples were collected to assess zafirlukast plasma concentrations versus effect. PC8SRaw was significantly higher 2 h after zafirlukast compared with placebo (3.1 versus 1.5 ppm; p = 0.02) and remained higher 10 h after treatment with zafirlukast (2.7 versus 1.9 ppm; p = 0.09). An association was found between zafirlukast plasma concentrations and increases in PC8SRaw 10 h after treatment (p = 0.001). The safety profile of zafirlukast was not clinically different from placebo. A single 20-mg dose of zafirlukast attenuated SO2-induced bronchoconstriction. We conclude that S02-induced bronchoconstriction involves release of leukotrienes and that treatment with zafirlukast attenuates the bronchoconstrictor response.

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3.) TI: [The anti-leukotrienes: their use in asthma]

TO: Les anti-leucotrienes: leur positionnement dans l'asthme.

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AU: Devillier-P; Millart-H; Advenier-C

AD: Laboratoire de Pharmacologie-Toxicologie, Hopital Maison Blanche, CHU de Reims.

SO: Rev-Med-Brux. 1997 Sep; 18(4): 279-85

ISSN: 0035-3639

PY: 1997

LA: FRENCH; NON-ENGLISH

CP: BELGIUM

AB: Inflammation in asthma plays a predominant role in the genesis of bronchial obstruction and hyperreactivity. Treatment of bronchial inflammation since the early stages of asthma has become an essential element of therapeutic strategy and rests chiefly on inhaled glucocorticoids. However, inhaled glucocorticoids pose some problems in terms of inhalation technique, compliance, local tolerance and, to a lesser extent and at high doses, of systemic tolerance. Antileukotrienes represent a new class of potential anti-asthma drugs. They act either by inhibition of 5-lipoxygenase, a key enzyme in the leukotriene (LT) synthesis pathway, or by blocking LT receptors. The LT antagonists developed in asthma are mainly specific for a receptor subtype, the CysLT1 receptor, involved in the bronchoconstrictor and inflammatory effects of sulfidopeptide leukotrienes (LTC4, D4 and E4). Two antagonists of CysLT1 receptors have been recently launched on the market: ONO-1078, pranlukast, Onon and ICI-204,219, zafirlukast, Accolate. The CysLT1 antagonists cause bronchodilatation with a beta 2-agonist additive effect, confer effective protection in bronchial provocation studies and particularly, they improve clinical scores, pulmonary function and beta 2-agonist rescue inhaler use. Additional studies, especially comparative with respect to reference treatments, mainly inhaled glucocorticoids, will be required to define their place in the global strategy for asthma management.

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4.) Results of the first U.S. double-blind, placebo-controlled, multicenter clinical

study in asthma with pranlukast, a novel leukotriene receptor antagonist.

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Grossman J; Faiferman I; Dubb JW; Tompson DJ; Busse W; Bronsky E; Montanaro A;

Southern L; Tinkelman D

University of Arizona, Tucson 85719, USA.

J Asthma (UNITED STATES) 1997 34 (4) p321-8 ISSN: 0277-0903

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED

CONTROLLED TRIAL

Journal Announcement: 9710

Subfile: INDEX MEDICUS

Pranlukast (SB 205312; ONO-1078), a potent, orally active selective cysteinyl-

leukotriene receptor antagonist (LTRA), was developed in Japan for the treatment of

asthma. This article reports results of the initial U.S. clinical evaluation of

pranlukast. The primary objective of this multicenter study was to evaluate the

safety and tolerability of pranlukast administered at doses of 337.5 mg b.i.d. and

450 mg b.i.d. in 65 patients with mild to moderate asthma. Pranlukast, a novel LTRA,

is safe and well tolerated at doses of 337.5 mg b.i.d. and 450 mg b.i.d. Pranlukast

has demonstrated clinical activity in patients with asthma.

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5.) Pranlukast, a novel leukotriene receptor antagonist: results of the first European,

placebo controlled, multicentre clinical study in asthma.

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Barnes NC; Pujet JC

London Chest Hospital, Department of Respiratory Medicine, UK.

Thorax (ENGLAND) Jun 1997 52 (6) p523-7 ISSN: 0040-6376

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED

CONTROLLED TRIAL

Journal Announcement: 9710

Subfile: INDEX MEDICUS

BACKGROUND: Leukotriene receptor antagonists have been shown to protect against

bronchoconstriction induced by antigens, exercise, and cold air. There are

relatively few clinical studies reported in patients with asthma. The present study

is the first clinical evaluation of pranlukast (SB 205312, ONO-1078) outside Japan in

patients with asthma. METHODS: A randomised, double blind, placebo controlled,

parallel group, multicentre four week study of the safety and tolerability of oral

pranlukast, 225 or 337.5 mg twice daily, was performed in patients with mild to

moderate asthma. Preliminary efficacy data were obtained; the main efficacy

variables evaluated were forced expiratory volume in one second (FEV1) and morning

domiciliary (home) peak expiratory flow rates (PEFR). Clinic PEFR and daytime and

night-time asthma symptom scores were also recorded. RESULTS: Compared with the

placebo group the improvement in morning home PEFR was statistically significant at

all time points for patients receiving pranlukast 337.5 mg twice daily and at weeks 1

and 2 for those treated with pranlukast in a dose of 225 mg twice daily. Mean

morning home PEFR increased by 10.8 to 18.61/min (95% CI 0.2 to 29.3 l/min) in

patients treated with pranlukast compared with a slight deterioration in those given

placebo. FEV1 significantly increased within one hour after the first dose of

pranlukast compared with baseline and this increase was maintained for eight hours.

Improvements in trough FEV1-that is, at the end of the dosing interval-were

statistically significant for the group treated with pranlukast 225 mg twice daily

compared with placebo at week 4. Mean increases in FEV1 ranged from 210 ml to 340 ml

(95% CI 60 to 500 ml) at trough in the pranlukast group. Patients treated with

pranlukast also showed improvements in summary symptom and night-time asthma scores.

Pranlukast was well tolerated, and no drug related changes in haematological and

biochemical variables were observed. CONCLUSIONS: Pranlukast, an oral leukotriene

receptor antagonist, is well tolerated and is effective for the treatment of asthma.

It increased FEV1 within one hour of dosing, improved patient summary symptom and

night-time asthma scores, and reduced the use of rescue bronchodilators, thus

providing further evidence of a role for leukotrienes in the pathogenesis of asthma.

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6.) Effect of pranlukast, an oral leukotriene receptor antagonist, on leukotriene D4 (LTD4) challenge in normal volunteers.

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O'Shaughnessy TC; Georgiou P; Howland K; Dennis M; Compton CH; Barnes NC

Department of Respiratory Medicine, London Chest Hospital, UK.

Thorax (ENGLAND) Jun 1997 52 (6) p519-22 ISSN: 0040-6376

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

Journal Announcement: 9710

Subfile: INDEX MEDICUS

BACKGROUND: There is increasing evidence to show that leukotrienes are important

mediators in asthma. Leukotriene receptor antagonists protect against antigen and

exercise challenges in patients with chronic asthma. A study was undertaken to

investigate the activity of the leukotriene receptor antagonist pranlukast (SB

205312, ONO-1078) in blocking bronchoconstriction induced by leukotriene D4 (LTD4)

inhalation. The selectivity of pranlukast was evaluated using histamine challenge.

METHODS: Pranlukast, 450 mg twice daily, was given to eight healthy non-smoking men

for five days in a randomised, double blind, placebo controlled, crossover study.

The specific airways conductance (sGaw) was measured before and after bronchial

provocation with inhaled LTD4 at 3.5 hours after the first dose and at 3.5 and 9.5

hours after the last dose of pranlukast on the morning of day 5. The concentration of

LTD4 required to produce a fall in sGaw of 35% (PC35) was calculated. Subjects also

underwent a histamine challenge 3.5 hours after a single dose of pranlukast, 450 mg,

or placebo. RESULTS: A single dose of pranlukast produced a 10.6 fold increase in

PC35sGaw (95% confidence interval (CI) 4.4 to 25.5; p < 0.001) for LTD4 at 3.5 hours

after dosing compared with placebo. Three and a half hours after the morning dose of

pranlukast on day 5 the PC35sGaw for LTD4 was increased 25.9 fold (95% CI 10.8 to

62.2; p < 0.001) and was still increased sevenfold (95% CI 2.9 to 16.7; p < 0.001)

relative to placebo 9.5 hours after administration of the morning dose. No

significant differences were noted for the PC35sGaw to histamine for pranlukast

compared with placebo. CONCLUSIONS: This study shows that pranlukast is a potent and

selective LTD4 receptor antagonist in humans which blocks LTD4 challenge after

initial and repeated administration when given twice daily for five days.

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7.) The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers.

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Brocks DR; Upward JW; Georgiou P; Stelman G; Doyle E; Allen E; Wyld P; Dennis MJ

College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Canada.

Eur J Clin Pharmacol (GERMANY) 1996 51 (3-4) p303-8 ISSN: 0031-6970

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

Journal Announcement: 9706

Subfile: INDEX MEDICUS

OBJECTIVE: The pharmacokinetics of pranlukast, a leukotriene LTD4 antagonist, were

studied in 48 young, healthy subjects after single and repeated oral doses (given

every 12 h) ranging from 112.5 to 675 mg. The doses were administered 30 minutes

after a light breakfast. RESULTS: Maximal drug concentrations generally occurred

between 2 and 6 h after dosing, and there was some evidence of an absorption lag-time.

Secondary peaks were observed in the plasma concentration vs. time profiles of many

of the study subjects after both single and repeated doses, particularly during the

period of maximum drug absorption. In general, after both single and repeated doses,

there were related increases in the corresponding Cmax and AUC with a rise in dose,

although the increase was diminished at doses above 450 mg. With repeated dosing of

pranlukast the mean AUC was generally higher (up to 1.6-fold), and the higher plasma

concentrations allowed characterisation of a longer mean t 1/2 than after single dose

administration. The mean steady-state trough plasma concentrations attained after

evening doses were considerably higher (up to 14-fold) than those obtained after the

morning dose. CONCLUSION: The data suggested that the pharmacokinetics of pranlukast

are influenced by the time of dosing. Based on analysis of urinary 6 beta-

hydroxycortisol excretion, there was no evidence that pranlukast modified the

metabolic activity of cytochrome P-450 3A isoenzymes.

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8.) Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by

stereoselective high-performance liquid chromatography with column-switching.

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Liu L; Cheng H; Zhao JJ; Rogers JD

Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486,

USA.

J Pharm Biomed Anal (ENGLAND) Feb 1997 15 (5) p631-8 ISSN: 0731-7085

Language: ENGLISH

Document Type: JOURNAL ARTICLE

Journal Announcement: 9709

Subfile: INDEX MEDICUS

A steoreoselective high-performance liquid chromatographic method was developed for

the quantification of montelukast (free acid of Singulair, or MK-0476), a potent and

selective leukotriene D4 (cysLT1) receptor antagonist, and it S-enantiomers (L-

768,232). The method involves protein precipitation and fluorescence detection.

Chromatographic separation of the enantiomers from endogenous components in plasma

and chiral resolution of the enantiomers are achieved by using column switching HPLC

and an alpha-acid glycoprotein chiral column. The assay is linear in the range of

28.9-386 ng ml-1 of free acids of montelukast and L-768,232. The intraday precision

(% relative standard deviation) values of this method were in the range of 2.5-9.1%

for montelukast, and 2.4-6.8% for L-768,232, while the intraday accuracy values were

in the range of 97-103% for montelukast and 96-104% for L-768,232. The interday

precision values of this method at 48.2 and 193 ng ml-1 were 5.3 and 3.6%,

respectively, for montelukast, and 4.2 and 3.7%, respectively, for L-768,232, while

the interday accuracy values at these concentrations were 97 and 103%, respectively,

for montelukast and 99 and 102%, respectively, for L-768,232. The utility of the

methodology was demonstrated by analysis of plasma samples from a study in which

healthy volunteers received 10 mg per day of montelukast orally for 7 days. Results

of this study indicate that there is no apparent bioinversion of montelukast to its S-

enantiomer in humans.

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9.) Effects of montelukast (MK-0476); a potent cysteinyl leukotriene receptor antagonist, on bronchodilation in asthmatic subjects treated with and without inhaled corticosteroids.

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Reiss TF; Sorkness CA; Stricker W; Botto A; Busse WW; Kundu S; Zhang J

Department of Pulmonary Immunology, Merck Research Laboratories, Rahway, New Jersey

07065, USA.

Thorax (ENGLAND) Jan 1997 52 (1) p45-8 ISSN: 0040-6376

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

Journal Announcement: 9705

Subfile: INDEX MEDICUS

BACKGROUND: Cysteinyl leukotriene release in association with airway inflammation

is a feature of clinical asthma. The acute effects of montelukast (MK-0476), a

potent, orally administered, specific cysteinyl leukotriene receptor antagonist, on

airways obstruction was assessed in patients with mild to moderately severe asthma.

METHODS: Twenty two asthmatic subjects were randomised to receive montelukast, 100 mg

or 250 mg, or placebo in a double blind, three period, crossover trial. Ten of the

patients were using concomitant inhaled corticosteroids. RESULTS: Montelukast

increased the forced expiratory volume in one second (FEV1) from predose baseline

values compared with placebo, the percentage point differences between montelukast

and placebo being 8.6% (95% CI 3.6 to 13.6) and 8.5% (95% CI 3.5 to 13.5) for the 100

mg and 250 mg doses, respectively. CONCLUSION: Single oral doses of montelukast 100

mg and 250 mg produced significant increases in FEV1 irrespective of the concurrent

use of inhaled corticosteroids in asthmatic subjects with airflow limitation.

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10.) Montelukast causes prolonged, potent leukotriene D4-receptor antagonism in the

airways of patients with asthma.

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De Lepeleire I; Reiss TF; Rochette F; Botto A; Zhang J; Kundu S; Decramer M

Merck Research Laboratories, Brussels.

Clin Pharmacol Ther (UNITED STATES) Jan 1997 61 (1) p83-92 ISSN: 0009-9236

Language: ENGLISH

Document Type: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL

Journal Announcement: 9705

Subfile: AIM; INDEX MEDICUS

Montelukast, a new specific oral cysteinyl LT3-receptor antagonist was evaluated

for its activity in attenuating inhaled leukotriene D4 (LTD4) bronchoconstriction in

patients with asthma. In two double-blind, placebo-controlled, randomized crossover

studies, patients with mild asthma (forced expiratory volume in 1 second [FEV1] > or

= 70%) were studied. In trial A, LTD4 challenge began 4 hours (peak plasma

concentration) after a single dose of placebo or 5, 20, 100, and 250 mg montelukast.

In trial B, and LTD4 challenge was started 20 hours after administration of placebo,

40 mg montelukast, or 200 mg montelukast. During each challenge, twofold increasing

concentrations of LTD4 were inhaled until specific airways conductance (sGaw)

decreased by at least 50% (PC50) or the highest concentration of LTD4 was inhaled.

In trial A with all doses and in trial B with the 200 mg dose, bronchoconstriction

was attenuated (50% fall in sGaw was not observed) up to the highest dose of LTD4

administered. In trial B, during the 40 mg period, only two of six patients

exhibited a 50% fall in sGaw; PC50 ratios (montelukast 40 mg/placebo) were 18 and 45

in these two patients. These results indicate that montelukast is a highly potent

and long-lasting antagonist of LTD4-induced bronchoconstriction in patients with asthma.

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11.) Determination of montelukast (MK-0476) and its S-enantiomer in human plasma by