| The
Anti-leukoriene./ Los Antileucotrienos. ***********************************
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****** DATA-MEDICOS *********
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ANTI-LEUCOTRIENOS
ANTI-LEUKOTRIENE
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***** DERMAGIC-EXPRESS No 7 *********
****** 27 OCTUBRE DE 1.998 *******
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EDITORIAL
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Hola amigos del cyber, DERMAGIC con ustedes de nuevo, hace unos meses en la red a traves de las listas americanas recogí el ensayo terapéutico que los colegas Americanos estan haciendo con 2 de estos productos, en algunas patologías dermatológicas, EL MONTELUKAST (Singulair) y el ZAFIRLUKAST (accolate), en mi busqueda 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. Estan siendo probados tambien en rinitis alergica, eccema dishidrotico, psoriasis, y dermatitis atópica, por esa conocida asiciación asma-atopia-eccema. El ZAFIRLUKAST Y MONTELUKAST ya salieron al mercado, desconozco si los otros ya estan disponibles. Estas REFERENCIAS que les traigo no estan 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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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.
=================================================================
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.
=================================================================
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.
=================================================================
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.
=================================================================
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
stereoselective high-performance liquid chromatography with column-switching.
=================================================================
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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12.) [Clinical pharmacology of leucotriene inhibitors]
Farmacologia clinica degli inibitori dei leucotrieni.
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Paggiaro PL; Bancalari L; Dente FL
Clinica Medica 2, Fisiopatologia Respiratoria, Universita degli Studi di Pisa.
Ann Ital Med Int (ITALY) Oct 1996 11 Suppl 2 p85S-89S ISSN: 0393-9394
Language: ITALIAN Summary Language: ENGLISH
Document Type:
JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL English Abstract
Journal Announcement: 9704
Subfile: INDEX MEDICUS
Leukotrienes have been demonstrated to play an important role as mediators of many
pathophysiologic alterations of asthma. Pharmaceutical companies have thus promode
many efforts to synthesize new drugs with inhibitory activity on 5-lypoxygenase or
with functional antagonism on cystenyl leukotriene receptors. Several compounds have
been studied in humans, and some of them should soon be on the market. One of these
compounds, ICI 204,219 ("accolate"), a receptor antagonist active by the oral route,
has been proven capable of preventing bronchoconstriction induced by several stimuli
(allergen, exercise, cold air, etc.) and of improving symptoms and lung function in
spontaneous asthma. This effect augments the bronchodilation induced by inhaled beta
2-agonists. On the other hand, no relevant side effects have been reported.
However, antiinflammatory properties of this compound must be demonstrated. This new
category of antiasthmatic drugs should be recommended for mild-to-moderate asthma,
although future studies might demonstrate their efficacy in potentiating or
substituting inhaled steroids. (39 References)
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13.) Leukotrienes in the pathogenesis of asthma.
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O'Byrne PM
Asthma Research Group, McMaster University, Hamilton, Ontario, Canada.
Chest (UNITED STATES) Feb 1997 111 (2 Suppl) p27S-34S ISSN: 0012-3692
Language: ENGLISH
Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
Journal Announcement: 9705
Subfile: AIM; INDEX MEDICUS
Asthma is a chronic inflammatory disease that is associated with widespread but
variable airflow obstruction. The mechanisms that lead to airflow obstruction in
asthma are bronchoconstriction, mucosal edema, increased secretion of mucus, and an
inflammatory-cell infiltrate that is rich in eosinophils. Leukotrienes (LTs) B4, C4,
D4, and E4 have been shown experimentally to play a role in each of these
inflammatory mechanisms and to mimic the pathologic changes seen in asthma. Inhaled
LTC4 and LTD4 are the most potent bronchoconstrictors yet studied in human subjects.
LTC4 and LTD4 also may cause migration of inflammatory cells into the asthmatic
airway. LTs are derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid
metabolism, and increased production of LTs has been demonstrated in patients who
have asthma. Leukotriene receptor antagonists and specific inhibitors of the 5-LO
pathway hold great promise as new therapies to treat asthma. Because LTC4, LTD4, and
LTE4 appear to interact with a common LTD4 receptor, selective LTD4 receptor
antagonists (eg, pranlukast [SB205312/ONO-1078], zafirlukast [ICI 204,219], MK-571,
and MK-679), as well as zileuton (A-64077, a direct inhibitor of 5-LO) have been
developed as antiasthma agents. Clinical and experimental studies have demonstrated
the efficacy of these compounds in reducing not only the symptoms of asthma, but use
of beta 2-agonists and bronchoconstriction induced by exposure to allergens,
exercise, aspirin, and cold air. (94 References)
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14.) Antileukotriene therapy for asthma.
=======================================================================
Larsen JS; Jackson SK
College of Pharmacy, University of Minnesota, Minneapolis, USA.
Am J Health Syst Pharm (UNITED STATES) Dec 1 1996 53 (23) p2821-30; quiz 2877-8
ISSN: 1079-2082
Language: ENGLISH
Document Type: JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
Journal Announcement: 9705
Subfile: INDEX MEDICUS
The role of leukotrienes (LTs) in asthma is reviewed, and research to develop anti-
LT agents for this condition is described. Greater understanding of the role played
by inflammatory cells and their mediators in the pathophysiology of asthma has
shifted the emphasis of research from the bronchoconstriction component of the
disease to the inflammatory one. LTs are believed to play a key role in the complex
interplay of inflammatory cells that occurs in asthma. Inhibiting the production of
LTs or blocking their receptor sites may decrease the inflammatory response and
thereby provide a useful therapeutic modality. Three approaches have been used in
attempts to affect the activity of LTs: inhibition of 5-lipoxygenase, inhibition of 5-
lipoxygenase-activating protein, and LTD4-receptor antagonism. Investigational
agents that have undergone clinical trials include zileuton (a 5-lipoxygenase
inhibitor), MK-591 (a 5-lipoxygenase-activating protein inhibitor), and zafirlukast,
pranlukast, and verlukast (three LT-receptor antagonists). Many studies suggest that
these orally administered agents are effective, particularly with respect to the
early asthmatic response to allergens and other challenges, and have a low adverse-
effect profile; the reaction of greatest concern is elevation of liver enzymes,
especially with zileuton. Larger trials conducted over longer periods, as well as
comparative trials, will be necessary to delineate the ultimate role of these agents
in asthma therapy. Because of the complexity of the inflammatory process in asthma,
anti-LT agents are likely to become part of multidrug regimens. Using drugs to
interfere with leukotrienes may prove beneficial in the treatment of asthma. (100
References)
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15.) ZAFIRLUKAST, revisión del producto
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VA CLASSIFICATION (Primary/Secondary)¾RE109
Commonly used brand name(s):
Accolate.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
bNot commercially available in Canada.
Category
Antiasthmatic (leukotriene receptor antagonist).
Indications
Accepted
Asthma, chronic (prophylaxis and treatment)¾Zafirlukast is indicated in patients with chronic asthma to improve daytime asthma symptoms, forced expiratory volume in 1 second (FEV1), and morning peak expiratory flow rates, and to decrease nighttime awakenings, mornings with asthma symptoms, and use of a rescue beta2agonist1,2. When used daily with an as-needed, inhaled beta2 agonist in patients with mild-to-moderate asthma, zafirlukast significantly reduces asthma symptoms and use of an as-needed, inhaled beta2agonist as compared with use of an as-needed, inhaled beta2 agonist alone1,3.
Only patients with mild-to-moderate asthma have been treated with zafirlukast in clinical trials; therefore, its use in the management of patients with more severe asthma and in those receiving antiasthma therapy other than as-needed, inhaled beta2 agonists remains to be studied, as does use of zafirlukast as an oral or inhaled corticosteroid-sparing agent.1
Unaccepted
Zafirlukast is not indicated for the treatment of bronchospasm in acute asthma attacks, including status asthmaticus; however, use of zafirlukast can be continued during an acute exacerbation1.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight¾
575.696
Mechanism of action/Effect:
Zafirlukast is a selective and competitive receptor antagonist of the cysteinyl leukotrienes D4 and E41. The cysteinyl leukotrienes, originally described as slow-reacting substances of anaphylaxis, produce airway edema, smooth muscle constriction, and altered cellular activity associated with the inflammatory process, all of which are associated with with the pathophysiology of asthma1,4. In humans, pretreatment with single oral doses of zafirlukast inhibited bronchoconstriction caused by sulfur dioxide and cold air and reduced the early- and late-phase reaction in patients with asthma caused by inhalation of various antigens, such as grass, cat dander, and ragweed. Zafirlukast reduced the increase in bronchial hyperresponsiveness to inhaled histamine that followed inhaled allergen challenge.1
Absorption:
Rapid1.
Bioavailability is reduced following administration with a high-fat or high-protein meal1.
Protein binding:
High (more than 99% bound to plasma proteins, predominantly albumin)1.
Biotransformation:
Hepatic; extensively metabolized by the cytochrome P450 2C9 enzyme pathway to metabolites that are 90 times less potent antagonists of leukotriene D4 receptors than zafirlukast in vitro1.
Half-life:
Elimination¾The mean terminal elimination half-life is approximately 10 hours1.
Onset of action:
In clinical trials, improvement in asthma symptoms was seen within 1 week of starting treatment with zafirlukast1.
Time to peak plasma concentration
3 hours after dosing1.
Elimination:
Fecal¾Approximately 90%1.
Renal¾Approximately 10%1.
Precautions to Consider
Carcinogenicity/Tumorigenicity
A 2-year study in mice given zafirlukast orally in doses of 10, 100, and 300 mg per kg of body weight (mg/kg) per day showed a greater incidence of hepatocellular adenomas in males and whole-body histocytic sarcomas in females given the highest dose, as compared with controls. Plasma concentrations of zafirlukast following the 100- and 300-mg-per-kg-per-day doses were approximately 70 and 220 times, respectively, the plasma concentrations found at the maximum recommended human daily oral dose.1
A 2-year study in rats given zafirlukast orally in doses of 40, 400, and 2000 mg/kg per day found a greater incidence of urinary bladder transitional cell papillomas at doses of 2000 mg/kg per day, as compared with controls. Plasma concentrations of zafirlukast following the 400- and 2000-mg-per-kg-per-day doses were approximately 170 and 200 times, respectively, the plasma concentrations found at the maximum recommended human daily oral dose.1
Mutagenicity
Zafirlukast was not mutagenic in reverse or forward point mutation assays or in human and rat assays for chromosomal abnormalities1.
Pregnancy/Reproduction
Fertility¾Reproduction studies in rats given oral zafirlukast in doses approximately 400 times the maximum recommended human daily oral dose on a mcg per square meter of body surface area (mcg/m2) basis showed no effect on fertility1.
Pregnancy¾Adequate and well-controlled studies have not been done in humans.
No teratogenicity was observed in mice, rats, or monkeys given oral zafirlukast in doses up to approximately 160, 400, and 800 times the maximum recommended human daily oral dose on a mg per square meter of body surface area (mg/m2) basis.1
In rats given oral doses of 2000 mg/kg per day, maternal toxicity and deaths were seen, as well as an increased incidence of early fetal resorptions. In monkeys, the same dose resulted in maternal toxicity and an increased incidence of spontaneous abortions.1
FDA Pregnancy Category B1.
Breast-feeding
Zafirlukast is distributed into human breast milk. Steady-state concentrations of zafirlukast in breast milk and plasma were 50 and 255 nanograms per mL, respectively, after administration of 40 mg two times a day. Because of the potential for tumorigenicity and adverse effects in the neonate shown in animal studies, use of zafirlukast during breast-feeding is not recommended.1
Pediatrics
Appropriate studies on the relationship of age to the effects of zafirlukast have not been performed in the pediatric population. Safety and efficacy in children up to 12 years of age have not been established1.
Geriatrics
In patients 65 years of age and older, the clearance of zafirlukast is reduced, resulting in peak plasma concentration and area under the plasma concentration-time curve (AUC) values that are approximately two to three times greater than those of younger patients. However, the recommended dose of 20 mg two times a day did not result in increased adverse effects or withdrawal from the study in elderly patients during clinical trials when compared with patients younger than 65 years of age.1
In clinical trials, a greater incidence of mild or moderate infections, predominantly affecting the respiratory tract, occurred in patients older than 55 years of age treated with zafirlukast, as compared with other age groups and placebo-treated patients. The number of infections was proportional to the amount, in milligrams, of zafirlukast administered and was associated with concurrent use of inhaled corticosteroids. The clinical significance of this finding is unknown.1
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)¾not necessarily inclusive (>> = major clinical significance):
Note: In in vitro studies using human liver microsomes, zafirlukast has been shown to inhibit the cytochrome P450 3A4 and 2C9 isoenzymes at concentrations close to those achieved following recommended dosing1.
In a 3-week study in females taking oral contraceptives, 40 mg of zafirlukast two times a day had no significant effect on ethinyl estradiol plasma concentrations or contraceptive efficacy1.
Aspirin¾(concurrent administration of 40 mg a day of zafirlukast with aspirin at a dosage of 650 mg four times a day increased mean plasma concentrations of zafirlukast by approximately 45%1)
>> Astemizole or¾
>> Cisapride or¾
>> Cyclosporine or¾
Dihydropyridine calcium channel blocking agents, such as:
>> Felodipine or
>> Isradipine or
>> Nicardipine or
>> Nifedipine or
>> Nimodipine¾¾(although studies have not been done with zafirlukast and medications known to be metabolized by the cytochrome P450 3A4 isoenzyme, such as astemizole, cisapride, cyclosporine, and the dihydropyridine calcium channel blocking agents, concurrent use of these medications with zafirlukast should be monitored carefully, since zafirlukast is known to inhibit cytochrome P450 3A4 in vitro1)
>> Carbamazepine or
>> Phenytoin or
>> Tolbutamide¾(although studies have not been done with zafirlukast and medications known to be metabolized by the cytochrome P450 2C9 isoenzyme, such as carbamazepine, phenytoin, and tolbutamide, patients in whom these medications are coadministered with zafirlukast should be appropriately monitored clinically, since zafirlukast is known to inhibit cytochrome P450 2C9 in vitro1)
Erythromycin¾(administration of a single 40-mg dose of zafirlukast during steady-state erythromycin therapy resulted in a 40% decrease in the mean plasma concentration of zafirlukast, due to decreased zafirlukast bioavailability1)
Terfenadine¾(concurrent administration of zafirlukast with terfenadine resulted in a 66% and 54% decrease in the mean peak plasma concentration and area under the plasma concentration-time curve, respectively, of zafirlukast; no effect was observed on terfenadine plasma concentrations or electrocardiogram results1)
Theophylline¾(concurrent administration of 80 mg a day of zafirlukast with a single 6-mg-per-kg dose of theophylline decreased the mean plasma concentration of zafirlukast by approximately 30%; no effect on theophylline plasma concentration was observed1)
>> Warfarin¾the concurrent use of a single 25-mg warfarin dose with multiple doses of zafirlukast resulted in an increase of approximately 35% in the mean prothrombin time, due to an inhibition of the cytochrome P450 2C9 isoenzyme; prothrombin times should be monitored closely and warfarin dose adjusted accordingly1
Side/Adverse Effects
Note: In clinical trials, a greater incidence of mild or moderate infections, predominantly affecting the respiratory tract, occurred in patients older than 55 years of age treated with zafirlukast, as compared with other age groups and placebo-treated patients. The number of infections was proportional to the amount, in milligrams, of zafirlukast administered and was associated with concurrent use of inhaled corticosteroids. The clinical significance of this finding is unknown.1
Rarely, elevation of one or more hepatic transaminases has occurred in patients receiving zafirlukast at doses four times higher than the recommended dose during controlled clinical trials. Most patients were asymptomatic. Hepatic enzyme values returned to normal after a variable period of time following discontinuation of zafirlukast. Rare cases of symptomatic hepatitis and hyperbilirubinemia have been reported in patients who received the recommended dosage of zafirlukast. In these patients, the hepatic transaminase elevations returned to normal or near-normal after discontinuation of the medication.5
Note: At least six cases of Churg-Strauss syndrome have been reported in adult asthma patients whose corticosteroid asthma medications were being gradually reduced or discontinued and who were also taking zafirlukast. Churg-Strauss syndrome is a systemic eosinophilic vasculitis, which may present as generalized, flu-like symptoms (fever, muscle aches or pains, and weight loss), eosinophilia, vasculitic rash, worsening pulmonary symptoms, cardiac complications, or neuropathy. If left untreated, Churg-Strauss syndrome can result in damage to major organs and death. Although a causal relationship between the use of zafirlukast and the development of Churg-Strauss syndrome has not been established, adult asthma patients should be monitored carefully when corticosteroids are being reduced or discontinued.1,7
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)¾not necessarily inclusive:
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Headache; nausea1
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Zafirlukast (Systemic).
In providing consultation, consider emphasizing the following selected information (>> = major clinical significance):
Before using this medication
>> Conditions affecting use, especially:
Breast-feeding¾Distributed into breast milk; use not recommended
Use in the elderly¾Mild to moderate respiratory infections may be more likely to develop in patients older than 55 years of age; whether this is related to taking zafirlukast or to other factors, such as use of inhaled corticosteroids, is not clear
Other medications, especially astemizole, carbamazepine, cisapride, cyclosporine, felodipine, isradipine, nicardipine, nifedipine, nimodipine, phenytoin, tolbutamide, and warfarin
Proper use of this medication
>> Importance of not using this medication to treat acute asthma symptoms
>> Taking medication on an empty stomach, 1 hour before or 2 hours after meals
>> Proper dosingMissed dose: Taking as soon as possible; if almost time for next dose, skipping missed dose; not doubling doses
>> Proper storage
Precautions while using this medication
>> Compliance with therapy by using every day in regularly spaced doses, even during symptom-free periods
>> Checking with health care professional before stopping or reducing therapy with any other asthma medications
Side/adverse effects
Signs of potential side effects, especially headache or nausea
General Dosing Information
Diet/Nutrition
In two separate studies, administration of zafirlukast with a high-fat and a high-protein meal resulted in a reduction of the mean bioavailability by approximately 40%; therefore, the medication should be taken on an empty stomach at least 1 hour before or 2 hours after meals1.
Oral Dosage Forms
Zafirlukast Tablets
Usual adult and adolescent dose
Antiasthmatic¾
Oral, 20 mg two times a day, one hour before or two hours after a meal1.
Usual adult and adolescent prescribing limits
20 mg two times a day.
Usual pediatric dose
Children up to 12 years of age¾Safety and efficacy have not been established1.
Usual geriatric dose
See Usual adult and adolescent dose1.
Strength(s) usually available
U.S.¾
20 mg (Rx)[Accolate (film-coated)].
Canada¾
Not commercially available.
Packaging and storage:
Store between 20 and 25 °C (68 and 77 °F). Protect from light and moisture.1
Auxiliary labeling:
· Take on empty stomach.
References
1Accolate package insert (Zeneca¾US), Rev 7/97.
2Spector SL, Smith LJ, Glass M, et al. Effects of 6 weeks of therapy with oral doses of ICI 204,219, a leukotriene D4 receptor antagonist, in subjects with bronchial asthma. Am J Respir Crit Care Med 1994; 150: 618-23.
3Suissa S, Dennis R, Ernst P, et al. Effectiveness of the leukotriene receptor antagonist zafirlukast for mild-to-moderate asthma. Ann Intern Med 1997; 126: 177-83.
4Holgate ST, Bradding P, Sampson AP. Leukotriene antagonists and synthesis inhibitors: new directions in asthma therapy. J Allergy Clin Immunol 1996; 98: 1-13.
5Personal communication, John K. Jenkins MD, Director, Division of Pulmonary Drug Products, Center for Drug Evaluation and Research, Food and Drug Administration, 5/7/97.
6Fleeger CA, editor. USP dictionary of USAN and international drug names 1997. Rockville, MD: The United States Pharmacopeial Convention, Inc.; 1996.
7Health advisory for new asthma drug. FDA Talk Paper 7/23/97. Available from: URL: http://www.fda.gov/bbs/topics/ANSWERS/ANS00810.html
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DATA-MEDICOS/DERMAGIC-EXPRESS No (9) 27/10/98 DR. JOSE LAPENTA R. DERMATOLOGO
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Dr. Jose Lapenta R.
Maracay Venezuela
[email protected]
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