Urticaria y Angioedema

Abril-04
MK y Alergia
1
MONTELUKAST EN
RINITIS ALERGICA
Dr Juan Carlos Miralles López
Unidad de Alergología
Hospital Provincial Universitario. Murcia (España).
Abril-04
MK y Alergia
GRADO DE ACUERDO CON DISTINTAS AFIRMACIONES
SOBRE EL ASMA: ALERGÓLOGOS
2
Muy+ Bastante de acuerdo
Ni de acuerdo, ni en desacuerdo
El FVE1, y el PEF a menudo tienen
una escasa correlación con los
síntomas
52
31
Los pacientes cumplen mejor el
tratamiento con comprimidos
que con inhaladores
73
Sería muy útil disponer de un
agente que tratara tanto el asma
como la RA
MK + ICS tiene un inicio de
acción más rápido que doblar la
dosis de ICS
17
16
81
El uso de 2 de larga duración
puede producir tolerancia
Muchos pacientes no están
controlados con el tratamiento
Muy+ Bastante en desacuerdo
11 8
71
56
69
11
19
24
11
20
17
13
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MK y Alergia
ASOCIACION ENTRE RINITIS
ALÉRGICA Y ASMA
3
* Aproximadamente el 80%
de los asmá
asmáticos
presentan síntomas de
rinitis alé
alérgica
Rinitis alérgica
sólo
Rinitis alérgica
+
asma
Asma
sólo
Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol
2001;108(5):S147 -S334; Sibbald B, Rink E Thorax 1991;46:8951991;46:895-901; Leynaert
B et al Am J Respir Crit Care Med 2000;162:13912000;162:1391-1396.
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Prieto L, Gutierrez V, Morales C, Marin J. Differences in sensitivity, maximal response and
position of the concentration-response curve to methacholine between asthmatics, patients
with allergic rhinitis and healthy subjects. Respir Med. 1998 Jan;92(1):88-94.
4
4 The aim of this study was to detect differences in maximal response and position of the concentration response curves to methacholine between asthmatics and subjects with allergic rhinitis . A total of 228
adults (107 mild asthmatics , 96 allergic rhinitics and 25 healthy control subjects ) were challenged with
methacholine . The test was interrupted when FEV1 dropped by more than 40% or when the highest
concentration of methacholine (200 mg ml-1) had been administered . Concentration -response curves
were characterized by their PC20 (concentration of methacholine that produced 20% fall in FEV1 =
airway sensitivity ), and if possible , by their EC50 (concentration of methacholine that produced 50% of
the maximal response = position ) and level of plateau . The proportion of subjects with plateau was
significantly lower in asthmatics (18.7%) than in either allergic rhinitics (57.3%) or healthy subjects
(92%). It was also significantly lower in allergic rhinitics than in healthy subjects . The level of plateau for
asthmatics was (means +/- SD) 31.5 +/- 5.5%, compared with 20.8 +/- 8.1% in allergic rhinitics and
13.7 +/- 6.7% in healthy subjects (P < 0.01). It was also higher in allergic rhinitics than in healthy
subjects (P < 0.01). The EC50 values were decreased in asthmatics when they were compared with
either allergic rhinitics or healthy subjects (geometric mean EC50: asthmatics = 2.7 mg ml-1, allergic
rhinitics = 6.2 mg ml-1, healthy subjects = 8.7 mg ml-1; P < 0.01), but no significant differences were
detected between allergic rhinitics and healthy subjects . These results demonstrate that in subjects with
allergic rhinitis , the prevalence and level of the plateau on the methacholine concentration -response
curve is intermediate between that of asthmatics and normals . Furthermore , while the asthmatic curves
differ from normal in having both an increased maximal response and a leftward shift , the rhinitic curves
differ only in terms of plateau level . These results suggest that airway responsiveness in asthma and
allergic rhinitis may be a consequence of mechanisms that are at least partially different .
Abril-04
MK y Alergia
SENSIBILIDAD A METACOLINA
ASMA vs RINITIS ALÉRGICA
5
100
100
PC20 (mg/ml)
(mg/ml
ml))
(mg/
PC20
10
10
11
0,1
0,1
0,01
0,01
P<0.01
ASMA
R. ALERGICA
SANOS
Prieto L. et al. Respir.
Respir. Med.
Med. 92: 88. 1998
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Djukanovic R, Lai CK, Wilson JW, Britten KM, Wilson SJ, Roche WR, Howarth PH, Holgate ST.
Bronchial mucosal manifestations of atopy : a comparison of markers of inflammation between atopic
asthmatics , atopic nonasthmatics and healthy controls . Eur Respir J. 1992 May;5(5):538 -44.
6
4 We studied the role of atopy , as defined by positive skin tests to common inhalant
allergens , in allergic bronchial inflammation . Endobronchial biopsies were taken via the
fibreoptic bronchoscope in 13 symptomatic atopic asthmatics , 10 atopic nonasthmatics , and
7 normals . The numbers of mast cells , identified in the submucosa
by
immunohistochemistry using the AA1 monoclonal antibody against tryptase , were no
different between the three groups , but electron microscopy showed that mast cell
degranulation , although less marked in atopic nonasthmatics , was a feature of atopy in
general. The numbers of eosinophils , identified by immunohistochemical staining using the
monoclonal anti -eosinophil cationic protein antibody , EG2, were greatest in the asthmatics ,
low or absent in the normals and intermediate in the atopic nonasthmatics . In both atopic
groups eosinophils showed ultrastructural features of degranulation . Measurements of
subepithelial basement membrane thickness on electron micrographs showed that the
collagen layer was thickest in the asthmatics , intermediate in the atopic nonasthmatics and
thinnest in the normals . The results suggest that airways eosinophilia and degranulation of
eosinophils and mast cells , as well as increased subepithelial collagen deposition , are a
feature of atopy in general and suggest that the degree of change may determine the
clinical expression of this immune disorder .
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INFLAMACION BRONQUIAL
RINITIS ALÉRGICA
N=10
N=13
EOSINOFILOS / mm2
1000
P<0.0005
Biopsia
Biopsia
P<0.05
P<0.005
7
N=7
bronquial
bronquial
100
10
1
0.1
ASMA
RINITIS ALERGICA
SANOS
Djukanovic.
Djukanovic. Eur. Respir.
Respir. J. 5: 538. 1992
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INFLAMACION BRONQUIAL
RINITIS ALÉRGICA
MEMBRANA BASAL
(m)
10
8
P<0.0005
P<0.05
8
P<0.005
6
4
2
0
ASMA
RINITIS ALERGICA
Djukanovic.
Djukanovic. Eur. Respir.
Respir. J. 5: 538. 1992
SANOS
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Prieto L, Gutierrez V, Uixera S. Exhaled nitric oxide and bronchial responsiveness to
adenosine 5'-monophosphate in subjects with allergic rhinitis. Chest. 2002
Jun;121(6):1853-9.
4 STUDY OBJECTIVES: To determine differences in exhaled nitric oxide (ENO) between subjects
with allergic rhinitis with and without increased responsiveness to direct and indirect
bronchoconstrictor agents. STUDY DESIGN: Cross-sectional study with the order of challenge
tests randomized. SETTING: Specialist allergy unit in a university hospital. PATIENTS: Thirty-eight
subjects without asthma with allergic rhinitis and 10 healthy nonatopic control subjects.
MEASUREMENTS AND RESULTS: Participants were challenged with increasing concentrations of
adenosine 5'monophosphate (AMP) and methacholine. ENO was measured with the singleexhalation method. A positive response to both bronchoconstrictor agents was detected in nine
subjects with allergic rhinitis, whereas four subjects showed increased responsiveness to AMP but
not to methacholine. The geometric mean (range) ENO values were significantly higher in
subjects with allergic rhinitis with increased responsiveness to either methacholine or AMP than in
subjects with normal responsiveness to both agonists: 51.3 parts per billion (ppb) [22.0 to 108.5
ppb] vs 25.1 ppb (5.7 to 102.9 ppb, respectively; p = 0.007) and healthy control subjects (11.2
ppb [5.0 to 31.9 ppb], p < 0.001). Subjects with allergic rhinitis with normal responsiveness to
both agonists also had higher concentrations of ENO than healthy control subjects (p = 0.007).
No correlation was found between ENO and either of the provocative concentrations of
methacholine or AMP causing a 20% fall in FEV(1). CONCLUSIONS: In subjects without asthma
but with allergic rhinitis, the presence of bronchoconstriction in response to methacholine or AMP
is associated with increased ENO concentrations. However, elevated concentrations of ENO are
detected even in subjects with allergic rhinitis without airway hyperresponsiveness. These results
suggest that the presence of airway hyperresponsiveness is not the only factor that determines
the increased NO levels detected in subjects with allergic rhinitis.
Abril-04
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MK y Alergia
INFLAMACION BRONQUIAL
RINITIS ALÉRGICA
10
N=38
N=10
NO EXHALADO (ppb)
125
P < 0.001
100
75
50
25
0
Rinitis alérgica
Prieto L, et al. Chest.
Chest. 121: 1853. 2002
Sanos
Abril-04
MK y Alergia
Gaga M, Lambrou P, Papageorgiou N, Koulouris NG, Kosmas E, Fragakis S, Sofios C, Rasidakis
A, Jordanoglou J. Eosinophils are a feature of upper and lower airway pathology in non-atopic
asthma, irrespective of the presence of rhinitis. Clin Exp Allergy. 2000 May;30(5):663-9.
11
4 BACKGROUND: Asthma and rhinitis often co-exist and there are data to suggest that they may be
two ends of the same disease spectrum. Immunohistochemical studies have shown that
eosinophilia in the airways is a feature of rhinitic patients without asthma. OBJECTIVE: The aim of
our study was to examine whether cellular infiltration exists in the nasal mucosa of asthmatics
even in the absence of symptoms and signs of rhinitis. METHODS: Nasal mucosa biopsies were
taken from 27 non-atopic subjects and comprised nine asthmatic rhinitic patients (AR), eight
asthmatic non-rhinitic patients (ANR) and 10 healthy control subjects (N). Bronchial mucosa
biopsies were also taken simultaneously from some of the patients (n = 10) to determine whether
there was an association between cellular infiltration in the nose and the lungs. The alkaline
phosphatase-anti-alkaline phosphatase (APAAP) method was used on 6 microm thick cryostat
sections using monoclonal antibodies against T cells (CD4, CD8), eosinophils (EG2) and mast cells
(mast cell tryptase). Slides were counted blind and results expressed as cells per field. RESULTS:
The results showed that eosinophil counts were higher in both asthma groups compared with
control nasal biopsies (median values AR 8.3, ANR 9.2, N 2.1 cells per field, P < 0.01).
Furthermore, there was a significant correlation between eosinophil cell counts in the nose and
the airways (r = 0.851 P < 0.001). No differences in eosinophil numbers were detected between
the two groups of asthmatics. Also, no differences were noted for any other cell type (i.e. CD4,
CD8, tryptase) among the three study groups. CONCLUSIONS: These results show that eosinophil
infiltration was present in the nasal mucosa of asthmatic patients even in the absence of rhinitis,
and add further support to the hypothesis that asthma and rhinitis are clinical expressions of the
same disease entity.
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MK y Alergia
INFLAMACION NASAL
PACIENTES ASMÁTICOS
12
18
(n=9)
(n=8)
(n=10)
EOSINOFILOS EN
MUCOSA NASAL
16
14
12
10
8
6
4
p<0.001
2
0
p<0.001
Rinitis
No rinitis
Asmáticos
Gaga M et al Clin Exp Allergy 2000;20:6632000;20:663-669.
Sanos
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Braunstahl GJ, Kleinjan A, Overbeek SE, Prins JB, Hoogsteden HC, Fokkens WJ. Segmental
bronchial provocation induces nasal inflammation in allergic rhinitis patients. Am J Respir Crit
Care Med. 2000 Jun;161(6):2051-7.
13
4 Allergic rhinitis and asthma often coexist and share a genetic background.
Pathophysiologic connections between the nose and lungs are still not entirely
understood. This study was undertaken to compare allergic inflammation and clinical
findings in the upper and lower airways after segmental bronchial provocation (SBP) in
nonasthmatic allergic rhinitis patients. Eight nonasthmatic, grass pollen-sensitive patients
with allergic rhinitis and eight healthy controls were included. Bronchial biopsies and blood
samples were taken before (T(0)) and 24 h (T(24)) after SBP. Nasal biopsies were
obtained at T(0), 1 h after SBP (T(1)), and T(24). Immunohistochemical staining was
performed for eosinophils (BMK13), interleukin (IL)-5, and eotaxin. The number of
eosinophils increased in the challenged and unchallenged bronchial mucosa (p < 0.05)
and in the blood (p = 0.03) of atopic subjects at T(24). We detected an increase of
BMK13-positive and eotaxin-positive cells in the nasal lamina propria and enhanced
expression of IL-5 in the nasal epithelium of atopic subjects only at T(24) (p < 0.05). SBP
induced nasal and bronchial symptoms as well as reductions in pulmonary and nasal
function in the allergic group. No significant changes could be observed in healthy
controls. The study shows that SBP in nonasthmatic allergic rhinitis patients results in
peripheral blood eosinophilia, and that SBP can induce allergic inflammation in the nose.
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EOSINOFILOS / mm2
RESPUESTA A ALERGENO
RINITIS ALÉRGICA
45
40
35
30
PROVOCACION
PROVOCACION SEGMENTARIA
SEGMENTARIA BRONQUIAL:
BRONQUIAL:
BIOPSIA
BIOPSIA BRONQUIAL
BRONQUIAL
BIOPSIA
BIOPSIA NASAL
NASAL
14
P<0.05
N=8
25
20
15
10
RINITIS ALERGICA
SANOS
N=8
5
0
BASAL
1h
TIEMPO TRAS PROVOCACION
Braunstahl.
Braunstahl. Am.
Am. J. Respir.
Respir. Crit. Care Med.
Med. 161: 2051. 2000
24h
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Braunstahl GJ, Overbeek SE, Kleinjan A, Prins JB, Hoogsteden HC, Fokkens WJ. Nasal allergen
provocation induces adhesion molecule expression and tissue eosinophilia in upper and lower
airways. J Allergy Clin Immunol. 2001 Mar;107(3):469-76.
15
4 BACKGROUND: Allergic rhinitis (AR) and asthma are characterized by means of a similar
inflammatory process in which eosinophils are important effector cells . The migration of
eosinophils from the blood into the tissues is dependent on adhesion molecules .
OBJECTIVE: To analyze the aspects of nasobronchial cross -talk, we studied the expression
of adhesion molecules in nasal and bronchial mucosa after nasal allergen provocation (NP).
METHODS: Nine nonasthmatic subjects with seasonal AR and 9 healthy control subjects
underwent NP out of season . Bronchial and nasal biopsy specimens were taken before
(T(0)) and 24 hours after NP (T(24)). Mucosal sections were analyzed for the presence of
eosinophils , IL-5, eotaxin , intercellular adhesion molecule 1 (ICAM -1), vascular cell
adhesion molecule 1 (VCAM -1), E-selectin , and human endothelium (CD31). RESULTS: At
T(24), an influx of eosinophils was detected in nasal epithelium (P =.01) and lamina
propria (P <.01), as well as in bronchial epithelium (P =.05) and lamina propria (P <.05),
of the patients with AR. At T(24), increased expression of ICAM-1, as well as increased
percentages of ICAM-1+, VCAM-1+, and E-selectin+ vessels , were seen in nasal and
bronchial tissue of patients with AR. The number of mucosal eosinophils correlated with the
local expression of ICAM-1, E-selectin , and VCAM-1 in patients with AR. CONCLUSION: This
study shows that NP in patients with AR results in generalized airway inflammation through
upregulation of adhesion molecules .
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RINITIS ALERGICA
EFECTO DE PROV. NASAL CON ALERGENO
MK y Alergia
16
VASOS POSITIVOS (%)
BASAL
90
TRAS PROVOCACION (24h)
P=0.01
Endotelio
Endoteliovascular:
vascular:
80
Mucosa
Mucosanasal
nasal
70
60
P=0.04
50
Mucosa
Mucosabronquial
bronquial
P=0.02
40
30
20
10
0
ICAM-1+
VCAM-1+
Braunstahl.
Braunstahl. J. Allergy Clin.
Clin. Imunol.
Imunol. 107: 469. 2001
ELAM-1+
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Chakir J, Laviolette M, Turcotte H, Boutet M, Boulet LP.Cytokine expression in the lower
airways of nonasthmatic subjects with allergic rhinitis: influence of natural allergen exposure. J
Allergy Clin Immunol. 2000 Nov;106(5):904-10.
17
4 BACKGROUND: Natural exposure to pollen provokes an increase in airway responsiveness
in nonasthmatic subjects with seasonal allergic rhinitis . This natural exposure may induce
inflammatory cell recruitment and cytokine release , leading to lower airway inflammation .
OBJECTIVE: The aim of this study was to characterize lower airway inflammation in
nonasthmatic pollen -sensitive subjects . METHODS: We performed immunohistochemical
tests on bronchial biopsy specimens from subjects with rhinitis who had no past or current
history of asthma to evaluate cytokine expression and inflammatory cell numbers and
activation both in and out of the pollen season . RESULTS: The number of CD4(+), CD8(+),
and CD45RO(+) lymphocyte subpopulations were significantly higher during the pollen
season compared with the out-of-season period (P <.04). Furthermore , EG1(+) cells
tended to increase after natural pollen exposure (P =.06). The number of IL-5(+) cells
increased significantly after natural exposure to pollen compared with out-of-season
numbers (P <.01). This increase in IL-5 expression was correlated with the numbers of
CD3(+), CD4(+), CD45RO(+), and EG1(+) cells . The numbers of tryptase -positive , IFNgamma(+), and IL-4(+) cells did not change after natural exposure . CONCLUSION: This
study showed that natural pollen exposure was associated with an increase in lymphocyte
numbers , eosinophil recruitment , and IL-5 expression in the bronchial mucosa of
nonasthmatic subjects with allergic rhinitis .
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INFLAMACION BRONQUIAL
RINITIS ALÉRGICA POLÍNICA
18
BIOPSIA BRONQUIAL
CD4+
CD4+
25
20
CD8+
CD8+
30
CELULAS / mm2
CELULAS / mm2
30
P<0.01
15
10
5
25
P<0.01
20
15
10
5
0
0
FUERA
ESTACION
ESTACION
FUERA
ESTACION
Chakir J et al. J. Allergy Clin.
Clin. Immunol.
Immunol. 106: 904. 2000
ESTACION
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Prieto L, Uixera S, Gutierrez V, Bruno L. Modifications of airway responsiveness to adenosine
5'-monophosphate and exhaled nitric oxide concentrations after the pollen season in subjects
with pollen-induced rhinitis. Chest. 2002 Sep;122(3):940-7.
19
4 STUDY OBJECTIVE:s : To determine the effect of cessation of exposure to pollen on airway
responsiveness to adenosine 5'-monophosphate (AMP) in subjects with pollen -induced rhinitis , and to
explore the relationship between changes in airway responsiveness and changes in exhaled nitric oxide
(ENO) levels . STUDY DESIGN: Subjects were studied during the pollen season and out of season .
SETTING: Specialist allergy unit in a university hospital. PATIENTS: Fourteen subjects without asthma
with pollen -induced rhinitis who showed bronchoconstriction in response to methacholine and AMP during
the pollen season and 10 healthy nonatopic control subjects . MEASUREMENTS AND RESULTS: In subjects
with pollen -induced rhinitis , ENO concentrations , provocative concentration of agonist causing a 20% fall
in FEV(1) (PC(20)) methacholine , and PC(20) AMP were determined during the pollen season and out of
season . Healthy control subjects were studied during the pollen season . In subjects with allergic rhinitis ,
PC(20) AMP increased from a geometric mean of 79.4 mg/mL (95% confidence interval [CI], 31.6 to
199.5 mg/mL) during the pollen season to 316.2 mg/mL (95% CI, 158.5 to 400.0 mg/mL) out of season
(p = 0.004). The ENO concentrations decreased from 63.1 parts per billion (ppb) [95% CI, 50.1 to 79.4
ppb] during the pollen season to 30.2 ppb (95% CI, 23.4 to 38.0 ppb) out of season (p < 0.001). The
ENO concentrations out of pollen season were still significantly increased in subjects with pollen -induced
rhinitis when compared with healthy control subjects . There was no relationship between individual
changes in ENO levels and changes in either PC(20) methacholine or PC(20) AMP. CONCLUSIONS: In
pollen -sensitive subjects with allergic rhinitis , the cessation of exposure to pollen is associated with a
significant reduction of airway responsiveness to inhaled AMP. However , no association was found
between allergen -induced changes in ENO values and in airway responsiveness to either direct or indirect
bronchoconstrictors . These findings suggest that modifications in ENO and in airway responsiveness are
the consequence of different alterations induced by allergen exposure on the lower airways .
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EXPOSICION NATURAL AL ALERGENO
RINITIS ALÉRGICA POLÍNICA
N=14
NO EXHALADO (ppb)
1000
P <0.001
100
10
ESTACION
Prieto et al. Chest.
Chest. 122: 940. 2002
FUERA
ESTACION
20
Abril-04
MK y Alergia
RINITIS AL
ÉRGICA Y ASMA
ALÉRGICA
POSIBLES MECANISMOS INTERACTIVOS
Aspiración de
secreciones inflamatorias
desde la´VAS hacia los
bronquios
Reflejo nasobronquial
21
Sustitución de
respiración nasal por oral
Liberación de
mediadores a
circulación sistémica
que alcanzan los
bronquios
Togias A. Allergy 1999;54(suppl 57):9457):94-105.
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SENSIBILIZACIÓN A ALERGENOS INHALADOS
ABORDAJE PARCELAR
DIAGNOSTICO 1
TRATAMIENTO 1
EVITACIÓN ALERGENOS
DIAGNOSTICO
2 TH
MODULACIÓN
RESP.
22
TRATAMIENTO 2
ANTAGONISTAS DE ILs
DIAGNOSTICO
MONOCLONAL
ANTI-3 IgE
TRATAMIENTO 3
ANTAGONISTAS DE LTs
22
Abril-04
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Nayak AS, Philip G, Lu S, Malice MP, Reiss TF; Montelukast Fall Rhinitis Investigator Group . Efficacy
and tolerability of montelukast alone or in combination with loratadine in seasonal allergic rhinitis : a
multicenter , randomized , double -blind , placebo -controlled trial performed in the fall. Ann Allergy
Asthma Immunol . 2002 Jun;88(6):592 -600.
23
4 BACKGROUND: Histamine and cysteinyl leukotrienes seem to be important mediators of allergic
rhinitis. OBJECTIVE: This multicenter, randomized, double-blind, parallel-group, placebocontrolled trial evaluated the effectiveness and tolerability of montelukast, loratadine, and
combination therapy with montelukast and loratadine for treating patients with fall seasonal
allergic rhinitis. METHODS: After a 1-week, single-blind, placebo run-in period, 907 male and
female patients aged 15 to 82 years were randomized to 1 of 4 treatments: montelukast 10 mg
(n = 155), loratadine 10 mg (n = 301), combination montelukast 10 mg and loratadine 10 mg (n
= 302), or placebo (n = 149), administered once daily at bedtime for 2 weeks. The primary
endpoint was the daytime nasal symptoms score (mean of congestion, rhinorrhea, pruritus, and
sneezing). RESULTS: Mean symptom scores at baseline were similar for the four treatment
groups. For each of the three active treatments, the difference was significant for the mean
change from baseline compared with placebo (P < or = 0.001). However, the effect of
montelukast/loratadine compared with loratadine alone, the primary comparison, was not
significantly different. Differences for each therapy alone compared with placebo were also
significant for most secondary endpoints, including nighttime symptom scores, eye symptoms
scores, and rhinitis-specific quality of life. Differences for montelukast/loratadine compared with
each therapy alone generally showed numerical superiority, and a few endpoints showed
differences that were statistically significant. All active treatments showed a safety profile
generally similar to placebo. CONCLUSIONS: Montelukast alone or in combination with loratadine
is well tolerated and provides clinical and quality-of-life benefits for patients with seasonal allergic
rhinitis.
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EFICACIA DE MONTELUKAST
RINITIS ALÉRGICA ESTACIONAL
Run-In
24
Doble-ciego
Montelukast 10 mg (n=155)
Placebo (n=149)
Placebo
Loratadina 10 mg (n=301)
Montelukast 10 mg + loratadina 10 mg (n=302)
–1
0
2
Semanas después de aleatorización
Nayak AS et al Ann Allergy Asthma Immunol 2002;88(6):5922002;88(6):592-600.
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 medio (SE) desde basal
EFICACIA DE MONTELUKAST
RINITIS ALÉRGICA ESTACIONAL
0
25
Síntomas dia
Síntomas noche
Pb
Pb Mk Lt
Mk Lt
Mk+Lt
Mk+Lt
–0.2
p0.003
p0.003
p0.003
–0.4
p0.003
p0.003
p0.003
–0.6
Placebo (n=149)
Montelukast 10 mg (n=155)
Loratadina 10 mg (n=301)
Montelukast + loratadina (n=302)
Nayak AS et al Ann Allergy Asthma Immunol 2002;88(6):5922002;88(6):592-600.
Abril-04
MK y Alergia
EFICACIA DE MONTELUKAST
RINITIS ALÉRGICA ESTACIONAL
Puntuación síntomas conjuntivales
 medio desde basal
0
Placebo
(n=148)
Montelukast
10 mg
(n=151)
Loratadina Montelukast
10 mg
+ loratadina
(n=299)
(n=298)
–0.1
–0.2
–0.3
–0.4
p0.001*
p0.001*
p0.001 *
–0.5
*vs. placebo
Nayak AS et al Ann Allergy Asthma Immunol 2002;88(6):5922002;88(6):592-600.
26
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Price DB, Hernandez D, Magyar P, Fiterman J, Beeh KM, James IG, Konstantopoulos S, Rojas R, van Noord JA, Pons
M, Gilles L, Leff JA; Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT)
International Study Group. Randomised controlled trial of montelukast plus inhaled budesonide versus double dose
inhaled budesonide in adult patients with asthma. Thorax. 2003 Mar;58(3):211 -6.
27
4 BACKGROUND: Inhaled corticosteroids (ICS) affect many inflammatory pathways in asthma but have
little impact on cysteinyl leukotrienes . This may partly explain persistent airway inflammation during
chronic ICS treatment and failure to achieve adequate asthma control in some patients . This double
blind , randomised , parallel group , non-inferiority , multicentre 16 week study compared the clinical
benefits of adding montelukast to budesonide with doubling the budesonide dose in adults with asthma .
METHODS: After a 1 month single blind run in period , patients inadequately controlled on inhaled
budesonide (800 microg /day) were randomised to receive montelukast 10 mg + inhaled budesonide 800
microg /day (n=448 ) or budesonide 1600 microg /day (n=441 ) for 12 weeks . RESULTS: Both groups
showed progressive improvement in several measures of asthma control compared with baseline . Mean
morning peak expiratory flow (AM PEF) improved similarly in the last 10 weeks of treatment compared
with baseline in both the montelukast + budesonide group and in the double dose budesonide group
(33.5 v 30.1 l/min). During days 1-3 after start of treatment , the change in AM PEF from baseline was
significantly greater in the montelukast + budesonide group than in the double dose budesonide group
(20.1 v 9.6 l/min, p<0.001), indicating faster onset of action in the montelukast group . Both groups
showed similar improvements with respect to "as needed " beta agonist use, mean daytime symptom
score , nocturnal awakenings , exacerbations , asthma free days , peripheral eosinophil counts , and asthma
specific quality of life. Both montelukast + budesonide and double dose budesonide were generally well
tolerated . CONCLUSION: The addition of montelukast to inhaled budesonide is an effective and well
tolerated alternative to doubling the dose of inhaled budesonide in adult asthma patients experiencing
symptoms and inadequate control on budesonide alone .
Abril-04
MK y Alergia
ESTUDIO COMPACT
DISEÑO DEL ESTUDIO
28
Periodo II
Tratamiento activo (12 sem) Doble-ciego
Periodo I
Run-in (4 sem) Ciego-simple
Montelukast 10 mg cada 24 h
+
Budesonida 400 µg cada 12 h
Budesonida 400 µg
cada 12 h
n=448
Budesonida 800 µg cada 12 h
n=441
0
1
4
8
Semanas
12
16
Abril-04
MK y Alergia
ESTUDIO COMPACT
OBJETIVO DEL PRESENTE ANÁLISIS
29
gDeterminar si el tratamiento con montelukast
asociado a budesonida proporcionaba
beneficio adicional, comparado con
budesonida sola, a los pacientes que
presentaban concomitantemente asma y
rinitis alérgica
Abril-04
MK y Alergia
ESTUDIO COMPACT
MEJORÍA DEL PEF DE LA MAÑANA
Población global
30
Cambios desde basal
(L/Min, LS Media ± SEM)
50.0
40.0
30.0
P=0.36
20.0
10.0
Montelukast (N=433)
Budesonida (N=425)
0.0
0
4
Semanas
8
12
Abril-04
MK y Alergia
ESTUDIO COMPACT
GRUPOS DE PACIENTES COMPARADOS
31
g Asma y Rinitis alérgica (AS/+RA)
Pacientes con asma y rinitis alérgica, definida
por una historia positiva y un diagnóstico
médico.
g Asma sin Rinitis alérgica (AS/-RA)
Pacientes con asma sin una historia y un
diagnóstico médico de rinitis alérgica.
Abril-04
MK y Alergia
ESTUDIO COMPACT
MEJORÍA DEL PEF DE LA MAÑANA
Población AS/+RA
32
Cambios desde basal
(L/Min, LS Media ± SEM)
50.0
40.0
30.0
20.0
P<0.03
10.0
Montelukast (N=216)
Budesonida (N=184)
0.0
0
4
8
Semanas
12
Abril-04
MK y Alergia
ESTUDIO COMPACT
MEJORÍA DEL PEF DE LA MAÑANA
Población AS/+RA con tratamiento para rinitis*
70.0
Montelukast (N=33)
Budesonide (N=23)
60.0
Cambio desde basal
(L/Min, LS Media ± SEM)
33
50.0
40.0
P<0.02
30.0
20.0
10.0
0.0
0
-10.0
-20.0
4
8
12
Semanas
*Esteroides intranasales o anti H1 u otros
Abril-04
MK y Alergia
CONCLUSIONES
34
1. Las consecuencias de la sensibilización a los alergenos
inhalados se observan en los diferentes órganos expuestos a
los mismos.
2. El concepto “organicista” de la enfermedad alérgica es
artificioso e irreal.
3. Diferentes estudios han demostrado la eficacia de
montelukast en el tratamiento de las manifestaciones nasooculares y pulmonares inducidas por la sensibilización a
alergenos inhalados.
4. Resultados preliminares sugieren que montelukast es una
buena opción para tratar conjuntamente todas las
manifestaciones clínicas inducidas por la sensibilización a
alergenos inhalados.